Karuppusamy Arunachalam

Xuefei Yang
Sreeja Puthanpura Sasidharan Editors

Bioprospecting
of Tropical
Medicinal
Plants
Bioprospecting of Tropical Medicinal Plants
Karuppusamy Arunachalam • Xuefei Yang
Sreeja Puthanpura Sasidharan
Editors

Bioprospecting of Tropical
Medicinal Plants
Editors
Karuppusamy Arunachalam Xuefei Yang
Center for Studies in Stem Cells Key Laboratory for Wild Plant Resources
Cell Therapy and Toxicological Kunming Institute of Botany
Genetics (CeTroGen) Kunming, Yunnan, China
Graduate Program in Health and
Development in the Midwest Region
Faculty of Medicine (FAMED)
Federal University of Mato
Grosso do Sul (UFMS)
Campo Grande, Cidade Universitária
Pioneiros, MS, Brazil

Sreeja Puthanpura Sasidharan

Department of Botany
NSS College Nemmara
Palakkad, Kerala, India

ISBN 978-3-031-28779-4    ISBN 978-3-031-28780-0 (eBook)

https://doi.org/10.1007/978-3-031-28780-0

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Preface

Natural or phyto-products, in particular medicinal plants and their derived products,

as an indispensable source of bioactive molecules serve as either drug candidates or
as source of compounds for drug design and discovery purposes. There are several
advantages for plant-derived therapeutics, including wide availability, diverse and
synergetic pharmacological actions, and a generally good profile of safety and toler-
ability. Over the recent years, there have been numerous reports from clinical stud-
ies testifying the efficacy and safety of medicinal plants and phytochemicals in
ameliorating several human diseases. A plethora of basic studies has also unravelled
molecular mechanisms underlying the health benefits of herbal medicines.
Nevertheless, issues such as identification of bioactive ingredients, standardization
of the products, and drug interactions remain to be further studied.
The book Bioprospecting of Tropical Medicinal Plants mainly focuses on the
medicinal properties and pharmacological action of natural products, the medicinal
plants, and phytochemicals, in different settings ranging from in vitro models to
clinical trials. The goal is to present the reader a comprehensive collection on most
of the therapeutic aspects of plant-derived natural products and molecular mecha-
nisms thereof. This book will be valuable to biodiversity and conservation research-
ers, ethnopharmacologist, ethnobiologists, ethnoecologists, naturalists,
phytochemists, pharmacists, policymakers, and anybody who cares about the envi-
ronment. It covers all areas of plant-based medicine evaluation and development,
including cultivation, collection, phytochemical and phytopharmacological analy-
sis, and therapeutic potential analysis in clinical trials. The focus is on describing
the whole range of evidence-based complementary medicine and bio-analytical
techniques used to define botanical products, such as therapeutic traditional knowl-
edge of herbs, phytochemical analysis, pharmacological studies, and hyphenated
techniques, among others. The book explains how medicinal plants are used for
phytotherapy in world countries. Moreover, this book will aid the bio-prospection of
herbal products as well as medication discovery and development based on tradi-
tional medicine.
We convey our heartfelt gratitude and appreciation to all contributors for their
prompt answers, good and up-to-date contributions, and persistent collaboration.

v
vi Preface

We also thank our colleagues and our research students for their cooperation and
critical suggestions. The technical support and continued encouragement received
from Dr. Kenneth Teng (Editor) and the book publishing team at Springer Nature,
Springer New York 233, Spring Street, New York, NY 10013-1522, USA, is also
acknowledged. We express deep gratitude to Kunming Institute of Botany (KIB),
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação
de Apoio ao Desenvolvimento do Ensino (FUNDECT), and Universidade Federal
de Mato Grosso do Sul (UFMS) for financial support. Also, this project work was
financially supported by the Chinese Academy of Sciences – President’s International
Fellowship for Postdoctoral Research (CAS-PIFI, Reference no. 2020PB0112),
Inventory and Database Construction Project of Herbal Medicine, along with the
“Belt and Road Countries” (Grantnumber 2018FY100700), the Southeast Asia
Biodiversity Research Institute, Chinese Academy of Sciences, Peoples Republic of
China (GrantnumberY4ZK111B01), and the Yunnan Province Science and
Technology Department (Grantnumber 202203AP140007). Finally, we acknowl-
edge Almighty God, who provided all the channels to work in cohesion and coordi-
nation right from the conception of the idea to the development of the final version
of this book.

Pioneiros, MS, Brazil  Karuppusamy Arunachalam

Kunming, Yunnan, China  Xuefei Yang
Palakkad, Kerala, India  Sreeja Puthanpura Sasidharan
Contents

Ethnobotanical Study of Medicinal Herbs Used by the Naga

Tribes of Eastern Himalayas������������������������������������������������������������������������     1
Khikeya Semy and Ruokuonuo Kuotsu
Ethnomedicinal Use Reports of Seeds as Tapped from Herbal
Vendors in North Maharashtra, India ��������������������������������������������������������    25
Y. A. Ahirrao, M. V. Patil, and D. A. Patil
An Ethnobotanical Study of Medicinal Plants Used
by Traditional Healers in Grizzled Squirrel Wildlife Sanctuary
(GSWS) Tamil Nadu, India ��������������������������������������������������������������������������    43
Pious Soris Tresina, Murugeswaran Santhiya Selvam,
Vallinayagam Sornalakshmi, and Veerabahu Ramasamy Mohan
Ethnomedicinal Plants Used by Irula Tribal Settlement
of Attappady in Palakkad District, Kerala, India ��������������������������������������   107
C. V. Jayalekshmi, Reshma K. Ramesh, M. Vijai, and V. Suresh
Folk Medicine of Chittur Taluk in Palakkad District, Kerala,
India����������������������������������������������������������������������������������������������������������������   123
C. V. Jayalekshmi, S. Reshma, and V. Suresh
Checklist Flora of Sunderdhunga Valley, Western Himalaya,
with Emphasis on Ethno-Medicinal Plants�������������������������������������������������   159
R. Manikandan, S. P. Nithya, and R. Mehala Devi
Phytomedicines Used in Respiratory Diseases by Traditional
Healers of Lakhimpur and Dhemaji Districts of Assam, India ����������������   227
Pinki Gogoi, Pyonim Lungphi, A. P. Das, and Victor Singh Ayam
Understanding Phytomedicinal Gastronomic Culture
of the Nagas in Nagaland, India�������������������������������������������������������������������   243
Lydia Yeptho and T. Ajungla

vii
viii Contents

Medicinal Plants in the Indian Traditional Medicine

and Current Practices������������������������������������������������������������������������������������   253
Ritee Basu, Sukanya Dasgupta, Spoorthy N. Babu, and Ayesha Noor
Conservation of RET Medicinal and Aromatic Plants,
Their Traditional Medicines and Current Practices in Indian
Himalayan Region������������������������������������������������������������������������������������������   287
Rajeev Ranjan Kumar, Jaidev Chauhan, V. K. Purohit, P. Prasad,
and M. C. Nautiyal

Traditional Amchi Medicinal Practice in Trans-Himalaya of Nepal:
Conservation and Bioprospecting����������������������������������������������������������������   307
Neva Chaudhary, Suresh K. Ghimire, and Ram P. Chaudhary

Appraisal of Medicinal Plants Diversity Inhabited in Deserts Areas��������   329
Salman Majeed, Muhammad Zafar, Mushtaq Ahmad, Shazia Sultana,
Fethi Ahmet Ozdemir, Omer Kilic, Ghulam Yaseen, and Nabila
Bush Medicinal Plants of the Australian Wet Tropics and Their
Biodiscovery Potential ����������������������������������������������������������������������������������   357
Karma Yeshi and Phurpa Wangchuk
Trillium govanianum – A Promising Endemic Medicinal
Herb of the Himalaya������������������������������������������������������������������������������������   381
Kausar Rashid, Sufiya Rashid, Aijaz Hassan Ganie, Irshad A. Nawchoo,
Mudasir A. Tantry, and Anzar A. Khuroo
Comprehensive Review on Wild Basil Genus Orthosiphon
of Lamiaceae��������������������������������������������������������������������������������������������������   409
K. Abirami, P. Revathi, K. Thenmozhi, and K. Sowndhararajan
Zingiberaceae Plants: A Cornucopia of Promising
Chemotherapeuticals for Cancer Cure��������������������������������������������������������   427
T. Soumya, P. R. Jayasree, and P. R. Manish Kumar
Moringa oleifera Accessions: Perspectives and Application
as Nutraceuticals and Phytomedicines��������������������������������������������������������   463
Nikita Patel and Ramar Krishnamurthy
 Overview of Ethnobotany, Phytochemicals, and Pharmacological
An
Properties of Ficus Species����������������������������������������������������������������������������   481
Sreeja Puthanpura Sasidharan, Xuefei Yang,
and Karuppusamy Arunachalam
Phytochemistry and Pharmacology of Catharanthus roseus
(L.) G. Don and Rauvolfia serpentina (L.) Benth. ex Kurz������������������������   511
Sunil Kumar and Bikarma Singh
Contents ix

Resilience Activity of Glycyrrhiza glabra in Relation to Cancer:

Chemistry and Mechanism ��������������������������������������������������������������������������   529
Naveen Dhingra, Shaligram Sharma, Pratima Kumari, and Anand Kar
Strobilanthes: A Plethora of Phytomedicine������������������������������������������������   545
Reshmi Chembrammal, Aswathi Pokkadath, and John Ernest Thoppil

Annonaceae: Tropical Medicinal Plants with Potential Anticancer
Acetogenins and Alkaloids����������������������������������������������������������������������������   565
Sonia Mol Joseph and A. R. Amala Dev
Biocolorant from Anisochilus carnosus: A Natural Food
Preservative����������������������������������������������������������������������������������������������������   589
Suman Thamburaj, Chayanika Sarma, Anju Mariam Johnson,
Akhila Etikala, and Suresh Kumar Kalakandan
Therapeutic Properties of Nardostachys jatamansi and Its Applications
in Post-­Chemotherapy-­Induced Hair Loss in Cancer Patients ����������������   611
Packirisamy Azhagu Saravana Babu, Basheer Vajiha Aafrin,
Sagorika Goyali, M. Geethika, Vallinayagam Sugumari,
and Muthusamy Sukumar

Phitotherapeutic Potential of Cassava (Manihot esculenta, Crantz) ��������   623
Marney Pascoli Cereda
Phytochemistry and Pharmacological Studies of Indian
Cinnamomum Schaeff ����������������������������������������������������������������������������������   649
Saranya Surendran and Raju Ramasubbu
Medicinal Properties and Population Studies on Sarcostigma kleinii
Wight & Arn.��������������������������������������������������������������������������������������������������   699
Silvy Mathew and Reshma Rajan
RETRACTED CHAPTER: The Utility of Natural Mucilage
from the Medicinal Plant, ‘Patha’ (Cyclea peltata) as an Alternative
for Solidifying Agent in Cell Growth Media������������������������������������������������   707
Anjana Krishnan, Jomy Joseph, and Sudha Kalyanikutty
Secondary Metabolites in Ophiorrhiza brunonis Wight & Arn.
(Rubiaceae): A Lead Towards Its Anticancer Potential ����������������������������   727
S. N. Preethamol and John E. Thoppil
Marine Macroalgae as a Treasure House of Bioactive Compounds
and Nutraceuticals ����������������������������������������������������������������������������������������   739
Kajal Chakraborty
Plant Metabolites as New Leads to Herbal Drug Discovery:
Approaches and Challenges��������������������������������������������������������������������������   767
Kapish Kapoor, Priyal Jain, and Joohee Pradhan
x Contents

Biochanin A Chemistry, Structural Modifications,

and Therapeutic Applications: An Update��������������������������������������������������   789
Mudasir Maqbool, Kitika Shenmar, Ansab Akther, Reyaz Hassan Mir,
Adil Farooq Wali, and Roohi Mohi-ud-din
Dietary Natural Polyphenols Against Bacterial and Fungal
Infections: An Emerging Gravity in Health Care and Food Industry������   807
Biswajit Patra, Nibedita Das, Mohammad Zaki Shamim,
Tapan Kumar Mohanta, Bishwambhar Mishra,
and Yugal Kishore Mohanta
Phyto-Constituents as Potential Leads for the Development
of Novel Antiepileptic Drugs ������������������������������������������������������������������������   821
Joohee Pradhan, Purnima Paliwal, Sunita Panchawat, Rohini Trivedi,
and Devshree Gayakwad

Role of Polyphenols in Cardiovascular Diseases����������������������������������������   863
Hitesh Chopra, Shabana Bibi, Yugal Kishore Mohanta, Sony Kumari,
and Atif Amin Baig
Steam Distillation: Principle and Applications for the Extraction
of Essential Oils from Plants ������������������������������������������������������������������������   893
Alankar Shrivastava
Key Factors Influencing Agrobacterium-Mediated Transformation
Efficiency in Plants: A Case Study ��������������������������������������������������������������   905
Durga Prasad Barik

Evaluation of Medicinal Plant with Reference to Its Substitute����������������   927
T. V. Binu and C. B. Athira
Biotechnology: Production of Natural Bioactive Compounds
from Leguminous Plants and Disease Management����������������������������������   971
Shipra Jha and Bhawana Jain
Novel Eco-Friendly Method of Extraction for Fixed Oils
Using Solvent Action of Solid Solubilizers ��������������������������������������������������   993
Pawan Mulani, Sweta S. Koka, Anirudh Padiyar, R. K. Maheshwari,
and G. N. Darwhekar
Conservation Attempts of Woody Medicinal Plants of India
by Biotechnological Tools������������������������������������������������������������������������������ 1005
Yasotha Jeyaram, Priya Prasannan, Arjun Pandian, and Ramasubbu Raju
Conservation of Endangered Medicinal Plants by In Vitro
Propagation Methods������������������������������������������������������������������������������������ 1035
M. V. Lakshmi, S. Jeyaraj, and T. S. Swapna
Application of Biotechnology to Produce Plant-Derived
Biologically Important Compounds ������������������������������������������������������������ 1047
Nadia Iqbal, Sidra Nisar Ahmed, Urooj Subhan, Nageen Arif,
Humaira Saleem, and Farah Deeba
Contents xi


Appraisal of Medicinal Plants for Pharmacological Properties���������������� 1061
Mehmet Zeki Kocak and Mustafa Güven Kaysim
Pharmacological Properties and Tissue Culture Method
of Endangered Medicinal Plants������������������������������������������������������������������ 1081
Yuhong Zheng, Xin Shi, and Li Fu
Natural Compounds with Pharmacological Properties
in Clinical Trials �������������������������������������������������������������������������������������������� 1097
Morvarid Noormohammadi and Farzad Shidfar

Phytopharmacological Aspects of the Genus Terminalia���������������������������� 1117
Aswathi Pokkadath, Reshmi Chembrammal, and John Ernest Thoppil
Anticancer Potential of Plant-Derived Compounds:
An Overview of Their Epigenetic Mode of Action�������������������������������������� 1135
Priyanka Soni, Md. Sajid Ghufran, and Govinda Rao Duddukuri
Treatment of Cancer Using Combination of Herbal and Novel
Drug Delivery System������������������������������������������������������������������������������������ 1177
Nikita Kale
Anti-inflammatory Potential of Lead Compounds and Their
Derivatives from Medicinal Plants �������������������������������������������������������������� 1199
Nisha Sam Nirmala, Navina Bala Krishnan, Vaishnavi Vivekanandan,
and Krishnaraj Thirugnanasambantham
Alzheimer’s Disease Treatment Using Natural Foods:
A Overview ���������������������������������������������������������������������������������������������������� 1233
Tanima Bhattacharya, Debashrita Das, Hitesh Chopra,
and Atif Amin Baig

Natural Products Used in the Treatment of Autoimmune Disorder���������� 1247
Anjali Saharan, Meenakshi Dhanawat, Chander Parkash Dora,
Rakesh Kumar Sindhu, and Inderjeet Verma

Strategies to Improve Antimicrobial Activity of Natural Products:
Approaches and Challenges�������������������������������������������������������������������������� 1265
Cristina M. Pérez Zamora, Carola A. Torres, and Ana M. Gonzalez

Plants with Immunomodulatory Potential Described in Ayurveda���������� 1299
Sinimol Peethambaran Thekkekkoottumughath
Plant-Derived Drugs for Alzheimer’s Disease and Other
Neurological Disorders���������������������������������������������������������������������������������� 1327
B. Sumithra, Sanjeeb Kumar Mandal, Bishwambhar Mishra,
K. V. S. S. N. Mounika, J. Caleb Joel Raj, and C. V. S. Aishwarya
xii Contents


Properties and Mechanism of Antimicrobial Agents from
Plant-­Derived Essential Oils ������������������������������������������������������������������������ 1347
Afroze Naveed Basha, Ramya Subramanian, Kandeepan Chithan,
Gopinath Gurulingam Vincent, Karthigeyan Murugesan,
Ananthavalli Ramachandran, Sivakumar Pethanan, Mani Panagal,
Chella Perumal Palanisamy, and Ramaraj Jayakumararaj

Nanotechnological Modus Operandi for the Delivery of Cytotoxic
Phytochemicals���������������������������������������������������������������������������������������������� 1365
Thomson Alex, Alankar Shrivastava, Damanpreet Kaur Lang,
Rakhi Khabiya, Sweta S. Koka, and Yasmin Sultana

Plant-Based Green Nanoparticles in Cancer Diagnosis and
Chemotherapy������������������������������������������������������������������������������������������������ 1387
Arun John and Rinu Elizabeth Roy

Use of Plant-Derived Nanoparticles in Cancer Therapy���������������������������� 1405
R. Sai Nandhini, S. Kalpana Shree, Phalguni Maity, G. S. Madhumathi,
Anindita Bhar, and Jeyanthi Palanivelu
The Global Concern for Cancer Emergence and Its Prevention:
A Systematic Unveiling of the Present Scenario������������������������������������������ 1429
Md. Sajid Ghufran, Priyanka Soni, and Govinda Rao Duddukuri
Commonly Used Poisonous Medicinal Plants in Unani System
of Medicine ���������������������������������������������������������������������������������������������������� 1457
Shaikh Ajij Ahmed Makbul and Sayeedur Rahman
Herbal Drugs: Safety, Cost-Effectiveness, Regulation,
Current Trends, and Future Directions ������������������������������������������������������ 1479
Sidra Nisar Ahmed, Mushtaq Ahmad, Mohammad Zafar, Ghulam Yaseen,
Nadia Iqbal, Neelum Rashid, Samina Kousar, and Adeela Haroon

Therapeutic Properties of Herbal Constituents Subjected for Clinical
Trials���������������������������������������������������������������������������������������������������������������� 1495
Esha Vatsa and Mehak Aggarwal
Plant-Derived Immunomodulators Targeting COVID-19
(SARS-CoV-2): Preclinical Evaluation and Clinical Trials������������������������ 1515
Robin, Pardeep Kaur, Jagdeep Kaur, Kamaljit Kaur, and Sunidhi Miglani

Correction to: Bioprospecting of Tropical Medicinal Plants ��������������������   C1
Karuppusamy Arunachalam, Xuefei Yang,
and Sreeja Puthanpura Sasidharan

Index���������������������������������������������������������������������������������������������������������������� 1533
About the Authors

Karuppusamy Arunachalam, PhD, is the Visiting

Professor of Center for Studies in Stem Cells, Cell
Therapy and Toxicological Genetics (CeTroGen),
Graduate Program in Health and Development of the
Midwest Region Faculdade de Medicina Dr. Hélio
Mandetta (FAMED), Federal University of Mato
Grosso do Sul (UFMS), Campo Grande, Mato Grosso
do Sul Brazil. He was awarded as a President’s
International Fellowship Initiative (PIFI), Chinese
Academy of Sciences (2020), Kunming Institute of
Botany, Chinese Academy of Sciences. Before join-
ing the KIB in 2020, he spent 5 years in the Area
Pharmacology Laboratory, Department of Basic
Sciences in Health, Faculty of Medicine, Federal
University of Mato Grosso (UFMT), Brazil, as a
Post-Doctoral Fellow. He is working on wide range
of topics, including Ethnobotany, Biotechnology,
Ethnopharmacology, and Pre-clinical pharmacology,
with a major focus being the herbal drug develop-
ment. In recent years, he has been exploring natural
products with an emphasis on phytochemical and
pharmacology, neutraceuticals, and polysaccharides.
Arunachalam has published more than 50 peer-
reviewed journal articles. He has published four
books and seven book chapters. In addition, he
secured four registered international patents (Brazil)
and one granted National patent (India).

xiii
xiv About the Authors

Xuefei Yang, PhD, Professor, is the group leader of

Ethnobotany and Natural Resource Management of
Kunming Institute of Botany (KIB), the Chinese
Academy of Sciences (CAS). She was trained in mul-
tidisciplinary such as Ethnoecology, Global Change
Biology, Natural Resource Management, Biodiversity
Conservation, Fungal Ecology, Spatial Ecology, and
Forestry Ecology. She holds a PhD in Biology granted
by the Chinese Academy of Sciences in 2006 and three
Master Degrees from KIB in China, International
Institute for Geo-Information Science and Earth
Observation (ITC) in the Netherlands, and the Center
for Space Science, Technology Education in Asia and
the Pacific (CSSTEAP, affiliated to the United Nations)
in India, respectively. Since 2006, she worked as a
Scientist at KIB on a broad range of research topics
and had been promoted as an Associate Professor in
2010 and group leader of Ethnobotany in 2014. She
has published around 70 research articles on peer-
reviewed journals and 3 books.

Sreeja Puthanpura Sasidharan, PhD, is an Assistant

Professor (contract) at the Department of Botany, NSS
College, Nemmara, Palakkad, Kerala, India. She has
completed her graduation from Calicut University,
Kerala, and post-graduation, MPhil and PhD from
Bharathiar University, Tamil Nadu. Presently she is
working in the field of bioprospection of medicinal
plants with phytochemical and pharmacological stud-
ies. She has published 13 research articles with the
citation number of 85 in google scholar and 4 book
chapters, in various reputed international journals/
publishers. In addition, she has published two books in
Springer International publisher. She has 2 years of
teaching and 5 years of research experiences.
Abbreviations

A549 lung cancer cell lines

ABTS (2,2′-Azino-Bis(3-Ethylbenzothiazoline-6-Sulfonic Acid) Diam-
monium Salt)
AChE Acetylcholinesterase
AD Alzheimer’s disease
ADCs antibodies – drug conjugates
Akt protein kinase B
ALP alkaline phosphatase
ANOVA one-way analysis of variance
AuNP gold nanoparticles
Bcl-2 B-cell lymphoma
BHA butylated hydroxyanisole
BHT butylated hydroxytoluene
BMI-1 B-cell-specific Moloney murine leukemia virus integration site 1
Caco-2 cancer coli-2
CADD computer-aided drug design
CD Crohn’s disease
CDK 2 cyclin-dependent kinase 2
CIA chemotherapy-induced alopecia
COVID-19 Coronavirus disease 2019
COX 1 cyclooxygenase enzyme 1
COX-2 Cyclooxygenase - 2
CRISPR clustered often interspaced short palindromic repeats
CSCD circulatory system/cardiovascular diseases
CVI Cultural Value Index
DC dental care
DID dermatological infections/diseases
DNMTs DNA methyltransferases
DPPH 1,1-diphenylpicryl-1-picrylhydrazyl
DTH delayed-type hypersensitivity
Ed endocrinal disorders

xv
xvi Abbreviations

EGCG epigallocatechin gallate

EGFR endothelial growth factor receptor
EJ138 urinary bladder cancer cell lines
EPR improved permeability and retention
ER estrogen receptors
ERK extracellular signal-regulated kinase
EZH2 enhancer of Zeste homolog 2
FC frequent citation
Fic informant consensus factor
FL fidelity level
FRAP ferric reducing antioxidant power
FTIR Fourier-transform infrared spectroscopy
Fvr fever
GC-MS gas chromatography-mass spectrometry
GIA gastro-intestinal ailments
GMO genetically modified organism
GPCR G-protein-coupled receptors
GSWS Grizzled Squirrel Wildlife Sanctuary
H2O2 hydrogen peroxide
HATs histone acetyltransferases
HC hair care
HDACs histone deacetylases
HepG2 liver cancer cell lines
HPLC high performance liquid chromatography
HSV1 herpes simplex virus
IBD inflammatory bowel disease
IL-1β interleukin-1β
IL-6 interleukin-6
INF interferon
iNOS inducible nitric oxide synthase
IR infrared spectroscopy
ITM India traditional medicine
LBDD ligand-based drug design
LDL low-density lipoprotein
LOX lipoxygenase
LP liver problems
LPS lipopolysaccharide
MAPK mitogen-activated protein kinases
MCF-7 Michigan Cancer Foundation-7 (breast cancer cell line)
MDA malondialdehyde
MIA monoterpene indole alkaloids
miRNAs microRNAs
MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide
NF-κb nuclear factor kappa light chain enhancer of activated B cells
NMR nuclear magnetic resonance
Abbreviations xvii

NO nitric oxide
NOS nitric oxide synthase
NSAIDs non-steroidal anti-inflammatory drugs
ONC oncology
OSCC squamous cell carcinoma
PGE2 prostaglandin E2
PGG2 prostaglandin G2
PGH2 prostaglandin H2
PNPs polymeric nanoparticles
PRC polycomb repressive complexes
RFC relative frequency of citation
RNS reactive nitrogen species
ROS reactive oxygen species
RSD respiratory systems diseases
SARS-CoV-2 severe acute respiratory syndrome coronavirus-2
SBDD structure-based drug design
SEM scanning electron microscopy
SMSD skeleto-muscular system disorders
SOD superoxide dismutase
SPE solid phase extraction
SRBC sheep red blood cells
STZ streptozotocin
SUZ12 suppressor of zeste 12 homologue
TBHQ tertiary butylhydroquinone
TEM transmission electron microscopy
TET ten eleven translocases
Th helper T cells
THC delta-9-tetrahydrocannabinol
TLC thin layer chromatography
TM traditional medicine
TNF-α tumor necrosis factor-α
TSGs tumor suppressor genes
UC ulcerative colitis
UV use value
WBC white blood cells
WHO World Health Organization
Ethnobotanical Study of Medicinal Herbs
Used by the Naga Tribes of Eastern
Himalayas

Khikeya Semy and Ruokuonuo Kuotsu

1 Introduction

Therapeutic herbs are the “backbone” of traditional medicine, accounting to more

than 3.3 billion people in the less developed countries utilizing medicinal plants on
a regular basis [1]. The medicinal potential of plant products’ can be traced back
over 5000 years, as the evidence of their use in the treatment of ailments and for
body system revitalization are found in India, Egypt, China, Greek and Roman civi-
lizations [2]. In many regions of the world, indigenous peoples’ usage of ethno-
medicine as an intrinsic part of their culture has a close relationship with local
ecosystems and cultural landscapes. In India, plants with therapeutic potential are
widely used as folk remedies in various indigenous medical systems such as Siddha,
Ayurveda and Unani as processed pharmaceutical products [3]. Ethnomedicine and
traditional knowledge are good examples of disadvantaged populations living in
rural places combating even terminal diseases with ancient methods and using
herbal treatments [4]. The collection of original data from traditional custodians of
such knowledge is necessary in order to acquire a full compilation of medicinal
plants that can be employed in disease prevention [5]. Various medicinal weed
plants are a serious problem in agriculture and tremendously reduce the productiv-
ity of agricultural lands by competing with crop plants for water, mineral nutrients,
space and light. Keeping this in view such losses can be compensated by exploring
the medicinal utility of weeds. Thus, making use of every medicinal plants widely

These authors contributed equally to this work.

K. Semy (*)
Department of Botany, Don Bosco College Kohima, Kohima, India
R. Kuotsu
Research Scholar, Department of Botany, Nagaland University, Lumami, Nagaland, India

© The Author(s), under exclusive license to Springer Nature 1

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_1
2 K. Semy and R. Kuotsu

available for the disposal of human needs. Furthermore, the extraction and develop-
ment of various medicines and chemotherapeutics from these plants, as well as from
traditionally used rural herbal remedies, has been linked to an increased reliance on
medicinal plants in industrialized countries.
Northeast Indian states are some of the richest repositories of medicinal and
aromatic plants in the world [6]. This region has high medicinal plant diversity due
to variance in topography and physiognomy [7]. Nagaland is a part of the Indo-­
Burma mega biodiversity hotspot, which includes an immense variety of plant spe-
cies and is one of the wealthiest in terms of biological wealth and endemism in the
Indian subcontinent [8]. Naga’s are part of the mongoloid race and since time
immemorial, forest products have aided in the socio-economic life of the Naga
tribes in their ever-growing demands for medicines, food and shelter. They have an
inextricable link with their forest and regard it as a provider, guide, healer and pro-
tector like most of the North-eastern tribal communities of India. Naga villages
encompass parts of the hilly Eastern Himalayas and are secluded from other cities,
and hence the local inhabitants developed a sense to rely on indigenous healing
knowledge using medicinal plants. However, tribal’s knowledge on therapeutic
herbs of northeast India and in particular Nagaland, when compared to the rest of
the country is still understudied. Meanwhile, the traditional knowledge is rapidly
degrading with the advancement of technology and modernization. During the ear-
lier years, many researchers have contributed to the studies on medicinal plants
from in and around Northeast India, Assam [9–11], Manipur [12, 13], Arunachal
Pradesh [14–17] and Nagaland [18–24]. However, in contrast to those documented
plants focused on the three plant forms (herb, shrub and trees), the present investiga-
tion has been chiefly focused on the medicinal herbs prevalent in Nagaland. In con-
cern with the growing awareness and need for medicinal herbs, documentation of
plants is of vital importance. As a result, the current study was conducted in the
region with the following aims: (1) To document medicinal uses of plants, their rela-
tive importance and information for future investigation in novel drug applications
and (2) to educate locals about the area’s declining wealth on traditional and medici-
nal flora.

2 Materials and Methods

2.1 Study Area

Nagaland lies in the North-eastern part of India between the latitude of 250 06´ N
and 270 04´ N and longitude of 930 20′ E and 950 15′ E. The state covers a geo-
graphical area of 16,579 km2 and is bordered by Assam in the northwest, Myanmar
and Arunachal Pradesh in the east and Manipur in the south. The state experience a
sub-tropical to warm temperate monsoonal climate with four seasons, viz., winter,
spring, summer and autumn. Annually, rainfall ranges between 1800 and 2500 mm
Ethnobotanical Study of Medicinal Herbs Used by the Naga Tribes of Eastern Himalayas 3

with July and August receiving the highest rainfall. Temperature may rise from 21
to 36 °C in summer and drops from 21 to 4 °C during winter months. Frost is com-
mon at high elevations with snowfall in certain places and strong northwest wind
blows across the state with the onset of spring season. About 70% of the state’s
economy is dependent on agriculture along with other prominent economic activi-
ties including forestry, tourism and miscellaneous cottage industries. The recorded
forest cover of the state in 2021 is 8629.30 km2 which is about 52% of its geographi-
cal area. Tropical and sub-tropical evergreen forests accounts to one-sixth of the
forest area including palms, bamboo and timber and mahogany forests.

2.2 Collection and Identification

The phyto-documentation on herbaceous plants and their uses in traditional healing

customs by the Naga tribes was conducted in various districts across Nagaland.
Random weed samples were collected, and the representative taxa sampled during
the field survey were processed for herbarium following Jain and Rao [25] and later
identified with the help of standard literature on regional floras [26–28]. Group
discussion was held with native herbalist, village elders, old folks, street vendors,
farmers and council members to identify the local names, uses and other required
descriptions on their medicinal values. Special attention was paid to record informa-
tion from traditional healers and practitioners having immense knowledge of plants
in local dialect and well versed with their therapeutic uses.

3 Results and Discussion

The history of medicinal plants is as long as the history of humans. Nagas have been
practicing the use of medicinal plants since time immemorial which has been passed
down from generation to generation through traditional practices and oral lore.
Before Christianity, Nagas practiced Totemism and Animism, which are primarily
indulged with worshipping nature. The core principle of this devotion is abided in
respecting and preserving nature through rituals and sustainable norms laid down
by the village priest. Supplementing such traditions, the practices of therapeutic
healing is also associated with the principles and beliefs of the tribes. In the present
study, a total of 161 herbaceous plant species belonging to 58 families and 127 gen-
era were documented during the survey. All the recorded herbs have certain medici-
nal values and have been extensively used by the tribes for treating several diseases
and ailments. The collected plant samples arranged in alphabetical order along with
their botanical and vernacular names, plant parts used, preparation and purpose/
mode of administration are enumerated in Table 1. The family Asteraceae (24) was
reported with the largest number of species followed by Lamiaceae (11), Poaeaea
(9), Solanaceae (7), Leguminosae, Polygonaceae, Malvaceae and Rubiaceae (6
 4

Table 1 Ethnomedicinal herbs used by the Naga tribes of Eastern Himalayas

Sl Vernacular
no. Scientific name name Family Parts used Preparation Purpose /usage/treatment
1. Acacia pinnata Link Chakragaing Leguminosae Leaves Leaf paste is applied on Toothache.
infected tooth
2. Aconitum palmatum D.Don Merimezem Ranunculaceae Roots Root is crushed grinded and Laryngitis, sedation, asthma.
taken orally
3. Acorus calamus L. Themeprii Acoraceae Rhizome Concoction with therapeutic Gastritis, stomach ulcer, stomach
herbs ailments, anorexia.
4. Adiantum caudatum L. Aviinuo Pteridaceae Aerial parts Dried and fresh aerial parts De-worming, antipyretic,
ingested astringent.
5. Ageratina riparia (Regel) Nhasa Asteraceae Leaves Fresh paste rubbed on wounds Treat fresh wound, cuts, and
R.M.King & H.Rob. burns.
6. Ageratum conyzoides (L.) Chinapatta Asteraceae Leaves and root Leaf paste used as haemostatic Dysentery, diarrhoea, cuts, burns,
L. on cuts and wounds; decoction insect bites.
of root taken orally
7. Ageratum houstonianum Chinapatta Asteraceae Leaves Fresh leaf paste applied on Burns, dysentery, eye problem,
Mill. cuts and wounds; dried leaf pneumonia, urinary tract infection.
powder mixed with water
taken orally
8. Allium porrum L. Repjee Amaryllidaceae Whole plant Crushed grinded with mustard Antiseptic, tonic, anti-­
oil, pond salt and ingested cholesteremic, kidney stones.
9. Alpinia malaccensis Sokriinuo Zingiberaceae Rhizome Fresh or dried rhizome Stomach ache, indigestion,
(Burm.f.) Roscoe grounded and eaten emetic, wounds, ringworm.
10. Amaranthus spinosus L. Nyiedza Amaranthaceae Seeds Dried seeds roasted and eaten Diuretic, stomach ailments, bowel
with local red rice movements, appetizer, mouth
ulcer, eczema, snake bites, boils.
11. Amaranthus viridis L. Tierhiitiepfii Amaranthaceae Seeds Either dried or roasted Eye disorder, venereal disease,
fever, asthma.
K. Semy and R. Kuotsu
Sl Vernacular
no. Scientific name name Family Parts used Preparation Purpose /usage/treatment
12. Amorphophallus bulbifer Teinyhiimidu Araceae Stem Boiled with pond salt and Maintain blood pressure,
(Roxb.) Blume consumed detoxification, cough, breast pain.
13. Amphineuron opulentum Maachai Thelypteridaceae Leaves Leaf paste applied on infected Toothache.
(Kaulf.) Holttum tooth
14. Ardisia crenata Sims – Primulaceae Berries Taken in small dosage Rheumatism, earache, traumatic
injuries, snake and insect bites,
fever,
Diarrhoea, improves blood
circulation
15. Artemisia nilagirica Cienakezhau Asteraceae Leaves Intake of dried grounded Antimicrobial, antiulcer,
(C.B.Clarke) Pamp. leaves with water antifungal, anti-asthmatic,
antioxidant, anti-cancer.
16. Artemisia indica Willd. Ciena Asteraceae Leaves Leaf paste is applied on Skin infection, mosquito repellent.
infected skin; fresh leaves
burnt used as natural mosquito
repellent
17. Asclepias curassavica L. – Apocyanaceae Aerial parts Fresh paste applied on Dysentery, skin ulcers, eye
infected skin; dried treatment, ringworm, sores,
precipitated with water and anti-prostatic.
taken orally
18. Asparagus officinalis L. Shieprii Begoniaceae Young shoot, Extract from roots taken Obesity, bladder infection,
roots and tubers orally; young shoots and constipation, stomach ulcers.
tubers cooked and eaten as
vegetable
19. Begonia picta Sm. Tichu Begoniaceae Whole plant Either fresh extract or cooked Indigestion, anti-inflammatory,
and taken as vegetable skin infection, insect bites.
Ethnobotanical Study of Medicinal Herbs Used by the Naga Tribes of Eastern Himalayas

(continued)
5
 6

Table 1 (continued)
Sl Vernacular
no. Scientific name name Family Parts used Preparation Purpose /usage/treatment
20. Bidens pilosa L. Zorha Asteraceae Leaves Fresh paste applied on Blood coagulation, wounds, burns,
wounds; dried leaves taken malaria, and arthritis.
orally
21. Breynia retusa (Dennst.) – Phyllanthaceae Leaves and Consumed either fresh or Diabetes, antioxidant, reduce
Alston roots dried blood sugar.
22. Brugmansia suaveolens Lalho Solanaceae Leaves Leaves wrapped in banana Ulcers, tonsillitis, body ache.
(Humb. & Bonpl. ex leaf warmed in fire and
Willd.) Bercht. & J.Presl dapped on affected area to
ease pain
23. Cannabis sativa L. Ganja Cannabaceae Leaves Leaf paste used as hemostatic Cuts and wounds, malaria,
to cuts and wounds; decoction stomach ache.
taken orally
24. Cardamine hirsuta L. Seguoga Brassicaceae Whole plant Cooked with other herbs and Digestive disorder.
eaten with rice
25. Catharanthus roseus (L.) Tsuinrinaro Apocyanaceae Leaves Leaf extract applied on Skin disease, irregular blood
G.Don infected skin; boiled and pressure, stomach problems.
consumed in small quantity
with Neem
26. Centella asiatica (L.) Urb. Gara Apiaceae Whole plant Boiled or raw leaves Diabetic, wounds, burns, known
Fresh to improve memory power,
diarrhoea, constipation.
27. Chloris barbata Sw. – Poaceae Leaves Leaf paste applied on infected Skin infection, antimicrobial.
area
28. Chromolaena odorata (L.) – Asteraceae Leaves Leaf paste or juice rubbed on Fresh wounds, burns, skin
R.M.King & H.Rob. wounds infection.
29. Clerodendrum bracteatum Khriehenyii Lamiaceae Leaves Juice is applied on scalp; paste Astringent, remove dandruff.
Wall. ex Walp. taken orally
K. Semy and R. Kuotsu
Sl Vernacular
no. Scientific name name Family Parts used Preparation Purpose /usage/treatment
30. Clerodendrum Gathere Lamiaceae Leaves Boiled leaves are eaten Lowers blood pressure.
glandulosum Lindl.
31. Clerodendrum serratum Atsuksuba Lamiaceae Leaves Decoction of leaves are Irregular menstruation.
(L.) Moon consumed
32. Clerodendrum villosum Akawa Lamiaceae Leaves Decoction is drunk; juice Kill lice, liver problems.
Blume massage on scalp
33. Coix lacryma-jobi L. Kesi Poaceae Fruit Fruits soaked in water Warts, appendicitis, lungs
overnight and taken orally disorder, arthritis.
34. Commelina benghalensis Akhovepii Commelinaceae Aerial parts Fresh leaves and roots used as Sun burns, anti- inflammatory,
L. poultice diuretic, laxative.
35. Colocasia esculenta (L.) Dziinuo Araceae Leaves and Cooked and consumed Anti-inflammatory, anti-fungal,
Schott tubers inhibit tumor and gastrointestinal
problems.
36. Costus speciosus Thevobuoto Costaceae Stem and Boiled or soaked rhizome in Skin infection, anti- cancer,
(J.Koenig) Sm. rhizome water and consumed; stem anti-microbial, obesity, urinary
paste applied on infested skin tract infection.
with maggots
37. Crassocephalum – Asteraceae Leaves Extract used orally with honey Indigestion, oral problems,
crepidioides (Benth.) S. epilepsy, inflammation.
Moore
38. Crotalaria juncea L. – Leguminosae Root, pod and Concoction of root, pods and Skin diseases, rashes, high blood
leaves leaves applied externally or pressure, and astringent.
ingested in small dosage
39. Curculigo capitulata Koritong Hypoxidaceae Root, flowers Decoction of young plant Conjunctivitis, ear-ache,
(Lour.) Kuntze and leaves parts; root soaked overnight in antiseptic, haemostatic.
Ethnobotanical Study of Medicinal Herbs Used by the Naga Tribes of Eastern Himalayas

water; and the liquid is

applied
(continued)
7
 8

Table 1 (continued)
Sl Vernacular
no. Scientific name name Family Parts used Preparation Purpose /usage/treatment
40. Curculigo orchioides Koritong Hypoxidaceae Root, flowers Decoction of young plants Ear-ache, antiseptic.
Gaertn. and leaves with lime
41. Curcuma angustifolia Chiecie Zingiberaceae Flower and Consumed both fresh and Fever, cough, antifungal,
Roxb. rhizome dried with other herbs analgesics, anticancer.
42. Curcuma aromatica Salisb. Hutou Zingiberaceae Flower and Taken both fresh and dried Gastrointestinal disorder, arthritis,
rhizome with therapeutic herbs skin infections and rashes.
43. Cuscuta chinensis Lam. Tsuiali Convolvulaceae Aerial parts Paste applied on pain affected Anti-depression, urinary bladder
area; juice taken orally problem, liver ailments, joint pain.
44. Cuscuta reflexa Roxb. Tsuiali Convolvulaceae Aerial parts Juice extract is boiled and Urination disorder, muscle cramp,
consumed; paste applied on cold cough, warts, carminative.
affected area
45. Cyanotis vaga (Lour.) – Commelinaceae Whole plant Plant extract is ingested in Liver dysfunction, weight loss,
Schult. & Schult.f. small quantity with honey enhance energy metabolism.
46. Cyperus iria L. – Cyperaceae Leaves Boiled with honey and juice is Stomach ache, diuretic, regulate
consumed menstruation, cure itching.
47. Datura innoxia Mill. Lhalho Solanaceae Flower and Either fresh or dried use as Malaria, antiseptic, cardiac arrest,
leaves poultice stomach ulcers.
48. Dicranopteris linearis Kajangtong Gleicheniaceae Leaves Poultice on painful body parts Fever, wounds, asthma, sores,
(Burm.f.) Underw. ulcers.
49. Dioscorea alata L. Thecu Dioscoreaceae Tuber Boiled and taken Gastritis, constipation, stomach
ache.
50. Diplazium esculentum Gasiilo Athyriaceae Leaves Taken either boiled or raw Measles, gastrointestinal, diabetes,
(Retz.) Sw. with aromatic rice and pond glandular swelling, bone fracture,
salt constipation.
51. Drymaria cordata (L.) Pfiipfiinyii Caryophyllaceae Whole plant Squeezed along with mustard Sinusitis, migraine, bronchitis.
Willd. ex Schult. oil and juice applied on
infected area; taken orally
K. Semy and R. Kuotsu
Sl Vernacular
no. Scientific name name Family Parts used Preparation Purpose /usage/treatment
52. Eclipta prostrata (L.) L. Bhringraj Asteraceae Leaves Extract mixed with honey, Hepatitis, snake bites, jaundice,
milk and ingested; leaf paste liver tonic, asthma, respiratory
rubbed on wounds ailments.
53. Elatostema sessile Gajo Urticaceae Leaves Leaves boiled and eaten with Gastrointestinal problems.
J.R.Forst. & G.Forst. rice
54. Eleusine indica (L.) – Poaceae Whole plant Boiled and drunk Laxative, hypertension, fever, cold
Gaertn. cough, malaria, relieves pain,
astringent, asthma.
55. Elsholtzia blanda (Benth.) Niepfii Lamiaceae Leaves and Consumed both fresh and Reduce tonsil swell, fever, cough,
Benth. flower dried and maintain blood pressure.
56. Entada pursaetha DC. Tholi Leguminosae Seed Cleansed in running water for Burns, jaundice in children,
several days, roasted and after-effects of stroke, helps in
consumed in small dosage. blood circulation, parasitic
infection.
57. Equisetum arvense L. Siihie Equisetaceae Aerial parts Boiled with water and lemon Kidney stone, bladder problems,
juice tuberculosis, heal ulcer.
58. Erigeron linifolius Willd. – Asteraceae Aerial parts Plant paste applied on infected Antibacterial, anti-inflammatory.
area
59. Eryngium foetidum L. Dunia Apiaceae Whole plant Consume both fresh and Infertility complications, ear ache,
cooked with other herbs de-worming, malaria.
60. Eupatorium adenophorum Japan nha Asteraceae Aerial parts Fresh paste applied on Anti-inflammatory, anti-microbial,
Spreng. infected area analgesic, blood coagulation.
61. Euphorbia heterophylla L. – Euphorbiaceae Leaves Boiled with pond salt and Asthma, anti-cancer, diarrhea.
consumed
62. Euphorbia hirta L. Dudiya Euphorbiaceae Aerial shoots Consumed either fresh or Cold cough, bronchitis,
Ethnobotanical Study of Medicinal Herbs Used by the Naga Tribes of Eastern Himalayas

dried mixed with other herbs gonorrhoea, anti- diabetic.

(continued)
9
Table 1 (continued)
10

Sl Vernacular
no. Scientific name name Family Parts used Preparation Purpose /usage/treatment
63. Fagopyrum esculentum Garei Polygonaceae Aerial parts Either fresh or dried young Cardiovascular, antioxidant,
Moench leaves cooked with local rice stomach congestion, diabetic.
and consumed
64. Galinsoga parviflora Cav. Bomara Asteraceae Leaves Fresh paste applied on Eczema, skin infection, rashes,
infected area bleeding wounds.
65. Gomphrena celosioides – Amaranthaceae Whole plant Extract taken orally; fresh Gastrointestinal, breathlessness,
Mart. paste applied on skin rashes skin rashes.
66. Gynura bicolor (Roxb. ex Liezienuo Asteraceae Aerial parts Young leaves boiled with local Constipation, diabetes, post-­
Willd.) DC. rice and taken orally labour recovery, migraines,
haemoptysis.
67. Hibiscus sabdariffa L. Gakhro Malvaceae Leaves and Consumed either dried-fresh Blood pressure, aids in digestion,
flower or made into porridge with skin rashes, inflammatory, food
rice poisoning.
68. Hibiscus syriacus L. Chakha ga Malvaceae Flower and Flower paste applied on scalp; Antifungal, hair and skin
leaves young leaves boiled and eaten treatment, gastrointestinal.
69. Hodgsonia macrocarpa Ketsamo Cucurbitaceae Seeds Roasted seeds mixed with Bacterial infection in feet, heal
(Blume) Cogn. aromatic herbs, pond salt and wounds, fever, nose ulcers, cure
consumed burns.
70. Houttuynia cordata Thunb. Gatha Saururaceae Whole plant Fresh plant mixed with Diuretic action, detoxification,
fermented soya bean and hypertension, improve appetite.
eaten
71. Hydrocotyle javanica – Araliaceae Leaves and Crushed leaf paste applied on Gastritis, eye infection, fresh cut
Thunb. tender shoots wounds: young shoots cooked wounds.
and consumed
72. Impatiens latiflora Hook.f. Ciikanyii Balsaminaceae Leaves Fresh paste is applied on skin Insect bites, allergies, indigestion,
& Thomson infection; leaves taken orally analgesic.
K. Semy and R. Kuotsu
Sl Vernacular
no. Scientific name name Family Parts used Preparation Purpose /usage/treatment
73. Imperata cylindrica (L.) Azu Poaceae Aerial shoots Paste is applied on wounds; Diuretic, gastrointestinal, urinary
Raeusch. leaves are consumed tract infection.
74. Ipomoea involucrata – Convolvulaceae Roots and Extract is taken orally Hypertension, diabetes, analgesic,
P. Beauv. leaves psychotomimetic, antimicrobial,
fatigue.
75. Ipomoea purpurea (L.) – Convolvulaceae Leaves and Plant extract taken orally Constipation, oedema in lungs,
Roth flower mental disorders, jaundice.
76. Ipomoea quamoclit L. Tamlata Convolvulaceae Leaves and Leaf paste applied on infected Insect bites, rashes, hairfall,
flower skin; young parts are antidiabetic, antimicrobial.
consumed
77. Justicia adhatoda L. Tsiesenyii Acanthaceae Leaves Decoction of young shoots Carminative, paralysis,
with therapeutic herbs gonorrhoea, chronic rheumatism.
78. Kaempferia rotunda L. Bhuichampa Zingiberaceae Flower and Paste applied on wounds; Stomach ache, food poisoning,
rhizome taken orally emetic, thermogenic.
79. Kalanchoe pinnata (Lam.) Tsatsovo Crassulaceae Leaves Fresh grinded with therapeutic Pulmonary infection, kidney
Pers. herbs and ingested stones, stomach ache, gastric
ulcer, allergies, diabetes.
80. Lantana camara L. Anitong Verbenaceae Leaves and Boiled with honey and juice Fever, cold cough, antimicrobial,
flowers taken in small dosage chicken pox, ulcers, skin rashes,
wheezing cough.
81. Leucas aspera (Willd.) Chota halkusa Lamiaceae Leaves Paste is applied on infected Antimicrobial, snake bites, insect
Link area bites.
82. Ludwigia perennis L. – Onagraceae Flower Fresh paste applied on Toothache and fever.
infected tooth
83. Lycopodium cernuum L. Mangrang Lycopodiaceae Aerial parts Dried-grinded, boiled with Constipation, chronic lung
Ethnobotanical Study of Medicinal Herbs Used by the Naga Tribes of Eastern Himalayas

naro other herbs and taken orally disorder, bronchitis.

(continued)
11
Table 1 (continued)
12

Sl Vernacular
no. Scientific name name Family Parts used Preparation Purpose /usage/treatment
84. Mentha arvensis L. Pudina Lamiaceae Aerial parts Consumed either fresh or Hypertension, heart disease,
boiled inflamed joints and arthritis.
85. Mikania micrantha Kunth Japanza Asteraceae Leaves Fresh leaves are grinded and Lower blood pressure; reduce
extract applied for sinus; blood sugar level, sinusitis.
extract taken orally
86. Mimosa pudica L. Keriinganha Leguminosae Root and leaves Freshly grinded and taken Asthma, jaundice, ulcer, small
orally pox, conjunctivitis.
87. Mirabilis jalapa L. Jamtangnaro Nyctaginaceae Roots and Concoction of roots and Purgative, cathartic inflammation,
leaves leaves taken orally antiviral, diuretic.
88. Mussaenda macrophylla Seirhobie Rubiaceae Fruits Boiled and juice consumed Antiviral, male impotency,
Wall. gastrointestinal problems
89. Ocimum sanctum L. Nieco Lamiaceae Aerial parts Mixed with ginger, honey and Asthma, eye sore, dysentery,
taken orally arthritis, gastritis, antimicrobial.
90. Ocimum tenuiflorum L. Nieco Lamiaceae Flower and Either dried, fresh and mixed Anti-ageing, cough, headache,
leaves with other herbs and acne, anticancer, heartache, fever,
consumed eye health.
91. Oenanthe javanica Gakra Apiaceae Young aerial Boiled or raw with soyabeans, Jaundice, abdominal pain,
(Blume) DC. parts garlic, ginger, pond salt and leukaemia, hepatitis.
eaten with aromatic red rice
92. Oxalis corniculata L. Keve Oxalidaceae Whole plant Fresh plants are eaten wholly Aids in digestion, antiseptic, fresh
cut wounds, burns.
93. Oxalis debilis Kunth Thezutsiituo Oxalidaceae Whole plant Fresh plants are eaten wholly Indigestion, constipation,
acid-reflux.
94. Paederia foetida L. Menyiero Rubiaceae Aerial parts Boiled with water, herbs, pond Gastrointestinal, abdominal pain,
salt and ingested rheumatism, stomach oedema,
gastritis, ulcers.
K. Semy and R. Kuotsu
Sl Vernacular
no. Scientific name name Family Parts used Preparation Purpose /usage/treatment
95. Panax ginseng C.A.Mey. Tsudiemozu Araliaceae Root, leaves Extract mixed with sorghum Heart problems, diabetes, cancer,
oil, pond salt, water and tuberculosis, ulcers.
drunk; dried powdered mixed
with honey and water
96. Panax pseudoginseng Wall. Takumtsu Araliaceae Root and leaves Dried or fresh root and leaves Anticancer, tuberculosis, diabetes.
mozu grounded and taken orally
97. Paris polyphylla Sm. – Melanthiaceae Rhizome Fresh or dried rhizome Diarrhoea, analgesic, burn, cut,
applied on infected area or anticancer, snake, spider and
taken orally scorpion bite, antispasmodic.
98. Paspalum distichum L. – Poaceae Whole plant Either fresh or dried plants are Bronchitis, arthritis, blood tonic,
boiled and ingested antibacterial.
99. Passiflora edulis Sims Bel Passifloraceae Leaves and Consumed either steamed or Asthma, snakebite, liver- tonic,
fruits fried; fruits eaten fresh or heart problems, maintains blood
fermented pressure, malaria.
100. Peperomia pellucida (L.) – Piperaceae Leaves Paste applied on infected skin; Anti-inflammatory, rheumatism,
Kunth eaten either fresh or boiled fatique, acne, boils.
101. Perilla frutescens (L.) Kenyie Lamiaceae Leaves and Leaves consumed either fresh Stomach problems, gastritis,
Britton seeds or steamed; seeds are roasted haemostatic.
made into paste and ingested
102. Persicaria chinensis (L.) Priizie Polygonaceae Whole plant Young leaves and stem are Antibacterial, snake bite, eye
H. Gross boiled with pond salt and treatment, mosquito repellent.
ingested
103. Persicaria hydropiper (L.) Priizie Polygonaceae Leaves Fresh leaves boiled and taken Neuro-protective effect, anti-­
Delarbre cancer, against rheumatism.
104. Phyllanthus fraternus – Phyllanthaceae Whole plant Paste directly applied on Diuretic, laxative, gonorrhoea,
Ethnobotanical Study of Medicinal Herbs Used by the Naga Tribes of Eastern Himalayas

G.L.Webster infected area; grounded dried spasms. It is directly applied on

leaves ingested skin for skin infection.
(continued)
13
Table 1 (continued)
14

Sl Vernacular
no. Scientific name name Family Parts used Preparation Purpose /usage/treatment
105. Physalis peruviana L. Chahacasi Solanaceae Fruit and leaves. Fresh fruits and leaves Antihistamine, antiviral, cancer,
grounded and taken in small asthma, dermatitis, gout, urinary
dosage tract disorder.
106. Pilea microphylla (L.) – Urticaceae Aerial parts Plant extract rubbed on Antibacterial, skin infection,
Liebm. infected skin antifungal, allergies.
107. Piper betle L. Seipanyii Piperaceae Leaves Fresh paste applied on wound Haemostatic.
108. Piper longum L. Pipali Piperaceae Leaves Eaten raw or steamed with Chronic malaria, spleen, tumours,
pond salt tongue paralysis, respiratory
infection.
109. Plantago asiatica L. Gapa Plantaginaceae Leaves Leaves are boiled and eaten Urinary tract infection, promote
urination, relieve phlegm
discomfort.
110. Plantago erosa Wall. Isabgol Plantaginaceae Whole plant Boiled with other herbs with Bleeding and inflammation,
local pond salt and taken with constipation, antibacterial,
aromatic rice indigestion.
111. Plantago major L. Gapa Plantaginaceae Whole plant Boiled and eaten Cuts and burns, sprains.
112. Polygonum molle D. Don Gazie Polygonaceae Leaves and Fresh leaves poultice on Anti-inflammatory, anticancer,
young stem infected area; young leaves skin rashes, astringent properties.
and stem taken orally
113. Polygonum plebeium R.Br. – Polygonaceae Leaves Taken either fresh or boiled Bowel movement, constipation,
stomach ailments.
114. Pouzolzia hirta Blume ex – Urticaceae Leaves Extracts are drunk Bowel movement, constipation,
Hassk. stomach ailments.
115. Pouzolzia zeylanica (L.) – Urticaceae Aerial parts Poultice on infected area Ulcers, syphilis, gonorrhoea,
Benn. galactagogue, stomachache.
K. Semy and R. Kuotsu
Sl Vernacular
no. Scientific name name Family Parts used Preparation Purpose /usage/treatment
116. Psophocarpus Charkona Leguminosae Fruit Consumed fresh mixed with Blood purifier, anti-oxidant,
tetragonolobus (L.) DC. pond salt, king chili and diabetes.
soybean
117. Pteridium aquilinum (L.) – Dennstaedtiaceae Roots Steam bath Diuretic, arthritis, old wound,
Kuhn aphrodisiac, de-worming.
118. Ricinus communis L. Louca Euphorbiaceae Leaves Dried leaves grounded and Backache, cramp, menstrual
taken in small dosage problems, constipation.
119. Rubia cordifolia L. Chenhu Rubiaceae Whole plant Extract or paste applied on Ringworm, leucoderma, skin
infected skin rashes disease.
120. Rubus ellipticus Sm. Ruomvii Rosaceae Berries and Grinded with water and Cold cough, sore throat,
leaves consumed indigestion, constipation, diuretic.
121. Rubus niveus Thunb. Temeirom Rosaceae Berries and Grinded with water and Snake bite, rheumatic,
leaves consumed detoxification, dysentery,
menstrual bleeding.
122. Rumex patientia L. Meza gakrie Polygonaceae Roots and Poultice on infected area; Constipation, fresh cut wounds,
leaves juice of roots and leaves taken skin rashes, aids in digestion.
in small dosage
123. Rungia pectinata (L.) Nees – Acanthaceae Leaves Fresh leaf paste applied on the Small pox, body ache, aperients
body effects.
124. Scutellaria rivularis Wall. Angamejep Lamiaceae Whole plant Paste mixed with sorghum oil Insect and spider bites.
ex Benth. talula and rubbed
125. Selaginella involvens (Sw.) – Selaginellaceae Aerial parts Taken orally with other herbs Internal haemorrhoid bleeding,
Spring blood expediting.
126. Senecio cappa Buch.-Ham. Mesakraza Asteraceae Whole plant Extract applied externally Skin disease, boils.
ex D.Don
Ethnobotanical Study of Medicinal Herbs Used by the Naga Tribes of Eastern Himalayas

(continued)
15
Table 1 (continued)
16

Sl Vernacular
no. Scientific name name Family Parts used Preparation Purpose /usage/treatment
127. Senna hirsuta (L.) – Leguminosae Leaves Dried, grinded-applied on Dysentery, ringworm, skin
H.S.Irwin & Barneby infected skin and taken orally infection, germicide, antiparasite.
in small dosage
128. Sesamum orientale L. Pingnak Pedaliaceae Seeds Roasted, consumed, or applied Laxative, skin hydration, hair
on skin and scalp growth.
129. Setaria glauca (L.) P. – Poaceae Whole plant Boiled and ingested Fever, cough.
Beauv.
130. Setaria pumila (Poir.) – Poaceae Aerial parts Boiled with other herbs, Rheumatic, fever.
Roem. & Schult. mixed with salt and consumed
131. Sida acuta Burm. f. Bala Malvaceae Leaves Dried, grinded with oil and Asthma, tuberculosis, oral
taken orally problems, urinary tract infection,
testicular swelling.
132. Smilax zeylanica L. Fiipro Smilacaceae Leaves and Fresh paste rubbed on infected Skin infections; maintain blood
roots skin; boiled with cow milk pressure, indigestion, joint pain,
and ingested sexual vigor.
133. Solanum gilo Raddi Ciepfi Solanaceae Fruits Roasted in hot ash and eaten Aids in digestion, maintains blood
pressure.
134. Solanum nigrum L. Gadzii Solanaceae Fruits Consumed either fresh or Mouth ulcers, skin infections,
boiled with pond salt asthma, tonic, and cough.
135. Solanum torvum Sw. Tsociepfii Solanaceae Fruits Roasted in ash, fried with Cardiac arrest, ulcers, fever,
sorghum or boiled with pond cough, wounds, liver disorder.
salt
136. Solanum viarum Dunal Chiikrii Solanaceae Fruits Dried and mixed with other Anticancer,
therapeutic herbs and taken antifungal, anti- inflammatory.
orally
K. Semy and R. Kuotsu
Sl Vernacular
no. Scientific name name Family Parts used Preparation Purpose /usage/treatment
137. Sonchus arvensis L. Nhana Asteraceae Leaves, stem, Fresh leaves steamed and Cough, digestive disorder,
young roots eaten increase appetite and improve
eyesight.
138. Sonchus asper (L.) Hill Nhana Asteraceae Leaves and Young leaves cooked and Sedative, anti-cancer, blood
stems eaten purifier, antidepressant.
139. Spermacoce hispida L. – Rubiaceaea Aerial parts Consumed fresh young shoots Gallstones, conjunctivitis,
haemorrhoids, tonic.
140. Spermacoce keyensis Small – Rubiaceaea Aerial parts Young shoots consumed either Malaria, boils, haemorrhage, skin
fresh or dried infection.
141. Spermacoce latifolia Aubl. – Rubiaceae Aerial parts Dried and mixed with water Leukemia, digestive problems,
and taken orally skin rashes, urinary tract infection,
respiratory ailments.
142. Sphaeranthus indicus L. – Asteraceae Aerial parts Either dried or fresh mixed Skin infection, cough, diabetic,
with other herbs epilepsy.
143. Spilanthes acmella (L.) L. Kevenha Asteraceae Flower and Fresh flowers paste is applied Toothache, inflammation,
leaves on infected tooth.; leaves are pain-reliever, diuretic, gastric
boiled and taken orally ulcer.
144. Sporobolus diandrus – Poaceae Aerial parts Boiled and consumed orally Gonorrhoea, pain reliever, blood
(Retz.) P.Beauv. circulation.
145. Synedrella nodiflora (L.) – Asteaceae Leaves Dried, grinded and taken Cardiac problems, epilepsy, liver
Gaertn. orally disease, inflammatory.
146. Thunbergia coccinea Wall. Nulidongmoli Acanthaceae Tubers Extracts taken orally in small Aphrodisiac and tonic.
dosage
147. Thysanolaena latifolia Phipfe Poaceae Leaves and Plant extract mixed with lime, Treat boils, sore in eye, fever, and
(Roxb. ex Hornem.) Honda roots pond salt and ingested reduce inflammation.
Ethnobotanical Study of Medicinal Herbs Used by the Naga Tribes of Eastern Himalayas

(continued)
17
Table 1 (continued)
18

Sl Vernacular
no. Scientific name name Family Parts used Preparation Purpose /usage/treatment
148. Tagetes erecta L. Puja niepou Asteraceae Leaves and Decoction of leaves Intestinal problems, gastritis,
flower mumps, sore eyes.
149. Taraxacum officinale (L.) – Asteraceae Whole plant Decoction and brewed for tea Reduce cholesterol, maintain
Weber ex F.H.Wigg. blood sugar level, improve
eyesight, cleans intestinal tract.
150. Tinospora sinensis (Lour.) Tsula Menispermaceae Stem Poulticed on affected area Applied to burns, bone fractures,
Merr. mesukzu sprains, stomach problems.
151. Tithonia diversifolia Mochitsiinara Asteraceae Leaves Paste applied on skin; dried or Antiseptic, indigestion, stomach
(Hemsl.) A.Gray fresh mixed with therapeutic ache, constipation, diabetes,
herbs ingested in small dosage menstrual pain.
152. Tridax procumbens (L.) L. – Asteraceae Leaves Paste rubbed on infected skin Anti-fungal, skin disease, insect
bites, anti-coagulant.
153. Triumfetta pilosa Roth Kuchii Malvaceae Leaves Dried and taken orally Inflammation, stomach ache,
jaundice.
154. Triumfetta rhomboidea Kuchii Malvaceae Leaves Dried and taken orally Gum problems, stomach ache,
Jacq. hepatitis, asthma.
155. Typha angustata Bory & – Typhaceae Shoot Concoction of leaves, honey, Male impotency, menstrual pain,
Chaub. ginger and consumed orally haemostatic.
156. Urena lobata L. Kouchii Malvaceae Root, stem and Concoction of leaves, root, Anticancer, anti-diabetic,
leaves stem with water and taken diarrhoea.
orally
157. Urtica dioica L. Zozie Urticaceae Leaves Leaves paste mixed with Hair fall, inflammations, prostate
essential oil and applied on cancer, hay fever, lower blood
scalp; leaves boiled and taken pressure, maintains blood sugar
orally level.
K. Semy and R. Kuotsu
Sl Vernacular
no. Scientific name name Family Parts used Preparation Purpose /usage/treatment
158. Wedelia chinensis Onnii Asteraceae Leaves Extract of leaves is rubbed on Hair growth, analgesic,
(Osbeck) Merr. scalp and ingested in minute antimicrobial, headache.
dosage
159. Zanthoxylum Ganyasei Rutaceae Leaves and Consumed either raw or Fever and toothache.
acanthopodium DC. fruits cooked with salt or soya
beans; paste applied on
infected tooth
160. Zanthoxylum oxyphyllum Ganyanyii Rutaceae Fruits, leaves, Poultice on infected area; Liver-tonic, toothache and fever.
Edgew. inflorescence cooked with sorghum oil,
pond salt and eaten with
aromatic rice
161. Zanthoxylum rhetsa DC. Ganya Rutaceae Fruits and Poultice on forehead; boiled Fever.
leaves and eaten with sticky rice
Ethnobotanical Study of Medicinal Herbs Used by the Naga Tribes of Eastern Himalayas
19
20 K. Semy and R. Kuotsu

species each), Convolvulaceae and Urticaceae (5 species each), Zingiberaceae (4),

Acanthaceae, Amaranthaceae, Apiaceae, Araliaceae, Plantaginaceae, Piperaceae
and Rutaceae (3 species each), Apocynaceae, Araceae, Begoniaceae, Commelinaceae,
Hypoxidaceae, Oxidaceae, Phyllanthaceae, Pteridaceae and Rosaceae (2 species
each)m while the rest 32 families had one species each. Most plants were found to
grow in wild conditions and very few cultivated. Some weed plants like Bidens
pilosa, Cannabis sativa and Datura innoxia have often been used as antiseptics for
treating cuts and wounds, burns and skin infections. Some of the common plants
like Ageratum conyzoides, A. houstonianum and Spilanthes acmella found in this
region are traditionally used as decoction with other therapeutic herbs for treating
diarrhoea and as an effective pain reliever against toothache. Invasive plants such as
Lantana camara, Chromoleana odorata and Ageratina riparia growing abundantly
in kitchen gardens are frequently considered a threat to the native flora but at the
same time highly efficient and useful in treating numerous diseases. Rare and
endangered species like Paris polyphylla, Panax pseudoginseng and Curculigo
orchiodes are known for their ample benefits in treating various diseases and their
anticancer properties.
The most common plant parts used are the leaves followed by shoots, roots, rhi-
zomes, seeds, flowers and fruits. Many plants were found to possess multiple thera-
peutic properties in treating different ailments. Leaves of Acacia pinnata,
Amphineuron opulatum, Cannabis sativa, Catharanthus roseus, Chloris barbata,
Hydrocotyle javanica, Ipomoea quaolit, Rungia pectinata, Centella asiatica,
Clerodendrum glandulosum, C. serratum, Commelina benghalensis, Hibiscus syri-
acus, Phyllanthus fraternus, Pilea microphylla, Polygonum molle and Rumex
patientia are used for treating skin infections (cuts, wounds, ringworm, skin ulcers
and skin rashes) and insect bites. Leaves of Ricinus communis, Rubus niveus,
Tithonia diversifolia and Typha angusta are used for treating menstrual cramps. The
tender shoots or aerial parts of Asparagus officinalis, Adiantum caudatum, Asclepias
curassavica, Euphorbia hirta and Imperata cylindrica are used for dysentery, de-­
worming, chronic lung diseases. Tender shoots of Cuscuta chinensis and C. reflexa
are used in the treatment of urinary tract infection, urinary bladder problems and
chronic liver ailments. Rhizome of Acorus calamus, Alpinia malaccensis, Costus
spesiocus, Curcuma angustifolia, C. aromatic and Kaemferia rotunda is extensively
used as a remedy for treating fever, indigestion and cough. Seeds of Amaranthus
spinosus, A. viridis, Entada pursaetha, Hodgsonia macrocarpa, Perilla frutescens
and Sesamum orientale are used for constipation, appetizer, skin hydration and hair
growth. Flowers of Curculigo capitula and C. orchioides are used for the treatment
of conjunctivitis and earache. Fruits(berries) of Psophocarpus tetragonolobus,
Solanum gilo, S. nigrum, S. torvum, S. viarum, Zanthoxylum oxyphyllum and
Z. rhetsa are used as liver tonic, aids in digestion, maintains blood pressure, reduce
fever, appendicitis including warts. Extracts of Eclipta prostrate, Amaranthus spi-
nosus, Persicaria chinensis, Paris polyphylla, Leucas aspera and Impatiens latiflora
are used as antidotes against snake and insect bites.
Traditionally, the mode of preparation is by using either fresh or dried plant
materials depending on the types of ailments the herbs are employed for treatment.
Ethnobotanical Study of Medicinal Herbs Used by the Naga Tribes of Eastern Himalayas 21

Most of the plants are processed in different ways like grinding, macerating, paste,
juice extracts and decoction in combination with other herbs or ingredients like
sorghum oil, pond salt, honey, milk and aromatic local rice. A warm poultice of
various medicinal herbs with sorghum oil is also applied to get relief from muscle
cramp, soreness, joint pain, body inflammation, body ache, fever and stomach con-
gestion. The gastronomic culture of Nagas involves in the intake of spicy and fer-
mented foods (bamboo shoots, soyabeans, mustard leaves, pickles, king chilies,
etc.) including smoked meat (pork, beef, mutton and wild animals). These habits
could have been a key reason for various health issues such as stomach pain, intes-
tinal disorders, asthma, chronic liver disease and lungs infection prevalent within
the tribal population. However, with these problems, the Nagas have developed a
sense to find sources in treating the associated ailments and thus majority of the
plants documented are known to be utilized for treating such gastrointestinal and
other associated ailments. In total, 34 herbs were recorded for treating gastrointes-
tinal problems (Acorus calamus, Alpinia malaccensis, Amaranthus spinosus,
Asparagus officinalis, Cannabis sativa, Catharanthus roseus, Curcuma aromatic,
Colocasia esculenta, Cyperus iria, Datura innoxia, Dicranopteris linearis,
Dioscorea alata, Diplazium esculentum, Elatostema sessile, Fagopyrum esculen-
tum, Gomphrena celosioides, Gynura bicolor, Hibiscus syriacus, Hydrocotyle
javanica, Kaempferia rotunda, Kalanchoe pinnata, Ocimum sanctum, Imperata
cylindrica, Mussaenda macrophylla, Paederia foetida, Polygonum plebium,
Pouzolzia hirta, P. zeylanica, Tagetes erecta, Tinospora sinensis, Tithonia diversifo-
lia, Triumfetta pilosa, T. rhomboidea and Typha angusta). From the present study, it
is evident that medicinal plants play a vital role in aiding to the health of indigenous
people in this region. Many of the tribes in the studied area still depend on the
medicinal plants for their daily healthcare routine over the modern system of medi-
cines. But over the years, this system may deteriorate due to the absence of interest
among the younger generations as most are influenced by modern technology and
their cultural importance are put aside. Moreover, the traditional healing systems
are passed down orally and hence detailed information is lost in the process.
Therefore, necessary steps should be taken up to encourage the upcoming genera-
tions as well as penned down the necessities in proper text for future references.
With the help of the government or village councils, robust regulations and manage-
ment plans should be laid to protect and educate the tribes about the benefits, medic-
inal purposes and conservation of these valuable herbs.

4 Conclusion

The study elucidated a very high number of therapeutic herbs accounting for 161
plants, which is one of the highest recorded data from Northeast India. According to
the current research, medicinal herbs will continue to play an essential role as a
health aid to the tribal communities of Eastern Himalayas. Traditional healing treat-
ments employing medicinal plants are widely used on a normative basis by the
22 K. Semy and R. Kuotsu

Nagas. Furthermore, due to the rising costs of personal health maintenance, herbal
therapies have grown more popular in these regions for treating various disorders.
However, as a result of developmental activities, deforestation, population growth
and indiscriminate exploitation, native medicinal plants are rapidly depleting and
have even lead to some plant species being endangered. Therefore, efforts must be
geared towards preserving them through sustainable management and enhance the
effectiveness, efficacy and rational use of medicinal plants, especially through the
integration into national, regional and local health policies and programmes. In situ
conservation techniques in home gardens and on-farm cultivation should be encour-
aged for socio-economic and sustainable growth. Also, these plants can fill the void
in the medical sector and become a new trend for upcoming research.

Acknowledgement The authors are thankful to the native healers, village elders, herbalist and
local inhabitants of Nagaland for sharing their traditional knowledge.

Declarations Authors Contribution: Khikeya Semy: Field survey, documentation

and construction of manuscript; Ruokuonuo Kuotsu: Plants identification and her-
barium preparation.
Ethics Approval: Not applicable.
Consent to Participate: All authors have their consent to participate.
Consent for Publication: All authors have their consent to publish their work.
Conflict of Interest: The authors declare no competing interests.
Availability of data and materials: Data made available on reasonable request.
Fundings: Not applicable.

References

1. Davidson-Hunt I (2000) Ecological ethnobotany: stumbling toward new practices and para-
digms. Mod Assis Stat App 16:1–13
2. Mahesh B, Satish S (2007) Antimicrobial activity of some important medicinal plant against
plant and human pathogen. J Agri Sci 4
3. Srinivasan D, Nathan S, Suresh T (2007) Antimicrobial of certain Indian medicinal plants used
in folkloric medicine. J Ethnopharmacol 74:217–220
4. Raut S, Sen SK, Satpathy S, Pattnaik D (2012) An ethnobotanical survey of medicinal plants
inSemiliguda of Koraput District, Odisha, India. Bot Res Intern 5(4):97–107
5. Tan AC, Konczak I, Sze DM, Ramzan I (2010) Towards the discovery of novel phytochemicals
for disease prevention from native Australian plants: an ethnobotanical approach. Asian Pac J
Clin Nutr 19(3):330–334
6. Chakraborty RDB, Devanna N, Sen S (2012) North-East India an ethnic storehouse of unex-
plored medicinal plants. Scho Res Lib 2:143–152
7. Majumder J, Battacharjee PP, Datta BK, Agarwala BK (2014) Ethno-medicinal plants used by
Bengali communities in Tripura, Northeast India. J For Res 25:713–716
8. Semy K, Singh MR (2021) Quality assessment of Tsurang River water affected by coal mining
along the Tsurangkong Range, Nagaland, India. Appl Water Sci 11:115
Ethnobotanical Study of Medicinal Herbs Used by the Naga Tribes of Eastern Himalayas 23

9. Taid TC, Rajkhowa RC, Kalita JC (2014) A study on the medicinal plants used by the local
traditional healers of Dhemaji district, Assam, India for curing reproductive health related
disorders. Adv Appl Sci Res 5(1):296–301
10. Bharali P, Sharma CL, Singh B, Sharma M (2017) Ethnobotanical studies of spice and condi-
ment plants used by some communities of Assam. Int J of Adv in Sci Res 3(01):1–11
11. Sharma M, Das B (2018) Medicinal plants of north-east region of India: a small review. Int J
Curr Pharm Res 10(4):11–12
12. Chakre L, Narasimhan D (2013) Ethnobotany of Mao-Naga tribe of Manipur, India. Pleione
7(2):314–324
13. Usharani L, Singh WR, Surodhani S (2015) An ethnomedicinal plant-A less known Spices
used by Meitei Community of Manipur. Asian J Plant Sci Res 5(6):84–87
14. Khongsai M, Saikia SP, Kayang H (2011) Ethnomedicinal plants used by different tribes of
Arunachal Pradesh. Indian J Trad Know 10(3):541–546
15. Perme N, Choudhury SN, Choudhury R, Natung T, De B (2015) Medicinal plants in traditional
use at Arunachal Pradesh, India. Int J Phytopharm 5(5):86–98
16. Tripathi AK, Shankar R, Limasenla, Neyaz S (2016) Medicinal plants of Arunachal Pradesh
used in treatment of various diseases
17. Kashung S, Gajurel PR, Singh B (2020) Ethnobotanical uses and socio-economic importance
of climbing species in Arunachal Pradesh, India. Plant Sci Today 7(3):371–377
18. Deorani SC, Sharma GD (2007) Medicinal plants of Nagaland. In: Singh B., Singh M.P (eds),
Dehra Dun
19. Changkija S, Ajungla L, Rongsensashi, Mozhui R (2010) Medicinal and Aromatic Flora of
Nagaland. MPDA, Dept. of Forest, Ecology, Environment and Wildlife, Govt. of Nagaland
20. Lokho A (2012) The folk medicinal plants of the Mao Naga in Manipur, North East India. Int
J Sci Res Pub 2(6):1–8
21. Shankar R, Devalla RB (2012) Conservation of folk hailing practices and commercial medici-
nal plants with special reference to Nagaland. Int J Biodivers Conserv 4(3):155–163
22. Rongsensashi, Mozhui R, Changkija S (2013) Limasenla.: medicinal plants diversity of Fakim
wildlife sanctuary, Nagaland, India. Pleione 7(1):110–126
23. De LC (2016) Medicinal and aromatic plants of Northeast India. Int J Dev Res
06(11):10104–10114
24. Shimray RA, Lunleng A (2017) Ethnomedicinal knowledge of plants among the Tangkhul
Nagas of Manipur. Ind J Res Anthro 3(1):29–36
25. Jain SK, Rao RR (1977) A handbook of field and herbarium methods. Today and tomorrow
printers and publishers, New Delhi, p 157
26. Kanjilal UN, Kanjilal PC, Das A, Purkayastha C (1934) Flora of Assam, Ranunculaceae to
Elaeocarpaceae, vol 1. Government of Assam, Shillong, p 184
27. Bennet SSR (1987) Name changes in flowering plants of India and adjacent regions. Triseas
Publishers, Dehradun, p 772
28. Dey S (2018) Studies of the diversity of flowering plants of Tuensang district, Nagaland.
Ph.D. thesis, Nagaland University, Nagaland
Ethnomedicinal Use Reports of Seeds
as Tapped from Herbal Vendors in North
Maharashtra, India

Y. A. Ahirrao, M. V. Patil, and D. A. Patil

1 Introduction

The word ‘Ethnobotany’ was almost unheard in India in the middle of last century.
‘Society of Ethnobotanists’ is a premier society in India established in 1980, which
filliped ethnobotanical studies particularly in India. This activity has well mush-
roomed and extended over nearly all Indian states and geographical regions inclu-
sive of majority of tribes and rural folks. It is needless to state that, throughout the
history of mankind, plants have been a major source of medicine. This central func-
tion still is continued worldwide particularly in the regions dominated by the tribal
communities and rural folks. The chief value of medicine in commerce in India was
stressed by Drury [1]. Prospects on ethnomedicinal studies in India are still bright
on account of remarkable phytodiversity and multiethnic culture inhabiting various
phytogeographical regions. Such investigations offer tremendous scope for bio-
prospecting in view of the sustainable development. Even today, medicinal sources
are sold in public places by herbal vendors in India. However, their traditional
knowledge is hardly documented yet. Probably, Sinha (1996) [2] is the first investi-
gator to tap their wisdom as an exclusive topic of research particularly in and around
Delhi. The present authors, therefore, extended inventory to document this much
neglected area of research in India, the results of which are being published [3–7].
This communication presents hitherto unprojected source of seeds sold by vendors
in northern part of Maharashtra (India).

Y. A. Ahirrao
S.S.V.P. Sanstha’s Arts, Commerce and Science College, Shindkheda,
Dhule, Maharashtra, India
M. V. Patil · D. A. Patil (*)
Department of Botany, S.S.V.P.Sanstha’s, L.K.Dr.P.R. Ghogrey Science College,
Dhule, Maharashtra, India

© The Author(s), under exclusive license to Springer Nature 25

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_2
26 Y. A. Ahirrao et al.

2 Methodology

The area under present study included five districts, namely, Nasik, Dhule,
Nandurbar, Jalgaon and Buldhana in northern part of Maharashtra state (India)
(Maps 1 and 2). The herbal vendors conduct their traditional family business of sell-
ing botanicals of medicinal importance. They carry on their business in public
places such as railway stations, bus stands, courts, Government offices, highways,
crossroads, chowks of cities, pilgrim centres, temples and places of weekly bazar

Map 1 Maharashtra, India

Ethnomedicinal Use Reports of Seeds as Tapped from Herbal Vendors in North… 27

Map 2 Nasik, Dhule, Nandurbar, Jalgaon and Buldhana districts in Maharashtra

days. The vendors were interviewed and their medicinal wisdom like common plant
name, part or product used, diseases treated, doses, recipes and their administration,
age and sex of the patients to be treated, etc., were recorded. The samples were also
purchased and photographed. Botanical identities deciphered consulting various
floras like Hooker, 1872–1897; Cooke, 1958; Naik, 1998; Lakshminarsimhan and
Sharma, 1951; Patil, 2003; Kshirsagar and Patil, 2008; Diwakar and Sharma, 2002,
etc. [8–14] The information obtained is presented in Table 1 with necessary details.

3 Results

The present inventory on medicinal use reports of seeds from herbal vendors in
some districts of North Maharashtra. It revealed 101 species pertaining to 101 gen-
era and 48 angiospermic families. Majority of them are dicotyledons (94 species, 94
genera and 42 families), whereas monocotyledons contributed for a lesser share (07
species, 07 genera and 06 families). Out of total 101 taxa, 38 species are found to be
exclusively under cultivation, whereas 51 species are exclusively wild. Few others
(12 species) are either wild or cultivated as well. Of these, 27 species exhibited tree
habit, others being shrubs, herbs or climbers. Cultigens are also traditionally useful
Table 1 Seeds employed for treating human diseases
28

Dicot/ Use reports

Wild (W)/ monocot/
Sr. cultivated gymno/ Recipe
No. Plant name and family Local name Habit (C) pterido used Disease Dose Period
1. Abelmoschus moschatus (L.) Ranbhendi Shrub W D Paste Cancer One teaspoon One month
Medik. twice a day
Malvaceae
2. Acacia nilotica (L.) Willd. Babhul Herb W D Powder Impotency One teaspoon Till cure
ex Del. Subsp. indica daily
(Benth.) Bernan Ash Cholesterol One teaspoon
Mimosaceac daily morning
3. Aconitum deinorrhizum Mohara Herb W D Powder Sexual vigour One teaspoon Ten days at
Stapf Slurry Snake bite One teaspoon night
Ranunculaceae Powder Chickenpox One teaspoon One months
twice a day
4. Albizia chinensis (Osb.) Shirish Tree W D Powder Sperm count One teaspoon One month at
Merr. morning
Mimosaceae
5. Alcea rosea L. Gulkhair Shrub C D Powder Piles One teaspoon Seven days at
Malvaceae night
6. Amomum subulatum Roxb. Motha Herb W D Powder Urinary Twice a day Three days
Zingiberaceae complaints
Powder Heart, Piles Twice a day Seven days
7. Anacardium occidentale L. Kaju Tree C D Oil Leprosy Twice a day One month
Anacardiaceae
8. Anethum graveolens L. Balant soap Herb C D Powder Diarrhoea Half cup Three days
Apiaceae twice a day
Powder Breastfeeding in One teaspoon
mother
Y. A. Ahirrao et al.
 Dicot/ Use reports
Wild (W)/ monocot/
Sr. cultivated gymno/ Recipe
No. Plant name and family Local name Habit (C) pterido used Disease Dose Period
9. Apama siliquosa L. Chakrani Shrub W D Infusion Kidney stone One glass One month
Aristolochiaceae twice a day
10. Arachis hypogea L. Bhuimung Herb W M Powder Diabetes – Daily
Fabaceae
11. Argyreia nervosa (Burm. f.) Gugguli Climber W D Powder Preliminary stage One teaspoon Twenty-one
Boj. cancer twice a day days
Convolvulaceae
12. Azadirachta indica A. Juss. Limba Tree W D Powder Hair-lice – Daily
Meliaceae C morning
13. Bacopa monnieri (L.) Bramhi Herb W D Extract Hair fall – Daily
Wettst.
Scrophulariaceae
14. Baliospermum montanum Danti Shrub W D Paste Scabies – Every
(Willd.) Muell.-Arg. morning three
Euphorbiaceae days
15. Bixa orellana L. Sendri Tree C D Powder Gonorrhoea One teaspoon Three days
Bixaceae
16. Blumea eriantha DC. Nirmali Herb W D Decoction Acidity Half cup Fifteen days
Asteraceae twice a day
17. Brassica nigra (L.) Koch. Rai Herb C D Oil Cough Rubbed on Daily at night
Brassicaceae chest of
Ethnomedicinal Use Reports of Seeds as Tapped from Herbal Vendors in North…

children
18. Butea monosperma (Lamk.) Palas Tree W D Powder Stomach worm One teaspoon Seven days
Taub. Paste Itching of skin twice a day Seven days
Fabaceae
(continued)
29
Table 1 (continued)
30

Dicot/ Use reports

Wild (W)/ monocot/
Sr. cultivated gymno/ Recipe
No. Plant name and family Local name Habit (C) pterido used Disease Dose Period
19. Caesalpinia decaptela Chilar Climber C D Powder Stomachache Once daily Till cure
(Roth) Alst.
Caesalpinaceae
20. Cajanus cajan (L.) Millsp. Tur Shrub C D Paste Eye infection – Till cure
Fabaceae
21. Carissa carandus L. Karvand Herb W D Paste Crack of foot – Daily at night
Apocynaceae for four days
22. Carum carvi L. Jire Herb C D Paste Improve eye sight –
Apiaceae Paste Night blindness Daily for
twenty-one
days
23. Celastrus paniculatus Willd. Malkangani Shrub W D Oil Rheumatism – Daily for one
Celastraceae Paralysis month
24. Celosia argentea L. Kardu Herb W D Powder Body heat One cup twice Four days
Amaranthaceae a day
25. Chenopodium album L. Cheel Herb W D Decoction Safe delivery Half cup Regular
Chenopodiaceae Powder Bile One teaspoon Three nights
26. Cleome viscosa L. Piwali Herb W D Paste Leprosy – Fifteen days
Capparidaceae
27. Corchorus capsularis L. Chuncha Herb W D Powder Abdominal pain Mixed with Two days
Tiliaceae glass of water
Powder Snake bite Pinch of Every five
powder minutes
28. Coriandrum sativum L. Kothambir Herb C D Decoction Malaria To teaspoons Fifteen days
Apiaceae Powder twice a day
Y. A. Ahirrao et al.
 Dicot/ Use reports
Wild (W)/ monocot/
Sr. cultivated gymno/ Recipe
No. Plant name and family Local name Habit (C) pterido used Disease Dose Period
29. Cressa cretica L. Khardi Herb W D Slurry Speaking defects Spoonful Fifteen days
Convolvulaceae at morning
30. Crotalaria medicaginea Raanmethi Herb W D Powder Dysentery One teaspoon Three days
Lamk. twice a day
Fabaceae
31. Croton tiglium L. Jamal gota Tree W D Decoction Diarrhoea Half teaspoon Three days
Euphorbiaceae C twice a day
32. Cucurbita maxima Duch. ex Tambada Climber C D Decoction Intestinal worms Two Three days
Lam. bhopala teaspoons
Cucurbitaceae
33. Datura metel L. Kala dhotra Shrub W D Decoction Wounds Twice a day One week at
Solanaceae Bruises of skin morning
Pellate Impotency Three nights
34. Daucus carota L. Gajar Herb C D Decoction Menstrual cycle One teaspoon Seven days
Apiaceae Powder Painful delivery Two
teaspoons
35. Dioscorea bulbifera L. Kadu karanda Climber W D Powder Rheumatism One teaspoon One month at
Dioscoriaceae C night
36. Diplocyclos palmatus (L.) Shivlingi Climber W M Powder Fertility rate in One teaspoon Fifteen days
Jeffery women at morning
Cucurbitaceae Powder Snake bite One cup
Ethnomedicinal Use Reports of Seeds as Tapped from Herbal Vendors in North…

37. Drypetes roxburghii (Wall.) Jivan putra Tree C D Powder Sperm count One teaspoon Seven days
Huru. twice a day
Euphorbiaceae
(continued)
31
Table 1 (continued)
32

Dicot/ Use reports

Wild (W)/ monocot/
Sr. cultivated gymno/ Recipe
No. Plant name and family Local name Habit (C) pterido used Disease Dose Period
38. Elaeocarpus sphaericus Rudraksha Tree W D Powder Pimples – Seven days
(Gaertn.) K. Schum.
Elaeocarpaceae
39. Elettaria cardamomum Veldoda Herb C M Paste Sperm count One teaspoon One month
Maton daily at night
Zingiberaceae Extract Irregular heart Glass of water One month
beat
Powder Urinary problems One teaspoon Three days
twice a day
40. Eleusine coracana (L.) Nagali Herb C M Paste Fever Twice a day Three days
Gaertn.
Poaceae
41. Emblica officinalis Gaertn. Awala Tree W D Paste Leucorrhoea Half cup Three days at
Euphorbiaceae C morning
Ash Scabies Seven nights
42. Ensete superbum (Roxb.) Jangli Keli Herb W M Powder Kidney stone Once a day Four days
Cheesm.
Musaceae
43. Entada rheedei Spreng. Garambi Climber W D Powder Hair loss – Daily night
Mimosaceae
44. Eulophia herbacea Lindl. Kukud Kand Herb W M Powder Body strength – Till cure
Orchidaceae
45. Euryale ferox Salisb. Makhane Herb C D Roasted Diarrhoea One teaspoon Four days at
Nymphaeaceae W night
Y. A. Ahirrao et al.
 Dicot/ Use reports
Wild (W)/ monocot/
Sr. cultivated gymno/ Recipe
No. Plant name and family Local name Habit (C) pterido used Disease Dose Period
46. Foeniculum vulgare Mill. Badi sepu Herb C D Paste Scant urination One teaspoon Four days
Apiaceae twice a day
47. Gomphrena globosa L. Makhamal Herb W D Paste Headache – Three nights
Amaranthaece
48. Holarrhena pubescens Indarjav Tree W D Powder Diabetes Half teaspoon Forty-five
(Buch.-Ham.) Wall. ex days at
G. Don morning
Apocynaceae
49. Holoptelea integrifolia Vavala Tree W D Paste Hydrocele Twice a day One week
(Roxb.) Planch.
Ulmaceae
50. Hordeum vulgare L. Satu Herb C M Decoction Acidity Half cup Three days
Poaceae
51. Hydnocarpus laurifolia Kutakvath Tree W D Oil Tuberculosis Five to six One month
(Dennst.) Sleum. Powder drops twice a
Flacourtiaceae day
52. Hyoscyamus niger L. Khurasani ova Herb W D Powder Tooth cavity – One month at
Solanaceae morning
53. Impatiens balsamina L. Terda Herb W D Paste Joint pains Twice a day One month
Balsaminaceae
54. Jatropha curcas L. Jamal-gota Tree C D Powder Stomachache Pinch of One day
Ethnomedicinal Use Reports of Seeds as Tapped from Herbal Vendors in North…

Euphorbiaceae powder
55. Lagenaria siceraria Dhudhi-­ Climber C D Paste Sleeplessness – Ten nights
(Molina) Standl. Bhopala Paste
Cucurbitaceae
(continued)
33
Table 1 (continued)
34

Dicot/ Use reports

Wild (W)/ monocot/
Sr. cultivated gymno/ Recipe
No. Plant name and family Local name Habit (C) pterido used Disease Dose Period
56. Lens culinaris Medic. Masur Herb C D Paste Burning – Seven days
Fabaceae sensation
Black spots Seven nights
57. Lepidium iberis L. Safed towari Herb W D Powder Swelling One teaspoon Fifteen nights
Brassicaceae respiratory track
58. Linum usitatissimum L. Javas Herb C D Decoction Painful One teaspoon Four days
Linaceae micturition twice a day
Powder Sperm count One teaspoon Fifteen days
twice a day
59. Madhuca longifolia (Koen.) Mahu Tree W D Extract Chronic Two drops at Fifteen days
Macbr. var. latifolia (Roxb.) C head-ache morning
Chev.
Sapaotaceae
60. Mangifera indica L. Aamba Tree C D Pulp Dysentery Half cup Three days
Anacardiaceae twice a day
61. Manilkara hexandra (Roxb.) Khairani Tree C D Paste Scorpion sting – Till cure
Dub.
Sapotaceae
62. Martynia annua L. Vinchu Herb W D Powder Ring worm Three nights
Martyniaceae Powder Tuberculosis One teaspoon One month
twice a day
63. Melia azedarach L. Limba Tree C D Oil Hair baldness Daily
Meliaceae morning
64. Melilotus indica (L.) All. Van methi Herv W D Powder Dysentery One teaspoon Three days
Fabaceae twice a day
Y. A. Ahirrao et al.
 Dicot/ Use reports
Wild (W)/ monocot/
Sr. cultivated gymno/ Recipe
No. Plant name and family Local name Habit (C) pterido used Disease Dose Period
65. Mesua ferrea L. Nagchafa Tree W D Decoction Menses One teaspoon Seven days
Clusiaceae twice a day
66. Mimusops elengi L. Bakul Tree C D Pellates Menstruation Twice a day Seven dasy
Sapotaceae
67. Mucuna pruriens (L.) DC. Kach-Kauri Climber W D Powder Sperm count One teaspoon Fort-five days
Fabaceae twice a day
Powder Gonorrhoea One teaspoon Five days
twice a day
68. Nelumbo nucifera Gaertn. Kamal Herb C D Powder Avoid abortion Half cup once Seven days
Nelumbonaceae W a day
Powder Anima in Half cup Ten days
children twice a day
69. Nephelium chinensis (Lour.) Litchi Tree W D Decoction Swelling of testes 10 to 15 ml Forty-five
Almeida nights
Sapindaceae
70. Nigella sativa L. Kale til Herb C D Oil Baldness
Ranunculaceae Powder Asthma 6 gm. One month at
night
Powder Skin Ten nights
71. Ocimum basilicum L. Sabja Shrub C D Infusion Heal infection Four days at
Lamiaceae around genitals morning
Ethnomedicinal Use Reports of Seeds as Tapped from Herbal Vendors in North…

72. Ocimum tenuiflorum L. Krishna Tulas Shrub C D Seeds Malarial fever Twice a day Three to four
Lamiaceae days
(continued)
35
Table 1 (continued)
36

Dicot/ Use reports

Wild (W)/ monocot/
Sr. cultivated gymno/ Recipe
No. Plant name and family Local name Habit (C) pterido used Disease Dose Period
73. Piper nigrum L. Kali meeri Climber C D Powder Paralysis – Daily
Piperaceae W Paste Pimples
74. Pisum sativum L. Vatane Climber C D Powder Skin problems – Daily
Fabaceae
75. Pongamia pinnata (L.) Karanj Tree W D Paste Skin problems – Four to five
Pierre C Oil Eczema nights
Fabaceae
76. Pterocarpus marsupium Vivala Tree W D Powder Toothache – Ten to fifteen
Roxb. mornings
Fabaceae
77. Quisqualis indica L. Madhumalati Climber C D Powder Fever One teaspoon Four nights
Combretaceae Powder Diarrhoea One teaspoon Three days
twice a day
Powder Intestinal worm One glass Seven days
twice a day
78. Salvia aegyptiaca L. Kammarkas Shrub W D Decoction Redness of eyes
Lamiaceae Powder Diarrhoea 2–4 gm Four nights
79. Sapindus emarginatus Vahl Ritha Tree W D Paste Insect bite – Till cure
Sapindaceae
80. Sapindus laurifolia Vahl Ritha Tree W D Powder Headache One teaspoon Fourteen
Sapindaceae nights
Powder Piles One teaspoon
81. Semecarpus anacardium L. Biba Tree W D Decoction Cough & Half cup Three to four
f. C twice a day days
Anacardiaceae Paste Rheumatism Fifteen nights
Y. A. Ahirrao et al.
 Dicot/ Use reports
Wild (W)/ monocot/
Sr. cultivated gymno/ Recipe
No. Plant name and family Local name Habit (C) pterido used Disease Dose Period
82. Sesamum orientale L Til Herb C D Powder Wetting bed One teaspoon Three nights
Pedaliacae
83. Strychnos potatorum L. f. Chilhara Tree W D Powder Aphrobisiac One teaspoon Fourteen
Longaniaceae mornings
84. Syzygium cumini (L.) Skeels Jambhul Tree C D Powder Diabetes One teaspoon One month at
Myrtaceae morning
85. Tagetes erecta L. Zendu Herb C D Powder Sexual vigour One teaspoon Ten nights
Asteraceae
86. Tamarindus indica L. Chincha Tree W D Powder Dysentery Two spoon Three days
Caesalpiniaceae C twice a day
87. Tectona grandis L. f. Sag Tree W D Paste Abdominal pains Twice a day Once a day
Verbenaceae C Powder Painful Half teaspoon Fifteen days
micturition twice a day
88. Teramnus labialis (L. f.) Ran udid Climber W D Decoction Diarrhoea 10–20 ml Three days
Spreng. twice a day
Fabaceae Powder Rat bite One teaspoon Four nights
89. Terminalia bellirica Beheda Tree W D Powder Improve One teaspoon One month at
(Gaertn.) Roxb. digestion morning
Combretaceae
90. Terminalia catappa L. Badam Tree C D Powder Hearing problems – Till cure
Combretaceae
Ethnomedicinal Use Reports of Seeds as Tapped from Herbal Vendors in North…

91. Terminalia chebula Retz. Hirada Tree C D Decoction Abdominal pain One cup twice Seven days
Combretaceae a day
(continued)
37
Table 1 (continued)
38

Dicot/ Use reports

Wild (W)/ monocot/
Sr. cultivated gymno/ Recipe
No. Plant name and family Local name Habit (C) pterido used Disease Dose Period
92. Trachyspermum ammi (L.) Owa Herb C D Powder Cough Twice a day Three days
Sprague Decoction Dropsy One teaspoon One month
Apiaceae thrice a day
Decoction Urinary stone One teaspoon One month at
night
93. Trigonella foenum-graecum Methi Herb C D Powder Reduce body One teaspoon One month
L. weight twice a day
Fabaceae Powder Diabetes One teaspoon
once a day
94. Urena lobata L. Van bhendi Herb W D Powder Intestinal worms 1–2 gm twice Four days
Malvaceae a day
95. Urtica dioica L. Vinchu vel Herb W D Slurry Scorpion sting – Till cure
Urticaceae
96. Vernonia anthelmintica (L.) Kale jire Herb W D Powder Diabetes One teaspoon Daily in
Willd. morning one
Asteraceae month
Decoction Body fever 10–15 ml Three days at
morning
Powder White spots of
leprosy
97. Vigna radiata (L.) Wilezek. Mugi Herb C D Pellate Increase sperm – Five nights
Fabaceae count
Y. A. Ahirrao et al.
 Dicot/ Use reports
Wild (W)/ monocot/
Sr. cultivated gymno/ Recipe
No. Plant name and family Local name Habit (C) pterido used Disease Dose Period
98. Vigna unguiculata (L.) Chavali Climber C D Decoction Vomiting 10–15 ml One day
Walp. var. cylindrica (L.) twice a day
Eseltine
Fabaceae
99. Wattakaka lanceolata Kewad Climber W D Paste Joint pain – One month
(T. Cooke) Jagtap & Sinsh. twice a day
Asclepiadaceae
100. Wrightia tinctoria R. Br. Dudhi Tree W D Powder Skin disease – Seven nights
Apocynaceae indrajao
101. Xanthium indicum Koen. Shankeshwar Herb W D Powder Jaundice Half cup with Seven nights
Asteraceae milk
Ethnomedicinal Use Reports of Seeds as Tapped from Herbal Vendors in North…
39
40 Y. A. Ahirrao et al.

for various miscellaneous purposes, e.g. food, spice, ornamental, oil, shade tree,
beauty care, etc. in this region. The 101 species yielding seeds are employed for
various 74 human diseases (Table 1). They are administered in various forms of
medicinal recipes: (i) powder (72), (ii) paste (25), (iii) decoction (20), (iv) slurry
(03), (v) pellates (03), (vi) extract (03), (vii) ash (02), (viii) infusion (02), (ix) pulp
(01) and (x) seeds (01). Thus powder is the most common recipes advised by the
herbal vendors. Others are important in descending order presented here. The fig-
ures in parenthesis denote number of use-reports.

4 Discussion

Plants form the basis for most life on earth; however, the field of ‘Botany’ has
declined worldwide, while the field of ‘Ethnobotany’ keeps emerging. In this latter
missionary activity, India stands at the forefront of nations devoting sustained sci-
entific attention to this discipline of natural science. India has also recognized the
danger of the loss of precious traditional knowledge for the benefit of all humanity.
Some neglected areas of research in ethnobotany and ethnomedicine are being paid
serious attention [15]. One such study is tapping wisdom of herbal vendors who
conduct traditional business of selling botanicals of medicinal significance in public
places. The review of literature indicated that exclusive ethnomedicinal use reports
on specific plant parts are rare in India [7, 15–18]. Mahekar and Yadav [19–22]
informed about their ethnomedicinal utilities in Maharashtra as obtained from
herbal vendors. Recently, there are also few exclusive reports on ethnomedicine by
Patel and Parekh [23] and Kalim et al [24]. The present authors worked on this line
of research, the results of which are being published [3–7]. This communication is
an attempt to shed more light particularly on ethnomedicinal importance of seeds.
The Indian researchers do not want to ignore the contribution of native biore-
sources. The vast role played by seeds as cereals, millets, pseudo-cereals, oils,
spices and condiments is obvious for sustenance of human life since the appearance
of mankind on the Blue Planet. The panorama of ‘Ethnobotany’ has now been quite
widened in India [25]. However, its role in medicine is hardly emphasized [26–28].
Although the importance of newer subjects such as biotechnology and molecular
biology is being emphasized, there is equal necessity to nurture traditional subjects
like ‘Ethnobotany’ vis-à-vis ‘Ethnomedicine‘. The aforesaid new subjects help pro-
mote the traditional subjects for searching new lead molecules and propagation of
bioresources besides value addition and sustainable use of Indian phytodiversity. It
is equally important to tap traditional ethnomedicinal wisdom of Indian herbal ven-
dors for the welfare of mankind.

Acknowledgements The authors are thankful to the authorities of SSVP Sanstha for laboratory
and library facilities.
Ethnomedicinal Use Reports of Seeds as Tapped from Herbal Vendors in North… 41

References

1. Drury CH (1873) The useful plants of India with notices of their chief value in commerce,
medicine and the arts. William H. Allen & Co., London, UK
2. Sinha R (1996) Ethnobotany: the renaissance of traditional herbal medicine. INA Shree
Publishers, Jaipur
3. Ahirrao YA, Patil MV, Patil DA (2015) Traditional sources of antidotes from botanicals sold by
herbal vendors in North Maharashtra (India). Acad Res 10(1):156–160
4. Ahirrao YA, Patil MV, Patil DA (2015) Botanicals sold by herbal vendors employed for skin
diseases in North Maharashtra, India. Species 13(37):1–5
5. Ahirrao YA, Patil MV, Patil DA (2016) Ethnomedicinal investigation of herbal vendors in
North Maharashtra (India) combating jaundice disease. IRMJCR (Scholar World) Special
Issue VI(January, 2016):152–155
6. Ahirrao YA, Patil DA (2018) Ethnomedicinal investigation of some common botanicals sold
by vendors in North Maharashtra (India). Res World IX(Special Issue):175–180
7. Ahirrao YA, Patil MV, Patil DA (2021) Ethnomedicinal uses of flowers enquired from herbal
vendors in North Maharashtra (Maharashtra) India. PARIPEX-Indian J Res 10(11):1–4.
https://doi.org/10.36106/paripex
8. Hooker JD (1872–1897) The Flora of British India, vol. I–III. L.Reeve & Co., London, UK
9. Cooke T (1958) The Flora of The Presidency of Bombay, vol I–II. Bot.Surv.India, Calcutta
10. Naik VN (1998) Flora of Maharashtra, vol I-II. Amrut Prakashan, Aurangabad (M.S.)
11. Lakshminarsimhan P, Sharma BD (1991) Flora of Nashik District. B.S.I, Calcutta
12. Patil DA (2003) Flora of Dhule and Nandurbar District (Maharashtra). Bishen Singh Mahendra
Pal Singh, Dehradun
13. Kshirsagar SR, Patil DA (2008) Flora of Jalgaon District (Maharashtra). Bishen Singh
Mahendra Pal Singh, Dehradun
14. Diwakar PG, Sharma BD (2000) Flora of Buldhana District. Bot.Surv. India, Calcutta
15. Jain SK, Mugdal V, Banerjee DK, Guha A, Pal DC, Das D (1984) Bot. Surv. India, Howrah
16. Jain SK (1991) Dictionary of Indian Folk Medicine and Ethnobotany. Deep Publications,
New Delhi
17. Maheshwari JK (1996) Ethnobotany in South Asia. Scientific Publishers, Jodhpur
18. Goel AK, Tripathi S (2009) Ethnobotanical spectrum of Indian flora: An overview during the
past 20 years. J Ethnobot 21(1–2):131–153
19. Mahekar P, Yadav SR (2004) Botanical identity of some tubers and rhizomes from south west-
ern Maharashtra used in folk medicines. In: Janarthanam MK, Narsimhan D (eds) Plant diver-
sity, human welfare and conservation. Goa University Publication, Goa, pp 204–218
20. Mahekar P, Yadav SR (2004) Correct identity of some barks used in folk medicines. In: Ghate
et al (eds) Focus on sacred groves and ethnobotany. Prism Publications, Mumbai, pp 237–253
21. Mahekar P, Yadav SR (2004) Correct identity of some folk medicines of South Western
Maharashtra. Bull Bot Surv India 46/9(1–4):300–324
22. Mahekar P, Yadav SR (2008) Fruit and seed drugs used in folk medicines in South Western
Maharashtra. In: Chaturvedi A (ed) Ethnobotany & taxonomy of angiosperms. Rashtrasant
Tukadoji Maharaj Nagpur University, Nagpur (Maharashtra), pp 187–202
23. Patel PK, Parekh PP (2013) Therapeutic uses of some seeds among the tribals of Banaskantha
district, Gujarat, India. Rom J Biol Plant Biol 58(1):79–82
24. Kalim A, Zahreer M, Uddin M, Siddiqui A, Ahmed S, Hassan MM (2021) Nutritional
value, ethnomedicine, phytochemistry and pharmacology of Vigna radiat (L.) R.Wilczek. J
Pharmacogn Phytochem 10(2):54–58
25. Jain SK (2019) The widening panorama of ethnobotany in India. J Indian Bot Soc
98(3–4):98–102
26. Patil DA (2010) Medicinal Plants: History, Culture and Usage. Manglam Publications, Delhi
27. Patil DA (2019) Food Crops: Evolution, Diversity And Advances. Scientific Publishers, Jodhpur
28. Patil DA, Dhale DA (2013) Spices And Condiments: Origin, History And Applications. Daya
Publishing House (A Division of Astral International Pvt. Ltd.), New Delhi
An Ethnobotanical Study of Medicinal
Plants Used by Traditional Healers
in Grizzled Squirrel Wildlife Sanctuary
(GSWS) Tamil Nadu, India

Pious Soris Tresina , Murugeswaran Santhiya Selvam ,

Vallinayagam Sornalakshmi , and Veerabahu Ramasamy Mohan

Abbreviations

FC Frequent citation
Fic Informant consensus factor
FL Fidelity level
GSWS Grizzled squirrel wildlife sanctuary
RFC Relative frequency of citation
UV Use value

1 Introduction

Ethnobotany is the relationship and dealing between people and plants with respect
to their cultural values. Interactions and relationship between people and plants are
different from place to place because of their relative importance, uses and different
social, ethnic and cultural factors. Cultural values of plant exploration play a key
role in pharmaceutical and nutritional industrial sectors [1]. Ethnobotanists are
growingly focusing on the function of diverse quantitative and statistical techniques
to understand and gather knowledge on precious plants in induced communities [2].
Ethnobotany and ethnopharmacological knowledge is considered to be an integral
part of the knowledge required for drug development. Traditional medicine is to be

P. S. Tresina · M. S. Selvam · V. R. Mohan

Ethnopharmacological Unit, Research Department of Botany, V.O. Chidambaram College,
Thoothukudi, Tamil Nadu, India
V. Sornalakshmi
Department of Botany, A.P.C. Mahalaxmi College for Women, Thoothukudi, Tamil Nadu,
India

© The Author(s), under exclusive license to Springer Nature 43

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_3
44 P. S. Tresina et al.

implicit as the sum total of the knowledge, talents and practices based on theories,
principles and understandings to different cultures that are employed to maintain
and improve health, as well as to prevent, diagnose and treat physical and mental
illnesses [3].
The World Health Organization (WHO) has a keen interest in documenting the
use of medicinal plants by native people from different parts of the world [4]
WHO further estimates that about 80% of the world’s population is dependent on
traditional medical practices for some aspect of primary health care [5]. According
to the FAO, in the last few decades, the number of known medicinal plants then
reaches up to 50,000 different species, which is 18.9% of the total world flora [6].
Still, valid scientific data on the practice of ethnomedicinal plants are moderately
incomprehensible. Recently, it is experimentally proved that plants offer immense
scope for researchers engaged in validation of traditional claims for the develop-
ment of novel drugs [7]. Since interest in traditional medicine has been increasing
world over, ethnobotanical studies have gained prominence to explore the tradi-
tional knowledge particularly in developing countries [8]. Therefore, collection of
ethnobotanical information and documentation of traditional knowledge have
gained prominence from the future prospective of drug development [9].
Conventional knowledge and applications have been marginalized due to political
and socio-economical grounds. Lately, interest in traditional medicine has been
initiated to explore the knowledge from various tribal groups across the country
[10–14]. Quite a few studies have related that tribal population in remote area, not
only rely on plant based resources for food, scavenge, medicines and fuel, but also
play a critical role in the administration of natural resources [8, 15–21]. A few
reports on ethnomedicinal uses of plants in the forests of Virudhunagar hills and
its adjoining areas were available [22–29], and most of the studies were conducted
qualitatively with a lacuna in data analysis. The present study was initiated with
an aim to identify knowledgeable resource persons among the Paliyar tribes in
Grizzled Squirrel Wildlife Sanctuary (GSWS), of Southern Western Ghats in
Tamil Nadu, India, and quantitatively analyze their indigenous ethnomedicinal
knowledge through various ethnobotanical tools on the utilization of commonly
used medicinal plants.

1.1 The Paliyar Tribe

The Paliyars belong to the Southern tribal zone. The Southern tribes are historically
more ancient tribe. There are as many as 36 types of Scheduled Tribes in Tamil
Nadu. In the serialized list notified by the Government of Tamil Nadu, the Paliyars
are placed at the 32nd position. They live in the low-altitude regions of the Western
Ghats and live in large number in the study area (Virudhunagar district and parts of
Madurai district). Out of the total population of the scheduled tribes in Tamil Nadu
(7.21 lakh), the Paliyar tribe accounts for 2294. This is according to the census of
India in 2011 and Paliyar tribe ranks 20th among the tribal population. The Paliyars
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled… 45

can be grouped into three categories based on their life style, namely (i) nomadic
Paliyars, the hunter gatherers, who live in rock shelters wandering in tracts of the
forest in search of food and non-timber forests product; (ii) semi nomadic Paliyars,
also the hunter gatherers, who build hut and do not practice agriculture, and go out
to collect food and non-timber forest products and return to their dwelling and (iii)
settled Paliyars, who have land holdings, practicing agriculture and living mainly in
Kerala [30].

1.2 Appearance and Habits of Paliyar

The Paliyars of the study area at present could be called semi nomadic type. Their
ancestors were nomadics. They live as individual families. Like other primitive
tribes, the Paliyars are short, dark complexioned, curly haired with thick protruding
lips and blunt nose with wide nostrils. Paliyars do not have any established mode of
dress (Fig. 1a,b). They are scantily dressed but freely wear whatever clothes are
available to them. They are non-vegetarians; however, they refrain from beef as
rigidly as the most orthodox Hindus [31]. Several species of Dioscorea provide the
basis of Paliyars staple food. Besides there are a wide variety of greens, stems,
tubers, unripe fruits and ripe fruits, which serve as alternative for food. Paliyars also
feed on wild animals and birds like rabbit, rat, deer, hen, etc.
The Paliyars live in small parties as isolated groups. Generally, a hamlet has
about 20 huts. Their small huts are exceptional with the walls prepared of mud or
with wiry intertwined stems of Lantana camara. Each hut is thatched with the
fronds of Cymbopogon citratus or Cymbopogon polyneuros or with the leaves of
Phoenix pusilla or Cocos nucifera (Fig. 1c). They sleep on mats, woven with the
leaves of the above said taxa. The Paliyars as a tribe do not possess much cohe-
siveness. Each settlement has its headman whose ability is never challenged, and
he is exclusively responsible for settling quarrels among the tribal people. They
are illiterate, but in recent years, they have started sending their children to nearby
schools.
The Paliyars are adroit in collecting honey. They collect honey from the branches
of towering tall trees and rock caves skilfully using special techniques. Paliyars
from four to seventy years old are agile on the trees. They also gather Kungillium
(resin) from the barks of Canarium strictum. They are also good hunters and they
trap deer, pig, boar, hare, wild fowl and flying squirrel. The meat obtained is divided
among the families within the settlement. They are good herbalists and often collect
medicinal plants from the forests. The knowledge about medicinal plant is rather
specialized and is limited to a few members in the community who are recognized
as “Vaidyars” or medicine men. They are normally respected the most and deemed
indispensable members inside the tribal society. Each medicine man cures all kinds
of illness, but some of them are concentrated in precise diseases. The remedies of
ordinary ailments such as cuts, fever, pain, headache and dysentery are recognized
by most members of the tribal society. There are several individuals in each locality,
46 P. S. Tresina et al.

Fig. 1 Paliyar tribes of area survey. (a) An old Paliyar tribal man of Athikoil sector of Grizzled
Squirrel Wildlife Sanctuary. (b) A tribal girl of Shenbagathoppu wearing a necklace made from the
seeds of Symplocoscochinchinensis. (c) A young tribal woman of Valliammal Nagar with her
children

who though not recognized as medicine men, possess such knowledge and act as
reliable informants. They maintain secrecy about the use of certain medicines
because they believe that the herbals will lose their healing power if too many peo-
ple know about them. Some practitioners have acceded to the knowledge of con-
vinced extraordinary remedies.
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled… 47

1.2.1 Rituals and Religious Ceremonies

Paliyars have strong faith in religious conventions and practices. They habitually
practice Hindu religion. The deity of their worship is explicit to their region. The
Paliyars in the select study area worship Lord Siva and Ayyanar, a village god. They
also worship ‘Forest Goddess’ and Goddess ‘Poomadevi’ (Goddess Earth). On spe-
cial occasions, they stay in the temples in groups for 2 days and worship by offering
goats as sacrifice. On these days, a large quantity of Mullvallikizhangu (Dioscorea
pentaphylla var. pentaphylla) are collected and offered to the Goddess Earth
‘Poomadevi’.

1.2.2 Customs Related to Marriage

Paliyars are monogamous. Elopement is a favorite form of marriage. The elders

search for the runaway couples and then bring them back and get them married. The
marriage of both widowed and divorced persons of either sex is allowable. The dead
are buried and on the eighth day after death, they execute the last rituals. The
Paliyars trust in witchcraft. They consider many inquisitive superstitious convic-
tions. The Government of Tamil Nadu has instituted a medicinal plant conservation
area in the forest for conservation and expansion of herbal wealth. It is maintained
and conserved with the assistance of the Paliyars.

2 Materials and Methods

2.1 Study Area

Paliyars form a tribal group, and they are settled in the reserve forest area of the
Grizzled Squirrel Wildlife Sanctuary located in the South-Eastern slopes of Western
Ghats, Tamil Nadu, India. This wildlife sanctuary lies between 9°35′ and 9°8′ north
latitude and 77°4′ and 77°9′ east longitude (Fig. 2). It encompasses an area of 480
sq. km and is lying mostly in the district Virudhunagar and partly in Madurai. The
sanctuary was instituted in the year 1989. The attitude ranges from 100 to 2210 m
(MSL). It receives rainfall during the South-West as well as North-East monsoons.
The diverse climatic and topographic conditions exist in the sanctuary near a nota-
ble diversity of both the flora and fauna. The study area consists of tropical ever-
green forest, semi-evergreen forests, dry teak forests, southern mixed deciduous
forests and dry grasslands (Fig. 3). The study was conducted in 10 villages of GSWS
(Saduragiri, Thanniparai, Vandipannai, Nellikka Kottam, Valliammal Nagar,
Saragupannai, Petchikeni Kottam, Athikoil, Shenbagapthoppu and Ayyanarkoil),
which are inhabited by Paliyar tribes each consisting of 15–62 families distributed
in the deep forest areas.
48 P. S. Tresina et al.

Fig. 2 Location map of GSWS in Tamil Nadu, South-Eastern slopes of Western Ghats

2.2 Data Collection

The study area was investigated to get information from the tribal practitioners and
also to cross check the information provided by the other tribal practitioner during
the earlier visits. During each field trip, at least 10 days were spent with the local
people in their tribal hamlets. In order to document the utilization of medicinal
plants, field trips were made during 24 months period (July 2017 – June 2019)
ensuring that the dry and monsoon seasons were accommodated. A total of 12
resource persons or informants or traditional healers were identified to get the eth-
nomedicinal information through direct/interviews/oral conversations. They have
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled… 49

Fig. 3 Area surveyed. (a) The South Eastern slopes of Western Ghats, Ayyanarkoil. (b)
Shenbagathoppu Hills
50 P. S. Tresina et al.

Fig. 4 Format of field datasheet used to record the plant details with ethnomedicinal information

sound knowledge on the medicinal plants found in their surrounding areas and they
practice medicine within their families and neighbours. A field datasheet has been
prepared to record the plant details with ethnomedicinal information gathered from
the traditional healers (Fig. 4). Information on local name of plants, plant pieces
used for curing, technique of preparation, other plants/agents employed as ingredi-
ents, and modes of direction, etc., were recorded for each gathered ethnomedici-
nal plants.

2.3 Preservation of Plant Specimens

The standard method of plant collection was followed, i.e. mounting, drying, prepa-
ration and conservation of plant specimens [32]. Coupon specimens of medicinal
plants in triplicate were gathered, organized and acknowledged. Plants with their
correct names were arranged alphabetically by family name, vernacular name, eth-
nomedicinal uses and other applications. The identification and nomenclature of the
assembled plants were supported by the Flora of Presidency of Madras [33] and the
Flora of Tamil Nadu Carnatic [34]. They were afterward confirmed at Botanical
Survey of India, Southern circle, Coimbatore, India. All the preserved herbarium
specimens were deposited at the herbarium of Ethnopharmacology Unit (EPH),
Research Department of Botany, V.O. Chidambaram College, Thoothukudi, Tamil
Nadu, India.
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled… 51

2.4 Ailment Categories

Based on the information obtained from the traditional healers in the study area, all
the reported ailments were categorized into 16 categories (Table 1), viz. gastro-
intestinal ailments (GIA), respiratory systems diseases (RSD), dermatological
infections/diseases (DID), genito-urinary ailments (GUA), skeleto-muscular system
disorders (SMSD), poisonous bites (PB), circulatory system/cardiovascular dis-
eases (CSCD), fever (Fvr), endocrinal disorders (ED), liver problems (LP), dental
care (DC), hair care (HC), ear, nose, throat problems (ENT), cooling agents (CA)
oncology (ONC) and general health (GH). Numerous diseases were placed in one
ailment group based on the body systems taken care of.

2.5 Data Analysis

2.5.1 Informant Consensus Factor (Fic)

The informant consensus factor (Fic) was employed to see if there was concurrence
in the usage of plants in the ailment categories connecting the plant users in the
study area. The Fic was computed using the following formula [35]

N ur  N t
Fic 
N ur  1

where Nur refers to the number of use reports for a particular ailment category and
Nt refers to the number of taxa used for a particular ailment category by all infor-
mants. The product of this factor ranges from 0 to 1. A high rate (close to 1.0) des-
ignates that quite few taxa are used by a large percentage of the informants. A low
value designates that the informants disagree on the taxa to be employed in the
treatment inside a category of illness.

2.5.2 Use Value (UV)

The comparative significance of each plant species known locally to be employed as

herbal remedy is accounted as use value (UV), and it was computed using the sub-
sequent formula [36]

U
UV 
n

where UV is the use value of a species, ‘U’ is the number of use reports cited by
each informant for a given plant species and ‘n’ is the total number of informants
interviewed for a given plant. UV is helpful in determining the plants with the
Table 1 Ailments grouped by different ailment categories
52

Ailment categories Biomedical terms Tamil terms Siddha terms

1. Circulatory system/ Cardiovascular disorder Irutayakolaru Thamaraga Noi
Cardiovascular disease (CSCD) Blood pressure Raththaazhutham Athi kuruthi azhutham
Cardiotonic Irutayavalimainiki Thamaraka veppamundakki
Blood purification Raththauthikarippu Kuruthisuthi
Cholesterol Koluppu Kozhupu
Heart strength Idayavalimai Thamaraka uramakki
Memory power Gnabagasakthi Ninaivu thiran ukki
Obesity Udalparuman Athi thoola noi
2. Cooling agent (CA) Bodycooling Udalkulircchi Kulirchi undakki
3. Dental care (DC) Mouthwash Vaaikoppalika Vaai koppalikka
Toothache Palvali Thantha soolai
Tooth strength Palvalimai Thantha uramakki
Worms in gums and teeth Palsothai Parpuzhu
4. Dermatological Allergy Ovwamai Ovammai
infections/Diseases (DID) Burns Theekaeyam Theepun
Boils Kath Koppulam
Cuts Vettukayam Vettukayam
Blister Koppulam Neer koppulam
Pimples Parukkal Paru
Scabies Sorisirangu Sirangu
Itching/Eczema Namaichaal/Arippu Ooral/karappan
Wounds Kaayam Pun
Weapon injuries Ayuthakaayamkal Vettukayangal
Skin diseases Thoalnoikal Tholnoikal
Leucoderma Thoalniramiillathel Venkuttam
Stomatitis Vaaippun Akkaram
Heal craker Piththavedippu Pithavedippu
Fissures in foot Patattilpilavu Pathapilavai
Thorn injury Mulkaayam Multhaithakayam
Bad body odour Udalturnarram Katrallai nattrum
P. S. Tresina et al.

Sore legs Punkalkal Kaalpun

Antiseptic Kiruminacinikal Azhukal akatri
 Ailment categories Biomedical terms Tamil terms Siddha terms
5. Ear, nose, throat, eye problems Eye pain Kanvali Nethira soolai
(ENT) Eye cooling Kankullirchi Kan kulirchi undaakki
Burning sensation in the eyes Kannileriyumunarvu Kanerichal
Ophthalmic ailments Kannoykal Kannoikal
Colour blindness Nirakkurudu Nirakurudu
Sore throat Thondappun Thondaikattu
Throat pain Thondaivali Thondai vali
Sore in ear Katil pun Sevipun
Oozing pus in ear Cilmikkakatitu Sevicheel
6 Endocrine disorder (ED) Diabetes Sakkarai/Neerilivunoi Madhumegam
7. Fever (Fvr) Fever Kaicchal Suram
Analgesic Valinivarani valinivarani
8. Gastrointestinal ailments (GIA) Anthelmintic Kutalpulunikum Kudalpuzhu kolli
Constipation Malachikkal Malakkattu
Bowel disorder Kotalkolaru Kudal noikal
Bile complaints Pittapukarkal Pithaneer pinikal
Colic pain Perunkutalvali Kudal soolai
Bedwetting Patukkaiiramakkutal Padukkai nanaithal
Digestive disorder Cerimanakolaru Seriyamai
Dysentry Seedhabaethi Seethapethi
Gastric complaints Vayvukolaru Kukki noikal
Indigestion Ajeeranam Seriyamai
Stomachache Vayitruvali Utharasoolai
Piles Mulaviyathi Moolam
Ulcer Kudalpun Gunmam
Laxative Malamilakkiyaku Malamilakki
Vomiting Vanti Sathi
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled…

(continued)
53
Table 1 (continued)
54

Ailment categories Biomedical terms Tamil terms Siddha terms

9. General health (GH) Body refreshment Udalputhunarcchi Thega puthunarchi
Body strength Udalvalimai Udal uramakki
Refrigerant Kuliruttal Kulirchi undakki
Thirst Takam Thakam
Fatigue Corvu Sorvu
Health tonic Arokkiyamnir Udalthetri
Puberty Paruvamataital Poopadaithal
Ill effects of evil spirit Tiyaaviyintavaranavilalvu Bootha paisasa thodangal
10. Genito-urinary ailments (GUA) Diuretic Siruneerperukki Siruneer perukki
Urinary disease Siruneernoykal Siruneer noikal
Antiurolithiatic Siruneerkalnikum Karkaraichi
Stones in the gallbladder Pittappaiyalkalkal Pithapai kal
Kidney stone Siruneerakallu Pirukka kal
Abortion Karukkalaippu Karuchithaivu
Breast pain Marbagavali Nakil soolai
Lactation Paalsurathal Paal perukki
Menstural Maadhavidaai Poopu
Delivery pain Pirasavavali Perukaalavali
Male fertility Anmaisakthiperukkuthal Aanmai undakki
Sperm production Uyirenuurpattai Ven neer perukki
Veneral disease Paalvinainoi Piramiya noi ( )
Over bleeding Raththapokku Perumpadu
Leucorrhoea Vellaipaduthal Vellai noi
Sexual vigour Viraippusakthi (Male) Aanmaiperukki
Fertility in women PenkalilKaruvurutal Soothaga uramakki
Postnatal disease Piracavathirlleumuntiaynoy Sool poopu noikal
P. S. Tresina et al.
 Ailment categories Biomedical terms Tamil terms Siddha terms
11. Haircare (HC) Dandruff Podugo Podugu/chundu
Greying of hair Mutinarrittal Narai mudi
Hair growth Mudivalardhal Mudivalarthal
Hair loss Mudiuthirdhal mudiuthirthal
12. Liver problem (LP) Jaundice ManjalKaamalai kaamalai
13. Oncology (ONC) Cancer Putrunoi Nachu maravai katti
Tumour Katti Maravai katti
14. Poisonous bite (Pb) Prison bite Vishakkadi Visha kadi
Scorpion sting Thaelkkadai Thelkadi
Snake bite Pambukkadi Pambu kadi
Bee bite Tanikadi Theni kadi
Insect bite Poochikadi Poochi kadi
Dog bite Naykadi Naai kadi
15. Respiratory system diseases Asthma Kaasanoi Iraippu
(RSD) Bronchitis Chali and irumal Swasakasam
Chest pain Nenjuvali Marbuvali
Expectorant Chalineekemarunthu Kozhai akatri
Cold Jalathosham Peenisam
Cough Irumal Erumal
Respiratory problem Cuvacanoi Swasa noikal
Wheezing Muccuttinaral Elaippu ( )
(continued)
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled…
55
Table 1 (continued)
56

Ailment categories Biomedical terms Tamil terms Siddha terms

16. Skeleto-muscular system Sedative Mayakkamarunthu Urakka mundaaki
disorder (SMSD) Body pain Udalvali Udal vali
Headache Thalaivali Thalai vali
Migraine Orraitalaivali Otrai thalaivali
Muscular pain Thasaipideppu Thasai vali
Giddiness Talaicurral Thalai chutral
Swelling Veekkam Veekkam
Inflamed joints Vikkamataintamuttukal Mootu thaabitham
Joint pain Moottuvali Keel vayu
Rickets Elumpunoi —
Rheumatic pain Moottuvadham Mootu vatham
Bone fracture Elumpumurivu Enbu murivu
Sprain Culukku Chulukku
Arthritis Kilvadham Keel vayu
Hydrocele Viraiveekamnoi Anda vatham
Lumbago Iduppuvalinoi Thandaga vatham
( )
P. S. Tresina et al.
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled… 57

highest use (most frequently indicated) in the treatment of an ailment. UVs are high
when there are many use reports for a plant and low when there are few reports
related to its use.

2.5.3 Fidelity Level (FL)

To determine the most frequently used plant species for treating a particular ailment
category by the informants of the study area, the fidelity level (FL) was calculated.
The FL was calculated using the following formula [37]

Np
FL  %    100
N

where ‘Np’ is the number of use reports cited for a given species for a particular ail-
ment category and ‘N’ is the total number of use reports cited for any given species.
Generally, high FLs are obtained for plants for which almost all use reports refer to
the same way of using it, whereas low FLs are obtained for plants that are used for
many different purposes [38].

2.5.4 Relative Frequency Citation (RFC)

The collected ethnomedicinal information was quantitatively analyzed using an

index of relative frequency citation (RFC) as

RFC  FC / N  0  RFC  1

This index proves the local significance of each species, and it is specified by the
regularity of citation (FC, the number of informants mentioning the exercise of the
species) divided by the total number of informants participating in the survey (N),
without considering the used categories [39].

3 Results and Discussion

3.1 Documentation of Indigenous Ethnomedicinal Knowledge

In the present study, 239 plants (224 plants collected and 15 plant parts/extracts
procured) belonging to 190 genera and 79 families were recorded, which were com-
monly used by most of the Paliyar traditional healers for the treatment of 122 types
of ailments. Of the recorded plants, 4 plants species belong to Pteridophytes and the
remaining 235 plants belong to the families of Angiosperms. Twelve informants
58 P. S. Tresina et al.

were selected from the study area based on their sound knowledge and long-term
experience of the use of medicinal plants. Information about the botanical name of
the plant, family, voucher specimen number, local (Tamil) name, life form, parts
used, mode of preparation, mode of administration, ailments treated, use reports,
use value and relative frequency citation are provided in Table 2. The prominent
family was Euphorbiaceae with 14 species, followed by Fabaceae, Apiaceae and
Lamiaceae with each 10 species, respectively (Fig. 5). Similarly, Yabesh et al. [18]
reported that the Euphorbiaceae family had the highest number of plant species
from a study carried out in Silent valley of Kerala.
The medicinal uses of plants gathered in the present study were compared with
the previously published information from other parts of India. It was found that
there were 44 claims from the plants such as Abrus precatorius, Acorus calamus,
Achyranthes aspera, Aloe vera, Allium sativum, Anisomeles malabarica, Asparagus
racemosus, Azadirachta indica, Acalypha fruticosa, Acalypha indica, Centella asi-
atica, Clitoria ternatea, Cardiospermum halicacabum, Capparis zeylanica,
Caralluma adscendens var. attenuata, Cocculus hirsutus, Bischofia javanica,
Evolvulus alsinoides, Euphorbia hirta, Gmelina asiatica, Ficus benghalensis,
Helicteres isora, Holopteles integrifolia, Leucus aspera, Lawsonia inermis, Lobelia
nicotianifolia var. nicotianifolia, Hybanthus enneaspermus, Mimosa pudica,
Morinda pubescens var. pubescens, Plumbago zeylanica, Plectranthus amboinicus,
Pergularia daemia, Pongamia pinnata, Phyllanthus emblica, Ocimum tenuiflorum,
Mimusops elengi, Mollugo pentaphylla, Rubia cordifolia, Sphaeranthus indicus,
Senna auriculata, Sida rhombifolia var. rhombifolia, Sterculia urens, Vitex negundo
and Ziziphus xylopyrus were reported for the first time from the study area. On the
other hand, no plants were reported as a fresh medicinal plant as all plants were
accounted with different uses.

3.2 Life Form and Parts Used

The majority of the medicinal plants reported were herbs (47%) followed by trees
(23%), climbers (18%) and shrubs (12%) (Fig. 6). The high tradition of herbs in the
study area could be a signal of their abundance, and it might also be due to the real-
ity that they are effortlessly accessible and might have high effectiveness in the
treatment of ailments in comparison to other growth forms [40]. In addition to this,
herbs can be maneuvered with easiness in herbal grounding methods and drawing
out of bioactive compounds [41]. Concerning the use of the different plant parts, the
traditional healers commonly harvest the leaves (44%), whole plant, root, fruit
(10%), stem bark (9%), seed (8%), stem latex, tuber (5%), stem, unripe fruit, flower
(4%), aerial part and endosperm (3%) (Fig. 7). They were used for the preparation
of medicine solely or mixed with other plant parts. Many indigenous communities
elsewhere also utilized mostly leaves for the preparation of herbal medicines [5, 8,
Table 2 Synopsis of the commonly used medicinal plants by Paliyar tribes in GSWS
Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
1 Abrus precatorius L. Kunnimuthu Cl Sd Paste Topical ENT 8 (Eye pain) 2.33 0.67
Fabaceae EPH 241 Rt Paste Oral SMSD 4 (Joint pain)
Lf Raw/paste Oral GUA2 (Improve sexual
chewed vigour)
Pb 6 (Poison bite)
DC 8 (Teeth sensitiveness)
2 Acacia columnaris Peiindu Cl Lf Paste Oral RSD 6 (Cold and cough) 0.50 0.33
Craib
Mimosaceae EPH
242
3 Acalypha fruticosa Sirusinni Sh Lf Paste/juice Topical/oral Pb 4 (Honey bee bite) 0.83 0.42
Forssk. SMSD 6 (Headache,
Euphorbiaceae EPH rickets)
243
4 Acalypha indica L. Kuppaimaeni He Lf Paste/juice Topical SMSD 4 (Headache) 1.00 0.50
Euphorbiaceae EPH DID 8 (Skin diseases)
258
5 Achyranthes aspera Nayurivi He Lf Paste/juice Oral Pb 4 (Dog bite) 1.50 0.75
L var. aspera DID 9 (Itches, skin
Amaranthacee EPH diseases)
261 GIA 5 (Dysentery)
6 Acorus calamus L. Vasambu He Rh Raw/juice Topical/oral SMSD12 (Sedative, 1.00 0.83
Araceae EPH 84 giddiness)
7 Actiniopteris radiata Mayilkalpul He Lf Paste Topical GIA 6 (Colic pain) 0.50 0.17
(Sw.) Link
Actinopteridacae
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled…

EPH 56
(continued)
59
Table 2 (continued)
60

Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
8 Aegle marmelos (L.) Vilvam Tr Lf Paste Topical DID 4 (Itches) 1.92 0.75
Correa UFt Paste Oral GIA 10 (Diarrhoea)
Rutaceae EPH 138 Ft Juice Oral GIA 9 (Ulcer)
9 Albizia amara Usilai Tr Sb Paste Oral GIA 6 (Stomachache) 0.50 0.58
(Roxb.) Boivin.
Mimosaceae EPH
244
10 Allium cepa L. Vengayam He Bb Paste Topical SMSD11 (Rheumatism, 1.75 0.91
Alliaceae EPH 245 headache)
DID10 (Skin diseases)
11 Aloe vera (L.) Chotthukathalai He Lf Raw (gel) Oral/topical CA12 (Body cooling) 1.75 0.91
Burm. f. DID 9 (Eczema, wound
Liliaceae EPH 246 burn)
12 Alstonia scholaris Ezhilaipalai Tr Sb Paste Oral GUA 8 (Lactation) 1.42 0.42
(L.) R. Br RSD 9 (Asthma)
Apocynaceae EPH 259

13 Amaranthus Mullukkirai He If Paste Topical DID 9 (Eczema, skin 0.75 0.50

spinosus L. diseases)
Amaranthacee EPH
260
14 Amorphophallus Kattukarunai He Tu Boiled (curry) Oral GIA 12 (Piles) 1.00 0.33
sylvaticus (Roxb.)
Kunth Araceae
EPH 76
15 Anaphalis Musakkalli He Rt Juice Topical SMSD 3 (Joint pain) 0.75 0.67
subdecurrens (DC.) Lf Paste Topical SMSD 6 (Joint pain)
Gamble
Asteraceae EPH 262
P. S. Tresina et al.
 Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
16 Andrographis Periyanangai He Wp Juice/Powder Oral Pb 6 (Snake bite, scorpion 0.50 0.50
lineata Wall. ex N sting)
ees
Acanthaceae EPH
148
17 Andrographis Siriyanangai He Wp Juice/powder/ Oral Pb 6 (Snake bite, scorpion 2.50 0.91
paniculata (Burm. decoction sting)
f.) Wall. ex Nees RSP12 (Respiratory
Acanthaceae EPH infection)
386 Fvr 12 (Fever)
18 Andrographis rothii Kayapatchilai He St Paste Topical DID 4 (Weapon injury) 0.35 0.50
Clarke
Acanthaceae EPH
344
Seivinaitheerkum
19 Anisochilus He Lf Paste Topical GH 3 (Illeffect of evil 0.25 0.17
carnosus (L. f.) patchilai spirit)
Wall. ex Benth.
Lamiaceae EPH 356
20 Anisomeles indica Periyathumbai He Lf Boiled (vapour) Topical SMSD 8 (Headache) 1.50 0.33
(L.) Kuntze (inhalation/ SMSD 10 (Rheumatism)
Lamiaceae EPH 324 foment
21 Anisomeles Periyathumbai He Lf Boiled (vapour) Topical SMSD11 (Rheumatism, 0.92 0.67
malabarica (L.) (inhalation) headache)
R.Br.ex Sims
Lamiaceae EPH278
22 Argyreia pilosa Arn Thettukkadi Cl Tu Roasted/boiled Oral GIA 8 (Gastric complaints) 0.67 0.33
Convolvulaceae
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled…

EPH 247
(continued)
61
Table 2 (continued)
62

Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
23 Aristolochia indica Thalaisurulivaer Cl Rt Paste/powder/ Topical/oral Pb 9 (Snake bite, scorpion 1.50 0.50
L. juice sting)
Aristolochiaceae SMSD 9 (Headache)
EPH 248 GIA 2 (Stomachache)
24 Aristolochia tagala Karudakkodi Cl Rt Paste/powder Topical/oral Pb 9 (Snake bite, scorpion 1.67 0.33
Cham. sting)
Aristolochiaceae SMSD 8 (Headache)
EPH 249 GIA 3 (Stomachache)
25 Asclepias Kuruthipoo He Lf Powder Oral DID 4 (Skin diseases) 1.08 0.42
curassavica L. Rt Decoction/paste Oral GIA 9 (Constipation, piles)
Asclepiadaceae
EPH 250
26 Asparagus Neervalli Cl Tu Boiled Oral GIA 4 (Bed wetting) 0.83 0.50
racemosus Willd. Lf Paste Topical Pb 6 (Honeybee sting)
Liliaceae EPH 251
27 Atalantia racemosa Kattuelumichai Tr Lf Decoction Topical DID 7 (Itches, skin 1.08 0.17
Wight & Arn. Ft Juice Oral diseases)
Rutaceae EPH 139 GIA 6 (Stomach disorder)
28 Azadirachta indica Vembu Tr Lf Boiled (vapour) Topical RSD 8 (Cold and cough) 2.50 0.83
A. Juss. Sb Decoction (inhalation) Fvr 10 (Fever)
Meliaceae EPH 140 Sd Juice Oral SMSD 12 (Rheumatism)
Tropical
29 Bambusa Mungil Tr Lf Juice/paste Oral/topical SMSD 4 (Sprain) 0.58 0.17
arundinacea (Retz.) RSD 3 (Chest pain)
Roxb.
Poaceae EPH 141
P. S. Tresina et al.
 Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
30 Basella alba L. var. Kattupasali Cl TU Paste Topical GIA 9 (Colic pain) 2.25 0.25
alba Lf Juice Oral CA 10 (Body cooling)
Chenopodiaceae St Infusion Oral GIA 8 (Laxative)
EPH 142
31 Bauhinia racemosa Aathi Tr Lf Juice Topical ENT 4 (Removal of dust 0.33 0.17
Lam. from eye)
Caesalpiniaceae
EPH 112
32 Bauhinia tomentosa Kanchini Sh Lf Infusion Oral CA 4 (Body cooling) 0.33 0.17
L.
Caesalpiniaceae
EPH 113
33 Begonia malabarica Narayana He Ap Paste Topical SMSD 11 (Rheumatism) 1.50 0.33
Lam. sanjivi Lf Raw/powder Oral RSD 7 (Astringent)
Begoniaceae EPH
114
34 Begonia picta Sm. Kalthamarai He Lf Raw Oral GH 7 (Refrigerant) 0.58 0.17
Begoniaceae
EPH 89
35 Benkara malabarica Kuthupidari Sh Sb Paste Topical Pb 6 (Scorpion sting) 0.50 0.17
(Lam.) Tirvengadam
Rubiaceae EPH 130
36 Bidens pilosa L. var. Kattu He Lf Juice Oral LP 6 (Jaundice) 0.50 0.25
minor (Blume) karisalankanni
Sherff
Asteraceae EPH 321
37 Bischofia javanica Omaviruchu Tr Sb Boiled Topical SMSD 8 (Body pain) 0.67 0.25
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled…

Blume (Filtrate)
Bischofiaceae EPH
63

322
(continued)
Table 2 (continued)
64

Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
38 Blepharis Sadhaiotti He Lf Paste Topical DID 5 (Weepon. injuries, 1.83 0.50
maderaspatensis Sd Infusion Oral wound)
(L.) Heyne ex Roth GIA 11 (Ulcer)
Acanthaceae EPH GUA 6 (Urinary infection)
301
39 Blumea barbata Mayakkam He Lf Raw (aroma) Topical SMSD 6 (Giddiness) 0.50 0.17
DC. neeki patchilai (inhalation)
Asteraceae EPH 93
40 Bupleurum wightii Kattuseeragam He Ft Infusion Oral CA 7 (Body cooling) 0.58 0.17
Mukh var.
ramosissimum
(Wight & Arn)
Chandrabose comb.
nov.
Umbelliferae (nom.
alter. Apiaceae)
EPH 94
41 Caesalpinia crista L Kalachichedi Sh Sd Paste Topical SMSD10 (Hydrocele) 0.83 0.17
Caesalpiniacee
EPH 95
42 Calotropis gigantea Erukku Sh Sl Paste Topical RSD 9 (Cold and Cough) 1.92 0.83
(L.) R. Br. Rt Juice Topical SMSD 6 (Headache, body
Asclepiadaceae Lf Warmed Topical pain)
DPH 303 (poultice) SMSD 8 (Rheumatism)
43 Canarium strictum Kungiliam Tr Re Powder Topical SMSD 6 (Headache) 1.17 0.67
Roxb. (burned) (inhalation) RSD 8 (Cold)
Burseraceae EPH
305
P. S. Tresina et al.
 Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
44 Canscora perfoliata Narayana He Wp Juice Oral Pb 7 (Poison bite) 0.58 0.50
Lam. vembu
Gentianaceae EPH
308
45 Capparis sepiaria Muruvilikodi Sh Sb Paste Topical DID 7 (Eczema, dandraff) 1.08 0.42
L. Lf Paste Oral CA 6 (Body cooling)
Capparaceae
EPH 57
46 Capparis zeylanica Kaathatikaai Cl Lf Paste Topical SMSD 11 (Arthritis) 0.92 0.33
L.
Capparaceae
EPH 60
47 Capsicum annum L. Periya He Ft Paste Topical DC 4 (Toothache) 0.58 0.67
Solanaceae EPH 61 usimilagai ENT 3 (Sore throat)
48 Caralluma Periya He AP Raw Oral GH10 (Refrigerant, reduce 0.83 0.83
adscendens (Roxb.) sirumankeerai body weight)
Haw. var. attenauta
(Wight) Grav &
Mayuranathan
Asclepiadaceae
EPH 401
49 Caralluma lasiantha Sirumankeerai He AP Raw Oral GH10 (Refrigerant, reduce 0.83 0.75
(Wight) N.E.Br body weight)
Asclepiadaceae
EPH 402
50 Cardiospermum Mudakkathan Cl Lf Paste/juice Topical/oral SMSD12 (Rheumatism, 1.67 0.50
halicacabum L. Decoction Oral Giddiness)
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled…

Sapindaceae EPH RSD 8 (Cold and Cough)

300
65

(continued)
Table 2 (continued)
66

Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
51 Carmona retusa Siruthani Sh Wp Raw Topical (touch) GH 4 (Puberty) 0.33 0.17
(Vahl) Masamune
Boraginaceae EPH
100
52 Centella asiatica Vallarai He Lf Raw/juice Oral RSD 6 (Cold and cough, 0.50 0.67
(L.) Urban chest pain)
Umbelliferae (nom.
alter. Apiaceae)
EPH 412
53 Ceropegia juncea Thiralankodi Cl Sl Raw Topical Pb 3 (Insect bite) 0.58 0.17
Roxb. St Juice Oral GIA 4 (Anthelmintic)
Asclepiadaceae
EPH 413
54 Cheilanthes Poorankadi- He Rh & Rc Paste Topical Pb 4 (Scorpion sting) 0.33 0.17
opposita Kaulf chedi
Sinopteridaceae
EPH 415
55 Chionanthus Vandukadipattai Tr Sb Paste Topical DID 4 (Itches) 0.33 0.17
mala-elengi
(Dennst.) P.S.Green
Oleaceae EPH 27
56 Cissampelos pareira Malaithangivaer Cl Rt Powder Oral Pb 9 (Poison bite) 1.33 0.33
L. var. hirsuta GIA7 (Stomachache)
(Buch-Ham. DC)
Forman
Menispermaceae
EPH 78
57 Cissus Perandai Cl Lf Juice/paste Oral ONC 4 (Tumor Tumor-like 1.33 0.50
quadrangularis L. swelling)
P. S. Tresina et al.

Vitaceae EPH 79 SMSD 12 (Rheumatism)

 Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
58 Cleome monophylla Kattukadugu He Lf Paste Topical SMSD 6 (Headache) 0.50 0.42
L..
C1eomaceae EPH
405
59 Cleome viscosa L. Naaikkadugu He Sd Infusion/paste Oral GUA 9 (Postnatal disease, 0.75 0.42
Cleomaceae EPH over bleeding)
406
60 Clitoria ternatea L. Vellai kakarthan Cl Rt Powder Oral GUA 6 (Kidney stone) 1.83 0.67
Fabaceae EPH 418 Wp Juice Topical DID 10 (Skin diseases,
Oral leucodema, stomatitis
GIA 6 (Piles)
61 Coccinia grandis Kovai Cl Uft/Lf Boiled Topical (bath) SMSD 6 (Body pain) 1.67 0.42
(L.) Voigt Oral ED 8 (Diabetic)
Cucurbitaceae EPH
434
62 Cocculus hirsutus Vellaikattukodi Cl Rt Paste Oral GIA 8 (Stomachache) 2.00 0.67
(L.) Diels Lf Powder/paste Oral/topical GH 6 (Refrigerant)
Menispermaceae SMSD 3 (Headache)
EPH 436 DID 7 (Eczema, ulcer, skin
diseases)
63 Cocos nucifera L. Thennai Tr Yes Raw Oral GUA 2 (Diuretic) 1.08 0.50
Arecaceae EPH 33 Rt Juice Oral GUA 3 (Diuretic)
Es oil Raw Topical DID 8 (Skin diseases)
64 Combretum albidum Maruthankodi Cl Uft/Sd/St Raw Topical DC 8 (Toothache) 0.67 0.17
G. Don
Combretaceae EPH
357
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled…

(continued)
67
Table 2 (continued)
68

Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
65 Commelina Amala He Ss Raw Topical ENT 10 (Removal of dust 0.83 0.83
benghalensis L. from the eyes)
Commelinaceae
EPH 368
66 Commelina ensifolia Amala He Ss Raw Topical ENT 10 (Removal of dust 0.83 0.83
R.Br. from the eyes)
Commelinaceae
67 Commiphora Mangkiluvai Tr Es Raw Oral GIA 7 (Stomachache) 0.58 0.17
caudata (Wight &
Arn.) Engler
Burseraceae EPH
371
68 Commiphoran Kodikiluvai Tr Es Raw Oral GIA 6 (Stomachache) 0.50 0.17
pubescens (Wight &
Am.) Engler
Burseraceae EPH
372
69 Coriandrum sativum Kothamalli He Lf Raw Oral GIA10 (Anthelmintic, 2.50 0.83
L. Ft Boiled Oral digestive stimulant, gastric
Umbelliferae (nom. complaints
alter. Apiaceae) GIA 12 (Indigestion)
EPH 341
70 Crataeva adansonii Mavulingam Tr Lf Boiled (Coconut Topical SMSD 8 Joint pain 1.00 0.25
DC. subsp. odora Sb oil) Oral SMSD 4 (Headache)
(Buch-Ham) Jacobs Decoction RSD 8 (Asthma, cough,
Capparaceae EPH bronchitis, skin diseases)
342
P. S. Tresina et al.
 Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
71 Croton Reilpoondu Ae Sl Raw Topical DID 4 (Thorn injury) 0.33 0.25
bonplandianum
Baill.
Euphorbiaceae EPH
343
72 Curcuma longa L. Manjal He Rh Roasted Oral GIA 8 (Bowel disorders) 1.00 0.67
Zingiberaceae EPH Powder Topical Pb 4 (Insect bite)
199 DID 10 (Antiseptic, skin
diseases)
73 Curculigo Kuluthupokie/ He Tu Powder Oral GUA 12 (Improve sexual 1.83 0.83
orchioides Gaertn. Nilapanai vigour)
Hypoxidaceae EPH
198
74 Cyanotis tuberosa Palvalikizhangu He Tu Roasted Topical DC 10 (Toothache) 0.83 0.25
(Roxb.) Schultes &
Schultes f.
Commelinaceae
EPH 200
75 Cymbopogon Taragupullu He Tu Roasted Topical SMSD 4 (Giddiness) 2.50 0.83
citratus (DC.) Stapf. Lf Juice (Inhalation) GIA10 (Stomachache,
Poaceae EPH 201 Oral dysentery, bowel
complaints, vomiting)
Fvr 8 (Fever)
SMSD 8 (Headache)
76 Cynodon dactylon Arugampullu He Lf Juice Oral CSCD 8 (Heart tonic) 3.08 0.91
(L.) Pers SMSD10 (Rheumatism)
Poaceae EPH 202 GIA 10 (Gastric
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled…

complaints, indigestion)
CA 9 (Body cooling)
69

(continued)
Table 2 (continued)
70

Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
77 Dichrostachys Vidathalai Tr Lf Paste Oral GIA 5 (Dysentery) 0.42 0.25
cinerea (L.) Wight
& Arn
Mimosaceae EPH
214
78 Dioscorea bulbifera Vethalaivalli/ Cl Tu Raw/cooked Oral GIA 9 (Dysentery) 0.75 0.17
L. var. vera Prain & Karuvalli
Burkill
Dioscoreaceae EPH
215
79 Dioscorea Vethalaivalli Cl Tu Raw/cooked Oral GIA 9 (Dysentery) 0.75 0.17
oppositifolia L. var.
dukhumensis Prain
& Burkill
Dioscoreaceae EPH
218
80 Dioscorea Mullvalli Cl Tu Cooked/roasted Oral GIA 11 (Piles) 0.92 0.25
pentaphylla L. var.
pentaphylla
Dioscoreaceae EPH
220
81 Dioscorea Noolvalli Cl Tu Cooked Oral GIA 10 (Bowel disorders) 0.83 0.50
tomentosa Koen. ex
Spreng.
Dioscoreaceae EPH
221
82 Diplocyclos Malaipusanni Cl Tu Roasted Oral GUA 8 (Abortion) 0.67 0.67
palmatus (L.)
Jeffrey
P. S. Tresina et al.

Cucurbitaceae EPH
101
 Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
83 Dodonaea viscosa Virali Sh Lf Boiled Topical SMSD 9 (Body pain) 0.75 0.50
(L.) Jacq (oil) (massages)
Sapindaceae EPH
102
84 Drynaria quercifolia Mudavathukaal He Rh Paste Topical SMSD12 (Rheumatic pain, 1.00 0.25
(L.) J. Sm. bone fracture)
Drynariaceae EPH
103
85 Drypetes sepiaria Kalvirai Tr Sb Paste Topical DID 4 (Katti) 0.33 0.17
(Wight & Arn.) Pax
& Hoffm.
Euphorbiaceae EPH
104
86 Eclipta prostrata Karisalankanni He Lf/Wp Juice Topical (bath) HC 12 (Graying Greying 1.50 0.83
(L.) L. of hair, hair loss)
Asteraceae EPH 177 CA 6 (Body cooling)
87 Eleusine coracana Kattukepai He Gr Cooked Oral ED 7 (Diabetes) 0.58 0.83
(L.) Gaertn.
Poaceae EPH 178
88 Ensete superbum Malaivazhai Tr Pd Juice Oral GUA 11 (Kidney stone) 0.92 0.75
(Roxb.) Cheesman
Musaceae EPH 179
89 Eugenia discifera Vellainaaval Tr Sb Powder Oral GIA 5 (Stomachache) 0.42 0.17
Gamble
Myrtaceae EPH 456
90 Euphorbia hirta L Amanpatcharisi He Sl Raw Topical GUA 4 (Lactation) 1.33 0.33
Euphorbiaceae EPH Lf Warmed Topical SMSD 6 (Swelling)
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled…

481 Wp Decoction (Poultice) DID 6 (Boils, skin

Oral diseases)
71

(continued)
Table 2 (continued)
72

Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
91 Euphorbia rosea Amanpatcharisi He Sl Raw Topical GUA 6 (Lactation) 0.50 0.17
Retz.
Euphorbiaceae EPH
462
92 Evolvulus alsinoides Vishnukarandi He Lf Decoction Oral Fvr 12 (Fever) 2.25 0.67
(L.) L. Rt RSD 10 (Cold and cough)
Convolvulaceae Wp GUA 5 (Venereal diseases)
EPH 463
93 Ficus benghalensis Aal Tr Sl Raw Topical DID10 (Heal cracker) 1.83 0.50
L. var. benghalensis Sb Powder Topical (tooth DC 12 (Tooth strength)
Moraceae EPH 464 powder)
94 Ficus microcarpa L. Punniyavirusu Tr Sl Raw Topical DID 12 (Heal cracker) 1.00 0.50
f.
Moraceae EPH 465
95 Ficus racemosa L. Atthi Tr Sl/Lx Raw Topical DC 12 (Heal cracker boils, 2.33 0.50
Moraceae EPH 466 Sb Infusion Topical (mouth Blisters
Paste wash) DC 10 (Mouth wash)
Topical DID 6 (Burns)
96 Ficus religiosa L. Arasu Tr Sl Raw Topical DID 9 (Fissures in foot) 0.75 0.42
Moraceae EPH 467
97 Flacourtia indica Mullumayilai Sh Ft Raw/powder Oral RSD 5 (Asthma) 0.42 0.17
(Burm. f.) Merr. Uft
Flacourtiaceae EPH
468
98 Foeniculum vulgare Sombu He Ft Raw/powder Oral GIA 9 (Improve digestion) 0.75 0.42
Mill
Umbelliferae (nom.
Alter Apiaceae)
P. S. Tresina et al.

EPH 32
 Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
99 Gardenia resinifera Kattu koiya/ Tr Re Raw Oral RSD 6 (Cough) 0.50 0.17
Roth Vetchi Pc Powder
Rubiaceae EPH 457 Isd
100 Givotia Vandalai Tr Es Powder Oral GID 8 (Improve digestion) 0.67 0.17
rottleriformis Griff.
Euphorbiaceae EPH
458
101 Globba marantina Kattumanjal He Rh Paste Topical DID 3 (Katti) 0.25 0.17
L.
Zingiberaceae EPH
459
102 Gloriosa superba L. Karthika Cl Uft Boiled (coconut Topical ENT 12 (Ophthalmic 1.00 0.67
Liliaceae EPH 482 kilangu oil) problem)
103 Gmelina asiatica L Kumulu Sh Lf Infusion Oral CA 6 (Body cooling) 0.92 0.42
Verbenaceae EPH Ft Juice Topical ENT 5 (Sore throat)
483
104 Gymnema sylvestre Shirukurinjan Cl Lf Powder Oral ED 12 (Diabetes) 1.75 0.91
(Retz.) R. Br. Ex Wp Decoction Oral CSCD 9 (Cardiovascular
Schultes disorders, obesity, lowering
Asclepiadaceae cholesterol)
EPH 484
105 Gyrocarpus Tanakku Tr Es Raw Oral GIA 6 (Stomachache) 0.50 0.17
asiaticus Willd.
Hemandiaceae EPH
485
106 Hedyotis brachiata Inbural He Lf Juice Oral GIA 6 (Vomiting) 0.50 0.17
Wight
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled…

Rubiaceae EPH 486

(continued)
73
Table 2 (continued)
74

Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
107 Hedyotis corymbosa Inbural He Lf Juice Oral GIA 7 (Vomiting) 0.58 0.33
(L.) Lam
Rubiaceae EPH 490
108 Hedyotis puberula Emburel He Lf Powder Oral ED 3 (Diabetes) 0.25 0.17
(G. Don) Arn.
Rubiaceae EPH 491
109 Helicteres isora L. Valamburi Sh Ft Ash Topical ENT 6 (Sore in ear) 1.50 0.50
Malvaceae EPH 492 Lf Paste Topical DID 5 (Skin diseases,
Rt Decoction Oral eczema, scabies)
RSD 7 (Asthma)
110 Hemidesmus indicus Nannari Cl Rt Powder Oral CA 12 (Body cooling) 2.83 0.83
(L.) R. Br. var. GIA 10 (Improve
indicus digestion)
Periplocaceae GH 12 (Thirstness)
EPH 62
111 Hemidesmus indicus Nannari Cl Rt Powder Oral CA 12 (Body cooling) 2.92 0.83
(L.) R. Br. var. GIA 11 (Improve
pubescens (Wight & digestion)
Arn) Hook.f GH 12 (Thirstness)
Periplocaceae
EPH 63
112 Heracleum rigens Kattu He Yp Subgy Oral GIA 3 (Bowel complaints) 0.25 0.17
Wall. ex DC. var. kothamalli
rigens
Umbelliferae (nom.
alter. Apiaceae)
EPH 45
113 Hibiscus vitifolius Periyathutthi He Fl Paste Topical DID 3 (Boils) 0.25 0.25
L.
P. S. Tresina et al.

Malvaceae EPH 501

 Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
114 Holoptelea Ayil ilai Tr Lf Paste Topical SMSD 4 (Headache) 0.33 0.25
integrifolia (Roxb)
Planch
Ulmaceae EPH 504
115 Hybanthus Orithalthamarai He Ap Powder Oral GUA12 (Improve sexual 1.00 0.67
enneaspermus (L.) vigour in male)
F. V. Muell
Violaceae EPH 505
116 Hydrocotyle Kodivallarai He Wp Powder Oral GH 6 (Refrigerant) 0.50 0.17
javanica Thunb
Umbelliferae (nom.
alter. Apiaceae)
EPH 510
117 Ichnocarpus Palvalli Cl Rt Powder Oral ED 4 (Diabetes) 1.00 0.33
frutescens (L.) GUA 8 (Stones in the gall
R. Br. bladder)
Apocynaceae EPH
511
118 Impatiens scapiflora Chinna He Lf Raw Oral GH 6 (Refrigerant) 0.50 0.17
Heyne ex Roxb. kalthamarai
Balsaminaceae EPH
512
119 Indigofera wightii Parisa Sh Rt Powder Oral GIA 9 (Stomachache) 0.75 0.17
Graham ex Wight & vayittruvali vaer
Arn.
Fabaceae
(continued)
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled…
75
Table 2 (continued)
76

Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
120 Ipomoea Thoolikkodi Cl Lf Paste Topical DID 3 (Wounds) 0.25 0.17
barlerioides Benth.
ex Clarke
Convolvulaceae
EPH 521
121 Ipomoea hederifolia Neelikodi Cl Lf Paste Topical DID 5 (Wounds) 0.42 0.25
L.
Convolvulaceae
EPH 523
122 Ipomoea obscura Thazhiilai Cl Lf Paste Topical DID 6 (Boils) 0.50 0.25
(L.) Ker- Gawl.
Convolvulaceae
EPH 524
123 Ipomoea staphylina Onaan kodi Cl Sl Raw Topical DID 7 (Fissures in foot) 0.58 0.17
Roem. & Schultes
Convolvulaceae
EPH 525
124 Jasminum Kattumalli Cl Fl Boiled Topical ENT 6 (Oozing pus in ear) 0.92 0.17
roxburghianum Rt Paste Oral GIA 5 (Colic pain)
Wall.
Oleaceae EPH 555
125 Jatropha curcas L. Kattamanaku Tr Lf Juice Topical SMSD 6 (Rheumatism) 1.08 0.58
Euphorbiaceae EPH Rt Raw Topical GUA 7 (Abortion)
556
126 Jatropha Vellaiadalai Sh Wp Juice Topical SMSD 10 (Rheumatism) 0.83 0.50
glandulifera Roxb
Euphorbiaceae
EPH557
P. S. Tresina et al.
 Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
127 Jatropha Sivappuatalai Sh Wp Juice Topical SMSD 9 (Rheumatism) 0.75 0.50
gossypifolia L.
Euphorbiaceae EPH
558
128 Justicia adhatoda L. Adatoda Sh Lf Decoction Oral RSD12 (Asthma, cold and 1.00 0.75
Acanthaceae EPH cough, respiratory
151 problems)
129 Justicia glauca Rottl Neemotchi/ He Lf Juice Oral Pb 6 (Poison bite) 0.50 0.25
Acanthaceae EPH Kattukurinchi
152
130 Kalanchoe olivacea Kulirthamarai He Lf Raw Oral CA 10 (Body cooling) 0.83 0.17
Dalz. & Gibs.
Crassulaceae EPH
154
131 Kalanchoe pinnata Megasanjeevi He Lf Raw Oral CA 10 (Body cooling) 0.83 0.17
(Lam.) Pers.
Crassulaceae EPH
158
132 Kleinia grandiflora Musakkalli Sh Rt/Lf Boiled (coconut Topical SMSD 8 (Joint pain) 0.67 0.25
(Wall. ex DC) oil)/Paste (massage)
N. Rani. Topical
Asteraceae EPH 156
133 Knoxia sumatrensis Vazhukkanangai He Lf Powder Oral Pb 3 (Poison bite) 0.25 0.17
(Retz.) DC. var.
linearis
Rubiaceae EPH 157
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(continued)
77
Table 2 (continued)
78

Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
134 Lantana camara L. Unnipoo Shrub Sh Fl Paste Topical Pb 4 (Insect bite) 0.33 0.25
var. aculeata (L.)
Mold
Verbenaceae EPH
146
135 Lantana wightiana Muraikaichal Sh Lf Paste Topical Fvr 5 (Fever) 0.42 0.25
Wall. ex Gamble chedi
Verbenaceae EPH
290
136 Launaea sarmentosa Sulukkupatchi- He Lf Paste Topical SMSD 6 (Sprain) 0.50 0.17
(Willd.) Sch-Bip.ex lai
Kuntze
Asteraceae EPH 641
137 Lawsonia inermis L. Marudondi Sb Lf Boiled (coconut Topical (head) HC12 (Hair growth, hair 1.83 0.67
Lythraceae EPH 44 oil) loss)
CA10 (Body cooling)
138 Lepisanthes Vaivumaram Tr Sb Paste Oral GIA 8 (Gastric complaints) 0.67 0.17
senegalensis (Juss.
ex Poir.) Leenh
Sapindaceae EPH
291
139 Leucas aspera Tumbai He Lf Juice Topical SMSD 10 (Migraine) 0.83 0.42
(Willd.) Link
Lamiaceae EPH 292
140 Leucas biflora Siru tumbai He Ap Boiled Topical SMSD 10 (Headache) 0.83 0.42
(Vahl) R. Br var. (inhalation)
biflora
Lamiaceae EPH 293
P. S. Tresina et al.
 Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
141 Limonia acidissima Vila Tr Lf Infusion Oral Fvr 6 (Fever) 0.50 0.17
L.
Rutaceae EPH 295
142 Lobelia Kattupugaiyilai He Lf Chawed Oral GH 3 (Fatigue) 0.25 0.17
nicotianifolia Roth
ex Schultes var.
nicotianifolia
Lobeliaceae EPH
298
143 Mangifera indica L. Maa Tr Es Powder Oral GIA 8 (Stomachache) 0.67 0.50
Anacardiaceae EPH
299
144 Memecylon edule Sarkarai vembu Tr Lf Powder Oral ED 8 (Diabetes) 0.67 0.83
Roxb.
Melastomataceae
EPH 216
145 Micromeria biflora Elumichai He Wp Infusion Topical HC 10 (Hair tonic, hair 0.83 0.58
(Buch.- Ham. ex vallarai growth, hair loss)
D. Don.) Benth.
Lamiaceae EPH 223
146 Mimosa pudica L. Thotalsinungi He LR/Wp Paste Topical DID 3 (Insect bite) 1.67 0.42
Mimosaceae EPH SMSD11 (Inflamed joints)
224
147 Mimusops elengi L. Mahilampoo Tr Sb Paste/juice Oral GUA 9 (Improve fertility 0.75 0.50
Sapotaceae EPH in women)
225
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled…

(continued)
79
Table 2 (continued)
80

Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
148 Mollugo cerviana Pappadai He Wp Decoction Oral RSD 9 (Cold and cough) 1.42 0.33
(L.) Ser. Paste Topical DID 8 (Eczema, bad body
Molluginaceae odour)
EPH 58
149 Mollugo pentaphylla Pappadai He Wp Infusion Oral GUA 7 (Menstrual 1.50 0.58
L. Roasted Topical discharge)
Molluginaceae Decoction Poultice DID 6 (Sore legs)
EPH 59 Oral ENT 5 (Eye diseases)
150 Momordica Kuruvithalai He Uft Cooked Oral GIA 10 (Anthelmintic) 1.83 0.83
charantia L. var. ED 12 ((Diabetes)
charantia
Cucurbitaceae
EPH 16
151 Morinda pubescens Manjanatti Tr Lf Infusion Oral GIA 6 (Digestion 1.83 0.83
J.E. Smith var. Sb Paste Topical disorders, piles)
pubescens Decoction Oral DID 4 (Weapon injury,
Rubiaceae DPH 560 leucoderma)
SMSD 12 (Rheumatism)
152 Moringa Kattumurungai Tr Lf Paste/juice Oral LP 6 (Jaundice) 1.67 0.58
concanensis Nimmo GIA 8 (Bowel disorder)
ex Gibs.
Moringaceae EPH
564
153 Mucuna Thellukkai Cl Sd Paste Topical SMSD 6 (Bone fracture) 0.50 0.58
atropurpurea DC.
Fabaceae EPH 570
P. S. Tresina et al.
 Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
154 Mukia Musumusukki Cl Lf Juice Oral RSD 10 (Asthma, cold and 2.33 0.67
maderaspatana (L.) Decoction Oral cough)
M. Roem. SMSD 12 (Rheumatism)
Cucurbitaceae EPH GUA 6 (Diuretic)
573
155 Mundulea sericea Vellaipurasu Tr Lf Paste Topical DID 6 (Leucoderma) 0.50 0.17
(Willd.) A. Cheval.
Fabaceae EPH 576
156 Murraya koenigii Kariveppilai Tr Lf Paste Topical HC 10 (Hair growth, hair 1.75 0.58
(L.) Spreng. Juice Oral loss, hair tonic)
Rutaceae EPH 66 ED 11 (Diabetes)
157 Nothopegia Karunthillai Tr Sd/Lf Powder Oral Pb 3 (Snake bite) 0.25 0.17
colebrookeana
(Wight) Blume
Anacardiaceae EPH
440
158 Ochna lanceolata Mayilai Tr Sb Powder/Juice Oral GIA 7 (Stomachache) 1.42 0.50
Spreng. GUA 10 (Abortion,
Ochnaceae EPH 443 menstrual disorder)
159 Ocimum tenuiflorum Tulsi He Lf Boiled (vapour) Topical SMSD 4 (Headache) 1.83 0.67
L. Paste (inhalation) DID 8 (Wounds)
Lamiaceae EPH 444 Raw Topical RSD 10 (Cold and cough)
Oral
160 Orthosiphon Kattutulsi He Lf Paste Topical DID 3 (Wounds) 0.25 0.17
thymiflorus (Roth)
Sleensen
Lamiaceae EPH 600
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(continued)
81
Table 2 (continued)
82

Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
161 Parahemionitis Mayilkal He Lf Paste Topical GIA 8 (Colic pain) 0.67 0.17
cordata (Roxb. ex patchilai
Hook. & Grev.)
Fras. Jenk.
Hemionitidaceae
EPH 601
162 Pavonia odorata Thuthi He Lf Paste Topical DID 8 (Wounds) 0.67 0.17
Willd.
Malvaceae EPH 611
163 Pergularia daemia Velipparuthi Cl Lf Paste Topical GIA 10 (Gastric 1.83 0.75
(Forssk.) Chiov. Rt/Lf Boiled Topical complaints)
Asclepiadaceae (massage) SMSD 12 (Joint pain)
EPH 612
164 Phyllanthus amarus Kilanelli He Ap Juice Oral LP 12 (Jaundice) 1.00 0.91
Schum. & Thonn.
Euphorbiaceae
EPH 83
165 Phyllanthus emblica Nelli Tr Ft Juice Oral GUA 6 (Diuretic) 1.17 0.83
L. GIA 8 (Digestive disorder)
Euphorbiaceae
EPH 82
166 Phyllanthus Kilaneli He Ap Juice Oral LP 12 (Jaundice) 1.00 0.83
maderaspatensis L.
Euphorbiaceae
EPH 81
167 Physalis minima L. Toppipalam He Lf Cooked Oral GIA 10 (Ulcer) 0.83 0.58
Solanaceae EPH 71
P. S. Tresina et al.
 Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
168 Pimpinella Kothuvallarai He Wp Powder Oral GH 3 (Refrigerant) 0.25 0.42
candolleana Wight
& Arn.
Umbelliferae (nom.
alter. Apiaceae)
EPH 72
169 Piper argyrophyllum Kattumilagu Cl Lf/Ft Raw Oral RSD 10 (Cold and cough) 1.75 0.67
Miq. Decoction RSD 11 (Cold and cough)
Piperaceae EPH 77
170 Piper trioicum Roxb Vethalaikodi Cl Lf/St Boiled Topical (bath) ENT 7 (Buring sensation 0.58 0.50
Piperaceae EPH 18 in the eye)
171 Plectranthus Omavalli He Lf Juice Oral RSD 12 (Asthma, cold and 1.58 0.67
amboinicus (Lour.) cough, bronchitis)
Spreng. GIA 7 (Anthelmintic)
Lamiaceae EPH 445
172 Plectranthus Poolankilangu He Rh Paste Topical DID 4 (Katti) 0.33 0.25
barbatus Andr.
Lamiaceae EPH 446
173 Plumbago zeylanica Vellaikoduvilai He Lf/Rt Paste Topical Pb 5 (Snake bite) 0.92 0.42
L. SMSD 6 (Arthritis)
Plumbaginaceae
EPH 630
174 Polygala javana Palapirantai He Lf Paste Topical GUA 6 (Breast pain) 0.50 0.17
DC. var. angustifolia
Polygalaceae EPH
631
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(continued)
83
Table 2 (continued)
84

Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
175 Pongamia pinnata Pongan Tr Sd Raw Topical RSD 6 (Cold & cough) 0.75 0.58
(L.) Pierre (Necklace) LP 3 (Jaundice)
Fabaceae EPH 160
176 Portulaca pilosa L. Pillaiva- He Tu Raw Oral GUA 3 (Prevent natural 0.25 0.67
subsp. pilosa larthikilangu abortion)
Portulacaceae EPH
161
177 Portulaca wightiana Pasalai chedi He Wp Paste Topical SMSD 5 (Arthritis) 0.42 0.58
Wall.ex Wight &
Arn.
Portulacaceae EPH
162
178 Pouzolzia zeylanica Kallazhingi He Rb Paste Topical He 6 (Dandruff) 1.17 0.67
(L.) Benn. Pi Raw/paste Topical SMSD 8 (Swelling,
Urticaceae EPH 155 muscular pain, bone
fracture)
179 Premna corymbosa Aadhandai Sh Lf Raw (crushed) Topical SMSD 3 (Giddiness) 0.25 0.67
(Burm, f.) Rottl. & (inhalation)
Willd.
Verbenaceae EPH
629
180 Priva cordifolia (L. Aadai otti He Lf Paste Topical DID 7 (Wounds) 0.58 0.17
f.) Druce.
Verbenaceae EPH
469
181 Pterocarpus Vengai Tr Re Soaked Topical SMSD 9 (Joint pain, 2.25 0.83
marsupium Roxb. Lf Paste Topical rickets)
Fabaceae EPH 470 St Decoction Oral DID 7 (Leucoderma, skin
diseases)
P. S. Tresina et al.

ED 11 (Diabetes)
 Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
182 Pupalia lappacea Pakkattikai He Ts/If Paste Topical Pb 2 (Unknown insect bite) 0.17 0.25
(L.) Juss. var.
lappacea
Amaranthaceae
EPH 619
183 Rhinacanthus Nagamalli Sh Lf Juice/ Oral Pb 10 (Snake bite) 0.83 0.83
nasutus (L.) Kurz powder
var. nasutus
Acanthaceae EPH
526
184 Rubia cordifolia L. Koduvili He Rt/Ts Paste Topical DID 3 (Weapon injury) 0.25 0.25
Rubiaceae EPH 360
185 Sansevieria Maurl He Lf Raw Topical (bite) DC 3 (Teeth growth in 0.25 0.33
roxburghiana young children)
Schultes & Schultes
Agavaceae EPH 98
186 Santalum album L. Sandanam Tr Hw Paste Topical CA 12 (Body cooling) 1.00 0.58
Santalaceae EPH 99
187 Scoparia dulcis L. Neernangai He Lf Raw Oral Pb 8 (Poison bite) 2.42 0.83
Scrophulariaceae Wp Decoction ED 12 (Diabetes)
EPH 120 GIA 9 (Stomachache)
188 Senna auriculata Aavarai Sh Fl Paste/juice Oral GIA 8 (Colic pain) 3.00 0.91
(L.) Roxb. Lf Ts Juice Topical (tied) ED 12 (Diabetes)
Caesalpiniaceae Raw GIA 10 (Laxative)
EPH 50 GIA 6 (Colic pain)
189 Sesamum indicum Kattuyellu He Sd Raw Oral GUA 8 (Abortion) 0.67 0.67
L.
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled…

Pedaliaceae EPH 51

(continued)
85
Table 2 (continued)
86

Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
190 Sesbenia sesban (L.) Chittakatti Sh Lf Boiled (coconut Topical HC 9 (Graying Greying of 1.50 0.50
Merr. oil) Oral hair, hair growth)
Fabaceae EPH 52 Juice GIA 9 (Bile complaints)
191 Sida cordata Nilathuti He Wp/Rt Decoction Oral RSD 10 (Asthma) 2.17 0.67
(Burm.f) Borssum Fl Paste Oral GUA 8 (Diuretic, urinary
Malvaceae EPH 660 disorder) GIA 8 (Ulcer,
piles)
192 Sida rhombifolia L. Karunthatti He Rt Decoction Oral Fvr 12 (Fever) 1.00 0.33
var. rhombifolia
Malvaceae EPH 661
193 Solanum anguivi Kattuthuduvalai He Uft Roasted (Curry) Oral RSD 7 (Dry cough) 0.58 0.50
Lam.
Solanaceae EPH
180
194 Solanum nigrum L. Thaka keerai He Lf Cooked Oral DID 7 (Somatitis) 1.92 0.67
Solanaceae EPH Uft (curry) Oral RSD 6 (Wheezing)
181 Cooked GIA 10 (Stomachache,
ulcer)
195 Solanum surattense Kandangathri He Lf Decoction Oral RSD 12 (Cold and cough) 1.00 0.83
Bunn. f.
Solanaceae EPH
182
196 Solanum torvum Sw Sundaikkai Sb Ft Raw/cooked Oral LP 6 (Jaundice) 2.5 0.83
Solanaceae EPH GIA 9 (Ulcer,
183 anthelmintic)
RSD 12 (Cold and cough)
197 Solanum trilobatum Thuduvalai Cl Lf Raw (roasted)/ Oral RSD 12 (Cold and cough) 1.00 0.83
L. Uft juice
P. S. Tresina et al.

Solanaceae EPH
184
 Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
198 Sphaeranthus Oothuchedi He Lf Raw (squeezed) Topical SMSD 6 (Giddiness) 0.50 0.50
indicus L (smelled)
Asteraceae EPH 620
199 Sterculia urens. Vennaali Tr Es Roasted Oral GUA 6 (Lactation) 0.50 0.17
Roxb
Sterculiaceae EPH
598
200 Strychnos Kanjirai Tr St Raw Topical (kept GH 3 (Ill effect of evil 0.75 0.25
nux - vomica L. Sd Ash inside the spirit)
Loganiaceae EPH house) SMSD 6 (Rickets/Rgchitis)
333 Topical
201 Swertia angustifolia Milagainagai He Wp Powder Oral Pb 4 (Snake bite) 0.83 0.42
Buch. – Ham var. GIA 6 (Stomachache)
pulchella (Buch-
Ham ex D.Don)
Burkill
Gentianaceae EPH
234
202 Swertia corymbosa Milagainagai He Wp Powder Oral Pb 3 (Snake bite) 0.75 0.33
(Griseb.) Wight ex GIA 6 (Stomachache)
Clarke var.
corymbosa
Gentianaceae EPH
235
203 Symplocos Tulsimanimarm Tr Sd Raw Topical SMSD 6 (Rickets/Rgchitis) 0.50 0.33
cochinchinensis (Necklace)
(Lour.) Moore
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled…

subsp. laurina
(Retz) Nooteb
Symplocaceae EPH
87

421
(continued)
Table 2 (continued)
88

Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
204 Syzygium cumini Naval Tr Sd Powder Oral ED 12 (Diabetes) 1.00 0.91
(L.) Skeels
Myrtaceae EPH 422
205 Tabernaemontana Nandhiavattai Sh Pt Juice Topical ENT 10 (Improve vision) 0.83 0.67
heyneana Wall.
Apocynaceae EPH
115
206 Tamarindus indica Puli Tr Ft Raw Oral CSCD 8 (Cholesterol 1.58 0.67
L. Sd Raw Topical lowering)
Caesalpiniaceae Sb Decoction (Rubbed) Pb 5 (Scorpion sting)
EPH 23 Oral ENT 6 (Sore throat)
207 Tephrosia purpurea Kolingi He Rb Juice Oral GIA 7 (Bowel disorder) 0.58 0.17
(L) Pers.
Fabaceae EPH 116
208 Tephrosia villosa Kuruttukolingi He Lf Paste Topical DID 6 (Eczema) 0.50 0.17
(L.) Pers.
Fabaceae EPH 117
209 Terminalia bellirica Tani Tr Pc Decoction Oral Fvr 7 (Fever) 2.33 0.67
(Gaertn.) Roxb. Ft Raw RSD 7 (Asthma,
Combretaceae EPH Sb Decoction bronchitis)
613 GIA 6 (Anthelmintic)
GUA 7 (Diuretic)
210 Terminalia chebula Kadukai Tr Pc Paste Oral GIA 7 (Dysentry) 2.58 0.67
Retz. Sb Decoction GUA 7 (Diuretic)
Combretaceae EPH Ft Powder CSCD 5 (Cardio tonic)
614 GIA 12 (Laxative)
211 Thespesia populnea Puvarasu Tr Ts Paste Topical Pb 5 (Scropion sting) 0.42 0.33
(L.) Soland.ex
P. S. Tresina et al.

Correa
Malvaceae EPH 621
 Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
212 Tinospora cordifolia Enthalkodi Cl St Infusion/ Oral LP 6 (Jaundice) 3.16 0.91
(Willd) Miers ex St decoction Oral GIA 6 (Anthelmintic)
Hook. f & Thomas Rt Juice Oral Fvr 10 (Fever)
Menispermaceae Wp Juice Pb 6 (Antidote, snake bite,
EPH 622 scorpion sting)
SMSD 10 (Rheumatism)
213 Toddalia asiatica Milagaranai Sh Sb Powder Oral SMSD 10 (Rheumatism) 0.83 0.58
(L.) Lam var.
floribunda
Rutaceae EPH 678
214 Toddalia asiatica Milagaranai Sh Ft Juice Oral GIA 8 (Improve digestion) 0.67 0.50
(L.) Lam var.
gracilis
Rutaceae EPH 679
215 Tribulus terrestris L. Sirunerinji He Ft Decoction Oral GUA 12 (Diuretic, urinary 1.67 0.67
Zygophyllaceae Wp Juice Oral disease, antiurolithic
EPH 24 aphrodisiac)
GIA 8 (Anthelmintic)
216 Trichodesma Kavuthumbai He Lf Roasted Oral GIA 7 (Piles) 0.58 0.67
zeylanicum (Burm.
f.) R. Br.
Boraginaceae EPH
662
217 Tridax procumbens Mukoothielai He Lf Juice Topical SMSD 6 (Shoulder pain) 1.50 0.67
L Paste DID 12 (Eczema, wounds,
Asteraceae EPH 15 weapon injury)
218 Tylophora indica Nanchianuppan Cl Lf Juice Oral GUA 6 (Diuretic) 2.17 0.58
(Burm. F.) Merr palai Powder RSD 10 (Asthma,
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled…

Asclepiadaceae whooping cough)

EPH 663 Pb 10 (Snake bite)
89

(continued)
Table 2 (continued)
90

Botanical name,
family, voucher Vernacular Part Ailment category: no. of
S. no. specimen no. name Life form used Preparation Application use-reports Use value RFC
219 Vetiveria zizanioides Vetiver He Rt Decoction Topical DID 10 (Skin diseases) 1.67 0.58
(L.) Nash HC 10 (Hair tonic, hair
Poaceae EPH 21 loss)
220 Vitex altissima L. f. Mayila- Tr Sb Boiled Topical (bath) ENT 3 (Burning sensation 0.25 0.17
Verbenaceae EPH dunkuringi in the eyes)
664
221 Vitex negundo L. Vennochi Sh Lf Roasted Topical SMSD 4 (Headache) 2.00 0.75
Verbenaceae Wp Decoction (foment) GUA 3 (Diuretic)
EPH 22 Oral GIB 7 (Anthelmintic)
RSD 10 (Expectorant)
222 Waltheria indica L. Thuverpuli He Rb Infusion Oral GIA 5 (Bowel disorder) 0.42 0.25
Sterculiaceae EPH
602
223 Wrightia tinctoria Vetpalai Tr Lf Soaked Topical DID 5 (Eczema) 0.42 0.33
(Roxb.) R.Br. var. (coconut oil)
tinctoria
Apocynaceae EPH
534
224 Ziziphus xylopyrus Mullukottai Tr Sb Infusion Oral GIA 6 (Stomachache) 0.50 0.42
(Retz.) Willd
Rhamnaceae EPH
702
Part used: Lf Leaf, St Stem, Sb Stem bark, Rt Root, Rb Root bark, Ap Aerial part, Wp Whole plant, Ts Tender shoot, Yp Young plant, Bb Bulb, Hw Heart wood,
Ft Fruit, Uft Unripe fruit, If Inflorescence, Fl flower, Sd Seed, Isd Immature seed, Rc Rachis, Re Resin, Pc Pericarp, Es Endosperm, Yes Young endosperm, Sl
Stem latex, Lx Latex, Ss Stem sap, Rh Rhizome, Tu Tuber
Life form: He Herb, Sh shrub, Tr Tree, Cl Climber, Wcl Woody climber, CHe Climbing herb, She Succulent herb, Su Succulent
P. S. Tresina et al.
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled… 91

Series1, others, 32, 14% Series1, Euphorbiaceae, 14,

Series1, Araceae, 2, 1% Series1, Apiaceae, 10, 4%
Series1, Alliaceae, 2, 1% 6%
Series1, Aristolochiaceae, 2, Series1, Lamiaceae, 10, 4%
Series1, Oleaceae, 2, 1% 1%
Series1, Boraginaceae, 2, 1% Series1, Fabaceae, 10, 4%
Series1, Molluginaceae, 2, 1% Series1, Asclepiadaceae, 9, 4%
Series1, Begoniaceae, 2, 1%
Series1, Myrtaceae, 2, 1% Series1, Rubiaceae, 8, 3%
Series1, Crassulaceae, 2, 1%
Series1, Anacardiaceae, 2, 1% Series1, Agavaceae, 8, 3%
Series1, Cleomaceae, 2, 1%
Series1, Portulacaceae, 2, 1%
Series1, Arecaceae, 3, 1% Series1, Solanaceae, 7, 3%
Series1, Commelinaceae, 3,
1% Liliaceae, 3, 1%
Series1,
Series1, Acanthaceae, 7, 3%
Series1, Amaranthaceae, 3,
1%
Series1, Gentianaceae, 3, 1% Series1, Verbenaceae, 7, 3%
Series1, Combretaceae, 3, 1%
Series1, Convolvulaceae, 6, 3%
Series1, Sapindaceae, 3, 1%
Series1, Poaceae, 6, 3%
Series1, Burseraceae, 3, 1% Series1, Malvaceae, 5, 2%
Series1, Sterculiaceae, 3, 1% Series1, Caesalpiniaceae, 5,
2%
Series1, Menispermaceae, 3, Series1, Rutaceae, 5, 2%
1%
Series1, Capparaceae, 3, 1% Series1, Piperaceae, 5, 2%
Series1, Mimosaceae, 4, 2%
Series1, Zingiberaceae, 4, 2%
Series1, Cucurbitaceae, 4, 2%
Series1, Dioscoreaceae, 4, 2%
Series1, Apocynaceae, 4, 2%

Fig. 5 Families of medicinal plants used in the study area

Series1, Climber,
18%, 18%
Series1, Tree, 23%,
23%

Series1, Shrub, 12%,

12%

Series1, Herb, 47%,

47%

Fig. 6 Life form of reported common medicinal plants

16, 18] [42–46]. Leaves are dominantly used in making herbal preparations due to
the presence of bioactive constituents. Leaves were preferably used by the local
people because leaves are easily removed as compared to whole plant and roots that
also damage the growth of plants, which leads to the decline in population of medic-
inal plants [47, 48].
92 P. S. Tresina et al.

Series1, Rhizome , Series1, Tuber , 5%,

3%, 2% 4%
Series1, Stem latex,
5%, 4%
Series1, Endosperm,
3%,2%
Series1, Resin, 2%, 2%

Series1, Seed , 8%, 7% Series1, Leaf , 44%,

36%
Series1, Flower, 4%,
3%
Series1, Unripe fruit,
4%, 3%

Series1, Fruit, 10%, 8%

Series1, Bulb, 1%, 1%

Tender shoot, 2%

Series1, Whole plant,

3%, 2% Series1, Stem, 4%, 3%
Series1, Aerial part, 3%,
2% Stem bark, 9%
Series1, Root bark, 1%,
1% Series1, Root, 10%, 8%

Fig. 7 Percentage of plant parts used for the preparation of medicine

3.3 Method of Preparation and Method of Administration

of Plants

The preparation and utilization of plant parts used were grouped into nine categories
(Fig. 8). Among these, majority of the plant remedies were prepared by paste (35%)
followed by juice (24%), raw (24%), powder (16%), roasted (13%), decoction
(12%), boiled (8%) infusion (7%) and cooked (5%). Preparation of paste for the
treatment of ailments is a common practice among the other tribal people in global
level [8, 18, 49–53]. The paste was prepared by grinding the fresh or dried plant
parts in the water or oil. The decoction was obtained by boiling the plant parts in
water until the volume of the water is reduced to minimum or the required quantity.
Infusion was prepared by soaking fresh plant parts in water over night. The inhala-
tion was done by the burning of plant parts and the smoke is inhaled through nose.
Most of the informants suggested taking herbal medicines orally (74%), rather
than external (55%) use, in consistent with comparable investigations [54, 55]. For
topical use, the most important methods used were direct application of paste or
medicated oil and mostly dealt with diseases such as skin disorders, wounds, heel
crackers, poison bite, rheumatism, body pain, headache and hair growth. Most of
the medicines were given orally which is in agreement with some other studies
conducted elsewhere [8, 12, 17, 56, 57]
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled… 93

Series1, Cooked, 5%, Series1, Boiled, 8%, 6% Series1, Decoction,

3% 12%, 8%
Series1, Roasted, 13%,
9%

Series1, Infusion, 7%,

5%
Series1, Paste, 35%,
24%

Series1, Powder, 16%,

11%

Series1, Juice, 24%,

17% Series1, Raw , 24%,
17%

Fig. 8 Paliyar’s mode of administration for the preparation of medicine

3.4 Ingredients Added

The medicinal arrangements were completed out of a single plant part or in mixture
of many plant parts. In case of Paliyar’s medicinal preparation, single mode (184
plants) of preparation was dominating over the multiple modes (40 plants) of prepa-
ration. In some cases, Paliyar traditional healers too frequently use some adjuvants
such as honey, cow/goat milk, coconut oil, salt, gingery oil and palm jagging
(Table 3). Paliyar traditional healers used in the multiple mode preparation, more
than two or more plant parts for the preparation of medicine in the treatment of
single or multiple ailments. Similar findings were reported by some researchers
[16–18]. The use of multiple plant remedies among the traditional healers could be
attributed to the belief of synergic reactions where one plant could have a potentiat-
ing effect than other [50]. In this study, mostly fresh plant parts were used for the
preparation of medicine. Similar findings were reported by Assae et al. [58]; Revathi
et al. [59]; Yabesh et al. [18] and Xavier et al. [17]. Local traditional healers too
frequently used other adjuvant like honey, milk, sugar, salt and oil to improve the
acceptability and medicinal property of certain remedies. The preparation of paste/
medicated oil was commonly used by the oil of coconut and gingery oil. They were
using specific plant parts and specific dosages for the treatment of diseases and the
dose given to the patient depends on their age, physical status and health conditions.
Before giving treatment, the condition of the patients was observed deeply and then
they were given the prepared medium.
94 P. S. Tresina et al.

Table 3 Ingredients added for the preparation of herbal medicines by the Paliyar traditional healers
Other plants added in medicinal
Botanical name preparation Other ingredients added
A. columnaris Terminalia chebula Honey
A. indica – Calcium hydroxide
A. aspera – Lime
A. scholaris – Milk, rice fermented
water
A. sylvaticus Tamarindus indica Coconut oil
A. subdecurvens – Black soil
A. tagala – Urine of a child of
opposite sex
A. racemosus Curcuma longa –
B. pilosa var. minor Phyllanthus amarus Milk
B. javanica Dodonaea viscosa Coconut oil
C. separia – Lemon juice
C. perfoliata – Rice fermented water
C. halicacabum Oriza sativa, Salt
Cuminum cyminum, Solanum
trilobatum,
S. surattense, Ferula asafoetida
C. asiatica – Milk
C. quadrangularis Ferula asafoetida –
C. hirsutus – Milk
C. adansonii – Coconut oil
C. dactylon Cumimum cyminum –
C. cinerea – Milk, rice fermented
water
D. palmatus – Ghee
D. viscosa Bischofia javanica Coconut oil
E. discifera – Milk, rice fermented
water
E. alsinoides Ocimum tenuiflorum, Sida –
rhombifolia var. rhombifolia
F. indica – Milk
G. resinifera – Milk (dry cough)
G. rottleriformis – Milk
G. marantina Plectranthus barbatus –
G. superba – Coconut oil
H. isora – Coconut oil
H. indicus var. indicus – Milk
H. indicus var. pubescens – Milk
H. rigens var. rigens – Salt
H. vitifolius Allium cepa –
H. integrifolia Allium cepa –
(continued)
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled… 95

Table 3 (continued)
Other plants added in medicinal
Botanical name preparation Other ingredients added
I. obscura Allium cepa –
J. roxbhurghianum Curcuma longa (colic pain) Gingelly oil (oozing pus
from the ear)
K. grandiflora – Coconut oil, black soil
L. camara var. aculeata Allium cepa, Mimosa pudica –
L. inermis – Coconut oil
L. nicotianifolia var. Piper betle, Areca catechu –
nicotianifolia
M. indica Curcuma longa –
M. biflora – Coconut oil
M. pudica Lantana camara var. aculeata, –
Allium cepa
M. elengi – Rice fermented water or
milk
M. cerviana Phyllanthus emblica, Terminalia Palm jaggery
bellirica, T. chebula, Zingiber
officinale, Alpinia calcarata, Piper
longum, Ocimum tenuiflorum,
Mukia maderaspatana, Evolvulus
alsinoides
M. pentaphylla Curcuma longa, Plectranthus –
barbatus
M. pubescens var. pubescens Allium cepa, curcuma longa Coconut oil
M. concanensis Piper nigrum, Allium sativum –
M. atropurpurea Tamarindus indica –
M. maderaspatana – Calcium hydroxide
M. koenigii Cocos nucifera –
N. colebrookeana – Milk
P. daemia Allium sativam –
Erythrina variegata, Papaver
somniferum
P. amarus – Milk
P. maderaspatensis – Milk
P. minima Ferula asafoetida, Allium cepa Coconut oil, salt
P. argyrophyllum Trachyspermum ammi, Piper –
longum, Zingiber officinale
P. trioicum Vitex altissima Coconut oil
R. nasutus var. nasutus – Milk
S. auriculata Ferula asafoetida, Papaver –
somniferum
S. indicum – Palm jaggery
S. sesban – Coconut oil
S. rhombifolia var. rhombifolia Evolvulus alsinoides, Ocimum –
tenuiflorum
(continued)
96 P. S. Tresina et al.

Table 3 (continued)
Other plants added in medicinal
Botanical name preparation Other ingredients added
S. anguivi var. anguivi – Coconut oil
S. surattense Solanum trilobatum, Cuminum –
cyminum, Ferula asafoetida
S. trilobatum Coriandrum sativum Ghee, salt
S. urens – Ghee
S. nux - vomica – Castor oil
Coconut oil
S. angustifolia var. pulchella – Urine of a child of
opposite sex
S. corymbosa var. corymbosa – Urine of a child of
opposite sex
T. purpurea Ferula asafoetida
T. bellirica Phyllanthus emblica, Terminalia Palm jaggery
chebula, Zingiber officinale,
Alpinia calcarata, Piper longum,
Ocimum tenuiflorum, Mollugo
cerviana, Mukia maderaspatana,
Evolvulus alsinoides
T. chebula Curcuma longa –
T. populnea Allium cepa –
T. zeylanicum Allium cepa –
T. procumbens – Calcium hydroxide
V. altissima Piper trioicum Coconut oil
V. zizanioides Hemidesmus indicus var. indicus, Coconut oil
Hedyotis puberula
W. tinctoria var. tinctoria – Coconut oil

3.5 Plant-Use Value (UV)

The most commonly used species was Tinospora cordifolia with 38 use reports by
12 informants, giving the highest use value of 3.16. T. cordifoliais attributed to its
use in the treatment of various diseases, and it is well recognized by all informants
as the plant having medicinal value. T. cordifoliais is known for its immense appli-
cation in the treatment of various diseases in the traditional Ayurvedic literature.
Recently, the discovery of active components from the plant and their biological
function in disease control have activated interest across the globe [60].
Other important plants with high use value were Cynodon dactylon (37 use
reports by 12 informants with a UV value of 3.08) followed by Senna auriculata (36
use reports by 12 informants with UV of 3.00), Hemidesmus indicus var. pubescens
(35 use reports by 12 informants with a UV of 2.92), H. indicus var. indicus (34 was
reported by 12 informant with UV of 2.83), Terminalia chebula (31 use reports by
12 informants with a UV of 2.58), Andrographis paniculata, Azadirachta indica,
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled… 97

Coriandrum sativum, Cynbopogon citratus, Solanum torvum (each 30 use reports

by 12 informants with a UV of 2.50), Scoparia dulcis (29 use reports by 12 infor-
mants with a UV of 2.42), Abrus precatorius, Ficus racemosa, Mukia maderaspa-
tana, Terminalia bellirica (each 28 use reports by 12 informants with a UV of 2.33),
Basella alba var. alba, Evolvulus alsinoides, Pterocarpus marsupium (each 27 use
reports by 12 informants with a UV of 2.25), Sida cordata, Tylophora indica (each
26 use reports by 12 informants with a UV of 2.17), Cocculus hirsutus, Vitex
negundo (each 24 use reports by 12 informants with a UV of 2.00), Aegle marmelos,
Calotropis gigantea, Solanum nigrum (each 23 use reports by 12 informants with a
UV of 1.92), Blepharis maderaspatensis, Curculigo orchioides, Lawsonia inermis,
Mormordica charantia var. charantia, Morinda pubescens var. pubescens, Ocimum
tenuiflorum and Pergularia daemia (each 22 use reports by 12 informants with a UV
of 1.83). Most of these plants were frequently used by the Kani tribes in Tirunelveli
district, Tamil Nadu and Silent valley of Kerala [16, 18].
The plant with a very low use value was Pupalia lappacea var. lappacea, which
is reported by only two informants with a UV of 0.17, but the informant has regu-
larly used this plant in the treatment of unknown insect bite. In general, scarce avail-
ability of the plants in the study area leads to a low UV [61], as in the case of
GSWS. In the present study, plants reported with a low use value (three use reports
by 12 informants with a UV of 0.25) were Anisochillus carnosus, Globba maran-
tina, Hedyotis puberula, Heracleum rigens var. rigens, Hibiscus vitifolius, Knoxia
sumatrensis, Lobelia nicotianifolia var. nicotianifolia, Nothopegia colebrookeana,
Orthosipbon thymiflorus, Pimpinellea candolleana, Portulaca pilosa subsp. pilosa,
Premna corymbosa, Rubia cordifolia, Sansevieria roxburghiana and Vitex altissima.
Among them, Sansevieria r oxburghiana is reported to have a very low UV of 0.33
among the Kani tribes of Tirunelveli district in Tamil Nadu, India, for treating ear
ache [16], but Paliyars used for dental care.

3.6 Informant Consensus Factor (Fic)

To gain credibility, scientific studies that use traditional knowledge must be depend-
able. In ethnobotanical studies, consensus analysis provides a measure of reliability
for any given claim providing reliable evidence. General Fic of local knowledge for
disease treatment depended on the availability of the plant species in the study area
[51]. In order to use the informant consumer factor (Fic), the researchers clarified
the illnesses into broad categories (16 categories).
The Fic values in the present study ranged from 0.83 to 1.00 (Table 4). The cat-
egories with more than 200 use reports were gastrointestinal ailments (541 use
reports, 65 species) skeleto-muscular system disorders (451 use reports, 56 spe-
cies), dermatological infections/diseases (317 use reports, 48 species), respiratory
system diseases (278 use reports, 31 species) and genitor-urinary ailments (208 use
reports, 29 species). In the present study, oncology, hair care, circulatory system/
cardiovascular disease, cooling agents, endocrine disorder and fever had the highest
98 P. S. Tresina et al.

Table 4 Informant consensus factor for different ailment categories

Numbers of use Number of taxa Informant consensus
Ailment categories reporter (Nur) (Nt) factor (Fic)
Circulatory system/ 30 4 0.90
cardiovascular disease
(CSCD)
Cooling agents (CA) 126 14 0.90
Dental care (DC) 55 7 0.89
Dermatological 317 48 0.85
infections/diseases (DID)
Ear, nose, throat, eye 95 14 0.86
problems (ENT)
Endocrine disorder (ED) 112 12 0.90
Fever (Fvr) 82 9 0.90
Gastro-intestinal ailments 541 65 0.88
(GIA)
General health (GH) 70 11 0.86
Genito-urinary ailments 208 29 0.86
(GUA)
Hair care (HC) 59 6 0.91
Liver problem (LP) 54 7 0.89
Oncology (ONC) 4 1 1.0.00
Poisonous bite (Pb) 148 26 0.83
Respiratory system diseases 278 31 0.89
(RSD)
Skeleto – muscular system 451 56 0.88
disorder (SMSD)
2630 341

Fic of 1.00, 0.91 and each 0.90, respectively. In this study, oncology had the highest
Fic of 1.00, and it is in the agreement with the previous studies among the neigh-
bouring indigenous communities in Kerala. India [18]. In the present study, hair
disease and endocrinal disorders also had the highest Fic of 0.91 and 0.90, respec-
tively, whereas hair disease and endocrinal disease had the highest Fic of 1.00
among the Kani tribes in Thoduhills of Kerala [17] and Irulas in the Tanjore district
[62]. Syzygium cumini, Gymnema sylvestris and Momordica charantia var. chara-
nita had been very commonly used for the treatment of diabetes, and Micromeria
biflora, Eclipta prostrata and Pouzolzia zeylanica were used for the treatment of
hair problems.
The least agreement between the informants was observed in poisonous bite with
a Fic of 0.83 followed by dermatological infections/diseases with a Fic of 0.85; ear,
nose, throat and eye problems; general health and genitor-urinary ailment with a Fic
of 0.86, respectively. Thus, the study indicates that the degree of knowledge shared
by the users in the study is regarding the use of medicinal plants in the treatment of
ailments is high. Dermatological infections/diseases had the lowest Fic of 0.85, but
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled… 99

this ailment category ranked third in the number of use reports 317 and of taxa 48
attributed to this category. It may be due to the lack of communication among the
informants in the study area who are involved in the ailment group [61] or it may be
due to the lack of dermatological disorders among the studied tribal people [17].

3.7 Fidelity Level (FL)

The analysed categories with major agreements from the higlight and the most
important plants in each category are shown in Table 5. Of the reported plants, 39
species had the highest fidelity level of 100% most of which were used in the single
ailment category with multiple informants. The plants with the highest FL of 100%
were Ficus microcarpa (DID), Gloriosa superba, Tabernaemontana heyneana,
Commelina benghalensis, C. ensifolia (ENT), Syzygium cumini, Memecylon edule,
Eleusine coracana (ED), Sida rhombifolia var. rhombifolia, Limonia acidissima,
Lantana wightiana (Fvr), Amorphophallus sylvaticus, Indigofera wightii, Physalis
minima, Lepisanthes senegalensis (GIA), Caralluma adscendens var. attenauta,
C. lasiantha (GH), Cleome viscosa, Curculigo orchioides, Diplocyclos palmatus,
Ensete superbum, Hybanthus enneaspermus, Mimusopis elengi (GUA), Micromeria
bifolra, Eclipta prostrata (HC), Bidens pilosa var. minor, Phyllanthus amarus,
P. maderaspatensis (LP) Rhinacanthus nasutus var. nasutus, Justicia glauca (Pb)
Justicia adhatoda, Piper argyrophyllum, Solanum trilobatum, S. surattense (RSD),
Acorus calamus, Anisomeles malabarica, A. indica, Capparis zeylanica and
Mucuna atropurpurea (SMSD).
The maximum FL for the above plants indicated the 100% choice of the inter-
viewed informants for treating specific ailments, and this could be an indication of
their healing potential. In support to our study, 100% FL was reported in P. amarus
for jaundice among the herbal healers in Shimoga district of Karnataka [51], Malasar
tribes in Velliangarihills of Tamil Nadu [63], Kani tribes of Tirunelveli hills of
Western Ghats, Tamil Nadu, India [16] and Kani tribes in Thodu hills of Kerala,
South India [17].

3.8 Relative Frequency of Citation (RFC)

The RFC shows the local importance of every species with reference to the infor-
mants who cited uses of these plant species [39]. In the present study, it ranged from
0.91 to 0.17 (Table 2). Achyranthes aspera, Acorus calamus, Aegle marmelos,
Allium cepa, Aloe vera, Andrographis paniculata, Azadirachta indica, Calotropis
gigantea, Caralluma adscendens var. attenauta, C. lasiantha, Commelina bengha-
lensis, C. ensifolia, Coriandrum sativum, Curculigo orchioides, Cymbopogon citra-
tus, Cynodon dactylon, Eclipta prostrata, Eleusine coracana, Ensete superbum,
Gymnema sylvestre, Hemidesmus indicus var. indicus, H. indicus var. pubescens,
Table 5 Fidelity level (FL) values for common medicinal plants used by Paliyar traditional healers by ailment categories
100

Ailment categories Most preferred species with specific ailment FL (%)

Circulatory system/cardiovascular disorders Gymnema sylvestre (Cardiovascular disorder, obesity, lowering cholesterol) 42.86
Cooling agents Aloe vera (Body cooling) 57.14
Hemidesmus indicus var. indicus (Body cooling) 35.29
Hemidesmus indicus var. pubescens (Body cooling) 34.29
Dental care Ficus benghalensis var. benghalensis (Tooth strength) 54.55
Dermatological infections/diseases Ficus microcarpa (Heal craker) 100.00
Ficus racemosa (Heal craker) 42.86
Tridax procumbens (Eczema, wounds, weapon injury) 66.70
Ear, nose, throat, eye problems Gloriosa superba (Ophthalmic problem) 100.00
Tabernaemontana heyneana (Improve vision) 100.00
Commelina benghalensis (Removal of dust from the eyes) 100.00
Commelina ensifolia (Removal of dust from the eyes) 100.00
Abrus precatorius (Eye pain) 28.57
Endocrine disorder Syzygium cumini (Diabetes) 100.00
Memecylon edule (Diabetes) 100.00
Eleusine coracana (Diabetes) 100.00
Gymnema sylvestre (Diabetes) 57.14
Momordica charantia var. charantia (Diabetes) 54.51
Fever Sida rhombifolia var. rhombifolia (Fever) 100.00
Limonia acidissima (Fever) 100.00
Lantana wightiana (Fever) 100.00
Evolvulus alsinoides (Fever) 44.44
Andrographis paniculata (Fever) 40.00
Gastro-intestinal ailments Amorphophallus sylvaticus (Piles) 100.00
Indigofera wightii (Stomachache) 100.00
Physalis minima (Ulcer) 100.00
P. S. Tresina et al.

Lepisanthes senegalensis (Gastric complaints) 100.00

Ailment categories Most preferred species with specific ailment FL (%)
General health Caralluma adscendens var. attenauta (Refrigerant, weight loss) 100.00
Caralluma lasiantha (Refrigerant, weight loss) 100.00
Genito-urinary ailments Cleome viscosa (Postnatal disease, over bleeding) 100.00
Curculigo orchioides (Improve sexual vigour) 100.00
Mimusops elengi (Improve fertility in women) 100.00
Ichnocarpus frutescens (Stones in the gall bladder) 66.70
Diplocyclos palmatus (Abortion) 100.00
Ensete superbum (Kidney stone) 100.00
Hybanthus enneaspermus (Sexual vigor, male) 100.00
Hair care Micromeria biflora (Hair tonic, hair growth, hair loss) 100.00
Eclipta prostrata (Gray Greying of hair, hair loss) 100.00
Pouzolzia zeylanica (Dandruff) 42.86
Liver problem Bidens pilosa var. minor (Jaundice) 100.00
Phyllanthus amarus (Jaundice) 100.00
Phyllanthus maderaspatensis (Jaundice) 100.00
Oncology Cissus quadrangularis (Tumour-like swelling) 25.00
Poisonous bite Rhinacanthus nasutus var. nasutus (Snake bite) 100.00
Justicia glauca (Poison bite) 100.00
Respiratory system diseases Justicia adhatoda (Asthma, cold and cough, Respiratory problems) 100.00
Piper argyrophyllum (Cold and cough) 100.00
Solanum trilobatum (Cold and cough) 100.00
Solanum surattense (Cold and cough) 100.00
Skeleto – muscular system disorder Acorus calamus (Sedative, giddiness) 100.00
Anisomeles malabarica (Rheumatism, headache) 100.00
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled…

Anisomeles indica (Rheumatism, headache) 100.00

Capparis zeylanica (Arthritis) 100.00
Mucuna atropurpurea (Bone fracture) 100.00
101
102 P. S. Tresina et al.

Justicia adhatoda, Momordica charantia var. charantia, Morinda pubescens var.

pubescens, Pergularia daemia, Phyllanthus amarus, P. emblica, P. maderaspaten-
sis, Pterocarpus marsupium, Rhinacanthus nasutus var. nasutus, Scoparia dulcis,
Senna auriculata, Solanum surattense, S. torvum, S. trilobatum, Syzygium cumini,
Tinospora cordifolia and Vitex negundo were the most cited ethnomedicinal plant
species. These plants are dominant in the study area and have been known to local
cultures over a long period. Thus, their open properties for curing diverse diseases
have become popular and well established among the indigenous people. These
results are important as they could form an essential research baseline for following
evaluation of plant-derived medicinal compounds, potentially resulting in prospect
drug discoveries. The plant species having high RFC values should be subjected to
pharmacological, phytochemical and biological studies to evaluate and prove their
authenticity for the development of marketable products [64, 65]. These species
should be prioritized for conservation as their referred uses may place their popula-
tions under threat due to over harvesting.
As the values for the UV and RFC are dynamic and change with location and
with the knowledge of the people, so the values of UV and RFC may fluctuate from
area to area and even within the same area. Plants with lower UV and RFC values
are not essentially significant, but their low values may allocate that the young peo-
ple of the area are not conscious about the uses of these plants and therefore that the
understanding of their use is at risk of not being transmitted to future generation,
thus their knowledge may eventually disapper [65, 66].
The present study was the first quantitative ethnobotanical investigation to be
carried out in the study area; therefore, in the present study, results were compared
with similar quantitative studies carried out in other parts of the Southern Western
Ghats, India [8, 12, 15–18]. This disclosed that there were variations in most of the
cited species and their quantitative values. In a study carried out by Xaiver et al.
[17], Plumbago zeylanica (UV of 1.86) was the most cited species, while Yabesh
et al. [18] reported that Moringa oleifera (UV of 2.62), Curculigo orchioides (UV
of 2.5) and Vitex negundo (UV of 2.37) had the highest use value. These differences
can be most likely accounted for by variations in the vegetation and geo-climate of
the study area and emphasizes the need for more quantitative studies in a wide range
of locations, but particularly in the more remote, mountainous regions where there
is still a strong reservoir of ethnomedicinal knowledge amongst the indigenous
communities.

4 Conclusion

The present study revealed that traditional medicines were still in common use by
the Paliyar tribal communities and accurate knowledge of the plants and their
medicinal properties were held by only a few individuals in this community. Hence,
a need for detailed investigation of ethnobotanical knowledge held by each tribal
community is required before such valuable knowledge vanishes. Thus, the present
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled… 103

study would be useful in preventing the loss of ethno medicinal traditions of Paliyar
tribal Communities. The plants with high fidelity level, use values and relative fre-
quency citation in the present study may indicate the possible occurrence of valu-
able phytochemical compounds, and it requires a search for probable new drugs to
cure different ailments. The efficacy and safety of all the reported ethnomedicinal
plants need to be evaluated for phytochemical and pharmacological studies espe-
cially the plants with high informant consensus factor, use value, fidelity level and
relative frequency citation should be given priority to carry out bioassay and toxic-
ity studies. The present study suggested that the plants having higher use reports
such as Tinospora cordifolia, Cynodon dactylon, Senna auriculata, Hemidesmus
indicus var. indicus, H. indicus var. pubescens, Terminalia chebula and Andrographis
paniculata need further investigation in regard to phytochemical and associated
pharmacological studies.

Acknowledgement The authors express their thanks to Paliyar tribes in the study area for reveal-
ing their traditional knowledge.
Conflict of Interest No conflicts of interest were reported by the authors.

References

1. Hassan N, Nisar M, Ur Rehman Kakar S, Ul Hassan F, Zhong Z et al (2017) Determination of

informant consensus factor of medicinal plants used as therapy in district Dir Lower Pakistan.
J Med Plant Stu 5:183–188
2. Ahmad M, Sultana S, Fazi-i-Hadi S, Ben Hadda T, Rashid S et al (2014) An ethnobotanical
study of medicinal plants in high mountainous region of Chail valley (District Swat- Pakistan).
J Ethnobio Ethnomed 10:4265–4210
3. World Health Organization (WHO) (2008) Address at the WHO congress on traditional medi-
cine (DR. Margaret Chan). Retrieved from: www.who.int/d2/speeches/2008/20081107/en/.
Accessed 16 June 2015
4. Mahwasane ST, Middleton L, Boaduo N (2013) An ethnobotanical survey of indigenous
knowledge on medicinal plants used by the traditional healers of the Lwamondo area, Limpopo
province, South Africa. South Afr J Bot 88:69–75
5. Omwenga EO, Hensel A, Shitandi A, Goycoolea FM (2015) Ethnobotanical survey of tradi-
tionally used medicinal plants for infections of skin, gastrointestinal tract, urinary tract and the
oral cavity in Borabu sub-county, Nyamira county, Kenya. J Ethnopharmocol 176:508–514
6. Baydoun S, Chalak L, Dalleh H, Amold N (2015) Ethnopharmacological survey of medici-
nal plants used in traditional medicine by the communities of Mount Hermon, Lebanon. J
Ethnopharmacol 173:139–156
7. Kola P, Metowogo K, Manjula SN, Katawa G, Elkhenany H et al (2022) Ethnopharmacological
evaluation of antioxidant, anti-angiogenic, and anti-inflammatory activity of some traditional
medicinal plants used for treatment of cancer in Togo/Africa. J Ethnopharmacol 283:283.
https://doi.org/10.1016/j.jep.2021.114673
8. Prabhu S, Vijayakumar S, Yabesh JEM, Prakashbabu R, Murugan R (2021) An ethnobotani-
cal study of medicinal plants used in Pachamalai Hills of Tamil Nadu. India J Herb Med 25.
https://doi.org/10.1016/j.hermed.2020.100400
104 P. S. Tresina et al.

9. Singh B, Singh B, Kishor A, Singh S, Bhat MN et al (2020) Exploring plant-based ethno-

medicine and quantitative ethnopharmacology: medicinal plants utilized by the population of
Jasrota Hill in Western Himalaya. Sustainability 12:7526. https://doi.org/10.3390/su12187526
10. Lalitha Rani S, Kalpana Davi V, Tresina PS, Maruthupandian A, Mohan VR (2011)
Ethnomedicinal plants used by Kanikkars of Agasthiamalai Biosphere Rereve, Western Ghats.
J Ecobiotechnol 3:16–25
11. Maruthupandian A, Mohan VR (2012) Ethnomedicinal plants used by Palliyar in Sirumalai
Hills, Western Ghats, Tamil Nadu for the treatment of various poisonous bites. Int J Curr Tr
Res 1:87–94
12. Prabhu S, Vijayakumar S, Yahesh JEM, Ravichandran K, Sakthivel B (2014) Documentation
and quantitative analysis of the local on medicinal plants in Kalrayan hills of Villupuram dis-
trict, Tamil Nadu, India. J Ethnophamacol 157:7–20
13. Kannadhasan M, Valarmathi S, Raju K (2016) Ethnomedicinal study of medicinal plants used
by Malayali in Pachaimalai Hills area of Tiruchirapalli district, Tamil Nadu, India. J Eng Res
App 6:1–5
14. Asif M, Haq SM, Yaqoob U, Hassan M, Jan HA (2021) Ethnobotanical study of indigenous
knowledge on medicinal plants used by the tribal communities in tehsil “Kannah” of district
Kupwara (Jammu and Kashmir) India. Ethnobot Resd & App 21:62. https://doi.org/10.32859/
era.21.02.1.14
15. Pandikumar P, Chellappandian M, Mutheeswaran S, Ignacimuthu S (2011) Consensus of local
knowledge on medicinal plants among traditional healers in Mayiladumparai block of Theni
district, Tamil Nadu, India. J Ethnopharmacol 134:354–362
16. Ayyanar M, Ignacimuthu S (2011) Ethnobotanical survey of medicinal plants commonly used
by Kani tribals in Tirunelveli Hills of Western Ghats, India. J Ethnopharmocol 134:851–864
17. Xavier TF, Kannan M, Lija L, Auxillia A, Freeda Rose AK, Senthilkumar S (2014)
Ethnobotanical study of Kani tribes in Thoduhills of Kerala, South India. J Ethnopharmacol
152:78–90
18. Yabesh JE, Prabhu S, Vijayakumar S (2014) An ethnobotanical study of medicinal plants used
by traditional healers in silent valley of Kerala, India. J Ethnopharmacol 154:774–789
19. Raj AJ, Biswakarma S, Pala NA, Shukla G et al (2018) Indigenous uses of ethnomedicinal
plants among forest-dependent communities of Northern Bengal, India. J Ethnobio Ethnomed.
14:8. https://doi.org/10.1186/s13002-­018-­0208-­9
20. Kumar M, Rawat S, Nagar B, Kumar A, Pala NA et al (2021) Implementation of the use of
ethnomedicinal plants for curing diseases in the Indian Himalayas and its role in sustainability
of livelihoods and socioeconomic development. Int J Environ Res Pub Health 18:1509. https://
doi.org/10.3390/ijerph18041509
21. Kumar M, Radha DH, Prakash S, Rathore S et al (2021) Ethnomedicinal plants used in the
health care system: survey of the Mid Hills of Solan district, Himachal Pradesh, India. Plan
Theory 10:1842. https://doi.org/10.3390/plants10091842
22. Maruthapandian A, Mohan VR (2010) Observation of ethnomedicinal plants from Sirumalai
hills in Western Ghats of Tamil Nadu, India. J Herbal Med Toxicol 4:89–92
23. Sutha S, Mohan VR, Kumaresan C, Mohan VR (2010) Ethnomedicinal plants used by the
tribals of Kalakad-Mundanthurai Tiger Reserve (KMTR), Western Ghats, Tamil Nadu for the
treatment of rheumatism. Indian J Trad Know 9:502–509
24. Subaramanian A, Mohan VR, Maruthapandian A, Kalidass C (2010) Ethnomedicobotany of
the Valaiyans of Madurai district Tamil Nadu. J Econ Taxon Bot 34:363–379
25. Mohan VR, Arnish Abragam D, Kalidass C (2010) Ethnomedicobotany of the Palliyars of
Saduragiri hills, Western Ghats, Tamil Nadu. J Econ Taxon Bot 34:658–662
26. Maruthupandian A, Mohan VR, Kottaimuthu R (2011) Ethnomedicinal plants used for the
treatment of diabetes and jaundice by Palliyar tribals in Sirumalai hills, Western Ghats, Tamil
Nadu, India. Indian J Nat Prod and Resou 2:493–497
27. Aadhan K, Anand SP (2017) Traditional herbal medicines for the treatment of snake bite and
scorpion sting by the Paliyar’s tribes of Sathuragiri hills. J Med Plants Stu 5:1–5
An Ethnobotanical Study of Medicinal Plants Used by Traditional Healers in Grizzled… 105

28. Balakrishnan V, Kalasalingam M (2018) Ethnomedicinal survey in the Paliyar hamlet of

Sathuragiri hills is Virudhunagar district, Tamil Nadu State, India. Res Rev J Bot 7:1–10
29. Mutheeswaran S, Mariappan A, Ragavendran K, Porchezhiyan V et al (2021) Quantitative
ethnobotany of Paliyar tribe in Sathuragiri hills, Virudhunagar district, Tamil Nadu, India. Adv
Trad Med. https://doi.org/10.1007/s13596-­021-­00609-­z
30. Sankarasivaraman K (2000) Ethnobotanical wealth of Paliyar tribe in Tamil Nadu. Ph.D. Thesis
Manonmaniam Sundaranar University, Tamil Nadu
31. Dehmen F (1908) The Paliyans, A hill-tribe of the Palni hills (South India). Anthropos 3:19–31
32. Jain SK (1964) The role of botanist in folklore research. Folklore 5:145–150
33. Gamble JS (1935) The Flora of the presidency of Madras. Adlasd & Son Ltd, London
34. Matthew KM (1983) The Flora of the Tamil Nadu Carnatic. The Rapinat Herbarium, 3. St.
Josephs College, Tiruchirapalli, India; p.1xxxiv (2154)
35. Heinrich M, Ankli A, Frei B, Weimann C, Stichor O (1998) Medicinal plants in Mexico: heal-
ers' consensus and cultural importance. Soc Sci Med 47:91–112
36. Phillips O, Gentry AH, Reynel C, Wilkin P, Galvez-Durand BC (1994) Quantitative ethno-
botany and Amazonian conservation. Cons Biol 8:225–248
37. Friedmen J, Yaniv Z, Dafni A, Palewitch D (1986) A preliminary classification of the healing
potential of medicinal plants, based on a rational analysis of an ethnopharmacological field
survey among Bedouins in the Negev desert, Israel. J Ethnopharmacol 16:275–287
38. Srithi K, Balslev H, Wangpakapattanawong P, Srisanga P, Trisonthi C (2009) Medicinal plant
knowledge and its erosion among the Mien (Yao) in northern Thailand. J Ethnopharmacol
123:335–342
39. Vitalini S, Iriti M, Puricelli C, Ciuchi D, Segale A, Fico G (2013) Traditional knowledge on
medicinal and food plants used in Val San Giacomo (Sondrio, Italy)–an alpine ethnobotanical
study. J Ethnopharmacol 145:517–529
40. Singh GA, Kumar A, Tewari DD (2012) An ethnobotanical survey of medicinal plants used in
Terai forest of western Nepal. J Ethnobiol Ethnomed 8:19
41. Shrestha N, Shrestha S, Koju L, Shrestha KK, Wang Z (2016) Medicinal plant diversity and
traditional healing practices in eastern Nepal. J Ethnopharmacol 192:292–301
42. Kadir MF, Karmoker JR, Alam MR, Jahan SR, Mahbub S, Mia MMK (2015) Ethno phar-
macological survey of medicinal plants used by traditional healers and indigenous people in
Chittagorg hill tracts, Bangladesh, for the treatment of snake bite. Evi based Comple Alter
Med. 2015:1. https://doi.org/10.1155/2015/871675
43. Ullah A, Hassan N, Amin R, Khan A, Shi L, Li M (2018) Quantitative ethnobotanical survey
of medicinal plants used as remedy in Mera, district Charasadda, KP, Pakistan. J Biodivers
Environ Sci 12:163–173
44. Faruque MO, Uddin SB, Barlow JW, Hu S, Dong S et al (2018) Quantitative ethnobotany of
medicinal plants used by indigenous communities in the Bandarban district of Bangladesh.
Front Pharmacol 9:40. https://doi.org/10.3389/fphar.2018.00040
45. Buwa-Komoreng LV, Mayekiso B, Mhinana Z, Adeniran AL (2019) An ethnobotanical and
ethnomedicinal survey of traditionally used medicinal plants in Seymour, South Africa: an
attempt toward digitization and preservation of ethnic knowledge. Pharmacogn Mag 15:15–123
46. Ahmad S, Zafar M, Shinwari S, Ahmad M, Shinwari ZK et al (2020) Ethno-medicinal plants
and traditional knowledge linked to primary health care among the indigenous communities
living in western hilly slopes of Dera Ghazi Khan, Pakistan. Pak J Bot 52:519–530
47. Giday M (2018) Traditional knowledge of people on plants used as insect repellents and insec-
ticides in Raya-Azebo district, Tigray region of Ethiopia. Ind J Trad Know 17:336–343
48. Pyakurel D, Sharma IB, Ghimine SK (2017) Trade and conservation of medicinal and aromatic
plants in western Nepal, Botanica Orientalis. J Plant Sci 11:27–37
49. Amri E, Eisangan DP (2012) Ethnomedicinal study of plants used in villages around Kimboza
forest reserve in Morogoro, Tanzania. J Ethnobiol Ethnomed 8:1
50. Giday M, Asfaw Z, Woldu Z (2010) Ethnomedicinal study of plants used by Sheko ethnic
group of Ethiopia. J Ethnopharmacol 132:75–85
106 P. S. Tresina et al.

51. Rajakumar N, Shivanna MB (2009) Ethno-medicinal application of plants in the eastern region
of Shimoga District, Karnataka, India. India J Ethnopharmacol 126:64–73
52. Ullah M, Usman Khan M, Mahmood A, Hussain M, Mehmood Wazir S (2013) An ethnobotan-
ical survey of indigenous medicinal plants in Wana district South Waziristanagency, Pakistan.
J Ethnopharmacol 150:918–924
53. Hussain S, Hussain W, Nawar A, Badshah L, Ali A, Ullah S et al (2022) Quantitative ethno-
medicinal study of indigenous knowledge on medicinal plants used by the tribal communi-
ties of central Kurram, Khyber, Pakhtunkhwa, Pakistan. Ethnobot Res App 23:5. https://doi.
org/10.32859/era23.5.1-­31
54. Kayani S, Ahmad M, Sultana S, Khan Shinwari Z, Zafar M, Yaseen G et al (2015) Ethnobotany
of medicinal plants among the communities of Alpine and Sub-alpine regions of Pakistan. J
Ethnopharmacol 164:186–202
55. Sadat-Hosseini M, Farajpour M, Boroomand N, Solaimani-Sardou F (2017)
Ethnopharmacological studies of indigenes medicinal plants in the South of Kerman, Iran. J
Ethnopharmacol 199:194–204
56. Ribeiro A, Romeiras MM, Tavares J, Faria MT (2010) Ethnobotanical survey in Canhane
village, district of Massingir, Mozambique: medicinal plants and traditional knowledge. J
Ethnobiol Ethnomed 6:33. http://www.ethnobiomed.com/content161133
57. Khan I, Abd Elsalam NM, Fouad H, Tariq A, Ullah R et al (2014) Application of ethnobotani-
cal indices on the use of traditional medicines against common diseases. Evi based Comple
Alter Med 2014:1. https://doi.org/10.1155/2014/635371
58. Assae A, Akwetey GA, Achel DA (2010) Ethnopharmacological use of herbal remedies for the
treatment of malaria in the Dangme West District of Chinna. J Ethnopharmacol 129:367–376
59. Revathi P, Parimelazhagan T, Manian S (2013) Ethnomedicinal plants and novel formulations
used by Hooralis tribe in Sathyamangalam forests, Western Ghats of Tamil Nadu, India. J Med
Plants Res 7:2083–2097
60. Saha S, Ghosh S (2012) Tinospora cordifolia: one plant, many roles. Anc Sci Life 31:151–159
61. Rokaya MB, Munzbergova Z, Timsina B (2010) Ethnobotanical study of medicinal plants
from the Humla district of western Nepal. J Ethnopharmacol 130:485–504
62. Regupathy S, Newmaster S (2009) Valorizing the ‘Irulas’ traditional knowledge of medicinal
plants in the Kodiakkarai Reserve Forest, India. J Ethnobiol Ethnomed 5:10
63. Regupathy S, Steven NG, Maruthakkutti M, Velusamy B, Ul Huda MM (2008) Consensus of
the Malasars traditional aboriginal knowledge of medicinal plants in the Velliangiri holy hills,
India. J Ethnobiol Ethnomed 4:8
64. Mukherjee PK, Nema NK, Venkatesh P, Debnath PK (2012) Changing scenario for promotion
and development of Ayurveda-way forward. J Ethnopharmacol 103:25–35
65. Amjad MS, Qaeem MF, Ahmed I, Khan SU, Chaudhari SK et al (2017) Descriptive study of
plant resources in the context of the ethnomedicinal relevance of indigenous flora: a case study
from Toli Peer National Park, Azad Jammu and Kashmir, Pakistan. PLoS One 12. https://doi.
org/10.1371/journal.pone.0171896
66. Camou-Guerrero A, Reyes-Garcia V, Martinez-Ramos M, Casas A (2008) Knowledge and
use value of plant species in a Raramuri community: a gender perspective for conservation.
Human Ecol 36:259–272
Ethnomedicinal Plants Used by Irula
Tribal Settlement of Attappady
in Palakkad District, Kerala, India

C. V. Jayalekshmi, Reshma K. Ramesh, M. Vijai, and V. Suresh

1 Introduction

Biologically active compounds present in plants account for their use in traditional
medicinal systems for centuries. 80% of the world’s population depends on plants
for their healthcare (World Health Organization,1993). Traditional communities are
intimately familiar with the use of medicinal plants, which is unknown the modern
society [1, 2]. This practice of health care is based on the belief and experience of the
traditional people, which is a part of their tradition and culture. The modern health
care system relies mainly on plant-based ingredients. The traditional use of wild
plants not only provides folk medicines for the health care system but also as a food
source for local communities. The ethnic people practiced indigenous system of folk
medicines for centuries and their knowledge about the usage and maintenance of
plants was passed from generation to generation especially through mouth [3–5].
Kerala is lying in the southern end of the Indian subcontinent. The state is known
for its cultural and biological diversity. As per the 2011 Census, the tribal popula-
tion in Kerala is 364,189, which is 1.14% of the total population of the state. The
decadal growth of tribal population in the state has been 13.75% [6, 7].
Attappadi is part of three states-Kerala, Tamil Nadu and Karnataka. It is located
in the mid-eastern part of Kerala. It is a segment of Western Ghats ranges. Attappadi
can be considered as an extension mountain valley, which has an area of 731 sq.km.
Attappadi is a part of Palakkad district, adjoining Coimbatore and Nilgiri districts of
Tamil Nadu. The population of Attappadi consists of both tribes and non-­tribes [8, 9].

The original version of this chapter was revised. The correction to this chapter is available at
https://doi.org/10.1007/978-3-031-28780-0_65

C. V. Jayalekshmi · R. K. Ramesh · M. Vijai · V. Suresh (*)

Post Graduate and Research Department of Botany, Government Victoria College,
Palakkad, Kerala, India

© The Author(s), under exclusive license to Springer Nature 107

Switzerland AG 2023, Corrected Publication 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_4
108 C. V. Jayalekshmi et al.

The name Attappadi means atta, the blood leach and pad, the habitation. There
are three different major tribal communities in Attappadi, they are Irulars, Mudugars
and Kurumbas. Tribal groups in Attappadi are the most backward than other tribal
communities of Kerala. Their culture is traditional in nature and they depend mainly
on land and forest for their livelihood [9].
Tribal settlements in Attappadi are known as Ooru (hamlet). There are 187 ham-
lets in Attappadi. The Irulas were inhabiting the plains and low elevations of
Attappadi constituted the majority tribal population [9, 10]. The Attappadi Block is
divided into the three Gram Panchayats—Agali, Pudur and Sholayur. The number
of Irula oorus is 53, 43 and 44 in Agali, Pudur and Sholayur, respectively [8].
Traditional knowledge of human health and medicine has recently become a
universal consideration. The value of medicinal plants and herbs is being lost due to
lack of awareness and deforestation. The ethnobotanical study is the collection of
ethnobotanical information and documentation of traditional knowledge. It has
gained importance as it saves knowledge that is transferred from generation to gen-
eration only inside a particular community. The present study aims to document the
plants used by Irula tribes of Palakkad district of Kerala state.

2 Materials and Methods

2.1 Study Area

The study was conducted in Attappadi, one of the tribal areas of Kerala, which is
part of the Western Ghats of India. The valley is an extensive east sloping plateau on
the Western Ghats of Kerala that covers an area of 745 km2, which is located in the
Mannarkad taluk of Palakkad district. Geographic coordinates of Attappadi are 3“N
and 76°33’43.4”E [9, 11].
Attappadi is a part of the Nilgiri Biosphere Reserve. The population of Attappadi
consists of adivasis and non-adivasis. Irulas, Mudugas and Kurumbas are three
tribal groups inhabiting the region of which, Irulas inhabiting the plains and low
elevations, constitute the majority (79%). There are 187 hamlets in Attappadi, which
are inhabited by both the adivasis and the non- adivasis. Each Ooru contains, on
average, 50 houses. The tribal people in attappadi were most backward among the
tribal groups of Kerala and their livelihood depends mainly on land and forest. The
Attappadi comprises three Gram Panchayats – Agali, Sholayur and Pudur [8, 12].

2.2 Data Collection

The data collection was done through field surveys conducted at the study area. It
was carried out by interviewing traditional healers in different locations of Irula
tribal settlement in a period between February to July 2020. Questionnaires were
structured for the interview and were applied to 29 informants (12 men and 17
Ethnomedicinal Plants Used by Irula Tribal Settlement of Attappady in Palakkad… 109

women) who are in age between 30 and 70 years to gather information about plants
that are used by the tribal people for various purposes. The informants were selected
based on their popularity among other local people with respect to the knowledge
about medicinal plants.
Data such as local names, uses for various ailments and disease were collected
from traditional healers and other tribes through individual interviews during the
survey. The plants were also documented by using digital photography, and voucher
specimens were collected along with the survey and the collected specimens were
identified using different floras. Voucher specimens of this study have been depos-
ited at the Herbarium of Department of Botany, Government Victoria College,
Palakkad. The botanical names of the plant specimens were updated according to
the Plant List.

2.3 Analysis of Collected Ethnobotanical Data

The ethnobotanical information collected was analysed for obtaining the impor-
tance of individual species. The data obtained were classified into relatively well-­
defined ethnomedical categories to get a clear picture about the use of particular
plant species.
Informant Consensus Factor (Fic)
The informant consensus factor (Fic) was used to see if there was agreement in the
use of plants in the ailment categories between the plant users in the study area. The
Fic was calculated.
by the following formula:

Nur  Nt
Fic 
Nur 1

Fic, which is the ratio of the number of use reports in each category (Nur) minus
the number of taxa used for a particular ailment category by all informants (Nt) and
the number of use reports in each category minus one. Thus, Fic value close to 1 was
taken as an indication of high intracultural consensus, i.e. more healers use the same
species, whereas a value close to zero was regarded as a low probability of medici-
nal use [13].

3 Results and Discussions

The present study aimed to document the plants used by the Irula tribal settlement
of Attappady, Palakkad district. Information regarding the use of medicinal plants
was collected from 29 informants, 12 males and 17 females aged about 30–70 years.
Informants were traditional healers and local people. From the study,
110 C. V. Jayalekshmi et al.

ethnobotanical information of 126 plant species was recorded. The most cited fami-
lies were Leguminosae, Apocynaceae, Amaranthaceae, Euphorbiaceae and
Lamiaceae. The photographs of some plants cited in the study are given in Fig. 1.
The Irula tribes use a lot of plants as food, medicine, fodder and for making mats,
hut, etc. Some plants are grown as sacred plants, such as Aerva lanata, Azadirachta
indica, Cynodon dactylon, Ficus religiosa and Ocimum sanctum.
The information on plants used by Irula tribes is given in Table 1. Scientific name,
family, common name and medicinal importance of plants are documented in Table 1.

Fig. 1 Plants cited in the study

Ethnomedicinal Plants Used by Irula Tribal Settlement of Attappady in Palakkad… 111

Table 1 Plants cited in the study

Sl. Medicinal use/
No. Scientific name Family Common name cures Other uses
1 Acacia caesia Leguminosae Arapu maram Good for hair
(L.) Willd.
2 Acacia pennata Leguminosae Seenkey dag Stomach pain,
(L.) Willd. control ring worms
3 Acalypha Euphorbiaceae Kattumunja Fever
fruticosa Forssk.
4 Achyranthes Amaranthaceae Nayuruvi Asthma,
aspera L. abortifacient,
diuretic, fever,
child care
5 Acorus calamus Acoraceae Vambu Cold, speech
L. clearness, fever
6 Aerva lanata (L.) Amaranthaceae Siru pula Cough, astringent
Juss.
10 Ageratum Asteraceae Communist Ulcer,
conyzoides (L.) apcha anti-inflammatory
L.
11 Allium cepa L. Amaryllidaceae Vengam Ulcer, oral Veterinary
infection, medicine
dysentery
12 Aloe vera (L.) Xanthorrhoeaceae Chothukathala Menstrual Veterinary
Burm. f. problem, face medicine
wash, dysentery
13 Amaranthus Amaranthaceae Porikeeri Cure ulcer,
caudatus L. stomach pain
14 Amaranthus Amaranthaceae Mullukeerrai Stomach pain,
spinosus L. ulcer
15 Amaranthus Amaranthaceae Pattikeeri Cure blood
viridis L. problems,
intestinal problems
16 Amomum Zingiberaceae Alum Anti-inflammatory Cosmetic
subulatum Roxb. preparation
17 Anacardium Anacardiaceae Mundhiri Snake bite and
occidentale L. anorexia
18 Angiopteris Marattiaceae Child care
evecta (G. Forst.)
Hoffm
19 Annona Annonaceae Sithapalam Mental depression,
squamosa L. sedative
20 Asparagus Asparagaceae Thannervettan Throat infection,
racemosus Willd. fever
21 Azadirachta Meliaceae Vembu Anti-inflammatory,
indica A. Juss. chickenpox, skin
problems
(continued)
112 C. V. Jayalekshmi et al.

Table 1 (continued)
Sl. Medicinal use/
No. Scientific name Family Common name cures Other uses
22 Bambusa bambos Poaceae Mungil Anti-inflammatory,
(L.) Voss febrifuge
23 Basella alba L. Basellaceae Vasala Fever, stimulant
and expulsion of
worms, used to
treat back pain
24 Basella Basellaceae Sivpuvasali Useful to diuretic,
paniculata gonorrhoea
Volkens
25 Bauhinia Leguminosae Ashamaram. Bark and fibre Veterinary
racemosa Lam. medicine
26 Bauhinia Leguminosae Mantharia Cough, stomach
variegata L. problem
27 Boerhavia Nyctaginaceae Cerandhia Stomach ulcer,
diffusa L. antibacterial,
diuretic,
anti-helminthic
28 Brassica juncea Brassicaceae Kaduku Treat inflammation
(L.) Czern. Treat abdominal
pain
29 Cajanus cajan Leguminosae Thuvarai Jaundice, oral
(L.) Millsp. problem
30 Calotropis Apocynaceae Losandi Anti-inflammatory
gigantea (L.)
Dryand.
31 Capsicum annum Solanaceae Mulaku Treatment of ulcer,
L. cancer,
anti-inflammatory
32 Cardiospermum Sapindaceae Stomach upset,
halicacabum L. headache
33 Carica papaya Caricaceae Pappaly Stomach ache,
L. digestive problem
34 Cascabela Apocynaceae Arali maram Controls back pain
thevetia (L.)
Lippold
35 Cassia fistula L. Leguminosae Kanikundri Febrifuge,
astringent, used
against ringworm,
jaundice
36 Cassia tora L. Leguminosae Thira Stomach pain, Veterinary
medicine
37 Catharanthus Apocynaceae Nithyakalyani Anti-neoplastic,
roseus (L.) sedative
G. Don
(continued)
Ethnomedicinal Plants Used by Irula Tribal Settlement of Attappady in Palakkad… 113

Table 1 (continued)
Sl. Medicinal use/
No. Scientific name Family Common name cures Other uses
38 Celastrus Celastraceae Laxative, digestive
paniculatus problems, skin
Willd. disease
39 Centella asiatica Apiaceae Vallarai Dysentery, Veterinary
(L.) Urb stomach pain medicine
increases memory
power, ulcer
40 Chamaecrista Leguminosae Gumul Joint pain and
mimosoides (L.) rheumatism
Greene
41 Chromolaena Asteraceae Communist Healing wound
odorata (L.) pacha and burns quickly
R. M. King & cure diarrhoea,
H. Rob. anti-viral,
anti-inflammatory
42 Cinnamomum Lauraceae Karuvapatta Bark used Flavouring
verum J. Presl digestion agent
43 Cissus Vitaceae Parandi Breathing trouble Veterinary
quadrangularis in cattle, stomach medicine
L. ache, dysentery
44 Citrus limon (L.) Rutaceae Elumichai Indigestion, cold
Osbeck and fever
45 Clitoria ternatea Leguminosae Shankupushpam. Antihelminthic
var. ternatea L. and Brain tonic
46 Cocos nucifera Arecaceae Thangai Antiviral and Coir
L. anti-fungal, making
indigestion
47 Colocasia Araceae Chembu Internal
esculenta (L.) haemorrhage
Schott.
48 Cucurbita pepo Cucurbitaceae Sacarakodi Fever, joint pain,
L. dysentery
49 Cuminum Apiaceae Chiragam Anti-helminthic,
cyminum L. stomach pain,
digestive problems
50 Curcuma Zingiberaceae Kasthuri manjal Antiviral,
aromatica Salisb. antifungal, skin
problems
51 Curcuma longa Zingiberaceae Manjal Itching, skin Veterinary
L. problem, antiviral, medicine
anti-fungal,
anti-microbial,
hepatic ulcer
52 Cycas circinalis Cycadaceae Inthpani Stomach pain
L.
(continued)
114 C. V. Jayalekshmi et al.

Table 1 (continued)
Sl. Medicinal use/
No. Scientific name Family Common name cures Other uses
53 Cyclea peltata Menispermaceae Kurupan Stomach pain,
(Lam) Hook. f. child care,
& Thomson anti-inflammatory
54 Cynodon Poaceae Arugampul Epistasis, Cattle feed
dactylon (L.) gastro-intestinal
Pers. problems
55 Cyperus rotundus Cyperaceae Koripul Febrifuge, diuretic
L. and child care
56 Datura metel L. Solanaceae Sipukaichedi Headache,
epilepsy, narcotic
57 Desmodium Leguminosae Orila Asthma, cough,
gangeticum (L.) diuretic, fever
DC.
58 Dioscorea Dioscoreaceae Nurankizhangu. For child care,
pentaphylla L. blood tonic
59 Diplazium Athyriaceae Pannal Used for the
esculentum treatment of
(Retz.) Sw vomiting, asthma
and fever.
60 Eclipta prostrata Asteraceae Kuyuni Laxative, hair
L. tonic,
anti-inflammatory
61 Eleusine Poaceae Ragi Increase strength
coracana (L.) of child bone
Gaertn.
62 Eucalyptus Myrtaceae Eucally Joint pain, cough, Timber
globulus Labill. cure dental
problems,
headache and cold
63 Ficus Moraceae Aalamaram Seminal weakness,
benghalensis L. nervous disorders,
laxative
64 Ficus racemosa Moraceae Atthi Antiseptic, skin
L. diseases
65 Foeniculum Apiaceae Koigerakam Cough, throat pain
vulgare L.
66 Gloriosa superba Colchicaceae Cure bone
L. problems
67 Glycosmis Rutaceae Malakuluki Stomach pain,
pentaphylla dysentery, acidity
(Retz.) DC. and malaria
68 Grewia tiliifolia Malvaceae Lumanmaram Laxative, good for Cattle feed
vahl hair, dysentery,
blood coagulant
(continued)
Ethnomedicinal Plants Used by Irula Tribal Settlement of Attappady in Palakkad… 115

Table 1 (continued)
Sl. Medicinal use/
No. Scientific name Family Common name cures Other uses
69 Helicteres isora Malvaceae Keveram Diabetes, ulcer Hair oil
L. and menstrual preparation
pain, stomach
pain, malaria
70 Hemidesmus Apocyanaceae Nannari Blood purifier, Water
indicus (L.) diarrhoea, purification
R. Br. ex Schult. dysentery, stomach
pain increases
memory power
71 Hibiscus rosa - Malvaceae Chemparuthi Hair tonic,
sinensis L. laxative, skin
diseases
72 Ixora coccinea L. Rubiaceae Theei Astringent,
antiseptic
73 Jatropha curcas Euphorbiaceae Kattukotta Anti-inflammatory,
L. wound healing
74 Justicia adhatoda Acanthaceae Adalodakam Bronchitis and
L. acidity, cough,
anti-inflammatory
75 Justicia Acanthaceae Karinochil To treat fractures
gendarussa and dislocated
Burm. f. bones and chronic
indigestion,
dysentery,
rheumatism, fever
and cough.
76 Kyllinga Cyperaceae Muthanga Dysentery and
nemoralis (J. R. white discharge
Forst & Forest).
77 Lantana camara Verbenaceae Paral Abdominal pain, Insecticides
L. rheumatism, tooth
pain
78 Lantana indica Verbenaceae Vettum paral Stomach pain and
Roxb. control vomiting
79 Lawsonia Lythraceae Maruthani Anti-fungal,
inermis L. anti-bacterial,
anti-inflammatory,
antiviral, nail
problems
80 Leucas aspera Lamiaceae Thumbai Headache, Veterinary
(Willd.) Link epilepsy medicine
anti-­helminthic,
jaundice,
febrifuge, fever
81 Lycopersicon Solanaceae Takkali Cure pimples on
esculentum Mill. face
(continued)
116 C. V. Jayalekshmi et al.

Table 1 (continued)
Sl. Medicinal use/
No. Scientific name Family Common name cures Other uses
82 Mangifera indica Anacardiaceae Mavu Cure teeth
L. problem,
dysentery
83 Mimosa pudica Leguminosae Thotavadi Kidney stone,
L. diuretic, anti-­
inflammatory, eye
problems
84 Momordica Cucurbitaceae Paval Intestinal worms,
charantia L. diabetes
85 Moringa oleifera Moringaceae Murungi Circulatory
Lam. stimulant,
anti-helminthic
86 Murraya koenigii Rutaceae Karivapu Stomach pain,
(L.) Spreng dysentery,
antiprotozoal,
antimicrobial,
antispasmodic,
87 Naravelia Ranunculaceae Kattu kodi Anti-inflammatory,
zeylanica (L.) colic wounds and
DC ulcer
88 Ocimum Lamiaceae Kattutulasi Child care, cough,
americanum L. breathing problem
89 Ocimum Lamiaceae Thiruneetu tulasi Cold, malaria,
basilicum L. antibacterial
90 Ocimum Lamiaceae Tulasi Asthma, cough,
tenuiflorum L. cold
91 Oxalis Oxalidaceae Puliyarali Liver tonic, fever,
corniculata L. hepato-protective
and burning
sensation
92 Passiflora foetida Passifloraceae Pottrichedi Edible
L.
93 Pavetta indica L. Rubiaceae Kollipu Treat poisonous
bite and skin
disease
94 Phyllanthus Euphorbiaceae Kelianelli Jaundice,
amarus dysentery
Schumach. &
Thonn.
95 Phyllanthus Euphorbiaceae Nelli Jaundice,
emblica L. antibiotic
96 Piper betle L. Piperaceae Vettilai Bronchitis,
stimulant, and
antiseptic, cough,
rheumatism
(continued)
Ethnomedicinal Plants Used by Irula Tribal Settlement of Attappady in Palakkad… 117

Table 1 (continued)
Sl. Medicinal use/
No. Scientific name Family Common name cures Other uses
97 Piper longum L. Piperaceae Tippili Cough, bronchitis,
asthma
98 Piper nigrum L. Piperaceae Kurmiluku Antiseptic
99 Plectranthus Lamiaceae Iruvali Fever, snake bite,
amboinicus cough, sore throat
(Lour.) Spreng.
100 Plectronia Rubiaceae Kari maram Joint pain,
parvifolia (Roxb) anti-inflammatory,
Benth & Hook. f. fever
exkurz
101 Plumbago Plumbaginaceae Ottachedi Stomach pain,
zeylanica L. anti-helminthic
102 Plumeria alba L. Apocynaceae Vella arali To treat ulcers and
cure nail infections
103 Pongamia Leguminosae Pongum Anti-helminthic,
pinnata (L.) jaundice,
Piere febrifuge,
haemorrhage,
fever
104 Psidium guajava Myrtaceae Koyya Laxative, tonic,
L. dysentery, stomach
pain and gas
trouble
105 Pterocarpus Leguminosae Bark for the Timber
marsupium Roxb. treatment of joint
pain
106 Punica granatum Lythraceae Madalam Good for
L. dysentery,
stomachic and
vomiting
107 Rauvolfia Apocynaceae Povaru Epilepsy,
serpentina (L). gastrointestinal
Benth. exkurz problems, fever
108 Ricinus Euphorbiaceae Kottimuttu Gastro-intestinal Veterinary
communis L. problem, cough, medicine
rheumatism,
stomach pain
109 Rubia cordifolia Rubiaceae Maruchedi Skin disease, ulcer
L. and cough,
anti-inflammatory
110 Santalum album Santalaceae Sandhanam Cooling diuretic,
L. antiseptic, skin
disease, anti-­
inflammatory,
antiviral
(continued)
118 C. V. Jayalekshmi et al.

Table 1 (continued)
Sl. Medicinal use/
No. Scientific name Family Common name cures Other uses
111 Sarcostemma Apocynaceae Karumparandi Cure boils
acidum (Roxb)
Voigt.
112 Scoparia dulcis Plantaginaceae Sedative, diuretic,
L. kidney stone
113 Senna Leguminosae Thira Stomach pain,
occidentalis (L.) control ring worms
Link
114 Sida cordifolia L. Malvaceae Maruchedi Fever, cough and
joint pain, nervous
diseases and
rheumatism,
burning and
sensation, cooling,
cough, hair wash
115 Solanum Solanaceae Manathali Wounds, ulcer,
americanum skin disease, fever
Mill.
116 Solanum Solanaceae Siru sundi Jaundice, diuretic
argenteum Dunal
117 Solanum torvum Solanaceae Sundi Respiratory, fever,
Sw. skin ailments,
ulcer, dysentery
118 Solanum Solanaceae Peetachedi Hair wash, cure
verbascifolium L. boils, skin diseases
119 Solanum Solanaceae Nilachundai Stomach pain
xanthocarpum
Schrad. & Wendl
120 Syzygium cumini Myrtaceae Naval Ulcer, diabetes,
(L.) Skeels dysentery
121 Tamarindus Leguminosae Puli Cure jaundice,
indica L. laxative,
astringent, cooling
122 Tephrosia Leguminosae Kolingi Urinary disorder,
purpurea (L.) vomiting
Pers.
123 Trichodesma Boraginaceae Kilukkamtumpa Anti-inflammatory, Veterinary
indicum (L.) rheumatism, medicine
Lehm cough
124 Tridax Asteraceae Sadukkupodukan Anti-inflammatory,
procumbens (L). stomach pain,
L. fever
125 Vitex negundo L. Verbenaceae Notchi Inhaled for cold
and cough
126 Zingiber Zingiberaceae Inji Stomach ache,
officinale Rosc. digestive
problems, gas
trouble
Ethnomedicinal Plants Used by Irula Tribal Settlement of Attappady in Palakkad… 119

Out of 126 plant species documented, 123 plants are angiosperms, 2 are pterido-
phytes and 1 is a gymnosperm. Cycas ciricinalis is used as edible plant by tribes in
Parambikulam wildlife sanctuary [14], and it is also used by Malayali tribe of
Servarayan hills for treating leucorrhoea [15]. Angiopteris evecta and Diplazium
esculentum were the Pteridophytes documented in this study. Medicinal importance
of both these plants were already documented [16, 17].
Out of 126 plant species, 37% of plants were herbs, 23% shrubs, 21% were trees
and 19% climbers. Figure 2 depicts the habit of plants. Most of the plants were used
to cure digestive system disorders (56), followed by fever (38) and skin disorders
(22). Figure 3 depicts the number of plants used for each disease category.

Fig. 2 Habit of plants Habit of Plants

19%
37%
21%
23%

Herb Shrub Tree Climer

No of plants used
Kidney stone
Rheumatism and joint pain
Healing of wounds
Malaria
Jaundice
Anti-inflammatory activity
Hair care
Fever
Urinary disorders
Epilepsy
Sexual and menstrual disorders
Skin diseases
Snake bite
Respiratory disorders
Digestive system Disorders
0 10 20 30 40 50 60

Fig. 3 Plants used to treat various diseases

120 C. V. Jayalekshmi et al.

Table 2 Fic value for different disease categories

Sl. No. Disease category Fic value
1 Digestive system disorders 0.35
2 Respiratory disorders 0.27
3 Snake bite 0
4 Skin diseases 0.275
5 Sexual and menstrual disorders 0
6 Epilepsy 0.33
7 Urinary disorders 0
8 Fever 0.412
9 Hair care 0.54
10 Anti-inflammatory activity 0.25
11 Jaundice 0
12 Malaria 0.33
13 Healing of wounds 0
14 Rheumatism and joint pain 0.2
15 Kidney stone 0.6

Eight plants were used to treat jaundice, three plants to treat malaria, two plants
to treat kidney stones and three plants to treat epilepsy. The most commonly cited
plants were Hibiscus rosa-sinensis, Leucas aspera and Ricinus communis by 4
informants. Hibiscus possessed analgesic, antipyretic, anti- asthmatic, anti-­
inflammatory, antioxidant, antifungal, antimicrobial and hair growth promoting
activity [18]. In the present study, Irula tribes mainly use Hibiscus rosa-sinensis for
hair care and also as laxative. Antioxidant, antibacterial, antifungal and cytotoxic
activities of Leucas aspera were already reported [19, 20]. Ricinus communis pos-
sessed antidiabetic, antimicrobial, antifungal, analgesic, insecticidal, antitumour,
antiasthmatic, antinociceptive, antifertility and bone degeneration activity [21].
Informant consensus factor or Fic value is high for kidney stone (0.6) followed
by fever (0.412). For kidney stone, 2 plants were cited with four used reports. High
Fic value indicates that a few taxa are used by the community for the treatment of a
particular disease category [22]. The Fic values for different disease categories are
given in Table 2.

4 Conclusion

The present study documented 126 plants used by the Irula tribal settlement. 29
informants participated in the survey, among them some were traditional healers.
Irula tribes use a wide variety of plants to treat various diseases. Documentation of
this traditional knowledge is essential as the tribal people do not share their knowl-
edge with a third person. Further studies on these plants may lead to the production
of new drug molecules.
Ethnomedicinal Plants Used by Irula Tribal Settlement of Attappady in Palakkad… 121

Acknowledgements The authors are thankful to the Principal, teachers, staff and students of
Department of Botany, Government Victoria College, Palakkad. The authors are thankful to the
informants of Irula tribal settlement Attappady for sharing their valuable traditional knowledge.
The authors are thankful to UGC and CSIR for financial assistance.

References

1. Rajith N, Ambily D, Dan VM, Devi PS, George V, Pushpangadan P (2012) A survey on eth-
nomedicinal plants used for menstrual disorders in Kerala. Indian J Tradit Knowl 11:453–460
2. Rehecho S, Uriarte-Pueyo I, Calvo J, Vivas LA, Calvo MI (2011) Ethnopharmacological sur-
vey of medicinal plants in Nor-Yauyos, a part of the Landscape Reserve Nor-Yauyos-Cochas,
Peru. J Ethnopharmacol 133:75–85
3. Tahira B, Mushtaq A, Rsool BT, Niaz MT, Rukhsana J, Saeed-Ur R, Shazia S, Muhammad
Z, Ghulam Y (2014) Ethnobotany of medicinal plants in district Mastung of Balochistan
province-­Pakistan. J Ethnopharmacol 157:79–89
4. Rahaman CH, Karmakar S (2014) Ethnomedicine of Santal tribe living around Susunia hill of
Bankura district, West Bengal, India: the quantitative approach. J Appl Pharm Sci 5:127–136
5. Phillips O, Gentry AH, Reynel C, Wilkin P, Galvez-Durand BC (1994) Quantitative ethno-
botany and Amazonian conservation. Conserv Biol 8:225–248
6. Chathukulam J, Reddy MG, Rao PT (2012) An assessment and analysis of tribal sub-plan
(TSP) in Kerala. Research Unit for Livelihoods and Natural Resources
7. Sulochana A, Raveendran D, Krishnamma A, Oommen O (2015) Ethnomedicinal plants used
for snake envenomation by folk traditional practitioners from Kallar forest region of South
Western Ghats, Kerala, India. J Intercult Ethnopharmacol 2015(4):47–51
8. Haseena VA (2015) Poverty and livelihood problems among the scheduled tribes in Kerala-a
study on Attappady. J Poverty Invest Dev 14:94–101
9. Varghese A, Nagaraj P (2012) A study on the tribal culture and folklore of Attappady. Galaxy
Int Multidiscip Res J 1:1–8
10. Alex A, Vidyasagaran K, Prema A, Kumar AVS (2016) Analyzing the livelihood opportunities
among the tribes of the Western Ghats in Kerala. Stud Tribes Tribals 14:11–17
11. Veena George M, Christopher G (2017) Nutritional value of selected wild edible leaves used
by tribal communities of Attappady, Southern Western Ghats. Int J Food Sci Nutr 2:126–132
12. Hoeschele W (2000) Geographic information engineering and social ground truth in Attappadi,
Kerala State, India. Ann Assoc Am Geogr 2000(90):293–321
13. Heinrich M, Ankli A, Frei B, Weimann C, Sticher O (1988) Medicinal plants in Mexico: heal-
ers’ consensus and cultural importance. Soc Sci Med 47:1859–1871
14. Yesodharan K, Sujana KA (2007) Wild edible plants traditionally used by the tribes in the
Parambikulam Wildlife Sanctuary, Kerala, India. Indian J Nat Prod Resour 6:74–80
15. Udayan PS, George S, Tushar KV, Balachandran I (2006) Medicinal plants used by the Malayali
tribe of Servarayan Hills Yercad Salem District Tamil Nadu India. Zoos’ Print J 21:2223–2224
16. Semwal P, Painuli S, Painuli KM, Antika G, Tumer TB, Thapliyal A, Setzer WN, Martorell
M, Alshehri MM, Taheri Y (2021) Diplazium esculentum (Retz.) Sw.: Ethnomedicinal, phyto-
chemical, and pharmacological overview of the Himalayan Ferns. Oxidative Med Cell Longev
2021:1–15
17. Udayan PS, George S, Tushar KV, Balachandran I (2005) Medicinal plants used by the Kaadar
tribes of Sholayar forest Thrissur district, Kerala. Indian J Tradit Knowl 4:159–163
18. Missoum A (2018) An update review on Hibiscus rosa sinensis phytochemistry and medicinal
uses. J Ayurvedic Herb Med 4:135–146
122 C. V. Jayalekshmi et al.

19. Babu A, Mohamed MSN, Jaikumar K, Anand D, Saravanan P (2016) In-vitro antifungal activ-
ity of leaf extracts of Leucas aspera and Leucas zeylanica. Int J Pharm Sci Res 7:752–756
20. Prajapati MS, Patel JB, Modi K, Shah MB (2010) Leucas aspera: a review. Pharmacogn
Rev 4:85–87
21. Jena J, Gupta AK (2012) Ricinus communis Linn: a phytopharmacological review. Int J Pharm
Pharm Sci 4:25–29
22. Heinrich M (2000) Ethnobotany and its role in drug development. Phytother Res 14:479–488
Folk Medicine of Chittur Taluk
in Palakkad District, Kerala, India

C. V. Jayalekshmi, S. Reshma, and V. Suresh

1 Introduction

Plants are widely used as a source of food, fodder, fuel, medicine, etc. India is rich in plant
diversity. The people of India mainly depend on plants to treat many diseases. Our Vedas,
Rigveda and Atharvaveda and ancient books like Charakasamhita, Sushruthasamhitha,
Dhanwanthari nighantu are the important sources of information on medicinal plants [1].
Traditional medicinal practices are still widely used in various parts of India.
According to WHO, about 80% people in developing countries depend on
medicinal plants for their primary health care. In India, Ayurveda, Yunani, Siddha,
folk medicine and tribal medicine depend mainly on plants to treat various diseases.
Kerala is the southernmost state of India with a vast diversity of medicinal plants.
The people of Kerala used plants as a source of medicine from very ancient times.
Folk medicine commonly called ‘Nattu chikitsa’ originated around the thirteenth
century A.D [2]. Folk medicine used around 25,000 plant-based formulations [3].
Folk medicine is still widely practiced in Kerala as it is safe and cheap. Palakkad
district is located in the eastern part of Kerala and has no sea coast. Chittur taluk is

The original version of this chapter was revised. The correction to this chapter is available at
https://doi.org/10.1007/978-3-031-28780-0_65

C. V. Jayalekshmi
Research Scholar, Post Graduate and Research Department of Botany, Government Victoria
College Palakkad, Palakkad, Kerala, India
S. Reshma
Post Graduate and Research Department of Botany, Government Victoria College Palakkad,
Palakkad, Kerala, India
V. Suresh (*)
Assistant Professor, Post Graduate and Research Department of Botany, Government Victoria
College Palakkad, Palakkad, Kerala, India

© The Author(s), under exclusive license to Springer Nature 123

Switzerland AG 2023, Corrected Publication 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_5
124 C. V. Jayalekshmi et al.

located 15 km South-east of Palakkad. The present study aimed to document the

plants used in folk medicine practices of Chittur taluk, Palakkad district.

2 Materials and Methods

The present study was conducted in Chittur taluk of Palakkad district. Frequent field
visits were conducted to the study area for collection of information on medicinal
plants used in folk medicine.

2.1 Study Area

Chittur taluk is located 15 km South-east of Palakkad with the geographical coordi-

nates 10°42″ North, 76° 45″ East. The total area of Chittur taluk is 445.99 sq. meters.
The temperature of the region ranges from 20 to 45 °C. Rice, coconut and sugarcane
are the important crops cultivated by people of this region.

2.2 Collection of Data

Survey was used to collect information regarding the use of plants in folk medicine.
Fifty-six informants from 15 villages were interviewed. The data were recorded in
survey sheets. Frequent field visits from February to July 2020 were conducted in
study areas for data collection. People within the age range of 30–80 years were
interviewed. Pothundy, Kuriyallur, Pottakkalpadam, Mettupalayam, Chunkam,
Kallandichalla, Thekkechalla, Ayyappankavu, Panniperunthala, Adichera,
Kattutheruvu, Athikode, Annikode, Arampadam and Attancheri are the villages
selected for the present study. Common name of plants, plant part used, mode of
delivery and curative properties of these plants were documented.
The plants documented in this study were collected and identified using available
taxonomic literatures. The voucher specimens are deposited in Government Victoria
College Herbarium.

2.3 Analysis of Data

Quantitative ethnobotanical tools are used for analysis of data.

Informant Consensus Factor (Fic)
Fic value was used to find out the use of plants in different disease categories by the
informants. It is calculated using the formula

FicValue  N ur  N t / N ur  1
Folk Medicine of Chittur Taluk in Palakkad District, Kerala, India 125

Fig. 1 Map of Palakkad district

Nur = Number of use-reports for a particular disease category

Nt = Number of taxa used by the informants in a particular disease category [4].
Fic value ranges from 0 to 1. Fic values will be high if the informants share their
knowledge between the community, and it will be low if the informants do not
exchange their use [5] (Fig. 1).

3 Results and Discussion

The present study deals with documentation of medicinal plants used in folk medicine
of Chittur taluk, Palakkad district, Kerala. The study reported 212 plants. The most
commonly cited families were Leguminosae, Euphorbiaceae, Apocynaceae by and
Malvaceae. Out of 212 plants, 75 plants were herbs, 52 plants were shrubs, 52 plants
were trees and 33 plants were climbers. Figure 2 depicts the habit of plants cited in the
study. The plants cited in this study are represented in Table 1 with their botanical
name, family, local name, medicinal value and mode of administration. Most fre-
quently used plant part is leaves followed by roots, flowers, fruits, rhizomes, seeds and
whole plant. Photographs of some plants cited in the study are given in Plate 1.
The most common ailments were fever, stomach problems and skin problems.
Seventy-three plants are used to treat digestive system disorders, 8 plants are used
to treat respiratory system disorders, 21 plants are used to treat snake bite, insect
bite and dog bite, 52 plants are used to treat skin diseases, 44 plants possess wound
126 C. V. Jayalekshmi et al.

Habit of plants

16%
36%

24%

24%

Herb Shrub Tree Climber

Fig. 2 Habit of plants

healing properties and 65 plants are used for general disorders, etc. Figure 3 depicts
the number of plants used for various diseases.
Single plant is used for more than one disease. For example, Tinospora sinensis
used for fever, kidney problem and diabetes, Sida cordifolia used to treat diarrhoea,
fever, urinary infection and skin disease, Ricinus communis was used to treat skin
diseases, joint pain, ear pain and constipation and Achyranthes aspera used for
fever, cough, cold and scorpion bite. The different parts of the same plant have dif-
ferent properties. For example, in the case of Ocimum tenuiflorum, the leaves are
used to treat throat infection, root extract was used to treat cough and the seeds were
used to treat eye irritations. Similarly, Sida cordifolia root extract is used to treat
fever and leaf extract was used for skin warts and wounds.
Tinospora sinensis and Azadirachta indica were the commonly cited plants in
this study followed by Curcuma longa. Anti-inflammatory, anti-oxidant, immuno-
modulatory, hepatoprotective and anti-leishmanial properties of T. sinensis were
already reported [6–10]. Anti-inflammatory, antipyretic, hepatoprotective, anti-­
microbial, anti-cancer, immunomodulatory, anti-candidal properties of A. indica
were also reported [11–13]. These properties indicate the medicinal importance of
these plants.
Five plants were used to treat jaundice and three plants were used to treat malaria.
All the five plants cited in this study were used for treating jaundice are already
reported. Ethnobotanical studies from Maharashtra reported that Luffa acutangula
fruits are used to treat jaundice [14]. Ethnobotanical studies from Bangladesh
reported the use of Asparagus racemosus to treat jaundice [15]. Studies on hepato-
protective plants used by the tribes of Wayanad, Malappuram and Palakkad reported
the use of Centella asiatica to treat jaundice [16]. The tribes of Akole taluk of
Maharashtra use Sesbania grandiflora to treat jaundice [17]. Studies on folk medi-
cine from Chittur district, Andhra Pradesh, reported the use of Phyllanthus amarus
Table 1 Plants cited in the study
Sl. Common name of
No plant Scientific name Family Used to cure Mode of delivery
1 Vendakka Abelmoschus esculentus (L.) Malvaceae (a) To improve memory power (a) Fruits used as a vegetable in daily
Moench and for abdominal disorders food
2 Kunni Abrus precatorius L. Leguminosae (a) Best to treat swellings and (a) Leaves mixed with coconut oil then
joint pain placed
(b) Treats inflammations (b) Leaf and stem extract are used
3 Cheeppika Abutilon indicum (L.) Sweet Malvaceae (a) Used as anti-inflammatory (a) Dried powder
agent
4 Munja Acalypha fruticosa Forssk. Euphorbiaceae (a) Protect new born babies (a) Leaves and flowers boiled in water
from cold and cough then to bath babies in the cooled water
5 Kuppameni Acalypha indica L. Euphorbiaceae (a) For the treatment of skin (a) Take juice extract from leaves and
allergies mixed with lime then applied on the skin
(b) Treat rheumatism (b) Leaf juice with coconut oil is applied
(c) Cure wounds (c) Powdered leaves can be applied
6 Sapota Achras sapota L. Sapotaceae (a) Fruits provide good diet (a) Ripened fruits are eaten
7 Kadaladi Achyranthes aspera L. Amaranthaceae (a) Cures cough and throat (a) Ash of spike is mixed with honey and
infection in infants and also applied
cure toothache (b) Paste made from spike and applied
(b) Against scorpion bite
Folk Medicine of Chittur Taluk in Palakkad District, Kerala, India

8 Venapacha Acmella radicans (Jacq) Asteraceae (a) Treat toothache, gum (a) Plant extract used as mouthwash
R. K. Jansen. infections and also for gum
swellings
10 Cherula Aerva lanata (L.) Juss. Amaranthaceae (a) The plant used for the (a) Decoction prepared with the root of
treatment of diarrhoea in cyperus and fennel seed
children (b) The extract of whole plant is mixed
(b) Cures bleeding during with milk
pregnancy time (c) Decoction of plant taken
(c) Treat urinary infection
127

(continued)
Table 1 (continued)
128

Sl. Common name of

No plant Scientific name Family Used to cure Mode of delivery
11 Vaaka Albizia saman (Jacq.) Merr. Leguminosae (a) For stomach cancer (a) Root decoction prepared in hot water
(b) Cure sore throat (b) Seeds chewed
12 Chuvannulli Allium cepa L. Amaryllidaceae (a) To treat nausea and (a) Juice from the bulb taken orally
vomiting (b) Outer covering of bulb heated in
(b) Used as dressing agent and mustard oil is applied
healing of wounds (c) Intake of bulb before sleep
(c) For good sleep
13 Kattarvazha Aloe vera (L.) Burm. f. Xanthorrhoeaceae (a) Cures skin diseases and (a) Just crush the leaves and applied
burns (b) Take the juice with leaves before
(b) To avoid problems during delivery
pregnancy (c) Sap of plant taken daily
(c) Menstrual problems
14 Ponnan Alternanthera sessilis (L.) Amaranthaceae (a) Used to cure snake venom (a) Leaf paste used externally
kannicheera R. Br. ex DC.
15 Mullucheera Amaranthus spinosus L. Amaranthaceae (a) For good health and to (a) Leaves used as vegetables or its
treat ulcers extract used
16 Kasumavu Anacardium occidentale L. Anacardiaceae (a) Treatment of snake bite (a) Grind the seeds and applied
(b) Used as a health drink (b) Fruit juice is taken
17 kiriyath Andrographis elongata Acanthaceae (a) To treat cough, cold and (a) Decoction of plant mixed with leaf
(Vahl) J. Anderson tonsillitis extract of Adhatoda, ginger and pepper
(b) To heal wounds, treat powder then consumed
scorpion bite and snake bites (b) Plant juice applied on wounds
18 Seethapazhm Annona squamosa L. Annonaceae (a) To stop diarrhoea (a) Decoction made with bark and taken
(b) For healing of wounds (b) Leaf extract applied externally
19 Nilakkada Arachis hypogaea L. Leguminosae (a) Source of protein (a) Seeds eaten raw or roasted
(b) Used as ear drop (b) Sap form grounded leaf
20 Garudakkodi Aristolochia indica L. Aristolochiaceae (a) Treatment of snake bite (a) Whole-plant extract is applied
C. V. Jayalekshmi et al.
Sl. Common name of
No plant Scientific name Family Used to cure Mode of delivery
21 Shathavari Asparagus racemosus Willd. Asparagaceae (a) Cures jaundice, bleeding (a) Plant extract is used to prepare a
and urinary problems decoction and consumed
22 Irimbampuli Averrhoa bilimbi L. Oxalidaceae (a) Treats itching and swelling (a) Leaf paste is applied
(b) Cure cough and cold (b) Decoction of leaves consumed
(c) Control obesity (c) Daily intake of fruit juice
(d) Treat mumps and joint (d) Leaf paste is applied
pain
23 Veppu Azadirachta indica A. Juss Meliaceae (a) Skin problems include (a) Leaf paste mixed with Ocimum leaves
pimples, itching and black and applied
marks (b) Leaves grind with sesame oil and
(b) To heal severe wounds honey is applied
(c) Treat nail infection with (c) Neem oil from leaf and seeds are
pain mixed with curcuma rhizome
(d) Used as snake poison (d) LLeaf paste applied on wound
(e) Used against chickenpox (e) Leaf paste
24 Brahmi Bacopa monnieri (L.) Wettst. Plantaginaceae (a) To improve memory (a) Whole-plant extract is used
power, (b) Cures bronchitis (b) Take the plant extract per day for
12 weeks
25 Mula Bambusa bambos (L.) Voss Poaceae (a) Treats kidney stone (a) Root decoction consumed
Folk Medicine of Chittur Taluk in Palakkad District, Kerala, India

(b) Treatment of difficulty in (b) Root boiled in water and steamed

urination and bladder pain
26 Manjakanakambaram Barleria prionitis L. Acanthaceae (a) To the treatment of (a) Leaves boiled in water with little salt
toothache and related gum then the decoction is used as mouth wash
problems (b) Leaves and stem were used to make
(b) Treats fever including decoction
whooping cough
(continued)
129
Table 1 (continued)
130

Sl. Common name of

No plant Scientific name Family Used to cure Mode of delivery
27 Vellamandaram Bauhinia acuminata L. Leguminosae (a) Cure wounds (a) Crushed bark mixed with Ocimum
and neem leaves were applied
28 Kattumandaram Bauhinia racemosa Lam. Leguminosae (a) Treat glandular infection (a) Bark decoction is applied externally
and used as external wash for (b) Stem and bark extract mixed equally
skin diseases (c) Extract from flower bud taken
(a) Used as anti-inflammatory
agent
(b) For peptic ulcers
29 Kumbalam Benincasa hispida (Thunb.) Cucurbitaceae (a) To treat difficulty in (a) Fruit juice or cooked fruits taken
Congh. urination specially for women
after delivery
30 Thazhuthama Boerhavia diffusa L. Nyctaginaceae (a) To treat rheumatism and (a) Leaf extract applied externally
swelling (b) Decoction prepared with leaf, root and
(b) Remedy for enlargement rice water
of spleen (c) Decoction from root is consumed
(c) Treat stomach ache and (d) Leaf decoction is used
internal inflammation
(d) Used treat liver diseases
31 Poolamaram Bombax ceiba L. Bombacaceae (a) To treat wounds (a) Bark extract mixed with neem leaves
(b) To improve immunity (b) The young root chewed raw
32 Kadalaspu Bougainvillaea Nyctaginaceae (a) To treat acidity problems, (a) Leaves decoction is taken
spectabilis Will N cure sore throat and cough
33 Kaduku Brassica juncea (L.) Czern. Brassicaceae (a) Treats inflammation (a) Seeds made into paste and applied
(b) Treats abdominal pain (b) Seed extract consumed
34 Plasu Butea monosperma (Lam.) Leguminosae (a) To treat diarrhoea (a) Leaf extract consumed
Taub. (b) For cold, cough and septic (b) Red juice from the bark is applied
sore throat externally
C. V. Jayalekshmi et al.
Sl. Common name of
No plant Scientific name Family Used to cure Mode of delivery
35 Rajamalli Caesalpinia pulcherrima (L.) Leguminosae (a) To induce abortion (a) Root extract is used
Sw. (b) For the treatment of cold, (b) Root, bark and leaves boiled to
cough and fever prepare tea and taken
(c) Used as an eye wash (c) Liquid extract from flower
36 Thuvara Cajanus cajan (L.) Millsp. Leguminosae (a) Treat cough, cold and (a) Take the extract of leaves and mixed
bronchitis with ginger juice then taken
37 Mashkhanchi Callicarpa tomentosa (L.) L. Verbenaceae (a) For the treatment of (a) Seed extract applied on swellings
malaria
38 Punna Calophyllum inophyllum L. Clusiaceae (a) For joint pain (a) Oil prepared from seeds is applied
(b) Used as an anti-microbial (b) Paste from seeds can be applied
agent
39 Erukku Calotropis gigantea (L.) Apocynaceae (a) Relief from neck pain (a) Leaves applied after mild heating
Dryand. (b) Cures toothache (b) Cotton soaked in plant latex is placed
(c) Treats joint pain and milky juice mixed with ginger and
applied
(c) Leaf juice applied on joints
40 Manoranjini Cananga odorata (Lam.) Annonaceae (a) Treatment of malaria (a) Fruits consumed
Hook. f. & Thomson (b) Used as a perfume (b) Flowers soaked in water and the water
Folk Medicine of Chittur Taluk in Palakkad District, Kerala, India

is applied
41 Pachamulak Capsicum annum L. Solanaceae (a) Used as an appetizer (a) Fruit as an ingredient of food
42 Uzhinja Cardiospermum halicacabum Sapindaceae (a) Treatment of ulcer (a) Leaf extract is applied on wounds
L. To cure fever (b) Leaves boiled in water and drink the
(b) Improves hair growth water
(c) Plant extract mixed with hibiscus
leaves and applied
43 Papaya Carica papaya L. Caricaceae (a) Remove intestinal worms (a) Ripe or unripe fruits take on empty
and treat kidney stone stomach
(continued)
131
Table 1 (continued)
132

Sl. Common name of

No plant Scientific name Family Used to cure Mode of delivery
44 Cherry Carissa carandas L. Apocynaceae (a) Improves appetite (a) Unripe fruit mixed with honey
(b) Removes intestinal worms (b) Root extract used as decoction
45 Kanikkonna Cassia fistula L. Leguminosae (a) For bronchial diseases (a) Powder of bark mixed with milk
(b) Skin disease and treats (b) Decoction from flower or the leaf
itching extract is applied or prepare a mixture
with leaves, turmeric, sesame seeds and
curd then apply on skin
46 Nithyakalyani Catharanthus roseus (L.) Apocynaceae (a) Reduce blood pressure and (a) Consume the flower extract or just
G. Don treat blood vomiting chew the flower
47 Kozhichutta Celosia argentea L. Amaranthaceae (a) To treat boils and wounds (a) Paste from leaves and stem is applied
(b) Reduce fever (b) Powdered seeds applied externally
48 Kudangal Centella asiatica (L.) Urb. Apiaceae (a) Used as brain tonic (a) Chewed 10 leaves per day
(b) To the treatment of (b) Fresh plant made into a paste with 1
jaundice and liver problems liter milk and consumed
(c) Relieve from acidity (c) Chew the tender leaves
49 Poombatta payar Centrosema molle Benth. Leguminosae (a) Treat snake bite and (a) Crushed seeds are applied
scorpion bite
50 Communistpacha Chromolaena odorata (L) Asteraceae (a) Healing wounds and burns (a) Just crush the leaves and applied
R. M. King & H. Rob. (b) Cures diarrhoea (b) Root decoction could consumed
51 Swarnapathry Chrysophyllum cainito L. Sapotaceae (a) Cure inflammations in (a) Fruit pulp made into juice and used
larynx and also to treat
pneumonia
52 Karuvappatta Cinnamomum verum J. Presl Lauraceae (a) For chest pain and cardiac (a) Leaves consumed
disorders (b) Dried bark used as a food ingredient
(b) For digestion and treats
acidity
C. V. Jayalekshmi et al.
Sl. Common name of
No plant Scientific name Family Used to cure Mode of delivery
53 Paadavalli Cissampelos pareira L. Menispermaceae (a) Used to treat diarrhoea (a) Leaves deep fried with wheat and used
(b) Removes dandruff from (a) Leaf extract mixed with hibiscus
hair leaves
(c) Used for menstrual (b) Decoction prepared with leaf, stem
disorders and rhizome is consumed
54 Changala paranda Cissus quadrangularis L. Vitaceae (a) Regulate menstrual cycle (a) Plant juice mixed with equal amount
and reduces menstrual pain of honey is taken
(b) To relieve ear pain (b) Boil the stem extract, cool it then used
as an ear drop
55 Naranga Citrus limon L. Rutaceae (a) Treatment of dysentery (a) Five drops of fruit juice mixed with
(b) Removes dandruff from black tea and taken
hair (b) Wash the hair with lemon juice
(c) Cures stomach pain (c) Root extract is used
(d) Stops vomiting (d) Lemon juice mixed with little salt
56 Aadunarivela Cleome viscosa L. Capparidaceae (a) To treat ear pain (a) Leaf juice used as ear drop
(b) Expelling intestinal worms (b) Seeds made into a powder, mixed with
(c) Improves appetite milk and consumed
(c) Leaf juice is taken
57 Paragu Clerodendron infortunatum Verbenaceae (a) Treats fever, cough and (a) Decoction made from leaves
Folk Medicine of Chittur Taluk in Palakkad District, Kerala, India

Gearth skin problems consumed

(b) Treats ulcers and swellings (b) Root grind with leaves and applied
58 Sankhupushpam Clitoria ternatea L. Leguminosae (a) Treatment of general (a) Prepare paste with flowers and cow
weakness milk
(b) To cure bleeding and (b) Decoction prepared with leaves and
uterus related issues flowers were taken
(continued)
133
Table 1 (continued)
134

Sl. Common name of

No plant Scientific name Family Used to cure Mode of delivery
59 Koval Coccinia grandis (L.) Voigt Cucurbitaceae (a) Cures fever, bronchitis and (a) Fruits can be used as fresh or cooked
regulate blood sugar in different way
(b) For good diet (b) Leaves used as a vegetable
60 Parappanji Cochlospermum religiosum Cochlospermaceae (a) Used as hair wash (a) The extract of young leaves is used
(L.) Alston (b) To treat throat swellings (b) Sweet gum obtained from the bark is
applied
61 Thengu Cocos nucifera L. Arecaceae (a) Energy drink (a) Drink coconut water in daily morning
(b) For hair growth (b) Oil prepared from the dried kernel is
(c) Treat urinary problems used
(c) Unfermented toddy
62 Kappi Coffea arabica L. Rubiaceae (a) Stimulate nervous system (a) Prepare coffee with seeds or coffee
and quick relief to throat mixed with pepper powder, Ocimum
infection and cough leaves and a little sugar
63 Insulincheera Costus speciosus (J. Konig) Zingiberaceae (a) Reduces blood sugar (a) Leaves were chewed
Sm.
64 Nagalinkham Couroupita guianensis Aubl. Lecythidaceae (a) Used as hand wash and (a) Flower and leaf extract used
anti-inflammatory
65 Kanakambaram Crossandra infundibuliformis Acanthaceae (a) For healing of wounds (a) Flower extract is applied
(L.) Nees
66 Kilukkampetti Crotalaria pallida Aiton Leguminosae (a) To cure urinary problems (a) Seeds boiled for 2 hours and wrapped
include pain during urination in banana leaves then made into a paste
(b) Treat pain on swellings and applied
(b) Decoction prepared with root is
applied
67 Mathan Cucurbita pepo L. Cucurbitaceae (a) Treatment of fever (a) Leaf extract mixed with Ocimum
leaves and taken
C. V. Jayalekshmi et al.
Sl. Common name of
No plant Scientific name Family Used to cure Mode of delivery
68 Nilappana Curculigo orchioides Gaertn. Amaryllidaceae (a) Treatment of urinary (a) Tuber extract is taken
problems
69 Manjal Curcuma aromatica L. Zingiberaceae (a) Remove marks due to (a) Rhizome extract mixed with honey is
itching applied
(b) Remove fungal infection (b) Rhizome grind with curd and applied
from mouth (c) Rhizome powder mixed with camphor
(c) Treats toothache and applied on tooth
(d)To treat lip problems (d) Rhizome extract mixed with ghee then
(e) Treat skin problems like applied on lip
pimples, black marks and (e) Rhizome extract mixed with cow milk
other irritations and Ocimum leaves, crushed it, then
(f) Remove bad odour from applied
body (f) Apply rhizome extract before bath
70 Moodillathali Cuscuta reflexa Roxb. Convolvulaceae (a) Cures inflammations (a) Paste prepared from whole plant is
applied
71 Puvamkurunthila Cyanthillium cinereum (L.) Asteraceae (a) Stomach problems (a) Root decoction is consumed
H.Rob. (b) To the treatment of urinary (b) Fresh juice prepared from the whole
problems includes pain plant is consumed
(c) Treats skin problems (c) Young leaves crushed and applied
Folk Medicine of Chittur Taluk in Palakkad District, Kerala, India

72 Poovamkurunthila Cyanthillium cinereum (L.) Asteraceae (a) Treatment of red eye and (a) Leaf extract mixed in honey then
H. Rob. irritations applied as eye drops
73 Karukapullu Cynodon dactylon (L.) Pers. Poaceae (a) To improve blood volume (a) Daily intake of plant extract
(b) Treatment of bleeding (b) Plant extract applied on nose
from nose (c) Plant extract mixed with cow milk
(c) Treatment of seasonal cleft then applied on lip
lip
(continued)
135
Table 1 (continued)
136

Sl. Common name of

No plant Scientific name Family Used to cure Mode of delivery
74 Appela Cyanotis axillaris (L.) Commelinaceae (a) Cures burns and boils (a) Crushed leaves applied on wounds
D. Don ex Sweet
75 Ummam Datura stramonium L. Solanaceae (a) To treat swellings (a) Leaves soaked in hot mustard oil and
(b) To treat rheumatism applied
(c) To treat wounds, boils (b) Leaves boiled in water and the water
(d) For throat infection applied externally
(c) Plant extract is consumed
(d) Leaves dried and used as a smoking
agent
76 Vattakakka Dregea volubilis (L. f.) Benth Apocynaceae (a) To cure inflammations in (a) Plant extract intake
ex Hook. f. urinary tract (b) Leaf extract is applied
(b) To treat boils or burns
77 Bushchedi Duranta erecta L. Verbenaceae (a) Treats malaria (a) Fruit juice is used
(b) Treats urinary problems (b) Mix the extract of leaves and fruits
then taken
78 Kunjunni Eclipta prostrata (L.) L. Asteraceae (a) Cure acidity, cough and (a) Decoction of fresh leaves take orally
cold (b) Prepare oil with the whole plant in it
(b) Prevent hair fall and give
cooling effect to hair
79 Muyalcheviyan Emilia sonchifolia (L.) DC. Asteraceae (a) Eye, ear irritations and (a) Juice from leaves used
ex DC. throat problems (b) Paste of the whole plant is applied
(b) Cures thyroid swelling (c) Crush the leaves and taken daily
(c) For intestinal worms
80 Eucaly Eucalyptus globulus Labill. Myrtaceae (a) Cure dental problems (a) Leaf extract is applied
(b) Treat headache, cough and (b) Leaf decoction used for steaming
cold
C. V. Jayalekshmi et al.
Sl. Common name of
No plant Scientific name Family Used to cure Mode of delivery
81 Nilappala Euphorbia hirta L. Euphorbiaceae (a) Treats itching and pus from (a) Juice from the stem is applied
the wounds (b) Stem sap is used as eye drop
(b) For a good feel to eyes (c) Leaf paste applied externally
(c) Treats swellings and burns
82 Arayal Ficus religiosa L. Moraceae (a) To relieve diabetes (a) Bark decoction taken
(b) Cures respiratory problems (b) Powder made with fruits consumed
(c) For skin problems (c) Paste from flower bud applied
(d) Treats stomach problems (d) Fruits are taken
and constipation
83 Perumjeerakam Foeniculum vulgare Mill. Apiaceae (a) Stimulate appetite and (a) Seeds as an ingredient of curries
good for digestion
84 Iravi Garcina morella (Geartn.) Clusiaceae (a) Stop bleeding from (a) Resin applied on wound
Desr. wounds (b) Fruit extract consumed
(b) Used as a weight loss
remedy
85 Parijatham Gardenia jasminoides J. Ellis Rubiaceae (a) Treats rheumatism (a) Paste made with flower and leaf is
applied
86 Varavalli Getonia floribunda Roxb. Combretaceae (a) Used as a source of (a) Stem store large amount of water
Folk Medicine of Chittur Taluk in Palakkad District, Kerala, India

drinking water (b) Fruit juice is used

(b) To treat skin problems
87 Parppadaka Glinus oppositifolius (L.) Molluginaceae (a) Cures stomach problems (a) Whole-plant extract is used with
Aug. DC. ginger extract
88 Menthonni Gloriosa superba L. Liliaceae (a) Remove lice from hair (a) Sap from the stem mixed with
Ocimum leaves and applied
(continued)
137
Table 1 (continued)
138

Sl. Common name of

No plant Scientific name Family Used to cure Mode of delivery
89 Paanal Glycosmis pentaphylla Rutaceae (a) Easy relief from headache (a) Root extract is applied
(Retz.) DC. (b) For the treatment of (b) Decoction from root and leaves were
intestinal ailments consumed
(c) Cures skin infections (c) Paste made from leaves applied
(d) To treat joint pain due to (d) Applied on joints before sleeping
fever
90 Seemakonna Gliricidia sepium Leguminosae (a) To protect dried seeds from (a) Put the seeds of it along with seeds to
(Jacq.) Walp pest attacks be protected
(b) Removes parasites from (b) Crushed leaves applied on it
skin
91 Cheera Gomphrena globosa L. Amaranthaceae (a) Treatment of cough in (a) Flowers boiled in water and prepared
children tea
92 Thettipoo Hamelia patens Jacq. Rubiaceae (a) Skin problems like rashes, (a) Boiling leaf, stem and flower with
wounds and also cures water for 10 minutes then applied
menstrual problems
93 Kalyana Hedychium coronarium Zingiberaceae (a) To treat tonsillitis (a) Decoction from stem or near the
sogandikam J. Konig. (b) Cure glandular swellings rhizome
(c) Treats joint pain (b) Chew the raw stem
(d) To treat tonsillitis (c) Rhizome extract applied
(d) Young bud and stem made into a paste
then applied on throat
94 Edampiri-valampiri Helicteres isora L. Malvaceae (a) To remove intestinal (a) Use fried pods
worms (b) Mature fruits boiled with oil then
(b) Treatment of rheumatic applied
complaints (c) Decoction of root bark is consumed
(c) For stomach problems
C. V. Jayalekshmi et al.
Sl. Common name of
No plant Scientific name Family Used to cure Mode of delivery
95 Thekkada Heliotropium indicum L. Boraginaceae (a) Cures wounds and skin (a) Leaf juice is consumed
problems (b) Leaf juice mixed with castor oil and
(b) Treatment of scorpion bite used
96 Nannari Hemidesmus indicus (L.) Apocynaceae (a) Treats rheumatism (a) Oil made with the whole plant is
R. Br. ex Schult. (b) Treats scorpion bite applied
(b) Leaf extract is applied on the wounds
97 Rubber Hevea brasiliensis (Willd. ex Euphorbiaceae (a) Heal wounds and cuts (a) Use crushed aerial parts
A. Juss.) Mull. Aug. (b) Stop bleeding from (b) Crushed bark applied on wounds
wounds
98 Chembarathi Hibiscus rosa-sinensis L. Malvaceae (a) Removes dirt from hair and (a) Extract from leaf, flower and bud can
to maintain it clean be applied directly on hair before bath
(a) Provide cooling effect to (b) Boil the flower in coconut oil for
hair and eye and for black hair 15 minutes, cooled and applied daily
(b) Treat cough, cold and fever (c) Root decoction consumed
99 Kattuppuliccai Hibiscus surattensis L. Malvaceae (a) To treat urinary infection (a) Leaf and stem decoction taken
100 Manjachemb arathi Hibiscus vitifolius L. Malvaceae (a) Used as an anti-­ (a) Leaves shade dried, grounded and
inflammatory agent applied
101 Vayalchulli Hygrophila schulli (Buch. Acanthaceae (a) Treat stomach pain and (a) Leaf extract is mixed with milk and
Folk Medicine of Chittur Taluk in Palakkad District, Kerala, India

Ham.) M. R. Almeidia & urinary tract infection sugar is taken

S. M. Almeidia
102 Kattulli Hymenocallis littoralis Amaryllidaceae (a) For wound healing (a) The extract of bulb is used
(Jacq.) Salisb. (b) Treat nail infections (b) Heated leaves dip in coconut oil then
placed around the nail
103 Kattuthulasi Hyptis suaveolens (L.) Poit. Lamiaceae (a) Treats joint pain (a) Leaf juice applied on infected part
(b) Cures stomach pain (b) Seeds and leaves were made into paste
and consumed
(continued)
139
Table 1 (continued)
140

Sl. Common name of

No plant Scientific name Family Used to cure Mode of delivery
104 Paarvalli Ichnocarpus frutescens (L.) Apocynaceae (a) Treats vomiting and (a) Root used to make a tonic and taken
W. T. Aiton weakness (b) Leaves used to make a paste and
(b) Cures headache applied
105 Kashithumba Impatiens balsamina L. Balsaminaceae (a) To treat burns and related (a) Direct application of crushed leaves or
pain
106 Nilambarananda Indigofera linnaei Ali. Leguminosae (a) Treatment of foot (a) Plant as a whole boiled in water and
infections applied
107 Cheriya kulavazha Ipomoea aquatica Forssk. Convolvulaceae (a) For diabetic patients (a) Leaves and stem used to prepare soup
or cooked together
108 Kulavazha Ipomoea carnea Jacq. Convolvulaceae (a) Treatment of leucoderma (a) Milky juice of the plant applied on the
and other skin diseases skin
109 Thiruthali Ipomoea marginata (Desr.) Convolvulaceae (a) Cures swellings in the (a) Root extract is applied on swellings
Verdc. body due to viper bite
110 Thechi Ixora coccinea L. Rubiaceae (a) Cures wound and skin (a) Root paste is applied
problems (b) Decoction prepared with the flowers
(b) Treatment of excessive and taken with honey
menstrual bleeding
111 Kodamulla Jasminum sambac (L.) Sol. Oleaceae (a) Used as a good sedative (a) Oil prepared with flower and taken
(b) For urinary infections (b) Tea prepared from whole plant is
(c) Cure skin diseases and taken
burns (c) Leaf paste and flower bud is used
112 Kotta Jatropha curcas L. Euphorbiaceae (a) To treat wounds and ulcers (a) Latex is applied on it
(b) Treats rashes due to (b) Oil prepared from seeds applied
parasitic attack (c) Stem extract applied on brow
(c) Treatment of headache
C. V. Jayalekshmi et al.
Sl. Common name of
No plant Scientific name Family Used to cure Mode of delivery
113 Kattukotta Jatropha glandulifera Roxb. Euphorbiaceae (a) Treatment of abdominal (a) Root extract mixed with water and
enlargement in children and boiled, after a while the cooled water is
also reduce glandular applied on swellings
swellings
114 Adalodakam Justicia adhatoda L. Acanthaceae (a) To the treatment of cough (a) Seven leaves boiled and take with
(b) Remove intestinal worms honey
(c) For rheumatism (b) Decoction from barks and leaves
consumed
(c) Oil made with leaves and bark is
consumed
115 Vathamkolli Justicia gendarussa Burm. f. Acanthaceae (a) To treat rheumatism and (a) Leaves boiled in water and daily
severe pain on joints applied on joint
116 Kacholam Kaempferia galanga L. Zingiberaceae (a) Treat toothache (a) Leaf extract mixed with salt and
(b) Remove black marks from applied
face (b) Rhizome extract mixed with milk and
applied on the face
117 Ilamulachi Kalanchoe blossfeldiana Crassulaceae (a) Treat infection and fire (a) Leaf juice is applied
Poelln. burns
Folk Medicine of Chittur Taluk in Palakkad District, Kerala, India

118 Muthanga Kyllinga nemoralis Cyperaceae (a) Relief from acidity (a) Prepared decoction with the plant and
(J.R.Forst. & G.Forst.) problems taken
Dandy ex Hutch. & Dalzel (b) To treat cold and fever (b) Whole-plant extract is used
(c) Treat dysentery (c) Fresh tubers made into paste and taken
with rice
119 Avara Lablab pupureus (L) Sweet. Leguminosae (a) To relieve internal fever (a) Decoction of leaves and seeds
(b) Treatment of vomiting consumed
(b) Paste of seeds consumed
120 Poochedipu Lantana camara L. Verbenaceae (a) Quick healing of wounds (a) Apply the extract from leaves on it
(continued)
141
Table 1 (continued)
142

Sl. Common name of

No plant Scientific name Family Used to cure Mode of delivery
121 Mylanji Lawsonia inermis L. Lythraceae (a) Cures itching and (a) Leaves made paste and applied
inflammation between fingers
and also used as henna on hair
122 Thumba Leucas aspera (Willd.) Link Lamiaceae (a) Treat acidity (a) Root decoction is consumed
(b) Treatment of stomach pain (b) Heat the root with curd and drink
(c) Cure shivering by fever, (c) Mix the plant extract with 1 spoon
cough and cold pepper
(d) Heals scorpion poison (d) Leaf paste is applied on the wounds
(e) Treat intestinal worms in (e)Decoction from flowers consumed
children
123 Mannanari Limnophila indica (L.) Druce Plantaginaceae (a) Treat wounds and (a) Leaves rubbed on affected part
infections
124 Peechinga Luffa acutangula (L.) Roxb. Cucurbitaceae (a) Treatment of jaundice (a) Fruit juice consumed
(b) Treats eye problems in (b) Fresh leaf juice used as eye drops
children
125 Thakkali Lycopersicon esculentum Solanaceae (a) Cure wounds due to (a) Leaf juice applied on wounds
Mill ringworm infection
126 Chempakam Magnolia champaca (L) Magnoliaceae (a) Cures fever (a) Decoction from bark is taken
Baill. ex Pierre (b) Cures eye problems (b) Fruit juice applied
(c) Treat joint pain (c) Crushed leaves mixed with coconut oil
and applied
127 Mulaku Malvaviscus penduliflorus Malvaceae (a) To heal wounds (a) Plant extract applied on wounds
chemparathi Moc. & Sesse ex DC. (b) Used as a beverage (b) Juice from the flower calyx is
consumed
C. V. Jayalekshmi et al.
Sl. Common name of
No plant Scientific name Family Used to cure Mode of delivery
128 Maavu Mangifera indica L. Anacardiaceae (a) Cures toothache and (a) Leafy twig is used as toothbrush
maintain hygiene (b) Leaf extract is applied
(b) Heal wounds (c) Ground the young leaves and taken
(c) To cure dysentery orally
(d) Treatment of excessive (d) Seeds grinded with honey and taken
menstrual bleeding
129 Poolakizhangu Manihot esculenta Crantz Euphorbiaceae (a) To treat skin problems (a) Tuber dried, powdered and mixed with
milk
130 Vellakakkapo Martynia annua L. Pedaliaceae (a) Treatment of sore throat (a) Leaf juice applied externally
(b) Treatment of snake venom (b) Root decoction taken
131 Kayampoo Memecylon umbellatum Melastomataceae (a) Treats inflammations (a) Leaf extract is used
Burm. f. (b) Treats menstrual pain (b) Root decoction used
(c) For healing of wounds (c) Leaf extract applied
132 Pothina Mentha piperita L. Merr. Lamiaceae (a) For good digestion (a) Leaves used to flavour curries
133 Keezharnelli Phyllanthus amarus Euphorbiaceae (a) Treatment of jaundice (a) Intake of plant extract with milk
Schumach. & Thonn
134 Maravalli Merremia vitifolia (Burm.f.) Convolvulaceae (a) Used to treat obesity (a) Grinded root is consumed
Hallier f. (b) To treat fever (b) Whole plant decoction is taken
Folk Medicine of Chittur Taluk in Palakkad District, Kerala, India

135 Thottavadi Mimosa pudica L. Leguminosae (a) Relief to chest pain (a) Root paste consumed
(b) To control diabetes (b) Juice from whole plant is consumed
(c) Control excessive bleeding (c) Plant juice takes along with honey
during menstruation (d) Leaf juice mixed with coconut water
(d) Cure breathing troubles in and taken
children
136 Nalumanipu Mirabilis jalapa L. Nyctaginaceae (a) Treat wounds and (a) Leaf juice is applied on the wounds
inflammations
(continued)
143
Table 1 (continued)
144

Sl. Common name of

No plant Scientific name Family Used to cure Mode of delivery
137 Kaypakka Momordica charantia L. Cucurbitaceae (a) Treatment of oral ulcers (a) Leaf paste applied directly
(b) To relieve ear pain (b) Leaf juice consumed
(c) For diabetic patients (c) Fresh fruit juice mixed with pepper
and takes decoction of leaves
138 Kakapola Monochoria vaginalis Pontederiaceae (a) Treat stomach pain and (a) Root juice taken
(Burm. f.) C Presl. toothache (b) Leaves with ginger and honey made
(b) Treatment of cough, cold, into a paste and consumed
fever and throat infection (c) Tuber extract can be applied
(c) For snake bite
139 Manjapavatta Morinda coreia Buch. Ham. Rubiaceae (a) For digestion and cure (a) Leaf juice is used
wounds (b) Root extract applied
(b) Treat inflammations
140 Muranga Moringa oleifera Lam. Moringaceae (a) Relieve from joint pain (a) Bark extract mix with cotton seeds
(b) For whooping cough applied
(b) Bark boiled in water and taken
141 Mulberry Morus alba L. Moraceae (a) Treats constipation (a) Fruits taken as raw or made wine with
dried fruits
142 Mindamindi Mukia maderaspatana (L.) Cucurbitaceae (a) To treat toothache (a) Seed powder is placed on teeth for
M. Roem. 2 hours then removed
143 Thanalmaram Muntingia calabura L. Malvaceae (a) To relieve headache (a) Flower decoction is applied on head
(b) Used as sweetener (b) Ripe fruits are used
144 Kariveppila Murraya koenigii (L.) Spreng Rutaceae (a) Easy relief from dysentery (a) Leaves boiled in curd for few minutes
(b) Treatment of cardiac then consumed after food
problems include pain (b) Leaves grinded with garlic and ginger
(c) To treat foot cleft and pain extract, boiled with curd then taken daily
(c) Leaves mixed with curcuma rhizome
and applied on leg
C. V. Jayalekshmi et al.
Sl. Common name of
No plant Scientific name Family Used to cure Mode of delivery
145 Arali Nerium oleander L. Apocynaceae (a) Treats bee sting and insect (a) Latex is applied
bite
146 Pavizhamulla Nyctanthes arbor-tristis L. Oleaceae (a) Expulsion of intestinal (a) Extract of leaves and flowers used
worms
147 Thulasi Ocimum tenuiflorum L. Lamiaceae (a) Remove rashes from skin (a) Leaves put in water and used to take
(b) Treat nail infection bath
(c) Cures cough, cold and (b) Paste made with leaves, turmeric and
throat infection henna leaves applied on infected parts
(d) Cures eye irritations like (c) Decoction made from leaves and root
dust allergy or tea prepared with all the parts, sugar
and coffee powder is consumed
(d) Put seeds on eye, then closed the eyes,
after few minutes the dust will be
removed
148 Parpadakapullu Oldenlandia corymbosa L. Rubiaceae (a) To cure fever, cough and (a) Decoction with Ocimum leaves taken
bronchitis
149 Nellu Oryza sativa L. Poaceae (a) To treat skin problems (a) Apply steam from boiling rice on face
(b) Treats cold and vocal (b) Chew rice with pepper
problems
Folk Medicine of Chittur Taluk in Palakkad District, Kerala, India

150 Poochapalam Passiflora foetida L. Passifloraceae (a) Treating digestive (a) Ripe fruits are taken
problems including diarrhoea
151 Vellathechi Pavetta indica L. Rubiaceae (a) Relief from wound pain (a) Crushed leaves applied on wounds
152 Thathamachedi Pedilanthus tithymaloides Euphorbiaceae (a) Treat insect sting (a) Plant latex is applied externally
(L.) Poit.
153 Mashithandu Peperomia pellucida (L.) Piperaceae (a) Treatment of fire burns (a) Plant juice applied on the affected skin
kunth
(continued)
145
Table 1 (continued)
146

Sl. Common name of

No plant Scientific name Family Used to cure Mode of delivery
154 Podathali Phyla nodiflora (L.) Greene. Verbenaceae (a) Treat swellings and (a) Apply paste from the leaves and
wounds, for the treatment of consumed
gastric problems
155 Arinellikka Phyllanthus acidus (L.) Euphorbiaceae (a) Treat cough and mouth (a) Leaf extract is consumed
Skeels sores (b) Fruits eaten raw
(b) Used as a tonic (c) Root bark mixed with turmeric
(c) Cures skin irritations powder and applied
156 Keezharnelli Phyllanthus amarus Euphorbiaceae (a) To treat stomach problems (a) Whole-plant extract is consumed
Schumach. & Thonn and urinary infections
157 Nainellikka Phyllanthus emblica L. Euphorbiaceae (a) To treat hair fall (a) Prepare oil with dried fruits and then
(b) Reduces blood pressure apply
(b) Fruit extract mixed with honey and
turmeric then takes one spoon per day
158 Neeluri Phyllanthus reticulatus Poir. Euphorbiaceae (a) To treat cold and fever (a) Leaf extract mixed with coconut oil
and applied
159 Vettila Piper betle L. Piperaceae (a) Cure cough in children (a) Leaves boiled in water and drunk
(b) Treatment of cough and (b) Heated leaves placed on the chest
asthma (c) Dry the stem, grind it and then chew
(c) To avoid bad breath at 4 or 5 times per day
160 Kurumulaku Piper nigrum L. Piperaceae (a) To the treatment of cold, (a) Pepper powdered and made a
cough, sore throat and vocal decoction or just chewed the pepper with
problems salt
(b) Cures stomach pain (b) Pulverize the pepper and mixed with
honey or sugar
161 Kodukkapuli Pithecellobium dulce (Roxb.) Leguminosae (a) Treats tooth ache and (a) Fruit pulp and extract of bark can be
Benth. related problems applied
C. V. Jayalekshmi et al.
Sl. Common name of
No plant Scientific name Family Used to cure Mode of delivery
162 Kanakoorka Plectranthus amboinicus Lamiaceae (a) Used for the treatment of (a) Leaf juice mixed with Ocimum leaves
(Lour.) Spreng. cough, sore throats and nasal and taken twice a day
problems (b) Leaves roasted with oil and placed at
(b) To cure fever in children the head
163 Karamullu Plectronia parviflora Harv. & Rubiaceae (a) Treat intestinal worms and (a) Extract prepared from leaves and root
Sond. constipation is taken
164 Vellakoduveli Plumbago zeylanica L. Plumbaginaceae (a) Treat rheumatic problems (a) Oil prepared from the tuber is applied
165 Vellaarali Plumeria alba L. Apocynaceae (a) To treat ulcers (a) Latex is applied
(b) Treatment of nail infection (b) Flower, stem and bark grind together
then mixed with oil and little salt, heating
166 Aranamaram Polyalthia longifolia (Sonn.) Annonaceae (a) Treatment of fever, cough, (a) Bark dried and boiled in water then
Thwaites cold and headache used as a steaming agent
(b) For skin itching and (b) Bark and leaves made into paste and
irritations applied
167 Parpadakam Polycarpaea corymbosa (L.) Caryophyllaceae (a) Heal inflammations and (a) Plant extract is taken
Lam. swellings
168 Cherucholam Polygonum barbatum L. Polygonaceae (a) Healing wounds (a) Leaf and stem extract used as a wash
169 Pongu Pongamia pinnata (L.) Leguminosae (a) Skin problems (a) Seed oil applied
Folk Medicine of Chittur Taluk in Palakkad District, Kerala, India

Pierre. (b) Quick healing of wounds (b) Paste made with leaves and seeds is
and relieve pain applied
170 Karincheera Portulaca oleracea L. Portulacaceae (a) Improve vision power (a) Leaves cooked and taken
(continued)
147
Table 1 (continued)
148

Sl. Common name of

No plant Scientific name Family Used to cure Mode of delivery
171 Mathalam Punica granatum L. Lythraceae (a) To improve appetite and (a) Mix seeds with sugar and taken
also health (b) Dried fruits taken per day
(b) Sudden relief from (c) Outer covering of fruits dried and
intestinal inflammations make powder then it mixes with ghee
(c) Treatment of acidity (d) Fruit juice is consumed
(d) Treatment to dryness on
mouth
172 Pampukalanchedi Rauvolfia tetraphylla L. Apocynaceae (a) Cures wound, treats snake (a) Prepare decoction with roots and
bite and for urinary problems leaves is taken
173 Avanakku Ricinus communis L. Euphorbiaceae (a) Expelling worms from the (a) Oil prepared from seeds consumed
skin (b) Castor oil used as soap
(b) Skin complaints (c) Leaves soaked in hot mustard oil is
(c) Relieves joint pain applied
(d) Cures ear pain (d) Leaves boiled with coconut oil and
(e) Treatment of constipation extract apply on ear as drops then take
rest
(e) Oil prepared from seeds is mixed with
milk and consume
174 Rose Rosa indica L. Rosaceae (a) To cure stomach troubles (a) Leaves, petals and root makes paste
(b) Used as an eye wash (b) Boil petals in water, cool and applied
175 Chandanam Santalum album L. Santalaceae (a) Treat skin problems (a) Bark extract applied on face
176 Ashokam Saraca asoca (Roxb.) de Leguminosae (a) Treats wounds due to (a) Bark used to make paste and applied
Wilde scorpion sting (b) Leaf juice mixed with cumin seeds is
(b) Stomach problems taken
(c) Used as an uterine tonic (c) Flower juice is consumed
177 Somalatha Sarcostemma acidum (Roxb.) Asclepiadaceae (a) Treatment of skin infection (a) Whole-plant extract is applied on
Voigt infected part
C. V. Jayalekshmi et al.
Sl. Common name of
No plant Scientific name Family Used to cure Mode of delivery
178 Maymasapoo Scadoxus multiflorus Amaryllidaceae (a) To heal wounds (a) Paste prepared from the bulb is
(Martyn) Raf. applied
179 Kallurukki Scoparia dulcis L. Plantaginaceae (a) To treat urinary problems (a) Tea made with aerial parts and takes
and to cure skin wounds (b) Plant extract mixed with cow milk
(b) Treatment of kidney stone then taken afternoon morning
180 Ponnamthakara Senna occidentalis (L.) Link Leguminosae (a) To cure skin problems, (a) Leaf and flower extract is applied
healing wounds and cuts (b) Seed paste mixed with water and
(b) Treat stomach pain taken
(c) Treatment to leukoderma (c) Ground the seeds then heated in
(d) Treatment of skin diseases mustard oil
includes itching (a) Prepare paste with its seeds and
Opuntia leaves
181 Thakara Senna tora (L.) Roxb. Leguminosae (a) Treatment of stomach (a) Leaves used as vegetable
problems
182 Ellu Sesamum indicum L. Pedaliaceae (a) Treat stomach problems (a) Seeds directly as food or the oil
and provide good digestion prepared from the seeds taken
183 Agathecheera Sesbania grandiflora (L.) Leguminosae (a) Treats stomach problems (a) Leaves cooked as vegetable
Pers. (b) Treatment of jaundice (b) Daily intake of leaf, stem and bark as
Folk Medicine of Chittur Taluk in Palakkad District, Kerala, India

vegetable
184 Kurunthotti Sida acuta Burm. f. Malvaceae (a) Relieve from fever and (a) Whole-plant extract is prepared into a
treats asthma decoction
(continued)
149
Table 1 (continued)
150

Sl. Common name of

No plant Scientific name Family Used to cure Mode of delivery
185 Vallikurunthotti Sida cordifolia L. Malvaceae (a) Treat diarrhoea (a) Leaf extract consumed
(b) For the treatment of fever (b) Root decoction consumed
and cough (c) Whole-plant extract is taken
(c) Treat urinary infection (d) Apply the leaf extract
(d) Treatment of skin warts (e) Root juices applied on wounds
(e) Healing of wounds (f) Oil prepared with root, bark and
(f) Treat nervous diseases sesame
186 Manathakkali Solanum americanum Mill. Solanaceae (a) To treat dysentery and (a) Decoction whole plant consumed
stomach problems (b) Make curry from the leaves or eaten
(b) Treats ulcer in the stomach raw
and mouth
187 Vazhuthana Solanum melongena L. Solanaceae (a) Treatment of liver (a) Daily intake of fruit juice or by
inflammations preparing curry
188 Chundanga Solanum rudepannum Dunal Solanaceae (a) Cure cough and cold (a) Fruit juice mixed in hot water and
(b) To reduce body taken
temperature (b) Leaf juice is consumed
(c) Used as an anti-­ (c) Whole-plant extract is applied
inflammatory agent
189 Adakkamanian Sphaeranthus indicus L. Asteraceae (a) For bronchial diseases and (a) Whole-plant extract is taken
treats swellings
190 Chamba Syzygium abbreviatum Merr. Myrtaceae (a) Provide cool feeling to (a) Daily intake of fruit juice
stomach (b) Fruit juice applied on wounds
(b) Wound healing
191 Njaval Syzygium cumini (L.) Skeels Myrtaceae (a) Strength to teeth and gum (a) Leaf extract used or chew tender
(b) Stop vomiting, provide leaves
cooling and sweet taste (b) Ripe fruits taken
C. V. Jayalekshmi et al.
Sl. Common name of
No plant Scientific name Family Used to cure Mode of delivery
192 Nandhyarvattam Tabernaemontana divaricata Apocynaceae (a) Used as anti-inflammatory (a) Flower extract applied on wounds
(L.) R. Br. ex Roem & Schult on wounds (b) 2 drops of flower extract applied on
(b) Treats redness on eye eye
193 Sambarcheera Talinum portulacifolium Portulacaceae (a) Reduce fatty liver (a) Leaves made into curry and consumed
(Forssk.) daily
194 Puli Tamarindus indica L. Leguminosae (a) To treats pain in urinary (a) Chew the seeds raw
tract (b) Leaf extract mixed with curd and
(b) Treatment of red eye applied
(c) For stomach pain due to (c) Fruits eaten raw or its extract is taken
Datura poisoning
195 Manjamani Tecoma stans (L.) Juss. ex Bignoniaceae (a) Cure swellings on spleen (a) Crush the bark and its extract is taken
Kunth (b) Treats stomach pain (b) Decoction prepared with flowers and
(c) For urinary problem bark
(c) Prepare tonic with root
196 Thekku Tectona grandis L. f. Verbenaceae (a) Cures headache (a) Paste from the wood applied on head
(b) Treats bronchitis (b) Dried flowers as an ingredient of
decoction
197 Badambi Terminalia catappa L. Combretaceae (a) Used as antidiabetic (a) Leaf extract is used
Folk Medicine of Chittur Taluk in Palakkad District, Kerala, India

(b) For good health of (b) Daily intake of seeds with milk
pregnant women (c) Oil prepared with seeds mixed in
(c) To maintain black and coconut oil then heated and applied
thick hair
198 Poovarasu Thespesia populnea (L.) Sol. Malvaceae (a) Treatment of psoriasis (a) Oil prepared by heating bark in
ex Correa coconut oil then applied on skin
(continued)
151
Table 1 (continued)
152

Sl. Common name of

No plant Scientific name Family Used to cure Mode of delivery
199 Chittamrutu Tinospora sinensis (Lour.) Menispermaceae (a) Treats fever, cold and (a) Leaf juice is mixed with honey
Merr. cough (b) Decoction from plant is mixed with
(b) Treatment of kidney juice of Plumbago leaves
problems and stomach (c) Extract from the plant is mixed with
problems ginger juice
(c) For the treatment of (d) Whole-plant extract is used
diabetes (e) Plant extract takes daily
(d) To treat vomiting (f) Plant extract mixed with cumin
(e) To improve immunity (g) Plant extract prepared in water then
(f) Treat acidity applied seeds and sugar
(g) Removes odour from body (h) Plant extract prepared in water then
(h) To treat gas trouble and applied
acidity
200 Charcoalmaram Trema orientalis (L.) Blume Ulmaceae (a) Treats cough, sore throat (a) Decoction of leaves and bark is taken
and toothache
201 Thalavetti Tridax procumbens (L.) L. Asteraceae (a) Healing wounds or skin (a) Leaf extract is applied on wounds
infections
202 Mullukaya Triumfetta rhomboidea Jacq. Tiliaceae (a) For easy delivery and relief (a) Plant extract is taken
from pain
203 Oorpam Urena lobata L. Malvaceae (a) Skin problems and related (a) Root extract applied
pain (b) Leaves powdered and boiled in water
(b) For urinary problems
204 Uzhunnu Vigna mungo (L.) Hepper Leguminosae (a) Cures wounds and (a) Root extract taken
inflammations (b) Seeds as an ingredient of food
(b) Avoid urinary diseases
205 Payar Vigna unguiculata (L.) Walp. Leguminosae (a) Treat skin complaints (a) Dried and powdered seeds applied on
skin
C. V. Jayalekshmi et al.
Sl. Common name of
No plant Scientific name Family Used to cure Mode of delivery
206 Mylazhaku Vitex altissima L. f. Verbenaceae (a) Treat wounds and (a) Leaf extract is applied externally
inflammations
207 Nochi Vitex negundo L. Verbenaceae (a) To cures skin diseases (a) Decoction of leaves applied
(b) Treats toothache, cavities (b) Leaf twig is used for chew
and gum bleeding (c) Leaf extract mixed in coconut oil,
(c) For the treatment of cold boiled it then cooled and applied on hair
(d) Treats swellings and (d) Decoction of bark and leaves applied
rheumatism
208 Mundiri Vitis vinifera L. Vitaceae (a) To improve beauty and (a) Prepare wine with fruits
health
209 Velvetchedi Waltheria indica L. Malvaceae (a) Used as a painkiller (a) Plant extract with Ocimum leaves is
(b) Cures sore throat taken
(b) The root bark is chewed
210 Dantapala Wrightia tinctoria R.Br. Apocynaceae (a) Treatment of stomach (a) Prepare decoction with the bark and
problems seeds
(b) To stop bleeding from (b) Latex from the bark could applied
wounds
211 Cholam Zea mays L. Poaceae (a) To improve skin health (a) Seed powder mixed with green gram
Folk Medicine of Chittur Taluk in Palakkad District, Kerala, India

powder and made a paste with water

212 Inchi Zingiber officinale L. Zingiberaceae (a) Treat stomach pain and (a) Rhizome extract mixed with garlic
digestive problems paste is taken
(b) To treat cough and sore (c) Decoction of dried rhizome is taken
throat treat cough and sore
throat
213 Ilanthi Ziziphus jujuba Mill. Rhamnaceae (a) For sore throat (a) Mucilaginous fruit is eaten
214 Chudali Ziziphus oenoplia (L.) Mill. Rhamnaceae (a) Used as dressing to (a) Stem bark is boiled in water and
wounds applied
(b) For sore throat (b) Chew the leaves
153

(c) For healing of wounds (c) Root decoction is used

154 C. V. Jayalekshmi et al.

Plate 1 Plants cited in the study

in treatment of jaundice [18]. Anti-malarial activity of Cananga odorata, Callicarpa

tomentosa and Delonix regia was also already reported [19–21].
Informant consensus factor (Fic value) for various disease categories are also
calculated. High Fic value is for rheumatism and swelling and is 0.35 followed by
pain (0.31). Fic value of various ailments is given in Table 2.
Folk Medicine of Chittur Taluk in Palakkad District, Kerala, India 155

Fig. 3 Plants used to treat Number of plants used

various diseases 80
70
60
50
40
30
20
10
0

Table 2 Fic value for different disease categories

SL.No. Disease category Fic value
1 Digestive system disorders 0.26
2 Respiratory disorders 0
3 Snake bite, dog bite and insect bite 0
4 Skin diseases 0.26
5 Sexual and menstrual disorders 0.2
6 Pain 0.31
7 Urinary disorders 0
8 General disorders (fever, high blood pressure, stimulants) 0.18
9 Hair treatment 0.2
10 Eye diseases 0
11 Jaundice 0
12 Malaria 0
13 Healing of wounds 0.085
14 Rheumatism and swelling 0.35

4 Conclusion

The present study aimed to document medicinal plants used in the folk medicine of
Chittur taluk, Palakkad district, Kerala. Traditional remedies used for the treatment
of various diseases are considered to be important in the primary health care of
people. Most of the people in village areas still depend on plants for first aid reme-
dies and to treat common health problems such as fever, stomach ache and some
simple ailments. Majority of the informants were aged above 50 years indicating
that younger generations are unaware of many medicinal plants. From the survey,
212 plants with different medicinal properties were recorded. The valuable
156 C. V. Jayalekshmi et al.

knowledge about medicinal plants was unwritten and depleted significantly from
generation to generation. So this documentation will help to save the traditional
medicines of Chittur taluk.

Acknowledgements The authors are thankful to the principal, teachers, staff and students of
Department of Botany, Government Victoria College, Palakkad. The authors are thankful to the
informants of Chittur taluk, Palakkad for sharing their valuable traditional knowledge. The first
author is thankful to UGC for financial assistance.

References

1. Rajith NP, Navas M, Thaha AM, Manju MJ, Anish N, Rajasekharan S, George V (2010) A
study on traditional mother care plants of rural communities of South Kerala. Indian J Tradit
Knowl 9:203–208
2. Rasiya BA, Nayar TS (2011) Plants used for natal healthcare in folk medicine of Kerala, India.
Indian J Tradit Knowl 10:523–527
3. Verma S, Singh SP (2008) Current and future status of herbal medicines. Vet World 1:347–350
4. Heinrich M (2000) Ethnobotany and its role in drug development. Phytother Res 14:479–488
5. Bulut G, Tuzlaci E (2013) An ethnobotanical study of medicinal plants in Turgutlu (Manisa-­
Turkey). J Ethnopharmacol 149:633–647
6. Lam SH, Chen PH, Hung HY, Hwang TL, Chiang CC, Thang TD, Kuo PC, Wu TS
(2018) Chemical constituents from the stems of Tinospora sinensis and their bioactivity.
Molecules 23:2541
7. Manjrekar PN, Jolly CI, Narayanan S (2000) Comparative studies of the immunomodulatory
activity of Tinospora cordifolia and Tinospora sinensis. Fitoterapia 71:254–257
8. Nagarkar B, Kulkarni R, Bhondave P, Kasote D, Kulkarni O, Harsulkar A, Jagtap S (2013)
Comparative hepatoprotective potential of Tinospora cordifolia, Tinospora sinensis and Neem-­
guduchi. Br J Pharm Res 3:906
9. Narkhede AN, Jagtap SD, Kasote DM, Kulkarni OP, Harsulkar AM (2014) Comparative
immunomodulation potential of Tinospora cordifolia (Willd.) Miers ex Hook. F., Tinospora
sinensis (Lour.) Merrill and Tinospora cordifolia growing on Azadirachta indica A. Juss.
Indian J Exp Biol 52:808–813
10. Singh N, Kumar A, Gupta P, Chand K, Samant M, Maurya R, Dube A (2008) Evaluation of
antileishmanial potential of Tinospora sinensis against experimental visceral leishmaniasis.
Parasitol Res 102:561–565
11. Lloyd AC, Menon T, Umamaheshwari K (2005) Anticandidal activity of Azadirachta indica.
Indian J Pharm 37:386–389
12. Malar TJ, Antonyswamy J, Vijayaraghavan P, Kim YO, Al-Ghamdi AA, Elshikh MS, Hatamleh
AA, Al-Dosary MA, Na SW, Kim HJ (2020) In-vitro phytochemical and pharmacological bio-­
efficacy studies on Azadirachta indica A. Juss and Melia azedarach Linn for anticancer activ-
ity. Saudi J Biol Sci 27:682–688
13. Okpanyi SN, Ezeukwu GC (1981) Anti-inflammatory and antipyretic activities of Azadirachta
indica. Planta Med 41:34–39
14. Mulay JR, Sharma PP (2003) Plants used in treatment of jaundice by folklore of Ahmednagar
district, Maharashtra, India. Sci Res Rep 3:216–222
15. Rahim ZB, Rahman MM, Saha D, Hosen SZ, Paul S, Kader S (2012) Ethnomedicinal plants
used against jaundice in Bangladesh and its economical prospects. Bull Pharma Res 2:91–105
16. Asha VV, Pushpangadan P (2002) Hepatoprotective plants used by the tribals of Wynadu,
Malappuram and Palghat districts of Kerala, India. Anc Sci Life 22:1–8
Folk Medicine of Chittur Taluk in Palakkad District, Kerala, India 157

17. Wabale AS, Petkar AS (2005) Ethnomedicinal plants used against jaundice by the tribals of
Akole taluka (MS). J Phytol Res 18:259–261
18. Reddy KR (1988) Folk medicine from Chittoor District, Andhra Pradesh, India, used in the
treatment of jaundice. Int J Crude Drug Res 26:137–140
19. Ankrah NA, Nyarko AK, Addo PG, Ofosuhene M, Dzokoto C, Marley E, Addae MM, Ekuban
FA (2003) Evaluation of efficacy and safety of a herbal medicine used for the treatment of
malaria. Phytother Res 17:697–701
20. Namdeorao Tankar A. Pharmacognostic phytochemical pharmacological evaluation of differ-
ent parts of callicarpa tomentosa ll and formulation development of bioactive extract. 2019
21. Tan LTH, Lee LH, Yin WF, Chan CK, Abdul KH, Chan KG, Goh BH (2015) Traditional uses,
phytochemistry, and bioactivities of Cananga odorata (Ylang-Ylang). Evid Based Complement
Alternat Med 2015:1–30
Checklist Flora of Sunderdhunga Valley,
Western Himalaya, with Emphasis
on Ethno-Medicinal Plants

R. Manikandan, S. P. Nithya, and R. Mehala Devi

1 Introduction

It is worth to explore any area with wide range of forest types and to identify eco-
nomically and medicinally important plants found there. Further, the reserve forests
and territorial forests are preserved for specific purposes, such as proper mainte-
nance of the wildlife in that area and prevention of human interference through
activities, like deforestation, cultivation and grazing of animals. It is a rewarding
experience to make available a systematic account of the floristic wealth of such
region or area. Moreover, the knowledge about the plants in any region is essential
with the increasing consciousness of people about the environment and its impact
on living organisms in general. Hence, it is very important to conserve our plant
wealth or diversity for the major role in providing food, fuel, fibres, medicine, shel-
ter, maintaining a stable environment and to study the scientific value of plants. This
is useful in assessing the periodic changes in flora that may occur in the study area.
With this conviction the Flora of Sunderdhunga and adjoining is being evaluated.
The Botanical Survey of India under the Ministry of Environment and Forest and
Climate Change has been allotted a project to document the floristic account of vari-
ous groups of wild plants of our country. The Sunderdhunga and adjoining in
Uttarakhand is one such area located in the Western Himalayas and together with
Eastern Himalaya which is one of the largest centres of endemism in India is among
the 34 biodiversity hotspots of the world [1]. According to Myers et al. [2] biodiver-
sity ‘hotspots’ are the regions containing a high proportion of global biodiversity in
a small area. Also biodiversity hotspots can be defined as areas having exceptional
concentration of endemic taxa. The Sunderdhunga and adjoining is situated in the
Bageshwar district of Uttarakhand a newly formed state from Uttar Pradesh.

R. Manikandan (*) · S. P. Nithya · R. M. Devi

Botanical Survey of India, Southern Regional Centre, Coimbatore, Tamil Nadu, India

© The Author(s), under exclusive license to Springer Nature 159

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_6
160 R. Manikandan et al.

1.1 Area Under Study

Sunderdhunga literally means ‘Valley of beautiful stones’. The famous glaciers of

this valley are Maiktoli Glacier and Sukhram glacier. Sunderdhunga glacier lies
over Sunderdhunga valley and is situated west of Pindari Valley. It is surrounded by
peaks Panwaldwar in north and Mrigthuni, Mongtoli and Tharkot in the west. The
elevation of the glacier spans from 3200 to 6050 m. It is situated in the higher
reaches of Kumaon Himalayas and it is a part of Nanda Devi Biosphere Reserve,
which is one of the World Heritage Sites, famous for its pristine and exceptional
beautiful landscape.
Sunderdhunga is bound in the north by Trisul glacier, to the east by Pindari and
Kafni glacier mountain peaks and to the south by the Bharadi village. It spreads
over an area of about 452 sq km and the altitude varies from 1300 to 6050 m and it
is located between 30°02′0.56″ to 30°16′48.13” N latitude and 79°57′14.47″ to
79°58′30.16″ E longitude in the Bageshwar district of Uttarakhand (Map 1
and Map 2).

1.2 Significance of Sunderdhunga and Its Surrounding Areas

The Sunderdhunga glacier and its surrounding areas encompass a rich biodiversity
of both flora and fauna and it is located at Bageshwar district in the Western
Himalaya. It covers of rich Sub-tropical Quercus forest, Himalayan moist temperate
forest, Himalayan dry-temperate forest, Sub-alpine forest and moist alpine forest.
The area is very rich in medicinal plants many of which form base for certain life-
saving drugs. It is a part of Nanda Devi Biosphere Reserve, which is one of the
World Heritage Sites, famous for its pristine and exceptional beautiful landscape.
The landscape of the study area is rolling large meadows, criss-cross dancing rivers
and streams, high-altitude lakes and snow clad peaks. The elevation varies from
1300 to 6050 m. It has unique social and cultural style of the area altogether repre-
sents sole scenic beauty which is unparalleled in the entire Himalayas. Also, it has
a great tourism potential especially glacier regions of Maiktoli glacier, Sukhram
glacier, etc. The area houses a lot of endangered fauna, e.g. Snow leopard, Brown
bear, Black bear, Bharal, Musk deer, Monal pheasant, etc. It is a significant compo-
nent of one of the snow leopard conservation areas in India. In addition, the India
Eco-development Project has also been implemented in the villages surrounding the
area in order to reduce the human pressures on wildlife habitat and also various
development programmes, such as research, monitoring, training and conservation,
are taken up by the Forest Department as well as other Government agencies to
meet various issues.
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 161

Map 1 Location map showing Sunderdhunga glacier track

1.3 Reasons for Undertaking the Present Work

and Its Importance

The present study was undertaken to explore this under-explored area which is
endowed with a rich floristic diversity. Extensive and intensive plant explorations
were undertaken to assess and prepare the floristic account and plant wealth of
Sunderdhunga and adjoining.
162 R. Manikandan et al.

Map 2 Location map of

Sunderdhunga valley and
its adjoining areas (From
Song to Devikund). (a)
From Song to way to
Dhakuri. (b) From way to
Dhakuri to Khati. (c) From
Khati to way to
Sunderdhunga. (d) From
way to Sunderdhunga to
Matkoli, Devikund
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 163

According to the report of FAO (1993) shows the rate of deforestation is esti-
mated to be 15 million hectares per annum. Besides, the Uruguay Round of the
General Agreement on Trade and Tariffs (GATT) has led to greater vulnerability of
forest elements owing to market prices, new seed varieties and patenting laws.
There is an alarming trend of forests transforming into agro industries. In addition,
introduction of exotic species of flora whether accidentally or intentionally in the
forests threatens local biodiversity. Recently, Pitman & Jorgensen [3] found that the
number of species unique to each country is a rough guide to the number that is
threatened and nearly half of the world’s plants could be close to extinction.
According to National Remote Sensing Agencies (NRSA), the natural forests
support the maximum biodiversity, which are depleting at a very fast rate. Our coun-
try too is losing its natural forests at the rate of 1.3 m ha every year [4]. Ahmedullah
& Nayar [5] have estimated about 1500 species accounting for about 10% of the
flowering plants of India are threatened. Thus, to protect and conserve the remain-
ing 90% of the flowering plants, a judicious management and innovative methods of
conservation are required. India is facing an alarming rate of loss of floristic diver-
sity particularly due to declining forest cover and species.
Major problems faced in the present study area are cattle grazing, forest fire, dif-
ficulty in managing wildlife corridors and human interference mostly due to tour-
ism. As the reserve forests/territorial forests are the prime centres of conservation
and diversity, scientific information on all taxa needs to be collected and docu-
mented. Therefore, it is very important to make an assessment of the existing floris-
tic diversity. Considering these reasons, Sunderdhunga valley and adjoining was
selected for an assessment of floristic diversity.

1.4 Objectives of the Study

• Survey, identification and inventorization of the floristic diversity of the valley

• Documentation of plant resources and their utilization practices by local com-
munities living in and around the valley and their traditional conservation
approaches
• Identification of endemic species and also listing the rare and threatened species
• Listing of economically important plants in the valley
• Listing of plants having medicinal, horticultural and fodder value

1.5 Past and Present Work

1.5.1 Past Work

Hooker & Thomson [6] in their ‘Flora Indica’ reported quite comprehensive infor-
mation on the flora of Garhwal Himalaya which includes the present study area.
Hooker and his collaborators have dealt with many species in The Flora of British
164 R. Manikandan et al.

India [7]. The work of Atkinson [8] on Flora of the Himalayas with special refer-
ence to Kumaon, Garhwal, Nepal and Tibet and Duthie’s [9] Flora of Garhwal
Himalaya can be conveniently considered as one of the eminent contributions in
the field.
Some scholars like Deva & Naithani [10], Garg [11], Aswal et al. [12], Dangwal
[13] and Nautiyal [14] have made efforts to study the flowering plants of the Garhwal
Himalaya in terms of certain families or groups of a given geographical entity.
Important information can be derived from Flowers of the Himalaya [15],
Blossoming Garhwal Himalaya [16], Flowers of Himalaya [17], Flowers of West
Himalaya [18] and Naithani’s Flora of Chamoli [19]. Other important unpublished
works include Manis Kandwal’s [20] Grass Flora of Uttarakhand. Many other bot-
anists, like Duthie [21, 22]; Issar & Uniyal [23]; Khullar [24], Osmaston [25]; Pande
[26–29]; Pangey, et al [30]; Rai et al. [31]; Randhwa [32]; Rau [33, 34]; Rawat [35];
Rawat & Sharma [36]; Singh et al. [37] and Uniyal et al. [38], have contributed for
the Flora of Kumaon Himalaya.

1.5.2 Present Work

The present comprehensive account of floristic diversity of the Sunderdhunga and

adjoining, Bageshwar district of Uttarakhand, is the outcome of intensive and exten-
sive studies on the vegetation of the area.

2 Materials and Methods

Intensive and extensive surveys have been undertaken periodically along different
topographic and climatic gradients within the potential area of Sunderdhunga and
adjoining, in order to achieve the above said objectives. The duration of each study
tour ranged from 15 to 20 days. While carrying out the assessment of floristic diver-
sity, efforts will be made to collect the plants in all seasons. The field observations
such as habit, habitat, flower colour, odour, distribution, along with local names and
uses, if any gathered from the tribes of the area has to be noted in the field itself and
any details which cannot be deduced from a herbarium specimen.

2.1 Herbarium Study

After returning from the field, plant specimens, which have been tentatively identi-
fied in the field, have been carefully and critically studied, before these could be
processed through conventional methods of drying, poisoning, mounting, stitching
and labelling [39, 40].
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 165

The identification of the collected specimens has to be done by comparing them

with authentic specimens available in different herbaria, such as BSD, CAL, KU and
DD protologues, journals and other relevant floras, such as The Flora of British
India [7], Plant Wealth of Nanda Devi Biosphere Reserve [41] and Flowering Plants
of Uttarakhand [42], besides many other recent monographs and revisions. These
specimens will be processed and deposited at the Herbarium of Botanical Survey of
India, Northern Regional Centre, Dehradun (BSD). In the preparation of the present
assessment of floristic diversity of Sunderdhunga, all the available information and
data will be gathered from some earlier collections pertaining to the study area,
which were available in the above-mentioned herbaria have also been taken into
account to incorporate and assess the distribution pattern of all species in this area.

2.2 Topography and General Features

2.2.1 Geology

The entire landform lies in the Himalaya stratigraphically zone and is in the vicinity
of main central propelled, which shows the serious impact of tectonic movements.
As a result, rocks are not only tightly folded but also broken into sheets and arranged
one over the other, forming tall heaps. The internal configurations of these sheets
are complicated cleavage and have developed inside thrust fold valley, which seri-
ously affected during heavy rains and earth quake. The whole area is prone to large-­
scale landslide. The elevation of the valley varies from 1300 to 6050 m.

2.2.2 Rocks

This area falls under Sub-Himalayan range; however, some parts of upper area
extend till Greater and Mid-Himalayan regions. The forest sections of this forest
regions extend between the longitudes of 79°28′30″ E to 80°29′30″ E and the lati-
tudes of 29°58′45″ N to 30°9′15″ N. This region consists of three main strips, which
are west, north-west, east and south-east, respectively. The whole terrain is broken
by numerous streams and nallahs. All aspects of gradients are occurs in the present
study area. The greater part being steep to precipitous and only a very few gentle
slopes occur in this area. Further, most of the valley or study area is covered by
metamorphic rocks. These rocks principally comprise quartzite, lime stone, magne-
tite, base metal and slate.

2.2.3 Soil

The structure and composition of the soil have a marked influence on the nature of
vegetation along with other factors, like climate, rainfall and biotic. The soil varies
from sandy loam to stiff clay depending on the nature of the schist.
166 R. Manikandan et al.

Decomposition and disintegration of rocks in the main cause of formation of soil

and the structure of soil depend upon types of rocks and specific atmosphere.
Actually, the formation of soil depends upon erosion by rivers. Decomposition of
quartzite is responsible for formation of gravels and light soil, which converts into
mold soil. Decomposition of rocks and slates forms clay. Lime stone decomposes
and forms red and black soil and decomposition of granite forms sandy and
mold soil.

2.2.4 Climate

The valley experiences greatly varying climate conditions, mainly due to large vari-
ation in altitudes, which is natural to encounter diversified climates in this forest
region. Severe cold can be felt during winters and regions higher than 1520 m
receive snowfall too. At times the lower parts also go through snowfall. The dura-
tion of December to February is of extreme cold in this region and mornings are full
of dense fog.

2.2.5 Rainfall

The valley receives rainfall from both monsoon and winter seasons. The monsoon
starts from the middle of June to the second week of September. The heaviest rain-
fall occurs during July and August.

2.2.6 Temperature

Three seasons, like summer, monsoon and winter, can be recognized in the present
study area. The monsoon starts from the middle of June and last till second week of
September. The peak rainfall occurs during July and August. The entire area of the
valley is subjected to light to heavy snowfall for about 3–4 months from December
to March in winter seasons. The summer season starts from March to the second
week of June. The temperature during summer goes up to 35 °C in lower parts of
Loharkhet and Song valley.

2.2.7 Water Sources

The Sunderdhunga and Pindari are the main rivers in the valley and they have sev-
eral tributaries and also a large number of perennial streams and nallahs, most of
which are snow fed.
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 167

2.2.8 Winds

The winds are light moderate, but sometimes, high and exposed ridges do experi-
ence strong winds.

2.3 Ethnic Groups

According to Lynch [43] in India, out of the human population of over 1 billion,
64% of the rural population and 100 million tribes depend on the forests for their
sustenance. Over 90 million cattle graze inside the forests [44]. According to
Regional Wood Energy Development Programme in Asia, the firewood consump-
tion in India is 1,73,412 k. tons with 62% derived from the forests [45]. According
to a survey carried out in the mid-1980s, over 65% of protected areas were charac-
terized by human settlement and resource use [46]. In the past two decades, these
factors have drawn the attention of policy makers who shifted their main concern
from protecting timber supplies to issues concerning local livelihoods, involvement
of local people in the forest management while formulating conservation agenda.
The inhabitants of Bhotia of Bageshwar district are geographically in Kumaon
region, but they are quite different from Garhwalis in their social and cultural group.
The distinct and unique feature of hill culture, polyandry, was in vogue in Bhotia
areas adjoining. Their houses are made up of Deodar wood and stone, which is three
to four storeyed. In these multi-storeyed houses, the lower one is used for cattle and
fodder storage and the uppermost one was used by human habitation. These storeys
are internally linked for adopting snowbound winters, when it is not possible to go
out of the house and away from hearth. Most of them engaged in marginal agricul-
tural and seasonal employment in various departmental works are the only source of
livelihood.

2.4 Vegetation

(a) Flora
The vegetation of the study area has been classified mainly as Sub-tropical
Quercus forest, Himalayan moist temperate forest, Himalayan dry-temperate forest,
Sub-alpine forest and moist alpine forest [47]. Further, the structural diversity and
representativeness of forest vegetation of Kumaun Himalayas studied by many
workers like Dhar et al. [48], Rau [49], Rawal et al. [50], Rikhari et al. [51], Singh
& Singh [52–54], Tewañ & Singh [55] and Upreti et al. [56].
168 R. Manikandan et al.

2.4.1 Floristic Diversity

During the above said period the following species were collected and identified
from the study area itself:
Acer caesium, Aesculus indica, Alnus nepalensis, Androsace sp., Anemone spp.,
Orchis nana, Arisaema spp., Arnaria ciliolata, Arnebia benthamii, Astragalus pin-
dreensis, Betula utilis, Brassica juncea, Calanthe tricarinata, Caltha palustris,
Cannabis sativa, Corydalis cashmeriana, C. stracheyi, Cupressus torulosa,
Fragaria nubicola, Gagea elegans, Gentiana spp., Indigofera spp., Iris kumaonen-
sis, Juglans regia, Lloydia serotina, Micromeria biflora, Ophiopogon intermedius,
Poa sp., Polygonum spp., Potentilla atrosanguinea, Primula denticulata, P. edge-
worthii, Primula spp., Rhododendron arboreum, R. campanulatum, R. lepidotum,
Rosa spp., Sinopodophyllum hexandrum, Schisandra grandiflora, Taxus wallichi-
ana, Trifolium spp., Vincetoxicum hirundinaria, Viola spp., etc.
1. Sub-tropical Quercus forest
This type of forests occurs in Song and Loharkhet areas where altitude ranges
up to 1300 m.
The upper storey comprises Acer oblongum, Alnus nitida, Lyonia ovalifolia,
Pyrus pashia, Quercus leucotrichophora, Rhododendron arboreum, etc., and the
lower storey comprises Chrysopogon fulvus, Debregeasia salicifolia, Flemingia
macrophylla, Heteropogon contortus, Prinsepia utilis, Rhamnus virgatus, Rubus
ellipticus, Woodfordia fruticosa, etc.
2. Himalayan moist temperate forest
(a) Ban oak forests (Quercus leucotrichophora forests):
This type of forests occurs in Dhakuri range where altitude ranges up to
2250 m. The forests are generally well-stocked and main associates are
Lyonia ovalifolia, Rhododendron arboreum, etc. and lower storey comprises
Berberis aristata, Coriaria nepalensis, Desmodium elegans, Lonicera quin-
quelocularis, Prinsepia utilis, Rubus ellipticus, R. niveus, Sinarundinaria
falcata, Toona sinensis, etc.
(b) Moru oak forests (Quercus dilatata forests)
It occurs only confined to nallahs above ban and below temperate moist
deciduous forests at an altitude of nearly 2250 m. The upper storey com-
prises Acer caesium, Aesculus indica, Alnus nepalensis, Lyonia ovalifolia,
Rhododendron arboreum, Quercus dilatata, etc., and the lower storey com-
prises Berberis aristata, Clematis montana, Desmodium elegans, Ilex dipy-
rena, Lonicera quinquelocularis, Parthenocissus semicordata, Rhamnus
virgatus, Rubus niveus, Sinarundinaria falcata, Viburnum cotinifolium, etc.
(c) Western mixed forests
This type of forest is found in Khati and Jatoli with altitudes from 2400
to 3000 m. The upper storey comprises Acer sp., Aesculus indica, Abies
spectabilis, Cedrus deodara, Juglans regia, Rhododendron arboreum,
R. campanulatum, Taxus baccata, Quercus dilatata, Q. leucotrichophora,
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 169

etc., and the lower storey comprises Adiantum venustum, Bromus unioloi-
des, Impatiens spp., Lonicera quinquelocularis, Oplismenus undulatifolius,
Strobilanthes atropurpureus, Valeriana jatamansi, Viburnum spp., Viola
pilosa, etc.
(d) Moist temperate deciduous forests
These forests occupy the cool and moist areas within the temperate region
between 2100 to 2750 m. Such forest occupy in between Jatoli and Kathalia.
The upper storey comprises Abies spectabilis, Aesculus indica, Betula alnoi-
des, Juglans regia, Quercus semicarpifolia, Rhododendron campanulatum,
Taxus baccata, etc., and the lower storey comprises Adiantum venustum,
Berberis sp., Bromus unioloides, Habenaria sp., Impatiens spp., Indigofera
cassioides, Lonicera quinquelocularis, Oplismenus undulatifolius, Pyrus
sp., Rosa macrophylla, R. sericea, Rubus niveus, Valeriana sp., Viburnum
grandiflorum, Viola pilosa, etc.
(e) Montane bamboo brakes
The occurrences of this type of ringals are in small patches found below
the Quercus leucotrichophora forests and near nallahs or running streams,
i.e. Loharkhet, Jatoli, Kathalia. It is confined between an altitude of 1500 m
and 2700 m. On higher altitudes, clumps of Gol ringal (Sinarundinaria fal-
cata) are replaced by deo-ringals (Thamnocalamus spathiflorus). Abies
spectabilis and Quercus semicarpifolia are common along with some high-­
level mixed deciduous species are also found.
3. Himalayan dry-temperate forests
This type is found in extremely small strips on the river bank in between Jatoli
and Kathalia, where it has colonized in association with Hippophae salicifolia
and Populus ciliata.
4. Sub-alpine forests
(a) West Himalayan sub-alpine high-level birch forests
It occupies large tracts above 2000 m. The forests are dense and the trees
are short boled and ill formed. The upper storey comprises mainly Betula
utilis, Berberis spp., Lonicera angustifolia, Quercus semicarpifolia,
Rhododendron campanulatum, Rosa sericea, Salix acmophylla, Sorbaria
tomentosa, Viburnum grandiflorum, etc., and the lower storey comprises
Aconitum spp., Anemone obtusiloba, Allium sp., Corydalis sp., Impatiens
spp., Senecio sp., Pedicularis spp., Polygonum vaccinifolium, Potentilla sp.,
Saxifraga sp., Sibbaldia sp., Salvia sp., Thalictrum sp., Viola pilosa, etc.
(b) Sub-alpine pastures
This type of pastures occurs in fragmented patches near Jatoli, Kathalia,
Baloni top, Devikund, Sukhram cave, etc. It comprises shrubs, such as
­Cotoneaster microphyllus, Juniperus sp., Rhododendron campanulatum,
Rosa sericea, Sorbaria tomentosa, Viburnum grandiflorum, etc., and herbs,
viz., Agropyron sp., Brachypodium sp., Bromus spp., Carex spp., Festuca
sp., Juncus spp., Poa spp., etc.
170 R. Manikandan et al.

5. Moist Alpine Scrubs

(a) Deciduous alpine scrubs
It is characterized by dense scrubs of Rhododendron campanulatum with
stunted shrub-like growth of Betula utilis and occurs locally above the tree
limit but extended down to the nallahs or snow slides. It is found above
3350 m in Baloni top, Devikund, Sukhram cave, etc.
(b) Alpine pasture land
It occurs throughout the study area above the timber limit except on rocky
precipitous areas. This type of forest is broken by colonies of Rhododendron
spp. and Juniperus spp. The ground cover is formed by grasses and alpine
herbs mainly Aconitum sp., Anemone sp., Fragaria nubicola, Iris kumaonen-
sis, Potentilla spp., Primula sp., etc.
(b) FAUNA
The present study area is endowed with a rich and abundant animal life.
I. Carnivores
Snow leopard (Panthera uncia), Panther (Panthera pardus), Jackal (Canis
aureus), Leopard cat (Felis bengalensis), Fishing cat (Felis vevirina), Indian
fox (Vulpus bengalensis), Jackal (Felis chaus), Indian grey mongoose
(Herpestes edwardsii), Yellow-throated pine marten (Martes flavigula), etc.
II. Herbivores
Sambar (Cervus unicolor), Himalayan tahr (Hemitragus jemlahicus),
Himalayan goat antelope (Naemorhedus goral), Blue sheep (Pseudois nayaur),
Barking deer (Muntiacus muntjak), Wild boar (Sus scrofa cristatus), Musk deer
(Moschus moschiferus), Black bear (Selenarctos thibetanus), Brown bear
(Ursus arctos), Giant flying squirrel (Petaurista petaurista), Orange bellied
Himalayan squirrel (Dremomys lokriah), Porcupine (Hystrix indica), Common
langur (Presbytes entellus), etc.
III. Avifauna
The bird life in the present study area is abundant and outstanding. Some of
the birds, such as Impeyan pheasant (Lophophorus impejanus), Koklass
medium tailed Himalayan pheasant (Pucrasia macrolopha), Cheer pheasant
(Catreus wallichii), Western tragopan (Tragopan melanocephalus), Rufous
turtle dove (Streptopelia decaocto), Green pigeon (Treron sphenurus), Snow
partridge (Lerwa lerwa), etc.
IV. Reptiles
Common Indian krait (Bungarus caeruleuns), Banded krait (B. fasciatus),
Indian python (Python molurus), Russell’s viper (Vipera russelii), Common
Indian monitor (Varanus bengalensis), Indian cobra (Naja naja), King cobra
(Ophiophagus hannah), Himalayan pit viper (Agkistrodon himalayanus), Saw-­
scaled viper (Echis carinatus), Coral snake (Calliophis sp.), etc.
V. Fishes
Hill trout (Schizothorax spp.), Indian trout (Raiamas bola), Garra spp., Tor
spp., Nemacheilus spp., etc.
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 171

(a) Endangered Animals: 7 species.

The present study area is also the natural habitat of several varieties of
wild endangered mammals namely Snow leopard (Panthera uncia), Black
bear (Selenarctos thibetanus), Brown bear (Ursus arctos), Musk deer
(Moschus chrysogaster), Bharal (Pseudois nayaur), Himalayan tahr
(Hemitragus jemlahicus) and Serow (Capricornis sumatraensis).
(b) Endangered birds: 8 species.
The endangered birds found in the area are Monal pheasant (Lophophorus
impejanus), Koklass pheasant (Pucrasia macrolopha), Western tragopan
(Tragopan melanoplus), Himalayan snow cock (Tetraogallus himalayensis),
Golden eagle (Aquila chrysaetos), Steppe eagle (Aquila nipalensis), Black
eagle (Ictinaetus malaiensis) and Bearded vulture (Gypaetus barbatus).

3 Results

Floristic composition of Sunderdhunga valley, Uttarakhand reveals that 99 families,

434 genera and 705 species of Angiosperms, were recorded. Among these, Dicots
represent 80 families, 348 genera and 586 species, whereas Monocots represent 19
families, 86 genera and 119 species were recorded from the study area. Besides,
Gymnosperms represented with 7 species under 5 genera belonging to 4 families
and Pteridophytes represented by 47 species under 28 genera belonging to 16 fami-
lies. Also information on ethno-medicinal plants of the valley, comprising 83 spe-
cies of Angiosperms, of these 10 species are Critically Endangered, 13 Endangered,
9 Vulnerable and 7 Least Concern are provided here. The documentation of plants
with families are tabularized in Table 1 (Plates 1, 2, 3, and 4).

3.1 Ethno-Medicinal Plants

The following some wild ethno-medicinal plants have been reported from the valley
are Aconitum heterophyllum, A. violaceum, Anaphalis contorta, A. triplinervis,
A. virgata, Androsace sarmentosa, Anemone vitifolia, Angelica glauca, Aster albe-
scens, Cassiope fastigiata, Chaerophyllum villosum, Corydalis cashmeriana,
C. meifolia, Cotoneaster duthieana, Cynoglossum nervosum, C. wallichii, C. zeyl-
anicum, Dactylorhiza hatagirea, Delphinium brunonianum, Epilobium angustifo-
lium, Fritillaria roylei, Galium asperuloides, Gaultheria trichophylla, Gentiana
albicalyx, G. stipitata, Gentianella pedunculata, Gnaphalium hypoleucum,
Impatiens sulcata, Jurinea dolomiaea, Malaxis muscifera, Meconopsis aculeata,
Nardostachys grandiflora, Nepeta eriostachya, Oxyria digyna, Pedicularis hoff-
meisteri, P. punctata, Picrorhiza kurrooa, Polygonum cognatum, P. molliaeforme,
P. polystachyum, Potentilla atrosanguinea, P. cuneata, Primula elliptica, P. macro-
phylla, Ranunculus hirtellus, Rheum webbianum, Rhododendron anthopogon,
172 R. Manikandan et al.

Table 1 Documentation of plants in Sunderdhunga valley

Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Ranunculaceae
Aconitum ferox Wall. ex Herb 3250 Plant is used to cure fever, enlarged
Ser. spleen, joint pains and
inflammation
Aconitum heterophyllum Herb 3400 Tuber extract is mixed with honey EN
Wall. ex Royle is used to cure fever
Aconitum laeve Royle Herb 2700 Root paste is used to treat
rheumatism, neuralgia and sciatica.
The dried root powder is used in
fever and body pains
Aconitum violaceum Herb 3200 Paste of tuber is applied on insect VU
Jacquem. ex Stapf stings
Anemonastrum Herb 2600 The oil extracted from the plant is
obtusilobum (D.Don) used to treat rheumatism
Mosyakin
Anemone raui Goel & Herb 2650 The plant possess anti-­
U.C. Bhattach. inflammatory, antioxidant, and
antimicrobial activities
Aquilegia pubiflora Wall Herb 3000 Plant cures skin problems and
ex Royle nervous disorders
Calathodes palmata Herb 2500– Plant is used to treat rheumatism
Hook.f. & Thomson 3500
Clematis barbellata Climber 2500 Leaf juice is used to cure stomach
Edgew. pain, indigestion, diarrhoea and
dysentery
Clematis buchananiana Climber 2600 Roots are used for treating sinusitis,
DC. headache and inflammation
Clematis montana Climber 2800 Plant paste is applied on blisters,
Buch.-Ham. ex DC. purulent wounds and ulcers
Clematis roylei Rehder Climber 2200 Plant is used against rheumatism,
head ache, varicose veins, syphilis,
gout, bone disorders, etc
Delphinium Herb 3300 Leaf decoction is mixed with honey
cashmerianum Royle to cure cough and cold
Delphinium vestitum Herb 2950 Plant is used to treat intestinal
Wall. ex Royle worms, fluid retention, poor
appetite, and insomnia
Eriocapitella rivularis Herb 2600 Leaf paste is applied to relieve head
(Buch.-Ham. ex DC.) ache. The paste of roots is applied
Christenh. & Byng on boils
Eriocapitella rupicola Herb 3100
(Cambess.) Christenh. &
Byng
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 173

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Eriocapitella vitifolia Herb 2680 Paste of roots and leaves are
(Buch.-Ham. ex DC.) applied externally on ringworm
Nakai
Oxygraphis endlicheri Herb 3400
(Walp.) Bennet & Sum.
Chandra
Ranunculus diffusus DC. Herb 2000 Leaves and stems used in
rheumatism
Ranunculus hirtellus Herb 1900 Plant paste externally used on
Royle wounds
Thalictrum alpinum L. Herb 2000 Plant is used for heat-clearing and
detoxification/
Thalictrum foliolosum Herb 2100 Root is a tonic for dyspepsia, peptic
DC. ulcers, indigestion, fevers,
toothache, haemorrhoids and
ophthalmia. Leaf juice is applied to
boils and pimples
Trollius acaulis Lindl. Herb 3000 Plant is used to treat respiratory
tract infections, pharyngitis,
tonsillitis, bronchitis
Paeoniaceae
Paeonia emodi Royle Herb 2000 Leaves used against urinary
infections
Schisandraceae
Schisandra grandiflora Climber 2200 Fruits edible
(Wall.) Hook. f. &
Thomson
Menispermaceae
Cissampelos pariera L. Climber 2000 Plant used in the treatment of ulcer,
wound, rheumatism, fever, asthma,
cholera, diarrhoea, inflammation,
snake bite, malaria, rabies
Cocculus laurifolius DC. Shrub 2000 Plant cures rheumatic pain,
epilepsy, hypertension, abdominal
pain, headache, and scalp wounds
Berberidaceae
Berberis aristata DC. Shrub 2600 Plant is used against opthalmia, LC
fever. It is a blood purifier
Berberis asiatica Roxb. Shrub 2200 Plant is used in treating ulcers,
ex DC. urethral discharges, ophthalmia,
jaundice and fever
Berberis chitria Shrub 2700 Plant cures jaundice, splenomegaly,
Buch.-Ham. ex Lindl. leprosy, rheumatism, fever, snake
bite
(continued)
174 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Berberis jaeschkeana Shrub 2650 Roots and stems are used to make
C.K.Schneid. an eyewash to treat a range of eye
problems. Fruits edible
Berberis kumaonensis Shrub 2650 Plant can act as a good blood
C.K.Schneid. purifier and treat jaundice
Berberis napaulensis Tree 2000– Plant treats dysentery. The bark
(DC.) Spreng. 2900 decoction is used as eye drops to
treat eye inflammation
Papaveraceae
Papaver guilelmi-­ Herb 3200 Extract of petals is used to cure
waldemarii (Klotzsch) fever
Christenh. & Byng
Lardizabalaceae
Stauntonia latifolia Climber 3000 Fruit pulp is used to cure dyspepsia
(Wall.) R.Br. ex Wall. and flatulence
Fumariaceae
Corydalis cashmeriana Herb 2900 Root extracts applied externally to
Royle reduce body swelling and
inflammation
Corydalis cornuta Royle Herb 2850 Leaf juice mixed with equal
amount of water is taken orally to
cure bone fractures, torn ligaments
Corydalis diphylla Wall. Herb 1900 Plant is used for weight loss and
body care
Corydalis govaniana Herb 2800 Plant extract is used in eye diseases
Wall.
Corydalis meifolia Wall. Herb 3150 Root extract cures fever
Corydalis thyrsiflora Herb 3250 Plant cures stomach problems and
Prain. emotional problems
Fumaria indica Herb 2150 Plant is used in diarrhoea, fever,
(Hausskn.) Pugsley influenza and liver diseases
Brassicaceae
Arabis pterosperma Herb 2700
Edgew.
Arcyosperma Herb 3050
primulifolium (Thomson)
O.E. Schulz
Capsella bursa-pastoris Herb 1600 Plant is used as vegetable and in the LC
(L.) Medik. treatment of eye diseases and
dysentery
Cardamine flexuosa With. Herb 2850 Leaves edible. Leaves and seeds
used to treat skin infections
Cardamine impatiens L. Herb 2200 Plant is antirheumatic, diuretic and
stimulant. Leaves and young shoots
are used as vegetable
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 175

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Descurainia sophia (L.) Herb 2200– Plant is antipyretic, antipruritic,
Webb ex Prantl 4000 purgative, helminthic, digestive
tonic, cardiotonic, astringent
Nasturtium officinale Herb 3000 Plant cures urinary tract infections, LC
W.T.Aiton swollen airways, cough, bronchitis,
and mild muscular pain
Thlaspi arvense L. Herb 2000 Plant is anti-inflammatory and
febrifuge, used in the treatment of
pus in the lungs, renal
inflammation, appendicitis, seminal
and vaginal discharges
Violaceae
Viola betonicifolia var. Herb 2100 Plant is diaphoretic, purgative,
nepalensis (Ging.) Back. astringent, anticancer, antipyretic,
and to treat nervous disorders,
cough, skin diseases, sinusitis,
kidney diseases, pneumonia, and
bronchitis
Viola biflora L. Herb 2800 Plant used in stomach and intestinal
swellings, digestion problems, gas,
heartburn, gall bladder disorders,
and loss of appetite
Viola hamiltoniana Herb 2500
D. Don
Viola pilosa Blume Herb 2000 Flower extract is used to cure
jaundice
Caryophyllaceae
Acanthophyllum Herb 2850
cerastioides (D. Don)
Madhani & Zarre
Arenaria neelgherrensis Herb 2050 Plant is used to treat urinary tract
Wight & Arn. disorders, kidney and bladder
stones
Eremogone festucoides Herb 2050 Taken as tonic to increase lactation
(Benth.) Pusalkar &
D.K. Singh
Sagina saginoides (L.) Herb 2700 Plant is used to treat food poisoning
H. Karst. and diarrheoa
Silene setaesperma Herb 2550
Majumdar
Silene vulgaris (Moench) Herb 2500 The extract of young shoot is used LC
Garcke to treat bronchitis and asthma
Stellaria decumbens Herb 2700
Edgew.
(continued)
176 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Stellaria media (L.) Vill. Herb 2100 Plant is used to relieve itching and LC
psoriasis and applied as a plaster
for broken bones and swellings
Stellaria monosperma Herb 2200 Plant parts can be used as vegetable
var. paniculata (Edgew.)
Majumdar
Tamaricaceae
Myricaria germanica (L.) Shrub 1800– Wood is used as fuel. Decoction of
Desv. 4000 the bark is aperient, used to treat
jaundice
Hypericaceae
Hypericum choisyanum Shrub 2050 Plant extracts an essential oil
Wall. ex N.Robson
Hypericum elodeoides Herb 2400 Plant is used in the treatment for
Choisy anxiety, depression, cuts, and burns
Hypericum hookerianum Shrub 2500 Plant is a potential wound-healing
Wight & Arn. agent
Hypericum japonicum Herb 2500 Plant is used in the treatment of
Thunb. asthma and dysentery, hepatitis,
appendicitis, boils and abscesses
Hypericum oblongifolium Shrub 2100 Plant is used against hepatitis,
Choisy gastric ulcers, and bee stings
Hypericum uralum Herb 2200
Buch.-Ham. ex D. Don
Theaceae
Eurya acuminata DC. Tree 2150 Leaf decoction is used to cure
cholera, diarrhoea and other
stomach diseases
Geraniaceae
Geranium collinum Herb 2940 Plant cures rheumatism, gout,
Stephan ex Willd. dysentery, external and internal
bleeding, eczema, scabies
Geranium nepalense Herb 2850 Plant used in the treatment of
Sweet. nervous disorders, limb numbness,
rheumatism, renal diseases
Geranium ocellatum Herb 2200 Decoction of whole plant is used to
Jacquem. ex Cambess. control dysentery in goats and
sheep
Geranium robertianum L. Herb 2740 Plant used to treat diarrheoa, to
improve functioning of the liver
and gallbladder, for toothache and
nosebleeds
Geranium wallichianum Herb 2950 Plant used in the treatment of LC
D. Don ex Sweet. peptic ulcers, toothache
Oxalidaceaea
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 177

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Oxalis corniculata L. Herb 2000 Plant is used in influenza, fever,
urinary tract infections, enteritis,
diarrhoea, traumatic injuries,
sprains and poisonous snake bites
Oxalis dehradunensis Herb 2800 Plant used in the treatment of fever,
Raizada pain, inflammation and wound
healing
Balsaminaceae
Impatiens devendrae Herb 2700
Pusalkar
Impatiens edgeworthii Herb 2250 Plant is used for gonorrhea, burns
Hook.f.
Impatiens racemosa DC. Herb 2150 Leaves and roots paste mixed with
mustard oil applied for rheumatic
pains
Impatiens scabrida DC. Herb 2000
Impatiens sulcata Wall. Herb 2750 Paste of flower buds applied on
pimples
Impatiens thomsonii Herb 2100
Hook. f.
Rutaceae
Boenninghausenia Herb 2100 Leaf paste is applied to cuts and
albiflora (Hook.) Rchb. wounds. Crushed leaves can be
ex Meisn. placed in the nostrils to treat
malaria
Skimmia anquetilia Shrub 2730 Leaves are used in religious
N.P.Taylor & Airy Shaw ceremonies and also as incense
‘dhup’
Skimmia laureola (DC.) Shrub 2400 Leaves are used in the treatment of
Decne. smallpox
Zanthoxylum oxyphyllum Shrub 2065 Bark is used in the treatment of
Edgew. rheumatism. A paste made from
immature fruits is held between the
teeth for about 10 minutes to
relieve toothache
Aquifoliaceae
Ilex dipyrena Wall. Tree 2200 The wood is used for fuel LC
Celastraceae
Euonymus echinatus Shrub 2700 Plant cures respiratory problems, LC
Wall. asthma. The root extract is effective
in treating whooping cough,
malarial fever and renal colic
Euonymus tingens Wall. Tree 2230 The juice of the bark is used in the
treatment of eye diseases, chronic
constipation and dyspepsia
(continued)
178 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Rhamnaceae
Rhamnus procumbens Shrub 2000 Plant is used as cardiac stimulant,
Edgew. CNS depressant and analgesic
Rhamnus purpurea Shrub 2700–
Edgew. 3000
Rhamnus virgata Roxb. Shrub 1950 The fruit is used in the treatment of LC
spleen disorders
Vitaceae
Ampelocissus latifolia Climber 2050 Plant used in the treatment of bone
(Roxb.) Planch. fractures, dysentery, leucorrhoea,
dental problems, stomach pain,
gout, tuberculosis, dyspepsia,
indigestion, body weakness
Parthenocissus Climber 2100 The poultice of the roots is used to
semicordata (Wall.) set dislocated bones
Planch.
Parthenocissus Climber 1900– Fruits edible
semicordata var. roylei 3000
(King ex R.Parker)
Nazim. & Qaiser
Tetrastigma obtectum Climber 2100 Plant possess anticancer, anti-­
(Wall. ex M.A. Lawson) inflammatory, antimicrobial
Planch. ex Franch. activities
Hippocastanaceae
Aesculus indica (Wall. ex Tree 2035 Plant is used in skin diseases, LC
Cambess.) Hook.f. rheumatism, headache
Aceraceae
Acer acuminatum Wall. Tree 2450 Leaves are used as a tea substitute LC
ex D. Don
Acer caesium Wall. ex Tree 2400 Plant is anti-rheumatic, purgative, LC
Brandis anti-inflammatory, emetic
Acer cappadocicum Gled. Tree 2350 Wood is used for construction, LC
ploughs, bedsteads and poles to
carry loads
Acer oblongum Wall. ex Tree 2300 Wood is used for agricultural LC
DC. implements, minor construction,
cups
Acer villosum Wall. Tree 2800 The wood is used for agricultural LC
implements. Leaves used as fodder
Staphyleaceae
Staphylea emodi Wall. ex Shrub 2100 Plant is used for making walking
Brandis sticks
Sabiaceae
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 179

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Meliosma dilleniifolia Tree 2200 Good fodder
(Wall. ex Wight & Arn.)
Walp.
Anacardiaceae
Pistacia chinensis subsp. Tree 2100 Plant used in the treatment of
integerrima (J.L. Stewart) asthma, diarrheoa, diabetes, liver
Rech.f. diseases, fever, pain and
inflammation
Brucea javanica (L.) Tree 2100 Leaves are used against enlarged LC
Merr. spleen, scurf, ringworm, boils and
centipede bites
Toxicodendron wallichii Tree 2100 Leaf juice is a corrosive vesicant LC
(Hook.f.) Kuntze
Papilionaceae
Astragalus chlorostachys Shrub 2950 Root juice taken as a tonic for
Lindl. longevity and strength
Astragalus himalayanus Herb 2750 Powdered flowers and seeds are
Klotzsch given in strangury
Biancaea decapetala Climber 2050 Roots, stems and pods act as pain LC
(Roth) O.Deg. reliever. Also the paste is applied to
burns
Campylotropis speciosa Shrub 2300
subsp. eriocarpa
(Schindl.) Iokawa & H.
Ohashi
Dumasia villosa DC. Climber 2500 Seeds contain essential oil LC
Hylodesmum podocarpum Herb 2100 Plant is used to cure fever, malaria,
subsp. oxyphyllum (DC.) coughs and bleeding wounds
H. Ohashi & R.R. Mill
Leptodesmia microphylla Shrub 1900
(Thunb.) H. Ohashi &
K. Ohashi
Lespedeza gerardiana Herb 2560 Seeds crushed and used for body
Wall. ex Maxim. massage
lndigofera cylindrica Shrub 2500 Plant cures cough and cold
Grah. & Baker.
Lndigofera heterantha Shrub 2100 Flowers are boiled and pickled.
Wall. ex Brandis Branches are used to make basket,
twig bridges
Lotus corniculatus L. Herb 2050 Plant is used against skin LC
inflammation
Ototropis multiflora (DC.) Shrub 2050 Branches and flowers are used for
H. Ohashi & K. Ohashi reducing fever by inducing sweat
Parochetus communis Creeper 2000– LC
Buch.-Ham. ex D.Don 3000
(continued)
180 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Piptanthus nepalensis Shrub 2150
(Hook.) Sweet
Senna occidentalis (L.) Shrub 1700 Plant is diuretic, laxative, blood LC
Link. purifier, antibacterial, and
antifungal. It is used in the
treatment of haemorrhoids, gout,
rheumatism, diabetes, whooping
cough
Senna tora (L.) Roxb. Shrub 1400 Young shoots and leaves are cooked
and eaten. The powdered and
fermented leaves are used as a
condiment
Shuteria involucrata Climber 2300 A paste of the plant is used to set
(Wall.) Wight & Arn. ex dislocated bones
Walp.
Smithia ciliata Royle Herb 1300
Sunhangia elegans (DC.) Shrub 2600 The juice of the bark is used in the
H. Ohashi & K. Ohashi treatment of peptic ulcers
Tateishia concinna (DC.) Shrub 2100
H. Ohashi & K. Ohashi
Trifolium repens L. Herb 2700 A tincture of the leaves is applied LC
to gout. An infusion of the flowers
is used as eyewash
Trigonella gracilis Benth. Herb 2200– A paste made from the plant is
3400 applied topically to treat skin
diseases
Vicia rigidula Royle Climber 1800
Zornia gibbosa Span. Herb 1200 Plant is anti-inflammatory and
astringent; is used in the treatment
of inflammations and dysentery
Rosaceae
Agrimonia pilosa Ledeb. Herb 2000 Plant is used for abdominal pain, LC
sore throat, headache, heat stroke,
boils, eczema and taeniasis
Agrimonia pilosa Ledeb. Herb 1000– Leaf decoction is effective against
subsp. japonica (Miq.) 3000 liver problems
Hara var. japonica (Miq.)
Nakai
Argentina lineata (Trevir.) Herb 2800
Soják
Argentina micropetala Herb 3100 Stolons and stems are astringent
(D.Don) Soják
Argentina microphylla Herb 3500
(D.Don) Soják
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 181

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Argentina polyphylla Herb 3200
(Wall. ex Lehm.) Soják
Aruncus dioicus (Walter) Herb 3050 A tea made from the roots is used
Fernald to allay bleeding after child birth, to
reduce profuse urination and to
treat stomach pains, diarrhoea,
gonorrhoea, fevers and internal
bleeding
Cotoneaster acuminatus Shrub 3000
Lindl.
Cotoneaster adpressus Shrub 2550 Young fruits taken to cure diarrhoea
Bois
Cotoneaster affinis Lindl. Shrub 3000
Cotoneaster microphyllus Shrub 2650 Stems are astringent. Leaves used
Wall. ex Lindl. as incense. Fruits edible
Dasiphora fruticosa (L.) Herb 2340
Rydb.
Filipendula vestita (Wall. Herb 3030
ex G.Don) Maxim.
Fragaria daltoniana Herb 3000 The juice of root is used in the
J.Gay treatment of fever. Fruits edible
Fragaria nubicola (Lindl. Herb 2750 The unripe fruit is chewed to treat
ex Hook.f.) Lacaita blemishes on tongue. Fruits edible
Geum elatum Wall. ex Herb 3000 Plant used in diarrheoa,
G.Don inflammation, haemorrhoids and
stomach problems
Geum urbanum L. Herb 2340 Plant is used to treat problems
affecting the mouth, throat and
gastrointestinal tract. It reduces
irritation of the stomach and gut
Griffitharia vestita (Wall. Tree 1960
ex G.Don) Rushforth
Potentilla argyrophylla Herb 2650
Wall. ex. Lehm.
Potentilla atrosanguinea Herb 3060 Crushed flowers applied to reduce
G.Lodd. ex D.Don the pain caused by insect stings
Potentilla crantzii Herb 1065
(Crantz) Beck ex Fritsch
Potentilla eriocarpa Wall. Herb 3300
ex Lehm.
Potentilla fulgens Wall. ex Shrub 1800 Root peel extract is used to get rid
Sims of intestinal parasitic infections
Potentilla indica Herb 2400
(Andrews) Th.Wolf
(continued)
182 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Potentilla nepalensis Herb 2100 Root is depurative. Ashes mixed
Hook. with oil and applied to burns
Potentilla purpurea Herb 3040 Plant used in the treatment of
(Royle) Hook.f. inflammations, wounds
Potentilla sundaica Herb 1400 Decoction of the plant is used in the
(Blume) W. Theob. treatment of colds, influenza, sore
throat
Prunus cornuta (Wall. ex Tree 2700 Fruits and seeds are edible
Royle) Steud.
Prunus nepalensis Ser. Tree 2500 A green dye can be obtained from
the leaves
Rosa brunonii Lindl. Climber 1700 Plant stimulates wound healing
Rosa macrophylla Lindl. Shrub 2200 Fruit paste is used against eye sight
issues
Rosa sericea Lindl. Shrub 2630 Plant cures uterine diseases. A
paste of the flowers is applied on
forehead to cure headache
Rubus ellipticus Sm. Shrub 2050 Plant juice can be used to treat LC
coughs, fevers, colic and sore throat
Rubus nepalensis Shrub 2500 Fruits edible
(Hook.f.) Kuntze
Rubus niveus Thunb. Shrub 2100 Fruits edible
Rubus paniculatus Sm. Climber 1750 A paste of the bark is used in the
treatment of scabies. Leaf paste is
used as a poultice on sprains
Rubus rosifolius Sm. Shrub 2200 A decoction of the root is used in
the treatment of diarrhoea. Leaf
paste is applied to itches
Sanguisorba diandra Herb 3000
(Hook.f.) Nordbong
Sibbaldia cuneata Edgew. Herb 3035
Sibbaldia cuneifolia Herb 3000
(Bertol.) Paule & Soják
Sorbus foliolosa (Wall.) Shrub 3000 LC
Spach
Spiraea bella Sims Shrub 3050
Spiraea canescens D.Don Shrub 1700 Plant is used to make walking LC
sticks
Saxifragaceae
Astilbe rivularis Shrub 2300 Plant is used for the treatment of
Buch.-Ham. ex D.Don ulcer, bleeding during child birth,
inflammation, body ache, diarrhoea
and dysentery
Bergenia ciliata (Haw.) Herb 2100 Plant treats urinary troubles. Leaf LC
Sternb. juice used as ear drops
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 183

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Bergenia pacumbis Herb 1500 Plant is a tonic in the treatment of LC
(Buch.-Ham. ex D.Don) fevers, diarrhoea and pulmonary
C.Y.Wu & J.T.Pan affections
Bergenia stracheyi Herb 3500
(Hook.f. & Thomson)
Engl.
Chrysosplenium tenellum Herb 2450
Hook.f. & Thomson
Chrysosplenium Herb 2840
trichospermum Edgew. ex
Hook.f. & Thomson
Micranthes pseudopallida Herb 2795
(Engl. & Irmsch.)
Losinsk.
Saxifraga asarifolia Herb 3200–
Sternb. 4600
Saxifraga brachypoda Herb 2960
D.Don
Saxifraga brunonis Wall Herb 3250
ex Ser.
Saxifraga diversifolia Herb 2400–
Wall. ex. DC. var. 4600
parnassifolia (D.Don)
Engl.
Saxifraga filicaulis Wall. Herb 2050
ex Ser.
Saxifraga flagellaris Herb 3000
Willd.
Saxifraga jacquemontiana Herb 4000 Plant extract is act as liver tonic
Decne.
Saxifraga parnassifolia Herb 3000
D.Don
Saxifraga sibirica L. Herb 3500
Saxifraga stenophylla Herb 2500 Root paste applied to cure
Royle toothache
Parnassiaceae
Parnassia nubicola Wall. Herb 3300 Plant extract is used for the
ex Royle treatment of food poisoning.
Rootstocks are used externally in
snakebites
Hydrangeaceae
Deutzia compacta Craib Shrub 2500
Deutzia staminea R.Br. ex Shrub 2250 Plant is diuretic
Wall.
(continued)
184 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Hydranzea anomala Shrub 2100 A boiled concoction of the leaves is
D.Don used to make a syrup
Philadelphus tomentosus Shrub 2000
Wall. ex G.Don
Grossulariaceae
Ribes glaciale Wall. Shrub 3000 Fruits edible
Ribes griffithii Hook.f. & Shrub 2500 Fruits edible
Thomson
Ribes himalense Royle ex Shrub 2000– The Leaf juice is used in the
Decne. 3300 treatment of diarrhoea and
dysentery
Crassulaceae
Crassula campestris Herb 3000 LC
(Eckl. & Zeyh.) Endl.
Hylotelephium ewersii Herb 3250
(Ledeb.) H.Ohba
Rhodiola bupleuroides Herb 3500 Juice of rhizomes given to cure
(Wall. ex Hook.f. & whooping cough
Thomson) S.H. Fu
Rhodiola Herb 2500
chrysanthemifolia
(H.Lév.) S.H. Fu
Rhodiola heterodonta Herb 3500 Shoots are used as a remedy against
(Hook. f. & Thomson) cold, cough and lung infections
Boriss.
Rhodiola quadrifida Herb 2860 Plant act as a tonic, antidepressant
(Pall.) Fisch. & C.A. Mey and anti-inflammatory drug
Rhodiola sinuata (Royle Herb 3000 Plant is used for increasing energy,
ex Edgew.) S.H. Fu endurance, strength, and mental
capacity
Rhodiola wallichiana Herb 3050 Plant is used in the treatment of
(Hook.) S.H. Fu cardiovascular diseases, diarrheoa,
hysteria, hernias, headache
Sedum multicaule Wall. Herb 3032 Plant is emollient and vulnerary
ex Lindl.
Sedum oreades (Decne.) Herb 3600 Leaf decoction is taken to cure
Raym.-Hamet cough and cold
Tillaea pentandra Royle Herb 1900– Root decoction is laxative and used
2500 to treat fevers
Melastomaceae
Osbeckia stellata Herb 2300
Buch.-Ham. ex D.Don
Onagraceae
Circaea alpina L. Herb 2100 Plant used to treat tumours, fresh
cuts or wounds
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 185

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Epilobium amurense Herb 3200
Hausskn.
Epilobium angustifolium Herb 2450 Root paste is applied for wounds LC
L.
Epilobium latifolium L. Herb 2780 Plant is used in the treatment of LC
fevers, inflammations, itching
pimples
Epilobium palustre L. Herb 4500 LC
Epilobium roseum Herb 1500–
(Schreb.) Schreb. 2000
Epilobium royleanum Herb 3300
Hausskn.
Cucurbitaceae
Solena amplexicaulis Climber 2600 Plant is used in anorexia, digestive
(Lam.) Gandhi problems, flatulence, asthma,
gonorrhoea, inflammation
Begoniaceae
Begonia picta Sm. Herb 2900 Plant juice is taken to relieve
headache, peptic ulcer. The paste is
applied to stop bleeding from cuts
and wounds
Apiaceae
Acronema tenerum (DC.) Herb 2800
Edgew.
Angelica glauca Edgew. Herb 3350 Root powder is mixed with milk EN
given in empty stomach to cure
severe stomach pain
Bupleurum hamiltonii Herb 3000 Root is used to regulate the
N.P. Balakr. metabolism, for the treatment of
fever, pain and inflammation
Bupleurum lanceolatum Herb 1400
Wall. ex DC.
Bupleurum longicaule Herb 3000 Plant is used against chronic
Wall ex DC. hepatitis, nephrotic syndrome and
autoimmune diseases
Centella asiatica (L.) Herb 600 Plant is a brain tonic, to improve LN
Urb. memory power also is used to treat
leprosy, lupus, varicose ulcers,
eczema, psoriasis, diarrhoea, fever,
amenorrhoea
Chaerophyllum reflexum Herb 3200
var. acuminatum (Lindl.)
Hedge & Lamond
Chaerophyllum villosum Herb 3000 Cooked roots are nutritious
Wall. ex DC.
(continued)
186 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Cortia candollei (DC.) Herb 2650
Leute
Heracleum candicans Herb 1800– Root is used for the treatment of
Wall.ex DC. 5000 leucoderma. Decoction of root and
stem cures fever. Root paste is
applied on snake bite
Hydrocotyle javanica Herb 2800 Plant is used to cure sore throats LC
Thunb. and lungs. Leaf juice is used as eye
drops to cure eye infection. Leaf
paste is used in dressing of wounds
to reduce swelling
Hydrocotyle Creeper 600– Plant cures fevers, wounds and LC
sibthorpioides Lam. 2500 boils
Hymenidium brunonis Herb 4000
(DC.) Lindl.
Hymenolaena candollei Herb 3800
DC.
Ligusticopsis wallichiana Herb 2900– Leaf extract applied on cut and
(DC.) Pimenov & 3100 wounds
Kljuykov
Ligusticum striatum DC. Herb 1500– Plant is used in the treatment of
3500 migraine, cardiovascular and
cerebrovascular diseases
Pimpinella diversifolia Herb 2300 Leaves used to treat stomach ache
DC.
Sanicula elata Buch.- Herb 2100
Ham. ex D.Don
Selinum vaginatum Herb 3000
(Edgew.) C.B.Clarke
Trachydium roylei Lindl. Herb 2990 Plant contains an essential oil that
is used in the treatment of
inflammation
Vicatia coniifolia DC. Herb 2800
Araliaceae
Hedera nepalensis Climber 2000 Plant used in the treatment of
K. Koch. diabetes
Cornaceae
Cornus macrophylla Wall. Tree 2400 Plant cures malaria, allergy, LC
inflammation, diabetes, cancer
Caprifoliaceae
Leycesteria formosa Wall. Shrub 2550 The hollow stems can be made into
whistles and flutes
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 187

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Lonicera angustifolia var. Shrub 2700
myrtillus (Hook.f. &
Thomson) Q.E.Yang,
Landrein, Borosova &
Osborne
Lonicera hispida Pall. ex Shrub 2900–
Schult. 4500
Lonicera japonica Thunb. Climber 1000 Plant is used to cure digestive
disorders, pain and swelling of
small intestine
Lonicera purpurascens Shrub 1500
(Jacquem. ex Decne.)
Walp.
Lonicera Shrub 2100 Powdered leaves are used for
quinquelocularis Hardw. healing wounds. Plant material is
used as fuel
Viburnum cotinifolium Shrub 2850 Leaf extract is used for the
D.Don treatment of menorrhagia. Fruits
edible
Viburnum erubescens Shrub 1500– The juice of the roots is used in the
Wall. ex DC. 2700 treatment of coughs. Fruits edible
Viburnum grandiflorum Shrub 2550 The fruit is used in the treatment of
Wall. ex DC. typhoid and whooping cough
Viburnum mullaha Shrub 2200 Juice of fruit is used to treat LC
Buch.-Ham.ex D.Don indigestion
Viburnum nervosum Shrub 2700 Fruits edible
D.Don
Rubiaceae
Galium acutum Edgew. Herb 3000
Galium aparine L. Herb 2100 Plant is used to treat painful
urination, infected lymph nodes,
psoriasis
Galium asperifolium Herb 2800
Wall.
Galium asperuloides Herb 2800 Plant paste applied on skin itching
Edgew.
Galium triflorum Michx. Herb 1500– LC
3000
Himalrandia tetrasperma Shrub 2050 Plant possess anti-inflammatory,
(Wall. ex Roxb.) anti-bacterial. Antifungal, anti-viral
T. Yamaz. and anti-malarial activities
Leptodermis lanceolata Herb 2000 Bark paste is applied on forehead to
Wall. treat migraine
Rubia cordifolia L. Herb 2600– Plant detoxifies the blood
4500
(continued)
188 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Spermadictyon Shrub 2050 Root extracts are used in the
suaveolens Roxb. treatment of diabetes, rheumatoid
arthritis and bloody dysentery
Valerianaceae
Nardostachys jatamansi Herb 3200 Plant extracts used in heart-pain, CR
(D.Don) DC. fits and rubbed in muscle fracture
to relieve pain also regulate
urination, menstruation and
digestion
Valeriana hardwickei Herb 2860 Plant helps to improve sleep quality
Wall. and reduce blood pressure
Valeriana himalayana Herb 3250 Plant helps reduce sleeping
Grubov disorders, especially insomnia,
anxiety, stress, etc
Valeriana jatamansi Jones Herb 2400 Plants are useful in epilepsy,
ex Roxb. hysteria, hypochondriasis, nervous
unrest, and skin diseases
Dipsacaceae
Dipsacus inermis Wall. Herb 2600 The root is used to promote bone
growth and to correct bone
fractures
Triplostegia glandulifera Herb 3000 Plant cures kidney problems
Wall. ex DC.
Morinaceae
Morina longifolia Wall. Herb 3000 Plant is used in the treatment of
ex DC. stomach disorders, such as
indigestion, vomiting and nausea
Asteraceae
Adenocaulon himalaicum Herb 2750 Plant is used in treating abscesses,
Edgew. haemorrhage
Ageratum conyzoides L. Herb 2500 Plant is used to treat constipation, LC
infective hepatitis, eczema,
epilepsy, fresh wounds, dizziness,
diarrhoea, dysentery, sore eyes,
fever, headache, intestinal worms,
filariasis, vomiting and nausea,
wounds and cuts
Ainsliaea aptera DC. Herb 2150 Roots paste is used to relieve
stomach ache, constipation, fever
Ainsliaea latifolia Herb 2450 Plant used in the treatment of
(D.Don) Sch.-Bip. rheumatism, traumatic injuries,
edema, stomach ache, and anorexia
Allardia glabra Decne. Herb 3700 Plant paste applied to heal wounds
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 189

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Anaphalis busua Herb 2450 Plant is used for diarrhoea,
(Buch.-Ham. ex D.Don.) dysentery and pulmonary
affections. A poultice of flowers or
the whole plant is applied to burns,
sores, ulcers, bruises, swellings and
rheumatic joints
Anaphalis contorta Herb 2300 Smoke of the plant is used as an
(D.Don.) Hook f. insect repellent and paste of young
flower heads applied on pimples
Anaphalis margaritacea Herb 3000 Plant is a good remedy for
(L.) Benth. & Hook f. diarrhoea, dysentery and pulmonary
affections
Anaphalis royleana DC. Herb 2750 Plant is antibacterial, anti-­
inflammatory, antirheumatic,
antiseptic, antiviral, diaphoretic,
expectorate, sedative
Anaphalis triplinervis Herb 2630 Paste of flower heads applied on
(Sims.) C.B Clarke cuts, wounds and boils
Anaphalis virgata Herb 2600 Smoke of the plant used as an
Thomson. ex C.B.Clarke insect repellent and paste of whole
plant applied on wounds
Artemisia capillaris Herb 100– Plant cures liver diseases
Thunb. 2700
Artemisia nilagirica Herb 2000 Seed oil is extracted and massaged
(C.B.Clarke) Pamp. on swollen joints in case of
arthritis, back pain and bone
fractures
Artemisia roxburghiana Herb 2600 Plant used against colic, diarrheoa,
Besser constipation, cramps, indigestion,
worm infestations, vomiting
Artemisia vestita Wall. ex Shrub 2100 The plant is used in anti-­
Besser inflammatory and antifebrile
medicines
Aster albescens (DC.) Herb 2700 Plant extracts cure tooth ache
Wall. ex Hand.-Mazz.
Aster diplostephioides Herb 2800 Flowers are used in the treatment of
(DC.) Benth. ex infectious fevers, influenza, nose
C.B.Clarke bleeds, poisoning, sores
Baccharoides Herb 1700 Seeds used in the treatment of skin
anthelmintica (L.) diseases, scorpion stings
Moench
Bidens pilosa L. Herb 2100 Roots are used to treat constipation
and malaria, toothache
(continued)
190 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Cirsium arvense (L.) Herb 2500 The root is tonic, diuretic,
Scop. astringent, antiphlogistic and
hepatic. It is chewed to cure
toothache. Root decoction is used
to treat worms in children
Cirsium verutum Herb 2200 Root extract is used to relieve
(D.Don.) Spreng. fevers. Root paste is used in the
treatment of stomach disorders. The
fresh root is chewed to treat
nosebleeds and throat pain
Cirsium wallichii DC. Herb 2300 Plant is used to treat fever and nose
bleeding
Cordiofontis peduncularis Herb 2750 Root decoction applied to wounds
(Wall. ex Nees)
G.L.Nesom
Cremanthodium dacaisnei Herb 3000
C.B.Clarke
Dolomiaea macrocephala Herb 3200 Incense of plant used to cure
DC. ex Royle breathing problems
Doronicum kamaonense Herb 2400
(DC.) Alv. Fern
Dubyaea hispida DC. Herb 2440
Duhaldea nervosa (Wall. Herb 1200–
ex DC.) Anderb. 2000
Erigeron alpinus L. Herb 3800 Plant is used for cough, cold,
nausea, gastric and rheumatism
Erigeron multiradiatus Herb 3300 Plant is used in inflammatory
(Lindl. ex DC.) Benth. & diseases
Hook.f.
Eschenbachia japonica Herb 2100
(Thunb.) J.Kost.
Eschenbachia stricta Herb 1550
(Willd.) Raizada
Galinsoga parviflora Cav. Herb 2200 Plant used to treat eczema, wounds
Gamochaeta pensylvanica Herb 4700 Plant is used against diabetes, high
(Willd.) Cabrera blood pressure, stomach ulcers,
diarrheoa, gut infections
Hippolytia longifolia Herb 3600
(Rech.f.) C.Shih
Jacobaea analoga (DC.) Herb 3000–
Veldkamp 3500
Jurinea albescens (DC.) Herb 3050
N.Garcia, Herrando &
Susanna
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 191

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Jurinea auriculata (DC.) Herb 3000
N.Garcia, Herrando &
Susanna
Leibnitzia nepalensis Herb 3200–
(Kunze) Kitam 4600
Leontopodium Herb 3700
himalayanum DC.
Ligularia amplexicaulis Herb 3400 Plant is used in the treatment of
DC. vomiting
Ligularia sibirica (L.) Herb 2750 Leaves cooked and eaten DD
Cass.
Melanoseris brunoniana Herb 2330
(Wall. ex DC.) N.Kilian
& Ze H.Wang
Melanoseris cyanea Herb 2400
(D.Don) Edgew.
Melanoseris macrorhiza Herb 3300 Juice of fresh rootstock is given to
(Royle) N.Kilian stomach pain
Melanoseris violifolia Herb 3000
(Decne.) N.Kilian
Mulgedium lacertianum Herb 3160
Wall. ex DC.
Myriactis wallichii Less. Herb 2730
Neobrachyactis anomala Herb 2900
(DC.) Brouillet
Oreoseris gossypina Herb 2300
(Royle) X.D.Xu &
V.A.Funk
Pentanema orientale Herb 2730
(Lam.) D.Gut.Larr.,
Santos-Vicente, Anderb.,
E.Rico & M.M.Mart.Ort.
Pseudognaphalium affine Herb 2100
(D.Don) Anderb.
Pseudognaphalium Herb 2100 Plant extract applied on cuts and
hypoleucum (DC.) wounds
Hilliard & B.L.Burtt
Saussurea Herb 3500
leontodontoides (DC.)
Sch.Bip.
Saussurea obvallata Herb 4100 Extract of petals applied for septic
(DC.) Sch.Bip. wounds
Saussurea roylei (DC.) Herb 3500 Plant is used in the treatment of
Sch.Bip. wounds Paste of the plant is used as
poultice for joint pains
(continued)
192 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Senecio graciliflorus DC. Herb 2500
Sigesbeckia orientalis L. Herb 2400 Plant used against arthritis,
rheumatism, and gout
Solidago virgaurea L. Herb 2500 Plant is used for gout, joint pain, LC
arthritis, eczema and other skin
diseases
Synotis alata (Wall.ex Herb 2400
DC.) C. Jeffrey &
Y.L. Chen
Synotis chenopodiifolia Herb 2660
(DC.) M.Tang, C.Ren &
Q.E.Yang
Synotis kunthiana (Wall. Herb 3050
ex DC.) Jeffrey &
Y.L.Chen
Synotis rufinervis (DC.) Herb 2400
C. Jeffrey & Y.L.Chen
Tagetes minuta L. Herb 2100 Plant used against digestive tract
problems including poor appetite,
gas, stomach pain, colic, intestinal
worms and dysentery
Taraxacum officinale Herb 4500 Roots extract cures headache LC
F.H.Wigg.
Tragopogon gracilis Herb 2300 Young shoots and fruits can be
D.Don eaten
Xanthium strumarium L. Herb 2000 Plant used in rhinitis, nasal
sinusitis, headache, gastric ulcer,
urticaria, rheumatism, arthritis and
microbial infections
Campanulaceae
Campanula argyrotricha Herb 3020
Wall.ex A.DC.
Campanula pallida Wall. Herb 2300
Codonopsis rotundifolia Climber 3000 Plant act as the protection against
Benth. side effects of radiation treatment,
heartburn
Codonopsis viridis Wall. Climber 1200–
3000
Cyananthus lobatus Wall. Herb 3000 Plant is used in the treatment of
ex Benth. papetic ulcer, serous disorders and
constipation
Cyananthus microphyllus Herb 3300
Edgew.
Lobelia pyramidalis Wall. Herb 1500– Plants are useful in treating asthma,
3000 bronchitis, and fever
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 193

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Ericaceae
Cassiope fastigiata Herb 3100 Incense of whole plant is inhaled to
(Wall.) D.Don ease respiration
Gaultheria Herb 2800 Fruits edible
nummularioides D.Don.
Gaultheria trichophylla Herb 3100 Plant used to given for cattle for
Royle lactation and immune disease
resistant
Lyonia ovalifolia (Wall.) Tree 1750 Young leaves and buds are used LC
Drude externally as an infusion to treat
skin diseases and external parasites
Rhododendron Shrub 3000 Decoction of young shoot given to
anthopogon D.Don cure fever
Rhododendron arboreum Tree 1500– Leaf paste is applied to the LC
Sm. 3300 forehead in the treatment of
headaches. The juice of the bark is
used in coughs, diarrhoea and
dysentery
Rhododendron barbatum Shrub 2400–
Wall ex G. Don 3700
Rhododendron Shrub 3600 Paste of flower buds applied on cuts
campanulatum D. Don.
Rhododendron lepidotum Shrub 2800 Leaf decoction is used against
Wall. ex D.Don colds, coughs, chronic bronchitis,
asthma and excessive mucus
formation in the nose or throat
Monotropaceae
Monotropastrum humile Herb 2500 Plant is used in the treatment of
(D.Don.) H.Hara cough
Primulaceae
Androsace geraniifolia Herb 2700–
Watt 3000
Androsace globifera Herb 2200
Duby
Androsace sarmentosa Herb 2300 Plant is used to cure tumours,
Wall. inflammations, serous fluid
disorders
Lysimachia lobelioides Herb 100–
Wall. 2000
Lysimachia prolifera Herb 2600
Klatt.
Primula denticulata Sm. Herb 3200 Raw flowers are used to make
salads
Primula elliptica Royle Herb 3200 Root paste applied for pimples and
to kill lice
(continued)
194 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Primula macrophylla Herb 3100 Plant extract is given to cure
D.Don urinary complaints
Primula munroi Lindl. Herb 3000–
4500
Primula stuartii Wall. Herb 3500
Myrsinaceae
Myrsine africana L. Shrub 2700 Plant cures skin allergies, boils
Symplocaceae
Symplocos Tree 1100 Plant is astringent, acrid,
cochinchinensis (Lour.) refrigerant, anti-inflammatory,
S. Moore depurative and febrifuge
Symplocos paniculata Tree 2400 Plant used in the treatment of
Miq. dysentery, bowel complaints,
inflammations, snake bites, vaginal
discharges and miscarriages
Symplocos ramosissima Tree 2200 LC
Wall. ex G.Don
Symplocos theifolia Tree 2000
D. Don
Oleaceae
Fraxinus micrantha Tree 2200 Plant is used against malaria and DD
Lingelsh. pneumonia
Jasminum dispermum Climber 2050 The roots and leaves are active
Wall. against ringworm and tapeworm
infections
Osmanthus fragrans Lour. Tree 1300– A paste of stem or bark is used in LC
3000 the treatment of boils, carbuncles,
whooping cough and retinitis
Syringa emodi Wall. ex Tree 2400
Royle
Asclepiadaceae
Marsdenia roylei Wight Climber 2100 The juice of the stem is used in the
treatment of gastric troubles and
peptic ulcers
Vincetoxicum auriculatum Herb 2100
(Royle ex Wight) Kuntze

Gentianaceae
Arnebia benthamii (Wall. Herb 3300 Flowering shoots are used in
ex G.Don) I.M.Johnst. preparation of syrup and jam which
cure fever, tongue and throat
infections, cardiac problems
Arnebia euchroma (Royle Herb 3650 Root extract is applied along with
ex Benth.) I.M.Johnst. hair oil will reduce hair fall
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 195

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Crawfurdia japonica var. Herb 2000–
luteo-viridis (C.B. Clarke) 3200
C.B. Clarke
Cynoglossum lanceolatum Herb 2300
Forssk.
Cynoglossum Herb 2300 Whole plant infusion is used to
microglochin Benth. cure cough and cold
Cynoglossum wallichii Herb 2800
G.Don
Cynoglossum zeylanicum Herb 2850 Decoction of leaves cures cold and
(Sw. ex Lehm.) Thunb. ex cough
Brand
Eritrichium canum Herb 2900
(Benth.) Kitam.
Gentiana albicalyx Herb 2350 Plant extract applied on cut wounds
Burkill.
Gentiana argentea Royle Herb 2400
ex D.Don.
Gentiana capitata Herb 3000
Buch.-Ham. ex D.Don.
Gentiana carinata Herb 3200
(D.Don ex G.Don)
Griseb.
Gentiana pedicellata Herb 700–
(D.Don) Griseb. 3800
Gentiana stipitata Edgew. Herb 2600 Plant juice used to cure fever
Gentiana tubiflora Herb 3500 Whole plant extract with curd is
(G.Don) Griseb. given to cure jaundice
Gentianella pedunculata Herb 2750 Plant extract is used to cure fever
(D.Don) H.Sm.
Hackelia uncinata (Royle Herb 3010
ex Benth.) C.E.C.Fisch.
Halenia elliptica D. Don. Herb 700–
4100
Lasiocaryum munroi Herb 3400–
(C.B.Clarke) I.M.Johnst. 4000
Lomatogonium Herb 3250 Plant cures liver and bile diseases
carinthiacum (Wulfen)
A.Braun
Swertia angustifolia Herb 2300 Decoction of whole plant cures
Buch.-Ham. ex D. Don fever
Swertia chirayita (Roxb.) Herb 1900 Plant treats liver disorders, malaria,
H.Karst. and diabetes
Swertia cordata (G.Don) Herb 2900 Plant shows antioxidant,
Wall. ex C.B.Clarke antibacterial and antidiabetic
activities
(continued)
196 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Swertia cuneata D. Don Herb 3200 Plant extract is given to cure fever
Swertia paniculata Wall. Herb 2800– Decoction of plant used in the
3300 treatment of malaria and other
fevers
Swertia purpurascens Herb 2500 Plant possess antibacterial and
(D.Don) C.B.Clarke anti-diabetic potential
Swertia speciosa D.Don Herb 2700 Plant is used in treating hepatitis,
cholecystitis, pneumonia,
osteomyelitis, dysentery, and
scabies
Tripterospermum volubile Climber 2300–
(D.Don) H.Hara 3100
Cuscutaceae
Cuscuta reflexa Roxb. Climber 2050 Plant is used in the treatment of LC
urinary disorders, muscle pain,
cough and also used as blood
purifier
Solanaceae
Nicandra physalodes (L.) Herb 2100 Plant is used in the treatment of
Gaertn. contagious disorders, toothache,
intestinal pain, impotence, fevers
Nicotiana rustica L. Herb 1000 Plant parts are used as a poultice
and a wash in the treatment of
rheumatic swelling, skin diseases
and scorpion stings
Solanum nigrum L. Herb 2000 Plant is used in ulcers, asthma, skin
diseases, whooping cough. The
juice from its roots is used against
asthma and
Solanum viarum Dunal Shrub 1000 Plant is used for the treatment of LC
cancer therapy, Addison’s disease,
rheumatism, chronic asthma, skin
disease, obesity, and leukaemia
Scrophulariaceae
Bonnaya ciliata (Colsm.) Herb 1500 Leaf juice is given after child birth LC
Spreng.
Euphrasia himalayica Herb 3000 Extract of whole plant is used to
Wettst. cure cuts and wounds
Euphrasia schlagintweitii Herb 3000 Plant cures eye diseases
Wettst.
Hemiphragma Herb 2500 Plant juice applied to cuts and
heterophyllum Wall. wounds. Fruits edible
Kashmiria himalaica Herb 3000
(Hook.f.) D.Y.Hong
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 197

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Lindenbergia grandiflora Herb 2050
Benth.
Lindenbergia indica (L.) Herb 500– Plant juice is given in chronic LC
Vatke 1500 bronchitis, skin eruptions
Majus japonicus (Thunb.) Herb
Kuntz.
Pedicularis bicornuta Herb 2800 Flowers are used in the treatment of
Klotzsch vaginal and seminal discharges
Pedicularis bifida Herb 2800
(Buch.-Ham. ex D.Don)
Pennell
Pedicularis gracilis Wall. Herb 3100
ex Benth.
Pedicularis hoffmeisteri Herb 2750 Root infusion is used to treat
Klotzsch flatulence and diarrhoea in cattle
Pedicularis megalantha Herb 2300–
D. Don 4200
Pedicularis pectinata var. Herb 3000 Plant used to alleviate stomach
rosea P.Agnihotri & T. pain, flatulence, intestinal problems
Husain and high blood pressure
Pedicularis porrecta Wall. Herb 3600–
ex Benth. 4500
Pedicularis punctata Herb 3400– Decoction of plant is given to expel
Decne. 3700 intestinal worms
Picrorhiza kurroa Royle Herb 3100 Root extract is used to cure severe EN
ex Benth. fever. Rhizomes are used as to treat
liver ailments
Scrophularia calycina Herb 3100
Benth.
Scrophularia himalensis Herb 2400
Royle ex Benth.
Torenia crustacea (L.) Herb 1500 Plant is used in treating bilious LC
Cham. & Schltdl. disorders, dysentery, amenorrhoea
and hepatitis. The powdered herb,
mixed with rice water, is drunk to
relieve diarrhoea, vomiting and
cholera
Verbascum thapsus L. Herb 2400 Leaf decoction is mixed with honey LC
to cure cough and other pulmonary
diseases
Veronica cana Wall. ex Herb 3300
Benth.
(continued)
198 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Veronica laxa Benth. Herb 2500 Plant is used in the treatment of
disorders of the nervous system,
respiratory tract, cardiovascular
system and metabolism
Orobanchaceae
Orobanche alba Stephan Herb 2700
ex Willd.
Gesneriaceae
Didymocarpus Herb 2000 Plant is used for respiratory
aromaticus D.Don problems and chronic asthma
Henckelia bifolia (D.Don) Herb 1000– Plant cures fever and skin allergy
A.Dietr. 2500
Henckelia pumila Herb 2200
(D.Don) A.Dietr.
Platystemma violoides Herb 2400
Wall.
Rhynchoglossum Herb 1800
obliquum Blume
Acanthaceae
Dicliptera bupleuroides Herb 2050
Nees
Dicliptera paniculata Herb 1000 The essential oil extracted from the
(Forssk.) I. Darbysh plant is used to cure tuberculosis.
The paste of the plant is used for
sprain and bone fracture
Justicia simplex D.Don Herb 2100 Plant used to treat fever, vomiting
Rostellularia procumbens Herb 2500 The leaf juice is used to treat
(L.) Nees ophthalmia, asthma, coughs,
rheumatism, back pain and
flatulence
Strobilanthes Herb 2600
atropurpurea Nees
Strobilanthes attenuata Herb 2400
(Wall. ex Nees) Jacq. ex
Nees
Strobilanthes Herb 2200 The root juice is used for the
penttemonoides (Nees) treatment of high fever. It is a good
T.Anderson fodder
Strobilanthes tomentosa Shrub 700–
(Nees) J.R.I Wood 2800
Strobilanthes wallichii Shrub 3000
Nees
Phrymaceae
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 199

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Phryma leptostachya L. Herb 4300 A tea made from the roots was
gargled to cure sore throats and was
drunk in the treatment of
rheumatism, fevers
Lamiaceae
Ajuga parviflora Benth. Herb 2400 Plant used in hypertension,
hepatitis, or inflammation of the
liver and jaundice
Callicarpa macrophylla Herb 2100 Plant cures tumour, polydipsia, LC
Vahl diarrhoea, dysentery, diabetes, fever
Clinopodium umbrosum Herb 2700 Leaf juice is applied to cuts and
(M. Bieb) C. Koch wounds
Clinopodium vulgare L. Herb 1400 Plant is used for healing wounds
and treating warts due to virus
infection
Coleus barbatus Herb 1600 The root is considered as analgesic,
(Andrews) Benth. ex G. ophthalmic, and febrifuge. It is very
Don useful in epilepsy
Elsholtzia ciliata (Thunb.) Herb 1500– An infusion is drunk, or vapour
Hyl. 3500 from the boiling decoction can be
inhaled, in the treatment of
common colds, fevers, headaches,
diarrhoea
Elsholtzia eriostachya Herb 3650 The seeds are chewed as a
(Benth.) Benth. treatment for coughs and colds
Elsholtzia fruticosa Herb 2300 Plant is used to cure bruises, head
(D. Don) Rehder ache, constipation, dysentery
Elsholtzia pilosa (Benth.) Herb 2500 Plant is used in the treatment of
Benth. common colds, fevers, headaches,
diarrhoea, oedema and oliguria
Elsholtzia strobilifera Herb 2350 Plant is used in the treatment of
(Benth.) Benth. colds, headaches, pharyngitis,
fever, diarrheoa, digestion disorder
Lamium album L. Herb 2400 Plant is used in the treatment of LC
fracture, hypertension, leucorrhoea,
paralysis, putrescence, trauma
Leucas lanata Benth. Herb 2200 The crushed leaves are used to treat
mild fevers, colds, rheumatism and
snake bites, roundworm infection
Micromeria biflora Herb 2100 A paste of the plant is used as a
(Buch.-Ham. ex D.Don) poultice to treat wounds. A paste of
Benth. the root is pressed between the jaws
to treat toothache
(continued)
200 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Nepeta eriostachya Herb 2300 Leaves extract is given for fever
Benth.
Nepeta govaniana (Wall. Herb 2500
ex Benth.) Benth.
Origanum vulgare L. Herb 2600 Leaves used against cold, for
digestive, and respiratory problems
Perilla frutescens (L.) Herb 600– An edible drying oil is obtained LC
Britton 2400 from seed. Seed is used in the
treatment of asthma, colds, nausea,
abdominal pain, food poisoning,
allergic reactions, bronchitis and
constipation
Phlomoides bracteosa Herb 2800 Powdered leaves are mixed in tea
(Royle ex Benth.) and used against cough and cold.
Kamelin & Makhm. Flowers are crushed and used
against toothache
Pogostemon benghalensis Herb 500– Leaves are utilized for relieving
(Burm.f.) Kuntze 1000 body pain, headache and fever
Prunella vulgaris L. Herb 2400 Leaves shows antibacterial, LC
antioxidant and anticancer activities
for the treatment of cardiovascular
diseases
Salvia hians Royle ex Herb 1800 Plant is a stimulant, used as a
Benth. remedy for dysentery. The pith of
tender stems is pickled
Salvia nubicola Wall. ex Herb 2400 Plant is used in the treatment of
Sweet. dysentery, boils, fall injuries,
hepatic problems and cancer
Stachys sericea Cav. Herb 2800 Plant is used for the treatment of
stress, skin inflammations,
gastrointestinal disorders, asthma
and genital tumours
Stachys splendens Wall. Herb 2400–
ex Benth. 3600
Thymus linearis Benth. Herb 2300– Seed extract is given for indigestion
3700 and stomach pain
Thymus serpyllum L. Shrub 1500– Plant is used in cough syrups, LC
2800 infusions, oil, tinctures and
infusions
Plantaginaceae
Plantago himalaica Pilg. Herb 2700 Leaves slightly bruised, to apply on
wounds. Oil from the seeds is
antimicrobial, for chronic diarrhoea
and shigellosis, a bacillary
dysentery
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 201

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Amaranthaceae
Achyranthes bidentata Herb 2400 Plant is used in the treatment of
Blume aching back and knees and asthenia
of the lower limbs
Amaranthus hybridus L. Herb 1300 Plant is used in the treatment of
intestinal bleeding, diarrhoea,
excessive menstruation
Cyathula capitata Moq. Herb 2500 A decoction of the aerial parts of
the plant are drunk as a treatment
for cough. An infusion of the whole
plant is taken as a remedy for fever
and dysentery
Cyathula tomentosa Herb 2300
(Schult.) Moq.
Chenopodiaceae
Chenopodium album L. Herb 2500 Plant is used in the treatment of
rheumatism, bug bites, sunstroke,
urinary problems, skin problems
Phytolaccaceae
Phytolacca acinosa Roxb. Herb 2000– The root is used in the treatment of
2700 urinary disorders, nephritis, oedema
and abdominal distension
Polygonaceae
Bistorta affinis (D.Don) Herb 2500– Paste of young shoot is given in
Greene 3800 empty stomach to cure dysentery
Bistorta amplexicaulis Herb 2500 Paste of rhizome is applied on sores
(D.Don) Greene and wounds
Bistorta macrophylla Herb 3000– Root paste is given to infants for
(D.Don) Soják 3700 stomach problems. Leaves paste is
applied on wounds
Bistorta vacciniifolia Herb 3300
(Wall. ex Meisn.) Greene
Bistorta vivipara (L.) Herb 4500 Plant is used in the treatment of
Delarbre abscesses, as a gargle to treat sore
throats and spongy gums and as a
lotion for ulcers
Fagopyrum cymosum Herb 1800– A decoction is used in the treatment
(Trevir.) Meisn. 2600 of traumatic injuries, lumbago,
menstrual irregularities, purulent
infections, snake and insect bites
Fagopyrum tataricum (L.) Herb 4400 Leaves are cooked. The sprouted
Gaertn. seeds are used in salads, or ground
into a powder and used as a cereal.
Edible oil is obtained from seeds
(continued)
202 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Fallopia pterocarpa Climber 2100
(Wall. ex Meisn.) Holub
Koenigia delicatula Herb 2600–
(Meisn.) H.Hara 3500
Koenigia mollis (D.Don) Herb 2050 Young shoots are cooked as a
T.M.Schust. & Reveal vegetable or pickled. The whole
plant is astringent
Koenigia nummulariifolia Herb 4000
(Meisn.) Mesicek &
Sojak
Koenigia polystachya Herb 3300
(Wall. ex Meisn.)
T.M.Schust. & Reveal
Koenigia rumicifolia Herb 3100– Young shoots and seeds are edible
(Royle ex Bab.) 3700
T.M.Schust. & Reveal
Oxyria digyna (L.) Hill Herb 3200 Decoction of young plant is used
for colic pain
Persicaria capitata Herb 2050 Plant treats urinary calculi and
(Buch.-Ham. ex D.Don) urinary tract infections
H.Gross
Persicaria chinensis (L.) Herb 1800– The juice of the plant is used in the
H.Gross 3300 treatment of eye diseases, eczema
of ears
Persicaria microcephala Herb 500– Young shoots are cooked as
var. sphaerocephala 3200 vegetable and condiment
(Wall. ex Meisn.) H.Hara
Persicaria nepalensis Herb 2700 Root extract is used in the treatment
(Meisn.) H.Gross of fevers. A paste of the root is used
as a poultice on fresh wounds
Persicaria sinuata (Royle Herb 3300
ex Bab.) H.Gross
Polygonum paniculatum Herb 3000 The infusion is used in the
L. treatment of stomach complaints
Polygonum recumbens Herb 1500–
Royle ex Bab. 4000
Rheum australe D.Don Herb 3400 The whole plant extract cures cuts
and wounds
Rheum moorcroftianum Herb 3250
Royle
Rheum webbianum Royle Herb 2500 Decoction of stem is given to cure
stomach pain
Rumex acetosa L. Herb 2900 Leaf extract applied on cut and
wounds
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 203

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Rumex nepalensis Spreng. Herb 3000 A paste of the root is applied to
swollen gums, pimples and
ringworm and applied externally to
relieve headache
Piperaceae
Peperomia tetraphylla Herb 2400 Plant treats kidney disorders
(Forst.) Hook. & Arn.
Lauraceae
Cinnamomum tamala Tree 1900 Plant used in the treatment of bad LC
(Buch.-Ham.) T.Nees & breath from mouth, black spots on
C.H.Eberm. face, tooth decay, swelling, cough
and also in complications of
tuberculosis
Litsea elongata (Nees) Tree 2300 The seeds are used as a source of LC
Hook.f. oil for industrial purposes. The
wood is used for construction,
furniture making
Machilus odoratissima Tree 1850 The wood is used in house LC
Nees construction and for furniture. Also
burned as firewood
Neolitsea cuipala Tree 2200 The oil from the fruit is used to
(D.Don) Kosterm. treat itchiness and other skin
complaints
Neolitsea umbrosa (Nees) Tree 2700 An oil obtained from the fruit is
Gamble used for burning
Thymelaeaceae
Daphne papyracea Wall. Shrub 2400
ex G.Don
Eleagnaceae
Elaeagnus umbellata Shrub 2400 Plant used in cardiac and LC
Thunb. respiratory diseases. Seed oil is
used for the treatment of pulmonary
infections, coughs
Hippophae rhamnoides Shrub 2000– A high-quality medicinal oil is LC
Serv. subsp. salicifolia 3700 extracted from the fruit and used in
(D.Don.) Serv. the treatment of cardiac disorders,
also to heal burns, eczema and
radiation injury
Hippophae salicifolia Tree 2700 The oil is made from the fruit is
D.Don used in cardiac disorders
Buxaceae
Buxus wallichiana Baill. Tree 2200 Leaves are useful in the treatment
of rheumatism and syphilis. A
decoction is used to combat
intestinal worms
(continued)
204 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Sarcococca hookeriana Shrub 2000 Plant used in the treatment of
Baill. stomach pain, rheumatism, swollen
sore throat and traumatic injury
Euphorbiaceae
Euphorbia maddenii Herb 2600
Boiss.
Euphorbia pilosa L. Herb 2200
Euphorbia prolifera Herb 500–
Buch.-Ham ex D. Don 2300
Euphorbia stracheyi Herb 2700
Boiss.
Flueggea virosa (Roxb. Shrub 2300 Plant is used in stomach problems, LC
ex Willd.) Royle dysentery, diarrhoea, eye problems
Leptopus cordifolius Shrub 1200–
Decne. 2100
Phyllanthus parvifolius Shrub 1700
Buch.-Ham. ex D.Don
Daphniphyllaceae
Celtis australis L. Tree 2100 The decoction can be used to LC
astringe the mucous membranes in
the treatment of diarrheoa,
dysentery, and peptic ulcers
Daphniphyllum himalense Tree 2200 A paste of the wood is applied as a
(Benth.) Mull.Arg. poultice to boils

Moraceae
Ficus auriculata Lour. Tree 1600 The plant helps to regulate blood LC
pressure and blood cholesterol
Ficus hederacea Roxb. Climber 2400 Wood is used as firewood
Ficus semicordata Tree 2100 Plant parts are used in leprosy, LC
Buch.-Ham. ex Sm. diarrheoa, headache, fever, earache,
ulcer, gastric problems and boils
Ficus subincisa Buch.- Tree 2100 Fruits edible LC
Ham. ex Sm.
Urticaceae
Boehmeria virgata subsp. Shrub 2050 A fibre is obtained from the bark is
macrophylla (Hornem.) of excellent quality, is used for
Friis & Wilmot-Dear making sacks, bags, rough clothes,
nets, rope
Boehmeria virgata var. Shrub 3000 An excellent quality of fibre is
macrostachya (Wight) obtained from the bark used for
Friis & Wilmot-Dear making sacks, bags, rough clothes,
nets, rope etc
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 205

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Boehmeria virgata var. Shrub 2100
scabrella (Dalzell &
A.Gibson) Friis &
Wilmot-Dear
Debregeasia longifolia Shrub 1500 Leaf juice is applied to scabies. LC
(Burm.f.) Wedd. Fruits are edible
Debregeasia saeneb Shrub 1800 The aerial parts of the plant are LC
(Forssk.) Hepper & dried and powdered, then mixed
J.R.I.Wood with mustard oil and then applied
topically as an antifungal for curing
skin rashes, dermatitis and eczema
Elatostema monandrum Herb 2800
(Buch.-Ham. ex D.Don)
H.Hara
Elatostema sessile Herb 1200– Poultice of leaves used for
J.R.Forst. & G.Forst. 2400 abdominal disorders, body pain.
Plant paste used on boils, pimples
and blisters. Tender leaves
consumed as vegetable. Shoots
boiled and eaten
Girardinia diversifolia Shrub 2200 The plant is a part of antidote to
(Link) Friis snake bites. Ash of the plant is
applied externally for the treatment
of ringworm and eczema
Gonostegia triandra Herb 2700 Plant is used to treat boils and
(Blume) Miq. abscesses, abdominal cramps in
females and leucorrhoea. Also used
to treat bone dislocations and
fractures
Laportea bulbifera Herb 3500 Young leaves cooked and used as
(Siebold & Zucc.) Wedd. spinach
Pilea racemosa (Royle) Herb 2300
Tuyama
Pilea scripta (Buch.- Herb 2200
Ham. ex D. Don) Wedd.
Pilea umbrosa Wedd. ex Herb 2500 Plant used in liver disorders,
Blume cancer, rheumatism and in skin
disorders
Pouzolzia zeylanica (L.) Herb 2200 Plant decoction is used to treat
Benn. cough, pulmonary tuberculosis,
sore throat, enteritis, dysentery
Urtica ardens Link Herb 2400– Plant is used for jaundice, sprain,
2700 fractures etc
Urtica dioica L. Shrub 2500 Plant is used in the control of LC
cardiovascular disorders especially
hypertension
(continued)
206 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Juglandaceae
Juglans regia L. Tree 2100 Plant helps to cure helminthiasis, LC
diarrheoa, sinusitis, stomach pain,
arthritis, asthma, eczema, scrofula,
skin disorders, and endocrine
diseases
Myricaceae
Myrica esculenta Tree 2300 Plant used to treat asthma, cough,
Buch.-Ham. ex D.Don chronic bronchitis, ulcers,
inflammation, anemia, fever,
diarrheoa, ear, nose, and throat
disorders
Betulaceae
Alnus nepalensis D. Don Tree 2100 LC
Betula alnoides Buch.- Tree 2200– Plant extracts is an antidote against LC
Ham. ex D.Don 2600 snakebites and is used to treat
dislocated bones
Betula utilis D.Don Tree 2800– Plant act as skin disinfectant, and LC
3700 cures diseases of the blood and ear,
convulsions, wound healing,
bronchitis, leprosy
Carpinus viminea Lindl. Tree 2100 Wood is used for making furniture, LC
ex Wall. articles of sports and weaving
shuttles
Fagaceae
Castanopsis tribuloides Tree 1700 The bark is a source of tannins and
(Sm.) A.DC. can be used as a dye. Seeds cooked
and eaten
Quercus floribunda Lindl. Tree 2000– The seeds are astringent and LC
ex A.Camus 2800 diuretic. They are used in the
treatment of diarrhoea, indigestion
and asthma
Quercus leucotrichophora Tree 1500– Plant is used to cure urinary
A.Camus 2400 infection, tooth ache and piles.
Leaves are used as an astringent
and in the treatment of diarrheoa.
Gum resin is used in stomach pain
Quercus semecarpifolia Tree 2400– Plant is used to treat acute LC
Sm. 3300 diarrheoa, dysentery and
haemorrhages. Also used as a
mouthwash to treat toothache or
gum problems and is applied
topically as a wash on cuts, burns,
various skin problems
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 207

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Salicaceae
Populus ciliata Wall. ex Tree 2500 A paste of the bark, mixed with the LC
Royle ash of cow dung, is used as a
poultice to treat muscular swellings
Salix calyculata Hook.f. Shrub 3300
ex Andersson
Salix denticulata Shrub 2500 Plant is used for malarial fever; the
Andersson leaf and seed as a diuretic, for
jaundice, cough, dropsy,
rheumatism, and urogenital
diseases
Salix flabellaris Shrub 3300 Decoction of bark is given to cure
Andersson fever
Salix fruticulosa Shrub 3000 Used as fodder
Andersson
Salix lindleyana Wall.ex Shrub 3200
Andersson
Orchidaceae
Calanthe plantaginea Terrestrial 2200 The dried and powdered rhizome is
Lindl. mixed with milk and taken as a
tonic and an aphrodisiac
Calanthe tricarinata Terrestrial 1500– Leaf paste is applied as a poultice
Lindl. 3300 to treat sores and eczema
Crepidium acuminatum Terrestrial 2300 Plant is used in the treatment of
(D.Don) Szlach. blood disorders, burning sensation
in the body, male sterility, fever,
dysentery, external and internal
haemorrhage and general weakness
Cypripedium elegans Terrestrial 2800 EN
Rchb.f.
Dactylorhiza hatagirea Terrestrial 3000 Tuber extract given to cure
(D.Don) Soó whooping cough and fever
Dendrobium amoenum Epiphytes 600–
Wall. ex Lindl. 2000
Dienia cylindrostachya Terrestrial 2500–
Lindl. 4000
Epipactis helleborine (L.) Terrestrial 2450
Crantz
Goodyera fusca (Lindl.) Terrestrial 2700
Hook.f.
Goodyera repens (L.) Terrestrial 2900 The infusion can be held in the LC
R.Br. mouth as a treatment for toothache.
The root and the leaves cure
bladder problems
(continued)
208 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Gymnadenia orchidis Terrestrial 2900
Lindl.
Herminium elisabethae Terrestrial 2700
(Duthie) Tang &
F.T.Wang
Liparis rostrata Rchb. f. Herb 1500– Tubers are used to treat stomach
3000 disorders and also used as a tonic
Malaxis muscifera Terrestrial 3000 Plant is used in sterility, VU
(Lindl.) Kuntze haemorrhages, dysentery, fever,
emaciation, burning sensation,
rheumatism and debility. Paste
applied externally for insect bites
Oberonia ensiformis Epiphytes 600–
(Sm.) Lindl. 1000
Oberonia micrantha Epiphytes 2500
Lindl.
Oberonia pachyrachis Epiphytes 2000
Rchb.f. ex Hook.f.
Oreorchis foliosa (Lindl.) Terrestrial 2500
Lindl.
Satyrium nepalense Terrestrial 2500 Plant is used as energetic tonic and
D. Don cure fevers
Spiranthes sinensis Terrestrial 2600 Tubers are used as tonic. Decoction LC
(Pers.) Ames of plants is used in intermittent
fever. Paste of stem and roots used
in sores
Zingiberaceae
Cautleya spicata (Sm.) Herb 2300 The juice of the rhizome is used in LC
Baker the treatment of stomach problems
Hedychium spicatum Sm. Herb 2200 Rhizome extract has antimicrobial
activity which used for making
various types of drugs including
anti cancerous drug and essential
oil
Hellenia speciosa Herb 1000 Rhizome is used to treat fever, LC
(J.Koenig) S.R.Dutta rashes, asthma, bronchitis, and
intestinal worms
Roscoea alpina Royle Herb 2000– Extract of whole plant is given for
4300 cough and cold. Dried powder of
leaves used in wounds and cuts of
cattle
Roscoea purpurea Sm. Herb 2600 Plant is used for the treatment of
diabetic, hypertension, diarrheoa,
fever, inflammation
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 209

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Nartheciaceae
Aletris pauciflora Herb 3200 The root is chewed as a treatment
(Klotzsch) Hand.-Mazz. for coughs and colds
Iridaceae
Iris domestica (L.) Herb 2500 The juice of the root is used to treat
Goldblatt & Mabb. liver complaints
Iris kemaonensis Wall. ex Herb 3200 Plant is used to treat ear pain and
D.Don weakening of the eyesight
Dioscoreaceae
Dioscorea bulbifera L. Climber 2050 Plant is used in the treatment of
piles, dysentery, syphilis, ulcers,
cough, leprosy, diabetes, asthma,
and cancer
Dioscorea deltoidea Wall. Climber 2400 Plant act as vermifuge and
ex Griseb. anthelmintic, to get rid of intestinal
worms
Amaryllidaceae
Allium stracheyi Baker Herb 3100 Dried flowers used to reduce blood
cholesterol levels, act as a tonic to
the digestive system and circulatory
system
Allium wallichii Kunth Herb 3300 The bulbs, boiled then fried in
ghee, are eaten in the treatment of
cholera and dysentery. The raw
bulb is chewed to treat coughs and
cold
Liliaceae
Asparagus curillus Shrub 2050
Buch.-Ham. ex Roxb.
Cardiocrinum giganteum Shrub 1500– The leaves are used as an external
(Wall.) Makino 2500 cooling application to alleviate the
pains of wounds and bruises. A
paste of the root is applied as a
poultice to treat dislocated bone
Clintonia udensis Trautv. Herb 3000 Young leaves and shoots are cooked
& C.A.Mey. as a vegetable
Disporum cantoniense Herb 1000– The juice of the roots is used in the
(Lour.) Merr. 3000 treatment of fevers. Tender leaves
and young shoots are cooked and
used as a vegetable
Fritillaria cirrhosa Herb 3200 The extract of root is used to cure
D.Don asthma
Lilium oxypetalum Herb 3500
(D.Don) Baker
(continued)
210 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Lloydia longiscapa Hook. Herb 3300
Maianthemum purpureum Herb 2800 Tender young leaves and shoots are
(Wall.) LaFrankie cooked as a vegetable
Ophiopogon intermedius Herb 2500 Plant is hacking dry coughs, dry
D. Don tongue, mouth, and constipation
Paris polyphylla Sm. Herb 1800– Roots are analgesic, antiphlogistic, VU
2800 antipyretic, antispasmodic,
antitussive, depurative, febrifuge
and narcotic. A decoction of the
roots is used in the treatment of
poisonous snake bites, boils and
ulcers, diphtheria
Polygonatum Herb 3200
geminiflorum Decne.
Polygonatum multiflorum Herb 2700 Plant is used in hair growth
(L.) All. promotion and hair blackening
Polygonatum Herb 2300 Plant is made into a salep, a
verticillatum (L.) All. strength giving food. Plant is
diuretic
Streptopus simplex D.Don Herb 2600

Theropogon pallidus Herb 2350

(Wall. ex Kunth) Maxim.
Trillium govanianum Herb 3550 Plant is used in treating cancer, EN
Wall. ex D.Don dysentery, open wounds, skin
infections, inflammation
Smilacaceae
Smilax aspera L. Climber 2100 LC
Smilax elegans Wall. ex Climber 2200
Kunth.
Commelinaceae
Commelina paludosa Herb 2200 Plant is used for treating microbial
Blume infections
Murdannia spirata (L.) Herb 2000 LC
G.Brückn.
Juncaceae
Juncus clarkei Buchenau Herb 2800
Juncus concinnus D.Don Herb 2600
Juncus himalensis Herb 3000–
Klotzsch 5000
Juncus leucomelas Royle Herb 3600–
ex D.Don. 4700
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 211

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Luzula campestris (L.) Herb 2600
DC.
Araceae
Acorus calamus L. Herb 2200 Rhizome paste is applied to treat LC
headache, skin diseases and
wounds. Powdered rhizomes are
used as insecticide
Arisaema intermedium Herb 2400– Plant is used to treat asthma,
Blume 3700 bronchitis, cold, cough, and
laryngitis
Arisaema jacquemontii Herb 2900 Roots may be cooked and eaten. LC
Blume The leaves are fermented before
being eaten
Arisaema propinquum Herb 2600 Plant exhibits anthelminthic
Schott property
Remusatia vivipara Herb 1200– Plant cures inflammation and
(Roxb.) Schott 2300 arthritis, and used as analgesic, for
disinfecting the genitourinary tract
and in the treatment of reddish
boils
Sauromatum diversifolium Herb 2400–
(Wall. ex Schott) 4200
Cusimano & Hett.
Eriocaulaceae
Eriocaulon nepalense Herb 2000 LC
J.D.Prescott ex Bong.
Cyperaceae
Bulbostylis capillaris (L.) Herb 2400 Plant is used to treat urinary tract LC
Kunth ex C.B. Clarke infections
Carex cardiolepis Nees Herb 2300–
3000
Carex cruciata Wahlenb. Herb 2300
Carex nivalis Boott Herb 3400
Carex norvegica Retz. Herb 1500– LC
2300
Carex nubigena D.Don. Herb 3000 Roots are cooked and eaten
Carex obscura Nees Herb 3200
Carex sanguinea L. var. Herb 1500
foliosa C.B. Clarke
Carex sanguinea Boott Herb 1300–
2500
Carex setosa Boott Herb 2700–
4800
(continued)
212 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Carex supina Willd. ex Herb 1300
Wahlenb.
Carex unciniiformis Herb 3600
Boeckeler
Cyperus cyperoides (L.) Herb 2200 The juice of the roots is used in the LC
Kuntz. treatment of coughs and fevers. The
ground-up rhizome is applied
topically to skin disorders
Erioscirpus comosus Herb 2200 The fibrous leaves are employed for
(Wall.) Palla making twine and cordage
Fimbristylis dichotoma Herb 2050 The culms are used to make an LC
(L.) Vahl inferior matting. Good soil binder
Poaceae
Agrostis pilosula Trin. Herb 2600 Fresh and dry aerial parts directly
palatable. Good fodder
Andropogon munroi Herb 2450 Good odder grass
C.B. Clarke
Apluda mutica L. Herb 2100 Leaf paste applied on wounds with
bleeding
Arthraxon lancifolius Herb 2100
(Trin.) Hochst.
Arundinella bengalensis Herb 2050
(Spreng.) Druce
Bothriochloa bladhii Herb 2100
(Retz.) S.T.Blake
Calamagrostis Herb 2600 LC
pseudophragmites (Haller
f.) Koeler
Calamagrostis Herb 3200
scabrescens Griseb.
Capillipedium assimile Herb 600–
(Steud.) A.Camus 2100
Cenchrus americanus (L.) Herb 2300
Morrone
Cenchrus orientalis Herb 2400 LC
(Rich.) Morrone
Chrysopogon gryllus (L.) Herb 2050 The plant can be used for thatching.
Trin An essential oil obtained from the
roots can be used as an adulterant
for rose oil
Cymbopogon distans Herb 2300 A lemon-scented essential oil is
(Nees ex Steud.) extracted from this species for
W. Watson medicinal and industrial purposes
Dactylis glomerata L. Herb 3800 Plant is used for tumours, kidney
and bladder ailments
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 213

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Digitaria ciliaris (Retz.) Herb 2100 Fodder grass
Koeler
Digitaria setigera Roth Herb 2500
Drepanostachyum Small tree 2100 Young shoots are cooked and used
falcatum (Nees) Keng f. as a vegetable. The leaves are used
as a roofing material
Eleusine indica (L.) Herb 2100 Plant is applied externally to open LC
Gaertn. wounds to stop bleeding. A poultice
of the leaves is applied to sprains
and back pains
Eragrostis nigra Nees ex Herb 2350
Steud.
Eulalia mollis (Griseb.) Herb 2200
Kuntze
Festuca rubra L. Herb 2900
Festuca valesiaca Herb 3000
Schleich. ex Gaudin
Glyceria tonglensis Herb 4100
C.B.Clarke
Himalayacalamus Shrub 2700 Young shoots are cooked and used
falconeri (Hook.f. ex as a vegetable
Munro) Keng f.
Lolium giganteum (L.) Herb 2600
Darbysh.
Melica scaberrima (Nees Herb 2700
ex Steud.) Hook.f.
Microstegium falconeri Herb 2400
(Hook.f.) Clayton
Microstegium nudum Herb 2050
(Trin.) A. Camus
Miscanthus nepalensis Herb 2400
(Trin.) Hack.
Muhlenbergia duthieana Herb 2000– Plant is used as fodder LC
Hack. 3600
Muhlenbergia huegelii Herb 900– Good fodder grass
Trin. 3000
Oplismenus compositus Herb 2050 Plant is antiseptic, astringent, LC
(L.) P. Beauv. demulcent for dropsy and dysentery
Oplismenus undulatifolius Herb 2100
(Ard.) P. Beauv.
Phleum alpinum L. Herb 3000 LC
Poa alpina L. Herb 3300
Poa annua L. Herb 3000 LC
(continued)
214 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Poa nepalensis (Wall. ex Herb 1900– Forage grass
Griseb.) Duthie 3000
Saccharum rufipilum Shrub 2300
Steud.
Stipa roylei (Nees) Mez. Herb 2640
Tenaxia cachemyriana Herb 3100
(Jaub. & Spach)
N.P.Barker & H.P.Linder
Thamnocalamus Shrub 2500
spathiflorus (Trin.) Munro
Tripogon filiformis Nees Herb 1000–
ex Steud. 4500
Trisetum clarkei (Hook. Herb 3000
f.) R.R.Stewart
Ephedraceae
Ephedra gerardiana Wall. Shrub 4000 Plant is used in the treatment for VU
ex Klotzsch & Garcke colds, coughs, bronchitis, asthma
and arthritis
Cupressaceae
Juniperus communis L. Shrub 3300 Plant is diuretic, anti-arthritis, LC
anti-diabetes, antiseptic as well as
used for the treatment of
gastrointestinal and autoimmune
disorders
Juniperus indica Bertol. Shrub 3400 Plant cures digestion problems LC
including upset stomach, intestinal
gas, heartburn, bloating and loss of
appetite
Taxaceae
Taxus wallichiana Zucc. Tree 2700 Plant is used to treat common cold, EN
cough, fever and throat pain
Pinaceae
Abies pindrow (Royle ex Tree 2700 Plant is a tonic for bronchitis, LC
D.Don) Royle haemoptysis, asthma, inflammatory
conditions, fever, hypoglycaemia
Abies spectabilis Tree 2800 Leaf juice is taken to treat asthma NT
(D.Don) Mirb. and bronchitis and is also given to
infants suffering from fever and
chest infection
Pinus roxburghii Sarg. Tree 2200 The wood is aromatic, deodorant, LC
haemostatic, stimulant,
anthelmintic, digestive, liver tonic,
diaphoretic, and diuretic
Selaginellaceae
Selaginella chrysocaulos Herb 2100
(Hook. & Grev.) Spring
(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 215

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Loxogrammaceae
Loxogramme involuta Herb 2300
(D.Don) C.Presl
Loxogramme porcata Herb 2200
M.G.Price
Polypodiaceae
Drynaria mollis Bedd. Climber 2400
Drynaria propinqua Climber 2200
(Wall. ex Mett.) J.Sm. ex
Bedd.
Goniophlebium amoenum Herb 2300
(Wall. ex Mett.) Bedd.
Goniophlebium Herb 2400
fieldingianum (Kunze ex
Mett.) T.Moore
Goniophlebium lachnopus Herb 2500
(Wall. ex Hook.) Bedd.

Lepisorus contortus Herb 2100

(Christ.) Ching.
Microsorum zippelii Herb 2400
(Blume) Ching
Pyrrosia porosa (C.Presl) Herb 2500 The whole plant paste is applied
Hovenkamp over cut injuries
Selliguea capitellata Herb 2200
(Mett.) X.C.Zhang &
L.J.He
Selliguea ebenipes Herb 2200
(Hook.) S.Linds.
Selliguea oxyloba (Wall. Herb 2400
ex Kunze) Fraser-Jenk.
Selliguea quasidivaricata Herb 2300
(Hayata) H.Ohashi &
K.Ohashi
Sinopteridaceae
Hemionitis albomarginata Herb 2050
(C.B.Clarke) Christenh.
Cryptogrammaceae
Onychium lucidum Herb 2100 Plant is used in the treatment of
(D.Don) Spreng. cardiovascular and cerebrovascular
diseases
(continued)
216 R. Manikandan et al.

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Lycopodiaceae
Huperzia verticillata Herb 1200– Plant is antioxidant, anti-­
(L.f.) Trevis. 1900 inflammatory and
acetylcholinesterase inhibitory
activities in the neural system, to
prevent Alzheimer’s disease
Pteridaceae
Pteris aspericaulis Wall. Herb 2600 The paste of rhizome is applied in
ex J.Agardh treatment of cuts, boils, and
muscular swellings
Pteris cretica L. Herb 2100 Fronds are antibacterial, is made LC
into a paste and applied to wounds
Pteris wallichiana Herb 2500 Fresh leaves are crushed and
C.Agardh applied to stop bleeding and
healing of wounds
Hemiontidaceae
Adiantum capillus-veneris Herb 2050 Leaf extracts used in coughs and LC
L. throat infections
Coniogramme affinis Herb 2200 Plant shows antioxidant,
Hieron antimicrobial or anti-inflammatory
activities. It is used for the
treatment of various chronic and
infectious diseases
Trisetopsis aspera Herb 2500
(Munro ex Thwaites)
Röser & A.Wölk
Vittariaceae
Haplopteris flexuosa Herb 2200
(Fée) E.H. Crane
Aspleniaceae
Asplenium dalhousieae Herb 2100 Plant is antibacterial
Hook.
Asplenium ensiforme Herb 2200 Young fronds and underground
Wall. ex Hook. & Grev. stem are edible
Asplenium laciniatum Herb 2500 Plant is used in folk medicine
subsp. tenuicaule
(Hayata) Fraser-Jenk.
Asplenium yoshinagae Herb 2100–
subsp. indicum (Sledge) 2400
Fraser-Jenk.
Woodsiaceae

(continued)
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 217

Table 1 (continued)
Altitude
Binomial Life form (m) Ethno-medicinal uses Remarks
Woodsia elongata Hook. Shrub 2200
Aspleniaceae
Athyrium atkinsonii Bedd. Herb 2100
Athyrium fimbriatum Herb 2050
T.Moore
Athyrium schimperi Moug Herb 2100 The sporophylls possess anti-­
ex Fee bacterial properties
Diplazium esculentum Shrub 2100 Plant is used for the treatment of LC
(Retz.) Sw. diabetes, smallpox, asthma,
diarrheoa, rheumatism, dysentery,
headache, fever, wounds, pain,
measles, and high blood pressure
Diplazium maximum Shrub 2100 Young fronds are edible
(D. Don) C.Chr.
Dryopteridaceae
Dryopteris cochleata Herb 2050 Plant is used to treat epilepsy,
(D. Don) C.Chr. leprosy, cuts, wounds, ulcers,
swelling
Dryopteris Herb 2400
redactopinnata Soumen
K.Basu & Panigrahi
Dryopteris wallichiana Herb 2500
(Spreng.) Hyl.
Polystichum squarrosum Herb 2200 The sporophyll extract of is used as
(D.Don) Fee an anti-bacterial agent. Fronds are
anti-rheumatic
Polystichum stimulans Herb 2100
(Kunze. ex Mett.) Bedd.
Davalliaceae
Davallodes pulchra Herb 2100
(D.Don) M.Kato &
Tsutsumi
Leucostegia truncata Herb 2100 Rhizome is used as antibacterial
(D.Don) Fraser-Jenk. and in the treatment of constipation
Blechnaceae
Woodwardia unigemmata Shrub 2300 The decoction of rhizome and
(Makino) Nakai fronds internally administrated in
dysentery. Dried rhizome is used as
purgative, fronds used in skin
diseases, and infertility
218 R. Manikandan et al.

Plate 1 Vegetation types of Sunderdhunga Valley

Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 219

Plate 2 Flowering plants of Sunderdhunga Valley

220 R. Manikandan et al.

Plate 3 Flowering plants of Sunderdhunga Valley

Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 221

Plate 4 Flowering plants of Sunderdhunga Valley

222 R. Manikandan et al.

R. campanulatum, Rumex acetosa, Salix flabellaris, Saussurea obvallata, Saxifraga

stenophylla, Sedum bupleuroides, S. heterodontum, S. oreades, Selinum elatum,
Sibbaldia parviflora, Swertia cuneata, Taraxacum officinale, Thymus linearis, Viola
pilosa, Waldheimia glabra [57–60].

3.2 EET Species

According to Walter and Gillett [61], over 60, 000 species have been evaluated for
conservation status as per the internationally accepted criteria, of which 34,000 are
classified as globally threatened with extinction. The Botanical Survey of India has
published Red Data Books [62] which contain information on 622 threatened plants.
Kandwal has developed an assessment system that prepares global Red List of
threatened species. IUCN Red List of Threatened Species, a comprehensive assess-
ment of the prevailing risk of extinction of thousands of plant and animal species.
The global IUCN Red List is updated on a regular basis and the latest version was
released in 2020 as version 2020–2 (IUCN Red List, 2020) [63]. According to the
criteria for critically endangered, endangered and vulnerable taxa are classified
mainly basing on reduction in population size, extent of occurrence and area of
occupancy.
Sunderdhunga glacier valley and its surroundings, the following Endemic,
Endangered and Threatened (EET) species have been reported, viz., Acer caesium,
Aconitum heterophyllum, Aconitum violaceum, Acorus calamus, Angelica glauca,
Berberis aristata, Cyananthus integer, Dactylorhiza hatagirea, Delphinium denu-
datum, Dioscorea deltoidea, Fritillaria roylei, Habenaria pectinata, Hedychium
spicatum, Holboellia latifolia, Jurinea dolomiaea, Malaxis muscifera, Meconopsis
aculeata, Morina longifolia, Nardostachys grandiflora, Parnassia nubicola,
Picrorhiza kurroa, Polygonatum verticillatum, Rheum webbianum, Rhododendron
anthopogon, Rhododendron campanulatum, Saussurea obvallata, Skimmia
anquetilia, Swertia alata, Thalictrum foliolosum, etc.
Among the threats to the indigenous flora of the valley, the most important
anthropogenic species, deforestation, cattle grazing, timber and fuel wood cutting,
soil erosion, construction schemes, plantation, plant collection, fire, tourist pressure
and the invasive species result in degradation of forests. In addition, environmental
factors, such as seismic activity or violent stress strokes and floods, chase landslides
or wash away top soil and then alter or destroy the vegetation. The prospective con-
servation of such unmatched scenic beauty of the floristic composition as well as
herbal wealth of the present study area is essential and also it is a home for a lot of
endemic plants and endangered animals which helps in maintaining genetic
diversity.
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 223

4 Conclusion

Several measures are underway for protection of the species reaching extinction and
endemic, endangered and threatened (EET) species. These measures include survey
and inventorization of plant resources in wild and to develop an accurate database
for their planning and monitoring purposes, the Protected Area Network (PAN) has
been created for in situ conservation which has been designated as species, habitats
and ecosystems oriented. Ex situ conservation of rare, endangered, threatened and
endemic species has been undertaken through botanic gardens, zoological parks,
gene banks, etc., and as per Biological Diversity Act, 2002, state-wise list of species
of plants which are on the verge of extinction along with guidelines to prohibit and
regulate their collection, rehabilitate and preserve these species have been proposed.

Acknowledgements The authors are thankful to the Director, Botanical Survey of India (BSI),
Kolkata, Head of Office (HoO), BSI, Northern Regional Centre, Dehradun, and HoO, BSI,
Southern Regional Centre, Coimbatore, for providing the facilities to carry out the said project.

References

1. Synge H (2005) Biodiversity hotspots revisited. Plant Talk 40:33–36

2. Myers NRA, Mittermeier CG, Mittermeier GAB, da Fonseca KJ (2000) Biodiversity hotspots
for conservation priorities. Nature 403:853–858
3. Pitman NA, Jorgensen PM (2002) Estimating the size of the world’s threatened flora.
Science 298:989
4. Kushalappa KA (1992) Saving natural forests. Indian Forester 118:344–347
5. Ahmedullah M, Nayar MP (1987) Endemic plants of the Indian region. Botanical Survey of
India, Calcutta
6. Hooker JD, Thomson T (1855) Flora Indica, London
7. Hooker JD (1872–1897) The Flora of British India, 7 vols. Reeve and Co, London
8. Atkinson ET (1882) The Himalayan Gazetter, vol 2 (Reprint 1973). Cosmo Publication,
New Delhi
9. Duthie JF (1903–1929) Flora of the upper Gangetic plain and of the adjacent Siwalik and sub-­
Himalayan tracts, Calcutta
10. Deva S, Naithani HB (1986) The orchid Flora of north west Himalaya. Scientific Publishers,
New Delhi
11. Garg S (1987) Gentianaceae of north West Himalayas (a revision). Today and Tomorrow’s
Print & Publishers, New Delhi
12. Aswal BS, Goel AK, Mehrotra BN (1988) An inventory of family Asteraceae from Garhwal
and Kumaon Himalaya. J Econ Taxon Bot 12(1):1–37
13. Dangwal LR (1993) A taxonomic survey of leguminous plants of Garhwal Himalaya.
Unpublished D.Phil. thesis. HNB Garhwal University, Srinagar (Garhwal)
14. Nautiyal DC (1996) A taxonomic survey of Poaceae of Garhwal Himalaya. Unpublished
D.Phil. thesis. HNB Garhwal University, Srinagar (Garhwal)
15. Polunin O, Stainton A (1984) Flowers of the Himalaya. Oxford Press, New Delhi
16. Rawat, JK, Semwal JK, Purohit AN (1985) Blossoming Garhwal Himalaya. New Delhi
17. Stainton A (1988) Flowers of Himalaya- a supplement. Oxford University Press, New Delhi
18. Rupin D (1993) Flowers of Western Himalaya. Indus Publication, New Delhi
224 R. Manikandan et al.

19. Naithani BD (1984–1985) Flora of Chamoli, vol 1 & 2. Botanical Survey of India, Howrah
20. Kandwal M (2009) Grass Flora of Uttarakhand Unpublished Ph.D. thesis. HNB Garhwal
University, Srinagar (Garhwal), Uttarakhand
21. Duthie JF (1906) Catalogue of the plants of Kumaon and of the adjacent portion of Garhwal
and Tibet based on the collections made by Strachey and Winterbottom during the years
1846–49. Revised and supplemented by J.F. Duthie
22. Duthie JF (1906) The Orchids of North-Western Himalaya, Calcutta
23. Issar SK, Uniyal MR (1967) Orchids of Uttarakhand Himalayas. Indian Forest 67:713–716
24. Khullar SP (1997) An illustrated flora of Western Himalaya, vol 1 & 2. International book
distributors, Bishen Singh Mahendra Pal Singh Dehradun, p 1100
25. Osmaston AE (1927) A Forest Flora of Kumaon. Government Press, Allahabad, p 600
26. Pande P (1985) Flora of Almora District. Ph.D. Thesis, Kumaon University, Nainital, Vol. 1 & 2
27. Pande PC (1991) Observation on the vegetation of Almora district in Western Himalaya. J
Econ Taxon Bot 15(3):539–551
28. Pande PC (2001) Diversity of monocotyledonous flora of Almora and Bageshwar districts.
(Kumaon Himalaya). In: Pande PC, Samant SS (eds) Plant diversity of Himalaya. Gyanodaya
Prakashan, Nainital, pp 193–210
29. Pande PC (2010) Diversity of dicotyledonous flora of Almora and Bageshwar districts of
Kumaun Himalaya. In: Tewari LM, Pangtey YPS, Tewari G (eds) Biodiversity potentials of the
Himalaya. Gyanodaya Prakashan, Nainital, pp 197–228
30. Pangey YPS, Pande PC, Sharma SD (1984) New plant record for Garhwal and Kumaon
Himalaya from Almora. J Econ Taxon Bot 5:827–830
31. Rai ID, Singh G, Rawat GS (2017) Flora of Kedamath Wildlife Sanctuary, Western Himalaya:
a field guide, vol 393. Bishen Singh Mahendra Pal Singh, Dehradun
32. Randhwa MS (1970) The Kumaon Himalaya. Oxford & IBH Publishing Co., New Delhi
33. Rau MA (1975) High altitude flowering plants of West Himalaya, Howrah
34. Rau MA (1981) Western Himalayan Flora. In: Lall JS (ed) The Himalaya-aspects of changes.
Oxford University Press, New Delhi, pp 50–63
35. Rawat GS (1984) Studies on high altitude flowering plants of Kumaon Himalaya. Ph.D. Thesis,
Kumaun university, Nainital
36. Rawat JK, Sharma SK (1992) Conservation of biological diversity in the Uttaranchal. Ind
Forest 118:352–360
37. Singh GN, Chandra P, Vineet LM, Tewari, Singh Bisht MP (2019) Observation on the
Phyto-diversity of Sunderdhunga valley, Uttarakhand, Western Himalaya. Indian Forester
145(12):1166–1175
38. Uniyal BP, Balodi B, Nath B (1994) The grasses of Uttar Pradesh-a checklist. Bishen Singh
Mahendrapal Singh, Dehradun
39. Fosberg FR, Sachet MH (1965) Manual for Tropical Herbaria. Int. Bur. Pl. Tax. & Nom.,
Regnum Vegetabile (Vol. 39), Utrecht
40. Bridson D, Forman L (1998) The Herbarium handbook, third edn. (Repr. 1999). Royal Botanic
Gardens, Kew
41. Hajra PK, Balodi B (1995) Plant wealth of Nanda Devi biosphere reserve. Botanical Survey
of India, Kolkata
42. Uniyal BP, Sharma JR, Choudhery U, Singh DK (2007) Flowering plants of Uttarakhand- a
checklist. Bishen Singh Mahendrapal Singh, Dehradun
43. Lynch OJ (1992) Securing community based tenurial rights in the tropical forests of Asia-
an overview of current and prospective strategies. Issues in Development, World Resources
Institute, Washington
44. Dwivedi AP (1993) Forests- the ecological ramifications. Natraj Publishers, Dehra Dun
45. Leach G (1987) Household energy in South-east Asia. International Institute for Environment
and Development, London
46. Kothari A, Pandey P, Singh S, Variava D (1989) Management of National Parks and Sanctuaries
in India. Status report. Indian Institute of Public Administration, New Delhi
Checklist Flora of Sunderdhunga Valley, Western Himalaya, with Emphasis… 225

47. Champion HG, Seth SK (1968) A revised survey of the forest types of India. Govt. of India
Press, Delhi
48. Dhar U, Rawat RS, Samant SS (1996) Structural diversity and representativeness of forest veg-
etation in a protected area of Kumaun Himalaya, India: implication for conservation. Biodivers
Conserv 6:1045–1062
49. Rau MA (1974) Vegetation and phytogeography of Himalaya. In: Mani MS (ed) Ecology and
biogeography in India, The Hague, pp 247–280
50. Rawal RS, Bankoti NS, Pangtey YPS (1994) Broad community identification of high altitude
forest vegetation in Pindari region of Kumaun (Central Himalaya). Proc India Vat Acad B
60(6):553–556
51. Rikhari HC, Chandra R, Singh SP (1989) Patterns of species distribution and community along
a moisture gradient within and Oak Zone of Kumaun Himalaya. Proc Indian Nat Acad B
55:431–438
52. Singh JS, Singh SP (1987) Forest vegetation of Himalaya. Bot Rev 53(1):80–191
53. Singh JS, Singh SP (1989) Forest vegetation of the Himalaya. Bot Rev 53:80–192
54. Singh JS, Singh SP (1992) Forests of Himalaya. Gyanodaya Prakashan, Nainital
55. Tewañ JC, Singh SP (1985) Analysis of woody vegetation in a mixed oak forest of Kumaun
Himalaya. Proc Indian Natl Sci Acad BSI:332–347
56. Upreti N, Tewari JC, Singh SP (1985) The oak forests of the Kumaun Himalaya (India)1:
composition, diversity and regeneration. Mt Res Dev 5(2):163–174
57. CCRIMH (1973) Medicinal Flora of Certain Districts in Uttar Pradesh. Central Council for
Research in Indian Medicine and Homoeopathy (CCRIMH)-Monograph-4
58. Chandrasekar K, Rawat B (2011) Diversity, utilization and conservation of ethnomedici-
nal plants in Devikund – a high altitude, sacred wetland of Indian Himalaya. Med Plants
3(2):105–112. https://doi.org/10.5958/j.0975-­4261.3.2.017
59. Rawat B, Sekhar KC, Gairola S (2013) Ethnobotanical plants of Sunderdhunga valley, Western
Himalaya, India - traditional use, current status and future prospect scenario. Indian Forester
139(1):61–68
60. Ved DK (2003) Conservation Assessment and Management Prioritization for the Medicinal
Plants of J & K, Himanchal and Uttaranchal. Proc. of a Regional Workshop held at Shimla
during May 22–25, 2003
61. Walter KS, Gillett HJ (1998) The 1997 IUCN red list of threatened plants. IUCN, Gland and
Cambridge, UK
62. Nayar MP, Sastry ARK (eds.) (1987, 1988, 1990) Red data book on Indian plants, vol 1–3.
Botanical Survey of India, Calcutta. (Repr. 2000)
63. IUCN (2020) IUCN Red List Categories and Criteria Version 3.1, Prepared by the IUCN
Survival Commission, IUCN, Gland, Switzerland. http://www.iucn-­csg.org/index.php/red-­
list-­categories, 2001. Accessed 24 Dec 2020
Phytomedicines Used in Respiratory
Diseases by Traditional Healers
of Lakhimpur and Dhemaji Districts
of Assam, India

Pinki Gogoi, Pyonim Lungphi, A. P. Das, and Victor Singh Ayam

1 Introduction

The knowledge of ethnomedicine is very ancient. It shares vast information regard-

ing the traditional uses of plants by the people. The use of plants and plant products
in human life is immense and their uses as medicines have been in practice since
time immemorial and can be traced from the beginning of human civilization. The
people of India are using medicinal plants since the prehistoric period [1]. Medicinal
plants have a long-standing history among indigenous communities and are an inte-
gral part of treating various diseases, particularly to cure day-to-day ailments and
this practice of traditional medicine is based on hundreds of years of belief and
observations [2]. The earliest record of medicinal plant use in the Himalayas is found
in Rigveda. This work was written between 4500 BC and 1600 BC, is supposed to
be the oldest repository of human knowledge and describes 67 plants. After the
Rigveda, Ayurveda (the foundation of the science of life and the art of healing of
Hindu culture) describes the medicinal importance of 1200 plants. This wealthy
inheritance of knowledge and the age-old wisdom of India might well be among the
earliest in the world. About 70% of the Indian population dwell in rural areas and
many of them reside in the neighbourhood of forest and use various plant parts as
food, medicines, and for many other purposes for their daily livelihood [3, 4]. Some
of the notable contributions in the state of Assam are medical plants used by the
Karbi Anglong of Mikir Hills [5, 6]; medicinal plants from the Tezpur district [7] and
plants used to cure jaundice in the Golaghat district documented by Pandey et al. [8].
The herbal remedy of the Nepalese of Assam was also reported by Borthakur et al.
[6]. Medicinal plants used by Garo tribes are also studied by Rao [9]. The present

P. Gogoi · P. Lungphi · A. P. Das · V. S. Ayam (*)

Department of Botany, Rajiv Gandhi University (Central), Rono Hills, Doimukh,
Arunachal Pradesh, India
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 227

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_7
228 P. Gogoi et al.

study also aims at highlighting the ethnomedicinal uses of plant resources. Like
other deadly diseases, respiratory diseases are also a major cause of mortality
worldwide. In most of the developing countries like India, it causes a nationwide
burden. Pneumonia, asthma, lung cancer, tuberculosis, etc., are some common
respiratory diseases that have been causing concern since ancient times. In the pres-
ent-day scenario, due to so many reasons like air quality, smoking tobacco, etc., the
rate of these kinds of patients is on the rise. Children are the most susceptible targets
of respiratory illnesses. Pneumonia is reported as the leading killer of young chil-
dren all over the world, while asthma affects about 14% of children globally each
year and is the most common chronic disease among children and adults. Although
modern medicines have advanced the quality and lifestyle of humankind in many
countries in recent decades yet the cost of health care for respiratory diseases is an
increasing burden of all the leading and underdeveloped countries. For example, in
the United States, asthma alone costs about $18 billion annually [10]. So, there is an
urgent need for information about alternate complementary medicines like tradi-
tional ways of curing these diseases using surrounding plants. There are many effi-
cient medicines for these respiratory diseases in the present allopathic medical
system. But, in areas where the modern medical system is not easily available, peo-
ple happily use traditional systems to treat these diseases even today. The knowl-
edge of their ethnomedicine is very ancient, transferred orally for generations and
generated mainly through the trial-and-error method. It shares just a part of the vast
information regarding traditional uses of common plants by the people. So, the sur-
vey of medicinal plants becomes extremely important for researchers because it
gives information about a particular plant in a particular area. The northeastern part
of India is the huge storehouse of traditional knowledge as the life of numerous
tribal communities in this area is almost fully forest dependent. They collect almost
everything to survive from the floristic vegetation of their areas. Assam is one of the
eight states of Northeast India covered mostly by forest with innumerable forest
villages that are yet to avail the benefits of modern developmental facilities [11, 12].
With its boundless forests and hills, Assam is a home of abundant medicinal plants
with different individual tribal communities [5, 6]. Lakhimpur and Dhemaji dis-
tricts of upper Assam are also mostly inhabited by many tribal communities who
practise traditional plant-based medicines. However, a few such preliminary works
have been done in the area that is quite insufficient against the potentiality of the
region [13–17].

2 Methodology

2.1 Study Area

The survey was carried out in Lakhimpur (26°48′ N to 27°53′ N latitudes and 93°42′
E to 94°20′ E longitudes) and Dhemaji (27°05′27″ N to 27°57′16″ latitudes and
94°12′ to 95°41′ longitude) districts of Assam (Fig. 1) during 2018–2020.
Phytomedicines Used in Respiratory Diseases by Traditional Healers of Lakhimpur… 229

Fig. 1 Map of study sites, Lakhimpur and Dhemaji districts of Assam, India

The area is located on the northern bank of the river Brahmaputra and the north-
eastern corner of the Indian state of Assam, with an area of 2227 sq km for
Lakhimpur and 3237 sq km for Dhemaji districts. Both districts encounter hot and
humid summer, cold and dry winter with high precipitation during monsoon [18,
19]. Inhabitants of the area belong to different tribes and communities including
Mishing, Tiwa, Boro, Sonowal-Kachari, Deuri and Adibasi are living in both
the districts. While they are having their respective languages, the main communi-
cating language is Assamese. Earlier the entire area was covered under forest and
people were living mainly in the forest. Even today, apart from small township
areas, most of the people live in such villages and survive well in their tradi-
tional ways.

2.2 Data Collection

A random and regular household survey was carried out from August 2018 to March
2020 in different villages of the area selected randomly. A semi-structured question-
naire was prepared for the survey following Jain and Mudgal [20]. Traditional heal-
ers, elderly villagers of both sexes, were interviewed for their knowledge about
traditional medicinal plants used in treating Pneumonia and asthma.
230 P. Gogoi et al.

2.3 Collection and Identification of Plants

Plants are initially identified in their local language (Assamese) and voucher speci-
mens were collected for scientific identification. The specimens were then pro-
cessed into mounted herbarium sheets [21, 22]. Plants were identified referring to
literatures [23–25] and compared with the Herbarium of Arunachal University
(HAU-Herbarium). Updated names of plants were obtained from websites of the
world online organization on plant taxonomy [26, 27]. Specimens were deposited in
the HAU-Herbarium for future reference.
Quantitative Evaluation: For a better understanding of the collected information,
(i) relative frequency of citations (RFC) and (ii) fidelity level (FL) were calculated
following Umair et al. [28].

(i) Relative frequency of citations (RFC): It describes the local significance of each
species from a study area. RFC is calculated by the formula
RFC = FC/N (0 < RFC > 1), where FC is the number of informants citing
for a particular species and N is the total number of informants.
(ii) Fidelity level (FL): It is the percentage of informants mentioning a plant species
for a single disease. FL is calculated as
FL (%) = (Np/N) × 100, where Np is the number of informants that sug-
gested the use of a plant in a particular disease and N is the number of infor-
mants. A high FL value indicates the high use of a particular plant species in
treating a particular disease by the healers of that area.

3 Result and Discussion

In the present study, a total of 61 plant species belonging to 35 families were

recorded that are used traditionally by local healers and elderly people in treating
pneumonia and asthma by interviewing 80 informants. The most dominating fami-
lies are Lamiaceae and Zingiberaceae with four species each. Young shoots are the
most used parts during crude medicine preparation with 22.95% followed by leaves
(14.75%), bark (13.11%), fruit, root and whole plant with 9.84% each. Table 1 enu-
merates all the recorded plants with field number, family, local names, habits, status
of all plants, diseases treated, RFC and FL% among 80 informants of the study area,
whereas Tables 2 and 3 show the name of the medicinal plants, parts used, mode of
preparations (traditional formulations) and nature of administration in managing the
diseases.
During the preparation of medicine/formulation, healers mainly used freshly col-
lected plants from the wild or their surroundings. Usually, they do not store pre-
pared medicine, for the next batch preparation, they used to collect all required
plants freshly from the wild. Crude preparations are in the form of fresh juice,
decoction, paste and tablets. The mode of administration is mainly oral but some
Phytomedicines Used in Respiratory Diseases by Traditional Healers of Lakhimpur… 231

Table 1 Plants recorded from Lakhimpur and Dhemaji districts of Assam for the treatment of
respiratory diseases such as pneumonia and asthma
Assamese FL
Plant names [Family]; field no. name Habit Status Disease (%) RFC
Acmella paniculata (Wall. ex DC.) Huhoni H Wi Pneumonia 1.25 0.025
R.K. Jansen [Asteraceae];
GPinki-119
Acorus calamus L. [Acoraceae]; Bosh H Wi Asthma 1.25 0.025
GPinki-062
Ageratum conyzoides L. Gundhua bon H Wi Pneumonia 2.5 0.062
[Asteraceae]; GPinki-031
Allium sativum L. Nohoru H Cu Pneumonia 1.25 0.025
[Amaryllidaceae]; GPinki-158
Alocasia macrorrhizos (L.) G.Don Nol kosu H Wi Pneumonia 1.25 0.012
[Araceae]; GPinki-169
Calotropis gigantea (L.) W.T. Aiton Palti S Wi Pneumonia 1.25 0.012
[Apocynaceae]; GPinki-200
Asplenium nidus L. [Aspleniaceae]; Biyonijupa H Wi Asthma 1.25 0.012
GPinki-075
Azadirachta indica A. Juss. Mohaneem T Wi Asthma 1.25 0.062
[Meliaceae]; GPinki-001
Capsicum annuum L. [Solanaceae]; Jolokia H Wi, Pneumonia 1.25 0.025
GPinki-022 Cu
Carica papaya L. [Caricaceae]; Omita Wi, Pneumonia 1.25 0.025
GPinki-035 Cu
Centella asiatica (L.) Urb. Bor maanimuni H Wi Pneumonia 3.75 0.162
[Apiaceae]; GPinki-011
Cinnamomum verum J. Presl Daalchini T Cu Pneumonia 1.25 0.037
[Lauraceae]; GPinki-112
Citrus x limon (L.) Osbeck Gulnemu S Cu Pneumonia 3.75 0.125
[Rutaceae]; GPinki-018 Asthma 1.25
Clerodendrum infortunatum L. Dhopat tita H, S Wi Pneumonia 1.25 0.05
[Lamiaceae]; GPinki-196
Croton caudatus Geiseler Hunghungi lota S Wi Pneumonia 2.5 0.025
[Euphorbiaceae]; GPinki-064
Curcuma caesia Roxb. Kola halodhi H Wi Asthma 1.25 0.012
[Zingiberaceae]; GPinki-089
Cynodon dactylon (L.) Pers. Dubori bon H Wi Pneumonia 1.25 0.037
[Poaceae]; GPinki-110
Cyperus rotundus L. [Poaceae]; Kera bon H Wi Pneumonia 2.5 0.025
GPinki-120
Deeringia amaranthoides (Lam.) Matuktuka C Wi Pneumonia 1.25 0.012
Merr. [Amaranthaceae]; GPinki-094
Drymaria cordata (L.) Willd. ex Ghuronia H Wi Pneumonia 2.5 0.075
Schult. [Caryophyllaceae]; laaijabori Asthma 1.25
GPinki-03
Elettaria cardamomum (L.) Maton Elichi H Cu Pneumonia 1.25 0.037
[Zingiberaceae]; GPinki-115
(continued)
232 P. Gogoi et al.

Table 1 (continued)
Assamese FL
Plant names [Family]; field no. name Habit Status Disease (%) RFC
Eleusine indica (L.) Gaertn Bobosa bon H Wi Pneumonia 1.25 0.025
[Poaceae]; GPinki-013
Ficus racemosa L. [Moraceae]; Dimoru T Wi Pneumonia 1.25 0.037
GPinki-087
Guilandina bonduc L. [Fabaceae]; Letaguti T Wi Pneumonia 5 0.187
GPinki-032 Asthma 2.5
Hellenia speciosa (J.Koenig) Jomlakhuti H Wi Pneumonia 1.25 0.087
S.R.Dutta [Costaceae]; GPinki-048
Heteropanax fragrans (Roxb.) Keseru T Wi, Pneumonia 1.25 0.012
Seem. [Araliaceae]; GPinki-093 Cu
Hydrocotyle sibthorpioides Lam. Horu H Wi Pneumonia 3.75 0.175
[Araliaceae]; GPinki-02 maanimuni
Hygrophila phlomoides Nees H Wi Pneumonia 1.25 0.012
[Acanthaceae]; GPinki-139
Kaempferia rotunda L. Bhumichampa H Wi Pneumonia 1.25 0.012
[Zingiberaceae]; GPinki-046
Leucas aspera (Willd.) Link Durun bon H Wi Asthma 1.25 0.1
[Lamiaceae]; GPinki-041
Macaranga denticulata (Blume) Murulia T Wi Pneumonia 3.75 0.075
Mull.Arg. [Euphorbiaceae];
GPinki-101
Mangifera indica L. Aam T Wi Pneumonia 1.25 0.025
[Anacardiaceae]; GPinki-067
Momordica dioica Roxb. Ex Willd. Bhatkerela C Wi, Pneumonia 1.25 0.012
[Cucurbitaceae]; GPinki-050 Cu
Myristica fragrans Houtt. Jaaifal T Cu Pneumonia 1.25 0.037
[Myristicaceae]; GPinki-113
Ocimum tenuiflorum L. Kola tulokhi H Wi Pneumonia 2.5 0.087
[Lamiaceae]; GPinki-107
Oldenlandia diffusa (Willd.) Roxb. Bonjaluk H Wi Pneumonia 3.75 0.087
[Rubiaceae]; GPinki-012
Oroxylum indicum (L.) Kurz Bhatghila T Wi Pneumonia 1.25 0.05
[Bignoniaceae]; GPinki-047
Oryza sativa L. [Poaceae]; Dhan H Cu Pneumonia 1.25 0.012
GPinki-200
Piper nigrum L. [Piperaceae]; Jaluk C Wi, Pneumonia 22.5 0.412
GPinki-004 Cu Asthma 5
Piper thomsonii (C.DC.) Hook.f. Aauni paan C Wi Pneumonia 1.25 0.025
[Piperaceae]; GPinki-014
Piper betle L. [Piperaceae]; Paan C Cu Pneumonia 3.75 0.075
GPinki-063 Asthma 1.25
Plumbago zeylanica L. Aagesita H Wi Asthma 1.25 0.012
[Plumbaginaceae]; GPinki-096
Potentilla indica (Andrews) Th. Gorokhia bon H Wi Asthma 1.25 0.012
Wolf [Rosaceae]; GPinki-201
(continued)
Phytomedicines Used in Respiratory Diseases by Traditional Healers of Lakhimpur… 233

Table 1 (continued)
Assamese FL
Plant names [Family]; field no. name Habit Status Disease (%) RFC
Psidium guajava L. Modhuri T Wi Pneumonia 5.00 0.15
[Myrtaceae]; GPinki-017
Ricinus communis L. Ara H Wi, Asthma 1.25 0.037
[Euphorbiaceae]; GPinki-034 Cu
Rubus alceifolius Poir. [Rosaceae]; Jetulipoka H, S Wi Pneumonia 2.5 0.087
GPinki-033
Scoparia dulcis L. [Plantaginaceae]; Meetha bon H Wi Pneumonia 1.25 0.05
GPinki-010
Sida rhombifolia (L.) [Malvaceae]; Hunboriyal H Wi Asthma 1.25 0.025
GPinki-143
Solanum violaceum Ortega Titabhekuri S Wi Pneumonia 1.25 0.012
[Solanaceae]; GPinki-043
Spondias pinnata (L.f.) Kurz Omora T Wi Pneumonia 1.25 0.012
[Anacardiaceae]; GPinki-066
Stephania rotunda Lour. Gumraaj C Wi Pneumonia 1.25
[Menispermaceae]; GPinki-102
Syzygium aromaticum (L.) Merr. & Lon S Cu Pneumonia 1.25 0.05
L.M.Perry [Myrtaceae]; GPinki-114
Tabernaemontana divaricata (L.) Kathana S Wi Asthma 2.5 0.037
R.Br. Ex Roem. & Schult.
[Apocynaceae]; GPinki-074
Tamarix dioica Roxb. ex Roth Jharu bon S Wi Asthma 1.25 0.012
[Asteraceae]; GPinki-168
Thunbergia coccinea Wall. Ex D. C Wi Pneumonia 1.25 0.012
Don [Acanthaceae]; GPinki-100
Typhonium trilobatum (L.) Schott Kosu H Wi Pneumonia 1.25 0.012
[Araceae]; GPinki-026
Urena lobata L. [Malvaceae]; Hunboriyal H Wi Pneumonia 2.5 0.025
GPinki-037
Vitex negundo L. [Lamiaceae]; Posotia S Wi Pneumonia 2.5 0.037
GPinki-044
Zanthoxylum nitidum (Roxb.) DC. Tezmui C Wi Pneumonia 1.25 0.062
[Rutaceae]; GPinki-059
Zehneria japonica (Thunb.) H.Y.Liu Belipoka C Wi Asthma 1.25 0.025
[Cucurbitaceae];
GPinki-053
Zingiber officinale Roscoe Aada H Cu Asthma 1.25 0.037
[Zingiberaceae]; GPinki-118
Ziziphus jujuba Mill. Bogori T, S Wi Pneumonia 1.25 0.012
[Rhamnaceae]; GPinki-065
Abbreviations used: Habit: C climber, H herb, S shrub, T tree. Status: Cu cultivated, Wi wild
Total number of informants/respondents = 80
234 P. Gogoi et al.

Table 2 Traditional remedies for pneumonia

Part
Plants used Preparation Administration
Eleusine indica R Extract juice from a handful of the root of Two tablespoons of the
Piper nigrum F E. indica by crushing, squeezing and mixture is orally
pressing method. Dry fruit powder of administered, once daily
P. nigrum (9 to 21 fruits) is added and the before breakfast
crude juice mixture is formed (Whenever consecutively for 3 days
fruits/seeds are used they are taken in odd
numbers as they belief in getting positive
results with uneven numbers. It is also
considered more effective with
higher amount of P. nigrum. Therefore, as
a recommended dose for minors only 9
fruits were added against 21 fruits for
matured peoples during preparation).
Drymaria YS A handful of leafy young shoots are Half a teaspoon of juice
cordata crushed, squeezed, pressed and extract the before breakfast is
juice. administered continuously
till cured.
Hydrocotyle WP A handful of all the three plants, viz. H. About 3–4 tablespoons are
sibthorpioides sibthorpioides, C. asiatica and orally administered before
Centella WP O. diffusa are grounded together and breakfast once a day for
asiatica extract the juice by squeezing and consecutive 3 days
Oldenlandia WP pressing. Dry fruits of P. nigrum are
diffusa grounded to powder (21 dry fruits) and
mixed with the juice.
Piper nigrum F
Typhonium T Tuber of T. trilobatum (300 g) and dry One teaspoon of the paste
trilobatum fruits of P. nigrum (21 fruits) are boiled in is given twice daily,
water for about 30 minutes and made a before or after food.
Piper nigrum F paste.

Calotropis R Equal amount of roots (200 g each) of both The paste is applied on
gigantea C. gigantea and C. gigantea and C. chest, once daily for 3
Capsicum R annuum are boiled in water and a decoction days in adults and once in
annuum is prepared. Grounded powder of two–four 48 h in children.
Piper nigrum F dry fruits of P. nigrum are added into the
decoction and made into a paste.
Scoparia dulcis R Roots of S. dulcis (150 g) and U. lobata About 1 ml of warm crude
Urena lobata R (50 g) are crushed together and juice are juice is orally
extracted by squeeze-press method, a little administered before
salt is added, warmed and the mixture is breakfast, once daily for 3
ready for treatment. days.
Solanum F Six fruits of S. violaceum, one seed of G. One teaspoon of the crude
violaceum bonduc, and root of P. thomsonii (of a juice is orally given on
Guilandina S plant) are grounded and pressed/squeezed empty stomach, once
bonduc and extract the juice. Dry grounded fruit daily consecutively for 3
Piper R powder (21 fruits) of P. nigrum is added to days.
thomsonii the juice mixture and warm.
Piper nigrum F
(continued)
Phytomedicines Used in Respiratory Diseases by Traditional Healers of Lakhimpur… 235

Table 2 (continued)
Part
Plants used Preparation Administration
Oroxylum B Bark of O. indicum (200 g) is grounded/ The crude mixture is
indicum pounded with a little water and juice is orally administered thrice
Piper nigrum F extracted. Dry powder of P. nigrum fruit daily before meal
(21 fruits) are added and the juice mixture consecutively for three
is ready for treatment. days.
Vitex negundo B About 200 g of bark of V. negundo, a About 3–4 tablespoons of
Rubus YS handful of young leafy twigs of R. crude mixture is orally
alceifolius alceifolius and P. guajava are grounded administered on an empty
Psidium YS and a crude mixture of juice is extracted by stomach daily,
guajava squeezing and pressing. A handful of P. continuously for three
nigrum powder is added to the crude juice days.
Piper nigrum F
mixture, and is administer.
Citrus x limon L Five leaves of C. limon, and five young One teaspoon of the juice
Ageratum YS shoots of A. conyzoides are grounded mixture is orally given on
conyzoides together and crude juice is extracted by empty stomach, once
Piper nigrum F squeezing & pressing and a handful of daily consecutively for 3
P. nigrum dry fruit powder is added to the days. (the preparation is
juice mixture. given only to adults)
Kaempferia Rh About 100 g of rhizome of K. rotunda is One teaspoon of the juice
rotunda grounded and juice is extracted by is given after meal, once
Piper nigrum F squeezing and pressing. Grounded powder daily for a week. (only for
of 1–2 dried fruits of P. nigrum is added to children below 5 years of
the juice. age. The Informants don’t
disclose the reason for not
applying to other age
groups)
Momordica T About 3–4 tubers (100 g approx.) are A teaspoon of the juice is
dioica pressed and juice is extracted and added a given on empty stomach,
little salt to it. daily for three days.
Croton YS A handful of young shoots of C. caudatus, Three tablets are given
caudatus P. guajava, Z. jujuba, S. pinnata, one seed thrice daily, before meal
Psidium YS of G. bonduc, 3 whole plants of consecutively for 3 days.
guajava C. rotundus, 3–4 leaves of M. indica and
Ziziphus jujube YS C. limon are grounded and a thick paste is
made. A handful of dry fruit powder of
Cyperus WP
P. nigrum is added to the paste and make
rotundus
tablets.
Guilandina S
bonduc
Mangifera L
indica
Citrus x limon L
Spondias YS
pinnata
Piper nigrum F
(continued)
236 P. Gogoi et al.

Table 2 (continued)
Part
Plants used Preparation Administration
Citrus x limon L A handful of all the ingredients except P. About (8–10) ml of crude
Piper nigrum F nigrum are mixed and juice is extracted by juice is given on empty
Clerodendrum YS grinding, squeezing and pressing. Dry fruit stomach, once daily
infortunatum powder of P. nigrum (21 fruits) is added to consecutively for 3 days.
the crude juice and ready to administer.
Croton YS
caudatus
Ageratum YS
conyzoides
Oryza sativa F
Zanthoxylum R A handful of root of Z. nitidum, a leaf of P. About 2 tablespoon of the
nitidum betle, young shoot of D. cordata crude juice extract is
Guilandina S (one shoot), a seed of G. bonduc are given on empty stomach,
bonduc grounded and by squeezing & pressing the once daily consecutively
Myristica F juice is extracted. Remaining ingredients for 3 days.
fragrans are added in a small quantities (0.5–1 fruit/
flower bud) to the crude juice mixture for
Syzygium FB
taste, warm a little.
aromaticum
Elettaria F
cardamomum
Piper betle L
Drymaria YS
cordata
Piper nigrum F
Cinnamomum B
verum
Urena lobata R Roots from one or two U. lobata plant(s), About (5–10) ml of the
Heteropanax B with handful of P. betle leaves and young juice is given on empty
fragrans shoot of V. negundo, 100 g (approx..) of stomach, once daily
Carica papaya B bark of H. fragrans and C. papoya, are consecutively for 3 days.
grounded and juice is extracted by
Piper betle L
squeezing and pressing. Dry fruit powder
Vitex negundo YS of P. nigrum (21 fruits) fruit with a little
Piper nigrum F salt is added to the crude mixture.
Deeringia R A handful of root of D. amaranthoides and About 1–2 tablespoon of
amaranthoides add dry fruit powder of P. nigrum (9 fruits) crude juice is given on
Piper nigrum F with a little salt and warm for a few empty stomach, once
minutes. daily till cured.
Ficus racemosa B About (50–100) g of bark of F. racemosa is About 1–2 tablespoon of
Piper nigrum F grounded and extracted in water by crude juice is given on
squeezing and pressing. Dry fruit powder empty stomach, once dail
of 21 fruits of P. nigrum is added to the for 3–4 days.
crude juice.
(continued)
Phytomedicines Used in Respiratory Diseases by Traditional Healers of Lakhimpur… 237

Table 2 (continued)
Part
Plants used Preparation Administration
Thunbergia L A handful of leaves of T. coccinea, tuber of About (3–5) ml of juice is
coccinea M. denticulate and small piece of S. given, once daily till
Macaranga L rotunda are grounded, and juice is cured.
denticulata extracted by squeezing-pressing. added dry
Stephania Tu fruit powder of P. nigrum (21 fruits) are
rotunda added to the juice mixture.
Piper nigrum F
Macaranga B The bark (200 g) of M. denticulate is About 2–3 teaspoon of
denticulate extracted by infusion for about 1 h, the crude juice is given on
Piper nigrum F extract filtrate is added with fruit powder of empty stomach, once
21 dry fruits of P. nigrum. daily consecutively for 3
days
Hygrophila YS Mix all ingredients (handful) except P. About 5–10 ml of the
phlomoides nigrum and extract the juice by crushing, crude juice is given on
Psidium YS squeezing and Pressing. Dry fruit powder empty stomach, once
guajava of P. nigrum (21 fruits) is added to the daily consecutively for 3
Rubus YS crude juice mixture. days.
alceifolius
Cyperus UN
rotundus
Ocimum YS
tenuiflorum
Guilandina S
bonduc
Piper nigrum F
Macaranga B A handful of all the ingredients except P. About 10 ml of the juice
denticulata nigrum are grounded and extracted the is given on empty
Psidium YS juice by squeezing and pressing. The juice stomach, once daily
guajava obtain is added with dry fruit powder of 21 consecutively for 3 days.
Cynodon WP fruits of P. nigrum and the mixture is ready
dactylon for use.
Hellenia St
speciosa
Piper betle L
Piper nigrum F
Acmella YS
paniculata
Oldenlandia WP
diffusa
Alocasia Tu A medium sized tuber (100–200) g of A tablespoon of the
macrorrhizos A. macrorrhizos is boiled in water with decoction is given after
Piper nigrum F 21–31 dry fruits of P. nigrum and the meal, twice daily
decoction is prepared. consecutively for 2–3
days.
Abbreviations used: Parts used: L leaf, F fruit, S seed, R root, B bark, T tuber, WP whole plant, YS
young shoot, Rh rhizome, St stem, FB flower bud, Fr frond; Extraction solvent: water; Method of
extraction: Fresh-Squeeze and Pressing
238 P. Gogoi et al.

Table 3 Traditional remedies for asthma

Part
Plants used Preparation Administration
Zehneria japonica T Tuber of Z. japonica 50 g is Two tablespoon of the juice
grounded and extracted by is given on empty stomach,
Fresh-Squeeze and Pressing, a little once daily consecutively for
salt is added in the juice for 3 days
improving taste and mixture is used
for the treatment.
Piper nigrum F A handful of leaf of P. nigrum and One tablets is administered
Guilandina S dry fruits and young leaves of R. until fully recovered.
bonduc communis with seeds (four) of G.
Ricinus communis L bonduc are grounded to powder and
make tablets.
Tabernaemontana B A handful of all the ingredients Within a month of its
divaricata except P. nigrum are grounded using preparation the crude juice
Asplenium nidus Fr pestle and mortar and extracted by of 10 ml is given on empty
Leucas aspera YS pressing & squeezing. Grounded stomach, once daily,
powder of dry fruits (21 fruits) of P. consecutively for 3 days.
Piper nigrum F
nigrum is added and the mixture is
ready to be used.
Curcuma caesia Rh Rhizome (200 g) of C. caesia is One teaspoon of the mixed
Citrus x limon F grounded and extracted by juice is given on empty
fresh-squeezing and pressing. The stomach, till fully recovered.
extracted juice is mixed with and the
juice extracted from fresh-squeezing
and pressing of one whole fruit of C.
limon.
Piper nigrum F Rhizome (200 g) of Z. officinale and About 10 ml of the juice is
Zingiber officinale Rh root (100 g) of S. rhombifolia are given on empty stomach,
Sida rhombifolia R mixed and grounded in mortar using once daily till fully
pestle with handful of dry fruit recovered.
powder of P. nigrum.
Plumbago L Leaves of P. zeylanica (2 leaves) and The paste is applied on the
zeylanica one leaf of P. piper are grounded and chest to recover from
Piper betle L extracted by squeezing and pressing. pneumonia.
The extract is mixed and a paste is
made.
Drymaria cordata YS Juice is extracted from a handful of Half a teaspoon of the crude
leaves of D. cordata and mixed with juice mixture is consumed
a cup of cow’s milk and is ready to regularly before breakfast till
be served. fully cured.
Azadirachta indica L A handful of A. indica leaves with a An amount of 10 ml of the
Guilandina S seed of G. bonduc are boiled in decoction is given thrice
bonduc water for 15–20 minutes and the daily before meal, till fully
decoction is prepared. cured.
(continued)
Phytomedicines Used in Respiratory Diseases by Traditional Healers of Lakhimpur… 239

Table 3 (continued)
Part
Plants used Preparation Administration
Acorus calamus Rh Dry rhizome powder of A. calamus Three tablets to be taken
is mixed with a little honey and thrice daily, till cured.
make tablets.
Tamarix dioica L A handful of T. dioica leaves are About 10 ml of the juice is
Piper nigrum F grounded using pestle and mortar given on empty stomach,
and crude juice is extracted, powder once daily consecutively for
of dry fruits (21 fruits) of P. nigrum 3 days.
is added to the juice, warmed and is
ready for use.
Potentilla indica WP Handful of the whole plant of About 10 ml of the juice is
P. indica is grounded using a pestle given on empty stomach,
and mortar and crude juice is once daily consecutively for
extracted by fresh-squeeze and press 3 days.
method and is ready for the ailment.
Abbreviations used: Parts used: L leaf, F fruit, S seed, R root, B bark, T tuber, WP whole plant, YS
young shoot, Rh rhizome, St stem, FB flower bud, Fr frond; Extraction solvent: water; Method of
extraction: Fresh-Squeeze and Pressing

practitioners also use the external mode of administration. Healers often recom-
mend a strict diet to the patients during the period of treatment like restrictions to
meat, fish, eggs, certain vegetables, etc.
Among the recorded plants, 48 species were found to be used in treating pneu-
monia (Table 2), while 18 species were used in asthma treatment (Table 3) with
some species such as P. nigrum, G. bonduc, C. limon, D. cordata, C. verum, E. car-
damomum, M. fragrans and S. aromaticum being used as common additives for
both the diseases during the preparation of crude medicines by various healers. A
similar ethnomedicinal survey related to respiratory disease was carried out in other
parts of India and reported similar plants such as O. tenuiflorum, L. aspera, Z. offi-
cinale, A. conyzoides, H. sibthorpioides, C. asiatica, O. diffusa, O. indicum, G. bon-
duc and P. Guajava [29–33] and for asthma L. aspera, P. nigrum [34] and A. calamus
[35]. However, in the present study, the use of Tamarix dioica and Potentilla indica
against asthma treatment and the use of Hygrophila phlomoides and Stephania
rotunda against pneumonia recorded from the region are new ethnobotanical
records.

4 Conclusion

The wild plants in Assam are in use in disease management in households and are
still popular. Often new ethnobotanical records also surface through similar field
studies, viz. Tamarix dioica and Potentilla indica (anti-asthma); Hygrophila phlo-
moides and Stephania rotunda (anti-pneumonia). Contrary to the anti-bacterial
240 P. Gogoi et al.

properties reported for Thunbergia coccinea [36] none of the informants cited the
species for pneumonia treatment from the region. Therefore, for understanding the
actual efficacy and for the scientific exploitation for the benefit of mankind phyto-
chemical analysis and biological validation is recommended for each of these
plants. Therefore, the present study will open up possibilities for further pharmaco-
logical research.

References

1. Ballabh B, Chaurasia OP (2007) Traditional medicinal plants of cold desert Ladakh-used in

treatment of cold, cough and fever. J Ethnopharmacol 112(2):341–345
2. Pandey MM, Rastogi S, Rawat AKS (2008) Indian herbal drug for general healthcare: an over-
view. Internt J Altern Med 6(1):1–10
3. Adhikari PP, Paul SB (2018) History of traditional medicine: a medical inheritance. Asian J
Pharm Clin Res 11(1):421–426
4. Patwardhan B, Warude D, Pushpangadan P, Bhatt N (2005) Ayurveda and traditional Chinese
medicine: a comparative overview. Evid Based Complement Altern Med 2(4):465–473
5. Borthakur SK (1976) Less known medicinal uses of plants among the tribes of Karbi-Anglong
(Mikir Hills) Assam. Bull Med-Ethno Res 18:166–171
6. Borthakur SK, Nath K, Gogoi P (1996) Herbal remedies of the Nepalese of Assam. Fitoterapia
67:231–237
7. Puri HS (1987) Medicinal plants of Tezpur, Assam. Bull Med-Ethno-Bot 4:1–13
8. Pandey AK, Bora HR, Deka SC (1996) An ethnobotanical studies of Golaghat District, Assam:
native plant remedies for jaundice. J Econ Taxon Bot Addl Ser 12:344–349
9. Rao RR (1981) Ethnobotany of Meghalaya: Medicinal Plants Used by Khasi and Garo Tribes.
Econ Bot 35(1):4–9. Springer & New York Botanical Garden Press. http://www.jstor.org/
stable/4254241
10. Ferkol T, Schraufnagel D (2014) The global burden of respiratory disease. Ann Am Thorac
Soc 11(3):404–406
11. Gangwar AK, Ramakrishnan PS (1990) Ethnobiological notes on some tribes of Arunachal
Pradesh, Northeastern India. Econ Bot 44(1):94–105
12. Toku B, Deuri M, Borah D, Tangjang S, Das AP (2021) Traditional phyto-medicines from the
districts along the course of Subansiri river in Arunachal Pradesh, India: a review. In: Deb CR,
Paul A (eds) Bioresources and sustainable livelihood of rural India. Mittal Publications, New
Delhi, pp 185–239
13. Kalita D, Deb B (2006) Folk medicines for some diseases prevalent in Lakhimpur district of
Brahmaputra valley, Assam. Nat Prod Radiance 5(4):319–322
14. Ayam VS, Doley P, Singh CB (2017) Ethnomedicinal plants used by the missing tribe of
Dhemaji District of Assam, India. Int Res J Biol Sci 6(8):37–43
15. Chetia DR, Das AK (2018) Diversity of ethnomedicinal plants used by Mising tribe of Dhemaji
district, Assam. Int J Adv Res Publ 6(3):815–825
16. Sharma UK, Hazarika D (2018) Study of ethnomedicinal plants used by the Mishing people of
Dhemaji district of Assam, India. J Nat Ayurvedic Med 2(4):000135
17. Borah S, Bora A (2020) Ethnomedicinal plants used for the treatment of common diseases by
the Deori community people of Lakhimpur district, Assam. Univers J Plant Sci 8(3):39–46
18. https://en.wikipedia.org/wiki/Lakhimpur_district
19. https://en.wikipedia.org/wiki/Dhemaji_district
20. Jain SK, Mudgal VN (1999) A hand book of ethnobotany. Bisen Singh, Mahendrapal Singh,
Dehradun
Phytomedicines Used in Respiratory Diseases by Traditional Healers of Lakhimpur… 241

21. Bridson D, Forman L (1998) The herbarium handbook, 3rd edn. Royal Botanic Garden, Kew
22. Das AP (2021) Herbarium Techniques. In: Bhandari JB, Gurung C (eds) Instrumentation man-
ual. Narosa Publishing House, New Delhi, pp 78–94
23. Hooker JD (1872–1897) The Flora of British India, 7 Vols. L. Reeve& Co. Ltd., Ashford,
Kent. London
24. Kanjilal UN, Das A, Kanjilal PC, Purkaystha C, De RN, Bor NL (1934–1940) Flora of Assam,
vol I–V. Govt of Assam Press, Shillong
25. Barooah C, Ahmed I (2014) Plant diversity of Assam – a checklist of angiosperms & gymno-
sperms. ASTEC, Guwahati
26. www.plantsoftheworldonline.org
27. http://www.worldfloraonline.org
28. Umair M, Altaf M, Abbasi AM (2017) An ethnobotanical survey of indigenous medicinal
plants in Hafizabad district, Punjab-Pakistan. PLoS One 12(6):1–22
29. Dwivedi N, Dwivedi S, Dwivedi A (2015) Herbal remedies for respiratory diseases among the
natives of Madhya Pradesh, India. Am J Life Sci Res 3(2):158–162
30. Kala CP (2020) Medicinal plants used for the treatment of respiratory diseases in Uttarakhand
state of India. Stud Ethno Med 14(1–2):1–8
31. Bushi D, Bam K, Mahato R, Nimasow G, Nimasow OD, Tag H (2021) Ethnomedicinal plants
used by the indigenous tribal communities of Arunachal Pradesh, India: a review. Ethnobot
Res Appl 22(34):1–40
32. Yadav N, Ganie SA, Singh B, Chhillar AK, Yadav SS (2019) Phytochemical constituents and
ethnopharmacological properties of Ageratum conyzoides L. Phytoter Res 33(9):2163–2178
33. Acharyya BK, Sharma HK (2004) Folklore medicinal plants of Mahmora area, Sivsagar dis-
trict, Assam. IJTK 3(4):365–372
34. Singh RK, Lego YJ, Sureja AK, Srivastava RC, Hazarika BN (2021) People and plant: learn-
ing with Adi community on ethnomedicinal practices and conservation in Arunachal Pradesh,
India. IJTK 20(1):74–82
35. Rana CS, Tiwari JK, Dangwal LR, Gairola S (2013) Faith herbal healer knowledge document
of Nanda Devi biosphere reserve, Uttarakhand, India. IJTK 12(2):308–314
36. Sultana N, Das S (2019) Preliminary phytochemical screening and in vitro antimicrobial
activity of the leaf extract of Thunbergia coccinea (family-acanthaceae). Int J Curr Pharm
Res:111–114
Understanding Phytomedicinal
Gastronomic Culture of the Nagas
in Nagaland, India

Lydia Yeptho and T. Ajungla

1 Introduction

Nagaland obtained its statehood on December 1, 1963, and lies between 25°06’N
and 27°04’N latitude and 93°20′E and 95°15′E covering an area of 16,579 sq. km.
The state offers a scenic beauty of mountains and terrains inhabited by several eth-
nolinguistic tribal groups characterized by similar yet unique traditions and prac-
tices. Traditionally the Nagas lived a hunter–gatherer lifestyle but the transition
influenced mainly by religion, education, and modernization has led to a sedentary
phase with changes in beliefs and palatable flavor profiles. Its land supports a con-
siderable amount of crops like corn, pulses, fibers, potatoes, tobacco, oilseeds, sug-
arcane, millets, and rice along with abundant wild fruits and vegetables. Historically
Nagas were dubbed as inhabitants of thick forests frequenting the bazaar of
Sivasagar bartering salt, iron, and other items in exchange for their fine agricultural
produce [1]. Christianity is the established religion of the state with social structures
and practices burgeoned by their religious beliefs.
Traditional food gastronomy reflects the interactions between the environment
and local societies which results in the biocultural heritage of traditional food items
that help sustain the local traditional foods and implements food sovereignty [2, 3].
It plays the dual nature of prolonging the dynamics of present consumption and
tends to idealize the local feebly to promote economic sources for the community.
In this context, Barthes [4] suggested the dynamics related to traditional food gas-
tronomy as an idea to express the beliefs and opinions of the individual and social
ethical orientation equally. Nagas were once known as “warrior tribes” marked by

Lydia Yeptho and T. Ajungla contributed equally with all other contributors.

L. Yeptho (*) · T. Ajungla

Department of Botany, Nagaland University, Lumami, India

© The Author(s), under exclusive license to Springer Nature 243

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_8
244 L. Yeptho and T. Ajungla

their bravery, but their bravery now manifests itself in the abominable cooking and
eating habits they create under the nose of their neighbors. The surprise and linger-
ing suspicion are palpable in the aroma of the fermented food products intriguing
celebratory chefs like Gordon Ramsay to broadcasting in shows like “gourmet goes
tribal.”
Cultural cuisine of local and traditional foods before modernization and industri-
alization provided a cultural identity among the societies [5]. The continuous inter-
action of cultures with the local ecosystems resulted in the traditional food systems
harboring indigenous knowledge over generations [6]. To recuperate the local gas-
tronomic condition, foodways pave way to an experienced progressive marginaliza-
tion that unites a community [7, 8] by analyzing the history and cultural roots of a
food product and also analyzing the value chains and productive structure of these
products [9].

2 Foodways as Phytomedicinal Medium

Foodways or the preparation and consumption of foods capture perceptive endow-

ment and strengthen community affiliation on various levels in a variety of ways
[10]. Foodways help shape the cultural identity by defining the what, where, how,
and when routine activities elaborated personally holding the bonds of families and
communities [11]. Thus, it involves the tools, techniques, ingredients, and food cul-
ture customs [12] and explicitly involves the cultural geography of the surroundings
as well. The gastronomy of Nagas parallels the age-old traditions and practices of
the past as food and medicine were synonymous with our way of living. The rich
knowledge of the past has lived on through oral traditions and the practices of
kitchen living with an emerging new façade of food culture existing at present. The
diverse forms of culinary preparations interlinked with indigenous and traditional
knowledge reflect the versatile nature of the food, linking the nutritional, health
benefits, and health-giving attributes of the food to prevent various health problems
and diseases. Foods to improve metabolism to foods that heal cancers are consumed
to face the challenges of daily life. A typical traditional Naga meal consists of
cooked rice, meat, or vegetable cooked with a fermented food product supplemented
with chutney and boiled leafy vegetables as a side dish on a traditional wooden
plate. A cup of red tea or water at the end of the meal wraps up the repast. Table 1
describes the traditional food gastronomy of the Nagas, its ingredients, methods of
preparation, and the phytomedicinal properties of the foods paving way for under-
standing the dynamics of non-communicable diseases and the diet at hand. The
themes involve lessons gleaned from ethnic patterns of family ties, experiences,
beliefs, the oral tradition of the ancestors on food used as traditional medicine,
availability and use of resources, culinary skills, and ingredients. Table 2 represents
some common plants used as phytomedicinal food with their common name, botan-
ical name, family, and parts used, while Fig. 1 represents some plants used as phyto-
medicinal foods.
Understanding Phytomedicinal Gastronomic Culture of the Nagas in Nagaland, India 245

Table 1 Metonymic food representing its culinary use as phytomedicinal food

Phytomedicinal benefits against
Main ingredients Method of preparation various diseases
Tulsi leaves and The leaves and inflorescence are Cold and cough, flu, and
inflorescence boiled and the brine is taken headache
Guava leaves Tender guava leaves are washed Irritable bowel syndrome
thoroughly and boiled with water
and the brine is taken
Pomegranate leaves Tender pomegranate leaves are Malaria and typhoid
washed thoroughly and boiled with
water and the brine is taken
Passion leaves The leaves are boiled and both the High blood pressure
juice and the leaves can be taken
Indian Pennywort The leaves are cleaned and boiled Diabetes, skin infection,
leaves or taken raw as a salad indigestion, gastritis
Papaya leaves Brine of the boiled leaves in hot Low level of blood platelets
water is taken or leaves are
pounded and the juice is taken
East Indian glory bower The leaves are either boiled or High blood pressure
prepared as a vegetable curry
Redwool plantain The leaves are either boiled or Stomach ailments
prepared as a vegetable curry
Stinging nettle The leaves are either boiled or Diarrhoea
made into curry
Cape periwinkle The leaves or flowers are boiled in Cancer
water
Mango leaves The tender leaves are boiled and Stomach ache
the juice is taken
Neem leaves The leaves are boiled and the juice Fever
is taken
Crab, tomato, garlic, Crabs are cleaned and cooked with The brine is believed to heal
and ginger salt, tomato, garlic, ginger and measles
chilly (optional) as a curry
Chinese Knotweed, Potato, tomato and a tablespoon of Cancer
tomato, potato, and fermented soybean are cooked and
fermented soybean the leaves of Chinese Knotweed
(optional) are added as a garnish rendering
the curry sour
Hooker’s chives, potato The leaves of chives are washed Stomach ailments
properly and cooked with potato,
salt and chilly
Yam The skin of the tubers is peeled off Gastritis
and salt is added and cooked
Indonesian lemon Prepared as a vegetable curry with Appetizer/diarrhoea/teeth enamel
pepper leaves, potato, fermented soybean diseases or bleeding gums
and tomato
Bitter gourd It is prepared as a curry added with High blood pressure
fermented soybean
(continued)
246 L. Yeptho and T. Ajungla

Table 1 (continued)
Phytomedicinal benefits against
Main ingredients Method of preparation various diseases
Goosefoot Young leaves are cooked as curry Ulcer, blood purifier, liver
or boiled or fried with chilly problem
Taro, longevity spinach The outer skin of the yam is peeled Increases appetite in children
off and prepared as a vegetable
curry along with longevity spinach
leaves
Indian nightshade The fruits are prepared as a curry High blood pressure and fever
with fermented soybean and potato
or deep-fried in oil
Mint The leaves are prepared with chilly Stomach ache, indigestion
and tomato as chutney or cooked
with fermented soybean as a curry
Sweet basil The leaves are cooked with High blood pressure
fermented soybean and potato as a
curry or boiled or prepared as a
chutney
Roselle Fresh/dried roselle leaves are High blood pressure
prepared as a vegetable side dish
or simply boiled.
Edible mushrooms, Boiled with ginger and salt as a Tonic to prevent food poising and
Chinese Sumac powder, curry or a pinch of Chinese Sumac stomach problems. Powdered
ginger, powder is added while preparing Chinese sumac is used to treat
mushroom curry allergies or nausea and vomiting
Wax gourd Prepared as a vegetable curry or Diabetes
taken as a boiled side dish
Vegetable fern, tomato, The leaves are prepared along with Headache, fever
fermented soybean, potato, tomato, a spoonful of
chilly, and potato fermented soybean and chilly as a
vegetable curry
Bitter tomato The fruits are boiled or prepared as High blood pressure
a vegetable curry along with potato
Beefsteak plant, The seeds are crushed and cooked Constipation
fermented soybean, with a small amount of fermented
tomato, chilly, ginger, soybean with chilly, salt, ginger,
garlic, and taro stems garlic, and dried taro stems
Stalkless Elatostema The leaves are prepared as a Gastritis
vegetable side dish or used for
making rice porridge with small
amount of fermented soybean
Black turtle bean The seeds are boiled with salt and Mouth ulcer
cooked until soft
May chang, chilly The fruits of May chang are Vomiting and nausea
crushed with chilly and salt and
prepared as chutney
(continued)
Understanding Phytomedicinal Gastronomic Culture of the Nagas in Nagaland, India 247

Table 1 (continued)
Phytomedicinal benefits against
Main ingredients Method of preparation various diseases
Chinese Scallion, The bulbs are crushed and Fever and loss of appetite
tomato, and chilly prepared as a chutney with roasted
chilly and tomato
Ginger and fermented Ginger is crushed and the juice is Used as an appetizer and during
soybean squeezed, roasted dry red chilly fever
along with salt and fermented
soybean is added and prepared as a
chutney
Fragrant Caper Vine, The fruits are either sundried, High blood pressure and diabetes
chilly, tomato made into pickles, or prepared as a
chutney with chilly and tomato
Fish mint, tomato and The leaves are taken as raw or Heart problem, blood purifier,
chilly prepared as a chutney with tomato high blood pressure
and chilly
Sawtooth coriander The leaves are taken as raw, Increases appetite
prepared as chutney, or added in
curries as a garnish
Tree bean, potato, The legumes are prepared with Dysentery
tomato, and chilly potato as a curry or taken raw as a
salad or added in chutneys
Rice porridge with Rice is soaked, ground, and cooked Stomach ailments, diarrhoea,
longevity spinach with water; longevity spinach fever, gastritis
leaves leaves are added as a garnish.
Jobs tears The seeds are soaked, pounded, Indigestion
and cooked with water till it turns
soft and served as a porridge
Millet, rice It is cooked with rice and water or Cancer
pressurized until soft and eaten as
a porridge
Ginger and honey Ginger is pounded properly and Cold and cough
one teaspoon of the juice is boiled
with one teaspoon of honey
Toothache plant The flower heads are either chewed Toothache
or mashed and applied to the
affected area
Lime The leaves are crushed are inhaled Nausea, appetizer
and the juice is taken with water
and honey or sugar
Sweet potato The tubers are boiled or roasted Low blood pressure
Holy basil and hooker Crushed with salt and chilly Headache
leaves (optional) and the brine is taken
Himalayan mint, The flowers and leaves are added Headache, loss of appetite
potato, tomato, chilly, as a garnish in curry preparation
and garlic with potato, tomato and garlic. It is
also prepared with chilly and salt
as a chutney
248 L. Yeptho and T. Ajungla

Table 2 Various plants used as phytomedicinal food with their common name, botanical name,
family, and parts used
Common name Botanical name Family Parts used
Tomato Lycopersicon lycopersicum (L.) Solanaceae Fruit
H. Karst.
Chilly Capsicum frutescens L. Solanaceae Fruit
Ginger Zingiber officinale Roscoe Zingiberaceae Rhizome, leaves
Chinese Knotweed Polygonum chinense L. Polygonaceae Leaves
Garlic Allium sativum L. Amaryllidaceae Bulb, leaves
Potato Solanum tuberosum L. Solanaceae Tuber
Tulsi Ocimum tenuiflorum L. Lamiaceae Leaves
Longevity spinach Gynura procumbens (Lour.) Merr. Compositae Tender shoots,
leaves
Guava Psidium guajava L. Myrtaceae Leaves, fruit
Pomegranate Punica granatum L. Lythraceae Fruit
May chang Litsea cubeba (Lour.) Pers. Lauraceae Fruit
Hooker’s chive Allium hookeri Thwaites Amaryllidaceae Leaves, bulb
Passion fruit Passiflora edulis Sims Passifloraceae Leaves, fruit
Jobs tears Coix lacryma-jobi L. Poaceae Seeds
Millet Setaria italica (L.) P.Beauv. Poaceae Seeds
Chinese Scallion Allium chinense G.Don Amaryllidaceae Leaves, bulb
Indonesian lemon Zanthoxylum acanthopodium DC. Rutaceae Leaves, fruit
pepper
Fragrant Caper Vine Stixis suaveolens (Roxburgh) Pierre Capparaceae Fruit
Indian pennywort Centella asiatica (L.) Urb. Apiaceae Whole plant
Bitter gourd Momordica charantia L. Cucurbitaceae Fruit
Papaya Carica papaya L. Caricaceae Leaves, fruit
East Indian glory Clerodendrum glandulosum Lindl. Lamiaceae Leaves
bower
Redwool plantain Plantago erosa Wall. Plantaginaceae Whole plant
Goosefoot Chenopodium album L. Amaranthaceae Leaves
Fish mint Houttuynia cordata Thunb. Saururaceae Whole plant
Sawtooth coriander Eryngium foetidum L. Apiaceae Leaves
Taro Colocasia esculenta (L.) Schott Araceae Rhizome
Indian nightshade Solanum indicum L. Solanaceae Fruit
Tree bean Parkia timoriana (DC.) Merr. Leguminosae Fruit/pod
Mint Mentha spicata L. Lamiaceae Leaves
Holy basil Ocimum sanctum L. Lamiaceae Leaves
Roselle Hibiscus sabdariffa L. Malvaceae Flowers
Toothache plant Spilanthes acmella (L.) L. Compositae Young shoots
Stinging nettle Urtica ardens Link Urticaceae Young leaves
Cape periwinkle Catharanthus roseus (L.) G.Don Apocynaceae Leaves, flower
Lemon Citrus limon (L.) Osbeck Rutaceae Fruit
Chinese Sumac Rhus semialata Murray Anacardiaceae Fruit
Mango Mangifera indica L. Anacardiaceae Fruit
(continued)
Understanding Phytomedicinal Gastronomic Culture of the Nagas in Nagaland, India 249

Table 2 (continued)
Common name Botanical name Family Parts used
Sweet potato Ipomoea batatas (L.) Lam. Convolvulaceae Tubers
Wax gourd Benincasa hispida (Thunb.) Cogn. Cucurbitaceae Fruit
Vegetable fern Diplazium esculentum (Retz.) Sw. Athyriaceae Fronds
Tree tomato Solanum betaceum Cav. Solanaceae Fruit
Neem Azadirachta indica A.Juss. Meliaceae Leaves
Beefsteak plant Perilla frutescens var. crispa Lamiaceae Seeds, leaves
(Thunb.) H.Deane
Bitter tomato Solanum gilo Raddi Solanaceae Fruit
Stalkless Elatostema Elatostema sessile J.R.Forst. & Urticaceae Leaves
G.Forst.
Black turtle bean Phaseolus vulgaris L. Leguminosae Fruit/pod
Sweet basil Ocimum basilicum L. Lamiaceae Leaves
Pleasant Himalayan Elsholtzia blanda (Benth.) Benth Lamiaceae Flowers and
mint leaves

Fig. 1 (a-h) Various plants used as phytomedicinal foods. (a) Gynura procumbens, (b) Ocimum
tenuiflorum, (c) Coix lacryma-jobi, (d) Hibiscus sabdariffa, (e) Elsholtzia blanda, (f) Eryngium
foetidum, (g) Diplazium esculentum, (h) Solanum indicum

3 Women’s Role in Shaping the Gastronomic

Metonymic Itinerary

Traditional foods form culturally accepted local products of a particular culture in a

community [13] and reflect the cultural identity, sensitivity, and health perception of
a community. With the onset of human civilization, the dietary cultures of tribal
communities across the world have been shaped by indigenous food products [14].
Ethnic people produce ethnic or traditional foods that are culturally and socially
250 L. Yeptho and T. Ajungla

acceptable to the consumer by using raw materials that are locally available [15–
17]. The essential concept of Crouch’s [18] 3:12:120 ratio on group of people expo-
nentially creating and enforcing cultural innovation is headed by a posse of mothers
or women whose food choices and preferences form the basis of food culture, espe-
cially with regard to local and traditional food items that shaped the sustainability
of the diet. The essence of ensuing tradition from shaping culture at home to healing
the soul with food reflects a woman’s individual ability to nurture and nourish. The
sociocultural context heavily influences food choices [19], while the social identity
is also contextual as the individual’s daily engagement with the historical, social,
and political aspects considered to study identity [20]. Acculturation preserves the
original culture while acquiring the new practices, processes, and customs function-
ing within the main culture [21]. It explains the cultural and psychological change
or alteration as a result of merging between cultures [22] and encompasses the
domains of language, socioeconomic, and cultural values [23]. Ethnicity, migration
to urban areas, education, tribal community, political party representation, and
social support are some of the ways that influence the multicultural social policies
in Nagaland. The motivation for such social policies has been the desire to ensure
tribal harmony among the diverse tribes inhabiting the state.
Drawing from culture women creates an organic outgrowth of community living,
creating cultural ties between the various tribes, home, and individual level. Her
food choice provides a unique camaraderie between the food she creates and the
individual pressing toward healing. Her choices, her skills, each story unique to her,
and her kitchen form a gastronomic diversity toward healing through food. The
Naga community is woven by the thread of religious occasions, festivity, and visita-
tion by friends, family, and neighbors, and each occasion is celebrated by preparing
festive foods. Women are dexterous in the preparation of food combining creativity
and skills with community ties, social regulations, and ancestral knowledge bring-
ing about food with healing properties. The various dishes create a multiculturalism
facet among the Nagas represented by totemic or emblematic dishes signifying a
particular tribe. The food culture in Nagaland has emerged to be a product over
centuries interspersed by religion, education, and modernity striving to maintain its
cultural identity while also abandoning some like the use of alcoholic rice beverages
which were once an integral part of the diet culture. Their picking up of a sedentary
lifestyle now includes the utilization of resources and practice of pot culture and
garden cultivation in the kitchen backyard. Women create foodways connecting the
race, ethnicity, or gastronomic culture of a community and help expound the food
choices by paving itinerary food pathways of that community. Foods connoisseur
social identities and central to foodways are sharing the common goal of healing
while seeking to improve an individual’s well-being. Simultaneously the knowledge
is inherited yet also created to upkeep the culinary tradition. Their role is prolifer-
ated with social structures dictating her foodways while in return they act as culture
keepers passionately committed to intrahousehold dynamics powered by the tradi-
tional knowledge governing the food choices and practices required for a healthy diet.
Understanding Phytomedicinal Gastronomic Culture of the Nagas in Nagaland, India 251

4 Conclusion

Culture acts as a catalyst in the evolutionary process of humans and reveals the most
profound of meanings that humans carry – their rationale, their origins, and their
purpose. Culture links to build a person and the level of values and norms fixed by
culture is often what is highlighted in human rights discourse. To encounter heroism
in the traditions of patriotic and communal society, women act as cultural keepers
creating and enforcing a unique camaraderie through the memories of family and
historical stories, rendering an irresistible call to preserve the identity of traditional
food practices in a constantly evolving culture. The socioeconomic and consump-
tion patterns reveal the diet culture acting as phytomedicinal foods. Nutrition and
health benefit claims reflect their lifestyle rooted in rich ancestral knowledge to
strengthen the integrative force of healing. Thus, the traditional gastronomy of
Nagaland prolongs the dynamics of the ancient culture which is evident in the daily
course of preparing, serving, and gifting of food items that ties the society at an
individualistic level, uniting and defining a community interwoven by cultural cui-
sines and unique food flavor profiles.

Declarations Author’s contributions: Lydia Yeptho contributed to the documentation and con-
struction of the manuscript.
T. Ajungla supervised the work.
Acknowledgment: The authors would like to thank all the informants for sharing their valu-
able knowledge. They thank Mrs. Nihoβli, Miss Viseranuo Pesieye, Miss Rokonuo Kuotsuo, and
Miss Andy for their assistance during the interview.
Ethics Approval: Not Applicable.
Consent to Participate: All the authors have their consent to participate.
Consent for Publication: All the authors have their consent to publish their work.
Conflict of Interest: The authors declare no competing interests.
Availability of data and materials: Not applicable.
Funding: Not applicable.

References

1. Chophy GK (2021) The empire and the pearly gates. In: Mukherjee R (ed) Christianity and
politics in tribal India. Permanent Black, pp 68–69
2. Nabhan GP (2010) Ethnobiology for a diverse world: microbial ethnobiology and the loss of
distinctive food cultures. J Ethnobiol. https://doi.org/10.2993/0278-­0771-­30.2.181
3. Pieroni A, Pwaera L, Ghulam MS (2016) Gastronomic ethnobiology. In: Albuquerque UP,
Nóbrega Alves RR (eds) Introduction to ethnobiology. Springer International Publishing,
Switzerland, pp 53–62
4. Barthes R (1961) Pour une psycho-sociologie de l’alimentation contemporaine. Ann Econ Soc
Civiliz 16(5):977–986
5. Jordana J (2000) Traditional foods: challenges facing the European food industry. Food Res
Int 33(3):147–152
6. Kuhleinin HV (2009) Why are indigenous peoples’ food systems important and why do they
need documentation? In: Kuhnlein HV, Erasmus B, Spigelski D (eds) Indigenous peoples’
252 L. Yeptho and T. Ajungla

food systems: the many dimensions of culture, diversity and environment for nutrition and
health. Food and Agriculture Organization of the United Nations and Centre for Indigenous
Peoples’ Nutrition and Environment, Rome, pp 1–7
7. Fontefrancesco MF (2015) Il futuro dei Comuni minori. Etnografia di una trasformazione in
corso. Dada Riv Antropol Post-Glob 5:161–178
8. Fontefrancesco MF (2018) La luce alla fine del tunnel: sviluppo locale, offerta turistica e valori
locali. In: Corvo P, Fassino G (eds) Viaggi enogastronomici e sostenibilità. Franco Angeli,
Milano, pp 111–122
9. Fontefrancesco MF (2020) Traditional festive food and fragile aspirations of development in
Italy: the case of agnolotti pasta. J Ethnic Foods 7:2
10. Bentley A (2008) Introduction. Food and foodways, vol 16. Routledge, London, pp 111–116
11. Lyons D (2007) Integrating African foods: rural food and identity in Tigray, highland Ethiopia.
J Soc Archaeol 7(3):346–371
12. Germann Molz J (2007) Eating difference: the cosmopolitan mobilities of culinary tourism.
Space Cult 10(1):77–93
13. Kuhnlein HV, Receveur O (1996) Dietary change and traditional food systems of indigenous
peoples. Annu Rev Nutr 16:417–442
14. Tamang JP (2010a) Diversity of fermented foods. In: Tamang JP, Kailasapathy K (eds)
Fermented foods and beverages of the world. CRC Press/Taylor and Francis, Boca Raton,
pp 41–84
15. Tamang JP (2010b) Diversity of fermented beverages and alcoholic drinks. In: Tamang JP,
Kailasapathy K (eds) Fermented foods and beverages of the world. CRC Press/Taylor and
Francis, Boca Raton, pp 85–125
16. Tamang JP (2010d) Himalayan fermented foods: microbiology, nutrition and ethnic value.
CRC Press/Taylor and Francis Group, New York
17. Tibor D (2007) Yeasts in specific types of foods, chapter 7. In: Handbook of food spoilage
yeasts, 2nd edn. CRC Press, Boca Raton, pp 117–201
18. Crouch A (2008) Community. In: Crouch A (ed) Culture making, recovering our creative call-
ing. Inter Varsity Press Books, pp 239–246
19. Roudsari AH, Vedadhir A, Amiri P, Kalantari N, Omidvar N, Eini-Zinab H et al (2017) Psycho-­
socio-­cultural determinants of food choice: a qualitative study on adults in social and cultural
context of Iran. Iran J Psychiatry 12(4):241
20. Reddy G, Gleibs IH (2019) The endurance and contestations of colonial constructions of race
among Malaysians and Singaporeans. Front Psychol 10:792
21. Newman AJ, Sahak SZ (2012) Purchasing patterns of migrant groups: the impact of accultura-
tion on ethnocentric behaviors. J Appl Soc Psychol 42(7):1551–1575
22. Sam DL, Berry JW (2010) Acculturation: when individuals and groups of different cultural
backgrounds meet. Perspect Psychol Sci 5(4):472–481
23. Lopez-Class M, Castro FG, Ramirez AG (2011) Conceptions of acculturation: a review and
statement of critical issues. Soc Sci Med 72(9):1555–1562
Medicinal Plants in the Indian Traditional
Medicine and Current Practices

Ritee Basu, Sukanya Dasgupta, Spoorthy N. Babu, and Ayesha Noor

1 Introduction

Traditional medicine (TM) has been the world’s ancient form of treatment, used to
diagnose and reduce mental and physical ailments [1]. It is also known as comple-
mentary and alternative medicine, as well as ethnic medicine, in most of the coun-
tries. Natural products, such as microbes, marine organisms, plants and animals,
have been used in traditional medication since ancient period. Natural products have
a chemical diversity that has emerged over decades, resulting in a variety of biologi-
cal and therapeutic properties [2]. These substances have proven to be a valuable
resource for producing new chemical constituents as well as scaffolds. Natural
products are being used to fulfil the urgent need for effective pharmaceuticals with-
out any side effects and thus play a key role in the development of drugs for the
prevention/treatment of diseases/disorders [3].
In the study and development of current medications, TM seems to be too vital
to be overlooked. Traditional medicine has a wide range of application despite the
presence of scientifically validated drugs and therapies. A single plant or formula-
tion may have numerous phytochemical compounds, namely flavonoids, alkaloids,
polyphenol, terpenoids, alkaloids, etc. [4]. These compounds exert their activity
independently or synergistically to impart the desired therapeutic activity [5]. It is
important to note that many of the plant-based medications used in clinical practice
nowadays are all derived from folk medicine. Also, they have no/lesser side effects
compared to the currently available drugs in the market, and hence, people are pre-
ferring to incorporate herbal remedies in their lifestyle. Pharmaceutical drugs treat
symptoms produced by certain diseases as defined by scientific pathology, whereas

R. Basu · S. Dasgupta · S. N. Babu · A. Noor (*)

Centre for Bio Separation Technology, Vellore Institute of Technology,
Vellore, Tamil Nadu, India
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 253

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_9
254 R. Basu et al.

herbal therapy, on the other hand, focuses on assisting the body’s own healing pro-
cess. Medicinal plants are commonly used in traditional medicine and considered to
be beneficial; however, they may be toxic. If medicinal plant toxicity has been docu-
mented, it is due to geographical location, mistaken identity of the plants in which
they are supplied, and improper preparation or administration by untrained clini-
cians [6].
Various societies have evolved in documenting beneficial healing strategies of
TM to tackle a variety of health- and life-threatening disorders throughout history
[7]. Traditional medicine system includes Ayurveda, Unani, Siddha, Kampo, tradi-
tional Korean medicine (TKM), and Traditional Chinese Medicine (TCM). These
therapies make use of natural ingredients and have also been widely practised for
many years across the globe, prospering in an orderly regulated medical systems
[8]. These may have some drawbacks such as lack of proper formulations and lack
of clinical trials, but they are still an important reservoir of human knowledge [2].
Indian Traditional Medicine (ITM) is the medical system believed to have origi-
nated in India, which has an ancient heritage of traditional medicine. The materia
medica of India provides a great deal of information on the folklore practices and
traditional aspects of therapeutically important natural products [9]. ITM is based
on various systems including Ayurveda, Siddha, Unani, and Homeopathy. India is
considered as a hot spot of various medicinal plants and herbs. In this chapter, an
attempt has been made to understand the Indian traditional medicine (ITM) system,
the historical background, concepts, and differences amongst the various disciplines
in the ITM. Further, the integration of ITM into the current lifestyle, their usage,
their scope, and future prospects have also been discussed.

2 Traditional Medicine Systems in the World

In most of the cultures, the TM is a comprehensive healthcare system which has

evolved over thousands of years. Some of the prominent TM include the Indian
traditional medicine (ITM), Traditional Chinese Medicine (TCM), Traditional
Korean Medicine (TKM), Kampo (Japan-based Traditional medicine), Traditional
Arabic and Islamic Medicine (TAIM), African Traditional Medicine (ATM), and
Traditional European Medicine (TEM) [2] (Table 1).
The TCM has its origin in China and is utilized to treat 200 million patients every
year. TCM records for nearly 40% of all medical services provided in China [10].
The TCM highlights classic East Asian natural philosophy principles which include
Yin and Yang and the five-element concept [Blood (Qi, xue), Essence (jing), Spirit
(shen), and Fluids (jin ye)] [11]. The Encyclopaedia of Traditional Chinese
Medicines provides a thorough examination of TCM, chemistry, pharmacological,
plant origin and therapeutic properties. This encyclopaedia contains over 8000
TCM constituents as well as a wide range of pharmaceutical information that is use-
ful not just for TCM research but also for the advancement of modern medicine [12].
Medicinal Plants in the Indian Traditional Medicine and Current Practices 255

Table 1 Different traditional medicine systems across the world

Name of the
medicine Origin Current role and scope in modern
system country Characteristics medicine and research
Traditional China TCM is based on Yin yang TCM division is present in most
Chinese and Wuxing concepts ordinary hospitals, and TCM
Medicine A TCM formula includes a services are provided to all patients
group of various drugs that Many TCM active compounds and
function to achieve a compound-based therapeutics have
synergistic effect been discovered and are being
studied to understand their
mechanism of action
Kampo Japan Kampo treats every patient as Kampo medicines are incorporated
a complete and self-­ into the healthcare system and
controlled whole in which approved. These are also covered
body and mind under insurance
impact mutually They are also being studied to
understand the molecular
mechanisms involved in the
disease and its treatment
Traditional Korea SCM classifies persons into 86% of the Korean population
Korean four Sasang types: Tac-Yang, prefers it, which has been covered
Medicine So-Yang, Tac-Eum, and in insurance schemes
So-Eum, according to inborn It is being studied for genetic
features diseases and also as a diagnostic
approach
Ayurveda India Ayurveda is based on the five Around 400,000 Ayurveda
elements theory and tridoshas practitioners are registered. In
Ayurvedic philosophy is to addition, the Indian government
live a healthy life to avoid the has an officially recognized body
appearance of imbalance and to ensure Ayurveda’s educational
unnecessary pain efforts, quality, and practice
Pharmacologically active
compounds of Ayurvedic medicine
and their therapeutic potential in
treatment have been increasingly
recognized
Unani India, Unani looks upon the human Unani is accepted by the
Greece body as a single unit, which Government of India as meeting
Also in consists of four basic the immediate healthcare needs of
Arab elements with four disparate people. Bioactive constituents
countries temperaments respectively from Unani medicine have been
developed and are available in
markets
Sidhha India Siddha is also based on five Siddha medicines have been
elements theory and tridoshas approved by the Indian
Government
Studies are being undertaken to
understand their underlying
molecular mechanisms
(continued)
256 R. Basu et al.

Table 1 (continued)
Name of the
medicine Origin Current role and scope in modern
system country Characteristics medicine and research
Homoeopathy Germany It is based on cures like the Many homoeopathy medicines are
and India principle available in the market and have
also been approved by the Indian
Government
Traditional Africa Traditional medicine doctors Most of the African population
African treat patients holistically. prefers traditional African
Medicine They generally seek to medicine
recombine the mental and Research is being carried out to
social equipoise of sufferers study the various pharmacological
according to social properties of African medicine
relationships and rules
Traditional Greece It has assimilated the The Traditional European
European principles of Ayurveda, medicines are being used by the
Medicine Unani, and Siddha European population. Research
needs to be carried out to
understand the mechanisms of
these medications

The Traditional Korean Medicine (TKM) was introduced in nineteenth century

and has its origin in Korea [13]. Around 86% of the Korean population use
TKM. TKM employs a holistic approach and is known for its personalized treat-
ment. The TKM classifies the person into 4 types depending on their inborn charac-
teristics such as Tac-Yang, So-Yang, Tac-Eum, and So-Eum [14] The Government
of Korea has supported the TKM to be integrated into modern research and TKM is
now being actively studied for diagnostic and therapeutic purposes and also for
treatment of genetic disorders [2].
Kampo medicines are the traditional medications used in Japan for more than
1500 years ago. Even though the kampo has its initial origin in China, it differs with
TCM based on the treatment principles [15]. While the TCM is based on five prin-
ciples, the Kampo utilized the principle of Shan Han Lung. Kampo medicines are
developed as formulations and abdominal examination is an important aspect of
kampo medicine [16]. The kampo medications have been fully integrated into mod-
ern medicine in Japan, with 148 formulations being officially approved for treat-
ment and have also been included in insurance.
Traditional Arabic and Islamic Medicine (TAIM) refers to healing practices
incorporating herbal medicines, spiritual therapies, and dietary practices, applied
singularly or in combination for the treatment of diseases [17]. The TAIM is based
on Islamic medical and prophetic influences and has its origin in the Middle East.
Around 200 to 250 medicinal plants are used in the preparation of TAIM medicine
system [18]. The TAIM has a great potential, and research studies are being carried
out so as to utilize it in the modern medicine.
African traditional medicine (ATM) is a comprehensive healthcare system
divided into three categories of specialization: divination, spiritualism, and
Medicinal Plants in the Indian Traditional Medicine and Current Practices 257

herbalism. Many plants are employed in traditional African medicine, and little is
known about their bioactive constituents [19]. Thousands of people in South Africa
rely on traditional medicine. It is estimated that 80 per cent of the population con-
sumes traditional medicines known as Muti. Muti is a term derived from the medici-
nal plant that is attributed to traditional herbal-, mineral-, and animal-based drugs.
The plant Muti is generally regarded as a long-term remedy for various treatments.
African traditional herbal remedies have a promising future that could be accom-
plished via collaboration, partnership, and transparency in practice, particularly
along with conventional healthcare personnel [20].
The Traditional European Medicine (TEM) is a combination of various systems
of medicine across the European continent with its origin beginning in ancient
Greece with Hippocrates. The various pharmacopoeias of different folk practitio-
ners contain numerous medicines made from leaves, roots, bark, and minerals found
in the nature. The TEM has assimilated concepts of Ayurveda, TCM, Unani, and
other traditional medicine systems [21]. However, it has only been partially incor-
porated into the modern medicine compared to other TMs.
Indian traditional medicine’s therapeutic knowledge has developed plenty of sig-
nificant traditional methods based on different concepts and theories. The ITM has
a unique distinction as it has six recognized medicine systems in this category.
These include Ayurveda, Siddha, Unani, Yoga, Naturopathy, and homeopathy [9].
Apart from these, there are tribal groups who practise their own ancient and folklore
medicine. For example, Maibaron is a medicinal system practised by the Meiteis,
and a tribal group from the Indian state of Manipur and a tribal group in Tamil Nadu
named Irular have developed their own folklore medicine [22]. The ITM is based on
the five elements theory and the three humoralisms theory [23]. The five elements
theory states that the all organisms in the world consist of the five elements which
are the earth (Prithvi), water (Jala), fire (Agni), air (Vayu), and ether (Akasha). The
three humoralisms theory suggests that the body is balanced by the three kinds of
doshas (tridoshas). These tridoshas are vata (gas), pitta (bile) and kapha (mucus).
Any imbalance in these doshas leads to diseases. All the medicine systems of ITM
have been formed on these above theories utilizing different herbs and medici-
nal plants.

3 Indian Traditional Medicine (ITM) System

India Traditional medicine system has a rich and diverse heritage of cultural tradi-
tions which use a variety of medicinal plants and herbs. The Western Ghats, the
north eastern region, and the Himalayan region are home to a rich source of medici-
nal plants [9]. These medicinal plants and herbs are the basis for more than 60% of
anticancer medications in the market or in therapeutic applications. Approximately
80% of antibacterial, immunosuppressive, cardiovascular, and anticancer medica-
tions are currently derived from plants. Over 70 per cent of the 177 anticancer medi-
cines that have been approved are based on natural compounds. Around 25% of the
258 R. Basu et al.

world’s prescription medications are derived from plants and there are nearly 121 of
them are in usage [24]. Ayurvedic medicine is thought to use between 1200 and
1800 distinct types of plants, whereas Indian folk therapists use about 7500 differ-
ent types of medicinal plants in various remedies. To regulate and standardize the
usage of traditional medicine, a new department, the Department of Indian System
of Medicine and Homoeopathy (ISM & H), was established in 1995. In 2003, ISM
& H was renamed AYUSH, which stands for Ayurveda, Yoga and Naturopathy,
Unani, Siddha, and Homoeopathy, as a separate Department within the Ministry of
Health and Family Welfare of India, India. The different sections of ITM are as
follows.

3.1 Ayurveda

Ayurveda is regarded as the world’s oldest known system of medicines. The Atreya
Inner Medicine School and the Dhanvantari Surgery School were the two branches
of Ayurvedic medicine that developed between 1500 BC and 1000 BC as one of the
four Upavedas [22]. The main characteristic of Ayurvedic medicine is holistic treat-
ment, which emphasizes the close relationship between both the brain and the body
[25]. The Ayurveda system utilizes processed natural drugs rather than derived or
synthetic compounds highlighting that maintaining the stability of all parts of the
human body is more important than eradicating external infectious agents. Ayurveda
employs the “Panchakarma” approach. Panchakarma treatment is used in a variety
of ways to promote body rejuvenation, detoxification, and longevity [26].
Panchakarma is made up of five karmas (activities) that are used to eliminate impu-
rities from the body. Virechan (purification by powder, paste, or hot water extract),
Rakta moksha (bloodletting), Vaman (force vomiting with medications), Nasya
(through nasal medication like smoking, oil, and decocting), and Basti (enema with
therapeutic oil) are the five karmas.
Ayurveda and biomedicine have different perspectives on how the human body
works. The tridoshas – pitta, vata, kapha – are the foundations of this system. It is
worth noting that vata, pitta, and kapha are responsible for both physiological as
well as psychological wellbeing [22]. The three doshas are in perfect equilibrium,
signifying homeostasis. Changes in one has an impact on the other two. The three
doshas have been used to categorize all clinical symptoms. Vata, for example, is
associated with dryness, lightness, weightlessness, coolness, roughness, minute-
ness, and mobility. Pitta refers to characteristics such as minor unctuousness, pen-
etrating, producing heat, lightness, foul odour, inducing movement, and liquidity and
kapha refers to cold, soft, stable, slow and heavy [27]. All symptoms, including
common cold, coughing, fevers, dysentery, oedema, and skin irritations, have
already been categorized as vata, pitta, or kapha. The diagnosis in Ayurveda is the
removal of toxins, preserve the body functions and remove the imbalance in the
body to prevent or reduce the manifestation of the disease [23].
Medicinal Plants in the Indian Traditional Medicine and Current Practices 259

3.2 Siddha

In regard to etiopathogenesis, the Siddha system is similar to Ayurveda, which was

then the most popular medical system in North India. Ayurveda was exclusively a
medical system, whereas Siddha medication evolved from the siddha yogi’s studies
in yoga and alchemy. Only South India possessed Siddha medicine, and the scrip-
tures are mostly written in Tamil and Telugu [28, 29]. The body, according to the
Siddha, is more than an organ system, and disease cannot be explained solely by the
organs. To prepare remedies, herbs, metals, poisons, and other esoteric elements
were used [30]. Yoga and meditation were also included. Siddha‘s contributions to
medicine expanded folklore by making it easier to make intricate medicinal prepa-
rations at home, similar to food preparations, premised on the idea that “food is
medicine and medicine is food“ [31]. The Tridosha theory and the Panchabootha
idea were used to define wellness and disease. Earth (prithvi), fire (agni), water
(jala), air (vayu), and ether (akasha) were the five elements that made up the uni-
verse of nature as well as the human body [32]. According to the Tridosha doctrine,
the body has three humours (known as the mukkuttrangal): vali (air), anal (hot), and
eeram (moisture) [33]. The three humours accounted for formation, preservation,
and elimination, which corresponds to anabolism, metabolism, and catabolism,
respectively. The principle of Panchabootha and tridoshas comprise the core archi-
tecture of Siddha and Ayurveda, yet their conceptual framework for medicine is the
same. Ayurvedic and Siddha pharmacological preparations implement similar
approaches when it comes to plant, animal, and mineral ingredients; however,
Siddha medications have more metal and mineral (sulphur and mercury) in their
formulations for the treatment of diseases [31].

3.3 Unani

Unani medicinal approach was developed by the Greeks and later urbanized by
Arabs into a sophisticated medical discipline based on the Greek philosopher and
physician Hippocrates’ framework [34]. The four circumstances of living, which
include hot, sodden, cold, and dry, as well as the four humours of Hippocratic the-
ory, namely mucus, yellow bile, dark bile, and blood, underlie the unani medicine.
Unani treatment was combined with ITM during the reign of the Mughal Emperors
and is now used by a large portion of India’s population. Afal (capacities), Mizaj
(temperaments), Quo (resouurces), Arawh (spirits), Arkan (components), Aklath
(humours), and Anza (organs) are the seven levels according to Unani medicine
system [34, 35]. Unani medicinal approach is a holistic treatment that remarkably
treats a wide range of disease conditions, whether in single doses or multiple doses
and or in formulations. This approach shows effective treatment options for gastro-
intestinal, neurological, and heart diseases [36].
260 R. Basu et al.

3.4 Homeopathy

Homeopathy is a treatment practice that uses drug preparations whose actions cor-
relate to the disorder’s presentations (associated symptoms, clinical findings, and
pathological conditions) in the specific patient. Homeopathy was invented by the
German physician Hahnemann and is today used all around the world [37].
Homeopathy works on the principle of law of similar and/or “like cures like”. For
example, substance causing a disease symptom in larger quantity can be used to
treat the same symptoms with smaller doses [38]. Homeopathic medicines are pre-
scribed in very high dilutions, thereby making them non-toxic. Special pharmacies
prepare these medicines with a vigilant and careful process of agitation and dilution.
The treatment and medications in homeopathy are patient specific. The physician
understands the complete history of the patient which includes the physical and
mental fitness and the lifestyle. Depending on the assessment, smaller doses of
medicines are initially prescribed and when the results are visible, the infinitesimal
doses are given thereafter [39].

3.5 Naturopathy

Naturopathy is a drug-free, scientific, non-surgical as well as substantial proof-­

based medical system that uses natural components and emphasizes the body’s
inherent ability to cure itself. Naturopathy is a medical approach focused on the key
principles of self-healing capacity of nature, which differ significantly from those of
other medical systems [40]. The human body’s vitality, or life energy, is the funda-
mental source of the body’s capacity to repair and regenerate. According to natu-
ropathy, basic causes of ailment in individuals are diminished altered lymph and
blood composition, vitality, the aggregation of morbid material as well as toxins that
are all caused by alteration of nature’s constitution. Its drug-free approach is one
area where it differs significantly from Western naturopathic therapy [41].
Throughout global networks, India is advancing in developing and promoting the
Traditional Medical System in the healthcare industry. Ayurveda, Yoga, Siddha,
Unani, Homeopathy and Naturopathy, generally known as AYUSH, have their own
department within the Ministry of health and family welfare, India. In 2014, the
Government of India created a separate ministry of ITM which is known as Ministry
of AYUSH.

4 Importance of AYUSH and the Medicinal Plants Used

Traditional medicine has a long history in India. India’s Materia Medica contains a
depth of information on traditional and folklore characteristics of therapeutically
useful natural ingredients [42, 43]. To meet the modern consumer’s needs, several
Medicinal Plants in the Indian Traditional Medicine and Current Practices 261

key areas of study must be concentrated on developing scientifically confirmed

studies of their reliability, security, and effectiveness. Validated products will be
extremely beneficial to the advancement of healthcare and will assist enterprises in
competing with their products for export to other countries. There are approximately
7000 therapeutic drug production companies like Himalaya drug company, Dabur
limited, Baidyanath, Patanjali Ayurved, Natural Remedies Pvt. Limited, etc., and
over 1.5 million traditional clinicians who use medicinal herbs for the diagnosis and
treatment of various diseases (Table 2). The Ministry of AYUSH supervises all sec-
tions of the development and promotion of natural products utilized in Indian medi-
cal systems.

Table 2 List of different Indian traditional medicine system products available in the Indian market
Product Ingredient Properties Dosage
AYUSH HERBS PVT LTD
A-OXY (AMLA) Standardized Extract of Antioxidant, Natural Adult 1–2 caplets/
capsules Amla (Emblica Vitamin C Provider, caps thrice a day
officinalis) Rasayana with water, Child –
1 caplet/cap twice a
day or as directed
Rentone capsules Standardized extracts of Urinary tract infections, Adult- 1–3 caplets/
Didymocarpus kidney stones, Bladder tablets thrice a day
pedicellata, Saxifraga stones, Cystitis, Prostatitis, with water
ligulata, Rubia cardfolia, Urethritis, Nephritis, depending upon the
Achyranthes aspera, Prostrate hypertrophy patient’s condition.
Tribulus terrestris, Child (less than
Ocimum basilicum, 10 years of age) –
Crataeva religiosa, 1–2 caplets/tablets
Mimosa pudica, Dolichus twice a day with
biforus, Cyperus water or as directed
rotundus, Asphaltum
Arjuna capsules Standardized extract of Strengthen the weakened Adult 1–2 caplet/
Arjuna (Terminalia heart muscles tablet with water,
arjuna) thrice a day after
meal and there after
adjust the dose
according to
monitored blood
pressure or as
directed by your
health provider
Carditone Standardized extracts of Strengthens the weakened Adult- 1–2 caplets/
Rauwolfia serpentina, heart muscles, CHF, high tablet twice a day
Convolvulus pluricaulis, blood pressure, heart with water after
Terminalia arjuna, palpitation, irregular meal and there after
Tribulus terrestris, Rosa heartbeat, and angina adjusting the dose
centifolia, Boerhavia according to
diffusa, Inula racemose, monitored blood
Onosma bracteatum pressure or as
directed
(continued)
262 R. Basu et al.

Table 2 (continued)
Product Ingredient Properties Dosage
Hepo forte (bhui Standardized extract of Strengthens the liver, and Adult- 1–2 tablets/
amla) capsules – Bhumi amla (Phyllanthus helps in hepatitis B caplets with water,
jaundice support Amarus) 2–3 times a day
before meal,
Child- 1 tablet/
caplets twice a day
with water before
meal
Livertone Standardized extracts of All hepatic issues like 1–2 caplet thrice a
capsules – Silybum marianum, cirrhosis of liver, fatty day with water
hepatoprotective Boerhavia diffusa, liver, hepatitis, anorexia, before meals
Picrorhiza kurroa, other drug-induced
Eclipta alba, Phyllanthus diseases, etc. It works as a
amarus, Tephrosia liver cleanser and detoxifier
purpurea, Andrographis
paniculata, Swertia
chirata
Karela capsules Standardized extract of Useful in type 2 diabetes 1–3 caplets/tablets
diabetes support Karela (Momordica (depends upon the
charantia) blood sugar) thrice
a day with warm
water or as directed
Bio Gymnema – Standardized extracts of Useful in type 2 diabetes, 1–3 cap/tab
Sugar Gymnema sylvestre, weakness due to diabetes, (depends upon the
Metabolism Pterocarpus marsupium, complication like blood sugar) thrice
Support Ocimum basilicum, retinopathy, nephropathy, a day with water
Momordica charantia, obesity, etc. half an hour before
Azadirachta indica, meal or as directed
Salacia chinensis, Aegle
marmelos, Trigonella
foenum-graecum,
Syzygium cumini, Vinca
rosea
Immunity kit (for Flucomune caplets Ayush Pharmaceuticals Ashwagandha DS:
whole family Ashwagandha DS recently launched an 1 capsules: twice or
protection) capsules immunity kit to provide thrice a day
Haldi capsules adequate immunity for Haldi capsules: 1
individuals in the event of a capsule twice or
pandemic. This Immunity thrice a day
Kit boosts one’s immune Flucomune
system to protect the body Capsules- 1–2
from infection tablets twice/thrice
a day
Rakat tone – Standardized extracts of Loss of memory, 1-caplet twice a day
memory and Ginkgo biloba, Bacopa Alzheimer’s disease, poor with water or as
nervous system monnieri, Centella circulation, stroke, tinnitus, directed
support asiatica, Ashtavarga, asthma and all kinds of
Pueraria tuberosa, neuritis degenerative
Asparagus adscendens, neuromuscular changes
Withania somnifera
(continued)
Medicinal Plants in the Indian Traditional Medicine and Current Practices 263

Table 2 (continued)
Product Ingredient Properties Dosage
Kuff sooth –Standardized extracts of Allergic sore throat, Adult – 2 tea
cough and Ephedra vulgaris, laryngitis, allergic spoonful thrice a
respiratory Emblica officinalis, rhinorrhea, sinusitis, day. Child – 1
support Ocimum sanctum, smokers cough, bronchial teaspoonful thrice a
Terminalia bellirica, asthma, and chronic and day with warm
Adhatoda vasica, acute bronchitis water or as directed
Glycyrrhiza glabra, by your health
Pistacia integerrima, provide
Trikatu, Achyranthes
aspera, Zizyphus
vulgaris, Nilgiri oil,
Solanum xanthocarpum,
Viola odorata, Cichorium
intybus, Mentha spicata
THE HIMALAYA DRUG COMPANY
Shigru Leaf extract of Moringa Used in the treatment of 1 tablet twice daily
pterygosperma inflammatory disorders
Ashwagandha Root extract of Withania Enhances immunity by 1 tablet twice daily
somnifera strengthening the antibody
and strengthens the body
Arjuna Bark extract of Reduces coronary artery 1 tablet twice daily
Terminalia arjuna blood flow and protects the
heart muscle
Gokshura Fruit extract of Tribulus Helps in managing erectile 1–2 tablets twice
terrestris dysfunction daily
LIV 52 Extract of Chicory and Protects the liver from As per the advice of
Capparis spinosa infection and also restores the doctor
the functioning of the liver
Septilin Extract of Indian Has immunomodulatory, As per the advice of
Bdellium, Licorice and anti-inflammatory and the doctor
Tinospora Gulancha antioxidant properties
Diabecon GS Extract of Gymnema Has antidiabetic potential As per the advice of
sylvestre, and has the ability to the doctor
Pterocarpus marsupium, improve pancreatic and
Asphaltum punjabianum liver function
BAIDYANATH
Triphala Emblica officinalis, Aids in easy bowel 1–2 tablets daily
Guggulu Terminalia chebula, movements, digestion and
Terminalia bellerica, helps in relieving
Commiphora mukul constipation. Also helps in
alleviation of inflammation
Ayush kwath Ocimum sanctum, Immunity booster, and 1 tablet daily with
tablet Cinnamomum verum, helps in relieving cough water
Zingiber officinale, and respiratory distress
Piper nigrum
Mahasudarshan Tinospora Immunity booster, removal 3–6 teaspoonful
Kadha cordifolia, Picrorhiza of intestinal worms and with equal amount
kurroa, aids in proper digestion of water twice
Terminalia chebula
(continued)
264 R. Basu et al.

Table 2 (continued)
Product Ingredient Properties Dosage
Chandraprabha Tinospora Relieves intermittent 1–3 tablets daily
Bati cordifolia, urination, burning urination with milk
Curcuma longa and prevents UTI infection
PATANJALI AYURVED
Divya Jivanti, Water, Ksheera, Used in the treatment of 1 teaspoonful in
Jeevantyadi Ghrita, Prapaundarika, eye problems water
Ghrit kakoli, Kshirakakoli
Pippali, Lodhra,
Saindhava lavana,
Shatahva, Madhuka,
Draksha Sita
Daruharidra, Triphala
Divya Manjishtha Rubia cordifolia Used in wound healing, As advised by
Churna skin diseases, gouty physician
arthritis
Amvatari Ras Triphala, Guggul, Used in the treatment of As advised by
Chitrak mool, Erand tel, rheumatoid arthritis physician
Gandhak, Parad

4.1 Medicinal Plants Used in Indian Traditional

Medicine (ITM)

As mentioned earlier, India is a rich and diverse source of different medicinal plants
and herbs. There are more than 7500 different medicinal plants which are used in
the various disciplines of the ITM. The formulation also changes in accordance to
the traditional medicine system. The Ayurveda medicines are available in tablet and
syrup forms, while the Siddha medicines are generally available in the form of paste
termed as “leha” and homeopathy medicines are in miniscule tablets. The therapeu-
tic properties depend on the composition and also the part from which the medicine
is prepared. There is never ending list of medicinal plants in India, some of which
are mentioned in Table 3 and a few of them have been discussed.

4.1.1 
Camellia sinensis

Camellia sinensis L. is commonly known as Tea, which is the second most widely
consumed beverage on the globe. People have been consuming it frequently since
3000 BC. Tea is a beverage made from the leaves of Tea originated in China, then
expanded to India, Japan, Europe, and Russia [44]. It is a frequently utilized medici-
nal herb in trials throughout India, and it is prominent in several traditional medical
approaches such as Unani, Ayurveda, and Homeopathy. Tea is broadly classified
into the following groups: green, yellow, white, oolong, black, and dark tea. Clinical
studies have shown that tea has both therapeutic and preventive benefits for
Medicinal Plants in the Indian Traditional Medicine and Current Practices 265

Table 3 List of different medicinal plants used in the Indian traditional medicine system
Common
Plant name Part used Properties
Allium sativum Garlic Bulbs Lowering cholesterol, infantile
convulsion

Camellia sinensis Tea Leaf Antioxidant

Anticancer

Aloe barbadensis Aloes Leaf Anti-inflammatory, laxative,

Gel Antidiabetic

Desmodium Salparni Leaf, Antidiabetic

gangeticum Root Anticancer
Antioxidant

Boswellia serrata Salai gum Gum Helps to treat arthritis, anti-inflammatory

Azadirachta indica Neem Leaves Antimicrobial (anti-fungal), antiseptic

Embelia ribes Vai vidang Seeds Piles, headache, skin disease, diabetes

Emblica officinalis Amla Fruit Antioxidant, rejuvenating agent

(continued)
266 R. Basu et al.

Table 3 (continued)
Common
Plant name Part used Properties
Ocimum sanctum Tulsi Leaves Cough, cold, cancer, diabetes,
hepatoprotective, bronchial asthma

Tinospora cordifolia Guduchi Leaves Anticancer

Antioxidant
Cardioprotective
Immunomodulatory

Terminalia chebula Myrobalan Leaves Antidiabetic

Fruits Antioxidant
Wound healing
Immunomodulatory

Solanum nigrum Makoy Fruit Digestive property, liver tonic

Withania somnifera Ashwagandha Leaf Anti-inflammatory

India Ginseng Diuretic
Sedative
Immunomodulatory

Bacopa monnieri Brahmi Leaf Memory enhancer

Immunomodulatory
Antidiabetic
Anticancer

Terminalia arjuna Arjuna Bark Cardioprotective, diabetes, antioxidant

Moringa oleifera Drumstick Leaf Antioxidant

Antidiabetic
Anti-inflammatory
Anticancer

(continued)
Medicinal Plants in the Indian Traditional Medicine and Current Practices 267

Table 3 (continued)
Common
Plant name Part used Properties
Curcuma longa Haldi Rhizome Treats cancer, arthritis, antioxidant,
anti-septic

Gingko biloba Maidenhair Leaf Antibiotic

Anti-inflammatory
Anticancer

Gymnema sylvestre Gudmar/ Leaves Antihyperglycaemic

Gurmar Anti-inflammatory

Asparagus racemosus Shatavari Leaf Antioxidant

Galactagogue
Anti-inflammatory
Anticancer

Momordica charantia Bitter gourd Fruit Antidiabetic

Anti-inflammatory
Anticancer

Picrorhiza kurroa Kutki Root Liver support, Neurosis of the stomach,

treats Malaria

Rubia cordifolia Manjistha Stem Purifies blood, removes gall stone, treats
diabetic ulcer

(continued)
268 R. Basu et al.

Table 3 (continued)
Common
Plant name Part used Properties
Swertia chirayita Chirayita Whole Treats liver disorders, dyspepsia,
plant diarrhoea, and diabetes

Trigonella Methi Seeds Blood sugar support, helps in cholesterol

foenum-­graecum management and atherosclerosis

Symplocos racemosa Lodhra Bark Menorrhagia, leucorrhoea, and

gonorrhoea

Punica granatum Dadamchhal Rind of the Treats hyper acidity, chronic diarrhoea,
fruit dysentery, piles, sore throat, prostate
cancer

Morinda citrifolia Noni Fruit Used to treat tuberculosis, asthma, broken

bones, and wounds

Glycyrrhiza glabra Mulethi Root Treats sore throats, cough, bronchial

infection

Cinnamomum Dalchini Bark Used for digestive purposes

Zeylanicum
Medicinal Plants in the Indian Traditional Medicine and Current Practices 269

oxidative stress-related ailments such as cancer, type 2 diabetes, liver disease, and
cardiovascular disease [44]. It has pharmacological activities like antistroke activ-
ity, antiparkinson, anti-Alzheimer activity, anti-ageing activity, and anti-caries
activity. It is effective for weight loss and treating skin disorders. Tea contains
approximately 4000 bioactive constituents, such as polyphenols (catechins and fla-
vonoids), volatile oil, amino acids, polysaccharides, lipids, vitamin C, inorganic
components (manganese, fluorine, aluminium), and alkaloids (caffeine, theobro-
mine). Green tea seemed to have the largest antioxidant potential as well as a higher
concentration of polyphenols, particularly catechins. Furthermore, multiple investi-
gations have revealed that polyphenols and caffeine are the primary components in
tea accountable for diverse bioactivities and different organoleptic properties [45].
Caffeine is the primary component of Camellia sinensis and serves as a secondary
metabolite. When compared to other plant extracts, the methanolic extract of white
tea inhibited DPP-IV enzyme the most [46]. As a result, tea is an appropriate nutri-
tional source of natural antioxidants, particularly phenolic components, which have
the ability to be utilized in beverages or nutritional supplements.

Desmodium gangeticum
4.2 

Desmodium gangeticum (L.) DC, also referred as Salparni or Sal Leaves Desmodium
or Salwan is a valuable medicinal herb that belongs to the legumes family (Fabaceae).
It is found throughout tropical as well as sub-tropical areas, and it is extremely fre-
quent in India’s lower Himalayan areas. It is also common in Tropical Africa, China,
Japan, Vietnam, Thailand, Indonesia, Cambodia, and northernmost part Africa.
D. gangeticum has been practised for centuries in traditional and folklore medicine
throughout India to cure a variety of diseases [47]. This medicinal plant is included
in many Ayurvedic formulations and is regarded as a “Master of Medicinal Plant” in
Ayurveda due to its extensive use in formulations [48]. D. gangeticum contains fla-
vonoids, polyphenols, alkaloids, steroids, terpenoids, phenylpropanoids, pterocar-
pans, coumarins, and volatile oil. Flavonoids, alkaloids, and pterocarpans are the
most important of these bioactive compounds. D. gangeticum exhibits significant
antioxidant, anti-inflammatory, anti-leishmanial, cardioprotective, anti-­ulcer, anti-
diabetic, wound healing, hepatoprotective, and renal protective activities. An aque-
ous extract of D. gangeticum showed a significant DPP-IV inhibitory potential [46].
The toxicity of D. gangeticum extract was investigated in mice at various dosages
(50–2000 mg), with hyperactivity, grooming, convulsions, sedation, hypothermia,
and mortality being reported. No mortality was reported following oral administra-
tion of the maximum dose (2000 mg/kg) of extract. Furthermore, gangetin was
found to have no toxic effect up to 7 g/kg orally, indicating that it is rather safe and
no data of D. gangeticum toxicity have been reported in traditional medicine [49].
270 R. Basu et al.

Aloe barbadensis Miller

4.3 

Aloe barbadensis Miller, commonly known as Aloe vera, is a succulent perennial

plant in the Aloeaceae family that has been used since many centuries. Aloe vera is
termed as the ‘Miracle plant’ due to the vast therapeutic properties in it [50]. Aloe
vera thrives in desert and subtropical conditions in countries such as India, Africa,
and Iran, and in India, it is found in Rajasthan, Haryana, Tamil Nadu, and Karnataka
[51]. Aloe vera is well known for its medical capabilities, which are utilized in
Ayurvedic, Homoeopathic, as well as allopathic medicines. For generations, it has
been used for cosmetic, health, therapeutic, and skin care benefits. The anti-fungal
activity, anti-bacterial activity, antidiabetic, anti-inflammatory, antioxidant, and
anticancer properties of Aloe vera have been documented, and these have been
attributed to the synergistic actions of several bioactive compounds present in Aloe
vera. There are over 75 distinct phytoconstituents in Aloe vera which include poly-
phenols, proteins, saccharides, sterols, vitamins, flavonoids, anthraquinones, miner-
als, etc. [52, 53]. All these constituents are responsible for the various pharmacological
properties and these have also been explored in pre-clinical and clinical trials.
Phytosterols from Aloe vera have been reported to have antidiabetic and anticholes-
terolemic property in vivo, while aloin and aloesin have been reported to reduce
glucose levels in clinical trials [54]. Virectin and polysaccharides have been
observed to reduce the sugar levels in clinical trials [55]. Peptide fraction of Aloe
vera is able to regulate the GLP-1 pathway and polysaccharide fraction is able to
activate the glycogenesis pathway to regulate the sugar levels [51, 56]. All the pre-­
clinical and clinical trials of Aloe vera and its phytoconstituents revalidate the use
of this medicinal plant in modern medicine proving that Aloe vera has massive
potential in modern medicine.

Moringa oleifera
4.4 

Moringa oleifera is a naturally cultured species of Moringa, which is a member of

the Moringaceae family. Moringa is also known as “Mother’s Best Friend” or
“Miracle Tree” and has been used in Ayurveda and Unani medications [57]. M. ole-
ifera is believed to have originated in Agra and Oudh, both of which are located in
India’s northwest area, south of the Himalaya Mountains. This plant is high in vita-
mins A, B1, B2, B3, B6, B7, D, C, K, and E. Copper, calcium, iron, magnesium,
potassium, zinc, and manganese are some of the essential minerals found in Moringa
[58]. It contains over 40 natural antioxidants. M. oleifera has been employed in
ancient diets for memory and concentration as well as healthy skin. M. oleifera
pods, leaves, gums, seeds, flowers, and bark are utilized in over many countries to
treat vitamin and mineral deficiencies, aid a healthy cardiovascular health, improve
blood glucose levels, scavenge free radicals, minimize tumour, offer incredible sup-
port for anti-inflammatory activity, and boost immunity. It also enhances vision,
Medicinal Plants in the Indian Traditional Medicine and Current Practices 271

mental acuity, and bone density. It may help treat malnourishment, general fatigue,
breastfeeding women, menopausal symptoms, anxiety, and osteoarthritis [59].
M. oleifera contains a unique mixture of minerals, amino acids, and antioxidants
that are beneficial to both nourishment and ability to heal. The World Health
Organization (WHO) has recommended M. oleifera as a substitute to food sources
to address malnutrition. It has the highest amount of isothiocyanates and glucosino-
lates, and it also contains rhamnose. M. oleifera leaf, seed, and root extracts have
been shown in vitro and in vivo to have anticancer, hypoglycaemic, hepatoprotec-
tive, antibacterial, anti-inflammatory, antiviral, antifungal, and anti-sickling proper-
ties [60]. Leaf extracts have the highest antioxidant activity, and aqueous leaf
extracts have been shown to be safe in a variety of animal experiments. The reported
effects are thought to be caused by a variety of phenolic acids, polyphenols, as well
as glucosinolates, flavonoids, and possibly alkaloids. Up to a dose of 2000 mg/kg,
M. oleifera leaves (aqueous extract) were proven to be safe. 250 and 500 mg/kg
doses of the extract were administered intraperitoneally in fasting streptozotocin-­
induced diabetic rats leading to remarkable reduction in blood glucose levels [61].
8 g of the powdered M. oleifera leaves per day for 40 days was administered to treat
type 2 diabetic individuals, and blood glucose during fasting and postprandial were
decreased by 28% and 26% in participants [61]. In terms of cost and efficacy, the
M. oleifera plant is the most cost-effective and dependable option for both healthy
nutrition, disease prevention, and cure.

Terminalia chebula
4.5 

Terminalia chebula Retz. belonging to family Combretaceae, commonly known as

black- or chebulic myrobalan, is also considered as the ‘King of medicine’ in Tibet
and is constantly charted as the priority of Ayurvedic Materia Medica due to the
exceptional medicinal properties [62]. The entire plant is highly therapeutic and has
been used for centuries to heal a variety of human diseases such as respiratory prob-
lems, sore throat, vomiting, dysentery, diarrhoea, haemorrhoids, ulcers, gout, and
heart and bladder problems [63]. The plant is reported to have antioxidant, antidia-
betic, antimicrobial, anti-inflammatory, hepatoprotective, antimutagenic, radiopro-
tective, antiproliferative, antiarthritic, anticaries, cardioprotective, gastrointestinal
motility, and wound healing property [63]. The tree’s fruit provides a variety of
health advantages and it has been utilized as household remedies in traditional med-
icine remedies for a variety of human illnesses. T. chebula is widely used in Unani,
Ayurveda, and Homoeopathy medicine and has been in focus as a modern medicine.
Tannins are abundant in the fruits of T. chebula (32–34%) [64]. Additionally, phe-
nolics like ellagic acid, chebulinic acid, and anthraquinones are present. Rest of the
compounds includes coumarin, triterpenoids, galloyl glucose, corilagin, punicala-
gin, maslinic acid, and terflavin A. Moreover, amino acids, fructose, betasitosterol,
succinic acid, and resin are also present. T. chebula at a dose of 300 mg/kg was
administered to diabetic rats induced with streptozotocin for up to four weeks and
272 R. Basu et al.

resulted in a considerable decrease in blood glucose. Phytoconstituents from T. che-

bula have also been studied for their therapeutic properties. Ellagic acid has been
reported to have antimicrobial property, while chebulinic acid has been known to
possess antioxidant and hepatoprotective potential [65]. T. chebula is one of the
versatile plants in ITM with a broad range of medicinal and pharmacological prop-
erties, and the changing scenario in the herbal industry makes it a promising plant
worth exploring for its various therapeutic potentials.

Tinospora cordifolia
4.6 

Tinospora cordifolia, also known as Guduchi, is an herbal shrub belonging to the

moonseed family Menispermaceae. It is found throughout India and also in China,
Bangladesh, and Sri Lanka. This plant has been used to treat wide variety of dis-
eases throughout the history of traditional medicine practices in Ayurveda and
Siddha medicine, which includes skin diseases, jaundice, and gout [66]. T. cordifo-
lia primarily consists of bioactive compounds like glycosides, alkaloids, aliphatic
compounds, essential oils, steroids, fatty acids mixture, polysaccharides, phospho-
rous, calcium, and protein. The stem and root contain alkaloids as active constitu-
ents. These include magnoflorine, tembetarine, tinosporin, choline, berberine,
jatrorrhizine, isocolumbin, aporphine alkaloids, palmatine, and tetrahydropalmatine
[67]. All these constituents contribute to different pharmacological activities like
anticancer, anti-inflammatory, antidiabetic, anti-psychiatric, anti-viral, and immu-
nomodulatory properties. T. cordifolia root extract (TCRE) was studied by Prince
et al. to lower tissue lipid as well as serum levels in diabetic male albino Wistar rats
[68]. The extract had a better effect than glibenclamide at doses of 2.5 and 5.0 g/kg
BW (body weight). The plant extract was administered for six weeks, which resulted
in a notable decrease in tissue and serum cholesterol, free fatty acids, and phospho-
lipids in the alloxan diabetic rats. The hypolipidaemic effect of TCRE is explained
by a direct decrease in blood glucose concentration. Apart from this T. cordifolia has
been studied for its antioxidant, hepatoprotective, anticancer, and anti-inflammatory
properties [67]. All these studies indicate the T. cordifolia is an incredible source
which can contribute extensively to the scientific world of medicine.

Withania somnifera
4.7 

Withania somnifera from the Solanaceae family, also called as Indian ginseng or
Ashwagandha, is widely available in India, Afghanistan, China, Africa, Yemen, and
Nepal. “Somnifera” in Withania somnifera in Latin is “sleep-inducer”, which justi-
fies its widespread use as a neuroprotective agent [69]. W. somnifera has been
widely used in Ayurveda, Siddha, and Unani medicine systems. Ashwagandha con-
tains over 35 phytochemicals that have been successfully isolated and
Medicinal Plants in the Indian Traditional Medicine and Current Practices 273

characterized. Alkaloids and steroidal lactones are the main chemical compounds
[70]. The alkaloids found in Ashwagandha include somniferine, somniferinine,
somnine, withanine, tropine, pseudo-withanine, pseudo-tropine, cuscohygrine,
3-a-­gloyloxytropane, and anaferine, amongst which withanine is the most abundant
[71]. Phytopharmacological studies have proved that Ashwagandha has antioxidant,
anti-­inflammatory, anticancer, antimalarial, antimicrobial, sedative, immunomodu-
latory, diuretic, and cardioprotective properties. Various researchers have examined
the use of Ashwagandha to treat Parkinson’s disease. A study by Bhatnagar et al.
2017 has proved that the ethanolic extract of Ashwagandha roots has been shown to
reverse Parkinson-like symptoms in MPTP (1-­methyl-­4-­phenyl-­1,2,3,6-­tetrahydrop
yridine) Parkinson induced Balb/c mice [72]. It has shown to restore behavioural
performance and significantly improve oxidative stress profile as a dose of 40 mg/
kg body weight. Ashwagandha has also been studied for its antidiabetic potential
wherein the phenolics present in the plant have been reported to reduce sugars levels
and Withaferin A is able to protect the islet cell damage through anti-inflammatory
property [73]. Withaferin A is also reported to have anticancer and antioxidant prop-
erty. Rasayana is a branch of Ayurveda which helps in promotion of body’s resis-
tance to diseases and increase the strength. W. somnifera is one of the prime rasayana
plants having a vast therapeutic property making it an excellent candidate to be used
in modern medications.

Bacopa monnieri
4.8 

Bacopa monnieri, commonly known as Brahmi (family Plantaginaceae), has been

used since ancient times in Indian and Chinese medicine. The use of B. monnieri in
India for the enhancement of memory dates back since 3000 years or more [74]. It
is often used as a tranquilizer, cardiotonic, and sedative and it is a nervine tonic and
diuretic for nervous and psychological strain, and it is used in epilepsy, hysteria,
asthenia, and nervous breakdown. B. monnieri is distinguished by its chemical com-
ponents, which consists primarily of dammarane-type triterpenes, saponins known
as bacosides. Bacopasides I–XII, a different group of saponins, have recently been
recognized as an essential component of the herbal extract [75]. In addition to her-
saponin, D-mannitol, cucurbitacin, apigenin, plantainoside B, and monnierasides
I–III, the alkaloids such as nicotine and herpestine have been also identified as
active compounds of the plant. Antioxidant, neuroprotection (via redox as well as
enzyme induction), choline acetyltransferase activation and/or acetylcholinesterase
inhibition, increase in cerebral blood flow, β-amyloid reduction, and moderation of
the neurotransmitters (5-hydroxytryptamine [5-HT], acetylcholine [ACh], dopa-
mine [DA]) are thought to be mechanisms involved in disorders related to nervous
system [76]. Brahmi is a medicinal wonder plant with numerous therapeutic proper-
ties. Brahmi has been extensively studied for its effects on nervous system but it is
a great plant with hidden potential whose other medicinal properties need to be
explored.
274 R. Basu et al.

Ginkgo biloba
4.9 

Ginkgo biloba, commonly known as ginkgo or the maidenhair tree, which is native
to Korea, China, and Japan, belongs to the family Ginkgoaceae. It is also found in
certain parts of India like Uttarakhand, Himachal Pradesh, West Bengal, Punjab,
and Meghalaya. It is used for weight loss effects along with antihypertensive, anti-­
lipidaemic, and antidiabetic properties which may be effective in treating of meta-
bolic syndrome [77]. G. biloba nuts have long been used as food as well as medicine
throughout Asia. Because of their antibiotic properties, raw G. biloba nuts have
been used in Chinese traditional medicine to treat bacterial pathogens, asthma,
bronchitis, bladder, and kidney disorders [78]. Terpene lactones (bilobalide as well
as ginkgolides C, B, and A) and flavone glycosides (kaempferol, isorhamnetin, and
quercetin) are the main components of the plant [79]. Studies have shown that
G. biloba extract has successfully reduced body fat in overweight high-fat diet fed
rats. An eight-week study where the rats were administered 500 mg/kg body weight
of the extract as treatment has shown to minimize both body weight gain as well as
food intake compared to untreated rats [80]. The anti-inflammatory effect of the
plant extract may diminish the negative effects of high-fat diet consumption through
the reduction of TNF-retroperitoneal fat depot levels [77] Apart from this, G. biloba
is also known to have antioxidant, anticancer, and anti-inflammatory effects. The
polysaccharides of G. biloba have also studied for their medicinal properties such
as antioxidant, anticancer, anti-inflammatory, anti-depressant properties [81].
G. biloba is one of the oldest plants in the ITM which has captivated the human
beings for centuries through its promising application in traditional medicine.

Asparagus racemosus
4.10 

Asparagus racemosus, also known as Satamuli, Satawar, and Shatavari, is a Liliaceae

plant that grows at low altitudes throughout India. A. racemosus is a very well
Ayurvedic rasayana and has also been used in Siddha and Unani medicine for treat-
ment of nervous disorders, dyspepsia, tumours, anti-ageing, neuropathy, inflamma-
tion, and hepatopathy [82]. It is also extremely efficient in issues regarding the
female reproductive system. Shatavari has been used for the treatment of gonor-
rhoea, piles, diabetes, gastric problems, etc. Treatment of mice with Shatavari
improved glutathione peroxidase activity and the glutathione content in the brain.
Shatavari was able to increase the antioxidant enzyme levels in rat at a dose of
100 mg/kg bw [83]. Shatavari’s antioxidant properties are because of the occurrence
of isoflavones, especially racemosol, racemofuran, and asparagamine A. Apart from
its well-known antioxidant property, Shatavari is known for its galactagogue activ-
ity, antiulcer activity, anti-bacterial activity, anticancer, antiprotozoal activity, and
cardio protective and gastro protective activity [82, 84]. The ITM’s usage of
Shatavari have been demonstrated by vast experimental and scientific studies indi-
cating the plants potential in healthcare industry.
Medicinal Plants in the Indian Traditional Medicine and Current Practices 275

5 Current Usage and Scenario of Indian Traditional

Medicine System

According to WHO, 80% of world population rely and use traditional medicine.
Even though a large population of these are present in India, China, and Africa, the
developed countries have also started to explore the traditional medicine system
[22, 33]. Nature has been a constant source of medicinal herbs and plants. Earlier,
aspirin, digoxin, morphine, and quinine have been derived from plants [85]. The use
of phytotherapy is being used on a regular basis and the trend has again shifted to
the use of herbal remedies for the treatment of various diseases and disorders [86].
The ITM has also seen a rise in its usage in the last few decades [87]. The prac-
titioners of ITM have started addressing the core issues due to which the ITM indus-
try has started gaining importance [88]. More recently, isolating the compounds
from the medicinal plants and studying their pharmacological properties have
gained interest (Fig. 1, Table 4). The phytocompounds isolated have been reported
to work in targeted therapy. However, India had already started isolating compounds
from the medicinal plants in 1930s. Sen and Bose isolated two alkaloids from
Rauwolfia serpentina in 1931 [33]. In the same year, Siddiqui and Siddiqui isolated
five alkaloids, namely Ajmaline, Ajmalinine, Ajmalicine, Scrpentine, and
Serpentinine from the same plant [89]. In the years that followed, several other stud-
ies were also conducted by Indian researchers. During that time period, around 90%
of Indian doctors prescribed Rauwolfia serpentina as a daily antihypertensive, and
with manufacturers selling approximately 50 million tablets due to the work of
Rustom Jal Vakil [90].

Fig. 1 Structures of different phytoconstituents isolated from the medicinal plants of the Indian
traditional medicine system
276 R. Basu et al.

Fig. 1 (continued)
Medicinal Plants in the Indian Traditional Medicine and Current Practices 277

Fig. 1 (continued)
278 R. Basu et al.

Table 4 List of phytoconstituents isolated from some of the medicinal plants and their
pharmacological properties
Plant Plant part Phytoconstituent Pharmacological properties
Aegle Unripe Marmelosin Antidiarrhoea, aids digestion
marmelos fruits
Allium cepa Dried Alliin and Allicin Cardioprotective, antidiabetic, antibiotic
bulbs
Allium sativum Dried Alliin and Allicin Antibacterial, antigout, anti-inflammatory
bulbs
Aloe Gel Aloin and aloesin Anti-inflammatory, wound healing,
barbadensis Halophenols antidiabetic, immunomodulation
emodin Antidiabetic
Antidiabetic, anti-inflammatory, wound
healing, anticancer
Cassia Dried sennosides Purgative, aids digestion
angustifolia leaves
Centella Herb Asiaticoside and Antianxiety, coolant
asiatica Madecassoside
Curcuma Rhizome curcumin Anti-inflammatory, anticancer, antidiabetic,
longa antiseptic, wound healing,
immunomodulation
Echinacea Dried herb Alkylamide, Anti-inflammatory, immunostimulatory
purpurea echinacoside
Ferula Oleo gum Ferulic acid, Immunostimulatory, relieves flatulence,
asafoetida resin umbellic acid expectorant
Gingko biloba Leaves Ginkgolide, Antioxidant, stimulates platelets formation,
bilobalide treatment of migraine, and other
cerebrovascular diseases
Glycyrrhiza Root Glycyrrhizin and Antioxidant, anti-inflammatory, expectorant
glabra liquiritin
Hydrastis Dried root Berberine and Anti-inflammatory, antimicrobial,
canadensis hydrastine antihaemorrhagic, antioxidant, antidiabetic
Hypericum Dried Hypericin and Anti-inflammatory, anti-allergic,
perforatum aerial part hyperforin expectorant, antioxidant,
Panax ginseng Dried root Panaxosides, Immunostimulant, treatment of nervous
Ginsenosides system disorders, anticancer, antioxidant,
anti-inflammatory
Valeriana Dried root Valerate, Valerenic Tranquilizer, anti-inflammatory, relieves
officinalis acid pain and menstrual cramps, migraine
treatment
Zingiber Rhizome Gingerol, Immunostimulant, antioxidant, anticancer,
officinale Zingiberene antidiabetic, immunomodulation
Camellia Leaves Catechin Antioxidant, antidiabetic, anticancer
sinensis Epigallocatechin
Terminalia Fruits and Chebulinic acid Antioxidant, antidiabetic,
chebula leaves Β-sitosterol anti-inflammatory
Tinospora Leaves Magnoflorine Antidiabetic, immunomodulation,
cordifolia anticancer
Withania Leaves Somniferine Memory enhancer, neuroprotective
somnifera
Medicinal Plants in the Indian Traditional Medicine and Current Practices 279

National/International research has discovered many medicines from plants that

have been used in ITM since ancient times. Phytoconstituents have been employed
as a source of lead and in the treatment of a variety of ailments and disorders [3]
Some of the in vivo studies have reported the isolation of vasicine and vasicinone
(Adhatoda vasica), asparanin A and B (Asparagus adscendens), morphine and
codeine (Papaver somniferum), Shatavarin (Asparagus racemosus), etc. [33].
Glycyrrhizin from Glycyrrhiza glabra has been shown to have anti-inflammatory
and anticancer activities in Wistar rats [91], whereas Aloin from Aloe vera has been
used to treat cancer in vivo [92]. Gingerol has been reported to have anti-tumour
potential [93] Several plant compounds are also being tested in clinical studies.
Amoora rohituka derivatives Binectariferum and flavopiridol are in the early stages
of human trials as anticancer agents. In Ayurveda, guggulu, an oleogum resin pro-
duced from the bark of the Commiphora wightii tree, is used to treat obesity, gout,
dyslipidaemia, inflammation, and rheumatism [94]. Several compounds have been
identified, such as Z-guggulsterone, E-guggulsterone, guggulsterol I, and gugguls-
terol II [95]. These constituents of guggulu have also been studied for their thera-
peutic effects with guggulsterone being studied for its cardioprotective effect in
clinical trials. In the development of alternative herbal medicines or formulations,
77 Council for Scientific and Industrial Research (CSIR), India and its member
laboratories are participating in the following areas [33, 94]:
(i) standardized fraction of Guglipid (Guglip®, Cipla Ltd) for marketing as a drug
for hyperlipidaemia and atherosclerosis.
(ii) Artemisia annua’s Artemisinin (a semi-synthetic derivative of the substance) is
being marketed by Themis Chemicals Ltd as an antimalarial medication.
(iii) Consap, which contains saponin from Sapindus mukorossi, has been developed
as a spermicidal cream.
(iv) Picroside and kutoside from Picrorhiza kurroa have been developed as a liver
protectant.
(v) A standardized herbal preparation has been developed as a memory enhancer
from B. monnieri.
(vi) An anti-diabetes drug (BGR34) has been co-developed by CSIR-NBRI and
CSIR-CIMAP.
Attempts are being undertaken to uncover numerous formulations and create
novel pharmaceuticals as part of the “Golden Triangle Partnership” effort involving
AYUSH, the Indian Medical Research Council (ICMR), and the CSIR. This part-
nership aims to increase the usage of ITM and its integration into modern medicine
so as to increase the prospects of herbal medicine industry in India as well as
the world.
280 R. Basu et al.

6 Scope and Future Prospects of Indian Traditional

Medicine System

The use of herbal medicines is booming and the market is growing tremendously as
sales of herbal medicines in India as over-the-counter products, ethical and conven-
tional formulations, and home treatments by ITM are approximately one billion
dollars, and export of plant extracts is about 80 million dollars [85]. Apart from this,
some Americans and Europeans come to India to enrol in courses and participate in
a comprehensive Indian medical treatment plan, which includes massage, food,
yoga, spiritual lectures, and meditation. This is turning into a unique marketing
feature for tourism in India. In addition, exports of medicinal plants and herbs have
been quite large in recent years. The main products of ITM from India are isabgol,
opium alkaloids, senna derivatives, Vinca rosa, Cinchona alkaloids, ipecac root
alkaloids, solasodine, diosgenin, menthol, gudmar grass, henna leaves, papian,
Rauwolfia guar gum, jasmine oil, sandalwood oil, etc. [96]. Indian pharmaceutical
companies and researchers with modern scientific knowledge and technology, and
ideas have begun rediscovering medicinal plants as a source of new drug candidates
based on traditional knowledge. Himalaya Drug Company, Dabur Limited,
Baidyanath, Patanjali Ayurved, Natural Remedies, etc., are some of the prominent
industries which have led to the introduction of ITM-based products in the Indian
market [94].
Modern technology and techniques have revolutionized the advancement of drug
research from the medicinal plants. Research using the latest equipment and meth-
ods have helped separate and develop plant components as new medicines present
in traditional herbal/medicinal plants formulations [22] (Fig. 2). Modern technol-
ogy monitors and maintains the quality of conventional formulations, using phyto-
chemicals as the basis for new drug discovery, determines pharmacokinetic profiles
and toxicity, and discovered mechanisms of existing herbal medicines [97]. It has
become an indispensable tool for finding new uses for prescribing, speeding up drug
discovery processes, synthetic and semi-synthetic processes for producing natural
ingredients, and more [98]. Traditional medicine is an important tool for discover-
ing new drugs as they are less expensive with minimal side effects and is readily
available locally. Quality control of marketed herbs/herbal formulations is critical
for obtaining maximum amount of phytochemicals/constituents for therapeutic effi-
cacy. As a result, herbal drug standards are essential. For comparing the quality of
herbal drugs, standard references such as the Indian Pharmacopoeia Reference
Substances, particularly botanical and phytochemical reference standards, are nec-
essary [99]. The Indian Pharmacopoeia Commission has now focused on standard-
izing the herbal products and promoting the usage of Indian traditional
medicine system.
Medicinal Plants in the Indian Traditional Medicine and Current Practices 281

Fig. 2 Prospect of drug discovery from the Indian traditional medicine system

7 Conclusion

Traditional medicine plays an important role in maintaining health in rural and

remote areas. The introduction of traditional herbal medicine into clinical practice
will help achieve the goal of “health for all” as it easily accessible, and are less
expensive and more importantly with no/minimal side effects. Traditional Indian
medicine like Ayurveda and others have a solid scientific basis for their effective-
ness and are well recognized by recent studies. However, efforts are needed to over-
come obstacles such as inappropriate usage, quality control and standardization
problems, and pharmacovigilance. Rigorous application of rules, monitoring, and
periodic revision of regulations are absolutely necessary to promote the traditional
Indian medicine. In general, adequate systematic knowledge, high-quality clinical
trials, and pertinent information about these drugs and their effectiveness in the
general population are needed to increase the awareness of herbal medication. The
integration of Ayurvedic medicine and other traditional Indian medicines into clini-
cal practice will help to improve the health of those who cannot properly access
modern medicine. The use of ITM along with conventional drugs is certainly more
valuable in promoting health or curing disease in a better way. Therefore, the com-
bination of IMT with the modern medication and technology will be very helpful in
providing the best medical services, not only in India but also all over the world.
282 R. Basu et al.

References

1. Sewell RDE, Rafieian-Kopaei M (2014) The history and ups and downs of herbal medicines
usage. J Herbmed Pharmacol 3:1–3
2. Yuan H, Ma Q, Ye L, Piao G (2016) The traditional medicine and modern medicine from natu-
ral products. Molecules 21:1–28. https://doi.org/10.3390/molecules21050559
3. Li FS, Weng JK (2017) Demystifying traditional herbal medicine with modern approaches.
Nat Plants 3:1–13
4. Shi Y, Zhang C, Li X (2021) Traditional medicine in India. J Trad Chin Med Sci 8:S51–S55.
https://doi.org/10.1016/j.jtcms.2020.06.007
5. Gu R, Wang Y, Long B et al (2014) Prospecting for bioactive constituents from traditional
medicinal plants through ethnobotanical approaches. Biol Pharm Bull 37:1–15
6. Subramoniam A (2014) Present scenario, challenges and future perspectives in plant based
medicine development. Annals Phytomedicine 3:31
7. Walker AF (2006) Herbal medicine: the science of the art. Proc Nutr Soc 65:145. https://doi.
org/10.1079/pns2006487
8. Arentz S (2018) Developing intellectual capacity in naturopathy and herbal medicine practice.
Aust J Herb Naturop Med 30:6–7
9. Adhikari PP, Paul SB (2018) History of Indian traditional medicine: a medical inheritance.
Asian J Pharm Clin Res 11:421. https://doi.org/10.22159/ajpcr.2018.v11i1.21893
10. Zhang R, Zhu X, Bai H, Ning K (2019) Network pharmacology databases for traditional
Chinese medicine: review and assessment. Front Pharmacol 10:123. https://doi.org/10.3389/
FPHAR.2019.00123/BIBTEX
11. Park HL, Lee HS, Shin BC et al (2012) Traditional medicine in China, Korea, and Japan:
a brief introduction and comparison. Evid Based Complement Alternat Med 2012:429103.
https://doi.org/10.1155/2012/429103
12. Zhang J, Zhang Q, Liu G, Zhang N (2019) Therapeutic potentials and mechanisms of the
Chinese traditional medicine Danshensu. Eur J Pharmacol 864:172710
13. Kang YM, Komakech R, Karigar CS, Saqib A (2017) Traditional Indian medicine (TIM) and
traditional Korean medicine (TKM): aconstitutional-based concept and comparison. Integr
Med Res 6:105–113. https://doi.org/10.1016/J.IMR.2016.12.003
14. Kim JY, Pham DD (2009) Sasang constitutional medicine as a holistic tailored medicine. Evid
Based Complement Alternat Med 6:11–19. https://doi.org/10.1093/ecam/nep100
15. Yu F, Takahashi T, Moriya J et al (2006) Traditional Chinese medicine and kampo:
a review from the distant past for the future. J Int Med Res 34:231–239. https://doi.
org/10.1177/147323000603400301
16. Witt CM, Watanabe K, Matsuura K et al (2011) Traditional Japanese Kampo medicine: clinical
research between modernity and traditional medicine – the state of research and methodologi-
cal suggestions for the future. Evid Based Complement Alternat Med 2011:513842
17. Alrawi SN, Fetters MD (2012) Traditional arabic & islamic medicine: a conceptual model
for clinicians and researchers. Global J Health Sci 4:164–169. https://doi.org/10.5539/gjhs.
v4n3p164
18. Azaizeh H, Saad B, Cooper E, Said O (2010) Traditional Arabic and Islamic medicine, a
re-emerging health aid. Evid Based Complement Alternat Med 7:419–424. https://doi.
org/10.1093/ecam/nen039
19. Ezekwesili-Ofili JO, Okaka AN (2019) Herbal medicine in African traditional medicine. In:
Herbal Medicine
20. Mabona U, van Vuuren SF (2013) Southern African medicinal plants used to treat skin dis-
eases. S Afr J Bot 87:175–193
21. Micke O, Hübner J (2009) Traditional European medicine—after all, is Hildegard von Bingen
really right? Eur J Integr Med 1:226. https://doi.org/10.1016/j.eujim.2009.08.009
Medicinal Plants in the Indian Traditional Medicine and Current Practices 283

22. Pandey MM, Rastogi S, Rawat AKS (2013) Indian traditional ayurvedic system of medicine
and nutritional supplementation. Evid Based Complement Alternat Med 2013:376327. https://
doi.org/10.1155/2013/376327
23. Jaiswal A (2018) Traditional health care and traditional medicine in India. Archaeol
Anthropol:Open Access 2. https://doi.org/10.31031/aaoa.2018.02.000537
24. Sahoo N, Manchikanti P (2013) Herbal drug regulation and commercialization: an indian
industry perspective. J Altern Complement Med 19:957–963. https://doi.org/10.1089/
acm.2012.0275
25. Patwardhan B, Warude D, Pushpangadan P, Bhatt N (2005) Ayurveda and traditional Chinese
medicine: a comparative overview. Evid Based Complement Alternat Med 2:465. https://doi.
org/10.1093/ecam/neh140
26. Elahee S, Mao H, Shen X (2019) Traditional Indian medicine and traditional Chinese medicine:
a comparative overview. Chin Med Cult 2:105. https://doi.org/10.4103/cmac.cmac_29_19
27. Jaiswal YS, Williams LL (2017) A glimpse of Ayurveda – the forgotten history and principles
of Indian traditional medicine. J Tradit Complement Med 7:50–53
28. Sundarrajan S, Arumugam M (2017) Documentation of traditional Siddha medicines for skin
diseases from Katpadi taluk, Vellore District, Tamil Nadu. India Eur J Integr Med 9:52. https://
doi.org/10.1016/j.eujim.2016.08.163
29. Sieler R (2014) Patient agency revisited: “Healing the hidden” in South India. Med Anthropol
Q 28:323. https://doi.org/10.1111/maq.12067
30. Thas JJ (2008) Siddha medicine-background and principles and the application for skin dis-
eases. Clin Dermatol 26:62–78. https://doi.org/10.1016/j.clindermatol.2007.11.010
31. Patil SB, Patil MS, Chittam KP, Wagh RD (2014) A review on Ayurveda and Siddha: Indian
systems of medicine. Pharma Science Monitor 5:40–49
32. Vamshi Ram V, Premavathy D, Preetha S (2020) Assessing of knowledge of Siddha medi-
cine having antiviral property. Int J Pharm Res 12:575–583. https://doi.org/10.31838/
ijpr/2020.SP2.075
33. Sen S, Chakraborty R (2017) Revival, modernization and integration of Indian traditional
herbal medicine in clinical practice: importance, challenges and future. J Tradit Complement
Med 7:234–244
34. Islam A (2018) Origin and development of unani medicine: an analytical study. Intellectual.
Discourse 26:23–49
35. Rai N, Joshi SK, Sharma RK (2021) Regulatory requirements for quality control of unani
medicines. J AOAC Int 103:634–648. https://doi.org/10.5740/JAOACINT.19-­0285
36. Itrat M (2020) Methods of health promotion and disease prevention in Unani medicine. J Edu
Health Prom 9:168
37. Manchanda R (2018) Experimentation in homoeopathy: history and prospects. Indian J Res
Homoeop 12:61. https://doi.org/10.4103/ijrh.ijrh_40_18
38. Cukaci C, Freissmuth M, Mann C et al (2020) Against all odds—the persistent popu-
larity of homeopathy. Wien Klin Wochenschr 132:232–242. https://doi.org/10.1007/
s00508-­020-­01624-­x
39. Kaur H, Chalia DS, Manchanda RK (2019) Homeopathy in public health in India. Homeopathy
108:76–87. https://doi.org/10.1055/s-­0038-­1673710
40. Fleming SA, Gutknecht NC (2010) Naturopathy and the primary care practice. Prim Care Clin
Office Pract 37:119–136. https://doi.org/10.1016/j.pop.2009.09.002
41. Bradley R, Harnett J, Cooley K et al (2019) Naturopathy as a model of prevention-oriented,
patient-centered primary care: a disruptive innovation in health care. Medicina (Lithuania)
55:603. https://doi.org/10.3390/medicina55090603
42. Nugent-Head JA (2014) The first Materia Medica: the Shen Nong Ben Cao Jing. J Chin Med
43. Sharma H, Chandola HM, Singh G, Basisht G (2007) Utilization of Ayurveda in health care:
an approach for prevention, health promotion, and treatment of disease. Part 1 – Ayurveda, the
science of life. J Altern Complement Med 13:1011–1019
284 R. Basu et al.

44. Sharangi AB (2009) Medicinal and therapeutic potentialities of tea (Camellia sinensis L.) – a
review. Food Res Int 42:529–535
45. Saeed M, Naveed M, Arif M et al (2017) Green tea (Camellia sinensis) and L-theanine:
medicinal values and beneficial applications in humans—a comprehensive review. Biomed
Pharmacother 95:1260–1275
46. Sharma D, Kumar S, Kumar S, Kumar D (2019) DPP-IV inhibitors from natural sources: an
alternative approach for treatment and management of diabetes. Indian J Nat Prod Resour
10:227–237
47. Mehla J, Gupta P, Pahuja M et al (2020) Indian medicinal herbs and formulations for
Alzheimer’s disease, from traditional knowledge to scientific assessment. Brain Sci 10:964
48. Vedpal DSP, Dhamodaran P et al (2016) Pharmacognostical characterization, phytochemical
screening and finger print profile of the plant Desmodium gangeticum DC. Int J Pharmacogn
Phytochem Res 8:1271–1277
49. Bhattacharjee A, Shashidhara SC, Saha S (2013) Phytochemical and ethno-pharmacological
profile of Desmodium gangeticum (L.) DC.: a review. Int J Biomed Res 4:507. https://doi.
org/10.7439/ijbr.v4i10.355
50. Babu SN, Noor A (2020) Bioactive constituents of the genus Aloe and their potential thera-
peutic and pharmacological applications: a review. J Appl Pharm Sci 10:133. https://doi.
org/10.7324/JAPS.2020.101118
51. Babu SN, Govindarajan S, Vijayalakshmi MA, Noor A (2021) Role of Zonulin and GLP-1/
DPP-IV in alleviation of diabetes mellitus by peptide/polypeptide fraction of Aloe vera in
Streptozotocin- induced diabetic Wistar rats. J Ethnopharmacol 272:113949. https://doi.
org/10.1016/j.jep.2021.113949
52. Hamman JH (2008) Composition and applications of Aloe vera leaf gel. Molecules
13:1599–1616. https://doi.org/10.3390/molecules13081599
53. Boudreau MD, Beland FA (2006) An evaluation of the biological and toxicological properties
of Aloe barbadensis (Miller), Aloe vera. J Environ Sci Health Part C Environ Carcinogenesis
Ecotoxicol Rev 24:103–154
54. Aloe Chromones Improve Insulin Sensitivity.pdf
55. Yagi A, Hegazy S, Kabbash A, Wahab EA-E (2009) Possible hypoglycemic effect of Aloe vera
L. high molecular weight fractions on type 2 diabetic patients. Saudi Pharm J 17:209–215.
https://doi.org/10.1016/j.jsps.2009.08.007
56. Govindarajan S, Babu SN, Vijayalakshmi MA et al (2021) Aloe vera carbohydrates regulate
glucose metabolism through improved glycogen synthesis and downregulation of hepatic
gluconeogenesis in diabetic rats. J Ethnopharmacol 281:114556. https://doi.org/10.1016/J.
JEP.2021.114556
57. Mahmood KT, Mugal T, Haq IU (2010) Moringa oleifera: a natural gift-a review. J Pharm Sci
Res 2:775–781
58. Lakshmana Prabu S, Umamaheswari A, Puratchikody A (2019) Phytopharmacological poten-
tial of the natural gift Moringa oleifera lam and its therapeutic application: an overview. Asian
Pac J Trop Med 12:485–498
59. Sodhi G, Das S, Mazumder A, Rana S (2019) Ethnopharmacological review of drum stick
(Moringa oleifera): prevalently used as an alternative medicine. Res J Pharm, Biol Chem Sci
10:458–468
60. Sujatha BK, Patel P (2017) Moringa oleifera–nature’s gold. Imperial J Interdiscip Res
3:1175–1179
61. Stohs SJ, Hartman MJ (2015) Review of the safety and efficacy of Moringa oleifera. Phytother
Res 29:796–804
62. Rathinamoorthy R, Thilagavathi G (2014) Terminalia chebula – review on pharmacological
and biochemical studies. Int J PharmTech Res 6:97–116
63. Rao NK, Nammi S (2006) Antidiabetic and renoprotective effects of the chloroform extract
of Terminalia chebula Retz. Seeds in streptozotocin-induced diabetic rats. BMC Complement
Altern Med 6:17. https://doi.org/10.1186/1472-­6882-­6-­17
Medicinal Plants in the Indian Traditional Medicine and Current Practices 285

64. Basha S, Reddy V, Sudha Rani Y et al (2017) A review on Terminalia chebula. Int J Pharmacol
Res 7:187–192. https://doi.org/10.7439/ijpr.v7i10.4431
65. Bag A, Bhattacharyya SK, Chattopadhyay RR (2013) The development of Terminalia chebula
Retz. (Combretaceae) in clinical research. Asian Pac J Trop Biomed 3:244–252. https://doi.
org/10.1016/S2221-­1691(13)60059-­3
66. Tiwari P, Nayak P, Prusty SK, Sahu PK (2018) Phytochemistry and pharmacology of Tinospora
cordifolia: a review. System Rev Pharm 9:70–78
67. Chi S, She G, Han D et al (2016) Genus Tinospora: ethnopharmacology, phytochemistry, and
pharmacology. Evid Based Complement Alternat Med 2016:9232593
68. Prince PSM, Menon VP, Gunasekaran G (1998) Hypolipidaemic action of Tinospora cor-
difolia roots in alloxan diabetic rats. J Ethnopharmacol 64:53–57. https://doi.org/10.1016/
S0378-­8741(98)00106-­8
69. Zahiruddin S, Basist P, Parveen A et al (2020) Ashwagandha in brain disorders: a review of
recent developments. J Ethnopharmacol 257:112876
70. Namdeo AG, Ingawale DK (2021) Ashwagandha: advances in plant biotechnological
approaches for propagation and production of bioactive compounds. J Ethnopharmacol
271:113709
71. Dhawan M, Parmar M, Sharun K et al (2021) Medicinal and therapeutic potential of withano-
lides from Withania somnifera against COVID-19. J Appl Pharm Sci 11:006–013. https://doi.
org/10.7324/JAPS.2021.110402
72. Bhatnagar M, Goel I, Roy T et al (2017) Complete Comparison Display (CCD) evaluation
of ethanol extracts of Centella asiatica and Withania somnifera shows that they can non-­
synergistically ameliorate biochemical and behavioural damages in MPTP induced Parkinson’s
model of mice. PLoS One 12:e0177254. https://doi.org/10.1371/JOURNAL.PONE.0177254
73. Paul S, Chakraborty S, Anand U et al (2021) Withania somnifera (L.) Dunal (Ashwagandha): a
comprehensive review on ethnopharmacology, pharmacotherapeutics, biomedicinal and toxi-
cological aspects. Biomed Pharmacother 143:112175
74. Mathur D, Goyal K, Koul V, Anand A (2016) The molecular links of re-emerging therapy: a
review of evidence of Brahmi (Bacopa monniera). Front Pharmacol 7:44
75. Srivastava P, Raut HN, Puntambekar HM, Desai AC (2012) Stability studies of crude plant
material of Bacopa monnieri and quantitative determination of bacopaside I and bacoside A
by HPLC. Phytochem Anal 23:502–507. https://doi.org/10.1002/pca.2347
76. Aguiar S, Borowski T (2013) Neuropharmacological review of the nootropic herb Bacopa
monnieri. Rejuvenation Res 16:313–316
77. Eisvand F, Razavi BM, Hosseinzadeh H (2020) The effects of Ginkgo biloba on metabolic
syndrome: a review. Phytother Res 34:1798–1811
78. Chassagne F, Huang X, Lyles JT, Quave CL (2019) Validation of a 16th century traditional
Chinese medicine use of Ginkgo biloba as a topical antimicrobial. Front Microbiol 10:775.
https://doi.org/10.3389/fmicb.2019.00775
79. Okhti ZA, Abdalah ME, Hanna DB (2021) Phytochemical structure and biological
effect of Ginkgo biloba leaves: a review. Int J Pharm Res 13. https://doi.org/10.31838/
ijpr/2021.13.02.180
80. Banin RM, Machado MMF, de Andrade IS et al (2021) Ginkgo biloba extract (GbE) attenu-
ates obesity and anxious/depressive-like behaviours induced by ovariectomy. Sci Rep 11:44.
https://doi.org/10.1038/s41598-­020-­78528-­3
81. Fang J, Wang Z, Wang P, Wang M (2020) Extraction, structure and bioactivities of the polysac-
charides from Ginkgo biloba: a review. Int J Biol Macromol 162:1897
82. Alok S, Jain SK, Verma A et al (2013) Plant profile, phytochemistry and pharmacology of
Asparagus racemosus (Shatavari): a review. Asian Pacific J Tropl Dis 3:242–251. https://doi.
org/10.1016/S2222-­1808(13)60049-­3
83. Sairam K, Priyambada S, Aryya NC, Goel RK (2003) Gastroduodenal ulcer protective
activity of Asparagus racemosus: an experimental, biochemical and histological study. J
Ethnopharmacol 86:1–10. https://doi.org/10.1016/S0378-­8741(02)00342-­2
286 R. Basu et al.

84. Pandey AK, Gupta A, Tiwari M et al (2018) Impact of stress on female reproductive health dis-
orders: possible beneficial effects of shatavari (Asparagus racemosus). Biomed Pharmacother
103:46–49
85. Pan SY, Litscher G, Gao SH et al (2014) Historical perspective of traditional indigenous
medical practices: the current renaissance and conservation of herbal resources. Evid Based
Complement Alternat Med 2014:1–20
86. Sen S, Chakraborty R, De B (2011) Challenges and opportunities in the advancement of
herbal medicine: India’s position and role in a global context. J Herb Med 1:7–75. https://doi.
org/10.1016/j.hermed.2011.11.001
87. Prakash J, Srivastava S, Ray RS et al (2017) Current status of herbal drug standards in the
Indian pharmacopoeia. Phytother Res 31:1817–1823. https://doi.org/10.1002/ptr.5933
88. Mukherjee PK, Wahile A (2006) Integrated approaches towards drug development from
Ayurveda and other Indian system of medicines. J Ethnopharmacol 103:25–35. https://doi.
org/10.1016/J.JEP.2005.09.024
89. Singh H, Chawla AS, Kapoor VK (1985) 5 medicinal chemistry research in India. Prog Med
Chem 22:243–266. https://doi.org/10.1016/S0079-­6468(08)70232-­7
90. Isharwal S, Gupta S (2006) Rustom Jal Vakil: his contributions to cardiology. Tex Heart Inst
J 33:161–170
91. Batiha GES, Beshbishy AM, El-Mleeh A et al (2020) Traditional uses, bioactive chemical
constituents, and pharmacological and toxicological activities of Glycyrrhiza glabra L. (faba-
ceae). Biomolecules 10:352
92. Pan Q, Pan H, Lou H et al (2013) Inhibition of the angiogenesis and growth of Aloin in human
colorectal cancer in vitro and in vivo. Cancer Cell Int 13:69–78. https://doi.org/10.1186/1475-
­2867-­13-­69
93. Surh YJ, Park KK, Chun KS et al (1999) Anti-tumor-promoting activities of selected pungent
phenolic substances present in ginger. J Environ Pathol Toxicol Oncol 18:131–139
94. Sen S, Chakraborty R (2015) Toward the integration and advancement of herbal medicine:
a focus on traditional Indian medicine. Botanics: Targets Therapy 5:33–44. https://doi.
org/10.2147/btat.s66308
95. Anurekha J, Gupta VB (2006) Chemistry and pharmacological profile of guggul-A review.
Indian J Trad Knowl (IJTK) 05:478–483
96. Singh K (2005) Development of supply chains for medicinal plants: a case study involving
the production of vinca rosa by small farmers in the Patna District of Bihar India. … Food
Chain, …:1–16
97. Payyappallimana U (2010) Role of traditional medicine in primary health care: an overview of
perspectives and challenges. Yokohama J Soc Sci 14:57–78
98. Patwardhan B, Mashelkar RA (2009) Traditional medicine-inspired approaches to drug dis-
covery: can Ayurveda show the way forward? Drug Discov Today 14:804–811
99. Mandal SC, Mandal M (2011) Quality, safety, and efficacy of herbal products through regulatory
harmonization. Ther Innov Regul Sci 45:45–53. https://doi.org/10.1177/009286151104500105
Conservation of RET Medicinal and
Aromatic Plants, Their Traditional
Medicines and Current Practices in Indian
Himalayan Region

Rajeev Ranjan Kumar, Jaidev Chauhan, V. K. Purohit, P. Prasad,

and M. C. Nautiyal

1 Introduction

India has been a hub of the treasure of traditional knowledge for ages which, besides
others, also explains the way outs for solving most of the present-day problems.
Plants are the primary source of all medicines worldwide, providing mankind with
new remedies. Natural sources of medicines maintain equilibrium between agricul-
ture and industrial sectors in terms of demand for natural medicine and economy,
and there is also a minimum harmful effect on human bodies. The traditional medic-
inal plant system plays a vital role in remote areas. In the primary healthcare sector,
little work so far has been done regarding the documentation and promotion of
associated knowledge [1]. Medicinal and aromatic plants are always in high demand
worldwide in both areas of health management, that is, traditional and modern sys-
tems of medicine. The traditional medicine system works through two distinct
streams, one is local, tribal or folk, and the other is codified or structured. Indian
Medicine Systems such as Ayurveda, Homoeopathy, Siddha, and Unani are formed
from both sources, plants and animals, but electrohomeopathy medicines are pre-
pared from purely herbal sources. Cultivation of medicinal and aromatic plants in
higher Himalayan ranges are new trends and is the only last option for maintaining
the wild population of medicinal plants, which are most endangered and fulfil the
industrial demands of pharmaceutical industries in global markets [2, 3]. In India
alone, less than 10% of the medicinal plants traded in the country are cultivated, and
about 90% are collected from the wild, very often in a destructive and unsustainable
manner [4].
However, in recent years, attention has been given to the development of propa-
gation methods and collection (which can support conservation objectives overall)

R. R. Kumar (*) · J. Chauhan · V. K. Purohit · P. Prasad · M. C. Nautiyal

High Altitude Plant Physiology Research Centre, Hemvati Nandan Bahuguna Garhwal
University, Srinagar Garhwal, Uttarakhand, India

© The Author(s), under exclusive license to Springer Nature 287

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_10
288 R. R. Kumar et al.

[5]. Most medicinal plants are being extracted from wild populations for drug and
pharmaceutical industries, traditional use and research purposes. These activities
adversely affect the existence of a number of plants, particularly those of high com-
mercial value. Further, the developmental activities in the higher Himalayan region
without rehabilitation work of these valuable resources are one of them.

1.1 ISM

India is a diverse rich country not only in terms of biodiversity but also in its unique
Traditional medicinal system and this integration leads to formation of AYUSH,
which is system of Ayurveda, Siddha, Yoga and Naturopathy. It’s an old Indian tradi-
tion medicine system and practiced in our country, multifaceted culture and tradi-
tional medicines evolved over centuries blessed with a plethora of traditional
medicines and practices. A separate department of Indian Systems of Medicine and
Homoeopathy (ISM & H) was set up in 1995 to ensure the optimal development and
propagation of AYUSH healthcare systems. The department of ISM & H was
renamed as the department of AYUSH (an acronym for – Ayurveda, Yoga and
Naturopathy, Unani, Siddha and Homoeopathy) in November 2003 [6] (Table 1).

1.2 ASM

The Ayurvedic System of Medicine is a natural Indian medicine system that origi-
nated in India more than 3000 years ago. The term Ayurveda originated from the
Sanskrit word, Ayur = life, Veda = Knowledge). This medicine system deals with
physical and mental health and covers the art of living. In the Ayurvedic system,

Table 1 Humours (vital force, OD force, bioforce) enlisted according to different alternative
medicine systems
Ayurveda Siddha Unani Homoeopathy Electrohomoeopathy
Pita (Bile) Azal Blood Syphilis Sanguine
Vayu (Wind) Vali Phlegm Sycosis Lymphatic
Kapha (Phlegm) Aiyam Yellow bile Psora Nervous
– – Black bile – Bilious
Notes: In future, it is obvious that the use of medicinal and aromatic plants will increase day by day
for fulfilling the industrial demands, hence for the preparation of any medicines in Indian Medicine
Systems (Ayurveda, Homoeopathy, Siddha, Unani, and Electrohomoeopathy) it totally depends on
plants supply. These medicines have no harmful effects on humans and animals, hence if these
MAP’s were not comes under cultivation it will lead them to face RET category due to over
exploitation from their natural habitats. So the need for developing efficient protocols of various
Agro-techniques, in vitro propagation methods and hydroponic techniques are required
Conservation of RET Medicinal and Aromatic Plants, Their Traditional Medicines… 289

diseases are cured by using drugs (phytocompound products, animal products, and
earth material products), diets, exercise, acupressure, massage, panchakarma, etc.
According to Ayurveda, it is classified into three essential elements: Vata, Pita and
Kapha, present in all living beings. Such elements originate from five elements –
Vayu (air), Tej (energy), Akash (space), Jal (water) and Earth (soil and minerals);
Space + Air = Vata, Tej+ Jal = Pita, Jal + Earth = Kapha. Diseases are caused by
such biological elements imbalance [6].

1.3 YNSM

Yoga and Naturopathy system is a culture and civilization of India. According to

Hindu mythology, God Dhanvantri was first described in Ayurveda. As texted from
ancient scholars, rishi muni such as Rishi Patanjali, Rishi Charak, Sushruta plays an
important role for developing this system. Yoga, naturopathy, mudra, and acupres-
sure are healing art for maintaining physical and mental health and preventive meth-
ods for diseases and cures [6].

1.4 USM

Unani System of Medicine is based on the principle of great physicians such as

Hippocrates and Galen. This alternative medicine system originated in Greece but
is now practised primarily in India. This system includes herbal remedies, dietary
practices, and prevention and treatment of disease. According to the Unani system,
health is based on the balance of bodily fluids called four humours (blood, phlegm,
yellow bile and black bile), which play an important role in a healthy body [6].

1.5 ISM

Indian Siddha System of medicine is the oldest traditional system of healing that
originated in south India. The system belongs to the Tamil civilization. The term
Siddha comes from Siddhi, which means achievement. The system is based on the
combination of ancient medicinal practices with spiritual disciplines, alchemy, and
mysticism. Six thousand species of medicinal plants were documented and pub-
lished in different research papers of ethnobotanical literature in India, among
which 750 species are generally used in the preparation of Siddha medicine from
both plant and animal kingdoms based on minerals and substances [6].
290 R. R. Kumar et al.

1.6 HMS

Homoeopathic system of medicine is an alternative medicine system that originated

in Germany more than 200 years ago but is now practised primarily in India. Dr.
Christian Friedrich Samuel Hahnemann is the father of Homoeopathy. In this medi-
cine system, extremely dilute amounts of certain natural substances from the plant
kingdom, animal kingdom, earth materials, etc., are used to treat various diseases.
According to the homoeopathic system of medicine, diseases are caused by three
constituents, Psora, Syphilis and Sycosis, which develop mental and physical symp-
toms in the human body [6].

1.7 ESM

Electrohomeopathic system of medicine from Italy, but now the Indian government
allow these practices and research development in this system. The term of electro-
homeopathy means that Electro = Electro word comes from the electro i.e, bioen-
ergy that is extracted from medicinal plants by cohabitation methods, While
Homeopathy word means a type of medical science which treats the diseases by
using similar amount of small doses of herbal remedies as prescribed by physician.
The father of electrohomeopathic system of medicine is Count Ceaser Mattei.
According to this system of electrohomeopathy remedies that have capability to
gently stimulate the natural body’s healing system (Immune system) and also equi-
librium between the blood and lymph, hypo, hyper function physical and chemical
consistency of the cells or tissues established in a same manners as that of healthy
state of the body [7, 8].

1.8 SEM

System of Ethnomedicine is an ancient traditional system in India. It is derived from

our ancestor’s continuous practices and experiments, which they applied, and passed
this knowledge from their generation to another but in a secret manner; hence, this
is the biggest drawback of this system since a lot more is needed to be documented
so that in future it can come under research. This system is now also under threat
because many traditional healers have discontinued this due to less attention taken
by local peoples; hence, it must be conserved [9].
Conservation of RET Medicinal and Aromatic Plants, Their Traditional Medicines… 291

2 Materials and Methods

2.1 Uses of High-Altitude and Temperate Medicinal

and Aromatic Plants

This chapter focuses on the uses of medicinal plants. Pharmaceutical companies use
nearly 90% of medicinal plants from natural sources, which is considered to be the
main cause for the extinction of various species of medicinal and aromatic plants in
the Himalayan region. Government agencies, institutions and non-government
organizations have taken steps to cultivate medicinal plants in suitable habitats for
conservation purposes and further use in future. Here we have presented the data
based on extensive surveys done during 2018–2021 all over the Uttarakhand state in
both temperate and subalpine villages (Fig. 1), along with some research papers
and books.

Fig. 1 Glimpses of various survey and awareness meetings for collecting TMK and other techni-
cal know-how
292 R. R. Kumar et al.

3 Results

Uses of medicinal plants are also discussed in many ancient texts like Ayurveda and
in many scientific books; these literatures also focus on the importance of medicinal
herbs. Several literature that discuss the importance of herbal philosophy are
available not only in India but also in other countries like Italy, Greece and China.
Bioactive or phytochemical compounds are found in whole parts (roots, tuber, rhi-
zome, stem, leaves and flowers) of medicinal plants. Parts used from medicinal
plants basically depend upon the amount of phytochemical and specific regions of
plants as varied species to species of medicinal and aromatic plants. Roots, rhi-
zomes, tubers, as discussed in Tables 2 and 3, underground (tubers, roots and rhi-
zomes) parts are used for some species (Aconitum species, Saussurea costus,
Saussurea obvallata, Inula recemosa, Nardostachys grandiflora, Valeriana walichii,
Podophyllum hexandrum, Rheum species, Picrorhiza kurroa) to cure human and
animal related health problems. Some species (Swertia chirayita, Swertia ciliata,
Swertia speciosa, etc., of whole parts of plants, are used for curing the disease of
animals and humans. Therefore, we should always use plant parts with proper post-­
harvest practices as well as Good Agricultural Practices (GAPs), that is, under-
ground parts or upper parts for the preparation of medicine.

4 Conclusion

MAPs are the spinal cord of the Indian AYUSH System since India is a rich hotspot
of many primary and secondary centres of origin, especially the Indian Himalayan
Region; hence the role of traditional medicinal knowledge is very important and
must be encouraged in a scientific, holistic manner by means of cultivation practices
so that the rich biodiversity would be maintained. Yet there is a lot of scope in eth-
nomedicinal concepts because very little scientific approach has been made related
to this field, and there is much more to be revealed, but before that, we have to
conserve these RET species of MAPs because all pharmaceutical products need to
be prepared from plant sources; hence, medicinal and aromatic plants will play a
crucial role in solving many futuristic health problems like COVID and its other
mutant variants like omicron, Alzheimer’s disease, Parkinson disease, etc.
Conservation of RET Medicinal and Aromatic Plants, Their Traditional Medicines… 293

Table 2 Name of species

Local (Garhwali)
S.no Latin name Sanskrit name Hindi name name
1. Aconitum heterophyllum Ativisha Atis Atis
Wall.ex Royle
2. Aconitum balfourii Stapf Vatsnabh Mithaa vish, Mithaa vish
Mohru
3. Aconitum violaceum Jacq. Vatsnabh Dudhia Atis Dudhia Atis,
Ex Stapf Dugdh Atis
4. Angelica glauca. Edgew Chorak Choru, Choru, Chora,
Chhipi
5. Dactylorhiza hatagirea Hatha jari Hatha jari Shalampanja/Hatha
(D. Don) jari
6. Malaxis muscifera (Lindl.) Rsabhaka Risbhak Rishbhak
Kuntze
7. Podophyllum hexandrum Bankakri Bankakri, Rikhpat, Kakhraya
Royle Banbaigan, Papri
8. Paris polyphylla Sm. Svetavaca Satuwa, Sankh Satuwa
puspi
9. Rheum emodi Wall. ex Amalparni pitmula, Archa, Archa, Archu
Meissin Revat-chini Revandchini
10. Rheum moorcroftianum Amlaparn Dolu Dolu
Royle
11. Saussurea costus (Falc.) Agada, Kushta Kuth Kuth
Lipsch.
12. Saussurea obvallata (DC Braham kamal Braham kamal Kaunl,
Edgew) brahamkaunl, Suraj
aul
13. Innula racemosa Hook. f Pushkaramula Pushkar mool Pushkar mool
14. Valeriana wallichii DC Tagar Tagar Saumaiya
15. Nardostachys grandiflora Jatamansi, Mansi Jatamansi, Masi, Mansi
DC Balchar
16. Bergiana ciliata (Haw.) Pasanved Pasanved Pakhanved, Silpado
Sternb
17. Picrorhiza kurroa Royle. Kutki, Katuka Kutki, Kuru Kardwi, Karvi
ex Benth
18. Swertia chirayita (Roxb. Kirata-tikta Chirayata Chiraytu
ex Flem) Karsten
19. Swertia ciliata (D. Don ex Kirata-tikta Chirayata Chiraytu
G. Don) BL Burtt.
20. Swertia speciosa Wall. Kirata-tikta Chirayata Chiraytu
ex.D.Don
Table 3 Importance of medicinal plants, habitats, bioactive compounds and current status
About species Habitats Bio active compound Pharmaceutical properties and uses CS
(1) Aconitum heterophyllum A. heterophyllum is grown on Anthorine [17] Such medicinal plant is non-poisonous, tubers are Endangered
Family-Rannunculaceae steep slopes at the alpine Atidine [18] generally used in Ayurvedic, Unani medicine
Parts used – Tuber region of Himalaya (Kashmir, Atisenol [19] preparations as anti-pyretic, analgesic, antiperiodic,
Cultivation status – Chamoli, Himachal Pradesh, 6-Benzoylheteratisine [19] aphrosidic, astringent, anti-venom, anti-inflammatory,
Uttarkashi, Bageshwar districts in Uttarakhand) at 3000–4000 m 11,13:11,16-Diepoxy-16,17-dihydro-11, ant-rheumatic, vermifuge, etc. It is also used in form
the state of Uttarakhand asl 12-ecohetisan-2-ol [14], of ethno medicine such as stomach disorder
Fig. 2k Dihydroatisine, (diarrhoea, dyspepsia, dysentery, anorexia, etc.), to
Heterophyllidine, Heterophylline, Hetidine, reduce obesity, cough, thirst associated with fever and
Hetisinone, O-Methylheterophylline headache problem caused from eating excessive
Isoatisine, Hetisine [17–19] amounts of greasy foods, yellowish sclera, nausea,
N- Di-ethyl-N-formylly aconitine [17] vomiting, throat pain and piles [10–12]
O-Methylaconitine (15)Methyl-N-succinoyl
anthranilate [17]
(2) Aconitum balfourii Aconitum balfourii 9-Hydroxysenbusine A [14] Used in treatment of arthritis, fever and rheumatism, Endangered
Family – Rannunculaceae is generally distributed in Balfourine, 8-O-Methylveratroyl leprosy and boils [10–12]
Parts used – Tuber Uttarakhand Himalaya region pseudaconine, pseudo-aconitine, aconitine,
Cultivation status – Chamoli, (Kedarnath, Tungnath, picroaconine, aconine, benzyl aconine, and
Uttarkashi, Bageshwar districts in Madhyamaheshwar, hemonapelline
the state of Uttarakhand Panwalikantha) at
Fig.2j 2800–3600 m asl
(3) Aconitum violaceum The alpine zone of the Indaconitine [11, 16] Nervine tonic [11, 16] Endangered
Family – Rannunculaceae Himalayas from Gilgit to
Parts used – Tuber Kumaon and Garhwal region
Cultivation status-Not applied (Hakidoon, Bednibugyal)
Fig.2i 3600–4000 m
About species Habitats Bio active compound Pharmaceutical properties and uses CS
(4) Angelica glauca Native and endemic to the Valeric acid, angelic acid, and Angeline resin stimulant, cardioactive, carminative, digestive, Endangered
Family – Apiaceae Himalayan region of Kashmir, bioactive compounds contained in the underground sudorific, expectorant and also for stomachic
Parts used – underground parts Himachal Pradesh, and part (Roots) [10–12] properties
(rhizome/roots) and leaves may Uttarakhand, Angelica glauca Also, it is useful in cough, ulcer of the palate,
also be used in vegetable spices Edgew (Apiaceae) is a menorrhoea, menopausal, anaemia, infantile atrophy,
and curry high-value perennial debility, bronchitis, vomiting, typhoid, fever, spasms,
Cultivation status – Chamoli, medicinal herb increasing appetite and in various stomach disorders
Uttarkashi, Bageshwar, in humans and animals (diarrhoea, rinderpest,
Pithoragarh districts in the state of dysentery, constipation, anorexia, flatulent colic, etc.)
Uttarakhand and to treat loss of kidney heat, accumulation of
Fig.2s excess lymph in the joints. The root powder is mixed
with warm water and given to children with stomach
ailments and vomiting. Due to its strong fragrant
odour,
it is widely used in industries, that is, fixative of
perfume [10–12]
(5) Dactylorhiza hatagirea India (Jammu and Kashmir, Tubers contain bioactive compounds, that is, Used in treatment for diarrhoea, dysentery, chronic Critically
Cultivation status – Not applied Uttarakhand, Sikkim, mucilage, phosphate, chloride and fever, leucorrhoea and also used in Unani medicine, Endangered
Fig. 2r Himachal Pradesh), Pakistan, glucoside-loroglossin and trace of volatile oil and ash Ayurvedic medicine preparation such as treatment for
Afghanistan, Nepal, Tibet and consisting major of potassium and lime [10–12] paralytic affection, seminal debility and general
Bhutan weakness in debilitated females after the delivery
period [10–12]
(6) Malaxis muscifera Malaxis muscifera Different types of alkaloids, flavonoids, glycosides, Used as an aphrodisiac to cure burning sensation, Vulnerable
Family – Orchidaceae is grow in temperate to phenols and sterols are bioactive compound present in dysentery, fever, febrifuge, internal and external
Part used – Underground parts sub-alpine region of Himachal Malaxis muscifera [12, 20] haemorrhage, seminal weakness, sterility etc [10–12,
Cultivation status – Not applied Pradesh, Uttarakhand at 20]
Fig. 2q 2400–3600 m asl
(continued)
Table 3 (continued)
About species Habitats Bio active compound Pharmaceutical properties and uses CS
(7) Podophyllum hexandrum Temperate, alpine, subalpine The rhizome contains phytochemical compounds, that Used as treatments for cancer, tumour, hepatic Endangered
Family-Podophyllaceae Himalayan regions from is, resin, podophyllin, podophyllotoxin, podophyllol, stimulant, cholagogue, purgative, vermifuge, control
Parts used – fruits and underground Afghanistan to South West querctin, kampferol, astragalin, essential oil, wax and watery stool and bitter tonic. Podophyllu pellatum is
parts China, Myanmar, and India mineral salt [12] American species, and it is used in
Cultivation status – Not applied (Jammu and Kashmir, electrohomeopathic medicine [8, 10–12]
Fig. 2t Uttarakhand, Sikkim,
Himachal Pradesh) grow at
2800–4000 m asl in a moist
shady area
(8) Paris polyphylla Temperate Himalayas Glucoside, Sedative, analgesic, Vulnerable
Family – Liliaceae from Uttarakhand, Shimla to alpha-paristyphnin, Steroids [14] haemostatic, anthelmintic rhizome of Paris polyphylla
Part used – Rhizome Bhutan and in Lushai and Aka contain medicinal properties antihelmintic,
Cultivation status – Not applied Hills antispasmodic, digestive stomachic, expectorant and
Fig. 2f vermifuge and also used as ethnomedicines, that is,
fever and food poisoning. Root paste is applied as an
antidote to snake bites and poisonous insect bites and
also to alleviate narcotic effects [10–12, 14]
(9) Rheum emodi Rheum emodi is grown in Anthraquinone (rhein, chrysophanol, aloe-­emodin, Rhizome and root of Rheum emodi contain medicinal Threatend
Family – Polygonaceae temperate and sub-­temperate emodin, physcion, and their glycosides) and stilbene properties such as anticancer, antioxidant, antidiabetic,
Cultivation status – Chamoli, in Kashmir, Uttarakhand, (picetannol, resveratrol and their glycosides) antifungal, antiulcer along with hepatoprotective and
Uttarkashi, Bageshwar, Sikkim at 2800–3000 m asl bioactive contain in underground parts [15] nephroprotective and also used as traditional systems
Pithoragarh, districts in the state of as laxative, tonic, diuretic and to treat fever, cough,
Uttarakhand indigestion, menstrual, gastrointestinal infections,
Fig. 2g respiratory infections, liver and skin infections
[11, 12, 15]
About species Habitats Bio active compound Pharmaceutical properties and uses CS
(10) Rheum moorcroftianum Rheum moorcroftianum grows Emodin and rutin, chrysophanol and chrysophenol Substitute of Rheum emodi R
Family – Polygonaceae in cold and dry desert alpine acid bioactive compounds in the rhizome part of
Cultivation status – Chamoli, places in Garhwal and Rheum moorcroftianum [11, 12]
Uttarkashi, Bageshwar, Kumaon Himalaya region at
Pithoragarh, districts in the state of 3000–5200 m asl
Uttarakhand
Fig. 2h
(11) Saussurea costus Kashmir, Himachal Pradesh Alkaloid, saussurine, sesquiterpene, resinoids, Root contains medicinal properties, such as Critically
Cultivation status – Pauri, and Uttarakhand in some and essential oil, alkaloid, inulin, saussurea lactone antispasmodic, expectorant, carminative, astringent, Endangered
Chamoli, Uttarkashi, Bageshwar, districts [11, 12] antiseptic. An ingredient of prescriptions for
Pithoragarh, districts in the state of dyspepsia, asthma, cough, chronic rheumatism, skin
Uttarakhand diseases. Applied locally to wounds and ulcerations
Fig. 2b [11, 12]
(12) Saussurea obvallata Uttarakhand, Kashmir to Saussurea obvallata is grow in alpine Roots contain medicinal properties antiseptic, styptic, Endangered
Family-Asteraceae Sikkim alpine and subalpine region of Himalaya (Kedarnath, Madhaymaheswar, and anti-inflammatory. Applied to wounds and cuts.
Parts used – Underground parts region of Himalaya at Hemkund) at 3600–4800 m asl Plant – hypothermic. – lower – CNS active, antiviral.
(Rhizome/Roots), Flowers are also 4000–4500 m The flowers, after frying, are used in rheumatism [11]
used for religious purposes
Cultivation status – Not applied
Fig. 2o
(13) Innula racemosa Innula racemosa is found in Inulin and sesquiterpene lactones, mainly Antispasmodic, stomachic, Endangered
Family – Compositae East Asia to Western alantolactone, isoalantolactone antihistaminic, expectorant, and anticatarrhal. Used
Part used – Underground parts Himalaya region at and their dihydro derivatives [11] for asthma, chronic bronchitis and pulmonary
(Rhizome/Roots) 2000–3200 m asl. Inula disorders [11]
Cultivation staus – Himachal grandiflora is found in
Pradesh (Lahu spiti) Uttarakhand Himalayan
Fig. 2a region (Tungnath, Uttarkashi)
and Inula racemosa is found
in Himachal Pradesh
(continued)
Table 3 (continued)
About species Habitats Bio active compound Pharmaceutical properties and uses CS
(14) Valeriana wallichii Valeriana wallichii is found in cyclopentapyrans, Antispasmodic, antitumor, antineoplastic, insomnia, Co
Family – Valerianaceae the temperate region of the acacetin-7-O-rutinosides, antianxiety, obesity, skin diseases, insanity, hysteria,
Parts used – Root/Rhizome Himalaya at 2000–2800 m asl valtrate, didrovaltrate, linarin cholera, muscle pain, carminative, etc [8, 12]
Cultivation status – Pauri, iso-valerinate, valepotriates and an iridoid, ester
Chamoli, Uttarkashi, Bageshwar, glycoside, valerosidatum [8, 12]
Pithoragarh, districts in the state of
Uttarakhand
Fig. 2e
(15) Nardostachys grandiflora Nardostachys grandiflora is d-nardostachone, valeranone and jatamansone as the Antiseptic, antispasmodic, aromatic, bitter, Critically
Family – Valerianaceae grown on moist rocks or major ketonic sesquiterpenes, Jatamansone [8, 10–12] deobstruent, Endamgered
Part used – Root/Rhizome stones in coarse sandy loame diuretic, emmenagogue, laxative, stomachic, tonic;
Cultivation status – Chamoli, and distributed of alpine, infusion given in chorea, epilepsy, hysteria,
Uttarkashi, Bageshwar, sub-alpine region of Himalaya palpitation of heart, fresh root used as an adjunct in
Pithoragarh, districts in the state of (Kashmir, Himachal Pradesh, the preparation of medicinal oils, as an important
Uttarakhand Uttarakhand) at 3200–3800 m ingredient in many useful Ayurvedic formulations;
Fig. 2p asl spikenard oil, hypotensive, having distinct depressant
action on central nervous system; promotes appetite
and digestion, growth and darkness of hair; useful in
leprosy and jaundice; tincture of rhizomes given for
intestinal colic and flatulence [8, 10–13, 15, 16]
(16) Bergiana ciliata Bergiana cilliata is distributed Bergenin, gallic acid, glucose, tannins, Vomiting, diarrhoea and Co
Family – Saxifragaceae in temperate to alpine region mucilage and wax; a C-glycoside and beta-sitosterol dysentery, indigestion, bile and liver disorders
Part uses – Rhizome Himalay at 2000–3400 m asl is present in the underground part of plants [8, 11, 12] Toxicity: Non-toxic [8, 11, 12]
Cultivation status – Not applied (Kashmir, Himachal Pradesh,
Fig. 2d Uttarakhand)
(17) Picrorhiza kurrooa Picrorhiza kurroa D-mannitol, kutkiol, kutkisterol, hepatic disorders; antipyretic; antiperiodic, effective in Endangered
Family – Plantaginaceae is distributed in the 4-hydroxy-3-methoxyacetophenone malaria. Stomachic is used in dyspepsia; in small
Part uses – Rhizome Himalayan region from (apocyanin); vanillic acid, cinnamoyl-a and doses, the powdered root acts as an anthelmintic and
Cultivation status – Chamoli, Kasmir to Sikkim at 6-cinnamoyl-D-glucopyranose; phenol glucosides; laxative; in large doses can be used for curing
Uttarkashi, Bageshwar, 3000–4000 m asl androsin and picein iridoid, glycosides; cathartic and dropsy. Combined with liquorice
Pithoragarh, districts in the state of 6-feruloylcatalpol, kutkin, kutkoside, picroside-I1, effective in heart diseases and hiccups. Used in
Uttarakhand III; minecoside, picrorhizin, veronicoside; scorpion sting [3, 6]
Fig. 2c cucurbitacin glycosides, arvenin III [8, 11–13, 15, 16]
About species Habitats Bio active compound Pharmaceutical properties and uses CS
(18) Swertia chirayita S. chirayita is found in the 1,3,8-tetrahyroxyxanthone, Antimicrobial, antidiabetic, skin disease, blood Critically
Cultivation status – Himachal Himalayas from Kashmir to 1,3,7,8-tetrahydroxyxanthone, 1,3,8-trihydroxy-5- purifier, fever [22] Endangered
Pradesh Bhutan has an altitude of methoxyxanthone, 1,5,8-trihydroxy-3-
Fig. 2l 1500–3000 m asl and is also methoxyxanthone,
found in the Khasi hills at an 1,8-dihydroxy-3,5-dimethoxyxanthone
altitude of 1200–1500 m asl (swercherin), 1,8-dihydroxy-3,7-dimethoxyxanthone
Chirayita can be cultivated at (7-o-methylswertanin), 1-hydroxy-3,5,8-
between 1200 and 2100 m asl trimethoxyxanthone,1-hydroxy-3,7,8-
trimethoxyxanthone,2,5-trihydroxyterephthalic acid
(aromatic
carboxylic acid), 21-α-H-hop-22(29)-en-3-β-ol
(triterpenoid), amarogentin, amaroswerin (Secoiridoid
glycoside), chiratanin (dimeric xanthone), chiratenol
(hopane – triterpenoid), chiratol (1,5-dihydroxy 3,8-
dimethoxyxanthone), decusstain (xanthone),
enicoflavine (xanthone), Episwertenol (Triterpenoid),
Erythroidiol (Hexane extract), Gammacer-16-en-β-ol
(Triterpenoid), Gentianine (Titerpenoid alkaloid),
Gentiocrucine (Triterpenoid alkaloid), Kairatenol
(Hexane extract), Lupeol (Triterpene alcohol),
Mangiferin
(Xanthone), Mangostin (Xanthone), Oleanolic acid
(Triterpenoid), Pichierenol (Swertane terpenoid),
Sweroside (Secoiridoid glycoside), Sweroside-2-o-
3,5-trihydroxy biphenyl-2”carboxylic acid ester
(Secoiridoid glycoside), Swerta-7,9(11)-dien-3-β-ol
(Swertane trepenoid), Swertanone (Triterpenoid),
Swertenol (Triterpenoid), Swertianin
(1,7,8-trihydroxy-3-methoxyxanthone), Syngaresinol
(Lignan), Taraxerol (Triterpenoid), Urosolic acid
(Triterpenoid), β-Amyrine (Triterpenoid alcohol), β-
Sitosterol-3-β-D-glucoside(Sterol), ϕ-Taraxasterol or
heterolupeol (Hexane extract) [22]
(continued)
Table 3 (continued)
About species Habitats Bio active compound Pharmaceutical properties and uses CS
(19) Swertia ciliata Himalayan Endemic, S. The whole plant contains a number of tetra- Decoction of plant is given three times a day for Common
Cultivation status – Not applied ciliata is found in Jammu and oxygenated and Penta-oxygenated 5–7 days to control cough, cold
Fig. 2m Kashmir, Himachal Xanthone. Amaroswerin, Amarogentin, and fever used as ethanomedicine. S. ciliata used as
Pradesh, Punjab, Uttarakhand, Xanthone –c – Glucoside (Mangiferin) were reported substitute for S. chirayita [22]
Meghalaya, Assam, Sikkim, from aerial
Nepal, Tibet, Afghanistan part of S. ciliata [22]
(20) Swertia speciosa S.speciosa is found in moist S. speciosa contains a new xanthone glycoside, two The roots of S. speciosa contain bioactive molecules Least
Cultivation status – Not applied alpine region of the Himalaya known xanthones and urosolic acid, Amaroswerin such as mangiferin, amaroswerin, amarogentin, Common
Fig. 2n from Kashmir to Arunachal (Bitter secoiridoid glucoside). Nine elements (Zn, Cu, bitterseco-iridiod-gluco-sides (amaroswerin),
Pradesh) at 3300–3600 m asl Mn, Fe, Co, Na, K, Ca and Li) [21, 22] xanthone–C-glucoside (mangiferin) and urosolic acid.
Chauhan et al. (2015) reported that the bioactive
compound of S. speciosa are used for its medicinal
properties such as hepato-protective, anti-hepatotoxic,
antimicrobial, anti-inflammatory, anti-carcinogenic,
anti-leprosy, hypo-glycemic, anti-malarial and
antitumor. The Monpa tribal people used the roots of
S. speciosa for curing cold, cough, fever and
dysentery, it has febrifuge, antipyretic nature and work
effectively against anorexia, can be used as substitute
of S. chirayita [21, 22]
a
Abbreviations Used: CS Current Status, C En Critically Endangered, En Endangered, Co Common, L Co Least Concern, R Rare, Vu Vulnerable
Conservation of RET Medicinal and Aromatic Plants, Their Traditional Medicines… 301

Fig. 2 (a) Inula racemosa, (b) Saussurea costus, (c) Picrorhiza kurroa, (d) Bergiana ciliata, (e)
Valeriana wallichii, (f) Paris polyphylla, (g) Rheum emodi, (h) Rheum moorcroftianum (i)
Aconitum violaceum, (j) Aconitum balfourii, (k) Aconitum heterophyllum, (l) Swertia chirayita
(m) Swertia ciliata, (n) Swertia speciosa, (o) Saussurea obvallata, (p) Nardostachys grandiflora,
(q) Malaxis muscifera, (r) Dactylorhiza hatagirea, (s) Angelica glauca, (t) Podophyllum
hexandrum
302 R. R. Kumar et al.

Fig. 2 (continued)
Conservation of RET Medicinal and Aromatic Plants, Their Traditional Medicines… 303

Fig. 2 (continued)
304 R. R. Kumar et al.

Fig. 2 (continued)

References

1. Gidey M, Asfaw Z, Woldu Z (2009) Medicinal plants of the meinit ethic group of Ethopia: an
ethnobotanical study. J Ethnopharmacol 5570:9
2. Dobhal P, Purohit VK, Chauhan J (2021) High frequency plant regeneration from fully mature
shoot portion of Nardostachys Grandiflora DC. Int J Conserv Sci 12:1053–1060
3. Purohit VK, Mengwal BS, Dobhal P, Chauhan J (2021) Cultivation of high altitude medicinal
and aromatic plants: a key for sustainable development and bioresource conservation in Higher
Himalayan Region (HHR) of Uttarakhand, India. Ed. Deb CR, Paul A. Mittal Publications
Daryaganj, New Delhi, pp 51–73
4. Natesh S (2000) Biotechnology in the conservation of medicinal and aromatic plants. In:
Chandha KL, Ravindran PN, Sajiram L (eds) Biotechnology in horticultural and plantation
crops. Malhotra Publishing House, New Delhi, pp 548–559
5. Rajasekharan PE, Ganeshan S (2002) Conservation of medicinal plant biodiversity in Indian
perspective. J Med Aromat Plant Sci 24:132–147
6. Ministry of AYUSH, CCRS, Government of India, New Delhi (2019) ISBN -978-81-937426-3-1
7. Kundu D (2019) The OD force. Int J Herb Plant Med 3:55. https://doi.org/10.5580/
IJHPM.54807
8. Pandey S, Pandey PS, Mohanty D (2019) Electrohomeopathy: a revolutionary system of plats
medicine. European J Biomed Pharm Sci 6:301–305
9. Parkash R (2015) Medicinal plants used by tribal communities: a study of Uttarakhand
Himalaya region. Int J Humunit Soc Sci Invit 4:55–61
10. Samant SS, Nandi KS (2009) Conservation status and cultivation of selected medicinal plants
in the Indian Himalayan region. In: Advances in agriculture environment and health. Satish
Serial Publication House, Azadpur
11. Khare CP (2007) Indian medicinal plants. In: An ilustrated dictionary, Springer-Verlag, Berlin/
Heidelberg, ISBN 978–0–387-70637-5
12. Nautiyal MC, Nautiyal BP (2004) Agrotechniques for high altitude medicinal and aromatic
plants. Bishen singh Mahendra pal singh, Publisher and Distributors of scientific books, ISBN:
81-211-0338-X
13. Chadha KL, Ravindran PN, Sahajram L, Natesh S (2000) Biotechnology in the conservation of
medicinal and aromatic plants. In: Chadha KL, Ravindran PN, Sahajram L (eds) Biotechnology
in horticulture and plantation crops. Malhotra Publishing House, New Delhi, pp 548–561
14. Madhu KS, Phoboo S, Jha KP (2010) Ecological study of Paris polyphylla ecological society
Nepal. Ecoprint 17:87–93
Conservation of RET Medicinal and Aromatic Plants, Their Traditional Medicines… 305

15. Malik AM, Bhatt AS, Fatima B, Ahmad BS, Sidiqui S, Shrivastava P (2016) Rheum emodi as
valuable medicinal plant. Int Acad Sci Eng Technol 5:35–44
16. Shyaula LS (2011) Phytochemicals, traditional uses and processing of Aconitum species in
Nepal. Nepal J Sci Technol 12:171–178
17. Pelletier SW, Aneja R, Gopinath KW (1968) The alkaloids of Aconitum heterophyllum wall:
isolation and characterization. Phytochemistry 7:625–635
18. Pelletier SW, Ateya AM, Finer-Moore J, Mody NV, Schramm LC (1982) Atisenol, a new enta-
tisene diterpenoid lactone from Aconitum heterophyllum. J Nat Prod 45:779–781
19. Aneja R, Locke DM, Pelletier SW (1973) The diterpene alkaloids: the structure and stereo-
chemistry of heteratisine. Tetrahedron 29:3297–3308
20. Kant R (2015) Survival threats and conservation of Malaxis muscifera (Lindl). Kuntze, a
threatened medicinal Orchid at Fagu, Himachal Pradesh. IJBASA 1:20
21. Chauhan SR, Dutt P (2015) Swertia speciosa wall: a new source of amaroswerin. Med
Plants 7:2
22. Kumar RR, Chandola V, Chauhan J, Prasad P, Purohit VK (2009) Medicinal importance of
Swertia speciosa. Wall.ex.D.Don. J Emerg Technol Innov Res 6:6
Traditional Amchi Medicinal Practice
in Trans-Himalaya of Nepal: Conservation
and Bioprospecting

Neva Chaudhary, Suresh K. Ghimire, and Ram P. Chaudhary

1 Introduction

Traditional medicines comprise ancient and culture-bound health practices that

existed before the application of science to health care in modern allopathic medi-
cine. Sowa Rigpa (gso ba rig pa), also referred to as “Amchi System of Medicine,”
“traditional Tibetan Medicine,” or “Himalayan Medicine” is an ancient synthesis of
arts of health care that is practiced traditionally in a wide region of South and
Central Asia. The practitioners of Sowa Rigpa are known as amchi. This medical
tradition, originated with influences mainly from traditional Chinese medicine and
Ayurveda, was established during the seventh to twelfth centuries A.D [1, 2].
However, the fundamental core text, known as the “Four Treatises” or “Four Tantra,”
upon which Sowa Rigpa is based, has both Bön (bum bzhi) and Buddhist (rgyud
bzhi) versions, and these texts were written as early as the third or fourth century
A.D. [3]. According to the Tibetan world view, this medicinal knowledge was
passed on by Shakyamuni Buddha himself [1].
Amchi Medicine (or Sowa Rigpa) is a holistic approach that explores the inter-
connectedness of the mind and body and involves the harmonious operation and
balance of all the energies that constitute the human psychophysical being [4]. It
uses a diverse array of biological resources and minerals for compounding

N. Chaudhary (*)
Central Department of Botany, Tribhuvan University, Kirtipur, Kathmandu, Nepal
Resources Himalaya Foundation, Sanepa, Lalitpur, Nepal
S. K. Ghimire
Central Department of Botany, Tribhuvan University, Kirtipur, Kathmandu, Nepal
R. P. Chaudhary
Research Centre for Applied Science and Technology (ReCAST), Tribhuvan University,
Kirtipur, Kathmandu, Nepal

© The Author(s), under exclusive license to Springer Nature 307

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_11
308 N. Chaudhary et al.

medications [5]. This system of medicine plays a pivotal role in health care in many
remote villages in the Himalaya. In addition, it also emphasizes water and spring
cleanliness, a good diet, and a healthy way of living [6].
The highlands of the Himalaya, the Tibetan mountain range, and its adjoining
areas are among the few remaining areas where the Amchi system of medicine
(Sowa Rigpa) remains effective [7]. This medicinal practice is extended northwards
to Mongolia and beyond, eastwards to Sichuan and Yunnan, westwards to Ladakh,
and Himachal Pradesh (north-western India) and a few parts of the former Soviet
Union, and southern regions to Nepal trans-Himalaya [1, 6]. It is the most legitimate
and popular medical system in the mountainous areas of Nepal adjoining the Tibetan
Plateau [2]. However, amchi in the Himalaya are now facing several challenges,
mostly related to the unavailability and increased cost of ingredients used in com-
pounding medications, financial constraints, lack of formal state recognition, and
loss of traditional knowledge [3, 8]. Especially, India, Nepal, and China have been
facing the loss of traditional knowledge along with the loss of species [1, 9–12].
Overexploitation of medicinal plants in response to the commercial demand from
natural product industries in the region and beyond has increased the risk of extinc-
tion of many valuable species [13]. Therefore, critical systematic review and
research is necessary on the traditional amchi practice and the status of medicinal
species. The objective of the review is to discuss about the amchi’s medicinal prac-
tice and the major issues related to this system in the trans-Himalaya of Nepal.
For a systematic review, we searched accessible literature related to Sowa Rigpa.
We used “Google Scholar” for the web-based search using keyword combinations
“Nepal,” “India,” “China,” “Tibet,” “Myanmar,” “Bhutan,” “Ladakh,” “Himachal
Pradesh,” “Himalaya,” “Trans-Himalaya;” and “amchi,” “Sowa Rigpa,” “Tibetan
traditional medicine.” A total of 92 literature were retrieved but most of them
described the use of plant species, where 12 of the literature were not able to
be downloaded. We downloaded 47 related articles and reports through the initial
screening. In addition, we used our own experience and observation while conduct-
ing field work in different parts of Nepal.

2 Amchis Medicinal Practice

Traditionally, amchi’s knowledge and practice have been passed down within a fam-
ily as a lineage-based tradition or from teacher to disciples under the guru–shisya
tradition. Most of the amchi in Nepal (mainly those in Dolpa and Mustang Districts)
are the sixth generation of an unbroken family lineage [3]. Medical knowledge is
also taught in the monastery as part of religious training. Some amchis in Nepal
have also obtained higher Sowa Rigpa degrees from formal Tibetan medical schools
in India or Tibetan Autonomous Region of China. Normally, amchis begin to treat
patients after at least five to seven years of study and practice as an assistant. Most
amchis in Nepal, except those in urban areas, provide health care services almost free
of cost.
Traditional Amchi Medicinal Practice in Trans-Himalaya of Nepal: Conservation… 309

According to Sowa Rigpa philosophy, a healthy mind and a healthy body are con-
nected, and health or illness is related to our relationship to attachment, anger, and
ignorance. Wind (rlung), bile (mkhris pa), and phlegm (bad kan) are the three dynam-
ics (humors), the imbalance of which leads to illness. In addition, earth, water, fire,
air, and space/consciousness are the five elements that help to regulate our health.
Amchis perform their diagnosis of disease by examining a person’s overall physical
condition. The following are the common approaches used for disease diagnosis [2,
3, 10, 14]: interviewing, visual examination, pulse analysis (tactile test), and urine
examination. First, the patient’s medical and social history, diet, and behavior are
carefully considered to find out the causative factor, the site of illness, and the signs
and symptoms. Then, patient’s physical characteristics and complexion of five sen-
sory organs (eyes, ears, nose, tongue, and skin) are visually examined. Pulse exami-
nation is the most important component of diagnosis, which involves the analysis of
the relationships between the three dynamics (wind, bile, and phlegm), the five ele-
ments and the seven bodily constituents. The other areas of concern include body
temperature and inflammations. Finally, a thorough examination of urine is done,
which includes the use of sight, smell, taste, and touch. Pulse analysis and urine
examination form the most distinctive and important parts of diagnosis.
Amchis apply a variety of approaches for the treatment of illnesses [2, 3, 10, 14];
the most important ones are diet, modification of behaviors, use of herbal medi-
cines, and physical therapy. In Sowa Rigpa, the first recommendation for the treat-
ment of disease constitutes diet and behavior practices. The behavioral approach
focuses on routine, seasonal, and incidental behaviors. When the diet and routine
behavior are not effective in relieving the disease conditions, then medicines as well
as physical therapy are prescribed. The medicines are prepared from natural
resources, including plants, minerals, and animal-derived products and adminis-
tered in different forms such as decoctions, pills, powder, gruel (thin porridge),
medicinal butter, medicinal calx (ash powder), concentrated extractions, medicinal
incense, medicinal wine, or other formulas. Apart from prescribing natural drugs,
the physicians may apply other therapeutic techniques such as massages, hot and
cold compresses, mineral spring bath therapy, medicinal baths, golden needle ther-
apy, bloodletting, and moxibustion (heat therapy by burning the leaves of moxa
herbs, which include several species of Artemisia, Ajania, Anaphalis, and
Leontopodium). Generally, surgery is no longer practiced by amchi; some minor
operations are done including the draining of abscesses.

3 Issues of Amchis Medicinal Practice in Nepal Himalaya

Amchis have been serving local communities in the remote mountainous areas of
Nepal since ancient times. Even today, in many of the remote high-altitude areas,
Amchi medicine is the only form of health-care service available. The modern allo-
pathic medicine with its less formal infrastructure has brought few benefits or is
virtually non-existent in most of the remote mountainous areas of Nepal. Therefore,
310 N. Chaudhary et al.

in such areas, amchi’s service has been indispensable for maintaining people’s
health. In addition to the health care services, the contribution of amchi from the
Himalayan region of Nepal and particularly those from Dolpo (present-day Dolpa
District) for the advancement of Sowa Rigpa theory and practice has been well
known [3, 15]. Now, this practice is under threat in Nepal as it faces several chal-
lenges of socio-political, economic, and ecological in nature, mostly related to the
lack of formal recognition, and inappropriate support from the governmental and
non-governmental sectors, loss of traditional knowledge, loss of biodiversity and
unavailability and increased cost of the ingredients, and lack of a mechanism for
sharing and integrating amchi’s knowledge and practices [2, 3].
In most of the Asian countries, including Bhutan, China, India, and Mongolia,
where Sowa Rigpa is practiced, this system has been recognized officially. In
Bhutan, Sowa Rigpa has been officially recognized as a Bhutanese Traditional
Medicine and it has been integrated in the state healthcare system. In India, it was
officially recognized as an Indian System of Medicine. In Nepal, despite more than
20 years of effort from the amchi community, Sowa Rigpa still lack full support and
recognition from the Government of Nepal [3]. Recently, the Public Health Service
Act, 2075 (2018), of the Government of Nepal has just listed Sowa Rigpa under the
alternative medicine but does not provide sufficient space to recognize it as a Nepali
System of Medicine. In order to help protect the traditional knowledge and practice
of amchi and provide efficient health services for remote high-altitude communi-
ties, Sowa Rigpa need full official recognition, and the profession of amchi should
be properly institutionalized with a full certification and registration system. Sowa
Rigpa should be supported through universities, hospitals, pharmacies, and depart-
ments within health and education ministries of the Government of Nepal [3].
In the trans-Himalaya of Nepal, amchis pass on their knowledge and skills
mostly from father to son/daughter or apprentices. However, only a few persons
take interest in Amchi medicine. Since amchi’s knowledge and profession are
declining, the standard of health care in the region is likely to suffer. The loss of
amchi’s knowledge can be attributed mostly to the lack of access to resources, lack
of infrastructure, and human resources and monetary problems. The traditional way
of collecting herbs for the preparation of medicines is labor-intensive and difficult
due to the migration of skilled human resources to the cities [3].
The most important challenge to sustain this practice in the remote trans-­
Himalayan region of Nepal is the unavailability and increased cost of several ingre-
dients traditionally being used in compounding medication [3]. Many amchi feel
difficulty in acquiring their full skills due to declining population or lack of proper
medicinal plants. Recent study by Ghimire et al. [3] has shown that amchi in Nepal
utilize ingredients from over 570 species of plants and 54 different types of minerals
(extracted from stones, gems, precious metals, and soil) for compounding medica-
tions. Of the plant-based medicines, over 100 species are locally rare, including
about 40 species which are either threatened and included in IUCN Red List or are
regulated by CITES. These also include medicinal plant species legally protected by
the Government of Nepal but are of great significance for the traditional Amchi
medicinal practice. Commercial overharvesting has been identified as the main
Traditional Amchi Medicinal Practice in Trans-Himalaya of Nepal: Conservation… 311

threat for the viability of medicinal plant populations in the high Himalaya of Nepal,
although habitat destruction, fragmentation and loss are also important. Harvesting
of plants for traditional use by amchi themselves does not necessarily pose a serious
ecological threat as they need very small quantity, usually 0.1–8 kg per amchi per
year (depending on the species and types of formulations) in the Nepal’s trans-­
Himalaya [3], and they use unique cultural criteria for the selection of medicinal
plants and apply harvesting methods, following the guidelines indicated in the stan-
dard Sowa Rigpa texts, which are often evaluated as sustainable [3, 15, 16].
Commercial harvesting has imposed extreme pressures on the populations of sev-
eral valuable species including Aconitum spp., Ophiocordyceps sinensis,
Neopicrorhiza scrophulariiflora, Dactylorhiza hatagirea, Nardostachys jatamansi,
Fritillaria cirrhosa, Valeriana spp., Dendrobium spp., so that these are no longer
available to most of the trans-Himalayan amchis.
In addition, ingredients from several exotic plant species (26 of such species)
have been documented recently [3], including Aquilaria malaccensis, A. sinensis,
Aucklandia costus, Commiphora wightii, and Pterocarpus santalinus, highly needed
for Amchi Medicine are now not easily available as these are threatened and included
under IUCN Red List or regulated by CITES. Price has dramatically increased for
such plant-based ingredients, which most amchi are unable to pay given their very
low annual income. The professional ethics of amchi is based on Buddhist and Bon
concepts of universal compassion and do not allow them to charge their patients
fees for their service. But in the present context, amchi cannot afford to purchase
plants and other products from the lowlands [3, 15]. Only a few amchi can place an
order and get sufficient plant materials and products supplied, whereas the majority
do visit the lowlands to sell medicinal herbs collected in their localities during win-
ter and to buy materials for ingredients. Similarly, most of the amchi also cannot
afford to purchase expensive minerals, precious metals, and gems due to high price.
Earlier, amchi also used wildlife parts such as musk pod, gall bladder of the
Himalayan black bear, rhino horn, etc., to prepare quality medicine; however, these
are endangered species and the GoN has put a ban on poaching of endangered wild
animals. Therefore, most learned amchis in Nepal practice plant- or mineral-based
substitute of animal parts [3].
Despite recent efforts in documenting amchis knowledge and practices from
trans-Himalayan region of Nepal, there is still a need to assess the availability and
ecological status of species used in Sowa Rigpa. Particularly, the use of rare and
threatened species in medicine has posed ethical and environmental challenges to
amchi. Therefore, eminent amchis have identified locally available common plants
and minerals as possible substitutes for rare and threatened plant and animal parts
used in the preparation of medicine [3, 15].
Thousands of substances are recorded as medicinal in Sowa Rigpa practiced in
Asia [17], and there are regional and local variations in the selection of these
resources. In many cases, the use of enormous resources is yet uncertain. There is
also a lack of mechanism for integrating knowledge and practices covering amchis
from all over Nepal and neighboring countries.
312 N. Chaudhary et al.

In several instances, misidentification of Tibetan plant names remained a great

challenge. Authentication of Tibetan names with botanical names is one important
step forward to conserve knowledge about traditional medicinal practices. Molvray
[17] considers that the identification of many plants referred to in the extensive
Tibetan medical literature or mentioned by Tibetan doctors and local informants
will now be difficult due to the inaccessibility and geographical bias of the extant
translations. Readers do not obtain proper information about the localities. However,
the list of medicinal plants used in Sowa Rigpa practiced in Nepal published by
WWF-Nepal provides authentic botanical names, Tibetan names and descriptions
of Tibetan medicinal plants in both the Nepali and Tibetan languages [3, 15]. Dawa
et al. [1], together with the Medical College of the Mentsi Khang in Dharamsala,
India, and the further help of Amchi Tsewang Smenla (Ladakh) and Amchi Sonam
Namgyal (Jharkot, Mustang) have extended the scope of Tibetan medicinal plants
by including correct nomenclature in a comprehensive manner in the book Tibetan
Medicinal Plants. Amchis believed that for the identification of Himalayan medici-
nal plants extensive experience is always needed [18].
Finally, proper policy and legal mechanisms provide a sound base for bio-
prospecting. The threat to biological resources in Nepal has, in the past, been due to
a lack of appropriate policies to guide the legal, institutional, and operational devel-
opment of this sector. Biodiversity policy in Nepal in the past has been shaped by
political and economic motives rather than social and ecological considerations [19].

4 Revitalizing Traditional Amchi Medicinal System

The Amchi medicinal system is suffering because it is based on a strong sense of

communal belief, which is now declining. In the last two decades, things have dra-
matically changed due to globalization. In the rural communities amchis hold strong
social status as a medical doctor and community leaders [20]; however, the amchi
medicinal practice has not been given the proper means to flourish alongside the
Western medical system in these impoverished areas. The intention behind intro-
ducing Western medicine in these areas may be worthy, but the result has been a
marginalization of the holistic skills which such communities used to depend upon.
As a result, the traditional skills of amchi have begun to disappear. Further, a very
few amchi get opportunities to acquire scholar training from formal institutions
[20]. Attempts are being made to revitalize the traditional Amchi medicinal practice
through increased support from the WWF Nepal, People and Plants Initiative,
DROPKA Foundation, the Japan Foundation Asia Centre, the Remote Area
Development Committee (RADC), HimalAsia Foundation, and Himalayan Amchi
Association (HAA) of Nepal. The HAA have been doing research on documenting
the Sowa Rigpa practice in Nepal and providing training on sustainable harvesting
practices of medicinal herbs from the wild (Box 1).
Traditional Amchi Medicinal Practice in Trans-Himalaya of Nepal: Conservation… 313

Box 1: Himalayan Amchi Association

The Himalayan Amchi Association (HAA) was formed in 1998 as an NGO
based in Kathmandu, Nepal, and comprises more than 200 amchi members
from across Nepal. HAA is dedicated to the preservation and development of
Sowa Rigpa (Amchi Medicine) and medicinal plants in Nepal. HAA’s long-­
term vision is to improve the quality and standard of amchi as professionals
and to obtain formal recognition from the Government of Nepal. The associa-
tion program goals include (i) improving the quality of medical care in remote
areas; (ii) conducting training programs on Sowa Rigpa and valuable
Himalayan medicinal resources, including their cultivation and sustainable
harvesting; (iii) creating educational opportunities for amchis through devel-
oping and establishing standard curriculum for existing amchi schools and
Sowa Rigpa curriculum for college level education in Nepal; (iv) conducting
research for cultivation and sustainable harvesting of medicinal herbs; and (v)
establishing networking with individuals and organizations in Asia and
the West.
Source: Sherpa et al. [2] and Lama et al. [15].

5 The Cultural Construction of Efficacy

The selection of plant species for medicine is guided by cultural practice, which is
directly related to the question of efficacy.
(i) Compound medicine Traditional Amchi medicinal practice is frequently com-
posed of more than one constituent. Compound medicines can be pharmacologi-
cally different from their individual plant constituents. In plant combinations, the
activities of two or more plants may add to increase efficacy such as (i) the action of
one constituent may be potentiated by another so that the effect is greater than the
additives themselves; (ii) one constituent may diminish the activity of another
through antagonistic interaction; or (iii) the effect may be synergistic, when one
constituent substantially amplifies the activity of another [21]. For example, plants
used as common additives, such as black pepper (Piper nigrum), long pepper (Piper
longum), and ginger (Zingiber officinalis), potentiate the action of additional plants
in the medicine by markedly increasing the bioactivity of their active constituents
[22]. The association of plants may diminish the toxicity of their individual con-
stituents (such as tannins and saponins) [23]. The Amchis in Dolpo use Nepal aco-
nite (Aconitum spicatum), a highly poisonous plant, for treating coughs, bile fever,
pulmonary and intestinal infections, headaches, cuts and wounds after detoxifying
the root tuber by boiling it with an extract of Terminalia chebula [15]. Amchis also
purchase medicinal plant resources from the lowlands Tarai that include
Cinnamomum zeylanicum, Phyllanthus emblica, Santalum album, Terminalia bel-
lirica, and Terminalia chebula, and these are mixed to make drugs with locally
314 N. Chaudhary et al.

available plants. In Nepal, the medicinal plants that are being used in treating
­common ailments and diseases need authentication and standardization of efficacy
and dosage with the help of pharmacognostic analyses in the laboratory so as to
encourage the indigenous peoples’ and local communities (IPLCs) to continue to
use the effective medicinal plants and discourage the use of ineffective and poten-
tially harmful ones.

(ii) Harvesting sustainability Amchis usually begin their studies early in their
teenage years. Apart from learning the diagnosis of illnesses/diseases and therapeu-
tic measures, they are trained to identify the high-altitude plants in their natural
setting during summer, and low-altitude plants during winter. In addition, they also
learn the related aspects of biology, distribution, habitat, density and local availabil-
ity, as well as sustainable harvesting and cultivation practices. Amchis possess an
in-depth knowledge of how to harvest plants at the proper stage for better medicinal
efficacy and sustainability. In the trans-Himalayas, such as upper part of Manang
District, harvesting is managed culturally, with the head lama restricting the har-
vesting of both fodder grass and important medicinal plants to a specific period
(September–October) just before crop harvesting begins, so that annual and biennial
plants can complete their full life cycle [24].

6 Threat to Medicinal Plants

The amchis possess in-depth knowledge about the ecology and economy of plant
species and are quite familiar with which species are becoming difficult to find, due
to either limited geographical distribution or habitat destruction or overexploitation.
They have a practical interest in the conservation of medicinal plants, which is valu-
able for developing management guidelines for plant conservation, as bulk of
medicinal resources is derived from plants (Box 2).

Box 2: The Kunphen Mentsi Khang, West Nepal

The Kunphen Mentsi Khang (House of Medicine and Astrology), established
in 2000, is supported by WWF/Nepal at Polam (Dolpa), the park headquarters
of Shey Phoksundo National Park, and is run by local amchi. The Lo Kunphen
Mentsi Khang in Lo Manthang was constructed in 1997/8 with the initial sup-
port of HimalAsia Foundation. These clinics are notable examples of medical
care centers using local resources to prepare drugs and providing health care
to both the local communities and visitors/tourists. Over 100 species of plants
collected locally along with some plant materials obtained from the lowland
Tarai are being used by amchi. Bioassay tests have been established to vali-
date herbal medicines, enhance an understanding of the etiology of illness and
compile knowledge for use in ethical collaboration. This initiative is an exam-
ple of a demonstration project that promotes the transfer of information on the
sustainable use of natural resources.
Source: Chaudhary [25] and Lama et al. [15].
Traditional Amchi Medicinal Practice in Trans-Himalaya of Nepal: Conservation… 315

The trade in medicinal plants from Nepal to Tibet dates back to the eighth century
(728 CE/AD) and constitutes a considerable part of Tibetan medicine’s materia
medica [26]. Some vulnerable plant species that are carefully collected by the amchi
in Nepal for traditional medicinal practice include Aconitum naviculare (bongkar),
Aconitum spicatum (bongnak), Arnebia benthamii (muktsi), Corallodiscus lanugi-
nosus, Cypripedium himalaicum (dakya habo), Dactylorhiza hatagirea (wanglag),
Halenia elliptica (tikta), Meconopsis grandis (upal ngon po), Meconopsis horridula
(ajaktsergun), Nardostachys grandiflora (pangpoe), Neopicrorhiza scrophulariiflora
(honglen), Rheum australe (churtsa), and Valeriana jatamansii (nahpoe) [15].
In general, the collection of medicinal plants for traditional local use is not a
problem, since this use has usually developed gradually, and in harmony with nearby
natural ecosystems. However, when selected species are gathered in large quantities
and supplied to meet increasing demand of national and international trade, then
pressure can quickly mount and cases of overexploitation are common [27].
It is obvious that medicinal plant species collected for commercial purposes rep-
resent the most popular and often most effective herbal remedies. The majority of
species that were popular in the past are still popular today. It is interesting to note
that the widespread commercial harvesting and sale of the same plants have been
going on for a long time in Nepal [28]. Commercial collectors of medicinal plants
are those people whose main aim is not resource management but earning money.
To obtain a clear view of the relationship between people and their natural environ-
ment and to suggest sustainable options, it is necessary to gather data, such as the
type, source, and quantity of the resources used, their importance within the cultural
context and alternatives if the resource is scarce and needs to be conserved for the
preservation of genetic diversity [29]. The knowledge possessed by the Dolpo
Amchis relating to the use and management of medicinal plants will contribute
towards devising appropriate systems for sustainable harvesting, which may ulti-
mately be transferred to commercial collectors who tend to overexploit the resources.
In trans-Himalaya (Dolpo, Mustang and Manang), amchis and women have a keen
interest in the conservation and management of medicinal plants [15, 30]. In terms
of conservation, climate change possess significant challenges for highly traded pri-
oritized medicinal plants [31]. It is experiencing the alternation of the habitat, dis-
tribution, ecology, and phenology of the medicinal plants in the Himalaya. As a
result, there is an adverse effect on medicinal plants, and some of the species may
get extinct too. These changes are likely to have negative consequences on the vul-
nerable population across the Himalaya [32].

7 Conservation Approach

Conservationists are much concerned about the protection of Amchi’s medicinal

practice and knowledge associated with it, and biological resources used by them.
Some important issues are as follows.
316 N. Chaudhary et al.

(i) Education Educational program for the young generation is an important way
of practicing medicinal practice. Supporting programs encourage children to study
the local uses of plants. This approach would ensure that the ancient lore of the
Himalayan plants will be protected within the communities and customary institu-
tions. This will raise awareness among the people that conservation education can
be a powerful means of preserving both their culture and nature [33]. In the educa-
tional program, attention should be given for the diversity of in-depth knowledge
within and cultural groups for the resource management and developing scientific
understanding of the ecological status of key resources [16].

(ii) Storage of medicinal plants Medicinal plants and their voucher specimens
(herbarium specimens) stored in the community center or school provide local peo-
ple with a permanent record of the useful species documented in the course of sus-
tainable use and conservation. It is important that the materials are stored in tightly
sealed cabinets protected from humidity and insects since the biological activity of
plant materials ceases after a few years of storage. An antibacterial and antifungal
study of a total of 19 medicinal plants in Nepal was conducted by Griggs et al. [34]
showing that after six years of storage, 3 ceased all activity, 6 retained all activity,
and the remaining 10 plants retained only partial activity. This type of study is
extremely important for assessing the “self-life” of herbal medicines which are
being utilized by the communities, herbal practitioners and amchi in Nepal and
provides a reason to test the efficacy of stored medicinal plants used by Amchis and
pharmaceutical companies.

(iii) Nature tourism In the Himalaya, nature tourism is based on spectacular land-
scapes, and rich and unique biodiversity combining with the context of a specific
cultural heritage – all interacted in sustainable manner. Nature tourism in Nepal is
largely confined to the activities of mountaineering and hiking, so that a sustainable
nature tourism that focuses on natural history, customary practices and culture is yet
to be explored and established [35].
Ethnoecologists can play a key role in designing interpretive programs for tour-
ists or other visitors that enhance the conservation of traditional ecological knowl-
edge. Naturalists in Kinabalu Park (a 735 km2 protected area in Sabah, Malaysia)
have been training local Dusum guides who are knowledgeable about the plants and
animals and speak Western and local languages. The bilingual Dusum guides
accompany the tourists, explaining the use of plants such as rattan palms and other
forest products both in the natural history museum located at the park headquarters,
and along the summit trails [33]. The prospects for such a program in the Himalaya
have yet to be adequately explored, strengthened, and popularized.
Traditional Amchi Medicinal Practice in Trans-Himalaya of Nepal: Conservation… 317

8 Bioprospecting

An important aspect of biodiversity prospecting or bioprospecting is the explora-

tion, extraction and screening of biodiversity of commercially valuable biochemi-
cals [36], and socially valuable genetic resources; and their associated indigenous
knowledge. Bioprospecting provides political, economic, and cultural values to
ensure the long-term conservation of natural biodiversity in countries rich in bio-
logical and cultural diversity.
Even today, biological resources are being collected around the world in order to
develop modern medicines and other products. Agents and collaborators of pharma-
ceutical companies obtain samples of plants and other evidence of biodiversity and
undertake research on local and traditional knowledge of medicinal plants. Due to
technological and other developments, many see today’s biodiversity as “green
gold” [37]. Today this activity is called bioprospecting. But, it is called biopiracy
when misappropriation of indigenous knowledge and biological resources
takes place.
People have been undertaking bioprospecting since the dawn of civilization.
Biodiversity prospecting does not always involve the use of indigenous knowledge.
However, it is clear that valuable chemical compounds derived from plants, animals,
and microorganisms are more easily identified and proved to be of greatest com-
mercial value when research is conducted based on the basis of indigenous knowl-
edge and/or found in territories traditionally inhabited by IPLCs [38].
(i) Ethical collaboration The biggest challenges in biodiversity prospecting from
the Nepalese perspective have remained not only to make a comprehensive inven-
tory and database of biodiversity and associated knowledge to ensure long-term
conservation, but also to address the social, economic, and political issues in an
integrated approach. The priority areas of biodiversity prospecting have not been
well identified by researchers, planners, and policy makers for the development of
the country. The conservation projects and aid for Nepal have, so far, not been fully
successful in conserving the biodiversity due to the lack of meaningful involvement
of IPLCs and utilization of their knowledge [39, 40].
The blending of indigenous knowledge with science and technology is a strategy
for bioprospecting; however, a gap exists in infrastructure, particularly in develop-
ing countries. Nepal’s position for bioprospecting is weakened by the lack of strong
research-based infrastructures. Establishing ethically motivated international col-
laboration for strengthening biodiversity prospecting will also require foreign
investment. Equally important from industry’s perspective is that most foreign com-
panies would prefer to work with institutions than individuals, under a stable politi-
cal and economic condition. But, there is a lack of clarity within biodiversity-related
national legislation in terms of biodiversity prospecting, technology transfer, access
to genetic resources, fair and equitable sharing of benefits, intellectual property
rights regimes and other incentives, and this may reduce the flow of foreign invest-
ment in Nepal [25, 39, 41].
318 N. Chaudhary et al.

(ii) Searching plants for new medicine One of the crucial questions is how we
should begin the search for new medicines with the vast number of plants to be
studied. Cox and Balick [42] have discussed three approaches. The first approach is
random screening; one can simply screen everything that can be collected in quan-
tity, the so-called mass or blind screening approach. Obviously, such a strategy
requires investment of time and money. The discovery of taxol from Taxus brevifo-
lia (the Pacific yew tree) is an example of a random-screening program conducted
by the National Cancer Institute (NCI). A second approach is the chemotaxonomy-­
oriented approach, which is more guided in that it screens those species that belong
to certain families or genera and are likely to contain certain classes of natural
compounds, such as alkaloids, steroids, terpenoids, and amino acids. A realistic
ethnopharmacological approach selects those plants which are being used for rem-
edies/medicines by the indigenous peoples and local communities for further study.
This approach calls for the exploration of biologically active agents, traditionally
employed or observed by traditional healers and indigenous communities.
A number of essential drugs used in allopathic medical practice are derived from
plants, and have been developed based on indigenous knowledge; a few examples
include aspirin from Filipendula ulmaria, codeine from Papaver somniferum, ipe-
cac from Psychotria ipecacuanha, pilocarpine from Pilocarpus jaborandi, pseudo-
ephedrine from Ephedra sinica, quinine from Cinchona pubescens, reserpine from
Rauvolfia serpentina, scopolamine from Datura stramonium, theophylline from
Camellia sinensis, and vinblastine from Catharanthus roseus [42].
Only 1.5% (about 4000 species) of the flowering plants of the world have been
screened for pharmaceutical compounds; and of this number, 3% currently provide
major drugs. Lower groups of plants, animals and microorganisms remain neglected
[43]. Some promising taxa that have yielded chemicals for major drug development
include Aesculus hippocastanum (horse chestnut), Fraxinus rhynchophylla, Camellia
sinensis (tea), Ephedra sinica (ma-hang), Podophyllum peltatum (may apple),
Hyoscyamus niger (henbane), Rhododendron molle (yellow azalea), Artemisia mari-
tima (levant wormseed), Corydalis ambigua (birthwort), Thymus vulgaris (common
thyme), Valeriana officinale (valerine), Justicia adhatoda (malabar nut), Daphne gen-
kwa (pinyin; yuan hua). These taxa indicated a positive correlation between tradi-
tional medical use of the plant and the current therapeutic use of the chemical extracted
from the plant [43]. The other species of the above genera found in the Himalayan
region could provide valuable information under the chemotaxonomy-­ oriented
approach, while the knowledge of the Amchis and indigenous peoples and local com-
munities in the Himalaya lend themselves to the ethnopharmacology approach.

9 Enabling Environment and Intellectual Property

Rights (IPRs)

The importance of and global commitment towards the conservation of biodiversity

and accessing genetic resources and sharing of benefits has been assured following
the United Nations Conference on Environment and Development adopted in 1992,
Traditional Amchi Medicinal Practice in Trans-Himalaya of Nepal: Conservation… 319

and the Nagoya Protocol on “access to genetic resources and fair and equitable shar-
ing of benefits arising from their utilization” adopted in 2010 [44]; however, there is
a continuing controversy over the impact of intellectual property rights (IPRs) sys-
tems on the traditional knowledge of indigenous peoples and local communities.
Many indigenous peoples’ representatives and outside commentators feel that exist-
ing IPR systems are inadequate for protecting indigenous intellectual and cultural
property rights (e.g., Mataatua Declaration [45]).
The UN Convention on Biological Diversity, particularly Article 8(j), addresses
traditional knowledge and equitable benefit sharing. The vital role of indigenous
peoples and local communities [including women] is focused in its call to “respect,
preserve, and maintain knowledge, innovations and practices of indigenous and
local communities embodying traditional lifestyles relevant for the conservation
and sustainable use of biological diversity and promote their wider application with
the approval and involvement of the holders of such knowledge, innovations and
practices and encourage the equitable sharing of the benefits arising from the utili-
zation of such knowledge, innovations and practices.” The article, however, does not
provide details on how to recognize, reward, and protect the contribution of local
communities, farmers, indigenous peoples, and women. The biggest challenge fac-
ing governments and society today is how to distribute the economic benefits of
biodiversity fairly and equitably. Because establishing a system of intellectual prop-
erty rights to biological resources has proved contentious. Biological diversity (both
wild and cultivated) is most prominent in developing countries, and the economic
benefits it generates are disproportionately captured by industrial nations at the
global level.
The Constitution of Nepal recognizes the importance of biodiversity conserva-
tion by incorporating different clauses on natural resource conservation (Article
51), intellectual property rights (IPRs) (Article 25) under different sections includ-
ing Fundamental Rights and Duties (Part 3), Directive Principles (Part 4), and other
sections [46]. The constitution also guarantees the rights of every person to live in a
clean environment as a fundamental right (Article 30). Article 51 of the Constitution
of Nepal requires all three tiers of the governments to protect, promote, and use
available natural resources of the country in agreement with national interest.
Further, it also adopts the concept of inter-generational equity and make equitable
distribution of benefits according to priority and preferential right to the local com-
munities (Article 51, Clause G) [47]; however, conservation of biological resources
for peoples’ livelihood, access to genetic resources and benefit sharing giving prior-
ity to the indigenous communities have yet to be addressed as Fundamental Rights
in the Constitution of Nepal.
Intellectual property is the human mind’s creation of ideas, information, and
knowledge that can be incorporated into creative or inventive works, such as inven-
tions, designs, trademarks, books, paintings, or other literary and artistic works.
Intellectual property rights (IPRs) provide legal rights to grant ownership to inven-
tors, who may be individuals, enterprises or other entities that create products by
intellectual effort. However, IPR protection is being developed to benefit the coun-
tries/companies in the developed countries that have access to high technology;
320 N. Chaudhary et al.

whereas the traditional healers, farmers, and indigenous communities in the devel-
oping countries are not given due recognition for their contribution. Therefore, the
most suitable approach for Nepal appears to be to define the role of indigenous
peoples and local communities, farmers, and their knowledge in the national legisla-
tion that brings the convention into effect [48].
Traditional knowledge is a valuable heritage for the communities and cultures
that develop and maintain it. Medicinal and food plant genetic resources represent
the most important category of all biological resources because of their importance
in primary health care and pharmaceutical products. Traditional knowledge and bio-
diversity conservation are complementary phenomena essential to human develop-
ment. Very little of the traditional knowledge has been recorded; yet, it represents an
immensely valuable source of information [49]. The indigenous knowledge of tra-
ditional healers and women, particularly in the Nepalese context, has long been
ignored. Today, however, a growing number of Nepalese researchers and institu-
tions, and international development agencies are recognizing that the traditional
knowledge, innovations and practices of indigenous peoples, and local communities
relevant to conservation and the sustainable use of biodiversity are under threat
[15, 28].
Nepal has made an attempt to incorporate such obligation as far as possible into
“Access to Genetic Resources and Benefit Sharing (AGRBS) Bill” awaiting for
approval from the parliament as national legislation. However, access to genetic
resources and benefit sharing (AGRBS) will remain incomplete unless the social
and economic well-being of people and governance issues related to the same are
addressed properly.
In this context, the Center for International Environment Law (CIEL) has pro-
posed several initiatives as the next steps in using intellectual property as a tool for
conserving traditional knowledge and biodiversity [50].
(i) Free Prior informed consent (FPIC) and mutually agreed terms (MAT) The
Nagoya Protocol ensures that the genetic resources and associated traditional
knowledge are accessed in accordance with the domestic legislative framework
meeting the provisions of Free and Prior Informed Consent (FPIC) and Mutually
Agreed Terms (MAT). Following CBD (Article 15.5), developing countries have
extended their demand to obtaining free prior informed consent (FPIC) from the
concerned country of origin before patent applications are filed. Developing coun-
tries are also demanding an amendment to Article 29 of TRIPS (The Agreement on
Trade-Related Aspects of Intellectual Property Rights) “Conditions on Patent
Application” that would be constraining patent applicants to make adequate
­disclosure of the “country of origin” of the biological resources or traditional knowl-
edge. It is obvious that without an amendment to TRIPS, there is a weak legal basis
for benefit sharing.
The FPIC of all peoples and their communities must be obtained before any
research is undertaken [51]. Indigenous peoples, traditional societies, and local
communities have the right to obtain information about any program, project or
study that affects them. It is generally presumed that all potentially affected com-
munities will be provided with complete information regarding the purpose and
Traditional Amchi Medicinal Practice in Trans-Himalaya of Nepal: Conservation… 321

nature of the research activities and the probable results through FPIC and
MAT. These will also help to reasonably foresee benefits and risks of harm (be they
tangible or intangible) to the affected communities.
Key elements of FPIC and MAT, and their application procedures have been
discussed by Oli and Dhakal [52]. In order to give full force to the FPIC and MAT
requirement, the Government of Nepal established an authority under the Ministry
of Forests and Environment (MoFE) at the national level as a focal point for coordi-
nating and implementing access to genetic resource agreements.
(ii) National registers of traditional knowledge Biodiversity cannot be protected
by regulations only; the active support and participation of IPLCs are fundamental.
There is a need to address various aspects of biodiversity use and conservation at the
community level. Our knowledge of Nepal’s biological resources and associated
traditional ecological knowledge need to be completed and consolidated.
Biodiversity registration involves a systematic documentation of the resources,
knowledge, and skills of the people at the local and national level by initiation of the
people themselves. The basic philosophy behind this endeavor is that it will rejuve-
nate both the ecological basis of the resources and the social, cultural, and economic
conditions of the people by making the people knowledgeable about, capable of,
and responsible for biodiversity management.
The National Biodiversity Registration (NBR) initiated in Nepal is the beginning
of a process of creating mechanisms to (i) ensure recognition of the indigenous
knowledge of communities, (ii) avoid the misappropriation of specialized varieties
and genetic resources used by farmers, and (iii) enhance future benefit sharing [53–
55]. The Ministry of Forests and Environment has been pursuing to extend biodiver-
sity registration at province and local levels throughout Nepal. Developing a
common agreement on the registration of biological resources and knowledge
among the countries in the Hindu Kush Himalaya has yet to be worked out. For
instance, the members of the Andes Pact (Bolivia, Columbia, Ecuador, Peru, and
Venezuela) have developed a common agreement on biosafety and a special regime
for the safeguarding of traditional knowledge [56].
(iii) Document case studies on sharing of benefits from specific uses Discussions
of the impact of IPRs on the sharing of benefits from the commercial use of tradi-
tional knowledge and associated genetic resources could benefit from more fact-­
based analysis of specific cases.
Traditional knowledge is usually accessed by companies through internet and
literature and, in some cases, through multiple intermediaries and reports. Rarely
companies provide grants to communities possessing traditional knowledge, with
which they work. Aveda Corporation, Minnesota, has developed production and
marketing of Bixa orellana, a common and widespread species throughout the neo-
tropics and in the “public domain” with the Yawanawa community of Brazil. Aveda
Corporation uses bixa as a colorant in lipstick and other personal care and cosmetics
products. In 1993, the partnership between Yawanawa and Aveda involved a pack-
age of benefits over the number of years that includes the supply of technical assis-
tance, start-up funds to begin initial production, local processing, transportation and
322 N. Chaudhary et al.

other logistics, facilitation of organic certification, guaranteed market for the prod-
uct; as well as distribution of benefits [57].
However, the following are some common examples of patents in which the
contribution of traditional knowledge has been ignored (Box 3).

Box 3: The Turmeric Patent

In 1995, the US Patent and Trademark Office granted patent number 5401504
for the use of powdered turmeric (Curcuma longa) to speed the healing of
wounds. The patent was held by the University of Mississippi Medical Center.
The Council of Scientific and Industrial Research (CSIR) of India filed a chal-
lenge to the patent in October 1996. The CSIR (Council of Scientific and
Industrial Research, New Delhi) argued that the patent failed the legal require-
ment of novelty, because the use of turmeric to heal wounds was part of a
prior art. The CSIR presented publications from India indicating that turmeric
was a well-known folk remedy in the south Asia. In August 1997, the US PTO
rejected the patent [58].
The Neem Patent
For hundreds of years at the least, rural people in Asian and African conti-
nents have turned to various parts of the neem tree (Azadirachta indica) for a
variety of uses ranging from toothpaste to pesticide. A number of corpora-
tions, both Indian and foreign, had taken patents out on various products that
employ materials derived from the neem tree for things that often relate to
traditional uses of neem. For instance, a US company, W.R. Grace, patented a
number of products relating to the neem tree. One patent taken out by W R
Grace and Co. in the US in 1990 covered a technique for improving the stor-
age stability of neem seed extracts containing ‘azadirachtin’ (US Patent No
4946681). Another obtained by the same company in 1994 covered a long-­
term storable stable insecticidal compound that includes neem seed, for
increased stability (US Patent No 5124349). The increase in stability of this
preparation over traditional neem preparations presumably made it more con-
venient for commercial distribution as well as on-farm use. Thus, the seed
itself-being a product of nature is not patentable unless considerably modified
(Jain and Mudgal 1999). India has won a ten-year battle at the European
Patent Office (EPO) against a patent granted to the US Department of
Agriculture and multinational WR Grace on anti-fungal product derived from
neem (http://news.bbc.co.uk/1/hi/sci/tech/4333627.stm accessed on 14
January 2022).

10 Women in Conservation and Bioprospecting

The vital contribution of women to the management of biological resources, and to

economic production generally, has been ignored or underestimated. Women pro-
duce 80 percent of the food in Africa, 60 percent in Asia, and 40 percent in Latin
Traditional Amchi Medicinal Practice in Trans-Himalaya of Nepal: Conservation… 323

America. Rural women are often the most knowledgeable about the patterns and
uses of local biodiversity (Box 4). Therefore, the important role of women in the
management of biological resources must be recognized, and they must be allowed
to participate in decision-making. Agenda 21 calls for women to be fully involved
in decision making and in the implementation of sustainable development activities.
In the Himalaya, for example, rural women normally play a major role in the collec-
tion of various forest products, including food and medicinal plants; in farming and
managing water resources. Hence, women’s knowledge needs to be recognized and
their participation at three levels of management be encouraged: national policy, the
meso-level and grassroots [59].

Box 4: Cleyera japonica var. wallichiana: A Tea Beverage Plant of the

Himalaya
During botanical exploration in eastern Nepal, a tea-like beverage was docu-
mented in 1999 from Makalu-Barun National Park, Eastern Nepal. The leaves
of Cleyera japonica var. wallichiana, locally available, are collected, pro-
cessed, stored and utilized to prepare tea, locally called chhasing, (Bhote
chiya in Nepali) by the indigenous communities. Sherpa women possess
knowledge about the plant species, and skill to prepare chhasing drink which
is prepared by boiling dried leaves for 10–15 min with water, sugar, and milk,
and then put in a long bamboo vessel. A small quantity of salt is added and the
mixture is churned for 5 min with a loosely fitted piston. The researchers, in
fact, could not tell the difference between chasing and regular tea by either the
taste of the beverage or by physiological effects upon the body.
On an investigation, the leaves tested with High Pressure Liquid
Chromatography (HPLC) for caffeine content revealed no detectable amount
of caffeine. Several elution peaks of chhasing matched with unknown com-
pounds in the black and green teas (Camellia sinensis). The authors were
surprised to learn that no caffeine is present in Chhasing. Whether or not there
are other alkaloids similar in chemical structure to caffeine that are present in
the leaves of Cleyera japonica is a question that other investigators can pursue.
The growing of this plant species yielding tea-like beverage has provided
self-sufficiency to the local communities in the upper Arun River basin of the
Makalu Barun region. Not only is the production of chhasing an interesting
local custom, but it may prove to be of economic importance to the people in
the area if it can be harvested in a sustainable manner, successfully marketed,
and benefit ensured to the local communities.
Source: Chaudhary et al. [60].
324 N. Chaudhary et al.

11 Conclusions

A comprehensive documentation of biological resources and traditional knowledge

of amchis and IPLCs focusing in the trans-Himalaya should be urgently carried out
on an institutional basis in order to promote conservation and strengthen bio-
prospecting. Policy and infrastructure development enabling policy should be
developed to flourish traditional Amchi medicinal practice and give it due national
recognition in Nepal. Conservation of landscapes where biological resources are
used by amchis to prepare drugs is urgently needed as the habitats are under threat
to degradation, commercial collection and over-exploitation. Similarly, institutions
should be promoted to protect the Amchis knowledge as well as to transfer the
knowledge to the youngers. Screening of medicinal plants for bioprospecting based
on ethnoecological knowledge is likely to be more successful to revitalize tradi-
tional amchi practice. Improving low-tech preservation techniques, collaborative
research, and bioassay screening will help to explore traditional Amchi medicinal
practice or Himalayan medicinal practice and enhance our understanding of holistic
traditional health care systems by conserving both indigenous knowledge and bio-
logical resources as well as establishing intellectual property rights to ensure benefit
sharing to the IPLCs. AGRBS should be endorsed as a fundamental right of the
indigenous peoples and local communities including women who are strongly
dependent upon the availability and sustainable use of biological resources for their
livelihoods. Nepal has made an attempt to incorporate such obligation as far as pos-
sible into Access to Genetic Resources and Benefit Sharing (AGRBS) Bill awaiting
for approval from the parliament as national legislation.

References

1. Dawa D, Dekhang TD, Holzner W, Kletter C, Krasser R, Kriechbaum M (2001) Tibetan

medicinal plants. In: Kletter C, Kriechbaum M (eds). Medpharm Scientific Publishers, Boca
Raton/London/New York/Washington, DC, pp 3–13
2. Sherpa P, Lama N, Sherpa PD (2019) Traditional amchi practices among indigenous commu-
nities in Nepal. Centre for Indigeneous Peoples Research and Development (CIPRED):1–46
3. Ghimire SK, Bista AG, Lama NS, Craig SR (2021) Without the plants, we have no medi-
cine: Sowa Rigpa, ethnobotany, and conservation of threatened species in Nepal. WWF Nepal,
Kathmandu
4. Gore DR (1999) Tibetan medicine. Prespective Biol zmedicine. 42(2):270–279
5. Kohli M, Devi M, Thakur K, Santavan VK, Bhatt AK, Jaswal S et al (2019) A brief profile
of prevalent traditional systems of medicine in Himachal Pradesh. Himachal Pradesh Univ J
7(2):3–13
6. Angmo K, Adhikari BS, Rawat GS. Sowa – Rigpa: a healthcare practice in trans -Himalayan
region of Ladakh, India. SDRP J Plant Sci. 2017;45–52.
7. Liu Y, Dao Z, Yang C, Liu Y, Long C (2009) Medicinal plants used by Tibetans in Shangri-la,
Yunnan, China. J Ethnobiol Ethnomed. 10:1–10
8. Anders AIM. Mental health in Tibetan medicine – Sowa Rigpa an analysis of the impact of
globalizing Tibetan medicine by the example of its approach to mental health and the current
use of the concept rlung -disease. 2021;1–20.
Traditional Amchi Medicinal Practice in Trans-Himalaya of Nepal: Conservation… 325

9. Kletter C, Kriechbaum M (eds) (2001) Tibetan medicinal plants. Medpharm Scientific

Publishers, Stuttgart
10. Gurmet P (2004) “Sowa – Rigpa”: Himalayan art of healing. Indian J Tradit Knowl.
3(April):212–218
11. Blaikie C (2009) Critically endangered? Medicinal plant cultivation and the reconfiguration of
Sowa Rigpa in Ladakh. Asian Med. 5:243–272
12. Craig SR, Gerke B (2016) Naming and forgetting: Sowa Rigpa and the territory of Asian medi-
cal systems. Med Anthropol Theory. 3(2):87–122
13. Gopi DK, Mattummal R, Narayana SKK, Parameswaran S (2018) IUCN Red listed medicinal
plants of Siddha. J Res Siddha Med. 1(1):15
14. Choedon T, Kumar V (2012) Medicinal plants used in the practice of Tibetan medicine. Recent
Prog Med plants. 34:385–402
15. Lama YC, Ghimire SK, Aumeeruddy-Thomas Y (2001) Medicinal plants of Dolpo. Amchis’
Knowl Conserv WWF Nepal Program, Kathmandu
16. Ghimire SK, Mckey D, Aumeeruddy-Thomas Y (2004) Heterogeneity in ethnoecological
knowledge and management of medicinal plants in the Himalayas of Nepal: implications for
conservation. Ecol Soc 9(3)
17. Molvray M (1988) Tibetan medicine (gSo-rig). In: Tshering G, Gyatsho K (eds) Gangchen
Kyishong, Dharamashala: Library of Tibetan Works & Archives, pp 1–85
18. Bhattarai S, Chaudhary RP, Quave CL, Taylor RS (2010) The use of medicinal plants in the
trans-himalayan arid zone of Mustang district, Nepal. Etnobiol Ethnomed 6(14)
19. Belbase N (1997) The implementation of environmental law in Nepal. IUCN/Nepal
20. Ghimire SK, Aumeeruddy-Thomas Y (2009) Ethnobotanical classification and plant nomen-
clature system of high altitude agro-pastoralists in Dolpo, Nepal. Bot Orient 6:56–68
21. Etkin NL (1990) Ethnopharmacology: biological and behavioral perspectives in the study of
indigenous medicines. In: Johnson TM, Sargent CF (eds) Medical anthropology:contemporary
theory and method. Praeger, New York, pp 149–158
22. Atal CK, Zutshi U, Rao PG (1981) Scientific evidence on the role of ayurvedic herbs bioavail-
ability of drugs. J Ethnopharmacol 4:229–232
23. Freeland WJ, Calcott PH, Anderson LR (1985) Tannins and saponin: interaction in herbivore
diets. Biochem Syst Ecol. 13(2):189–193
24. Chaudhary RP, Aase TH, Vetaas OR, Subedi BP (2007) Local effects of global changes in the
Himalayas: Manang Nepal. Tribhuvan University/Uniforskning Bergen, Nepal/Norway, p 199
25. Chaudhary RP (2002) Medicinal plants of Nepal- approaches to conservation. In: Watanabe T,
Takano A, Bista MS, Saiju HK (eds) Proceeding of Nepal-Japan joint symposium on conserva-
tion and utilization of Himalayan medicinal resources. Non-Profit Organization (NPO)/Society
for the Conservation and Development of Himalayan Medicinal Resources (SCDHMR),
Japan, pp 288–292
26. Chapagain A, Wang J, Pyakurel D (2021) An overview of Nepalese medicinal plant trade with
China. Environ Sci Nat Resour 28(1)
27. Cunningham AB (1994) Integrating local plant resources and habitat management. Biodivers
Conserv 3:104–115
28. Chaudhary RP (1998) Biodiversity in Nepal – status and conservation. S. Devi/Tecpress
Books, Saharanpur/Bangkok. 224 p
29. Sequeira V (1994) Medicinal plants and conservation in Sao Tome. Biodivers Conserv.
3:910–926
30. Bhattarai S, Chaudhary RP, Taylor RSL (2007) Prioritization and trade of ethnomedicinal
plants by the people of Manang district, central Nepal. In: Chaudhary RP, Aase TH, Vetaas OR
(eds) Local effects of global changes in the Himalayas: Manang, Nepal. Tribhuvan University/
University of Bergen, Nepal/Norway, pp 151–169
31. Rana S, Kala H, Ranjitkar S, Kumar S, Mohan C, Robert A et al (2020) Climate-change threats
to distribution, habitats, sustainability and conservation of highly traded medicinal and aro-
matic plants in Nepal. Ecol Indic [Internet] 115(April):106435. Available from: https://doi.
org/10.1016/j.ecolind.2020.106435
326 N. Chaudhary et al.

32. Aryal P (2015) Climate change climate change and its impact on medicinal and aromatic
plants: a review. Clim Chang 1(1):49–53
33. Martin GJ (1995) Ethnobotany: a methods manual. Chapman & Hall, London
34. Griggs JK, Manandhar NP, Towers GHN, Taylor RSL (2001) The effect of storage on the bio-
logical activity of medicinal plants from Nepal. J Ethnopharmacol 77:247–252
35. Chaudhary RP (2001) Ecotourism: bridge between biodiversity conservation and develop-
ment in Nepal. In: Watanabe T, Sicroff T, Khanal NR, Gautam MP (eds) Proceedings of the
international symposium on the himalayan environments: mountain sciences and ecotourism/
biodiversity. Hokkaido University/Tribhuvan University, Japan/Nepal, pp 31–39
36. Cushnie TPT, Cushnie B, Echeverría J, Fowsantear W, Thammawat S, Dodgson JLA et al
(2020) Bioprospecting for antibacterial drugs: a multidisciplinary perspective on natural prod-
uct source material, bioassay selection and avoidable pitfalls. Pharm Res 37(7):1–24
37. Svarstad H, Dhillion SS (2000) Responding to bioprospecting: rejection or regulation? In:
Svarstad H, Dhillion SS (eds) Bioprospecting from -biodiversity in the South to Medicines in
the North, pp 9–15
38. Pushpangadan P (2018) Traditional medicine & clinical naturopathy biodiversity, bioprospect-
ing, traditional knowledge, sustainable development and value added products: a review. Tradit
Med Clin Naturop 7(1):1–7
39. Chaudhary RP (2000a) Biodiversity prospecting in Nepal-constraints and opportunities. In:
Bio-technology applications for reforestation and biodiversity conservation Proceeding of the
8th International Workshop of BIO-REFOR, Kathamndu, Nepal, November 28-December 2,
1999. BIO-REFOR/IUFRO/SPDC, International Union of Forest Research Programme for
Development and Capacities, Austria, pp 256–260
40. Brondízio ES, Aumeeruddy-Thomas Y, Bates P, Carino J, Fernández-Llamazares Á, Ferrari
MF et al (2021) Locally based, regionally manifested, and globally relevant: indigenous and
local knowledge, values, and practices for nature. Annu Rev Environ Resour 46:481–509
41. Chaudhary RP (2000b) Biodiversity prospecting, systematics and intellectual property rights
(IPR). In: Jha PK, Karmacharya SB, Baral SR, Lacoul P (eds) Environment and agriculture: at
the crossroad of the new millennium. Ecological Society (ECOS), Nepal, pp 251–260
42. Cox PA, Balick MJ (1994) The ethnobotanical approach to drug discovery. Sci Am
270(6):82–87
43. Farnsworth NR (1988) Screening plants for new medicines. In: Wilson EO (ed) Biodiversity.
National Academy of Science, Washington, DC, pp 83–97
44. Oberthur S (2015) In: Oberthur S, Rosendal GK (eds) Global governance of genetic resources.
Routledge
45. Declaration M (1993) Mataatua declaration on cultural and intellectual property rights of indig-
enous peoples. Comm Hum Rights, Sub-Commission Prev Descrimination Prot Minor, Geneva
46. GoN (2015) Constitution of Nepal 2015. Singha Durbar, Kathmandu
47. Chaudhary RP, Uprety Y, Devkota S, Adhikari S, Rai SK, Joshi SP (2020) Plant biodiversity
in Nepal: status, conservation approaches, and legal instruments under new federal structure.
Plant Divers Nepal (March):167–206
48. Belbase N (1999) National implementation of the convention on biological diversity: policy
and legislative requirements. IUCN/Nepal
49. Warren DM (1996) Indigenous knowledge, biodiversity conservation, and development. In:
James VU (ed) Sustainable development in third world countries applied and theoritical per-
spectives, pp 81–88
50. Dowens D (1997) Using intellectual property as a tool to protect traditional knowledge: rec-
ommendations for next steps. Cent Int Environ Law:1
51. Uprety Y, Oli KP, Paudel KC, Pokharel DM, Thapa P, Chaudhary RP (2020) Accessing genetic
resources and sharing the benefits: the implications for research on biodiversity. In: Siwakoti
M, Jha PK, Rajbhandary S, Rai SK (eds) Plant diversity in Nepal. Botanical Society of Nepal,
Kathmandu, pp 2016–2224
Traditional Amchi Medicinal Practice in Trans-Himalaya of Nepal: Conservation… 327

52. Oli KP, Dhakal TD (2009) Access and benefit sharing from genetic resources and associated
traditional knowledge. International Centre for Integrated Mountain Development (ICIMOD),
Kathmandu
53. HMGN/MFSC (2002) Nepal biodiversity strategy. Ministry of Forest and Soil Conservation,
His Majesty’s Government of Nepal
54. GoN/MFSC (2014) Nepal national biodiversity strategy and action plan. Singha Durbar,
Kathmandu
55. MoFE (2018) Nepal’s sixth national report to the convention on biological diversity. Singha
Durbar, Kathamndu
56. Acharya R (1995) Biodiversity prospecting: prospects for private sector participation in the
Asia-Pacific region. Biodivers Conserv Asia Pasific Reg – Constraints Oppor Asian Dev Bank,
Manila, pp 367–388
57. ten Kate K, Laird SA (2000) The commercial use of biodiversity. Earthscan Publications
Ltd, London
58. Marshall E, Bagla P (1997) India applauds U.S. patent reversal. Science 277:1429
59. Gurung JD (1997) Gender dimensions in biodiversty management in Nepal. A Pap Present
a Natl Semin’ Conserving Bio-diversity Nepal’s Community for Organ by Dep for Nepal
Biodivers Action Plan 3
60. Chaudhary RP, Gupta VNP, Taylor RSL (2004) Cleyera japonica Thunb. var. wallichiana (DC.)
Sealy (Theaceae): a tea beverage plant of the Himalayas. Econ Bot 58(December):114–117

Website

http://news.bbc.co.uk/1/hi/sci/tech/4333627.stm. Accessed 14 Jan 2022

Appraisal of Medicinal Plants Diversity
Inhabited in Deserts Areas

Salman Majeed, Muhammad Zafar, Mushtaq Ahmad, Shazia Sultana,

Fethi Ahmet Ozdemir, Omer Kilic, Ghulam Yaseen, and Nabila

1 Introduction

1.1 Medicinal Plants

Medicinal herbs have been used as a source of medicine to treat various ailments
from ancient times. Methodological approaches used in ethno-biological and ethno-­
pharmacological surveys for collecting information on traditional applications of
plants and their natural products have improved over time. Plants with significant
medicinal significance that are utilized in primary health care have been the subject
of a number of research [1, 2]. Traditional medicine is used by 70–95% in Asia,
Africa, Latin America, and the Middle East for their fundamental health needs [3].
Natural products have emerged as an alternative form of treatment for a variety of

S. Majeed (*) · M. Zafar · S. Sultana · Nabila

Department of Plant Sciences, Quaid-i-Azam University, Islamabad, Pakistan
e-mail: [email protected]
M. Ahmad
Department of Plant Sciences, Quaid-i-Azam University, Islamabad, Pakistan
Pakistan Academy of Sciences, Islamabad, Pakistan
F. A. Ozdemir
Faculty of Science and Art, Department of Molecular Biology and Genetics, Bingol
University,
Bingol, Turkey
O. Kilic
Faculty of Pharmacy, Department of Basic Science of Pharmacy, Adıyaman University,
Adıyaman, Turkey
G. Yaseen
Department of Botany, Division of Science and Technology, Township Campus,
University of Education, Lahore, Pakistan

© The Author(s), under exclusive license to Springer Nature 329

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_12
330 S. Majeed et al.

disorders in recent decades, as traditional drugs have been linked to a number of

side effects [4]. The local people always disturb the availability of plants in their
natural habitat due to excessive usage of natural remedies [5]. Plants are commonly
used by local people in many underdeveloped nations to cure their daily health
issues because allopathic drugs are expensive and health-care facilities are difficult
to reach [6]. In Pakistan, the majority of rural communities live in poverty and are
completely reliant on traditional medicine for their health care [7, 8]. The country is
rich in natural resources, with a diverse range of climates, ecological, and geo-
graphical zones, and a wide range of medicinal plants. It also contains a large diver-
sity of floral plants (6000 species), of which 600 are reported to be medicinal [9].

1.2 Desert Areas

Rangelands cover around 40% of the world’s geographical area and are just as vital
to the environment as rain forests. One-third of the world’s land surface is covered
by arid environments, is home to 14% of the world’s population, and produces a
major portion of global agriculture [10]. Rangelands are one of the most significant
ecosystems, offering pastoral and agro-pastoral inhabitants a wide range of services
and houses. They encompass a wide range of environments and biological commu-
nities in particular. They are also economically significant due to the abundance of
culinary, fodder, medicinal, and economic plant species. Rangeland plant biodiver-
sity is more visible and profound than in other habitats; therefore, any disturbance
has a greater impact [11]. Deserts, which have low and irregular rainfall, nutrient-­
poor soils, and limited vegetation cover, cover about a third of the earth’s land sur-
face. Deserts offer a variety of features that can suit the needs of both local residents
and those in the nearby communities. Water, food, medicine, and raw resources are
among the advantages. Desert rangelands are subjected to harsh natural factors such
as high rates of soil erosion and extremely low rainfall patterns, which may be
induced in part by climate due to their geographic location [12].
The distribution, pattern, and quantity of plant species and communities in desert
environments have all been associated with physical ecological factors such as
water availability, soil chemistry, and anthropogenic disturbance [13]. Desert veg-
etation is adapted to extreme temperature and moisture changes, as well as edaphic
environments. Plants in this region grow slowly but respond fast to climatic changes,
and a major portion of the species can regrow even if there is not enough rain [14].
Traditional folk knowledge preservation, traditional medicine preference over oth-
ers, and biodiversity conservation have all gained popularity among many groups,
researchers, academicians, and policymakers. Traditional medical knowledge (a
source of low-cost herbal medicine) required effective techniques for its preserva-
tion in indigenous communities in order to ensure its long-term sustainability [15]
(Figs. 1 and 2).
Appraisal of Medicinal Plants Diversity Inhabited in Deserts Areas 331

Fig. 1 Field pictorial photographs of desert dicot species: (a) Acacia jacquemontii, (b) Achyranthes
aspera, (c) Aerva javanica, (d) Amaranthus viridis, (e) Boerhavia diffusa, (f) Capparis decidua,
(g) Carthamus oxyacantha, (h) Chenopodium album, (i) Chenopodium murale, (j) Corchorus oli-
torius, (k) Cucumis melo var.agrestis, (l) Cuscuta reflexa, (m) Fagonia indica, (n) Heliotropium
europaeum, (o) Launaea procumbens
332 S. Majeed et al.

Fig. 2 Field pictorial photographs of desert dicot species: (a) Leptadenia pyrotechnica, (b) Malva
parviflora, (c) Peganum harmala, (d) Prosopis cineraria, (e) Prosopis juliflora, (f) Rhazya stricta,
(g) Rumex dentatus, (h) Salvadora oleoides, (i) Solanum surratense, (j) Tamarix aphylla, (k)
Tecomella undulate, (l) Trianthema portulacastrum, (m) Tribulus terrestris, (n) Withania coagu-
lans, (o) Ziziphus nummularia
Appraisal of Medicinal Plants Diversity Inhabited in Deserts Areas 333

1.3 Ethnomedicine in Deserts of Pakistan

Ethnomedicinal appraisals of plant species are vital for conservation and preserva-
tion, as well as for the development of herbal medications. Plants have been used
extensively, and their therapeutic potential has been documented globally. Around
400–600 medicinal plants have been recognized as being used in Pakistan’s tradi-
tional health-care system. Pakistan is blessed with a diverse range of temperatures,
ecological zones, and topographical regions that are endowed with a variety of
medicinal plants, and the desert sections of Pakistan are believed to be as of yet
untouched in terms of ethnomedicinal surveys of medicinal plants [16]. The desert
supports a substantial human and livestock inhabitants. The majority of the popula-
tion is made up of nomads who follow the distribution of rainfall and the forage it
provides. The only source of income for the residents of the study region is livestock
keeping [17].
Despite the fact that 88% of Pakistan’s total land area is categorized as dry or
semi-arid, less focus is given to conducting research on desert environments [18].
Much research has been made in Pakistan on ethnomedicinal investigations in
northern hilly areas and plains, but the vegetation of the deserts has been ignored for
a number of reasons. Pakistan has a distinct geographical location in Asia’s Deserts.
Pakistan’s deserts have a peculiar plant richness, with an estimated 400–600 medic-
inal species. Based on a review of earlier studies, we uncovered only a few refer-
ences to medicinal plants from Pakistan deserts. Traditional plant-based treatments
are still more popular in desert communities than allopathic and biomedical medi-
cine. People with poor income and social status, in particular, must rely on tradi-
tional medication due to the unavailability of drugs and access to contemporary
health--care systems [19].

1.4 Ethnobotanical Prospective in Pakistan

Ethnobotany is now a well-recognized discipline in Pakistan, exploring various

prominent medicinal plant species for herbal drug development and sustainable uti-
lization, but many regions, such as deserts and arid lands, remain unexplored.
Communities of remote areas and mountainous regions in Northern regions have
been practicing traditional medicines for many generations. Knowledge of tradi-
tional herbal medicine helps researchers discover new therapeutic plants with valu-
able pharmacological qualities in Pakistan’s most remote areas. Local populations
in several rural regions of Pakistan still use the old folk medicinal system. In rural
areas and villages, herbal traditional remedies are mostly practiced by traditional
health practitioners (THPs), often known as Hakims. These hakims market profit-
able medicinal plants and educate from their elders [20]. Many botanical inventories
on medicinal plants have been surveyed in various regions of Northern Pakistan
(KPK and GB), Azad and Jammu Kashmir, Plain areas of Punjab, Baluchistan, and
334 S. Majeed et al.

Sindh, but the majority of the studies have been conducted in Northern mountainous
regions of Pakistan, while the southern plain regions of Pakistan have either fewer
studies or are still unexplored. Among these areas, the deserts of Thal, Punjab, have
yet to be explored. Only a few studies from the Thal desert area have been docu-
mented in the literature [21, 22]. In addition, [23] reported 63 species from Sindh’s
northern deserts, while another study collected ethnomedicinal data on 51 plant
species from the Nara desert [17].
Although Thal desert area in Punjab province of Pakistan has a rich diversity of
medicinal plants and culturally important indigenous people that have a very strong
cultural link with medicinal plants used as herbal drugs, but the ethnobotanical doc-
umentation of important and precious medicinal plant species is still lacking behind.
The goal of this chapter is to deepen the knowledge of sustainable ethnomedicinal
uses of medicinal plants along with cultural recipes as practiced in the Thal desert.
An annotated list of dicot plants traditionally used as medicinal products has been
compiled along with a quantitative data analysis of specific herbal medicines used
in the desert area rangelands.

2 Methods

2.1 Data Documentation

Field surveys were conducted to acquire data from rural communities in Thal desert
zones in order to obtain quantitative data on dicot medicinal plants, followed by
participant observation and interviews. Traditional healers, herbalists, and local
residents are among the interviewers. Men and traditional healers provided the
majority of the medicinal data during open conversations. Because the majority of
the population speak Saraiki dialect, the interviews were conducted within this lan-
guage. A total of 87 people between the ages of 40 and 95 were interviewed, includ-
ing 74 men and 13 women. Plants’ local names, modes of use, parts used, and
medicinal uses were all recorded and represented in Table 2. Plants have been col-
lected, pressed, dried, poisoned, mounted, and submitted to the Herbarium of
Pakistan (ISL) for future research. Medicinal plant names were validated via the
plant list (www.theplantlist.org). Specimens were identified by Flora of Pakistan
and authenticated by comparing with herbarium specimens.
Table 2 Ethnomedicinal uses of dicot medicinal species inhabited in the deserts of Pakistan
Botanical name/ Common Flowering Part
S. No family name Habit season used Preparation Medicinal aspects FC*1 UR*2 RFC*3 CI*4 CV*5
1. Acacia Vachellia Tree July– Bark Paste The dried bark is 19 1 0.13 0.007 0.00007
jacquemontii jacquemontii September converted in the form of
Benth (Fabaceae) paste with water. The
paste is applied on the
cut by snake bite.
2. Achyranthes Prickly chaff Herb July– Root, Juice Juice of fresh leaves is 22 3 0.15 0.020 0.0005
aspera L. flower September leaves, used in aching teeth.
(Amaranthaceae) flowers Paste of spike is applied
as anti-venom against
scorpion sting. Root
paste is applied to
regulate the
menstruation cycle.
3. Aerva javanica Kapok bush Herb October– Whole Powder The flower is consumed 31 2 0.21 0.014 0.0003
(Burm.f) Juss.ex December plant against stomach
Schult. problems and stem is
(Amaranthaceae) applied for ear pain.
Inflorescence is used in
making cushions.
Appraisal of Medicinal Plants Diversity Inhabited in Deserts Areas

Young shoots are also

browsed by camels.
4. Alhagi maurorum Camelthorn-­ Herb April– Whole Powder Roasted seeds are 63 3 0.43 0.020 0.0014
Medik. (Fabaceae) bush September plant mixed with Gur (raw
sugar) to make specific
recipe, which is used in
dry and chronic cough,
cold, and fever.
(continued)
335
Table 2 (continued)
336

Botanical name/ Common Flowering Part

S. No family name Habit season used Preparation Medicinal aspects FC*1 UR*2 RFC*3 CI*4 CV*5
5. Amaranthus Green Herb July– Leaves, Paste Paste of fresh leaves is 22 2 0.15 0.014 0.0002
viridis L. amaranth September stem used for ulcerated
(Amaranthaceae) mouth and throat.
Leaves are cooked as
vegetable which is an
effective laxative.
6. Anethum Dill Herb February– Fruits, Raw Dried fruits and seeds 41 2 0.28 0.014 0.0004
graveolens Linn. April seeds are used as spices and
(Apiaceae) condiments due to their
specific flavor and
aroma. Dried seeds
have aromatic,
carminative, and
diuretic properties.
7. Boerhavia diffusa Red Herb July– Leaves, Paste Fresh leaves are grinded 21 3 0.14 0.020 0.0005
L. (Nyctaginaceae) spiderling September stem into a paste, and it is
applied as plaster on
boils to release the pus.
Juice of fresh leaves is
used in asthma and
dropsy.
8. Capparis decidua Karel Shrub March– Fruits, Raw Fruits are sweet in taste 55 2 0.37 0.014 0.0005
(Forssk.) Edgew. April bark, and eaten by local
(Capparaceae) leaves people. Bark has
laxative and
anthelmintic properties.
S. Majeed et al.
 Botanical name/ Common Flowering Part
S. No family name Habit season used Preparation Medicinal aspects FC*1 UR*2 RFC*3 CI*4 CV*5
9. Carthamus Wild Herb February– Flowers, Decoction, Decoction of flowers is 17 2 0.12 0.014 0.0002
oxyacantha safflower April seeds oil given to children for
M.Bieb. anthelmintic.
(Asteraceae) Seed oil is also helpful
for ulcer patients.
10. Chenopodium White Herb February– Whole Juice Juice of fresh leaves is 44 4 0.30 0.027 0.0017
album L. goosefoot April plant used as an anthelmintic,
(Amaranthaceae) antifungal, and
insecticidal effect. It
has laxative and
purgative properties.
Whole plants after
slight heating are used
as a bandage on the
parts where the patient
feel pain and on
invisible injuries to
convert them into
wounds.
Appraisal of Medicinal Plants Diversity Inhabited in Deserts Areas

11. Chenopodium Nettle-leaved Herb August– Aerial Decoction Decoction made from 35 1 0.24 0.007 0.00001
murale L. Goosefoot October parts the aerial part of plant
(Amaranthaceae) is used for
gastrointestinal
disorders.
(continued)
337
Table 2 (continued)
338

Botanical name/ Common Flowering Part

S. No family name Habit season used Preparation Medicinal aspects FC*1 UR*2 RFC*3 CI*4 CV*5
12. Citrullus Bitter apple Herb May, June, Fruits, Juice, raw Fruit pulp and juice is 76 4 0.49 0.027 0.0030
colocynthis (L.) July, August seeds, traditionally used in
Schrad. roots treating yellow fever
(Cucurbitaceae) and jaundice. Fruits are
highly purgative and
used in cattle for
gastrointestinal
disorders. The dried
fruit powder is also
mixed with honey and
used against
constipation. Careless
use of fruits and seeds
may also be fatal.
13. Cleome Ponwar Herb August– Leaves, Paste Young shoots with 26 1 0.18 0.007 0.00009
brachycarpa September flowers leaves are grinded and
(Forssk.) Vahl ex mixed with mustard oil
DC. (Cleomaceae) and the paste is applied
on arms and legs relieve
from fever. Vegetative
parts are aromatic and
insect repellent.
14. Corchorus Nalta jute Herb August– Leaves, Decoction Leaves and roots are 29 3 0.20 0.020 0.0006
olitorius L. October roots used for treating many
(Malvaceae) problems such as thirst,
biliousness, vomiting,
and leprosy.
S. Majeed et al.
 Botanical name/ Common Flowering Part
S. No family name Habit season used Preparation Medicinal aspects FC*1 UR*2 RFC*3 CI*4 CV*5
15. Cucumis melo Muskmelon Herb June– Leaves, Raw Locally ripened fruits 12 2 0.08 0.014 0.0001
var.agrestis September stem, and seeds are used as an
Naudin fruits, edible fruit. Ripened
(Cucurbitaceae) seeds fruits are effective
laxative and are also
useful in painful
urination.
16. Cuscuta reflexa Giant dodder Climber End of Whole Juice The juice of the plant, 11 1 0.07 0.007 0.00004
Roxb. October plant mixed with the juice of
(Convolvulaceae) Saccharum officinarum,
is used in the treatment
of jaundice.
17. Datura Thorn apple Herb July– Leaves, Juice, Juice of leaves and 28 4 0.19 0.027 0.0010
stramonium L. September flowers, infusion flowers is used in the
(Solanaceae) fruits treatment of asthma and
pains. Leaves in fresh
form are soaked in hot
mustard oil and then
fastened over the area
Appraisal of Medicinal Plants Diversity Inhabited in Deserts Areas

under inflammation.
(continued)
339
Table 2 (continued)
340

Botanical name/ Common Flowering Part

S. No family name Habit season used Preparation Medicinal aspects FC*1 UR*2 RFC*3 CI*4 CV*5
18. Fagonia indica Dhamasa Herb April–June Whole Decoction, The plant is acrid and 73 5 0.50 0.034 0.0044
Burm.f. plant paste bitter and has cooling
(Zygophyllaceae) properties. Decoction of
leaves is used in
asthma, fever, thirst,
vomiting, and
dysentery. Paste of
leaves is applied on
tumors and swellings of
neck.
19. Heliotropium Common Herb July– Leaves, Juice The juice of fresh 33 7 0.22 0.048 0.0039
europaeum L. heliotrope October stem leaves is laxative and
(Boraginaceae) diuretic. It is also used
for the treatment of sore
eyes, boils, sores,
wounds, ulcer, and
snakebite.
20. Heliotropium Gorakh pam Herb July– Leaves Poultice Laxative, diuretic, and 32 3 0.22 0.020 0.0007
strigosum Willd. September as a treatment for snake
(Boraginaceae) bites and stings of
nettles
21. Launaea Creeping Herb April–June Leaves, Paste, latex Latex of leaves is taken 23 2 0.16 0.014 0.0002
procumbens Launaea stem to treat constipation.
(Roxb.) Ramayya Paste of leaves is
& Rajagopal applied on the head of
(Asteraceae) children which are
suffering from fever.
S. Majeed et al.
 Botanical name/ Common Flowering Part
S. No family name Habit season used Preparation Medicinal aspects FC*1 UR*2 RFC*3 CI*4 CV*5
22. Lepidium Lesser Herb July– Whole Decoction A decoction of the 12 2 0.08 0.014 0.0001
didymium L. swine-cress September plant whole plant is drunk to
(Brassicaceae) treat headache and
fevers.
23. Leptadenia Broom bush Shrub January, Whole Infusion The plant is macerated 9 2 0.06 0.014 0.00006
pyrotechnica November, plant in water and the
(Forssk.)Decne. December macerate is taken as a
(Apocynaceae) diuretic to treat
urine-retention.
24. Malva parviflora Little mallow Herb April– Whole Poultice The whole plant is 17 2 0.12 0.014 0.0007
L. (Malvaceae) November plant emollient and pectoral.
It can be used as a
poultice on swellings,
running sores, and
boils. The seeds are
demulcent.
25. Melilotus indicus Yellow Herb March– Whole Poultice It is used externally as a 8 1 0.05 0.007 0.00003
(L.) All. sweetclover May plant poultice or plaster on
(Fabaceae) swellings.
Appraisal of Medicinal Plants Diversity Inhabited in Deserts Areas

26. Mukia N/A Herb July– Leaves Powder Dry leaf powder is 34 1 0.23 0.007 0.0001
maderaspatana September mixed with butter and
(L.) M.Roem. used in dermatological
(Cucurbitaceae) problems.
27. Oxystelma Rosy Herb June– Whole Decoction A decoction of the plant 11 1 0.07 0.007 0.00004
esculentum (L.f) Milkweed September plant is useful as a gargle in
Sm. Vine infections of throat and
(Apocynaceae) mouth.
(continued)
341
Table 2 (continued)
342

Botanical name/ Common Flowering Part

S. No family name Habit season used Preparation Medicinal aspects FC*1 UR*2 RFC*3 CI*4 CV*5
28. Peganum harmala Wild rue Herb April– Seeds Powder Seeds of the plant is 69 1 0.47 0.007 0.0002
L. (Nitrariaceae) September used in treating skin
cancer
29. Phyla nodiflora Sawtooth Herb July– Leaves, Paste Paste of fresh leaves is 29 2 0.20 0.014 0.0003
(L.) Greene fogfruit September stem applied on the head to
(Verbenaceae) prevent premature
graying of hair.
Vegetative parts are also
used as teeth cleanser
that also strengthen the
poor teeth.
30. Prosopis cineraria Ghaf Tree May–June Bark Decoction The bark of the tree is 66 8 0.45 0.054 0.010
(L.) Druce dry, acrid and bitter
(Fabacaeae) with a sharp taste;
cooling anthelmintic
tonic also cures leprosy,
dysentery, bronchitis,
asthma, leukoderma,
hemorrhoids, and
muscle tremors.
31. Prosopis juliflora Mesquite Tree March– Seeds Powder Syrup made from 25 1 0.17 0.007 0.00009
(Sw.) DC. May powder of pods is used
(Fabaceae) to increase lactation.
S. Majeed et al.
 Botanical name/ Common Flowering Part
S. No family name Habit season used Preparation Medicinal aspects FC*1 UR*2 RFC*3 CI*4 CV*5
32. Rhazya stricta N/A Herb December– Leaves Extract Extract of leaves is used 72 4 0.49 0.027 0.0028
Decne March. for the treatment of
(Apocynaceae) diabetes, sore throat,
helminthiasis,
inflammatory
conditions, and
rheumatism.
33. Rumex dentatus L. Toothed dock Herb February– Root Powder The root is used as an 8 2 0.05 0.014 0.00006
(Polygonaceae) April astringent and also used
in the treatment of
cutaneous disorders.
34. Salvadora Large Evergreen March– Whole Raw Fruits are edible and 78 6 0.53 0.041 0.0068
oleoides Decne. toothbrush tree or April plant have a digestive role.
(Salvadoraceae) tree shrub They are also used in
removing kidney and
gall bladder stones. The
leaves after heating,
bound in the form of
poultice on areas
Appraisal of Medicinal Plants Diversity Inhabited in Deserts Areas

affected by rheumatism.
The root bark is highly
effective in toothache
and gum inflammation.
Short cuttings of roots
and young shoots are
used as a Miswaak.
(continued)
343
Table 2 (continued)
344

Botanical name/ Common Flowering Part

S. No family name Habit season used Preparation Medicinal aspects FC*1 UR*2 RFC*3 CI*4 CV*5
35. Solanum nigrum Blackberry Herb July– Leaves Poultice Fresh leaves are used to 13 1 0.09 0.007 0.00005
L. (Solanaceae) nightshade August relieve pain and reduce
inflammation.
36. Solanum Yellow-­ Herb July– Fruits Raw Used against 7 3 0.05 0.020 0.0002
surratense L. berried August indigestion, diarrhea,
(Solanaceae) nightshade stomach ache.
37. Sonchus asper (L.) Spiny Herb July– Leaves, Poultice The plant is pounded 22 3 0.15 0.020 0.0005
Hill (Asteraceae) sowthistle September latex and applied as a
poultice to wounds and
boils. The latex in the
plant has been used as a
treatment on warts
38. Tamarix aphylla Athel tree Tree July– Galls Powder The galls are astringent; 12 2 0.08 0.014 0.0001
(L.) H.Karst. September it is used for treating
(Tamaricaceae) eczema and other skin
diseases.
39. Tecomella Rohida Tree Small tree February– Stem, Paste The paste of fresh 21 4 0.14 0.027 0.0008
undulate (Sm.) March leaves, leaves is applied on the
Seem flowers head in relieving
(Bignoniaceae) headache. The
decoction of bark is
used in constipation and
gastric pain. Fresh
flowers are used in tea
which is used by sterile
woman.
S. Majeed et al.
 Botanical name/ Common Flowering Part
S. No family name Habit season used Preparation Medicinal aspects FC*1 UR*2 RFC*3 CI*4 CV*5
40. Trianthema Desert Herb June– Whole Juice In villages, juice of 18 2 0.12 0.014 0.0002
portulacastrum L. horsepurslane October plant leaves is considered as
(Aizoaceae) diuretic and also useful
in thirst and kidney
problems.
41. Tribulus terrestris Bindii Herb July– Leaves, Decoction, Decoction of mature 66 2 0.45 0.014 0.0006
L. September fruits, powder seeds is locally used to
(Zygophyllaceae) seeds remove kidney
obstruction and to ease
urination. Powdered
form of fruits is used to
enhance the sexual
desire in males.
42. Withania Vegetable Herb July– Whole Decoction Decoction of dried 76 3 0.52 0.020 0.0017
coagulans rennet September plant fruits is used in
(Stocks) Dunal digestive and liver
(Solanaceae) complaints. Leaves and
root extract is also used
as blood purifier.
Appraisal of Medicinal Plants Diversity Inhabited in Deserts Areas

43. Withania Poisonous Herb June– Roots Powder Roots are ground and 10 1 0.07 0.007 0.00004
somnifera (L.) gooseberry September mixed with honey to
Dunal prepare a tonic for hair
(Solanaceae) growth.
44. Ziziphus Wild jujube Shrub July– Leaves, Decoction The leaves are 14 3 0.10 0.020 0.0003
nummularia September bark antipyretic and reduce
(Burm.f.) Wight. obesity. Bark is used as
& Arn a remedy for diarrhea
(Rhamnaceae) and cures boils.
345
346 S. Majeed et al.

2.2 Validation of Data Through Literature

The ethnomedicinal data were confirmed from scientific literature catalogues such
as Pubmed, Web of Science, Google Scholar and Science Direct. The scientific
name of the desert species were authenticated with the comprehensive list of plant
species (https://wfoplantlist.org/).

2.3 Quantitative Analysis

The data were quantitatively analyzed via following parameters.

2.3.1 Relative Frequency Citation Percentage (RFC)

Based on the number of informants, RFC is calculated to illustrate the local rele-
vance of indigenous species in the study area. It is calculated using the formula
provided by [24].

RFC = FC / N

where FC represents frequency citation and N is the number of total informants.

2.3.2 Informants Consensus Factor (ICF)

This statistical indicator is used to determine the information’s homogeneity. All

references were categorized according to the illness categories that each plant was
reported to address. The formula calculates the informant consensus factor [25, 26].

ICF  NUR  Nt / NUR  1

Where NUR is the number of use citations in each category and Nt is the species
number taken as medicine.

2.3.3 Cultural Value Index

This statistical index is calculated using the formula given by [27, 28].

CV   NU / NC    FC / N   UR / N 

NU is an abbreviation for the number of uses documented in the study. The word
NC denotes the total number of participants in the study. The relative frequency of
Appraisal of Medicinal Plants Diversity Inhabited in Deserts Areas 347

citation is the second component, while the overall number of use reports is the
third. The numbers UR and N denote the total number of people participated.

2.3.4 Cultural Importance (CI)

This is calculated by using formula of [29].

CI = UR / N

UR signifies use reports, and N is the total number of informants. This index is used
to determine the number of uses, and the range of applications for each species.

3 Results

3.1 Informants Demography

Totally 87 informants were interviewed (Table 1). Dominant informants were males;
females were less in number because of the strict culture and traditions of the rural
areas of the study area. As compared to urban communities of the area, the rural
peoples in deserts have much knowledge about the herbal remedies. Mostly infor-
mants who were interviewed have average ages between 40 and 90 years (Table 1).
Even in previous studies regarding medicinal plants utilization in Pakistan, the same

Table 1 Demographic information of Informants in Thal Deserts

S. No Variables Participants Number Percentage
1. Categories THPs 19 22
Local people 68 78
Gender Male 73 91
Female 14 9
2. Age 40–50 35 40
50–60 21 24
60–70 15 17
70–80 9 23
80–90 5 10
90–95 2 2
3. Education Illiterate 46 53
05 years 14 16
08 years 9 10
10 years 7 8
12 years 5 6
Undergraduate 4 5
Graduated 2 2
348 S. Majeed et al.

fact was recorded regarding the male dominancy in informants [30–32]. Regarding
the informants’ ages, recent research has shown that elderly folks have more knowl-
edge than younger people [33]. In this study, most of the informants were illiterate
(46%), and it is also observed after interviews that the usage of medicinal plants was
dominant in desert areas as compared to urban areas as these results were similar in
accordance with the previously published literature [34, 35].

3.2 Medicinal Plant Diversity

In the present study, 79% species are herbs. Other highly observed species are trees
12% and shrubs 8.6% (Fig. 3). Herbaceous plants are commonly used in previous
reports of [36]. Herbs are used most commonly in making herbal medicine due to
the wide distribution and presence of bioactive phytochemicals in them [37, 38].
The plant species used as medicine is mentioned in Table 3 with complete infor-
mation about the part used, mode of administration and their recipes. In this study,
44 medicinal plants classified to 22 families were recorded (Fig. 4). The most domi-
nant family was Amaranthaceae (six species) followed by Fabaceae and Solanaceae

Fig. 3 Dominant plant families along with number of species

Appraisal of Medicinal Plants Diversity Inhabited in Deserts Areas 349

Table 3 Informant consensus factor of plants and diseases treated in the desert area
Total number of Total number of plants that treat this
Disease categories disease disease ICF
Cardiovascular disorder 3 5 1.00
Digestive disorders 21 33 0.60
Eye disorders 3 4 0.50
Fever 3 4 0.50
Gastro intestinal 3 4 0.50
disorders
Gynecological disorders 7 8 0.17
Hormonal disturbance 2 3 0.25
Liver disorders 4 7 1.00
Musco-skeleton disorder 7 10 0.50
Oral disorders 7 11 0.67
Urinary tract disorders 10 15 0.56
Respiratory diseases 11 18 0.70
Sexual diseases 4 5 0.33
Skin disorders 18 35 1.00
Wounds 2 3 0.50

Fig. 4 Pie chart of Life

form/Habit in desert dicot
species

with five species each, Asteraceae, Cucurbitaceae, and Malvaceae (three species
each), Polygonaceae, and Apocynaceae, Boraginaceae, and Zygophyllaceae (two
species each) (Table 2). The family Amaranthaceae has a high potential for medici-
nal plants as previously reported by [39] as this family and its species are widely
distributed in the world desert areas [40]. Fabaceae, Solanaceae, and Asteraceae are
also effective in the treatment of common ailments [41, 42].
350 S. Majeed et al.

Fig. 5 Graphical illustration showing mode of utilization in dicot species

3.3 Parts of Plants Used for Herbal Medicine

The ways medicinal plants prepared for utilization are mentioned in Table 1. The
plant parts used in this study are leaves, whole plant, and stem. Roots, seeds, and
fruits of some trees and shrubs are also used to make herbal medicine. The most
frequently used part of the medicinal plant is leaves (28%) followed by whole plant
(19%), stem (11%), fruits (10%), roots and flower (8% each), roots (7%), and bark
(6%) (Fig. 5). Leaves are the most used part of the plant in making herbal medicine
as most of the people belonging to rural communities of Pakistan utilize them [30,
36]. Also, the leaves contain a large amount of different phytochemicals and also
plays a vital role during photosynthesis process [43]. The same results were docu-
mented in studies carried out in the previous literature of [44]. The stem leaves and
flowers of different medicinal plants are used for treating several diseases such as
digestive disorders, hypertension, colic, respiratory disorders, and others [45].

3.4 Mode of Utilization of Herbal Medicine

In this study, herbal medicine is utilized in the form of decoction, powder, paste,
juice, infusion, poultice, extract, and raw form (Fig. 6). The majority of these medi-
cines are made in the form of decoction (25%) followed by powder (23%), paste
(20%), juice (18%), and raw form (14%). Decoction is considered to be the most
mode of administration in previous studies conducted by [46, 47]. It is easily made
by simply boiling plant parts in water. Powder form of plant is also mixed with but-
ter to treat skin problems (e.g., Mukia maderaspatana). Similar results were
obtained from previous studies reported by [48]. Traditional therapies for joint pain,
fever, muscular pain, cramps, wounds, and other ailments include oil, juice, infu-
sions, and paste made from various herbal remedies [49].
Appraisal of Medicinal Plants Diversity Inhabited in Deserts Areas 351

Fig. 6 Graphical representation of plant parts used among desert dicots

3.5 Use Reports and Aliments Treated

UR (Use report) is commonly used to determine the significance of a specific plant

species. In total, 114 use reports were documented in this survey, which are catego-
rized into 15 different diseases. The highest disease category is for digestive and
respiratory disorders with eight reports (Table 2). Plants with a high use value are
reported by a large number of informants, whereas plants with a low use value are
considered to have low UV. Plant species with a high UR value may have a good
medicinal potential for treating specific disorders. Plant species that have been
shown to have a high use value should be treated further for their pharmacological
properties in order to obtain important compounds for biological drug discovery
development [50].

3.6 Quantitative Analysis

3.6.1 Relative Frequency of Citation (RFC) and Cultural Index (CI)

The highest RFC value commonly refers to utilization, priority, and popularity of
plants listed by the informants for curing the specific ailment. Highest RFC values
are observed in Salvadora oleoides (0.53), Withania coagulans (0.52), and Fagonia
indica (0.50) (Table 2). The most cited species were most importantly used by peo-
ple for medicinal purposes [40]. The plants with the highest RFC value should be
involved in pharmacological, phytochemical, and biological actions [51]. Prosopis
352 S. Majeed et al.

cineraria has a maximum number of use reports (UR = 8) followed by Heliotropium

europaeum with (UR = 7) and Salvadora oleoides with (UR = 6), respectively;
hence the values of the cultural index are also high for such species (Table 2). Plants
with highest values indicate that they were mentioned by many people and are the
most commonly used plants of that area. The highest values also indicate the diverse
uses of that particular species.

3.6.2 Informant Consensus Factor

The informant consensus factor of 15 reported disorders is represented in Table 3.

The ICF values in this study vary (0.17–1). The highest value is obtained for liver
disorders, cardiovascular complaints, and skin disorders (ICF = 1.00), while the
lowest value of ICF is shown by gynecological ailments (ICF = 0.17). This study
revealed that although most people in rural desert areas have access to health care,
they still use traditional medicinal plants for their diseases. Medicinal plants have
not lost their importance among folk people. Higher ICF values were measured in
order to identify medicinal plants for the purpose of searching for essential phyto-
chemical bioactive ingredients [26].

3.6.3 Cultural Value

In this study, CV values ranges from 0.01 to 0.00001. Prosopis cineraria shows the
highest value CV = 0.010 followed by Salvadora oleoides CV = 0.0068 and Fagonia
indica with CV = 0.0044. The highest CV values indicate that these plants have
more than one medicinal use; for example, Prosopis cineraria is used in treating
leprosy, bronchitis, asthma, leukoderma, dysentery, hemorrhoids, and muscle
cramps (Table 2). The lowest CV would be seen in Chenopodium murale
(CV = 0.0001) followed by Amaranthus viridis, Carthamus oxyacantha, Peganum
harmala, Solanum surratense with the same CV = 0.0002 lowest value indicates
single uses of plant species.

3.7 Study Limitations

Ethnomedicinal study on deserts in Pakistan reveals a widespread usage of wild

medicinal herbs by indigenous communities. The research presented in this book
chapter confirms traditional bio-resource use and ethnomedicine of wild desert
plants. Global industrial expansion and rapid technical innovation have resulted in
ecological changes within urban civilization, followed by cultural changes in rural
and remote communities. As a result, knowledge about using plant richness and
resources is diminishing in desert places. This study also reveals a decrease in indig-
enous knowledge among the younger generation on the health benefits of medicinal
Appraisal of Medicinal Plants Diversity Inhabited in Deserts Areas 353

flora. Indigenous peoples in deserts typically lose a considerable percentage of the

medicinal plant due to a lack of sufficient expertise in plant collection and process-
ing. Over time, such irresponsible behavior might lead to a decline in plant diversity.
As a result, this study is also useful in raising awareness about desert plants and
assisting pharmaceutical industries in paying close attention to these valuable plants
for the manufacture of novel pharmaceuticals.

4 Conclusion

This chapter demonstrated the rich diversity of medicinal plants used to cure a wide
range of illnesses in desert settings. The chapter was prepared to document ethno-
medicinal knowledge in the desert rangeland using quantitative indices. Totally 44
medicinal species from 22 families have been reported to be utilized to treat a vari-
ety of disorders. The leaves were reported to be the most commonly utilized plant
part (28%) while herbs were the most commonly used life form (79%) and decoc-
tion was the most commonly used route of administration (25%). Due to the obvi-
ous growing awareness of medicinal plants and the relevance of ethnomedicinal
research, it is considered critical to record traditional medicinal plant knowledge
gathered from indigenous peoples of desert areas before it is lost forever. The
research establishes a baseline for future phytochemical and pharmacological
screening to evaluate the efficacy of medicinal plants in the development of herbal
drugs. It is thus recommended that policies for conservation of important medicinal
plant species should be planned.

Acknowledgement The authors would like to thank the Herbarium of Pakistan, Quaid-i-Azam
University, (ISL) for identification of plant specimens and providing lab facilities. We are also
grateful to Higher education commission of Pakistan for funding under project No NRPU-7837.
Conflict of Interest The authors declare no potential conflict of interest regarding publication of
this book chapter.

References

1. Kapoor L (2017) Handbook of ayurvedic medicinal plants: herbal reference library. Routledge,
Taylor and Francis group, CRC Press. Florida, United States of America
2. Iwu MM (2014) Handbook of African medicinal plants. CRC Press, Boca Raton
3. Van Wyk B-E, Wink M (2017) Medicinal plants of the world. CABI, Wallingford
4. Kewessa G, Abebe T, Demessie A (2015) Indigenous knowledge on the use and management
of medicinal trees and shrubs in Dale district, Sidama zone, Southern Ethiopia. Ethnobot Res
Appl 14:171–182
5. Tadesse A, Kagnew B, Kebede F (2018) Ethnobotanical study of medicinal plants used to treat
human ailment in Guduru District of Oromia Regional State. Ethiopia J Pharmacogn Phytother
10(3):64–75
354 S. Majeed et al.

6. Aziz MA, Khan AH, Adnan M, Izatullah I (2017) Traditional uses of medicinal plants reported
by the indigenous communities and local herbal practitioners of Bajaur Agency, Federally
Administrated Tribal Areas, Pakistan. J Ethnopharmacol 198:268–281
7. Abbas Z, Khan SM, Alam J, Khan SW, Abbasi AM (2017) Medicinal plants used by inhabit-
ants of the Shigar Valley, Baltistan region of Karakorum range-Pakistan. J Ethnobiol Ethnomed
13(1):53
8. Aziz MA, Khan AH, Adnan M, Ullah H (2018) Traditional uses of medicinal plants used
by indigenous communities for veterinary practices at Bajaur Agency, Pakistan. J Ethnobiol
Ethnomed 14(1):11
9. Shinwari ZK (2010) Medicinal plants research in Pakistan. J Med Plants Research 4(3):161–176
10. Gamoun M, Belgacem AO, Louhaichi M (2018) Diversity of desert rangelands of Tunisia.
Plant Divers 40(5):217–225
11. Gamoun M, Louhaichi M (2021) Botanical composition and species diversity of arid and des-
ert rangelands in Tataouine, Tunisia. Land 10(3):313
12. Bidak LM, Kamal SA, Halmy MWA, Heneidy SZ (2015) Goods and services provided by
native plants in desert ecosystems: examples from the northwestern coastal desert of Egypt.
Glob Ecol Conserv 3:433–447
13. Enright NJ, Miller BP, Akhter R (2005) Desert vegetation and vegetation-environment rela-
tionships in Kirthar National Park, Sindh, Pakistan. J. Arid Environ 61(3):397–418
14. Ansari KA, Mahar AR, Malik AR, Sirohi MH, Saand MA, Simair AA, Mirbahar AA (2017)
Impact of grazing on plant biodiversity of desert area of district Khairpur, Sindh, Pakistan. J
Anim Plant Sci 27(6):1931–1940
15. Yaseen G, Ahmad M, Potter D, Zafar M, Sultana S, Mir S (2018) Ethnobotany of medicinal
plants for livelihood and community health in deserts of Sindh-Pakistan. In: Plant and human
health, vol 1. Springer, Cham, pp 767–792
16. Yaseen G, Ahmad M, Sultana S, Alharrasi AS, Hussain J, Zafar M (2015) Ethnobotany of
medicinal plants in the Thar Desert (Sindh) of Pakistan. J Ethnopharmacol 163:43–59
17. Qureshi R, Bhatti GR (2008) Ethnobotany of plants used by the Thari people of Nara Desert,
Pakistan. Fitoterapia 79(6):468–473
18. Shaheen H, Qureshi R, Akram A, Gulfraz M (2014) Inventory of medicinal flora from Thal
desert, Punjab, Pakistan. Afr J Tradit Complement Altern Med 11(3):282–290
19. Yaseen G, Ahmad M, Shinwari S, Potter D, Zafar M, Zhang G, Sultana S (2019) Medicinal
plant diversity used for livelihood of public health in deserts and arid regions of Sindh-­
Pakistan. Pak J Bot 2(31):2409–2419
20. Mahmood A, Malik RN, Shinwari ZK, Mahmood A (2011) Ethnobotanical survey of plants
from Neelum, Azad Jammu and Kashmir, Pakistan. Pak J Bot 43(105):10
21. Bhatti GR, Qureshi R, Shah M (2001) Ethnobotany of Qadanwari of Nara Desert. Pak J Bot
33:801–812
22. Panhwar AQ, Abro H (2007) Ethnobotanical studies of Mahal Kohistan (Khirthar national
park). Pak J Bot 39(7):2301–2315
23. Qureshi R, Bhatti GR, Memon RA (2010) Ethnomedicinal uses of herbs from northern part of
Nara desert, Pakistan. Pak J Bot 42(2):839–851
24. Fatima A, Ahmad M, Zafar M, Yaseen G, Khan MPZ, Butt MA, Sultana S (2017)
Ethnopharmacological relevance of medicinal plants used for the treatment of oral diseases in
Central Punjab-Pakistan. J Herb Med 12:88–110
25. Logan MH (1986) Informant consensus: a new approach for identifying potentially effec-
tive medicinal plants. In: Plants in indigenous medicine and diet: biobehavioral approaches.
Redgrave Publishing Company, Bedford Hills, p 91
26. Canales M, Hernández T, Caballero J, De Vivar AR, Avila G, Duran A, Lira R (2005) Informant
consensus factor and antibacterial activity of the medicinal plants used by the people of San
Rafael Coxcatlán, Puebla. Méx J Ethnopharmacol 97(3):429–439
27. Tardío J, Pardo-de-Santayana M (2008) Cultural importance indices: a comparative analysis
based on the useful wild plants of Southern Cantabria (Northern Spain). Econ Bot 62(1):24–39
Appraisal of Medicinal Plants Diversity Inhabited in Deserts Areas 355

28. Zhang Y, Xu H, Chen H, Wang F, Huai H (2014) Diversity of wetland plants used traditionally
in China: a literature review. J Ethnobiol Ethnomed 10(1):72
29. Menendez-Baceta G, Aceituno-Mata L, Reyes-García V, Tardío J, Salpeteur M, Pardo-de-­
Santayana M (2015) The importance of cultural factors in the distribution of medicinal plant
knowledge: a case study in four Basque regions. J Ethnopharmacol 161:116–127
30. Malik K, Ahmad M, Zhang G, Rashid N, Zafar M, Sultana S, Shah SN (2018) Traditional plant
based medicines used to treat musculoskeletal disorders in Northern Pakistan. Eur J Integr
Med 19:17–64
31. Butt MA, Ahmad M, Fatima A, Sultana S, Zafar M, Yaseen G, Ashrfa MA, Shinwari ZK,
Kayani S (2015) Ethnomedicinal uses of plants for the treatment of snake and scorpion bite in
Northern Pakistan. J Ethnopharmacol 168:164–181
32. Ahmad M, Sultana S, Fazl-i-Hadi S, Ben Hadda T, Rashid S, Zafar M, Khan MA, Khan PZ,
Yaaseen G (2014) An ethnobotanical study of medicinal plants in high mountainous region of
Chail valley (District Swat-Pakistan). J Ethnobiol Ethnomed 10(1):36
33. Kayani S, Ahmad M, Sultana S, Shinwari ZK, Zafar M, Yaseen G, Hussian M, Bibi T (2015)
Ethnobotany of medicinal plants among the communities of Alpine and Sub-alpine regions of
Pakistan. J Ethnopharmacol 164:186–202
34. Bibi T, Ahmad M, Tareen RB, Tareen NM, Jabeen R, Rehman S-U, Sultan S, Zafar M, Yaseen
G (2014) Ethnobotany of medicinal plants in district Mastung of Balochistan province-­
Pakistan. J Ethnopharmacol 157:79–89
35. Bibi S, Sultana J, Sultana H, Malik RN (2014) Ethnobotanical uses of medicinal plants in the
highlands of Soan Valley, Salt Range, Pakistan. J Ethnopharmacol 155(1):352–361
36. Ullah M, Khan MU, Mahmood A, Malik RN, Hussain M, Wazir SM, Daud M, Shinwari
ZK (2013) An ethnobotanical survey of indigenous medicinal plants in Wana district South
Waziristan agency, Pakistan. J Ethnopharmacol 150(3):918–924
37. Uniyal SK, Singh K, Jamwal P, Lal B (2006) Traditional use of medicinal plants among the
tribal communities of Chhota Bhangal, Western Himalaya. J Ethnobiol Ethnomed 2(1):14
38. Sanz-Biset J, Campos-de-la-Cruz J, Epiquién-Rivera MA, Canigueral S (2009) A first sur-
vey on the medicinal plants of the Chazuta valley (Peruvian Amazon). J Ethnopharmacol
122(2):333–362
39. Santhiya E, Banu AR, Anushiya DC, Vengadeswari A, Mahesh R (2021) Survey of medicinal
plants in Kariyamanikapuram, Nagercoil, Kanyakumari District, Tamil Nadu. India Bot Rep
10(2):4–9
40. Koti M, Katrahalli K (2021) Wild edible fruits and vegetables of Yadahalli Chinkara Wildlife
Sanctuary, Bagalkot, Karnataka, India. J Glob Biosci 10(9):8998–9008
41. Menendez-Baceta G, Aceituno-Mata L, Molina M, Reyes-García V, Tardío J, Pardo-de-­
Santayana M (2014) Medicinal plants traditionally used in the northwest of the Basque
Country (Biscay and Alava), Iberian Peninsula. J Ethnopharmacol 152(1):113–134
42. Akerreta S (2009) Etnobotánica farmacéutica en Navarra: del uso tradicional de las plantas
medicinales a su evidencia científica. Faculty of Science. 831: University of Navarra Pamplona
43. Ahmad M, Khan MPZ, Mukhtar A, Zafar M, Sultana S, Jahan S (2016) Ethnopharmacological
survey on medicinal plants used in herbal drinks among the traditional communities of
Pakistan. J Ethnopharmacol 184:154–186
44. Shil S, Choudhury M, Das S (2014) Indigenous knowledge of medicinal plants used by the
Reang tribe of Tripura state of India. J Ethnopharmacol 152(1):135–141
45. Leporatti M, Ivancheva S (2003) Preliminary comparative analysis of medicinal plants used in
the traditional medicine of Bulgaria and Italy. J Ethnopharmacol 87(2–3):123–142
46. Bano A, Ahmad M, Hadda TB, Saboor A, Sultana S, Zafar M, Khan MPZ, Arshad M, Ashraf
MA (2014) Quantitative ethnomedicinal study of plants used in the skardu valley at high alti-
tude of Karakoram-Himalayan range, Pakistan. J Ethnobiol Ethnomed 10(1):43
47. Özcan MM, Ünver A, Uçar T, Arslan D (2008) Mineral content of some herbs and herbal teas
by infusion and decoction. Food Chem 106(3):1120–1127
356 S. Majeed et al.

48. Okwu DE, Josiah C (2006) Evaluation of the chemical composition of two Nigerian medicinal
plants. Afr J Biotechnol 5(4):357–361
49. Schempp C, Winghofer B, Lüdtke R, Simon-Haarhaus B, Schöpf E, Simon J (2000) Topical
application of St John’s wort (Hypericum perforatum L.) and of its metabolite hyperforin
inhibits the allostimulatory capacity of epidermal cells. Br J Dermatol 142(5):979–984
50. Kartal M (2007) Intellectual property protection in the natural product drug discovery, tradi-
tional herbal medicine and herbal medicinal products. Phytother Res 21(2):113–119
51. Mukherjee PK, Nema NK, Venkatesh P, Debnath PK (2012) Changing scenario for promotion
and development of Ayurveda–way forward. J Ethnopharmacol 143(2):424–434
Bush Medicinal Plants of the Australian
Wet Tropics and Their Biodiscovery
Potential

Karma Yeshi and Phurpa Wangchuk

1 Introduction

The “Wet Tropics” encompasses 450 km along the northeast coast of Australia,
covering approximately 8940 km2 of Australian tropical rainforest with latitude
−17° 29′ 59.99″ South and longitude 145° 44′ 59.99″ East (Fig. 1) [1]. The Wet
Tropics stretch from low sea level to high mountains, such as Mt. Bartle Frere,
which is at an altitude of 1622 m above sea level. It is listed as one of the 35 inter-
national global hotspots in 2010 [2], and it covers 0.12% of Australia [3]. The Wet
Tropics bioregion on large scale has seven different vegetation groups: rainforest,
sclerophyll and sclerophyll rainforest transition vegetation groups, sclerophyll for-
ests and woodlands, vegetation complex and mosaics, shrublands and heathlands,
non-woody vegetation, and mangroves with 24 plant communities [4, 5]. The Wet
Tropics experience an early wet season from October to December and a monsoon
season from January to April [6]. The Wet Tropics bioregion is home to more than
2800 plant species, out of which more than 700 species (i.e., approximately 25%)
are endemic to the area [2]. The “Wet Tropics” is significant not only from an eco-
logical point of view but also for preserving important historical, cultural, and
anthropogenic activities, including Aboriginal people’s vast knowledge about edi-
ble and medicinal plants [7].
At present, about 20 Aboriginal communities comprising 120 clans speaking
eight languages live in the “Wet Tropics” [7]. These Rainforest Aboriginal people
have lived in harmony with nature for thousands of years and their knowledge in
utilising plants for food, shelter, and medicine is commendable. They are the pio-
neers in managing biodiversity and landscapes, through activities such as plant

K. Yeshi · P. Wangchuk (*)

Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine,
James Cook University, Cairns, QLD, Australia
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 357

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_13
358 K. Yeshi and P. Wangchuk

Fig. 1 Map of Australia showing the Wet Tropics World Heritage Area

cultivation and active traditional mosaic burning, even before the onset of Australia’s
early colonial period (1788–1850) [8–10]. For instance, cultivation of cycads and
fruit trees and mosaic burning among Yalanji country people in the northern Wet
Tropics is well-documented [9], and their cultural burning is valued and incorpo-
rated into the forest management practices. At least two seats in the Wet Tropics
Management Board of Directors are reserved for Aboriginal people as custodians
and traditional knowledge owners [7]. About 87.5% of the Wet Tropics World
Heritage Area is constituted by native titles and other rainforest Aboriginal land
interests [11]. Two native title representative bodies (North Queensland Land
Council and Cape York Land Council) in the Wet Tropics region are responsible for
protecting and securing native titles [12].
Aboriginal peoples’ ecological legacy is recognized with increasing administra-
tive support for the documentation, preservation, and promotion of their ancestral
knowledge, through establishing rangers’ groups, traditional owner leadership
groups, indigenous protected areas, and research collaborations with researchers,
scientists, and various academic institutions across Australia. Tropical Indigenous
Ethnobotany Centre (TIEC) is one such example of indigenous initiatives. TIEC is
the first indigenous-driven ethnobotanical research center in Australia, established
Bush Medicinal Plants of the Australian Wet Tropics and Their Biodiscovery Potential 359

in 2009 by Traditional Owners in North Queensland in partnership with the

Queensland government, the Commonwealth Scientific and Industrial Research
Organisation (CSIRO), James Cook University’s (JCU) Cairns Institute, and the
Australian Tropical Herbarium (ATH) [13]. TIEC is headed by Gerry Turpin
(Fig. 2), a trained Indigenous Ethnobotanist. Its main aims are to document, pre-
serve, and promote traditional knowledge, including bush medicines and bush
tucker knowledge.
Archaeobotanical evidence from tropical rainforest areas occupied by Aboriginal
people suggests that they might have used plants more than 5000 years ago for food
and medicine [7]. Many medicinal plant species have been reported to grow in the
tropical region (including Wet Tropics) of Australia [14]. Some of these Bush medi-
cines have been exported to other countries. For instance, before synthetic drugs
were available, Duboisia myoporoides, commonly called soft corkwood, were
grown commercially to be used as ophthalmic and sedative drugs [15]. This plant is
rich in hyoscine alkaloids, and a large quantity of hyoscine is known to have been
exported during World War II to treat travel sickness and shell shock among military

Fig. 2 An Indigenous Ethnobotanist (Mr. Gerry Turpin at work) collecting herbarium specimens.
He is leading a Tropical Indigenous Ethnobotany Centre (TIEC) at Australian Tropical Herbarium
(ATH), James Cook University, Cairns. (Courtesy: Phurpa Wangchuk)
360 K. Yeshi and P. Wangchuk

troops. More than 500 tonnes of dried and powdered leaves were exported to
German and Swiss pharmaceutical industries in 1989 [15].
While the Rainforest Aboriginal communities still practice bush food and bush
medicine cultures, only a limited number of plants have been explored for commer-
cial activities. Some Traditional Knowledge requires rediscovery, and TIEC is
working closely with various Aboriginal communities to document and protect their
bush medicine knowledge. Part of this documentation identifies plants on their lands
that offer new business potential in the food, beverage, ornamental, health-­
promoting, and nursery industries. There is an urgent need to develop a complete
inventory list of plants that grow in the Wet Tropics and determine their economic
values and market potential.
This chapter highlights 30 medicinal plants that grow in the ‘Wet Tropics’ region.
We identified only three medicinal plant species endemic to the Wet Tropics and
Cape York region. Many medicinal plants listed here are reported to grow in other
parts of Australia. The traditional uses, phytochemical content, and pharmacologi-
cal properties were extracted from the published documents, including journal arti-
cles, books, book chapters, and official websites. The botanical names of the plants
were confirmed using ‘The World Flora Online’ (https://wfoplantlist.org/plant-­list).
The information on the distribution of plants was obtained using ‘The Australian
Virtual Herbarium’ (https://avh.chah.org.au/) and the ‘Discover Life’ (https://www.
discoverlife.org/20/q). The information gathered from these sources is presented
below individually.

2 Ethnobotany, Phytochemistry and Pharmacology

of Individual Medicinal Plant Grouped by
Disease Categories

2.1 Narcotics and Painkillers

2.1.1 
Alphitonia excelsa (Fenzl) Reissek ex Benth. (Rhamnaceae)

Alphitonia excelsa is a medium-size tree with grey to golden-brown hairy buds and
stems, when young. It grows up to a height of 21 m. It is commonly called the ‘red
ash’ or ‘soapbush’ (because the wet leaves create a lather) or ‘leatherjacket.’
Ethnomedicine: People bath in warm infusions prepared from leaves to relieve
headache [16]. Leaves are also applied to eyesore [17]. While infusion prepared
from roots, bark, and wood is applied to the body to heal pain [17]. Wood and bark
decoction is effective for toothache [16]. Young shoot tips are chewed to ease stom-
ach upset [16]. Aboriginal people of Yaegl country use leaves to treat sores, wounds,
and skin infections [18].
Phytochemistry and Pharmacology: γ-sitoserol, nonanal, n-tetracontane, doco-
sane, 1,54-dibromotetrapentacontane, tetradecane, and hexadecane were identified
Bush Medicinal Plants of the Australian Wet Tropics and Their Biodiscovery Potential 361

from leaves [18]. Betulinic acid was also isolated from its twigs [19]. The crude leaf
extract (dichloromethane and hexane extract) showed moderate antibacterial activ-
ity (Staphylococcus aureus) at MIC of 312.5–625 μg/mL and 1250–2500 μg/mL,
respectively [18]. Betulinic acid showed antiproliferative activity against human
ovarian cancer cell line A2780 with an IC50 value of 20.6 μM [19].

2.1.2 
Clerodendrum floribundum R.Br. (Lamiaceae) (Fig. 3a)

Clerodendrum floribundum is a tall shrub or a small tree that produces black seed
surrounded by red calyxes, leading to the common name ‘lolly bush.’
Ethnomedicine: Decoction prepared from wood is used to treat aches and pains
[16]. A water extract made from the leaves was used on the skin to reduce itch-
ing [20].
Phytochemistry and Pharmacology: No phytochemical and pharmacological
studies reported for this plant.

2.1.3 
Cymbopogon bombycinus (R.Br) Domain (Poaceae)

Cymbopogon bombycinus is a grass, and it is commonly called ‘Cymbopogon,’

‘silky oilgrass,’ ‘citronella grass,’ ‘lemongrass,’ and ‘lemon-scented grass.’
Aboriginal languages have various names, such as Giwiri, Guwuru (Jaru), Naliny

Fig. 3 Selected bush medicinal plant photos. (Courtesy: Paul Williams and Phurpa Wangchuk).
(a) Clerodendrum floribundum. (b) Excoecaria parvifolia. (c) Canarium australianum. (d)
Erythrophleum chlorostachys. (e) Flagellaria indica. (f) Macaranga tanarius
362 K. Yeshi and P. Wangchuk

(Mal), Jorroy (Mang), Guruguruny, and Gububu (Yarr) [21]. This grass is native to
Northern Territory.
Ethnomedicine: A whole grass is burnt and rubbed on the body for pain and
colds. In some cases, the grass is soaked in water and the liquid treats sore eyes [17].
Phytochemistry and Pharmacology: There is no record of phytochemical studies.

2.1.4 
Ehretia saligna R.Br. (Boraginaceae)

Ehretia saligna is a shrub or a small tree that grows up to 6 m tall. It has common
names such as ‘Ehretia,’ ‘coonta,’ ‘peachwood,’ ‘peach bush,’ ‘false cedar,’ and
‘native willow.’ Aboriginal people call it Warlagarri [21]. This plant occurs in the
Gulf of Carpentaria and the coastal area of Northern Queensland.
Ethnomedicine: The latex and chopped inner bark are boiled, and the resulting
red liquid is applied to cuts and sores [22]. The decoction prepared from the wood
has been taken orally to alleviate aches and pains [16].
Phytochemistry and Pharmacology: No phytochemical and pharmacological
studies reported for this plant.

2.1.5 
Excoecaria parvifolia Müll.Arg. (Euphorbiaceae) (Fig. 3b)

Excoecaria parvifolia is a semideciduous tree that grows up to 7 m tall. It is also

commonly called ‘Excoecaria,’ ‘guttapercha,’ ‘gutta percha’ (because it exudes
white latex), and ‘northern brown birch.’ Aboriginal people call it Gurniny, Yilili
(Mal), Yeworr (Mat), Gilirr (Mang), and Manyingila [21].
Ethnomedicine: A heated infusion prepared from the mashed bark is applied to
all body parts to ease pain and sickness, and as an antiseptic for sores [17]. The
white sap can cause short-term blindness [20].
Phytochemistry and Pharmacology: Isolated 12 beyerane diterpenes, including
ent-3-oxa-beyer-15-en-2-one, ent-15,16-epoxy-2-hydroxy-19-norbeyer-1,4-dien-3-­
one, methyl ent-2,4-seco-15,16-epoxy-4-oxo-3,19-dinorbeyer-15-en-2-oate,
ent-2,17-dihydroxy-19-norbeyer-1,4,15-trien-3-one, stachenone, stachenol,
Diosphenol, and the triterpene lupeol from the heartwood [23]. Diosphenol showed
a potent cytotoxic effect against leukemia cells (L1210) [23].

2.1.6 
Pandanus spiralis R.Br. (Pandanaceae)

Pandanus spiralis is a small tree that grows up to 8 m tall. It is commonly known as

Pandanus, Screw-palm, and Pandanus palm. In Aboriginal language, it is known by
various names: Gulmarri (Jam, Ngal, Nung), Wirnbu, Muram muram (Mal),
Tyangatya (Mat), Mangarrayi, Jamog, Jangawa, Merriny (plant), and Gujangak
(fruit) [21]. This plant is also reported from Northern Territory and Western
Australia.
Bush Medicinal Plants of the Australian Wet Tropics and Their Biodiscovery Potential 363

Ethnomedicine: The inner core of the upper section of the trunk of young trees is
eaten by Aboriginal people to heal stomach pain and diarrhea [24].
Phytochemistry and Pharmacology: Not studied for its phytochemical and phar-
macological activities.

2.1.7 
Pteridium esculentum (G. Frost.) Cockayne (Dennstaedtiaceae)

Pteridium esculentum is a perennial fern with an extensive creeping rhizome, and

the stem grows up to 1.5 m long. It is commonly called ‘common bracken.’
Aboriginal people called it ‘Gunggai’ (Dharawal).
Ethnomedicine: Young fronds are crushed and rubbed on the area when bitten by
insects and ticks to ease the pain of stings. Moreover, tea made from leaves and leaf
stalks is used against rheumatism [25].
Phytochemistry and Pharmacology: Ptesculentoside, ptaquiloside, and caudato-
side were isolated from immature croziers [26]. No pharmacological study was con-
ducted for this plant.

2.1.8 
Rhaphidophora australasica F.M.Bailey (Araceae)

Rhaphidophora australasica is a climber. It is commonly called ‘needle berry.’ It

occurs in Northern Queensland and its coastal areas.
Ethnomedicine: Aboriginal people have used the decoction prepared from leaves
and roots to get rid of rheumatic pains. However, decoction causes an itchy sensa-
tion [27].
Phytochemistry and Pharmacology: There is no record of phytochemical and
pharmacological studies for this plant.

2.1.9 
Zieria smithii Jacks. (Rutaceae)

Zieria smithii is a robust shrub that grows up to 2 m high with glandular stems and
leaves, which emit a pungent smell when crushed. There are many common names
including ‘turmeric,’ ‘sandfly bush,’ ‘lanoline bush,’ ‘stunk wood,’ and ‘sandfly
zieria.’
Ethnomedicine: Leaves are crushed and then inhaled to cure headache, but
excessive use may make headache worse [28].
Phytochemistry and Pharmacology: Identified α-pinene, thymol, chrysanthe-
none, citronellol, safrole, bicyclogermacrene, and butylated hydroxytoluene from
its essential oil [29]. The hexane extract of Zieria smithii showed anti-bacterial and
anti-fungal activities [29].
364 K. Yeshi and P. Wangchuk

2.2 Headaches, Colds, and Fevers

2.2.1 
Calamus caryotoides A.Cum. Ex Mart. (Arecaceae)

Calamus caryotoides is a climber slender cane-like stem about 15 mm in diameter

[21]. It is commonly called a ‘fish-tail lawyer cane’ and ‘wait-a-while.’ It only
occurs in Wet Tropics of Queensland, with other species of Calamus in Southern
Australia.
Ethnomedicine: Aboriginal people usually eat the young shoot of this plant to
treat headache [30].
Phytochemistry and Pharmacology: There is no record of phytochemical and
pharmacological studies for this plant.

2.2.2 
Melaleuca quinquenervia (Cav.) S.T.Black (Myrtaceae)

Melaleuca quinquenervia is a tree of wetlands that grows up to 25 m tall with

slightly a dull green or yellowish-green crown and spreading twigs. It is commonly
called a ‘broad-leaved tea tree’ or ‘paperbark.’
Ethnomedicine: Young leaves are bruised in water, and the resultant liquid is
drunk to heal headache, colds, and general sickness [31]. The oil obtained from
leaves is used for cough and colds and also applied externally for neuralgia and
rheumatism [30].
Phytochemistry and Pharmacology: Isolated from leaves – gallic acid, ellagic
acid, 3-O-methylellagic acid, 3,4,3′-tri-O-methylellagic acid,
2,3-O-hexahydroxydiphenoyl-(α/β)-D-4C1-glucopyranose, castalin, and grandinin
[32]. Leaf essential oil has longifolene and eucalyptol as major constituents [33].
5,7,3′,4′-Tetrahydroxyflavone 2′-O-beta-D-glucopyranuronide is also present in the
leaves [34].
Grandinin showed free-radical (DPPH, 2,2-diphenyl-1-picrylhydrazyl) scaveng-
ing antioxidant activity at EC50 of 4.3 ± 0.3 μg mL−1 and was found non-toxic in
mice at LD50 of 316 mg Kg−1 body weight [32]. Leaf essential oil showed anthel-
minthic activity by inhibiting the larval development of Haemonchus contortus
Embrapa2010-resistant isolate at IC50 and IC90 values of 0.44 and 0.94 mg/mL,
respectively [33]. Essential oil (EO) and its major constituents (1,8-cineole,
α-pinene, and α-terpineol) showed anti-tyrosinase and anti-melanogenic activities
by decreasing melanin content in α-melanocyte-stimulating hormone (α-MSH)-
stimulated murine B16 melanoma cells [35]. The EO also showed antioxidant activ-
ity by restoring glutathione levels, glutathione peroxidase, superoxide dismutase,
and catalase activities in α-MSH-stimulated B16 cells [35].
Bush Medicinal Plants of the Australian Wet Tropics and Their Biodiscovery Potential 365

2.2.3 
Tephrosia varians (Bailey) C.T.White (Fabaceae)

Tephrosia varians is a shrub and it is native to Northern Queensland.

Ethnomedicine: The root of this plant is considered medicinal, and they are
either eaten raw/or boiled in water and drank its decoction to cure rheumatism by
Aboriginal people [30].
Phytochemistry and Pharmacology: There is no report on its phytochemicals and
pharmacological activities.

2.3 Digestive and Bowel Disorders

2.3.1 
Canarium australianum F.Muell. (Burseraceae) (Fig. 3c)

Canarium australianum is a deciduous tree that grows up to 30 m tall. It is com-

monly called ‘Canarium’ or ‘mango bark.’ In Aboriginal languages, the plant is
called Kunerre, Bird (Mang, Yang) and Yangman, Birnak or Birnalin in Wangiman,
and Gal in Warray [21]. Canarium is native to the Northern Territory and occurs on
the Gulf coast of Carpentaria, NW Australia, and the North coast of New South Wales.
Ethnomedicine: The bark is crumbled in water to make a resinous milky liquid
that is strained and can be drunk for treating intestinal problems such as troubles-­
stomachache and diarrhea. In Northern Territory, it is not used for consumption as
it is considered hazardous. They refer to it as a septic tree as inner bark is used for
stopping bleeding (only for minor cuts). Single crushed fruit can be infused in a
small amount of water, softened pulp is then put on the end of a thin twig and used
as an applicator to insert the pulp into the uterus. The residual mixture is discarded
as it is considered poisonous [30, 36].
Phytochemistry and Pharmacology: There is no record of phytochemical and
pharmacological studies on this plant.

2.3.2 
Cymbidium madidum Lindl. (Orchidaceae)

Cymbidium madidum is an epiphytic herb with stem-like pseudobulbs covered with

a sheathing base of leaves. It is commonly called a ‘giant boat-lip orchid.’
Ethnomedicine: Stem-like pseudobulbs is chewed by Aboriginal people of
Northern Queensland when they suffer from dysentery [17].
Phytochemistry and Pharmacology: Vitexin 7-glucoside, isovitexin-7-glucoside
(Saponarin), and vitexin were identified from the leaves [37].
366 K. Yeshi and P. Wangchuk

2.4 Antiseptics and Bactericides

2.4.1 
Ajuga australis R.Br. (Lamiaceae)

Ajuga australis is an herb, and it is also known by the common name ‘Australian
bugle,’ which is widespread over East Australian states.
Ethnomedicine: The whole bruised plant is mixed with hot water to make an
infusion and used for bathing sores and boils [30].
Phytochemistry and Pharmacology: Ajugapitin and (15R)-14,15-dihydro-15-­
hydroxyajugapitin are isolated from aerial parts [38]. A crude foliar extract showed
contact toxicity against the crop pest Tetranychus urticae [39].

2.4.2 
Brachychiton diversifolius R.Br. (Malvaceae)

Brachychiton diversifolius is a tree that grows to 3–25 m tall. The plant is com-
monly known as ‘Brachychiton,’ ‘kurrajong,’ and ‘northern kurrajong.’ In
Aboriginal languages, it is referred to as Birdba (Ngal, Nung), Dagdag (Jam),
Ngaliwurru, Nungali, Pinkyekper (Mal), Pinyengertpe (Mat), Dirlay (Mang,
Yang), Dakdakkin and Gulguldum in Warray [18]. It is often harvested for its
edible seeds and fibre. This tree is also spotted in Northern Queensland, Northern
Territories, and Western Australia. It usually grows along stony hills, riversides,
red sandy soils, basalt, and limestone areas. Seeds are usually cooked and eaten
but have low protein and fats [40, 41]. The plant is also harvested to sell as a
decorative plant [42].
Ethnomedicine: An extract prepared from the inner bark is used as an eye-
wash. Leaves, usually from the young plant, are pounded and soaked in water
for one hour, and the resultant infusion is used as body wash and a little liquid
placed in each ear. Such liquid is also used for treating skin lesions. A flexible
bark, stripped from the tree, serves as a handy bandage to wrap cuts and
wounds [28].
Phytochemistry and Pharmacology: The phytochemical analysis of the crude
ethanol extract of wood branches showed the presence of tannins, flavonoids,
alkaloids, saponins, phenols, and steroids [43]. The seed oil contains triacylg-
lycerols, such as linoleic and oleic acids, and amino acids [41]. Essential oils
from wood, bark, and leaves were analysed using gas chromatography and iden-
tified 21 methyl esters of fatty acid, out of which myristic acid in the wood and
palmitic acid in bark and leaves were major methyl esters of fatty acid [44].
There is no record of isolation of pure compounds from any plant parts of this
plant. The fatty acid fraction obtained from the wood, bark, and leaves showed
mild to moderate anti-bacterial (Bacillus subtilis and Sarcina lutea), anti-fungal
(Penicillium selerotigenum, Paecilomyces variotii, and Aspergillus niger), and
antioxidant activities [43, 44].
Bush Medicinal Plants of the Australian Wet Tropics and Their Biodiscovery Potential 367

2.4.3 
Erythrophleum chlorostachys (F.Muell.) Baill. (Fabaceae) (Fig. 3d)

Erythrophleum chlorostachys is a medium-sized tree (height of 18 m tall). The tree

is valued for its timber. It usually grows in the open forest but is also found in mon-
soon forests and rainforest margins up to 500 m above sea level. Its common names
are ‘ironwood,’ ‘leguminous ironwood,’ and ‘camel poison’ [21]. Incidents of poi-
soning caused by the leaves being washed into the water reservoirs or the roof gut-
ters have been reported. It also occurs in the northern territory, Queensland, and
Western Australia.
Ethnomedicine: A bark infusion is applied on spear wounds and over the body
for general malaise. The root infusion is applied for cuts and open sores [16, 25].
Phytochemistry and Pharmacology: Alkaloid β-dimethylaminoethyl cinnamate
was isolated from the leaves [45]. Norerythrostachaldine hydrochloride, noreryth-
rostachamine hydrochloride, and norerythrophlamine hydrochloride are isolated
from the bark [46]. There is no pharmacological studies conducted on the plant.

2.4.4 
Persoonia falcata R.Br. (Proteaceae)

Persoonia falcata is a shrub commonly called ‘Persoonia,’ ‘wild Pear,’ and ‘milky
Plum.’ In Aboriginal languages, it is called by different names as Warlwaya (Jam,
Ngal, Nung), Gilayi, Ngerrinytya, Ningggij (Mang), Gayabam (Yang), Warlaya,
Garttan, and Makbuny [21]. The plant is native to Northern Territory but also occurs
in Queensland and Western Australia.
Ethnomedicine: Fruits are eaten raw. Leaves and bark are considered medicinal.
An infusion of the leaves and barks are used as a treatment against sore throat and
colds [27]. An infusion from wood is applied externally to eyesores [16].
Phytochemistry and Pharmacology: The crude extract from the leaves and stem
showed anti-inflammatory activities by inhibiting pro-inflammatory cytokines in
the human peripheral blood mononuclear cells assay [47]. There is no report on its
phytochemicals.

2.5 Skin Disorders

2.5.1 
Acacia falcata Willd. (Leguminosae)

Acacia falcata is a shrub or tree that grows about 2–5 m tall (erect or spreading).
The plant is commonly called a ‘sickle wattle.’ It also occurs as far as inland to the
tablelands in Queensland and on the central coast of New South Wales, including
Narooma. It usually grows in sclerophyll forests, particularly coastal areas [21].
Ethnomedicine: The tree’s bark is used by Aboriginal communities (Yaegl peo-
ple of North NSW) to prepare embrocation to treat cutaneous diseases [48, 49].
368 K. Yeshi and P. Wangchuk

Moreover, in the counties of Cumberland and Camden, the people used bark (based
on tannin content) to stupefy fish.
Phytochemistry and Pharmacology: Leaves contain alkaloids, phenolics, flavo-
noids, terpenoids, anthraquinones, and condensed tannins [48]. Exudate contains
glucuronic acid, galactose, arabinose, and traces of rhamnose [50].
A crude extract of leaves showed anti-bacterial activity against multi-drug-­
resistant Staphylococcus aureus with the MIC value ranging from 250 to 1000ug/
mL. It is also anti-oxidative through DPPH (2,2-diphenyl-1-picryl-hydrazyl-­
hydrate), ABTS (3-ethylbenzothiazoline-6-sulfonic acid), and FRAP (ferric reduc-
ing antioxidant power) assays [48]. There is no record of isolation of pure compounds
from any parts of this plant.

2.6 Anti-inflammatory or Wound-Healing Plants

2.6.1 
Ageratum conyzoides (L.) L. (Compositae)

Ageratum conyzoides is an erect branched and hairy annual herb, that grows up to
30–60 cm tall. Herb is commonly called ‘billygoat weed’ or ‘billygoat plant.’ It is
not native to Australia, where it is a weed, but it originates from Central and South
America.
Ethnomedicine: Aboriginal people of Northern Queensland mash the whole
plant and then apply it to wounds to promote healing [51].
Phytochemistry and Pharmacology: 5′-methoxy nobiletin, coumarin, and eupal-
estin are isolated from aerial parts [52]. All these three compounds exhibited anti-­
inflammatory activity in a carrageenan-induced inflammation of mouse model by
inhibiting inflammatory cytokines such as IL-6, IFN-γ, p65 NF-kB, and MAPK
activation. Coumarin also increases the level of anti-inflammatory cytokine IL-10
[52]. The activity shown by these compounds is relatable to the wound-healing
property of the herb. Other active constituents: 5,6,7,8,3′,4′,5′-heptamethoxyflavone
[53], coumarin, [54, 55], lycopsamine, dihydrolycopsamine, and acetyl-­lycopsamine,
stigmasterol, precocene II, encecalol, demethoxyencecalol, sesamin, linderoflavone
B, 3′-hydroxy-5,6,7,8,4′,5′-hexamethoxyflavone, 2-hydroxycinnamic acid, and
3,4-dihydrocoumarin [56]; eupalestin, 5,6,7,5′-tetramethoxy-3′,4′-
methylenedioxyflavone, 5,6,7,3′,4′,5′-hexamethoxyflavone, ageconyflavone C [57];
ageconyflavones A-B, sinensetin, and 5,6,7,8,3′,5′-hexamethoxy-4′-
hydroxyflavone [58].

2.6.2 
Cynanchum viminale subsp. australe (P.I.Forst.) Liede &
Meve (Apocynaceae)

Cynanchum viminale subsp. australe is a succulent shrub that grows up to 5 m tall,

and it is commonly called a ‘caustic bush’ because of the white sap it exudes.
Bush Medicinal Plants of the Australian Wet Tropics and Their Biodiscovery Potential 369

Ethnomedicine: Aboriginal people use latex of this plant to treat bleeding wounds
sores, skin lesions, and cuts [59].
Phytochemistry and Pharmacology: There is no record of any phytochemical and
pharmacological studies on this plant so far.

2.6.3 
Dodonaea polyandra Merr. & L.M.Perry (Sapindaceae)

Dodonaea polyandra is a small tree growing up to 30 cm tall. It bears winged fruits

and becomes brown when ripened. It is commonly called ‘hop bush.’ Aboriginal
people of Kuuku I’yu centered on the Wenlock and Pascoe Rivers in the Cape York
Peninsula called it Uncha.
Ethnomedicine: The root is considered medicinal. The Aboriginal people of
Northern Kaanju of Cape York Peninsula prepare decoction from the roots and
apply it on cuts, wounds, sores and skin lesions [60].
Phytochemistry and Pharmacology: 5,7,4′-trihydroxy-3′(3-methylbut-2-enyl)-3-­
methoxy flavone, 5,7-dihydroxy-3′(3-methylbut-2-enyl)-3,4′-dimethoxy flavone
and 5,7,4′-trihydroxy-3′,5′(3-methylbuyt-2-enyl)-3-methoxy flavone, viscosol, and
5,4′-dihydroxy-3,7-dimethoxyflavone were isolated from the leaves and stems [61].
Non-polar hexane and methylene chloride/methanol extracts prepared from leaves
inhibited inflammation in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced
mouse (male Balb/c) ear oedema by 72.12 and 79.81%, respectively, after 24 h at
0.4 mg/ear dose [62].

Flagellaria indica L. (Flagellariaceae) (Fig. 3e)

Flagellaria indica is a semi-woody climbing plant with stems 10–15 m long and
1–2 cm thick. It is commonly called as ‘false rattan.’
Ethnomedicine: Astringent leaves are used for treating wounds [63].
Phytochemistry and Pharmacology: There is no record of analysing phytochemi-
cal constituents of this plant, but the aqueous leaf extract had phenolic content of
65.88 ± 1.84 mg gallic acid equivalent/g. The crude extract showed a protective
effect against carbon tetrachloride (CCl4)-mediated liver injury by suppressing oxi-
dative stress markers (4-hydroxynonenal and 8-hydroxydeoxyguanosine) and pro-­
inflammatory cytokines, such as TNF-α, IL-6, and PGE2 [64].

2.6.4 
Grevillea coriacea McGill (Proteaceae)

Grevillea coriacea is a shrub, and it is usually differentiated from other species of

the same genus by its convex leaves. It is commonly called a ‘fine-leafed beefwood.’
Ethnomedicine: Leaves are considered medicinal, and a bitter infusion made
from leaves is used as a gargle for sore throat in Cape York [65].
370 K. Yeshi and P. Wangchuk

Phytochemistry and pharmacology: There is no record of phytochemical and

pharmacological studies on this plant.

2.6.5 
Grevillea striata R.Br. (Proteaceae)

Grevillea striata is a 10 m tall tree with dark, persistent fissured bark. It is com-
monly known as ‘Grevillea’ and ‘beefwood.’ In Aboriginal languages, it is known
as Iyltenty, Lyent, Gulburru, Jirrirndi, Jawilyi, Piltentye, Wubgaji, Yiltilypa, Iltilpa,
Yiltilypa and Yilykinji, and ltyantye [21]. This species is easily distinguishable from
other species of the same genus as it has long strap-like leaves, cream flowers, and
a unique growth form. This plant is native to Northern Territory. It also occurs near
the coast in Queensland and the Northwest of Western Australia [21].
Ethnomedicine: Fruit is edible. Sap and wood are considered medicinal. The sap
is used to treat sores and wounds, and charcoal made from wood is used for stop-
ping bleeding from certain spear wounds [17].
Phytochemistry and Pharmacology: Striatol is isolated from heartwood [66].
Striatol showed a potent inhibition of PM Ca2+-ATPase, with an IC50 value of
16 μM [67].

2.6.6 
Macaranga tanarius (L.) Mull.Arg. (Euphorbiaceae) (Fig. 3f)

Macaranga tanarius is a deciduous shrub or small tree and grows up to 4–15 m tall.
It is commonly called ‘macaranga.’ It is also known as Dokoo-ral among the
Aboriginal people of Yirrganydji and Djabugay.
Ethnomedicine: Aboriginal people apply red sap to cure skin wounds and deep
cuts [28]. Aboriginal people also use leaves for cooking and wrapping food.
Phytochemistry and Pharmacology: Diterpene macarangonol isolated from the
leaf and stem [68]. Macaflavanones A-G, nymphaeol, nymphaeol C, tanariflavanone
A & B, and kolavenol are isolated from leaves [69, 70]. Macaflavanone G showed
toxicity against the KB cells (epidermal nasopharyngeal carcinoma, human cell
line) and A549 cell lines (lung cancer cell line) using 3-[4,5-dimethylthiazol-­2
-yl]-2,5- diphenyltetrazolium bromide (MTT) assay with IC50 values of 12.3 and
13.4 (3.0 and 2.1 μM for KB and A549 cells), respectively [69, 70].

2.6.7 
Melaleuca leucadendra L. (Myrtaceae)

Melaleuca leucadendra is a large tree often called paperback tree and prefers to
grow in the moist forest where fresh water is available all year round. Leaves
become hairless upon maturity, which is why sometimes it is also called ‘white-­
leafed tea tree.’
Bush Medicinal Plants of the Australian Wet Tropics and Their Biodiscovery Potential 371

Ethnomedicine: The bark of the tree is used as a bandage to wrap around

wounds [71].
Phytochemistry and Pharmacology: Oil from leaves is extensively studied for its
chemical constituents. Active constituents in leaves include ellagitannin and casua-
rinin [72], methylisoeugenol, trans-Ocimene and linalool [73]. Myricetin 3-O-β-­
4
C1-galactopyranuronoid, gallic acid, catechin, caffeic acid, myricetrin, methyl
gallate, isoquercitrin, astragalin, myricetin 3-O-glucoside, rutin, myricetin
3-­rutinoside, myricetin, and quercetin are also present [74]. Viridiflorol, eucalyptol,
α-terpineol, and limonene are present in the leaf oil [75]. Globulol, guaiol, and
α-pinene are present in the fruit oil [76];
Ellagitannin and casuarinin (100 mg/kg) reduced ulceration in rats, and this
activity can be relatable to its wound-healing property [72].

2.6.8 
Pterocaulon serrulatum (Montrouz.) Guillaumin (Compositae)

Pterocaulon serrulatum is a strongly scented, hairy perennial herb that grows about
40–90 cm tall. It is commonly known as ‘ragweed’ or ‘pintye-pintye.’ In Aboriginal
languages, it is called Tjungarai, Alworm-angka-ina, and Penja-pemja [77].
Ethnomedicine: Aboriginal people rub the whole plant over wounds and stuff
them with this herb [17].
Phytochemistry and Pharmacology: Ayapin, 5-methoxy-6,7-­
methylenedioxycoumarin, 6,7,8-trimethoxycoumarin, 5,7-dihydroxyflavanone, and
5-methoxyscopoletin were isolated from aerial parts [78]. Pharmacological data is
not reported for this species.

2.6.9 
Sterculia quadrifida R.Br. (Malvaceae)

Sterculia quadrifida is a tree that grows up to 20 m tall. When ripened, it has an

attractive bright orange or red pod containing seeds that are edible. Aboriginal peo-
ple have different names for this plant: Redfruit kurrajong, Kurrajong, Calool,
Gorarbar, Ko-ral-ba, Dundil, Balkpalk, and Ku-man [77].
Ethnomedicine: Aboriginal people of Northern Queensland apply crushed leaves
over their wounds to promote healing [51].
Phytochemistry and Pharmacology: Major constituents identified from extracts
of leaves, seeds, and bark: Tributyl acetyl citrate, 2,6,10,14,18,22-Tetracosahexaene,
and hexadecanoic acid [79]. Hexadecanoic acid possesses anti-inflammatory activ-
ity, which could be responsible for wound healing. Leaves are also known to contain
steroid compounds [80].
372 K. Yeshi and P. Wangchuk

2.7 Miscellaneous

2.7.1 
Doryphora aromatica (F.M.Bailey) L.S.Sm. (Atherospermataceae)

Doryphora aromatica is a medium-sized tree with smooth bark and dark-green

leaves, both possessing a strong aromatic smell. It is commonly called a ‘northern
grey sassafras,’ ‘grey sassafras,’ and ‘net sassafras.’
Ethnomedicine: A decoction prepared from bark is taken as a tonic [27]. Due to
its strong fragrance, Aboriginal women inhale its strong aroma to rid of nausea dur-
ing menstrual periods [28].
Phytochemistry and Pharmacology: Isolated (R)-nomimantharine trifluoroace-
tate, 12-demethylphaeantharine trifluoroacetate, nominanthranal trifluoroacetate,
1-hydroxy-6,7-dimethoxy-2-methylisoquinoline trifluoroacetate, and phaeantharine
trifluoro-acetate from leaves [81]. Other active constituents are alkaloids including
isocorydine, daphnoline, homoaromoline, daphnandrine, aromoline, isotetrandrine,
1,2-dehydroapateline [82]. (R)-nomimantharine trifluoroacetate and phaeantharine
trifluoroacetate showed moderate activity against Mycobacteria and multi-drug
resistant Staphylococcus aureus [81].

3 Scope for Drug Discovery from Wet Tropics

About two-thirds of medicinal plant species used worldwide are sourced from their
natural habitats [83]. Australia’s tropical forests, including ‘Wet Tropics,’ are home
to vast numbers of medicinal plant species. Many plants growing in the Wet Tropics
are affected by climate change and to survive, and the plants produce interesting and
higher concentration of biomolecules that could be exploited for pharmaceutical
research and development [84]. Most of these medicinal species remain least
explored for their phytopharmaceutical properties and have huge potential for dis-
covering natural product solutions for infectious and chronic diseases [85]. For
instance, only 16 out of 30 plant species included in this chapter have been studied
for their phytochemical or pharmacological properties. Rest 14 medicinal plants are
either not studied or only partially studied. Of the studied plants, 71 compounds
have been isolated from 16 medicinal plants included in this chapter. Out of 71
compounds, 10 compounds showed potent pharmacological activities, including
anti-inflammatory, anti-microbial, antioxidant, and anti-proliferative activities (see
Fig. 4 for the representative structures of bioactive molecules isolated from Wet
Tropics medicinal plants). Many compounds remain unassessed for their pharmaco-
logical properties.
Compounds such as coumarin from Ageratum conyzoides, ellagitannin and casu-
arinin from Melaleuca leucadendron, grandinin from Melaleuca quinquenervia,
and hexadecenoic acid from Sterculia quadrifida showed potent anti-inflammatory
activities [32, 52, 72, 80]. These medicinal plants are used by Aboriginal people to
Bush Medicinal Plants of the Australian Wet Tropics and Their Biodiscovery Potential 373

Betulinic acid Coumarin

Diosphenol Casuarinin

Eupalestin

Striatol Macaflavanone G 5’-Methoxy nobitelin

Fig. 4 Chemical structures of selected bioactive compounds isolated from Wet Tropical medici-
nal plants

heal wounds and inflammations, which makes it interesting. Thus, these compounds
are worth assessing further to develop wound-healing drugs or creams.
Macaflavanone G isolated from the leaves of Macaranga tanarius and diosphenol
from Excoecaria parvifolia (Fig. 4) are found to be toxic against human cancer cell
lines [23, 69, 70]. Betulinic acid isolated from leaves and twigs of Alphitonia excelsa
(Fig. 4) also showed anti-proliferative activity against human ovarian cancer cell
lines [19]. These compounds could be potential candidates for developing anti-­
cancer drugs. The crude extract obtained from the leaves of Acacia falcata showed
potent anti-bacterial activity, including against multi-drug resistant species
Staphylococcus aureus, and thus, this medicinal plant may contain promising anti-­
microbial drug leads.
Overall, many bush-medicinal plants included in this chapter remain less
explored for their phytochemical profiles and pharmaceutical applications. This
could be partially due to limited accessibility as their collection is strictly regulated
by The Convention on Biological Diversity [86], Queensland Biodiversity Act and
other local state and federal Biodiversity Protection Acts, requiring collection per-
mits for accessing and studying the plants.
Recently, there has been a renewed interest among TOs aspiring to collaborate
with scientists to investigate their bush food and medicine and add value to it. A few
374 K. Yeshi and P. Wangchuk

successful collaborations between the indigenous communities and research institu-

tions have been conducted. For example, the Mbabaram people in Far North
Queensland work with the University of Western Sydney’s National Institute of
Complementary Medicine to develop new medicines based on bush medicine rem-
edies. The same community is also working with the TIEC and the Australian
Institute of Tropical Health and Medicine (AITHM) at James Cook University,
Cairns, to discover and develop novel anti-inflammatory drugs for inflammatory
bowel disease from a few FNQ medicinal plants used to treat inflammatory condi-
tions. A biodiscovery pathways including screening for antioxidant, anti-­
inflammatory, anthelmintic, and antimicrobial properties have been established by
the senior author of this chapter at JCU [87, 88]. This is expected to help the Wet
Tropics’ Aboriginal communities commercialise their knowledge and protect their
intellectual property rights. While undertaking such initiatives, it is crucial to respect
their culture and knowledge and engage them with their consent by signing a formal
collaborative and benefit-sharing agreement as per the Queensland Biodiscovery
Act [89].

4 Conclusion

Wet Tropics has both cultural and ecological significance to Australia. Culturally,
“Wet Tropics” is home to many indigenous communities, whose ancestors were
highly skilled and knowledgeable explorers of the Wet Tropics vegetation. They
learned to survive for millennia utilising their rich flora and fauna in food, medicine,
shelter, and protection. Even today, the Aboriginal communities possess vast tradi-
tional knowledge of plants, and they play a critical role in conserving the Rainforests
of the Wet Tropics of Australia. Most medicinal plants growing in the “Wet Tropics”
are either native or endemic to Australia, and they are least explored for their phy-
tochemical properties. Of many tropical medicinal plants of Australia, 30 medicinal
plants included in this chapter grow in the Wet Tropics region. Of 71 compounds
that have been isolated from 16 of these medicinal plants, ten compounds showed
potent pharmacological activities, including anti-inflammatory, anti-microbial, anti-
oxidant, and anti-proliferative. Thus, “Wet Tropics” presents an excellent resource
for drug discovery. Traditional custodians and their younger generations have
started documenting their traditional knowledge and establishing research collabo-
ration with bigger academic institutions across Australia, especially with James
Cook University. Such initiatives are a welcoming sight as they could validate the
traditional uses of wild plants, develop bush foods and health-promoting products,
and provide novel drug lead molecules for treating many diseases.

Acknowledgement We would like to thank Mr. Gerry Turpin (Ethnobotanist) of TIEC, JCU and
Paul Williams (Botanist) of Vegetation Management Science, Malanda, Queensland for their sug-
gestions and comments.
Bush Medicinal Plants of the Australian Wet Tropics and Their Biodiscovery Potential 375

References

1. WHC (n.d.) World heritage conservation. Wet Tropics of Queensland. Retrieved on February
28, 2022 from https://whc.unesco.org/en/list/486/
2. Wet Tropics Nanagement Authority. Endemic and rare species. Retrieved on February 12,
2022 from https://www.wettropics.gov.au/endemic-­species
3. Wet Tropics Management Authority (2016) State of wet tropics report 2015–2016. Ancient,
endemic, rare and threatened vertebrates of the wet tropics. https://www.wettropics.gov.au/
site/user-­assets/docs/sowt2015-­16b5-­lres.pdf
4. Webb LJ, Tracey JG (1994) The rainforests of northern Australia. In: Groves RH (ed) Australian
vegetation, 2nd edn. Cambridge University Press, pp 87–130
5. Sanderson R (2008) Re-writing the history of Australian tropical rainforests: ‘alien invasives’
or ‘ancient indigenes’? Environ Hist 14:165–185
6. CSIRO (2019) Bureau of Meteorology and the CSIRO. Regional weather and climate guides.
Retrieved on February 28, 2022 from http://www.bom.gov.au/climate/climate-­guides/
guides/027-­Wet-­Tropics-­QLD-­Climate-­Guide.pdf
7. Roberts P, Buhrich A, Caetano-Andrade V, Cosgrove R, Fairbairn A, Florin SA et al (2021)
Reimagining the relationship between Gondwanan forests and Aboriginal land management in
Australia’s “Wet Tropics”. iScience. 24(3):102190. https://doi.org/10.1016/j.isci.2021.102190
8. Lourandos H, David B (1998) Comparing long-term archaeological and environmental trends:
North Queensland, arid and semi-arid Australia. The Artefact. 21:105–114
9. Hill R, Griggs P, Incorporated BBN (2000) Rainforest, agriculture and Aboriginal fire-regimes.
Aust Geogr Stud. 38:138–157
10. Pascoe B (2018) Dark Emu: Aboriginal Australia and the birth of agriculture. Magabala Books
11. WTMA. Wet Tropics Management Authority (WTMA) (n.d.) Wet tropics cultural landscape:
rainforest Aboriginal people. Retrieved on March 2, 2022 from https://www.wettropics.gov.
au/our-­cultural-­landscape
12. Wet Tropics Management Authority (WTMA) (n.d.) Wet tropics cultural landscape: rain-
forest Aboriginal people. Retrieved on March 2, 2022 from https://www.wettropics.gov.au/
our-­cultural-­landscape
13. Anonymous. Tropical Indigenous Ethnobotany Centre. Accessed on February 12, 2022 from
https://www.tiec.org.au/about-­tiec
14. Cock IE (2011) Medicinal and aromatic plants—Australia. In: Ethnopharmacology Section,
Biological, Physiological and Health Sciences, Encyclopedia of Life Support Systems
(EOLSS), Developed under the Auspices of the UNESCO. EOLSS Publishers, Oxford.
Available online: http://www.eolss.net. Accessed 30 Apr 2022
15. Wet Tropics Management Authority. Australia’s tropical rainforests world heritage: Fact sheet-­
bush medicine. Accessed on February 13, 2022 from https://www.wettropics.gov.au/site/user-­
assets/docs/bushmedicine.pdf
16. Webb LJ (1969) The use of plant medicines and poisons by Australian aborigines.
Mankind. 7:137
17. Roth W (1903) Superstition, magic, and medicine, North Queensland Ethnography Bulletin
No. 5. Government Printer, Brisbane
18. Tithi NA (2017) Chemical and biological investigations of the Yaegl medicinal plant Alphitonia
excelsa. Accessed on February 28, 2022 http://hdl.handle.net/1959.14/1267484
19. Fuentes RG, Valenciano AL, Cassera MB, Kingston DGI (2020) Antiproliferative and
antiplasmodial investigation of Alphitonia excelsa and Arcangelesia flava. Philipp J Sci
149(1):115–120
20. Lassak EV, McCarthy T (2011) Australian medicinal plants: a complete guide to identification
and usage. Reed New Holland, Chatswood
21. FloraNT: Nothern territory flora online. Accessed on February 14, 2022 from http://eflora.
nt.gov.au/home
376 K. Yeshi and P. Wangchuk

22. Smith N, Wididburu B, Harrington RN, Wightman G (1993) Ngarinyman ethnobotany:

Aboriginal plant use from the Victoria river area, Northern Australia. Northern Territory
Bulletin No. 15, Conservation Commision of the Northern Territory, Darwin
23. Grace MH, Faraldos JA, Lila MA, Coates RM (2007) ent-Beyerane diterpenoids from the
heartwood of Excoecaria parvifolia. Phytochemistry. 68(4):546–553. https://doi.org/10.1016/j.
phytochem.2006.11.010
24. Levitt D (July/Aug 1979) Unwritten pharmacopoeia. Hemisphere:14–19
25. Webb LJ (1948) Guide to the medicinal and poisonous plants of Queensland. CSIRO
Bulletin No. 232
26. Fletcher MT, Hayes PY, Somerville MJ, De Voss JJ (2010) Ptesculentoside, a novel norses-
quiterpene glucoside from the Australian bracken fern Pteridium esculentum. Tetrahedron Lett
51(15):1997–1999. https://doi.org/10.1016/j.tetlet.2010.02.032
27. Webb LJ (1959) Some new records of medicinal plants used by the Aborigines of tropical
Queensland and New Guinea, vol 71. Royal Society of Queensland, Brisbane, p 103
28. Williams C (2010) Medicinal plants in Australia volume I: bush pharmacy. Rosenberg
29. Sadgrove NJ, Jones GL (2013) Antimicrobial activity of essential oils and solvent extracts
from Zieria species (Rutaceae). Nat Prod Commun 8(6):741–745
30. Lassak EV, McCarthy T (1992) Australian medicinal plants. Mandarin. Octopus Publishing
Group, Melbourne
31. Maiden JH (1904) The forest flora of New South Wales, vol I. Government Printer, Sydney
32. Moharram FA, Marzouk MS, El-Toumy SAA, Ahmed AAE, Aboutabl EA (2003) Polyphenols
of Melaleuca quinquenervia leaves – pharmacological studies of grandinin. Phytother Res
17(7):767–773
33. Gaínza YA, Domingues LF, Perez OP, Rabelo MD, López ER, Chagas ACS (2015)
Anthelmintic activity in vitro of Citrus sinensis and Melaleuca quinquenervia essential oil
from Cuba on Haemonchus contortus. Ind Crops Prod 76:647–652. https://doi.org/10.1016/j.
indcrop.2015.07.056
34. el-Toumy SA, Marzouk MS, Moharram FA, Aboutabl EA (2001) Flavonoids of Melaleuca
quinquenervia. Pharmazie 56(1):94–95. https://doi.org/10.1002/chin.200117207
35. Chao WW, Su CC, Peng HY, Chou ST (2017) Melaleuca quinquenervia essential oil inhibits
alpha-melanocyte-stimulating hormone-induced melanin production and oxidative stress in B16
melanoma cells. Phytomedicine. 34:191–201. https://doi.org/10.1016/j.phymed.2017.08.024
36. Levitt D (1981) Plants and people: Aboriginal uses of plants on groote eyelandt. Australian
Institute of Aboriginal Studies, Canberra
37. Williams CA (1979) The leaf flavonoids of the orchidaceae. Phytochemistry. 18(5):803–813
38. de la Torre MC, Rodríguez B, Bruno M, Piozzi F, Vassallo N, Bondí ML et al (1997) Neo-­
clerodane diterpenoids from Ajuga australis and A. orientalis. Phytochemistry. 45(1):121–123
39. Rasikari HL, Leach DN, Waterman PG, Spooner-Hart RN, Basta AH, Banbury LK et al (2005)
Acaricidal and cytotoxic activities of extracts from selected genera of Australian lamiaceae. J
Econ Entomol 98(4):1259–1266
40. Low T (1989) Wild food plants of Australia. Angus and Robertson, Melbourne
41. Rao KS, Jones GP, Rivett DE, Tucker DJ (1989) Fatty acid and amino acid compositions of
Brachychiton discolor, Brachychiton diversifolius, and Brachychiton acerifolius seeds. J Agric
Food Chem. 37:916–917
42. Gorman J, Pearson D, Whitehead P (2008) Assisting Australian indigenous resource manage-
ment and sustainable utilization of species through the use of GIS and environmental modeling
techniques. J Environ Manage 86(1):104–113. https://doi.org/10.1016/j.jenvman.2006.11.033
43. Abdel-Megeed A, Salem MZM, Ali HM, Gohar YM (2013) Brachychiton diversifolius as
a source of natural products: antibacterial and antioxidant evaluation of extracts of wood
branches. J Pure Appl Microbiol 3:1843–1850
44. Salem MZM, Ali HM, Mansour MM (2014) Fatty acid methyl esters from air-dried wood,
bark, and leaves of Brachychiton diversifolius R.Br: antibacterial, antifungal, and antioxidant
activities. BioResources. 9(3):3835–3845
Bush Medicinal Plants of the Australian Wet Tropics and Their Biodiscovery Potential 377

45. Griffin WJ, Phippard JH (1971) Alkaloids of the leaves of Erythrophleum chlorostachys.
Phytochemistry. 10:2793–2797
46. Falkiner MJ, Faux AF, Loder JW, Nearn RH (1975) Isolation of unstable alkaloids from
Erythrophleum chlorostachys (Leguminosae). Aust J Chem. 28:645–650
47. Yeshi K, Turpin G, Wangchuk P. Anti-inflammatory activities of medicinal plants from
Mbabaram community of the Far North Queensland (unpublished data). 2020.
48. Akter K, Barnes EC, Brophy JJ, Harrington D, Community Elders Y, Vemulpad SR et al (2016)
Phytochemical profile and antibacterial and antioxidant activities of medicinal plants used by
Aboriginal people of New South Wales, Australia. Evid Based Complement Alternat Med.
2016:4683059. https://doi.org/10.1155/2016/4683059
49. Maiden JH (1913) Appendix: Aboriginal method of obtaining water. In: The Forest Flora of
New South Wales, vol 6, Part LI. NSW Government Printer, Sydney
50. Anderson DMW, Bell PC, McNab CGA (1972) Analysis of six Acacia gum exudates of the
series phyllodineae. Phytochemistry 11:1751–1754
51. Webb LJ (1959) Proc Royal Soc Queensland. 71:103
52. Vigil de Mello SV, da Rosa JS, Facchin BM, Luz AB, Vicente G, Faqueti LG et al (2016)
Beneficial effect of Ageratum conyzoides Linn (Asteraceae) upon inflammatory response
induced by carrageenan into the mice pleural cavity. J Ethnopharmacol. 194:337–347. https://
doi.org/10.1016/j.jep.2016.09.003
53. Adesogan EK, Okunade AL (1979) A new flavone from Aegeratum conyzoides. Phytochemistry.
18(11):1863–1864
54. Moreira MD, Picanco MC, Barbosa LC, Guedes RN, Barros EC, Campos MR (2007)
Compounds from Ageratum conyzoides: isolation, structural elucidation and insecticidal
activity. Pest Manag Sci. 63(6):615–621. https://doi.org/10.1002/ps.1376
55. Vyas AV, Mulchandani NB (1984) Structure reinvestigation of Conyzorigun, a new chromone
from Ageratum conyzoides. J Chem Soc Perkin Trans. 1:2945–2947
56. Bosi CF, Rosa DW, Grougnet R, Lemonakis N, Halabalaki M, Skaltsounis AL et al (2013)
Pyrrolizidine alkaloids in medicinal tea of Ageratum conyzoides. Revista Brasileira de
Farmacognosia. 23(3):425–432. https://doi.org/10.1590/s0102-­695x2013005000028
57. Nour AM, Khalid SA, Kaiser M, Brun R, Abdalla WE, Schmidt TJ (2010) The antiproto-
zoal activity of methylated flavonoids from Ageratum conyzoides L. J Ethnopharmacol.
129(1):127–130. https://doi.org/10.1016/j.jep.2010.02.015
58. Vyas AV, Mulchandani NB (1986) Polyoxygenated flavones from Aegeratum conyzoides.
Phytochemistry. 25(11):2625–2627
59. Cribb AB, Cribb JW (1981) Wild medicine in Australia. Collins, Sydney
60. Webb LJ (1959) The use of plant medicines and poisons by Australian Aborigines. Mankind.
7:137–172
61. Simpson BS, Claudie DJ, Smith NM, Gerber JP, McKinnon RA, Semple SJ (2011) Flavonoids
from the leaves and stems of Dodonaea polyandra: a Northern Kaanju medicinal plant.
Phytochemistry. 72(14-15):1883–1888. https://doi.org/10.1016/j.phytochem.2011.05.006
62. Simpson B, Claudie D, Smith N, Wang J, McKinnon R, Semple S (2010) Evaluation of
the anti-inflammatory properties of Dodonaea polyandra, a Kaanju traditional medicine. J
Ethnopharmacol. 132(1):340–343. https://doi.org/10.1016/j.jep.2010.07.012
63. Maiden JH (1889) The useful native plants of Australia. Turner & Henderson, Sydney
64. Gnanaraj C, Shah MD, Makki JS, Iqbal M (2016) Hepatoprotective effects of Flagellaria indica
are mediated through the suppression of pro-inflammatory cytokines and oxidative stress mark-
ers in rats. Pharm Biol. 54(8):1420–1433. https://doi.org/10.3109/13880209.2015.1104697
65. Williams C (2011) Medicinal plants in Australia. Volume II gums, resins, tannin and essential
oils. Rosenberg Publishing Pty Ltd., Kenthurst
66. Rasmussen M, Ridley DD, Ritchie E, Taylor WC (1968) Chemical studies of proteaceae
III. The structure determination and synthesis of striatol, a novel phenol from Grevillea striata
R.Br. Aust J Chem. 21:2989–2999
378 K. Yeshi and P. Wangchuk

67. Roufogalis BD, Li Q, Tran VH, Kable EPW, Duke CC (1999) Investigation of plant -derived
phenolic compounds as plasma membrane Ca2+-ATPase inhibitors with potential cardiovascu-
lar activity. Drug Develop Res 46:235–249
68. Hui WH, Ng KK, Fukamiya N, Koreeda M (1971) Isolation and structure of macarangonol,
a diterpene ketol from Macaranga tanarius. Food Agric Org United Nations 10:1617–1620
69. Kawakami S, Harinantenaina L, Matsunami K, Otsuka H, Shinzato T, Takeda Y (2008)
Macaflavanones A-G, prenylated flavonones from the leaves of Macaranga tanarius. J Nat
Prod. 71:1872–1876
70. Tseng M-H, Chou C-H, Chen Y-M, Kuo Y-H (2001) Allelopathic prenylflavanones from the
fallen leaves of Macaranga tanarius. J Nat Prod. 64:827–828
71. Fletcher TG (2007) Thanakupi’s guide to language & culture: a Thaynakwith dictionary.
Jennifer Isaacs Arts & Publishing, North Sydney
72. Al-Sayed E, Michel HE, Khattab MA, El-Shazly M, Singab AN (2020) Protective role of
casuarinin from Melaleuca leucadendra against ethanol-induced gastric ulcer in rats. Planta
Med. 86(1):32–44. https://doi.org/10.1055/a-­1031-­7328
73. Brophy JJ (1988) Melaleuca leucodendra L. leaf oil: two phenylpropanoid chemotypes. Flav
Fragr J 3:43–46
74. Hashim AN, Swilam NF, Moustafa ES, Bakry SM, Labib RM, Barakat HH et al (2018) A cyto-
toxic flavonol glycoside from Melaleuca leucadendra leaves extract with immunostimulant
activity. Pharmazie. 73(1):61–64. https://doi.org/10.1691/ph.2018.7785
75. Pino J, Bello A, Urquiola A, Aguero J, Marbot R (2002) Chemical composition of Cajuput
oil (Melaleuca leucadendra L.) from Cuba. J Essential Oil Res 14(1):10–11. https://doi.org/1
0.1080/10412905.2002.9699744
76. Pino JA, Regalado ELR, J.L., Fernández MD. (2010) Phytochemical analysis and in vitro free-­
radical-­scavenging activities of the essential oils from leaf and fruit of Melaleuca leucadendra
L. Chemistry and Biodiversity. 7(9):2281–2288
77. Lassak EV, McCarthy T (1983) Australian medicinal plants. Methuen Australia
78. Macleod JK, Rasmussen HB (1999) A hydroxy-β-caryophyllene from Pterocaulon serrula-
tum. Phytochemistry. 50(1):105–108. https://doi.org/10.1016/S0031-­9422(98)00460-­9
79. Siswadi S, Saragih GS (2021) Phytochemical analysis of bioactive compounds in ethanolic
extract of Sterculia quadrifida R.Br. International Conference on Life Sciences and Technology
(ICoLiST 2020)
80. Taebe B, Imrawati I, Rachman CN (2019) Isolation and characterisation of the steroid com-
pounds from aceton extract of Faloak leaves (Sterculia quadrifida R.Br). J Pharm Med Sci 3(2)
81. Liu M, Han J, Feng Y, Guymer G, Forster PI, Quinn RJ (2021) Antimicrobial
benzyltetrahydroisoquinoline-­derived alkaloids from the leaves of Doryphora aromatica. J
Nat Prod. 84(3):676–682. https://doi.org/10.1021/acs.jnatprod.0c01093
82. Bick IC, Leo W, Richards M (1980) Alkaloids of Doryphora aromatica. Aust J Chem
33(1):225–228
83. Canter PH, Thomas H, Ernst E (2005) Bringing medicinal plants into cultivation: opportunities
and challenges for biotechnology. Trends Biotechnol. 23(4):180–185
84. Yeshi K, Crayn D, Ritmejeryte E, Wangchuk P (2022) Plant secondary metabolites produced
in response to abiotic stresses has potential application in pharmaceutical product develop-
ment. Molecules. 27(1):1–31. https://doi.org/10.3390/molecules27010313
85. Adegboye O, Field MA, Kupz A, Pai S, Sharma D, Smout MJ et al (2021) Natural-product-­
based solutions for tropical infectious diseases. Clin Microbiol Rev 34(4):e0034820. https://
doi.org/10.1128/CMR.00348-­20
86. United Nations: Convention on Biological Diversity (1992). http://www.cbd.int/doc/legal/cbd-
­en.pdf. Accessed 2021
87. Yeshi K, Kashyap S, Yangdon P, Wangchuk P (2017) Taxonomical identification of himala-
yan edible medicinal plants in Bhutan and the phenolic contents and antioxidant activity of
selected plants. JBAPN. 7(2):89–106. https://doi.org/10.1080/22311866.2017.1325008
Bush Medicinal Plants of the Australian Wet Tropics and Their Biodiscovery Potential 379

88. Nugraha AS, Dayli IR, Sukrisno Putri CPZ, Firli LN, Widhi Pratama AN, Triatmoko B
et al (2022) Isolation of antibacterial depside constituents from Indonesian Folious Lichen,
Candelaria fibrosa. J Biol Active Prod Nature. 12(1):24–32
89. Anonymous. Biodiscovery and bussiness, Queensland Government. Retrieved on February
27, 2022 from https://www.business.qld.gov.au/industries/science-it-creative/science/bio-
discovery/qld#:~:text=The%20Biodiscovery%20Act%202004%20aims,equitable%20
benefit%20to%20the%20community.&text=This%20obligation%20applies%20to%20
biodiscovery,collection%20from%20anywhere%20in%20Queensland
Trillium govanianum – A Promising
Endemic Medicinal Herb of the Himalaya

Kausar Rashid, Sufiya Rashid, Aijaz Hassan Ganie, Irshad A. Nawchoo,

Mudasir A. Tantry, and Anzar A. Khuroo

1 Introduction

Plants have been used for medicinal purposes long before recorded history. Even
today, the traditional medicinal uses of plants play an important role in providing
primary health care [1, 2]. The World Health Organization (WHO) has documented
over 21,000 plant species all over the world used as medicinal [3]. About 70–80% of
people around the globe rely on medicinal plants for primary healthcare and liveli-
hood [4]. About 3.5–4 billion people in the world are dependent on plants as potent
sources of drugs [5]. However, simultaneously, the recent increase in market demand
for herbal products has resulted in huge pressure on natural populations of medicinal
plants, which in turn has brought many prized species to the brink of extinction [6–8].
A systematic review of medicinal plant species especially with a detailed focus
on their botanical, ethnomedicinal, phytochemical, and pharmacological aspects
effectively integrates the precious information but scattered in research studies [9].
The reviews critically synthesize the disparate research knowledge at a single scien-
tific platform and help researchers to assess the progress achieved so far, highlight
knowledge gaps and suggest future research directions. In recent times, reviews on
several medicinal plant species with a focus on their ethnomedical use, phytochem-
istry and pharmacology have been published [10]. These critical review help in

K. Rashid (*) · S. Rashid · A. H. Ganie · I. A. Nawchoo

Plant Reproductive Biology, Genetic Diversity and Phytochemistry Research Laboratory,
Department of Botany, University of Kashmir, Srinagar, J & K, India
M. A. Tantry
Department of Chemistry, S. P. College, School of Sciences, Cluster University Srinagar,
Srinagar, J & K, India
A. A. Khuroo
Centre for Biodiversity & Taxonomy, Department of Botany, University of Kashmir, Srinagar,
J & K, India

© The Author(s), under exclusive license to Springer Nature 381

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_14
382 K. Rashid et al.

linking the novel leads from ethnomedicinal uses of plant species to active phyto-
chemical constituents and pharmacological properties. These studies show that the
use of medicinal plant products has been growing not only as therapeutically active
agents, but also unlock the rich reservoir of naturally occurring lead compounds in
drug discovery [11].
Trillium govanianum Wall. ex D.Don (English Name: Himalayan Trillium) has
recently emerged as one of the most important medicinal species of the Himalayan
region with a high therapeutic value [12]. The market demand for the raw material
of this medicinal plant has increased manifold owing to its high concentration of
diosgenin; and the quantity of the diosgenin is almost threefold higher than reported
from other plant sources: Asparagus, Chlorophytum, Dioscorea and Trigonella spe-
cies [13]. Diosgenin has many pharmaceutical uses: it is used as anti-cancerous,
anti-ageing, anti-inflammatory and precursor for manufacturing many steroidal
drugs [14, 15]. However, the collection of this medicinal plant species to meet the
rising demand of the pharmaceutical industry, and more worryingly its unsustain-
able harvesting from the wild, is alarmingly depleting its natural populations across
the Himalaya. The species is almost threatened now in the entire Himalayan region
[7]. Its slow life cycle taking several years to reach the flowering stage, specific
habitat requirement, low population density, no commercialization alternatives, her-
bivory and overharvesting for pharmaceutical industries has brought this species to
the threatened status [16].
It is in this background that the present review provides a comprehensive synthe-
sis of the research studies conducted on the botanical, ethnomedicinal, phytochemi-
cal and pharmacological aspects of T. govanianum. Hopefully, this scientific
synthesis on T. govanianum will help in stocktaking the research progress achieved
so far and prospects of future research opportunities on this promising endemic
medicinal plant from the Himalaya.

2 Materials and Methods

The published literature on T. govanianum were retrieved using popular and rele-
vant science search engines and database including scientific journals, books, theses
and electronic search (Google Scholar, Science Direct, Research Gate, JSTOR and
PubMed). We used the following keywords: “Trillium”, “Trillium govanianum”,
“T. govanianum”, “Himalayan Trillium” independently, and combined with other
terms: “botany”, “morphology”, “taxonomy”, “phenology”, “biogeography”, “tra-
ditional uses”, “ethnic uses”, “ethnomedicine”, “local uses”, “ethnomedicinal uses”,
“phytochemistry”, “steroids”, “saponins”, “steroidal saponins”, “active com-
pounds”, “chemical constituents”, “pharmacology”, “biological activity”, “activ-
ity”, “toxic”, “toxicity”, “propagation”, “threat” and “conservation”. In total, 54
studies spanning from the year 1994 to April 2020 were critically read, evaluated
and incorporated in this review (Fig. 1).
The chemical structures and formulae of compounds have been sourced and vali-
dated by using the PubChem database. Chemical structures were drawn using Chem
Trillium govanianum – A Promising Endemic Medicinal Herb of the Himalaya 383

Fig. 1 Temporal trends in research publications on ethnomedicine, phytochemistry, and pharma-

cology of Trillium govanianum

Draw Ultra Version 6 software. Ethnomedicinal data compiled include species

name, part used, local name, location, medicinal uses (Table 1). Data on phyto-
chemicals reported from T. govanianum include chemical constituents extracted
and their chemical structure, the identification method and source(s) (Table 2).

2.1 Botany

Trillium govanianum Wall. ex D. Don, an endemic species from the Himalaya, is

one of the 49 species known in the genus Trillium [44, 45]. Previously, the members
of the Trillium were placed within the family Liliaceae, because sepals and petals
both resembled: often large and shiny as commonly seen in Lilies (Lilium) [46].
However, the genus Trillium along with other genera is now placed in its own sepa-
rate family Melanthiaceae under the order Liliales [46–48]. T. govanianum is
reported to be an allotetraploid species [x = 5, 2n = 4x = 20] composed of two
genomes – an intergeneric hybrid between Trillium tschonoskii and the diploid
Daiswa polyphylla [49, 50].
It is a perennial herb, having stout rhizome with numerous fibrous adventitious
roots possessing three leaves in one whorl at the top of the scapose stem and a soli-
tary, purple flower in the centre [51]. Plant is up to 12–20 cm tall. Rhizome is creep-
ing, slightly elongate and terete. Stem solitary. Leaves petiolated, leaf blade ovate to
cordate, leaf apex acute to acuminate, glabrous, and venation reticulate. Flowers are
bisexual, solitary, terminal, pedicellate and pedicel 0.9–2.3 cm long. Perianth seg-
ments dark purple, narrowly lanceolate, outer segments 2–4 mm broad, inner nar-
rower; perianth spreading in flower, and reflexed in the fruiting stage. Stamens 6, in
384 K. Rashid et al.

2 whorls, shorter than the perianth; filaments ca. 4 mm long; anthers basifixed,
4–5 mm long, curved, and dehiscence longitudinal. Ovary superior, purple-red,
ovoid-globose, 3-loculed and ovules few to many per locule. Fruit red, globose
berry, 1–2 cm in diameter, seeds numerous, oblong, ca. 2.5 mm long, with a pulpy
lateral appendage (Fig. 2).

Fig. 2 Trillium govanianum. (a) Habitat, (b) Habit, (c) Rhizome, Individual plants with (d) one
leaf, (e) two leaves, (f) threes leaves, (g) Bisexual flower, (h) Dark purple tepals (i) Berry fruit
Trillium govanianum – A Promising Endemic Medicinal Herb of the Himalaya 385

2.2 Biogeography

The genus Trillium, with ca. 49 species world over, is one of the representative ele-
ments of the northern temperate forests. It has been reported that the genus origi-
nated in Arcto-Tertiary and shows geographical distribution between North America
and eastern Asia including Japan [52, 53]. About 40 species occur in North America,
the remaining nine species are found in Asia [54]. T. govanianum (Himalayan
Trillium), one of the Asian species, is endemic to the Himalayan region. It is distrib-
uted in temperate and subalpine zones of the Himalaya at altitudes ranging from
1800 to 3500 m (m.s.l.), especially in Afghanistan, Pakistan, India, Bhutan, Nepal
and China (Tibet) [55, 56]. In the Indian Himalaya, this species is primarily distrib-
uted in the western region (Jammu and Kashmir, Himachal Pradesh, Uttarakhand)
and is less common in the eastern region [16]. The species usually prefers moist
shady areas in forest understory for its profuse growth [57, 58].

2.3 Phenology and Life Cycle

T. govanianum is a typical early spring geophyte. It grows each year in late March
after snow melts, flowering starts usually in April and fruiting season lasts from
May to June. Leaf senescence occurs in July/August at lower altitudes and
September/October at higher altitudes. During the flowering phase, both vegetative
and flowering individuals can be found on the forest floor. The vegetative individu-
als comprise three morphologically distinct forms: individuals bearing 1-leaf,
2-leaves and 3-leaves (Fig. 2). As the plant shows a relatively slower growth rate,
taking many years to enter the reproductive phase, the life span of the species is
reported to be ca. 30 years [16, 59].

2.4 In Vitro Regeneration

Plant tissue culture refers to the culturing of different plant explants such as leaves,
seeds, tissues, cells or protoplasts on a chemically defined synthetic nutrient media
under sterile and controlled conditions of light, temperature, humidity, etc. [60].
The in vitro multiplication technique has an advantage over in vivo conditions, as it
can yield a definite and uniform production system of quality and yield [61, 62]. In
fact, in contrast to the time-consuming indigenous techniques, micro-propagation
has led to the easy generation of somatic clones (ramets) of selected genotypes [63].
T. govanianum, being a rich treasure of novel phytochemicals, has led to its overex-
ploitation from its natural habitats rendering it endangered [12]. Therefore, plant
tissue culture offers an important and potential alternative method for rapid multi-
plication and germplasm conservation of this medicinally important plant species.
386 K. Rashid et al.

Recently, Chauhan et al. [64] reported to have standardized a micro-propagation

protocol for T. govanianum, wherein shoot tip and complete shoot bud explants
regenerated into shoots and callus-like structures when cultured on MS media sup-
plemented with hormones. They also reported that the in vitro-raised plantlets were
acclimatized in greenhouse with a survival rate of more than 90% in the first grow-
ing season.

2.5 Ethnomedicinal Uses

T. govanianum has been widely used in traditional medicinal systems because of its
broad therapeutic properties. It is commonly known as “tri pater”, “nag chhatri” or
“chotasatwa” in India, “teenpatra” or “matarzela” in Pakistan, and “Xizangyan ling
cao” in Tibet (China). The underground part of the plant, i.e. rhizome is a prime raw
material used in trade. The plant is used in several traditional medicine systems and
used for the treatment of ailments such as boils, dysentery, inflammation, menstrual
disorders, sex-related disorders, wounds, as an antiseptic, and for improving general
health [18, 20, 25, 65–67]. It has been reported that the powdered rhizome is used
as body and sexual tonic [28]. In Jammu and Kashmir (India), the Gujjar and
Bakerwal tribes make tea from dried rhizomes to cure inflammation and kidney
diseases [17]; and fresh rhizome is consumed with herbal tea to treat appetite disor-
der [33]. In Himachal Pradesh (India), tribal communities take dried form of rhi-
zome with cow milk in early morning to cure menstrual and reproductive disorder
[18]. In Shimla district of Himachal Pradesh people use leaves and root paste to cure
minor cuts, wounds, and foot cracks [35]. The migratory shepherds in Kinnaur dis-
trict in Himachal Pradesh use dried leaves and root powder for curing cough, fever,
vomiting [37], and the juice of fresh leaves and roots is used for the treatment of
body pain, internal injury and foot and mouth diseases [38]. In Azad Jammu and
Kashmir (Pakistan), dried root powder is applied externally to cure wounds [19].
Besides human diseases, the leaves of this plant are used for treating indigestion and
parasites in livestock [28]. In the Bandipora area of Jammu and Kashmir (India), the
crushed rhizome is given in the form of balls to livestock against worms [21]. The
summary of the reported ethnopharmacological uses of different parts of T. gova-
nianum is presented in Table 1.

2.6 Phytochemistry

T. govanianum synthesizes a suite of chemical compounds including glycosides,

terpenoids, tannins, sterols, saponins, sapogenins, flavonoids and carbohydrates
[39, 68, 69]. Rehman et al. [26] carried out the phytochemical investigation of the
species and reported the isolation of four steroidal saponins from the methanolic
extract of rhizome of the species. Among the steroidal saponins reported,
Trillium govanianum – A Promising Endemic Medicinal Herb of the Himalaya 387

Table 1 Ethnomedicinal uses of Trillium govanianum under different traditional systems

Plant part used/ Local name(s)/
S. No. Diseases Mode of use Place Reference(s)
1. Backache; fever; Rhizome/ Lardli/ [17]
inflammation; headache; Tea prepared from 5 Rajouri and Poonch
kidney problems to 10 g dry rhizome Districts, Jammu and
is given once in a day Kashmir, India
for 3 to 4 days.
2. Reproductive disorder Rhizome/ Nag chhatri/ [18]
(erectile dysfunction and Dried form of Chamba District,
sexual tonic) and rhizome taken with Himachal Pradesh,
menstrual disorder cow milk in early India
morning
3. Infectious diseases; Rhizome/ Lar-ri-saag/ [19]
healing of wounds; Topical application Leepa Valley, Azad
antiseptic; bacterial of dried rhizome Jammu and Kashmir,
diarrhea; dysentery powder Pakistan
4. Dysentery Rhizome/ Satwa/ [20]
Oral application of Parbati valley, Kullu
dried powder District, Himachal
Pradesh, India
5. Anti-helminthic and skin Rhizome/ Gildi/Surnganda/ [21–24]
infections Reechkijadi/Tripater/
Crushed rhizome is Bandipora District,
given in the form of Jammu and Kashmir,
balls to livestock India
against worms. It is
used to cure boils by
applying externally.
6. Cancer Rhizome/ Matarzela, [25]
MatajarraMatajarai,
Matajarra/
Dried form of Khyber Pakhtunkhwa,
rhizome powder is Pakistan.
used
7. Gastro-intestinal Rhizome/ Surnganda, [25, 26]
disorders(abdominal Reechkijadi, Tripater,
spasms) Matarzela/
Oral application of Bandipora District,
dried form of Jammu and Kashmir,
rhizome India; Khyber
Pakhtunkhwa, Pakistan.
8. Bleeding and diarrhea Rhizome/ Yakhajarrai/ [27]
Dried powder is used District Shangla,
Khyber Pakhtunkhwa,
Pakistan.
(continued)
388 K. Rashid et al.

Table 1 (continued)
Plant part used/ Local name(s)/
S. No. Diseases Mode of use Place Reference(s)
9. Body and sexual tonic Rhizome/ Tandhijarri/ [28]
Powdered form used Saifalmaluk Lake,
as body and sexual Naran Valley, Pakistan
tonic.
10. Arthritis Rhizome/ Nag chhatri/ [29]
Dried powder along Churah subdivision,
with buttermilk is District Chamba,
used Himachal Pradesh,
India
11. Rheumatism, fever, and Rhizome/ ChhotaSatuwa, Nag [30]
sexual disorder chhatri/
Powder or paste is Uttarkashi District,
given with warm Uttarakhand, India
water
12. Body weakness Rhizome/ Nag chhatri/ [31]
Rhizome are boiled North western
in milk and taken Himalaya, Jammu and
orally Kashmir, India
13. Impotency; tumor Root/ Tripatra/ [32]
Dried powder is used Bheri, Muzaffarabad,
Pakistan
14. Appetite disorder Rhizome/ Sheethkhar/ [33]
Fresh rhizomes Bandipora District,
consumed in herbal Jammu and Kashmir,
tea India
15. Tonic and emetic Rhizome/ Matarjarai/ [34]
Oral administration Hindukush Range,
of watery extract of District Swat, Pakistan
rhizome.
16. Wounds and cut healing Rhizome, Leaves/ Nag chhatri/Satwa [35, 36]
Fresh leaves or dry Chopal region, District
rhizome paste and Shimla, Himachal
slurry is applied Pradesh, India
externally on
wounds, minor cuts
and foot cracks till it
heals
17. Cough; fever; vomiting Leaves, Rhizome/ Nag chhatri/ [37]
Oral application of Rakchham area,
dried powder of District Kinnaur,
leaves and rhizome Himachal Predesh,
India
18. Body pain; internal Leaves, Rhizome/ Nag chhatri, [38]
injury The juice of fresh Baspa valley, District
leaves and rhizome Kinnaur, Himachal
are given orally Predesh, India
Trillium govanianum – A Promising Endemic Medicinal Herb of the Himalaya 389

Table 2 Phytochemicals isolated and characterized from Trillium govanianum

Molecular Identification
S. No. Compound name formula method Reference(s)
1. 2,4-Decadienal C10H16O GC-MS [39]
2. Pentanoic acid-5-hydroxy-2,4-di-t C19H30O3 GC-MS [39]
butylphenyl ester
3. 9-Hexadecenoic acid methyl ester C17H32O2 GC-MS [39, 40]
4. 9,12-Octadecadienoic acid methyl ester C19H34O2 GC-MS [39]
5. 9,12-Octadecadienoic acid ethyl ester C20H36O2 GC-MS [39]
6. 9,12-Hexadecadienoic acid methyl ester C17H30O2 GC-MS [39]
7. 9-Octadecanoic acid methyl ester C19H36O2 GC-MS [39]
8. cis-13-Eicosenoic acid C20H38O2 GC-MS [39]
9. 9,12-Octadecadienoic acid-2-hydroxy-1- C21H38O4 GC-MS [39]
(hydroxy methyl) ethyl ester
10. 6-Octadecenoic acid, methyl ester C19H36O2 GC-MS [40]
11. Govanic acid (7, 8,9-trihydroxy-(10Z)-10-­ C18H34O5 NMR [41]
octadecenoic acid
12. 9,12-Octadecadienoic acid C18H32O2 GC-MS [40]
13. Ethyl 13-methyl-tetradecanoate C17H34O2 GC-MS [39]
14. Hexadecanoic acid methyl ester C17H34O2 GC-MS [39, 40]
15. 2-Methyl hexadecanoic acid methyl ester C18H36O2 GC-MS [39]
16. Octadecanoic acid C18H36O2 GC-MS [40]
17. Isopropyl 9-oxononanoate C12H22O3 GC-MS [40]
18. Nonanedioic acid monomethyl ester C10H18O4 GC-MS [40]
19. 10-Hydroxydecanoic acid C10H20O3 GC-MS [40]
20. Quercetin C15H10O7 HPLC-PDA [42]
21. Myrecetin C15H10O8 HPLC-PDA [42]
22. Kaempferol C15H10O6 HPLC-PDA [42]
23. Gallic acid C7H6O5 HPLC-PDA [40]
24. Govanoside A [(1β,3β,23S,24S)-1-[O-β-D-­ C56H88O29 NMR [43]
glucopyranosyl(1 → 3)-O-β-D-­
glucopyranosyl
(1 → 6)-O-β-D-apiofuranosyl]-3,23
dihydroxyspirosta-5,25-dienyl-24-[O-β-L-­
rhamnopyranosyl(1 → 4)-β-D-6-­
deoxygulopyranoside]
25. Borassoside E C45H72O16 NMR [43]
26. Pennogenin (Spirost-5-ene-3,17-diol) C27H42O4 NMR [43]
27. Diosgenin (Spirost-5-en-3-ol) C27H42O3 NMR [43]
28. Ecdysone (20-hydroxyecdysone) C27H44O7 NMR [41]
29. 5 Hydroxy, β-ecdysone (5,20 C27H44O8 NMR [41]
dihydroxyecdysone)
390 K. Rashid et al.

borassoside E, pennogenin (Spirost-5-ene-3,17-diol), and diosgenin (Spirost-5-

en-3-ol)were already known whereas govanoside A(1β,3β,23S,24S)-1-[O-β-D-­
glucopyranosyl(1 → 3)-O-β-D-glucopyranosyl (1 → 6)-O-β-D-apiofuranosyl]-3,23
dihydroxyspirosta-­5,25-dienyl-24-[O-α-L-rhamnopyranosyl(1 → 4)-β-D-6-­
deoxygulopyranoside) was a new report and was found only in this species.
According to this study, NMR spectra of two significant compounds govanoside A
and diosgenin indicated the same aglycone structure whereas the only difference
was in the number of sugar moieties. These steroidal saponins were synthesized
from squalene through isopentenyl diphosphate (IPP) and dimethylallyl diphos-
phate (DMAPP) via cytosolic mevalonate (MVA) and plastidial 2-C-methyl-D-
erythritol4-­phosphate (MEP) pathways. Rehman et al. [39, 43] studied the metabolite
profile of this species using 1H-NMR and 13C-NMR spectrometry and gas
chromatography-­ mass spectrometry (GC–MS). The GC/MS analysis of the n-­
hexane fraction of the methanolic rhizome extract identified 12 compounds, which
included 70% unsaturated and 30% saturated fatty acids.
Preliminary phytochemical screening of T. govanianum has indicated the pres-
ence of phenolics and flavonoids. The total phenolic (TP) and flavonoid (TF) con-
tents of methanolic extract of leaf, stem and rhizome were quantified by
Folin-Ciocalteu photometric, colorimetric, and UV-spectrophotometric methods,
respectively. From the results, the mean amounts of TP content (mg GAE/gfw) in
leaf, stem and rhizome were in the range 0.14–2.73, 0.01–2.64 and 0.20–2.80,
respectively, and TF content (mgQE/g fw) 0.36–2.57 in leaf, 0.03–0.97 in stem and
0.07–0.67 in rhizome [70]. Khan et al. [42] based on reverse-phase HPLC-PDA
quantification and GC/MS analysis revealed the presence of significant amounts of
flavonoids, phenolics and fatty acids. Three flavonoids namely: Quercetin (0.221 μg/
mg DW), Kaempferol (0.528 μg/mg DW) and Myrecetin (0.09 μg/mg DW) were
quantified from the methanolic extract of roots of this species. GC/MS analysis of
the n-hexane fraction of methanolic extract of root identified six fatty acids; and
among these then-Hexadecanoic acid methyl ester, n-Hexadecanoic acid, 9,
12-Octadecadienoic acid and Octadecanoic acid were the major constituents found.
Khan et al. [40] reported the total phenolic and flavonoid contents of the methanolic
extract of T. govanianum were 20.27 ± 3.03 mg GAE/g DW (measured for gallic
acid) and 9.250 ± 0.50 mg QE/g DW (measured for quercetin). In another study,
phytochemical screening of chloroform soluble fraction of the methanolic extract of
rhizome revealed the isolation of a new trihydroxylated fatty acid, named govanic
acid (7,8,9-trihydroxy-(10Z)-10-octadecenoic acid) along with phytoecdysteroids,
i.e. 20-hydroxyecdysone and 5, 20-dihydroxyecdysone. The structure of isolated
compounds was elucidated through 1D, 2D-NMR spectroscopic analysis [41]. The
results confirm that phytochemicals and their concentration is more in underground
parts. The bio-active compounds isolated also depend upon the chemical nature of
the extract. The rhizome is a rich source of steroids, such as trillarin, which on
hydrolysis yields diosgenin, a corticosteroid hormone used in the preparation of
steroidal medicine and sex hormones, such as testosterone, glucocorticoids and pro-
gesterone besides being useful in rheumatism and regulation of menstrual flow in
traditional medicine [71, 72]. The phytochemical constituents identified and iso-
lated from T. govanianum are illustrated in Table 2 and Fig. 3.
Trillium govanianum – A Promising Endemic Medicinal Herb of the Himalaya 391

Fig. 3 Structure of phytochemicals isolated and identified from Trillium govanianum: Unsaturated
fatty acids (1–12); Saturated fatty acids (13–19); Phenolics (20–23); Steroids (24–29)
392 K. Rashid et al.

Fig. 14.3 (continued)

Trillium govanianum – A Promising Endemic Medicinal Herb of the Himalaya 393

Fig. 14.3 (continued)

394 K. Rashid et al.

Fig. 14.3 (continued)

Trillium govanianum – A Promising Endemic Medicinal Herb of the Himalaya 395

Fig. 14.3 (continued)

2.7 Pharmacology

The crude extracts as well as pure compounds obtained from T. govanianum have
been used to validate the ethnomedicinal uses and further assessed for novel bio-
logical activities. The key bioactive constituents from the species have been recently
subjected to various pharmacological investigations and this has revealed promising
antibacterial, antifungal, anticancer, antifertility contraceptive, analgesic, anti-­
inflammatory, antioxidant and anti-parasitic properties of the species.

2.7.1 Antibacterial Activity

In recent times, antibiotic resistance of pathogenic microorganisms has emerged as

a major concern. Therefore, researchers have shifted their focus towards plants for
new possible antimicrobial compounds. The rhizome extracts of T. govanianum,
being a rich source of alkaloids, phenolics and flavonoids possess considerable anti-
bacterial activity. Sagar et al. [73] screened the rhizome extracts of the species
against three pathogenic bacteria: Staphylococcus aureus, Escherichia coli and
Yersinia pestis. Agar well diffusion method was used for in vitro study with different
concentrations of plant parts extracts (25%, 50%, 75% and 100%). T. govanianum
396 K. Rashid et al.

Fig. 14.3 (continued)

Trillium govanianum – A Promising Endemic Medicinal Herb of the Himalaya 397

Fig. 14.3 (continued)

was found to be more effective against S. aureus at all the concentrations as com-
pared to E. coli and Y. pestis in three solvents: ethanol, methanol and acetone; and
in case of distilled water rhizome extract, Y. pestis was found to be more effective as
compared to S. aureus and E. coli. In another study [40], antibacterial activity of the
MeOH extract of rhizome of T. govanianum and its solid phase extractions (SPE)
was tested on three gram-positive bacteria (Staphylococcus aureus, Bacillus subti-
lis, Micrococcus luteus), and two gram-negative bacteria(Escherichia coli,
Klebsiella oxytoca). Using Resazurin microtiter plate assay method, higher
398 K. Rashid et al.

Fig. 14.3 (continued)

antibacterial activity was detected against gram-positive bacteria. In case of its SPE
fraction TGMF1, the most significant activity was detected against M. luteus (MIC:
0.156 mg/mL). The SPE fraction TGMF2 showed the most significant antibacterial
activity against B. subtilis and M. luteus (MIC: 0.615 and 1.25 mg/mL). The SPE
fraction TGMF3 showed the most significant antibacterial activity against B. subti-
lis, M. luteus and S. aureus (MIC: 0.0195, 0.039 and 0.31 mg/mL). The SPE frac-
tion TGMF4 exhibited a notable antibacterial activity against S. aureus, B. subtilis
and M. luteus (MIC: 0.615, 0.039 and 0.156 mg/mL) and showed no activity against
E. coli and K. oxytoca (MIC: 1.25 and 0.615 mg/mL).
Trillium govanianum – A Promising Endemic Medicinal Herb of the Himalaya 399

2.7.2 Antifungal Activity

The steroidal saponins govanoside A, borassoside E, pennogenin and diosgenin iso-

lated from the rhizome of T. govanianum were tested against fungal strains:
Aspergillus niger ATCC 16888, A. flavus ATCC 9643, A. fumigates ATCC1022,
Candida albicans ATCC 18804 and C. glabrata ATCC 90030. The results showed
that steroidal saponins govanoside A and borassoside E were active against C. albi-
cans and C. glabrata with effects more prominent against C. albicans. In case of
filamentous fungi, A. niger and A. flavus responded well while A. fumigates
remained unaffected. However, compounds pennogenin and diosgenin were inac-
tive at the highest test concentration of 20 μg/ml [43]. The sugar moieties attached
to aglycone steroidal nuclei has been found to be responsible for the antifungal
activity. Borassoside E that has three sugar units showed better antifungal activity in
comparison to govanoside A which has five sugar units. The hetero-sugar moiety
causes the hetero-polarity of these compounds leading to different membrane per-
meability and selectivity [74]. In another study [41], hydro-methanolic extract of
T. govanianum rhizomes and its subsequent solvent-soluble fractions were tested
against different fungal strains, i.e. Trichophyton rubrum ATCC 40051, A. niger
ATCC 16888, C. albicans ATCC 18804, Microsporum canis ATCC 32903 and
Fusarium lini ATCC 16888. The hydro-methanolic extract showed significant activ-
ity against T. rubrum and M. canis with 80% and 75% inhibitions, respectively.
Among the fractions, chloroform soluble fraction showed 90% inhibition, with a
minimum inhibitory concentration (MIC) of 10 μg/mL against T. rubrum followed
by ethyl acetate, butanol and n-hexane fractions. A new trihydroxylated fatty acid
named govanic acid isolated from T. govanianum showed significant activity against
T. rubrum with 70% inhibition and MIC value of 5 μg/mL, but lacked activity
against the other test strains.

2.7.3 Anticancer Activity

Khan et al. [67] evaluated the cytotoxic potential of methanolic extracts of the rhi-
zomes of T. govanianum and its solid phase extraction (SPE) fractions and also their
application on the breasts (MCF7), liver (HepG2), lungs (A549) and urinary bladder
(EJ138) cancer cell lines using in vitro MTT (3-(4, 5-dimethylthiazol-2-yl)-2,
5-diphenyltetrazolium bromide) cytotoxicity/viability assay, demonstrated their
concentration-dependent activity. The MeOH extract displayed the highest level of
cytotoxicity against the urinary bladder cell line (EJ138; IC50 = 5 μg/mL). The SPE
fraction TGMF1 showed the most significant cytotoxicity against EJ138 (IC50 = 6 μ­ g/
mL). The SPE fraction TGMF2 showed the most prominent cytotoxicity against the
lung cancer cell line A549 (IC50 = 6 μg/mL) and the SPE fraction TGMF3 showed
the most significant cytotoxicity against the EJ138 cell line (IC50 = 9 μg/mL). The
SPE fraction TGMF4, which contained the least polar components of the parent
MeOH extract, exhibited notable cytotoxicity against the EJ138 cell line
(IC50 = 13 μg/mL). In another study, Sharma et al. [75] showed cytotoxicity of
400 K. Rashid et al.

rhizome and hydroalcoholic extract which were carried out by the MTT (3-(4,
5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay on three cell lines:
MDCK, MCF-7 and MDA-MB-23. The results indicated that hydrolyzed extract
showed less toxicity in MDCK (normal cell line) cells but significantly reduced the
proliferation of MCF-7 and MDA-MB-231 cancer cells. Rehman et al. [39] studied
the cytotoxic activity of methanol extract and its fractions against two cancer cell
lines, HeLa (cervical cancer cells) and PC-3 (prostate cancer cells) by using the
MTT(3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay. In
this study, based on IC50 (μg/mL) values, chloroform (0.8 ± 0.2), ethyl acetate
(1.4 ± 0.1) and butanol (1.6 ± 0.3) fractions exhibited anti-proliferative activity on
HeLa cells in comparison to anticancer drug doxorubicin (0.3 ± 0.0). Similarly, the
chloroform fraction was effective against PC-3 cells while ethyl acetate and butanol
fractions were least effective.

2.7.4 Antifertility Activity and Contraceptive Potential

Being a rich source of steroids, T. govanianum has been shown to possess antifertil-
ity properties. The anti-implantation activity of T. govanianum rhizome extract was
performed in female wistar rat with proven fertility and its estrogenic/anti-­estrogenic
effect was evaluated in ovariectomized females. A dose-dependent anti-­implantation
effect and a significant increase in uterus weight were observed. It was observed
that, at 250 mg/kg dose, 100% inhibition of implantation was found. This anti-­
implantation effect was attributed to endometrial thickening and changes in the
estrogenic profile [76].

2.7.5 Anti-inflammatory and Analgesic Activities

The inflammation produces reactive oxygen species (ROS), which in turn further
perpetuate inflammation. The ROS produced during the inflammatory process
causes tissue damage [77]. The production of highly reactive species such as ROS,
reactive nitrogen species (RNS) and hypochlorous acid (HOCl) at the site of inflam-
mation exacerbates tissue damage as well as the inflammatory cascade [78, 79].
This ROS-induced tissue damage forms the basis of the pathogenesis of many
chronic inflammatory diseases [80].
The anti-inflammatory and analgesic properties of extracts of T. govanianum
have been evaluated in animal models to confirm its pharmacological properties.
Both in vivo and in vitro anti-inflammatory activity have been determined through
carrageenan-induced paw edema assay and luminol-enhanced chemiluminescence
assay, respectively. The in vivo results demonstrated significant anti-inflammatory
activity possibly by inhibiting release of iNOS, COX2 and inhibiting the production
of tissue necrosis factor (TNF), cytokines (IL-1, IL-2) and nitric oxide synthase
(NOS) release associated with inflammation. This anti-inflammatory activity of
T. govanianum may provide a new path in pharmacological development. The in
Trillium govanianum – A Promising Endemic Medicinal Herb of the Himalaya 401

vitro study also depicted anti-inflammatory activities associated with the quenching
of reactive oxygen species or inhibiting the enzymes involved in their production.
The isolated compounds such as pennogenin showed a significant in vitro inhibitory
activity by controlling the release of ROS with an IC50 of 5.0 ± 0.8 μg/mL while
borassoside E and diosgenin showed a weaker inhibition activity. The in vivo anal-
gesic activity was assayed in chemical and thermal-induced nociceptive pain mod-
els. The methanol extract and its solvent fractions showed analgesic responses,
which were exhibited by significant tonic visceral chemical and acute phasic ther-
mal nociception. Therefore, the rhizomatous part of this plant species could act as a
potential and novel source of compounds, which are analgesic and anti-­
inflammatory [81].

2.7.6 Free Radical Scavenging Activity

Free radicals being highly reactive species have the potential to cause oxidative
damage to life-essential molecules such as lipids, proteins and nucleic acids, which
eventually leads to atherosclerosis, ageing, cancer and several other diseases in
humans [82–84]. Besides the antioxidant vitamins, a number of several other com-
pounds such as vitamins E, C, beta-carotene and folic acid have been reported to
have strong antioxidant potential [85]. There are continuous research efforts being
made to search for new and elite compounds and the identification of food ingredi-
ents with an antioxidant potential [86].
The in vitro antioxidant activity of methanol extracts and its fractions (EtOAc.Fr,
CHL.Fr, BuOH.Fr, Hex.Fr) of T. govanianum rhizome was determined by the DPPH
(1, 1-diphenylpicryl-1-picrylhydrazyl) free radical scavenging assay. This activity
was analyzed against the synthetic antioxidants BHT and ascorbic acid. The results
have shown that a higher scavenging capacity was measured in Hex-Fr and CHL-Fr
when compared with other fractions. This was due to the presence of certain anti-
oxidant fatty acids (9, 12-octadecadienoic acid and hexadecanoic acid) in n-Hex-fr,
and glycosides, saponins and flavonoids in CHL-fr. However, the antioxidant poten-
tial of the MeOH extract as well as its successive solvent soluble fractions was
lower than some synthetic antioxidants BHT (butylated hydroxytoluene) and ascor-
bic acid. This low scavenging property might be due to the presence of large-size
fatty acids [39]. In another study [70], the antioxidant potential of methanolic
extracts of leaf, stem and rhizome of T. govanianum was determined using
1,1-­diphenyl-2-pycrylhydrazyl (DPPH); 2, 20–azinobis, 3-ethylbenzothiazoline-­6-
sulfonic acid (ABTS) and ferric-reducing antioxidant power (FRAP) free radical
scavenging assay. It was shown that DPPH, FRAP, activities in the methanolic
extract of rhizome were maximum, whereas ABTS activity was maximum in the
methanolic extract of leaf. IC50 values were found maximum for rhizome (0.15 mg/
ml) followed by leaf (0.165 mg/ml) and least for stem (0.192 mg/ml). Therefore, the
rhizome part was having stronger antioxidant potential than leaf and stem.
402 K. Rashid et al.

β-Glucuronidase Inhibiting Activity

2.7.7 

An enzyme, β-glucuronidase catalyzes the hydrolysis of β-glucuronides produced

in the body such as benzo[α]pyrene glucuronides and natural plant glucuronides
such as glycyrrhizin [87]. This enzyme occurs in animals, plants and bacteria. It has
been demonstrated that liver injury causes an increase in the levels of this enzyme
in blood. Overexpression of this enzyme has also been related to liver cancer, arthri-
tis and AIDS; and β-glucuronidase of intestinal bacteria in humans and rats is related
to colon cancer. In addition, β-glucuronidase of bacteria, which are present in the
biliary tract, is also associated with the gallstone formation [88, 89].
Phytochemical screening of T. govanianum has revealed the presence of steroidal
glycosides, flavonoids and saponins. The methanolic extract of its rhizome and its
butanol fraction possesses a promising level of β-glucuronidase inhibiting activity
with an IC50 value of (140.8 ± 3.8) and (196.2 ± 1.9) compared to the IC50 value of
(46.7 ± 2.2) shown by the standard inhibitor, D-saccharic acid 1,4 lactone [39].
Thus, the rhizome of this species may be effective in the treatment of liver and colon
cancers associated with an increased activity of β-glucuronidase enzyme.

2.7.8 Anti-leishmanial Activity

The anti-leishmanial potential of the methanolic extract of T. govanianum rhizome

and its SPE fractions was evaluated against Leishmania tropica KWH23 strain. The
methanolic extract and its SPE fraction TGMF1 showed the most significant results.
The rest of SPE fractions TGMF2, TGMF3 and TGMF4 also showed promising
leads [42].

2.7.9 Cytotoxic Activity

Cytotoxicity potential of the MeOH extract of rhizome of T.govanianum and its SPE
fractions was determined through brine shrimp lethality assay, and concentration-­
dependent lethality was observed. In this cytotoxicity assay, the LC50 value of meth-
anolic extract was 38.5 μg/mL which was most toxic, while LC50 values of its SPE
fractions TGMF1, TGMF2, TGMF3 and TGMF4 were 40.5, 189.2, 105.6 and
66.5 μg/mL, respectively. The doxorubicin, as a positive control, showed an LC50
value of 1.98 μg/mL [42].

2.7.10 Protein Kinase Inhibitory Activity

The protein kinase inhibition assay of the MeOH extract of rhizome of T.govanianum
and its SPE was performed by observing hyphae formation in purified isolates of
Streptomyces 85E strain. The effect of MeOH extract and its SPE fractions was
Trillium govanianum – A Promising Endemic Medicinal Herb of the Himalaya 403

assessed through the formation of different levels of protein kinase inhibition zones.
The results revealed distinguishable protein kinase inhibitory activity against
Streptomyces 85E strain with 18 mm bald phenotype. This effect might be attributed
to the presence of quercetin which has been reported to inhibit multiple kinases,
thus playing an important role in cancer cell biology [42].

3 Conclusions

Trillium govanianum, an endemic medicinal plant of the Himalayas, is used in the

treatment of various ailments without any documented adverse effects so far. The
available scientific literature is replete with its importance in various ethnomedical
treatments. The plant species is a rich reservoir of some of the major phytochemi-
cals, particularly steroidal saponins, with promising pharmacological efficacy
against several human diseases. The future scope of the species lies in the advanced
phytochemical characterization of other bioactive compounds, including the gen-
eration of more novel derivatives which can reveal more novel biological activities.
T. govanianum has been shown to possess a number of distinct pharmacological
activities. However, the mechanisms of action of component molecules are lacking
and require further investigation. Various bioactive phytochemical classes including
glycosides, terpenoids, tannins, sterols, sapogenins and carbohydrates were identi-
fied by qualitative analysis. Further investigation is required for their quantitative
estimation. So far, most of the pharmacological studies that have been conducted
are under in vitro conditions. Future in vivo studies must be carried out exploring
their activities in model animals to validate the in vitro activities. Most of the phar-
macological activities are reported from plant extract and its fractions. Future inves-
tigation is needed to evaluate the exact bioactive metabolites which are responsible
for certain bioactivity and thus extend the area of potential applications. No infor-
mation is available about the pharmacokinetics and toxicity and no major side
effects have yet been discovered. Further studies on the pharmacokinetics and toxi-
cology are needed in order to evaluate the uses of this plant, its extract and isolated
compounds in clinical practice and validate its safety in humans. Therefore, toxico-
logical investigations should be carried out in order to validate its safety. In vitro
studies have revealed the cytotoxic potential against various cell lines. Further stud-
ies must be conducted evaluating T. govanianum cytotoxic activity through in vivo
studies and clinical trials to prove its role as an anticancer agent. The active com-
pounds studied are those identified in the rhizome of the plant, so more studies are
required of the chemical constituents of the aerial parts of species. Furthermore, the
peculiar life cycle, habitat specificity, unaccounted harvesting for herbal drug prep-
arations and increased market demand have made T. govanianum alarmingly threat-
ened plant species. The plant has recently attracted attention from pharmaceutical
industry which has led to its overexploitation and depletion of its natural popula-
tions across the Himalaya. Effective measures are required to conserve the dwin-
dling wild populations of this plant species. Formulation of cultivation techniques
404 K. Rashid et al.

should be prioritized for effective and sustainable utilization of the plant at com-
mercial scale. Therefore, for the proper conservation and management of this pre-
cious plant species, it is incumbent to carry out conservation-focused research as
well. Since there is no scientific breakthrough in its commercial farming and pro-
duction, the review recommends further research toward its ex situ propagation and
in vitro regeneration, so as to reduce pressure on the natural populations. It is also
recommended that public awareness and sensitization campaigns should be carried
out to prevent the destructive harvesting by local people in natural habitats across
the Himalaya.

References

1. Ganie AH, Tali BA, Shapoo GA, Nawchoo IA, Khuroo AA (2019) Ethno-survey of traditional
use of plants as aphrodisiacs in Kashmir Himalaya, India. J Herb Med 17:100256
2. Ganie AH, Tali BA, Nawchoo IA, Khuroo AA, Reshi ZA, Dar GH (2020) In: Dar GH, Khuroo
AA (eds) Biodiversity of the Himalaya: Jammu and Kashmir State. Springer, Singapore,
pp 545–563
3. WHO World Health Organization (2002) Traditional medicine strategy, p. 11
4. Singh JS (2002) The biodiversity crisis: a multifaceted review. Curr Sci 82:638–647
5. Patwardhan B, Warude D, Pushpangadan P, Bhatt N (2005) Ayurveda and traditional Chinese
medicine: a comparative overview. Evid Based Complement Alternat Med 2:465–473
6. Uniyal SK, Singh KN, Jamwal P, Lal B (2006) Traditional use of medicinal plants among the
tribal communities of Chhota Bhangal, Western Himalaya. J Ethnobiol Ethnomed 2:14. https://
doi.org/10.1186/1746-­4269-­2-­14
7. Tali BA, Khuroo AA, Ganie AH, Nawchoo IA (2019a) Diversity, distribution and traditional
uses of medicinal plants in Jammu and Kashmir (J&K) state of Indian Himalayas. J Herb Med
17:100280
8. Hamid M, Khuroo AA, Ahmad R, Rasheed S, Malik AH, Dar GH (2020) In: Dar GH, Khuroo
AA (eds) Biodiversity of the Himalaya: Jammu and Kashmir State. Springer, Singapore,
pp 957–995
9. Dhiman B, Sharma P, Pal PK (2020) Biology, chemical diversity, agronomy, conservation
and industrial importance of Valeriana jatamansi: a natural sedative. J Appl Res Med Aroma
16:100243
10. Rathore S, Debnath P, Kumar R (2020) Kuth {Saussurea costus (Falc.) Lipsch.}: a critically
endangered medicinal plant from Himalaya. J App Res Med Aro Plants:100277
11. Tali BA, Khuroo AA, Nawchoo IA, Ganie AH (2019b) Prioritizing conservation of medici-
nal flora in the Himalayan biodiversity hotspot: an integrated ecological and socioeconomic
approach. Environ Conserv 46:147–154
12. Vidyarthi S, Samant SS, Sharma P (2013) Dwindling status of Trillium govanianum Wall.
ex. D. Don- A case study from Kullu district of Himachal Pradesh, India. J Med Plants Res
7:392–397
13. Singh G, Singh P, Bhandawat A, Singh G, Parmar R, Seth R, Sharma RK (2017) Spatial tran-
scriptome analysis provides insights of key gene(s) involved in steroidal saponin biosynthesis
in medicinally important herb Trillium govanianum. Sci Rep 7:45295. https://doi.org/10.1038/
srep45295
14. Raju J, Rao CA (2012) Diosgenin, a steroid saponin constituent of yams and fenugreek:
emerging evidence for applications in medicine. Bio Com Phytomed:125–142
15. Chaudary S, Chikara SK, Sharma MC, Chaudary AA, Alam Syed B, Chaudary PS, Mehta
A, Patel M, Gosh A, Iriti M (2015) Elicitation of diosgenin production in Trigonella foenum-­
graecum (Fenugreek) seedlings of methyl jasmonate. Int J Mol Sci 16:29889–29899
Trillium govanianum – A Promising Endemic Medicinal Herb of the Himalaya 405

16. Chauhan HK, Bisht AK, Bhatt ID, Bhatt A, Gallacher D, Santo A (2018) Population change
of Trillium govanianum (Melanthiaceae) amid altered indigenous harvesting practices in the
Indian Himalayas. J Ethnopharmacol 213:302–310
17. Shah A, Bharati KA, Ahmad J, Sharma M (2015) New ethnomedicinal claims from Gujjar
and Bakerwals tribes of Rajouri and Poonch districts of Jammu and Kashmir, India. J
Ethnopharmacol 166:119–128
18. Rani S, Rana J, Rana P (2013) Ethnomedicinal plants of Chamba district, Himachal Pradesh,
India. J Med Plant Res 7:3147–3157
19. Mahmood A, Mahmood A, Malik RN (2012) Indigenous knowledge of medicinal plants from
Leepa valley, Azad Jammu and Kashmir. Pakistan J Ethnopharmacol 143:338–346
20. Sharma P, Samant S (2014) Diversity, distribution and indigenous uses of medicinal plants
in Parbati valley of Kullu district in Himachal Pradesh, Northwestern Himalaya. Asian J Adv
Basic Sci 2:77–98
21. Lone PA, Bhardwaj AK, Shah KW, Tabasum S (2014) Ethnobotanical survey of some threat-
ened medicinal plants of Kashmir Himalaya, India. J Med Plant Res 8:1362–1373
22. Lone PA, Bhardwaj AK, Bahar FA (2013) Traditional knowledge on healing properties of
plants in bandipora district of Jammu and Kashmir, India. Int J Recent Sci Res 4:1755–1765
23. Bhardwaj AK, Lone PA, Dar M, Parray JA, Shah KW (2013) Ethnoveterinary medicinal uses
of plants of district Bandipora of Jammu and Kashmir, India. Int J Trad Nat Med 2:164–178
24. Wagay NA (2016) Ethnobotany from North Kashmir: a review. Life Sci Leafl 80:38–60
25. Ur Rahman S, Ismail M, Khurram M, Haq IU (2015) Pharmacognostic and ethnomedicinal
studies on Trillium govanianum. Pakistan J Bot 47:187–192
26. Lone PA, Bhardwaj AK, Bahar FA (2015) Study of indigenous/traditional medicinal plant
knowledge- an Endeavour towards new drug discovery. Afr J Tradit Complement Altern Med
12:73–95
27. Tabani AA, Khan SM, Majid A, Hussain I, Saeed M, Khan SA, Naveed K, Ali S (2016)
Ethnomedicinal studies of plants from Shangla district with special reference to economically
important species. ARPN J Agri Biol Sci 11:223–229
28. Khan SM, Page S, Ahmad H, Shaheen H, Ullah Z, Ahmad M, Harper DM (2013) Medicinal
flora and ethnoecological knowledge in the Naran Valley, Western Himalaya, Pakistan. J
Ethnobiol Ethnomed 9:4–16
29. Rana D, Bhatt A, Lal B (2019) Ethnobotanical knowledge among the semi-pastoral Gujjar tribe
in the high altitude (Adhwari’s) of Churah subdivision, district Chamba, Western Himalaya. J
Ethnobiol Ethnomed 15:10. https://doi.org/10.1186/s13002-­019-­0286-­3
30. Nand K, Naithani S (2018) Ethnobotanical uses of wild medicinal plants by the local commu-
nity in the Asi Ganga sub-basin, Western Himalaya. J Complement Med Res 9:34–46
31. Dutt HC, Bhagat N, Pandita S (2015) Oral traditional knowledge on medicinal plants injeop-
ardy among Gaddi shepherds in hills of northwestern Himalaya, J&K, India. J Ethnopharmacol
168:337–348
32. Ahmed MJ, Akhtar T (2016) Indigenous knowledge of the use of medicinal plants in Bheri,
Muzaffarabad, Azad Kashmir, Pakistan. Eur J Integr Med 8:560–569
33. Singh B, Sultan P, Hassan QP, Gairola S, Bedi YS (2016) Ethnobotany, traditional knowledge,
and diversity of wild edible plants and fungi: a case study in the Bandipora District of Kashmir
Himalaya, India. Int J Geogr Inf Syst 22:247–278
34. Ali A, Badshah L, Hussain F (2018) Ethnobotanical appraisal and conservation status of
medicinal plants in Hindukush Range, District Swat, Pakistan. Int J Geogr Inf Syst 24:332–355
35. Singh J, Singh J, Kumar N, Jishtu V, Sharma S, Dhupper R (2017a) Ethno-medicinal plants
used by indigenous people of Kanda range, Chopal forest division, Himachal Pradesh. World
J Pharm Pharm Sci 7:697–710
36. Singh J, Singh J, Sharma D (2018) Traditional wisdom to treat the most common ailments in
Chopal region of Shimla district, Himachal Pradesh, India. Plant Arch 18:2759–2769
37. Radha PS (2019) Assessment of wild medicinal plant used by migratory shepherds in alpine
area of Rakchham-Chitkul wild life sanctuary of district Kinnaur in Himachal Pradesh. Plant
Arch 19:418–429
406 K. Rashid et al.

38. Radha PS, Saha S (2020) Documenting traditional wisdom before they are forgotten: a study on
the ethnoveterinary uses of mountain plants among the trans-Himalayan Migratory Shepherds
in the Kinnaur District of Himachal Pradesh, India. Preprints 2020:2020010343
39. Ur Rahman S, Ismail M, Shah MR, Iriti M, Shahid M (2015c) GC/MS analysis, free radical
scavenging, anticancer and glucuronidase inhibitory activities of Trillium govanianum rhi-
zome. Bangladesh J Pharmacol 10:577–583
40. Khan KM, Sarker SD, Khan GA, Saleem H, Khan AS, Mannan A (2019) Phytochemical pro-
filing and evaluation of modified resazurin microtiter plate assay of the roots of Trillium gova-
nianum. Nat Prod Res:1–5. https://doi.org/10.1080/14786
41. Ur Rahman S, Adhikari A, Ismail M, Shah MR, Khurram M, Anis I, Ali F (2017) A new trihy-
droxylated fatty acid and phytoecdysteroids from rhizomes of Trillium govanianum. Rec Nat
Prod 11:323–327
42. Khan KM, Nahar L, Mannan A, Haq I, Arfan M, Khan GA, Hussain I, Sarker SD (2017)
Cytotoxicity, in vitro anti-Leishmanial and fingerprint HPLC- photodiode array analysis of the
roots of Trillium govanianum. Nat Prod Res 32:2193–2201
43. Ur Rahman S, Ismail M, Shah MR, Adhikari A, Anis I, Ahmad MS, Khurram M (2015b)
Govanoside A, a new steroidal saponin from rhizomes of Trillium govanianum. Steroids
104:270–275
44. WCSP World Checklist of Selected Plant Families, Royal Botanic Gardens, Kew 2013. http://
apps.kew.org/wcsp/qsearch. do
45. Christenhusz MJM, Byng JW (2016) The number of known plants species in the world and its
annual increase. Phytotaxa 261:201–217
46. Zomlefer WB, Williams NH, Whitten WM, Judd WS (2001) Generic circumscriptions and
relationships in the tribe Melanthieae (Liliales, Melanthiaceae), with emphasis on Zigadenus:
evidence from ITS and TRNL-F sequence date. Am J Bot Bot Soc Amer 88:1657–1669
47. Fuse S, Tamura MN (2000) A phylogenetic analysis of the plastid matK gene with emphasis
on Melanthiaceae sensulato. Plant Biol 2:415–427
48. Chase MW, Christenhusz MJM, Fay MF, Byng JW, Judd WS, Soltis DE, Mabberley DJ et al
(2016) An update of the Angiosperm Phylogeny Group classification for the orders and fami-
lies of flowering plants: APG IV. Bot J Linn Soc 181:1–20
49. Fukuda I (2001) The origin and evolution in Trillium.1. The origin of the Himalayan Trillium
govanianum. Cytologia 66:105–111
50. Pellicer J, Kelly LJ, Leitch IJ, Zomlefer WB, Fay MF (2014) A universe of dwarfs and giants:
genome size and chromosome evolution in the monocot family Melanthiaceae. New Phytol
201:1484–1497
51. Chandola V, Nautiyal AR, Chandra S, Kumar RR (2019) A review on prioritizing conservation
of Himalayan medicinal plant species: case of Trillium govanianum (Wall.ex.D.Don) Kunth.
J Med Plants Stud 7:23–27
52. Li HL (1952) Floristic relationships between eastern Asia and eastern North America. Trans
Amer Phil Soc 42:371–424
53. Axelrod DI (1966) Origin of deciduous and evergreen habitats in temperate forests.
Evolution 20:1–15
54. Ohara M, Kawano S (2005) Life-history monographs of Japanese plants. 2: Trillium camschat-
cense Ker-Gawl. (Trilliaceae). Plant Spec Biol 20:75–82
55. Polunin O, Stainton A (1984) Flowers of the Himalaya. Oxford University Press, New Delhi
56. Roskov Y, Abucay L, Orrell T, Nicolson D, Bailly N, Kirk PM, Bourgoin T, DeWalt RE,
Decock W, DeWever A, Nieukerken E, Zarucchi J, Penev L (eds) (2018) Species 2000 &ITIS
Catalogue of Life, 28th March 2018. Digital resource at www.catalogueoflife.org/col. Species
2000: Naturalis, Leiden. ISSN 2405–8858
57. Samant SS, Dhar V, Palni LMS (1998) Medicinal plants of Indian Himalaya: diversity distribu-
tion potential volumes, vol 163. Gyanoday Prakhasan, Nainital
58. Kubota S, Kameyama Y, Ohara M (2006) A reconsideration of relationship among Japanese
Trillium species based on karyology and AFLP data. Plant Syst Evol 261:129–137
Trillium govanianum – A Promising Endemic Medicinal Herb of the Himalaya 407

59. Chauhan HK, Bisht AK, Bhatt ID, Bhatt A, Gallacher D, Santo A (2019) Trillium—toward
sustainable utilization of a biologically distinct genus valued for traditional medicine. Bot Rev
85:252–272
60. Bhojwani SS, Razdan MK (1986) Plant tissue culture: theory and practice. Elsevier, Amsterdam
61. Fay MF (1992) Conservation of rare and endangered plants using in vitro methods. In Vitro
Cell Dev Biol Plant 28:1–4
62. Zhao P, Iwamoto Y, Kouno I, Egami Y, Yamamoto H (2004) Stimulating the production of
homoisoflavonoids in cell suspension cultures of Caesalpinia pulcherrima using cork tissue.
Phytochemistry 65:2455–2461
63. Nin S, Morosi E, Schiff S, Bennici A (1996) Callus cultures of Artemisi absinthium L.: initia-
tion, growth optimization and organogenesis. Plant Cell Tiss Org 45:67–72
64. Chauhan HK, Bisht AK, Bhatt ID, Bhatt A (2020) Protocol for vegetative propagation of
Trillium govanianum Wall ex D. Don. J Appl Res Med 16:100233. https://doi.org/10.1016/j.
jarmap.2019.100233
65. Shah R (2006) Nature’s medicinal plant of Uttaranchal. Gyanodaya Prakhasan, Nainital
66. Pant S, Samant S (2010) Ethnobotanical observations in the Mornaula reserve forest of
Komoun, est Himalaya, India. Ethnobot Leafl 14:193–217
67. Khan KM, Nahar L, Al-Groshi A, Zavoianu AG, Evans A, Dempster NM (2016) Cytotoxicity
of the roots of Trillium govanianum against breast (MCF7), liver (HepG2), lung (A549) and
urinary bladder (EJ138) carcinoma cells. Phytother Res 30:1716–1720
68. Okigbo RN, Anuagasi CL, Amadi JE (2009) Advance in selected medicinal and aromatic
plants indigenous to Africa. J Med Plants Res 3:86–95
69. Li Y, Liu C, Xiao D, Han J, Yue Z, Sun Y, Fan L, Zhang F, Meng J, Zhang R, Wang Z (2015)
Trillium tschonoskii steroidal saponins suppress the growth of colorectal cancer cells in vitro
and in vivo. J Ethnopharmacol 168:136–145
70. Kundra R, Samant S, Sharma RK (2019) Assessment of antioxidant potential of Trillium
govanianum Wall ex. D. Don, a critically endangered medicinal plant of Northestern Indian
Himalaya. Proc Natl Acad Sci, India. Sect B Biol Sci 90:95–101
71. Raghuram TC, Sharma RD, Sivakumar B, Sahay BK (1994) Effect of fenugreek seeds on intra-
venous glucose disposition in non-insulin dependent diabetic patients. Phytother Res 8:83–96
72. Chauhan NS (1999) Medicinal and aromatic plants of Himachal Pradesh. Indus Publishing,
New Delhi
73. Sagar A, Thakur L, Thakur JS (2017) Studies on entophytes and antibacterial activity of
Trillium govanianum Wall. ex D. Don. Int J Bot Stud 2:63–67
74. Zhu L, Tan J, Wang B, Guan L, Liu Y, Zheng C (2011) In-vitro antitumor activity and antifun-
gal activity of Pennogenin steroidal saponins from Paris polyphylla var. yunnanensis, Iran. J
Pharm Res 10:279–286
75. Sharma S, Sharma A, Mehta V, Chauhan RS, Malairaman U, Sood H (2016) Efficient hydroal-
coholic extraction for highest diosgenin content from trillium govanianum (nag chhatri) and
it’s in vitro anticancerous activity. Asian J Pharm Clin Res 9:386–392
76. Sharma S, Mehta V, Sharma P, Jaggi K, Udayabanu M, Sood H (2018) Antifertility activity
and contraceptive potential of the hydro alcoholic rhizome extract of Trillium govanianum in
female wistar rats. Asian J Pharm Clin Res 11:329–332
77. Pawliczak R (2003) The role of radical oxygen species in airway inflammation. Pol Merkur
Lekarski 14:493–496
78. Salvemini D, Wang ZQ, Bourdon DM, Stern MK, Currie MG, Manning PT (1996) Evidence
of peroxynitrite involvement in the carrageenan-induced rat paw edema. Eur J Pharmacol
303:217–220
79. Fridovich I (1997) Superoxide anion radical (O2), superoxide dismutases, and related matters.
J Biol Chem 272:18515–18517
80. Cuzzocrea S, Mazzon E, Dugo L, Serraino I, Ciccolo A, Centorrino T, De Sarro A, Caputi AP
(2001) Protective effects of n-acetylcysteine on lung injury and red blood cell modification
induced by carrageenan in the rat. FASEB J 15:1187–1200
408 K. Rashid et al.

81. Ur Rahman S, Adhikari A, Ismail M, Shah MR, Khurram M, Shahid M, Ali F, Haseeb A,
Akbar F, Iriti M (2016) Beneficial effects of Trillium govanianum rhizomes in pain and inflam-
mation. Molecules 8:20–21
82. Saez TG, Oliva MR, Muniz P, Valls V, Iradi A, Ramos M (1994) Oxidative stress and genetic
damage. In: Health and orange. Fundacion Valenciana de Estudios Avanzados, Valencia,
Spain, pp 51–60
83. Maxwell SR (1995) Prospects for the use of antioxidant therapies. Drugs 49:345–361
84. Braca A, Sortino C, Politi M, Morelli I, Mendez J (2002) Antioxidant activity of flavonoids
from Licania licaniaeflora. J Ethnopharmacol 79:379–381
85. Dasgupta A, Klein K (2014) Antioxidants in food, vitamins and supplements. Prevention and
treatment of disease. Elsevier, pp 277–294
86. Yazdanparast R, Ardestani A (2007) In vitro antioxidant and free radical scavenging activity of
Cyperus rotundus. J Med Food 10:667–674
87. Saleem M, Afza N, Anwar MA, Hai SMA, Ali MS (2003b) A comparative study of essential
oil of C. citratus and some members of the genus citrus. Nat Prod Res 17:369–373
88. Kim DH, Shim SB, Kim NJ, Jang IS (1999) Beta-glucuronidase-inhibitory activity andhepato-
protective effect of Ganoderma lucidum. Biol Pharm Bull 22:162–164
89. Saleem M, Afza N, Anwar MA, Hai SMA, Ali MS, Shujrat S, Rahman A (2003a) Chemistry and
biological significance of essential oils C. Citratus from Pakistan. Nat Prod Res 17:159–163
Comprehensive Review on Wild Basil
Genus Orthosiphon of Lamiaceae

K. Abirami, P. Revathi, K. Thenmozhi, and K. Sowndhararajan

1 Introduction

Phytochemicals possess significant biological activity and are used in human ther-
apy, agriculture, and scientific research [1]. Scientific validation of such phyto-
chemical constituents has been used to discover novel therapeutic agents and
synthesize complex chemical substances [2]. Molecular biology has become tools
and assays prerequisite factors for medicinal plant drug discovery by determining
and implementing appropriate screening assays directed toward physiologically rel-
evant molecular targets. Modern pharmacognosy also encapsulates all these rele-
vant novel arenas of a distinct interdisciplinary science [3].
For cultivating and processing medicinal plants and for manufacturing herbal
medicines, agro-industrial technologies must be applied [4]. The importance of tra-
ditional medicine has been well recognized by the World Health Organization
(WHO) which has created strategies, guidelines, and standard procedures for botan-
ical medicines. Medicinal plants are the resources of novel drug sources, and many
modern treatments are produced indirectly from them. The development and recog-
nition of medicinal plants increase at an exponential rate in both industrialized and
developing nations [5]. The manufacture of morphine on an industrial scale by
E. Merck, Germany, in 1826 marks the beginning of the commercialization of plant-­
derived drugs [6]. Nearly half of the top-selling pharmaceuticals in 1991 were based
on either natural products or their analogs derived from them [7].
Flowering plants embark on the most numerous, highly diverse, and successful
extant higher plants in the tropics. India is one of the megadiversity nations with
wide variations in climate, soil, altitude, latitude, and all known types of

K. Abirami · P. Revathi · K. Thenmozhi (*) · K. Sowndhararajan

PG and Research Department of Botany, Kongunadu Arts and Science College,
Coimbatore, India
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 409

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_15
410 K. Abirami et al.

agroclimatic, ecologic, and edaphic conditions [8]. The present knowledge records
over 47,500 species of plants belonging to various groups documented from India
[9]. Angiosperms from the most dominant and conspicuous vegetation cover over
18,000 species, representing more than 11.4% of the world’s known flowering plant
species. It has about 19,530 flowering plants, of which 5400 are endemic [10]. On a
global basis, the International Union of Conservation of Natural (IUCN) has esti-
mated that about 12.5% of the world’s vascular plants, totaling about 34,000 spe-
cies, are under varying degrees of extinction. The International Union of
Conservation of Natural resources (IUCN) has enlisted 560 Red List of threatened
plant species in India, of which 247 species are on the red list of threatened species
category [11].
Drug research based on ethnobotanical evidence discovered hundreds of benefi-
cial compounds and pharmacologically active substances in nature, including com-
mon drugs such as aspirin, digoxin, quinine, and opium. Natural constituents have
become the basis and great promise for novel drug sources, and it gratifies abiding
interest in plant-derived medicines described in the folkloric claims of various
countries [12]. In the Indian traditional system of medicine, plants attain novel
interest in finding novel lead molecules for treating various ailments. Medicinal
plants contain substances used for therapeutic purposes or as precursors to synthe-
size valuable drugs due to their inherent active ingredients [13]. Herbal products are
produced by extraction, fractionation, purification, concentration, or other physical
or biological processes of plant materials [14].
In the last few decades, global interest in studying various medicinal plants has
rapidly increased. Investigations have focused on medicinal plants as potential
regimes for treating oxidant-induced diseases. The plant-based chemical constitu-
ents could protect against chronic oxidative stress-related diseases because they
contain variable contents of chemical families and good antioxidants. Certain
classes of secondary metabolites namely, vitamins, and carotenoids have been wit-
nessed in several experiments suggesting that natural compounds have more robust
inhibitive ability than synthetic radical inhibitors. They are natural agents character-
ized by numerous biological activities used in humans, such as antimicrobial, anti-
fungal, anti-inflammatory, antiproliferative, and countless other physical activities
[15]. However, drug development from natural resources is also associated with
certain disadvantages; particularly, it is expected that about 25,000 plant species
would cease to exist by the end of this century [16]. So, it is necessary to identify
novel drug lead molecules for the treatment from alternate sources with low prices,
high efficiency, and fewer side effects. Hence, revealing new indigenous medicinal
herbs is the required uphill task for this recent scenario.
Hence, the current study was focused on scientifically validating the traditional
importance, phytochemical constituents, and biological activity of the endemic
plant species, Orthosiphon. Based on the varied reasons, assessments and explora-
tion of its potential are essential for conserving them from extinction. In this point
of view, in the present study, detailed investigation on the validation of phytochemi-
cal constituents and their role on metabolism have been majorly emphasized to
Comprehensive Review on Wild Basil Genus Orthosiphon of Lamiaceae 411

reveal the therapeutic efficacy of Orthosiphon species. In addition to the problems

encountered in medicinal plant research, usage and applications were also discussed.

2 Traditional Health Benefits

Plants have always been a common source of medicaments, either in traditional

preparations or pure active principles. It is thus reasonable for decision-makers to
identify locally available plants or plant extracts that could usefully be added to the
national list of drugs or even replace some pharmaceutical preparations that need to
be determined. The genus Orthosiphon comprises an impressive number of species,
some of which have been used in traditional medicine. Orthosiphon species are
considered as an important medicinal plant used in herbalism which exerts great
therapeutic properties. To date, the genus provided many chemical compounds, of
which some species provide dynamic pharmacological activity [17]. Plants belong-
ing to the family Lamiaceae have traditionally and historically been exploited
worldwide for their numerous applications as flavoring agents, food preservation
agents, and as a source drug of medicinally active compounds. Each species has a
unique blend of bioactive compounds, exhibiting antibacterial, antioxidant, anti-­
inflammatory, antiviral, and anticancer properties [18].
In ethnobotanical surveys, genera Orthosiphon (Lamiaceae), Orthosiphon aris-
tatus, O. pallidus, O. thymiflorus, and O. stamineus are widely used in traditional
medicine to prevent various ailments such as diabetes, kidney stone, edema, rheu-
matism, hepatitis, hypertension, and jaundice. Orthosiphon aristatus has a long his-
tory of medicinal use in Indonesia, Malaysia, and Southeast Asia for various
biological activities (Table 1). O. aristatus Benth. (Lamiaceae) is also an essential
plant in traditional folkloric medicine. The plant has extensively been exploited
traditionally to treat several human ailments. It is widely used to manage various
diseases [19]. The traditional indigenous uses and pharmacological claims of ethno-
botanical herbs provide fundamental knowledge for further developing medicinal
plants and practical drug discovery approaches [20].
O. diffusus (Benth.) ‘Senthulasi’ synonym of Endostemon viscosus (Roth)
M. Ashby. is widely used by folkloric medicinal practitioners of Western Ghats,
India, for treating inflammation, hepatitis, and jaundice for many years and its effec-
tiveness is widely acclaimed among the tribal communities [21]. O. pallidus is a
herbaceous shrub native to South East Asia and India and has been used to treat vari-
ous infectious diseases (Table 1).
The plant O. stamineus is known for its several ailments and is used extensively
in several countries, especially in Indonesia, Malaysia, Thailand, Vietnam, and
Myanmar. The traditional use of O. stamineus meets its scientific evidence in phy-
tochemical, pharmacological, toxicological, and clinical trials and is developed as a
new source of drugs [22].
The members of the family Lamiaceae include aromatic plants that are being
used in traditional medicine for various disorders. Pieces of information about the
412 K. Abirami et al.

Table 1 Medicinal and health effects of Orthosiphon spp.

S.
no Plant name Biological activity References
1. Orthosiphon Diabetes, kidney stone, and hypertension treatment [71–74]
aristatus Antioxidant activities [19]
Antimicrobial activities [75]
2. Orthosiphon Inflammation, hepatitis, and jaundice treatment [21]
diffuses Repel ticks [76]
Hepatoprotection and antioxidant activities [21]
Cytotoxic activity [64]
3. Orthosiphon Urinary infections, edema, fever, influenza, rheumatism, [77]
pallidus hepatitis, and jaundice treatments
Antioxidant, antimicrobial activities, and anticancer activities [78]
against human breast cancer cell lines
Fever, hepatitis, edema, jaundice, rheumatism, antioxidant [79, 80]
activities, and the cytotoxicities
4. Orthosiphon Diabetes, hypertension, edema, epilepsy, fever, influenza, and [54,
stamineus jaundice treatments 81–83]
Epilepsy [84]
Inhibit proliferation and induced apoptosis [85]
Improved effect on memory and treatment of [86]
neurodegenerative diseases such as Alzheimer’s disease
Diabetes, gallstone, jaundice, and menstrual disorder [87]
remedies
Diuretic, anti-inflammatory, antioxidant, antiangiogenic, and [88]
hepatoprotective properties
Anti-proliferative activity against HeLa, PC3, HCT116, [89]
HL-60, SK-UT-1 cells, and HepG2 cells
Antimicrobial activity and antioxidant immunomodulatory [90]
properties
Antidiabetic effects [91]
Antiulcer activity [92]
Protect liver against hepatocellular carcinoma [93]
Antioxidant activity [94]
Hepatoprotective activity [95]
Anti-inflammatory activity, antioxidant, and free-radical [53, 96,
scavenging abilities 97]
Diuretic, hypouricemic, renal protective, antioxidant, [29]
anti-inflammatory, hepatoprotective, gastroprotective,
antihypertensive, antidiabetic, antihyperlipidemic,
antimicrobial, and anorexic activities
5. Orthosiphon Cytotoxic, diabetic, anti-inflammatory, and hypertensive [17, 98,
thymiflorus activities 99]
Antioxidant activity [19]
Cytotoxic potential [63]
Antibacterial properties [100]
Comprehensive Review on Wild Basil Genus Orthosiphon of Lamiaceae 413

medicinal aspects of Becium obovatum (E. Mey. ex Benth) N.E.Br, Calamintha

nepeta (L) Savi, Fuestia Africana T.C.E. Fries, Hyptis pectinata (L) Poit, Hoslundia
opposita Vahl, Leonotis nepetifolia (R. Br. ex Ait. F), Leucas calostachys Oliv,
Ocimum kilimandscharicum Baker Ex. Gurke, Plectranthus barbatus Andrews
Satureja biflora (Ham Ex. D.Don) Brig were studied. These plants were used widely
to treat gastrointestinal infections, urinary infections, cold and sore throat, rheuma-
tism, and skin infections [23].

3 Phytochemical Constituents

Since ancient times, herbs and spices have improved food‘s sensory characteristics,
nutritional, and health properties. Herbs and spices are generally recognized as safe
(GRAS) and excellent chemical additive substitutes. Essential oils are mixtures of
volatile compounds obtained mainly by steam distillation from medicinal and aro-
matic plants, and they are an alternative source to synthetic additives for the food
industry. They are considered potential sources of natural food preservatives due to
the growing interest in developing safe, effective raw food and additives in order to
reduce food demand. Lamiaceae is one of the most influential families producing
essential oils with potent antioxidant and antimicrobial properties. Aromatic plants
are rich in essential oils and are mainly found in the Mediterranean region, where
such oils are a good source of ecological and economic development. The use of
essential oils with antimicrobial and antioxidant properties to increase the shelf life
of food is a promising technology. The vital oils of the family Lamiaceae such as
rosemary, thyme, and sage have been studied extensively concerning their use as
food preservatives [24].
The phytochemical research approach is considered effective in discovering the
bioactive profile of plants of therapeutic importance. Phytochemicals are essential
in cosmetic and medicinal preparations as antimicrobial agents and antioxidants.
The application of investigated plant species in various medicinal aspects is based
on their phytochemical constituents and pharmacological activities. Herbal-based
medicines have gained more popularity due to less toxicity and easy accessibility,
along with technological advances in manufacturing processes [25].
Therefore, it is imperative to search for novel, practical, accessible drug sources
without toxicity. There has been a broad spectrum of action to face various mala-
dies, and medicinal plants are considered as a significant asset [26]. Hyptis suaveo-
lens and Ocimum gratissimum plants were endowed with nutrients, mineral
compounds, and secondary metabolites (flavonoids, alkaloids, tannins, phenolic
compounds, saponins, steroids, glycosides, and essential oils). Antibacterial, anti-
fungal, antioxidant, antiparasitic, antidiabetic, anticancer, antiulcer, wound healing,
and insecticidal activities were well reported for both the species, H. suaveolens and
O. gratissimum. Further, in phytochemical profiling, both the plant species also evi-
denced substantial variation in essential oil composition. This variation is the
414 K. Abirami et al.

consequence of several chemotypes of essential oils, which can influence the bio-
logical activities of the species [27].
Phytochemical screening also revealed that sterols, terpenoids, tannins, sapo-
nins, alkaloids, flavonoids, and glycosides contributed to the medicinal aspects of
the Lamiaceae. This research has provided insight into the use of secondary metab-
olites in traditional medicine in maintaining proper human health [23]. O. aristatus
(Blume) Miq. of the family Lamiaceae is called kumis kucing in Indonesia, which
is a valuable medicinal plant known for its pharmacological properties. Fifteen gen-
otypes of O. aristatus obtained from the ethanolic leaf extracts were undertaken
based on its phytochemical content and pharmacological activities. Chemometric
analysis was also used to investigate the genetic variability based on the phyto-
chemical content and pharmacological activities of O. aristatus genotypes [28].
Extensive research has been carried out on O. stamineus Benth. (Lamiaceae)
since 1930s. Phytochemical studies reported 116 isolated compounds from O. sta-
mineus. Different in vitro and in vivo model studies have been addressed, along with
a survey of all phytochemicals identified in this plant O. stamineus, including flavo-
noids, terpenoids, and essential oils. Previous studies revealed that O. stamineus
possess several pharmacological activities attributed to its phytochemical content. It
has broad conventional and pharmacological uses in various pathophysiological
conditions [29]. Phytochemical studies for O. stamineus also revealed the presence
of abundant bioactive compounds, including terpenoid, phenolic compounds, flavo-
noids, saponin, essential oil, and organic acids [30]. Choo et al. [31] also registered
that the ethanolic extract of O. stamineus, exhibited anticonvulsive activity in
Zebrafish Choo, Kundap [32]. Coelho et al. [33] demonstrated the anticonvulsant
potential of rosmarinic acid in mice, which is considered as an active chemical con-
stituent in the extract Coelho, Vieira [34]. The proteins extracted from the leaves of
O. stamineus leaves may also hold valuable protective potential for central nervous
system (CNS) disorders such as epilepsy.

3.1 Essential Oil

Many Lamiaceae members are consumed in Lebanese cuisine as food or condiment

and are primarily used in traditional medicine to treat various diseases, including
microbial infections. In a survey, the traditional medicinal uses of Lamiaceae spe-
cies, namely, Coridothymus capitatus L., Lavandula stoechas L., L. Angustifolia
Mill., Mentha spicata L. subsp. condensata, Origanum syriacum L., Rosmarinus
officinalis, Salvia fruticosa Miller., Satureja cuneifolia Ten., S. thymbra L., Thymbra
spicata L., and Vitex agnus-castus L., and the chemical composition and antimicro-
bial activity of their essential oils were well documented. The survey evidenced that
Lamiaceae species are mainly used against gastrointestinal disorders and microbial
infections. Chemical analysis of the essential oils obtained from these plants has led
to the identification of 75 compounds describing more than 90% of the relative
Comprehensive Review on Wild Basil Genus Orthosiphon of Lamiaceae 415

composition of each essential oil. Essential oils with high thymol and carvacrol
determined the most potent antimicrobial activity. As expected, these two com-
pounds demonstrated an interesting antifungal efficacy against the filamentous fun-
gus T. rubrum. Results confirmed that some of the species of Lamiaceae members
used in ethnopharmacological practices as antimicrobial agents possess antibacte-
rial and antifungal potential consistent with their use in alternative or complemen-
tary medicine [35].

Essential Oils with Principled Antimicrobial Properties [36]

3.1.1 Structural Properties of Essential Oil

Thymol, chemically known as 2-isopropyl-5-methylphenol is a colorless crystalline

monoterpene phenol [37]. Dietary thymol and its isomer, carvacrol, were evaluated
as alternatives for antibiotic feed additives in female broiler chickens [38]. In recent
years, medicinal herbs have been used for the prevention and protection against
infectious diseases. Thymol and carvacrol are active ingredients of the family
Lamiaceae; these components possess antibacterial and antifungal effects [36].

Essential oil from Endostemon tereticaulis

Endostemon tereticaulis (Poir.) M.Ashby is used in traditional medicine due to

its varied biological potentialities. Therefore, the chemical composition of their
essential oil and its antibacterial effect for the ethanolic extract and essential oil of
E. tereticaulis were tested against resistant pathogenic bacterial strains. Gas
chromatography-­ mass spectrometric analysis of the fractionated crucial crude
extract has identified 43 bioactive compounds representing 99.55% of total essential
oil. The major components were caryophyllene oxide (15.17%) followed by
416 K. Abirami et al.

α-humulene (13.96%), α-copaene (11.75%), (E)-β-caryophyllene (8.44%), and

δ-cadinene (6.78%) [39].

3.2 GC-MS Phytochemical Profile

In the last few decades, gas chromatography-mass spectrometry (GC-MS) has

become firmly established as a critical technological platform for secondary metab-
olite profiling in plants and non-plant species [40, 41]. The GC-MS identified phy-
tochemicals were found reasonably responsible for multitherapeutic uses and effects
of herbs in various health disorders. The advances in analytical techniques including
GC-MS and FT-IR were considered as powerful tools for identifying and determin-
ing phytochemical compounds, providing valuable insight into their use in tradi-
tional medicine [42]. The chemical composition of essential oils obtained from
Lamiaceae members has been analyzed using GC-MS and GC-FID to examine their
volatile compound profiles, responsible for their respective flavors and fragrance.
Experimental data revealed a typical volatile constituent pattern for the family
Lamiaceae. Monoterpenes and sesquiterpenes, accountable for these plants‘taste
and medicinal use, were the most abundant group of volatile constituents. The prin-
cipal component analysis also grouped these analyzed species into four main clus-
ters [43].

Sesquiterpene Hydrocarbon [47]

Gas chromatography-mass spectrometric (GC-MS) analysis for various extracts

of Orthosiphon showed that the crude extract was composed of different phyto-
chemical components. They comprised hydrocarbons, aldehydes, terpenoids, phe-
nolics, and fatty acids. Sesquiterpenes were found to be at higher composition,
contributing to the total amount of 41.63%, 31.32%, and 22.58% in hexane, ethyl
acetate, and methanol extract of Syzygium polyanthum, respectively [44].
The traditional indigenous uses and pharmacological aspects of ethnobotanical
herbs provide basic knowledge for the further development of medicinal plants and
a useful approach to drug discovery [20]. Solid-phase microextraction of Nepeta
conferta, Origanum onites, Satureja cuneifolia, and a few other Lamiaceae species
Comprehensive Review on Wild Basil Genus Orthosiphon of Lamiaceae 417

was analyzed for GC-FID/MS. The main components of the volatile organic com-
ponents were p-cymene (25.5%), eucalyptol (9.8%), limonene (5.0%), sabinene
(4.8%), carvacrol (3.7%), E-linalool oxide (3.3%), Z-linalool oxide (3.0%) in
N. conferta; carvacrol (47.3%), p-cymene (15.8%), γ-terpinene (8.6%), myrcene
(8.6%), caryophyllene (2.0%) in O. onites and carvacrol (32.6%), p-cymene
(22.2%), γ-terpinene (15.1%), myrcene (5.5%), and caryophyllene (3.3%) in
S. cuneifolia. Carvacrol was the most abundant component in the volatile organic
compounds of O. onites (47.3%), S. cuneifolia (32.6%), and N. conferta (3.7%) [45].
The hydro-distilled essential oil from the aerial parts of O. pallidus Royle, ex
Benth (Lamiaceae), was investigated using gas chromatography equipped with
flame ionization detector (GC-FID) and gas chromatography coupled with mass
spectrometry (GC-MS). Fifty-two compounds representing 98.4% of the total oil
constituents were identified. The major constituents were β-caryophyllene (17.4%)
and 7-epi-α-selinene (15.2%). The other minor constituents were terpinolene
(6.9%), β-pinene (6.8%), β-element (5.1%), α-humulene (4.9%), α-copaene (4.8%),
epi-cubebol (4.5%), and zonarene (3.9%). The oil was found to be rich in sesquiter-
pene hydrocarbon-type constituents [46].
The chemical composition of the essential oil of O. diffusus was investigated.
Extraction by hydrodistillation followed by gas chromatography and mass spec-
trometry (GC-MS) yielded 25 compounds representing 95.3% of the oil. The major
volatile components of the oil were n-eicosane (19.5%), t-caryophyllene (18.6%),
octocosane (12.2%), limonene (11.6%), β-ocimene (4.2), methyl palmitate (2.8%),
and elemol (2.6%) [47].
The chemical composition of the volatile oil from the leaves of Endostemon
obtusifolius (E.Mey. ex Benth.) N.E.Br. was investigated. The composition of oils
obtained by hydrodistillation followed by gas chromatography and mass spectrom-
etry (GC-MS) yielded 50 compounds representing 99.8% of the oil. The major vola-
tile components of the oil were phenol (26.92%), 1,3,6,10-cyclotetradecatetraene,
3,7,11-trimethyl-14-(1-methylethyl)-,[S-(E,Z,E,E)] (19.13%), acetic acid,
1,7,7-­trimethyl-bicyclo[2.2.1]hept-2-yl ester (6.44%), cyclooctene (5.25%),
1H-cyclopropa[a]naphthalene,decahydro-1,1,3a-trimethyl-7-methylene-[1aS-(1a.
alpha.,3a.alpha.,7a.beta.,7b.alpha.)] (4.98%), 3-cyclohexen-1-ol,4-methyl-1-(1-­
methylethyl) (3.81%), cycloisolongifolene, 8,9-dehydro (3.52%), and
1H-cycloprop[e] azulene, decahydro-1,1,7-trimethyl-4-methylene (3.12%). Phenol
was the major compound detected from E. obtusifolius used as an oral anesthetic
and analgesic agent to treat pharyngitis. It is considered as a versatile precursor for
large collection of drugs including aspirin, herbicides, and pharmaceutical
drugs [47].

3.2.1 Structural Activity of Sesquiterpene Hydrocarbon

Sesquiterpene structural diversity arises in the assemblage of 15-carbon skeletons

making up the backbone of all sesquiterpenes. They are found particularly in higher
plants and in many other living systems such as marine organisms and fungi. The
418 K. Abirami et al.

second source of diversity is due to the layering of functional groups and substitu-
ents upon the structural scaffolds in distinct regio- and stereospecific manners.
Sesquiterpenes also include essential oils and aromatic constituents with several
pharmacological activities [49, 50].
Essential oils are widely used in pharmaceutical, sanitary, cosmetic, agriculture,
and food industries for their bactericidal, viricidal, fungicidal, antiparasitical, and
insecticidal properties. Their anticancer activities are well documented. Over a hun-
dred essential oils from more than 20 plant families have been tested on more than
20 types of cancers in last 10 years [48]. In addition, cytotoxic effects have been
reported for many essential oils [51, 52]. However, very few studies have been done
on the combination of essential oils and their major compounds to find assumed
synergistic constructive effects.

3.3 Bioactive Flavonoid Compounds of O. stamineus

The flavonoid-rich chloroform extract fraction (CF2) of O. stamineus leaf contain-

ing sinensetin (2.86% w/w), eupatorin (5.05% w/w), and 3′-hydroxy-5,6,7,4′-
tetramethoxyflavone (1.101% w/w) significantly reduced rat hind paw edema due to
the presence of flavonoid compounds capable of affecting the NO pathway [53].
Akowuah et al. [54] also registered that sinensetin, eupatorine, 30-hydroxy-5,6,7,40-­
tetramethoxyflavone, rosmarinic acid, and quercetin form the major components in
an O. stamineus extract which possess significant free-radical scavenging and anti-
oxidant ability. Thus, the properties of O. stamineus combined with its traditional
usage have made it a therapeutic drug for the treatment of epilepsy.

Bioactive flavonoid compounds of O. stamineus

Comprehensive Review on Wild Basil Genus Orthosiphon of Lamiaceae 419

3.3.1 Properties of Sinensetin and Eupatorin

In vitro and in vivo studies have shown that sinensetin possesses strong anticancer
activities and a wide range of pharmacological activities such as anti-inflammatory,
antioxidant, antimicrobial, antiobesity, antidementia, and vasorelaxant activities
[55]. Eupatorin, as a major bioactive flavonoid constituent in O. stamineus, pos-
sesses numerous strong biological activities, including anticancer, anti-­inflammatory,
and vasorelaxation activities [53, 56–62].

Major terpene of Orthosiphon pallidus (https://www.brenda-­enzymes.org/enzyme.

php?ecno=4.2.3.86)

Plant-derived compounds with high therapeutic effects are gaining more concern
all over the Globe. Researchers are mainly targeting ethnic and folkloric knowledge
to explore novel drug candidates. Orthosiphon thymiflorus is a medicinal, aromatic
herb used in folkloric medicine and in Ayurvedic preparations. Hence, it is impera-
tive to evaluate the cytotoxic potential and chemical profile of the plant [63].
Phytochemical profiling of O. diffusus has resulted in the isolation of four relatively
rare, novel polychiral furanopyrans, namely, orthodiffenes A–D, characterized from
the detailed studies of their 1D and 2D NMR spectral analysis. The X-ray crystal-
lographic analysis of orthodiffene A was also accomplished. The in vitro cytotoxic
activity of orthodiffenes A–C was tested against Jurkat and HL-60 cells using camp-
tothecin as a positive control. Orthodiffenes A and B showed comparable camptoth-
ecin activity against HL-60 and Jurkat cells, respectively [64].

3.3.2 Structural Properties of Major Terpenes of Orthosiphon pallidus

Due to its unique ability to bind with CB2 receptors, beta-caryophyllene has potent
anti-inflammatory, antimicrobial, antibacterial, and antioxidant properties. It is
known to relieve anxiety, pain, reduce cholesterol, prevent osteoporosis, and treat
seizures. Also, some research has shown that it may help against certain neurode-
generative diseases and cancers. It is considered as a therapeutic agent to prevent
and treat osteoporosis [65]; it acts as a local anesthetic agent by releasing the same
endorphins as morphine without any additives. Additionally, when used together
420 K. Abirami et al.

with alpha-humulene and caryophyllene, it increased their anticancer activity in

human tumor cell lines. Also, it can reduce inflammation connected with multiple
sclerosis and immune system dysfunctions. The interaction of Humulene + Beta-
Caryophyllene can have anti-inflammatory properties that make it practical for
treating arthritis, bursitis, and fibromyalgia (https://foreverest.cn/news-­list/the-­
benefits-­of-­the-­%CE%B2-­caryophyllenebcp). 7-Epi-α-selinene—An isomer of
selinene where the double bond in the octahydronaphthalene ring system is endocy-
clic with (2S,4aR,8aR)-configuration. (https://www.ebi.ac.uk/chebi/searchId.do?ch
ebiId=CHEBI:62224).

4 Problems Encountered and Future Directions

The publication trend shows that increasing interest in medicinal plant research and
analysis is reflected in the number of recent publications, with more than a threefold
increase from 4686 publications during the year 2008 to 14,884 in 2018. Output
published during the 8 years of the present decade alone outnumbered all those
combined before 2000 [66].
There is good scope for medicinal plants as there are about half a million plants
worldwide, and most of them were not investigated for their medicinal properties.
The hidden potential of therapeutic activities could be decisive in treating diseases
[67]. Among the variety of modern medicines, many are produced indirectly from
medicinal plants, such as aspirin. Studying medicinal plants helps to understand
plant toxicity and protects humans and animals from synthetic poison. The medici-
nal effects of plants are due to the nature of secondary metabolites inherent in them.
Keeping this in consideration, there has been a renowned interest in the field of
natural product chemistry. This interest can be due to several factors, including ther-
apeutic needs, the remarkable diversity of both chemical structure and biological
activities of naturally occurring secondary metabolites, the utility of novel bioactive
natural compounds as biochemical probes, the development of novel and sensitive
techniques to detect biologically active natural products, improved approaches to
isolate, purify, and structurally characterize these bioactive constituents and
advances in solving the demand for supply of complex natural products [68].
Most of the pharmaceutical industry is highly dependent on the wild population
to supply raw materials to extract medicinally essential compounds. Unfortunately,
the genetic diversity of medicinal plants in the world is getting endangered at an
alarming rate due to ruinous harvesting practices and over-harvesting for the pro-
duction of medicines, with little or no regard for the future. Also, extensive destruc-
tion of plant-rich habitats has been made due to forest degradation, agriculture
encroachment, and urbanization. In modern medicine, plants are used as a source of
direct therapeutic agents, a model for new synthetic compounds, and a taxonomic
marker for elaborating more complex semi-synthetic chemical compounds [69].
The ability to process data using multivariate analysis software has opened up
new vistas to metabolomics, giving us greater capacity to understand many
Comprehensive Review on Wild Basil Genus Orthosiphon of Lamiaceae 421

variations of chemical compounds occurring within medicinal plants, allowing us to

have greater certainty of not only the quality of the plants and medicines but also of
their suitability for clinical research [66]. In addition to that, conservation strategies
and resource management should adequately be taken into account mere consider-
ation for the sustainable utilization of medicinal plant resources as well [70].

5 Conclusion and Comments

Plants are sessile organisms dependent on the deployment of secondary metabolites

to respond to biotic and abiotic challenges. A trade-off is envisioned between
resources allocated to growth, development, reproduction and biosynthesis, storage,
and maintenance of secondary metabolites [101]. However, increasing shreds of
evidence suggest that secondary metabolites serve auxiliary roles, including func-
tions associated with primary metabolism. An additional benefit is that the small
molecules can be applied in a conditional, reversible, and dose-dependent fashion,
thus allowing a temporary perturbation of its biological system. Although the use of
small molecules to alter biological systems has a rich repository of service through
the therapeutic aspects of plant compounds, its true potential has been recognized
only recently. Besides, evaluating the effects of plant secondary metabolites on a
biological system rather it is imperative to predict its future perspectives.
Research has specified that the genus Orthosiphon possesses active components
with biological potentials like anticancer, anti-inflammatory, antibiotic, antioxidant,
antidiabetic, antiulcer, antimicrobial, and hepatoprotective activities. Traditional
validation of Orthosiphon has a remarkable pertinence in emerging drug discovery.
Therefore, further research is essential to manifest a comprehensive background
that has to evident their pharmaceutical effects along the concerns of conservation
and sustainable utilization. Lamiaceae, or Labiatae, is a family of flowering plants
comprising valuable medicinal plants used in traditional folkloric medicine. Various
potent phytochemical constituents have been isolated from the Orthosiphon spe-
cies, and subsequent phytoconstituents correlated pharmacological studies have
also been well reported. This family and the genus are special for their essential oil,
though only a few are in the market. The research is focused on tapping plant com-
ponents and delivering the most beneficial health products out of them.

References

1. Vasu K, Goud JV, Suryam A, Singara MA (2009) Biomolecular and phytochemical analyses
of three aquatic angiosperms. Afr J Microbiol Res 3(8):418–421
2. Akrout EI, Jani H, Zammouri T, Mighri H, Neffati M (2010) Phytochemical screening and
mineral contents of annual plants growing wild in the southern of Tunisia. J Phytology
2(1):034–040
3. Sarker SD (2012) Pharmacognosy in modern pharmacy curricula. Pharmacogn Mag 8(30):91
422 K. Abirami et al.

4. World Health Organization (1993) Research guidelines for evaluating the safety and efficacy
of herbal medicines. WHO Regional Office for the Western Pacific, Manila
5. World Health Organization (1998) Regulatory situation of herbal medicines. A worldwide
review, Geneva, pp 1–5
6. Galbley S, Thiericke R (1999) Drug discovery from nature, Series: Springer Desktop Editions
in Chemistry
7. Cragg GM, Newman DJ (2013) Natural products: a continuing source of novel drug leads.
Biochim Biophys Acta 1830(6):3670–3695
8. Dar JA, Subashree K, Sundarapandian S et al (2019) Invasive species and their impact on
tropical forests of Central India: a review. In: Tropical ecosystems: Structure, functions and
challenges in the face of global change, pp 69–109
9. Raju VS, Reddy CS, Suthari S (2010) Flowering plant diversity and endemism in India: an
overview. Algae 2(40,000):6–25
10. Singh R (2015) Medicinal plants: a review. J Plant Sci 3(1):50–55
11. Rajasekharan PE, Wani SH (2020) Conservation and utilization of threatened medicinal
plants. Springer Nature- Science, p 565
12. Rangari VD (2007) Pharmacognosy & Phytochemistry, 1st edn. Career Publication,
Pune, pp 4–7
13. Okigbo RN, Eme UE, Ogbogu S (2008) Biodiversity and conservation of medicinal and
aromatic plants in Africa. Biotechnol Mol Biol Rev 3(6):127–134
14. Kumar P, Mishra S, Malik A, Satya S (2011) Insecticidal properties of Mentha species: a
review. Ind Crop Prod 34(1):802–817
15. Lourenco SC, Moldao-Martins M, Alves VD (2019) Antioxidants of natural plant origins:
from sources to food industry applications. Molecules 24(22):4132
16. Mahidol C, Ruchirawat S, Prawat H et al (1998) Biodiversity and natural product drug dis-
covery. Pure Appl Chem 70(11):2065–2072
17. Sundarammal S, Thirugnanasampandan R, Selvi MT (2012) Chemical composition analy-
sis and antioxidant activity evaluation of essential oil from Orthosiphon thymiflorus (Roth)
Sleesen. Asian Pac J Trop Biomed 2:S112–S115
18. Mishra LK, Sarkar D, Shetty K (2019) Human health-relevant bioactives and associated
functionalities of herbs in the Lamiaceae family. In: Functional Foods and Biotechnology.
CRC Press, pp 115–131
19. Chithra V, Adersh M, Reji SR, Nair GM (2013) Screening biological activities of Orthosiphon
aristatus. Int J Adv Res 5:594–600
20. Heinrich M, Gibbons S (2001) Ethnopharmacology in drug discovery: an analysis of its role
and potential contribution. J Pharm Pharmacol 53(4):425–432
21. Ghaffari H, Venkataramana M, Nayaka SC et al (2013) Hepatoprotective action of
Orthosiphon diffusus (Benth.) methanol active fraction through antioxidant mechanisms: an
in vivo and in vitro evaluation. J Ethnopharmacol 149(3):737–744
22. Adnyana IK, Setiawan F, Insanu M (2013) From ethnopharmacology to clinical study of
Orthosiphon stamineus Benth. Studies 1(2)
23. Okach DO, Nyunja ARO, Opande G (2013) Phytochemical screening of some wild plants
from Lamiaceae and their role in traditional medicine in Uriri District-Kenya. Int J Herb Med
1(5):135–143
24. Nieto G (2017) Biological activities of three essential oils of the Lamiaceae family.
Medicines 4(3):63
25. Masih NG, Singh BS (2012) Phytochemical screening of some plants used in herbal based
cosmetic preparations. In: Chemistry of Phytopotentials: health, energy and environmental
perspectives. Springer, Berlin, Heidelberg, pp 111–112
26. Garba ABH, Arya MA, Traore A, Ouedraogo S (2017) Etude des effets vermicide et anti-­
diarrheique du macere aqueux des feuilles de Salvadora persica, L. (Salvadoraceae). Int J
Biol Chem 11(1):54–66
Comprehensive Review on Wild Basil Genus Orthosiphon of Lamiaceae 423

27. Degla LH, Olounlade PA, Amoussa AMO et al (2021) Pharmacological and biochemical
aspects of the Lamiaceae Family used in the treatment of intestinal Parasitosis in West and
Central Africa. Pharmacogn Rev 15(29):69–75
28. Batubara I, Komariah K, Sandrawati A et al (2020) Genotype selection for phytochemical
content and pharmacological activities in ethanol extracts of fifteen types of Orthosiphon
aristatus (Blume) Miq. leaves using chemometric analysis. Sci Rep 10:20945
29. Ameer OZ, Salman IM, Asmawi MZ, Ibraheem ZO (2012) Orthosiphon stamineus: tra-
ditional uses, phytochemistry, pharmacology, and toxicology. Mun Fei Yam J Med Food
15:8678–8690
30. Maheswari C, Venkatnarayanan R, Manavalan R et al (2015) Phytochemical screening and
in vitro free radical scavenging activity of Orthosiphon stamineus and Coccinia grandis. Int
Res J Pharm 6:627–630
31. Choo BKM, Kundap UP, Kumari Y, Hue SM et al (2018) Orthosiphon stamineus leaf extract
affects TNF-and seizures in a zebrafish model. Front Pharmacol 9:139
32. Zhu HL, Wan JB, Wang YT et al (2014) Medicinal compounds with antiepileptic/anticonvul-
sant activities. Epilepsia 55:3–16
33. Coelho VR, Vieira CG, De Souza LP et al (2015) Antiepileptogenic, antioxidant and geno-
toxic evaluation of rosmarinic acid and its metabolite caeic acid in mice. Life Sci 122:65–71
34. Rabiei Z (2017) Anticonvulsant effects of medicinal plants with emphasis on mechanisms of
action. Asian Pac J Trop Biomed 7:166–172
35. Khoury M, Stein D, Eparvier V et al (2016) Report on the medicinal use of eleven Lamiaceae
species in Lebanon and rationalization of their antimicrobial potential by examination of the
chemical composition and antimicrobial activity of their essential oils. eCAM 2016:17
36. Memar Mohammad Y, Parisa R, Naser A et al (2017) Carvacrol and thymol: strong antimicro-
bial agents against resistant isolates. Rev Med Microbiol 28(2):63–68
37. Fizur NMM, Hayate J, Hasan AT et al (2017) Pharmacological properties and molecular
mechanisms of thymol: prospects for its therapeutic potential and pharmaceutical develop-
ment. Front Pharmacol 8:380
38. Lee KW, Everts H, Kappert HJ et al (2003) Dietary Carvacrol lowers body weight gain but
improves feed conversion in female broiler chickens. J Appl Poult Res 12(4):2003
39. Namata Abba B, Romane A, Ilagouma AT (2020) Antibacterial activity of Endostemon tereti-
caulis (Poir.) M. Ashby essential oil and ethanolic extract against resistant pathogenic bacte-
ria. Nat Prod Commun 15(9):1–9
40. Robertson DG (2005) Metabonomics in toxicology: a review. Toxicol Sci 85:809–822
41. Kanthal LK, Dey A, Satyavathi K, Bhojaraju P (2014) GC-MS analysis of bio-active com-
pounds in methanolic extract of Lactuca runcinata DC. Pharm Res 6(1):58
42. Pakkirisamy M, Kalakandan SK, Ravichandran K (2017) Phytochemical screening, GC-MS,
FT-IR analysis of Methanolic extract of Curcuma caesia Roxb (Black Turmeric). Pharm J
9(6):952–956
43. Hajdari A, Mustafa B, Hyseni L et al (2020) Phytochemical study of eight medicinal plants of
the lamiaceae family traditionally used as tea in the Sharri Mountains region of the Balkans.
Sci World J 2020:9
44. Asmira AREN, Azlini I, Nor OM et al (2018) GC-MS analysis of phytochemical com-
pounds in Syzygium polyanthum leaves extracted using ultrasound-assisted method. Pharm
J 10(1):110–119
45. Yayli B, Tosun G, Karaköse M et al (2014) SPME/GC-MS analysis of volatile organic com-
pounds from three Lamiaceae species (Nepeta conferta Hedge & Lamond, Origanum onites
L. and Satureja cuneifolia Ten.) growing in Turkey. Asian J Chem 26(9):2541
46. Joshi RK (2020) GC-MS analysis of the volatile constituents of Orthosiphon pallidus Royle,
ex Benth. Nat Prod Res 34(3):441–444
47. Sadashiva CT, Naidoo Y, Naidoo J R, Naidoo G (2013) Chemical composition of the essen-
tial oil from the leaves of Endostemon obtusifolius (E.Mey. ex Benth.) N.E.Br. Biochem
Pharmacol 2:4
424 K. Abirami et al.

48. Bayala B, Bassole IHN, Scifo R et al (2014) Anticancer activity of essential oils and their
chemical components - a review. Am J Cancer Res 4(6):591–607
49. Chappell J, Robert M (2010) Coates, 1.16 - Sesquiterpenes. In: (Ben) Liu H-W, Mander L
(eds) Comprehensive Natural Products II. Elsevier, pp 609–641
50. Awouafack MD, Tane P, Kuete V, Jacobus N (2013) Eloff, 2 - Sesquiterpenes from the medici-
nal plants of Africa. In: Kuete V (ed) Medicinal Plant Research in Africa. Elsevier, pp 33–103
51. Cavalieri E, Mariotto S, Fabrizi C et al (2004) Alpha-Bisabolol, a nontoxic natural compound,
strongly induces apoptosis in glioma cells. Biochem Biophys Res Commun 315:589–594
52. Lampronti I, Saab AM, Gambari R (2006) Antiproliferative activity of essential oils derived
from plants belonging to the Magnoliophyta division. Int J Oncol 29:989–995
53. Yam MF, Lim V, Salman IM et al (2010) HPLC and anti-inflammatory studies of the flavonoid
rich chloroform extract fraction of Orthosiphon stamineus leaves. Molecules 15:4452–4466
54. Akowuah GA, Ismail Z, Norhayati I et al (2005) The effects of different extraction solvents
of varying polarities on polyphenols of Orthosiphon stamineus and evaluation of the free
radical-scavenging activity. Food Chem 93:311–317
55. Han Jie L, Jantan I, Yusoff SD et al (2021) Sinensetin: an insight on its pharmacological
activities, mechanisms of action and toxicity. Front Pharmacol 11:553404
56. Razak NA, Abu N, Ho WY et al (2019) Cytotoxicity of eupatorin in MCF-7 and MDA-MB-231
human breast cancer cells via cell cycle arrest, anti-angiogenesis and induction of apoptosis.
Sci Rep 9:1514
57. Lee K, Hyun Lee D, Jung YJ et al (2016) The natural flavone eupatorin induces cell cycle
arrest at the G2/M phase and apoptosis in HeLa cells. Appl Biol Chem 59:193–199
58. Estevez S, Marrero MT, Quintana J (2014) Eupatorin-induced cell death in human leukemia
cells is dependent on caspases and activates the mitogen-activated protein kinase pathway.
PLoS One 9:e112536
59. Androutsopoulos V, Arroo RRJ, Hall JF et al (2008) Antiproliferative and cytostatic effects
of the natural product eupatorin on MDA-MB-468 human breast cancer cells due to CYP1-­
mediated metabolism. Breast Cancer Res 10(3):R39
60. Doleckova I, Rarova L, Gruz J et al (2012) Antiproliferative and antiangiogenic effects of fla-
vone eupatorin, an active constituent of chloroform extract of Orthosiphon stamineus leaves.
Fitoterapia 83:1000–1007
61. Laavola M, Nieminen R, Yam MF et al (2012) Flavonoids eupatorin and sinensetin present in
Orthosiphon stamineus leaves inhibit inflammatory gene expression and STAT1 activation.
Planta Med 78:779–786
62. Yam MF, Tan CS, Ahmad M, Shibao R (2016) Mechanism of vasorelaxation induced by
eupatorin in the rats aortic ring. Eur J Pharmacol 789:27–36
63. Devi SR, Thoppil JE (2016) Cytotoxic studies and phytochemical analysis of Orthosiphon
thymiflorus (Roth) Sleesen. Int J Pharm Sci 8(2):249–255
64. Holla H, Srinivas Y, Majhi A et al (2011) Novel cytotoxic constituents of Orthosiphon dif-
fusus. Tetrahedron Lett 52(1):49–52
65. Yamaguchi M, Levy RM (2016) β-Caryophyllene promotes osteoblastic mineralization, and
suppresses osteoclastogenesis and adipogenesis in mouse bone marrow cultures in vitro. Exp
Ther Med 12(6):3602–3606
66. Martin F, Michael H, Anthony B (2020) Medicinal plant analysis: a historical and regional
discussion of emergent complex techniques. Front Pharmacol 10
67. Singh R (2015) Medicinal plants: a review. J Plant Sci, Special Issue: Medicinal Plants
3(1–1):50–55
68. Clark AM (1996) Natural products as a resource for new drugs. Pharm Res 13(8):1133–1141
69. Karthika C, Manivannan S (2018) Pharmacognostic, physicochemical analysis and phyto-
chemical screening of the leaves of W. trilobata. L. Int J ChemTech Res 11(02):124–131
70. Chen SL, Yu H, Luo HM et al (2016) Conservation and sustainable use of medicinal plants:
problems, progress, and prospects. Chin Med 11:37
Comprehensive Review on Wild Basil Genus Orthosiphon of Lamiaceae 425

71. Masuda T, Masuda K, Shiragami S et al (1992) Orthosiphol A and B, novel diterpenoid

inhibitors of TPA (12-O-tetradecanoylphorbol-13-acetate)-induced inflammation, from
Orthosiphon stamineus. Tetrahedron 48(33):6787–6792
72. Matsubara T, Bohgaki T, Watarai M et al (1999) Antihypertensive actions of methylripario-
chromene A from Orthosiphon aristatus, an Indonesian traditional medicinal plant. Biol
Pharm Bull 22(10):1083–1088
73. Shibuya H, Bohgaki T, Matsubara T et al (1999) Chemical structures of two new isopimarane-­
type diterpenes, Orthosiphonones A and B and a new benzochromene, orthochromene a from
the leaves of Orthosiphon aristatus (Lamiaceae). Chem Pharm Bull 47:695–698
74. Ohashi K, Bohgaki T, Matsubara T et al (2000) Indonesian Medicinal Plants XXIII: Chemical
Structure of two new migrated Pimarene-type Diterpenes, Neoorthosiphols A and B and sup-
pressive effect on rat Thoracic Aorta of chemical constituents isolated from the leaves of
Orthosiphon aristatus (Lamiaceae). Chem Pharm Bull 48(3):433–435
75. Mangali GR (2019) Antimicrobial activity of Orthosiphon aristatus (Balbas pusa) nano par-
ticle and leaf extract against E. coli and S. aureus. World. J Pharm Pharm Sci 9(3):174–199
76. Kottaimuthu R (2008) Ethnobotany of the Valaiyans of Karandamalai, Dindigul District,
Tamil Nadu, India. Ethnobot Leafl 12:195–203
77. Kiruthika A, Meenakshi SM (2011) Anticancer studies on Orthosiphon pallidus royle. and
Peristrophe bicalyculata nees. J Pharm Res 4:2654–2656
78. Singh MK, Dhongade H, Tripathi DK (2017) Orthosiphon pallidus, a potential treatment for
patients with breast cancer. J Pharmacopunct 20(4):265–273
79. Ashokan K, Muthuraman MS (2011) Anticancer studies on Orthosiphon pallidus royle and
Peristrophe bicalyculata nees. J Pharm Res 4:2654–2656
80. Regina KMM, Adama H, Jeanne M et al (2015) Ethnobotany and Ethnopharmacognosy of
Lamiaceae species from Central Burkina Faso: Leucas martinicensis (Jacquin) R. Brown,
Hoslundia opposita Vahl and Orthosiphon pallidus Royle Ex Benth. Am J Ethnomed
2(4):219–232
81. Awale S, Tezuka Y, Banskota AH et al (2003) Siphonols A-E: novel nitric oxide inhibitors
from Orthosiphon stamineus of Indonesia. Bioorgan Med Chem Lett 13:31–35
82. Arafat OM, Tham SY, Sadikun A et al (2008) Studies on diuretic and hypouricemic effects of
Orthosiphon stamineus methanol extracts in rats. J Ethnopharmacol 118(3):354–360
83. Ho CH, Noryati I, Sulaiman SF et al (2010) In vitro antibacterial and antioxidant activi-
ties of Orthosiphon stamineus Benth. extracts against food-borne bacteria. Food Chem
122:1168–1172
84. Hossain MA, Mizanur Rahman SM (2015) Isolation and characterisation of flavonoids from
the leaves of medicinal plant Orthosiphon stamineus. Arab J Chem 8:218–221
85. Pauzi N, Mohd KS, Halim NHA et al (2018) Orthosiphon stamineus extracts inhibits prolifer-
ation and induces apoptosis in uterine fibroid cells. Asian Pac J Cancer Prev 19(10):2737–2744
86. Retinasamy T, Shaikh MF, Kumari Y et al (2020) Orthosiphon stamineus standardized
extract reverses Streptozotocin-induced Alzheimer’s disease-like condition in a rat model.
Biomedicine 8:104
87. Rao NK, Bethala K, Sisinthy SP, Rajeswari KS (2014) Antidiabetic activity of Orthosiphon
stamineus Benth roots streptozotocin induced type 2 diabetic rats. Asian J Pharm Clin Res
7:149–153
88. Ahamed Basheer M, Abdul Majid A (2010) Medicinal potentials of Orthosiphon stamineus
Benth. Webmed Central Cancer 1:1–13
89. Halim NH, Pauzi N, Hamil SHR et al (2017) Standardization of Orthosiphon stamineus raw
materials and extracts for anti-uterine fibroid. Int J Pharmacogn Phytochem Res 9:512–515
90. Alshawsh MA, Abdulla MA, Ismail S et al (2012) Free radical scavenging, antimicrobial and
immunomodulatory activities of Orthosiphon stamineus. Molecules 17(5):5385–5395
91. Lokman EF, Saparuddin F, Muhammad H et al (2019) Orthosiphon stamineus as a potential
antidiabetic drug in maternal hyperglycemia in streptozotocin-induced diabetic rats. Integr
Med Res 8(3):173–179
426 K. Abirami et al.

92. Yuniarto A, Susilawati ELIS, Khairunnisa ISMI et al (2017) Antioxidant and gastric ulcer
healing effect of Orthosiphon stamineus (Benth.) leaves extract in aspirin-induced rats. Asian
J pharm. Clin Res 10(2):397–399
93. Movahedi A, Basir R, Rahmat A et al (2015) Orthosiphon stamineus: an Asian tea with sub-
stantial anticancer properties. J Nutr Sci Diet:44–52
94. Nair GM (2011) Evaluation of antioxidant properties of some species of Lamiaceae. J Med
Aromat Plant Sci 33(1):27–30
95. Alshawsh MA, Abdulla MA, Ismail S et al (2011) Hepatoprotective effects of Orthosiphon
stamineus extract on thioacetamide-induced liver cirrhosis in rats. Evidence-Based
Complement Alternat Med 2011:103039
96. Yam MF, Basir R, Asmawi MZ et al (2007) Antioxidant and hepatoprotective effects of
Orthosiphon stamineus benth. Standardized extract. Am J Chin Med 35:115–126
97. Yam MF, Asmawi MZ, Basir R (2008) An investigation of the anti-inflammatory and analge-
sic effects of Orthosiphon stamineus leaf extract. J Med Food 11:362–368
98. Kavimani S, Ilango R, Thangadurai JG et al (1997) Diuretic activity of aqueous extract of
Orthosiphon thymiflorus in rats. Indian J Pharm Sci 59(2):96
99. Sini KR, Haribabu Y, Sajith MS, Sreekumar SK (2012) In-vitro Cytotoxic activity of
Orthosiphon thymiflorus(Roth.) sleensen leaf extract against dalton lymphoma ascites cell
line. J Chem Pharm Res 4(1):917–921
100. Mercy Lavanya S, Gnanamani A, Ilavarasan R (2015) Evaluation of the antibacterial activity
of the extracts of the whole plant of Orthosiphon thymiflorus (Roth.) Sleesen. J Chem Pharm
Res 7(2):872–875
101. Neilson EH, Goodger JQ, Woodrow IE et al (2013) Plant chemical defense: at what cost?
Trends Plant Sci 18(5):250–258
Zingiberaceae Plants: A Cornucopia
of Promising Chemotherapeuticals
for Cancer Cure

T. Soumya , P. R. Jayasree, and P. R. Manish Kumar

1 Introduction

Cancer, the second leading cause of human death worldwide, behind cardiovascular
disease, might soon rank as the leading cause of death. It is the single most impor-
tant barrier to increasing life expectancy in every country of the world in the 21st
century [1]. Cancer is an abnormal growth of cells caused by multiple changes in
gene expression which leads to dysregulation in balancing cell proliferation and cell
death. As a consequence, a population of cells evolve at the site of origin, capable
of invading into tissues at distant sites, causing significant morbidity and death of
the host, if untreated [2–5]. Cancers are conventionally treated using a combination
of three major modes - surgery, radiation, and chemotherapy. Chemotherapy
involves treatment of cancer with one or more chemicals known to have cytotoxic,
antineoplastic activity. Traditional chemotherapeutic agents, which act by killing
rapidly dividing cancer cells, also harm cells that divide rapidly under normal cir-
cumstances, thereby resulting in side effects such as immunosuppression and muco-
sitis among others. Newer anticancer drugs (targeted chemotherapy) are not
indiscriminately cytotoxic, but rather target proteins that are abnormally expressed
in cancer cells and are essential for their growth [6]. It is believed that anticancer
effects of plants develop by suppressing pathways involved in cancer progression,
DNA repair, increasing body immunity, and inducing antioxidant effects [7–9].
During the last few decades, ethnomedicinal plants have played a significant role
in the development of anticancer drugs with fewer side effects in different conti-
nents of the world. Out of 121 prescription drugs that are being used today for

T. Soumya · P. R. Manish Kumar (*)

Department of Biotechnology, University of Calicut, Malappuram, Kerala, India
e-mail: [email protected]
P. R. Jayasree
School of Health Sciences, University of Calicut, Malappuram, Kerala, India

© The Author(s), under exclusive license to Springer Nature 427

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_16
428 T. Soumya et al.

cancer treatment, 90 are plant-based and 75% of them were discovered from folk-
lore claims. Secondary metabolites from plants, including alkaloids, terpenoids, and
polyphenolic compounds with promising anticancer potential, have been developed
for clinical practice [10, 11]. Classical examples include Vinca alkaloids (vinblas-
tine and vincristine), isolated from Catharanthus roseus G. Don. (Apocynaceae),
paclitaxel and docetaxel - semisynthetic derivatives of Taxanes (diterpenoids) from
the Pacific Yew tree, Taxus brevifolia and T. baccata respectively, irinotecan and
topotecan - semisynthetic derivatives of Camptotheca alkaloids, isolated from
Camptotheca acuminate and Podophyllum lignans from mayapple tree, Podophyllum
peltatum and P. hexandrum [11–13].
Zingiberaceae is one of the largest families of the plant kingdom, distributed
widely throughout the tropics, particularly in Southeast Asia [14, 15]. The family
consists of a large number of economically and medicinally important plants well
known for their use in ethnomedicine. The Zingiberaceae plants contain a number
of volatile and essential oils including terpenoids, phenylpropanoids, flavonoids,
and sesquiterpenes, which have been reported to possess anticancer activity [16–
19]. Hence, these plants are considered to be excellent candidates for development
of novel chemotherapeutics. Various extracts and pure compounds / secondary
metabolites isolated from Curcuma, Zingiber, Kaempferia, Alpinia, Amomum, and
Hedychium genera reportedly possess anticancer activity as evidenced by in vitro
and in vivo studies [20–24]. Few notable examples for anticancer compound include
curcumin/curcuminoids (Curcuma longa), zerumbone (Zingiber zerumbet), gin-
gerol, and shogaol (Zingiber officinale) among many others [25–29]. Even though a
number of review articles were available about various biological activities of dif-
ferent genera of Zingiberaceae family, a comprehensive scrutiny about anticancer
potential of these plants was found lacking. Hence, this chapter aims to overview
anticancer potential of organic solvent extracts and compounds identified therein
belonging to different genera of Zingiberaceae plants.

2 Zingiberaceae

The taxonomic position of the Family Zingiberaceae is as follows:

Kingdom: Plantae
Subkingdom: Trachebionta
Superdivision: Spermatophyta
Division: Magnoliophyta
Subdivision: Angiospermae
Class: Monocotyledonae (Liliopsida)
Subclass: Zingiberidae
Order: Zingiberales
Family: Zingiberaceae
Zingiberaceae Plants: A Cornucopia of Promising Chemotherapeuticals for Cancer Cure 429

Zingiberaceae commonly known as ginger family is a one of the largest families

of flowering plants comprising 52 genera divided into more than 1300 species.
These aromatic herbs, with creeping horizontal or tuberous rhizomes, are distrib-
uted throughout tropical Africa, Asia, and the America [14, 15]. India is one of the
richest regions displaying high diversity of Zingiberaceae with 21 genera and
around more than 200 species, confined to northeastern, southern parts of India and
Andaman-Nicobar Islands [15]. The members of Zingiberaceae are perennial rhi-
zomatous herbs. The rhizome is sympodially branched and composed of distinct
segments. The rhizomes are variously colored ranging from pale yellow, orange-­
yellow, deep yellow, blue, greenish blue, pink, or combinations of these in different
species. The young rhizomes and axillary buds are protected by scale leaves. Leafy
shoots are generally unbranched and true aerial stem is present in some genera and
absent in others; yet others have very short true stem or pseudostem with clasping
leaf sheaths. Other general characteristics of Zingiberaceae include distichous sim-
ple leaves, presence of terminal or lateral inflorescence on the leafy shoot, highly
modified - ephemeral - delicate flower and capsular fruit [15, 30]. Members of the
family are usually aromatic in all plant parts, have functions as natural sources of
spices, herbal medicine, natural dyes, perfumes, and as multipurpose aesthetic com-
pounds [31, 32].
Zingiberaceae is well known for its use in ethnomedicine. It constitutes a vital
group characterized by the presence of volatile oils and oleoresins. Generally, the
rhizomes and fruits are aromatic, tonic, stimulant, and occasionally nutritive. Some
are used as food as they contain starch in large quantities, while others yield an
astringent and diaphoretic juice. Some of the medicinally and economically impor-
tant genera of Zingiberaceae include Alpinia, Amomum, Curcuma, and Zingiber,
followed by Boesenbergia, Kaempferia, Elettaria, Hedychium, Elettariopsis, and
Etlingera [30, 33, 34]. Detailed literature survey reveals that many species of the
family are used for treatment of various ailments due to their unique medicinal val-
ues. They are part of many herbal preparations in Chinese, Thai, African, and Indian
traditional medicinal systems including Ayurveda [33, 35–38]. Zingiberaceae spe-
cies Alpinia, Amomum, Curcuma, Elettaria, Hedychium, Kaempferia, and Zingiber
play a major role in the preparation of many Ayurvedic drugs [33]. Various species
from Zingiberaceae reported with different biological activities include antimicro-
bial, antifungal, anti-inflammatory, anticancer, antioxidant, antiviral, antidiabetic,
antiarthiritic, larvicidal, neuroprotective, and heptoprotective activities [25, 39–52].

3 Phytochemistry of Zingiberaceae

Various pharmacological activities of Zingiberaceae plants are credited to the pres-

ence of phytochemicals / secondary metabolites therein. Phytochemical analyses of
different genera of Zingiberaceae have revealed the presence of a wide range of
pharmacologically active phytochemical groups which mainly include terpenoids,
diarylheptanoids, phenylpropanoids, and flavanoids [16]. Interestingly, these
430 T. Soumya et al.

phytochemical groups have been considered to be potential candidates for chemo-

therapeutics development [17–19, 53]. Close to 100 terpenoid compounds have
been identified from Zingiberaceae. Mono- and sesquiterpenoids such as α-pinene,
β-pinene, 1,8-cineole, camphor, terpinen-4-ol, β-caryophyllene, and zingiberene are
common chemical constituents of most of Zingiberaceae species, especially in
essential oils extracted from rhizome [26, 39, 54]. Among diterpanoids, labdane-­
type diterpenes occur commonly in species of Alpinia, Amomum, Hedychium,
Curcuma, and Zingiber [55–59] and pimarane diterpenes have been reported from
Kaempferia species [60]. Diarylheptanoids is another pharmacologically prominent
group of secondary metabolites from Zingiberaceae plants, commonly found in
Curcuma, Alpinia, and Zingiber species. Curcuminoids, isolated from several
Curcuma sp., is a good example for diarylheptanoids with remarkable biological
activities [61]. Another group of bioactive phytochemicals are phenylpropanoids,
mostly reported from Alpinia, Kaempferia, Curcuma, and Zingiber spp. [62–66].
Flavonoids and related derivatives are the constituents of plants such as Alpinia,
Amomum, Boesenbergia, Kaempferia, and Zingiber genera [67–71]. Phenylbutanoids
are yet another rare group in nature found only in the genus Zingiber [72, 73]. The
molecular structures of some of the well known bioactive phytochemical com-
pounds from Zingiberaceae plants reported with anticancer activity have been
shown in Fig. 1.

4 Anticancer Activities Reported from Different Genera

of Zingiberaceae Family

Anticancer activities reported from various Zingiberaceae species can be catego-

rized according to different genera. This in itself reveals the hidden treasure trove
within the Zingiberaceae plant family, which can contribute tremendously to che-
motherapeutic drug development. Table 1 highlights the significant anticancer activ-
ities of different extracts, essential oils, and pure compounds from different genera
of Zingiberaceae family.

4.1 Genus Alpinia Roxb.

The tropical and subtropical genus, Alpinia Roxb., with about 230 species, is mainly
distributed in the Indo-Pacific region [15]. The genus is generally called as ‘shell
ginger’ and several species are cultivated as ornamentals. Alpinia species are well
known medicinal herbs with incredible biopharmaceutical potential. The presence
of bioactive substances such as terpenoids, diarylheptanoids, phenylpropanoids,
and flavonoids is key to their therapeutic efficiency [175]. Many in vitro studies car-
ried out in diverse cancer cell lines and in vivo studies with animal models reflect
Zingiberaceae Plants: A Cornucopia of Promising Chemotherapeuticals for Cancer Cure 431

Fig. 1 Molecular structures of some phytochemicals from Zingiberaceae plants reported with
anticancer activities

clearly the anticancer potential of Alpinia species. Antiangiogenic potential of

n-hexane and ethyl acetate fractions from A. oxyphylla fruits has been tested against
zebrafish model, human umbilical vein endothelial cells, and tumor cell lines [74].
Hexane and chloroform extract of A. galanga rhizome lead to the isolation of two
compounds, viz. 1’(S)-1’-acetoxychavicol acetate and p-coumaryl alcohol γ-O-­
methyl ether, both of which were found to exhibit significant cytotoxicity against
human cancer cell lines like A549, SNU638, HT1080, HL60, and HCT116 [75].
1’S-1’-acetoxychavicol acetate (ACA) is a phenylpropanoid compound reported
from various Alpinia spp. such as A. galanga and A. conchigera, and is known to
induce apoptotic cell death in various cell lines [76, 176]. ACA was found to inhibit
432 T. Soumya et al.

Table 1 List of anticancer bioactive extracts, fractions, and pure compounds of various genera of
Zingiberaceae family
Parts Bioactive extract / fractions /
Species name used compounds Anticancer activity References
Genus Alpinia Roxb.
A. oxyphylla Fruits Hexane and ethyl acetate Antiangiogenic against [74]
fractions zebrafish model,
human umbilical vein
endothelial cells and
tumor cell lines
A. galanga Rhizome 10S-10-Acetoxychavicol Cytotoxicity against [75]
acetate and p-coumaryl alcohol A549, SNU638,
c-O-methyl ether HT1080, HL60 and
HCT116 human cancer
cell lines
A. conchigera Rhizome 10S-10-Acetoxychavicol Apoptotic induction in [76]
acetate MCF-7, HSC-2,
HSC-4, HepG2 and
CaSki
A. officinarum Rhizome Galangin Prevents skin cancer [77]
7-(3,4-Dihydroxyphenyl)-1-(4-­ Cytotoxicity against [78]
hydroxy-­3-methoxyphenyl)-4-­ HepG2, MCF-7 and
en-­3-heptanone SF-268 cancer cell
lines
Diarylheptanoids Induces mitochondrial [79]
apoptosis and S-phase
cell cycle arrest in
neuroblastoma IMR-32
cell line
A. mutica Rhizome Pinostrobin Cytotoxic against KB, [80]
MCF-7 and Caski
cancer cells
A. purpurata Leaves Ethyl acetate extract Cytotoxicity against [81, 82]
OAW42 and HeLa
cells
A. Rhizome Hexane and ethyl acetate Cytotoxic against KB, [83]
pahangensis extracts CaSki and HCT116
cancer cells
A. murdochii Rhizome Hexane and dichloromethane Cytotoxic effect [84]
and extracts against SKOV-3 cells
leaves
A. katsumadai Seeds Rubraine, isorubraine, and Cytotoxicity against [85]
sumadain HepG2, MCF7 and
MDA-MB-435 cancer
cell lines
(continued)
Zingiberaceae Plants: A Cornucopia of Promising Chemotherapeuticals for Cancer Cure 433

Table 1 (continued)
Parts Bioactive extract / fractions /
Species name used compounds Anticancer activity References
A. zerumbet Flowers Dichloromethane and methanol Antitumor activity [86]
extracts against Ehrlich Ascites
Carcinoma (EAC) cells
in vivo
Flowers 5,6,dehydrokawain Cytotoxicity against
MCF7, HepG2, HEP-2
cancer cell lines
A. nantoensis Rhizome Ethanol extract Inhibit cell migration [87]
and leaf and invasion MCF-7
extracts and MDA-MB-231
breast cancer cell lines
A. scabra Leaves Hexane and chloroform extract Cytotoxic against [88]
and MCF7 and SKOV-3
rhizome cell lines
A. Seeds Diarylheptanoids Antiproliferative [89]
blepharocalyx against HT-1080
(human) and 26-L5
(murine) carcinoma
cell lines
A. pricei Rhizome Ethanolic extract Induce apoptosis [90]
against KB carcinoma
cell lines through
mitochondria-­
dependent pathway
Genus Amomum Roxb.
A. subulatum Fruit Cardamonin Induce apoptosis in [91]
HCT116 cancer cell
lines through extrinsic
apoptotic pathway
Seeds Hexane and ethyl acetate Cytotoxicity against [92]
extracts MCF7 and HeLa
cancer cell lines
A. aculeatum Leaves Aculeatin A and B Cytotoxic against [93]
MCF7 breast cancer
cell line
A. kravanh Fruit Ethanol extract Cytotoxicity against [46]
SMMC-7721 cell lines
(continued)
434 T. Soumya et al.

Table 1 (continued)
Parts Bioactive extract / fractions /
Species name used compounds Anticancer activity References
A. tsao-ko Fruit Tsaokoarylone Cytotoxic against A549 [94]
and SK-Mel-2 cancer
cell lines
Essential oil Induces apoptosis [95]
against HepG2 cell line
Isotsaokoin, hannokinol, Cytotoxicity against [96]
2,3-dihydro-2-(4′-hydroxy-­ HepG-2, SMMC-7721,
phenylethyl)-6-[(3″,4″- HeLa and A549 cancer
dihydroxy-5″-methoxy) cell lines
phenyl]-4-pyrone and
4-dihydro-2-(4′-hydroxy-­
phenylmethyl)-6-[(3″,4″-
dihydroxy-5″ methoxyphenyl)
methylene]-pyran-3,5-dione
Ethanol extract Antitumor activity [97]
against ovarian cancer
SKOV3 cells with
antiangiogenic activity
in vivo
A. villosum Seeds Polysaccharides Cytotoxic effects [98]
against human
hepatocellular
carcinoma cell lines
Hep G2
A. verum Shoots Essential oils Cytotoxic against [99]
Human prostate
DU145 cancer cell line
A. xanthioides Seeds Monoterpenoids, Cytotoxicity against [100–103]
Sesquiterpenoids, Terpene SK-OV-3, SK-MEL-2,
Glycosides, Amoxantin A A549 and HCT15
(diterpenoid) cancer cell lines
A. maximum Roots Labdane diterpenoids Cytotoxicity against [104]
and MCF-7, SMMC-7721,
Fruits MG-63 and HepG2
cancer cell lines
Genus Kaempferia L.
K. rotunda Rhizome Pinostrobin Antitumor activity [105]
against human breast
cancer, T47D cell line
(in vitro) and xenograft
model (in vivo)
Lectin Induces apoptosis in [106, 107]
Ehrlich ascites
carcinoma cells, SW48
and SW480 colorectal
cancer cell lines
(continued)
Zingiberaceae Plants: A Cornucopia of Promising Chemotherapeuticals for Cancer Cure 435

Table 1 (continued)
Parts Bioactive extract / fractions /
Species name used compounds Anticancer activity References
K. galanga Rhizome Alcoholic extracts and Antitumor activity [108, 109]
Ethyl-p-methoxycinnamate against Ehrlich ascites
carcinoma cells and
human
cholangiocarcinoma
CL-6 cell line (in vitro)
as well as in vivo
model
Polysaccharides Antitumor activity on [110]
H22 solid tumor (in
vivo)
Ethyl-p-methoxycinnamate Cytotoxicity against [111]
HSC-3 and Ca922 cell
lines
K. parviflora Rhizome Ethanol extract Apoptosis induction in [112]
leukemic HL60 and
U937 cell lines
inhibition of cell [113, 114]
migration and invasion
and induction of
apoptosis in HeLa
(cervical) and SKOV3
(ovarian) cells
Polymethoxyflavones Cytotoxicity against [115]
human cervical (HeLa)
and gastric
adenocarcinoma (AGS)
cell lines
5,7,4-trimethoxyflavone Cytotoxicity against [116]
human
cholangiocarcinoma
HuCCA-1 and
RMCCA-1 cell lines
K. Rhizome Abietene diterpene and Cytotoxicity against [117]
angustifolia kaempfolienol HL-60 and MCF-7
cancer cell lines
K. elegans Rhizome Labdane and clerodane Cytotoxicity against [118]
K. pulchra Rhizome diterpenoids leukemic HL60 cell
line
Genus Curcuma L.
(continued)
436 T. Soumya et al.

Table 1 (continued)
Parts Bioactive extract / fractions /
Species name used compounds Anticancer activity References
C. longa Rhizome Various extracts Cytotoxicity against [119–122]
U937, Molt4, A549,
T98G, HeLa,
MDA-MB-231 human
cancer cell lines and
murine melanoma cell
line, B164A5
Curcuminoids / Curcumin Anticancer activity [123–128]
against multiple human
carcinomas including
melanoma, head and
neck, breast, colon,
pancreatic, prostate and
ovarian cancers
C. amada Rhizome Supercritical CO2 extract Cytotoxicity against [129]
human glioblastoma
(U-87MG) cell line
Rhizome Methanol extracts Cytotoxicity against [130]
and human MCF7 and
leaves MDA-MB-231 breast
cancer cell lines
C. aromatica Rhizome Aqueous extract Induces apoptosis and [131]
G2/M arrest in colon
carcinoma cell
lineLS-174-T
Essential oil Antitumor and [132–134]
chemoprevention
against hepatoma in
mice models (in vivo)
Ethanolic extract Antiangiogenic and [135]
proapoptotic activity in
Ehrlich ascites tumor
model (in vivo)
C. caesia Rhizome Methanol extract Antitumor activity on [136]
Ehrlich’s ascites
carcinoma (EAC)
bearing mice.
Antitumor potential [137]
against DEN-induced
hepatocellular
carcinoma
(continued)
Zingiberaceae Plants: A Cornucopia of Promising Chemotherapeuticals for Cancer Cure 437

Table 1 (continued)
Parts Bioactive extract / fractions /
Species name used compounds Anticancer activity References
C. zedoaria Rhizome Ethanolic extract Antiproliferative and [138]
invasive activities
against human
esophageal squamous
carcinoma TE-8 cells
(in vitro) and suppress
tumor formation in
mice (in vivo)
Hexane and chloroform Cytotoxicity against [139]
extracts ovarian cancer cells
SKOV3
Essential oil Cytotoxic effects on [140]
gastric cancer AGS
cells and induce cell
cycle arrest and
apoptosis
Cytotoxic and induces [141]
apoptosis in non-small
cell lung carcinoma
H1299 cells and
antitumor activity
against H1299
xenograft mice model
(in vivo)
Antiangiogenic activity [142]
both in vitro and in
vivo -suppressing
melanoma growth and
lung metastasis
Isocurcumenol Cytotoxicity against [21]
human cancer KB,
A549, K562 cell lines
and mice DLA
(Daltons Lymphoma
Ascites) cells
(continued)
438 T. Soumya et al.

Table 1 (continued)
Parts Bioactive extract / fractions /
Species name used compounds Anticancer activity References
C. Rhizome Xanthorrhizol Inhibit tumor nodules [143]
xanthorrhiza in a spontaneous
mouse lung metastasis
model (in vivo)
Induce apoptosis via [144, 145]
activation of p53-­
dependent
mitochondrial pathway
in HCT 116 MCF 7
and MDA-MB-231
cancer cell lines
Induce caspase-­ [146]
independent apoptosis
in oral squamous cell
carcinoma SCC-15 cell
line
C. Rhizome Dichloromethane extract Induces apoptosis [147]
purpurascens through mitochondrial-­
dependent pathway in
colon cancer HT-29
cells
Essential oil Cytotoxicity against [148]
MCF7, Ca Ski, A549,
HT29, and HCT116
human carcinoma cell
lines
C. mutabilis Rhizome Petroleum ether extract and Induce apoptosis in [149]
labdane diterpenoid (Cm colorectal cancer
epoxide) HCT116 and leukemic
K562 cells
C. Rhizome Essential oil Cytotoxicity against [150]
kwangsiensis B16 and LNCaP cancer
cells
C. Rhizome Ethanol extract Antiproliferative [142]
phaeocaulis activity and induces
apoptosis in breast
cancer MCF7 cell lines
Genus Zingiber Boehmer
(continued)
Zingiberaceae Plants: A Cornucopia of Promising Chemotherapeuticals for Cancer Cure 439

Table 1 (continued)
Parts Bioactive extract / fractions /
Species name used compounds Anticancer activity References
Z. officinale Rhizome Ethanol extract Cytotoxicity against [151]
Human pancreatic
cancer cell lines
(Panc-1, AsPC-1,
BxPC-3, CAPAN-2,
CFPAC-1, MIAPaCa-2
and SW1990) as well
as induces autophagic
cell death in Panc 1
cells both in vitro and
in vivo (xenograft mice
model)
6-shogaol and 6-gingerol Induce apoptosis in [48]
against B164A5
murine melanoma cells
6-shogaol Induce cell cycle arrest [152]
and apoptosis against
in colon cancer cell
line HCT-116.
Antitumor activity
against colon cancer
cells (in vivo)
Induces endoplasmic [153]
reticulum stress and
mitochondrial
apoptosis induction in
cervical cancer HeLa
cells
Gingerol Induce apoptosis in [154]
SW-480 and HCT116
cancer cells
Induce apoptosis in [155]
A549 cells via extrinsic
pathway
Leaves Methanol extract Induce apoptosis in [156]
human colorectal
cancer HCT116 and
SW480 cells
(continued)
440 T. Soumya et al.

Table 1 (continued)
Parts Bioactive extract / fractions /
Species name used compounds Anticancer activity References
Z. zerumbet Rhizome Petroleum ether extract Cytotoxicity against [157]
fractions human breast cancer
MCF 7 cell lines
Zerumbone Induction of [158]
mitochondria-mediated
apoptosis in chronic
myelogenous leukemia
K562cells
Induces apoptosis in [159, 160]
CEM-ss, H1299,
HCT116, NB4,
P-388D1 and Raji
cancer cell lines.
Antitumor activity
against colorectal,
liver, lung and cervical
in vivo mice models
Z. Rhizome Chloroform extract Cytotoxicity against [161]
cassumunar Cis-3-(3’, human T-acute
4’-dimethoxyphenyl)-4-[(E)-3, lymphoblastic
4 dimethoxystyryl] cyclo-hex-­ leukemia (CEMss) and
1-ene and cervical (HeLa) cancer
8-(13,14-dimethoxyphenyl)-2-­ cell lines
methoxynaphto-­1,4-quinone
Genus Elettaria Maton
E. Seeds Aqueous extract Cytotoxicity against [162]
cardamomum mouse lymphoma
YAC-1 cells.
Genus Hedychium J. Koenig
(continued)
Zingiberaceae Plants: A Cornucopia of Promising Chemotherapeuticals for Cancer Cure 441

Table 1 (continued)
Parts Bioactive extract / fractions /
Species name used compounds Anticancer activity References
H. Rhizome Ethanol extract Induce G1 phase cell [163]
coronarium arrest, apoptosis and
inhibition of migratory
potential of cervical
cancer HeLa cells
Labdane diterpenes Chemo preventive and [164]
antiproliferative
activity against HepG2
cancer cells
Cytotoxicity against
A-549, SK-N-SH,
MCF-7 and HeLa
cancer cell lines
Labdane diterpenoids Antiangiogenic activity [165]
(Hedycoronals A and B) and and cytotoxic activity
Diarylheptanoids against B16, HT-29,
HepG2 and HeLa
cancer cell lines
Coronarin D Induces G2/M arrest, [166]
apoptosis and
autophagy in human
nasopharyngeal
carcinoma NPC-BM
and NPC-039 cells
Induce apoptotic cell [167]
death through the
upregulation of JNK/
MAPK pathways in
human hepatocellular
carcinoma (HCC)
Huh7 and Sk-hep-1
cells
(continued)
442 T. Soumya et al.

Table 1 (continued)
Parts Bioactive extract / fractions /
Species name used compounds Anticancer activity References
H. spicatum Rhizome Labdane-diterpenoids Cytotoxic activity [168]
against Colo-205,
A-431, MCF-7, A549,
HL-60, THP-1, A-375
cancer cell lines and
Chinese hamster ovary
cells (CHO)
Sesquiterpenes Cytotoxicity against [169]
A549, B-16, HeLa,
HT-29, NCIH460,
PC-3, IEC-6 and L6
cancer cell lines
Essential oil Cytotoxicity against [170]
A549, DLD-1, SW
620, FaDu, HeLa
MCF-7 and
MDA-MB-231 cancer
cell lines
Genus Boesenbergia Kuntze
B. rotunda Rhizome Methanolic extract Cytotoxicity against [171]
MCF-7,
MDA-MB-231,
CaOV3, HT-29 and
HeLa cancer cell lines
Panduratin A Cytotoxicity and [172]
apoptosis induction
against HT-29 and
MCF-7 cancer cell
lines
Boesenbergin A Cytotoxicity against [173]
A549, PC3, HepG2
and HT-29 cancer cell
lines
Hexane and methanol extracts, Antiproliferative [174]
Cardamonin activity, induce cell
cycle arrest and
apoptosis against
nasopharyngeal
carcinoma, HK1 cells

inflammatory transcription factor NF-κB, growth of oral squamous cell carcinoma,

and potentiate effect in combination with cisplatin by modulating pro-inflammatory
microenvironment [177, 178]. Flavonoid mixture as well as galangin (3, 5,
7-­
trihydroxyflavone) isolated from A. officinarum reportedly exhibits a broad
absorption band at 270–290 nm related to the UV-B area, supporting that galangin
could be a potential whitening agent capable of preventing skin cancer [77].
Zingiberaceae Plants: A Cornucopia of Promising Chemotherapeuticals for Cancer Cure 443

Recently, galangin was found to induce apoptosis via p53-dependent pathway in

ovarian cancer cells, A2780/CP70 and OVCAR-3 [179]. A compound,
7-(3,4-dihydroxyphenyl)-1-(4-hydroxy-3methoxyphenyl)-4-en-3-heptanone iso-
lated from A. officinarum, was found to possess remarkable cytotoxicity against
HepG2, MCF-7, and SF-268 [78]. Diarylheptanoids isolated from A. officinarum
have been shown to wield multiple antitumor effects in neuroblastoma cell lines
[79]. A novel compound, pinostrobin chalcone, has been isolated from A. mutica
which displays notable cytotoxic potential against various human carcinoma cell
lines (KB, MCF-7, and Caski) with significant IC50 values [80]. A. purpurata ethyl
acetate extract exhibited antioxidant and anticancer activity against OAW42 and
HeLa cells [81, 82]. Crude extracts from A. pahangensis and A. murdochii, endemic
to Malaysia, have shown cytotoxic activity against different cancer cell lines [83,
84]. A novel monoterpene-chalcone conjugate, sumadain, isolated from A. katsuma-
dai showed potent cytotoxicity against HepG2, MCF7, and MDA-MB-435 cancer
cell lines [85]. Dichromethane and methanol extracts from A. zerumbet flowers
exhibit potent antitumor activity against Ehrlich Ascites Carcinoma (EAC) cells in
vivo and 5,6,dehydrokawain (DK) isolated from the extract displayed potent antip-
roliferative activity against various human cancer cell lines, MCF7, HepG2, HEP-2
with noteworthy IC50 values [86]. Ethanol extracts prepared from A. nantoensis rhi-
zome and leaf were reported to inhibit cell migration, invasion, and sphere forma-
tion in breast cancer cell lines, MCF-7 and MDA-MB-231. This study also revealed
the extracts’ capability to inhibit signal transductions in EGFR as well as the PI3K/
AKT and Ras-ERK pathways, which are crucial players of tumor cell migration and
invasion [87].

4.2 Genus Amomum Roxb.

Amomum is the second largest genus after Alpinia within Zingiberaceae with about
150 -180 species, widely distributed in Southeast Asia. In India, the genus is repre-
sented by 22 species, mostly restricted to North-Eastern and southern India. A chal-
cone, namely, cardamonin (2′,4′-dihydroxy-6′-methoxychalcone), first isolated
from A. subulatum (black cardamom) fruit, has been reported to affect cell growth
by modulation of a variety of cell signaling pathways, including mammalian target
of rapamycin (mTOR), NF-κB, cell surface receptors, and Wnt/β-catenin pathways
[180, 181]. Cardamonin also potentiates TNF-related apoptosis-inducing ligand
(TRAIL) for induction of apoptosis through ROS-CHOP (CCAAT/Enhancer-­
Binding Protein Homologous Protein)-mediated upregulation of death receptors
(DRs), which makes TRAIL more effective as an anticancer therapy [91]. Hexane
and ethyl acetate extracts of A. subulatum seeds exhibited cytotoxicity against
MCF7 and HeLa cancer cell lines besides being immunosuppressive effect against
peripheral blood mononuclear cells [92]. Activity-guided fractionation of hexane-
and chloroform-soluble extracts of A. aculeatum leaves led to the isolation of acu-
leatin A and B, found to be cytotoxic against MCF7 breast cancer cell line (in vitro)
444 T. Soumya et al.

and in vivo hollow fiber assay [93]. A. villosum and A. kravanh have cytotoxic
effects against human hepatocellular carcinoma cell lines SMMC-7721 and Hep
G2, respectively [46, 96, 182]. Essential oil and various pure compounds such as
tsaokoarylone, isotsaokoin, hannokinol, 2,3-dihydro-2-(4′-hydroxy-phenylethyl)-6-
[(3″,4″-dihydroxy-5″-methoxy)phenyl]-4-pyrone, and 4-dihydro-2-(4′-hydroxy-
phenylmethyl)-6-[(3″,4″-dihydroxy-5″-methoxyphenyl)
methylene]-pyran-3,5-dione isolated from A. tsao-ko fruit (part of traditional
Chinese medicine) have been reported with cytotoxicity against various human can-
cer cell lines [94–96]. Ethanol extract from this plant was found to inhibit ovarian
cancer and decrease angiogenesis in vivo, through endoplasmic reticulum (ER)
stress-mediated interruption in p-STAT3/NF-κB/IL-6 and VEGF loop of angiogen-
esis regulation [97].

4.3 Genus Kaempferia L.

The genus includes about 70 species, two third of which are found in Asia and
remaining one third in Africa [33]. The flavanone, pinostrobin, isolated from
Kaempferia rotunda rhizome chloroform extract, has been shown to possess anti-
cancer activity against human breast cancer in vitro (T47D cell line) and in vivo
(Xenograft model). Repair of breast tissue and suppression of c-Myc expression
were evident on mice with T47D breast cancer xenograft [105]. Lectin isolated from
K. rotunda was found to inhibit proliferation of Ehrlich ascites carcinoma cells and
induce mitochondrial apoptosis in colorectal cancer cells, SW48 and SW480 [106,
107]. Alcoholic extracts of K. galanga rhizome were reported to possess antineo-
plastic activities in both in vivo and in vitro model systems [108, 109]. Interestingly,
water-soluble polysaccharides purified from K. galanga rhizome reportedly protect
thymus and spleen of solid tumor bearing mice and also capable of enhancing
immunoregulatory ability of CD4+ T cells, the cytotoxic effects of CD8+ T cells and
NK cells, thereby inhibiting tumor [110]. Additionally, major constituent of volatile
oil of K. galangal, Ethyl-p-methoxycinnamate, has been reported with anticancer
potential against oral cancer HSC-3 and Ca922 cell lines [111]. Ethanol extract of
K. parviflora rhizome, commonly known as Thai black ginger used in traditional
medicine, showed dose-dependent inhibition of cell proliferation and induction of
apoptosis in leukemic HL60 and U937 cell lines [112]. The ethanol extracts of
K. Parviflora rhizome supercritical CO2 fluid extracts (SFEs) of K. parviflora have
been contained in higher concentration of polymethoxyflavones (PMFs), which
showed potent antiproliferative activity against both human cervical (HeLa) and
gastric adenocarcinoma (AGS) cell lines [115]. It is also reported to possess anti-
cancer properties as evidenced by suppression of growth and survival signaling
pathways, inhibition of metalloproteinase 2 activity, inhibition of cell migration,
and invasion and induction of apoptosis in cancer cell lines such as HeLa (cervical)
and SKOV3 (ovarian) cells [113, 114]. Extracts and flavone derivatives from the
rhizome of K. parviflora have been shown to suppress multidrug
Zingiberaceae Plants: A Cornucopia of Promising Chemotherapeuticals for Cancer Cure 445

resistance-­associated proteins (MRP) in A549 (lung cancer) cells, making it useful

as modulators of drug resistance in cancer cells [183]. 5,7,4-trimethoxyflavone iso-
lated from K. parviflora rhizome extract reportedly possesses anticancer activity
against human cholangiocarcinoma HuCCA-1 and RMCCA-1 cell lines [116].
Methoxyflavones isolated from K. parviflora have been demonstrated to exhibit
melanogenesis inhibition in theophylline-stimulated murine B16 melanoma 4A5
cells, without notable cytotoxicity to normal cells [23, 184]. K. angustifolia rhizome
extracts and pure compounds abietene diterpene and kaempfolienol present therein
were found to be cytotoxic against Leukemic HL-60 and breast cancer MCF-7 cell
lines [117]. Labdane and clerodane diterpenoids isolated from K. elegans and
K. pulchra found cytotoxic against leukemic HL60 cell line [118].

4.4 Genus Curcuma L.

The genus Curcuma L., with around 120 species, is distributed mainly in tropical
and subtropical Asia. Curcuma longa, commonly known as turmeric and a major
source of curcumin, has been consumed as a dietary spice and a cure for human ail-
ments for thousands of years in Asian countries. The potential anticancer activity of
turmeric and curcumin was demonstrated by Kuttan et al. 1985 [185] in both in vitro
and in vivo models. Various crude extracts of C. longa were reported to have antip-
roliferative activity against different human cancer cell lines such as, U937 (myeloid
leukemia), Molt4 (acute lymphoblastic leukemia), A549 (lung carcinoma), T98G
(glioblastoma), HeLa (cervical cancer), MDA-MB-231 (breast cancer), and murine
melanoma cell line (B164A5) [119–122]. The immunomodulatory activities of the
polar fractions of C. longa hot water extracts were investigated using human periph-
eral blood mononuclear cells (PBMC). High polarity fraction containing polysac-
charides exhibited stimulatory effects on PBMC proliferation, thereby attesting to
its potential use as an adjuvant supplement for cancer patients with suppressed
immunity due to exposure to chemotherapeutic drugs [186].
Other Curcuma sp. reported with antiproliferative potential include C. amada
(mango ginger), C. aromatica (wild turmeric), C. caesia (black turmeric), C. zedo-
aria (white turmeric), and C. xanthorrhiza (Java turmeric). Supercritical CO2 extract
of C. amada rhizome reported to have specific anticancer potential against human
glioblastoma (U-87MG) cell line induces apoptosis or drug resistance in a dose-­
dependent manner [129]. Methanol extracts from C. amada leaves and rhizome also
reportedly possess antiproliferative activity against breast cancer cell lines MCF7
and MDA-MB-231 [130].
Aqueous extract of C. aromatica inhibited LS-174-T (colon carcinoma) cell pro-
liferation in a dose- and time-dependent manner, inducing extrinsic and intrinsic
apoptosis by activation of caspase-8, -9, and -3 and G2/M phase arrest.
Downregulation of cyclin B1 and CDK1 without the participation of p53 was also
observed in a study by Hu et al. [131]. Treatment with C. aromatica oil also inhib-
ited growth of implanted hepatoma in mice models which could be correlatable with
446 T. Soumya et al.

suppression of PCNA (Proliferating cell nuclear antigen) protein [132–134].

Alcoholic extracts of C. aromatica and C. caesia rhizome have been found to pos-
sess potent antiangiogenic and proapoptotic activity under in vivo conditions [121,
135–137].
C. zedoaria rhizome termed Ezhu in Chinese is extensively used in traditional
Chinese medicine to treat various ovarian and cervical cancers. Ethanolic extract of
C. zedoaria rhizome is known to exhibit strong antiproliferative and invasive activi-
ties against human esophageal squamous carcinoma TE-8 cells and suppress tumor
formation in mice. Upregulation of PTEN and downregulation of phosphorylated
Akt, mTOR and STAT3 expressions, attenuation of FGFR1 and MMP-2, activation
of caspase-9, -3 and PARP, and suppression of Bcl-2 leading to apoptosis were
observed in the same study [138]. Hexane and chloroform extracts of C. zedoaria
were found to have moderately potent cytotoxic activity on ovarian cancer cells
(SKOV3) as well as umbilical vein endothelial cells [139]. Essential oil obtained
from C. zedoaria, known as ‘zedoary’, possesses efficient cytotoxic effects on
H1299 (non-small cell lung carcinoma) and AGS (gastric cancer) cells and can
induce cell cycle arrest and apoptosis. Potential active compounds of Zedoary oil,
detected using gas chromatography and mass spectrometry (GC-MS), were
8,9-dehydro-9-formyl-cycloisolongifolene, 6-ethenyl-4,5,6,7-tetrahydro-3,6-­
dimethyl-­5-isopropenyl-trans-benzofuran, eucalyptol, and γ-elemene [141, 142].
Zedoary oil also reportedly exhibits antiangiogenic activity both in vitro and in vivo,
resulting in suppressing melanoma growth and lung metastasis, associated with
downregulating MMPs [140]. Isocurcumenol isolated from C. Zedoaria rhizome
shows antiproliferative potential in KB (nasopharyngeal carcinoma), A549 (lung
carcinoma), K562 (leukemic), and DLA (Daltons Lymphoma Ascites) cells [21].
Methanol extract of C. xanthorrhiza rhizome possesses cancer chemopreventive
potential [187]. Xanthorrhizol is the most active and abundant compound isolated
from the essential oil of C. xanthorrhiza, rhizomes. Studies have shown that xan-
thorrhizol is an attractive chemopreventive agent as it inhibited tumor nodules in a
spontaneous mouse lung metastasis model and TPA (12-O tetradecanoylphorbol-­13-­
acetate) - induced skin cancer promotion in mice, by decreasing phosphorylated
ERK (pERK), JNK, and p38 expression [143, 188]. This compound is known to
induce apoptosis via activation of p53-dependent mitochondrial pathway in HCT
116 (colon cancer), MCF 7, and MDA-MB-231 (breast cancer) cell lines [144, 145].
Xanthorrhizol also reported to induce caspase-independent apoptosis through ROS-­
mediated p38, MAPK, and JNK (c-jun N-terminal kinase) activation in SCC-15
(oral squamous cell carcinoma) cells [146]. A combination of xanthorrhizol with
other compound(s) like tamoxifen, astaxanthine, and α-tocopherol showed more
effective antiproliferatve activity against breast and esophageal cancer cell
lines [189].
Dichloromethane extract from Javanese medicinal plant C. purpurascens rhi-
zome induces apoptosis through mitochondrial-dependent pathway in colon cancer
HT-29 cells [147]. C. mutabilis is an endemic Zingiberaceae plant confined to
Western Ghats of India and the petroleum ether extract of this plant rhizome as well
as a novel labdane diterpenoid isolated from this extract reported to be cytotoxic to
Zingiberaceae Plants: A Cornucopia of Promising Chemotherapeuticals for Cancer Cure 447

various cancer cell lines and induce apoptosis in colorectal cancer HCT116 and
leukemic K562 cells [149]. Essential oil isolated from various Curcuma species,
such as C. elata, C. kwangsiensis, C. yunnanensis, C. nankunshanensis, C. sichua-
nensis, C. rubescens, C. purpurascens, and C. mutabilis, also exhibited cytotoxicity
against various cell lines [148, 150, 190, 191].
Curcumin : Anticancer activity of curcumin need a special mention, as it’s a most
studied compound from Curcuma species of Zingiberaceae family. Curcuminoids
represent a major component of the phytoconstituents found in various Curcuma
species [192]. Of the various curcuminoids known, curcumin (1,7-bis(4-hydroxy-­3-
methoxyphenyl)-1,6-heptadiene-3,5-dione), also called iferuloylmethane, deserves
a special mention. It is one of the most studied curcuminoids displaying a wide
spectrum of biological actions, including cholesterol-lowering, chemopreventive,
antidiabetic, anti-inflammatory, antimicrobial, and antioxidant activities [193–195].
Other commonly found curcuminoids are derivatives of curcumin which are known
as demethoxycurcumin and bisdemethoxycurcumin [196].
Curcumin has been studied in multiple human carcinomas including melanoma,
head and neck, breast, colon, pancreatic, prostate, and ovarian cancers [123–128].
Curcumin’s potent antioxidant and free-radical quenching properties play an impor-
tant role in the inhibitory effects of the compound on the initial stages of carcino-
genesis as demonstrated by animal models of various tumor types [197]. NF-κB and
AP-1 are two transcription factors intimately involved in the cellular pathways lead-
ing to tumorigenesis. NF-κB and AP-1 expression is induced by various stressful
stimuli (tumor promoters including oxidative stress, UV irradiation and infectious
antigens, pro-inflammatory cytokines such as TNF-α and IL-1), resulting in expres-
sion of genes involved in inflammation and cellular proliferation [198]. Curcumin
has an inhibitory effect on both NF-κB and AP-1 activation. Its effect on NF-κB, is
mediated through inhibition of IκK and results in inactive NF-κB remaining bound
to IκBα in the cytoplasm leading to suppression of a variety of gene products
involved in carcinogenesis and tumor growth including cyclin D1, VEGF (Vascular
endothelial growth factor), COX-2 (cycloxygenase-2), c-myc, Bcl-2, ICAM-1, and
MMP-9 (Matrix metalloproteinase-9) [199]. Curcumin also has a stimulatory effect
on the extrinsic apoptotic pathway, which is triggered by the binding of ‘death acti-
vators’ such as TNF-α and Fas-ligand to their corresponding cell surface receptors.
In addition to proapoptotic effect, curcumin also induces autophagic cell death in
chronic myelogenous leukemia, esophageal cancer, and malignant glioma cells,
mediated through inhibition of the Akt/mTOR/p70S6 kinase pathway and the
ERK1/2 pathway [200, 201]. Curcumin has demonstrated antiangiogenic effect in
vivo xenograft models, by regulating a variety of proangiogenic growth factors,
enzymes, and transcription factors like bFGF (basic fibroblast growth factor),
VEGF, angiopoetin-1 and 2, COX-2 MMP-9 [126, 202]. Its derivative, demethoxyc-
urcumin (DMC), has been reported to affect a number of cellular adhesion mole-
cules involved in the processes of metastasis [203].
Curcumin is known to target mTOR, which is recognized as a key therapeutic
target for the prevention and / or treatment of cancer [204]. Curcumin has been
shown to have numerous cytotoxic effects on cancer stem cells (CSCs) by
448 T. Soumya et al.

suppressing the release of cytokines, particularly interleukin (IL)-6, IL-8, and IL-1,
which stimulate CSCs [205]. It is an inhibitor of enzymes involved in epigenetic
changes of chromatin such as DNA methyltransferase, histone acetyl transferase,
and histone deacetylase (HDAC) leading to selective activation or inactivation of
genes (oncogenes/tumor suppressors) implicated in cancer death and progression.
Curcumin also modulates miRNAs (miR-15a, miR-16, miR-21, miR-22, miR-26,
miR-101, miR-146, miR-200, miR-203, and let-7) and their multiple target genes.
Altogether, curcumin is able to restore the epigenetic regulation balance and appears
as an attractive preventive and/or therapeutic approach against human cancer
[206, 207].
Although curcumin has long been used extensively to treat several inflammatory
diseases including cancer, poor aqueous solubility and reduced bioavailability limit
its efficacy as a promising therapeutic agent in cancer therapy. Various research
groups have focused on increasing the bioavailability of curcumin by combining
other phytochemicals as adjuvants. For instance, curcumin has often been used in
combination with other phytochemicals such as resveratrol, quercetin, sulfora-
phane, retinoic acid, and folates in cancer treatment [208–210]. The chemosensitiz-
ing effect of curcumin has been reported in cancers of the breast, colon, pancreas,
gut, liver, lung, prostate, brain, lymphoma, and leukemia [211, 212]. Various types
of curcumin nanoparticles appropriate for cancer treatment have been developed,
such as polymer nanoparticles, liposomes, micelles, solid lipid nanoparticles
(SLNs), and polymer conjugates, with improved bioavailability, devoid of degrada-
tion and further metabolism and with enhanced targeting capacities [207, 213, 214].

4.5 Genus Zingiber Boehmer

The genus Zingiber represented by 141 species is distributed mainly in tropical

Asia. Z. officinale rhizome extract and its major pungent components, 6-shogaol
and 6-gingerol, have been reported to induce antiproliferative effects on several
tumor cell lines [48]. Ginger extract significantly reduced the elevated expression of
NF-κB and pro-inflammatory TNF-α in in vivo model with liver cancer, thereby
acting as an anticancer and anti-inflammatory agent [215]. Ethanol extract of ginger
is also reported to have potent anticancer activity against pancreatic cancer cells,
inhibit cell cycle progression, and induce ROS-mediated apoptosis [151].
Experimental studies also showed that ginger extracts as well as the purified con-
stituents therein such as 6-gingerol and 6-shogaol exerted anticancer activity against
gastrointestinal cancer cells by modulating several signaling molecules like NF-κB,
STAT3, MAPK, PI3K, ERK1/2, Akt, TNF-α, COX-2, cyclin D1, cdk, MMP-9, sur-
vivin, cIAP-1, XIAP, Bcl-2, caspases, and other cell growth regulatory proteins
[22]. The remarkable increase of shogaols in steamed ginger contributed to its
improved anticancer potential [216, 217]. 6-shogaol significantly inhibited cell pro-
liferation in colon cancer cell lines HCT-116 and SW-480, with IC50 values of 7.5
and 10 μM, respectively, and can cause cell cycle arrest in G2/M phase by p53/
Zingiberaceae Plants: A Cornucopia of Promising Chemotherapeuticals for Cancer Cure 449

p21-mediated pathway [152]. It is known to act through endoplasmic reticulum

stress and mitochondrial pathways involved in apoptosis induction in HeLa (cervi-
cal cancer) cells [153]. Gingerol was also found to sensitize A549 cells to TRAIL-
induced apoptosis by inhibiting the autophagy flux [155], inhibit cell proliferation,
and induce apoptosis in SW-480 cells and HCT116 (colon cancer) cells [154].
Methanol extract of ginger leaves also reportedly induce apoptosis and reduction of
cell viability in human colorectal cancer cells [156].
Various organic solvent extracts and bioactivity guided column chromatography
subfractions of Z. zerumbet rhizome displayed strong antiproliferative effects on
breast cancer MCF7 cells [157]. Zerumbone, a natural cyclic sesquiterpene from
Z. zerumbet, reported to have a diverse range of biological activities, including anti-
cancer and antitumor activities. Studies have demonstrated that zerumbone has little
or no cytotoxic effect on normal human cells but induces apoptosis in many cancer
cell lines [158–160]. Chloroform extract of Z. cassumunar rhizome and compounds
therein cis-3-(3’, 4’-dimethoxyphenyl)-4-[(E)-3, 4 dimethoxystyryl] cyclo-hex-1-­
ene and 8-(13,14-dimethoxyphenyl)-2-methoxynaphto-1,4-quinone showed strong
activity against human T-acute lymphoblastic leukemia (CEMss) and cervical
(HeLa) cancer cell lines [161].

4.6 Other Zingiberaceae Plants with Anticancer Potential

Experimental evidence suggests that aqueous extracts of Elettaria cardamomum

(cardamom) extracts exert anti-inflammatory roles (immunomodulatory). It is evi-
dent that black pepper and cardamom aqueous extracts together significantly
enhance the cytotoxic activity of natural killer cells, thereby indicating their poten-
tial anticancer effects [162]. E. cardamomum extract also possesses potential che-
mopreventive effects evidenced by preventing diethylnitrosamine (DENA)-induced
hepato-cellular carcinoma through blocking oxidative stress, decreasing pro-­
inflammatory cytokine, NF-κB, and ornithine decarboxylase (ODC) [218].
Labdane diterpenes (isocoronarin D, methoxycoronarin D, ethoxycoronarin D,
and benzoyl eugenol) from Hedychium coronarium ethanol extract reported to pos-
sess chemopreventive effect [164]. Other labdane-type diterpenes reported from this
plant showed moderate to potent cytotoxic activities against different cancer cell
lines. They are reported with antiangiogenic activity, proved through inhibition of
human vascular endothelial cells [165]. Coronarin D from H. coronarium induces
significant G2/M arrest, apoptosis, and autophagy in various human cancer cell
lines including nasopharyngeal carcinoma (NPC) cells [166, 219]. It is also reported
to induce cell death through the upregulation of JNK/MAPK and caspase-­dependent
apoptosis pathways in human hepatocellular carcinoma (HCC) Huh7 and Sk-hep-1
cells [167]. H. coronarium rhizome ethanol extract can induce apoptosis-mediated
G1 phase cell arrest, while inhibiting the migratory potential of cervical cancer
HeLa cells [163].
450 T. Soumya et al.

Two novel labdane-diterpenes isolated from chloroform extract of Hedychium

spicatum rhizomes have shown good cytotoxic activity against Colo-205 (Colon
cancer), A-431 (skin cancer), MCF-7 (breast cancer), A549 (lung cancer), and
Chinese hamster ovary cells (CHO) [168]. Six new sesquiterpenes, including two
potent cytotoxic (against HeLa cells) compounds, have been isolated from this
extract [169]. Essential oil isolated from Hedychium spicatum rhizome also reported
cytotoxicity against various cancer cell lines [170].

5 Conclusion

To conclude, members of family Zingiberaceae continue to provide innumerable

bioactive extracts and compounds reported with potent cytotoxic and anticancer
activities. As a matter of fact, many of these plants are utilized either as ingredients
of traditional food varieties or additives in time-tested, traditional ethnomedicinal
herbal preparations, well known for their efficacious cure of a plethora of diverse
ailments. Discovery of various anticancer compounds from these plants is emerging
as a highly enriched, promising, and biocompatible bioresource for modern /com-
plementary or alternative medicine systems. Compared to the notorious and unde-
sirable side effects of chemotherapeutics used in the past decades, these compounds
can be developed for effective and specific targeting of key proteins of cancer-­
related signaling pathways. Despite an impressive array of such compounds, the
hunt needs to continue for hitherto unexplored, yet to be discovered drug candidates
within the Zingiberaceae family of plants.

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statis-
tics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185
countries. CA Cancer J Clin. 68:394–424. http://www.ncbi.nlm.nih.gov/pubmed/30207593
2. Ruddon RW (2007) Cancer biology, 4th edn. Oxford University Press
3. Anand P, Kunnumakara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B,
Aggarwal BB (2008) Cancer is a preventable disease that requires major lifestyle changes.
Pharm Res 25:2097–2116
4. Cohen L, Jefferies A (2017) Comprehensive lifestyle change: Harnessing synergy to improve
cancer outcomes. J Natl Cancer Inst. 2017:33–36
5. Weinberg RA (2014) The Biology of Cancer, 2nd edn. Garland Science, Taylor and
Francis group
6. Ke X, Shen L (2017) Molecular targeted therapy of cancer: The progress and future prospect.
Front Lab Med 1:69–75. https://doi.org/10.1016/j.flm.2017.06.001
7. Kooti W, Servatyari K, Behzadifar M, Asadi-Samani M, Sadeghi F, Nouri B, Zare MH (2017)
Effective medicinal plant in cancer treatment. J Evidence-Based Complement Altern Med
22(4):982–995
Zingiberaceae Plants: A Cornucopia of Promising Chemotherapeuticals for Cancer Cure 451

8. Thapliyal A, Khar RK, Amrish ChandraChandra A (2018) Overview of cancer and medicinal
herbs used for cancer therapy. Asian J Pharm 12:1–8. https://www.asiapharmaceutics.info/
index.php/ajp/article/view/2033
9. Guerra B, Issinger O-G (2019) Natural compounds and derivatives as Ser/Thr protein kinase
modulators and inhibitors. Pharmaceuticals 12:4. https://doi.org/10.3390/ph12010004
10. Tariq A, Sadia S, Pan K, Ullah I, Mussarat S, Sun F, Abiodun OO, Batbaatar A, Li Z, Song
D, Xiong Q, Ullah R, Khan S, Basnet BB, Kumar B, Islam R, Adnan M (2017) A systematic
review on ethnomedicines of anti-cancer plants. Phyther Res 31:202–264
11. Seca AML, Pinto DCGA (2018) Plant secondary metabolites as anticancer agents: Successes
in clinical trials and therapeutic application. Int J Mol Sci 19(1):263
12. Cragg GM, Pezzuto JM (2016) Natural products as a vital source for the discovery of cancer
chemotherapeutic and chemopreventive agents. Med Princ Pract 25:41–59
13. Iqbal J, Abbasi BA, Kanwal S, Khalil AT, Mahmood T, Shah SA, Ali B (2017) Plant-derived
anticancer agents: a green anticancer approach. Asian Pac J Trop Biomed 7:1129–1150.
https://doi.org/10.1016/j.apjtb.2017.10.016
14. Kress WJ, Prince LM, Williams KJ (2002) The phylogeny and a new classification of the
gingers (Zingiberaceae): evidence from molecular data. Am J Bot 89(11):1682–1696
15. Sabu M (2006) Zingiberaceae and Costaceae of South India. Indian Association for
Angiosperm Taxonomy
16. Pancharoen O, Prawat U, Tuntiwachwuttikul P (2000) Phytochemistry of the Zingiberaceae.
Stud Nat Prod Chem 23:797–865
17. Fadilah F, Yanuar A, Arsianti A, Andrajati R (2017) Phenylpropanoids, eugenol scaffold, and
its derivatives as anticancer. Asian J Pharm Clin Res 10:41–46
18. Ansari IA, Akhtar MS (2019) Chapter 3 - Current insights on the role of terpenoids as anti-
cancer agents: a perspective on cancer prevention and treatment. In: Swamy MK, Akhtar
MS (eds) Nature Bio-active Compound. Springer Nature Singapore, pp 53–80. https://doi.
org/10.1007/978-­981-­13-­7205-­6_3
19. Kopustinskiene DM, Jakstas V, Savickas A, Bernatoniene J (2020) Flavonoids as anticancer
agents. Nutrients 12:457. https://doi.org/10.3390/nu12020457
20. Basak S, Sarma GC, Rangan L (2010) Ethnomedical uses of Zingiberaceous plants of
Northeast India. J Ethnopharmacol 132:286–296
21. Lakshmi S, Padmaja G, Remani P (2011) Antitumour effects of Isocurcumenol isolated from
Curcuma zedoaria rhizomes on human and murine cancer cells. Int J Med Chem. https://doi.
org/10.1155/2011/253962
22. Prasad S, Tyagi AK (2015) Ginger and its constituents: role in prevention and treatment of
gastrointestinal cancer. Gastroenterol Res Pract. https://doi.org/10.1155/2015/142979
23. Chen D, Li H, Li W, Feng S, Deng D (2018) Kaempferia parviflora and its Methoxyflavones:
chemistry and biological activities. Evidence-Based Complement Altern Med. https://doi.
org/10.1155/2018/4057456
24. Alkandahri MY, Shafirany MZ, Rusdin A, Agustina LS, Pangaribuan F, Fitrianti F, Farhamzah
KAH, Sugiharta S, Mardiana LA (2021) Amomum compactum: a review of pharmacological
studies. Plant Cell Biotechnol Mol Biol 22:61–69
25. Kirana C, Record IR, McIntosh GH, Jones GP (2003) Screening for antitumor activity of 11
species of Indonesian Zingiberaceae using human MCF-7 and HT-29 cancer cells. Pharm
Biol 41:271–276
26. Afzal A, Oriqat G, Khan AM, Jose J, Afzal M (2013) Chemistry and biochemistry of terpe-
noids from Curcuma and related species. J Biol Active Prod Nat 3:1–55. http://www.tandfon-
line.com/doi/abs/10.1080/22311866.2013.782757
27. Ghosh S, Rangan L (2013) Alpinia: the gold mine of future therapeutics. 3 Biotech 3:173–185
28. Hartati R, Suganda AG, Fidrianny I (2014) Botanical, phytochemical and pharmacological
properties of Hedychium (Zingiberaceae) – a review. Procedia Chem 13:150–163. http://link-
inghub.elsevier.com/retrieve/pii/S1876619614002095
452 T. Soumya et al.

29. Wallace D (2016) Natural products as a source of anti-cancer lead compounds: Ginger and
breast cancer. J Pharmacol Clin Res 1(3):1–5
30. Joy PP, Thomas J, Mathew S, Skaria BP (1998) Zingiberaceous medicinal and aromatic
plants. Aromatic and Medicinal Plants Research Station, Odakkali
31. Sirirugsa P (1998) Thai Zingiberaceae: Species diversity and their uses. Pure Appl Chem
70:23–27
32. Jatoi SA, Kikuchi A, Watanabe KN (2007) Genetic diversity, cytology, and systematic and
phylogenetic studies in Zingiberaceae fleshy roots. Genes Genome Genom 1(1):56–62
33. Prabhu KKM, Asish G, Sabu M, Balachandran I (2013) Significance of gingers (Zingiberaceae)
in indian system of medicine - Ayurveda: an overview. Anc Sci Life 32:253
34. Zahara M, Hasanah M, Zalianda R (2018) Identification of Zingiberaceae as medicinal plants
in Gunung cut village, Aceh Barat Daya, Indonesia. J Trop Hortic. 1:24–28
35. Chhabra SC, Mahunnah RLA, Mshiu EN (1993) Plants used in traditional medicine in Eastern
Tanzania. VI. Angiosperms (Sapotaceae to Zingiberaceae). J Ethnopharmacol 39:83–103
36. Peng L, Zou HQ, Bauer R, Liu Y, Tao O, Yan SR, Han Y, Li JH, Ren ZY, Yan YH (2014)
Identification of Chinese herbal medicines from Zingiberaceae family using feature extraction
and cascade classifier based on response signals from E-Nose. Evidence-based Complement
Altern Med. https://doi.org/10.1155/2014/963035
37. Ujang Z, Subramaniam T, Nordin NI (2015) Ginger species and their traditional uses in mod-
ern applications. J Ind Technol 23:59–70
38. Kasarkar AR, Kulkarni DK (2016) Traditional knowledge of medicines belonging to family
Zingiberaceae from South Western Maharashtra, India. Int J Bot Stud 1(4):20–23
39. Jantan IB, Yassin MSM, Chin CB, Chen LL, Sim NL (2003) Antifungal activity of the essen-
tial oils of nine Zingiberaceae species. Pharm Biol 41(5):392–397
40. Cheenpracha S, Karalai C, Ponglimanont C, Subhadhirasakul S, Tewtrakul S (2006) Anti-­
HIV-­1 protease activity of compounds from Boesenbergia pandurata. Bioorganic Med Chem
14:1710–1714
41. Tewtrakul S, Subhadhirasakul S (2007) Anti-allergic activity of some selected plants in the
Zingiberaceae family. J Ethnopharmacol 109:535–538
42. Chen IN, Chang CC, Ng CC, Wang CY, Shyu YT, Chang TL (2008) Antioxidant and antimi-
crobial activity of Zingiberaceae plants in Taiwan. Plant Foods Hum Nutr 63:15–20
43. Hanish Singh JC, Alagarsamy V, Diwan PV, Sathesh Kumar S, Nisha JC, Narsimha RY
(2011) Neuroprotective effect of Alpinia galanga (L.) fractions on Aβ(25–35) induced amne-
sia in mice. J Ethnopharmacol 138:85–91
44. Kalaivani K, Senthil-Nathan S, Murugesan AG (2012) Biological activity of selected
Lamiaceae and Zingiberaceae plant essential oils against the dengue vector Aedes aegypti
L. (Diptera: Culicidae). Parasitol Res 110:1261–1268
45. Salama SM, Abdulla MA, AlRashdi AS, Ismail S, Alkiyumi SS, Golbabapour S (2013)
Hepatoprotective effect of ethanolic extract of Curcuma longa on thioacetamide induced
liver cirrhosis in rats. BMC Compl Alter Med 13:56. http://www.biomedcentral.
com/1472-­6882/13/56
46. Lu CL, Zhao HY, Jiang JG (2013) Evaluation of multi-activities of 14 edible species from
Zingiberaceae. Int J Food Sci Nutr 64(1):28–35
47. Al-Nahain A, Jahan R, Rahmatullah M (2014) Zingiber officinale: A potential plant
against rheumatoid arthritis. Evidence-Based Complement Altern Med. https://doi.
org/10.1155/2014/159089
48. Danciu C, Vlaia L, Fetea F, Hancianu M, Coricovac DE, Ciurlea SA, Şoica CM, Marincu I,
Vlaia V, Dehelean CA, Trandafirescu C (2015) Evaluation of phenolic profile, antioxidant
and anticancer potential of two main representants of Zingiberaceae family against B164A5
murine melanoma cells. Biol Res 48:1–9. http://www.biolres.com/content/48/1/1
49. Lakhan SE, Ford CT, Tepper D (2015) Zingiberaceae extracts for pain: a systematic review
and meta-analysis. Nutr J 14:50. https://doi.org/10.1186/s12937-­015-­0038-­8
Zingiberaceae Plants: A Cornucopia of Promising Chemotherapeuticals for Cancer Cure 453

50. Nithya R, Jayshree N (2017) A review on herbs of the Zingiberaceae family with beneficial
effects on cardiovasular diseases. World J Pharm Pharm Sci 6:635–643
51. Aghasi M, Ghazi-Zahedi S, Koohdani F, Siassi F, Nasli-Esfahani E, Keshavarz A, Qorbani
M, Khoshamal H, Salari-Moghaddam A, Sotoudeh G (2018) The effects of green Cardamom
supplementation on blood glucose, lipids profile, oxidative stress, Sirtuin-1 and Irisin in type
2 diabetic patients: a study protocol for a randomized placebo-controlled clinical trial. BMC
Complement Altern Med 18:1–6. https://doi.org/10.1186/s12906-­017-­2068-­6
52. Raju R, Singh A, Gunawardena D, Reddell P, Münch G (2019) Diarylheptanoids with anti-­
inflammatory activity from the rhizomes of Pleuranthodium racemigerum (Zingiberaceae).
Phytochem Lett 30:10–13
53. Ganapathy G, Preethi R, Moses JA, Anandharamakrishnan C (2019) Diarylheptanoids as
nutraceutical: a review. Biocatal Agric Biotechnol 19:101109
54. Gurib-Fakim A, Maudarbaccus N, Leach D, Doimo L, Wohlmuth H (2002) Essential oil com-
position of Zingiberaceae species from Mauritius. J Essent Oil Res 14:271–273
55. Abe M, Nakamura Y, Yamada Y, Osawa T, Morimitsu Y, Uda Y (2003) Labdane-type diter-
pene dialdehyde, pungent principle of Myoga, Zingiber mioga Roscoe. Biosci Biotechnol
Biochem 66(12):2698–2700
56. Chimnoi N, Sarasuk C, Khunnawutmanotham N, Intachote P, Seangsai S, Saimanee B,
Pisutjaroenpong S, Mahidol C, Techasakul S (2009) Phytochemical reinvestigation of
labdane-­type diterpenes and their cytotoxicity from the rhizomes of Hedychium coronarium.
Phytochem Lett 2:184–187
57. Manse Y, Ninomiya K, Nishi R, Kamei I, Katsuyama Y, Imagawa T, Chaipech S, Muraoka
O, Morikawa T (2016) Melanogenesis inhibitory activity of a 7-O-9’-linked neolignan from
Alpinia galanga fruit. Bioorganic Med Chem 24:6215–6224. https://doi.org/10.1016/j.
bmc.2016.10.001
58. Win NN, Ito T, Ngwe H, Win YY, Prema OY, Tanaka M, Asakawa Y, Abe I, Morita H (2017)
Labdane diterpenoids from Curcuma amada rhizomes collected in Myanmar and their antip-
roliferative activities. Fitoterapia 122:34–39
59. Ji KL, Fan YY, Ge ZP, Sheng L, Xu YK, Gan LS, Li JY, Yue JM (2019) Maximumins A-D,
rearranged Labdane-type diterpenoids with four different carbon skeletons from Amomum
maximum. J Org Chem 84:282–288
60. Sematong T, Pongprayoon U, Tuchinda P, Claeson P, Reutrakul V, Nahar N (1996) Topical
antiinflammatory activity of two pimarane diterpenes from Kaempferia pulchra. Phyther Res
10:534–535
61. Alberti Á, Riethmüller E, Béni S (2018) Characterization of diarylheptanoids: an emerging
class of bioactive natural products. J Pharm Biomed Anal. 147:13–34
62. Kim NJ, Byun SG, Cho JE, Chung K, Ahn YJ (2008) Larvicidal activity of Kaempferia
galanga rhizome phenylpropanoids towards three mosquito species. Pest Manag Sci
64:857–862
63. Kuddus R, Rumi F, Kaisar A, Hasan CM (2010) Sesquiterpene and phenylpropanoids from
Curcuma longa. Bangladesh Pharm J 13(2):31–34
64. Hong SS, Oh JS (2012) Phenylpropanoid ester from Zingiber officinale and their inhibitory
effects on the production of nitric oxide. Arch Pharm Res 35:315–320
65. Samarghandian S, Hadjzadeh MAR, Afshari JT, Hosseini M (2014) Antiproliferative activ-
ity and induction of apoptotic by ethanolic extract of Alpinia galanga rhizhome in human
breast carcinoma cell line. BMC Complement Altern Med 14:192. http://www.biomedcen-
tral.com/1472-­6882/14/192
66. Chouni A, Paul S (2018) A review on phytochemical and pharmacological potential of
Alpinia galanga. Pharmacogn J 10(1):9–15
67. Rao CH, Namosiva T, Suryaprakasam S (1976) Cardamonin and Alpinetin from the seeds of
Amomum subulatum. Planta Med 29:391–392
68. Jang DS, Han A-R, Park G, Jhon G-J, Seo E-K (2004) Flavonoids and aromatic compounds
from the rhizomes of Zingiber zerumbet. Arch Pharm Res 27(4):386–389
454 T. Soumya et al.

69. Ching AYL, Wah TS, Sukari MA, Lian GEC, Rahmani M, Khalid K (2007) Characterization
of flavonoid derivatives from Boesenbergia rotunda (L.). Malay J Anal Sci 11:154–159
70. Sutthanut K, Sripanidkulchai B, Yenjai C, Jay M (2007) Simultaneous identification and
quantitation of 11 flavonoid constituents in Kaempferia parviflora by gas chromatography. J
Chromatogr A 1143:227–233
71. Liu D, Qu W, Liang JY (2013) Flavonoids and other constituents from Alpinia sichuanensis
Z.Y. Zhu. Biochem Syst Ecol 46:127–129
72. Sabulal B, Dan M, John JA, Kurup R, Purushothaman CS, George V (2007) Phenylbutanoid-­
rich rhizome oil of Zingiber neesanum from Western Ghats, Southern India. Flavour Fragr J
22:521–524
73. Taechowisan T, Suttichokthanakorn S, Phutdhawong WS (2018) Antibacterial and cyto-
toxicity activities of phenylbutanoids from Zingiber cassumunar Roxb. J Appl Pharm Sci
8:121–127
74. He ZH, Ge W, Yue GGL, Lau CBS, He MF, But PPH (2010) Anti-angiogenic effects of the
fruit of Alpinia oxyphylla. J Ethnopharmacol 132:443–449
75. Nam JW, Kim SJ, Han RM, Lee SK, Seo EK (2005) Cytotoxic phenylpropanoids from the
rhizome of Alpinia galanga. J Appl Pharm 13:263–266
76. Awang K, Nurul Azmi M, Lian Aun LI, Nazif Aziz A, Ibrahim H, Hasima NN (2010) The
apoptotic effect of 1’S-1’-Acetoxychavicol acetate from Alpinia conchigera on human can-
cer cells. Molecules 15:8048–8059
77. Lu Y, Wang Z, Wei D, Xiang H (2007) Mechanism and inhibitory effect of galangin and its
flavonoid mixture from Alpinia officinarum on mushroom tyrosinase and B16 murine mela-
noma cells. J Enz Inhibit Med Chem 22(4):433–438
78. An N, Zou Z, Tian Z, Luo X, Yang S, Xu L (2008) Diarylheptanoids from the rhizomes of
Alpinia officinarum and their anticancer activity. Fitoterapia 79:27–31
79. Tabata K, Yamazaki U, Okada M, Fukumura K, Shimada A, Sun Y, Yasukawa K, Suzuki T
(2009) Diarylheptanoids derived from Alpinia officinarum induce apoptosis, S-phase arrest
and differentiation in human neuroblastoma cells. Anticancer Res 29:4981–4988
80. Malek ANS, Phang CW, Ibrahim H, Wahab NA, Sim KS (2011) Phytochemical and cytotoxic
investigations of Alpinia mutica rhizomes. Molecules 16:583–589. https://doi.org/10.3390/
molecules16010583
81. Raj CA, Ragavendran P, Sophia D, Rathi MA, Gopalakrishnan VK (2012) Evaluation of in-­
vitro antioxidant and anticancer activity of Alpinia purpurata. Chin J Nat Med 10(4):263–268
82. Oirere EK, Anusooriya P, Malarvizhi D, Raj CA, Gopalakrishnan VK (2016) Antioxidant,
cytotoxic and apoptotic activities of crude extract of Alpinia purpurata on cervical cancer cell
line. Int J Pharm Sci Rev Res 36(2):28–34
83. Phang C, Nurestri S, Malek A, Ibrahim H (2013) Antioxidant potential, cytotoxic activity
and total phenolic content of Alpinia pahangensis rhizomes. BMC Complement Altern Med
13:243. http://www.biomedcentral.com/1472-­6882/13/243
84. Sim KS, Ibrahim H, Malek ANS, Syamsir DR, Awang K (2014) Cytotoxic activity of Alpinia
murdochii Ridl: a mountain ginger species from Peninsular Malaysia. Pharmaco Mag
10:70–72
85. Hua SZ, Luo JG, Wang XB, Wang JS, Kong LY (2009) Two novel monoterpene-chalcone
conjugates isolated from the seeds of Alpinia katsumadai. Bioorganic Med Chem Lett
19:2728–2730. https://doi.org/10.1016/j.bmcl.2009.03.117
86. Zahra MH, Salem TAR, El-Aarag B, Yosri N, EL-Ghlban S, Zaki K, Marei AH, EL-Wahed
AA, Saeed A, Khatib A, AlAjmi MF, Shathili AM, Xiao J, Khalifa SAM, El-Seedi HR (2019)
Alpinia zerumbet (Pers.): Food and medicinal plant with potential in vitro and in vivo anti-­
cancer activities. Molecules 24:2495. https://doi.org/10.3390/molecules24132495
87. Kuo C-Y, Teng-Song Weng T-S, Senthil Kumar KJ, Tseng Y-H, Tung T-W, Wang S-Y,
Wang H-C (2019) Ethanol Extracts of Dietary Herb, Alpinia nantoensis, exhibit anti-
cancer potential in human breast cancer cells. Integr Cancer Ther 18:1–12. https://doi.
org/10.1177/153473541986692
Zingiberaceae Plants: A Cornucopia of Promising Chemotherapeuticals for Cancer Cure 455

88. Reddy AS, Abd Malek SN, Ibrahim H, Sim KS (2013) Cytotoxic effect of Alpinia scabra
(Blume) Náves extracts on human breast and ovarian cancer cells. BMC Complement Altern
Med 13:314. https://doi.org/10.1186/1472-­6882-­13-­314
89. Ali MS, Banskota AH, Tezuka Y, Saiki I, Kadota S (2001) Antiproliferative activity of diaryl-
heptanoids from the seeds of Alpinia blepharocalyx. Biol Pharm Bull 24(5):525–528
90. Yang HL, Chen SC, Chen CS, Wang SY, Hseu YC (2008) Alpinia pricei rhizome extracts
induce apoptosis of human carcinoma KB cells via a mitochondria-dependent apoptotic path-
way. Food Chem Toxicol 46:3318–3324
91. Yadav VR, Prasad S, Aggarwal BB (2012) Cardamonin sensitizes tumour cells to TRAIL
through ROS- and CHOP- mediated up-regulation of death receptors and down- regulation of
survival. Brit J Pharma 165:741–753
92. Sharma V, Lohia N, Handa V, Baranwal M (2017) Amomum subulatum seed extract exhibit
antioxidant, cytotoxic and immune-suppressive effect. Indian J Biochem Biophys 54:135–139
93. Chin YW, Salim AA, Su BN, Mi Q, Chai HB, Riswan S, Kardono LBS, Ruskandi A,
Farnsworth NR, Swanson SM, Kinghorn AD (2008) Potential anticancer activity of naturally
occurring and semisynthetic derivatives of aculeatins A and B from Amomum aculeatum. J
Nat Prod 71:390–395
94. Moon SS, Cho SC, Lee JY (2005) Tsaokoarylone, a cytotoxic diarylheptanoid from Amomum
tsao-ko fruits. Bull Korean Chem Soc 26:447–450
95. Yang Y, Yue Y, Runwei Y, Guolin Z (2010) Cytotoxic, apoptotic and antioxidant activity of
the essential oil of Amomum tsao-ko. Bioresour Technol 101:4205–4211
96. Zhang T-T, Lu C-L, Jiang J-G (2015) Antioxidant and anti-tumour evaluation of compounds
identified from fruit of Amomum tsaoko Crevost et Lemaire. J Funct Foods. 18:423–431
97. Chen C, You F, Wu F, Luo Y, Zheng G, Xu H, Liu Y (2020) Antiangiogenesis Efficacy of
Ethanol Extract from Amomum tsaoko in Ovarian Cancer through Inducing ER Stress to
Suppress p-STAT3/NF-kB/IL-6 and VEGF Loop. Evidence-based Complement Altern
Med:2390125. https://doi.org/10.1155/2020/2390125
98. Zhang D, Li S, Xiong Q, Jiang C, Lai X (2013) Extraction, characterization and biological
activities of polysaccharides from Amomum villosum. Carbohydr Polym 95:114–122
99. Tangjitjaroenkun J, Tangchitcharoenkhul R, Yahayo W, Supabphol S, Sappapan R, Supabphol
R (2020) Chemical compositions of essential oils of Amomum verum and Cinnamomum par-
thenoxylon and their in vitro biological properties. J Herbmed Pharmacol 9(3):223–231
100. Choi JW, Kim KH, Lee IK, Choi SU, Lee KR (2009) Phytochemical constituents of Amomum
xanthioides. Nat Prod Sci 15(1):44–49
101. Kim KH, Choi JW, Choi SU, Lee KR (2010a) Terpene glycosides and cytotoxic constituents
from the seeds of Amomum xanthioides. Planta Med 76(5):461–464
102. Kim KH, Choi JW, Choi SU, Seo EK, Lee KR (2010b) Amoxantin A: a new bisnorlabdane
diterpenoid from Amomum xanthioides. Bull Kor Chem Soc 31(4):1035–1037
103. Kim KH, Choi JW, Choi SU, Lee K (2011) Cytotoxic sesquiterpenoid from the seeds of
Amomum xanthioides. Nat Prod Sci 17(1):10–13
104. Luo JG, Yin H, Fan BY, Kong LY (2014) Labdane diterpenoids from the roots of Amomum
maximum and their cytotoxic evaluation. Helv Chim Acta 97(8):1140–1145
105. Atun S, Arianingrum R (2015) Anticancer activity of bioactive compounds from Kaempferia
rotunda rhizome against human breast cancer. Int J Pharmacogn Phytochem Res 7:262–269
106. Kabir SR, Reza MA (2014) Antibacterial activity of Kaempferia rotunda rhizome lectin
and its induction of apoptosis in Ehrlich ascites carcinoma cells. Appl Biochem Biotechnol
172:2866–2876
107. Islam F, Gopalan V, Lam AKY, Kabir SR (2019) Kaempferia rotunda tuberous rhizome lectin
induces apoptosis and growth inhibition of colon cancer cells in vitro. Int J Biol Macromol
141:775–782. https://doi.org/10.1016/j.ijbiomac.2019.09.051
108. Amuamuta A, Plengsuriyakarn T, Na-Bangchang K (2017) Anticholangiocarcinoma activity
and toxicity of the Kaempferia galanga Linn. Rhizome ethanolic extract. BMC Complement
Altern Med 17:213. https://doi.org/10.1186/s12906-­017-­1713-­4
456 T. Soumya et al.

109. Ali H, Yesmin R, Satter Mohammed A, Habib R, Yeasmin T (2018) Antioxidant and antineo-
plastic activities of methanolic extract of Kaempferia galanga Linn. Rhizome against Ehrlich
ascites carcinoma cells. J King Saud Univ Sci 30:386–392
110. Yang X, Ji H, Feng Y, Yu J, Liu A (2018) Structural characterization and antitumor activity of
polysaccharides from Kaempferia galanga L. Oxid Med Cell Longev:9579262. https://doi.
org/10.1155/2018/9579262
111. Ichwan SJA, Husin A, Suriyah WH, Lestari W, Omar MN, Kasmuri AR (2019) Anti-­
neoplastic potential of ethyl-p-methoxycinnamate of Kaempferia galanga on oral cancer cell
lines. Mater Today Proc 16:2115–2121. https://doi.org/10.1016/j.matpr.2019.06.100
112. Banjerdpongchai R, Chanwikruy Y, Rattanapanone V, Sripanidkulchai B (2009) Induction
of apoptosis in the human leukemic U937 cell line by Kaempferia parviflora Wall.Ex.Baker
extract and effects of Paclitaxel and Camptothecin. Asian Pac J Cancer Prev 10:1137–1140
113. Potikanond S, Sookkhee S, Takuathung MN, Mungkornasawakul P, Wikan N, Smith DR,
Nimlamool W (2017) Kaempferia parviflora extract exhibits anti-cancer activity against
HeLa cervical cancer cells. Front Pharmacol 8:630. https://doi.org/10.3389/fphar.2017.00630
114. Paramee S, Sookkhee S, Sakonwasun C, Takuathung MN, Mungkornasawakul P,
Nimlamool W, Potikanond S (2018) Anti-cancer effects of Kaempferia parviflora on ovar-
ian cancer SKOV3 cells. BMC Complement Altern Med 18:178. https://doi.org/10.1186/
s12906-­018-­2241-­6
115. Wongsrikaew N, Kim H, Vichitphan K, Cho SK, Han J (2012) Antiproliferative activity and
polymethoxyflavone composition analysis of Kaempferia parviflora extracts. J Korean Soc
Appl Biol Chem 55:813–817
116. Leardkamolkarn V, Tiamyuyen S, Sripanidkulchai BO (2009) Pharmacological activity of
Kaempferia parviflora extract against human bile duct cancer cell lines. Asian Pac J Cancer
Prev 10:695–698
117. Tang SW, Sukari MA, Neoh BK, Yeap YSY, Abdul AB, Kifli N, Cheng Lian Ee G (2014)
Phytochemicals from Kaempferia angustifolia Rosc. and their cytotoxic and antimicrobial
activities. Biomed Res Int. https://doi.org/10.1155/2014/417674
118. Chawengrum P, Boonsombat J, Kittakoop P, Mahidol C, Ruchirawat S, Thongnest S (2018)
Cytotoxic and antimicrobial labdane and clerodane diterpenoids from Kaempferia elegans
and Kaempferia pulchra. Phytochem Lett 24:140–144
119. Kaneshiro T, Suzui M, Takamatsu R, Murakami A, Fujino T, Yoshimi N (2005) Growth inhib-
itory activities of crude extracts obtained from herbal plants in the Ryukyu Islands on several
human colon carcinoma cell lines. Asian Pac J Cancer Prev 6:353–358
120. Ahmad R, Srivastava AN, Khan MA (2016) Evaluation of in-vitro anticancer activity of rhi-
zome of Curcuma longa against human breast cancer and Vero cell lines. Int J Bot Stud 1:1–6
121. Hadem KLH, Sen A (2017) Curcuma species: a source of anticancer drugs. J Tumor Med
Prev 1(5):1–7
122. Kukula-Koch W, Grabarska A, Jarogniew Ł, Czernicka L, Nowosadzka E, Gumbarewicz E,
Jarzab A, Audo G, Upadhyay S, Głowniak K, Stepulak A (2018) Superior anticancer activity
is demonstrated by total extract of Curcuma longa L. as opposed to individual curcuminoids
separated by centrifugal partition chromatography. Phytother Res 32:933–942
123. Liu D, Chen Z (2013) Breast cancer the effect of curcumin on breast cancer cells. J Breast
Can 16(2):133–137
124. Mukhopadhyay A, Bueso-ramos C, Chatterjee D, Pantazis P, Aggarwal BB (2001) Curcumin
downregulates cell survival mechanisms in human prostate cancer cell lines. Oncogene
20:7597–7609
125. Hanif R, Qiao L, Shiff SJ, Rigas B (1997) Curcumin, a natural plant phenolic food additive,
inhibits cell proliferation and induces cell. J Lab Clin Med 130(6):576–584
126. Lin YG, Kunnumakkara AB, Nair A, Merritt WM, Han L, Armaiz-pena GN, Kamat AA,
Spannuth W, Gershenson DM, Lutgendorf SK, Aggarwal BB, Sood AK (2007) Curcumin
inhibits tumor growth and angiogenesis in ovarian carcinoma by targeting the Nuclear
Factor-κB pathway. Clin Cancer Res 13(11):3423–3431
Zingiberaceae Plants: A Cornucopia of Promising Chemotherapeuticals for Cancer Cure 457

127. Siwak DR, Shishodia S, Aggarwal BB, Kurzrock R (2005) Curcumin-induced antiprolifera-
tive and proapoptotic effects in melanoma cells are associated with suppression of IκB kinase
and Nuclear Factor-κB activity and are independent of the B-Raf / mitogen- a­ ctivated / extra-
cellular signal-regulated protein kinase pathway and the Akt pathway. Cancer 104(5):879–890
128. Wang D, Veena MS, Stevenson K, Tang C, Ho B, Suh JD, Duarte VM, Faull KF, Mehta
K, Srivatsan ES, Wang MB (2008) Liposome-encapsulated Curcumin suppresses growth of
head and neck squamous cell carcinoma in vitro and in xenografts through the inhibition
of Nuclear Factor-κB by an AKT-independent pathway. Clin Cancer Res 14(19):6228–6237
129. Ramachandran C, Lollett IV, Escalon E, Quirin K, Melnick SJ (2015) Anticancer potential
and mechanism of action of Mango ginger (Curcuma amada Roxb.) supercritical CO2 extract
in human glioblastoma cells. J Evid-Based Compl Altern Med 20(2):109–119
130. Sivaprabha J, Dharani B, Padma PR, Sumathi S (2016) Apoptosis-induced in-vitro anticancer
activity of methanolic extract of leaves and rhizomes of Curcuma amada Roxb. against breast
cancer cells. Int J Green Pharm 10(2):98–103
131. Hu B, Shen K-P, An H-M, Wu Y, Du Q (2011) Aqueous extract of Curcuma aromatica
induces apoptosis and G2/M arrest in human colon carcinoma LS-174-T cells independent of
p53. Can Biother Radiopharm 26:97–104
132. Wu WY, Xu Q, Shi LC, Zhang WB (2000) Inhibitory effects of Curcuma aromatica oil on
proliferation of hepatoma in mice. World J Gastroentero 6(2):216–219
133. Li Y, Wo JM, Ms QL, Li X, Martin RCG (2009) Chemoprotective effects of Curcuma aro-
matica on esophageal carcinogenesis. Ann Surg Oncol 16:515–523
134. Li Y, Shi X, Zhang J, Zhang X, Martin RCG (2014) Hepatic protection and anticancer activ-
ity of Curcuma: a potential chemopreventive strategy against hepatocellular carcinoma. Int
J Oncol 44:505–513
135. Thippeswamy G, Salimath BP (2006) Curcuma aromatica extract induces apoptosis and
inhibits angiogenesis in Ehrlich Ascites tumor cells in-vivo. mySCIENCE 1(1):79–92
136. Karmakar I, Dolai N, Kumar RBS, Kar B, Roy SN, Haldar PK (2013) Antitumor activity and
antioxidant property of Curcuma caesia against Ehrlich’s ascites carcinoma bearing mice.
Pharm Biol 51(6):753–759
137. Hadem KLH, Sharan RN, Kma L (2016) Phytochemicals of Aristolochia tagala and Curcuma
caesia exert anticancer effect by Tumor Necrosis Factor-α mediated decrease in Nuclear
Factor κ B binding activity. J Basic Clin Pharma 7:1–11
138. Hadisaputri YE, Miyazaki T, Suzuki S, Kubo N, Zuhrotun A (2015) Molecular characteriza-
tion of antitumor effects of the rhizome extract from Curcuma zedoaria on human esophageal
carcinoma cells. Int J Oncol 47:2255–2263
139. Khaing SL, Omar SZ, Looi CY, Arya A, Mohebali N, Mohd A (2017) Identification of active
extracts of Curcuma zedoaria and their real- time cytotoxic activities on ovarian cancer cells
and HUVEC cells. Biomed Res 28(18):9182–9187
140. Shi H, Tan B, Ji G, Lu L, Cao A, Shi S, Xie J (2013) Zedoary oil (Ezhu You) inhibits prolifera-
tion of AGS cells. Chin Med 8:13. http://www.cmjournal.org/content/8/1/13
141. Chen C-C, Chen Y, His Y-T, Chang C-S, Huang L-F, Ho C-T, Way T-D, Kao J-Y (2013)
Chemical constituents and anticancer activity of Curcuma zedoaria Roscoe essential
oil against non-small cell lung carcinoma cells in-vitro and in-vivo. J Agric Food Chem
61:11418–11427
142. Chen W, Lu Y, Gao M, Wu J, Wang A, Shi R (2011) Anti-angiogenesis effect of essential oil
from Curcuma zedoaria in-vitro and in-vivo. J Ethnopharmacol 133:220–226
143. Choi M, Kim SH, Chung W, Hwang J, Park K (2005) Xanthorrhizol, a natural sesquiterpe-
noid from Curcuma xanthorrhiza, has an anti-metastatic potential in experimental mouse
lung metastasis model. Biochem Biophys Res Commun 326:210–217
144. Cheah YH, Nordin FJ, Tee TT, Azimahtol HL, Abdullah NR, Ismail Z (2008) Antiproliferative
property and apoptotic effect of Xanthorrhizol on MDA-MB-231 breast cancer cells. Antican
Res 28:3677–3690
458 T. Soumya et al.

145. Kang Y, Park K, Chung W, Hwang J, Lee SK (2009) Xanthorrhizol, a natural sesquiterpenoid
, induces apoptosis and growth arrest in HCT116 human colon cancer cells. J Pharmacol Sci
111:276–284
146. Kim JY, An JM, Chung W, Park K, Hwang JK, Kim DS, Seo SR, Seo JT (2012) Xanthorrhizol
induces apoptosis through ROS- mediated MAPK activation in human oral squamous cell
carcinoma cells and inhibits DMBA-induced oral carcinogenesis in Hamsters. Phytother Res
27:493–498
147. Rouhollahi E, Zorofchian Moghadamtousi S, Paydar M, Fadaeinasab M, Zahedifard
M, Hajrezaie M, Abdalla Ahmed Hamdi O, Yeng Looi C, Ameen Abdulla M, Awang K,
Mohamed Z (2015) Inhibitory effect of Curcuma purpurascens BI. rhizome on HT-29 colon
cancer cells through mitochondrial-dependent apoptosis pathway. BMC Complement Altern
Med 15:15. https://doi.org/10.1186/s12906-­015-­0534-­6
148. Hong SL, Lee GS, Syed Abdul Rahman SN, Ahmed Hamdi OA, Awang K, Aznam Nugroho
N, Abd Malek SN (2014) Essential oil content of the rhizome of Curcuma purpurascens Bl.
(Temu Tis) and its antiproliferative effect on selected human carcinoma cell lines. Sci World
J:397430. https://doi.org/10.1155/2014/397430
149. Soumya T, Lakshmipriya T, Klika KD, Jayasree PR, Manish Kumar PR (2021) Anticancer
potential of rhizome extract and a labdane diterpenoid from Curcuma mutabilis plant endemic
to Western Ghats of India. Sci Rep 11:552. https://doi.org/10.1038/s41598-­020-­79414-­8
150. Zhang L, Yang Z, Huang Z, Zhao M, Li P, Zhou W, Zhang K, Zheng X, Lin L, Tang J, Fang
Y, Du Z (2017) Variation in essential oil and bioactive compounds of Curcuma kwangsien-
sis collected from natural habitats. Chem Biodivers 14:e1700020. https://doi.org/10.1002/
cbdv.201700020
151. Akimoto M, Iizuka M, Kanematsu R, Yoshida M, Takenaga K (2015) Anticancer effect
of Ginger extract against pancreatic cancer cells mainly through reactive oxygen species-­
mediated autotic cell death. PLoS ONE 10(5):e0126605. https://doi.org/10.1371/journal.
pone.0126605
152. Qi L, Zhang Z, Zhang C, Anderson S, Liu Q, Yuan C, Wang C (2015) Anti-colon cancer
effects of 6-Shogaol through G2/M cell cycle arrest by p53/p21-cdc2/cdc25A crosstalk. Am
J Chin Med 43(4):743–756
153. Liu Q, Peng Y, Qi L, Cheng X, Xu X, Liu L, Liu E, Li P (2012) The cytotoxicity mechanism
of 6-Shogaol-treated HeLa human cervical cancer cells revealed by label-free shotgun pro-
teomics and bioinformatics analysis. Evidence-Based Complement Altern Med. https://doi.
org/10.1155/2012/278652
154. Radhakrishnan EK, Bava SV, Narayanan SS, Nath LR, Thulasidasan AKT, Soniya EV, Ruby
JA (2014) Prevents PMA-induced proliferation in colon cancer cells by inhibiting MAPK
/ AP-1 signaling. PLOS ONE 9(8):e104401. https://doi.org/10.1371/journal.pone.0104401
155. Nazim U, Jeong J, Seol J, Hur J, Eo S, Lee J, Park S (2015) Inhibition of the autophagy flux
by Gingerol enhances TRAIL-induced tumor cell death. Oncol Reports 33:2331–2336
156. Park GH, Park JH, Song HM, Eo HJ, Kim MK, Lee JW, Lee MH, Cho K, Lee JR, Cho HJ,
Jeong JB (2014) Anti-cancer activity of Ginger (Zingiber officinale) leaf through the expres-
sion of activating transcription factor 3 in human colorectal cancer cells. BMC Complement
Altern Med 14:408. http://www.biomedcentral.com/1472-­6882/14/408
157. Rashid RA, Pihie AHL (2005) The antiproliferative effect of Zingiber zerumbet extracts and
fractions on the growth of human breast carcinoma cell lines. Malay J Pharm Sci 3(1):45–52
158. Rajan I, Jayasree PR, Kumar PRM (2015) Zerumbone induces mitochondria-mediated apop-
tosis via increased calcium, generation of reactive oxygen species and upregulation of soluble
histone H2AX in K562 chronic myelogenous leukemia cells. Tumor Biol 36(11):8479–8489
159. Prasannan R, Kalesh KA, Shanmugam MK, Nachiyappan A, Ramachandran L, Nguyen
AH, Prem A, Lakshmanan M, Seok K, Sethi G (2012) Key cell signaling pathways modu-
lated by Zerumbone: role in the prevention and treatment of cancer. Biochem Pharmacol
84:1268–1276
Zingiberaceae Plants: A Cornucopia of Promising Chemotherapeuticals for Cancer Cure 459

160. Koga AY, Beltrame FL, Pereira AV (2016) Several aspects of Zingiber zerumbet: a review.
Braz J Pharmacogn 26:385–391
161. Zulkhairi AM, Aspollah SM, Lian EGC, Bustamam AA (2017) Phytochemicals and cyto-
toxic studies of Zingiber cassumunar phytochemicals and cytotoxic studies of Zingiber cas-
sumunar Roxb. J Trop Agric Food Sci 45(2):187–197
162. Majdalawieh AF, Carr RI (2010) In-vitro Investigation of the potential immunomodulatory
and anti-cancer activities of Black Pepper (Piper nigrum) and Cardamom (Elettaria carda-
momum). J Med Food 13(2):371–381
163. Ray A, Jena S, Dash B, Sahoo A, Kar B, PatnaikJ PPC, Nayak S, Mahapatra N (2019)
Hedychium coronarium extract arrests cell cycle progression, induces apoptosis, and impairs
migration and invasion in HeLa cervical cancer cells. Cancer Manage Res 11:483–500
164. Endringer DC, Taveira FSN, Kondratyuk TP, Pezzuto JM, Bragaa FC (2014) Cancer chemo-
prevention activity of labdane diterpenes from rhizomes of Hedychium coronarium. Braz J
Pharmacogn 24:408–412
165. Zhana Z-J, Wena Y-T, Rena F-Y, Raob G-W, Shana W-G, Li C-P (2012) Diterpenoids and a
diarylheptanoid from Hedychium coronarium with significant anti-angiogenic and cytotoxic
activities. Chem Biodivers 9:2754–2760
166. Chen J, Hsieh M-C, Lin S, Lin C, Hsi Y-T, Lo Y-S, Chuang Y-C, Hsieh M-J, Chen MK
(2017) Coronarin D induces reactive oxygen species-mediated cell death in human naso-
pharyngeal cancer cells through inhibition of p38 MAPK and activation of JNK. Oncotarget
8(64):108006–108019
167. Lin H, Hsieh M, Hsieh Y, Yeh C, Hsueh K, Yang S (2018) Coronarin D induces apoptotic
cell death through the JNK pathway in human hepatocellular carcinoma. Environ Toxicol
33(9):946–954
168. Reddy PP, Ranga Rao R, Shashidhar J, Sastry BS, Madhusudana Rao J, Suresh Babu K
(2009) Phytochemical investigation of labdane diterpenes from the rhizomes of Hedychium
spicatum and their cytotoxic activity. Bioorg Med Chem Lett 19:6078–6081
169. Suresh G, Poornima B, Babu KS, Yadav PA, Rao MSA, Siva B, Prasad KR, Nayak VL,
Ramakrishna S (2013) Cytotoxic sesquiterpenes from Hedychium spicatum: isolation, struc-
ture elucidation and structure-activity relationship studies. Fitoterapia 86:100–107
170. Mishra T, Pal M, Meena S, Datta D, Dixit P, Kumar A, Meena B, Rana TS, Upreti DK (2016)
Composition and in-vitro cytotoxic activities of essential oil of Hedychium spicatum from
different geographical regions of western Himalaya by principal components analysis. Nat
Prod Res 30:1224–1227
171. Jing LJ, Bakar MFA, Mohamed M, Rahmat A (2011) Effects of selected Boesenbergia spe-
cies on the proliferation of several cancer cell lines. J Pharmacol Toxicol 6:272–282
172. Kirana C, Jones GP, Record IR, McIntosh GH (2007) Anticancer properties of panduratin A
isolated from Boesenbergia pandurata (Zingiberaceae). J Nat Med 61:131–137. https://doi.
org/10.1007/s11418-­006-­0100-­0
173. Isa NM, Abdelwahab SI, Mohan S, Abdul AB, Sukari MA, Taha MME, Syam S, Narrima P,
Cheah SC, Ahmad S, Mustafa MR (2012) In vitro anti-inflammatory, cytotoxic and antioxidant
activities of boesenbergin A, a chalcone isolated from Boesenbergia rotunda (L.) (fingerroot).
Braz J Med Biol Res 45(6):524–530. https://doi.org/10.1590/S0100-­879X2012007500022
174. Break MKB, Chiang M, Wiart C, Chin C-F, Khoo ASB, Khoo T-J (2020) Cytotoxic Activity of
Boesenbergiarotunda Extracts against nasopharyngeal carcinoma cells (HK1). Cardamonin,
a Boesenbergiarotunda constituent, inhibits growth and migration of HK1 cells by induc-
ing caspase-dependent apoptosis and G2/M–Phase arrest. Nutr Cancer. https://doi.org/10.108
0/01635581.2020.1751217
175. Ma XN, Xie CL, Miao Z, Yang Q, Yang XW (2017) An overview of chemical constituents
from Alpinia species in the last six decades. RSC Adv 7:14114–14144
176. Sok SPM, Arshad NM, Azmi MN, Awang K, Ozpolat B, Nagoor NH (2017) The apoptotic
effect of 1′S-1′-Acetoxychavicol Acetate (ACA) enhanced by inhibition of non-canonical
460 T. Soumya et al.

autophagy in human non-small cell lung cancer cells. PLoS One 12(2):e0171329. https://doi.
org/10.1371/journal.pone.0171329
177. Ito K, Nakazato T, Xian MJ, Yamada T, Hozumi N, Murakami A, Ohigashi H, Ikeda Y, Kizaki
M (2005) 1′-acetoxychavicol acetate is a novel nuclear factor κB inhibitor with significant
activity against multiple myeloma in vitro and in vivo. Cancer Res 65:4417–4424
178. In LLA, Arshad NM, Ibrahim H, Azmi MN, Awang K, Nagoor NH (2012) 1’-Acetoxychavicol
acetate inhibits growth of human oral carcinoma xenograft in mice and potentiates cisplatin
effect via proinflammatory microenvironment alterations. BMC Complement Altern Med
12:179. http://www.biomedcentral.com/1472-­6882/12/179
179. Huang H, Chen AY, Ye X, Guan R, Rankin GO, Chen YC (2020) Galangin, a flavonoid
from lesser galangal, induced apoptosis via p53-dependent pathway in ovarian cancer cells.
Molecules 25:1579. https://doi.org/10.3390/molecules25071579
180. Kim Y, Ko H, Park J, Han I, Amor EC, Wha J, Ok H (2010) International immunopharmacol-
ogy Dimethyl cardamonin inhibits lipopolysaccharide-induced inflammatory factors through
blocking NF-κB p65 activation. Int Immunopharmacol 10:1127–1134
181. Liao Q, Shi DH, Zheng W, Xu XJ, Yu YH (2010) Antiproliferation of cardamonin is involved
in mTOR on aortic smooth muscle cells in high fructose-induced insulin resistance rats. Eur
J Pharmacol 641:179–186. https://doi.org/10.1016/j.ejphar.2010.05.024
182. Machana S, Weerapreeyakul N, Barusrux S, Nonpunya A, Sripanidkulchai B, Thitimetharoch
T (2011) Cytotoxic and apoptotic effects of six herbal plants against the human hepatocarci-
noma. Chin Med 6:39. http://www.cmjournal.org/content/6/1/39
183. Patanasethanont D, Nagai J, Matsuura C, Fukui K, Sutthanut K, Sripanidkulchai B, Yumoto
R, Takano M (2007) Modulation of function of multidrug resistance associated-proteins by
Kaempferia parviflora extracts and their components. Euro J Pharma 566:67–74
184. Ninomiya K, Chaipech TMS, Katsuyama SMY (2016) Simultaneous quantitative analysis of
12 methoxyflavones with melanogenesis inhibitory activity from the rhizomes of Kaempferia
parviflora. J Nat Med 70:179–189
185. Kuttan R, Bhanumathy P, Nirmala K, George MC (1985) Potential anticancer activity of
Turmeric (Curcuma longa). Cancer Lett 29:197–202
186. Yue GGL, Chan BCL, Hon P, Kennelly EJ, Yeung SK, Cassileth BR, Fung K, Leung P, Lau
CBS (2010) Immunostimulatory activities of polysaccharide extract isolated from Curcuma
longa. Int J Biol Macromol. 47:342–347
187. Park JH, Park KK, Kim MJ, Hwang JK, Park SK, Chung WY (2008) Cancer chemoprotective
effects of Curcuma xanthorrhiza. Phytother Res 22:695–698
188. Chung WY, Park JH, Kim MJ, Kim HO, Hwang JK, Lee SK, Park KK (2007) Xanthorrhizol
inhibits 12- O-tetradecanoylphorbol-13-acetate-induced acute inflammation and two-stage
mouse skin carcinogenesis by blocking the expression of ornithine decarboxylase , cycloox-
ygenase-­2 and inducible nitric oxide synthase through mitogen-activated protein kinases and
/ or the nuclear factor- kB. Carcinogenesis 28:1224–1231
189. Oon SF, Nallappan M, Tee TT, Shohaimi S, Kassim NK, Sa’ariwijaya MSF, Cheah YH
(2015) Xanthorrhizol: a review of its pharmacological activities and anticancer properties.
Cancer Cell Int 15:100. https://doi.org/10.1186/s12935-­015-­0255-­4
190. Xiang H, Zhang L, Xi L, Yang Y, Wang X, Lei D, Zheng X, Liu X (2018) Phytochemical
profiles and bioactivities of essential oils extracted from seven Curcuma herbs. Ind Crops
Prod 111:298–305
191. Soumya T, Jayasree PR, Deepak M, Manish Kumar PR (2019) Chemical composition, anti-
oxidant and antiproliferative activities of essential oil from rhizome and leaves of Curcuma
mutabilis Škorničk., M. Sabu & Prasanthk., endemic to Western Ghats of India. Nat Prod Res
34(16):2336–2340. https://doi.org/10.1080/14786419.2018.1533826
192. Itokawa H, Shi Q, Akiyama T, Morris-natschke SL, Lee K (2008) Recent advances in the
investigation of curcuminoids. Chin Med 3:11. https://doi.org/10.1186/1749-­8546-­3-­11
193. Hatcher H, Planalp R, Chob J, Tortia FM, Torti SV (2008) Curcumin: from ancient medicine
to current clinical trials. Cell Mol Life Sci 65:1631–1652
Zingiberaceae Plants: A Cornucopia of Promising Chemotherapeuticals for Cancer Cure 461

194. Wilken R, Veena MS, Wang MB, Srivatsan ES (2011) Curcumin: a review of anti-cancer
properties and therapeutic activity in head and neck squamous cell carcinoma. Mol Can
10:12. http://www.molecular-­cancer.com/content/10/1/12.
195. Gupta SC, Patchva S, Koh W, Aggarwal BB (2012) Discovery of Curcumin, a component
of golden spice, and its miraculous biological activities. Clini Exp Pharmacol Physiol
39:283–299
196. Amalraj A, Pius A, Sreerag G, Sreeraj G (2017) Biological activities of curcuminoids,
other biomolecules from turmeric and their derivatives - A review. J Trad Chinese Med Sci
7:205–233
197. Collett GP, Robson CN, Mathers JC, Campbell FC (2001) Curcumin modifies Apcmin apop-
tosis resistance and inhibits 2-amino 1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP)
induced tumour formation in Apcmin mice. Carcinogenesis 22:821–825
198. Hsu T-C, Young MR, Cmarik J, Colburn NH (2000) Activator protein 1 (AP-1) and Nuclear
Factor κB (NF-κB) – dependent transcriptional events in carcinogenesis. Free Radical Biol
Med 28(9):1338–1348
199. Kunnumakkara AB, Diagaradjane P, Anand P, Kuzhuvelil HB, Deorukhkar A, Gelovani J,
Guha S, Krishnan S, Aggarwal BB (2009) Curcumin sensitizes human colorectal cancer to
Capecitabine by modulation of cyclin D1, COX-2, MMP-9, VEGF and CXCR4 expression
in an orthotopic mouse model. Int J Cancer 125:2187–2197
200. Bush JA, Cheung KJ, Li G (2001) Curcumin induces apoptosis in human melanoma cells
through a Fas receptor/Caspase-8 pathway independent of p53. Exper Cell Res 271:305–314
201. Aoki H, Takada Y, Kondo S, Sawaya R, Aggarwal BB (2007) Evidence that curcumin sup-
presses the growth of malignant gliomas in-vitro and in-vivo through induction of autophagy:
role of Akt and extracellular signal-regulated kinase signaling pathways. Mol Pharmacol
72:29–39
202. Gururaj AE, Belakavadi M, Venkatesh DA, Marm D, Salimath BP (2002) Molecular mecha-
nisms of anti-angiogenic effect of Curcumin. Biochem Biophysi Res Commun 297:934–942
203. Yodkeeree S, Ampasavate C, Sung B, Aggarwal BB, Limtrakul P (2010) Demethoxycurcumin
suppresses migration and invasion of MDA-MB-231 human breast cancer cell line. Eur J
Pharmacol 627:8–15
204. Beevers CS, Chen L, Liu L, Luo Y, Webster NJG (2009) Curcumin disrupts the mammalian
target of rapamycin- raptor complex. Cancer Res 69(3):1000–1009
205. Sordillo PP, Helson L (2015) Curcumin and cancer stem cells: Curcumin has asymmetrical
effects on cancer and normal stem cells. Anticancer Res 35:599–614
206. Teiten M-H, Dicato M, Diederich M (2013) Curcumin as a regulator of epigenetic events.
Mol Nutr Food Res 57:1–11. https://doi.org/10.1002/mnfr.201300201
207. Allegra A, Innao V, Russo S, Gerace D, Alonci A, Musolino C (2016) Anticancer activity of
Curcumin and its analogues: Preclinical and clinical studies. Cancer Invest. https://doi.org/1
0.1080/07357907.2016.1247166
208. Narayanan NK, Nargi D, Randolph C, Narayanan BA (2009) Liposome encapsulation of
Curcumin and Resveratrol in combination reduces prostate cancer incidence in PTEN knock-
out mice. Int J Cancer 125:1–8
209. Liu Y, Wu Y, Yu Y, Cao C, Zhang J, Li K, Zhang P (2014) Curcumin and Resveratrol in
combination modulate drug-metabolizing enzymes as well as antioxidant indices during lung
carcinogenesis in mice. Human Exp Toxicol. https://doi.org/10.1177/0960327114551396
210. Zeng X, Cai D, Zeng Q, Chen Z, Zhong G, Zhuo J, Gan H, Huang X, Zhao Z, Yao N,
Huang D, Zhang C, Sun D, Chen Y (2017) Selective reduction in the expression of UGTs and
SULTs, a novel mechanism by which Piperine enhances the bioavailability of Curcumin in
rat. Biopharm Drug Dispos 38(1):3–19
211. Siddique RA, Harvey KA, Walker C, Altenburg J, Xu Z, Terry C, Camarillo I, Jones-hall Y,
Mariash C (2013) Characterization of synergistic anti-cancer effects of docosahexaenoic acid
and curcumin on DMBA-induced mammary tumorigenesis in mice. BMC Cancer 13:418.
http://www.biomedcentral.com/1471-­2407/13/418
462 T. Soumya et al.

212. Bordoloi D, Kunnumakkara AB (2018) Chapter 2 - The potential of Curcumin: a multitarget-

ing agent in cancer cell chemosensitization. In: Role of nutraceuticals in cancer chemosensi-
tization. Vol 2, pp. 31-60. Academic Press, Elsevier Inc.
213. Yallapu MM, Jaggi M, Chauhan SC (2012) Curcumin nanoformulations: a future nanomedi-
cine for cancer. Drug Discov Today 17:71–80
214. Panda AK, Chakraborty D, Sarkar I, Khan T, Gaurisankar SA (2017) New insights into thera-
peutic activity and anticancer properties of Curcumin. J Exp Pharm 9:31–45
215. Habib SHM, Makpol S, Aini N, Hamid A, Das S, Ngah WZW, Yusof YAM (2008) Ginger
extract (Zingiber officinale) has anti-cancer and anti-inflammatory effects on ethionine-­
induced hepatoma rats. Clinics 63(6):807–813
216. Cheng XL, Liu Q, Peng YB, Qi LW, Li P (2011) Steamed ginger (Zingiber officinale):
changed chemical profile and increased anticancer potential. Food Chem 129:1785–1792
217. Ghasemzadeh A, Jaafar HZE, Rahmat A (2015) Optimization protocol for the extraction
of 6-gingerol and 6-shogaol from Zingiber officinale var. rubrum Theilade and improving
antioxidant and anticancer activity using response surface methodology. BMC Complement
Altern Med 15:258. https://doi.org/10.1186/s12906-­015-­0718-­0
218. Elguindy NM, Yacout GA, El-Azab EF, Maghraby HK (2016) Effect of Elettaria carda-
momum against chemically induced hepatocellular carcinoma in rats by inhibiting NF-κB,
oxidative stress, and activity of ornithine decarboxylase. South African J Bot 105:251–258
219. Bailly C (2020) Anticancer activities and mechanism of action of the labdane diterpene coro-
narin D. Pathol Res Pract 216:152946. https://doi.org/10.1016/j.prp.2020.152946
Moringa oleifera Accessions: Perspectives
and Application as Nutraceuticals
and Phytomedicines

Nikita Patel and Ramar Krishnamurthy

1 Introduction

Moringa oleifera Lam., commonly known as drumstick tree or horse radish tree, is
an important tropical medicinal plant known for its multifarious nutritional and
phytomedicinal property. It is frequently used by ethnic and local people of devel-
oped and emerging nations for their medicinal value and culinary use [1]. According
to the report of World Health Organization (WHO), nearly 70–80% of the global
population relies on herbal plants for their basic health care needs. The genus
Moringa comprises 13 species, out of which Moringa oleifera, Moringa stenopetala,
and Moringa peregrina are mostly studied because of their availability and multi-
functional properties [2]. Moringa is distributed in India, Africa, America, and
Madagascar. They are drought-resistant, fast grower (propagated through seeds/cut-
tings), and can withstand wide range of soil with minimum nutrient requirement [3].
Being a tropical deciduous tree, Moringa oleifera possesses bipinnate/tripinnate
leaves on grayish white stem with drooping branches. It also bears pendulous
25–35 cm long pods with isodiametric/ovate seeds (Fig. 1) [4].
Leaves and seeds are known to have wide range of amino acids, minerals, pro-
tein, carbohydrates, and vitamins. In addition to that, they are also known to have
important plant secondary metabolites such as polyphenols, flavonoids, moringin,
alkaloids, and tannins [5, 6]. Traditionally, Moringa was used by warriors to gain
energy and also by queens and king to maintain healthy skin and bones [7].
Medicinal, aromatic, or horticultural plants in general have nutraceutical value as
these plants are preferred as tonic or in maintaining vitality and sometimes aphro-
diasic. They are medicinally used and exploited for commercial purpose by plant-­
based industries. For instance, Gymnema sylvestre is having gymnemic acid

N. Patel · R. Krishnamurthy (*)

C.G. Bhakta Institute of Biotechnology, Uka Tarsadia University, Surat, Gujarat, India
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 463

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_17
464 N. Patel and R. Krishnamurthy

Fig. 1 Moringa oleifera field

recommended for antidiabetic potential [8, 9].There has been an unprecedented

growth in use of plants with nutraceutical and phytomedicinal value because of the
non-toxic effect of plants with great medicinal value. Currently, studies are going on
to boost the nutraceutical value of less nutritious food and Moringa, being an impor-
tant food and medicinal plant, plays a vital role in increasing the health promoting
effects of food via food fortification. Hence, the present book chapter deals with
phytomedicinal, functional, nutraceutical, and cosmo-nutraceutical property of
Moringa oleifera with a view to enhance the use of Moringa in developed and
emerging nations in combating malnutrition and protein deficiency to harmonize
cultural and modern medicine system with minimal side effects.

2 Ethnobotany and Phytochemistry of Moringa oleifera

The application of phytocompounds as medicine/ drug is well known since time

immemorial when the willow tree leaves were prescribed by Hippocrates to treat
fever. Since then, different parts of plants are used in classical and modern medicine
system. Phytochemicals are the plant secondary metabolites which are present in
abundance with no relation to plant health and development [3, 10]. There are cer-
tain classes of phytochemicals (Fig. 2) classified into alkaloids, polyphenols, triter-
penoids, sulphur-based compounds, and terpenoids [11, 12]. Almost all the classes
of phytochemicals are present in Moringa which confers disease resistance poten-
tial. Alkaloids are the main group of phytochemical present in form of phenylaceto-
nitrile pyrrolemarumine, 4′-hydroxyphenylethanamide-α-l-rhamnopyranoside – its
glucopyranosyl derivative and N,α-l-rhamnopyranosyl vincosamide.These alka-
loids are organic nitrogen-containing compounds generated from amino acids.
Moringa oleifera Accessions: Perspectives and Application as Nutraceuticals… 465

Fig. 2 Classes of phytochemicals in Moringa oleifera

Efforts were made to isolate and identify the potentiality of alkaloids from Moringa
leaves which indicated that they possess cardioprotective activity along with the
antihypertensive property [13].
Polyphenols are the second group of phytocompound found in both fresh and dry
leaves of Moringa conferring them antimicrobial and antioxidant properties.
Chemically, polyphenols are either in form of phenolic acid with one phenol ring or
in form of flavonoids with more than one phenol ring and they are often quantified
as tannic acid equivalent and gallic acid equivalent, respectively [12, 14, 15]. Several
researchers have identified presence of quercetin, myrecytin, and kaempferol along
with 11 more compounds through GC-MS profiling of leaves except roots, seeds,
and flowers [16, 17]. Chemical and agronomical variations were observed in acces-
sions collected and identified from India, Pakistan, and Africa which shows that
there is higher possibility of genetic variation among them regulating their meta-
bolic pathway [16, 18, 19]. Geographical and environmental variations were also
observed in some accessions of Moringa with predominant difference in tannins,
flavonoids, and polyphenols including major quantities of ellagic acid, coumaric
acid, and caffeic acid [20–22].
Another group of phytochemical known as carotenoids are coloured molecules
found in Moringa oleifera leaves as provitamin A or β-carotene which implicate
vitamin A deficiency. Carotenoids are generally characterized by their colour either
in form of yellow, red, or orange and are mostly present in vegetables and fruits
imparting their coloured complexity. Several compounds such as lutein, luteoxan-
thin, and zeaxanthin were isolated and purified from Moringa exploring their health
benefits [23]. Apart from polyphenols, flavonoids, and pigmented compounds,
Moringa leaves, pods, and seeds are known to have isothicyanate and glucosinolate
compounds. Basically, these compounds are synthesized from amino acid moieties.
A group of researchers have identified glucosinolate from wild and cultivated source
466 N. Patel and R. Krishnamurthy

of Moringa as glcomoringin and glucosoonjnain, suggesting that they may differ in

taste but not in their myrosinase activity or protein content [24, 25]. Recently,
denovo computational biology studies have suggested the probability of using com-
pounds from Moringa against SARS CoV- 2 M-Pro [26]. A total of 35 compounds
were identified from Moringa leaves, peduncle, roots, and flowers which include
tetradecanoic acid, n- hexadecenoic acid, gamma sitosterol, anthonin, siphorochin,
vanillin and β-sitosterol, isoquercitrin, rhamnetin, and kaempferitrin [27–29].
Whole gum exudates of Moringa revealed the presence of sugars such as rhamnose,
l-arabinose, d-glucuronic acid, d-mannose, d-xylose, d-galactose, and
leucodelphinidin-­3-O-B-D-galactopuranosy (1 -> 4)-O-B-D-glucopyranoside [30].
Furthermore, tannins are also present in Moringa. They are hydrophilic compounds
which aid in precipitation of gelatin, alkaloids, and other proteinaceous compounds
and hence they are not desirable for human or animal consumption. However, it can
be removed by proper processing techniques [31]. Isoprenoidal aglycone also
known as saponins is also found in Moringa in appreciable amounts, which exhibits
anticancer effects [32].
Each and every tribal or local culture has different perspectives on utilization of
medicinal plant and hence, it is imperative to study their geographical and ethnobo-
tanical variation to expand the knowledge regarding drug designing, value addition,
and genotypic variation. This information helps in expanding the economic impor-
tance of medicinal plant exponentially. Information and knowledge about geograph-
ical diversity of plant is a pivotal part of diversity study to ascertain the superior and
high yielding accession for commercialization [33]. Ethnomedicinally, different
parts of Moringa such as seeds, stem, leaves, fruits, flowers, bark, and gum exudates
are used in treatment of malaria, fever, stomach pain, wound healing, diabetes,
sores, piles, tooth ache, anaemia, dropsy, and hysteria [34, 35].

3 Phytomedicinal Property of Moringa oleifera

Over the past years, utilization of plants with medicinal properties has increased
rapidly. Current research is focused on medicinal and nutritional property of plants
covering phytochemistry, horticulture, pharmacology, and nutraceuticals. However,
the potent phytomedicinal action often results from consortia of plant secondary
metabolites/bioactives [36]. Studies have revealed the incidence of various diseases
associated with different age groups. It was observed that the key factor responsible
for this situation is generally the weakened immune system, autoimmune diseases,
or immunosenescence [37]. Phytomedicines are termed as use of plant or plant parts
in treatment and improvement of human health. It was first coined by Henry Leclerc
in 1913. Phytomedicines are advantageous in terms of minimum side effects caused
by synthetic drugs. Moringa being a food plant has many phytomedicinal properties
(Fig. 3).
Moringa oleifera Accessions: Perspectives and Application as Nutraceuticals… 467

Fig. 3 Phytomedicinal property of Moringa oleifera

Moringa oleifera as Potent Antioxidant Agent

3.1 

Moringa leaf, seeds, flowers, and roots are known to have remarkable DPPH radical
scavenging activity. This activity is conferred to any plant/ plat tissue because of
high amount of polyphenols in it. They help to scavenge reactive oxygen species
(ROS) by reducing oxidative stress. Study on antioxidant capacity of saline and
alcoholic extracts revealed that the extracts of flowers, leaf rachis, and leaves were
able to react and scavenge free radicals; however, ethanolic seed extract and saline
extracts were able to react slowly [38]. A compound myrecitin isolated from seeds
showed higher antioxidant activity when compared to BHT and α- tocopherol [39].
Free radicals are generally categorized into hydroperoxyl, hydroxyl, superoxide,
halogen, hydrogen, and nitrogen dioxide along with reactive oxygen species (ROS).
A study on methanolic extract of M. oleifera leaves depicted higher antioxidant
activity through in vitro FRAP, DPPH, and metal chelating assay [40]. Hence, the
bioactives from plants help them to stabilize/neutralize free radicals enabling them
to be used as phytomedicine.
468 N. Patel and R. Krishnamurthy

Moringa oleifera as Antihypertensive Agent

3.2 

Hypertension or high blood pressure is a global health concern affecting around

1.13 million people worldwide. Blood pressure can be lowered by inhibiting ACE
enzymes [41]. Moringa leaf is known to reduce blood pressure. It was reported
that two flavonoid glycosides from ethyl acetate fraction of Moringa leaves were
able to inhibit ACE enzyme attributing it to antihypertensive property [42]. Apart
from this, thiocarbamate glycosides, glycosides, and nitrites isolated from the
leaves alleviate vascular dysfunction and promote vasorelaxation [13]. A com-
parative study of seed and leaf diet conducted by [43] revealed that this supple-
mented diet could improve the systolic and diastolic blood pressure by increasing
nitric oxide and minimizing lipid peroxidation (LPO) in hypertensive state.
Secondary bioactives such as α-L- rhamnopyranosyl vincosamide, acetonitrile,
glucopyranosyl derivatives, 40- hydroxyphenylethanamide-α-L-
rhamnopyranoside, and its derivatives along with β- sitosterol (a cholesterol low-
ering compound) were identified and isolated from Moringa and showed potent
antihypertensive activity [44–46].

3.3 Antispasmodic and Hepatoprotective Behaviour

of Moringa oleifera

Herbal antispasmodic agents help relieve gastrointestinal muscle spasm by their

therapeutic action [47]. Moringa seeds, roots, and leaves exhibited antispasmodic
activity against acetylcholine-induced contractions. As leaf is the most studied
part of Moringa oleifera, the ethanolic fraction of leaves exhibited antispasmodic
effect by blocking the calcium channel. Hence, this information provides the base
for traditional use of Moringa [13, 48, 49]. Liver plays an important role in detox-
ifying certain drugs and xenobiotic compounds. Study on carbon tetrachloride-
induced hepatotoxicity revealed that leaves’ extract of Moringa helps in
improvement of hepatic fatty disintegration and balancing their architecture [50].
Several researchers have observed an increase in liver functioning enzymes, but
they did not report any histopathological kidney or liver damage which stated that
Moringa ameliorates the hepatic damage induced by certain chemicals. Recent
studies on Thiamethoxam-­induced hepatotoxicity also suggested that Moringa
can inhibit the deleterious effect TMX to normal levels [51]. On the other hand,
several chemical compounds, rifampicin, isoniazid, gentamicin pyrazinamide,
and acetaminophen, that cause hepatotoxicity also revealed the beneficial role of
Moringa in treating them [52–55].
Moringa oleifera Accessions: Perspectives and Application as Nutraceuticals… 469

Moringa oleifera as Antidepressant

3.4 
and Neuroprotective Agent

Depression is a widely known mental disorder across the globe and almost half of
the population is suffering from anxiety and mood swings. The constant state of
depression is due to oxidative stress and neurological imbalance [56]. An approach
was made to identify the efficacy of Moringa as antidepressant agent through in
vivo animal model study. It was depicted that ethanolic fraction of Moringa leaves
along with fluoxetine has potential antidepressant activity [57]. Ethanolic leaf
extract of this plant was able to minimize the chronic stress in zebrafish model [58].
Antidepressant study through tail suspension and forced swim test also indicated
the potential of n-hexane and ethanolic fraction of Moringa in relieving stress and
depression [59, 60].
Neurological disorders are also associated with nervous system mostly affecting
brain cells and spinal cord along with ganglia and nerves. Dementia (Memory loss)
mostly seen in aged people is a form of neurodegenerative disorder. Alzheimer’s
disease, Parkinson disease, Schizophrenia, and Huntington disease are associated
with reactive oxygen species and oxidative stress [61, 62]. Many efforts were made
to treat these diseases, but none of them were effective to halt their progression [63].
As the cost production of synthetic drugs is higher, natural phytocompounds were
searched and synthesized. Moringa leaf extracts (MLE) were proved to have noot-
ropic and antioxidant properties and hence several studies stated that solvent frac-
tions of Moringa can be beneficial in terms of colchicine-induced Alzheimer’s
disease in animal model study [64, 65]. Current in vitro studies using SHSY5Y
neuroblastoma cells also noted the neuroprotective effect of Moringa leaf extract
(MLE) [62].

Moringa oleifera as Antimicrobial Agents

3.5 

Many studies have been undertaken to determine the role of Moringa as antimicro-
bial agent. The bioactives from Moringa leaf, stem, roots, seeds, and bark exert
potent antimicrobial property against various pathogens [66, 67]. They show inhibi-
tory activity by altering their cell permeability, growth, and multiplication rate.
Various aqueous, hexane, methanolic, and ethanolic extracts have shown potent bio-
activity against Enteropathogens, Salmonella sp., Vibrio sp., Pseudomonas sp.,
Erwinia sp., and Bacillus sp. [3, 67, 68]. Moringa roots were also found to have
antibacterial activity against peptic ulcer caused by Helicobacter pylori. It was
noted in another study that presence of pterygospermin and isothiocyanate mole-
cules in the roots attributed this phytomedicinal property to Moringa [69, 70].
Different solvent preparations of Moringa showed potent inhibitory activity against
various fungal strains such as Aspergillus sp., Fusarium sp., Alternaria sp. and
Candida sp. [71, 72]. In vitro studies of n-hexane, ethyl acetate, aqueous,
470 N. Patel and R. Krishnamurthy

methanolic, and alcoholic fraction of Moringa leaves predominantly decreased the

fungal strains affecting the productivity of Papaya [73].

Moringa oleifera as Anticancer Agents

3.6 

Various physical and environmental stress lead to accumulation of reactive oxygen

species leading to cell death. Several approaches are made to mitigate the cell death
caused by oxidative stress. However, radiotherapy, surgery, and chemotherapy are
expensive and toxic to humans [74]. Recent advances in phytomedicine have led to
the development of plant-based drugs with minimal side effects. The cold water
extract of leaf demonstrated potent antiproliferative effects against A549 lung can-
cer cell line in an in vitro assay [75]. Mostly, glucosinolates and niazimicin isolated
from leaves are known to have chemopreventive property. Fruits and leaves were
apparently reported to have anticancer property against B16 F10 melanoma tumor
with a sizeable rise in survival rate and lifespan of cancer patients [76].
The in-depth study on apoptotic and cytotoxic property carried out by Sreelatha
et al. [77] showed the inhibition of cell proliferation of KB cell line in a dose-­
dependent manner. Other than that, several in vitro studies on acute lymphoblastic
leukaemia, acute myeloid leukaemia, and hepatocarcinoma cell line through MTT
assay also proved the efficiency of Moringa as anticancer agent [78]. Recently,
nanotechnology has evolved into great dimension by their enhanced functionality.
Green synthesized gold nanoparticles were also found to be effective against MCF-7
breast cancer cell line [79]. Colorectal cancer (CRC) or colorectal carcinoma is
considered as the most prevalent type of gastrointestinal cancer affecting both men
and women equally. A study on Moringa-based silver nanoparticles found that they
were able to prevent quantitative and qualitative alteration in colon carcinoma
induced by chemicals exploring them to be employed as phytomedicine [80].

Moringa oleifera as Antidiabetic Agent

3.7 

Diabetes is a common metabolic disorder usually marked by chronic hyperglycae-

mia often resulting into aberrant insulin action or production with major conse-
quence. Later it develops into macro/micro vascular complications leading to cell
death. Several synthetic medications and insulin treatment are mostly detrimental to
health. Hence, there is always a need to search non-toxic natural plant-based prod-
uct to treat diabetes type I and type II with lesser side effects [81, 82]. Many studies
were reported on hypoglycaemic property of leaf, roots, and pods of Moringa [83].
The presence of polyphenols, alkaloids, flavonoids, and carotenoids is known to
attribute antidiabetic property to Moringa. The Moringa leaves were proven to ame-
liorate diabetes in Streptozotocin-induced diabetic albino rats STZ [84]. Another
Moringa oleifera Accessions: Perspectives and Application as Nutraceuticals… 471

study conducted on antidiabetic property of Moringa seed and aqueous leaf extract
also showed reduced level of Interleukin 6 in STZ-induced rats [85].
According to International Federation of Diabetes (IDF), about 360 million peo-
ple are affected by Diabetes mellitus (type 2) globally and it is expected to rise by
552 million by 2040 [86]. In silico study was conducted to identify the targeted
therapeutic drug that can bind the protein moiety. It was identified that anthraqui-
nones, anthocyanins, hemlock tannins, and phenolics from Moringa oleifera could
easily bind the targeted protein molecule which assisted in treatment of diabetes
mellitus [87]. Alloxan-induced diabetic rats were treated with hydroalcoholic
extract (95%) of Moringa leaves by reducing the serum glucose levels at the level of
250 mg/kg [88]. Generally, the mechanistic action of Moringa works by inhibiting
the activity of glucose transporter proteins- GLU 1 and GLU 4, thereby increasing
insulin production and treating damaged pancreatic β-cells [89].

Moringa oleifera as Anti-asthmatic Agent

3.8 

Asthma is a chronic syndrome caused due to increased responsiveness of bronchi

and trachea manifested by chronic and recurrent attacks due to narrowing of airway
passage. It is mostly expressed by inflammation of pulmonary airway and hyper-­
responsiveness of bronchi. Mostly, lymphocytes, cytokines, histamines, and eosino-
phils are involved in constriction of bronchi leading to asthma [90, 91]. Asthma
accounts for more than 90% of population worldwide [92]. Several studies on
guinea pigs demonstrated low levels of lung tissues and plasma of the animal [93,
94]. Studies on seed kernel and butanol extracts were carried out against ovalbumin
and acetylcholine-induced bronchial constriction which showed potent anti-­
asthmatic effect [90, 95]. It has been observed from several studies that phytocom-
pounds such as rutin, apigenin, quercetin, and kaempferol are helpful in prevention
of asthma and airway inflammatory response [96, 97]. Methanolic (MeOH) leaf
extract of Moringa was also found effective against bronchospasm, oedema, and
mucus secretion confirming its potent anti-asthmatic activity [98].

Moringa oleifera as Antiviral Agents

3.9 

Therapeutic potential of Moringa has been traced long time back in yielding potent
antiviral activity owing to the profound activity against HIV, EBV, HBV, HSV,
NDV, and FMDV [99–103]. The flowers, seeds, gum, root bark, and leaves were
reported to be used as immunobooster and antiviral drugs. However, evidence-based
reports were revealed to be scanty on the use of Moringa against small pox virus/
Chicken pox as world health organization has declared countries to be free from
small pox virus since May-1980 (World Health Organization, 1980) [123]. Recently,
baseline study carried out against Influenza virus depicted that Moringa A isolated
472 N. Patel and R. Krishnamurthy

from seed material was able to decrease the expression of transcription factor EB
and weaken the autophagy in virus-infected cells [104].

Moringa oleifera as Wound-Healing Agent

3.10 

Skin is one of the important protective barriers and first defence system towards the
noxious pathogenic micro-organisms. As result of wound or injury, this barrier gets
disrupted which results into impairment into the connectivity of epithelial tissues. It
represents significant burden on patients affecting their mental state [105]. Generally,
the tissue regeneration/wound healing process involves hemostasis, inflammation,
proliferation, and remodelling of tissues [106]. Study on bioguided solvent fractions
of leaf was carried to ascertain the cell viability, proliferation, and wound scratch
test which depicted enhanced wound healing property. This property was known to
be attributed by vicenin-2compound isolated from methanolic fraction [107].
Recently, the intervention of nanotechnology has paved an effective way in phyto-
medicine through green synthesis. The polysaccharide extracted from Moringa seed
and its nanocomposite prepared from silver were found to be better candidate as
optimal wound dressing material [108].

4 Nutraceutical/Cosmo-Nutraceutical Value
of Moringa oleifera

The cruciferous plant Moringa oleifera (Drumstick tree) is a staple food in majority
of the countries across the globe. Due to its versatile nutritional and medicinal prop-
erty, Moringa is known as “Miracle Tree”. During ancient period, both leaves and
fruits were known to maintain skin and health of Queens and King [109]. Leaves of
this tree are worthy and precious in terms of providing nourishment to the malnour-
ished and pregnant woman. The drumstick leaves are highly packed with minerals,
vital amino acids, fatty acids, protein, and carbohydrates [110]. Most of the studies
on leaves have suggested its efficacy for combating malnutrition and also for preg-
nant women and infants [111, 112]. Moreover, Moringa oleifera is known to pro-
vide 7 × more of Vitamin C, 17 × more of Calcium, 10 × more of Vitamin A, and
25 × more of iron [113]. In emerging and underdeveloped countries where food
security is a major concern, Moringa is a great healthy diet for them. Apart from
this, immature pods are good source of fibres, minerals, and proximates [114].
As per the report suggested by Moyo and his coworkers, dietary polysaturated
fatty acid and unsaturated fatty acids were identified in dehydrated leaves of
Moringa where linolenic acid, α-linolenic acid, and linolenic acid were present in
considerate amount [115]. The culinary usage of this plant ranges from soup, salads,
to main dishes. The seed portion of this plant is well-known for highly valued ben
Moringa oleifera Accessions: Perspectives and Application as Nutraceuticals… 473

oil used as cosmeceutical, cooking, and perfume industry. The specific protein pep-
tides are also used for premature skin ageing and maintaining skin health [116]. The
inflorescence/ flowers of this miracle tree are also used in brewing infused tea and
chutney preparation due to high mineral content in them [117]. The oil separated
from Moringa seeds is also used in aromatherapy process [118]. Furthermore, the
sunscreen prepared from different herbs along with kernel oil of Moringa effec-
tively reduced UV radiation associated with conjugation system [119]. Additionally,
the facial mask prepared from leaves extracts was also demonstrated to be efficient
as cosmeceutical agent [120]. It was also observed by several researchers that the
protein and nutritional content of accessions vary from cultivar to source with sub-
stantial difference among mineral content (approx.270–271 mg/100 g Vit C;17–27%
leaf protein and 36–38% seed protein) [121, 122].

5 Conclusion

People’s accessibility to food has three dimensions including physical, social, and
pecuniary and the condition of life in the contemporary world is often alternating in
which poverty and malnutrition are the major factors. The increasing comorbidities,
malnutrition, and viral infection have become a major concern for all the age groups
and use of synthetic drug has increased the complications through their side effects.
The multipurpose phytomedicinal and nutraceutical plant Moringa could help in
maintaining food security by providing vital micronutrients, antioxidants, and pro-
tein at an economical cost. Therefore, it can be concluded that Moringa-based
phytomedicine can be a great paradigm for the future.

References

1. Anwar F, Latif S, Ashraf M, Gilani AH (2007) Moringa oleifera: a food plant with multiple
medicinal uses. Phytother Res 21(1):17–25
2. Abd Rani NZ, Husain K, Kumolosasi E (2018) Moringa genus: a review of phytochemistry
and pharmacology. Front Pharmacol 9:108. https://doi.org/10.3389/fphar.2018.00108
3. Patel N, Krishnamurthy R (2021) In-vitro Phytochemical Screening and Bioactivity of
Moringa oleifera Accessions. Biosci Biotechnol Res Commun 14(1):335–339
4. Padayachee B, Baijnath H (2012) An overview of the medicinal importance of Moringaceae.
J Med Plants Res 6(48):5831–5839
5. Rodríguez-Pérez C, Quirantes-Piné R, Fernández-Gutiérrez A, Segura-Carretero A (2015)
Optimization of extraction method to obtain a phenolic compounds-rich extract from
Moringa oleifera Lam leaves. Ind Crop Prod 66:246–254
6. Borgonovo G, De Petrocellis L, Schiano Moriello A, Bertoli S, Leone A, Battezzati A,
Mazzini S, Bassoli A (2020) Moringin, a stable Isothiocyanate from Moringa oleifera, acti-
vates the somatosensory and pain receptor TRPA1 channel in vitro. Molecules 25(4):976
7. Mahmood KT, Mugal T, Haq IU (2010) Moringa oleifera: a natural gift-A review. J Pharm
Sci Res 2(11):775–781
474 N. Patel and R. Krishnamurthy

8. Krishnamurthy R, Chandorkar MS, Pathak JM, Animasaun DA, Gupta R (2015) Selection
of elite lines from accessions of Gymnema sylvestre (Gudmar) based on characterization of
foliage and gymnemic acid yield. Int J Med Plants Photon 108:596–605
9. Krishnamurthy R, Animasaun DA, Patel RT, Ingalhalli RS (2016) Phytochemical constitu-
ents and hypoglycemic effect of gymnemic acid extracts from big and small leaf varieties of
Gymnema sylvestre R. Br. Indonesian J Pharm 27(2):59
10. Kim HS (2005) Do not put too much value on conventional medicines. J Ethnopharmacol
100(1–2):37–39
11. Bohn T, Blackwood M, Francis D, Tian Q, Schwartz SJ, Clinton SK (2013) Bioavailability of
phytochemical constituents from a novel soy fortified lycopene rich tomato juice developed
for targeted cancer prevention trials. Nutr Cancer 65(6):919–929
12. Ma ZF, Ahmad J, Zhang H, Khan I, Muhammad S (2020) Evaluation of phytochemical and
medicinal properties of Moringa (Moringa oleifera) as a potential functional food. S Afr J
Bot 129:40–46
13. Dangi SY, Jolly CI, Narayanan S (2002) Antihypertensive activity of the total alkaloids from
the leaves of Moringa oleifera. Pharm Biol 40(2):144–148
14. Tesfay SZ, Magwaza LS, Mbili N, Mditshwa A (2017) Carboxyl methylcellulose (CMC)
containing Moringa plant extracts as new postharvest organic edible coating for Avocado
(Persea americana Mill.) fruit. Sci Hortic 226:201–207
15. Kumar S, Pandey AK (2013) Chemistry and biological activities of flavonoids: an overview.
Sci World J 2013:1–16
16. Saini RK, Sivanesan I, Keum YS (2016) Phytochemicals of Moringa oleifera: a review of
their nutritional, therapeutic and industrial significance. 3 Biotech 6(2):1–14
17. Igwe KK, Nwankwo PO, Otuokere IE, Ijioma S, Amaku F (2015) GCMS analysis of phy-
tocomponents in the methanolic extract of Moringa oleifera leave. Int J Res Pharm Sci
2(11):1–6
18. Rajalakshmi R, Rajalakshmi S, Parida A (2017) Evaluation of the genetic diversity and
population structure in drumstick (Moringa oleifera L.) using SSR markers. Curr Sci
112:1250–1256
19. Popoola J, Igwe D, Jegede O, Iwu V, Adegbite A, Omonhinmin C (2019) Agronomic prac-
tices, genetic diversity and population structure of Moringa oleifera (Lam.) in Nigeria. J Adv
Res Dynam Control Syst 12:659–670
20. Vongsak B, Sithisarn P, Gritsanapan W (2013) Simultaneous determination of crypto-­
chlorogenic acid, isoquercetin, and astragalin contents in Moringa oleifera leaf extracts by
TLC-densitometric method. Evid-Based Complement Alternat Med 2013
21. Oboh G, Ademiluyi AO, Ademosun AO, Olasehinde TA, Oyeleye SI, Boligon AA, Athayde
ML (2015) Phenolic extract from Moringa oleifera leaves inhibits key enzymes linked to
erectile dysfunction and oxidative stress in rats’ penile tissues. Biochem Res Int 2015
22. Leone A, Spada A, Battezzati A, Schiraldi A, Aristil J, Bertoli S (2015) Cultivation, genetic,
ethnopharmacology, phytochemistry and pharmacology of Moringa oleifera leaves: an over-
view. Int J Mol Sci 16(6):12791–12835
23. Saini RK, Prashanth KH, Shetty NP, Giridhar P (2014) Elicitors, SA and MJ enhance carot-
enoids and tocopherol biosynthesis and expression of antioxidant related genes in Moringa
oleifera Lam. leaves. Acta Physiol Plant 36(10):2695–2704
24. Chodur GM, Olson ME, Wade KL, Stephenson KK, Nouman W, Fahey JW (2018) Wild
and domesticated Moringa oleifera differ in taste, glucosinolate composition, and antioxidant
potential, but not myrosinase activity or protein content. Sci Rep 8(1):1–10
25. Amaglo NK, Bennett RN, Curto RBL, Rosa EA, Turco VL, Giuffrida A et al (2010) Profiling
selected phytochemicals and nutrients in different tissues of the multipurpose tree Moringa
oleifera L., grown in Ghana. Food Chem 122(4):1047–1054
26. Nair A, James TJ (2020) Computational screening of phytocompounds from Moringa oleif-
era leaf as potential inhibitors of SARS-CoV-2 Mpro
Moringa oleifera Accessions: Perspectives and Application as Nutraceuticals… 475

27. Bhattacharya A, Naik MR, Agrawal D, Rath K, Kumar S, Mishra SS (2014) Antipyretic, anti-­
inflammatory and analgesic effects of leaf extract of drumstick tree. J Young Pharm 6(4):20
28. Saini RK, Manoj P, Shetty NP, Srinivasan K, Giridhar P (2014) Dietary iron supplements
and Moringa oleifera leaves influence the liver hepcidin messenger RNA expression and
biochemical indices of iron status in rats. Nutr Res 34(7):630–638
29. Mensah JK, Ikhajiagbe B, Edema NE, Emokhor J (2012) Phytochemical, nutritional and
antibacterial properties of dried leaf powder of Moringa oleifera (Lam.) from Edo Central
Province, Nigeria. J Nat Prod Plant Resour 2(1):107–112
30. Bhattacharya A, Tiwari P, Sahu PK, Kumar S (2018) A review of the phytochemical and phar-
macological characteristics of Moringa oleifera. J Pharm Bioallied Sci 10(4):181
31. Du Toit ES, Sithole J, Vorster J (2020) Leaf harvesting severity affects total phenolic and tan-
nin content of fresh and dry leaves of Moringa oleifera Lam. trees growing in Gauteng, South
Africa. S Afr J Bot 129:336–340
32. Tian X, Tang H, Lin H, Cheng G, Wang S, Zhang X (2013) Saponins: the potential che-
motherapeutic agents in pursuing new anti-glioblastoma drugs. Mini Rev Med Chem
13(12):1709–1724
33. Popoola JO, Obembe OO (2013) Local knowledge, use pattern and geographical distribution
of Moringa oleifera Lam.(Moringaceae) in Nigeria. J Ethnopharmacol 150(2):682–691
34. Balakrishnan V, Prema P, Ravindran KC, Robinson JP (2009) Ethnobotanical studies among
villagers from Dharapuram taluk, Tamil Nadu, India. Glob J Pharmacol 3(1):08–14
35. Gandji K, Chadare FJ, Idohou R, Salako VK, Assogbadjo AE, Kakaï RG (2018) Status and
utilisation of Moringa oleifera Lam: a review. Afr Crop Sci J 26(1):137–156
36. Briskin DP (2000) Medicinal plants and phytomedicines. Linking plant biochemistry and
physiology to human health. Plant Physiol 124(2):507–514
37. Hong H, Wang Q, Li J, Liu H, Meng X, Zhang H (2019) Aging, cancer and immunity. J
Cancer 10(13):3021
38. Santos AF, Argolo AC, Paiva PM, Coelho LC (2012) Antioxidant activity of Moringa oleifera
tissue extracts. Phytother Res 26(9):1366–1370
39. Lalas S, Tsaknis J (2002) Extraction and identification of natural antioxidant from the seeds
of the Moringa oleifera tree variety of Malawi. J Am Oil Chem Soc 79(7):677–683
40. Mahmoud KB, Wasli H, Mansour RB, Jemai N, Selmi S, Jemmali A, Ksouri R (2022)
Antidiabetic, antioxidant and chemical functionalities of Ziziphus jujuba (Mill.) and Moringa
oleifera (Lam.) plants using multivariate data treatment. S Afr J Bot 144:219–228
41. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Daniel WJ, Barry
JM, Suzzane O, Jackson TW, Edward JR, National High Blood Pressure Education Program
Coordinating Committee (2003) Seventh report of the joint national committee on prevention,
detection, evaluation, and treatment of high blood pressure. Hypertension 42(6):1206–1252
42. Acuram LK, Chichioco Hernandez CL (2019) Anti-hypertensive effect of Moringa oleifera
Lam. Cogent Biol 5(1):1596526
43. Adefegha SA, Oboh G, Iyoha AE, Oyagbemi AA (2019) Comparative effects of horserad-
ish (Moringa oleifera) leaves and seeds on blood pressure and crucial enzymes relevant to
hypertension in rat. Pharma Nutr 9:100–152
44. Singh BN, Singh BR, Singh RL, Prakash D, Dhakarey R, Upadhyay G, Singh HB (2009)
Oxidative DNA damage protective activity, antioxidant and anti-quorum sensing potentials
of Moringa oleifera. Food Chem Toxicol 47(6):1109–1116
45. Hammam MA, Kalil GA, El-Sayed SM, Ahmed IA (2016) Effects of Moringa oleifera Lam
(Moringaceae) seeds in rats fed with high-fat diet. J Pharm Chem Biol Sci 4(1):76–87
46. Randriamboavonjy JI, Rio M, Pacaud P, Loirand G, Tesse A (2017) Moringa oleifera seeds
attenuate vascular oxidative and nitrosative stresses in spontaneously hypertensive rats.
Oxidative Med Cell Longev 2017
47. Rauf A, Akram M, Semwal P, Mujawah AA, Muhammad N, Riaz Z, Khan H (2021)
Antispasmodic potential of medicinal plants: a comprehensive review. Oxid Med Cell
Longev 2021
476 N. Patel and R. Krishnamurthy

48. Cáceres A, Saravia A, Rizzo S, Zabala L, De Leon E, Nave F (1992) Pharmacologie proper-
ties of Moringa oleifera. 2: screening for antispasmodic, anti inflammatory and diuretic activ-
ity. J Ethnopharmacol 36(3):233–237
49. Gilani AH, Aftab K, Suria A, Siddiqui S, Salem R, Siddiqui BS, Faizi S (1994) Pharmacological
studies on hypotensive and spasmolytic activities of pure compounds from Moringa oleifera.
Phytother Res 8(2):87–91
50. El-bakry K, Toson ES, Serag M, Aboser M (2016) Hepatoprotective effect of Moringa oleif-
era leaves extract against carbon tetrachloride-induced liver damage in rats. World J Pharm
Pharm Sci 5:76–89
51. Elhamalawy OH, Al-Anany FS, El Makawy AI (2022) Thiamethoxam-induced hematologi-
cal, biochemical, and genetic alterations and the ameliorated effect of Moringa oleifera in
male mice. Toxicology Reports
52. Fakurazi S, Hairuszah I, Nanthini U (2008) Moringa oleifera Lam prevents acetamino-
phen induced liver injury through restoration of glutathione level. Food Chem Toxicol
46(8):2611–2615
53. Ouédraogo M, Lamien-Sanou A, Ramdé N, Ouédraogo AS, Ouédraogo M, Zongo SP,
Guissou PI (2013) Protective effect of Moringa oleifera leaves against gentamicin-induced
nephrotoxicity in rabbits. Exp Toxicol Pathol 65(3):335–339
54. Aristianti A, Nurkhaeri N, Tandiarrang VY, Awaluddin A, Muslimin L (2021) Formulation
and pharmacological studies of leaves of Moringa (Moringa oleifera), a novel hepatoprotec-
tion in oral drug formulations. Open Access Macedonian J Med Sci 9(A):151–156
55. Singh SK, Rajoria K, Kushal A, Dadhich S (2021) Moringa oleifera lam. a drug with
ayurvedic and biomedicine approaches. J Ayurveda 15(4):293
56. Pedersen ME, Szewczyk B, Stachowicz K, Wieronska J, Andersen J, Stafford GI et al
(2008) Effects of South African traditional medicine in animal models for depression. J
Ethnopharmacol 119(3):542–548
57. Kaur G, Invally M, Sanzagiri R, Buttar HS (2015) Evaluation of the antidepressant activity of
Moringa oleifera alone and in combination with fluoxetine. J Ayurveda Integr Med 6(4):273
58. Rosdy MS, Rofiee MS, Samsulrizal N, Salleh MZ, Kek TL (2021) Understanding the effects
of Moringa oleifera in chronic unpredictable stressed zebrafish using metabolomics analysis.
J Ethnopharmacol:114290
59. Yunusa S, Kura AU, Ladan AA, Magaji SY (2018) Preliminary phytochemical analysis and
antidepressant activity of n-hexane fraction of Moringa oleifera ethanol leaf extract in mice.
Acta Sci Pharm Sci 2:84–88
60. Yadav J, Satish KS, Lalit S (2016) Evaluation of antidepressant activity of leaves extract of
Moringa oliefera by using FST and TST model on Swiss Albino Mice. World J Pharm Res
5:967–976
61. Feng C, Luo T, Zhang S, Liu K, Zhang Y, Luo Y, Ge P (2016) Lycopene protects human
SH-SY5Y neuroblastoma cells against hydrogen peroxide-induced death via inhibi-
tion of oxidative stress and mitochondria-associated apoptotic pathways. Mol Med Rep
13(5):4205–4214
62. Hashim JF, Vichitphan S, Boonsiri P, Vichitphan K (2021) Neuroprotective assessment of
Moringa oleifera leaves extract against oxidative-stress-induced cytotoxicity in SHSY5Y
neuroblastoma cells. Plan Theory 10(5):889
63. Kou X, Chen N (2017) Resveratrol as a natural autophagy regulator for prevention and treat-
ment of Alzheimer’s disease. Nutrients 9(9):927
64. Ganguly R, Guha D (2008) Alteration of brain monoamines & EEG wave pattern in rat model
of Alzheimer’s disease & protection by Moringa oleifera. Indian J Med Res 128(6)
65. Ghimire S, Subedi L, Acharya N, Gaire BP (2021) Moringa oleifera: a tree of life as a prom-
ising medicinal plant for neurodegenerative diseases. J Agric Food Chem 69:14358–14371
66. Kou X, Li B, Olayanju JB, Drake JM, Chen N (2018) Nutraceutical or pharmacological
potential of Moringa oleifera Lam. Nutrients 10(3):343
Moringa oleifera Accessions: Perspectives and Application as Nutraceuticals… 477

67. Prabakaran M, Kim SH, Sasireka A, Chandrasekaran M, Chung IM (2018) Polyphenol com-
position and antimicrobial activity of various solvent extracts from different plant parts of
Moringa oleifera. Food Biosci 26:23–29
68. Rahman MM, Rahman MM, Akhter S, Jamal MA, Pandeya DR, Haque MA et al (2010)
Control of coliform bacteria detected from diarrhea associated patients by extracts of
Moringa oleifera. Nepal Med Coll J 12(1):12–19
69. Farooq F, Rai M, Tiwari A, Khan AA, Farooq S (2012) Medicinal properties of Moringa
oleifera: an overview of promising healer. J Med Plants Res 6(27):4368–4374
70. Mishra G, Singh P, Verma R, Kumar S, Srivastav S, Jha KK, Khosa RL (2011) Traditional
uses, phytochemistry and pharmacological properties of Moringa oleifera plant: an overview.
Pharm Lett 3(2):141–164
71. Aondo TO, Odiaka NI, Akesa TM, Olaleye OO (2018) Phytochemical and antifungal effi-
cacy of different parts of Moringa oleifera plant extracts. Asian J Biotechnol Bioresour
Technol:1–8
72. Patel N, Mohan JSS (2018) Antimicrobial activity and phytochemical analysis of Moringa
oleifera Lam. crude extracts against selected bacterial and fungal strains. Int J Pharmacogn
Phytochem Res 10(02):68–79
73. Oniha M, Eni A, Akinnola O, Omonigbehin EA, Ahuekwe EF, Olorunshola JF (2021) In vitro
antifungal activity of extracts of Moringa oleifera on phytopathogenic fungi affecting Carica
papaya. Open Access Macedonian J Med Sci 9(A):1081–1085
74. Kamuhabwa A, Nshimo C, de Witte P (2000) Cytotoxicity of some medicinal plant extracts
used in Tanzanian traditional medicine. J Ethnopharmacol 70(2):143–149
75. Jung IL (2014) Soluble extract from Moringa oleifera leaves with a new anticancer activity.
PLoS One 9(4):e95492
76. Purwal L, Pathak AK, Jain UK (2010) In vivo anticancer activity of the leaves and fruits of
Moringa oleifera on mouse melanoma. Pharmacol Online 1:655–665
77. Sreelatha S, Jeyachitra A, Padma PR (2011) Antiproliferation and induction of apoptosis by
Moringa oleifera leaf extract on human cancer cells. Food Chem Toxicol 49(6):1270–1275
78. Khalafalla MM, Abdellatef E, Dafalla HM, Nassrallah AA, Aboul-Enein KM, Lightfoot DA
et al (2010) Active principle from Moringa oleifera Lam leaves effective against two leuke-
mias and a hepatocarcinoma. Afr J Biotechnol 9(49):8467–8471
79. Kiran MS, Kumar CR, Shwetha UR, Onkarappa HS, Betageri VS, Latha MS (2021) Green
synthesis and characterization of gold nanoparticles from Moringa oleifera leaves and assess-
ment of antioxidant, antidiabetic and anticancer properties. Chem Data Collect 33:100714
80. Aboulthana WM, Shousha WG, Essawy EAR, Saleh MH, Salama AH (2021) Assessment of
the anti-cancer efficiency of silver Moringa oleifera leaves nano-extract against colon cancer
induced chemically in rats. Asian Pac J Cancer Prev 22(10):3267–3286
81. Schnell O, Standi E (2006) Impaired glucose tolerance, diabetes, and cardiovascular disease.
Endocr Pract 12:16–19
82. Edoga CO, Njoku OO, Amadi EN, Okeke JJ (2013) Blood sugar lowering effect of Moringa
oleifera Lam. in albino rats. Int J Sci Technol 3(1):88–90
83. Rana TS, Singh KK, Rao RR (2000) Studies on indigenous herbal remedies for diabetes
mellitus in India. In: Ethnobotany and medicinal plants of Indian subcontinent. Scientific
Publishers Jodhpur, p 115
84. Yassa HD, Tohamy AF (2014) Extract of Moringa oleifera leaves ameliorates streptozotocin-­
induced diabetes mellitus in adult rats. Acta Histochem 116(5):844–854
85. Al-Malki AL, El Rabey HA (2015, 2015) The antidiabetic effect of low doses of Moringa
oleifera Lam. seeds on streptozotocin induced diabetes and diabetic nephropathy in male rats.
BioMed Res Int
86. Ogurtsova K, da Rocha Fernandes JD, Huang Y, Linnenkamp U, Guariguata L, Cho NH,
Makaroff LE (2017) IDF Diabetes Atlas: global estimates for the prevalence of diabetes for
2015 and 2040. Diabetes Res Clin Pract 128:40–50
478 N. Patel and R. Krishnamurthy

87. Zainab B, Ayaz Z, Alwahibi MS, Khan S, Rizwana H, Soliman DW, Abbasi AM (2020)
In-silico elucidation of Moringa oleifera phytochemicals against diabetes mellitus. Saudi J
Biol Sci 27(9):2299–2307
88. Kar A, Choudhary BK, Bandyopadhyay NG (2003) Comparative evaluation of hypogly-
caemic activity of some Indian medicinal plants in alloxan diabetic rats. J Ethnopharmacol
84(1):105–108
89. Pradana DLC, Rahmi EP, Muti AF (2021) Hypoglycemic effect of Moringa oleifera aqueous
extract in diabetic animal studies: a mechanisms review. Diabetes 57:6
90. Agrawal B, Mehta A (2008) Antiasthmatic activity of Moringa oleifera Lam.: a clinical
study. Indian J Pharmacol 40(1):28
91. Shifren A, Witt C, Christie C, Castro M (2012) Mechanisms of remodeling in asthmatic
airways. J Allergy 2012
92. Mahajan SG, Banerjee A, Chauhan BF, Padh H, Nivsarkar M, Mehta AA (2009) Inhibitory
effect of n-butanol fraction of Moringa oleifera Lam. seeds on ovalbumin-induced airway
inflammation in a Guinea pig model of asthma. Int J Toxicol 28(6):519–527
93. Bartosch R, Feldberg W, Nagel E (1932) Release of a histamine-like substance in Guinea pig
anaphylaxis. Pfluger’s Arch Complete Physiol Man Anim 230(1):129–153
94. Irie M, Nagata S, Endo Y (2002) Effect of isolation on classical conditioned histamine release
in Guinea pigs. Neurosci Res 44(1):31–35
95. Li RR, Pang LL, Du Q, Shi Y, Dai WJ, Yin KS (2010) Apigenin inhibits allergen-induced
airway inflammation and switches immune response in a murine model of asthma.
Immunopharmacol Immunotoxicol 32(3):364–370
96. Wang J, Fang X, Ge L, Cao F, Zhao L, Wang Z, Xiao W (2018) Antitumor, antioxidant and
anti-inflammatory activities of kaempferol and its corresponding glycosides and the enzy-
matic preparation of kaempferol. PLoS One 13(5):e0197563
97. Suresh S, Chhipa AS, Gupta M, Lalotra S, Sisodia SS, Baksi R, Nivsarkar M (2020)
Phytochemical analysis and pharmacological evaluation of methanolic leaf extract of
Moringa oleifera lam. In ovalbumin induced allergic asthma. S Afr J Bot 130:484–493
98. Nworu CS, Okoye EL, Ezeifeka GO, Esimone CO (2013) Extracts of Moringa oleifera Lam.
showing inhibitory activity against early steps in the infectivity of HIV-1 lentiviral particles
in a viral vector-based screening. Afr J Biotechnol 12(30)
99. Murakami A, Kitazono Y, Jiwajinda S, Koshimizu K, Ohigashi H (1998) Niaziminin, a thio-
carbamate from the leaves of Moringa oleifera, holds a strict structural requirement for inhi-
bition of tumor-promoter-induced Epstein-Barr virus activation. Planta Med 64(04):319–323
100. Imran I, Altaf I, Ashraf M, Javeed A, Munir N, Bashir R (2016) In vitro evaluation of antiviral
activity of leaf extracts of Azadirachta indica, Moringa oleifera, and Morus alba against the
foot and mouth disease virus on BHK-21 cell line. Sci Asia 42(6):392–396
101. Eze DC, Okwor EC, Okoye JO, Onah DN (2013) Immunologic effects of Moringa oleifera
methanolic leaf extract in chickens infected with Newcastle disease virus (kudu 113) strain.
Afr J Pharm Pharmacol 7(31):2231–2237
102. Feustel S, Ayón-Pérez F, Sandoval-Rodriguez A, Rodríguez-Echevarría R, Contreras-Salinas
H, Armendáriz-Borunda J, Sánchez-Orozco LV (2017, 2017) Protective effects of Moringa
oleifera on HBV genotypes C and H transiently transfected Huh7 cells. J Immunol Res
103. Xiong Y, Rajoka MSR, Mehwish HM, Zhang M, Liang N, Li C, He Z (2021) Virucidal activ-
ity of Moringa A from Moringa oleifera seeds against Influenza A Viruses by regulating
TFEB. Int Immunopharmacol 95:107561
104. Nagori BP, Solanki R (2011) Role of medicinal plants in wound healing. Res J Med Plant
5(4):392–405
105. Guo SA, DiPietro LA (2010) Factors affecting wound healing. J Dent Res 89(3):219–229
106. Muhammad AA, Pauzi NAS, Arulselvan P, Abas F, Fakurazi S (2013) In vitro wound healing
potential and identification of bioactive compounds from Moringa oleifera Lam. BioMed
Res Int 2013
Moringa oleifera Accessions: Perspectives and Application as Nutraceuticals… 479

107. Mehwish HM, Liu G, Rajoka MSR, Cai H, Zhong J, Song X, He Z (2021) Therapeutic
potential of Moringa oleifera seed polysaccharide embedded silver nanoparticles in wound
healing. Int J Biol Macromol 184:144–158
108. Sujatha BK, Patel P (2017) Moringa oleifera–Nature’s Gold. Imp J Interdiscip Res
3(5):1175–1179
109. Rathnayake ARMHA, Navaratne SB, Uthpala TG (2019) Moringa olifera plant and the nutri-
tional and medicinal properties of Moringa olifera leaves. In: Trends & prospects in process-
ing of horticultural crops, pp. 251–268
110. Okiki PA, Osibote IA, Balogun O, Oyinloye BE, Idris OO, Adelegan O, Olagbemide PT
(2015) Evaluation of proximate, minerals, vitamins and phytochemical composition of
Moringa oleifera Lam. cultivated in Ado Ekiti, Nigeria. Adv Biol Res 9(6):436–443
111. Mishra SP, Singh P, Singh S (2012) Processing of Moringa oleifera leaves for human con-
sumption. Bull Environ Pharmacol Life Sci 2(1):28–31
112. Rockwood JL, Anderson BG, Casamatta DA (2013) Potential uses of Moringa oleifera and
an examination of antibiotic efficacy conferred by M. oleifera seed and leaf extracts using
crude extraction techniques available to underserved indigenous populations. Int J Phytother
Res 3(2):61–71
113. Mahato DK, Kargwal R, Kamle M, Sharma B, Pandhi S, Mishra S et al (2022)
Ethnopharmacological properties and nutraceutical potential of Moringa oleifera. Phytomed
Plus 2(1):100168
114. Moyo B, Masika PJ, Hugo A, Muchenje V (2011) Nutritional characterization of Moringa
(Moringa oleifera Lam.) leaves. Afr J Biotechnol 10(60):12925–12933
115. Sandeep G, Anitha T, Vijayalatha KR, Sadasakthi A (2019) Moringa for nutritional security
(Moringa oleifera Lam.). Int J Bot Stud 4:21–24
116. Brilhante RSN, Sales JA, Pereira VS, Castelo DDSCM, de Aguiar Cordeiro R, de Souza
Sampaio CM et al (2017) Research advances on the multiple uses of Moringa oleifera: a sus-
tainable alternative for socially neglected population. Asian Pac J Trop Med 10(7):621–630
117. Armand-Stussi I, Basocak V, Pauly G, McCaulley J (2003) Moringa oleifera: an interesting
source of active ingredients for skin and hair care. SÖFW-J 129(9):45–52
118. Kale S, Gaikwad M, Bhandare S (2011) Determination and comparison of in vitro SPF of
topical formulation containing Lutein ester from Tagetes erecta L Flowers, Moringa oleifera
Lam seed oil and Moringa oleifera Lam seed oil containing lutein ester. Int J Res Pharm
Biomed Sci 2(3):1220–1224
119. Hendrawati H, Azizah YN, Hapsari NK (2021) Facial mask formulation enriched with
Moringa leaves (Moringa oleifera) extract and their activity as antioxidants and Antibacterials.
J Kimia Valensi 6(2):198–207
120. Jongrungruangchok S, Bunrathep S, Songsak T (2010) Nutrients and minerals con-
tent of eleven different samples of Moringa oleifera cultivated in Thailand. J Health Res
24(3):123–127
121. Saini RK, Shetty NP, Prakash M, Giridhar P (2014) Effect of dehydration methods on reten-
tion of carotenoids, tocopherols, ascorbic acid and antioxidant activity in Moringa oleifera
leaves and preparation of a RTE product. J Food Sci Technol 51(9):2176–2182
122. Goswami D, Mukherjee PK, Kar A, Ojha D, Roy S, Chattopadhyay D (2016) Screening
of ethnomedicinal plants of diverse culture for antiviral potentials. Indian J Tradit Knowl
15:474–481
123. World Health Organization (1980) The global eradication of smallpox: final report of the
Global Commission for the Certification of Smallpox Eradication, Geneva, December 1979.
World Health Organization
An Overview of Ethnobotany,
Phytochemicals, and Pharmacological
Properties of Ficus Species

Sreeja Puthanpura Sasidharan, Xuefei Yang,

and Karuppusamy Arunachalam

1 Introduction

Nature has been a source of medicinal agents for thousands of years and an impres-
sive number of modern drugs have been derived from natural sources; many of these
isolations were based on the uses of the agents in traditional medicine [1]. The
World Health Organization (WHO) defines traditional medicine as the “diverse
health practices, approaches, knowledge and beliefs incorporating plant, animal-
and/or mineral-based medicines, spiritual therapies, manual techniques and exer-
cises applied singularly or in combination to maintain well-being, as well as to treat,
diagnose, or prevent illness”. It is clear, however, that there is a need to validate the
information through an organized infrastructure for it to be used as an effective
therapeutic means, either in conjunction with existing therapies, or as a tool in novel
drug discovery. It is therefore imperative to study medicinal plants and to determine
and evaluate their potential biological activities and efficacy. The use of natural

S. P. Sasidharan
Department of Botany, NSS College Nemmara, Palakkad, Kerala, India
X. Yang
Key Laboratory of Economic Plants and Biotechnology and the Yunnan Key Laboratory for
Wild Plant Resources, Kunming Institute of Botany, Chinese Academy of Sciences,
Kunming, China
Center for Studies in Stem Cells, Cell Therapy and Toxicological Genetics (CeTroGen),
Faculty of Medicine, Federal University of Mato Grosso do Sul,
Campo Grande, Mato Grosso do Sul, Brazil
K. Arunachalam (*)
Center for Studies in Stem Cells, Cell Therapy and Toxicological Genetics (CeTroGen),
Faculty of Medicine, Federal University of Mato Grosso do Sul,
Campo Grande, Mato Grosso do Sul, Brazil

© The Author(s), under exclusive license to Springer Nature 481

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_18
482 S. P. Sasidharan et al.

products with therapeutic properties is as ancient as human civilization. For a very

long time, mineral, plant, and animal products were the main sources of drugs [2].
The development of organic chemistry resulted in a preference of synthetic prod-
ucts for pharmacological treatment. The reasons for this were that structural modi-
fication of synthetic compounds to produce potentially more active and safer drugs
could be performed. Furthermore, the treatment of diseases with natural products
differed from place to place as various cultures had different points of view regard-
ing the treatment of various diseases [3].
Thus, the twentieth century became a triumph for the synthetic-chemistry-­
dominated pharmaceutical industry, which replaced natural extracts with synthetic
molecules that often had no connection to natural products. The spectacular rise of
the pharmaceutical industry had a tremendous impact on disease treatment and pre-
vention, saved countless lives, and became one of the outstanding achievements of
the twentieth century. Inclusion of traditional medicines in the development of
twenty-­first century treatment paradigms can help assure their convenience, accept-
ability, and accessibility. Furthermore, pharmacological synergism, a principle
employed by many traditional medicines, lessens the likelihood of 2 development of
genetic resistance by the pathogen or disease against drug monotherapies. Synergy
research inspired by a “reverse pharmacological approach” could lead to a “new
generation of phytopharmaceuticals”. Inclusion of traditional medicines in the
development of the use of powerful ‘omics’ technologies facilitates disentangling
such complexity: metabolomics analyses enable profiling of major and minor
metabolites and bioactive components that contribute to synergism; and computa-
tional approaches for analysis of multiple-activity networks have become powerful
tools for defining the principal components of mixtures with synergistic modes of
action, for prediction of drug metabolism and toxicity, and for high-throughput pri-
oritizing of agent combinations [4]. Thus, conventional medicine by and large
brought serious infectious diseases under control, although there were worrying
signs that infectious organisms were becoming resistant to antibiotic treatment [5].
However, some synthetic drugs had serious side effects. There has been a renewed
interest for plants as source of pharmaceuticals [6].
Some herbal preparations are now so commonly used that they are accepted as
part of everyday life. An example is evening primrose oil, which is used by hun-
dreds of thousands of women in Britain to help relieve premenstrual tension [5].
About 25% of the drugs prescribed worldwide come from plants, with 121 such
active compounds being in current use [3]. Of the 252 drugs considered as basic and
essential by the World Health Organization (WHO), 11% are exclusively of plant
origin and a significant number are semisynthetic drugs obtained from natural pre-
cursors [6]. Examples are the cardiotonic glycosides of Digitalis species such as
digoxin, the analgesics morphine and codeine obtained from the Opium poppy
Papaver somniferum, the antispasmodic tropane alkaloids hyoscine and atropine
from Atropa belladonna, quinine and quinidine from Cinchona species, and vincri-
strine and vinblastine from Catharanthus roseus [3]. It is estimated that 60% of
antitumor and antiinfectious drugs in use or under clinical trials are of natural origin
[7]. The vast majority of these cannot be synthesized and are still obtained from
An Overview of Ethnobotany, Phytochemicals, and Pharmacological Properties… 483

wild or cultivated plants. Natural compounds can thus be lead compounds, allowing
the design, development, and the discovery of new therapeutic agents [8].
A search in the natural product alert database suggested that only about 15% of
all plant species had been studied to some extent for their phytochemistry and only
about 5% for one or more biological activities [9]. Although extensive research on
medicinal plants is published every year, only a few plants have been comprehen-
sively studied for their pharmacological properties. Thus, traditional medicines and
medicinal plants obviously represent a great source of novel medicines and leads for
drug development.
Living organisms require ample amount of oxygen for their metabolism and
energy production. However, free radicals are produced during the energy produc-
tion process [10], as the unavoidable consequence of respiration in aerobic organ-
isms. Free radicals have very important role in origin of life and biological evolution,
leaving beneficial effects on the organisms [11]. Free radicals are atomic or molecu-
lar species with unpaired electrons in the outermost bonding orbital and are likely
to take part in chemical reactions. Electrons prefer to be in pairs and when an elec-
tron is alone in its orbital, it will try to take an electron from another atom to become
more stable. When the other atom loses its electron, it tries on its turn to steal an
electron from another atom, often resulting in a dangerous chain reaction. Free radi-
cal can cause damage to our cells, but they also play an important role in a number
of biological processes, such as the intracellular killing of bacteria by the white
blood cells and some cell signaling processes. Overproduction of free radicals can
cause oxidative damage to biomolecules (lipids, proteins, and DNA), eventually
leading to many chronic diseases such as atherosclerosis, cancer, diabetics, rheuma-
toid arthritis, postischemic perfusion injury, myocardial infarction, cardiovascular
diseases, chronic inflammation, stroke and septic shock, aging, and other degenera-
tive diseases in humans [12, 13].
Pain and inflammation are associated with virtually all diseases. Typical inflam-
matory diseases such as rheumatoid arthritis, asthma, colitis, and hepatitis are the
leading cause of disability and death [14]. Recently, chronic inflammation has been
found to contribute to the development of cancer, cardiovascular, and neurodegen-
erative diseases [15]. Analgesic and anti-inflammatory 4 drugs relieve mild to mod-
erate pain and reduce inflammation. All these analgesic and anti-inflammatory
agents produce their therapeutic effects by inhibiting various prostaglandins sub-
stances involved in development of pain and inflammation as well as regulation of
body temperature. Due to extensive use of analgesic and anti-inflammatory agents,
the toxicity and untoward effects do occur many times especially when therapy of
pain and inflammation involves use of higher dose for longer period [16].
The conventional drugs used for the management of pain and inflammation
include the steroidal and nonsteroidal anti-inflammatory agents as well as the opi-
ates. It is estimated that about 30 million people worldwide take nonsteroidal anti-­
inflammatory drugs [17, 18]. However, their prolonged use has been associated with
serious side effects such as gastric ulceration, hemorrhage, bronchospasm, and kid-
ney dysfunction [19]. Also, because of adverse effects of such dyslipidaemia,
Cushing’s syndrome, hypertension and immunosuppression by steroidal
484 S. P. Sasidharan et al.

anti-inflammatory drugs and tolerance and dependence induced by opiates, the use
of these drugs as anti-inflammatory and analgesic agents has not been successful in
some cases [20]. Therefore, there has been an intense search for new anti-­
inflammatory and analgesic drugs lacking these side effects as alternatives to these
drugs. In this direction, attention has been focused on the investigation of the effi-
cacy of plant-based drugs used in traditional medicine. This is because investigation
of the efficacy of certain plant-based drugs used in traditional medicine led to the
discovery of potent anti-inflammatory agents in clinical use such as aspirin and
colchicine [21].
Other natural products, with marked anti-inflammatory effects, which have pro-
vided effective adjuncts to the management of inflammatory conditions include:
omega 3-fatty acids from fish oil, curcumin from the spice turmeric (Curcuma
longa), frankincense from Boswellia serrata, capsaicin from Capsicum annum, and
ginger root extract from Zingiber officinalis [22]. These agents have been used suc-
cessfully as adjuncts in several chronic inflammatory diseases [23]. Thus, plants
still present a large source of compounds that might serve as leads for the develop-
ment of novel anti-inflammatory drugs. Unlike their synthetic counterparts, they
have not been shown to accelerate cartilage destruction or produce 5 liver and kid-
ney toxicities [24]. For these reasons, natural products can be considered as viable
alternatives to conventional anti-inflammatory drugs in a large percentage of patients
suffering from various inflammatory diseases.
The excessive production of reactive oxygen metabolites by phagocytic leuco-
cytes during the inflammatory process, as part of host defence, deregulates cellular
function causing tissue injury which in turn augments the state of inflammation
leading to chronic inflammatory diseases [25]. These oxidants also inhibit wound
healing. Antioxidants, which scavenge these reactive oxygen metabolites, have
been found to complement the anti-inflammatory process, promoting tissue repair
and wound healing. A number of plant secondary metabolites such as apigenin,
quercetin, luteolin, and silymarin have been found to exhibit anti-inflammatory
activities due to their antioxidant properties [26, 27]. Thus, antioxidative phyto-
chemicals, especially phenolic compounds, found in vegetables, fruits, and medici-
nal plants could be explored for their potential role in the prevention of inflammatory
diseases.

2 Historical Importance of Herbal Drugs

Plants have also been a source of various anti-infective agents. The bacteriostatic
and fungicidal properties of lichens and the antimicrobial action of allicin in garlic
(Allium sativum) are a few examples of age-old antibacterial therapy [28]. An
expansive range of plants belonging to an equally wide variety of plant families has
yielded products with antibacterial properties. Such families include the Asteraceae,
Euphorbiaceae, Apocynaceae, Fabaceae, Leguminoceae, and Rutaceae [29].
Although no major antimicrobial drug has been developed from higher plants,
An Overview of Ethnobotany, Phytochemicals, and Pharmacological Properties… 485

innumerable studies have generated data showing antimicrobial properties of

medicinal plants [30]. This body of results indicates that medicinal plants, even if
not fully developed into new mainstream antimicrobial drugs, could indeed be an
effective alternative if properly processed and incorporated into primary health care
systems. In the past, our ancestors made new discoveries of the healing power of
plants through trial and error. Although some of the therapeutic properties attributed
to plants have proven to be erroneous, medicinal plant therapy is based on the
empirical findings of hundreds and thousands of years [31].
Wound infection is one of the most common diseases in developing countries
because of poor hygienic conditions [32]. Wounds are the physical injuries that
result in an opening or breaking of the skin and appropriate method for healing of
wounds is essential for the restoration of disrupted anatomical continuity and dis-
turbed functional status of the skin [33]. In other words, wound is a break in the
epithelial integrity of the skin and may be accompanied by disruption of the struc-
ture and function of underlying normal tissue and may also result from a contusion,
haematoma, laceration, or an abrasion [34]. Healing of wounds starts from the
moment of injury and can continue for varying periods of time depending on the
extent of wound and the process can be broadly categorized into three stages;
inflammatory phase, proliferative phase, and finally the remodeling phase which
ultimately determines the strength and appearance of the healed tissue [35].
Wound healing process holds several steps which involve coagulation, inflamma-
tion, formation of granulation tissue, matrix formation, remodeling of connective
tissue, collagenization, and aquisation of wound strength [36]. Research on wound
healing agents is one of the developing areas in modern biomedical sciences and
many traditional practitioners across the world particularly in countries like India
and China have valuable information of many lesser-known hitherto unknown wild
plants for treating wounds and burns [37]. Traditional forms of medicine practiced
for centuries in Africa and Asia are being scientifically investigated for their poten-
tial in the treatment of wound-related disorders [38].
Free radicals may play an important role in the causation and complications of
Diabetes Mellitus [39]. In Diabetes mellitus, alterations in the endogenous free radi-
cal scavenging defense mechanisms may lead to ineffective scavenging of reactive
oxygen species, resulting in oxidative damage and tissue injury. Oxidative stress is
currently suggested as mechanism underlying diabetes and diabetic complications
[40]. Enhanced oxidative stress and changes in antioxidant capacity, observed in
both clinical and experimental diabetes mellitus, are thought to be the etiology of
chronic diabetic complications [41]. In recent 7 years, much attention has been
focused on the role of oxidative stress, and it has been reported that oxidative stress
may constitute the key and common event in the pathogenesis of secondary diabetic
complications [42].
Diabetes mellitus is a metabolic disorder characterized by hyperglycemia and
disturbances of carbohydrate, protein, and fat metabolisms, secondary to an abso-
lute or relative lack of insulin [43]. The WHO estimates that more than 220 million
people worldwide have diabetes, and this number is liable to double by 2030 [44].
Hyperglycemia is known to produce reactive oxygen species (ROS) which plays a
486 S. P. Sasidharan et al.

central role in complications of diabetes [45, 46]. Antioxidants play a major role in
protection against molecular oxidative damage [47]. In integration to oxidative
stress, insulin action is also impaired in diabetes, which leads to increased hepatic
glucose production. Due to the side effects of the existing synthetic drugs, plant-­
derived food drugs are in great demand in industrially developed countries as alter-
native approach to treat diabetes. The WHO expert committee has recommended
that plants possessing hypoglycaemic activity may provide a utilizable source of
new oral antidiabetic drug for the development of pharmaceutical entities or may act
as simple dietary adjuncts to the existing therapies [48].
Until today, there is no treatment that can completely cure diabetes mellitus. In a
study by Maria et al. [49], it was found that insulin-dependent diabetes mellitus
(IDDM) or type I, otherwise, depends on insulin therapy to prevent the pathology
that would arise from insulin deficiency due to a dysfunction of the β-cells. However,
exogenous therapy which is the main treatment does not permit glycemic control as
precise as that provided by natural secretion from functional islet β-cells, and acute
decompositions and long-term complications are always present [50]. It is therefore
appropriate to look at possible alternative therapeutic strategies for IDDM. Type II
diabetes, otherwise known as adult-onset diabetes, results from a combination of
insulin resistance and inadequate secretion of insulin [51]. Management of type II
diabetes is rarely straightforward. It requires rigorous control of blood glucose and
special attention to a syndrome of associated vascular risk factors including hyper-
tension, dyslipidemia, and abdominal obesity. The pharmacological agents cur-
rently used for the 8 treatment of type II diabetes include sulfonylureas, biguanide,
thiazolidinedione, and α-glucosidase inhibitor. These agents, however, have
restricted use due to several undesirable side effects including haematological
effects, coma, and disturbances of the liver and kidney. In addition, they are not suit-
able for use during pregnancy [52]. Furthermore, the synthetic hypoglycemic agents
also fail to significantly alter the course of diabetic complications [53].
Therefore, the search for more effective and safer antidiabetic agents has contin-
ued to be an area of active research [54]. Moreover, studying the antidiabetic prop-
erty of herbal remedies will increase the chance of finding new antidiabetic drugs
and possibly finding a cheaper treatment for diabetes mellitus. Historical accounts
of diabetes mellitus first appeared in medical texts of several ancient cultures over
2000 years ago, and since ancient times, diabetes has been treated orally with sev-
eral medicinal plants. Ethnobotanical information indicates that more than 800
plants belonging to 28 families are used as traditional remedies for the treatment of
diabetes [55].
However, only a few of these plants have undergone comprehensive scientific
investigation, while 81% of these plants are hitherto unreported as antidiabetic
agents. Traditional medicines may be of considerable benefit especially during the
early stages of the illness, but most of the researchers worry about the side effect of
these products. Normally, herbs have ingredients with therapeutic activity, but their
preparation must be standardized to yield consistent products, which therefore can
be given in doses that are maximally safe and effective. In the absence of such stan-
dardization, the use of herbs in diabetes mellitus must be approached cautiously. So,
An Overview of Ethnobotany, Phytochemicals, and Pharmacological Properties… 487

WHO has recommended that the research focus should now be directed to this area.
Sawarkar et al. [56] reported that numerous plants synthesize substances that are
useful in the maintenance of health in humans and animals. With a view to increas-
ing the wide range of medicinal uses, now the present day entails new drugs with
more potent and desired activity with lesser or no side effects against particular
disease [57].
The genus Ficus (Moraceae) constitutes one of the largest genera of angiosperms
includes with more than 800 species and 2000 varieties of Ficus genus, occur in the
most tropical and subtropical forests and this plant is commonly known as fig [58].
Sirisha et al. [59] reported that all Ficus species possess latex-like material within
their vasculatures that provide protection and self-healing from physical assaults.
Various studies indicated that Ficus species are widely used in the management of
various types of diseases like respiratory diseases, sexual disorders, central nervous
system diseases (CNS), cardiovascular disorders (CVS), gastric problems, skin
infections and diabetics, etc. [59].
Fig fruits hold the highest levels of polyphenols, flavonoids, and anthocyanins
and exhibited the highest antioxidant capacity, which can be free of side effects than
those of synthetic antioxidants [60]. Shukla et al. [61] revealed the significant anti-
oxidant effect of F. bengalensis. In addition, Duduku et al. [62] reported that
F. microcarpa bark contains highest free radical scavenging activity. Further, epide-
miological studies have shown that many of these antioxidant compounds possess
anti-inflammatory, analgesic, antimutagenic, anticarcinogenic, antibacterial, and
antiviral activities to a greater extent [63].
A large number of plants/plant extracts/decoctions or pastes are equally used by
tribal and folklore traditions in India for treatment of cuts, wounds, and burns [37].
Besides, in Ayurvedic medicine, F. racemosa L. is used as a wound-healing agent
[64], whereas the aqueous extract of F. deltoidea was reported to have wound-­
healing activity [65].
Medicinal plants play an important role in cure of diabetes mellitus all over the
world. A variety of ingredients present in medicinal plants are thought to act on a
variety of targets by various modes and mechanisms. They have potential to impart
therapeutic effect in complicated disorders like diabetes and its complications [66].
According to Ayurvedic system of medicine, F. bengalensis, F. carica, F. glomerata
[67, 68], F. exasperate Vahl, and F. arnottiana Miq [69–71]. are well known in the
treatment of diabetes. F. carica [60], F. bengalensis extract of bark [72], and F. glom-
erata were reported to have hypoglycemic effect.

3 The Family Moraceae

Moraceae, often called the mulberry family, is a family of flowering plants com-
prising of about 40 genera and over 1000 species of which over 800 species are
members of the genus Ficus (http://science.jrank.org/pages/4494/Mulberry-­
FamilyMoraceae.html). They occur primarily in tropical and semitropical regions
488 S. P. Sasidharan et al.

and include a wide variety of herbs, shrubs, and trees, characterized by a milky sap
[73–75]. Moraceae have been divided into five tribes: Artocarpeae, Moreae,
Dorstenieae, Ficeae, and Castilleae [76]. Ficeae has only one genus, Ficus, with
approximately about 750 species largely distributed in 58 the tropics and subtrop-
ics [77]. They can be either monoecious with bisexual inflorescences or dioecious
[78]. Taxonomically, Ficeae is divided into two main groups [79]; one group, com-
prising the subgenera Urostigma and Pharmacosycea, consists of approximately
370 species, all of which are monoecious.

4 Genus Ficus

The genus Ficus L. (Moraceae) was first published in “Systema Naturae by Carolus
Linnaeus in 1735”. Ficus is one of the largest genus among angiosperms. Among
the genera of seed plants it ranked as the twenty-first [80]. The use of foods and
medicinal plants to improve health is nearly as old as humanity. Among such, none
may be older than the fig, which recent investigations have indicated has been culti-
vated for over 11,000 years, possibly predating cereal grains [81]. However, this
finding has recently been challenged [82]. A number of Ficus species are used as
food and for medicinal properties in Ayurvedic and Traditional Chinese Medicine
(TCM), especially among people where these species grow. These uses, however,
originated and are most widely found in the Middle East. It is reasonable to consider
that a survey of ethnomedical uses of a plant may provide useful clues for drug
discovery.

4.1 Ethnobotanical Studies of Ficus Species

Ayurvedic medicine utilizes at least three different Ficus species [83, 84]. Figs are
used as external treatments for eczema, leprosy, rheumatism, sores, ulcers, and
pains. Like TCM, Ayurvedic medicine recommends gargling with fig decoctions for
sore throats and the ingestion of figs as a treatment for 59 diarrhea. Other Ayurvedic
uses include treatment of dysentery, gonorrhoea, and menorrhagia and as an aphro-
disiac [83]. In TCM, the fig is only rarely used, partly because this fruit is found
only in the most Southern regions of China, but also because the fruits are regarded
more as a food rather than a medicine and served after being salted like pickles,
cooked in water, or sun-dried. Medicinally, figs are recommended both for improv-
ing the appetite and as treatment for diarrhea. For hemorrhoids, a decoction of the
leaves is applied locally, while simultaneously cooked figs are also ingested orally.
Ficus religiosa (Peepal), F. benghalensis (Bar), F. benjamina (Sami), F. race-
mosa (Dumri), etc., possess high religious value for both Hindus and Buddhists [85]
and are deemed sacred. Ficus religiosa is not uprooted; it grows on shrines and
buildings, because it represents the Hindu god lord Vishnu, the god of sustenance. It
An Overview of Ethnobotany, Phytochemicals, and Pharmacological Properties… 489

is widely worshipped as Bodhi tree under which lord Buddha attained enlighten-
ment [86].
Ficus benjamina is locally known as “Beringin, Waringin and Jejawi” [87]. It is
traditionally used as a stomachic, hypotensive, and anti-dysentry agent [88].
Previous studies on Ficus species revealed the presence of several compounds such
as alkaloids [89], triterpenes [90], ascorbic acid [91], and flavonoids [92].
Ficus exasperata is commonly known as sand paper tree and is spread in West
Africa in all kinds of vegetation and particularly in secondary forest regrowth. The
leaf extract from F. exasperata reported to have diverse uses such as treating hyper-
tensive patients [93], hemostative ophthalmia, coughs, and hemorrhoid [94]. In
Nigeria, young leaves of F. exasperata are prescribed as common anti-ulcer remedy.
Various pharmacological actions such as antidiabetic, lipid lowering, and antifungal
activities have been reported in F. exasperata [69].
F. bengalensis is the world’s largest tree in terms, its spread with some old trees
covering over an acre of ground. The tree’s name “banyan” refers to the merchants
who set up shop under the spreading trees. It is commonly found throughout India
and grows at deciduous and semi evergreen forests. F. bengalensis, known as Vata
in Sanskrit, is one of the reputed panchavalkala drugs of Ayurveda [95]. Different
parts of the tree have been found to possess medicinal properties; leaves are good
for ulcers, aerial roots are useful in gonorrhea, seeds and fruits are cooling and
tonic. The roots of F. bengalensis are given for obstinate vomiting and infusion of
its bark is considered as a tonic and astringent and is also used in diarrhea, dysen-
tery, and diabetes. Ayurvedic practitioners in India are using the milky juice (latex)
of F. bengalensis stem bark for the treatment of rheumatism and other inflammatory
diseases.
Ficus religiosa is commonly known as peepal in India. The plant is used to treat
gout, stomatitis, leucorrhea, ulcers, inflammation, and glandular swelling of the
neck [96]. F. religiosa has been reported for its wound healing [97], antibacterial
[98], and acetylcholinesterase inhibitory activities [99]. F. religiosa has been used
in the traditional system of Ayurveda to treat diabetes [100]. The leaves of F. reli-
giosa have been studied for antihyperglycemic activity [101].
F. glomerata Roxb. Syn. F. racemosa L. is commonly known as Gular in Hindi
and Cluster fig in English. It is medium sized to large evergreen or occasionally
deciduous tree and found all over India and Southeast Asia. Its fruits are mixed with
rice for making bread and used in several dishes. Traditionally, the bark, fruits, and
latex are used to treat anemia and gastrointestinal disorders like constipation and
dysentery [102].
F. racemosa L. (Indian fig) bark and fruits are well known to be useful in diabetes
[103] and found that Fistein and Resveratol were as effective as vitamin E in their
inhibitory action of lipid peroxidation. F. racemosa showed significant anticancer
[104] and antihelminthic activities [105]. The bark is antiseptic, antipyretic, and
vermicidal and a decoction of the bark is used in treating various skin diseases and
ulcers. It is used as a plaster in inflammatory swellings and boils. It is also effective
in the treatment of piles, dysentery, asthma, gonorrhea, hemoptysis, and urinary
diseases.
490 S. P. Sasidharan et al.

Ficus retusa has been used as aphrodisiac, antihypertensive, anticancer, antioxi-

dant, hepatoprotective, gastroprotective, antidiabetic, anti-helmintic, antimalarial,
anti-inflammatory, analgesic, and antimicrobial. Root barks and leaves are used in
wounds and bruises. Dried roots mixed with salt are applied to decaying or aching
tooth. Roots are used in the treatment of liver diseases [106].
Ficus septica fresh root sap is taken orally for treating whooping cough. Leaves
are chewed and saps swallowed to relieve cough. Fresh leaves are used for head-
aches and decoction of the dried leaf is taken to prevent fever. Leaf buds are eaten
for treating upset stomach and to prevent diarrhea. Leaves are crushed, mixed with
seawater, and the solution is drunk to treat stomachache. Crushed leaves are applied
on sores and to treat fungal infections. Moistened leaves with salt are used as a hot
compress to the forehead; other body pains are treated in similar manner. Fresh root
sap is used orally as poison antidote. Leaves mixed with coral lime and water are
rubbed on the body to treat aches and pains normally experienced with fever [107].

4.2 Phytochemistry of Ficus Species

Several authors have isolated and identified various classes of compounds from the
genus Ficus. They include flavonoids, alkaloids, phenolic acids, steroids, saponins,
tannins, terpenoids, and coumarins (Fig. 1).

4.2.1 Steroids

β-sitosterol was isolated from the leaves and roots of F. carica and F. septica,
respectively. Stigmasterol has been reported in the leaves and roots of F. hirta and
F. septica [108]. 24-methylenecycloartenol, ψ-taraxasterol ester, lupeol, and baure-
nol have been isolated from the leaves of F. carica [109], whereas sitosterol-3-O-β-
D-­glucoside has been reported from the leaves of F. septica [110].
β-sitosterol-α-D-glucoside has been isolated from the stem bark of F. benghalen-
sis [60].

4.2.2 Alkaloids

Few alkaloids, mostly phenanthroindolizidine alkaloids, have been isolated from

the leaves and stem bark of F. septica and F. hispida. The alkaloids, ficuseptine-A,
62 antofine, and tylophorine have been isolated from the leaves of F. septica,
whereas ficuseptine-B ficuseptine-C, and ficuseptine-D have been reported from the
stem bark. Tylocrebrine and isotylocrebrine have been isolated from both the leaves
and stem bark of F. septica [107, 111, 112]. Hispidin and 2-demethoxytylophorine
have been reported from the stem bark and leaves of F. hispida, respectively [113].
An Overview of Ethnobotany, Phytochemicals, and Pharmacological Properties… 491

Fig. 1 Various classes of compounds from the genus Ficus

492 S. P. Sasidharan et al.

Fig. 18.1 (continued)

4.2.3 Coumarins

Another class of constituents commonly found in this genus are coumarins particu-
larly, of the furanocoumarin type. They have been isolated from the stem, leaves,
and roots of some Ficus species and are reported to be responsible for the contact
dermatitis associated with Ficus species [114]. The coumarins psoralen, bergapten,
An Overview of Ethnobotany, Phytochemicals, and Pharmacological Properties… 493

Fig. 18.1 (continued)

marmesin, umbelliferone, and 41, 51-dihydropsoralen have been reported in the

leaves and stem bark of F. carica [115]. Psoralen has also been reported in the roots
of F. hirta [108]. Chang et al. [116] isolated 5-O-β-Dglucopyranosyl-6-­­
hydroxyangelicin, 6-O-β-D-glucopyranosyl-5-hydroxyangelicin, 5-O-β-D-
glucopyranosyl-­8-hydroxypsoralen, 8-O-β-D-glucopyranosyl-5- hydroxypsoralen,
and 5, 6-O-β-D-diglucopyranosylangelicin from the leaves of F. ruficaulis. Esculin
has also been isolated from the leaves of F. septica [110]. Bergapten and oxypeuce-
danin hydrate have been isolated from the aerial parts of F. pumilla. The stem bark
of F. religiosa has also been found to contain coumarins bergaptol and bergap-
ten [117].

4.2.4 Flavonoids

Genistin and kaempferitrin have been isolated from the leaves of F. septica [110].
Also, the leaves of F. ruficaulis and F. carica are reported to contain rutin and iso-
quercitrin [116]. Sheu et al. [118] reported the isolation of carpachromene, isogla-
branin, and norartocarpetin from the stem bark of F. formosana. Luteolin has also
been isolated from the aerial parts of F. pumilla [119]. The flavonoid apigenin has
been reported in the stem bark and roots of F. hirta and F. formosana. Also, the root
of F. hirta is reported to contain hesperidin, 5-hydroxy-41, 6, 7, 8- tetramethoxy
flavone, and 41, 5, 6, 7, 8-pentamethoxyflavone [108, 118]. Several other flavo-
noids, including alpinumisoflavone, cajanin, derrone, 5, 7-dihydroxy-4-methoxy-
31-(2,3-dihydroxy-3-methylbutyl) isoflavone, erycibenin A, erycibenin C, genistein,
31-(3-methylbut-2-enyl) biochanin A, and 5,7, 21- trihydroxy-41-­methoxyisoflavone,
have been isolated from the stem bark of F. nymphaeifolia [120].
494 S. P. Sasidharan et al.

4.2.5 Triterpenoids

Squalene has been isolated from the leaves of F. septica [110]. Li et al. [108], iso-
lated 3β-acetoxy-α-amyrin, 3β-acetoxy-β-amyrin, and 3β-hydroxystigmast-5-en-7-
one from the roots of F. hirta. A number of triterpenoids with C-28 carboxylic acid
functional group have been isolated from the aerial roots of F. microcarpa. They
include betulonic acid, oleanonic acid, 3-oxofriedalan-28-oic acid, ursolic acid, and
ursonic acid [106]. Lupenol, lupenol acetate, 20-taraxastene-3β, 22α-diol, 29,
30-dinor-3β-acetoxy-18, 19-secolupane, 3, 22-dioxo-20- taraxastene, and
3β-hydroxy-20-oxo-29(20 → 19) abeolupane have also been isolated from the aerial
roots of F. microcarpa. Others include 3-acetoxy-12, 19-dioxo- 13(18)- oleanene,
3-acetoxy-1,11-epidioxy-12-ursene, 3-acetoxy-12,13-epoxy-11- hydroperoxyur-
sane, 3-acetoxy-11,12-epoxy-16-oxo-14-taraxerene, 3-acetoxy-11, 12- epoxy-­14-­
taraxerene, 3-acetoxy-20, 21-epoxytaraxastane, 3-acetoxy-21,
22- epoxytaraxastan-20-ol, 3-acetoxy20, 21-epoxytaraxastan-22-ol, and
3-­acetoxy-18- hydroperoxy-12-oleanen-11-one [106].

4.2.6 Miscellaneous

Other compounds which have been isolated from this genus include bergenin and
racemosic acid from the stem bark of F. racemosa [108], cyanidin 3-O-glucoside
and cyanidin- 3-O-rhamnoglucoside from the fruits of F. carica [121], ficuformo-
diol A and ficuformodiol B from the stem bark of F. formosana [118].

4.3 Pharmaceutical Activities of Ficus Species

A number of Ficus species have shown diverse biological and pharmacological

activities. They have been investigated as potential repository of natural products
for the treatment of various diseases including tumors, diabetes, pain, inflammatory,
microbial diseases, and wound healing and as antioxidants (Fig. 2).

4.3.1 Analgesic Activity

Analgesic activity of the leaf extract of Ficus glomerata Roxb. and stem bark of
F. bengalensis Linn has been confirmed, respectively, by Sehgal [122] and Patil and
Patil [71]. The ethanol extracts of F. racemosa bark and leaves were evaluated for
analgesic activity by analgesiometer at 100, 300, and 500 mg/kg and were found to
possess dose-dependent analgesic activity [123].
An Overview of Ethnobotany, Phytochemicals, and Pharmacological Properties… 495

Anti-
inflammatory

Anti-microbial Anti-diabetic

Ficus Wound
Anti-cancer
species healing

Immunomodu
Anti-ulcer
latory

Analgesic

Fig. 2 Pharmacological activities of Ficus species

4.3.2 Anticancer Activity

Medicinal plant products exhibiting anticancer activity continue to be the subject of

extensive research aimed at the development of new or alternative drugs for the
treatment of different human tumors. Lalla [124] reported F. glomerata and F. rac-
emosa Linn. for the treatment of skin cancer. Both the natural and compounds syn-
thesized from F. carica showed in vitro inhibitory effects on proliferation of various
cancer cell lines [60]. Fruit extracts of F. benjamina Linn., F. bengalensis, F. reli-
giosa Linn., and F. sycomorus Linn., an African species, exhibited antitumor activ-
ity in the potato disc bioassay [125].

4.3.3 Antiulcer Activity

The healing activity of whole plant extract of F. deltoidea Jack. was studied in gas-
tric ulcer induced by ethanol in rats; the extract promoted ulcer protection as ascer-
tained by the comparative significant decreases in ulcer areas and inhibition of
496 S. P. Sasidharan et al.

submucosal edema and leucocytes infiltration of submucosal layer [126]. Sivaraman

and Muralidharan [127] reported F. hispida as a potent anti-ulcerogenic as well as
ulcer healing properties and could act as a potent therapeutic agent against peptic
ulcer disease. The antiulcer potential of the ethanol extract of stem bark of F. reli-
giosa against in vivo indomethacin, cold restrained stress-induced gastric ulcer and
pylorus ligation assays was validated.
The extract (100, 200, and 400 mg/kg) significantly reduced the ulcer index in all
assays used. The extract also significantly increased the pH of gastric acid, while at
the same time reduced the volume of gastric juice, free, and total acidities. The
study provides preliminary data on the antiulcer potential of Ficus religiosa stem
bark and supports the traditional uses of the plant for the treatment of gastric
ulcer [84].

4.3.4 Antioxidant Activity

Cell membranes are especially vulnerable to the aggression of free radicals. When
the nucleus is damaged, the cell loses its ability to replicate itself. The impaired cell
replication results in the weakened immune system, skin aging, and many age-­
related disorders. Various antioxidants deactivate the free radicals and prevent oxi-
dation on a cellular level. Some commonly used plants as antiaging agents include
F. bengalensis [72, 84].
The water extract (WE) and crude hot-water soluble polysaccharide (PS) from
F. carica fruit were investigated for scavenging abilities on DPPH, superoxide and
hydroxyl radicals, and reducing power. The immune activities of PS were evaluated
using the carbon clearance test and serum hemolysin analysis in mice. Both WE and
PS have scavenging activities on DPPH with the EC50 0.72 and 0.61 mg/ml, respec-
tively. The PS showed higher scavenging activity than WE on superoxide radical
(EC50, 0.95 mg/ml) and hydroxyl anion radical (scavenging rate 43.4% at 4 mg/ml).
The PS (500 mg/kg) also has a significant increase in the clearance rate of carbon
particles and serum hemolysin level of normal mice. This indicates the scavenging
activity and immune responses of the extract [60].
The antioxidant effect of species of Ficus may be attributed to the polyphenolic
compounds they possess. The antioxidant effect of aqueous extract of the bark of
F. bengalensis has been evaluated in hypercholesterolemia rabbits by Shukla et al.
[61] and confirmed its significant antioxidant effect. The potential health-promoting
constituents of fig fruits were studied with six commercial fig varieties differing in
color (black, red, yellow, and green) for total polyphenols, total flavonoids, antioxi-
dant capacity, and profile of anthocyanins. In the dark-colored mission and the red
Brown-Turkey varieties, the anthocyanin fraction contributed 36 and 28% of the
total antioxidant capacity, C3R (cyanidin- 3-O-rutinoside) contributed 92% of the
total antioxidant capacity of the anthocyanin fraction. Fruits of the mission variety
contained the highest levels of polyphenols, flavonoids, and anthocyanins and
exhibited the highest antioxidant capacity [60].
An Overview of Ethnobotany, Phytochemicals, and Pharmacological Properties… 497

The ethanolic extract of leaves of Ficus religiosa was evaluated for antioxidant
(DPPH), wound healing (incision, excision, histopathological, and dead space
wound model), and anti-inflammatory (Carrageenan-induced paw edema) activity.
The tested extract of different dilutions in range 200 μg/ml to 1000 μg/ml shows
antioxidant activity in range of 6.34% to 13.35%. Significant increases in wound
closure rate, skin breaking strength, and granuloma breaking strength were observed.
The extract shows prominent anti-inflammatory activity as compared to that of stan-
dard (Ibuprofen gel) [128].

4.3.5 Antidiabetic Activity

The aqueous extract of Ficus religiosa Linn. was assessed at doses of 100 and
200 mg/kg orally and it decreased the fasting blood glucose in streptozotocin-­
induced type 2 diabetic rats. The drug had enzyme induction effect with respect to
catalase (CAT) and glutathione peroxidase (GSHPx) activity, however, decreased
the exaggerated activity of superoxide dismutase (SOD) in type 2 diabetic rats.
F. religiosa modulated the enzymes of significant antioxidant defense system to
combat oxidative stress. Drug at higher dose (200 mg/kg) had more pronounced
effect. F. religiosa, a rasayana group of plant drug having antidiabetic activity along
with antioxidant potential, was beneficial in treatment of type-2 diabetes [129].
According to Ayurvedic system of medicine, F. bengalensis is well known in the
treatment of diabetes [67]. This attracted the attention of many earlier workers who
studied the hypoglycemic effect of extracts from its bark and tried to isolate active
compounds. Bark of this plant has antidiabetic properties. The hypoglycemic effect
of extract of bark was demonstrated in alloxan-induced diabetic rabbits, rats, and in
humans. Potent hypoglycemic water-insoluble principle was isolated from the bark
and a water-soluble hypoglycemic principle was also isolated from the bark which
was effective at a low dose of 10 mg/kg, bw/day [72]. Both the banyan bark prin-
ciples were effective in mild as well as severe alloxan-induced diabetes in rabbits
and improved lipid profile [130].
The aqueous leaf extract of F. carica induced a significant hypoglycaemic effect
in oral or intraperitoneal administration in streptozotocin - diabetic rats. Weight loss
was prevented in treated diabetic rats and the survival index was significantly altered
by plasma insulin levels [60]. Singh et al. [68] reported that F. bengalensis, F. car-
ica, and F. glomerata are effective in the treatment of diabetes. The hypoglycemic
activity of ethanol extracts of leaves of F. glomerata has significant antihyperglyce-
mic effect in experimental albino rat model of diabetes mellitus [71]. Hypolipidemic
effect of the water extract of the bark of F. bengalensis was investigated in alloxan-­
induced diabetes mellitus in rabbits; showing a good glycemic control also corrects
the abnormalities in serum lipid profile associated with diabetes mellitus in view of
the ability of the extract to improve carbohydrate and lipid metabolism [61].
The fruits of F. glomerata, locally known as Gular, have been used since ancient
times in the ethnomedicine including as a remedy of diabetes mellitus [102]. The
aqueous extract of F. bengalensis at a dose of 500 mg/kg/day exhibits significant
498 S. P. Sasidharan et al.

antidiabetic and ameliorative activity as evidenced by histological studies in normal

and F. bengalensis-treated streptozotocin-induced diabetic rats. F. exasperata Vahl
and F. arnottiana Miq. are also reported to have antidiabetic activity by Sonibare
et al. [69] and Mazumdar et al. [70], respectively.
The antidiabetic effect of aqueous extract of F. religiosa bark (FRAE) in normal
glucose-loaded hyperglycemic and streptozotocin (STZ)-induced diabetic rats, at
the dose of 25, 50 and 100 mg/kg, was investigated. The effect was more pronounced
in 50 and 100 mg/kg than 25 mg/kg. FRAE also showed significant increase in
serum insulin, body weight, and glycogen content in liver and skeletal muscle of
STZ- induced diabetic rats, while there was significant reduction in the levels of
serum triglyceride and total cholesterol. FRAE also showed significant antilipidper-
oxidative effect in the pancreas of STZ-induced diabetic rats [131].
The glucose-lowering efficacy of methanol extract of F. racemosa stem bark was
evaluated both in normal and in alloxan-induced diabetic rats at the doses of 200
and 400 mg/kg p.o. The activity was also comparable to that of the effect produced
by a standard antidiabetic agent, glibenclamide (10 mg/kg), proving its folklore
claim as antidiabetic agent [132–134]. The relationship of the post-absorptive state
to the hypoglycemic studies on F. racemosa showed that the absorption of the drug
leads to a better hypoglycemic activity [135].
The ethanol extract (250 mg/kg/day, p.o.) lowered blood glucose level within
2 weeks in the alloxan diabetic albino rats confirming its hypoglycemic activity.
β-sitosterol isolated from the stem bark was found to possess potent hypoglycemic
activity when compared to other isolated compounds [136]. F. racemosa methanol
extract of powdered fruits at the dose 1, 2, 3, and 4 g/kg reduced the blood glucose
level in normal and alloxan-induced diabetic rabbits [137]. Ethanolic extract of
F. racemosa leaves lowered the blood glucose levels by 18.4 and 17.0% at 5 and
24 h, respectively, in sucrose challenged streptozotocin-induced diabetic rat model
at the dose of 100 mg/kg body weight [138].

4.3.6 Skin Diseases

As one of the oldest known human foods, figs as a fruit have a very high safety
profile. However, the toxicological evaluation of other fig products is in an early
stage. Skin contact with latex may provoke allergic reactions like dermatitis, asthma,
and anaphylaxis, while orally administered latex may induce hallucinosis [139].
Effects other than discussed above may be therapeutic or toxic, depending on the
clinical context [140].

4.3.7 Hepatoprotective Activity

The ethanol extract of F. carica, at doses of 100, 200, and 300 mg/kg, showed sig-
nificant dose-dependent reduction in normal body temperature and yeast-provoked
elevated temperature. The effect extended up to 5 h after drug administration when
An Overview of Ethnobotany, Phytochemicals, and Pharmacological Properties… 499

compared to that of paracetamol (150 mg/kg.), a standard antipyretic agent. This

shows the antipyretic effect of ethanol extract of F. carica [60]. F. bengalensis also
shows antipyretic activity [72]. F. racemosa methanol extract of stem bark was eval-
uated on normal body temperature and yeast-induced pyrexia in albino rats, at doses
of 100, 200, and 300 mg/kg body wt. p.o. It showed significant dose-dependent
reduction in normal body temperature and yeast-provoked elevated temperature
which extended up to 5 h after drug administration. The anti-pyretic effect was
comparable to that of paracetamol [141].
Shade-dried leaves of Ficus carica were extracted using petroleum ether
(60–80 °C) and tested for antihepatotoxic activity on rats treated with 50 mg/kg of
rifampicin orally. The result indicated promising hepatoprotective activity [142].
The ethanolic extract of F. benjamina possesses hepatoprotective activity against
CCl4-induced hepatotoxicity in rats [143]. An ethanolic extract of Ficus racemosa
leaves was evaluated for hepatoprotective activity in rats by inducing chronic liver
damage by subcutaneous injection of 50% v/v carbon tetrachloride in liquid paraffin
at a dose of 3 mL/kg on alternate days for a period of 4 weeks. The biochemical
parameters SGOT, SGPT, serum bilirubin, and alkaline phosphates were estimated
to assess the liver function [144].
In another study, the methanol extract of stem bark at the doses of 250 and
500 mg/kg was evaluated for its hepatoprotective activity in rats against carbon
tetrachloride-induced liver damage with silymarin as standard. It showed significant
reversal of all biochemical parameter to normal when compared to carbon
tetrachloride-­treated control rats in serum, liver, and kidney [145].

4.3.8 Anthelmintic Activity

The latex of F. glabrata has been evaluated clinically and shown to be a potent and
well-tolerated anthelmintic agent [146], 1986). The methanolic, chloroform, and
petroleum ether extracts of the roots of F. bengalensis have potent anthelmintic
activity when compared with conventionally used drug and are equipotent to stan-
dard anthelmintic drug [147]. The aqueous extract of F. racemosa possesses wormi-
cidal activity and thus may be used as an anthelmintic [148].

4.3.9 Anti-inflammatory Activity

The anti-inflammatory effects of ethanolic and petroleum ether extracts of the bark
of F. bengalensis were evaluated in carrageenan-induced hind paw edema in rats
and the paw volume was measured plethysmometrically at 0 to 3 h after injection.
The results indicated that the ethanolic extract of F. bengalensis exhibited more
significant activity than petroleum ether in the treatment of inflammation compared
with the standard drug Indomethacin [72]. The methanolic extract of the stem bark
of Ficus religiosa L. was screened for its anti-inflammatory activity in Wistar albino
rats. A significant inhibition of carrageenan-induced rat paw edema, comparable to
500 S. P. Sasidharan et al.

that produced by indomethacin, was obtained with all the three doses of the extract.
The anti-inflammatory activity of F. racemosa extract was evaluated on carrageenan,
serotonin, histamine, and dextran-induced rat hind paw edema models where the
extract (400 mg/kg) exhibited anti-inflammatory effect of 30.4, 32.2, 33.9, and
32.0%, respectively. In a chronic test, the extract (400 mg/kg) showed 41.5% reduc-
tion in granuloma weight, which was comparable to that of phenylbutazone [144].
The acetone extract of Ficus amplissima leaves was studied for antioxidant activ-
ity, anti-inflammatory by using carrageenan and histamine-induced rat paw edema
models and wound healing activity. In this study, the acetone extract of Ficus
amplissima leaves exhibited better anti-inflammatory, wound healing, and in vivo
antioxidant activity probably due to phenols constituents [149]. In addition, the
effect of methanolic extract of the bark of Ficus amplissima (FAB) in streptozotocin-­
induced diabetic rats and found that 50 mg/kg and 100 mg/kg than 150 mg/kg, three
doses, caused significant reduction in blood glucose levels. Also showed significant
increase in serum insulin and body weight, glycogen content in liver, skeletal mus-
cle, total protein contents, and significant reduction in the levels of serum triglycer-
ide and total cholesterol [150].

4.3.10 Immunomodulatory Activity

Gabhe [151] evaluated the immunomodulatory activity of the aerial roots of F. ben-
galensis. The successive methanol and water extracts exhibited a significant increase
in the percentage of phagocytosis versus the control. In the in vivo studies, the suc-
cessive methanol extract was found to exhibit a dose-related increase in the hyper-
sensitivity reaction to the SRBC antigen. It also resulted in a significant increase in
the antibody titter value to SRBC. The immunomodulatory effect of alcoholic
extract of the bark of F. religiosa in mice was investigated. Administration of extract
remarkably ameliorated both cellular and tic rats, while there was humoral antibody
response [152]. In Ayurvedic medicine, F. racemosa L. is used as a wound healing
agent [64]. The aqueous extract of the whole plant of F. deltoidea was investigated
by Abdulla et al. [65] to evaluate the rate of wound healing enclosure and the histol-
ogy of healed wounds in rats and results strongly document the beneficial and sig-
nificant effects to accelerate the rate of wound healing enclosure in the experimentally
induced wounds in rats. The wound-healing activity (incision and excision model)
of Ficus religiosa leaf extract prepared as ointment form (5 and 10%) was investi-
gated. Povidone iodine 5% was used as standard drug. The healing of wound was
assessed by the rate of wound contraction, decreased in the period of epithelializa-
tion, high skin breaking strength was observed in animals. Ten percent ointment
shows better wound healing activity than 5% concentration [57].
An Overview of Ethnobotany, Phytochemicals, and Pharmacological Properties… 501

4.3.11 Other Pharmacological Activities

Mukherjee et al. [153] evaluated ethanol extracts of F. bengalensis (hanging roots),

Eugenia jambolana Lam. (bark), F. racemosa (bark), and Leucas lavandulaefolia
Rees (aerial parts) and showed significant inhibitory activity against castor oil-­
induced diarrhea and PGE2-induced enter pooling in rats. These extracts also
showed a significant reduction in gastrointestinal motility in charcoal meal tests in
rats. The results obtained establish the efficacy of all these plant materials as antidi-
arrheal agents. Mandal and Kumar [144] reported F. hispida Linn. leaf extract as an
antidiarrheal agent.
Extracts of F. bengalensis bark were screened for its antiallergic and anti-stress
potential in asthma by milk-induced leucocytosis and milk-induced eosinophilia.
Aqueous, ethanol, and ethyl acetate extracts showed significant decrease in leuco-
cytes and eosinophils in the order given, while petroleum ether and chloroform
extracts were inactive. This shows the application of polar constituents of F. benga-
lensis bark as anti-stress and antiallergic agents in asthma [154]. F. religiosa is also
used for the treatment of bronchial asthma. Malhotra et al. [155] were the first who
investigated the antiasthmatic potential of the alcoholic bark extract of the F. reli-
giosa. The extract showed inhibitory effect on both acetylcholine-induced and
histamine-­induced experimental asthma [155].
The majority of the medicinal uses of figs in humans are based on historical
reports or anecdotal evidence with only a few reports coming from modern clinical
trials. In one such report, 40 g/day of dried figs were fed to healthy volunteers and
found to potently reduce oxidation of low density lipoprotein (LDL) as measured by
the trolox equivalent antioxidant capacity (TEAC) antioxidant assay [156]. In a sec-
ond study, an aqueous decoction of Ficus carica leaves was found to be effective in
ameliorating postprandial hyperglycemia in Type 1 diabetes mellitus and was well
tolerated [157]. Most recently, Ficus carica leaf latex proved as effective as cryo-
therapy when applied externally to common warts [158].

5 Significance of Ficus Species

Fig trees of several different species show multiple cancer preventive, cancer thera-
peutic, and anti-inflammatory activities from their bark, roots, leaves, fruits, and
latex. Pharmacological and chemical studies have demonstrated antineoplastic or
anti-inflammatory activity of both the crude extract and pure compounds, of par-
ticular promise, due to their potent cytotoxic activity against a number of cancer cell
lines, which are the phenanthroindolizidine alkaloids and the triterpenoids with
C-18 carboxylic acid functional groups. In fact, these alkaloids, which have also
been found in a small number of other plant genera, are currently under active inves-
tigation as potential therapeutic leads [159]. In addition to these cytotoxic com-
pounds, several flavonoids, including anthocyanins, as well as other phenolic
compounds, demonstrated antioxidant and anti-inflammatory activities [108, 161].
502 S. P. Sasidharan et al.

Furthermore, lectins in the seeds may function as immune modulators [161]. The
sterols found in figs may also help bolster immunity, as well as inhibiting inflamma-
tion and invasion while promoting apoptosis and differentiation [162]. Coumarins,
in many cases, are selectively cytotoxic to cancer cells and also have antioxidant
activity and may interfere with formation of the lipoxygenase product 5-HETE to
suppress inflammation [163]. Some correlation between the ethnomedical employ-
ment and the pharmacological activities has been duly observed and noted in the
present review. As only a small fraction of the known Ficus spp. and parts has been
evaluated for anticancer and anti-inflammatory activities, figs may constitute a
rather large untapped source for new chemical entities with anticancer actions. In
last few years, there has been an exponential growth in the field of herbal medicines
to cure various diseases including diabetes.

6 Conclusions and Future Perspective

Ficus species have been identified as a potential and significant medicinal plant used
to treat a variety of diseases, according to a comprehensive literature assessment.
The world is abundant in therapeutic herbs, which is quite pleasurable. The scien-
tific work of the Ficus genus was reviewed in this article. The traditional uses, phy-
tochemical components, and medicinal action of these plants were discussed. The
goal of this research is to compile a list of articles on Ficus species. Secondary
metabolites such as triterpenoid, steroid, saponin, flavonoid, phenolic compound,
and alkaloid were discovered in various Ficus species, according to a critical study
of the literature. Quercetin, quercetin 3-O—L-arabinopyranoside, epilupeol acetate,
oleanolic acid, friedelin, elastiquinone, pinocembrin-7-O—D-glucoside, and ficu-
soside B were all isolated as pure compounds.
These opportunities derive primarily from the extremely benign safety profile of
fig fruit products, pleasant taste, and its antioxidant constituents. Because the anti-
oxidant action is also a means of lowering chronic anti-inflammatory action and
insulin resistance, fig fruits hold potential in functional food approaches aimed at
normalizing metabolic syndrome and boosting wellness beyond the widely accepted
role of figs in the diet for improving bowel performance and as a source of naturally
sweet, readily available, quick energy. Ficus species are rich source of polyphenolic
compounds, flavonoids, which are responsible for strong antioxidant properties that
help in prevention and therapy of various oxidative stress-related diseases such as
pain reliever, cancer, anti-ulcerogenic, aging, diabetes, fever, antherogenesis, hel-
minths infections, inflammation, immune system, diarrhea, allergy, and stress [160].
Traditional uses, phytochemical components, and medicinal activities of Ficus
plants were summarized. The majority of the species were utilized as traditional
medicine in Asian nations such as Indonesia, Papua New Guinea, Vietnam, Pakistan,
Thailand, and Vanuatu, according to the literature review. Some Ficus species
require additional research into their pharmacological properties, based on pro-
cesses and chemical content.
An Overview of Ethnobotany, Phytochemicals, and Pharmacological Properties… 503

References

1. Omonkhelin JO, Eric KIO, Osahon O (2007) Antifungal and antibacterial activities of the
ethanolic and aqueous extract of Kigelia africana (Bignoniaceae) stem bark. Afr J Biotechnol
6(14):1677–1680
2. De Pasquale A (1984) Pharmacognosy: the oldest modern science. J Ethnopharmacol 11:1–16
3. Rates SMK (2001) Plants as source of drugs. Toxicon 39:603–613
4. Ngo LT, Okogun JI, William R (2013) Folk 21st century natural product research and drug
development and traditional medicines. Nat Prod Rep 30:584
5. Chevalier A (1995) Encyclopedia of medicinal plants. Amazon Press, pp 3–8
6. Houghton PL (1995) The role of plants in traditional medicine and current therapy. J Altern
Complement Med 1:131–143
7. Shu Y-Z (1998) Recent natural products based drug development: a pharmaceutical industry
perspective. J Nat Prod 61:1053–1071
8. Hamburger M, Hostettmann K (1991) Bioactivity in plants: the link between phytochemistry
and medicine. Phytochemistry 30(12):3864–3874
9. Verpoorte R (2000) Pharmacognosy in the new millenium: leadfinding and biotechnology. J
Pharm Pharmacol 52:253–262
10. Cadenas E, Packer L (2002) Handbook of antioxidants. Marcel Dekker, New York
11. McCord JM (2000) The evolution of free radicals and oxidative stress. Am J Med 108:652
12. Freidovich I (1999) Fundamental aspects of reactive oxygen species, or what’s the matter
with oxygen? N.Y. academic. Science 893:13
13. Yun-Zhong F, Sheng Y, Guoyao W (2002) Free radicals, antioxidants, and nutrition. Nutrition
18:872–879
14. Emery P (2006) Treatment of rheumatoid arthritis. Br Med J 332:152–155
15. Willerson JT, Ridker PM (2004) Inflammation as a cardiovascular risk factor. Circulation
109, II:2–10
16. Rang HP, Dale MM (1991) The endocrine system pharmacology, Second edn. Longman
Group Ltd, pp 504–508
17. McGettigan MP, Henry D (2000) Current problems with non-specific COX inhibitors. Curr
Pharm Des 6:1693–1724
18. Derle DV, Gujar KN, Sagar BSH (2006) Adverse effect associated with the use of nonsteroi-
dal anti-inflammatory drugs: an overview. Indian J Pharm Sci 68:409–414
19. Lin CR, Amaya F, Barrett L, Wang H, Takada J, Samad T, Woolf CJ (2006) Prostaglandin E2
receptor EP4 contributes to inflammatory pain hypersensitivity. J Pharmacol Experimental
Therap 319:1096–1103
20. Dharmasiri JR, Jayalcody AC, Galhena G, Liyanage SSP, Ratansooriya WD (2003)
Antiinflammatory and analgesic activities of mature fresh leaves of Vitex negundo. J
Ethanopharmacol 87:199–206
21. Berman B (2004) Willow bark. University of Maryland Medical Center, Baltimore. http://
www.umm.edu/altmed/Cons Herbs/WillowBarkch.html
22. Satoskar RR (1996) Evaluation of anti-inflammatory property of curcumin in patients with
post-operative inflammation. Int J Clin Pharmacol Ther Toxicol 24:651–654
23. Srivastava KC, Mustafa T (1992) Ginger (Zingiber officinale) in rheumatism and musculo-
skeletal disorders. Med Hypotheses 39:342–348
24. Boon H, Smith M (1997) Natural anti-inflammatory supplements: research status and clinical
applications. In: Meschino DJ (ed.) Health care professional training program in complemen-
tary medicine
25. Wu SJ, Tsai JY, Chang SP, Lin DL, Wang SS, Huang SN, Ng LT (2006) Supercritical carbon
dioxide extract exhibits enhanced antioxidant and anti-inflammatory activities of Physalis
peruviana. J Ethnopharmacol 108:407–413
504 S. P. Sasidharan et al.

26. Chi YS, Jong HG, Son KH, Chang HW, Kang SS, Kim HP (2001) Effects of naturally occur-
ring prenylated flavonoids on enzymes metabolising arachidonic acid: lipoxygenases and
cyclooxygenases. Biochem Pharmacol 62:1185–1191
27. Eleni P, Dimitra HL (2003) Review in quantitative structure activity relationships on lipoxy-
genase. Mini-Rev Med Chem 3:487–499
28. Robbers J, Speedie M, Tyler V (1996) Pharmacognosy and pharmacobiotechnology. Williams
and Wilkins, Baltimore, pp 1–14
29. Roy A, Saraf S (2006) Ethnomedicinal approach in biological and chemical investigation of
phytochemicals as antimicrobials. Pharm Rev 4(2)
30. Ellof JN (1990) It is possible to use herbarium specimens to screen for antibacterial compo-
nents in some plants. J Ethnopharmacol 67:355–360
31. Gurib-Fakim A (2006) Medicinal plants: tradition of yesterday and drugs of tomorrow. Rev
Article Mol Aspects Med 27(1):1–93
32. Senthilkumar GP, Arulselvan P, Sathishkumar D, Subramanian SP (2006) Antidiabetic
activity of fruits of Terminalia chebula on streptozotocin induced diabetic rats. J Health Sci
52:283–291
33. Meenakshi S, Raghavan G, Nath V, Ajay Kumar SR, Shanta M (2006) Antimicrobial,
wound healing and antioxidant activity of Plagiochasma appendiculatum Lehm. Et Lind. J
Ethnopharmacol 107:67–72
34. Enoch S, John LD (2005) Basic science of wound healing. Surgery 23:37–42
35. Sumitra M, Manikandana P, Suguna L (2005) Efficacy of Butea monosperma on dermal
wound healing in rats. Int J Biochem Cell Biol 37:566–573
36. Suresh RJ, Rao PR, Reddy MS (2002) Wound healing effects of Heliotropium indicum,
Plumbago zeylanicum and Acalypha indica in rats. J Ethnopharmacol 79:249–251
37. Kumar B, Vijayakumar M, Govindarajan R, Pushpangadan P (2007) Ethnopharmacological
approaches to wound healing – exploring medicinal plants of India. J Ethnopharmacol
114:103–113
38. Krishnan P (2006) The scientific study of herbal wound healing therapies: current state of
play. Curr Anaesth Crit Care 17:21–27
39. Mohamed AK, Bierhaus A, Schiekofer S, Tritschler H, Ziegler R, Nawroth PP (1999) The
role of oxidative stress and NF-κB activation in late diabetic complications. Biofactors
10:157–167
40. Halliwell B, Gutteridge JMC (1989) Free radicals, other reactive species and disease. In: Free
radicals in biology and medicine. Clarendon Press, Oxford, pp 617–623
41. Baynes JW (1991) Perspective in diabetes. Role of oxidative stress in development of com-
plication in diabetes. Diabetes 40:405–412
42. Ceriello A (2000) Oxidative stress and glycemic regulation. Metabolism 49:27–29
43. Fatima SS, Rajasekhar MD, Kumar KV, Kumar MTS, Babu KR, Rao CA (2010) Antidiabetic
and antihyperlipidemic activity of ethyl acetate:isopropanol (1:1) fraction of Vernonia anthel-
mintica seeds in streptozotocin induced diabetic rats. Food Chem Toxicol 48:495–501
44. WHO (World Health Organization) (2009) Prevalence data of diabetes world wide
45. Dewanjee S, Das AK, Sahu R, Gangopdhyay M (2009) Antidiabetic activity of Diospyros
peregrine fruit: effect on hyperglycemia, hyperlipidemia and augmented oxidative stress in
experimental type 2 diabetes. Food Chem Toxicol 47:2679–2685
46. FAO/WHO (1990) Energy and protein requirements. Report of joint FAO/WHO/UNU Expert
Consultation Technical Report. FAO/WHO and United Nations University, Geneva
47. Evans JL (2007) Antioxidants: do they have a role in the treatment of insulin resistance.
Indian J Med Res 125:355–372
48. WHO (1980) Expert committee on diabetes mellitus second report. Technical Report Series
646. World Health Organization, Geneva, p 61
49. Maria AB, Assimina GT, Drakoulis D, Alexandra F, Panayiotis HP (1999) Salivary altera-
tions in insulin-dependent diabetes mellitus. Int J Paediatr Dent 8(1):29–33
An Overview of Ethnobotany, Phytochemicals, and Pharmacological Properties… 505

50. Larsen MO, Raun K, Ribel U, Gotfredsen CF, Brand CL, Wilken M, Carr RD, Rolin B (2003)
Insulin sensitivity is negatively correlated to total body mass in Göttingen minipigs. Diab
Metab 29:S98
51. Reaven G (1988) Role of insulin resistance in human disease. Diabetes 37:1595–1607
52. Pari L, Uma M (1999) Hypoglycaemic effect of Musa sapientum L. in alloxaninduced dia-
betic rats. J Ethnopharmacol 68:321–325
53. Rang HP, Dale MM, Ritter JM (1999) Anti-inflammatory and immunosuppressant drugs. In:
Pharmacology, 5th edn. Churchil Livingstone Edinburgh, London, p 248
54. Pari L, Venkateswaran S (2002) Hypoglycaemic activity of Scopariadulcis L. extract in
alloxan induced hyperglycaemic rats. Phytother Res 16(7):662–664
55. Eidi M, Eidi A, Zamanizadeh H (2005) Effect of Salvia officinalis L. leaves on serum glu-
cose and insulin in healthy and streptozotocin induced diabetic rats. J Ethnopharmacol
100:310–313
56. Sawarkar HA, Singh MK, Pandey AK, Biswas D (2011) In vitro anthelmintic activity of
Ficus bengalhensis, Ficus caria and Ficus religiosa: a comparative anthelmintic activity. Int J
Pharm Tech Res 3:152–153
57. Roy K, Shivkumar H, Sarkar S (2009) Wound healing potential of leaf extracts of Ficus reli-
giosa on Wistar albino strain rats. Int J Pharm Tech Res 1(3):506–508
58. Hamed MA (2011) Beneficial effect of Ficus religiosa Linn. On highfat- induced hypercho-
lesterolemia in rats. Food Chem 129:162–170
59. Sirisha N, Sreenivasulu M, Sangeeta K, Chetty CM (2010) Antioxidant properties of Ficus
species-A review. Int J PharmTech Res 4:2174–2182
60. Joseph B, Raj SJ (2011a) Pharmacognostic and phytochemical properties of Ficus carica
Linn –an overview. Int J PharmTech Res 3(1):8–12
61. Shukla R, Gupta S, Gambhir JK, Prabhu KM, Murthy PS (2004) Antioxidant effect of aqueous
extract of the bark of Ficus bengalensis in hypercholesterolaemic rabbits. J Ethnopharmacol
92:47–51
62. Duduku K, Rosalam S, Leenah NJ (2007) Recovery of phytochemical components from
various parts of Morinda citrifolia extracts by using membrane separator. J Appl Sci
7(15):2093–2098
63. Owen RW, Giacosa A, Hull WE, Haubner R, Spiegelhalder B, Bartsch H (2000) The anti-
oxidant/anticancer potential of phenolic compounds isolated from olive oil. Eur J Cancer
36:1235–1247
64. Biswas TK, Mukherjee B (2003) Plant medicines of Indian origin for wound healing activity:
a review. Int J Lower Extreme Wounds 2(1):25–39
65. Abdulla MA, Ahmed KA, Abu-Luhoom FM, Muhanid M (2010) Role of Ficus deltoidea
extract in the enhancement of wound healing in experimental rats. Biomed Res 21(3):241–245
66. Tiwari AK, Rao MJ (2002) Diabetes mellitus and multiple therapeutic approaches of phyto-
chemicals: present status and future prospects. Curr Sci 83:30–38
67. Rashid ABA (2008) The chemical constituents from the stems of Ficus deltoids. B.Sc. Final
Year Project Report. University Teknologi Mara, Selangor
68. Singh S, Gupta SK, Sabir G, Gupta MK, Seth PK (2009) A database for antidiabetic plants
with clinical/experimental trials. Bioinformation 4(6):263–268
69. Sonibare MO, Isiaka AO, Taruka MW, Williams NS, Soladoye M, Emmanuel O (2006)
Constituents of Ficus exasperata leaves. Nat Prod Commun:23–26
70. Mazumdar PM, Farswan M, Parcha V (2009) Hypoglycaemic effect of Ficis arnottiana Miq.
Bark extracts on streptozotocin induced diabetea in rats. Nat Prod Radiance 8(5):478–482
71. Sharma VK, Kumar S, Patel HJ, Hugar S (2010) Hypoglycemic activity of Ficus glomerata in
alloxan induced diabetic rats. Int J Pharmaceut Sci Rev Res 1(2):18–22
72. Patil VV, Patil VR (2010) Ficus Benghalensis Linn.-an overview. Int J Pharm Bio Sci 6:2
73. Everett TH (1968) Living trees of the world. Doubleday, New York. Retrieved at (http://sci-
ence.jrank.org/pages/4494/Mulberry-­Family-­Moraceae.ecologyeconomic-­ value.html)
506 S. P. Sasidharan et al.

74. Duncan WH, Duncan MB (1988) Trees of the southeastern United States. University
of Georgia Press. Retrieved at http://science.jrank.org/pages/4494/Mulberry-­Family-­
Moraceae.html
75. Godfrey RK (ed) (1988) Trees, shrubs, and Woody vines of northern Florida and adja-
cent Georgia and Alabama. University of Georgia Press. Retrieved at http://science.jrank.
org/pages/4493/Mulberry-­Family-­Moraceae-­Ecologydistribution-­economic-­value.html on
29/09/09
76. Rohwer JG, Kubitzki K, Bittrich V (eds) (1993) The families and genera of vascular plants.
Springer Verlag, Berlin, Germany, pp 438–453
77. Shannon L, Datwyler and Weiblen, G.D. (2004) On the origin of the fig: phylogenetic rela-
tionships of moraceae from NDHF sequences. Am J Bot 91(5):767–777
78. Weiblen GD (2000) Phylogenetic relationships of functionally dioecious Ficus (Moraceae)
based on ribosomal DNA sequences and morphology. Am J Bot 87:1342–1357
79. Berg CC, Hijman MEE (1989) Moraceae. In: Polhill RM (ed) Flora of tropical East Africa.
Rotterdam, Netherlands, p 95
80. Lansky EP, Paavilainen HM, Pawlus AD, Newman RA (2008) Ficus spp. (fig): ethnobotany
and potential as anticancer and anti-inflammatory agents. J Ethnopharmacol 119:195–213
81. Kislev ME, Hartmann A, Bar-Yosef O (2006) Early domesticated fig in the Jordan Valley.
Science 312:1372–1374
82. Lev-Yadun S (2006) Defensive coloration in plants: a review of current ideas about anti-­
herbivore coloration strategies. In: Teixeira da Silva JA (ed) Floriculture, ornamental and
plant biotechnology. Advances and topical issues, vol VI. Global Science Books Ltd, London,
UK, pp 292–299
83. Kapoor LD (1990) CRC handbook of Ayurvedic medicinal plants. CRC Press, BocaRaton
84. Khan I, Alam S, Akhter S, Shahin N, Ansari FZ (2007) Ageing and its herbal treatment.
Pharma Rev 12:131–134
85. Subedi A, Paudyal G (2001) Some notable orchid of Pokhara valley and their habitats.
Botanica Orientalis 2:172–174
86. Majupuria TC, Joshi DP (1989) Religious and useful plants of Nepal and India. M. Gupta,
Lashkar, India
87. Holttum RE (1969) Plant life in Malaya. London Longman Group Limited, p 87
88. Trivedi CP, Shinde S, Sharma RC (1969) Prelimnary phytochemical and pharmacological
studies on Ficus racemosa extract (gular). Indian J Med Res 57(6):1070–1074
89. Beat B, Clemens AJ, Wright D, Rali T, Orro S (1990) An antimicrobial alkaloid from Ficus
septic. Phytochemistry 29(10):3327–3330
90. Mohammad A, Sutradhar A, Ahmad M, Ranjit K (1991) Chemical constituents of Ficus
glomerata Roxb. J Bangaladesh Chem Soc 4(2):247–250
91. Ikhals AK, Rali T, Sticher O (1993) Alkaloids from Ficus pachyrhachis. Planta Med 59(3):286
92. Ilyas M, Ilyas N (1990) Flavonids from the leaves of Ficus capensis. Ghana J Chem
1(3):176–178
93. Buniyamin AA, Eric KIQ, Fabian CA (2007) Pharmacognosy and hypotensive evaluation
of Ficus exasperata Vahl.(moraceae) leave. Acta Poloniae Pharm Drug Res 64(6):543–546
94. Odunbaku OA, llusanya O.A., Akasoro K.S. (2008) Antimicrobial activity of ethanolic leaf
extract of Ficus exasperata on Escherchia coli and staphylococcus albus. Sci Res Essay
3(11):562–564
95. Shantha TR, Shetty JK, Indira A, Bikshapathi T (2006) Pharmacognostical studies on Vata
shrung (Ficus benghlensis Linn. Leaf primordium). Ind J Trad Knowledge 5(3):388–393
96. Kirtikar KR, Basu BD (1933) Indian medicinal plants, vol 1–4. Publisher L M Basu,
Allahabad
97. Naira N, Rohini R, Asdag S, Das A (2009) Wound healing activity of the hydro alcoholic
extract of Ficus religiosa leaves in rats. Int J Alternative Med 6:2
98. Aqil F, Ahamd I (2003) Broad spectrum antibacterial and antifungal properties of certain
traditionally used Indian medicinal plants. World J Microbiol Biotechnol 19:653–657
An Overview of Ethnobotany, Phytochemicals, and Pharmacological Properties… 507

99. Vinutha B, Prashanth D (2007) Screening of selected Indian medicinal plants for acetylcho-
lineesterase inhibitory activity. J Ethnopharmacol 109:359–363
100. Simmonds M, Howes M (2006) Plants used in the treatment of diabetes. In: Soumyanath A
(ed) Traditional medicines for modern time-antidiabetic plants, vol 6. CRC Press/Taylor and
Francis Group, pp 19–82
101. Deshmukh T, Yadav B, Badole Bodhankar S, Dhaneshwar S (2007) Antihyperglycemic activ-
ity of alcoholic extract of Ficus religiosa leaves in alloxian induced diabetic mice. J Herbal
Med Toxicol 1:80–86
102. Chopra RN, Nayar SL, Chopra IC (2002) Glossary of Indian medicinal plants. Council of
Scientific and Industrial Research, NISCAIR, New Delhi, p 199
103. Bhardwaj, A., Hundal, M.K., Pathania, V., Syal, N., Sohi, K.K., Khanduja, K.L., (2000).
Evaluation of antioxidant and antiradical activity of reveratrol, paper presented at the 19th
annual convention of Indian association for cancer research and symposium on cancer biol-
ogy, 21–23
104. Rubnov S, Kashman Y, Rabinowitz R, Schlesinger Mechoulam R (2001) Suppressors of can-
cer cell proliferation from fig (Ficus carica) resin; isolation and structure elucidation. J Nat
Prod 64:993–996
105. Hansson A, Veliz G, Naquira C, Amren M, Arroyo M, Arevalo G (1986) Preclinal and clini-
cal studies with latex from Ficus glabrata HBK, a traditional intestinal anthelinthic in the
Amazonian area. J EthnopharmacolJournal of Ethnopharmacology 2:105–138
106. Chiang YM, Chang JY, Kuo CC, Chang CY, Kuo YH (2005) Cytotoxic triterpenes from the
aerial roots of Ficus microcarpa. Phytochemistry 66:45–501
107. Baumgartner B, Erdelmeier CAJ, Wright AD, Rali T, Sticher O (1990) An antimicrobial
alkaloid from Ficus septica. Phytochemistry 29:3327–3330
108. Li C, Bu PB, Yue DK, Sun YF (2006) Chemical constituents from roots of Ficus hirta.
Zhongguo Zhong YaoZaZhi 31:131–133
109. Saeed MA, Sabir AW (2002) Irritant potential of triterpenoids from Ficus carica leaves.
Fitoterapia 73:417–420
110. Wu PL, Rao KV, Su CH, Kuoh CS, Wu TS (2002) Phenanthroindolizidine alkaloids and their
cytotoxicity from the leaves of Ficus septica. Heterocycles 57:2401–2408
111. Damu AG, Kuo PC, Shi LS, Li CY, Kuoh CS, Wu PL, Wu TS (2005) Phenanthroindolizidine
alkaloids from the stems of Ficus septica. J Nat Prod 68:1071–1075
112. Yang CW, Chen WL, Wu PL, Tseng HY, Lee SJ (2006) Anti- inflammatory mechanisms of
phenanthroindolizidine alkaloids. Mol Pharmacol 69:749–758
113. Venkatachalam SR, Mulchandani NB (1982) Isolation of phenanthroindolizidine alkaloids
and a novel biphenylhexahydroindolizine alkaloid from Ficus hispida. Naturwissenschaften
69:287–288
114. Zaynoun ST, Aftimos BG, Abi AL (1984) Ficus carica; isolation and quantification of the
photoactive components. Contact Dermatitis 11:21–25
115. Innocenti G, Bettero A, Caporale G (1982) Determination of the coumarinic constituents of
Ficus carica leaves by HPLC. Farmaco 37:475–485
116. Chang YF, Chi CW, Chern YT, Wang JJ (2005) Effects of 1,6-Bis[4-(4-amino3- hydroxyphe-
noxy)phenyl]diamantane (DPD), a reactive oxygen species and apoptosis inducing agent, on
human leukemia cells in vitro and in vivo. Toxicol Appl Pharmacol 202:1–12
117. Makhija IK, Sharma IP, Khamar D (2010) Phytochemistry and pharmacological properties of
Ficus religiosa: an overview. Ann Biol Res 1(4):171–180
118. Sheu YW, Chiang LC, Chen IS, Chen YC, Tsai IL (2005) Cytotoxic flavonoids and new
chromenes from Ficus formosana. Planta Med 71:1165–1177
119. Pistelli L, Chiellini EE, Morelli I (2000) Flavonoids from Ficus pumila. Biochem Syst Ecol
28(3):287–289
120. Darbour N, Bayet C, Rodin-Bercion S, Elkhomsi Z, Lurel F, Chaboud A, Guilet D (2007)
Isoflavones from Ficus nymphaeifolia. Nat Prod Res 21:461–464
508 S. P. Sasidharan et al.

121. Solomon A, Golubowicz S, Yablowicz Z, Grossman S, Bergman M, Gottlieb HE, Altman

A, Kerem Z, Flaishman MA (2006) Antioxidant activities and anthocyanin content of fresh
fruits of common fig (Ficus carica L.). J Agric Food Chem 54:7717–7723
122. Sehgal A (2003) Herbal medicines-harmless or harmful. Anesthesia 57:947–948
123. Malairajan P, Gopalakrishnan G, Narasimhan S (2007) Anti-ulcer activity of crude alcoholic
extract of Toona ciliata Roemer (heartwood). J Ethopharmacol 110(2):348–351
124. Lalla JK (2005) Herbal medicines revisited. Pharma Rev 12:101–105
125. Mousa O, Vuorela P, Kiviranta J, Wahab SA, Hiltohen R, Vuorela H (1994) Bioactivity of
certain Egyptian Ficus species. J Ethnopharmacol 41:71–76
126. Zahra MASF, Mahmood AA, Hapipah MA, Suzita MN, Salmah I (2009) Anti–ulcerogenic
activity of aqueous extract of Ficus deltoidea against ethanol induced gastric mucosal injury
in rats. Res J Med Sci 3(2):42–46
127. Sivaraman D, Muralidharan P (2010) Anti-ulcerogenic evaluation of root extract of Ficus
hispida Linn. In aspirin ulcerated rats. Afr J Pharm Pharmacol 4(2):079–082
128. Charde RM, Dhongade HJ, Charde MS, Kasture AV (2010) Evaluation of antioxidant, wound
healing and anti-inflmmatory activity of ethanolic extract of leaves of Ficus religiosa. Int J
Pharma Sci Res 19:73–82
129. Kirana H, Agrawal SS, Srinivasan BP (2009) Aqueous extract of Ficus religiosa Linn reduce
oxidative stress in experimentally induced type 2 diabetic rats. Indian J Exp Biol 47:822–826
130. Vohra SB, Parasar GC (1970) Antidiabetic studies on Ficus bengalensis Linn. Indian J Pharm
32:68–69
131. Pandit R, Phadke A, Jagtap A (2010) Antidiabetic effect of Ficus religiosa extract in
streptozotocin-­induced diabetic rats. J Ethnopharmacol 128:462–466
132. Basla RK, Agha R (1985) Isolation of a hypoglycaemic principle from the bark of Ficus
glomerata Roxb. Himalayan Chem Pharm Bull 2:13–14
133. Bhaskara RR, Murugesan T, Sinha S, Saha BP, Pal M, Mandal SC (2002) Glucose lowering
efficacy of Ficus racemosa bark extract in normal and alloxan diabetic rats. Phytother Res
16:590–592
134. Sophia D, Manoharan S (2007) Hypolipidemic activities of Ficus racemosa L. bark in alloxan
induced diabetic rats. African J Trad Complement Alternative Med 4(3):279–288
135. Shrotri DS, Ranita A (1960) The relationship of the post-absorptive state to the hypoglycemic
action studies on Ficus bengalensis and Ficus racemosa. Indian J Med Res 48:162–168
136. Kar A, Choudhary BK, Bandyopadhyay NG (2003) Comparative evaluation of hypogly-
caemic activity of some Indian medicinal plants in alloxan diabetic rats. J Ethnopharmacol
84:105–108
137. Akhtar MS, Qureshi AQ (1988) Phytopharmacological evaluation of Ficus glomerata, Roxb.
Fruit for hypoglycaemic activity in normal and diabetic rabbits. Pak J Pharm Sci 1(2):87–96
138. Rahuman AA, Gopalakrishnan G, Venkatesan P, Geetha K, Bagavan A (2008) Mosquito lar-
vicidal activity of isolated compounds from the rhizome of Zingiber officinale. Phytother Res
22(8):1035–1039
139. Chelminska M (2004) Latex allergy. Part I Pneumonologia Alerologia Polska 72:143–149
140. Ayinde BA, Omogbai EK, Amaechina FC (2007) Pharmacognosy and hypotensive evaluation
of Ficus exasperata Vahl (Moraceae) leaf. Acta Pol Pharm 64:543–546
141. Rao RB, Anupama K, Swaroop KR, Murugesan T, Pal M, Mandal SC (2002) Evaluation of
antipyretic potential of Ficus racemosa bark. Phytomedicine 9:731–733
142. Gond NY, Khadabadi SS (2008) Hepatoprotective activity of Ficus carica leaf extract on
rifampicin-induced hepatic damage in rats. Indian J Pharm Sci 70(3):364
143. Kanaujia VK, Rirchhaiya HK, Kailasiya SD, Verma M, Yadav RD, Shivhare D (2011)
Evaluation of hepatoprotective activity on the leaves of Ficus benjamina Linn. J Nat Prod
Plant 1:59–69
144. Mandal SC, Kumar CKA (2002) Studies on anti-diarrhoeal activity of Ficus hispida. Leaf
Extract Rats Fitoterapia 73(7–8):663–667
An Overview of Ethnobotany, Phytochemicals, and Pharmacological Properties… 509

145. Channabasavaraj KP, Badami S, Bhojraj S (2008) Hepatoprotective and antioxidant activity
of methanol extract of Ficus glomerata. J Nat Med 62:379–383
146. Morton AD, Mc Manus IC (1986) Attitudes to and knowledge about the acquired immune
deficiency syndrome: lack of a correlation. Br Med J 293:1212
147. Aswar M, Aswar U, Watkar B, Vyas M, Wagh A, Gujar KN (2008) Anthelmintic activity of
Ficus bengalensis. Int J Green Pharm 2(3):170–172
148. Chandrashekhar CH, Latha KP, Vagdevi HM, Vaidya VP (2008) Anthemintic activity of the
crude extracts of Ficus racemosa. Int J Green Pharm 2:100–103
149. Arunachalam K, Parimelazhagan T (2013) Anti-inflammatory, wound healing and in-­
vivo antioxidant properties of the leaves of Ficus amplissima Smith. J Ethnopharmacol
145(1):139–145
150. Arunachalam K, Parimelazhagan T (2013) Antidiabetic activity of Ficus amplissima Smith.
Bark extract in streptozotocin induced diabetic rats. J Ethnopharmacol 147(2):302–310
151. Gabhe SY, Tatke PA, Khan TA (2006) Evaluation of the immunomodulatory activity of the
methanol extract of Ficus bengalensis roots in rats. Indian J Pharmacol 38(4):271–275
152. Mallurwar VR, Pathak AK (2008) Studies on immunomodulatory activity of Ficus religiosa.
Indian J Pharm Educ Res 42(4):341–343
153. Mukherjee PK, Saha K, Murugesan T, Mandal SC, Pal M, Saha BP (1998) Screening of
anti-diarrhoeal profile of some plant extracts of a specific region of West Bengal. India J
Ethnopharmacol 60:85–89
154. Taur DJ, Nirmal SA, Patil RY, Kharya MD (2007) Antis tress and ant allergic effects of Ficus
bengalensis bark in asthma. Nat Prod Res 21(14):66–70
155. Malhotra CL, Das PK, Dhalla NS (1960) Parasympatholytic activity of Ficus religiosa Linn.
Indian J Med Res 48:734–742
156. Vinson JA, Zubik L, Bose P, Samman N, Proch J (2005) Dried fruits: excellent in vitro and
in vivo antioxidants. J Am Coll Nutr 24(1):44–50
157. Serraclara A, Hawkins F, Peez C, Dominguez E, Campillo JE, Torres MD (1998)
Hypoglycemic action of an oral fig-leaf decoction in type-1 diabetic patients. Diabetes Res
Clin Pract 39:19–22
158. Bohlooli S, Mohebipoor A, Mohammadi S, Kounhavard M, Pashapoor S (2007) Comparative
study of fig tree efficacy in the treatment of common warts (verruca vulgarisvs. Cryotherapy).
Int J Dermatol 46:524–526
159. Gao W, Lam W, Kaczmarek C, Baker DC, Cheng YC (2004) Novel mode of action of tyloph-
orine analogs as antitumor compounds. Cancer Res 64:678–688
160. Priya D, Purnima D, Borthakur SK (2013) Pharmaceutical properties of Indian species of
Ficus Linn. Int J Pharm Life Sci 4(1):2314–2319
161. Rabinovich GA, Liu FT, Hirashima M, Anderson A (2007) An emerging role for galectins
in tuning the immune response: lessons from experimental models of inflammatory disease,
autoimmunity and cancer. Scand J Immunol 66:143–158
162. Bradford PG, Awad AB (2007) Phytosterols as anticancer compounds. Mol Nutri Food Res
51:161–170
163. Kulkarni MV, Kulkarni GM, Lin CH, Sun C (2006) Recent advances in coumarins and
1-azacoumarins as versatile biodynamic agents. Curr Med Chem 13:2795–2818
Phytochemistry and Pharmacology
of Catharanthus roseus (L.) G. Don
and Rauvolfia serpentina (L.) Benth. ex
Kurz

Sunil Kumar and Bikarma Singh

1 Introduction

Catharanthus roseus (L.) G.Don and Rauvolfia serpentina (L.) Benth. ex Kurz are
important and the most explored plant species belonging to the dogbane family
Apocynaceae. These species recorded as endemic to Madagaskar and originate
from India (Fig. 1). C. roseus is commonly known as pink periwinkle, rose peri-
winkle, Cape periwinkle, bright eyes, Madagascar periwinkle, graveyard plant, and
old maid, whereas Indian snakeroot, sarpagandha, Chandrika and devil pepper, or
serpentine wood are common names of R. serpentina [1–5]. In the Ayurvedic sys-
tem of medicine, different parts of C. roseus and R. serpentina are used in folklore
herbal medicine for the treatment of many types of cancer, diabetes, stomach disor-
ders, kidney, liver, snakebites, hypertension, and associated cardiovascular diseases
by the local people of tropical regions of Africa, Asia, America, and various Oceanic
islands [6–11]. C. roseus is an ornamental plant that has flowers of a different color
for most of the year. Both the plant species have been distributed throughout the
world and used in traditional medicine for ages in various parts of the world [11].
The extracts, fractions and compounds of C. roseus and R. serpentina plants are
extensively studied for their pharmacological activities such as antimicrobial, anti-
oxidant, antiprotozoal, antitrypanosomal, antipsychotic, cardioprotective, cholines-
terase inhibitory, and hepatoprotective due to the rich content of bioactive

S. Kumar
Department of Chemistry, Ma. Kanshiram Government Degree College, Ninowa (affiliated to
Chhatrapati Shahu Ji Maharaj University (CSJM) Kanpur), Farrukhabad, Uttar Pradesh, India
B. Singh (*)
Botanic Garden Division, CSIR-National Botanical Research Institute, Rana Pratap Marg,
Lucknow, Uttar Pradesh, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 511

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_19
512 S. Kumar and B. Singh

Fig. 1 Pictures of Catharanthus roseus (a), Rauvolfia serpentina (b), and Rauvolfia serpentina
root (c)

monoterpene indole alkaloids (MIAs) and bisindole alkaloids [11–17]. Reserpine,

ajmalicine, ajmaline, serpentine, and yohimbine (aphrodisiac) are MIAs reported as
antihypertensive and antiarrhythmic, cerebral vasodilators, and anticancer agents
(vincristine and vinblastine) and included in the World Health Organization (WHO)
Model List of Essential Medicines [18–25]. In the 1960s, vinblastine and vincristine
were isolated from C. roseus and approved by the US Food and Drug Administration
as chemotherapeutic agents for the treatment of several types of cancer [26, 27].
This chapter aims to provide updated and comprehensive information on the phyto-
chemistry and pharmacological activities of C. roseus and R. serpentina (Table 1).

2 Phytochemistry

2.1 The Biosynthetic Pathway of Terpenoid Indole Alkaloids

The biosynthesis of indole alkaloids in MIAs is very complex, involving more than
50 metabolic steps to synthesize the most important alkaloids (Fig. 2). About 20 of
the 50 enzymes necessary for their biosynthesis have been identified and character-
ized by different techniques. Thus, there are still a number of important enzymes
that are essential to be characterized, which can only be done after the isolation and
Table 1 Different classes of Secondary metabolites with mass, molecular formula, their distribution in parts, and pharmacological properties of Catharanthus
roseus and Rauvolfia serpentina
Molecular
Serial no. Compound/subclass MS (Da) formula Distribution or source Species Activity
1. Sitsirikine 354 C21H26N2O3 Leaves, stem bark, and C. roseus, R. Immunosuppressive
twigs serpentina
2. 10-Methoxynormacusine 324 C20H24N2O2 Leaves, stem bark, root R. serpentina Immunosuppressive
B (Lochnerine) (10-O- bark
Methylsarpagine)
3. Tetraphyllicine 308 C20H24N2O Leaves, stem bark, and C. roseus, R. Myocardial excitation
(serpinine) root bark serpentina
4. Ajmaline 326 C20H26N2O2 Leaves, stem bark, and C. roseus, R. Antiarrhythmia, antifibrillation, cardiac and liver
root bark serpentina toxicity, immunosuppressive
5. Isoreserpiline 412 C23H28N2O5 Leaves, stem bark, and C. roseus, R. Antipsychotic
root serpentina

6. Reserpiline 412 C23H28N2O5 Leaves, stem bark, and C. roseus, R. Antipsychotic, antigastric secretion,
root serpentina antihypertension

7. Ajmalicine 352 C21H24N2O3 Leaves, stem, and root C. roseus, R. Immunosuppressive

serpentina

8. Serpentinic acid 334 C20H18N2O3 Whole plant R. serpentina Immunosuppressive

Phytochemistry and Pharmacology of Catharanthus roseus (L.) G. Don…

9. Serpentine 348 C21H20N2O3 Stem bark R. serpentina Antioxidant, possible anticancer

10. Rauvoyunnanine B 414 C22H23ClN2O4 Whole plants R. serpentina Immunosuppressive

11. Yohimbinic acid 340 C20H24N2O3 Root C. roseus, R. Cytotoxic

(Yohimbic acid) serpentina
(continued)
513
Table 1 (continued)
514

Molecular
Serial no. Compound/subclass MS (Da) formula Distribution or source Species Activity
12. Isorauhimbinic acid 340 C20H24N2O3 Root C. roseus, R. Cytotoxic
serpentina
13. α-Yohimbine 354 C21H26N2O3 Leaves, stem bark, and C. roseus, R. Immunosuppressive, antibacterial, cytotoxic,
root serpentina pre- and postsynaptic α2-adrenoceptor inhibitor,
stimulant and aphrodisiac effect, antidiabetic
14. β-Yohimbine 354 C21H26N2O3 Leaves, stem bark, and C. roseus, R. Cytotoxic
root serpentina
15. 18-Hydroxyyohimbine 370 C21H26N2O4 Stem, stem bark, and C. roseus, R. Antipsychotic, antihypertension, antidepression,
root bark serpentina anticancer, carcinogenesis
16. Reserpine 608 C33H40N2O9 Leaves, stem bark, and C. roseus, R. Immunosuppressive
root serpentina
17. Rescinnamine 634 C35H42N2O9 Leaves and root bark R. serpentina Antihypertension
18. Akuammine 382 C22H26N2O4 Root R. serpentina Antimalarial
19. Catharanthine 336 C21H24N2O2 Leaves, stem bark, and C. roseus Acethylcholinesterase inhibition
root
20. Vindoline 456 C25H32N2O6 Leaves, stem bark, and C. roseus
root
21. Vinblastine 811 C46H58N4O9 Leaves, stem bark, and C. roseus Chemotherapy
root
22. Vincristine 825 C46H56N4O10 Leaves, stem bark, and C. roseus Chemotherapy
root
S. Kumar and B. Singh
Phytochemistry and Pharmacology of Catharanthus roseus (L.) G. Don… 515

Fig. 2 Biosynthetic pathways of indole alkaloids in Catharanthus roseus, Rauvolfia serpentina

cloning of the relevant genes. It is also of fundamental importance to identify the

regulatory aspects of TIA biosynthesis, both at the cellular and the molecular levels,
to address the question of their function in the plants and to increase their produc-
tion by biotechnological approaches. In the biosynthetic pathways, tryptamine and
monoterpenoid secologanin are starting materials for the biosynthesis of MIAs.
Tryptamine and secologanin are the precursors for the synthesis of terpenoid (iso-
prenoid) and indole biosynthesis, respectively. The stereospecific condensation of
tryptamine and secologanin yields the universal MIAs precursor, strictosidine,
516 S. Kumar and B. Singh

which has S-configuration at C-5 and is produced through Pictet-Spengler-type

reaction. The major dehydrogeissoschizine is formed as an intermediate due to loss
of glucose moiety which is a starting material for the biosynthesis of sarpagine,
ajmaline, ajmalicine, and reserpine classes of MIAs. Biosynthetic pathways of
ajmaline, ajmalicine, sarpagine, and reserpine classes of compounds have been
illustrated in R. serpentina, but some enzymes and synthetic processes are yet unex-
plored (Ruppert et al., 2005; O’Connor and Maresh, 2006). Various enzymatic con-
densations, rearrangement, oxidation, and reduction lead to the synthesis of different
types of MIAs from dehydrogeissoschizine in R. serpentina [28–32].
Vindoline and catharanthine, which are produced by 3α (S)-strictosidine via mul-
tistep enzymatic reaction, can form α-3, 4-anhydrovinblastine by condensation
reaction. In the biosynthesis of bisindole alkaloids like vincristine and vinblastine,
combination of catharanthine and vindoline is modified and converted into iminium
ions. The iminium ions and 3′,4′-anhydrovinblastine are interconvertible to each
other and biosynthesized vinblastine. Furthermore, vincristine and leurosine are
synthesized from vinblastine, but convertible enzymes are involved during the bio-
synthesis. Only 26 genes involved in the assembly of these two bisindole alkaloids
are known; two key reactions have eluded characterization to complete the docu-
mentation of the vinblastine pathway in C. roseus [33–40].
Many traditional methods have been reported for analysis of indole alkaloids
from C. roseus and R. serpentina for more than five decades. In this study, a rapid
and validated method was developed for fingerprinting roots, leaves, and culture of
R. serpentina by direct analysis in real-time mass spectrometry (DART-MS) for
tentative identification of ten MIAs on the basis of their exact mass measurements
from the intact plant parts [41]. More than 40 MIAs were identified by using high-­
performance liquid chromatography-tandem mass spectrometry, along with reser-
pine, ajmalicine, ajmaline, serpentine, and yohimbine that were unambiguously
identified and quantified by comparison with their authentic standards in ethanolic
extracts of R. serpentina [42, 43]. More advanced strategies have been reported for
the identification and characterization of the same classes of MIAs using multistage
mass analysis (MSn). More than 30 MIAs have been reported in R. serpentina on the
basis of chromatographic and mass spectrometric features as well as HRMS/MS, an
MSn analysis [44, 45].
Similarly, the rapid and realizable HPLC-MSMS methods were reported for
identification and characterization of total of 72 MIAs, out of which 11 were unam-
biguously identified by comparison with their standards and the remaining 61 were
tentatively identified on the basis of diagnostic fragmentation pathways for vinpo-
cetine, vindesine, catharanthine, vinblastine, vindoline, and vincristine. Ajmaline,
ajmalicine, reserpine, vincristine, vinblastine, vindesine, yohimbine, and serpentine
were quantified by a rapid, sensitive, reproducible, and validated method using
ultra-high-performance liquid chromatography coupled with electrospray ioniza-
tion hybrid triple quadrupole-linear ion trap mass spectrometry in multiple reaction
monitoring (MRM) mode [46–48].
Phytochemistry and Pharmacology of Catharanthus roseus (L.) G. Don… 517

Fig. 3 Flowchart of isolation of MIAs

2.2 Isolation of Bioactive Alkaloids

Various studies available that reported the isolation procedure of different compo-
nents from C. roseus and R. serpentina in detail and identified bisindole alkaloids
(Fig. 3). The various objective behind the old extraction procedures were designated
as selective or distinction extraction, since a weak organic acid (tartaric acid) was
used to bind the stronger bases with the help of acidic proton, allowing the separa-
tion of alkaloids that complex only weakly with the acid, and in this form, are solu-
ble in benzene. The partially deactivated chromatography on alumina with 10%
acetic acid follows, then another form of differential extraction was used. The pH
plays an important role and involved stepwise adjustment of the pH, and extraction
with benzene after each adjustment of pH values. Following this procedure, vincris-
tine and vinrosidine were separated and isolated. Vinblastine and vinleurosine did
not need this procedure, since they could be separated by crystallization rather read-
ily. Vinleurosine was crystallized from methanol, whereas vinblastine could be
crystallized with ethanol but not methanol [17, 20, 49–55].
518 S. Kumar and B. Singh

3 Pharmacological Activities

The crude extracts and isolated MIAs from different parts of C. roseus and R. ser-
pentina have been reported for various pharmacological activities (Fig. 4). The etha-
nolic and methanolic crude extracts of both species have strong pharmacological
bioactivities in both in vivo and in vitro studies. The crude extracts of R. serpentina
and its MIAs have been shown to have effects on the central nervous system and
CVD. C. roseus has been used in chemotherapies. Anthelminthic, antibacterial,
anticancer, antidiabetic, antidiarrheal antihyperlipidemic, antihypertensive, anti-­
inflammatory, antimalarial, antimicrobial, antioxidant, antitrypanosomal, cardio-
protective, cholinesterase inhibitory, hepatoprotective, and cytotoxic activities were
reported in different extracts/fractions of plant parts [56–60].

3.1 Chemotherapy

The pharmacological actions of the C. roseus and R. serpentina were reported due
to the presence of indole alkaloids that localized most parts of the plants. Both
C. roseus and R. serpentina are as well one of the most extensively explored

Fig. 4 Different biological activities of the various extracts of C. roseus and R. serpentina
Phytochemistry and Pharmacology of Catharanthus roseus (L.) G. Don… 519

medicinal herbs. C. roseus is more important and in high demand due to its antican-
cerous bisindole alkaloids, vinblastine and vincristine. Besides, the significance of
C. roseus plant in modern system of medicine has been recognized only after the
coincidence discovery of vinblastine and vincristine which are localized in its
leaves. Currently, four main alkaloids derived from Catharanthus are clinically
accepted – vinblastine, vincristine, vinorelbine, and vindesine; however, only vin-
cristine, vinblastine, and vinorelbine are allowed for clinical use in the United States
[60, 61]. Ajmalicine, ajmaline, reserpine, and serpentine are also isolated from
stems and roots of C. roseus and R. serpentina because of their clinical importance
in the management of high blood pressure and obstructive circulatory problems as
well as enhanced cerebral blood circulation [42, 43]. C. roseus plant parts such as
leaves, stems, and roots also contain serpentine, which is used in the management
of hypertension [46–48]. The discovery of bisindole alkaloids, vincristine and vin-
blastine, isolated from C. roseus symbolizes one of the most imperative introduc-
tions of plant-derived products into cancer chemotherapy. These alkaloids are used
for the treatment of malignant and nonmalignant cancers. Besides chemotherapy,
vincristine and vinblastine are also used in the treatment of thrombocytopenic dis-
orders such as Moschcowitz syndrome (thrombotic thrombocytopenic purpura) and
immune thrombocytopenia (idiopathic thrombocytopenic purpura), and microangi-
opathic hemolytic anemia arises [62, 63]. Even though vincristine and vinblastine
are efficient in platelet and platelet-associated disorders, they are required parts of
the pharmacopoeia that is used for the treatment of malignancy. Vincristine and
vinblastine are also used in a broad spectrum of biochemical applications within the
cells and tissues. The exact mechanism of vincristine and vinblastine within tissue
and cell for cytotoxic action is stated as the interactions with tubulin protein and
disruption of microtubule (spindle fibers) actions, particularly of microtubules com-
prising the mitotic spindle apparatus, directly inducing metaphase arrest. Vinblastine
is also used for the treatment of testicular cancer effectively. Hodgkin lymphomas
and the non-Hodgkin lymphomas are other types of blood cancer that may be treated
with combination regimens that comprise vinblastine. Vinblastine is also useful as
an effective therapy for the treatment of Kaposi’s sarcoma, Alibert-Bazin syndrome
(granuloma fungoides), and breast cancer. Vincristine is also a potent drug of cancer
therapy recommended for the treatment of Hodgkin’s lymphoma and other lympho-
mas, as well as pediatric tumors, for example, nephroblastoma (Wilms tumor) and
embryonal rhabdomyosarcoma. These drugs were initially available in the 1960s;
today, the C. roseus alkaloids are incorporated in each efficient combination chemo-
therapy curriculum, due to their uniqueness in relation to therapeutic action and tox-
icities. Vincristine and vinblastine are unusually imperative in both regimens
(curative and palliative). Some of its alkaloids are approved as antineoplastic agents
for the treatment of leukemia, Hodgkin’s disease, malignant lymphomas, neuroblas-
toma, rhabdomyosarcoma, Wilms’ tumor, and other cancers. Its vasodilating and
memory-enhancing properties have experimentally been showing to alleviate vas-
cular dementia and Alzheimer’s disease [64–66]. The plant also has antihyperten-
sive and antispasmodic properties [67]. The cytotoxic activities of eight bisindole
alkaloids, including catharine, leurosidine, leurosine, vinamidine, etc., have been
520 S. Kumar and B. Singh

reported on MDA-MB-231 cells and were tested by MTT assay. These alkaloids
might induce a marked reduction of the cell viability after 72 h treatment. Among
these, leurosine has exhibited the most potent inhibitory activity, while catharinine
(vinamidine) the weakest activity. It is found that leurosidine showed much weaker
activity than that of vinblastine. The 17-deacetoxyvinamidine has a more potent
activity than catharinine (Vinamidine), implying that the lack of acetoxy at C-17
seems to be an advantage in increasing cytotoxicity. These results provided a clear
indication for further structural modification in bisindole alkaloids [39, 68, 69].
Reserpine (100 ng/ml) significantly enhanced the cytotoxicity of heat-shocked-­
activated T cells against both Molt-4 and T98G tumor cells [70]. Yohimbinic acid
and reserpine were found to be the most significant inhibitors against human topoi-
somerase I and II than α-yohimbine, 18-hydroxyepialloyohimbine,
Nb-methylajmaline, Nb-methylisoajmaline, 3-hydroxysarpagine, isorauhimbinic
acid, and reserpinine. Both compounds, yohimbinic acid and reserpine, showed
50% inhibition for topoisomerase I and II at doses of 30 and 20 μM and 20 and
40 μM, respectively, under the same conditions. α-Yohimbine,
18-­hydroxyepialloyohimbine, and reserpinine were inactive and had no effect as
inhibitors of topoisomerase I and II. Yohimbinic acid, isorauhimbinic acid, and
reserpine also inhibited human promyelocytic leukemia (HL-60) cell growth, and
reserpine showed an IC50 value of 67 μM. This inhibitory effect of reserpine was
approximately the same as that of dehydrotramentenoic acid which was reported as
an inhibitor of both topo II effect and HL-60 cancer cell growth [71]. Among them,
compound 11-hydroxyburnamine showed promising effects. The crude extract, its
fractions, and its isolated compounds, lupeol, N-methylsarpagine, and spegatrine,
showed inactive cytotoxicity at 50 μg/mL against HeLa cells [72].

3.2 Antihypertensive Therapy

These clinical trials were undertaken to determine whether the hypotensive action
of extracts or tablets of R. serpentina is strictly limited to the period of its adminis-
tration and whether it has prolonged effect. The hypotensive effect of extract of
R. serpentina root (tablets) has been exposed to clinical trial in a series of 55 cases
of important benign hypertension. After treatment for two weeks, the results showed
that the R. serpentina root (tablets) was effective and safe for the treatment of hyper-
tension [73, 74]. Mild to moderate hypertension has been studied via a double-blind
controlled trial using 381 patients in the random distribution. During treatment, the
elevation of the blood pressure effect was reported. A combination of chlorothiazide
(500 mg/kg BWT) and R. serpentina root (100 mg/kg BWT) was more effective if
taken twice daily and did not show any serious side effects. Controlled double-blind
studies showed that compound reserpine acted as a mild antihypertensive agent at
oral doses of 0.8 to 1.5 mg/day BWT; a reduction of blood pressure has also been
reported [75–77]. In a study, the hypertensive effect of a whole-root preparation of
R. serpentina with compound reserpine carried out on 58 patients. It has been
Phytochemistry and Pharmacology of Catharanthus roseus (L.) G. Don… 521

observed that the whole-root preparation of R. serpentina (400 mg/day) and reser-
pine (0.4 mg/day) showed hypertensive effect without any significant difference.
About 40% of patients who used the preparation showed a satisfactory reduction in
blood pressure without any serious side effects [78]. The extract of the whole root
of R. serpentina or compound reserpine was significantly effective in the treatment
of hypertension with the optimal dose varied from 0–75 to 6–0 mg/kg (serpasil
tablet) and 150–800 mg/kg (raudixin tablet) in 19 ambulatory patients. Sixteen
patients showed reduced blood pressure but with some unavoidable side effects
such as temporary heart failure and weight gain [79]. Thirty-eight patients were
treated with R. serpentina preparations at a dose of 1 g per day for 6 to 20 months.
About 67% of patients showed a reduction of blood pressure (10–20 mm. Hg) con-
sistently after being treated with R. serpentina preparation. The effect of crude root
extract (dosage from 150–450 mg/per day) and compound reserpine (dosage from
0.75–3 mg/ per day) along with addition of apresoline or hexamethonium in a group
of 76 patients with arterial hypertension was studied for time varying between two
and twelve months. The combination of apresoline or hexamethonium with crude
root extract of Rauvolfia showed better results than when given alone. A cases study
was reported for reserpine confirmed as a treatment for constitutional leanness [81].
A comparative study of compounds reserpine and rescinnamine for periods ranging
from 5 to 12 weeks with doses ranging from 1 to 2 mg/ daily in 32 patients showed
that reserpine is more effective than rescinnamine with comparatively minimum
side effects [82].

3.3 Antipsychotic Activity

The alkaloids (compounds 10-methoxytetrahydroalstonine, isoreserpiline, reserpi-

line, 10-demethoxyreserpiline, 11-demethoxyreserpiline and α-yohimbine) were
tested in vivo for their antipsychotic potential on amphetamine-induced hyperactive
mouse model, and the results showed that alkaloids, the mixture of compounds
11-demethoxyreserpiline and 10-demethoxyreserpiline, α-yohimbine, and reserpi-
line, were significantly active with 75%, 81%, and 69% inhibition, respectively,
while compound isoreserpiline was moderately active (57%) and
10-­methoxytetrahydroalstonine inactive (12%). α-Yohimbine was even active at
6.25 mg/kg dose followed by a mixture of alkaloid reserpiline (25 mg/kg) and
10-Demethoxyreserpiline (12.5 mg/kg) and 11-demethoxyreserpiline [82, 83]. A
study showed that the root bark extract of R. vomitoria and its alkaloid reserpine
with antipsychotic agent chlorpromazine in mice using 0.25, 1.0, 2.0, and 4.0 mg/
kg for extract and 0.1, 0.4, 0.8, 1.6 mg/kg for reserpine were administered 24 h
before testing. The extracts as well as chlorpromazine decreased locomotors’ behav-
ior at 4.0 mg/kg (p < 0.5) but did not alter exploration and motor coordination [84].
Similarly, compound reserpine, however, decreased locomotion and exploration and
impaired motor coordination at 0.8 and 1.6 mg/kg (p < 0.05). Chlorpromazine also
increased anxiety-related behavior at 1.0, 2.0 mg/kg (p < 0.05), whereas the extract
522 S. Kumar and B. Singh

dose-dependently decreased anxiety from 1.0 to 4.0 mg/kg (p < 0.01) in the light/
dark box. In contrast to extract, the application of reserpine increased anxiety-­
related behavior from 0.4 to 0.6 mg/kg using dose-dependently. Therefore, root bark
extract from R. vomitoria could be a better option with great potential as an alterna-
tive antipsychotic agent due to its better behavioral effects with less distortion in
motor coordination as compared to chlorpromazine [85].

3.4 Cardiovascular Diseases

Most common CVD such as cardiomyopathies, coronary heart, dyslipidaemias,

heart attack, heart failure, peripheral vascular (myocardial infarction), stroke, and
hypertension, among others, are the diseases associated with the blood vessels that
have been treated by many traditional and pharmacological scientists by traditional
medicine [85]. More than 17 million deaths are caused by CVD globally every year
and it is the most common cause of death and a major economic and health burden.
Last many decades, Rauvolfia species have been reported for the treatment of
CVD. For the first time, Vakil (1955) has reviewed their cardioprotective activity
such as treatment of high blood pressure by R. serpentina and claimed that Rauvolfia
therapy started in 1949 [73, 74].

3.5 Psoriasis

During the treatment of arterial hypertension, a patient with long-standing psoriasis

showed a marked improvement in her blood pressure as well as almost complete
relief of her skin condition after five weeks of treatment with the extract. After that,
14 cases with a severe degree of psoriasis have been properly studied and dramatic
improvement in some patients occurred. It appears that the root of R. serpentina is
reported in the treatment of cases of psoriasis, provided high doses are used for at
least two months [80].

4 Conclusions

The growing trend of industrialization and the appearance of many unknown and
tenacious diseases are among the extreme challenges to scientists in near future.
MIAs from C. roseus, R. serpentina have demonstrated novel therapeutic character-
istics as a result of a large number of scientific investigations over the past five
decades. Therefore, vincristine and vinblastine replacing chemical and synthesized
drugs with naturally derived drugs seem highly rationale for the treatment of cancer.
Similarly, various herbal formulations of the R. serpentina and its bioactive
Phytochemistry and Pharmacology of Catharanthus roseus (L.) G. Don… 523

compounds ajmaline, ajmalicine, and reserpine are used for the treatment of high
blood pressure and hypertension. Additionally, more efforts need to gain insights
into the therapeutic mechanism and toxicological actions of the herb, different
extracts/fractions, and main active MIAs in future studies.

Acknowledgments The authors are thankful to the Principal, MK Govt. Degree College, Ninowa,
Farrukhabad, Uttar Pradesh, India, and Director, CSIR-National Botanical Research Institute
(NBRI), Lucknow, India for encouragement and facilities.

References

1. Oudin A, Mahroug S, Courdavault V et al (2007) Spatial distribution and hormonal regulation

of gene products from methyl erythritol phosphate and monoterpene-secoiridoid pathways in
Catharanthus roseus. Plant Mol Biol 65(1):13–30
2. Musetti R, Favali MA (2003) Cytochemical localization of calcium and X-ray microanalysis
of Catharanthus roseus L. infected with phytoplasmas. Micron 34(8):387–393
3. Das A, Sarkar S, Bhattacharyya S et al (2020) Biotechnological advancements in Catharanthus
roseus (L.) G. Don. Appl Microbiol Biotechnol 104(11):4811–4835
4. Shitiz K, Gupta SP (2021) Rauvolfia serpentina. Himalayan Medicinal Plants, 111–149.
https://doi.org/10.1016/B978-­0-­12-­823151-­7.00009-­X
5. Phillips DD, Chadha MS (1955) The alkaloids of Rauvolfia serpentina benth. J Am Pharm
Assoc 44(9):553–567
6. Dey A, De JN (2011) Ethnobotanical aspects of Rauvolfia serpentina (L). Benth. ex Kurz. in
India, Nepal and Bangladesh. J Med Plant Res 5(2):144–150
7. Sharma S, Rathi N, Kamal B et al (2010) Conservation of biodiversity of highly important
medicinal plants of India through tissue culture technology-a review. Agric Biol J N Am
1(5):827–833
8. Rahmatullah M, Mollik AH, Rahman S et al (2010) A medicinal plant study of the Santal tribe
in Rangpur district, Bangladesh. J Altern Complement Med 16(4):419–425
9. Nisar A, Mamat AS, Hatim MI et al (2016) An updated review on Catharanthus roseus: phy-
tochemical and pharmacological analysis. Indian J Pharm Sci 3(2):631–653
10. van de Venter M, Roux S, Bungu LC et al (2008) Antidiabetic screening and scoring of 11
plants traditionally used in South Africa. J Ethnopharmacol 119(1):81–86
11. Kumar S, Singh B, Singh R (2022) Catharanthus roseus (L.) G. Don: a review of its eth-
nobotany, phytochemistry, ethnopharmacology and toxicities. J Ethnopharmacol 284:114647
12. Almagro L, Fernández-Pérez F, Pedreño MA et al (2015) Indole alkaloids from Catharanthus
roseus: bioproduction and their effect on human health. Molecules 20(2):2973–3000
13. Pereira DM, Ferreres F, Oliveira J et al (2009) Targeted metabolite analysis of Catharanthus
roseus and its biological potential. Food Chem Toxicol 47(6):1349–1354
14. Dhayanithy G, Subban K, Chelliah J et al (2019) Diversity and biological activities of endo-
phytic fungi associated with Catharanthus roseus. BMC Microbial 19(1):1–14
15. Pereira DM, Ferreres F, Oliveira JM et al (2010) Pharmacological effects of Catharanthus
roseus root alkaloids in acetylcholinesterase inhibition and cholinergic neurotransmission.
Phytomedicine 17(8–9):646–652
16. Nath A, Chattopadhyay A, Joshi SR et al (2015) Biological activity of endophytic fungi of
Rauvolfia serpentina Benth: an ethnomedicinal plant used in folk medicines in Northeast
India. Proc Natl Acad Sci India Sect B: Biol Sci 85(1):233–240
17. Sheludko Y, Gerasimenko I, Kolshorn H et al (2002) New alkaloids of the sarpagine group
from Rauvolfia serpentina hairy root culture. J Nat Prod 65(7):1006–1010
524 S. Kumar and B. Singh

18. Svoboda GH, Neuss N, Gorman M et al (1959) Alkaloids of Vinca rosea Linn.(Catharanthus
roseus G. Don.) V. preparation and characterization of alkaloids. J Am Pharm Assoc
48(11):659–666
19. Plummer AJ, Earl A, Schneider JA et al (1954) Pharmacology of Rauwolfia alkaloids, includ-
ing reserpine. Ann N Y Acad Sci 59(1):8–21
20. Itoh A, Kumashiro T, Yamaguchi M et al (2005) Indole alkaloids and other constituents of
Rauvolfia serpentina. J Nat Prod 68(6):848–852
21. Sagi S, Avula B, Wang YH et al (2016) Quantification and characterization of alkaloids from
roots of Rauvolfia serpentina using ultra-high performance liquid chromatography-photo
diode array-mass spectrometry. Anal Bioanal Chem 408(1):177–190
22. Batista CVF, Schripsema J, Verpoorte R (1996) Indole alkaloids from Rauwolfia sellowii.
Phytochemistry 41(3):969–973
23. World Health Organization (2006) The selection and use of essential medicines: report of the
WHO Expert Committee, 2005 (including the 14th Model List of Essential Medicines) (vol
933). World Health Organization
24. Lindenberg M, Kopp S, Dressman JB et al (2004) Classification of orally administered drugs
on the World Health Organization model list of essential medicines according to the biophar-
maceutics classification system. Eur J Pharm Biopharm 58(2):265–278
25. Salam A, Kanukula R, Esam H et al (2019) An application to include blood pressure lowering
drug fixed dose combinations to the model list of essential medicines lists for the treatment of
essential hypertension in adults. World Health Organization, Geneva
26. Arora R, Malhotra P, Mathur AK et al (2010) Anticancer alkaloids of Catharanthus roseus:
transition from traditional to modern medicine. Herbal medicine: a cancer chemopreven-
tive and therapeutic perspective. Jaypee Brothers Medical Publishers Pvt. Ltd, New Delhi,
pp 292–310
27. Ming KJ, Khang GN, Sai CL (2003) Recent advances in traditional plant drugs and orchids.
Acta Pharmacol Sin 24(1):7–21
28. Gao Y, Yu AL, Li GT et al (2015) Hexacyclic monoterpenoid indole alkaloids from Rauvolfia
verticillata. Fitoterapia 107:44–48
29. Gerasimenko I, Sheludko Y, Ma X et al (2002) Heterologous expression of a Rauvolfia cDNA
encoding strictosidine glucosidase, a biosynthetic key to over 2000 monoterpenoid indole
alkaloids. Eur J Biochem 269(8):2204–2213
30. Mehrotra S, Goel MK, Srivastava V et al (2015) Hairy root biotechnology of Rauvolfia ser-
pentina: a potent approach for the production of pharmaceutically important terpenoid indole
alkaloids. Biotechnol Lett 37(2):253–263
31. O'Connor SE, Maresh JJ (2006) Chemistry and biology of monoterpene indole alkaloid bio-
synthesis. Nat Prod Rep 23(4):532–547
32. Stöckigt J, Barleben L, Panjikar S et al (2008) 3D-structure and function of strictosidine syn-
thase–the key enzyme of monoterpenoid indole alkaloid biosynthesis. Plant Physiol Biochem
46(3):340–355
33. Zhu J, Wang M, Wen W et al (2015) Biosynthesis and regulation of terpenoid indole alkaloids
in Catharanthus roseus. Pharmacogn Rev 9(17):24–28
34. Zhu X, Zeng X, Sun C et al (2014) Biosynthetic pathway of terpenoid indole alkaloids in
Catharanthus roseus. Front Med 8(3):285–293
35. Verpoorte R, van der Heijden R, Moreno PR (1997) Biosynthesis of terpenoid indole alka-
loids in Catharanthus roseus cells. In: The alkaloids: chemistry and pharmacology, vol 49.
Academic Press, pp 221–299
36. Zhao J, Zhu WH, Hu Q et al (2001) Effects of light and plant growth regulators on the bio-
synthesis of vindoline and other indole alkaloids in Catharanthus roseus callus cultures. Plant
Growth Regul 33(1):43–49
37. El-Sayed M, Verpoorte R (2007) Catharanthus terpenoid indole alkaloids: biosynthesis and
regulation. Phytochem Rev 6(2):277–305
Phytochemistry and Pharmacology of Catharanthus roseus (L.) G. Don… 525

38. DeLuca V, Balsevich J, Tyler RT et al (1986) Biosynthesis of indole alkaloids: developmental

regulation of the biosynthetic pathway from tabersonine to vindoline in Catharanthus roseus.
J Plant Physiol 125(1–2):147–156
39. Wang CH, Wang GC, Wang Y et al (2012) Cytotoxic dimeric indole alkaloids from
Catharanthus roseus. Fitoterapia 83(4):765–769
40. Pan Q, Mustafa NR, Tang K (2016) Monoterpenoid indole alkaloids biosynthesis and its regu-
lation in Catharanthus roseus: a literature review from genes to metabolites. Phytochem Rev
15(2):221–250
41. Kumar S, Bajpai V, Singh A et al (2015) Rapid fingerprinting of Rauwolfia species using direct
analysis in real time mass spectrometry combined with principal component analysis for their
discrimination. Anal Methods 7(14):6021–6026
42. Kumar S, Singh A, Bajpai V et al (2016) Structural characterization of monoterpene indole
alkaloids in ethanolic extracts of Rauwolfia species by liquid chromatography with quadrupole
time-of-flight mass spectrometry. J Pharm Anal 6(6):363–373
43. Kumar S, Singh A, Bajpai V et al (2016) Simultaneous determination of bioactive monoter-
pene indole alkaloids in ethanolic extract of seven Rauvolfia species using UHPLC with hybrid
triple quadrupole linear ion trap mass spectrometry. Phytochem Anal 27(5):296–303
44. Kumar S, Singh A, Bajpai V et al (2016) Identification, characterization and distribution of
monoterpene indole alkaloids in Rauwolfia species by Orbitrap Velos pro mass spectrometer.
J Pharm Biomed Anal J 118:183–194
45. Kumar S, Singh A, Kumar B (2019) Screening of monoterpene indole alkaloids in six
Rauwolfia species by ultra-high performance liquid chromatography orbitrap velos pro mass
spectrometer. Sep Sci Plus 2(8):300–308
46. Kumar S, Bajpai V, Singh A et al (2018) Identification, characterization and distribution of
terpene indole alkaloids in ethanolic extracts of Catharanthus roseus using high-­performance
liquid chromatography/electrospray ionization quadrupole time-of-flight tandem mass spec-
trometry and the study of their geographical variation. Rapid Commun Mass Spectrom
32(4):319–332
47. Kumar S, Singh A, Kumar B et al (2018) Simultaneous quantitative determination of bioactive
terpene indole alkaloids in ethanolic extracts of Catharanthus roseus (L.) G. Don by ultra-­
high performance liquid chromatography–tandem mass spectrometry. J Pharm Biomed Anal
151:32–41
48. Hisiger S, Jolicoeur M (2007) Analysis of Catharanthus roseus alkaloids by HPLC. Phytochem
Rev 6(2–3):207–234
49. Kumar A, Ahmad A (2013) Biotransformation of vinblastine to vincristine by the endophytic
fungus fusarium oxysporum isolated from Catharanthus roseus. Biocatal Biotransformation
31(2):89–93
50. Wang L, Zhang Y, He HP et al (2011) Three new terpenoid indole alkaloids from Catharanthus
roseus. Planta Med 77(07):754–758
51. Zeng J, Zhang DB, Zhou PP et al (2017) Rauvomines a and B, two monoterpenoid indole
alkaloids from Rauvolfia vomitoria. Org Lett 19(15):3998–4001
52. Kato L, Braga RM, Koch I (2002) Indole alkaloids from Rauvolfia bahiensis a.
DC.(Apocynaceae). Phytochemistry 60(3):315–320
53. Gao Y, Zhou DS, Kong LM et al (2012) Rauvotetraphyllines AE, new indole alkaloids from
Rauvolfia tetraphylla. Nat Prod Bioprospecting 2(2):65–69
54. Kumar B, Kumar S, Bajpai V et al (2020) Phytochemistry of plants of genus Rauvolfia.
CRC Press
55. Wachsmuth O, Matusch R (2002) Anhydronium bases from Rauvolfia serpentina.
Phytochemistry 61(6):705–709
56. Lahare RP, Yadav HS, Dashhare A et al (2020) An updated review on phytochemical and phar-
macological properties of Catharanthus rosea. Saudi J Med Pharm Sci 6(12):759–766
57. Mahroug S, Burlat V, St-Pierre B (2007) Cellular and sub-cellular organisation of the mono-
terpenoid indole alkaloid pathway in Catharanthus roseus. Phytochem Rev 6(2–3):363–381
526 S. Kumar and B. Singh

58. Abhijit D, De JN (2010) Rauvolfia serpentina (L). Benth ex Kurz-a review. Asian J Plant Sci
9(6):285–298
59. Kumari R, Rathi B, Rani A (2013) Rauvolfia serpentina L. Benth. Ex Kurz.: phytochemical,
pharmacological and therapeutic aspects. Int J Pharm Sci Rev Res 23(2):348–355
60. Neuss N, Neuss MN (1990) Therapeutic use of bisindole alkaloids from catharanthus. In: The
alkaloids: chemistry and pharmacology, vol 37. Academic Press, pp 229–240
61. Nelson RL (1982) The comparative clinical pharmacology and pharmacokinetics of vin-
desine, vincristine, and vinblastine in human patients with cancer. Indian J Med Paediatr
10(2):115–127
62. Pennanen S, Huhtikangas A (1990) Photochemical one-pot synthesis of vinblastine and vin-
cristine. Photochem Photobiol 51(5):515–518
63. Barkat MA, Abul H, Rahman MA (2017) Agricultural, pharmaceutical, and therapeutic inte-
rior of Catharanthus roseus (L.) G. Don. In: Catharanthus roseus. Springer, Cham, pp 71–100
64. Tsuruo T, Iida H, Tsukagoshi S (1981) Overcoming of vincristine resistance in P388 leukemia
in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil.
Cancer Res 41(5):1967–1972
65. Qu Y, Safonova O, De Luca V (2019) Completion of the canonical pathway for assembly of
anticancer drugs vincristine/vinblastine in Catharanthus roseus. Plant J 97(2):257–266
66. Alam MM, Naeem M, Khan MMA et al (2017) Vincristine and vinblastine anticancer cath-
aranthus alkaloids: pharmacological applications and strategies for yield improvement. In:
Catharanthus roseus. Springer, Cham, pp 277–307
67. Kabesh K, Senthilkumar P, Ragunathan R et al (2015) Phytochemical analysis of Catharanthus
roseus plant extract and its antimicrobial activity. Int J Pure App Biosci 3(2):162–172
68. Wang XD, Li CY, Jiang MM et al (2016) Induction of apoptosis in human leukemia cells
through an intrinsic pathway by cathachunine, a unique alkaloid isolated from Catharanthus
roseus. Phytomedicine 23(6):641–653
69. Parthasarathy R, Shanmuganathan R, Pugazhendhi A (2020) Vinblastine production by the
endophytic fungus Curvularia verruculosa from the leaves of Catharanthus roseus and its
in vitro cytotoxicity against HeLa cell line. Anal Biochem 593:113530
70. Jin GB, Hong T, Inoue S et al (2002) Augmentation of immune cell activity against tumor cells
by Rauwolfia radix. J Ethnopharmacol 81(3):365–372
71. Chen Q, Lu X, Guo X (2017) Metabolomics characterization of two Apocynaceae plants,
Catharanthus roseus and Vinca minor, using GC-MS and LC-MS methods in combination.
Molecules 22(6):997
72. Tlhapi DB, Ramaite ID, Anokwuru CP et al (2020) In vitro studies on antioxidant and anti-­
parasitic activities of compounds isolated from Rauvolfia caffra Sond. Molecules 25(17):3781
73. Vakil RJ (1949) A clinical trial of Rauvolfia serpentina in essential hypertension. Br Heart J
11(4):350–355
74. Vakil RJ (1955) Rauvolfia serpentina in the treatment of high blood pressure: a review of the
literature. Circulation 12(2):220–229
75. Smith WM, Damato AN, Galluzzi NJ et al (1964) The evaluation of antihypertensive ther-
apy cooperative clinical trial method: I. Double-blind control comparison of chlorothiazide,
Rauvolfia serpentina, and hydralazine. Ann Intern Med 61(5_Part_1):829–846
76. Smith WM, Bachman B, Galante JG et al (1966) Co-operative clinical trial of alpha-­
methyldopa: III. Double-blind control comparison of alpha-methyldopa and Chlorothiazide,
and Chlorothiazide and Rauwolfia. Ann Intern Med 65(4):657–671
77. Smith WM, Thurm RH, Bromer L (1969) Comparative evaluation of Rauwolfia whole root and
reserpine. Clin Pharmacol Ther 10(3):338–343
78. Healy D, Savage M (1998) Reserpine exhumed. Br J Psychiatry 172(5):376–378
79. McGregor M, Segel N (1955) The Rauwolfia alkaloids in the treatment of hypertension. Br
Heart J 17(3):391–396
80. Genest J, Adamkiewicz L, Robillard R et al (1955) Clinical uses of Rauwolfia: I. In arterial
hypertension. Can Med Assoc J 72(7):483–489
Phytochemistry and Pharmacology of Catharanthus roseus (L.) G. Don… 527

81. Lemieux G, Davignon A, Genest J (1956) Depressive states during Rauwolfia therapy for arte-
rial hypertension: a report of 30 cases. Can Med Assoc J 74(7):522
82. Bisong SA, Brown RE, Osim EE (2013) Comparative extrapyramidal effects of Rauwolfia
vomitoria, chlorpromazine and reserpine in mice. J Nat Med 67(1):107–112
83. Gupta S, Khanna VK, Maurya A et al (2012) Bioactivity guided isolation of antipsychotic
constituents from the leaves of Rauwolfia tetraphylla L. Fitoterapia 83(6):1092–1099
84. Bisong SA, Brown R, Osim EE (2010) Comparative effects of Rauwolfia vomitoria and chlor-
promazine on locomotor behaviour and anxiety in mice. J Ethnopharmacol 132(1):334–339
85. Surendran S, Raju R, Prasannan P et al (2021) A comprehensive review on ethnobotany, phy-
tochemistry and pharmacology of Rauvolfia L.(Apocynaceae). The Bot Rev:1–66
Resilience Activity of Glycyrrhiza glabra
in Relation to Cancer: Chemistry
and Mechanism

Naveen Dhingra, Shaligram Sharma, Pratima Kumari, and Anand Kar

1 Introduction

From ancient times, plants are considered major sources of medicine and are used
in the prevention and elimination of diseases. Today across the world, there has
been enormous demand for herbal medicines because of their safety, efficacy, and
lesser toxicity in comparison to synthetic drugs [1]. Glycyrrhiza glabra (Family:
Fabaceae), also known as licorice derived from the Greek words glykos (sweet) and
rhiza (root), is one of the most popular medicinal plants used in traditional medicine
to treat varieties of diseases [2–7]. Glycyrrhiza glabra has long history of folk and
traditional medicines and it is one of the oldest known botanical medicinal herbs.
About 90% of G. glabra is used as flavouring agents in tobacco products, chewing
tobacco, pipe tobacco, and American blend cigarettes [8, 9]. G. glabra-based fla-
vouring agents are added in soft drinks, herbal teas, candies, chewing gum, tooth-
paste, and herbal remedies for stomach problems and cough [7, 10]. Annual
consumption of licorice is about 1.5 kg/person worldwide [11].
G. glabra is known for various pharmacological, anticarcinogenic, antitussive,
antimicrobial, anticoagulant, antiviral, antiulcer, antioxidant, antiinflammation,
antidiabetic, immunomodulatory, hepatoprotective, and antiatherogenic activities
(Fig. 1) [6, 12–32].
Researchers have reported that various secondary metabolites are present in
G. glabra. It is reported that G. glabra contains more than 300 flavonoids and 20

N. Dhingra (*)
Department of Agriculture, Medi-Caps University, Indore, Madhya Pradesh, India
S. Sharma · P. Kumari
Department of Biology, College of Arts and Sciences, Georgia State University,
Atlanta, GA, USA
A. Kar
School of Life Sciences, Devi Ahilya University, Indore, Madhya Pradesh, India

© The Author(s), under exclusive license to Springer Nature 529

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_20
530 N. Dhingra et al.

Fig. 1 Pharmacological activities of G. glabra

triterpenoids. Diversified secondary metabolites found in G. glabra are glycosides,

flavonoids, saponins, triterpenoids, glycyrrhizin, ligoargone, licochalcone, liqcou-
marin, quercetins, licoargone, liquiritigenin, licuraside, glyzaglabrin, isoliquiriti-
genin, prenylated biaurone, 4-methyl coumarin, 7-acetoxy-2-methyl-isoflavone,
and 7-hydroxy-2 methyl isoflavone. Besides these, other constituents are glycyr-
rhetinic acid, glycyrrhizic acid, glabridin, glabrolide, glyzarin, glabrol, liquoric
acid, liquiritoside, liquiritic acid, liquiritin, licoflavonol, licoisoflavones A, B, licoi-
soflavon, glyzaglabrin, isoliquiritin, isoglabrolide, and 18α-hydroxy glycyrrhetic
acid [33–40].
Though many bioactive compounds are found in G. glabra, which showed vari-
ous pharmacological activities, glycyrrhizin, glycyrrhetic acid, iso-liquiritigenin,
isoangustone A, and licochalcones are known to possess potential anti-cancer activ-
ity (Fig. 2). In this chapter, we have reviewed the phytochemistry and pharmaco-
logical activities of extract and bioactive components of G. glabra in relation
to cancer.

2 Phytochemistry/Chemistry

Many bioactive components have been isolated from the roots of Glycyrrhiza gla-
bra, using different solvents such as chloroform, petroleum ether, n-butanol, metha-
nolic and water [34]. Qualitative analysis of these extracts shows the presence of a
wide range of bioactive components, categorized into different groups, including
saponin, mucilage (from rhizome), terpenoids, amino acids, flavonoids, phenols,
Resilience Activity of Glycyrrhiza glabra in Relation to Cancer: Chemistry… 531

Fig. 2 Major bioactive components in G. glabra

and various other substances [7, 41]. Flavonoid-rich fraction includes liquirtin,
liquiritigenin, glucoliquiritin apioside, coumarin-GU-12, etc., while four new
isoprenoids-­phenolic substitutes such as isoangustone A, semilicoisoflavone B, lic-
oriphenone, and 1-methoxyficifolinol were reported [42, 43]. Some of the volatile
components identified include pentanol, tetramethyl pyrazine, hexanol,
terpinene-­4-ol, linalool oxide A and B, geraniol, and α-terpineol. Triterpenoid sapo-
nin glycyrrhizin, a key ingredient in Glycyrrhiza glabra root extracts, is known for
its anti-cancerous sweetener (60 times more potent than regular cane sugar) activity
[42]. However, methanolic extract showed a strong bactericidal effect against both
gram-positive and gram-negative bacteria, with most robust activity against
Staphylococcus aureus with the zone of inhibition 22 mm [43].
532 N. Dhingra et al.

2.1 Glycyrrhizin

Representing 10% of the root dry weight, glycyrrhizin (dry weight) makes up most
of the Glycyrrhiza glabra plant root. Chemically, glycyrrhizin is a mixture of potas-
sium, calcium, and magnesium salts of glycyrrhizin acid (2–25%) [7]. Structurally,
glycyrrhizin consists of glycyrrhizin acid that is composed of a hydrophobic frag-
ment, two molecules of glucuronic acid, and a hydrophilic part [44]. Glycyrrhizin,
a triterpenoid of aglycone, and glycyrrhetic acid bonded with a glucuronic acid
disaccharide can exist as stereoisomers of 18α and 18β. Licorice extract was used to
obtain ammoniated salt of glycyrrhizin, which is further used in the food industry
for flavour [45]. An analog of glycyrrhizin acid, carbenoxolone, is used to treat
digestive disorders, such as peptic ulcers [45].

2.2 Liquorice

Flavonoids identified in Glycyrrhiza glabra have been categorized into various

classes, including flavanones, flavones, flavanonols, chalcones, isoflavans, isofla-
venes, isoflavones, and isoflavanones. Rizzato et al. (2017) identified additional fla-
vonoids from the roots of Glycyrrhiza glabra, including liquiritigenin
(4′,7-dihydroxyflavanone), and isoliquiritigenin (2′,4,4′-trihydroxychalcone), such
as liquiritin, isoliquiritin, liquiritin apioside, and licuraside, while the principal iso-
flavone was glabridin (0.08–0.35% root dry weight) [7, 46]. Additionally, Fukui,
Goto, & Tabata et al. (1988) identified Pinocembrin and licoflavanone (flavonoids)
extracted from leaves of the Glycyrrhiza glabra [47]. Methanolic extract of
Liquorice has been studied extensively for its anti-cancerous activity on intestinal
carcinoma cell line (Caco2) and prostate carcinoma (PC-3), owing to the richness of
phytoestrogen compounds in the extracts [45].

3 Pharmacological Properties

Glycyrrhiza glabra extracts prepared in various solvents have been used to identify
the pharmacological potential of the plant. In vivo and in vitro experiments using
the root and leave extracts have shown potent anti-inflammatory, antimicrobial,
antiproliferative, and cytotoxic activities. Nonetheless, the biological activity varies
following the geographical distribution of the plants, extraction methodology, dry-
ing, and harvesting methods.
Resilience Activity of Glycyrrhiza glabra in Relation to Cancer: Chemistry… 533

3.1 Antioxidant and Anti-inflammatory Effects

Glycyrrhiza glabra has been primarily studied because of its antioxidant potential.
Phenolic and flavonoid extracts were attributed to their antioxidant effect, while
their derivatives enhance antioxidant potential. Glabridin, hispaglabridin A, and
30-hydroxy-40-methylglabridin are the major phenolic composition in ethanolic
extract, conferring the antioxidant potential through metal chelating, donation of
hydrogens, reducing ability, and scavenging assay. Phenolic compounds protect
against oxLDL, lipid peroxidation (microsomal and mitochondrial), and oxidative
stress, making them an ideal candidate for cardiovascular research, in addition to
known health benefits [48]. Retrochalcone, derivative from Glycyrrhiza glabra,
exerts strong antioxidant and protect RBC from oxidative haemolysis. Licochalcone
C supresses superoxide radicals and promotes nitric oxide synthesis [49]. Methanolic
extract mixed with DPPH (1,1-diphenyl-2-picrylhydrazyl) showed scavenging
potential of 67.2% at a concentration of 500ug/ml [50].
Licorice extract from Glycyrrhiza exhibits anti-inflammatory activity through
inhibition of nitric oxide, IL-6, PGE2 (prostaglandin E2) in LPS (lipopolysaccha-
ride) induced macrophages [51]. Mueller et al. (2010) confirmed that Glycyrrhiza of
root extract (0.5–0.2 mg/ml) promotes anti-inflammatory activity by suppressing
COX2, iNOS, TNFa, IL1b, and IL8 [52, 53]. Oral administration of Male albino rats
(Sprague Dawley strain) with Glycyrrhiza glabra root extract (200-800 mg/kg BW)
was done for 4-weeks. Significant improvements in total cholesterol and triglycer-
ides decrease serum liver enzyme (AST and ALT), inducing potent anti-­inflammatory
and anti ulcerative effects [54]. Mechanistically, digested Glycyrrhiza is broken
down into various subunits, part of which act similar to hydrochortison (steroid
hormone) to inhibit PLA2 (phospholipase) and platerlet aggregations [55].
Glycyrrhizin, a potent anti-inflammatory compound isolated from the Glycyrrhiza,
is known to increase blood coagulation time and plasma recalcification, therefore
categorized as the first plant-based thrombin inhibitor without affecting the collagen
or platelet aggregation factors [16, 56]. Collectively, in vitro and in vivo analyses
suggest that Glycyrrhiza glabra is a potent antioxidant and anti-inflammatory as
compared to known vitamins [57].

3.2 Immunomodulatory and Antiviral Effects

At the current pandemic, viral disease has been a significant concern around the
globe. According to Baltina et al. (2003) glycoprotein derivatives of Glycyrrhizic
Acid have been shown to possess immunomodulatory activity in mice. Intraperitoneal
injection of Glycyrrhizic Acid (2 mg/kg) derivatives with methyl esters of amino
acids stimulated the immune system in stressed mice. In combination with zinc
(45 mg/kg), Glycyrrhiza root extracts (1.5 g/kg BW) protect against systemic ana-
phylactic reactions and promote immunomodulation in rodents [58]. However,
534 N. Dhingra et al.

alcoholic and polysaccharide extracts of Glycyrrhiza induce macrophage-mediated

immunomodulation and phagocytosis [59]. Studies confirm that licorice (100 ug/
ml) can enhance TCD69 lymphocytes and granulocytes production stimulating the
immune system, and protecting against autoimmune diseases, including systemic
lupus erythematosus [57, 59].
Glycyrrhizic acid (salts, amides, and glycoproteins), the significant component
of Glycyrrhiza extracts, has been shown to be effective against viral infections.
Salts, amides, and glycoproteins of Glycyrrhizic effectively inhibited replication of
HIV-1, H5N1-induced apoptosis, herpes simplex virus (HSV1), and decreased
reverse transcriptase activity in vitro [60–62]. Additionally, Soufy et al. established
that glycyrrhizic acid could inhibit duck hepatitis virus (DHV) and promote immu-
nostimulation. In contrast, Fukuchi et al. (2016) suggested that alkaline extract of
licorice exceeds antiviral potential than aqueous extract on HIV [60, 63, 64]. Due to
modified Glycyrrhizic Acid’s antiviral potential, additional insertion of 2-acetamido-­
β-D glucopyranosylamine into the glycoside side-chain enhanced its activity by
ten-fold against replication, absorption, and penetration of SARS-CoV in tissues. In
vitro and in vivo experiments are required to establish how Glycyrrhizic promotes
antiviral activity [65].

3.3 Neuromodulatory Effects (Memory Antidepressant

and Sedative)

Free radicals generated during the cellular process promote neurological disorders,
including memory loss and depression. The antioxidant effect of licorice (flavonoid)
is attributed to its ability to neutralize free radicles to improve neurological disor-
ders [42, 66]. 500 mg tablets prepared from grounded roots (crude) of Glycyrrhiza
glabra were used to evaluate intelligence and memory function in male adult kids
(n = 123) aged 13-14 years [67]. Non-verbal intelligence test (NVIT) among the test
and placebo group showed that oral consumption of 500 mg tablets for 6 months
improved student intelligance in the test group compared with the placebo group
[67]. The drug treatment showed overall improvement in general intelligence rather
than short-term intelligence improvement [67]. In a similar experiment on rodents
(3 months old, Wistar albino rats), Chakravarthi et al. (2012) used Elevated plus-­
maze and Morris water maze tests to evaluate the effect of Glycyrrhiza glabra root
extract on memory. Rats were fed with variable concentration of root extracts (aque-
ous) for 2 weeks followed by evaluation of cognitive functions. 150 mg/kg dose
effectively enhanced cognitive ability in rats; additionally, a liner dosage-dependent
improvement on learning and memory was also reported [68]. Additionally, the
principle isoflavone glabridin exhibits strong sedative and hypnotic effects through
the inhibition in dorsal raphe neurons by the activation of γ-amino butyric acid-A
(GABAA) receptor [69]. Isoliquiritigenin, a key phytocompound of glycyrrhiza,
forms a significant portion of Japanese Kampo Medicine Yokukansan, promoting
Resilience Activity of Glycyrrhiza glabra in Relation to Cancer: Chemistry… 535

neuroptotective effects. Mechanistically, Isoliquiritigenin inhibits NMDA receprots

to improve dementia and neurological disorder, similar to that of known drug for
dementia, memantine, while glycycoumarin protects neuron by inhibiting pro-­
apototoc action of caspase-3 [70, 71].

4 Anti-cancer Activity of Glycyrrhiza glabra

In vitro and In vivo experiments using Glycyrrhiza extracts have shown promising
results. Some of the primary compounds that have been tested against anti-­cancerous
activity include glabridin, licochalcone E, licochalcone A, 18β-glycyrrhetinic, etc.
The principal isoflavonoid compound, glabridin at a concentration of 0-100uM
(in vitro), or 0-20 mg/kg (in vivo), can effectively supress cancerous properties in
breast cancer stem cells and can induce apoptosis in hepatic cell lines such as Huh7,
HepG2, Sk-Hep-1 in vitro and in vivo. Glabridin enhances the expression of
microRNA-148 through DNA methylation, followed by the binding of
microRNA-148 at 3’UTR of SMAD2 to supress TGFb-induced stemness in breast
cancer cells (microRNA-148/TGFb-SMAD2 signalling) [72, 73]. Licochalcone E
and licochalcone A induce apoptosis in pharyngeal squamous cells (FaDu) and gas-
tric cell lines in a caspase and mitochondrial-dependent manner, like that of cell
death in human oral keratinocytes (hNOKs) cell line [74, 75]. FaDu cells when
treated with 50uM of licochalcone E for 24 hr. resulted in increased expression of
pro-apoptotic factors such as caspase 8, BAX, Bcl-2, caspase 9, cleaved caspase3,
and poly (ADP-ribose) polymerase [74].
Scientific literature suggests that 18β-glycyrrhetinic and glycyrrhizic acids effec-
tively supress the growth of cervix and uterine tumours through activation of pro-­
apoptotic Bax, cytochrome C, caspase-3, and by disruption of mitochondrial
membrane permeability [76]. In hepatic tissue, 18β-glycyrrhetinic inhibited prolif-
eration and migration of cancerous cells while promoting a healthy tumour micro-
environment by suppressing NF-kB, iNOS, and COX2 activity [41, 77]. In breast
cancer cell lines and mammary epithelial cells, 100uM of 18β-glycyrrhetinic inacti-
vates and inhibits nuclear translocation of FOXO3a, thereby inhibiting the Akt
kinase activity mediated by caspase-9 [78]. In HL-60 (human leukaemia), glycyr-
rhetinic induced cell death through intrinsic and extrinsic pathways [79]. Methanolic
extract of Glycyrrhiza possesses cytotoxic, antimicrobial, and antioxidant activity.
Brine shrimp lethality bioassay showed cytotoxicity with LC50 of 0.77ug/ml [43].
Treatment of colorectal cancer cell lines such as LoVo, SW480, and SW620 with 18
β-glycyrrhetinic acids suppressed proliferation and migration in a dosage-­dependent
manner in vitro and in vivo. Annexin V-FITC staining showed reduced survivin
expression and increased PARP expression, along with suppression of p-PI3K,
p-AKT, p-STAT3, p-JNK p-p38, and p-NF-κB p65, thereby regulating apoptosis,
invasion, migration, and proliferation of colorectal cancer [80].
Hydromethanolic Glycyrrhiza extract protected against cyclophosphamide-­
induced mutagenicity in bone marrow cells of Swiss albino mice. Intra-peritoneally
536 N. Dhingra et al.

administered extract (450–600 mg/kg BW -LD50) showed protection against muta-

genesis, micronuclei formation, and chromosomal aberration [26]. In the xenograft
mice model, glycyrrhizin profoundly suppressed PCNA, thromboxane synthase,
and facilitated body weight recovery rescued kidney and liver damage as compared
to mice injected with A549 (human lung adenocarcinoma) [81].
Isoliquiritigenin (2′,4,4′-trihydroxychalcone), another flavonoid obtained from
the root of Glycyrrhiza, effectively supresses tumour growth through inhibiting cell
cycle protein and depolarization of mitochondrial membrane potential in hepatoma
and pulmonary metastasis of renal carcinoma in rodents, without any adverse effects
[82, 83]. In hepatocytes, isoliquiritigenin inhibits tumours in the G2/M phase and
induced programmed cell death by inducing p53, p21, NOXA, Fas receptor, and
ligand [82]. On the other hand, it down-regulates ckd2, cyclin E, and E2F-1 to pro-
mote the secretion of cytochrome C, caspase-9 activation and upregulating p53,
Bax, caspase-7 and p21, thereby changing mitochondrial membrane potential. That
leads to apoptosis and cell death of cancer cells [78].
Angiogenesis is one of the hallmarks of tumour biology. Moreover, it is targeted
to test anti-cancerous therapy; blocking or inhibiting angiogenesis is presumed to
supplement cancer therapy. The powered root of Glycyrrhiza was filtered and used
for extraction using solvents with increasing polarity, with final extraction using
water. 6–8 weeks old Swiss albino mice were injected with Ehrlich ascites tumour
cells (ETA - intraperitoneally) and then fed with the crude extracts. In comparison
with control, mice fed methanolic and water extract showed significant inhibition of
EAT cell growth in vivo and in vitro. Similarly, there was a significant reduction in
neovascularization and angiogenesis in treated mice [22]. Individual components of
licorice extract were tested for anti-cancerous activity against gastric and epithelial
cells. Seven licorice compounds include glycyrrhizic acid, glycyrrhetinic acid,
ammonium salt, licochalcone A, liquiritigenin, isoliquiritigenin, and glabridin.
Among the compounds, licochalcone A showed maximum toxicity through regula-
tion of cell cycle and apoptosis. Licochalcone A, in a dosage-dependent manner,
was able to inhibit the growth of gastric cancer cells at a concentration of 40uM
(IC50). Licochalcone A-treated cells showed increased expression of Rb, but cell
cycle progressor proteins cyclin A and D were significantly reduced, keeping the
cells in G2/M phase. Activation of PARP, Caspase-3, Bcl-2 and Bax by licochalcone
A resulted in cell death and apoptosis [75].

5 Mechanism

Glycyrrhizin (GL), a triterpene glycoside (saponin), is the chief sweet tasting con-
stituent of Glycyrrhiza glabra (liquorice) root. It is one of the major components of
licorice, also known as glycyrrhizin acid. Various mechanisms of GL have been
reported such as reduction in the expression of proliferation of proliferative cell
nuclear antigen (PCNA), exhibition of fewer TUNEL (terminal deoxynucleotidyl
transferase-mediated dUTP nick end labelling)-positive cells, and increased
Resilience Activity of Glycyrrhiza glabra in Relation to Cancer: Chemistry… 537

expression of p53 and p21/Cip1 in epidermis. Researchers have observed inhibition

of cyclooxygenase, NF-kF, prostaglandin E2 (PGE2), and nitric oxide (NO) levels
in various cancers. Farooqui et al. (2018) had reported that glycyrrhizin signifi-
cantly reduced the cell viability of HeLa cells with the mechanism of DNA frag-
mentation and nuclear condensation. Is also induces the process of cell cycle arrest
in G0/G1 phase and apoptosis in cervical cancer by mitochondrial depolarization by
enhanced ROS production [84]. Kabe et al. (2021) reported that GL and its deriva-
tive inhibit the human colon cancer HCT116 cells progression by significantly sup-
pressing the Endothelial Growth Factor Receptor (EGFR)-mediated signalling [85].
GL and its derivatives inhibit the binding interaction between Progesterone receptor
membrane component 1and EGFR. Similarly, it also inhibits the interaction between
PGRMC1 and the LDL receptor (LDLR) and thus suppresses the intracellular
uptake of low-density lipoprotein (LDL) [85].

5.1 Isoliquiritigenin

Isoliquiritigenin (ISL) with a chalcone structure is one of the most important bioac-
tive components derived from licorice root [82, 83, 86]. ISL is known to possess
antitumour activity by various mechanisms which include cell proliferation, angio-
genesis, invasion, epigenesis, and autophagy in different types of cancer [82, 83].
Various researchers reported that ISL significantly acts on various breast cancer
cells by enhancing the expression of presenilin2 mRNA level, WIF1, HIF-1α pro-
teasome degradation, cleaved caspase-3 & 9, RECK, PTEN, Bax, MMP-7, PIAS3,
and many more. Similarly, it suppresses the expression of estrogen receptor α,
DNMT1, β-catenin, c-myc, VEGF/VEGFR-2, and many more [87, 88]. In colon
cancer, ISL inhibits AMPK and AKT/mTOR pathway and mediates HIF-1α which
inhibits glycolysis and lactate degeneration. ISL downregulates antiapoptotic pro-
teins Bcl-2 and Bcl-x(L), arrested in G2, and thus inhibits tumour growth. It also
induces apoptosis by reducing PGE2 and nitric oxide (NO) in mouse and human
colon carcinoma cells. Studies have shown that ISL induces apoptosis and cytotox-
icity by suppressing PI3K/AKT/mTOR pathway, increasing Beclin-1, by regulating
calcium and Delta psi(m)-dependent pathways, inhibiting m-TOR, by increasing
p21Cip1/Waf, reducing Bcl-2, cdk 2/4, and E2F, elevation of FAS ligand in many
cancerous cells including ovary, prostate, gastric, osteosarcoma, glioma, bladder,
etc. [82, 83, 86–88].

5.2 Isoangustone A

Isoangustone A (IAA), a novel flavonoid from licorice root, is known to suppress

proliferation of cancer cells. Song et al. (2013) reported that IAA supresses human
melanoma cells by significantly blocking cell cycle progression by regulating cyclin
538 N. Dhingra et al.

D1 and cyclin E protein. They also reported that IAA suppressed the phosphoryla-
tion of PI3k, MKK4, MKK7, GSK3β, Akt, and JNK1/2 [89]. In one of the studies,
it has been reported that IAA induces apoptosis in human colorectal adenocarci-
noma cells by disrupting mitochondrial functions. IAA induces apoptosis by disrup-
tion of mitochondrial structures, dissipation of mitochondrial membrane potential,
and release of cytochrome C. It also inhibited the phosphorylation of Akt and acti-
vated AMPK in colorectal cancer. Lee et al. (2013) reported that IAA suppresses the
growth of human prostate cancer cell by supressing the kinase activity of CDK2 and
mTOR and thus inhibits the phosphorylation of Akt and p27 [81–117] (Table 1).

5.3 Licochalcone

Licochalcones (LC) which are found in and extracted from the roots of Glycyrrhiza
species G. glabra are derivatives of phenol chalconoid and are known to possess
anti-cancer property. There has been reported that LC-A increase reactive oxygen
species (ROS), human gastric cancer cells, and thus cause apoptosis. LC-A is
reported to activate ERK, JNK, and p38 MAPK in BGC-823 cells which leads to the
apoptosis of cells. Lee et al. (2008) reported that LC-A significantly inhibited the
size of solid tumours in CT-26 cells-inoculated Balb/c mice. Various researchers
reported the effect of LC-A in various cancers including bladder, colorectal, colon,
human oesophageal squamous carcinoma, etc., by diversified mechanism, viz.,
decreased expression of cyclin A, cyclin B, MDM2, and many more. Oh et al.
(2019) reported that LC-B directly binds to the ATP binding pocket of EGFR and
MET kinase and induces apoptosis in human non-small-cell lung cancer cells. LC-C
is known to induce apoptosis in human oral squamous cell carcinoma cells by regu-
lating JAK2/STAT3 signalling pathways. Kwak et al. (2020) reported that LC-C
induced cycle arrest by increase in the expression p21 and p27 and by decreased
cyclin D1. LC-C induced the phosphorylation JNK, c-Jun, and p38 protein [74, 75].

6 Conclusion

Glycyrrhiza glabra is considered one of the most popular medicinal plants used in
traditional medicine. It is used in various industrial products, viz. candies, chewing
gum, herbal teas, tobacco products, etc. It consists of diversified pharmacological
activities including cancer. It is known to have enormous bioactive components
including flavonoids, tannins, saponins, terpenoids glycyrrhetic acid, glycyrrhizin,
glabridin, etc. Different extracts and bioactive components of G. glabra are known
to possess anti-cancer activity on different types of cancers. Various mechanisms
are proposed for their anti-cancer activity like chromatin condensation, DNA frag-
mentation, apoptosis, and down- and up-regulation of many proteins. G. glabra
Resilience Activity of Glycyrrhiza glabra in Relation to Cancer: Chemistry… 539

Table 1 Molecular targets of bioactive components of G. glabra against cancer

Cancer type Protein expression References
Glycyrrhizin
Lung cancer HMGB1 , JAK/STAT , CDK4-Cyclin D1 complex , [81, 91–93]
CD8+ T cell infiltration , PARP , Thromboxane Synthase
(inhibition), Proliferating cell nuclear antigen
Cortactin , FAK , Src , PI3-K, MKK4, MKK7, JNK1, mTOR,
and Cdk2 ( )
Prostate cancer Cdc42/GSK-3β/Snail , E-cadherin , Bcl-2 , mTOR [94]
Cervical cancer Nuclear condensation , DNA fragmentation , mitochondrial [84]
depolarization
Liver cancer Progesterone receptor membrane component 1 [85, 95]
Interaction between PGRMC1 and EGFR
EGFR , ECAR , phosphorylated-AKT , HK2 , OCR
Glycyrrhetinic acid
Lung cancer p65, VEGF and MMP-9 , NF-κB (p65), VEGF, and MMP-9 [96]
expression
Ovarian cancer Fas and FasL [97]
Non-small cell Thromboxane Synthase (inhibition), ERK ½ , cyclic adenosine [98]
lung cancer monophosphate
Gastric cancer cyclin D1, D2, D3, E1, and E2 , Bax, cleaved PARP, and [99]
pro-caspase-3, −8, −9 , AKT/mTOR/STAT3
Isoliquiritigenin
Human MiR-301b [100]
melanoma Leucine Rich Repeats and Immunoglobulin Like Domains 1
Breast cancer miR-200c/C-JUN/β-Catenin , miR-374a/BAX , β-catenin/ [101–103]
ABCG2 (inhibition), DNMT1 methyltransferase (inhibition),
WIF1 , STAT3 , PIAS3 , PTEN , Akt
Prostate cancer CDK inhibitor p27(KIP1) [104]
Lung cancer E-cadherin , N-cadherin and vimentin , pro-apoptotic proteins [105]
Bcl-2-associated X protein and active caspase-3 B-cell
lymphoma 2 , PI3K/AKT
Isoangustone
Colorectal Mitochondrial respiration (inhibition), AMPK , cellular ATP [106, 107]
cancer level (inhibition), Akt Mitochondria membrane potential ,
Cellular ATP
Human Cyclins D1 and E (inhibition). Akt, GSK-3β, and JNK1/2 [89]
melanoma (suppression), phosphoinositide 3-kinase (PI3K), MKK4, and
MKK7 (inhibition)
Licochalcone
Gastric cancer Rb , cyclin A, cyclin B and MDM2 [75, 108,
Akt, ERK and NF-κB , MAPKs, and PI3K 109]
Lung cancer MDM2, cyclin B1, Cdc2 and Cdc25C , caspase-3 [110–112]
p-EIF2α and ATF4 , EGFR , MET kinase , mitochondrial
membrane potential , caspase activation
PD-L1 , PERK-eIF2α , 4EBP1 phosphorylation
Colon cancer p65 and Ras , Specificity protein 1 , p27, p21, cyclin D1, Mcl-1 [113, 114]
and surviving
Breast cancer LC3-II , PI3K/Akt/mTOR , p21 , cytochrome C , Caspase 3, [115–117]
Caspase 9 and Bax , Bcl-2 , Specificity Protein 1
540 N. Dhingra et al.

possesses strong agent for new molecules which could have immense medicinal
properties and might be a therapeutic target for various cancer.

References

1. Kamboj VP (2000) Herbal medicine. Curr Sci 78(1):35–39

2. Hayashi H, Sudo H (2009) Economic importance of licorice. Plant Biotechnol 26(1):101–104
3. Herrera M, Herrera A, Ariño A (2009) Estimation of dietary intake of ochratoxin a from
liquorice confectionery. Food Chem Toxicol 47(8):2002–2006
4. Sen S, Chakraborty R (2017) Revival, modernization and integration of Indian traditional
herbal medicine in clinical practice: importance, challenges and future. J Tradit Complement
Med 7(2):234–244
5. Tang J et al (2009) Study on the pharmacokinetics drug–drug interaction potential of
Glycyrrhiza uralensis, a traditional Chinese medicine, with lidocaine in rats. Phytother Res
23(5):603–607
6. Yang R et al (2015) The pharmacological activities of licorice. Planta Med 81(18):1654–1669
7. Rizzato G et al (2017) A new exploration of licorice metabolome. Food Chem 221:959–968
8. Armanini D et al (2002) History of the endocrine effects of licorice. Exp Clin Endocrinol
Diabetes 110(06):257–261
9. Food U (1985) GRAS status of licorice (Glycyrrhiza), ammoniated glycyrrhizin and mono-
ammonium glycyrrhizinate. Fed Regist 5099
10. Johns C (2009) Glycyrrhizic acid toxicity caused by consumption of licorice candy cigars.
Can J Emergency Med 11(1):94–96
11. Spinks E, Fenwick G (1990) The determination of glycyrrhizin in selected UK liquorice
products. Food Addit Contam 7(6):769–778
12. Hikino H (1985) Recent research on oriental medicinal plants. Economic and medicinal plant
research/edited by H. Wagner, Hiroshi Hikino, Norman R. Farnsworth
13. Kamei J et al (2003) Antitussive principles of Glycyrrhizae radix, a main component
of the Kampo preparations Bakumondo-to (Mai-men-dong-tang). Eur J Pharmacol
469(1–3):159–163
14. Varsha S, Agrawal R, Sonam P (2013) Phytochemical screening and determination of anti-­
bacterial and anti-oxidant potential of Glycyrrhiza glabra root extracts. J Environ Res Dev
7(4A):1552
15. Mauricio I et al (1997) Identification of glycyrrhizin as a thrombin inhibitor. Biochem
Biophys Res Commun 235(1):259–263
16. Mendes-Silva W et al (2003) Antithrombotic effect of glycyrrhizin, a plant-derived thrombin
inhibitor. Thromb Res 112(1–2):93–98
17. De Clercq E (2000) Current lead natural products for the chemotherapy of human immuno-
deficiency virus (HIV) infection. Med Res Rev 20(5):323–349
18. Badam L (1997) In vitro antiviral activity of indigenous glycyrrhizin, licorice and glycyrrhi-
zic acid (sigma) on Japanese encephalitis virus. J Commun Dis 29(2):91–99
19. Biondi DM, Rocco C, Ruberto G (2003) New dihydrostilbene derivatives from the leaves of
Glycyrrhiza g labra and evaluation of their antioxidant activity. J Nat Prod 66(4):477–480
20. Malek JM, Ghazvini K (2007) In vitro susceptibility of Helicobacter pylori to licorice extract.
Iran J Pharm Res 6(1)
21. Aly AM, Al-Alousi L, Salem HA (2005) Licorice: a possible anti-inflammatory and anti-­
ulcer drug. AAPS PharmSciTech 6(1):E74–E82
22. Sheela M, Ramakrishna M, Salimath BP (2006) Angiogenic and proliferative effects of
the cytokine VEGF in Ehrlich ascites tumor cells is inhibited by Glycyrrhiza glabra. Int
Immunopharmacol 6(3):494–498
Resilience Activity of Glycyrrhiza glabra in Relation to Cancer: Chemistry… 541

23. Salvi M et al (2003) Glycyrrhetinic acid-induced permeability transition in rat liver mito-
chondria. Biochem Pharmacol 66(12):2375–2379
24. Fiore C et al (2004) On the mechanism of mitochondrial permeability transition induction by
glycyrrhetinic acid. Biochim Biophysi Acta 1658(3):195–201
25. Watanabe M et al (2002) Identification of licocoumarone as an apoptosis-inducing compo-
nent in licorice. Biol Pharm Bull 25(10):1388–1390
26. Sharma V, Agrawal R, Shrivastava VK (2014) Assessment of median lethal dose and anti-­
mutagenic effects of Glycyrrhiza glabra root extract against chemically induced micronu-
cleus formation in Swiss albino mice. Int J Basic Clin Pharmacol 3:292–297
27. Acharya S et al (1993) A preliminary open trial on interferon stimulator (SNMC) derived from
Glycyrrhiza glabra in the treatment of subacute hepatic failure. Indian J Med Res 98:69–74
28. Sato H et al (1996) Therapeutic basis of glycyrrhizin on chronic hepatitis B. Antivir Res
30(2–3):171–177
29. Van Rossum T et al (1998) Glycyrrhizin as a potential treatment for chronic hepatitis
C. Aliment Pharmacol Ther 12(3):199–205
30. Jeong HG et al (2002) Hepatoprotective effects of 18β-glycyrrhetinic acid on carbon
tetrachloride-­induced liver injury: inhibition of cytochrome P450 2E1 expression. Pharmacol
Res 46(3):221–227
31. Chan H-t, Chan C, Ho JW (2003) Inhibition of glycyrrhizic acid on aflatoxin B1-induced
cytotoxicity in hepatoma cells. Toxicology 188(2–3):211–217
32. Sharma V, Agrawal R (2014) In vivo antioxidant and hepatoprotective potential of Glycyrrhiza
glabra extract on carbon tetra chloride (CCl4) induced oxidative-stress mediated hepatotoxic-
ity. Int J Res Med Sci 2(1):314–320
33. Takii H et al (2001) Antidiabetic effect of glycyrrhizin in genetically diabetic KK-ay mice.
Biol Pharm Bull 24(5):484–487
34. Husain A et al (2015) Quantitative analysis of total phenolic, flavonoid contents and HPTLC
fingerprinting for standardization of Glycyrrhiza glabra Linn. Roots. Herb Med 1(1):1–9
35. Bradley PR (1992) British herbal compendium. Volume 1. A handbook of scientific informa-
tion on widely used plant drugs. Companion to Volume 1 of the British Herbal Pharmacopoeia.
British Herbal Medicine Association
36. Isbrucker R, Burdock G (2006) Risk and safety assessment on the consumption of Licorice
root (Glycyrrhiza sp.), its extract and powder as a food ingredient, with emphasis on the phar-
macology and toxicology of glycyrrhizin. Regul Toxicol Pharmacol 46(3):167–192
37. Capasso F, De Pasquale R, Grandolini G (2011) Farmacognosia: Botanica, chimica e farma-
cologia delle piante medicinali. Springer Science & Business Media
38. Li J-R, Wang Y-Q, Deng Z-Z (2005) Note: two new compounds from Glycyrrhiza glabra. J
Asian Nat Prod Res 7(4):677–680
39. Wren RC, Wren RW (1972) Potter’s new cyclopaedia of medicinal herbs and preparations.
Harper & Row
40. Kinoshita T, Tamura Y, Mizutani K (2005) The isolation and structure elucidation of minor
isoflavonoids from licorice of Glycyrrhiza glabra origin. Chem Pharm Bull 53(7):847–849
41. Hasan MK et al (2021) Phytochemistry, pharmacological activity, and potential health ben-
efits of Glycyrrhiza glabra. Heliyon 7:e07240
42. Yu J-Y et al (2015) Anti-inflammatory activities of licorice extract and its active com-
pounds, glycyrrhizic acid, liquiritin and liquiritigenin, in BV2 cells and mice liver. Molecules
20(7):13041–13054
43. Sultana S et al (2010) Antimicrobial, cytotoxic and antioxidant activity of methanolic extract
of Glycyrrhiza glabra. Agric Biol J N Am 1(5):957–960
44. Obolentseva G et al (1999) Pharmacological and therapeutic properties of licorice prepara-
tions (a review). Pharm Chem J 33(8):427–434
45. Experts, U.S.P.C.C.o. and U.S.P.C.F.I.E. Committee, Food Chemicals Codex (2010) US
Pharmacopeia Conv
542 N. Dhingra et al.

46. Simmler C, Pauli GF, Chen S-N (2013) Phytochemistry and biological properties of gla-
bridin. Fitoterapia 90:160–184
47. Fukui H, Goto K, Tabata M (1988) Two antimicrobial flavanones from the leaves of
Glycyrrhiza glabra. Chem Pharm Bull 36(10):4174–4176
48. Sharma V, Katiyar A, Agrawal R (2018) Glycyrrhiza glabra: chemistry and pharmacological
activity. Sweeteners:87
49. Franceschelli S et al (2011) Licocalchone-C extracted from Glycyrrhiza glabra inhibits
lipopolysaccharide-interferon-γ inflammation by improving antioxidant conditions and regu-
lating inducible nitric oxide synthase expression. Molecules 16(7):5720–5734
50. Chopra P et al (2013) Antimicrobial and antioxidant activities of methanol extract roots of
Glycyrrhiza glabra and HPLC analysis. Int J Pharm Pharmacol Sci 5(2):157–160
51. Fu Y et al (2013) Antioxidant and anti-inflammatory activities of six flavonoids separated
from licorice. Food Chem 141(2):1063–1071
52. Bodet C et al (2008) A licorice extract reduces lipopolysaccharide-induced proinflammatory
cytokine secretion by macrophages and whole blood. J Periodontol 79(9):1752–1761
53. Mueller M, Hobiger S, Jungbauer A (2010) Anti-inflammatory activity of extracts from
fruits, herbs and spices. Food Chem 122(4):987–996
54. Shalaby MA et al (2004) Some effects of Glycyrrhiza glabra (liquorice) roots extract on male
rats. Egy J Nat Toxins 1:83–94
55. Harwansh RK, Patra KC, Pareta SK, Singh J, Biswas R (2011) Pharmacological studies on
Glycyrrhiza glabra: a review. Pharmacologyonline 2:1032–1038
56. Bhuiyan MYH et al (2015) Standardization, quality control and pharmacological review on
Glycyrrhiza glabra L. A potential medicinal herb in Unani and Ayurvedic systems of medi-
cine. Hamdard Med 58:45–72
57. Damle M (2014) Glycyrrhiza glabra (Liquorice)-a potent medicinal herb. Int J Herb Med
2(2):132–136
58. Mazumder PM et al (2012) Evaluation of immunomodulatory activity of Glycyrhiza glabra L
roots in combination with zing. Asian Pac J Trop Biomed 2(1):S15–S20
59. Vikhe G et al (2013) In vitro effect of G. glabra and T. Cordifolia plant extracts on phagocy-
tosis by human neutrophils. Pravara Med Rev 5(2)
60. Laconi S, Madeddu MA, Pompei R (2014) Autophagy activation and antiviral activity by a
licorice triterpene. Phytother Res 28(12):1890–1892
61. Michaelis M et al (2010) Glycyrrhizin inhibits highly pathogenic H5N1 influenza a virus-­
induced pro-inflammatory cytokine and chemokine expression in human macrophages. Med
Microbiol Immunol 199(4):291–297
62. Baltina L (2003) Chemical modification of glycyrrhizic acid as a route to new bioactive com-
pounds for medicine. Curr Med Chem 10(2):155–171
63. Soufy H et al (2012) Antiviral and immune stimulant activities of glycyrrhizin against duck
hepatitis virus. Afr J Tradit Complement Altern Med 9(3):389–395
64. Fukuchi K et al (2016) Antiviral and antitumor activity of licorice root extracts. In Vivo
30(6):777–785
65. Cinatl J et al (2003) Glycyrrhizin, an active component of liquorice roots, and replication of
SARS-associated coronavirus. Lancet 361(9374):2045–2046
66. Kim HJ et al (2012) Antioxidant activities of licorice-derived prenylflavonoids. Nutr Res
Pract 6(6):491–498
67. Teltumbde A et al. (2013) Effect of Yashtimadhu (Glycyrrhiza glabra) on intelligence and
memory function in male adolescents. Sch J App Med Sci 1(2):90–95
68. Chakravarthi KK, Avadhani R, Narayan RS (2012) Effect of Glycyrrhiza glabra root extract
on learning and memory in wistar albino rats. Drug Invent Today 4(7):387–390
69. Jin Z et al (2013) Potentiating effect of glabridin on GABAA receptor-mediated responses in
dorsal raphe neurons. Planta Med 79(15):1408–1412
70. Ikarashi Y, Mizoguchi K (2016) Neuropharmacological efficacy of the traditional Japanese
Kampo medicine yokukansan and its active ingredients. Pharmacol Ther 166:84–95
Resilience Activity of Glycyrrhiza glabra in Relation to Cancer: Chemistry… 543

71. Danysz W, Parsons CG (2003) The NMDA receptor antagonist memantine as a symptom-
atological and neuroprotective treatment for Alzheimer’s disease: preclinical evidence. Int J
Geriatr Psychiatry 18(S1):S23–S32
72. Jiang F et al (2016) Glabridin inhibits cancer stem cell-like properties of human breast cancer
cells: an epigenetic regulation of miR-148a/SMAd2 signaling. Mol Carcinog 55(5):929–940
73. Hsieh M-J et al (2016) Glabridin induces apoptosis and autophagy through JNK1/2 pathway
in human hepatoma cells. Phytomedicine 23(4):359–366
74. Yu SJ et al (2017) Licochalcone-E induces caspase-dependent death of human pharyngeal
squamous carcinoma cells through the extrinsic and intrinsic apoptotic signaling pathways.
Oncol Lett 13(5):3662–3668
75. Xiao X-Y et al (2011) Licochalcone a inhibits growth of gastric cancer cells by arresting cell
cycle progression and inducing apoptosis. Cancer Lett 302(1):69–75
76. Lee CS et al (2008) 18β-Glycyrrhetinic acid induces apoptotic cell death in SiHa cells
and exhibits a synergistic effect against antibiotic anti-cancer drug toxicity. Life Sci
83(13–14):481–489
77. Hasan SK et al (2016) Chemopreventive effect of 18β-glycyrrhetinic acid via modulation of
inflammatory markers and induction of apoptosis in human hepatoma cell line (HepG2). Mol
Cell Biochem 416(1–2):169–177
78. Sharma G et al (2012) 18β-glycyrrhetinic acid induces apoptosis through modulation of Akt/
FOXO3a/Bim pathway in human breast cancer MCF-7 cells. J Cell Physiol 227(5):1923–1931
79. Huang Y-C et al (2016) 18α-glycyrrhetinic acid induces apoptosis of HL-60 human leu-
kemia cells through caspases-and mitochondria-dependent signaling pathways. Molecules
21(7):872
80. Wang S et al (2017) 18 β-glycyrrhetinic acid exhibits potent antitumor effects against colorec-
tal cancer via inhibition of cell proliferation and migration. Int J Oncol 51(2):615–624
81. Deng Q-P et al (2017) Effects of glycyrrhizin in a mouse model of lung adenocarcinoma. Cell
Physiol Biochem 41(4):1383–1392
82. Hsu Y-L, Kuo P-L, Lin C-C (2005) Isoliquiritigenin induces apoptosis and cell cycle arrest
through p53-dependent pathway in Hep G2 cells. Life Sci 77(3):279–292
83. Yamazaki S et al (2002) Isoliquiritigenin suppresses pulmonary metastasis of mouse renal
cell carcinoma. Cancer Lett 183(1):23–30
84. Farooqui A et al (2018) Glycyrrhizin induces reactive oxygen species-dependent apoptosis
and cell cycle arrest at G0/G1 in HPV18+ human cervical cancer HeLa cell line. Biomed
Pharmacother 97:752–764
85. Kabe Y et al (2021) Glycyrrhizin derivatives suppress cancer chemoresistance by inhibiting
progesterone receptor membrane component 1. Cancers (Basel) 13(13):3265
86. Wang K-L, Yu Y-C, Hsia S-M (2021) Perspectives on the role of Isoliquiritigenin in cancer.
Cancers (Basel) 13(1):115
87. Maggiolini M et al (2002) Estrogenic and antiproliferative activities of isoliquiritigenin in
MCF7 breast cancer cells. J Steroid Biochem Mol Biol 82(4–5):315–322
88. Wang N et al (2015) Dietary compound isoliquiritigenin prevents mammary carcinogenesis
by inhibiting breast cancer stem cells through WIF1 demethylation. Oncotarget 6(12):9854
89. Song NR et al (2013) Isoangustone A, a novel licorice compound, inhibits cell proliferation by
targeting PI3K, MKK4, and MKK7 in human melanoma. Cancer Prev Res 6(12):1293–1303
90. Lee E et al (2013) CDK2 and mTOR are direct molecular targets of isoangustone A in the
suppression of human prostate cancer cell growth. Toxicol Appl Pharmacol 272(1):12–20
91. Huang R-Y et al (2014) Glycyrrhizin suppresses lung adenocarcinoma cell growth through
inhibition of thromboxane synthase. Cell Physiol Biochem 33(2):375–388
92. Zhu J et al (2021) Licorice extract inhibits growth of non-small cell lung cancer by down-­
regulating CDK4-cyclin D1 complex and increasing CD8+ T cell infiltration. Cancer Cell
Int 21(1):1–18
93. Wu X et al (2018) Glycyrrhizin suppresses the growth of human NSCLC cell line HCC827
by downregulating HMGB1 level. Biomed Res Int 2018
544 N. Dhingra et al.

94. Chang H-Y et al (2019) Glycyrrhizin attenuates the process of epithelial-to-mesenchymal

transition by modulating HMGB1 initiated novel signaling pathway in prostate cancer cells.
J Agric Food Chem 67(12):3323–3332
95. Sun Z et al (2021) HK2 is associated with the Warburg effect and proliferation in liver can-
cer: targets for effective therapy with glycyrrhizin corrigendum in/10.3892/mmr.2021.12143.
Mol Med Rep 23(5):1–8
96. Shetty AV et al (2011) 18α-glycyrrhetinic acid targets prostate cancer cells by down-­
regulating inflammation-related genes. Int J Oncol 39(3):635–640
97. Haghshenas V et al (2014) Glycyrrhetinic acid inhibits cell growth and induces apoptosis in
ovarian cancer a2780 cells. Adv Pharm Bull 4(Suppl 1):437
98. Huang R-Y et al (2014) 18β-Glycyrrhetinic acid suppresses cell proliferation through inhibit-
ing thromboxane synthase in non-small cell lung cancer. PLoS One 9(4):e93690
99. Wang H et al (2020) Glycyrrhizic acid inhibits proliferation of gastric cancer cells by induc-
ing cell cycle arrest and apoptosis. Cancer Manag Res 12:2853
100. Xiang S et al (2018) Isoliquiritigenin suppresses human melanoma growth by targeting
miR-­301b/LRIG1 signaling. J Exp Clin Cancer Res 37(1):1–16
101. Peng F et al (2020) Isoliquiritigenin derivative regulates miR-374a/BAX axis to suppress
triple-negative breast cancer tumorigenesis and development. Front Pharmacol 11:378
102. Peng F et al (2021) Isoliquiritigenin suppresses EMT-induced metastasis in triple-negative
breast cancer through miR-200c/C-JUN/β-catenin. Am J Chin Med 49(02):505–523
103. Ning S et al (2017) Isoliquiritigenin attenuates MiR-21 expression via induction of PIAS3 in
breast cancer cells. RSC Adv 7(29):18085–18092
104. Lee YM et al (2009) Induction of cell cycle arrest in prostate cancer cells by the dietary com-
pound isoliquiritigenin. J Med Food 12(1):8–14
105. Tian T et al (2018) Isoliquiritigenin inhibits cell proliferation and migration through the
PI3K/AKT signaling pathway in A549 lung cancer cells. Oncol Lett 16(5):6133–6139
106. Tang S et al (2021) Isoangustone A induces autophagic cell death in colorectal cancer cells
by activating AMPK signaling. Fitoterapia 152:104935
107. Huang W et al (2014) Isoangustone A induces apoptosis in SW480 human colorectal adeno-
carcinoma cells by disrupting mitochondrial functions. Fitoterapia 94:36–47
108. Wu J et al (2018) Licochalcone A suppresses hexokinase 2-mediated tumor glycolysis in
gastric cancer via downregulation of the Akt signaling pathway. Oncol Rep 39(3):1181–1190
109. Hao W et al (2015) Licochalcone A-induced human gastric cancer BGC-823 cells apoptosis
by regulating ROS-mediated MAPKs and PI3K/AKT signaling pathways. Sci Rep 5(1):1–8
110. Qiu C et al (2017) Licochalcone A inhibits the proliferation of human lung cancer cell lines
A549 and H460 by inducing G2/M cell cycle arrest and ER stress. Int J Mol Sci 18(8):1761
111. Oh H-N et al (2019) Licochalcone B inhibits growth and induces apoptosis of human non-­
small-­cell lung cancer cells by dual targeting of EGFR and MET. Phytomedicine 63:153014
112. Yuan L-W et al (2021) Licochalcone A inhibits interferon-gamma-induced programmed
death-ligand 1 in lung cancer cells. Phytomedicine 80:153394
113. Liu X et al (2021) Licochalcone A inhibits proliferation and promotes apoptosis of colon
cancer cell by targeting programmed cell death-ligand 1 via the NF-κB and Ras/Raf/MEK
pathways. J Ethnopharmacol 273:113989
114. Cho JJ et al (2014) Licochalcone A, a natural chalconoid isolated from Glycyrrhiza inflata
root, induces apoptosis via Sp1 and Sp1 regulatory proteins in oral squamous cell carcinoma.
Int J Oncol 45(2):667–674
115. Xue L et al (2018) Licochalcone A inhibits PI3K/Akt/mTOR signaling pathway activation
and promotes autophagy in breast cancer cells. Oncol Lett 15(2):1869–1873
116. Yu L et al (2016) Licochalcone B arrests cell cycle progression and induces apoptosis in
human breast cancer MCF-7 cells. Recent Pat Anticancer Drug Discov 11(4):444–452
117. Kang TH et al (2017) Licochalcone A suppresses specificity protein 1 as a novel target in
human breast cancer cells. J Cell Biochem 118(12):4652–4663
Strobilanthes: A Plethora of Phytomedicine

Reshmi Chembrammal , Aswathi Pokkadath ,

and John Ernest Thoppil

1 Introduction

Traditional medicine was purely based on plant and plant products. The vast variety
of medicinal plants were explored by our ancestors in ancient times itself where
modern technology had not even named them. Each plant has its medicinal property
which can be used as a potential drug against diseases. With the help of modern
sophisticated technologies, the underexplored and unknown pharmaceutical activi-
ties of plants were revealed nowadays. Likewise, the genus Strobilanthes were used
in traditional medicine from time immemorial; still, the complete picture in respect
of the bioactivities and medicinal quality of the genus is not discovered so far. The
bioactivities, phytochemicals revealed, and the chromosome reports of the species
in the genus so far discovered are discussed here.

2 Medicinal Use of Strobilanthes

In Kerala, some species of Strobilanthes were widely used in Ayurveda, especially

the therapeutic drug ‘Sahachara’ which is widely used against rheumatism, neuro-
logical disorders, ulcers, glandular swellings, poisonous affections, skin diseases,
leprosy, and gum diseases [1]. Traditional medicine in Malaysia and Indonesia uses
filtrates of boiled S. crispus leaves as antidiabetic, diuretic, antilytic, and laxative
[2]. The plant is a woody shrub which is locally known in Malaysia as Pecah kaca,
Pecah beling, Karang jin, Bayam karang, and yellow Strobilanthes in English [3].
It is used by villagers in West Java to treat hepatitis and postpartum remedy. In

R. Chembrammal (*) · A. Pokkadath · J. E. Thoppil

Cell and Molecular Biology Division, Department of Botany, University of Calicut,
Calicut, Kerala, India

© The Author(s), under exclusive license to Springer Nature 545

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_21
546 R. Chembrammal et al.

Chinese, it is called Hei Mian Jiang Jun which means Black-faced General. Chinese
drug ‘Shengma’ is a combination of Serratula and Strobilanthes [4].
Ban-lan-gen is used to describe root tissues of several indistinguishable plant
species in China which are used as medicine. Indigo, indirubin, and tryptanthrin are
the key compounds of Ban-len-gen [5]. S. cusia is one of them which is widely used
in the textile industry due to rich indigo. Transcriptomic analysis revealed that the
genes encoding the indigo biosynthesis were monooxygenase, uridine diphosphate-­
glycosyl transferase, and b-glucosidase. The genetic information of dye-yielding
plants can increase the application of genetic engineering in industries [6]. S. ban-
tonensis is called ‘purple Ban-len-gen’ due to its similarity in root with S. cusia.
This herb is used against influenza virus infection in China and Vietnam [7].
Indigo Naturalis is used against skin psoriasis and nail psoriasis. Nail psoriasis
includes nail dystrophy, thickening, loss of lustre, raising, color changes, and fria-
bility. It is a powder extracted from the branches and leaves of indigo-producing
plants by fermenting in fresh water for several days of decomposition. Ethyl acetate
extract of Indigo Naturalis isolated from S. formosanus inhibits gram-positive bac-
teria, mildly inhibits non-dermatophytic onychomycosis pathogen, and has no effect
on dermatophytes [8].
In ancient times, the tribals used roots of S. callosus for the treatment of inflam-
matory disorders and its stem bark in formulations for painful and ineffectual
attempts to urinate or defecate [9]. The roots of S. cilliatus were used for the treat-
ment of rheumatalgia, limping, chest congestion, strangury, fever, leucoderma, skin
diseases, and inflammation [10]. Its stem is widely used for whooping cough, bron-
chitis, dropsy, leprosy, and pruritus [11]. Indigo Naturalis is used from earlier times
as textile dye and paint pigment. Modern research has revealed that Indigo Naturalis
is used as an antipyretic, anti-inflammatory, antiviral, antimicrobial, anticancer, and
detoxicant agents [12]. Strobilanthes is a good source of Indigo Naturalis, which is
used in Chinese medicine also [8].
S. cilliatus leaves are rich in potassium. Lupeol derived from its root is used to
treat skin problems and postdelivery treatments. The plant juice is taken as an anti-
diabetic drug [13]. It is good against toothache too. The essential oil from S. crispus
can be used as a nutraceutical towards degenerative diseases [14]. The high content
of calcium carbonate in the plant makes the boiled water mildly alkaline and func-
tion in ease of urination [15]. A survey in Malaysia revealed its application to treat
kidney stones by placing heated leaves on hips [16]. Traditional medicine in
Malaysia and Indonesia uses filtrates of boiled Strobilanthes leaves as antidiabetic,
diuretic, antilytic, and laxative [2]. Blood sugar, leprosy, urinal problems, jaundice,
inflammation, and excess menstruation can be treated using S. heyneanus roots and
leaves [17].
The genus, Strobilanthes, has been widely used in traditional herbal practices of
India, China, Indonesia, etc. Moreover, its leaf extract can minimize the glucose
level in blood and also reduces the risk of heart muscle/cardiovascular ailment [18].
Empirical shreds of evidences support the use of traditional herbs that cured the
disease of thousands, but the role of many of these herbs remains largely lacking.
Strobilanthes: A Plethora of Phytomedicine 547

3 Phytochemical Constituents

In developing countries, according to World Health Organization, 80% of the peo-

ple depend upon traditional medicine for their primary healthcare and 85% of them
are derived from plant extracts [3]. The pharmaceutical activity of the herb can be
correlated to the phytochemical components present in it such as flavonoids, alka-
loids, phenolic acids, ester glycosides, etc.
S. crispus is rich in squalene, stigmasterol, sitosterol, campesterol as well as tri-
terpenoids such as lupeol, amyrin, and botulin [19]. The ethnomedical values of the
species were not well known, but the biological properties of many species are
reported so far. The pharmaceutical quality and presence of secondary metabolites
change with the environment. It was found to be decreased in North East of North
Malaysia, while examining the S. crispus leaf extract. The notable number of phe-
nolic compounds in this plant has enhanced the anticancer effect on HeLa cells [3].
Hence, collection locality and environmental parameters have to be considered
while quantifying the phytoconstituents. Polyphenols, catechins, alkaloids, caf-
feine, tannins, vitamins (C, B1 and B2) and also high mineral content including
potassium, calcium, sodium, iron, and phosphorus were identified from this species
by Maznah et al. [20].
The Chinese medicine Qing Dai (Indigo Naturalis) is prepared from S. cusia
which is used against psoriasis and for targeting interleukin-17 (IL-17). Within
these formulations, three indole derivatives and seven other compounds were iso-
lated [21]. A novel isocoumarin with an unusual tetrahydro-4 H-pyran-4-one
moiety-­fused isocoumarin core skeleton was isolated from S. cusia which exhibits
anti-influenza virus activity in vitro [22]. S. flaccidifolius which is locally known as
‘kum’ in Manipur is used as a dyeing agent. Laitonjam and Wangkheirakpam [23]
analyzed the water extracts of S. flaccidifolius and confirmed three indigo precur-
sors such as indican, isatan B, and isatin. In this study, three days of fermented fresh
leaves gave the highest amount of indigo. In dried leaf water extract, the enzyme
might have been inactivated in the drying procedure. Hence, indigo was not obtained
after solvent extraction with chloroform.
When female Sprague Dawley rats were administered with S. crispus ethanol
leaf extract for two weeks, no bad effects were observed. In comparing between the
treatment groups and control, no significant changes were observed regarding the
serum biochemical parameters, relative organ weights, body weights, food intake,
and water consumption [24].
A study was conducted on five Strobilanthes species, viz. S. callosus Nees, S. cil-
iata Nees, S. integrifolia Kuntze, S. ixiocephala Benth, and S. heyneanus Nees.
From the leaf and stem extracts, a total of 43 compounds were revealed of which 13
were found to be common in leaves and stems across the species. In both the leaves
and stems, lupeol was the major bioactive compound [25]. Strobilanthes species
show variations in phytoconstituents in the pre- and post-flowering period. The
extracted oil from the post-flowering plants of Strobilanthes callosus contained
trans-sabinene hydrate, cis-sabinene hydrate, terpinen-4-ol, α-terpineol, and methyl
548 R. Chembrammal et al.

chavicol. However, the oil from pre-flowering plants contains all four compounds
except methyl chavicol [26].
Anticestodal drugs are used mainly against tapeworms. With the help of
Hymenolepis diminuta (rat tapeworm) experimental model, anticestodal efficacy of
S. discolor leaf extract was investigated. It was analyzed by checking the eggs per
gram of feces counts and percentage worm recovery rates. It was followed by treat-
ing different groups of rats infected by Hymenolepis diminuta with methanol leaf
extract. There was a significant reduction in both parameters considered. Interesting
results were obtained in the larval stages of the parasite. In this stage, not a single
worm had escaped from the 800 mg/kg dose, which is given twice daily for a con-
tinuous three days. These findings suggest the high potential of the plant against
cestodes and support its use in folk medicine [27].
The GC-TOF mass spectroscopy of the methanolic and aqueous extracts of
S. crispus dried leaves of the plant revealed potential phytoconstituents [28]. About
32 compounds were identified such as 3-octadedecene, α-sitosterol, campesterol,
hexadecanoic acid methyl ester, lupeol, phytol, and stigmasterol in the methanolic
extract, while in the aqueous extract, 3,5-dithiahexanol 5,5-dioxide, cyclobutanol,
hydrazine carboxamide, monoethanolamine, n-propyl acetate, and undecane have
been identified. Moreover, the plant leaf contains ester glycosidic compound of caf-
feic acid (a verbascoside), voumaric acid, caffeic acid, vanilic acid, ferulic acid, and
syringic acids [19].
The wound healing capacity of S. crispus was studied in the rat. The wounds
dressed with leaf extracts showed less inflammatory cells and high collagen in his-
tological analysis [29]. The antiviral activity of human coronavirus
NL63(HCoV-NL63) using extracts of S. crispus leaf and its major components
revealed a positive result. Among the components, trypanthrin and indigodole B (5a
R-ethyl trypanthrine) were potential against viral activity and thereby reduce the
cytopathic effect and progeny virus production [30]. The HPLC analysis of S. cris-
pus opens up eight flavonoid compounds. They were catechin, epicatechin, rutin,
myricetin, luteolin, apigenin, naringenin, and kaempferol [31]. The compounds
from S. crispus will cohere the proteins that bind to the active part of the reverse
transcriptase. It inhibits retrovirus proliferation which causes acquired immune
deficiency syndrome (AIDS) and Adult T-cell leukemia [32]. The isolated and iden-
tified compounds in the taxa are summarized (Table 1).
The synergistic activity of alkaloids, steroids, terpenoids, phenols, flavonoids,
tannins, saponins, glycosides, and carbohydrates are together responsible for the
antioxidant and antibacterial efficacy of S. heyneanus [17]. A significant amount of
phenols, flavonoids, and tannins were observed in aqueous plant extract rather than
ethanol extract [33]. In S. cilliatus, triterpenoids were present in petroleum ether
and benzene-soluble parts, flavonoids and phenols in water, and alcohol-soluble
parts, whereas mucilage was present in water-soluble parts only [34].
Strobilanthes: A Plethora of Phytomedicine 549

Table 1 Phytochemical compounds from different species of Strobilanthes

Sl.
No Plant Compounds identified/isolated
1. S. callosus Taraxerol, Taraxasterol, Indomethacin
[95]
2. S. cilliatus 4-Acetyl-2, 7-dihydroxy-1, 4, 8-triphenyl-octane-3, 5-dione
[96]
3. S. cilliatus Lupeol, Stigmasterol, Betulin, Stigmasterol glycoside
[97]
4. S. crispus p-Hydroxy benzoic acid, p-Coumeric, Caffeic acid, Vanillic acid, Gentisic
[98] acid, Ferulic acid, Syringic acid
5. S. crispus Verbascoside
[99]
6. S. crispus Verbascoside
[100]
7. S. crispus Stigmasterol, Tetracosanoic acid, 1-Heptacosanol
[101]
8. S. crispus Tritriacontane, Stigmasterol
[102]
9. S. cusia [70] Lupeol, Betulin, Lupenone, Indigo, Indirubin, 4(3H)-quinazolinone, 2,4 (1H,
3H)-quinazolinedione
10. S. cusia [71] Indole alkaloid glycoside, Indole alkaloid glucoside, Phenylethanoid
glycoside
11. S. cusia [59] Tryptanthrin
12. S. cusia [22] Isocoumarin
13. S. 3′-Hydroxy-5,7-dimethoxyflavone 4′-O-β-D-apiofuranoside;
formosanus 5,7-Dimethoxyflavone 4′-O-[β-D-apiofuranosyl(1 → 5)-β-D-­
[103] glucopyranoside]; 4′-Hydroxy-5,7-dimethoxyflavone; 2, 6 -Dimethoxy-1,4-­
benzoquinone; Lupeol; Betulin
14. S. crispus Catechin; Epicatechin; Rutin; Myricetin; Luteolin; Apigenin; Naringenin;
[31] Kaempferol
15. S. kunthiana 9,12-Octadecadienoic acid (Z,Z); Hexadecanoic acid methyl ester;
[41] 9-octadecenoic acid; Methyl ester; Heptadecanoic acid 16-methyl-, methyl
ester; 2,6-bis(1,1-dimethylethyl)-4-methyl phenol; 3-methyl-2-ketobutyric
acid tbdms,; 2,2,3,4-Tetramethyl-5-hexen-3-ol; N-(tert-butoxycarbonyl)-2-
(4-methoxyphenyl) allylamine; Cyclotrisiloxane hexamethyl;
Benzenesulfonamide
16. S. crispus 5-Hydroxymethylfurfuralpalmitic acid; Octadec-9-enoic acid;
[64] Cyclopentadecane, Linoleic acid; Methyl 7,10,13-hexadecatrienoate; Acetic
acid; Phytol; Isopropyl linoleate; Linolenoyl glycerol; Oleic acid; Elaidic
acid; Glycerol oleate; Squalene
17. S. crispus 3-Octadedecyne; α-sitosterol; Campesterol; Hexadecanoic acid; Methylester;
[28] Lupeol; Phytol; Stigmasterol; 3,5-Dithiahexanol; 5,5-dioxide; Cyclobutanol;
Hydrazine carboxamide; Monoethanolamine, n-Propyl acetate; Undecane
550 R. Chembrammal et al.

4 Bioactivities

4.1 Antioxidant Activity

Antioxidants are the only way to fight against the double-edged sword ‘reactive oxy-
gen species’. The wise use of reduction of them can delimit the diseases to an extent.
Plant-derived secondary metabolites such as flavonoids, phenolic acids, and tannins
are well-known scavenging activators against reactive species. The oxidative human
diseases such as cancer, tissue damage, and DNA injury can be controlled with the
help of antioxidants. The ability of phytocompounds against these necessary evils is
well researched and discussed from time immemorial. Any substance which is pres-
ent in low concentrations compared to an oxidizable substrate and delays or inhibits
the oxidation of that substrate is called a biological antioxidant. An ideal antioxidant
at the physiological level will be completely absorbed by the body and undertake
quenching of free radicals or chelate redox metals [35] (Fig. 1).

Fig. 1 Mechanism of reactive oxygen species

Strobilanthes: A Plethora of Phytomedicine 551

Reactive oxygen species (ROS) are of both free radical and non-free radical
oxygen-­containing species, which increase oxidative stress and impair the redox
balance [36]. They include hydrogen peroxide (H2O2), superoxide (O2-), singlet
oxygen (½O2), hydroxyl radical (∙OH), and reactive nitrogen, iron, copper, and sul-
phur species. Among them, hydroxyl radical is a potent ROS that causes cell dam-
age by reacting with phospholipids of the cell membrane. Superoxide is a weak one
that produces hazardous hydroxyl radicals and singlet oxygen [37]. According to
Sies [38], the oxidative stress is a disturbance in the prooxidant to antioxidant bal-
ance in service of the former, leading to potential damage. The oxidative stress
experienced by a cell depends on the activity of ROS generated and the ROS scav-
enging system. For favoring mild oxidative stress, the balance between prooxidant
and antioxidant substances is kept slightly in favor of prooxidant products [36].
The consumption of leaf extract of S. crispus as herbal tea increased the defense
system especially towards degenerative diseases due to the high number of water-­
soluble vitamins [20]. The wide spectrum of its activities includes antiviral, antitu-
mor, anti-inflammatory, and anticoagulant [39]. The plant has been suggested as a
potential resource of squalene [40]. The aqueous extracts of S. crispus leaves col-
lected from North-east Malaysia (Kelantan) showed 73.8% in DPPH radical scav-
enging assay and 267.5 μM of Fe (II) activity in ferric reducing antioxidant power
assay (FRAP) with an IC50 value of 44.1 μg/mL [3].
The highest percentage of inhibition in antioxidant property of S. kunthianus
ethanolic extract (79.23 ± 0.37) was 250 μg/mL and followed by methanolic extract
(90.35 ± 0.54) against ascorbic acid as standard [41]. They suggested it as an herbal
alternative for various diseases. In S. barbatus, the concentration of the extract for
fifty percentage inhibition for DPPH, superoxide, and hydroxyl radical scavenging
activity were 15, 250, and 525 μg/mL, respectively [42].
The reduced awareness of pain is called analgesia. The analgesic effect of etha-
nolic extracts of S. cilliatus against the standard pain killer diclofenac is proved by
the tail clip method in Swiss Albino mice [43]. A strong correlation between anti-
oxidant activity and the total phenol contents was proposed by Qader et al. in 2011
[44]. S. crispus extracts showed nontoxic effects against a normal human lung fibro-
blast cell line (Hs888Lu). The ethanolic extracts contain high antioxidant activities
compared to aqueous extracts in 1,1-diphenyl-1-picrylhydrazyl (DPPH) and FRAP
assays. The methanolic extracts of S. crispus offer a richer source of dietary antioxi-
dants [45]. The convective dried S. crispus showed potential for preserving antioxi-
dant constituents by achieving the highest antioxidant values that were significantly
higher than those obtained after freeze-drying [46].
The antioxidant properties of aqueous and methanolic extracts were studied
using DPPH free radical, xanthine oxidase activity, and β-carotene-linoleate model
system in S. crispus by Muslim et al. [28]. The inhibitory activity of the S. crispus
extracts towards the xanthine oxidase enzyme was high but they demonstrated mod-
erate antioxidant properties. It can be witnessed by the quenching of the DPPH-free
radical and preventing the bleaching of β-carotene by linoleic acid. The higher anti-
oxidant activity of methanolic extract of S. glutinosus can be correlated to the high
content of phenol (247.85 mg GAE/g extract) and flavonoid (71.91 mg QAE/g
552 R. Chembrammal et al.

Fig. 2 General classification of antioxidants

extract). But the n-hexane extract exhibited the highest anti-urease activity with IC50
value of 0.244 mg/ml [47] (Fig. 2).
In the case of S. kunthiana flowers, the ethyl acetate extract and n-butanol extract
exhibited promising antioxidant activity and the n-hexane extract was devoid of any
activity [48]. In the ABTS method, the ethyl acetate extracts of the root and stem of
the plant showed potent in vitro antioxidant activity. Among the different extracts
studied, crude methanolic flower extract was the most potent one. The weak cyto-
toxic activity against Hep2 and HeLa cell lines was exhibited by all the extracts
studied [49]. A dose-dependent activity was shown by ethanolic extract of S. asper-
rimus in serum biochemical parameters like hepatic antioxidant enzymes like gluta-
thione peroxidase (GPX), superoxide dismutase (SOD), catalase (CAT), and
malondialdehyde (MDA). When compared with the standard silymarin, significant
antioxidant activity was detected by decreasing MDA and increasing SOD, GPX,
and CAT [50]. The significant increase in glutathione peroxidase and superoxide
dismutase activities proves the antioxidant effect in streptozotocin-induced diabetic
rats treated with S. crispus juice [51].

4.2 Antidiabetic Activity

A combination of metabolic disorders resulting in an elevated levels of glucose in

the blood (hyperglycemia) and lack of production or action of insulin from the pan-
creas results in diabetes mellitus [52]. Traditional plants have been used to treat
hyperglycemia throughout the world. Hypoglycemic plants and plant-derived com-
pounds have been used nowadays to fight against blood sugar variations. But their
scientific effectiveness to ascertain it as a drug is still not validated. Phytomolecules
such as flavonoids, alkaloids, glycosides, saponins, glycolipids, dietary fibers,
Strobilanthes: A Plethora of Phytomedicine 553

polysaccharides, peptidoglycans, carbohydrates, and amino acids act as potent

hypoglycemic agents [53].
Diabetes mellitus or diabetes is the high glucose level in blood due to lack of
sufficient insulin for absorption. S. crispus tea reduced the blood glucose level in
experimental rats and thereby proved its nutraceutical supplement to diabetic
patients [18]. In literature, S. asperrimus which is a native of India, Japan, Malaysia,
and the rest of Asia is used as a medicine for goiter, tumor, tuberculosis, and possess
bactericidal as well as fungicidal activities. Samal [54] suggested the hypoglycemic
effect of S. asperrimus, which is possibly due to the presence of flavonoids, alka-
loids, and tannins. The effect of S. cuspidata as an antidiabetic was comparable with
the drug Metformin during in vitro assays and Acarbose in in vivo studies [18].
The hypoglycemic effect of hydroalcoholic extract of S. cuspidata leaf showed a
significant dose-dependent fall in blood sugar. The daily treatment for 14 days has
lowered the glucose levels by 38 and 41% in extract treated with 150 and 300 mg/
kg, respectively. The compounds isolated from the extract were tested for antidia-
betic potential in vivo by inhibiting α-amylase enzyme. The antidiabetic potential of
the extract can be confirmed by the isolated molecules such as total saponins, lupeol,
and stigmasterol [55]. Both fermented and unfermented hot water extracts of S. cris-
pus tea were evaluated for their antidiabetic activity in normal rats. The two extracts
showed high lipid profile in them. The antihyperglycemic and antilipidemic activi-
ties may be derived from the antioxidant and polyphenol content of the hot water
extracts [18].

4.3 Antimicrobial Activity

Susceptibility to microbes must be tested for drug discovery, epidemiology, and

prediction of the therapeutic outcome of a product. Natural resources, especially
plants, can provide a huge range of complex and structurally diverse compounds
having antimicrobial activity [56].
S. crispus leaf extract showed tremendous susceptibility to strains of
Staphylococcus pneumoniae and Staphylococcus aureus which are gram-positive
bacteria [57]. The result was rediscovered by Shahni and Handique [58] in S. cusia
as a potent one against gram-positive bacteria. The isolated compounds from S. cal-
losus such as taraxerol and sitosterol showed inhibition against Klebsiella pneu-
moniae and Escherichia coli, respectively. Okinawa people used fresh S. cusia leaf
juice for athletes foot; later, it was scientifically proved and isolated tryptanthrin, an
antifungal substance against dermatophytes [59]. The volatile oil from S. sessilis
flower tops has proved to be antifungal [60]. Strong antibacterial activity was exhib-
ited by methanolic extract of S. crispus in Streptococcus agalactiae, Aeromonas
hydrophila, and Enterobacter cloacae [61]. Ethyl acetate of Indigo Naturalis iso-
lated from S. formosanus inhibits gram-positive bacteria and causes mild inhibition
on non-dermatophytic onychomycosis and no effect on dermatophytes [8].
554 R. Chembrammal et al.

The synthesized silver nanoparticles from S. flaccidifolius proved high antimi-

crobial activity against Pseudomonas aeruginosa, moderate against Proteus mirabi-
lis, Klebsiella pneumoniae, Escherichia coli, and Salmonella paratyphi [62]. The
leaf of S. kunthiana contains different phytochemicals which could have contributed
to its antibiofilm potency against the throat infectious Staphylococcus aureus [63],
which implies the phytopharmaceutical importance of the plant. The ethanolic
extracts of S. crispus exhibited tremendous antibacterial activity against
Staphylococcus epidermidis at 250 μg/mL, but no significant effect for Phytophthora
aeruginosa [64].
The accumulation of organic salts or inorganic salts (calcium, oxalate, phospho-
rous, and ammonia) results in urolithiasis [65]. The diet, genetics, and environment
can be the reasons for the formation of kidney stones [66]. When compared with the
marketed formulations of cystone, the ethyl acetate extracts of S. crispus have effec-
tive calcium stone inhibition, whereas the methanolic extracts were effective against
calcium oxalate dissolution [67].

4.4 Antiproliferative Activity

The use of phytocompounds to protect uncontrolled cell growth has immense

importance in the modern world due to the alarming increase of various dreadful
diseases. Plants and plant-derived compounds have been investigated for the past
several years to counteract against the diseases as a natural alternative.
The oil extracted from the aromatic herb, S. heyneanus, is effective in inflamma-
tion treatments [68]. Agarwal and Rangari [69] showed anti-inflammation activity
of lupeol and α-lupeol isolated from S. callosus and S. ixiocephalus, respectively. Li
et al. [70] showed the anticancer activity of the indole alkaloid, indirubin isolated
from S. cusia. Even though S. sessilis is not suitable for human consumption due to
its toxicity, it is used by the local Adivasi tribals and villagers for inflammatory
diseases [60]. From the aerial parts of S. cusia, three indole alkaloid glycosides,
strobilanthosides A−C, two known indole alkaloid glucosides, and five phenyletha-
noid glycosides, were isolated [71].
The high anticancer activity of S. crispus is due to its phytochemical constitu-
ents, especially mineral contents, antioxidant vitamins as well as catechin [20]. The
findings of Chong et al. [72] suggest that its leaf extract can induce apoptosis and
DNA fragmentation on hormone-dependent breast cancer cell lines. Moreover, it is
powerful in reducing hepatic necrosis in rats by inhibiting the enzymes involved in
boosting carcinogens [73]. But its crude leaf extract, as well as essential oil, was
reported to be nontoxic to normal Chang liver cell line [14, 74]. The antiprolifera-
tion of water extracts of S. crispus towards retroviruses is due to the presence of
compounds with high binding affinity to protein molecules [75]. Among the sub-
fraction of the dichloromethane extract of S. crispus, SC/D-F9 constantly killed
breast and prostate cancer cell lines, but it doesn’t affect the normal breast cells
MCF-10A. This fraction exhibited higher cytotoxicity when compared with
Strobilanthes: A Plethora of Phytomedicine 555

tamoxifen, paclitaxel, docetaxel, and doxorubicin. It induced apoptotic cell death

with the help of caspase 3 and/or 7. Hence, the plant has potent anticancer activity
and can be studied further [76].
Endophytic fungi have been used beneficially in various fields such as pharma-
ceutical, agricultural, and biotechnological applications due to the presence of sec-
ondary metabolites [77]. Jinfeng et al. [78] have isolated two endophytic fungi from
S. crispus using potato dextrose agar medium which shows antimicrobial and anti-
cancer activities. They were named as (PDA) BL3 and (PDA) BL5. The anticancer
studies were performed in human prostatic adenocarcinoma cells, human hepatocel-
lular carcinoma cells, human alveolar adenocarcinoma cells, human colorectal ade-
nocarcinoma cells, and human breast adenocarcinoma cells. Among the two isolates
(PDA), BL5 has high anticancer activity when compared with (PDA) BL3.
The potential death of MCF-7 cells was characterized by cell regulation, DNA
degradation, cytochrome c release, and caspase activation. The ethanolic extracts of
S. crispus were apoptotic for p53, cdk2 protein, and caspase 3/7 and downregulation
of XIAP protein which is an apoptotic inhibitor [72]. The antiglycolytic activities of
S. crispus fraction and its bioactive components on triple-negative breast cancer
cells (MDA-MB-231) are attributed to the bioactivity of the plant [79]. The plant
was cytotoxic against human liver cancer (Hep G2) and breast cancer (MCF-7) with
an IC50 value of 0.3 and 24.8 μg/mL. But it was not toxic against colon cancer cell
Caco-2. The C-myc is a proto-oncogene that is an indicator of cell proliferation and
it is expressed in cancer cell lines. So, its downregulation is mandatory for inducing
apoptosis. The crude extract of S. crispus suppressed the C-myc gene [32]. The
studies in oral toxicity effect of S. crispus in ethanolic leaf extract were done in 20
female Sprague–Dawley rats. In the two weeks experiment, no signs of toxicity,
lethality, and abnormal behavioral changes were observed [24]. The phytocom-
pound γ-sitosterol isolated from S. crispus was tested on Caco2 cells. It exerted
strong antiproliferative ability with an IC50 value of 8.3 μg/mL [80].
The blue hill slopes of Western Ghats are due to the blooming by S. kunthianus
once in twelve years. It is a shrub that grows abundantly in the Shola Forest of the
Western Ghats in South India [81]. The ethanolic extract of S. kunthianus and S. cus-
pidatus showed in vitro anti-inflammatory and anti-osteoarthritic activity. S. kunthia-
nus was tested in the RBC membrane stabilization method, whereas S. cuspidatus
was done in the Rabbit cartilage explants culture method [82]. In another study [83],
the same species was analyzed for its anti-inflammation in ‘carrageenan induced rat
edema method’ and ‘cotton pellet induced granuloma formation’ in rats.
The in vitro analysis of ethyl acetate and n-Butanol flower extracts of S. kunthia-
nus proves that it is a promising free radical scavenger in DPPH and H2O2 radical
scavenging assays [48]. In in vivo, the histopathological evaluation of kidney and
liver tissues of rats revealed the antioxidant and hepatoprotective effect of methano-
lic extract of S. kunthianus. The unique components in the plant are having anti-­
inflammatory, antigiardial, anti-osteoarthritic, analgesic, antioxidant, antibiofilm,
enzyme inhibitor, central nervous system depressant, antifungal, antibacterial, anti-
septic, antimicrobial, anticancer, cytotoxic, hypocholesterolemic 5-alpha reductase
inhibitor activities, and protect skin against UV [81, 84].
556 R. Chembrammal et al.

S. callosus has protective efficacy towards acute and chronic inflammation in rat
models [85]. They administered ethanol, chloroform, and petroleum ether extracts
in different doses (100, 200, and 400 mg/kg). The inflammation was induced by
carrageenan and Freund’s complete adjuvant model in the plantar surface of rats. In
the carrageenan-induced model, petroleum ether extract showed a significant effect,
whereas in Freund’s complete adjuvant model, both extracts were found to be effec-
tive. In vivo protection of CRC of S. crispus extract was done in HT29 cell lines [86].
According to Fernández et al. [87], pentacyclic terpenes could decrease edema
formation. Roots of S. callosus and S. ixiocephala have long been used for inflamma-
tion disorders in folk medicine [68] and their medicinal property is thought to be
conferred by pentacyclic terpene, lupeol. Lupeol at its effective doses exhibits no
toxicity to normal cells Vietnam [88]. Baraya et al. [89] studied the anti-migration,
anti-invasion, and anti-metastasis effects of S. crispus leaves on breast cancer cells
(MDA-MB-231) by using a subfraction F3. The fraction contains β-sitosterol, stig-
masterol, campesterol, lutein, pheophytin a, 131-hydroxy-132-oxo-pheophytin a, and
132-hydroxy-pheophytin a. Thus, the fraction exerted an antiproliferative effect with
the IC50 value of 84.27 μg/mL after 24 h of exposure and 74.41 μg/mL after 48 h of
exposure. Similarly, the subfraction F3 from S. crispus was capable of triggering the
immune system in rats-bearing NMU-induced mammary tumor. So, this may support
the traditional use of leaves of the plant to boost the immune system [90]. Another
study conducted by Gordani et al. [91] investigated the antiproliferative effects of
S. crispus on MCF-7 cells using different extracts of leaves and the stem (methanol,
hexane, chloroform, ethyl acetate, and aqueous extracts). The essential oil from
S. crispus did not show any effect on both MCF-7 and MDA-MB-231 cells [74].
The dichloromethane fraction (F3) of S. crispus was evaluated for the immuno-
modulatory effects. The administration of F3 enhanced the expression of CIITA and
MHC-II on the mammary cancer cells and the number of infiltrating CD4+ and
CD8+ immune cells. Along with that after 2 months, the serum level of chemokine
ligand 2 (CCL2) decreased significantly, while the level of interferon-gamma (IFN-­
γ) increased [90]. Among the five different leaf extracts of S. crispus studied (hex-
ane, chloroform, ethyl acetate, methanol, and aqueous) in CNE-1 cells, the ethyl
acetate extract showed the strongest antiproliferative effect on the cells with an
IC50 value of 119.00 ± 48.10 μg/mL. It was followed by an IC50 value of
119.00 ± 48.10 μg/mL [92]. The previous cell line studies conducted in the taxa are
tabulated (Table 2).
There are two types of lung cancers: non-small cell lung cancer and small cell
lung cancer. The symptoms include a slight cough or shortness of breath and may
become severe. The methanolic leaf extract of S. crispus was analyzed for its cyto-
toxic effect on the NCI-H23 lung cell line. But there was no considerable effect in
it with an IC50 value greater than 200 μg/mL [93]. The methanolic extract of S. cris-
pus exhibited a cytotoxic response towards the T-47D and MCF7 cells and the aque-
ous extract was found to be nontoxic towards all cell lines used. A notable
antiangiogenic activity was shown by both aqueous and methanolic extracts [28].
There was a significant decrease in serum glucose levels in both male and female
diabetic and normal rats when treated with S. crispus juice. It has reduced the
Strobilanthes: A Plethora of Phytomedicine 557

Table 2 Previous reports on the cell line studies in Strobilanthes

Sl. No. Plant Cell line
1. S. crispus [72, 91] MCF-7
2. S. crispus [76] MCF-7, MDA-MB-231, PC-3, DU-145
3. S. crispus [104] MCF-7, MDA-MB-231
4. S. crispus [87] CCD-841, HT-29
5. S. crispus [4] MCF-7, MDA-MB-231
6. S. crispus [106] HeLa
7. S. crispus [76] MCF-7, MDA-MB-231, PC-3, DU-145
8. S. crispus [105] MCF-7, MDA-MB-231
9. S. crispus [107] HepG-2, MDA-MB-231
10. S. crispus [92] CNE-1 NPC
11. S. crispus [14] Caco-2, MDA-MB-231, HepG-2

cholesterol, triglyceride, and LDL-cholesterol level, but the HDL-cholesterol

decreased insignificantly in treated diabetic and normal rats. Hence, the plant can be
an alternative for lowering glucose, cholesterol, and triglyceride for diabetic
patients [51].
Da-Ching-Yeh is the local name for S. cusia in China and is used in Chinese
traditional medicine. It is widely used against influenza, epidemic cerebrospinal
meningitis, encephalitis B, viral pneumonia, and mumps and to treat sore throat,
aphthae, and inflammatory diseases with redness of the skin, etc. The extract of the
plant suppressed the writhing responses of mice and it reduced the paw edema
induced by carrageenan in rats. It potently attenuated pyrexia induced by lipopoly-
saccharide [94]. Hence, the taxa are considerably effective against various diseases.

5 Conclusion

Phytotherapy or herbal medicine or herbalism is the use of plants’ extracts for either
treatment or health-promoting purposes. The phytochemical constituents synergi-
cally act each other to enhance the bioactivity and pharmacological efficacy of a
plant. Most of the Strobilanthes species are underexplored. The various potential
bioactivities of the plant support their use in traditional medicine. Despite the medic-
inal properties, the economic utility of the genus is not explored. The present study
highlights the pharmacological value of the Strobilanthes species in the literature.
Thus, it opens up a wide area of future research in the taxa in drug discoveries.

Acknowledgments The first author acknowledges the financial grant supported by the Council of
Scientific and Industrial Research (CSIR) in the form of Senior Research Fellowship
(09/043(0186)/2017-EMR-1). The second author acknowledges University of Calicut for the
financial assistance rendered.
Declarations The authors declare no conflict of interest.
558 R. Chembrammal et al.

References

1. Sivarajan V, Balachandran I (1994) Ayurvedic drugs and their plant sources. Oxford and IBH
Publishing Co. Pvt. Ltd, New Delhi
2. Bakar MFA, Teh AH, Rahmat A, Hashim N, Othman F, Fakurazi S (2006) Antiproliferative
properties and antioxidant activity of various types of Strobilanthes crispus tea. Int J Cancer
Res 2:152–158
3. Ghasemzadeh A, Jaafar HZ, Rahmat A (2015) Phytochemical constituents and biological
activities of different extracts of Strobilanthes crispus (L.) Bremek leaves grown in different
locations of Malaysia. BMC Complement Altern Med 15(1):1–10
4. Li XB, Komatsu K, Zhou GC, Namba T (1997) Pharmacological studies on the Chinese
crude-drug “Shengma” (IV) 1. Nat Med 51:408–416
5. Chen H, Shao J, Zhang H, Jiang M, Huang L, Zhang Z et al (2018) Sequencing and analy-
sis of Strobilanthes cusia (Nees) Kuntze chloroplast genome revealed the rare simultaneous
contraction and expansion of the inverted repeat region in angiosperm. Front Plant Sci 9:324.
https://doi.org/10.3389/fpls.2018.00324
6. Xu W, Zhang L, Cunningham AB, Li S, Zhuang H, Wang Y, Liu A (2020) Blue genome:
chromosome-scale genome reveals the evolutionary and molecular basis of indigo biosynthe-
sis in Strobilanthes cusia. Plant J 104(4):864–879
7. Wu W, Li J, Liu Y, Jiang M, Lan M, Liu C (2021) Peculiarities of the inverted repeats in the
complete chloroplast genome of Strobilanthes bantonensis Lindau. Mitochondrial DNA Part
B 6(4):1440–1447
8. Chiang YR, Li A, Leu YL, Fang JY, Lin YK (2013) An in vitro study of the antimicrobial
effects of indigo naturalis prepared from Strobilanthes formosanus Moore. Molecules
18:14381–14396
9. Jain SK, Defilipps RA (1991) Medicinal plants of India (pp. 92). Reference Publications,
Inc., Algonac Michigan
10. Warrier PK, Nambiar VPK, Raman Kutty C (1994) Indian medicinal plants, vol 5. Orient
Longman Ltd, Madras, pp 142–145
11. Thomas J, Joy PP, Mathew S, Skaria BP, Duethi PP, Joseph TS (2000) Agronomic practices
for aromatic and medicinal plants. Kerala Agricultural University, Calicut
12. Fatima I, Ahmad I, Anis I, Malik A, Afza N (2007) Isatinones a and B, new antifungal oxin-
dole alkaloids from Isatis costata. Molecules 12:155–162
13. George M, Joseph L, Sony S (2017) A review on pharmacological and biological activities of
Strobilanthes ciliatus Nees. World J Pharm Pharm Sci 6:504–512
14. Rahmat A, Edrini S, Ismail P, Taufiq Y, Yun H, Abu Bakar MF (2006) Chemical constitu-
ents, antioxidant activity and cytotoxic effects of essential oil from Strobilanthes crispus and
Lawsonia inermis. J Biol Sci 6:1005–1010
15. Noraida A (2005) Penyembuhan semula jadi dengan herba. Medicinal Plants Malaysia. Herbs
Thearapic Use in Malaysia
16. Ong HC, Norzalina J (1999) Malay herbal medicine in Gemencheh, Negeri Sembilan.
Malaysia Fitoterapia 70(1):10–14
17. Sundaram V, Sadhasivam S, Chandrasekaran S, Nanjian R, Pandian A (2021) Strobilanthes
heyneanus root extract as a potential source for antioxidant and antimicrobial activity. Future
J Pharm Sci 7(1):1–12
18. Fadzelly AM, Asmah R, Fauziah O (2006) Effects of Strobilanthes crispus tea aqueous
extracts on glucose and lipid profile in normal and streptozotocin-induced hyperglycemic
rats. Plant Foods Hum Nutr 61(1):6–11
19. Cheong BE, Zakaria NA, Cheng AYF, Teoh PL (2016) GC-MS analysis of Strobilanthes
crispus plants and callus. Trans Sci Technol 3(1–2):155–161
20. Maznah I, Manickam E, Danial AM, Rahmat A, Yahaya A (2000) Chemical composition and
antioxidant activity of Strobilanthes crispus leaf extract. J Nutr Biochem 11:536–542. https://
doi.org/10.1016/S0955-­2863(00)00108-­X
Strobilanthes: A Plethora of Phytomedicine 559

21. Lee CL, Wang CM, Hu HC, Yen HR, Song YC, Yu SJ et al (2019) Indole alkaloids ind-
igodoles A-C from aerial parts of Strobilanthes cusia in the traditional Chinese medicine
Qing Dai have anti-IL-17 properties. Phytochemistry 162:39–46. https://doi.org/10.1016/j.
phytochem.2019.02.016
22. Gu W, Wang W, Li XN, Zhang Y, Wang LP, Yuan CM, Huang LJ, Hao XJ (2015) A novel iso-
coumarin with anti-influenza virus activity from Strobilanthes cusia. Fitoterapia 107:60–62.
https://doi.org/10.1016/j.fitote.2015.10.009
23. Laitonjam WS, Wangkheirakpam SD (2011) Comparative study of the major components
of the indigo dye obtained from Strobilanthes flaccidifolius Nees. And Indigofera tinctoria
Linn. Int. J Plant Physiol Biochem 3(5):108–116. https://doi.org/10.5897/IJPPB.9000010
24. Lim KT, Lim V, Chin JH (2012) Subacute oral toxicity study of ethanolic leaves extracts
of Strobilanthes crispus in rats. Asian Pac J Trop Biomed 2(12):948–952. https://doi.
org/10.1016/S2221-­1691(13)60005-­2
25. Fernandes MC, Krishnan S (2019) GC-MS analysis of metabolites in leaf and stem of medic-
inally important Strobilanthes species from North Western Ghats of India. Phytomorphology
69:67–79
26. Weyerstahl P, Marschall-Weyerstahl H, Manteuffel E, Kaul VK (1992) Constituents of the
essential oil of Strobilanthes callosus Nees. J Essent Oil Res 4(3):281–285. https://doi.org/1
0.1080/10412905.1992.9698062
27. Tangpu V, Yadav AK (2006) Anticestodal property of Strobilanthes discolor: an experimental
study in Hymenolepis diminuta - rat model. J Ethnopharmacol 105(3):459–463. https://doi.
org/10.1016/j.jep.2005.11.015
28. Muslim NS, Ng KW, Itam A, Nassar ZD, Ismail Z, Abdul Majid AMS (2010) Evaluation of
cytotoxic, anti-angiogenic and antioxidant properties of standardized extracts of Strobilanthes
crispus leaves. Int J Pharmacol 6(5):591–599
29. Al-Henhena N, Mahmood AA, Al-Magrami A, Syuhada AN, Zahra AA, Summaya MD, Suzil
MS, Salmah I (2011) Histological study of wound healing potential by ethanol leaf extract
of Strobilanthes crispus in rats. J Med Plant Res 5(16):3660–3666. https://doi.org/10.5897/
JMPR.9000704
30. Tsai YC, Lee CL, Yen HR, Chang YS, Lin YP, Huang SH, Lin CW (2020) Antiviral action of
tryptanthrin isolated from Strobilanthes cusia leaf against human coronavirus NL63. Biomol
Ther 10(3):366. https://doi.org/10.3390/biom10030366
31. Liza MS, Rahman RA, Mandana B, Jinap S, Rahmat A, Zaidul ISM, Hamid A (2010)
Supercritical carbon dioxide extraction of bioactive flavonoid from Strobilanthes cris-
pus (Pecah Kaca). Food Bioprod Process 88(2–3):319–326. https://doi.org/10.1016/j.
fbp.2009.02.001
32. Endrini S, Rahmat A, Ismail P, Taufiq-Yap YH (2007) Comparing of the cytotoxicity proper-
ties and mechanism of Lawsonia inermis and Strobilanthes crispus extract against several
cancer cell lines. J Med Sci 7(7):1098–1102
33. Kavitha CCI, Indira G (2016) Quantitative estimation of total phenolic, flavonoids, tannin and
chlorophyll content of leaves of Strobilanthes kunthiana (Neelakurinji). J Med Sci 4:282–286
34. Shirwaikar A, Sajith Kumar PN, Rajagopal PL (2018) Preliminary phytochemical and
physicochemical analysis on Strobilanthes ciliatus Nees. Research review. Int J Multidiscip
3(4):125–127
35. Halliwell B, Gutteridge JMC (1999) Free radicals in biology and medicine. Clarendon
Press, Oxford
36. Poljsak B, Šuput D, Milisav I (2013) Achieving the balance between ROS and antioxidants:
when to use the synthetic antioxidants. Oxidative Med Cell Longev 2013:1. https://doi.
org/10.1155/2013/956792
37. Alam MN, Bristi NJ, Rafiquzzaman M (2013) Review on in vivo and in vitro methods evalu-
ation of antioxidant activity. Saudi Pharma J 21(2):143–152
38. Sies H (1991) Oxidative stress: from basic research to clinical application. Am J Med
91(3):31–38
560 R. Chembrammal et al.

39. Chen TQ, Wu YB, Wu JG, Wang HY, Mao FH, Wu JZ (2013) Fatty acids, essential oils,
and squalene in the spore lipids of Ganoderma lucidum by GC-MS and GC-FID. Chem Nat
Compd 49:143. https://doi.org/10.1007/s10600-­013-­0536-­x
40. Yang T, Wu Q, Li SY, Lv ZJ, Hu B, Xie BJ, Sun ZD (2014) Liposoluble compounds with anti-
oxidant activity from Strobilanthes tonkinensis. Chem Nat Compd 49(6):1166–1167. https://
doi.org/10.1007/s10600-­014-­0852-­9
41. Prabakaran R, Kirutheka E (2018) GC-MS, phytochemicals and antioxidant activities of in
vitro callus extracts of Strobilanthes kunthiana (Nees) T. Anderson ex Benth: an endemic
plant of Acanthaceae. Braz. J Biol Sci 5(10):359–372
42. Subbulekshmi KO, Godwin SE, Vahab AA (2015) Phytochemical and in-vitro antioxidant
activity of ethanolic extract of Strobilanthes barbatus Nees leaves. Asian J Pharm Res Dev
3(2):13–20
43. Mathew G, Lincy J, Sony S (2017) Evaluation of analgesic activity of ethanolic extract of
Strobilanthes ciliatus Nees. Pharma Innov 6(7):326–328
44. Qader SW, Abdulla MA, Chua LS, Najim N, Zain MM, Hamdan S (2011) Antioxidant,
total phenolic content and cytotoxicity evaluation of selected Malaysian plants. Molecules
16(4):3433–3443. https://doi.org/10.3390/molecules16043433
45. Tan HM, Leong KH, Song J, Mohd Sufian NSF, Mohd Hazli UHA, Chew LY, Kong KW
(2020) Antioxidant and LC-QToF-MS/MS analysis of polyphenols in polar and non-polar
extracts from Strobilanthes crispus and Clinacanthus nutans. Int Food Res J 27(5):903–914
46. Chua LYW, Chua BL, Figiel A, Chong CH, Wojdyło A, Szumny A, Choong TSY (2019)
Antioxidant activity, and volatile and phytosterol contents of Strobilanthes crispus dehy-
drated using conventional and vacuum microwave drying methods. Molecules 24. https://doi.
org/10.3390/molecules24071397
47. Aziz M, Ahmad S, Iqbal MN, Khurshid U, Saleem H, Rehman KU, Alamri A, Anwar S,
Alamri AS, Chohan TA (2021) Phytochemical, pharmacological, and in-silico molecular
docking studies of Strobilanthes glutinosus Nees: an unexplored source of bioactive com-
pounds. S Afr J Bot. https://doi.org/10.1016/j.sajb.2021.07.013
48. Singh BB, Das S, Maithi A (2014) Antioxidant property for lipophilic extract of Strobilanthes
kunthiana flowers. Indian J Res Pharm Biotechnol 2(1):1005–1009
49. Balasubramaniam G, Sekar M, Badami S (2021) In-vitro antioxidant and cytotoxic properties
of Strobilanthes kunthianus. Res J Pharm Technol 14(5):2522–2528
50. Samal PK (2013) Antioxidant activity of Strobilanthes asperrimus in albino rats. Asian J
Pharm Clin Res 3:71–74
51. Norfarizan-Hanoon NA, Asmah R, Rokiah MY, Fauziah O, Faridah H (2009)
Antihyperglycemic, hypolipidemic and antioxidant enzymes effect of Strobilanthes crispus
juice in normal and streptozotocin-induced diabetic male and female rats. Int J Pharmacol
5(3):200–207
52. Maritim AC, Sanders A, Watkins JB III (2003) Diabetes, oxidative stress, and antioxidants: a
review. J Biochem Mol Toxicol 17(1):24–38. https://doi.org/10.1002/jbt.10058
53. Mukherjee PK, Maiti K, Mukherjee K, Houghton PJ (2006) Leads from Indian medici-
nal plants with hypoglycemic potentials. J Ethnopharmacol 106(1):1–28. https://doi.
org/10.1016/j.jep.2006.03.021
54. Samal PK (2013) Antidiabetic and antioxidant activity of strobilanthes asperrimus in rats. J
Glob Trends Pharma Sci 4(2):1067–1072
55. Joseph S, Kumar L, Bai VN (2016) Evaluation of anti-diabetic activity of Strobilanthes cus-
pidata in alloxan induced diabetic rats and the effect of bioactive compounds on inhibition of
α-amylase enzyme. J Pharmacogn Phytochem 5(3):169–175
56. Balouiri M, Sadiki M, Ibnsouda SK (2016) Methods for in vitro evaluating antimicrobial
activity: a review. J Pharm Anal 6(2):71–79. https://doi.org/10.1016/j.jpha.2015.11.005
57. Lim V, Yap CS, Chong HW, Shukkoor MSA, Priya M (2013) Antimicrobial evaluation and
GC-MS analysis of Strobilanthes crispus ethanolic leaf extract. Methodology 10(4):1–8.
https://doi.org/10.9734/EJMP/2015/20075
Strobilanthes: A Plethora of Phytomedicine 561

58. Shahni R, Handique PJ (2013) Antibacterial properties of leaf extracts of Strobilanthes

cusia (Nees) Kuntze, a rare ethno-medicinal plant of Manipur, India. I J PharmTech Res
5:1281–1285
59. Honda G, Tabata M (1979) Isolation of antifungal principle tryptanthrin, from Strobilanthes
cusia O. Kuntze Planta Medica 36(05):85–86. https://doi.org/10.1055/s-­0028-­1097245
60. Shende VS, Jadhav SD, Aloorkar NH, Kulkarni AS, Suryavanshi SV (2015) Pharmacognostic
and phytochemical evaluation of Strobilanthes sessilis Nees. Leaves. Int J Pharmacogn
2:310–314
61. Raina MS, Hassan MD (2016) Screening of phytochemical properties and antimicro-
bial activity of Malaysian medicinal plants against aquatic bacteria. Malays J Microbiol
12(4):284–290
62. Wangkheirakpam SD, Devi WR, Singh CB (2016) Green synthesis of silver nanoparticles
using Strobilanthes flaccidifolius Nees. leaf extract and its antibacterial activity. Journal of.
Adv Chem 8(1):1523–1532
63. Everlyne IM, Darsini TP, Yadav SA (2016) Unraveling antibiofilm potency of Strobilanthes
kunthiana (Nees) T. Anderson ex Benth. against throat-infectious methicillin-resistant
Staphylococcus aureus. Pharm Res 6:5706–5716
64. Mohamad Razak AS (2019) Phytochemical analysis, toxicity and antibacterial avtivities of
Strobilanthes crispus (Doctoral dissertation, Universiti Teknologi MARA Cawangan Perlis).
Local Continent Hub
65. Gupta AK, Dobriyal R, Victorian TD (2018) In vitro evaluation of antiurolithiatic activ-
ity of Euphorbia thymifolia L. plant extracts. Int Res Med Health Sci 1(1):3–7. https://doi.
org/10.36437/irmhs.2018.1.1.B
66. Edvardsson VO, Ingvarsdottir SE, Palsson R, Indridason OS (2018) Incidence of kidney
stone disease in Icelandic children and adolescents from 1985 to 2013: results of a nation-
wide study. Pediatr Nephrol 33:1375–1384. https://doi.org/10.1007/s00467-­018-­3947-­x
67. Gul MT, Dheyab AS, Shaker EK, Muhammad N, Pauzi AN (2020) In vitro evaluation of anti-­
urolithiatic properties of Strobilanthes crispus extracted using different solvents. Res J Chem
Environ 24(1):117–121
68. Nayar RB, Ravishankar B, Vijayan NP, Sasikala CK, Saraswathy VN (1988) Anti-­
inflammatory effect of Strobilanthus heyneanus leaves - a biochemical study. J Res Ayurv-­
Sidha 9(1–2):46
69. Agarwal RB, Rangari VD (2003) Antiinflammatory and antiarthritic activities of lupeol and
19 α-H lupeol isolated from Strobilanthus callosus and Strobilanthus ixiocephala roots.
Indian J Pharmacol 35(6):384–387
70. Li L, Liang HQ, Liao SX, Qiao CZ, Yang GJ, Dong TY (1993) Chemical studies of
Strobilanthes cusia. Acta Pharm Sin 28:238–240
71. Gu W, Zhang Y, Hao XJ, Yang FM, Sun QY, Morris-Natschke SL, Lee KH, Wang YH, Long
CL (2014) Indole alkaloid glycosides from the aerial parts of Strobilanthes cusia. J Nat Prod
77(12):2590–2594. https://doi.org/10.1021/np5003274
72. Chong HZ, Rahmat A, Yeap SK, Akim AM, Alitheen NB, Othman F, Gwendoline-Ee CL
(2012) In vitro cytotoxicity of Strobilanthes crispus ethanol extract on hormone dependent
human breast adenocarcinoma MCF-7 cell. BMC Complement Altern Med 12(1):1–10.
https://doi.org/10.1186/1472-­6882-­12-­35
73. Hanachi P, Fauziah O, Asmah R (2008) Lesion scoring and p450 isoenzyme activity in liver of
hepatocarcinogenesis rats treated with Strobilanthes crispus. Sci Inform Database 1(1):11–15
74. Rahmat A, Edrini S, Akim AM, Ismail P, Taufiq Y, Yun H, Abubakar MF (2006)
Anticarcinogenic properties of Strobilanthes crispus extracts and its compounds in vitro. Int
J Cancer Res 2:47–49
75. Kusumoto IT, Shimada I, Kakiuchi N, Hattori M, Namba T, Supriyatna S (1992) Inhibitory
effects of Indonesian plant extracts on reverse transcriptase of an RNA tumour virus (I).
Phytother Res 6(5):241–244
562 R. Chembrammal et al.

76. Yaacob NS, Hamzah N, Kamal NNNM, Abidin SAZ, Lai CS, Navaratnam V, Norazmi MN
(2010) Anticancer activity of a sub-fraction of dichloromethane extract of Strobilanthes
crispus on human breast and prostate cancer cells in vitro. BMC Complement Altern Med
10(1):1–14. https://doi.org/10.1186/1472-­6882-­10-­42
77. Strobel G, Daisy B (2003) Bioprospecting for microbial endophytes and their natural products.
Microbiol Mol Biol Rev 67:491–502. https://doi.org/10.1128/MMBR.67.4.491-­502.2003
78. Jinfeng EC, Rafi MIM, Hoon KC, Lian HK, Kqueen CY (2017) Analysis of chemical constit-
uents, antimicrobial and anticancer activities of dichloromethane extracts of Sordariomycetes
sp. endophytic fungi isolated from Strobilanthes crispus. World J Microbiol Biotechnol
33(1):1–19. https://doi.org/10.1007/s11274-­016-­2175-­4
79. Muhammad SN, Yaacob NS, Safuwan NA, Fauzi AN (2021) Antiglycolytic activities
of Strobilanthes crispus active fraction and its bioactive components on triple-negative
breast cancer cells in vitro. Anti Cancer Agents Med Chem 22:1363. https://doi.org/10.217
4/1871520621666210427104804
80. Endrini S, Rahmat A, Ismail P, Taufiq-Yap YH (2014) Cytotoxic effect of γ-sitosterol from
Kejibeling (Strobilanthes crispus) and its mechanism of action towards c-myc gene expres-
sion and apoptotic pathway. Med J Indones 23(4):203–208. https://doi.org/10.13181/mji.
v23i4.1085
81. Paulsamy S, Vijayakumar KK, Murugesan M, Padmavathy S, Senthilkumar P (2007)
Ecological status of medicinal and other economically important plants in the shola under-
stories of Nilgiris, the Western Ghats. Nat Prod Radiance 6:55–61
82. Desu BSR, Elango K, Satish Kumar MN, Suresh B, Manimaran S, Nanjan MJ (2011)
In-vitro anti-inflammatory and anti-osteoarthritic activities of Strobilanthes kunthianus and
Strobilanthes cuspidatus. Int J Res Pharm Chem 1(4):1265–1268
83. Desu BS, Elango K, Satish Kumar MN, Suresh B, Manimaran S, Nanjan MJ (2011)
Investigation of selected medicinal plants (Strobilanthes kunthianus, Strobilanthes cuspida-
tus) and marketed formulation (Shallaki) for their anti-inflammatory and anti-osteoarthritic
activity. Pharmanest 2:492–499
84. Balasubramaniam G, Sekar M, Varadarajan M, Badami S (2020) Antioxidant and hepatopro-
tective activities of Strobilanthes kunthianus against carbon tetrachloride-induced hepatotox-
icity in rats. Pharm J 12(5):1143–1151. https://doi.org/10.5530/pj.2020.12.161
85. Kumar S, Bhatia M, Garg LN, Gupta S (2013) Acute and chronic inflammation studies of
Strobilanthes callosus leaves extract on rat model. Inflammopharmacology 21(3):233–239.
https://doi.org/10.1007/s10787-­012-­0150-­8
86. Al-Henhena N, Khalifa SA, Ying RPY, Ismail S, Hamadi R, Shawter AN, Idris AM, Azizan A,
Al-Wajeeh NS, Abdulla MA, El-Seedi HR (2015) Evaluation of chemopreventive potential of
Strobilanthes crispus against colon cancer formation in vitro and in vivo. BMC Complement
Altern Med 15:419. https://doi.org/10.1186/s12906-­015-­0926-­7
87. Fernández MA, de las Heras B, Garcia MD, Sáenz MT, Villar A (2001) New insights into
the mechanism of action of the anti-inflammatory triterpene lupeol. J Pharm Pharmacol
53(11):1533–1539
88. Siddique HR, Saleem M (2011) Beneficial health effects of lupeol triterpene: a review of
preclinical studies. Life Sci 88(7–8):285–293. https://doi.org/10.1016/j.lfs.2010.11.020
89. Baraya YS, Wong KK, Yaacob NS (2019) Strobilanthes crispus inhibits migration, invasion
and metastasis in breast cancer. J Ethnopharmacol 233:13–21. https://doi.org/10.1016/j.
jep.2018.12.041
90. Yankuzo HM, Mustapha Z, Wong KK, Yaacob NS (2018) Immunomodulatory effects of a
bioactive fraction of Strobilanthes crispus in NMU-induced rat mammary tumor model. J
Ethnopharmacol 213:31–37. https://doi.org/10.1016/j.jep.2017.10.024
91. Gordani N, Cheong BE, Teoh PL (2017) Antiproliferative effect of Strobilanthes crispus on
MCF-7 cell line. Trans Sci Technol 4:414–419
92. Koh RY, Sim YC, Toh HJ, Liam LK, Ong RSL, Yew MY, Tiong YL, Ling APK, Chye SM,
Ng KY (2015) Cytotoxic and apoptogenic effects of Strobilanthes crispa Blume extracts
Strobilanthes: A Plethora of Phytomedicine 563

on nasopharyngeal cancer cells. Mol Med Rep 12(4):6293–6299. https://doi.org/10.3892/

mmr.2015.4152
93. Ng MG, Ng CH, Ng KY, Chye SM, Ling APK, Koh RY (2021) Anticancer properties of
Strobilanthes crispus: a review. PRO. https://doi.org/10.3390/pr9081370
94. Ho YL, Kao KC, Tsai HY, Chueh FY, Chang YS (2003) Evaluation of antinociceptive, anti-­
inflammatory and antipyretic effects of Strobilanthes cusia leaf extract in male mice and rats.
Am J Chin Med 31(01):61–69. https://doi.org/10.1142/S0192415X03000783
95. Singh B, Sahu PM, Sharma MK (2002) Anti-inflammatory and antimicrobial activities of
triterpenoids from Strobilanthes callosus Nees. Phytomedicine 9(4):355–359. https://doi.org/
10.1078/0944-­7113-­00143
96. Reneela P, Sripathi SK (2010) Triterpenoid and sterol constituents of Strobilanthes ciliatus
Nees. Nat Prod 6(1):35–38
97. Reneela P, Sripathi SK (2011) Structural characterization of a new compound from
Strobilanthes ciliatus Nees. Indian J Nat Prod Resour 7:287–290
98. Soediro I, Pellecuer J, Andary C, Privat G (1983) Strobilanthes crispus (L.) B1 I: Pemeriksaan
senyawaan turunan asam kafeat verbascosid. Acta Pharmaceutical. Indonesia VIII:1–10
99. Soediro I, Pellecuer J, Andary C, Privat G (1987) Strobilanthes crispus (L.) B1 I: Pemeriksaan
asam fenolat. Acta Pharma Indonesia XII:1–7
100. Ahmed FHAM (1999) Isolation, identification and evaluation of antibacterial activity of the
semi-purified compound from Strobilanthes crispus L. Bremek (M.Sc. Thesis, Universiti
Putra, Malaysia)
101. Koay YC, Wong KC, Osman H, Eldeen I, Asmawi MZ (2013) Chemical constituents and
biological activities of Strobilanthes crispus L. Rec Nat Prod 7(1):59–64
102. Afrizal A (2008) Analytical, bioactivity and stability studies on Strobilanthes crispus
L. Bremek and Sonchus arvenis L. extracts. (Doctoral dissertation, Universiti Sains Malaysia)
103. Kao KC, Ho YL, Lin IH, Ho LK, Chang YS (2004) Flavone glycosides from Strobilanthes
formosanus. J Chin Chem Soc 51(1):199–204. https://doi.org/10.1002/jccs.200400030
104. Yaacob NS, Kamal NNNM, Norazmi MN (2014) Synergistic anticancer effects of a bio-
active subfraction of Strobilanthes crispus and tamoxifen on MCF-7 and MDA-MB-231
human breast cancer cell lines. BMC Complement Altern Med 14. https://doi.org/10.1186/
1472-­6882-­14-­252
105. Yaacob NS, Kamal NNNM, Wong KK, Norazmi MN (2016) Cell cycle modulation of
MCF-7 and MDA-MB-231 by a sub-fraction of Strobilanthes crispus and its combina-
tion with tamoxifen. Asian Pac J Cancer Prev 16(18):8135–8140. https://doi.org/10.7314/
APJCP.2015.16.18.8135
106. Chong YH, Koh RY, Ling APK, Chye SM, Yew MY (2014) Strobilanthes crispus extract
induces apoptosis through enhanced caspases activities in cervical cancer cells. In:
International conference on biological, environment and food engineering, Bali, pp 42–46
107. Koh RY, Lim FP, Ling LSY, Ng CPL, Liew SF, Yew MY, Tiong YL, Ling APKL, Chye
SM, Ng KY (2017) Anticancer mechanisms of Strobilanthes crispa Blume hexane extract
on liver and breast cancer cell lines. Oncol Lett 14(4):4957–4964. https://doi.org/10.3892/
ol.2017.6821
Annonaceae: Tropical Medicinal Plants
with Potential Anticancer Acetogenins
and Alkaloids

Sonia Mol Joseph and A. R. Amala Dev

1 Introduction

Cancer continues to claim lives globally, and as per data published by WHO, in
2020, cancer claimed ten million lives that accounts for one in every six deaths and
it is the second leading cause of death in the world. Cancer affects human around
the globe with no bars to color, creed, or geographical barriers. Though the number
of people receiving a cancer diagnosis has steeply increased over the years, the sur-
vival rates are improving remarkably. The scientists and research scholars in this
field are dedicated to develop various noninvasive drugs for treating cancer. The
mental and physical agony caused due to the side effects of conventional treatment
methods like chemotherapy and anticancer drugs are beyond words to describe and
continue to haunt patients even after recovery form the disease. During treatment,
patients suffer from anemia, appetite loss, hair loss (Alopecia), nerve problems
(Peripheral neuropathy), organ-related inflammation, sleep problems, and insom-
nia. In this context anticancer drugs of natural origin, herbal remedies, and natural
phytochemicals have been the focus area for managing the adverse side effects of
cancer treatment. Plant-based anticancer drugs containing bioactive compounds of
medicinal plants like vinblastine, taxol, vincristine, epipodophyllotoxins, and camp-
tothecine derivatives have proved efficacy in treating human cancers. Most interest-
ingly, some of these drugs act like a natural defensive mechanism against formation
of cancer cells in human body. This throws light into the arena of cancer prevention
rather than cancer treatment with phytochemicals derived from medicinal plants
which we see around us.

S. M. Joseph (*) · A. R. Amala Dev

PG & Research Department of Chemistry, Mar Ivanios College (Autonomous),
Thiruvananthapuram, Kerala, India
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 565

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_22
566 S. M. Joseph and A. R. Amala Dev

2 Annonaceae Plant Species: A Focus on its

Anticancer Studies

The family Annonaceae is commonly called Custard-apple Family, which is one of

the most diverse families of plants with flowers consisting of more than 132 genera
and 2300 species. Genus Annona belonging to this family comprises over 119 spe-
cies, majority of them are evergreen trees and shrubs. It is one of the well-­investigated
medicinal plant in Annonaceae family due to its potent pharmacological activities.
Majority of them are traditionally used around the globe for curing variety of human
ailments including different types of cancers. Most of them are cultivated in tropical
countries around the world particularly for edible fruits. The most widely distrib-
uted and well known anticancer Annona species are described below.

3 Taxonomy of Major Plant Species from Annonacea

Annona cherimola is an erect plant with long and light green leaves and white,
fleshy fragrant flowers. Fruits are conical, oval, or heart-shaped with fingerprint-like
markings on its surface. Snow-white juicy flesh contains oval-oblong, slightly flat-
tened brown or black, bean-like, glossy seeds. Annona crassiflora is a deciduous
tree having ovate leaves, their yellow-greenish leathery flowers have a jellyfish like
appearance. Fruits are sweet and have fibrous, succulent, and creamy pulp. Annona
dioica is a small shrub with oval, light green hairy leaves. Fleshy, leathery leaves
and yellowish flowers are present. Yellowish green spiky edible fruits are present in
the plant with a creamy pulp inside it. Annona glabra is semi-deciduous tropical
plant having ovate to oblong leaves in it. Leaves are glossy and hairless having the
smell similar to green apples. Annona montana is an evergreen or semievergreen
shrub or tree with large glossy and glabrous leaves and slightly scented flowers. Its
fruits are dark-green in color, studded with spines, and have yellow-orange flesh. Its
seeds are light-brown and waxy in nature. A. glabra have creamy or pale-yellow
leathery flowers. The mango-shaped fruits having smooth and shiny surface are
edible and it contains pinkish-orange pulp with many light yellows to brown seeds.
Annona muricata is small, evergreen plant with green glossy leaves which are
oblong to oval and slightly hairy branches. Flowers are thick and yellowish which
appear singly on a woody stalk on twigs, branches, or trunks. Fruits contain black
colored seeds in a creamy white flesh inside it with cotton-like fibers. They are
heart-shaped with curved spines covering the leathery rough skin and dark green in
color. Annona reticulata is a small shrub or semievergreen tree. Leaves are alternate
and hairless pointed at the apex. Flowers are yellow-green in color generally seen in
clusters. The reddish-yellow to brown fruitsvary in shape, heart-shaped, spherical,
or oblong having white pulp. Blackish brown glossy seeds are present in the fruit
and it is covered in polygonal plates. Annona purpurea is a deciduous shrub or tree
with hairy, elliptical, or oval-shaped leaves and large, strong-scented flowers. The
Annonaceae: Tropical Medicinal Plants with Potential Anticancer Acetogenins… 567

edible fruit is rounded with a felt-textured brown skin and having hook like projec-
tions on the surface. The fruit of the plant appears as stringy and fibrous. Bigger
spiky and hard-shelled fruits have yellowish orange sweet flesh with black seeds.
Annona squamosa is semi-deciduous shrub with very simple leaves having fine
hairs underneath and glaring greenish yellow pendulous flowers. The edible fruit is
greenish yellow in color with a knobby surface and have brown to black oblong
seeds embedded in soft creamy pulp. Annona senegalensis is a small tree with green
to bluish leaves without hairs on the top, but having brownish colored hairs under-
side. The flowers are yellowish in color, waxy, closely petalled, and very fragrant.
The fruits are yellow to orange in color, are sweet in taste, have pineapple-like odor,
and carry cylindrical orange-colored seeds.
Different Annonacea plant species can be seen in many parts of India and cap-
tures researcher’s attention due to its high nutritional value and medical applica-
tions. Pharmacological analysis on bark, fruit, leaves, and seeds of genus Annona
explored its anti-inflammatory, antitumor, anti-HIV, anticancer, antiprotozoal, anti-
diabetic, analgesics, antiparasitic, antihypertensive, gastroprotective, and hepato-
protective properties. Annonaceous acetogenins and alkaloids were potential
candidates believed to be responsible for significant biological activities [1].
Investigation on the discovery of anticancer agents from nature especially from this
plant origin is currently going on. Reports showed that annonaceous acetogenins
inhibits mitochondria complex I and NADH oxidase activity of plasma membranes
of tumor cells [2]. Selective suppression of cell growth of cancerous cells and drug
resistance cancerous cells in a dose-dependent manner were also reported [3].
Annonaceous acetogenins and alkaloids possessed antitumor potential and exhibit
cytotoxic effect through various mechanisms including inhibition of caspase, arrest-
ing the cell cycle, apoptosis, etc. [4]. Recent reports also showed acetogenins
extracted from the Annonacea family have pronounced cytotoxicity against respira-
tory complex [5]. Many studies have been reported till now elaborating the thera-
peutical applications of Annona genus as a potent anticancer agent. This chapter
comprises the reported antitumor activities of different Annonacea plant species
from Annona genus which showed potent activities in various types of cancer cells
in order to demonstrate their importance in cancer research and their mechanism of
action in detail [Fig. 1].
Annona cherimola commonly called cherimoya is a small deciduous tree with
edible fruits commonly found in the tropical or subtropical regions. Phytochemical
investigation of this plant has revealed the presence of flavonoids, alkaloids, glyco-
sides, tannins, steroids, saponins, amino acids, carbohydrates, proteins, and pheno-
lic compounds. Essential oil and ethanol extract of A. cherimola exhibited potent
anticancer effect against colon (CACO-2), liver (HEPG-2) and breast (MCF-7), and
carcinoma cell lines [6]. Two acetogenins namely, Aromin-A and squamocin, iso-
lated from methanolic extract of A. cherimola stem inhibited cell proliferation activ-
ity as reported in a study conducted in 1999 [7]. Seed extracts reported the
programmed cell death in Acute Myeloid Leukemia (AML) cell lines by the excita-
tion of both the intrinsic and extrinsic pathways [8]. Cytotoxic acetogenins, namely,
annomolin and annocherimolin reported from ethanolic extract of seeds of Annona
568 S. M. Joseph and A. R. Amala Dev

Fig. 1 Reported anticancer effects of some common Annona species

cherimola, was found to exhibit selectivity to human prostate tumor cell line (PC-3),
breast (MCF-7), and colon (HT-29) cancer cell lines, respectively [9, 10]. Previous
studies confirmed the potent inhibitory effect of terpene rich fraction of A. cheri-
mola leaf extract on Acute Myeloid Leukemia (AML), MDBK, and Hep-2cells
[11]. Evaluation of A. cherimola seed extract on human stomach gastric adenocar-
cinoma cell line [12], molvizarin, and motrilin which was the first C-29 hydroxyl-
ated acetogenin reported from the methanolic extracts of A. cherimola seeds
exhibited promising anticancer activity [13]. Bioactive acetogenins from A. cheri-
mola seeds proved its suppression efficiency similar to that of chemotherapeutic
drug namely Daunorubicin [14]. Cis-Potent cytotoxicity of annonacin, (2,4)-cis-and
trans-isoannonacins against pancreatic, prostate cancer cell line and almunequin,
cherimolin-2 reported from A. cherimola seeds against human KB carcinoma cell
line and monkey VERO cell line were reported [15, 16].
Another species Annona coriacea is an endemic species of the Brazilian Cerrado
that exhibits promising biological activities. A new acetogenin, coriadienin, is
reported from A. coriaea roots along with a known cytotoxic compound, gigantet-
ronenin. Coriadienin is attributed to the anticancer activity in VERO and KB cell
lines [17]. The extract showed autophagy inhibition in the cervical cancer cell line
which is an asset in cancer treatment. Acetogenins and alkaloids present in the
A. coriacea fraction were responsible for the cytotoxicity in cervical cancer cell
lines via DNA damage. Mode of action is found to be in a dose-dependent manner.
Annonaceae: Tropical Medicinal Plants with Potential Anticancer Acetogenins… 569

Further research is required to explore the cytotoxicity activity of A. coriacea [18].

Annona cornifolia is a rare slow-growing shrub with sweet edible fruit found in the
Brazilian savannah and is popularly known as “araticum-mirim”. Sucrose octaace-
tate from acetylation of ethanol extract of A. cornifolia seeds exhibited antitumor
activity against human melanoma (UACC-62), renal carcinoma (TK -10), and breast
cancer (MCF-7) cell lines. Interestingly, antitumor activity of component was
reported initiatory as its use as a drug candidate [19]. Further studies revealed Fatty
Acid Methyl Esters (FAME) of seeds of plant have shown cytostatic and cytocidal
effects against human cancerous cells [20]. Annona crassiflora is a deciduous tree
native to the Cerrado of Brazil reported to possess potential biological effects. The
phytochemical composition of trees includes alkaloids, phenolic compounds,
annonaceous acetogenins, tocols, phytosterols, dietary fiber, carotenoids, vitamins,
minerals, and fragrant essential oils that can be utilized in pharmaceutical composi-
tions [21]. Kaempferol glucosides isolated from A. crassiflora are attributed for
antitumor activity [22]. Hexane extract of A. crassiflora was tested against the
human cervical cancer cells and decreased p21 expression by ubiquitin - protea-
some pathway-indicated apoptosis [23]. Recent reports showed in vivo cytotoxic
activity in Ehrlich solid tumor-bearing swiss mice by wood extract of the plant.
Interestingly, α, β-unsaturated γ-lactone in bis-THF acetogenins was accountable
for the reported activity [24]. A. crassiflora seed extract demonstrated suppression
of proliferation of multidrug-resistant ovary adenocarcinoma cell line (NCI-ADR/
RES). Bioactive flavonoid, epicatechin, and quercetin from the peel and seed
extracts were isolated from the plant and were reported in a recent study [25].
Annona dioica is a smallish shrub native to Brazil with rich flavonoids and alka-
loids. Previous reports indicated its uses in traditional medicine. Annonacin, cheri-
molin-­1, and squamocin, from chloroformic extracts of A. dioca root, were found to
have in vitro antiproliferative effect on histiocytic lymphoma (U-937) [26].
Kaempferol type flavonoids isolated from the root methanolic extracts of A. dioca
exhibited concentration-dependent inhibitory effects against murine Ehrlich
Carcinoma cells and DNA topoisomerase I and II [27]. Methanolic extract of the
plant was tested against NCL H-460 lung cell lines, HT −29 colon cells, OVCAR-3
ovarian cells, MCF7 breast cells, NCI/ADR-RES, and potent anticancer activity
with GI50 values range from 0.03–83.47 μg/mL was found [28]. Annona glabra is an
evergreen shrub introduced from tropical America and West Africa as an important
rootstock for profit-oriented Annona species. It was considered an invasive species;
reports showed that it was enriched with terpenoids, flavonoids, glycosides, anthra-
quinones, steroids, tannins, saponins, and phenolic compounds. Earlier studies sug-
gested that A. glabra was a good source of effective compounds which can be used
as anticancer agents. Extract of A. glabra in human leukemia cell lines showed a
potency to reduce oxidative stress, ATP content, and induced apoptosis [29].
Annoglacins A and B reported from A. glabra that leaf extract suppressed the pro-
liferation of pancreatic carcinoma and human breast cell lines with a more potent
result compared to the drug adriamycin [30]. Icariside D2 was found to alter the
expression of apoptosis-related proteins, decreased phosphorylation of AKT in
HL-60 cells [31]. Annonin-I isolated from methanolic extract of A. glabra seeds
570 S. M. Joseph and A. R. Amala Dev

possessed very high anticancer activity against glioblastoma multiforme, lung car-
cinoma A-549, and breast adenocarcinoma [32]. Annoglabasin H, a component pre-
viously reported from A. glabra fruits, also showed significant cytotoxic activity in
SK-Mel2, LU-1, MCF-7, and KB with IC50 values ranging from 3.7 to 4.6 μM [33].
A. glabra extracts showed cytotoxicity to drug variant cancer cell lines. Seed extract
promoted cell arrest at the G0/G1 phase. Seed extract showed necrosis and apopto-
sis in both sensitive and resistant leukemia cells. The mode of action was found to
be in a concentration-dependent way [34]. A. glabra stem bark extract exhibited
cytotoxic activity and kaur-16-en-19-oic acid isolated by extract fractionation was
responsible for the therapeutical applications of the extract [35]. Previous studies
indicated that annomontacin being an anticancer compound caused variations in
mitochondrial transmembrane and induce apoptosis human liver cancer cell line
(Hep G2). The isolated diterpenoid compounds ent-kauran-19-al-17-oic acid
cunabic acid from A. glabra Linn was tested against liver Cancer (HLC) cell line
SMMC-7721 and found that it exhibited proliferation activity by apoptosis via
downregulating the gene expression of the BCL-2 gene and upregulating that of
Bax gene.
Annona hypoglauca, also known as wild cherimoya, were found in Amazon
floodplains. Chemical profile and bioactivity studies of A. hypoglauca are not much
available. Acid-base partitioning of A. hypoglauca stem yields aporphine alkaloids,
namely anonaine, actinodaphnine, isoboldine and nornuciferine. Actinodaphnine in
Annona species was reported for the first time and it was found that alkaloid-free
fraction does not show anticancer activity. Earlier reports indicated the cytotoxicity
of the crude extract against colon and breast cancer cells. Treatment of breast cancer
cell line by fraction containing isoboldine and actinodaphnine inhibited tumor for-
mation [36]. Cytotoxic potential of hexane and ethanolic extracts of leaves of
A. hypoglauca was investigated on Artemia salina and found that ethanolic extract
showed potent antitumor activity [37]. A plant Annona jahnii which is native to
Brazil, Colombia, and Venezuela is a tree having rich fruits. Acetogenins reported
from A. jahnii exhibited cytotoxic activities. Two new acetogenins, namely annodi-
enin and jahnonacin isolated from twigs of A. jahnii, indicated selective cytotoxicity
to six human tumor cell lines [38]. Another study showed that annojahnin isolated
from the twig found to exhibit potent cytotoxicity in six human solid cancerous cell
lines compared to standard drug Adriamycin [39].
Annona montana or mountain soursop was native to South America.
Annonacinand montanacin F isolated from leaves of A. montana showed in vivo and
in vitro cytotoxic activity, respectively, against the Lewis lung carcinoma (LLC) cell
lines [40]. Bioactive cytotoxic compounds such as iso-acetogenin, montanacin G,
three pairs of acetogenins, montanacin H-J and 34-epi-montanacin H-J, montana-
cins B and C, annonacin and cis-annonacin, gigantetrocins A and B were isolated
from A. montana leaves exhibited in vitro cytotoxic effect against Meth-A and LLC
tumor cell lines [41]. Further studies conducted in organic extracts of A. montana
fruit showed cytotoxicity on human astrocytoma, breast, lung, colon, and prostate
cancers [42]. Among the compounds montacin, cis-montacin, annonacin, cis-­
annonacin, annomontacin and cis-annomontacin isolated from A. montana seeds,
Annonaceae: Tropical Medicinal Plants with Potential Anticancer Acetogenins… 571

montacin and cis-montacin showed moderate in vitro anticancerous activity against

the ovarian human cancer cell lines [43]. HPLC of A. montana seeds gave on to the
isolation of Montalicins G and H, monlicins A and B, (+)-monhexocin and (−)-mon-
hexocin murisolin, 4-deoxyannomontacin, and muricatacin and reported selectivity
in cytotoxicity against human hepatoma cells (Hep G2) [44]. Similarly, reports on
stem bark also confirmed its potential cytotoxic activity and were attributed due to
the presence of new naturally occurring phenanthrene-1, 4-quinone; annoquinone
A, and β-sitostenone isolated from A. montana bark [45]. Another species Annona
muricata, widely known as Graviola, is a tropical shrub that demonstrated antican-
cer potential in various types of tumors. Reports show alkaloids, lactones, cardiac
glycosides, flavonoids, coumarins, anthraquinones, phenols, tannins, terpenoids,
phytosterols, and saponins, etc., were rich in A. muricata extracts. Earlier studies
have proven that acetogenins and other major secondary metabolites were attributed
to anticancer activity [46–52]. Muricatocins A and B reported from A. muricata
leaves possessed significant anticancer activity against the A-549 cell line [53].
Concentration-dependent antitumor effect in colon cancer cells was also reported
from A. muricata leaves [54]. A. muricata extract was found to be shown antimeta-
static features and induces apoptosis in 4 T1 cells [55]. Ethylacetate fraction of
A. muricata indicated excessive accumulation of ROS, upregulation of Bax, down-
regulation of Bcl-2 proteins, and activation of the initiator and executioner caspases
in HT-29 and HCT-116 cells [56, 57]. Ethyl acetate fraction of A. muricata results
in apoptosis by promoting mitochondria-mediated signaling pathway through
inhibiting NF-kB factor in A549 cells [58]. However, in pancreatic cancer (PC) cell
lines, A. muricata extracts demonstrated necrosis and inhibition of tumorigenicity
[59]. A. muricata leaves afforded cytotoxic acetogenins, namely (E)-caryophyllene
and eugenol which were found to be active against MCF-7 cells [60]. Annomuricins
A and B reported from ethanolic extract of A. muricata leaves exhibited cytotoxic
activity [61].
Chemopreventive potential of ethanolic extract of A. muricata leaves reduced
proliferative indexes in rat’s breast cancer cell [62, 63]. The earlier study confirmed
the in vitro cytotoxic activity of ethanolic extract of leaves in human breast cancer
cell lines [64]. Apoptosis by chloroform extract of leaves in cancer-causing virus
[65] and antiproliferative activity of ethanol extract of leaves of A. muricata in
HepG2 [66] were also reported. Phytochemical investigation of A. muricata leaf
extract indicated the presence of alcohols, steroids, terpenoids, phenolic com-
pounds, sugars and vitamin E, etc. Different extract of plant leaves inhibits tumor
growth in MDA-MB-231 and MCF7, respectively [67]. Mucoxin from A. muricata
has the potential to increase apoptotic cells and reduce cell proliferation in T47D
breast cancer cells [68]. Hexane fraction was found to exhibit in vitro anticancer
activity in pancreatic cancer cells and flavonoids attributed for the activity [69]. A
study conducted in 2020 proved dose-dependent antitumor activity of silver
nanoparticles coupled with A. muricata leaf extracts in human lung cancer cell line
(A549) [70]. Anti-BPH as well as apoptosis activity of A. muricata leaf extract was
also reported [71]. Promising bioactive components such as annomuricine and
muricapentocin isolated from A. muricata leaves were found to exhibit repressive
572 S. M. Joseph and A. R. Amala Dev

effects against PACA-2 and HT-29 cell lines [72]. Muricin M and N from fruit pow-
der of A. muricata also possessed potent cytotoxicity against human prostate cancer
(PC-3) cells [73]. Cis annonacin from the seeds of A. muricata indicated selective
cytotoxicity to HT-29 cells with potency 10,000 times that of Adriamycin [74].
Antitumor potential of chloroform fraction of seeds was also confirmed [75].
Annona purpurea is commonly known as Soncoya, a common small to medium
deciduous tree best suited to tropical climates. New aporphine alkaloid
Oxoaporphine, isolated from A. purpurea, possessed moderate in vitro cytotoxicity
against 9-KB tumor [76]. Previous studies showed bis-THF acetogenins were the
most important components found in the roots of A. purpurea [77]. Annopurpuricin
A previously reported from A. purpurea dichloromethane extract of root indicated
mitochondrial necrosis, depolarization, and apoptosis in tumor cells. Purpuracenin,
annoglaucin purpurediolin, and purpurenin isolated from seeds of A. purpurea were
previously evaluated against various types of human cancer cells indicated in vitro
cytotoxic activity [78, 79]. Recently, a study quantified the anticancer agent, anno-
purpuricins, present in the plant using diode array high-performance liquid chroma-
tography detector (HPLC-DAD) [80]. Annona reticulata generally referred as
‘custard apple or bullock’s heart’ is a small, evergreen to the deciduous, tropical
tree. Phytoconstituents identified from the plant include flavanoida, alkaloids, tan-
nins, glycosides, steroids, amino acids, carbohydrates, acetogenins, etc. The plant
has several medicinal properties. Phytochemicals derived from different plant parts
are reported as potential anticancer compounds [81]. Evaluation of A. reticulata
extract indicated dose-dependent chemotherapeutic effect against HT-29, SCC9,
MCF-7, A549, and HCT116 [82–85]. Methanolic extract of leaves indicated cyto-
toxicity against breast carcinoma (T-47D), colon, hepatoma liver, and lung cancer
cell lines [86–90]. A study conducted in 2003 confirmed apoptotic cell death in T24
cells by annonacin isolated from the A. reticulata seeds [91]. Petroleum ether extract
of seeds was found to cause apoptosis in breast cancer cell line (MCF-7) and leuke-
mia cell line (K562) [92]. A previous study reported cytotoxic activity of ethanolic
extract of A. reticulata root against human lung, melanoma, chronic myelogenous
leukemia, cervix, and breast cancer cell line [93].
Annona salzmannii or Beach sugar apple is an extremely rare, tropical, evergreen
tree native to Brazil. Methanolic extract of A. salzmannii root yielded a new bis
tetrahydrofuran acetogenin, Salzmanin, along with previously known compounds
such as squamocin, almunequin, bullatalicin, and annonacin. Antitumor activities of
salzmanin and squamocin were reported [94]. A study conducted in 2013 showed
cytotoxic activity of essential oil isolated from A. salzmannii leaf extract [95].
Annona scleroderma, the poshe-te, is a species of tree in the Annonaceae family,
with an edible fruit native to the Atlantic coast of Central America, from Mexico
and Guatemala to Honduras. Methanol extract of A. scleroderma seeds yielded new
cytotoxic cyclononapeptide, sclerin, and known compound cyclosenegalin
A. Sclerin exhibited anticancer activity against human prostate carcinoma cell line
Annonaceae: Tropical Medicinal Plants with Potential Anticancer Acetogenins… 573

DU-145 [96]. Annona senegalensis, frequently known as wild custard apple and
wild soursop, is native to Senegal and also found in semi-arid to subhumid regions
of Africa. Most parts of the plant were used in traditional medicine. A. senegalensis
afforded annogalene, acetogenins, annosenegalin, kaurenoic acid, and (−)-roemer-
ine which indicted cytotoxic activity [97]. Further studies in organic extracts of
A. senegalensis revealed anticancer potential against HCC-1396, HEp-2, and CT-26
cancer cell lines, and highest selectivity was observed in HEP-2 cells with an IC50
value of 0.42 ± 0.09 μg/ml [98]. Methanolic extract of A. senegalensis exhibited in
vitro cytotoxic against ovarian cancer cells (A2780 with an IC50 of 28.8 μg/ml) [99].
The previous study showed methanol, butanol as well as crude extract of A. senega-
lensis showed dose - dependent anticancer activity in MDA-MB-231 cells via bind-
ing Lys −53 of the eL42 protein and preventing the crosslinking reaction with
tRNAox. Sub-fractionated extract of roots reported cytotoxicity against 293 T,
PANC-1, and HeLa with TC50 value 125.89, 211.35, and 266.07 μg/ml respec-
tively. Ent-kaurenoids reported from A. senegalensis stem bark indicated anticancer
activity against MCF-7 and PC-3 cells. Alcoholic fraction A. senegalensis was
found to possess antitumor activity against Sarcoma-180 ascites. A. senegalensis
leaf extract showed moderate cytotoxic effect against A549, HT29, MCF-7, RPMI,
and U251 cell lines. Evaluation of kaur-16-en-19-oic acid reported from the root
bark of Nigerian A. senegalensis on the pancreatic tumor (PANC-1) and Henrietta
Lacks’ cervical (HeLa) cell lines showed cytotoxic activity with an IC50 value of
0.52 and 0.74 M concentrations, respectively. Kaurenoic acid (KA) was a promising
component in the synthesis of chemotherapeutic drugs. Previous reports evidenced
apoptosis and necrosis in HL-60 cells caused by kaurene-19-oic-acid [100]. It was
also found active against human glioblastoma cell line (U87) and reported reduced
viability, and an increase in annexin V- and annexin V/PI-positive cells. Acetogenins
attributed the anticancer activity of A. senegalensis seed extract against KB and
VERO cell lines.
One of the most widely grown species Annona squamosa, also known as custard
apple, was reported to possess different pharmacological activities including antitu-
mor properties. Previous reports proved dose-dependent anticancer effect was found
in MCF-7 cell lines from silver nanoparticles made from A. squamosa leaf extract.
Silver nanoparticles made from leaf extract possessed selectivity in mammalian
cells (HEK-293) and cancerous cells (HeLa). A. squamosa leaf extract on DMBA-­
induced epithelial tumor in swiss albino mice confirmed its anticancer potential.
Ethanolic extract of the A. squamosa seeds was tested for MCF-7 cells and reported
significant anticancer activity. Squamotin A-D, annosquatin IV-V, muricin O, and
squamosten B isolated from the seeds of A. squamosa were found cytotoxic in mul-
tidrug resistance cancer cells. Bistetrahydrofuran acetogenins isolated from the
ethanolic extract of A. squamosa seeds found to be showing in vitro cytotoxicity in
human cancer cell lines tested [101]. Seed extracts of A. squamosa demonstrated
DNA fragmentation and nuclear condensation and generating reactive oxygen
574 S. M. Joseph and A. R. Amala Dev

species, reducing intracellular glutathione levels, and regulating Bcl-2 and PS exter-
nalization in MCF-7 and K-562 cells. Interestingly, seed extract was found to exhibit
cytotoxicity in COLO-205 cell lines. Annotemoyin-1, annotemoyin-2, cholesteryl
glucopyranoside, and squamocin reported from seed extracts reported cytotoxic
activity. Promising anticancer constituents such assquamocin, bullatacin, uvarigran-
din A, and squamostanin A-D were reported from seed extract of A. sqamosa.
Annotemoyin-1, annotemoyin-2, squamocin, and cholesteryl glucopyranoside iso-
lated from the seeds possessed antitumor activity. Earlier investigations in A. squa-
mosa seed extract proved potent cytotoxic potential in MCF-7 and Hep G2 cells.
N-methylated lactam-containing compounds isolated from seed extracts also pos-
sessed anticancer activity. Inhibition of IL-6/Jak/Stat3 pathway was observed in a
study conducted using A. squamosa seed oil in H22 solid tumor. Fruit pericarp
extract of A. sqamosa has shown anticancer activity in Dalton’s lymphoma cells and
HeLa cells. A. squamosa bark extract possessed mono-tetrahydrofuran ring aceto-
genins found to be active against PACA-2 with a high potency of about 10–100
times than the most commonly used anticancer drug Adriamycin [102].
The following table [Table 1] comprises potent anticancer compounds reported
from different Annona species and their mode of action in various cancer cell lines.
The chemical structures of some of the isolated compounds including annonaceous
acetogenins and alkaloids are presented in the below figures [Figs. 2 & 3].

4 Conclusions

Medicines developed from bioactive compounds of medicinal plants are always

preferred to those with synthetic components owing to lesser side effects. An effec-
tive anticancer drug of natural origin which can be an alternative to chemotherapy
will be a great relief to the hardships suffered by cancer patients during treatment.
Annonaceae family is naturally enriched with bioactive molecules which can be
formulated into an effective anticancer drug. The antitumor and cytotoxic potential
of the major phytochemicals, acetogenis and alkeloids, found in Annona genus of
Annonacea family have been elaborated in this article. The researches have proven
that Annona genus has significant anticancer activity against wide range of human
tumor cell lines. The present book chapter highlights the anticarcinogenic potential
of plants from these genera and its anticancer activities. Further researches based on
these data may derive in the formulation of an effective anticancer drug which offers
a holistic cure for cancer rather than invasive methods like chemotherapy. These
natural anticancer drugs act as antitumor agents, which prevents the mechanism of
cancer cell formation. This also calls for a shift in focus in cancer medicinal research
from cancer treatment to cancer prevention.
Annonaceae: Tropical Medicinal Plants with Potential Anticancer Acetogenins… 575

Table 1 Anticancer compounds of Annona species and their mode of action in various cancer
cell lines
Sl. Annona Plant Animal model / Cell
No. Species part Components identified line Mode of action
1 A. Seeds Annomolin, Prostate tumor cell Exhibited potent
cherimola annocherimolin line (PC-3), Breast cytotoxicity
(MCF-7), and Colon
(HT-29) cancer cell
lines
Leaves Asimilobine Acute myeloid Upregulation of
leukemia cell line Bax,
downregulation of
BC-l2, and
cleavage of PARP
2 A. coriacea Roots Coriadienin, VERO and KB cell Exhibited
gigantetronenin lines anticancer activity
3 A. Seeds Sucrose octaacetate Human melanoma Exhibited potent
cornifolia (UACC-62), renel cytotoxicity
carcinoma (TK -10),
breast cancer
(MCF-7) cell line
4 A. Crude Catechin Cervical cancer cell Apoptosis via
crassiflora extract intrinsic pathway
and decreased p21
expression by
ubiquitin
proteasome
pathway
5 A. dioca Roots Squamocin, Histiocytic Exhibited
cherimolin-1, lymphoma (U-937) cytotoxicity
annonacin
Leaves Kaempferol, Ehrlich carcinoma Exhibited
3-O-[3″,6″-di-O-p-­ cells inhibitory effects
hydroxycinnamoyl]-
beta-galactopyranosyl-­
kaempferol,
6”-O-p-­
hydroxycinnamoyl-­
beta-galactopyranosyl-­­
kaempferol
6 A. glabra Leaves Asinicin Human monocytic Mitochondria
leukemia cells mediated
(CRL-12253) anticancer and
antiproliferative
effects
Leaves Annoglacin A and B Human breast Suppressed
carcinoma (MCF-7) proliferation
and pancreatic
carcinoma
(PACA-2) cell lines
(continued)
576 S. M. Joseph and A. R. Amala Dev

Table 1 (continued)
Sl. Annona Plant Animal model / Cell
No. Species part Components identified line Mode of action
Leaves Icariside D2 Human leukemia Induced apoptosis
cell line (HL-60) and decreased
phosphorylation of
AKT in cells
Fruits Annoglabasin H Lung Exhibited
adenocarcinoma cell significant
line (LU-1), human cytotoxic activity
breast carcinoma
(MCF-7), human
melanoma
(SK-Mel2), KB
Seeds Bullatacin CEM/VLB cell line Induced apoptosis,
necrosis and
upregulated the
expression of
cyclin kinase
inhibitor (WAF1/
p21). Induced cell
cycle arrest at the
G0/G1 phase
Fruits Annoglabayin Human liver cancer Apoptosis via
cell line (Hep G2) mitochondrial
pathway
Fruits Cunabic acid and Liver cancer (HLC) Apoptosis via
ent-kauran-19-al-17-oic cell line downregulation of
acid SMMC-7721 BCL-2 gene and
upregulation of bax
gene
7 A. Stem Actinodaphnine, Breast and colon Inhibited tumor
hypoglauca anonaine, isoboldine, cancer cells. formation
nornuciferine
8 A. jahnii Twigs Annodienin, Human solid Cytotoxicity
jahnonacin, annojahnin cancerous cell lines
9 A. montana Leaves Montanacin F Lewis lung Exhibited cytotoxic
carcinoma (LLC) activity
tumor cell lines
Seeds Montacin and Human ovarian Exhibited cytotoxic
cis-Montacin cancer cell line activity
(1A9)
Seeds Montalicins G and H, Human hepatoma Exhibited cytotoxic
monlicins A and B, cells (Hep G2) activity
(+)-monhexocin and
(−)-monhexocin
murisolin
4-deoxyannomo-ntacin,
muricatacin
(continued)
Annonaceae: Tropical Medicinal Plants with Potential Anticancer Acetogenins… 577

Table 1 (continued)
Sl. Annona Plant Animal model / Cell
No. Species part Components identified line Mode of action
10 A. muricata Leaves Muricatocins A and B Lung tumor cell lineEnhanced cytotoxic
(A-549) activity
Leaves Muricoreacin, Colon cancer cell Upregulation of
murihexocin (HT-29, HCT-116) Bax,
downregulation of
Bcl-2 proteins and
activated initiator
and executioner
Caspases
Leaves Annomutacin A-549 cells of lungs Apoptosis by
promoting
mitochondria
mediated signalling
pathway through
inhibiting NF-kB
factor
Leaves (E)-Caryophyllene, Breast cancer cell Exhibited cytotoxic
eugenol (MCF-7) effect
Leaves Annomuricine Rat breast cancer Reduced
cell proliferative
indexes
Leaves Annopentocin BPH-1 cells Exerted
antiproliferative
effect via
upregulation of bax
gene and
downregulation of
Bcl-2
Leaves Annomuricine, Pancreatic Exhibited
muricapentocin carcinoma repressive effect
(PACA-2) and colon
adenocarcinoma
(HT-29) cell
Fruits Muricin M and muricin Prostate cancer Exhibited
N (PC-3) cells cytotoxicity
11 A. purpurea Roots Annopurpurici-ns A–D HeLa and HepG2 Mitochondrial
cells membrane
depolarization and
apoptosis
12 A. reticulata Leaves Annomonicin Colon cancer Exhibited cytotoxic
(HCT15), Human effect
lung cancer
(Hop65), and
Human hepatoma
(Hep G2) cell lines
(continued)
578 S. M. Joseph and A. R. Amala Dev

Table 1 (continued)
Sl. Annona Plant Animal model / Cell
No. Species part Components identified line Mode of action
Leaves Rolliniastatin Breast cancer cell Caspases
(T-47D) dependent
apoptosis.
Downregulated
Bcl-2 and
upregulated Bax,
Bak
Seeds Annonacin T-24 Bladder cancer Bax expression was
cells induced, caspase-3
activity enhanced
and caused
apoptosis
Seeds Bullatacin Leukemia cell line Cell death via
(K-562) and breast apoptosis
cancer cell line
(MCF-7)
Fruits Catechin Breast cancer cell Inhibition via
line (MCF-7) apoptosis
13 A. Seeds Sclerin, cyclosenegalin Human prostate Exhibited
scleroderma A carcinoma cell line anticancer activity
DU-145
14 A. Leaves (-)-Roemerine Breast cancer Exhibited
senegalensis MDA-MB-231 cells dose-dependent
cytotoxicity via
targeting the
ribosomal protein
eL42 and arresting
the crosslinking
reaction with
tRNAox
Stem Ent-kaurenoids Breast cancer Exhibited
bark (MCF-7) cells, cytotoxicity
prostate cancer
(PC-3) cells
Bark Kaurenoic acid Human embryonic Exhibited
kidney cells cytotoxicity
expressing SV40
Large T-antigen
(293 T), pancreatic
tumor (PANC-1)
cell lines and
henrietta lacks’
cervical cancer cell
line (HeLa)
15 A. Leaves Annoreticuin Breast cancer cell Induced Apoptosis
squamosa (MCF-7)
(continued)
Annonaceae: Tropical Medicinal Plants with Potential Anticancer Acetogenins… 579

Table 1 (continued)
Sl. Annona Plant Animal model / Cell
No. Species part Components identified line Mode of action
Seeds Annosquatin A, B Human breast Induction of
cancer cell line reactive oxygen
(MCF-7), human species generation,
leukemia cell line reduced
(K-562), human intracellular
colon carcinoma glutathione levels
(COLO-205) and regulation of
Bcl-2 and PS
externalization
Seeds (-)-Anonaine H-22 solid tumor Inhibition of IL-6/
cell Jak/Stat3 pathway
Fruit (-)-Ent-kaur-16-en-19-­­ Dalton’s lymphoma Exhibited cytotoxic
oic acid, 16α,17-­ cells, HeLa cells activity
dihydroxy-­ent-kauran-
19-­oic acid
Seeds Asimilobine Human colon cancer Increased
cell (WiDr) expression of
caspase-3, induced
G2/M phase and
apoptosis
Seeds Squamoxinone-D Nasopharyngeal Inhibited
cancer (KB) cells, proliferation
breast cancer
(MCF- 7) cells, lung
cancer (A-549)
cells, leukemic
(K-562) cells
Seeds Dieporeticenin B, SMMC 7721/T, Exerted inhibitory
squamocin, annosquatin MCF-7/ADR activity
III
Seeds Squadiolins A, B Hep G2 hepatoma Exhibited
cells, significant
MDA-MB-231 cytotoxic activity
breast cancer cells
Seeds Squafosacin B Human Hep G2, 3B Exhibited
Hepatoma and significant
Breast cancer cells cytotoxic activity
(MCF-7)
Seeds Annosquatin A, MCF-7, A-549 cell Exhibited high
annosquatin B lines cytotoxic
selectivity
(continued)
580 S. M. Joseph and A. R. Amala Dev

Table 1 (continued)
Sl. Annona Plant Animal model / Cell
No. Species part Components identified line Mode of action
Seeds Squamocin - I, II, III, Hep G2, SMMC Exhibited cytotoxic
squamoxinone-D 7721, human activity
hepatocellular
carcinoma cell line
(BEL 7402), gastric
cancer cells (BGC
803), lung cancer
cells (H460)
Bark Coclaurine DMBA painted Enhanced lipid
hamsters peroxidation

Fig. 2 Structures of major anticancer annonaceous acetogenins from Annonacea

Annonaceae: Tropical Medicinal Plants with Potential Anticancer Acetogenins… 581

Fig. 3 Chemical structures of major anticancer alkaloids from Annonacea

582 S. M. Joseph and A. R. Amala Dev

References

1. Alali FQ, Liu XX, McLaughlin JL (1999) Annonaceous acetogenins: recent progress. J Nat
Prod 62:504–540. https://doi.org/10.1021/np980406d
2. Oberlies NH, Jones JL, Corbett TH, Fotopoulos SS, McLaughlin JL (1995) Tumor cell
growth inhibition by several annonaceous acetogenins in an in vitro disk diffusion assay.
Cancer Lett 96:55–62. https://doi.org/10.1016/0304-­3835(95)92759-­7
3. Quílez AM, Fernandez Arche MA, García Giménez MD, De La Puert R (2018) Potential
therapeutic applications of the genus Annona: local and traditional uses and pharmacology. J
Ethnopharmacol 225:244–270. https://doi.org/10.1016/j.jep.2018.06.014
4. Jacobo Herrera N, Pérez Plasencia C, Castro-Torres VA, Martínez Vázquez M, González
Esquinca AR, Zentella DA (2019) Selective acetogenins and their potential as anticancer
agents. Front Pharmacol 10:783. https://doi.org/10.3389/fphar.2019.00783
5. Zafra Polo MC, Gonzalez MC, Estornell E, Sahpaz S, Cortes D (1996) Acetogenins from
Annonaceae, inhibitors of mitochondrial complex I. Phytochemistry 42:253–271. https://doi.
org/10.1016/0031-­9422(95)00836-­5
6. Elhawary SS, Tantawy MEE, Rabeh MA, Fawaz NE (2013) DNA fingerprinting, chemical
composition, antitumor and antimicrobial activities of the essential oils and extractives of
four Annona species from Egypt. J Nat Sci Res 3:59–68
7. Chen CY, Chang FR, Chiu HF, Wu MJ, Wu YC (1999) Aromin-A, an annonaceous ace-
togenin from Annona cherimola. Phytochemistry 51:429–433. https://doi.org/10.1016/
s0031-­9422(99)00002-­3
8. Haykal T, Nasr P, Hodroj MH, Taleb RI, Sarkis R, Moujabber MNE, Rizk S (2019) Annona
cherimola seed extract activates extrinsic and intrinsic apoptotic pathways in leukemic cells.
Toxins 11:506. https://doi.org/10.3390/toxins11090506
9. Jyothi BA, Venkatesh KP, Chakrapani RAR (2011) Phytochemical and pharmacological
potential of Annona cherimola - A review. Int J Phytomedicine 3:439–447
10. Kim DH, Ma ES, Suk KD, Son JK, Lee JS, Woo MH (2001) Annomolin and annocheri-
molin, new cytotoxic annonaceous acetogenins from Annona cherimola seeds. J Nat Prod
64:502–506. https://doi.org/10.1021/np000335u
11. Ammoury C, Younes M, Khoury ME, Haykal T, Nasr P, Sily M, Taleb RI, Sarkis R, Khalife
R, Rizk S (2009) The pro-apoptotic effect of a terpene-rich Annona cherimola leaf extract
on leukemic cell lines BMC. Complement Altern Med 19:365. https://doi.org/10.1186/
s12906-­019-­2768-­1
12. Macuer-Guzmán J, Bernal G, Jamett-Díaz F, Ramírez-Rivera S, Ibanez C (2019) Selective
and apoptotic action of ethanol extract of Annona cherimola seeds against human stom-
ach gastric adenocarcinoma cell line AGS. Plant Foods Hum Nutr 74:322–327. https://doi.
org/10.1007/s11130-­019-­00742-­w
13. Cortes D, Myint SH, Hocquemiller R (1991) Molvizarin and motrilin two novel cytotoxic
bistetrahydrofuranic gamma lactone acetogenins from Annona cherimola. Tetrahedron
47:8195–8202. https://doi.org/10.1016/S0040-­4020(01)91014-­2
14. Woo MH, Chung SO, Kim DH (1999) Cis-Annonacin and (2,4)-cis-and trans-Isoannonacins:
cytotoxic monotetrahydrofuran annonaceous acetogenins from the seeds of Annona cheri-
mola. Arch Pharm Res 22:524–528. https://doi.org/10.1007/bf02979164
15. Cortes D, Myint SH, Dupont B, Davoust D (1993) Bioactive acetogenins from seeds of Annona
cherimola. Phytochemistry 32:1475–1482. https://doi.org/10.1016/0031-­9422(93)85162-­k
16. Gomes INF, Silva-Oliveira RJ, Oliveira Silva VA, Rosa MN, Vital PS, Barbosa MCS, dos
Santos FV, Junqueira JGM, Severino VGP, B. G. Oliveira, W. Romao, R.M. Reis, de de
Azambuja Ribeiro RIM. Annona coriacea Mart. fractions promote cell cycle arrest and
inhibit autophagic flux in human cervical cancer cell lines. Molecules. 2019;24:3963
17. Roblot JF, Mahuteau A, Cavé A (1996) Coriadienin. The first annonaceous acetogenin with
two double bonds isolated from Annona coriaceae. J Nat Prod 59:528–530
Annonaceae: Tropical Medicinal Plants with Potential Anticancer Acetogenins… 583

18. Lima LARS, Alves TMA, Zani CL, Santos LP, Boaventura MAD (2013) Cytotoxic potential
of sucrose octaacetate from the ethanol extract of the seeds of Annona cornifolia A. St.-Hil.
(Annonaceae). Sucrose: Properties, Biosynthesis and Health Implications:143–154
19. Lima LARS, Alves TMA, Zani CL, Santos LP, Pimenta BMAD (2012) Antioxidant and cyto-
toxic potential of fatty acid methyl esters from the seeds of Annona cornifolia A. St.-Hil.
(Annonaceae). Food Res Int 48:873–875
20. Arruda HS, Pastore GM (2019) Araticum (Annona crassiflora Mart.) as a source of nutrients
and bioactive compounds for food and non-food purposes: A comprehensive review. Food
Res Int 123:450–480. https://doi.org/10.1016/j.foodres.2019.05.011
21. Rocha RS, Kassuya CAL, Formagio ASN, Mariana de Oliveira Mauro M, Andrade-Silva
MACD, Cunha-Laura AL, Vieira MC, Oliveira RJ (2016) Analysis of the anti-­inflammatory
and chemopreventive potential and description of the antimutagenic mode of action of
the Annona crassiflora methanolic extract. Pharm Biol 54:35–47. https://doi.org/10.310
9/13880209.2015.1014567
22. Silva VAO, Alves ALV, Rosa MN, Silva LRV, Melendez FP, Cury FP, Gomes INF, Tansini
A, Longato GB, Martinho O, Oliveira BG, Pinto FE, Romao W, Ribeiro RIMA, Reis RM
(2018) Hexane partition from Annona crassiflora Mart. Promotes cytotoxity and apoptosis on
human cervical cancer cell lines. Investig New Drugs 37:602–615. https://doi.org/10.1007/
s10637-­018-­0657-­y
23. Pimenta LPS, Mendonça DD, Pretti DL, Cruz BLD, Leite EA, DeOliveira MC (2011)
Evaluation of in vivo antitumor activity of Annona crassiflora wood extract. Int J Pharm Sci
Drug Res 3:270–273. https://doi.org/10.1080/14786419.2014.900496
24. Prado LG, Arruda HS, Araujo NMP, Braga LEO, Banzato TP, Pereira GA, Figueiredo MC,
GoisRuiz ALT, Eberlinf MN, Carvalho JE, Vendramini-Costa DB, MariaPastore GM (2020)
Antioxidant, antiproliferative and healing properties of araticum (Annona crassiflora Mart.)
peel and seed. Food Res Int 133:109168. https://doi.org/10.1016/j.foodres.2020.109168
25. Kanashiro MM, Paes MM, Vega MRG, Cortes D, Cabedo N (2015) Cytotoxic activities of
acetogenins from Annona dioica roots. Int J Mol Sci 4:19–29
26. Vega MRG, Esteves-Souza A, Vieira IJC, Mathias L, Braz-Filho R, Echevarria A (2007)
Flavonoids from Annona dioica leaves and their effects in Ehrlich carcinoma cells,
DNA-topoisomerase I and II. J Am Chem Soc 18:1554–1559. https://doi.org/10.1590/
S0103-­50532007000800016
27. Formagio AS, Kassuya CA, Neto FF, Volobuff CR, Iriguchi EK, Vieira Maria do C, Foglio
MA (2013) The flavonoid content and antiproliferative, hypoglycaemic, anti-inflammatory
and free radical scavenging activities of Annona dioica St. Hill. BMC Complement Altern
Med 13:14. https://doi.org/10.1186/1472-­6882-­13-­14
28. Liu XX, Alali FQ, Pilarinou E, McLaughlin JL (1999) Two bioactive mono-tetrahydrofuran
acetogenins, annoglacins A and B, from Annona glabra. Phytochemistry 50:815–821. https://
doi.org/10.1016/s0031-­9422(98)00466-­x
29. Hien NTT, Nhiem NX, Yen DTH, Hang DT, Tai BH, Quang TH, Anh HLT, Kiem PV, Minh
CV, Kim EJ, Kim SH, Kang HK, Kim YH (2015) Chemical constituents of the Annona gla-
bra fruit and their cytotoxic activity. Pharm Biol 53:1602. https://doi.org/10.3109/1388020
9.2014.993042
30. Abdel-lateff A, El-Menshawi BS, Hagag MY, Nawwar MA (2009) Cytotoxic acetogenins
from Annona glabra cultivated in Egypt. Pharm Res 1:130–135
31. Anh Hle T, Hien NT, Hang DT, Ha TM, Nhiem NX, Hien TT, Thu VK, Thao do T, Van Minh
C, Kiem PV (2014) Ent-kaurane diterpenes from Annona glabra and their cytotoxic activi-
ties. Nat Prod Commun 9:1681–1682
32. Cochrane CB, Nair PK, Melnick SJ, Resek AP, Ramachandran C (2008) Anticancer effects
of Annona glabra plant extracts in human leukemia cell lines. Anticancer Res 28:965–971
33. Padmaja V, Thankamany V, Hara N, Fujimoto YY, Hisham A (1995) Biological activities of
Annona glabra. J Ethnopharmacol 48:21–24. https://doi.org/10.1016/0378-­8741(95)01277-­k
584 S. M. Joseph and A. R. Amala Dev

34. Chen CH, Hsieh TJ, Liu TZ, Chern CL, Hsieh PY, Chen CY (2004) Annoglabayin, a novel
dimeric kaurane diterpenoid and apoptosis in Hep G2 cells of annomontacin from the fruits
of Annona glabra. J Nat Prod 67:1942–1946. https://doi.org/10.1021/np040078j
35. Zhang YH, Peng HY, Xia GH, Wang MY (2004) Anticancer effect of two diterpenoid com-
pounds isolated from Annona glabra Linn. Acta Pharmacol Sin 25:937–942
36. Rinaldi MVN, Díaz IEC, Suffredini IB, Moreno PRM (2017) Alkaloids and biological activ-
ity of beribá (Annona hypoglauca). Rev Bras 27:77
37. dos Santos RC, Chagas EA, de Melo Filho AA, Takahashi JA, Montero IF, Chagas PC,
Ribeiro PRE, de Melo ACGR (2018) Bioactive extracts from Annona hypoglauca. Chem
Eng Trans 64
38. Colman-saizarbitoria T, Liu X, Craig Hopp D, Johnson HA, Alali FQ, Rogers LL, McLaughlin
JL (1999) Annodienin and Jahnonacin: new bioactive nontetrahydrofuran annonaceous ace-
togenins from twigs of Annona jahnii. J Nat Prod 14:65
39. Colman-Saizarbitoria T, Johnson HA, Alali FQ, Hopp DC, Rogers LL, McLaughlin JL
(1998) Annojahnin from Annona Jahnii: A possible precursor of mono-tetrahydrofuran ace-
togenins. Phytochemistry 49:1609–1616
40. Wang LQ, Min BS, Li Y, Nakamura N, Qin GW, Li CJ, Hattori M (2002) Annonaceous
acetogenins from the leaves of Annona montana. Bioorg Med Chem 10:561–565. https://doi.
org/10.1016/s0968-­0896(01)00303-­0
41. Wang LQ, Li Y, Min BS, Nakamura N, Qin GW, Li CJ, Hattori M (2001) Cytotoxic mono-­
tetrahydrofuran ring acetogenins from leaves of Annona montana. Planta Med 67:847–852
42. Bailon-Moscoso N, Benavides JCR, Orellana MIR, Ojeda K, Granda G, Ratoviski EA (2016)
Ostrosky- Wegman P. cytotoxic and genotoxic effects of extracts from Annona montana fruit.
Food Agric Immunol 27:559–569. https://doi.org/10.1080/09540105.2016.1148121
43. Liaw CC, Chang FR, Wu YC, Wang HK, Nakanishi Y, Bastow KF, Lee KH (2004) Montacin
and cis-montacin, two new cytotoxic mono tetrahydrofuran annonaceous acetogenins from
Annona montana. J Nat Prod 67:1804–1808. https://doi.org/10.1021/np030216p
44. Liaw CC, Chang FR, Chen SL, Wu CC, Lee KH, Wu YC (2005) Novel cytotoxic mono-
tetrahydrofuranic annonaceous acetogenins from Annona montana. Bioorg Med Chem
13:4767–4776
45. Wu TS, Jong TT, Tien HJ, Kuoh CS, Furukawa H, Lee KH (1987) Annoquinone-A, an anti-
microbial and cytotoxic principle from Annona montana. Phytochemistry 26:1623–1625.
https://doi.org/10.1016/S0031-­9422(00)82257-­8
46. Moghadamtousi SZ, Fadaeinasab M, Nikzad S, Mohan G, Ali HM, Kadir HA (2015) Annona
muricata (Annonaceae): A review of its traditional uses, isolated acetogenins and biological
activities. Int J Mol Sci 16:15625–15658. https://doi.org/10.3390/ijms160715625
47. Prasad Shashanka K, Varsha V, Devegowda D (2019) Anti-cancer properties of Annona
muricata (L.): A review, Medicinal Plants. Int J Phytomed Relat Ind 11:123. https://doi.
org/10.5958/0975-­6892.2019.00016.9
48. Dilipkumar JP, Agliandeshwari D (2017) Preparation & evaluation of Annona muricata
extract against cancer cells with modified release. Pharma Tutor 5:63–106
49. Abdul Wahab SM, Jantan I, Haque MA, Arshad L (2018) Exploring the leaves of Annona
muricata as a source of potential anti-inflammatory and anticancer agents. Front Pharmacol
9. https://doi.org/10.3389/fphar.2018.00661
50. Moghadamtousi KHA, Paydar M, Rouhollahi E, Karimian H (2014) Annona muri-
cata leaves induced apoptosis in A549 cells through mitochondrial-mediated pathway
and involvement of NF-κB. BMC Complement Altern Med 14:299–302. https://doi.
org/10.1186/1472-6882-14-299
51. Patrikios I, Stephanou A, Andreas Y (2015) Graviola: A systematic review on its anticancer
properties. Asian Pac J Cancer Prev 3:128–131. https://doi.org/10.11648/j.ijpc.20170306.14
52. Qazi AK, Siddiqui JA, Jahan R, Chaudhary S, Walker LA, Sayed Z, Jones DT, Batra SK,
Macha MA (2018) Emerging therapeutic potential of graviola and its constituents in cancers.
Carcinogenesis 39:522–533. https://doi.org/10.1093/2Fcarcin/2Fbgy024
Annonaceae: Tropical Medicinal Plants with Potential Anticancer Acetogenins… 585

53. Wu FE, Zeng L, Gu ZM, Zhao GX, Zhang Y, Schwedler JT, McLaughlin JL, Sastrodihardjo
S (1995) Muricatocins A and B, two new bioactive monotetrahydrofuran annonaceous aceto-
genins from the leaves of Annona muricata. J Nat Prod 58:902–908. https://doi.org/10.1021/
np50120a013
54. Daud NM, Yaakob H, Rosdi M (2016) Acetogenins of Annona muricata leaves: charac-
terization and potential anticancer study. Integr Cancer Sci Ther 3:543–551. https://doi.
org/10.15761/icst.1000202
55. Syed Najmuddin SUF, Romli MF, Hamid M, Alitheen NB, Afizan NM, Rahman NA (2016)
Anti-cancer effect of Annona muricata Linn leaves crude extract (AMCE) on breast cancer
cell line. BMC Complement Altern Med 16:311. https://doi.org/10.1186/s12906-­016-­1290-­y
56. Growther L (2018) Anticancer activity of Annona muricata leaf extracts and screening of
bioactive phytochemicals. Int J Pharm Biol Sci 201(8):475–481
57. Moghadamtousi MZ, Karimian H, Rouhollahi E, Paydar M, Fadaeinasab M, Kadir HA (2014)
Annona muricata leaves induce G1 cell cycle arrest and apoptosis through mitochondria-­
mediated pathway in human HCT-116 and HT-29 colon cancer cells. J Ethnopharmacol
156:277–289. https://doi.org/10.1016/j.jep.2014.08.011
58. Moghadamtousi SZ, Kadir HA, Paydar M, Rouhollahi E, Karimian H (2014) Annona
muricata leaves induced apoptosis in A549 cells through mitochondrial-mediated path-
way and involvement of NF-Κb. BMC Complement Altern Med 14:299. https://doi.
org/10.1186/1472-6882-14-299
59. Torres MP, Rachagani S, Purohit V, Pandey P, Joshi S, Moore ED, Johansson SL, Singh PK,
Ganti AK, Batra SK (2012) Graviola: A novel promising natural-derived drug that inhibits
tumorigenicity and metastasis of pancreatic cancer cells in vitro and in vivo through altering
cell metabolism. Cancer Lett 323:29–40. https://doi.org/10.1016/j.canlet.2012.03.031
60. Owolabi MS, Ogundajo AL, Dosoky NS, Setzer WN (2013) The cytotoxic activity of Annona
muricata leaf oil from Badagary. Nigeria Am J Essent Oil 1:1–3
61. Wu FE, Gu ZM, Zeng L, Zhao GX, Zhang Y, McLaughlin JL, Sastrodihardjo S (1995) Two
new cytotoxic monotetrahydrofuran annonaceous acetogenins, annomuricins A and B from
the leaves of Annona muricata. J Nat Prod 58:830–836. https://doi.org/10.1021/np50120a002
62. Hamizah S, Roslida AH, Fezah O, Tan KL, Tor YS, Tan CI (2012) Chemo preventive poten-
tial of Annona muricata L leaves on chemically-induced skin papillomagenesis in mice.
Asian Pac J Cancer Prev 13:2533–2539. https://doi.org/10.7314/apjcp.2012.13.6.2533
63. Sulistyoningrum E, Rachmani EPN, Baroroh HN, Rujito L (2017) Annona muricata leaves
extract reduce proliferative indexes and improve histological changes in rat's breast cancer. J
App Pharm Sci 7:149–155. https://doi.org/10.7324/japs.2017.70120
64. Gavamukulya Y, Abou-Elella F, Wamunyokoli F, AEl-Shemy H. (2014) Phytochemical
screening, anti-oxidant activity and in vitro anticancer potential of ethanolic and water
leaves extracts of Annona muricata (Graviola). Asian Pac J Trop Med 7:355–363. https://doi.
org/10.1016/S1995-­7645(14)60258-­3
65. Astirin O, Artanti A, Fitria M, Perwitasari E, Prayitno A (2013) Annona muricata Linn leaf
induces apoptosis in cancer cause virus. J Cancer Ther 4:1244–1250. https://doi.org/10.4236/
jct.2013.47146
66. Yang H, Liu N, Lee SC (2016) Ethanol extract of Annona muricata. L induces liver cancer cell
apoptosis through ROS pathway. Biomed Pharmacol J 9:919–925. https://doi.org/10.13005/
bpj/1030
67. Rahman HA, Wan-Ibrahim WS, Ismail N, Ismail TN, Mohd-Salleh SF, Pak-Kai Wong M,
Samad MA, Hashim MM (2018) Phytocompounds of Annona muricata leaves extract and
cytotoxic effects on breast cancer cells. Asian Pac J Trop Med 11:659–665. https://doi.
org/10.4103/1995-­7645.248337
68. Muhartono A, Sutyarso S, Kanedi M (2016) Anti-proliferative and apoptotic effects of
mucoxin (acetogenin) in T47D breast cancer cells. Biomed Pharmacol J. 9:491–498. https://
doi.org/10.13005/bpj/963
586 S. M. Joseph and A. R. Amala Dev

69. Rosdi M, Daud NM, Zulkifli RM, Yaakob H (2015) Cytotoxic effect of Annona muricata
Linn leaves extract on capan-1 cells. J Appl Pharm Sci 5:45–48. https://doi.org/10.7324/
japs.2015.50508
70. Meenakshisundaram S, Krishnamoorthy V, Jagadeesan Y, Vilwanathan R, Balaiah A (2020)
Annona muricata assisted biogenic synthesis of silver nanoparticles regulates cell cycle arrest
in NSCLC cell lines. Bioorg Chem 95:103451. https://doi.org/10.1016/j.bioorg.2019.103451
71. Asare GA, Afriyie D, Ngala RA, Abutiate H, Doku D, Mahmood SA, H. Rahman
H. (2015) Antiproliferative activity of aqueous leaf extract of Annona muricata L. on the
prostate, BPH-1 cells, and some target genes. Integr Cancer Ther 14:65–74. https://doi.
org/10.1177/1534735414550198
72. Kim GS, Zeng L, Alali F, Rogers LL, Wu FE, McLaughlin JL, Sastrodihardjo S (1998) Two
new mono-tetrahydrofuran ring acetogenins, annomuricin E and muricapentocin from the
leaves of Annona muricata. J Nat Prod 61:432–436. https://doi.org/10.1021/np970534m
73. Sun S, Liu J, Zhou N, Zhu W, Dou QP, Zhou K (2016) Isolation of three new annonaceous
acetogenins from graviola fruit (Annona muricata) and their anti-proliferation on human
prostate cancer cell PC-3. Bioorg Med Chem Lett 26:4382–4385. https://doi.org/10.1016/j.
bmcl.2015.06.038
74. Rieser MJ, Gu ZM, Fang XP, Zeng L, Wood KV, McLaughlin JL (1996) Five novel mono-­
tetrahydrofuran ring acetogenins from the seeds of Annona muricata. J Nat Prod 59:100–108.
https://doi.org/10.1021/np960037q
75. Li DY, Yu JG, Zhu JX, Yu DL, Luo XZ, Sun L, Yang SL (2001) Annonaceous aceto-
genins of the seeds from Annona muricata. J Asian Nat Prod Res 3:267–276. https://doi.
org/10.1080/10286020108040366
76. Sonnet PE, Jacobson M (1971) Tumor inhibitors II: cytotoxic alkaloids from Annona pur-
purea. J Pharm Sci 60:1254–1125. https://doi.org/10.1002/jps.2600600835
77. Hernandez-Fuentes GA, García-Argaez AN, Peraza Campos AL, Delgado-Enciso I, Muniz-­
Valencia R, Martínez-Martínez FJ, Toninello A, Sandoval ZG, Mojica-Sánchez JP, Via LD,
Parra-Delgado H (2019) Cytotoxic acetogenins from the roots of Annona purpurea. Int J Mol
Sci 20:1870. https://doi.org/10.3390/ijms20081870
78. Chávez D, Mata R (1999) Purpuracenin: A new cytotoxic adjacent bis-tetrahydrofuran
annonaceous acetogenin from the seeds of Annona purpurea. Phytochemistry 50:823–828.
https://doi.org/10.1016/s0031-­9422(98)00553-­6
79. Chávez D (1998) R. Mata R. Purpurediolin and purpurenin, two new cytotoxic adjacent bis-­
tetrahydrofuran annonaceous acetogenins from the seeds of Annona purpurea. J Nat Prod
61:580–584. https://doi.org/10.1021/np970410
80. Hernandez-Fuentes GA, Peraza Campos AL, Silvia G (2020) Ceballos-Magana, Roberto
Muniz-Valencia, Hortensia Parra-Delgado, HPLC-DAD method for the detection of five
annopurpuricins in root samples of Annona purpurea. Phytochem Anal 31:472–479. https://
doi.org/10.1002/pca.2910
81. Pathak K, Zaman MK (2014) An overview on medicinally important plant - Annona reticu-
lata Linn. Int J Pharmacogn Phytochem Res 5:299–301
82. Shivanna LM, Urooj AM (2019) Apoptotic effects of Annona reticulata leaves extract in
HT-29 cell lines. Asian J Biol Sci 12:820–831. https://doi.org/10.3923/ajbs.2019.820.831
83. Rajarajan AP, Senthil KR (2016) Assessment of antineoplastic potential of Annona reticulata
Linn. On human cancer cells. Asian J Pharm Clin Res 9:408–411
84. Chang FR, Wu YC, Duh CY, Wang SK (1993) Studies on the acetogenins of formosan annona-
ceous plants. II. Cytotoxic acetogenins from Annona reticulata. J Nat Prod 56:1688–1694.
https://doi.org/10.1021/np50100a005
85. Jamkhande PG, A.S. Wattamwar AS. (2015) Annona reticulata Linn. (bullock's heart):
plant profile, phytochemistry and pharmacological properties. J Tradit Complement Med
5:144–152. https://doi.org/10.1016/j.jtcme.2015.04.001
86. Gingine AP, Mandge SV, Jamkhande PG (2016) In vitro evaluation of anticancer activity of
methnaolic extract of Annona reticulata Linn. (Ramphal) leaves on different human cancer
cell lines. J Anal Pharm Res 2016 3. https://doi.org/10.15406/japlr.2016.03.00087
Annonaceae: Tropical Medicinal Plants with Potential Anticancer Acetogenins… 587

87. Mondal SK, Mondal NB, Mazumder UK (2007) In vitro cytotoxic and human recombi-
nant caspase inhibitory effect of Annona reticulata leaves. Indian J Pharmacol 39:253–254.
https://doi.org/10.4103/0253-­7613.37279
88. Roham PH, Kharat KR, Mungde P, Jadhav MA, Surinder JM (2016) Induction of mito-
chondria mediated apoptosis in human breast cancer cells (T-47D) by Annona reticulata
L. leaves methanolic extracts. Nutr Cancer 68:305–311. https://doi.org/10.1080/0163558
1.2016.1142583
89. Yuan SS, Chang HL, Chen HW, Yeh YT, Kao YH, Lin KH, Wu YC, Su JH (2003) Annonacin,
a mono-tetrahydrofuran acetogenin, arrests cancer cells at the G1 phase and causes
­cytotoxicity in a bax- and caspase-3-related pathway. Life Science 72:2853–2861. https://
doi.org/10.1016/s0024-­3205(03)00190-­5
90. Yogananth Y (2018) Evaluation of antitumor properties of Annona reticulata (L) seeds on
cancer cell lines. J Pharma Res 7:132–135. https://doi.org/10.5281/zenodo.1308605
91. Suresh HM, Shivakumar B, Hemalatha K, Heroor SS, Hugar DS, KRS SR (2011) In vitro
antiproliferative activity of Annona reticulata roots on human cancer cell lines. Pharm Res
3:9–12. https://doi.org/10.4103/0974-­8490.79109
92. Suresh HM, Shivakumar B, Shivakumar SI (2011) Inhibitory potential of the ethanol extract
of Annona reticulata Linn. against melanoma tumor. J Nat Prod 2:168–172. https://doi.
org/10.4103/2229-­5119.92846
93. Rayar A, Manivannan R (2016) Antioxidant and anticancer activities of (+)-catechin isolated
from Annona reticulata Linn. Int J Recent Sci Res 7:9451–9456
94. Queiroz EF, Roblot F, Cavé A, Hocquemiller R, Serani L, Laprévote O, de Paulo MA
(1999) New bistetrahydrofuran acetogenin from the roots of Annona salzmanii. J Nat Prod
62:710–713
95. Costa EV, Dutra LM, Salvador MJ, Ribeiro LHG, Gadelha FR (2013) Ernesto de Carvalho
J. chemical composition of the essential oils of Annona pickelii and Annona salzmannii
(Annonaceae) and their antitumor and trypanocidal activities. Nat Prod Res 27:997–1001
96. Cen-Pacheco F, Valerio-Alfaro G, Santos-Luna D, Fernández J (2019) Sclerin, a new cyto-
toxic cyclononapeptide from Annona scleroderma. Molecules 24:554
97. Okhale SE, Akpan E, Fatokun OT, Esievo KB, Kunle OF (2016) Annona senegalensis
Persoon (Annonaceae): A review of its ethnomedicinal uses, biological activities and phyto-
compounds. J Pharmacogn Phytochem 5:211–219
98. Biseko EZ, Swai HS, Mbugua RW, Ndungu JW, Chepng’etich JC, Gathirwa JW (2019) In
vitro antiproliferative potential of Annona senegalensis Pers. and Allophylus africanus P
Beauv plant extracts against selected cancer cell lines. J Med Plants Res 13:304–311. https://
doi.org/10.5897/jmpr2019.6785
99. Ajaiyeoba EO, Falade MO, Ogbole O, Okpako LC (2006) In vivo antimalarial and cytotoxic
properties of Annona senegalensis extract. Afr J Tradit Complement Altern Med 3:137–141
100. Cavalcanti BC, Bezerra DP, Magalhães HIF, Moraes MO, Lima MAS, Silveira ER, Câmara
CAG, Rao VS, Pessoa C, Costa-Lotufo LV (2009) Kauren-19-oic acid induces DNA dam-
age followed by apoptosis in human leukemia cells. J Appl Toxicol 29:560–568. https://doi.
org/10.1002/jat.1439
101. Chen Y, Chen JW, Li X (2011) Cytotoxic bistetrahydrofuran annonaceous acetogenins from
the seeds of Annona squamosa. J Nat Prod 74:2477–2481. https://doi.org/10.1021/np200708q
102. Hopp DC, Zeng L, Gu ZM, Kozlowski JK, McLaughlin JL (1997) Novel mono-­
tetrahydrofuran ring acetogenins, from the bark of Annona squamosa, showing cytotoxic
selectivities for the human pancreatic carcinoma cell line, PACA-2. J Nat Prod 60:581–586.
https://doi.org/10.1021/np9701283
Biocolorant from Anisochilus carnosus:
A Natural Food Preservative

Suman Thamburaj, Chayanika Sarma, Anju Mariam Johnson,

Akhila Etikala, and Suresh Kumar Kalakandan

1 Introduction

Color plays a significant role in the consumer’s acceptance of food products. Since
color is associated with flavor, it affects the food quality perception and stimulates
appetite. The variety of naturally derived colors are often used to enhance the
appearance and acceptability of foods such as annatto, paprika, indigo, cochineal,
and turmeric [1]. Generally, food colorants have been added to many foods to make
them more appealing and acceptable. Synthetic food colors come in a variety of
color shades, but many studies have carried out on the toxicity of synthetic food
colors. Toxic and carcinogenic properties of approved synthetic colors have been
reported. The use of large number of synthetic colors pollutes the environment,
disrupts the ecological balance, and rises many health risks [2].
Natural colors also act as a potent antioxidant when added to foods. Plant anti-
oxidants can be classified into three categories: phenolic compounds, carotenoids,
and vitamins. In addition to being the most abundant plant compounds with antioxi-
dant activity, certain phenolic compounds often have antimicrobial and antifungal
properties, as well as significant effects on flavors and textures of foods. Some natu-
ral pigments like β-carotene, lycopene, quercetin, and rutin have antioxidant activ-
ity which are also used as food colorants [3]. Many compounds can inhibit oxidation,
but due to safety concerns, a few are suitable for human consumption and generally

Suman Thamburaj, Chayanika Sarma, Anju Mariam Johnson and Akhila Etikala contributed
equally with all other contributors.

S. Thamburaj · C. Sarma · A. M. Johnson · A. Etikala · S. K. Kalakandan (*)

Department of Food Biotechnology, National Institute of Food Technology, Entrepreneurship
and Management - Thanjavur (NIFTEM-T), Ministry of Food Processing Industries,
Government of India, Thanjavur, Tamil Nadu, India
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 589

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_23
590 S. Thamburaj et al.

recognized as safe food grade antioxidants approved by regulatory bodies that are
applied to foods.
Synthetic phenolic antioxidants with antimicrobial action include butylated
hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and monotertiary butyl-
hydroquinone (TBHQ). The presence of a hydroxyl group on the molecule, the
compound’s lipid solubility, and the degree of steric hindrance appear to influence
the antibacterial action of phenolic antioxidants. The antibacterial action of pheno-
lic antioxidants in foods has been studied against bacterial growth and by-products
(gram positive and negative, spore and nonspore formers, spoilage and pathogenic),
moulds, and yeasts. The concentration of phenolic antioxidants with antibacterial
action in food products ranged from 30 to 10,000 ppm. The mechanism of inhibition
by phenolic antioxidants has been discovered to alter the function and composition
of the cellular membrane, DNA, RNA, protein, and lipid production, and mitochon-
drion function.
Phenolic antioxidants are insoluble in water, but soluble in organic solvents such
as ethanol and propylene glycol. BHA and BHT, both of which have one hydroxyl
group, are soluble in fats and oils (up to 50%). Butylated hydroxyanisole (BHA)
and butylated hydroxytoluene (BHT) are antioxidants that are often found in cere-
als, grains, cooking oils, canned goods, snacks, and other similar foods. They pro-
tect foods from oxidative rancidity by contributing hydrogen ions to release fatty
acids [4]. BHA serves as antioxidant and antimicrobial properties. BHA may oper-
ate as a membrane perturbed by inserting into the bacterial cell’s lipid layer and
disrupting the ordered state of the alkyl chains. Because of its alkyl substituents,
BHT may be inefficiently adsorbed at the membrane interface [5]. TBHQ is a
hydroquinone derivative containing a tert-butyl group in the phenolic ring, which
gives this molecule a more hydrophobic property, allowing it to penetrate gram-­
positive bacteria .
Natural food colorants are still used around the world and are proven to provide
considerable benefits when taken, are in high demand due to their long or short-term
impacts, as well as their reliability, functionality, biological potential, and health
effects. To be termed natural, food color additives must exist in nature and contain
natural raw components. They can be derived from plants, animals, minerals, or
microorganisms, and the chromophore should not be chemically altered during
extraction or production [6]. Natural colorants are perceived as safer by consumers
than synthetic colorants, which are regarded to be hazardous. These chemical effects
on children can manifest as behavioral problems, hyperactivity, neurotoxicity, and
attention deficiencies, with significant individual variability [5]. In addition to the
detrimental impact of synthetic colorants on health, natural colorants have a favor-
able influence on health. The carotene, a key pigment in skin protection and cell
growth, revealed a beneficial association between health and carotenoids. Lycopene,
a natural pigment present in tomatoes, is helpful in lowering the incidence of all
types of cancer, including breast, prostate, and cervical cancer. Curcumin has been
shown to be a potent antioxidant that protects against oxidative damage in cellular
components and is useful in the treatment of wounds and burns. Few of the natural
color tend to have antioxidant, anti-inflammatory, and pharmacological properties.
Biocolorant from Anisochilus carnosus: A Natural Food Preservative 591

However, due to safety concerns, consumers choose natural colorants over syntheti-
cally generated colorants [7].
Anisochilus carnosus (L) Wall is an annual herb; flowers of this plant are pale
purple, in dense cylindric spikes. They are also known as Karpuravalli and
Padukurkka and are commonly distributed in moist mixed forests in southern hemi-
sphere. These plants have medicinal value because they contain chemically active
compounds that have specific physiological action on the human body. Alkaloids,
flavonoids, tannins, and phenolic compounds are some of the most essential chemi-
cally active constituents of plants [8]. These are multipurpose ethnomedical plants
that are used to treat variety of ailments such as gastrointestinal disorders, respira-
tory problems, cold, cough, and fever. It has also been stated that plant has anti-­
inflammatory, anti-ulcer, antifungal, and anticancer properties [9]. Natural colors
originate from sources like plants, animals, insects, and minerals that are found in
nature. Plant-based pigments provide a wide variety of medicinal benefits among all
natural colors [10]. A. carnosus is commonly known as a color yielding plant.
Therefore, the present study was aimed to study the functional groups and antioxi-
dant and antibacterial properties of biocolorant from Anisochilus carnosus for better
understanding the food preservation practice.

2 Results

The extract yield percentage, total phenolics, and flavonoids content of A.carnosus
extract were analyzed, calculated, and results are tabulated in Table 1. The 70%
methanol solvent yielded 1.77% extract recovery under maceration extraction
method. The methanolic extract of A.carnosus showed total phenolics content of
178.98 ± 7.57 mg GAE/g extract and flavonoids were found to be 299.33 ± 14.46 mg
RE/g extract.
The UV-Vis spectroscopy and thin layer chromatography were performed for
qualitative analysis of A.carnosus extract. The spectra of UV-Vis spectroscopy of
methanolic flower extract of A.carnosus were recorded between 200 and 1000 nm
and are presented in Fig. 1. The methanolic extract of A.carnosus showed high
absorbance intensity between ranges of 200–500 nm with a peak absorbance at
263 nm. In TLC analysis, the accumulation of phyto-compounds and pigments in
the extract was higher in the 70% methanol solvent. Both analyses confirmed that
the A.carnosus extract has higher amount of pigments, aromatic phytocompounds,
hydroxyl, carbonyl, and other chromophores groups.

Table 1 Yield of extract and its polyphenolics content

Yield Total phenolics Flavonoids
Sample (%) (mg GAE/g extract) (mg RE/g extract)
A.carnosus 1.77 178.98 ± 7.57 299.33 ± 14.46
Values are mean of triplicate determination (n = 3) ± standard deviation
GAE Gallic Acid Equivalents, RE Rutin Equivalents
592 S. Thamburaj et al.

(263.0, 0.7943)
(285.0, 0.7246)
0.9

0.8

0.7

(383.0, 0.4839)
(246.0, 0.6684)

0.6
Abs

0.5

0.4
(351.0, 0.4085)

0.3

0.2

0.1

0.0
200 300 400 500 600 700 800 900 1000
Wavelength(nm)

Fig. 1 Uv-Vis spectroscopy of A.carnosus extract

Table 2 FTIR analysis of A.carnosus extract

S. No. Wave number (cm−1) Molecular motion Functional group
1. 2924.09 C–H stretching Alkanes
2. 2854.65 C–H stretching Alkanes
3. 1734.01 C=O stretching Carboxylic acids
4. 1689.64 C=C stretching Alkenes
5. 1660.71 C=C stretching Alkenes
6. 1460.11 C=C bending Aromatic
7. 1377.17 C=O bending Nitro groups
8. 1332.81 C-O stretching Carboxylic acids
9. 1251.80 C-O stretching Alcohols
10. 1166.93 C-O stretching Alcohols
11. 1035.77 C-O stretching Alcohols
12. 1008.77 C-O stretching Alcohols
13. 758.02 C-H bending Aromatic

The FTIR spectral analyses were carried out to understand the functional compo-
nents and also predict the pharmaceuticals groups is present in the A.carnosus
(Tables 2 and 3, Fig. 2). FTIR analysis revealed that A. carnosus methanolic extract
showed beneficial number of phytochemicals and its functional groups which were
responsible for the antioxidant and antibacterial activities. The spectra of A.
Biocolorant from Anisochilus carnosus: A Natural Food Preservative 593

Table 3 FTIR analysis of A.carnosus extract for IRs Pharmaceuticals library

Mass
S.No. Score Library Name Molecular formula (g/mol)
1 627 56 - IRs Erythromycin C37H67NO13 733.93
pharmaceuticals
2 626 105 - IRs Vincristine sulfate C46H56N4O10.H2SO4 923.04
pharmaceuticals
3 617 34 - IRs Lanatoside C C49H76O20 985.13
pharmaceuticals
4 609 106 - IRs Vinblastine sulfate C46H58N4O9.H2SO4 909.06
pharmaceuticals
5 606 94 - IRs Bacitracin zinc C66H103N17O16SZn 1488.1
pharmaceuticals
6 599 157 - IRs Aclarubicin hydrochloride C42H53NO15.HCl 848.33
pharmaceuticals
7 599 88 - IRs Bromocriptinemesylate C32H40BrN5O5. 750.7
pharmaceuticals CH3SO3H
8 595 100 - IRs Amikacin sulfate C22H43N5O13.2H 781.76
pharmaceuticals 2SO4

9 595 68 - IRs Dexamethasoneacetate C24H31FO6 434.503

pharmaceuticals
10 590 31 - IRs Lincomycin hydrochloride C18H35ClN2O6S 442.99
pharmaceuticals CRS
11 587 85 - IRs Ceftriaxone sodium CRS C18H16N8Na2O7S3 598.53
pharmaceuticals
12 587 24 - IRs Methyldopa C10H13NO4 211.217
pharmaceuticals
13 583 65 - IRs Diethyl Carbamazine C10H21N3O.C6H8O7 391.42
pharmaceuticals dihydrogen citrate
14 581 52 - IRs Fluorometholone C22H29FO4 376.462
pharmaceuticals
15 576 109 - IRs Tobramycin C18H37N5O9 467.51
pharmaceuticals
16 574 156 - IRs Actinomycin D C62H86N12O16 1255.42
pharmaceuticals
17 574 151 - IRs Bleomycin sulfate C55H84N17O21S3 1512.6
pharmaceuticals
18 574 135 - IRs Cefroximeaxetil C20H22N4O10S 510.47
pharmaceuticals
19 572 37 - IRs Imipramine HCl C19H25ClN2 438.31
pharmaceuticals
20 569 146 - IRs Cefamandole sodium C18H17N6NaO5S2 484.48
pharmaceuticals

carnosus methanolic extract sample have a different characteristic peak value with
various functional compounds as presented. A broad peak was found around
2930–2850 cm−1 and showed stretching of C–H bond which was attributed to
alkanes group. Stretching of C=O bond around 1730 cm−1 indicated the presence of
594 S. Thamburaj et al.

Fig. 2 FTIR spectrum of A. carnosus extract (a); Chloramphenicol (b); Quercetin and Rutin (c);
BHT and BHA (d)

carboxylic group. The stretching of C=C bond was observed around peak
1690–1660 cm−1 which correspond to alkenes group. The peak around 1370 cm−1
showed medium intermolecular bending vibration of C=O and the peak around
1330 cm−1 showed stretching of C-O bond. The alcoholic group attributed to peak
around 1260–1000 cm−1 which indicated the presence of intermolecular stretching
of C-O bond. The presence of aromatic compounds was observed in a peak around
1460 cm−1 (C=C bending) and 758 cm−1 (C-H bending), respectively.
The major pharmaceuticals groups in A. carnosus methanolic extract were iden-
tified by FTIR spectral analyses with Shimadzu FTIR library (IRs Pharmaceuticals
library). The FTIR spectrum showed the presence of most important pharmaceutical
compounds with similar functional groups in the A. carnosus methanolic extract
(Table 3). Pharmaceutical compounds with their library ID, molecular formula, and
molecular weight (MW) in the extract are given in Table 6. Twenty major pharma-
ceuticals chemical compounds were found in A. carnosus methanolic extract. All
chemical compounds have diversity of pharmaceutical properties and were identi-
fied by these analyses. Similarly, the natural (Quercetin and rutin), synthetic anti-
oxidant (BHA and BHT), and chloramphenicol (Antibacterial agent) functional
groups were compared with A. carnosus methanolic extract under FTIR spectros-
copy analysis. This analysis confirmed that A. carnosus has antioxidant and antibac-
terial functional groups.
The antioxidant activities of free radical scavenging for A.carnosus extract were
studied and results are illustrated in Table 4. The DPPH scavenging activity was
calculated as % inhibition for methanolic extract of A.carnosus which showed that
Biocolorant from Anisochilus carnosus: A Natural Food Preservative 595

Table 4 Antioxidant activity of A.carnosus extract

DPPH• scavenging activity FRAP
Samples (% inhibition at 5 μg/ml) mM Fe (II)/1 mg
Quercetin 47.20 ± 0.27a 253.43 ± 5.84a
Rutin 40.39 ± 0.21b 109.50 ± 5.44d
BHT 28.28 ± 0.19e 98.58 ± 3.63e
BHA 34.90 ± 0.17d 125.91 ± 7.03b
A. carnosus extract 39.47 ± 0.09c 118.94 ± 2.25c
Values are mean of triplicate determination (n = 3) ± standard deviation, statistically significant at
p < 0.05 where a > b > c > d > e in each column

Table 5 Antibacterial activities of A. carnosus against selected food pathogens

Chloramphenicol A. carnosus extract
Pathogens Gram + ve or -ve ZOI (mm/30 μg) ZOI (2 mg) MIC (μg/ml) MBC(μg/ml)
S.aureus +ve 23.50 ± 0.50d 23.66 ± 0.57c 450 500
S.abony -ve 27.16 ± 0.28b 23.16 ± 0.76c 450 500
P.aeruginosa -ve 13.16 ± 0.28g 00.00 ± 0.00 / /
B.cereus +ve 14.66 ± 0.57f 00.00 ± 0.00 / /
S.typhi -ve 25.00 ± 0.50c 28.00 ± 0.50a 300 350
E.coli -ve 21.66 ± 0.57e 20.50 ± 0.50d 500 550
S.flexneri -ve 28.16 ± 0.28a 26.66 ± 0.28b 400 450
Data are presented in mean values (n = 3) ± Standard deviation, statistically significant at p < 0.05
where a > b > c > d > e > f in each column
ZOI Zone of inhibition, MIC Minimum inhibitory concentration, MBC Minimum bactericidal con-
centration, / Not analyzed

Quercetin has higher scavenge activity for DPPH radical and the lowest was
recorded for BHA. A.carnosus extract showed higher antioxidant activity than the
synthetic antioxidants (BHT and BHA) indicating it to be a potential antioxidant. As
per the results, A. carnosus extract had the degree of reduction of 118.94 mM Fe
(II)/1 mg which was greater than BHT (28.29 mM Fe (II)/ 1 mg) and rutin (109 mM
Fe (II)/ 1 mg), whereas A. carnosus extract value was almost equal to BHA
(125.91 mM Fe (II/ 1 mg).When A. carnosus extract was compared to quercetin, it
has shown highest degree of reduction 253.43 mM Fe (II)/1 mg.
The antibacterial activity of methanolic extract of A. carnosus was tested for dif-
ferent pathogens such as S. aureus, S. abony, P. aeruginosa, B. cereus, S. typhi,
E. coli, and S. flexneri (Table 5 and Fig. 3). The antibacterial effect of methanolic
extract of A. carnosus was evaluated using agar well diffusion method. The diame-
ter of ZOI was calculated for each pathogen which includes a well size of 6 mm in
diameter. The higher antibacterial activity was observed against S. flexneri (ZOI
28.16 ± 0.28 mm; MIC 400 μg/mL; MBC 450 μg/mL). The A. carnosus methanolic
extract was tested against the pathogens and was compared with the standard chlor-
amphenicol. The pathogen S. typhi showed higher susceptibility against A. carnosus
methanolic extract with ZOI of 28.00 ± 0.50 mm; MIC 400 μg/mL; MBC 450 μg/
mL; respectively. Similarly, the antimicrobial activity for other pathogens such as
596 S. Thamburaj et al.

Table 6 Total aerobic bacterial count for stored health mix with A. carnosus extract
Incubation period Control (CFU/gm) Treated (CFU/gm) % Inhibition
0 week 2.7 × 105 2.5 × 105 05.18
1 week 6.2 ×105 1.9 × 105 68.48
2 week 1.3 ×106 1.2 × 105 90.39
3 week 2.6 ×106 9.8 × 104 96.23
4 week 6.8 ×106 1.4 × 105 97.80
Control: Untreated health mix with target bacterial cultures; Treated: Health mixes with target
bacterial cultures were thoroughly sprayed with mg/ml A. carnosus extract and left to air-dry

Fig. 3 A. carnosus (a); Color from A. carnosus (b); Antibacterial activity- B. cereus (c) and
S. typhi (d)

S. aureus (ZOI 23.66 ± 0.57 mm; MIC 450 μg/mL; MBC 500 μg/mL), S. abony
(ZOI 23.16 ± 0.76 mm; MIC 450 μg/mL; MBC 500 μg/mL), E. coli (ZOI
20.50 ± 0.50 mm; MIC 500 μg/mL; MBC 550 μg/mL), and S. flexneri (ZOI
26.66 ± 0.28 mm; MIC 400 μg/mL; MBC 450 μg/mL) was also observed. An incon-
sequential antibacterial activity was observed in A. carnosus methanolic extract
Biocolorant from Anisochilus carnosus: A Natural Food Preservative 597

against P. aeruginosa and B. cereus as there was no ZOI observed; it may be attrib-
uted to their phytoconstituent‘s inability to control the pathogens. When compared
with standard chloramphenicol, all the pathogens were inhibited and showed a
higher zone of inhibition.
Total plate count for storage of health mix with A. carnosus extract was analyzed
by standard IS method. The storage study of A. carnosus extract against selected
pathogens in health mix is represented in Table 6. Gram-positive organisms include
S. aureus and B. cereus and gram-negative microbes include S. abony, P. aerugi-
nosa, S. typhi, E. coli, and S. flexneri; their inhibition for about 4 weeks was studied
in the present work. The A. carnosus extract showed maximum inhibition (97.80%)
in fourth week in which health mix had only the microbial count of 1.4 × 105 cfu/g
followed by third and second week where inhibition was observed to be 96.23% and
90.39% with microbial loads of 9.8 × 104 cfu/g and 1.2 × 105 cfu/g, respectively.

3 Methods

3.1 Sample Collection

The flowers of Anisochilus carnosus were collected from Chithannavasal, Thanjavur

district (Longitude-10.4665°N, Latitude-78.7335°E), Tamil Nadu, India. The taxo-
nomical identification was performed by SKC Herbarium (SKCH), Sri Kaliswari
College (Autonomous), Sivakasi, Tamil Nadu, India. Freshly obtained flowers were
cleaned to remove the external adhering dust and were freeze-dried for 24 hrs at
−80 °C in Labard freeze dryer (Model no. LI-LYFO-56). The dried sample was then
utilized for the further analysis.

3.2 Preparation of Extracts

Extraction of freeze-dried powdered sample was done through maceration process.

10 g of freeze-dried powdered sample was soaked with 70% methanol and was
subjected to maceration process in shaking incubator at 120 rpm for 3 days at
37 °C. Further, the extracts were segregated through filtration process via Whattmann
no.1 filter paper. The extracts were collected and allowed to freeze drying for 24 hrs
at a temperature of −80 °C. The yield percentage was determined after the mass of
crude extracts recuperated was weighed. The dried extracts can be preserved at
room temperature for quantitative and qualitative analysis [11].
598 S. Thamburaj et al.

3.3 Total Phenolics

The analysis of total phenol content in A. carnosus extracts was measured spectro-
metrically by using Folin-Ciocalteu assay [12]. About 0.5 mL of the flower extract
was mixed with 2.5 mL of 20% sodium carbonate and incubated at room tempera-
ture for 4 minutes. 0.5 mL of 1 N Folin-Ciocalteu reagent was added and the tube
was further incubated for 40 minutes. The blue absorbance was read at 723 nm in
UV-spectrometer (Shimadzu Japan 1800) against the blank for total phenolics. On
the basis of the standard curve: y = mx + c, the results were in the form of gallic acid
equivalents (mg GAE/g); where x is the absorbance and y is the gallic acid equiva-
lents (mg GAE/g).

3.4 Total Flavonoids

The total flavonoid content in A. carnosus extract was determined using a conven-
tional method [13] with some modifications and represented in the form of rutin as
equivalents per gram of extract (mg RAE/g). To the 300 μL of flower extract, 2 mL
of distilled water was added followed by 150 μL of sodium nitrite. At room tem-
perature, the contents in the test tube were allowed for incubation for 6 minutes.
After the incubation, 150 μL of aluminim chloride was added and subjected to
6-minute incubation. Then 2 mL of 4% NaOH was added and incubated for another
20 min. The absorbance of pink color was read at 510 nm at UV-spectrometer. The
results were based on the calibration curve (y = mx + c) where x is the absorbance
and y is the rutin equivalence (mg/g) value.

3.5 Ultraviolet/Visible Spectral Measurement

The qualitative analysis of phyto-compounds in flower extracts and the detection of

some group of polyphenolic compounds was carried out using ultraviolet (UV)-
visible spectroscopy. In comparison to other methods, this technique is simple and
time saving. Using a UV-Vis double beam spectrophotometer 1800 PC (Shimadzu),
the UV-visible (Vis) spectra of methanolic flower extracts (100 μL from 1 mg/mL
concentration of extract) was determined in the range of 200-1000 nm [17].

3.6 Thin Layer Chromatography Separation

The thin layer chromatography (TLC) analysis of A. carnosus methanol flower

extract was performed using the silica gel. Pre-activation of silica gel plates was
done at 120 °C for 2 minutes. The extracts to be separated were spotted (5 μL from
Biocolorant from Anisochilus carnosus: A Natural Food Preservative 599

1 mg/mL concentration of extract) with a capillary tube, 1.0 cm above from the end
of the silica gel plate. The mobile phases used were hexane (60%): ethyl acetate
(30%): methanol (10%). The spotted TLC plates were kept in solvent-filled cham-
ber. A chromatogram was produced by movement of solute (mobile phase) across a
thin layer of silica (stationary phase). After the chromatogram was generated, the
resolved spots were identified by detection under UV light at both longer and shorter
wavelengths of 365 nm and 254 nm, respectively, which helped to detect the colored
and fluorescence compounds [18].

3.7 FTIR analysis of A. carnosus Extract

The identification of functional groups of A. carnosus flower methanolic extract

was characterized by Fourier transformed infrared spectroscopy (FTIR). It is a tech-
nique of rapid evaluation of whole infrared spectrum of biological samples. The
FTIR spectra was obtained at frequency regions from 400 to 4000 cm−1 with a reso-
lution of 4 cm−1 using a Shimadzu FTIR spectrometer (IR Tracer 100). In FTIR, the
identification of functional groups for pharmaceutical compounds was conducted
using the database of Shimadzu FTIR library (IRs Pharmaceuticals library) [19].

3.8 DPPH Radical Scavenging Activity

The DPPH radical scavenging activity of the samples was evaluated by the stan-
dardized method of DPPH radical scavenging activity [14]. 2 mL methanolic DPPH
solution (0.1 mM) was added to the samples and incubated for 20 min at
27 °C. Absorbance of the solution was monitored by using UV VIS spectrophotom-
eter at 517 nm. The mixture of methanol, DPPH and standards rutin, quercetin,
BHA, and BHT served as the positive control [28].

3.9 Ferric Reducing Antioxidant Power (FRAP)

The antioxidant activity of A. carnosus extract was assessed according to the proce-
dure mentioned by Pulido et al. [15] with few modifications. The antioxidant poten-
tial of the A. carnosus extract was estimated to analyze their ability to reduce from
Fe3+ to Fe2+. About 100 μl of extract sample was added to freshly prepared 900 μl of
FRAP solution in 40 mM HCl with 2.5 mL of 20 mM FeCl3·6H2O and 25 mL of
0.3 M acetate buffer with pH 3.6 and was incubated at 37 °C in water bath for
30 min. At the end of incubation period, the absorbances were read at 593 nm in UV
spectrophotometer. Blank was served as FRAP reagent, and instead of sample,
600 S. Thamburaj et al.

methanol was added. The FRAP value was expressed as mM Fe (II) equivalents/ mg
extract.

3.10 Test Pathogens

Pure cultures of Bacillus cereus NCIM-2217, Shigella flexneri NCIM 1457 were
obtained from National Collection of Industrial Microorganisms (NCIM), Pune.
And others, Escherichia coli (MTCC- 443), Salmonella enterica Typhimurium
MTCC-98, Pseudomonas aeruginosa MTCC 1934, Staphylococcus aureus MTCC-
737, and Salmonella enterica ser. Abony MTCC- 3858, were obtained from micro-
bial culture collection and gene bank, IMTECH, Chandigarh. The pure culture was
cultured on a nutrient agar medium.

3.11 Antibacterial Activity by Agar Well Diffusion Method

The modified agar well diffusion method was used to assess the antibacterial activ-
ity of A. carnosus flower extracts against various bacterial pathogens. Using sterile
cotton swabs, bacterial broth cultures were swabbed in MHA media plates. A steril-
ized cork borer (6 mm Hi-Media) was used to create the wells on agar plates. The
plates were aerobically incubated at 37 °C for 18–24 h with diluted samples (100 μL
of 10 mg/mL concentration). Chloramphenicol (5 μg) was considered as positive
and negative control. The zones of inhibition (ZOI) (mm) of each sample were mea-
sured after the necessary time of incubation, and the activity index was determined
as well. The reading was taken for three times in total with the average values
reported. The whole experiment was carried out in vitro conditions [16].

3.12 Determination of Minimum Inhibitory Concentration

(MIC) of A. carnosus Flower Extract

MICs was carried out for the serial extract of A. carnosus in broth dilution method,
for those showed ≥8 mm diameter growth ZOI in well diffusion method. The 5 mg/
mL concentration of extract was serially diluted in 900 μL sterile broth (Bacteria-
MHA broth). All the broth were filled with 100 μL of the culture (1 × 105 CFU/mL)
and one was kept as control for each test organisms; further all the culture tubes
were incubated at 37 °C. After incubation, OD values were taken in spectrophotom-
eter (Shimadzu UV-spectrophotometer, UV 1800) at 570 nm. From OD values, the
percentage of growth inhibition and MIC was calculated against test pathogens. The
MBC was evaluated by subculturing the test dilution used in MIC. The culture
Biocolorant from Anisochilus carnosus: A Natural Food Preservative 601

obtained from the MIC test by centrifugation after incubation period was suspended
in 100 L sterile broth and the suspension was swabbed onto the MHA plates and
allowed to incubate for 24–48 h at 37 °C on to a fresh medium and incubated further
for 24 h. MBC was defined as the concentration of plant extract that fully killed the
organisms [16, 28] .

3.13 Storage Study

Commercially available health mix was collected from local market Thanjavur,
Tamil Nadu, India. The health mix was sterilized by autoclaving at 15 lbs. pressure
(121 °C) for 15 minutes and allowed to cool down. After cooling, the health mix
samples were divided into an experimental group and a control group. Experimental
group consists of sterile health mix sample (25 g) which was first sprayed thor-
oughly with extract solution (2× concentration of MIC/g of sample), allowed to dry
in a sterile container. The desired mixed bacterial culture (3 × 105 CFU/ g of sample)
was mixed well and incubated at room temperature set at 26 °C for 4 weeks. The
control group health mix was not treated with extract and placed for incubation at
room temperature for 4 weeks.
Sample groups were monitored every week to determine shelf-life and to subcul-
ture bacterial spoiling agents. Each group that showed bacterial growth was deter-
mined by standard plate count method. The percentage of bacterial inhibition at
every week was also determined.

3.14 Statistical Analysis

All the experimental data were conducted in triplicates and analyzed statistically.
All data were expressed as mean ± standard deviation (n = 3). All the parameters
were analyzed using factorial by SPSS Inc. 25.0 (2020, IL, USA).

4 Discussion

In present investigations, the methanolic extract of A. carnosus flower was used to

evaluate the total phenolics, flavonoids, antioxidant, and antibacterial activity
against food pathogens. Phenolics and flavonoids compounds exhibit good biologi-
cal and functional effects, such as antioxidant and antibacterial properties [13, 20,
21]. In this study, we observed that the A. carnosus flower extract has higher pheno-
lics and flavonoids contents. Therefore, polyphenolics content of A. carnosus flower
extract may possibly have the biological properties. Similarly, previous reports sug-
gest that the polyphenolic content possesses significant characteristic like
602 S. Thamburaj et al.

anticarcinogenic, antioxidant, anti-inflammatory, antimicrobial, antimutagenic and

free radical scavenging, etc. Flavonoids contain phenolic compounds which are pri-
mary antioxidants [22].
The accumulation of phytocompounds and pigments of A. carnosus flower
extract was screened by UV-Vis spectroscopy and TLC analyses. From these analy-
ses, we found that the A. carnosus flower extract has more color and colorless com-
pounds. According to Kemp (1991), UV-Vis spectroscopy and TLC utilized to
identify the polyphenolic compounds, namely, anthocyanins, dyes, flavonoids, phe-
nols, polymer, and tannins. The absorbance between 246 to 383 nm is linked to
n → π*electronic transitions and it originated from aromatic phytocompounds,
hydroxyl, carbonyl, and other chromophores. These transitions are due to the pres-
ence of a high amount of total phenolics in the extract (246 nm). Moreover, flavones
(263 nm), phenolic acids (285 nm), flavonoids (351 nm), total anthokyanids
(383 nm), and tannins (710 nm) and other secondary metabolite compounds are also
present in the plant extract. These phyto-compounds are highly responsible for
defense mechanism of the plant against pathogens, parasites, predators, and
color [23].
FTIR spectroscopy is one of the most widely used methods for identification of
the chemical composition and functional groups of the compounds [21]. FTIR spec-
troscopy shows speed and accuracy in measurements of whole range of biological
specimens at infrared spectrum. The spectrum of FTIR spectral analysis of A. car-
nosus methanolic extract reveals the presence of peaks of functional group like
alkanes, carboxylic, alcoholic, and aromatic compounds. Mostly all the researchers
applied for FTIR spectrum as a tool for distinguishing the medicinal plants based on
their chemical constituents [6, 24, 25]. The phyto-constituents such as flavonoids,
inorganic acids, alkaloid, phenol, tannin, carboxylic acid, terpenes, and amino acids
are present in medicinal plants [26]. The functional components or secondary
metabolites of plant are vital sources for the growth of new pharmaceutical agents.
In this investigation of A. carnosus, methanolic flower extract revealed the presence
of various functional groups of phytochemicals such as phenolics, flavonoids, gly-
coside, alkaloid, saponins, and tannins. Similarly, Wulandari et al. [24] described
that phyto-chemical screening assists as the preliminary step in predicting the types
of potential active compounds. Therefore, this study revealed that the functional
components of A. carnosus origin are utilized for developing new pharmaceuticals
and food preservatives.
Antioxidant assay consisting of DPPH and FRAP has been conducted to deter-
mine the antioxidant activity of the flower extract with natural and synthetic antioxi-
dants. DPPH activity is a free radical scavenging method that was used for
determining the antioxidant activity by electron transfer which generates a violet
solution in methanol. The presence of antioxidant molecule in sample causes the
free radicals to be stable at room temperature that yields a colorless methanol solu-
tion. DPPH can accept an electron or hydrogen radical to form a stable, diamagnetic
molecule, but it can only be oxidized slowly and irreversibly. Due to its odd elec-
tron, DPPH exhibits a strong absorption band at 517 nm, and the solution appears a
deep violet color; however, the absorption dissolves as the electron pairs off [27,
Biocolorant from Anisochilus carnosus: A Natural Food Preservative 603

28]. The DPPH activity was measured through the percentage inhibition of extract
with other antioxidant compounds. According to the results, A. carnosus extract had
the inhibition percentage, whereas natural antioxidant such as rutin and quercetin
also had higher inhibition of 47.20% and 40.39%. When compared with synthetic
antioxidants, the A. carnosus extract arrayed higher inhibition percentage. The
highly enhanced DPPH radical scavenging activity of the extract was observed in
the present study. It may be due to the polar nature of the solvent and the extracting
ability of the phenolics from the A. carnosus extract.
The ferric reducing antioxidant power (FRAP) assay is a common antioxidant
method used to measure the reduction of ferric ion (Fe3+)-ligand complex by anti-
oxidants in an acidic medium to the intensely blue-colored ferrous (Fe2+) complex.
The FRAP assay is performed at an acidic pH 3.6 to maintain iron dispersibility
and, more notably, to boost electron transfer. This elevates the redox potential,
resulting in a shift in the dominant reaction mechanism. Antioxidant activity is mea-
sured as an increase in absorbance at 593 nm, and the responses were recorded as
micromolar Fe2+ equivalents or as a percentage of an antioxidant standard [28, 29].
The ferric reducing power of A. carnosus extract revealed that the presence of phy-
toconstituents in the extract has a strong affinity for ferric ions, and thus redox reac-
tions were extinguished through redox reaction. The reducing power of the bioactive
phytoconstituents present in A. carnosus methanolic extract is associated with high
antioxidant activity. When the antioxidant assay of DPPH and FRAP activity is
compared with each other, it was observed that A. carnosus extract value was higher
than synthetic antioxidants (BHA and BHT), whereas A. carnosus extract value was
equal or lesser than the natural antioxidants such as rutin and quercetin because they
are well-known polyphenolic compounds. Similarly, previous studies have shown
that antioxidant potential of methanolic and aqueous extract of A. carnosus leaf
showed a similar scavenging activity when compared with natural antioxidants such
as rutin and ascorbic acid (Bhagat et al., 2011). From the results above, the high
radical scavenging activity of A. carnosus extract indicates it is highly potent and
can scavenge free radicals in the body.
Quercetin is an aglycone that does not have an attached sugar and it is known to
be the most abundant flavonoid molecules from group of polyphenols [30].
Generally, quercetin can be found in a wide range of foods including apples, berries,
Brassica vegetables, capers, grapes, onions, shallots, tea, and tomatoes, as well as
numerous seeds, nuts, flowers, barks, and leaves [31]. Similarly, rutin is a glycoside
combination of flavanol quercetin and disaccharide rutinose. It is also known as
Vitamin P which is found in a variety of vegetables, fruits, and medicinal herbs,
including asparagus and buckwheat. Additionally, buckwheat is regarded as one of
the best dietary sources of rutin [32]. Previously, it is reported that quercetin and
rutin were proved to have several pharmacological activities including antioxidant,
anticarcinogenic, neuroprotective, cardioprotective, and anti-inflammatory activi-
ties [33–36]. Due to exorbitant rate of natural antioxidants, the synthetic antioxi-
dants have been preferred as a preservative in food industry.
In case of synthetic compounds, BHA and BHT are two of several synthetic
antioxidants that are widely used in a variety of product categories such as food,
604 S. Thamburaj et al.

food packaging, pharmaceuticals, and cosmetics. BHA is an isomeric mixture as

well as analogue of BHT. Since the late 1950s, it has been used as a food additive.
It is also found in animal feed, cosmetics, pharmaceuticals, rubber, biodiesel, and
petroleum. BHA has been shown in some studies to have antitumor and nephropro-
tective properties [37]. It plays an important role in food preservation by preventing
oxidative rancidity of fats and oils and also the loss of activity of oil-soluble vita-
mins [38]. BHT is a cresol derivative that is a synthetic phenolic antioxidant addi-
tive found in foods like packet cake mixes, potato crisps, salted peanuts, and
dehydrated mashed potatoes as well as in mineral oil, rubber, plastic and printing
inks, pharmaceuticals, and cosmetics [39]. BHT toxicity and side effect reports have
been quite conflicting, since BHT has been shown to have positive effects in previ-
ous studies, such as increasing intracellular levels of glutathione and related
enzymes in rats, protecting against cancer due to its antioxidant activity, and having
tumor-reducing effects. On the other hand, it has been shown in rats to cause renal
and hepatic damage, increase in liver weight, decrease the activities of several
hepatic enzymes, and have toxic effects on lung tissue. BHT toxic effect has been
attributed primarily to its metabolism [37]. Due to the toxicity effects, the synthetic
antioxidants are used in limited amount in food industry.
The free radicals scavenging activity of A. carnosus extract was analyzed by
DPPH and FRAP methods. Both methods are widely used for estimation of free
radicals scavenging effect of biological compounds. In the present antioxidant
assay, A. carnosus flower extract was measured and compared with natural and
synthetic compounds such as rutin, quercetin, BHT, and BHA. Antioxidants are
food preservatives which are in the form of natural or synthetic antioxidants that
help to preserve food from farm to final product by preventing oxidative deteriora-
tion during storage and processing. Due to their high stability and low volatility,
antioxidants aid in the preservation of nutrients, texture, color, taste, freshness,
functionality, aroma, and appeal to consumers such as the elderly, among others.
Antioxidants are found not only in food additives, but also in food supplements
[40]. A. carnosus showed higher antioxidant activity than the synthetic antioxidants
(BHT and BHA), indicating it to be a potential antioxidant and food preservative.
Plants and the by-products with antimicrobial properties have various therapeu-
tic benefits [25]. The activity of antimicrobial for methanolic extract of A. carnosus
was tested for different food pathogens such as S. aureus, S. abony, P. aeruginosa,
B. cereus, S. typhi, E. coli, and S. flexneri. Food-borne pathogens can cause various
health hazards such as diarrhea, vomiting, and nausea. To control the various health
hazards caused by food-borne pathogens, they are being subjected to a board spec-
trum of antibiotics. One of the major antibiotics is chloramphenicol. Chloramphenicol
was the first antibiotic to be fully broad-spectrum. Chloramphenicol has antibacte-
rial activity against both gram-positive and gram-negative aerobic and anaerobic
microorganisms [39]. Though chloramphenicol was widely used in the beginning,
the developed countries abandoned it later due to their concerns about toxicity. In
the United Kingdom, systemic chloramphenicol is no longer widely recommended
as first-line therapy for any disease due to the adverse effects; the longer use of
chloramphenicol has been reported to cause bone marrow suppression, grey baby
Biocolorant from Anisochilus carnosus: A Natural Food Preservative 605

syndrome, renal impairment, and childhood leukemia. Due to the adverse effects of
antibiotics, the natural substances such as plant extracts are being explored more for
their antibacterial activity [41].
The present study confirmed that the A. carnosus extract has good antibacterial
effect against tested food pathogens except P. aeruginosa and B. cereus. Similarly,
previous studies reported that natural extracts of several plants such as Cleistanthus
collinus, Elaeocarpus tectorius, and rubius fruits have shown zone of inhibition
against several food-borne pathogens [13, 42, 43]. According to the result, antibac-
terial activity may be related to the total polyphenolic content of A. carnosus extract.
Hence, it showed that A. carnosus methanolic extract could inhibit the food borne
pathogens.
B.cereus produces two types of toxins; emetic and diarrhoeal causing vomiting
and diarrhea. S. aureus generally causes infections of skin, bacteremia, urogenital
tract, and central nervous system. Likewise, S. abony, P. aeruginosa, and S. typhi
also cause opportunistic infections. Antibiotic resistance in these food pathogens is
a major problem in food industries that keep on challenging the healthcare sector in
worldwide. The appearance and spread of drug-resistant pathogens have signifi-
cantly threatening the existing antibacterial therapy. Therefore, there is a need to
search for a new source of antibacterial chemical substances to control the multidrug-­
resistant pathogens (MDR) in food packaging and preservation. This study con-
firmed that the A. carnosus showed higher antibacterial activity against selected
food pathogens, indicating it should be a potential food preservative to control
unwanted pathogens in any food matrix.
The selected bacterial consortium was used for evaluating the preservative prop-
erties of A. carnosus flower extract. The total plate count method was adopted to
estimate the percentage of inhibition of bacterial growth in the sterile health mix
(Multi grains) with A. carnosus flower extract about 4 weeks. According to best of
our knowledge, this is the first study reporting on A. carnosus leaf extract against
the pathogens in health mix. From this investigation, A. carnosus extract showed
maximum inhibition in fourth week and confirmed that the A. carnosus extract has
antibacterial properties to inhibit the unwanted pathogens in food matrix. This may
be due to the flavonoids and antioxidants present in the A. carnosus extract.
Flavonoids can form complexes with extracellular and soluble proteins, as well as
bacterial cell walls. Lipophilic flavonoids have the potential to damage bacterial
membranes as well [44]. Previous studies have reported the antibacterial activity of
flavonoids against wide variety of human and environmental pathogens [45–47].
Antioxidants in leaf extracts have the ability to break the chain reaction and thus
stops the generation of radical oxygen species (ROS) and helps in decreasing the
oxidation stress which may lead to pathogenesis and inflammation [48]. The activ-
ity of antioxidants against pathogens has been mentioned in previous reports
[49–51].
Antimicrobial activities of medicinal plants and isolated natural antimicrobials
have been linked to variety of processes. These natural compounds influence mac-
romolecular metabolic pathways that have been proved to be targets for antibiotic
intervention. Protein and cell wall production are clearly the targets of the broadest
606 S. Thamburaj et al.

array of natural compounds now available as antibacterial agents. Shalayel et al.

[52] reported the antibacterial activity of pepper mint (Mentha piperita) against
S. pyogenes, E. faecalis, methicillin-resistant Staphylococcus aureus, E. coli, and
Klebsiella pneumoniae clinical isolates. Similarly, findings [25] revealed that etha-
nolic extracts of Betel leaf (Piper betle L.) potentially inhibited the growth of the
food-borne pathogens and include Vibrio cholerae, E. coli, Shigella dysenteriae,
and Staphylococcus aureus and demonstrated that betel leaf can be used as a natural
food preservative to improve the microbiological safety of the foods. The antibacte-
rial activity of Typha angustifolia Linn leaves, which can be used as source of food,
medicines, and fibers against gram-negative microbes such as Enterobacter aero-
genes, Salmonella typhimurium, Klebsiella pneumoniae, Pseudomonas aeruginosa,
and E. coli, was also studied [41]. Plants which are made up of a variety of com-
pounds can hinder bacterial cell wall development, protein synthesis, and interfere
with microbial metabolic pathways. As a result, crude extract’s antibacterial activity
could be attributed to multiple mechanisms. Furthermore, depending on their rela-
tive concentrations, distinct chemicals in the extract can function synergistically or
oppose each other’s effect. Because medicinal plant extracts contain a vast variety
of chemical components, their antimicrobial action is most likely due to many anti-
microbial mechanisms [53].
The bioactive components present in plants include phenols, flavanols, proantho-
cyanins, and flavonoids reported to possess antibacterial, strong antioxidant, and a
variety of biological activities because their molecules contain a hydroxyl group or
a phenolics rings [50]. Antimicrobial action of phyto-chemicals is mediated by a
variety of methods; changes in cell morphology, reduction of membrane potential,
membrane disruption associated with ion leakage, impairment in the intracellular
pH homeostasis, inhibition of ATP-ase activity, toxins biosynthesis, changes in pro-
teome and transcriptome, enzymatic reaction, and biofilm formation are all part of
phytochemicals’ antimicrobial mechanism of action. In addition to these antiquo-
rums sensing, nucleic acid synthesis inhibition, virulence factors suppression,
impairment in the carbon source utilization, lipid profile composition alteration, and
mitochondrial dysfunction activities can also be observed. Thus, the plant bioactive
chemicals produce significant changes in the cells’ diverse biological functions,
resulting in disruption of critical cellular processes essential for the cell’s survival.
Therefore, the overall in vitro results suggest that the A. carnosus flower extract is a
potential source of natural preservative to replacement of chemical preservatives.

5 Conclusion

Colorant is a characteristic property of food as it plays an important role in con-

sumer preferences. Food colorant of natural origin has a great importance as it is
safer, confers various health benefits, provides organoleptic characteristics and
functional benefits, and acts as antioxidants and antimicrobial agent, though there
are more availability of synthetic colors which are identical and inexpensive when
Biocolorant from Anisochilus carnosus: A Natural Food Preservative 607

compared to natural colors, the synthetic colors are not acquired due to its adverse
effects on human health. Hence, consumers tend to adopt the addition of natural
colors in food. A. carnosus methanolic extract showed significant polyphenolics,
antioxidants, and antibacterial activity against various enteric pathogens.
Furthermore, A. carnosus methanolic extract can act as a potent preservative. Thus,
this natural food color can also be of great commercial importance.

Acknowledgments The authors gratefully acknowledge the Department of Biotechnology at

National Institute of Food Technology, Entrepreneurship and Management-Thanjavur (NIFTEM-
T) Thanjavur, Tamil Nadu, India, for granting permission to use the required laboratory facilities.
Declarations I, hereby declare the following:

• This work was funded by National Institute of Food Technology, Entrepreneurship

and Management-Thanjavur (NIFTEM- T).
• There is no conflict of interest on publication of the manuscript.
• Ethical approval: Not applicable.
• Consent to participate: The authors participated with their willingness and par-
ticipated equally.
• Availability of data and materials: The data and materials in this chapter are
authentic.
• Code availability: Not applicable.
• Authors’ contribution: The authors contributed equally to this work.

References

1. Oplatowska-Stachowiak M, Elliott CT (2017) Food colors: existing and emerging food safety
concerns. Crit Rev Food Sci Nutr 57:524–548. https://doi.org/10.1080/10408398.2014.889652
2. Jadhav RV, Bhujbal SS (2020) A review on natural food colors. Pharma Resonance 2(2):12–20.
3. Lourenço SC, Moldão-Martins M, Alves VD (2019) Antioxidants of natural plant origins:
from sources to food industry applications. Molecules 24:14–16. https://doi.org/10.3390/
molecules24224132
4. Fung DYC, Taylor S, Kahan J (1977) Effects of butylated hydroxyanisole (BHA) and butyl-
ated hydroxytoluene (BHT) on growth and aflatoxin production of Aspergillus flavus. J Food
Safety 1(1):39–51.
5. Gutiérrez-Larraínzar M, Rúa J, de Arriaga D et al (2013) In vitro assessment of synthetic
phenolic antioxidants for inhibition of foodborne Staphylococcus aureus, Bacillus cereus
and Pseudomonas fluorescens. Food Control 30:393–399. https://doi.org/10.1016/j.
foodcont.2012.07.047
6. Grube M, Muter O, Strikauska S et al (2008) Application of FT-IR spectroscopy for control
of the medium composition during the biodegradation of nitro aromatic compounds. J Ind
Microbiol Biotechnol 35:1545–1549
7. Sezgin A, Ayyıldız S, Sezgin AC (2017) Food additives: colorants. Science within Food:
Up-to-Date Advances on Research and Educational Ideas: 87–94.
8. Kiruthiga N, Sathish Sekar D (2278) Studies on phytochemicals and steroid isolation from
N-hexane extract of Anisochilus carnosus. Int J Adv Biotechnol Res:976–2612
608 S. Thamburaj et al.

9. Reshi NA, Sudarshana MS, Girish HV (2017) In vitro micropropagation of Anisochilus carno-
sus (L) Wall. J Appl Pharm Sci 7:098–102. https://doi.org/10.7324/JAPS.2017.70715
10. Scotter MJ (2011) Emerging and persistent issues with artificial food colours: natural colour
additives as alternatives to synthetic colours in food and drink. Quality Assurance Safety Crops
Foods 3:28–39. https://doi.org/10.1111/j.1757-­837X.2010.00087.x
11. Shang HM, Zhou HZ, Li R et al (2017) Extraction optimization and influences of drying meth-
ods on antioxidant activities of polysaccharide from cup plant (Silphium perfoliatum L.). PLoS
One 12:e0183001. https://doi.org/10.1371/JOURNAL.PONE.0183001
12. Biswas AK, Chatli MK, Sahoo J (2012) Antioxidant potential of curry (Murraya koenigii
L.) and mint (Mentha spicata) leaf extracts and their effect on colour and oxidative stability
of raw ground pork meat during refrigeration storage. Food Chem 133:467–472. https://doi.
org/10.1016/j.foodchem.2012.01.073
13. Muniyandi K, George E, Sathyanarayanan S et al (2019) Phenolics, tannins, flavonoids
and anthocyanins contents influenced antioxidant and anticancer activities of Rubus fruits
from Western Ghats, India. Food Sci Human Wellness 8:73–81. https://doi.org/10.1016/j.
fshw.2019.03.005
14. Singh R, Shushni MAM, Belkheir A (2015) Antibacterial and antioxidant activities of Mentha
piperita L. Arab J Chem 8:322–328. https://doi.org/10.1016/j.arabjc.2011.01.019
15. Pulido R, Bravo L, Saura-Calixto F (2000) Antioxidant activity of dietary polyphenols as
determined by a modified ferric reducing/antioxidant power assay. J Agric Food Chem
48:3396–3402. https://doi.org/10.1021/jf9913458
16. Thamburaj S, Ramaraj E, Sethupathy S et al (2020) Antibacterial and antibiofilm activities
of diphyllin against fish pathogens. Microb Pathog 145:104232. https://doi.org/10.1016/j.
micpath.2020.104232
17. Karpagasundari C, Kulothungan S (2014) Analysis of bioactive compounds in Physalis min-
ima leaves using GC MS, HPLC, UV-VIS and FTIR techniques. J pharmacogn phytochem
3:196–201
18. Lydia MA, Thamburaj S, Jagadeesan G, et al (2020) UV/Vis Spectrophotometric
Characterization of the leaf polyphenolics content in Elaeocarpus tectorius and its therapeutic
potential against selected urinary tract infection pathogens. Phytomedicine 169–178.
19. Jain PK, Soni A, Jain P, Bhawsar J (2016) Phytochemical analysis of Mentha spicata plant
extract using UV-VIS, FTIR and GC/MS technique. J Chem Pharm Res 8:1–6. Available
online www.jocpr.com
20. Murugan R, Parimelazhagan T (2014) Comparative evaluation of different extraction methods
for antioxidant and anti-inflammatory properties from Osbeckia parvifolia Arn. - an in vitro
approach. J King Saud University Sci 26:267–275. https://doi.org/10.1016/j.jksus.2013.09.006
21. Thamburaj S, Rajagopal V, Palanivel R, Pugazhendhi S (2022) Effect of different drying treat-
ments on total polyphenolics content and in-vitro biological properties of Ficus benghalensis
fruit: a comparative study. Biocatal Agric Biotechnol 39:102249. https://doi.org/10.1016/j.
bcab.2021.102249
22. Saravanan S, Parimelazhagan T (2014) In vitro antioxidant, antimicrobial and anti-diabetic
properties of polyphenols of Passiflora ligularis Juss. Fruit pulp. Food Sci Human Wellness
3:56–64. https://doi.org/10.1016/j.fshw.2014.05.001
23. Muniyandi K, George E, Mudili V et al (2017) Antioxidant and anticancer activities of
Plectranthus stocksii Hook. f. Leaf and stem extracts. Agri Nat Res 51:63–73. https://doi.
org/10.1016/j.anres.2016.07.007
24. Wulandari L, Retnaningtyas Y, Nuri LH (2016) Analysis of flavonoid in medicinal plant extract
using infrared spectroscopy and Chemometrics. J Analyt Meth Chem 2016:1. https://doi.
org/10.1155/2016/4696803
25. Kumar A, Kumari P, Arun K, et al (2016) Phenolic composition, antioxidant activity and FT-IR
spectroscopic analysis of halophyte Sesuvium portulacastrum L. extract. Int Res J Biological
Sci 5(1):1–13
Biocolorant from Anisochilus carnosus: A Natural Food Preservative 609

26. Kavitha A, Mary Kensa V (2019) Preliminary phytochemical screening and FTIR analysis on
Rivina humilis L. (mixture). Adalyajournal 8(9):208–215
27. Kedare SB, Singh RP (2011) Genesis and development of DPPH method of antioxidant assay.
J Food Sci Technol 48:412–422
28. Manoharan AL, Thamburaj S, Muniyandi K et al (2019) Antioxidant and antimicrobial inves-
tigations of Elaeocarpus tectorius (Lour.) Poir. Fruits against urinary tract infection patho-
gens. Biocatalysis and agricultural. Biotechnology 20:101260. https://doi.org/10.1016/j.
bcab.2019.101260
29. Zhong Y, Shahidi F (2015) Methods for the assessment of antioxidant activity in foods. In:
Handbook of antioxidants for food preservation. Elsevier Inc., pp 287–333
30. Li Y, Yao J, Han C et al (2016) Quercetin, inflammation and immunity. Nutrients 8:167
31. Wiczkowski W, Romaszko J, Bucinski A, et al (2008) Quercetin from shallots (Allium cepa
L. var. aggregatum) is more bioavailable than its glucosides. J Nutrition 138(5):885–888
32. Patel K, Patel DK (2019) The beneficial role of Rutin, a naturally occurring flavonoid in health
promotion and disease prevention: a systematic review and update. In: Bioactive food as
dietary interventions for arthritis and related inflammatory diseases. Elsevier, In, pp 457–479
33. Afanas’ev IB, Ostrakhovitch EA, Mikhal’chik EV et al (2001) Enhancement of antioxidant
and anti-inflammatory activities of bioflavonoid rutin by complexation with transition metals.
Biochem Pharmacol 61(6):677
34. Enogieru AB, Haylett W, Hiss DC et al (2018) Rutin as a potent antioxidant: implica-
tions for neurodegenerative disorders. Oxidative Med Cell Longev 2018:1–17. https://doi.
org/10.1155/2018/6241017
35. Ganeshpurkar A, Saluja AK (2017) The pharmacological potential of Rutin. Saudi Pharmaceut
J 25:149–164
36. Lesjak M, Beara I, Simin N et al (2018) Antioxidant and anti-inflammatory activities of quer-
cetin and its derivatives. J Funct Foods 40:68–75. https://doi.org/10.1016/j.jff.2017.10.047
37. Ousji O, Sleno L (2020) Identification of in vitro metabolites of synthetic phenolic antioxidants
BHT, BHA, and TBHQ by LC-HRMS/MS. Int J Mol Sci 21:1–13. https://doi.org/10.3390/
ijms21249525
38. Thakore KN (2014) Butylated Hydroxyanisole. In: Encyclopedia of toxicology, 3rd edn.
Elsevier, pp 581–582
39. Cannon M, Harford S, Darks J (1990) A comparative study on the inhibitory actions of
chloramphenicol, thiamphenicol and some fluorinated derivatives. J Antimicrob Chemother
26(3):307
40. Wilson DW, Nash P, Singh Buttar H et al (2017) The role of food antioxidants, benefits of
functional foods, and influence of feeding habits on the health of the older person: an overview.
Antioxidants (Basel) 6:81. https://doi.org/10.3390/antiox6040081
41. Londonkar RL, Madire Kattegouga U, Shivsharanappa K, Hanchinalmath JV (2013)
Phytochemical screening and in vitro antimicrobial activity of Typha angustifolia Linn leaves
extract against pathogenic gram negative micro organisms. J Pharm Res 6:280–283. https://
doi.org/10.1016/j.jopr.2013.02.010
42. Elangomathavan R, Suman T, Nancy Beaulah S et al (2015) Comparative analysis of
Cleistanthus collinus aqueous leaf extract and fractions for its antibacterial potential. Int J
Enteric Pathogens 3. https://doi.org/10.17795/ijep22946
43. Dailin DJ, Gomaa S, Enshasy H et al (2019) Mycology project view project Tifus KIT diagnos-
tic view project natural colorant for food: a healthy alternative. Int J Sci Technol Res 8:3161
44. Selvi TA, Chandrasekaran B, Murugan D, Satyan SR (2011) Leaf and Seed extracts of
Bixa orellana L. exert anti-microbial activity against bacterial pathogens. J Appl Pharm Sci
1:116–120
45. Mathesius U (2018) Flavonoid functions in plants and their interactions with other organisms.
Plant 7(2):30
610 S. Thamburaj et al.

46. Wu SC, Yang ZQ, Liu F et al (2019) Antibacterial effect and mode of action of flavonoids from
licorice against methicillin-resistant Staphylococcus aureus. Front Microbiol 10:2489. https://
doi.org/10.3389/fmicb.2019.02489
47. Song M, Liu Y, Li T et al (2021) Plant natural flavonoids against multidrug resistant pathogens.
Adv Sci 8:2100749. https://doi.org/10.1002/advs.202100749
48. Afzal F, Khurshid R, Ashraf M, Gul Kazi A (2014) Reactive oxygen species and antioxidants
in response to pathogens and wounding. In: Oxidative damage to plants: antioxidant networks
and signaling. Elsevier Inc., pp 397–424
49. Sharifzadeh A, Jebeli Javan A, Shokri H et al (2016) Evaluation of antioxidant and antifungal
properties of the traditional plants against foodborne fungal pathogens. Journal de Mycologie
Medicale 26:e11–e17. https://doi.org/10.1016/j.mycmed.2015.11.002
50. Sagbo IJ, Afolayan AJ, Bradley G (2017) Antioxidant, antibacterial and phytochemical proper-
ties of two medicinal plants against the wound infecting bacteria. Asian Pac J Trop Biomed
7:817–825. https://doi.org/10.1016/j.apjtb.2017.08.009
51. Salem MZM, EL-Hefny M, Ali HM et al (2021) Plants-derived bioactives: novel utilization as
antimicrobial, antioxidant and phytoreducing agents for the biosynthesis of metallic nanopar-
ticles. Microb Pathog 158:105107
52. Shalayel MHF, Asaad AM, Qureshi MA, Elhussein AB (2017) Anti-bacterial activity of pep-
permint (Mentha piperita) extracts against some emerging multi-drug resistant human bacte-
rial pathogens. J Herbal Med 7:27–30. https://doi.org/10.1016/j.hermed.2016.08.003
53. Ullah F, Ayaz M, Sadiq A et al (2020) Potential role of plant extracts and phytochemicals
against foodborne pathogens. Appl Sci (Switzerland) 10:10
Therapeutic Properties of Nardostachys
jatamansi and Its Applications
in Post-­Chemotherapy-­Induced Hair Loss
in Cancer Patients

Packirisamy Azhagu Saravana Babu, Basheer Vajiha Aafrin,

Sagorika Goyali, M. Geethika, Vallinayagam Sugumari,
and Muthusamy Sukumar

1 Introduction

Hair loss due to chemotherapeutic agents is one of the most common ectodermal
conflicting effects and is rated as one of the most troubling side effects of cancer
therapy. As per the clinical trials done by Howard (Jack) West, MD; Abdul Rafeh
Naqash, MD, we can infer that not all cancer treatments cause hair loss, and among
which it may be total or partial hair loss and may include some areas that can cover
all over the body. Chemotherapy usually acts by interloping with the more rapidly
proliferating cells of the body, including cancer cells and hair follicles. As we are
aware of the fact that chemotherapy is a common cause of hair loss, some chemo-
therapy agents rigorously cause hair loss that are usually complete ones, while other
chemotherapy agents cause hair loss far more rarely [1]. Damage to hair follicles
following susceptibility to toxic chemotherapeutics can cause notable hair loss,
commonly known as chemotherapy-induced alopecia (CIA) [2].
Chemotherapy drugs are powerful medications that attack rapidly growing can-
cer cells. Unfortunately, these drugs also attack other rapidly growing cells in the
human body, including those in your hair roots. Chemotherapy may cause hair loss
all over the human body, not just on the scalp. Sometimes eyelash, eyebrow, armpit,
pubic, and other body hair also falls out. Some chemotherapy drugs are more likely
than others to cause hair loss, and different doses can cause anything from mere

P. Azhagu Saravana Babu (*) · S. Goyali · M. Geethika · V. Sugumari

Department of Biotechnology, Vel Tech Rangarajan & Dr Sagunthala R&D Institute of
Science and Technology, Avadi, Chennai, India
e-mail: [email protected]
B. Vajiha Aafrin · M. Sukumar
Centre For Food Technology, Department of Biotechnology, Anna University, Chennai, India

© The Author(s), under exclusive license to Springer Nature 611

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_24
612 P. Azhagu Saravana Babu et al.

thinning to complete baldness. Chemotherapy-induced alopecia (CIA) is probably

one of the most shocking and psychologically disturbing side effects for oncologi-
cal patients. Hair loss occurs because chemotherapy targets all rapidly dividing
cells, healthy cells, and cancer cells. Hair follicles, the structures in the skin filled
with tiny blood vessels that make hair, are some of the fastest-growing cells in the
body. Hair follicles divide every 23–72 hours. The chemo not obly works against
cancer cells but it also destroys hair cells. To the best of our knowledge, no guide-
lines are available about CIA management. In spite of that, the likelihood of devel-
oping CIA and the rigorousness of the hair loss is often dependent on the drug type
and the type of treatment [3].

1.1 Botanical Profile of Nardostachys jatamansi

Nardostachys jatamansi is a rhizomatous herb that belongs to a member of the plant

family Valerianaceae, which grows in grassy, steep, moist, rocky slopes of India,
Nepal, China, and Bhutan. N. jatamansi is an important medicinal plant mentioned
in Ayurveda and Unani systems used for the treatment of various disorders, includ-
ing the circulatory system, digestive system, respiratory system, nervous system,
urinary system, reproductive system, and skin diseases. In addition, the essential oil
extracted from the roots shows various pharmacological activities, including hypo-
tensive, antimicrobial, antifungal, anti-arrhythmic, and anticonvulsant activity [4].
Nardostachys jatamansi consists of chemical constituents, such as calarenol,
alpha-patchoulene, angelicin, beta-eudesmol, beta-patchoulene, beta-sitosterol,
calarene, elemol, jatamansinol, jatamansone, n-hexacosanol, jatamansin,
n-­hexacosane, n-hexacosanyl arachidate, n-hexacosanyl isolverate, nardol, nardoste-
chone, norsechelanone, oroselol, patchouli alcohol, seychellene, valeranal, and val-
eranone, volatile essential oil, sugar, resins, starch, bitter extractive matter, gum,
ketone, spirojatamol, sesquiterpene ketone, etc. [5].

2 Hair Follicle Anatomy

• The hair follicle (HF) is a complex, dynamically vital, and potent skin appendage
that creates a filamentous hair shaft through rapid keratinocyte proliferation and
terminal differentiation [6].
• Hair follicle is composed of a series of concentric keratinocyte layers and even-
tually functions to produce a central hair shaft. Mature hair follicles in the termi-
nal portion can be split up into
–– A permanent, non-cycling upper section
–– A lower section, which is continuously reassembled during the hair cycle [7].
Therapeutic Properties of Nardostachys jatamansi and Its Applications… 613

• Throughout the life of a human being, the hair follicle undergoes continuous
cycles of enfolding and rebuilding. The hair growth cycle can be classified into
three phases:
1. Growth phase (anagen––lasts an average of 2–6 years)
2. Involution phase (catagen––lasts approximately 1–2 weeks)
3. Rest phase (telogen––lasts for around 5–6 weeks) [8].
• After chemotherapy treatment, the normal hair growth cycle is interrupted, lead-
ing to one of the two distinct pathways, dystrophic anagen or dystrophic catagen.
The dystrophic catagen pathway results in substantial hair loss [9].
• Recovery from hair loss is substantially faster if dystrophic catagen pathway is
induced in the process, with a normal anagen phase that must be initiated after
cessation of chemotherapy.
• Trichoscopy has been demonstrated to be a useful tool for the diagnosis of alo-
pecia through non-invasive analysis of hair shaft formation.

2.1 Molecular Pathways and Structural Hair Alterations

Associated With CIA

In human skin, hair loss (alopecia) starts approximately 2–4 weeks after the initial
course of chemotherapy, and hair begins to regrow 3–6 months after the end of treat-
ment. The degree of hair loss varies, depends on the specific drug (or drug combina-
tions) used and drug dosages and regimen (such as the number of cycles undertaken).
Drugs with a high potential for inducing alopecia include cisplatin, doxorubicin,
cyclophosphamide, cytosine arabinoside, and etoposide. The metabolic and mitotic
processes in rapidly growing hair follicles are damaged due to anti-cancer drugs
leading to the thinning of hair shaft, which becomes fragile. The disruption of hair
growth and eventual hair loss involves conserved intrafollicular events. This includes
the activation of damage response pathways leading to reduced proliferation and
unusual levels of apoptosis in the hair matrix [10].

3 Trichoscopy

Trichoscopy has demonstrated to be a useful tool for the diagnosis of alopecia

through non-invasive analysis of hair shaft formation. Trichoscopy features of
chemotherapy-­induced alopecia. The scalp of the patient who is undergoing the
treatment of chemotherapy shows the following:
• Pohl-Pinkus constrictions (represented by yellow lines), exclamation mark hairs
(represented by red circle), and black dots (represented by green circles)
• Hair with a wave pattern of thickening and thinning within a single hair shaft
614 P. Azhagu Saravana Babu et al.

• Flame hairs
• Circle hairs along with a black and white hair
• The hair shaft is depigmented, excluding the base; in the base, the damaged fol-
licular melanocytes recover, resulting in re-pigmentation of the hair follicle
[11, 12].
Pohl-Pinkus constrictions of the hair shaft led to the wave-like pattern of the hair
shaft due to the cyclic nature of chemotherapeutic drugs. When chemotherapy drug
is delivered into the patient’s body, the drug blends with the blood and travels to all
the fast-growing regions (cells). Therefore, the hair matrix cells are damaged by the
cessation of propagation of hair and causing thinning of the hair shaft. On termina-
tion of the chemotherapy treatment, the hair shaft production recommences before
being prevented once more during the next round of chemotherapy. This produces a
hair shaft that has a series of constrictions [13].
• A more analytical response to injury results in exclamation marks, in which frac-
turing of hair appears as a regular sign of chemotherapeutic damage. These frac-
tures develop due to the thinning of the hair shaft, which is a direct result of
declining hair matrix proliferation, which is followed by premature telogen
entry [14].
• Kowalska-Olędzka et al. have reviewed that the black dots represent the most
severe cessation of proliferation with total breakage of the hair shaft [15].
• Circle hairs were often present following prolonged chemotherapy, as per the
observations made after the studies [16].
• Miteva M and Tosti A have reviewed in their study that flame hairs, on the other
hand, result from melanocyte damage rather than a loss of keratinocyte prolifera-
tion. They are caused by ectopic melanin accumulation around the damaged hair
shaft [17].
When the chemotherapy treatment was terminated, the number of hair follicles
in the anagen phase of the hair growth cycle increased extensively; however, these
were repeatedly depigmented due to chemotherapy-induced melanocyte loss. After
one year of the termination of CIA, normal hair shaft production usually resumes,
and it was detected that some hairs are pigmented at the base and white at the tips,
which indicated melanocyte accumulation in the hair bulb [15, 16].

3.1 Apoptotic Pathways

The off-target effects of chemotherapy are often caused by stimulation of apoptosis

in normal, highly proliferative cells. Hair loss with excessive apoptosis in hair
matrix keratinocytes is responsible for chemotherapy-associated hair loss.
p53 is a transcription factor and tumor suppressor protein that plays a critical role
in mediating apoptotic cell death induced by chemotherapeutic agents, and deletion
of P53 prevents chemotherapy-induced hair loss and also reduces the protein expres-
sion of direct P53 transcriptional targets, namely, Fas and IGFBP3, both of which
Therapeutic Properties of Nardostachys jatamansi and Its Applications… 615

stimulate apoptosis [10]. In addition, doxorubicin-induced toxicity in human HFs

suggests that other members of the tumor necrosis factor (TNF) family of death
receptors, namely, TNF-related apoptosis-inducing ligand (TRAIL) receptors, also
have prominent roles in associated apoptosis in the HF [18].
A distinct pathway enhances the molecular controls of HF apoptosis in response
to chemotherapy, namely, sonic hedgehog (Shh) signaling. The Shh pathway is a
vital element in HF morphogenesis. Disruption of Shh signaling was found to be a
critical event in the pathogenesis of chemotherapy damage, with cyclophosphamide
treatment decreasing Shh levels and pharmacologic inhibition of Shh. The deactiva-
tion of Shh signaling may result from chemotherapy-induced metabolic stress,
which could be governed via mammalian target of rapamycin (mTOR) or AMP-­
activated protein kinase (AMPK) signaling or reactive oxygen species (ROS) induc-
tion/extracellular signal-regulated kinase (ERK)/p38/c-Jun N-terminal kinase
(JNK) activation. The loss of Shh activity, alongside activation of P53-dependent
apoptosis, may provide an indication of the likely severity of CIA [19].

3.2 Proliferation of Keratinocytes

In addition to apoptosis, loss of matrix keratinocyte proliferation is a hallmark of

chemotherapy-induced in HF. The proliferation rate of matrix keratinocytes in
healthy anagen hair follicles is extremely high and easily beats that of most malig-
nant tumors and also makes the HF highly sensitive to chemotherapy. Loss of Ki67,
an M-phase cell-cycle marker, is a prominent feature of exposure to chemothera-
peutic agents. The specialized melanocytes of the hair follicle pigmentary unit gen-
erate huge amounts of melanin (packaged into melanosomes) during anagen but
need to transfer them into terminally differentiating hair follicle keratinocyte popu-
lations that form the hair shaft. These tissue systems, therefore, are most sensitive to
toxins and drugs in the mammalian body and can easily undergo rapid apoptosis
during chemotherapy. Telogen hair follicles are less sensitive than anagen hair fol-
licles to chemotherapy.
Chemotherapeutic agents damage the hair follicle vasculature and the sebaceous
gland, which affects hair follicle health and function [20].

3.3 Hair Growth Studies on the Rhizomes of Nardostachys

jatamansi DC

The effect of jatamansi is used for protection from hair loss. Ethanol extract of
jatamansi was investigated for hair growth in albino rats. The hair growth activity
that worked on CIA model was studied by various parameters like hair density,
lymphocyte count, and testosterone level, along with histopathological studies. Hair
growth initiation time was reduced to half on treatment with the extract. The time
required for hair growth was also reduced considerably.
616 P. Azhagu Saravana Babu et al.

4 Methods of Prevention of CIA in Cancer Patients

• Hindrance of cyclin-dependent kinase 2 (CDK2) reduces hair loss at the site of

local application. Cyclin-dependent kinase 2 (CDK2) is a positive regulator of
eukaryotic cell-cycle development, whose inhibition may constitute a therapeu-
tic strategy for countering chemotherapy-induced alopecia (CIA) by arresting
the cell cycle and also by reducing the sensitivity of the epithelium to many of
the cell-cycle active anti-tumor agents. By using structure-based methods, many
potent small-molecule inhibitors of CDK2 were developed. Hughes BT et al.
have observed that topical application of these compounds reduced hair loss at
the site of application. Thus, the hindrance of the CDK2 molecule represents a
potentially useful appeal for the prevention of CIA in cancer patients [21].
• Trueb RM. et al. have studied that calcitriol (1,25-dihydroxyvitamin D3) has
many effects on keratinocytes: it arrests the cell-cycle progression by DNA syn-
thesis inhibition and induces cell differentiation [22]. In addition, calcitriol has
been manifested to prevent CIA caused by cyclophosphamide, etoposide, and
doxorubicin-cyclophosphamide combination therapy in the neonatal rats [23].
However, in humans, no obvious protective effects have been described [24, 25].
• Parathyroid hormone collagen binding domain (PTH-CBD) of Clostridium his-
tolyticum collagenase, which is an agonist fusion protein, results in rapid growth
and re-pigmentation of hair post-chemotherapy-induced hair loss [26]. Cline
BW has observed in his literature review that the parathyroid hormone (PTH)
agonists and antagonists improve hair growth after chemotherapy; however, their
rapid clearance and systemic side effects make their usage complicated [27]. To
promote the delivery and maintenance of the PTH to skin, the PTH agonists and
antagonists are integrated to the collagen binding domain (CBD) of Clostridium
histolyticum collagenase. In vitro studies have conveyed that the agonist fusion
protein, PTH-CBD, binds collagen and stimulates the PTH/parathyroid hormone-­
related peptide receptor present in the SaOS-2 cells [10]. The agonist PTH-CBD
had dominant effects in lowering the damage of hair follicles due to chemother-
apy and may show the effect as a therapy for chemotherapy-induced alopecia.
• Hussein AM and Jimenez JJ have observed in their study that ImuVert/
N-­acetylcysteine is known as a biological response modifier [28]. It is produced
by Serratia marcescens, topical calcitriol, and subcutaneous/intradermal injec-
tion of geldanamycin or 17-demethoxygeldanamycin. Recently, ImuVert has
been shown to protect from cytarabine-induced alopecia but not from alopecia
induced by cyclophosphamide. Cyclophosphamide-induced alopecia can be ade-
quately prevented by N-acetylcysteine, when it is administered parenterally or
applied topically in liposomes [29, 30]. Alopecia that is caused by the combina-
tion of cyclophosphamide and cytarabine could be countered by the parenteral or
topical administration of ImuVert plus N-acetylcysteine. The potential relevance
of these observations to the clinical settings remains to be determined.
• Imanishi H et al. have deliberated that Laminin-332 and its receptor α6β4 integ-
rin are elevated both quantitatively and spatially after mid- to late dystrophic
Therapeutic Properties of Nardostachys jatamansi and Its Applications… 617

catagen in the lower third portion of hair follicles in chemotherapy-induced alo-

pecia [31]. In contrast, laminin-511 is suppressed after mid-dystrophic catagen at
the protein level. In some experimental models, it has been observed that injec-
tion of a laminin-511-rich protein extract retarded hair loss in cyclophosphamide-­
induced alopecia.
• YH0618 is a medicinal and edible compound that flourished based on the ancient
prescription of the “homology of medicine and food,” theory, and long clinical
practice. Previous studies on animals have shown that YH0618 decoction did not
hamper the anti-tumor effects of chemotherapy drugs [32]. You JS et al. have
studied that a spontaneous clinical trial also showed that YH0618 significantly
hastened hair regrowth and reduced thumbnail pigmentation in cancer patients
who have accomplished the treatment [33].
YH0618 is composed of five medicinal and edible foods (black soybean, lico-
rice, etc.) which are largely prescribed for cancer patients by clinicians. According
to You JS et al., each of the components of YH0618 acquires a distinct pharmaco-
logical profile, including removing free radicals in the body, regulating the immune
system, preventing cancer, detoxifying, and enhancing the sense of taste [34–36].
The kidney is an essential detoxification organ of the human body. It helps filter
out toxins from the blood and also the other waste particles through urine.
Chemotherapy drugs might not cause renal organic lesions, but they “consume”
kidney essence, breaking the body’s balance [37–39]. Rodriguez R et al. have
observed from their study that the chemotherapy agents not only directly generate
toxic effects on the cells of the hair follicle, but it also drains blood and other body
fluids, especially the kidney cells, and breaks the balance of the human body, which
leads to the hindrance of microcirculation and turns down the immune function, that
will further result in the nutritional disorders of hair follicles [40, 41]. Therefore, the
study will also interpret the mechanism of YH0618 granule to reduce hair loss from
the outlook of kidney deficiency or a renal disorder. Gajewski W et al. have con-
cluded that the assumption of the study is that YH0618 granules could retard che-
motherapy-induced hair loss by refining kidney deficiency and renal disorder
[41, 42].
• Peck HJ, Mitchell H, and Stewart AL. have made few studies, among which their
12 studies included patients treated with doxorubicin-containing or epirubicin-­
containing chemotherapy, and two studies included patients treated with cyclo-
phosphamide or docetaxel-containing chemotherapy not including doxorubicin
or epirubicin. Some of their studies have been taken as a reference at the end of
this paper [42–44].
• Nardostachys jatamansi, which belongs to the family Valerianaceae, is a peren-
nial herb. The extract of this perennial herb also helps prevent CIA due to its vari-
ous pharmacological properties [45, 46]. Jadhav VM and Swee Keong Yeap have
reviewed in their study that jatamansi is a small shrub whose rhizomes may
speed up the growth of hair. It has been shown to increase hair growth in alopecia
caused by chemotherapy [47].
618 P. Azhagu Saravana Babu et al.

4.1 Trichoscopy

S. Inui et al. have concluded in their Clinical and Experimental Dermatology that
trichoscopy is the technique of dermoscopic imaging of the hair and scalp. This is a
novel diagnostic methodology that is both simple and non-invasive. This technique
can be used as a convenient bedside tool for diagnosing common hair and scalp
disorders. Trichoscopy shows small nodules along the shaft. In this technique, the
hairs bend and break. Trichoscopy of pili torti (a rare hair condition characterized
by fragile hair) shows twists of flattened hair shafts along their long axis. In pili
annulati (a genetic trait resembling “ringed hair”) hair shafts with alternating seg-
ments of light and dark color bands are visible [48].
There are different types of hair shaft abnormalities that are observed. It includes
the following:
• Exclamation mark hairs (alopecia areata, trichotillomania, chemotherapy-­
induced alopecia) studied by L. Peralta and P. Morais in their study [49].
• Pohl-Pinkus constrictions (alopecia areata, chemotherapy-induced alopecia,
blood loss, malnutrition)
• Comma hairs (tinea capitis)
• Corkscrew hairs (tinea capitis)
• Coiled hairs (trichotillomania)
• Flame hairs (trichotillomania)
• Tulip hairs (trichotillomania, alopecia areata)
Trichoscopy allows differential diagnosis of most genetic hair shaft disor-
ders [50].

4.2 Aid of Trichoscopy

By using the technique of trichoscopy, we can assess the damage to hair follicles,
and it would help us understand different chemotherapeutics, dosages, and treat-
ments’ impacts on hair damage. It also provides valuable information on the effi-
cacy of current or new treatments in preventing this.

4.3 Scalp Cooling Caps

It is a cap filled with some frozen material, which may be an ice pack or cold pack
that is to be secured to the head during chemotherapy treatment. When the cap
increases temperature due to scalp heat, it is replaced with another cooling cap to
maintain the cold scalp temperature until treatment is finished [50]. The primary
assumption of the working of those caps is that cooling of the scalp results in
Therapeutic Properties of Nardostachys jatamansi and Its Applications… 619

vasoconstriction, i.e., reducing the flow of blood in the scalp microvasculature, and
therefore reduces drug delivery to prevent the damage of the sensitive hair follicles.
Furthermore, Grevelman EG has studied that the reduction in temperature reduces
active drug uptake into the hair matrix keratinocytes [3, 51].

4.4 Effect of Scalp Cooling Caps

The primary supposition is that cooling of the scalp results in vasoconstriction (nar-
rowing blood vessels), which reduces the blood flow in the tiny blood vessels of the
scalp and thereby reduces drug delivery and damages the sensitive hair follicles [3,
9]. Furthermore, Hussain O et al. have used in vitro human keratinocyte models to
study the effect of cooling on chemotherapy drug-induced cytotoxicity and have
derived that when the temperature of the scalp reduces, the active drug uptake
reduces into the hair matrix keratinocyte [3, 52].
Schneider MR et al. have examined the drug concentrations within the hair
shafts, or the plucked hair follicles would likely provide an important biomarker to
ascertain whether cooling or other potential therapies could prevent the accumula-
tion of toxic drug concentrations [6]. McGarvey EL et al. have studied that measur-
ing the concentration of the drug and correlating it with the levels of hair loss, as
well as the signs of damage stipulated by trichoscopy, give even greater perception
into the protective perspective of these treatments which is enabling enhancement
of treatments for the greatest efficacy on the prevention of CIA [53].

5 Discussion

The reported mechanisms of chemotherapy-induced hair loss mainly involve deoxy-

ribonucleic acid (DNA) damage, hair follicle cell-cycle inhibition, hair follicle cell
apoptosis, reactive oxygen species, and signal transduction, etc. As a result, animal
model studies have found that vasoconstrictors, antioxidants, hair growth cycle
regulators, and parathyroid hormones can boost hair loss caused by chemotherapy
[3, 54]. The seriousness of the hair loss is often drug or regimen dependent. Anagen
effluvium is a very common form of hair loss amalgamated with cancer therapy. It
is usually noticed within 1–2 weeks of the beginning of the therapy and becomes
clearer and more distinct in the next 4–8 weeks of therapy. In clinical practice, it has
been outlined that minoxidil, AS101, and vitamin D3 can treat chemotherapy-­
induced hair loss, but the effect is not remarkable [55]. Chemotherapy-induced hair
loss can also induce anxiety, depression, a negative body image, lowered self-­
esteem, and a reduced sense of well-being.
The most common combination resulting in hair loss was the combination of
cyclophosphamide and doxorubicin, among the various drugs used to treat
CIA. Chemotherapy-induced hair loss is proposed to be a result of the termination
620 P. Azhagu Saravana Babu et al.

of mitotic activity in the hair matrix resulting in a slender and crippled portion of the
hair shaft known as Pohl-Pinkus constriction, which is prone to fracture. All the
shafts break at the same time when the extremely slender portion reaches the sur-
face of the scalp. Chemotherapeutic drugs such as doxorubicin, daunorubicin,
docetaxel, and cyclophosphamide are commonly accompanied by hair loss. Other
drugs inculpated with hair loss are paclitaxel and carboplatin, cyclophosphamide,
doxorubicin and vincristine, vincristine and daunorubicin, cisplatin, carboplatin,
and a combination of cisplatin and 5 FU [7].

6 Conclusion

Chemotherapy-induced alopecia in cancer patients appears to be a true potential

adverse effect of drugs with high potential that include cisplatin, doxorubicin,
cyclophosphamide, cytosine arabinoside, and etoposide, and it is important to dis-
tinguish it properly so that its mechanism can be realized and apt treatment and
counseling can take place. However, it may not impact clinical decision-making,
and patients should be alerted that hair loss with chemotherapy can be permanent.
Treatment with scalp cooling can reduce the risk of severe chemotherapy-induced
alopecia, but it is unclear if it reduces the risk of permanent CIA. Topical or oral
minoxidil may be helpful in the treatment of CIA once it has developed. Nardostachys
jatamansi, a rhizomatous herb, consists of active chemical constituents and is used
in the treatment of PCIA (permanent chemotherapy-induced alopecia). Therapeutic
characterization of these phytochemicals and polyphenols from this plant material
may elucidate to reduce the risk factors for permanent alopecia in a natural way.
This study may provide the evidence that this plant extract has the property of hair
growth-stimulating activity and it can be used as phytotherapeutic agent for chemo-
therapy induced hair loss.

References

1. JAMA Oncol (2017) 3(8):1147. https://doi.org/10.1001/jamaoncol.2017.1026

2. JAMA Oncol (2021) 7(7):1080. https://doi.org/10.1001/jamaoncol.2021.0896
3. Dunnill CJ, Al-Tameemi W, Collett A, Haslam IS, Georgopoulos NT (2018) A clinical and bio-
logical guide for understanding chemotherapy-induced alopecia and its prevention. Oncologist
23:84–96
4. Sahu R, Dhongade HJ, Pandey A, Sahu P, Sahu V, Patel D, Kashyap P (2016) Medicinal
Properties of Nardostachys jatamansi (A Review). Orient J Chem 32:32(2)
5. Chatterjee B, Basak U, Datta J, Banerji A, Neuman TP (2005) Studies on the Chemical
Constituents of N. jatamansi DC [Valerianaceae]. Cheminform 36:17
6. Schneider MR, Schmidt-Ullrich R, Paus R (2009) The hair follicle is a dynamic miniorgan.
Curr Biol 19:R132–R142
7. Hendrix S, Handjiski B, Peters EM, Paus RJ (2005) Invest Dermatol 125(1):42–51
Therapeutic Properties of Nardostachys jatamansi and Its Applications… 621

8. Hendrix S, Handjiski B, Peters EM, Paus R (2005) A guide to assessing damage response path-
ways of the hair follicle: lessons from cyclophosphamide-induced alopecia in mice. J Invest
Dermatol 125:42–51
9. Paus R, Haslam IS, Sharov AA, Botchkarev VA (2013) Pathobiology of chemotherapy-induced
hair loss. Lancet Oncol 14:e50–e59
10. Botchkarev VA (2003) Molecular mechanisms of chemotherapy-induced hair loss. J Investing
Dermatol Symp Proc 8(1):72–75. https://doi.org/10.1046/j.1523-­1747.2003.12175.x
11. Mill P, Mo R, Fu H et al (2003) Sonic hedgehog-dependent activation of Gli2 is essential for
embryonic hair follicle development. Genes Dev 17:282–294
12. Loomis CA, Joyner AL (2011) Nerve-derived sonic hedgehog defines a niche for hair follicle
stem cells capable of becoming epidermal stem cells. Cell Stem Cell. 8:552–565
13. Bleiker TO, Nicolaou N, Traulsen J, Hutchinson PE (2005) ‘Atrophic telogen effluvium’ from
cytotoxic drugs and a randomized controlled trial to investigate the possible protective effect
of pretreatment with a topical vitamin D analogue in humans. Br J Dermatol 153:103–112
14. Pirmez R, Pineiro-Maceira J, Sodre CT (2013) Exclamation marks and other trichoscopy signs
of chemotherapy-induced alopecia. Australas J Dermatol 54:129–132
15. Kowalska-Olędzka E, Slowinska M, Rakowska A et al (2012) ‘Black dots’ seen under trichos-
copy are not specific for alopecia areata. Clin Exp Dermatol 37:615–619
16. Rossi A, Caterina Fortuna M, Caro G et al (2018) Monitoring chemotherapy-induced alopecia
with trichoscopy [published online ahead of print July 11, 2018]. J Cosmet Dermatol 18:575.
https://doi.org/10.1111/jocd.12687
17. Miteva M, Tosti A (2015) Flame hair. Skin Appendage Disord 1:105–109
18. Cheng H, Hong B, Zhou L et al (2012) Mitomycin C potentiates TRAIL-induced apopto-
sis through p53-independent upregulation of death receptors: evidence for the role of c-Jun
N-terminal kinase activation. Cell Cycle 11:3312–3323
19. Haslam I, Xie G, Zhou G et al (2015) Shh signaling regulates the damage response of murine
and human hair follicles in chemotherapy-induced alopecia. J Invest Dermatol 135:S7
20. Adapted alf Paus, Haslam IS, Sharov AA, Botchkarev VA (2013) Pathobiology of
chemotherapy-­induced hair loss. The Lancet Oncology 14(2):e50–e59
21. Hughes BT, Sidorova J, Swanger J, Monnat RJ Jr, Clurman BE (2013) Proc Natl Acad Sci U S
A 110(22):8954–8959. https://doi.org/10.1073/pnas.1302927110. Epub 2013 May 13
22. Trueb RM (2009) Chemotherapy-induced alopecia. Semin Cutan Med Surg 28:11–14
23. Jimenez JJ, Yunis AA (1992) Protection from chemotherapy-induced alopecia by
1,25-­dihydroxyvitamin D3. Cancer Res 52:5123–5125
24. Hidalgo M, Rinaldi D, Medina G et al (1999) A phase I trial of topical topitriol (calcitriol,
1,25-dihydroxyvitamin D3) to prevent chemotherapy-induced alopecia. Anti-Cancer Drugs
10:393–395
25. Bleiker TO, Nicolaou N, Traulsen J et al (2005) ‘Atrophic telogen effluvium’ from cytotoxic
drugs and a randomized controlled trial to investigate the possible protective effect of pretreat-
ment with a topical vitamin D analogue in humans. Br J Dermatol 153:103–112
26. Lotfi-Jam K, Carey M, Jefford M, Schofield P, Charleson C, Aranda S (2008) Nonpharmacologic
strategies for managing common chemotherapy adverse effects: a systematic review. J Clin
Oncol 26:5618–5629
27. Cline BW (1984) Prevention of chemotherapy-induced alopecia: a review of the literature.
Cancer Nurs 7:221–228
28. Hussein AM, Jimenez JJ, McCall CA, Yunis AA (1990) Science. 249(4976):1564–1546.
https://doi.org/10.1126/science.2218498. PMID: 2218498
29. Hussein AM (1995) Int J Dermatol. 34(7):470–3. https://doi.org/10.1111/j.1365-­4362.1995.
tb00612.x. PMID: 7591409
30. Hussein AM (1993) South Med J. 86(5):489–96. https://doi.org/10.1097/
00007611-­199305000-­00001.PMID: 8488392
31. Imanishi H, Tsuruta D, Tateishi C, Sugawara K, Paus R, Tsuji T et al (2010) Laminin-511,
inducer of hair growth, is down-regulated and its suppressor in hair growth, laminin-332 up-­
regulated in chemotherapy-induced alopecia. J Dermatol Sci 58:43–54
622 P. Azhagu Saravana Babu et al.

32. You J, Gao F, Tang H, Peng F, Jia L, Huang K, Chow K, Zhao J, Liu H, Lin Y, Chen J (2019)
A medicinal and edible formula YH0618 ameliorates the toxicity induced by doxorubicin via
regulating the expression of Bax/Bcl-2 and FOXO4. J Cancer 10(16):3665–3677
33. You JS et al (2016) Effect of YH0618 soup on chemotherapy-induced toxicity in patients with
cancer who have completed chemotherapy: study protocol for a randomized controlled trial.
Trials 17(1):354
34. Chan YC et al (2009) Nanonized black soybean enhances immune response in senescence-­
accelerated mice. Int J Nanomedicine 4:27–35
35. Yim JH et al (2009) Antinociceptive and anti-inflammatory effects of ethanolic extracts of
Glycine max (L.) Merr and Rhynchosia nulubilis seeds. Int J Mol Sci 10(11):4742–4753
36. Kusano S, Abe H, Tamura H (2001) Isolation of antidiabetic components from white-skinned
sweet potato (Ipomoea batatas L.). Biosci Biotechnol Biochem 65(1):109–114
37. Macduff C, Mackenzie T, Hutcheon A et al (2003) The effectiveness of scalp cooling in pre-
venting alopecia for patients receiving epirubicin and docetaxel. Eur J Cancer Care 12:154–161
38. Mols F, Van Den Hurk CJ, Vingerhoets AJJM et al (2009) Scalp cooling to prevent
chemotherapy-­induced hair loss: practical and clinical considerations. Support Care Cancer
17:181–189
39. Kennedy M, Packard R, Grant M et al (1983) The effects of using chemocap on occurrence of
chemotherapy-induced alopecia. Oncol Nurs Forum 10:19–24
40. Lovejoy NC (1979) Preventing hair loss during adriamycin therapy. Cancer Nurs 2:117–121
41. Rodriguez R, Machiavelli M, Leone B et al (1994) Minoxidil (mx) as a prophylaxis of
doxorubicin-­induced alopecia. Ann Oncol 5:769–770
42. Granai CO, Frederickson H, Gajewski W et al (1991) The use of minoxidil to attempt to
prevent alopecia during chemotherapy for gynecologic malignancies. Eur J Gynaecol Oncol
12:129–132
43. Villani C, Inghirami P, Pietrangeli D (1986) Prevention by hypothermic cap of antiblastic
induced-alopecia. Eur J Gynaecol Oncol 7:15–17
44. Edelstyn GA, MacDonald M, MacRae KD (1977) Doxorubicin-induced hair loss and possible
modification by scalp cooling. Lancet 2:253–254
45. Peck HJ, Mitchell H, Stewart AL (2000) Evaluating the efficacy of scalp cooling using the
penguin cold cap system to reduce alopecia in patients undergoing chemotherapy for breast
cancer. Eur J Oncol Nurs 4:246–248
46. Jadhav VM, Throat RM, Kadam VJ, Kamble SS (2009) Herbal Anxiolyte, Nardostachs jata-
mansi. J Pharm Res 2(8):1208–1211
47. Yeap SK, Rahman MBA, Alitheen NB, Ho WY et al (2011) Evaluation of immunomodulatory
effect, selection of the correct targets for Immunostimulation study. Am J Immunol 7(2):17–23
48. Inui S, Nakajima T, Itami S (2010) Coudability hairs: a revisited sign of alopecia areata
assessed by trichoscopy. Clin Exp Dermatol 35(4):361–365
49. Peralta L, Morais P (2012) Photoletter to the editor: the friar tuck sign in trichotillomania. J
Dermatol Case Rep 6(2):63–64
50. Wu MY, Li J. (2021) CMAJ. 193(4):E126. https://doi.org/10.1503/cmaj.200894
51. Grevelman EG, Breed WP (2005) Prevention of chemotherapy-induced hair loss by scalp cool-
ing. Ann Oncol 16:352–358
52. Al-Tameemi W, Dunnill C, Hussain O et al (2014) Use of in vitro human keratinocyte models
to study the effect of cooling on chemotherapy drug-induced cytotoxicity. Toxicol In Vitro
28:1366–1376
53. McGarvey EL, Baum LD, Pinkerton RC, Rogers LM (2001) Psychological sequelae and alo-
pecia among women with cancer. Cancer Pract 9:283–289
54. Botchkarev V, Sharov AA, Syska W, Maurer M, Gilchrest BA (2002) Involvement of p53 and
Fas in hair follicle apoptosis in human skin/SCID model for chemotherapy-induced hair loss.
J Invest Dermatol 119:286
55. Food and H.H.S. Drug Administration (2016) Medical devices; general and plastic surgery
devices; classification of the scalp cooling system to reduce the likelihood of chemotherapy-­
induced alopecia. Final order. Fed Regist 81(29):7452–7454
Phitotherapeutic Potential of Cassava
(Manihot esculenta, Crantz)

Marney Pascoli Cereda

1 Introduction

Cassava as Food
Cassava is the best known roots crop used as food. Results of the evaluation of cul-
tivars selected among the most used in commercial crops in the southeastern region
of Brazil point to a variation in productivity from 25.0 to 36.0 t ha−1, with humidity
around 65% [1]. The percentage of dry mass reflects the starch content, which
approaches 40% (Table 1); this explains more than 1500 kcal kg−1 of raw roots. The
same table highlights the reduced content of other components, such as protein and
lipids, but highlights the presence of dietary fiber, which is close to the recom-
mended amount of 2 g day−1, in whatever form it is consumed, cooked or fried.
Even so, it is necessary to acknowledge that it is a caloric food.
Cassava leaves are not widely known as food, although in Brazil they are con-
sumed in the north and some northeastern regions as a typical dish known as
maniçoba. But fresh leaves can be collected separately from the roots, with mois-
ture around 77% [1], and consumed as a vegetable. Values ​​obtained in Paraná, a
Brazilian state in the southeastern region, allowed us to estimate the production of
leaves at 3400 kg ha−1 year−1, considering the average annual harvest after pruning,
carried out for 3 years for four varieties of commercial use [2]. In this case, the
leaves complement the harvest of the roots as a source of protein, but also of fiber,
cyanogenic, and phenolic compounds. Despite this potential, the international con-
sumption of cassava has been restricted due to the presence of cyanogenic com-
pounds, which are not included in the Brazilian Food Composition Table [3]. This
omission is explained by the lack of dissemination of national and international
research results, which scares consumers who are not familiar with their

M. P. Cereda (*)
University of São Paulo State (UNESP), Botucatu, São Paulo, Brazil

© The Author(s), under exclusive license to Springer Nature 623

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_25
624 M. P. Cereda

Table 1 Cassava root composition in raw, cooked and fried, according to the (Brazilian Food
Composition Table [3]) and literature data
Cassava Leaves
Food products Unity Crude Cooked Fried Fresh Dehydrated (**)
Energia (kcal 100 grams−1) 151 125 300 -*- 469.3
Moisture (g 100 grams−1) 61.8 68.7 38.8 (**) (**)
Ash (g 100 grams−1) 0.6 0.4 0.6 0.70 7.37
Fat (g 100 grams−1) 0.3 0.3 11.2 0.70 7.36
Protein (g 100 grams−1) 1.1 0.6 1.4 3.48 22.36
Carbohydrate (g 100 grams−1) 38.2 30.1 50.3 3.90 10.84
Dietary fiber (g 100 grams−1) 1.9 1.8 1.9 1.21 (*) 52.07 (*)
Note: part of the nitrogen present, used to establish the protein content, may come from the CN-
radical (FAO/WHO [13])
-*- data not available, (*) as total fiber, (**) data from Fasuyi [71], adjusted for dry basis

consumption and makes exporting cassava difficult. It is common for cassava flour
to be exported as “animal feed” for consumption by expatriate Brazilians.
To justify the potential of cyanogenic compounds, the review by Cressey and
Reeve [4] and others, for example, for human and animal poisoning by Gensa [5],
for phenolic compounds, a review of functional fibers [6], and as a phitotherapic by
Fuentes-Zaragoza et al. [7], was used as a basis for this chapter. Especially with
respect to the toxic effects of cyanide, justifications will be presented as to why the
risk of its consumption is of little concern if the consumer is well nourished.

1.1 Cyanogenic Compounds in Cultivated Plants

It has long been known that some cultivated plants have toxic principles, but only
around the year 1700 was cyanide recognized for its pharmacological properties,
even though it is a toxic substance widely present in food crops. In 1817, Magendie
suggested that Hydrogen cyanide (HCN), in appropriate doses, could be used to
control cough and lung diseases. This assumption was also accepted by Granville,
an English physician, who included HCN-rich wild cherry water in the British
Pharmacopoeia, where it remained until 1948 [8].
Seigler [9] pointed out that cyanogenic glycosides occur in more than 2650 plant
species, from 550 genera and 130 families. These plants are responsible for the
production of more than 60 cyanogenic glycosides, some of which are present in
edible plants. Among the plant species that produce cyanogenic glycosides, many
also produce a hydrolytic enzyme from the β-glycosidase group. The enzyme and
cyanogenic glycosides remain in separate compartments of the plant [10] and only
come into contact when this cellular structure is disrupted, with subsequent release
of HCN, in addition to an aldehyde or a ketone [11, 12]. The release of HCN from
cyanogenic glycosides can also result from enzymatic hydrolysis by intestinal
microflora [13, 14]. Among the plants that present glycosides, cassava stands out for
Phitotherapeutic Potential of Cassava (Manihot esculenta, Crantz) 625

its status as a staple food in tropical regions. Nambisan [15] reports on its consump-
tion in connection with food security and its economic importance, since it is tradi-
tionally used as a reserve in case of natural disasters, such as cyclones and droughts.
Cassava produces reasonable yields in low-fertility soil with a flexible harvesting
period, which makes it a crop of great importance in many countries, but always
with a focus on subsistence food. According to Onyenwoke and Simonyan [16] the
postharvest activities with cassava include grating or grinding, followed by drying,
operations that are not complicated and do not require large investments, so they can
be carried out in rural areas, on farms or in farming villages. In addition to its con-
sumption as a subsistence food, cassava roots have increasingly been traded interna-
tionally, in part because of the migration of consumers from countries where it is a
staple of the diet to other parts of the world where there is no tradition of consump-
tion. Knudsen et al. [17] point out that in cooking, cassava is consumed in various
ways, such as flour, chips, grated root mass (baked, steamed, or fried), whole
steamed roots, and tapioca pearls.

1.2 Information About Cyanogenic Compounds

Considerable confusion exists concerning the forms used in the literature, standards
and legislation that deal with cassava cyanogenic glycosides and their metabolites,
because, unlike other toxic substances, nontoxic organic molecules bind to a radical
toxin to all forms of life. For more in-depth knowledge, the reader is encouraged to
read the reviews of Cressey and Reeve [4] on the metabolism of cyanogenic glyco-
sides and Rosling [18] on cassava toxicity and food security. These texts will deepen
the reader’s knowledge about the presence of cyanogenic compounds in cassava.
The term “HCN” is recommended by the International Union of Pure and
Applied Chemists (IUPAC) [19] to indicate hydrogen cyanide, but it is not necessar-
ily appropriate when the cyanide radical comes from a cyanogenic glycoside. These
forms of expression and spelling cause considerable confusion, so this chapter will
follow the recommendations of Bokanga et al. [20], who prefer and justify express-
ing the cyanogenic potential of a food (CN−p), which is spelled differently, in the
form “total hydrocyanic acid” or “bound” or “free and combined” hydrocyanic acid.
The free cyanide radical may be denoted by CN−. Because it is clear and precise,
this concept and spelling have been adopted in this chapter.
According to Conn [10], cyanide is a common substance in the environment and
can affect both humans and animals [5]. According to Rosling [18], once released,
the CN− radical can be solubilized in water to form HCN, establish secondary cya-
nide compounds, or simply volatilize.
Vegetables are an important source of cyanide, present in the form of cyanogenic
glycosides. Table 2 highlights the most common cyanogenic glycoside-containing
food crops and their botanical sources. Amygdalin and prunasin are the best-known
cyanogenic glycosides and are present in the seeds of apricots, apples, and other
plants. Linamarin and lotaustralin, in addition to other sources, are both present in
626 M. P. Cereda

Table 2 Food crops and the cyanogenic glycosides identified in them

Food crops Botanical name Glycoside founded
Wheat Triticum aestivum Dhurrin
T. spelta Linamarin
T. monococcum Lotaustralin
Epilotaustralin
Barley Hordeum vulgare Epieterodendrin
Oat Avena sativa Linamarin
Sorghum Soghum bicolor Dhurrin
Cassava Manihot esculenta Linamarin
e Lotaustralin
Bean sprouts Phaseolus luantus Linamarin
e Lotaustralin
Beans P. vulgaris Linamarin
e Lotaustralin
Millet Eleusina caracana Triglochin
Apple Malus pumila hybrids Amigdalin e Prunasin
Taro Colocasia esculenta Triglochin
Source: Jones [100]

cassava (Manihot sp.). In all examples, the CN− radical is linked to glucose by a
ß-type bond that can only be broken by the action of a β-glucosidase enzyme, releas-
ing cyanide.
Ingestion can release cyanide in the intestine, where the environment is alkaline,
favoring the action of linamarase [18], human β-glucosidase [21], or bacterial
enzymes, which results in the release and absorption of cyanide in the small
intestine.

1.2.1 Cassava Cyanogenic Compounds

Among the plants listed in Table 2, cassava stands out for being one of the few spe-
cies in which the cyanogenic glycoside is found in edible parts of the plant (roots
and leaves). The main toxic principle is linamarin [22], which coexists with its
methyl homologue, called methyl linamarin or lotaustralin (Fig. 1), both of which
occur in variable amounts in all parts of the plant, with a predominance of linama-
rin, over 90%.
The synthesis of linamarin and lotoaustralin occurs in the leaves and roots of
cassava throughout all its botanical cycle [23], but the leaves have the highest con-
tent of both glycosides and the enzyme linamarase [24]. In cassava, lotoautralin
occurs at low concentrations, which is why this chapter will only use linamarin as a
reference.
The literature reports that in cassava, potential HCN concentrations can vary
greatly with altitude, geographic location, and seasonal and production conditions
[25]. Cardoso et al. [26] considered cassava roots as sweet or bitter based on the
Phitotherapeutic Potential of Cassava (Manihot esculenta, Crantz) 627

Fig. 1 Structural formulas of Linamarin e Lotaustralin. (Source: Behera and Ray [101]. Published
in CRC Press)

HCN content, established at 50 mg of HCN kg−1 [27]. However, the literature

reports [28] that under drought conditions there is an increase in HCN content due
to water stress. Thus, a variety considered sweet under one set of conditions may be
bitter in a different geographic location or under other climatic conditions. Oluwole
et al. [25] cite values of​​ 15–400 mg HCN kg−1 fresh weight in cassava roots,
although Cardoso et al. [26] pointed to reports of even higher levels, depending on
the planting location and harvest season. All these variables make specific labora-
tory analyses necessary to recognize the presence and establish the content of cya-
nogenic compounds in cassava. They also relativize any classification in terms of
cyanide content.
The cyanogenesis of lotoautralin is similar to that of linamarin, and both only
occur under favorable conditions of temperature and pH, because the ß bond is heat
stable and requires more energy to break [5–30]. The conversion of linamarin into
acetone cyanohydrin occurs by the action of the enzyme linamarase in a tempera-
ture range between 40 and 45 °C and a pH range between 5.5 and 6.0. In turn, ace-
tone cyanohydrin decomposes spontaneously or aided by hydroxylase, rapidly
under neutral or alkaline pH conditions, at a temperature of 30 °C and pH 5.0.
Cagnon et al. [31] and Ramalho et al. [32] reported the releasing of acetone and
CN− at the same time [33], which is the only component of linamarin [32–36].
Acetone cyanohydrin, also known as 2-methyl lactonitrile or 2 –
Hydroxyisobutyronitrile, has a molecular mass of 85.11, a density of 0.925 at 25 °C,
and a melting point of −19 °C, and is an aqueous, colorless liquid with a mild odor
of almond. Miscible in water, it is widely used in the manufacture of the acrylic
material poly(methyl methacrylate) [34, 35] (Fig. 2).
It is noteworthy that ß-type binding gives the mechanism of CN-release particu-
larities, initially because it is a type of binding that requires more energy and, in
addition, microorganisms and plants with this class of binding are less frequent
in nature.
Therefore, before this ß-type bond is broken, the cyanogenic compounds present
in cassava roots are not toxic, and the degree of toxicity will depend on this break.
For this reason, Bokanga et al. [20] recommended and the Food and Agriculture
628 M. P. Cereda

Fig. 2 Summarizes the release of HCN from Linamarin. (Source: Adapted from Sayre et al. [102]
and Gomez and Stuefer [103])

Table 3 Distribution of total potential cyanide by cassava root parts selected for food use
Potencial Cyanide
Portion of the root Weight Moisture (CNp)
% % mg/kg %
Root Entire 100.00 57.0 32.18 100.0
Córtex Inner bark 14.0 76.0 156.16 81.0
Reserve parenchyma Pulp 85.0 58.0 6.12 19.0
Source: Cereda [1]

Organization (FAO)/World Health Organization (WHO) [36]) reinforced that the

dosage of linamarin should be presented as the potential cyanide content (CNp)
because if conditions are not favorable, or if the hydroxylase-lyase is not present in
sufficient quantity or is deactivated, linamarin (and lotaustralin) can pass through
the human body unharmed and without showing toxicity [37].
As a result of the nonuniform distribution of substrate and enzyme, the amount
of potential cyanide may vary in different parts of the plant, as shown in Table 3.
Table 3 highlights the features of cassava cultivars used for food, in which the
highest potential cyanide content is concentrated between bark or cortex, the por-
tion that is removed, because it is harder and more difficult to cook.

1.2.2 Mechanism of Intoxication and Lethal Dose of Linamarin

Cressey and Reeve [4] reviewed the literature on the metabolism of cyanogenic
glycosides, which is the key to the safe consumption of foods that may contain these
compounds. The authors point out that the potential for toxicity of cyanogenic gly-
cosides arises from enzymatic degradation, which produces hydrogen cyanide.
Information on the metabolism of cyanogenic glycosides is available from in vitro,
animal, and human studies. In the absence of β-glucosidase enzymes from the
source plant material, two processes appear to contribute to the production of
Phitotherapeutic Potential of Cassava (Manihot esculenta, Crantz) 629

cyanide from cyanogenic glycosides. The first one is the proportion of the glycoside
dose that reaches the large intestine, where most of the bacterial hydrolysis occurs,
and the rate of hydrolysis of cyanogenic glycosides to cyanohydrin and cyanide.
Some cyanogenic glycosides, such as prunasin, are actively absorbed in the jejunum
by utilizing the epithelial sodium-dependent monosaccharide transporter (SGLT1).
The rate of cyanide production from cyanogenic glycosides due to bacterial
β-glycosidase activity depends on the sugar moiety in the molecule and the stability
of the intermediate cyanohydrin following hydrolysis by bacterial β-glucosidase.
Cyanogenic glycosides with a gentiobiose sugar, amygdalin, linustatin, and neoli-
nustatin, undergo two-stage hydrolysis, with gentiobiose initially being hydrolyzed
to glucose to form prunasin, linamarin, and lotaustralin, respectively. While the
overall impact of these metabolic factors is difficult to predict, the toxicity of cya-
nogenic glycosides will be less than the toxicity suggested by their theoretical
hydrocyanic acid equivalents.
It is accepted that the potential toxicity of a food produced from a cyanogenic
plant also depends on reducing, during preparation, the concentration of HCN to
harmless levels for human exposure after consumption [38]. In order for this reduc-
tion in toxicity to occur and for the residual cyanide content to remain at a safe level,
the amount of active available ß-glucosidase must be adequate, in addition to having
temperature and pH conditions for the reaction to occur, neither of which is always
well established.
According to Logsdon et al. [39], three main factors determine the degree of
toxicity of HCN: amount to which the organism is exposed, exposure route, and
exposure time. Therefore, it is clear that it is the released CN− radical that causes
damage to health, whether due to acute intoxication or the risks of prolonged con-
sumption. To express full CN toxicity, several factors must be considered. Closed
environments are more prone to poisoning symptoms than open, ventilated environ-
ments, but once inhaled, the risks are severe.
However, the release of cyanide as a gas allows the formation of stable com-
plexes with metals with which CN− has a high affinity. Especially with iron, the
reaction forms potassium ferrocyanide (K4[Fe (CN)6]), where each iron molecule
can immobilize six CN− molecules and give rise to a blue complex (Prussian blue)
[40]. In water, CN− disperses spontaneously as HCN, but when the equipment used
to extract starch or process cassava roots is made of iron, it is common for the prod-
ucts to show blue spots.
The FAO/WHO [41] reports that cyanogenic glycosides can cause acute poison-
ing in humans, as well as several chronic diseases associated with the consumption
of underprocessed cassava.
In relation to human beings, the most serious problem of toxicity occurs in inha-
lation. In this case, the CN− radical can easily bind iron in the ferric state (Fe3+) of
mitochondrial cytochrome oxidase, in the enzyme that mediates the transfer of elec-
trons to molecular oxygen, the last step of oxidative phosphorylation. This affinity
allows free cyanide to combine with hemoglobin to form cyanohemoglobin, block-
ing electron transfer between cytochrome b and cytochrome c1. As a consequence,
ATP formation is inhibited [42, 43]. The mechanism of mitochondrial oxidation
630 M. P. Cereda

inhibition interrupts the electron transport chain of the inner mitochondrial mem-
brane [44] and, consequently, the transport of oxygen [42], producing tissue anoxia.
The reduction in tissue oxygen utilization produces a state of histotoxic anoxia.
Cyanide bound to the ferric ion of cytochrome c oxidase reduces by 90% the total
uptake of oxygen in most cells through the electronic transport chain [45]. Clinical
symptoms associated with acute toxicity may occur within a few minutes with head-
ache, nausea, vomiting, dizziness, palpitations, hyperpnea and then dyspnea, brady-
cardia, unconsciousness, and violent convulsions, followed by death, depending on
the dose of CN− [38]. Cyanide is not cumulative, so either death from asphyxia and
cardiac arrest occurs or the body is able to eliminate the cyanide in urine, in the form
of ammonium thiocyanate, which is also used as a reference for cyanide intoxication.
If, when inhaled in the form of HCN, cyanide gas is rapidly absorbed from the
respiratory tract, absorption from the gastrointestinal tract is slower, even when cya-
nide salts (sodium and potassium salts) and cyanogenic glycosides are ingested.
Poisoning by skin contact with concentrated solutions of sodium and potassium
cyanide may also occur, with absorption being even slower than by inhalation [46].
When consumed and absorbed in the intestine, linamarin is transported in the
blood, always in the form of an intact glycoside. According to Philbrick [37], it will
be excreted unchanged in the urine, without causing any harm to the organism.
If the lethal dose is reached or exceeded, there is a risk of death, but the lethal
dose is related to the body weight of the consumer.
Lethal Dose
Burtis and Ashwood [47] remind us that the limit between intoxication and death by
a toxic substance is called the lethal dose (LD), which is established in experiments
with animals, never using humans as test subjects. The LD represents the amount of
toxic substance that in a single dose causes the death of all animals, while LD50 is
the single dose that causes the death of 50% of the animals used in the test. The LD
for linamarin from cassava cited by Joint FAO/WHO food standards programme is
10 mg HCN kg−1 body weight [13].
To establish the LD of a compound, it is very important to establish how it is
consumed. For cassava and its derivatives, the culinary products are ingested and
not inhaled. Therefore, it is more appropriate to express the results in potential cya-
nide (CN−p), as recommended by Bokanga et al. [20]. Many of the experiments to
determine the LD were set up with HCN or with potassium cyanide, an inorganic
compound where CN− is covalently linked. That is why it is important to establish
the LD with the cyanogenic compound present in cassava roots, in this case
linamarin.
To establish this limit, Ramalho et al. [32] used linamarin extracted from cassava
cultivars and administered orally to mice and obtained a LD50 of 35.35 mg of CN ±
1.5 mg kg−1 of body weight seven times higher than the LD established by FAO/
WHO. The surviving animals did not show anoxia in noble tissues (cortex neurons
and Purkinje cells), nor were significant changes detected in the biochemical levels
of albumin, glucose, alanine transaminase, aspartate transaminase, and lactate dehy-
drogenase. The results obtained by the authors would allow us to predict the LD for
Phitotherapeutic Potential of Cassava (Manihot esculenta, Crantz) 631

the oral consumption of linamarin extracted from cassava, in about 70 mg of CN−

kg−1 of body weight.
Therefore, it is possible to consider that the dose established by FAO/WHO [13]
is quite safe. It remains to be seen what happens when sublethal doses are consumed
for longer periods of time.

1.3 Sublethal Dose Effect

According to Esser [48] and Oke [49], if the limits for acute intoxication are not
reached, the cyanogenic compounds in cassava can be eliminated by a detoxifica-
tion mechanism, which involves a two-step reaction. The first step involves the
binding of cyanide to a protein. In the second step, cyanide binds to heme iron.
The first step in the detoxification mechanism occurs with the reaction of cyanide
with sulfur (S) to form thiocyanate, which may have the enzyme rhodanase as a
catalyst. Thiocyanate is a less toxic compound that is eliminated via the kidneys
[46]. Diniz et al. [50] pointed out that the source of sulfur could be cysteine, a sulfur
donor amino acid, to give rise to thiocyanate, which is eliminated in the urine. Since
the effect of linamarin, acetone cyanohydrin, and/or HCN is not cumulative, sub-
lethal doses depend only on available S for cyanide to be slowly and efficiently
eliminated from the body, which depends on adequate nutrition. Piste [51] pointed
out that meat is a good source of cysteine.
Therefore, a balanced diet that contains meat is a decisive factor in circumvent-
ing the deleterious effect of the presence of cyanide residues. Chronic conditions
after prolonged exposure to low levels of cyanide can result in breathing difficulties,
eye irritation, chest pain, vomiting, loss of appetite, headaches, nosebleeds, an
enlarged thyroid gland (goiter), and death. Tropical ataxic neuropathy (TAN) is also
a syndrome attributed to exposure to cyanide from improperly prepared cassava.
Other diseases or syndromes related to the consumption of cassava food and prepa-
ration processes could be mentioned, but the relevant reports, such as in the case of
Konzo syndrome, are still poorly substantiated.
Kashala-Abotnes et al. [52] highlight that Konzo is an irreversible upper motor
neuron disease in sub-Saharan Africa, generally linked to the chronic consumption
of insufficiently processed cassava. Epidemics of neurodegenerative diseases puta-
tively caused by food toxins have been reported in the tropics with no clear under-
standing of their pathogenetic mechanisms. Factors of susceptibility, including
genetics, poor nutrition, poverty, and dietary cyanide exposure, or their interactions,
have been proposed. For the WHO [53], the consequences of chronic exposure to
subacute toxic doses of CN− may be involved in the pathogenesis of certain condi-
tions, including disturbances of thyroid function in the presence of iodine deficiency
and neuropathies. Human populations that eat cassava have ophthalmic and neuro-
logical symptoms associated with exposure to CN−, although it is likely that other
nutritional or metabolic deficiencies that affect the cyanide detoxification
632 M. P. Cereda

mechanism are also involved, e.g., deficiency of sulfur-containing amino acids,

vitamin B12, and sulfate and zinc deficiencies [14]. These subacute symptoms are
dependent on the nutritional conditions of the consumer, becoming more serious in
malnourished populations, in which the food base is deficient in sulfur-bearing pro-
teins, such as in meats, which are involved in the process of converting CN− into
thiocyanate.
Therefore, they are syndromes that are difficult to dissociate from other prob-
lems and stresses, which explains the acute and chronic impacts of consumers in
regions plagued by food insecurity, whether due to the amount or unavailability of
animal protein in the diet. In South America, the highest consumption of cassava
occurs in Brazil and Paraguay; however, confirmed reports of intoxication by the
consumption of cassava or its products are rare. The continent with the highest num-
ber of cases is undoubtedly Africa, for social, economic, and cultural reasons.
Therefore, the consumption of cyanogenic compounds in cassava does not nec-
essarily cause harm to consumers’ health, as long as they have an adequate diet. It
should also be considered that the effect of cyanide is not cumulative, and the resid-
ual amount depends not only on the preexisting cyanide content in the roots but also
on its content of linamarase, an enzyme that promotes cyanide release (CN−p) [1].

1.4 Presence of Linamarin in Processed Cassava-Based Foods

JECFA-WHO [53], although endorsing the maximum limit of 10 mg kg−1 of HCN

established as a limit for the consumption of flour, associated doses above this limit
with acute toxicity, and a review of the data available by the European Food Safety
Authority Food in 2004 led to a similar conclusion.
When a portion of tissue containing linamarin is digested, its hydrolysis with
cyanide release will depend on autochthonous enzymes, but also on β-glycosidases
that can be found in the intestine or liver. The presence of β-glucosidase in the
human small intestine has been studied and reported for a long time [21].
As the amount of cyanide released in cassava products intrinsically depends on
the action of the linamarase enzyme and intestinal β-glucosidase, predicting the
amount released will depend on the water activity (aw), pH, and temperature.
This mechanism explains why the detoxification process of cassava roots and its
derivatives is not always complete and, above all, is unequal. Drying processes can
retain 7 mg kg−1 of CN−p as potential cyanide in cassava chips, and freezing can
retain even higher levels [54]. The cyanide radical attached to the glycoside,
although determined as potential, only develops its full toxicity if it is transformed
into free cyanide, which will either be volatilized or removed from the consumer’s
body through the urinary tract [31].
The CN−p dosages in samples of Brazilian cassava flour highlight the residual
cyanide present. The variation of the potential cyanide content reported by Chisté
and Cohen [55] was from 7.68 to 20.57 mg CN−p kg−1 in flour samples in the
Amazon region, but in the central region, artisanal flour samples make it possible to
Phitotherapeutic Potential of Cassava (Manihot esculenta, Crantz) 633

differentiate seven groups, ranging from 2.57 to 24.35 mg CN−p kg−1 [56]. These
values are much lower than the range cited by Sulyok et al. [57] in flour samples
collected in Tanzania, with values ranging from 0.45 to 50.0 mg CN−p kg−1 with a
sample with 400 mg of CN−p kg−1.
The example analyses carried out in Africa to confirm the limits established by
the Coordinating Committee for Africa (CCAFRICA). FAO/WHO [58–60] results
of HCN dosage in processed foods in Nigeria showed that the incidence of HCN in
fresh cassava samples was 6 in 8, while in dried cassava all 12 samples showed the
presence of HCN. In another study considering 10 samples of fermented cassava
flour called gari, it was possible to detect HCN above 1.5 mg CN−p kg−1 in half of
the samples, but HCN was not detected in 10 samples of fufu. This traditional food
is made from whole or pieces of roots that are naturally fermented for 3–7 days. At
the same time, 9 out of 10 samples of cassava flour without fermentation had HCN,
with 5 above 2.0 mg of HCN kg−1. In summary HCN was detected at high rates in
fermented cassava products, but in low concentrations. Experts say that processing
can reduce HCN to a minimum or eliminate it.
These results are explained when the conditions for the action of linamarase are
analyzed, where the local temperature was probably within the optimal range of
30–45 °C for the activity of the enzyme. On the other hand, fresh samples probably
had higher water activity, so the enzyme had a greater opportunity to remain active
and hydrolyze linamarin, releasing HCN to the atmosphere, which did not occur in
the dry samples, where the low humidity kept the enzyme inactive, generating high
levels of inactive CN−p. As for the results for fermented cassava products, the pH of
fresh cassava is within a range of 5.0–6.0, but cassava fermentation favors the pres-
ence of lactic acid bacteria, which reduce the pH to values ​​below the optimum.
Paralyzing the action of the enzyme. Reporting of results obtained for ready-to-eat
cassava chips marketed in Australia and New Zealand showed levels equivalent to a
limit of 10 mg HCN kg−1 body weight. These chips are obtained by frying at tem-
peratures above 120 °C, which certainly inactivates the enzyme responsible for
releasing cyanide.
The fact that the cyanide content present in cassava roots is influenced by several
factors, including climatic conditions and cultivation, limits the only factor that can
be considered safe for cassava-derived foods, the determination of the potential cya-
nide content (CN−p) and free cyanide (CN−), keeping in mind that the potential
cyanide content can transform into free cyanide if conditions are favorable for the
occurrence of hydrolysis, enzymatic or acidic, even in the human body, during
digestion.
Significant cases of cyanide poisoning are reported only among people whose
diet is composed almost exclusively of cassava and, in addition, are malnourished.
Compared with African countries, there are few reliable reports of cyanide poison-
ing in South America, where consumption can be high, but malnutrition is rarer.
634 M. P. Cereda

2 Cassava Phenolic Compounds

The phenolic compounds, until very recently, were classified as antinutritional

agents, but later they were reclassified as health promoters, with various biochemi-
cal and pharmacological activities. In foods, they provide color, astringency, and
aroma. During plant growth, phenolic compounds generally increase in concentra-
tion. They interact with proteins, carbohydrates, and minerals [61].
This chapter will focus on phenolic compounds found in the cassava plant, but
readers interested in the topic are encouraged to consult the review by Kyselova
[62], who reports that phenolic compounds have one or more hydroxyl groups
linked to a benzene ring. Edible plants contribute to the human diet with over 8000
different phenolic compounds, which can be classified as flavonoid and non-­
flavonoid compounds. The author emphasizes that even with the new focus of phe-
nolic compounds with bioactives, it cannot be assumed that they are health
promoters.
Cassava is a source of various phenolic compounds. In general, they are charac-
teristic of the plant, so they can occur in any part of it, including starch, although in
different amounts. But recently, with greater availability of analysis tools, more
articles have been made available explaining this.

2.1 Phenolics Present in Cassava Roots, Stalks, and Leaves

As already mentioned, the cassava plant is more analyzed and referred to as a sub-
sistence food. There are few references to phenolic compounds.
According to Rickard [63] and Padmaja [64] the phenolic compounds that pre-
dominate in the cassava plant are tannins. Ferraro et al. [65] discuss cassava root as
an example of a variety of phenolic compounds, and Uarrota et al. [66] cite ascor-
bate and guaiacol peroxidase as enzymes with antioxidant effects.
Yi et al. [67] report on the occurrence of 10 phenolic compounds in cassava stalk
grown in Hainan in southern China. The compounds were extracted with ethyl ace-
tate and n-butanol and were identified as coniferaldehyde, isovanillin,
6-Deoxyisojacareubin, scopoletin, syringaldehyde, pinoresinol, p-Coumaric acid,
ficusol, balanophonin, and ethamivan, all with significant antioxidant activities. The
results of the study showed that these phenolic compounds contributed to the anti-
oxidant activity of cassava.
In the same material, Suresh and Saravanakumar [68] reported that stalk was a
waste product in cassava root harvesting. It is a renewable raw material rich in anti-
oxidant compounds. To take advantage of them, the authors developed a procedure
to extract anthocyanins and analyze their antioxidant properties. Total phenol, quer-
cetin, and gallic acid were measured. The authors concluded that the phenolic com-
pounds and anthocyanins were responsible for the free radical and that the cassava
Phitotherapeutic Potential of Cassava (Manihot esculenta, Crantz) 635

leaf stalk could be used as a valuable source of anthocyanin extraction that would be
applicable in clinical settings and in the food industry.
Cassava leaves are the organs with the most reported phenolic compounds in the
literature. Some authors discuss the collection of leaves specifically for human or
animal consumption. Ravindran and Ravindran [69] evaluated their use for animal
feed, while Ortega-Flores et al. [70] used leaves from shoot pruning focused on
human consumption, evaluating drying in an oven with air circulation and lyophili-
zation. Table 4 shows the levels of phenolic compounds in cassava leaves dehy-
drated by heat in an oven (50 °C) and by lyophilization. The results show that in
relation to lyophilization, which better preserves phenolics, the leaves maintained
high levels of potential cyanide content.
Ravindran and Ravindran [69] established the variation of nutritional value at
three stages of cassava leaf maturity (very young, young, and mature leaves). The
nutritional composition and antinutritive properties of the crude protein and carbo-
hydrate contents decreased with maturity, whereas all other proximal and fiber com-
ponents increased. The mineral profile showed cassava leaves to be good sources of
most minerals, particularly of calcium and trace minerals. The phosphorous and
sodium contents, however, were low. The values for K, Mg, P, Zn, and Mn decreased
with leaf maturity, while those for Ca, Na, and Fe increased. The researchers also
found that cassava leaves were rich in all essential amino acids except methionine
and phenylalanine. As the leaves matured, the tendency was for the amino acid con-
centrations to decrease. Only glutamic acid, proline, and glycine contents increased,
while those of valine and phenylalanine were unaffected. The levels of phytic acid
increased with leaf aging, while tannin and hydrocyanic acid contents decreased.
Fasuyi [71] worked in animal feed aiming to reduce the content of cyanide and
phenolics in it, which are considered as antinutritional compounds. The HCN con-
tent in fresh leaves varied from 40 to 60 mg 100 g−1, phytates ranged from 107 to
249 mg 100 g−1, and tannic acid varied from 7.5 to 15.0 mg 100 g−1. The author
evaluated the cassava leaves of four Pakistani varieties, researching drying pro-
cesses, sun-drying, oven-­drying, steaming, shredding, and steeping, and combina-
tions of these methods, to reduce the cyanogenic glycoside content. Table 5 presents
HCN and phenolic content expressed as phytate acid and tannic acid. The combina-
tion of shredding and sun-­drying was the most effective technique to reduce the
HCN content.

Table 4 Distribution of the phenolics and total potential cyanide by the parts of the cassava root
used for food
Dehydrated cassava leaves
Compounds found Dry in oven Dry by lyophilization
Phenolics (g 100 g−1) 0.65 2.66
Tannins (g 100 g−1) 0.10 0.90
Phytic acid (g 100 g−1) 0.35 0.51
Potencial cyanide (mg kg−1) 85.17 269.39
Source: Ortega-Flores et al. [70]
636 M. P. Cereda

Table 5 Distribution of hydrocyanic acid (HCN) and polyphenols in cassava leaves, expressed as
Phytate and Tannic acid
HCN Phytate Tannic acid
Variedades mg 100 g−1 g 100 g−1
MS 6 56.5 249.1 7.5
TSM 30555 40.2 197.8 15.0
TSM 30572 54.1 213.8 9.2
Ege Oda 60.6 107.3 6.9
Source: Fasuyi [71]

Linn and Mynt [72] reported a proximate composition of 10.70% moisture,

3.19% crude fat, 29.28% protein, 16.25% dietary fiber, 33.71% carbohydrate,
6.87% ash, and 279 kcal 100 g−1 in the dry base of cassava leaves collected in
Myanmar. They identified alkaloids, alpha amino acid, carbohydrates, glycosides,
tannins, phenolic compounds, cyanogenic glycosides, saponins, starch, steroids,
terpenoids, flavonoids, and reducing sugars. The authors concluded that cassava
leaves have a high antioxidant power. In addition to the direct consumption of plant
components, it is possible to find bioactive principles also in processed cassava
products.

2.2 Anticancer Properties of Phenolic Compounds

The effects of phenolic compounds are many, but for the scope of this chapter the
anticancer effect is highlighted, as a complement to the effects of cyanogenic
compounds.
Kyselova [62] points out that as a control mechanism of cancer cells, the proper-
ties of some phenolic compounds to induce the apoptosis of tumor cells and antican-
cer activity of pro-oxidant phenoxyl radicals stand out. Apoptosis is the mechanism
of programmed cell death, necessary to maintain a balance between cell prolifera-
tion and cell loss. Poor regulation of this balance can lead to malignant transforma-
tion, while induction of apoptosis suppresses cancer development [73, 74]. Several
diet-derived compounds, e.g., resveratrol, have been shown to induce apoptosis in
malignant cells and provide a promising natural strategy for preventing cancer [67,
75–80]. In general, the anticancer activity is linked to the antioxidant activity of the
phenolic compounds, which characterize all the phenolic compounds identified in
the cassava plant [67].
Specifically with respect to the resveratrol phenolic compounds present in red
grape skins, Bhat and Pezzuto [73] point out that cancer chemo preventive agents
reduce the incidence of tumorigenesis by intervening at one or more stages of car-
cinogenesis. Resveratrol was first shown to act as an antioxidant and antimutagenic
agent, thus acting as an anti-initiation agent, but it has also been established that it
acts to suppress and inhibit the formation of carcinogen-induced preneoplastic
lesions.
Phitotherapeutic Potential of Cassava (Manihot esculenta, Crantz) 637

Of the phenolic compounds identified in the cassava plant, only scopoletin, from
the Coumarin group, was specifically mentioned among the phenolic compounds of
cassava. Scopoletin is a phenolic compound identified in the cassava plant that may
have characteristics attributed to linamarin. Obidoa and Obasi [77] describe scopol-
amine as isolated and identified in gari, a fermented flour consumed in Nigeria. Its
content in gari and unfermented flours is not altered by sun drying, refrigeration,
and storage processing, unlike what happens with linamarin. Scopolamine has also
been identified as an active ingredient in fruit infusions of Tetrapleura tetraptera,
used as medicine in East Africa. It is a potent hypotensive and nonspecific spas-
modic agent. These pharmacological effects of scopolamine are likely underlying
factors in the effect showed in tropical neuropathy characterized by optic nerve
atrophy, dizziness of nervous origin, and ataxia endemic among the population,
which consumes cassava and gari as subsistence foods. These symptoms are usually
attributed to cyanogenic glycosides present in cassava.
Ezeanyika et al. [78] describe the effects of scopoletin (6-methoxy-7-hydroxy-
coumarin) compared to cyanide on female Wistar rats serum Na+, K+, urea, creati-
nine, and some hematological parameters. Rats were randomly given doses of
7 g ml−1, 21 g ml−1, 35 g ml−1 scopoletin, 1.8 mg ml−1 cyanide, 10% dimethyl sulf-
oxide (the vehicle for the administration of scopoletin), and 1 ml distilled water
orally per kilogram of body weight at 24-h intervals. Scopoletin at the level found
in processed cassava diet (7 g ml−1) increased symptoms equivalent to 1.8 mg ml−1
cyanide, which is approximately the level consumed on a daily basis by a 70-kg man
in cassava-consuming populations. Among the groups administered with scopole-
tin, the serum levels of K+ and creatinine increased with increasing concentration of
scopoletin, while Na+ and Urea level were decreased. The results of this study sug-
gest further investigations on the effects of scopoletin and cyanide on hematopoiesis
and kidney function.
In addition to scopoletin, other phenolics present in the cassava plant have effects
very similar to the effects attributed to cyanide. Curcumin, a dietary phenolic com-
pound, also showed such effect by opening high conductance permeability transi-
tion pores in mitochondria, through initiates onset and induced mitochondrial
swelling, calcium release, impaired respiration, and through decreased mitochon-
drial membrane potential [79].
Tannins are also present in cassava. Rickard [63] reports the presence of low
levels of tannins (proanthocyanidins) detected in dried cassava samples using stan-
dard methods of analysis based on extraction procedures. The direct vanillin assay
method was compared with other direct methods of analysis based on acid hydroly-
sis and protein precipitation. The specificity of the methods is discussed in relation
to the levels of tannins detected and their potential biological activity in freeze-dried
and dried/processed samples. The results are discussed with respect to the amount
of indigestible material present in the samples. The results of these experiments
indicate that tannins present in dried/processed cassava products may be a factor
limiting their nutritional value. This characteristic, duly controlled, is nowadays
considered a positive characteristic, in view of the need to control excess weight,
which is increasing among adults and children.
638 M. P. Cereda

General data from in vitro and in vivo laboratory studies, epidemiological inves-
tigations, and human clinical trials indicate that phenolic compounds are beneficial
to human health. A large number of studies have identified cellular targets of plant
phenolic compounds in the diet that could be involved in health-promoting actions.
They also point out that dietary supplements are not classified as drugs and do not
require Food and Drug Administration (FDA) approval and that this is a sufficient
reason to evaluate and consider potential toxicities and drug interactions of phenolic
compounds [61].

3 Dietary Fiber

Awareness of the need to promote health and well-being has led to growing demand
for healthy food consumption, which research has shown to be intrinsically linked
to dietary habits [79]. The positive effects of dietary fiber are partly related to the
fact that a portion of its components go through a fermentation process that takes
place in the large intestine, which impacts the speed of intestinal transit, the pH of
the colon, and the production of byproducts with important physiological functions.
Individuals with high fiber intake appear to be at lower risk for developing coronary
heart disease, hypertension, obesity, diabetes, and colon cancer. Increased fiber
intake reduces serum cholesterol levels, improves blood glucose in patients with
diabetes, reduces body weight, and has been associated with lower serum levels of
ultrasensitive C-reactive protein. Fiber consumption of more than 14 g 1000 kcal−1
is generally regarded to confer health benefits, including the reduction of low-grade
inflammatory processes. The consumption of more fiber triggers numerous benefi-
cial effects, reducing by up to 27% the risk of nondegenerative chronic diseases
such as type 2 diabetes mellitus and other pathologies such as cardiovascular dis-
ease and colon cancer [81]. Therefore, it can be said that, although dietary fibers do
not have a curative effect, they can prevent or improve conditions for coping with
diseases and are therefore treated as another health-promoting factor [6]. According
to Ortega-Flores et al. [70], fibers are part of the cell walls of plants, and in humans,
they are responsible for regulating the intestinal tract and weight, carbohydrate and
lipid metabolism, and colon functioning.
The desirable properties of fibers and resistant starches differ with botanical
sources. These include swelling, gelation, increased viscosity, and water-binding
capacity [7–81].
Classified as soluble or not in water, insoluble fiber can help control constipation,
diverticular disease, atherosclerosis, and cardiovascular diseases. Soluble fiber con-
trols cholesterol and insulin metabolism. However, excess fiber in the diet can
reduce the absorption of nutrients in the intestine due to the speed of transit [6].
The solubility and insolubility of dietary fibers determine their physiological
effects when ingested in the diet. Soluble fibers have the ability to increase stomach
viscosity, reducing postprandial blood glucose and cholesterol levels. Therefore,
they interfere with the ability to retain water, accelerate intestinal transit, increase
Phitotherapeutic Potential of Cassava (Manihot esculenta, Crantz) 639

fecal volume, and stimulate colonic fermentation, in addition to reducing the risk of
diseases of the gastrointestinal tract [82].
Understanding of the physiological importance of dietary fiber has increased
considerably over the last 10 years. The degree of indigestibility of the fibers con-
tained in foods, of which they are an integral part, can prevent some gastrointestinal
and metabolic diseases. They pass through the digestive tract without modification
and increase the stool, stimulating and making bowel movements more frequent. In
general, they remain in the gut environment longer, with important interference in
peristalsis performance [83].
In addition to this more mechanical importance, more recently, functional prop-
erties have been added to their positive effects, which include the ability to retain
water by increasing fecal volume, increasing intestinal viscosity, and controlling
intestinal transit time by increasing or decreasing it, with the consequent influence
on nutrient absorption [81].
In addition to other benefits, fiber promotes the reduction of digestion and
absorption of macronutrients, reduces the levels of serum lipids and postprandial
glucose, promoting glycemic control.
The effects of fiber are mainly attributed to the degree of viscosity and fermenta-
tion [81–85]. They produce short-chain fatty acids (SCFAs), mainly propionic acid,
when they are fermented in the large intestine by intestinal bacteria. In in vitro tests,
this generation of short-chain fatty acids, such as butyrate, has been associated with
benefits for gut health, with the modulation of cell proliferation, apoptosis, and the
regulation of angiogenesis [86]. The type of fatty acid formed varies with the dietary
fiber consumed [85], which results in the importance of evaluating the dietary fibers
available on the market and those potentially available for consumption.
In addition to being available, dietary fibers have evaluated for their performance.
Fiber characterization is vital for food manufacturers so that they can provide valid
and accurate information on product labeling. It is also fundamental for the activity
of the regulatory authorities regarding claims of nutritional and health properties.
Such information is still necessary for consumers, who use nutritional information
declared on food labels and associated materials.
Among the components of dietary fiber and its associated compounds, the phe-
nolic compounds that were included as a result of changes in the concept of healthy
foods stand out. These are secondary compounds with important beneficial func-
tions for the human body, preventing injuries caused by free radicals, which are
oxidized by them and are more stable. The biological effects of these molecules are
related to anti-inflammatory, anticarcinogenic activity and reduced incidence of car-
diovascular diseases [87, 88].
The fact that it has a high content of crude fiber does not mean that the raw mate-
rial is a source of fiber of good nutritional quality. Fiber is considered a functional
food and performs important functions in the body, such as promoting a feeling of
satiety, facilitating with the metabolism of lipids and carbohydrates and the physiol-
ogy of the gastrointestinal tract, and ensuring a slower absorption of nutrients [89].
For Bernaud and Rodrigues [90] the positive effects of dietary fiber are related,
in part, to the fact that a portion of the fermentation of its components occurs in the
640 M. P. Cereda

large intestine, which has an impact on the speed of intestinal transit, on the pH of
the colon, and on the production of byproducts with an important physiological
function. Individuals with high fiber intake appear to be at lower risk for developing
coronary heart disease, hypertension, obesity, diabetes, and colon cancer. Increased
fiber intake reduces serum cholesterol levels, improves blood glucose in patients
with diabetes, reduces body weight, and has been associated with lower serum lev-
els of ultrasensitive C-reactive protein. Higher fiber intake and intake of more fiber
in proportion to the energy consumed, currently recommended at 14 g 1000 kcal−1,
may bring greater health benefits, including the reduction of low-grade inflamma-
tory processes. The authors conclude that to meet increased need for fiber, the intake
of at least 3 g day−1 of fiber is necessary for the benefits to be realized, requiring the
consumption of a wide variety of sources of fiber, such as fruits, vegetables, whole
grains, and bran.
However, in modern life, these recommendations are not always easily met,
especially regarding the amount of fiber to be consumed daily. For this reason, spe-
cialized stores and gyms value, make available, and feature these products as food
supplements and encourage the use of new ranges of products such as oat bran, rice
bran, corn, wheat and passion fruit fiber, coconut flour, and eggplant, among others.
In response to this demand, food companies have been developing functional
food formulations, capable of meeting nutritional needs and delivering health ben-
efits, without losing sight of the needs of modern life; however, for these foods to be
considered health-promoting, there is a need to prove their beneficial
characteristics.
Among all sources of dietary fiber, cereal bran and rice and wheat bran are the
most studied and popular dietary supplements. Specific studies on the phytochemi-
cal composition of rice bran have proven its richness in phenolic compounds, vita-
mins with an emphasis on vitamin E, dietary fiber, oils, steroid derivatives,
polysaccharides, antioxidants, and proteins (essential amino acids, especially
lysine). For wheat bran, in addition to fiber, lignin and lignans, oligosaccharides,
polyphenols, phytic acid, minerals, alkyl resorcinols, glutathione, sulfur com-
pounds, α-linoleic acid, carotenoids, and vitamins B and E [91]. Wheat bran is
known and consumed globally. It is an important byproduct of cereal production,
especially when the grain has significant amounts of fermentable carbohydrates and
dietary fiber, in addition to resistant starch. About 50% fiber can be found in its
composition, 40% of which is hemicellulose, which represents a strong indication
of being a good source of dietary fiber [92, 93], considered a standard fiber [94].
Wheat fiber is easily found in Brazil and stands out globally as a relevant byproduct
of cereal production [95]. Due to its valorization, wheat fiber fetches high prices, so
other residues rich in fibers produced from Brazilian raw materials have been stud-
ied with a view to its valorization, including cassava bran.
Cassava fibers are considered compatible with the concept of dietary fiber.
According to the Brazilian Food Composition Table [3], raw cassava roots have up
to 2 g fiber/100 g, with 133 kcal, but with cooking it absorbs more water, and this
content reduces to 1.78, as does the caloric content (121 kcal) in the same 100 g. In
contrast, when dehydrated in the form of flour, the energy content rises to 160 kcal
and the dietary fiber content exceeds 5.0 g/100 g.
Phitotherapeutic Potential of Cassava (Manihot esculenta, Crantz) 641

The bran obtained in the commercial extraction of cassava starch has been exten-
sively studied because it is abundant, obtained in good sanitary conditions, and
available at low cost. Its production on an industrial scale was quantified by Cereda
[1], at an average of 140 kg of dry mass per ton of processed cassava.
Based on a description by Leonel et al. [96] in the characterization of cassava
bran from the point of view of dietary fiber, the authors highlighted that 80% of
residual starch would provide a very high calorie content when consumed, as glu-
cose predominated in this sample, followed by of 22.3% hemicellulose. Discounting
the starch, we arrive at 58% fiber, 4% protein, and 6% ash.
By the year 2000, this content had already been reduced to 30–50% starch on a
dry weight basis. The authors comment that this fibrous material, a byproduct of
cassava processing, may be valuable thanks to its rich organic nature and low ash
content, as an ideal substrate for microbial processes for the production of value-­
added products. Attempts have been made to make several products from cassava
bran, such as organic acids, flavor and aroma compounds, and mushrooms [97].
Silva et al. [98] characterized cassava bran and reported a caloric value of 179.32 kcal
due to the presence of residual starch, reduced by the use of amylolytic and cellulo-
lytic enzymes, with a consequent increase in its functionality and its value as a
source of dietary fiber. Later, Lacerda [99] compared cassava bagasse fiber with
wheat fiber, a commercial and standard product for dietary fiber (Tables 6 and 7).
In general appearance, commercial wheat bran and cassava bran are similar, but
wheat fiber is darker, whereas cassava bran is more red and yellow. As sources of
dietary fiber, commercial fiber and cassava fiber are very comparable. Wheat bran
has a much higher phenolic content. In terms of quality, a higher rate of water and
oil absorption is observed for cassava fiber and, surprisingly, greater water solubil-
ity for wheat fiber. The results presented only highlight the potential of finding qual-
ity fiber in tropical raw materials.

Table 6 Aspect and color of wheat fiber (Yoki®), arrowroot and cassava bran and standard
deviation of the mean
Wheat fiber Cassava bran

General aspect
Brightness (L%) 52.65 58.51
Red 7.26 4.40
Yellow 18.30 16.53
Source: Lacerda et al. [99]
Averages of three repetitions
642 M. P. Cereda

Table 7 Physicochemical characterization and nutritional aspects of wheat fiber, arrowroot and
cassava bran
Análises Unities [DM] Wheat fiber Cassava bran
Sugars
-TRS g 100 g−1 26.37 29.16
-RS g 100 g−1 3.54 7.42
Protein g 100 g−1 6.90 1.80
Fat g 100 g−1 1.8 2.37
Calorific value Kcal 100 g−1 149c 144b
Ash g 100 g−1 2.62 1.44
FDN g 100 g−1 60.04 60.04
FAD g 100 g−1 12.91 29.22
Phenolics μg 100 g−1 29.04 1.53
Dietary fiber total g 100 g−1 46.21 44.32
Functional properties
WAI 3.85 4.92
OAI 2.84 3.36
WSI 12.20 1.73
Source: Lacerda et al. [99]
Averages of three replicates expressed in dry mass
TRS Total Reducing Sugars, RS Reducing Sugars, FND Fiber by acid detergent, FAD Fiber by
neutral detergent, FAT Dietary fiber total, WAI water absorption index, OAI oil absorption index,
WSI water solubility index

4 Final Considerations

To explore the potential of the phototherapeutic use of cyanogenic, phenolic, and

fiber compounds, it is necessary to disseminate information on these compounds
already available in the literature in order to increase the confidence of researchers
and consumers.
• On the potential of cassava cyanide as a phytotherapy
• There is enough information in the literature to prove that it is possible to ingest
linamarin in safe amounts, without risk of serious intoxication, especially for
well-nourished consumers. For this to occur, it is necessary to spread informa-
tion about the detoxification mechanism in the human body, considering that free
cyanide is not cumulative. There is also a need to standardize the results of analy-
ses of potential cyanide (CN−p), which corresponds to total cyanide and free
cyanide (CN−), which is capable of causing toxication. Finally, its specific effect
on cancer cells is proven at doses far below the lethal dose.
• On the potential of cassava phenolic compounds as a phytotherapy
• Unlike cyanogenic compounds, there is very little information about phenolic
compounds, much of which is expressed generically without identifying these
compounds. Existing information shows that many compounds belong to the
group of antioxidants and could influence the viability of cancer cells or reduce
Phitotherapeutic Potential of Cassava (Manihot esculenta, Crantz) 643

the possibility that they will be generated. In the specific case of scopoletin, it
would be important to verify to what extent it can be an origin or an adjuvant in
chronic diseases such as Konzo, which is generally attributed to linamarin.
• On the potential of cassava root fiber as a phytotherapy
• The evaluation of cassava products (e.g., roots, leaves, starch, industrial resi-
dues) as dietary fibers is even less researched than cyanogenic compounds and
phenolic compounds. The available information shows potential for cassava
bagasse, as it is a safe and abundant industrial waste.
• To guide the complementary research needed to configure the cyanogenic com-
pounds present in the cassava plant as a phytotherapeutic agent with an effect on
cancer, it would be important to relate cassava consumption per inhabitant/year
with diagnosed cases of cancer, especially with cancer of the digestive system,
with an emphasis on the intestine, which is where cyanide would be released and
absorbed.

References

1. Cereda MP (2002) Characterization of starchy raw materials. In: Cereda MP, Vilpoux OF
(Org). General properties of starch, 1st edn. Fundação Cargill: São Paulo, Livro 1, v.1,
pp 88–133. (In Portuguese)
2. Sagrilo E, Pequeno MG, Vidigal Filho P, Scapim C (2002) Effect of harvest time on vegeta-
tive growth, yield and root quality of three cassava cultivars. Bragantia 61(August):115–125.
https://doi.org/10.1590/S0006-­87052002000200005. (In Portuguese)
3. TACO- Brazilian Food Composition Table (2011) Núcleo de Estudos e Pesquisas em
Alimentação, Universidade Estadual de Campinas, 4 edn. NEPA-UNICAMP: Campinas, 161
p. (In Portuguese). Avaiable in: http://www.fcf.usp.br/tbca/. Consulted in January 3th/2021.
(In Portuguese)
4. Cressey P, Reeve J (2019) Metabolism of cyanogenic glycosides: a review. Food Chem
Toxicol 125:225–232. https://doi.org/10.1016/j.fct.2019.01.002. PMID: 30615957
5. Gensa U (2019) Review on cyanide poisoning in ruminants. J Biol Agric Healthcare
9(6):1–12. https://doi.org/10.7176/JBAH
6. Fuller S, Beck E, Salman H et al (2013) New horizons for the study of dietary fiber
and health: a review. Plant Foods Hum Nutr 43(1):408–416. https://doi.org/10.1590/
S1983-­40632013000400005
7. Fuentes-Zaragoza E, Riquelme-Navarrete MJ, Sánchez-Zapata E, Pérez-Álvarez JA (2010)
Resistant starch as functional ingredient: a review. Food Res Int 43(4):931–942. https://doi.
org/10.1016/j.foodres.2010.02.004
8. Sykes AH (1981) Early studies on the toxicology of cyanide. Cyanide Biol:1–9
9. Seigler DS (1991) Cyanide and cyanogenic glycosides. In: Rosenthal GA, Berenbaum MR
(eds) Herbivores: their interactions with secondary plant metabolites. Academic Press, San
Diego, pp 35–77
10. Conn EE (1978) Cyanogenesis, the production of hydrogen cyanide, by plants. In: Effects of
poisonous plants on livestock. Academic Press, pp 301–310. https://doi.org/10.1016/B978-­0
-­12-­403250-­7.50035-­2
11. Hösel W (1981) Cyanide in biology. Academic Press, London, pp 217–232
644 M. P. Cereda

12. Møller BL, Seigler DS (1999) Biosynthesis of cyanogenic glycosides, cyanolipids and related
compounds. In: Plant amino acids biochemistry and biotechnology. CRC Press, pp 563–609
13. FAO/WHO (1991) Joint FAO/WHO food standards programme. Codex Alimentarius
Commission XII, Suppl. 4, FAO, Rome
14. EFSA (2004) Evaluation of the health risks related to the presence of cyanogenic glycosides in
foods others than raw apricot kernels. J EFSA:89. https://doi.org/10.2903/j.efsa.20YY.NNNN
15. Nambisan B (2011) Strategies for elimination of cyanogens from cassava for reducing toxic-
ity and improving food safety. Food Chem Toxicol 49(3):690–693. https://doi.org/10.1016/j.
fct.2010.10.035
16. Onyenwoke CA, Simonyan KJ (2014) Cassava post-harvest processing and storage in Nigeria:
a review. Afr J Agric Res 9(53):3853–3863. https://doi.org/10.5897/AJAR2013.8261
17. Knudsen I, Søborg I, Eriksen F, Pilegaard K, Pedersen J (2008) Risk management and
risk assessment of novel plant foods: concepts and principles. Food Chem Toxicol
46(5):1681–1705. https://doi.org/10.1016/j.fct.2008.01.022
18. Rosling H (1988) Cassava toxicity and food security. A review of health effects of cyanide
exposure from cassava and of ways to prevent these effects, 40 p. ISBN: 91-971029-0-3
19. Union of Pure and Applied Chemists. Available in https://iupac.org/who-­we-­are/. Consulted
in 24th February 2022
20. Bokanga M, Essers S, Pouler N, Rosling H, Tewe O, Asiedu R, Brader L (1994) Preface. Acta
Horticult, Wageningen 375:1–2
21. Day AJ, DuPont MS, Ridley S, Rhodes M, Rhodes MJ, Morgan MR, Williamson G
(1998) Deglycosylation of flavonoid and isoflavonoid glycosides by human small ­intestine
and liver β-glucosidase activity. FEBS Lett 436(1):71–75. https://doi.org/10.1016/
S0014-­5793(98)01101-­6
22. Nartey F (1981) Cyanogenesis in tropical feeds and foodstuffs. In: Vennesland B, Conn
EE, Knowles CJ, Westley J, Wissing F (eds) Cyanide in biology. Academic Press, London,
pp 115–132
23. De Bruijn GH (1973) Cyanogenic character of cassava (Manihot esculenta). In: Chronic cas-
sava toxicity. IDRC, Ottawa
24. Bokanga M (1992) Contraints in food and nutrition research. In: Thottapplly G, Monti LM,
Mohan Raj DR, Moore AW (eds) Biotechnology: enhancing research on tropical crops in
Africa. International Institute of Tropical Agriculture, Ibadan, pp 33–38
25. Oluwole OSA, Onabolu AO, Mtunda K, Mlingi N (2007) Characterization of cassava (Manihot
esculenta Crantz) varieties in Nigeria and Tanzania, and farmers’ perception of toxicity of
cassava. J Food Compos Anal 20(7):559–567. https://doi.org/10.1016/j.jfca.2007.04.004
26. Cardoso Júnior NDS, Viana AES, Matsumoto SN, Sediyama T, Carvalho FMD (2005)
Effect of nitrogen on agronomic characteristics of cassava. Bragantia 64(4):651–659. (In
Portuguese)
27. Bourdoux P, Seghers P, Mafuta M, Vanderpas J, Vanderpas-Rivera M, Delange F et al (1982)
Nutritional factors involved in the goitrogenic action of cassava. IDRC, Ottawa
28. Boakye Peprah B, Parkes EY, Harrison OA, van Biljon A, Steiner-Asiedu M, Labuschagne
MT (2020) Proximate composition, cyanide content, and carotenoid retention after boiling of
provitamin A-rich cassava grown in Ghana. Foods 9(12):1800
29. EFSA Panel on Contaminants in the Food Chain (CONTAM), Schrenk D, Bignami M, Bodin
L, Chipman JK, del Mazo J et al (2019) Evaluation of the health risks related to the presence
of cyanogenic glycosides in foods other than raw apricot kernels. EFSA J 17(4):e05662.
https://doi.org/10.2903/j.efsa.2019.5662
30. Zhu C, Krumm C, Facas GG, Neurock M, Dauenhauer PJ (2017) Energetics of cellulose
and cyclodextrin glycosidic bond cleavage. React Chem Eng 2(2):201–214. https://doi.
org/10.1039/C6RE00176A
31. Cagnon JR, Cereda MP, Pantarotto S (2002) Cassava cyanogenic glycosides: biosynthesis,
distribution, detoxification and dosage methods. In: Agricultura: tuberosas amiláceas Latino
Americanas, vol 2. Fundação Cargill, São Paulo, pp 83–99. (In Portuguese)
Phitotherapeutic Potential of Cassava (Manihot esculenta, Crantz) 645

32. Ramalho RT, Aydos RD, Cereda MP (2010) Evaluation of acetone cyanohydrin effect in “in
vitro” inativation of the Ehrlich ascites tumor cells. Acta Cir Bras 25(1):111–116. https://doi.
org/10.1590/S0102-­8650201400140008
33. Hughes J, de Carvalho JPC, Hughes MA (1994) Purification, characterization, and cloning
of α-hydroxynitrile lyase from cassava (Manihot esculenta Crantz). Arch Biochem Biophys
311(2):496–502. https://doi.org/10.1006/abbi.1994.1267
34. Idibie CA, Davids H, Iyuke SE (2007) Cytotoxicity of purified cassava linamarin to a
selected cancer cell lines. Bioprocess Biosyst Eng 30(4):261–269. https://doi.org/10.1007/
s00449-­007-­0122-­3
35. Orjiekwe CL, Solola A, Iyen E, Imade S (2013) Determination of cyanogenic glucosides in
cassava products sold in Okada, Edo State, Nigeria. Afr J Food Sci 7(12):468–472. https://
doi.org/10.5897/AJFS2013.1012
36. FAO/WHO (2019) Discussion paper on the establishment of MLs for HCN in cassava and
cassava-based products and occurrence of mycotoxins in these products. Joint FAO/WHO
Food Standards Programme Codex Committee on Contaminants in Foods. 13th Session.
Yogyakarta, Indonesia, 29 April – 3 May 2019: [s.n.]. Disponível em: https://www.google.
com/search?client=firefox-­b-­d&sxsrf=ALeKk00yvKwTdmWTDiTHE04CytocXyRm_A:16
12304652672&q=datatable+FAO/WHO+(1988)+established+10+mg+HCN/kg+live+weigh
t&spell=1&sa=X&ved=2ahUKEwiJ_N3wnszuAhXJHLkGHbB1AqwQBSgAegQIBxA1&b
iw=1366&bih=666. Consultado em 2 Fev. 2021
37. Philbrick DJ, Hill DC, Alexander JC (1977) Physiological and biochemical changes associ-
ated with linamarin administration to rats. Toxicol Appl Pharmacol 42(3):539–551. https://
doi.org/10.1016/S0041-­008X(77)80039-­2
38. EFSA Journal (2007) Opinion of the scientific panel on contaminants in the food chain
on a request from the commission related to cyanogenic compounds as undesirable sub-
stances in animal feed. EFSA J 434:1–67. www.efsa.europa.eu Page 1 of 67 Question N°
EFSA-Q-2003-064 Adopted on 23 November 2006
39. Logsdon MJ, Hagelstein K, Mudder T (1999) The management of cyanide in gold extraction.
International Council on Metals and the Environment, Ottawa, p 10
40. Tomasik P, Jane JL, Spence K, Andernegg JW (1995) Starch ferrates. Starch-Stärke
47(2):68–72. https://doi.org/10.1002/star.19950470207
41. FAO/WHO (2013) Proposed draft maximum levels for hydrocyanic acid in cassava and cas-
sava products. Codex Committee on Contaminants in Foods. Joint FAO/WHO Food Standards
Programme Codex Committee on Contaminants in Foods. Seventh Session, Moscow,
Russian Federation, 8–12, April, 2013: [s.n.]. Disponível em: https://www.google.com/url?s
a=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwiR-­sXynszuAhUpD7kGHRSPD
b8QFjAAegQIAxAC&url=https%3A%2F%2F2.zoppoz.workers.dev%3A443%2Fhttp%2Fwww.fao.org%2Ftempref%2Fcodex%2FMeet
ings%2FCCCF%2Fcccf7%2Fcf07_10e.pdf&usg=AOvVaw1e6FYAdKN0UmRow_sEKa6i.
Consultado em 2 Fev. 2021
42. Poulton JE (1993) Cyanogenic compounds in plants and their toxic effect. In: Keler RF, Tu
AT (eds) Handbook of natural toxins, Plant and fungal toxins, vol v. 1. M. Dckker, New York,
pp 117–157
43. Nelson L (2006) Acute cyanide toxicity: mechanisms and manifestations. J Emerg Nurs
32(4):S8–S11. https://doi.org/10.1016/j.jen.2006.05.012
44. Cheeke PR (1989) Toxicants of plant origin: alkaloids (v.1). CRC Press, Boca Raton. ISBN
0-8493-6990-8
45. Baskin SI, Kurche JS, Maliner BI (2004) Cyanide. In: Roy MJ (ed) Physician’s guide to ter-
rorist attack. Humana Press, Totowa. https://doi.org/10.1007/978-­1-­59259-­663-­8_19
46. Ballantyne B (1987) Toxicology of cyanides. In: Ballantyne B, Marrs TC (eds) Clinical and
experimental toxicology of cyanides. IOP Publishing Limited, Bristol, pp 41–126
47. Burtis CA, Ashwood ER (1996) Enzymes. In: Teitz fundamentals of clinical chemistry. NB
Saunders Company, Philadelphia, pp 4312–4335
646 M. P. Cereda

48. Essers AJA (1994) Further improving the enzymic assay for cyanogens in cassava products.
Acta Horticult 375:97–101
49. Oke OL (1969) The role of hydrocyanic acid in nutrition. World Rev Nutr Diet 11:170–198.
https://doi.org/10.1159/000387578
50. Diniz M, de Mattos MCY, Cereda MP (1996) Linamarin: the toxic compounds of cassava. J
Venomous Toxins 2(1):06–12
51. Piste P (2013) Cysteine–master antioxidant. Int J Pharm Chem Biol Sci 3(1):143–149
52. Kashala-Abotnes E, Okitundu D, Mumba D, Boivin MJ, Tylleskär T, Tshala-Katumbay D
(2019) Konzo: a distinct neurological disease associated with food (cassava) cyanogenic poi-
soning. Brain Res Bull 145:87–91. https://doi.org/10.1016/j.brainresbull.2018.07.001
53. WHO World Health Organization (1993) Hydrogen cyanide and cyanides: human health
aspects. United Nations Environmental Programme, Geneve, 45 p
54. Burns AE, Bradbury JH, Cavagnaro TR, Gleadow RM (2012) Total cyanide content of cas-
sava food products in Australia. J Food Compos Anal 25:79–82. https://doi.org/10.1016/j.
jfca.2011.06.005
55. Chisté RC, Cohen KO (2008) Determination of total cyanide in cassava flour of the
dry and water group commercialized in the city of Belém-PA. Revista Brasileira
de Tecnologia Agroindustrial 2(2):96–102. Avaiable in: https://doi.org/10.3895/
S1981-­36862008000200010. Consulted in: February 16th 2022. (In Portuguese)
56. Oliveira OSD, Brito VHDS, Cereda MP (2018) Establishing a standard for handmade
Brazilian cassava flour from Baixada Cuiabana (Mato Grosso, Brazil) to support its process-
ing and sale. Food Sci Technol 39:559–566. https://doi.org/10.1590/fst.30117
57. Sulyok M, Beed F, Boni S, Abass A, Mukunzi A, Krska R (2015) Quantitation of multiple
mycotoxins and cyanogenic glucosides in cassava samples from Tanzania and Rwanda by an
LC-MS/MS-based multi-toxin method. Food Addit Contam Part A 32(4):488–502. https://
doi.org/10.1080/19440049.2014.975752
58. Joint FAO/WHO (2016) Expert Committee on Food Additives. Meeting, & World Health
Organization. Evaluation of Certain Food Additives and Contaminants: Eightieth Report of
the Joint FAO/WHO Expert Committee on Food Additives, vol 80. World Health Organization
59. Expert Committee on Food Additives (JECFA) (2016) World Organization for Health.
Disponivel em: https://www.who.int/foodsafety/chem/jecfa/ARfd/en/. Consultado em 21
Fevereiro 2021
60. Food and Agriculture Organization of the United Nations, Codex Alimentarius Commission
(2007) Cereals, pulses, legumes and vegetable proteins, 1st edn. Committee Food and
Agriculture Organization of the United Nations, Rome. Retrieved from http://www.fao.
org/3/a-­a1392e.pdf
61. Shahidi F, Naczk M (1995) Food phenolics: sources, chemistry, effects and aplications. Dent
Tech 37(1/2):75–107
62. Kyselova Z (2011) Toxicological aspects of the use of phenolic compounds in disease preven-
tion. Interdiscip Toxicol 4(4):173–183. https://doi.org/10.2478/v10102-­011-­0027-­5
63. Rickard JE (1986) Tannin levels in cassava, a comparison of methods of analysis. J Sci Food
Agric 37(1):37–42. https://doi.org/10.1002/jsfa.2740370106
64. Padmaja G (1989) Evaluation of techniques to reduce assayable tannin and cyanide in cas-
sava leaves. J Agric Food Chem 37(3):712–716
65. Ferraro V, Piccirillo C, Tomlins K, Pintado ME (2016) Cassava (Manihot esculenta Crantz)
and yam (Dioscorea spp.) crops and their derived foodstuffs: safety, security and nutritional
value. Crit Rev Food Sci Nutr 56(16):2714–2727
66. Uarrota VG, Moresco R, Schmidt EC, Bouzon ZL, da Costa Nunes E, de Oliveira Neubert
E et al (2016) The role of ascorbate peroxidase, guaiacol peroxidase, and polysaccharides
in cassava (Manihot esculenta Crantz) roots under postharvest physiological deterioration.
Food Chem 197:737–746. https://doi.org/10.1016/j.foodchem.2015.11.025
Phitotherapeutic Potential of Cassava (Manihot esculenta, Crantz) 647

67. Yi B, Hu L, Mei W, Zhou K, Wang H, Luo Y et al (2011) Antioxidant phenolic compounds

of cassava (Manihot esculenta) from Hainan. Molecules 16(12):10157–10167. https://doi.
org/10.3390/molecules161210157
68. Suresh R, Saravanakumar M, Suganyadevi P (2011) Anthocyanins from Indian cassava
(Manihot esculenta Crantz) and its antioxidant properties. Int J Pharm Sci Res 2(7):1819.
ISSN: 0975-8232
69. Ravindran G, Ravindran V (1988) Changes in the nutritional composition of cassava
(Manihot esculenta Crantz) leaves during maturity. Food Chem 27(4):299–309. https://doi.
org/10.1016/0308-­8146(88)90014-­3
70. Ortega-Flores CI, Costa MALD, Cereda MP, Penteado MDVC (2003) Bioavailability of
beta-carotene in dehydrated cassava leaves (Manihot esculenta Crantz). Food Sci Technol
23:473–477
71. Fasuyi AO (2005) Nutrient composition and processing effects on cassava leaf (Manihot
esculenta, Crantz) antinutrients. Pak J Nutr 4(1):37–42. ISSN 1680-5194
72. Linn KZ, Myint PP (2018) Estimation of nutritive value, total phenolic content and in vitro
antioxidant activity of Manihot esculenta Crantz. (Cassava) leaf. J Med Plants 6(6):73–78.
ISSN: 2320-3862
73. Tang DG, Porter AT (1996) Apoptosis: a current molecular analysis. Pathol Oncol Res
2:117–131. https://doi.org/10.1007/BF02903515
74. Bhat KP, Pezzuto JM (2002) Cancer chemopreventive activity of resveratrol. Ann N Y Acad
Sci 957(1):210–229. https://doi.org/10.1111/j.1749-­6632.2002.tb02918.x
75. Katdare M, Osborne M, Telang NT (2002) Soy isoflavone genistein modulates cell cycle pro-
gression and induces apoptosis in HER-2/neu oncogene expressing human breast epithelial
cells. Int J Oncol 21(4):809–815. https://doi.org/10.3892/ijo.21.4.809
76. Surh YJ (2002) Anti-tumor promoting potential of selected spice ingredients with antioxida-
tive and anti-inflammatory activities: a short review. Food Chem Toxicol 40(8):1091–1097.
https://doi.org/10.1016/S0278-­6915(02)00037-­6
77. Obidoa O, Obasi SC (1991) Coumarin compounds in the cassava diets. Two health implica-
tions of cassava in gari. Plant Food Hum Nutr 41:283–289
78. Ezeanyika LUS, Obidoa O, Oluwashemire NB, Tekeudo DL, Umar IA (2002) Comparative
effects of scopoletin and cyanide on serum electrolytes, urea, creatinine and some
Haematological parameters of rats. Global J Pure Appl Sci 8(3):311–314. https://doi.
org/10.4314/gjpas.v8i3.16013
79. Özkaya B, Turksoy S, Özkaya H, Duman B (2017) Dephytinization of wheat and rice brans
by hydrothermal autoclaving process and the evaluation of consequences for dietary fibre
content, antioxidant activity and phenolics. Innovative Food Sci Emerg Technol 39:209–215.
https://doi.org/10.1016/j.ifset.2016.11.012. ISSN 1466-8564
80. Kim JS, He L, Lemasters JJ (2003) Mitochondrial permeability transition: a common path-
way to necrosis and apoptosis. Biochem Biophys Res Commun 304:463–470. https://doi.
org/10.1016/S0006-­291X(03)00618-­1, https://doi.org/10.1111/j.1749-­6632.1999.tb08742.x
81. Kendall CW, Esfahani A, Jenkins DJ (2010) The link between dietary fibre and human health.
Food Hydrocoll 24(1):42–48. https://doi.org/10.1016/j.foodhyd.2009.08.002
82. Peerajit P, Chiewchan N, Devahastin S (2012) Effects of pretreatment methods on health-­
related functional properties of high dietary fibre powder from lime residues. Food Chem
132(4):1891–1898. https://doi.org/10.1016/j.foodchem.2011.12.022
83. Elleuch M, Bedigian D, Roiseux O, Besbes S, Blecker C, Attia H (2011) Dietary fibre and
fibre-rich by-products of food processing: characterisation, technological functionality and
commercial applications: a review. Food Chem 124(2):411–421. https://doi.org/10.1016/j.
foodchem.2010.06.077
84. Barber TM, Kabisch S, Pfeiffer AF, Weickert MO (2020) The health benefits of dietary fibre.
Nutrients 12(10):3209. https://doi.org/10.3390/nu12103209
648 M. P. Cereda

85. Kaczmarczyk MM, Miller MJ, Freund GG (2012) The health benefits of dietary fiber: beyond
the usual suspects of type 2 diabetes mellitus, cardiovascular disease and colon cancer.
Metabolism 61(8):1058–1066. https://doi.org/10.1016/j.metabol.2012.01.017
86. Phillips GO, Cui SW (2011) An introduction: evolution and finalisation of the regula-
tory definition of dietary fibre. Food Hydrocoll 25(2):139–143. https://doi.org/10.1016/j.
foodhyd.2010.04.011
87. Bruneton J (1999) Pharmacognosy & phytochemistry medicinal plants. In: Techniques &
documentation, vol 81, 2nd edn. Lavoisier Publishers, Paris, pp 106–109
88. Kuskoski EM, Asuero AG, Parilla MCG, Troncoso AM, Fett R (2004) Antioxidant activity in
anthocianics pigments. Ciencia e Tecnologia de Alimentos (Brazil)
89. Alvarez T, Magnoni D, Cukier C (2005) Skin nutrition and healing. In: Nutrition based on the
physiology of organs and systems, pp 8–15. (In Portuguese)
90. Bernaud FSR, Rodrigues TC (2013) Dietary fiber: adequate intake and metabolism health
effects. Arquivos Brasileiros de Endocrinologia & Metabologia 57:397–405. https://doi.
org/10.1590/S0004-­27302013000600001. (In Portuguese)
91. Sharif MK, Butt MS, Anjum FM, Khan SH (2014) Rice bran: a novel functional ingredient.
Crit Rev Food Sci Nutr 54(6):807–816. https://doi.org/10.1080/10408398.2011.608586
92. Yuan X, Wang J, Yao H, Chen F (2005) Free radical-scavenging capacity and inhibitory activ-
ity on rat erythrocyte hemolysis of feruloyl oligosaccharides from wheat bran insoluble dietary
fiber. LWT-Food Sci Technol 38(8):877–883. https://doi.org/10.1016/j.lwt.2004.09.012
93. Wang J, Sun B, Cao Y, Wang C (2010) In vitro fermentation of xylooligosaccharides from
wheat bran insoluble dietary fiber by Bifidobacteria. Carbohydr Polym 82(2):419–423.
https://doi.org/10.1016/j.carbpol.2010.04.082
94. Raupp DDS, Rosa DA, Marques SHDP, Banzatto DA (2004) Digestive and functional prop-
erties of a partially hydrolyzed cassava solid waste with high insoluble fiber concentration.
Sci Agric 61(3):286–291
95. Giuntini EB, Lajolo FM, Menezes ED (2003) Dietary fiber potential in Ibero-American coun-
tries: food, products and residues. Arch Latinoam Nutr 53(1):14–20. (In Portuguese)
96. Leonel M, Cereda MP, Roaux X (1998) Cassava bagasse as a dietary food product. Trop
Sci 38(4):224–228. Available in: http://hdl.handle.net/11449/65385. Consulted in: 18th
February 2022
97. Pandey A, Soccol CR, Nigam P, Soccol VT, Vandenberghe LPS, Mohan R (2000)
Biotechnological potential of agro-industrial residues. II: cassava bagasse. Bioresour Technol
74(1):81–87. https://doi.org/10.1016/S0960-­8524(99)00143-­1
98. Silva ÉC, Cereda MP, Colman TD, Demiate IM, Schnitzler E (2015) Characterisation of
cassava bagasse in different granulometries from two starch processing plants. J Microbiol
Biotechnol Food Sci 05(02):99–102. https://doi.org/10.15414/jmbfs.2015.5.2.99-­102
99. Lacerda AM, de Camargo L, Cereda MP (2021) Potential of arrowroot bran from starch
extraction as a fiber source. (In Portuguese). Article in writing based on the Dissertation
(Master in Biotechnology, Catholic University of Campo Grande, MS, Brazil, 2015. (In
Portuguese)
100. Jones DA (1998) Why are so many food plants cyanogenic? Phytochemistry 47(2):155–162.
https://doi.org/10.1016/S0031-­9422(97)00425-­1
101. Behera SS, Ray RC (2017) Microbial linamarase in cassava fermentation. In: Microbial
enzyme technology in food applications. CRC Press, pp 333–346
102. McMahon JM, White WL, Sayre RT (1995) Cyanogenesis in cassava (Manihot esculenta
Crantz). J Exp Bot 46(7):731–741
103. Gomez S, Stuefer JF (2006) Members only: induced systemic resistance to herbivory in a
clonal plant network. Oecologia 147(3):461–468
Phytochemistry and Pharmacological
Studies of Indian Cinnamomum Schaeff

Saranya Surendran and Raju Ramasubbu

1 Introduction

Plants have been used for therapeutic purposes since the ancient times and about
400,000 plant species were reported around the world [1]. But only a small fraction
of these plant species, i.e., about 35,000–70,000, has been screened for their medici-
nal use [2]. India has a vast geographical area with high potential medicinal plants
used in Ayurveda, Sidha, Unani, and traditional medicines. The WHO reported that
of the 21,000 medicinal plants used all around the world, 2500 are found in India
[3]. The primary sources of medicine for early drug discovery are plants that are
reported to have ethno-pharmacological uses. Plant-derived compounds have better
patient tolerance and acceptance. Plant-derived compounds also have a long history
of clinical use [4] Many currently prescribed drugs were originally isolated from
plants and/or are semisynthetic analogues of phytochemicals [5].
The genus Cinnamomum belongs to the Lauraceae family consisting of 250 spe-
cies of trees and shrubs distributed in Southeast Asia, Australia, China, and Africa.
Most of Cinnamomum species are aromatic with a lot of medicinal and economic
importance as sources of essential oils, spices, and therapeutic drugs. Cinnamomum
species are widely used in herbal therapy in treating bronchitis, colds, sinusitis, and
fungal infections [6]. Their barks and leaves were used in foods as flavoring agent
and seasoning [7]. Several species of this genus such as C. malabatrum, C. walai-
warense, and C. trivancoricum were used to treat stomach pain. Cinnamomum
riparium, C. sulphuratum, C. filipedicellatum and C. wightii were used for treating
headaches, wounds, fever, and menstrual problems [8].
In traditional medicine, the cinnamon bark infusion was used as a remedy for
arthritis, rheumatism, nasopharyngeal infections, and stomach pain, whereas its

S. Surendran · R. Ramasubbu (*)

Department of Biology, The Gandhigram Rural Institute (Deemed to be University),
Dindigul, India

© The Author(s), under exclusive license to Springer Nature 649

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_26
650 S. Surendran and R. Ramasubbu

leaves, barks, and roots are used to treat diarrhea and dysentery [9], rheumatism and
inflammation [10], and neuralgic headaches. Mustaffa et al. [11] reported that the
leaves of C. iners are used to relieve fever and digestive problems and are used as
carminative [12]. Cinnamomum sulphuratum is reported to have anti-inflammatory
[13], hepatoprotective, and antimicrobial properties and is used for treating wounds,
fever/pyrexia, headache, backache [14], cholera, dyspepsia [15], menstrual prob-
lems, and worm infestation [16].
Cinnamomum zeylanicum leaf oil is used to treat toothache and its dried leaves
are used to induce menstruation [17] and also it has been used as a sweating agent
and an analgesic [18]. A wide range of pharmacological effects has been reported in
C. cassia including antitumor, anti-inflammatory, analgesic, neuroprotective, anti-
bacterial, antiviral, cardiovascular protective, immunoregulatory, antidiabetic, anti-­
obesity, cytoprotective, and anti-tyrosinase effects. Barks of Cinnamomum
camphora are used as antispasmodic, anodyne, sedative, anthelmintic, diaphoretic,
stimulative, and carminative agents [19]. Moreover, barks of Cinnamomum malaba-
trum are used as carminative agents and are reported to have antispasmodic, astrin-
gent, antiseptic, hemostatic, stomachic, and germicidal properties. It is reported that
oil from the barks of Cinnamomum malabatrum has the ability to cure diarrhea,
cough, and dysentery, and its roots and leaves are used to treat rheumatism. The
plant has been known to have several pharmacological effects such as analgesic and
anti-inflammatory [20], antioxidant [21], and anticancer effects [22]. Kurokawa
et al. [23] reported that C. verum possesses significant antiulcerogenic, antiallergic,
anesthetic, and antipyretic activities. Barks and leaves of C. tamala are used as
stimulant and carminative agents to treat gonorrhea, rheumatism, and diabetes [24].
Phytochemicals are biologically active, naturally occurring chemical compounds
found in plants, which provide health benefits for humans [25]. They are found in
different parts of plants such as roots, stems, flowers, fruits, leaves, or seeds [26].
Bioactive compounds include an extremely heterogeneous class of compounds such
as tocopherols, polyphenolic compounds, phytosterols, carotenoids, and organosul-
fur compounds [27]. The present review aims to compile the detailed information
on phytocompounds and pharmacological properties reported in different species of
Cinnamomum in India.

2 Phytochemicals Reported in Cinnamomum spp.

The species of Cinnamomum are potential sources of several medicinal phytocom-

pounds. Leela et al. [28] isolated the essential oils obtained from aerial parts of
C. malabatrum such as petiole, terminal shoot, leaf, and shoot and subjected to GC-­
MS analysis. Thirty-nine compounds are found in the leaves with (E)-caryophyllene,
(E)-cinnamyl acetate, bicyclogermacrene, and benzyl benzoate as the major con-
stituents. Moreover, 28 and 34 compounds are found in the petioles and shoots and
terminal shoots, respectively. Linalool is commonly found in the essential oils of
shoots, terminal shoots, and petioles. The leaf oil is found to be rich in sesquiterpene
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff 651

hydrocarbons, whereas other parts of the plant contained monoterpene alcohols.

The oil is also reported to have oxides: humulene epoxide II and caryophyllene
oxide. Humulene epoxide II is found only in the leaf oil, whereas petioles, terminal
shoots, and shoots contain caryophyllene oxide (Fig. 1).
Agrawal et al. [22] reported that C. malabatrum leaves contain cinnamic alde-
hyde, benzaldehyde, eugenol, camphor, cadinene, α-terpineol, limonene, geraniol,
eugenol acetate, ocimene, β-caryophyllene, γ-terpinene, β-phellandrene, benzyl
cinnamate, and benzyl acetate. The major constituents of bark oil such as cinnamal-
dehydes, kaempferol-3-O-sophoroside, 3,4′,5,7-tetra hydroxyl flavones, quercetin
3-O- rutin, and 3,3′,4′,5,7-pentahydroxy flavones are also present in C. malabatrum.
Aravind et al. [29] carried out the study on GCMS analysis of the C. malabath-
rum bark oil and identified 61 individual components, with linalool (68.21%) as the
dominant one. Other constituents, such as limonene, myristyl aldehyde, geraniol,
camphene, and eugenol, were also reported. Anil et al. [30] carried out the GC-MS
analysis of C. malabathrum and revealed the presence of 5-benzyloxy-4-butyl-2-­
methyl-2-nonene (17.26%), hexadecanoic acid methyl ester (16.48%), and 1-deoxy-­
D-ribitol as the major constituents. Natarajan et al. [31] reported chemical
compounds such as alkaloids, tannins, glycosides, triterpenoids, saponins, and fla-
vonoids in the ethanolic extract of C. malabatrum. Nath et al. [32] reported eight
components from the essential oil of C. sulphuratum leaf, of which linalool alone
constitutes about 92.66% and other components such as geraniol (2.2%) and citro-
nellol (l.47%) constitute over 1% of the oil. Baruah et al. [33] carried out the GC-­
MS analysis of stem and leaf bark oils of C. sulphuratum. Forty-six compounds
were isolated from the leaf and 29 from the bark. Geranial, neral, and geraniol were
the major constituents of the leaf oil. The bark oil was rich in (E)-cinnamaldehyde.
Phytochemical screening of C. sulphuratum barks and leaves reported four chemo-
types of C. sulphuratum such as linalool type [32], citral and cinnamaldehyde type
[33], cinnamaldehyde type [34], and methyl cinnamate type [35].
Apart from this, a new natural chemotype, benzyl benzoate type, of C. sulphura-
tum was reported by analyzing leaf and stem bark oils collected from the
Agasthyamalai forest area of the southern Western Ghats. Benzyl benzoate was the
major constituent, followed by phenylethyl benzoate (4.9%). Benzyl benzoate con-
tent in stem bark oil was about 98.2%, and leaf oil was about 89.5%. The obtained
results varied considerably from the earlier reports of C. sulphuratum, suggesting
that it was a new natural chemotype [15]. Maridass [13] reported that the crude
methanol extract of C. sulphuratum showed the presence of phenolic groups and
triterpenoids. Kumar et al. [36] detected several constituents such as α-phellandrene,
Z-β-ocimene, 1,1-dicyclopropyl-2-methyl-l-pentene, linalool, eugenol,
β-phellandrene β-caryophyllene, and benzyl benzoate by GC-MS analysis of leaf
essential oil from C. sulphuratum collected from Kodagu, Karnataka.
Singh et al. [37] isolated essential oils from the leaves of C. sulphuratum from
Champawat, Uttarakhand, and detected the presence of 1,8-cineole and α-terpineol
(major compounds) and terpinen-4-ol, sabinene, α-terpinene, α-phellandrene, lin-
alool, and limonene (minor compounds). Rameshkumar and George [15] reported
that the stem bark oils of C. verum contain cinnamaldehyde as the major
652 S. Surendran and R. Ramasubbu

(E)-caryophyllene, cinnamyl acetate Benzyl benzoate

3,3’,4’,5,7-pentahydroxy flavones Cinnamaldehyde

Quercetin 3-O- rutin kaempferol-3-O-sophoroside

Fig. 1 Phytochemicals of Cinnamomum spp

Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff 653

Coumarin

Terpinolene alpha terpineol Linalool

Eugenol Camphor

Cinnamic acid Alpha cubebene

Caryophyllene oxide alpha-phellandrene Isoeugenol

Fig. 26.1 (continued)

654 S. Surendran and R. Ramasubbu

component, and also moderate levels stem bark oils were detected in C. citriodorum
and C. sinharajanse. An unidentified Cinnamomum accession of Gammaduwa also
reported the presence of cinnamaldehyde. Rao et al. [38] isolated 25 compounds
from essential oils from the petiole of C. verum and carried out a GC-MS analysis.
The major components were (E)-cinnamaldehyde, eugenol, (E)-cinnamyl acetate,
and linalool.
Simic et al. [39] reported that the GC-MS analysis of C. verum detected eugenol,
cinnamaldehyde, cinnamaldehyde propylene, and limonene and a variety of terpe-
noid compounds (α-pinene, camphene). Mollenbeck et al. [40] reported a study on
C. verum essential oil. Trans-cinnamyl acetate was much higher in the flowers and
fruit volatile oils than in buds. The minor compounds included α-humulene and
α-muurolene. Leaf and bark oils of C. verum were rich in cinnamaldehyde [41] and
eugenol [42, 43]. Nath et al. [44] reported a chemotype of C. verum yielding benzyl
benzoate-rich leaf and bark essential oils from northeast India. The root-bark essen-
tial oil was reported to contain camphor as its main component in contrast to the
stem bark essential oil [45]. Linalool and (E)-cinnamyl acetate were the main con-
stituents of tender twigs’ essential oil [47].
Linalool, β-caryophyllene, and (E)-cinnamyl acetate were reported in essential
oils obtained from pedicels of buds, flowers, and fruits of C. verum [46, 47].
Mariappan et al. [48] analyzed chemical constituents of C. verum methanolic bark
extracted by GC-MS analysis. Trans-cinnamaldehyde, (E)-3-(2-methoxyphenyl)-2-­
propenoic acid, 4-vinyl benzoic acid, and coumarin were the major chemical con-
stituents identified. Cinnamomum verum dried leaves collected from Delhi were
reported to contain 1,2-trans-sabinene hydrate, (Z)-β-ocimene, and germacrene A as
the major compounds and α-gurjunene, myrcene, α-pinene, and β-sabinene as the
minor compounds. Trans-sabinene hydrate, (Z)-β-ocimene, and germacrene A were
the chemotypes reported [49].
Kapoor et al. [50] reported eugenol as a significant constituent of C. verum dried
leaves collected from Gorakhpur, Uttar Pradesh. The minor constituents were
spathulenol, aromadendrene, viridiflorene, and methyl eugenol. Joshi et al. [51]
reported GC-MS analysis of fresh leaf oil collected from Jeolikote, Uttarakhand.
The oil contains (E)-cinnamaldehyde and linalool as major compounds and
(E)-cinnamyl acetate, β-pinene, and α-copaene as minor compounds. Chanotiya
et al. [52] reported the chemical constituents of C. verum from Nainital district,
Uttarakhand. (E)-Cinnamyl acetate, linalool, and (Z)-cinnamaldehyde were the sig-
nificant compounds isolated, whereas camphene, α-Pinene, 3-phenylpropanal,
benzaldehyde, bornyl acetate, (Z)-cinnamyl acetate, coumarin, salicylaldehyde, and
β-copaen-4α-ol were reported with meager amount.
Agrawal et al. [53] collected fresh aerial parts of C. verum samples from three
areas of Uttarakhand and analyzed their chemical compositions. Linalool and
(E)-cinnamaldehyde were the major constituents, and 1,8-cineole was the minor
constituent of samples collected from Munsiyari. Linalool, (E)-cinnamaldehyde,
and camphor were the major compounds of Lohaghat and Champawat samples.
Pithoragarh and Tanakpur samples were reported to contain significant compounds
such as linalool, (E)-cinnamaldehyde, and cinnamyl acetate. Eugenol,
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff 655

(E)-cinnamaldehyde, (E)-cinnamyl acetate, and epicubenol were the compounds

reported from Pantnagar samples. Cinnamomum verum leaf samples collected from
Chandigarh Botanical Garden were reported to contain methyl eugenol, eugenol,
(E)-cinnamyl acetate, and β-caryophyllene (major components) and cinnamalde-
hyde and ascabin (minor components) [54]. Rana et al. [55] reported chemical con-
stituents such as eugenol and eugenyl acetate (major components), and
α-phellandrene (minor component) from fresh leaves of C. verum.
Lohani et al. (2015) [56] collected leaves of many populations of C. verum from
Nainital, Pithoragarh, Pauri, Champawat, Tehri, Rudraprayag, Almora, and Chamoli.
The shade-dried leaves of C. verum detected cinnamaldehyde (major compound)
and caryophyllene oxide, cinnamyl acetate, benzaldehyde, β-pinene, and 1,8-­cineole
as minor compounds in 13 populations. Three populations contain cinnamyl ace-
tate, cinnamaldehyde, benzaldehyde, β-pinene, 1, 8-cineole, and caryophyllene
oxide (minor compounds). Linalool, cinnamaldehyde (major), β-pinene, 1,8-­cineole,
caryophyllene oxide, and benzaldehyde were reported in 6 populations. Thirteen
populations were reported with cinnamaldehyde and linalool. The minor constitu-
ents were caryophyllene oxide, benzaldehyde, 1,8-cineole, and β-pinene. Shade-­
dried leaves of C. verum from Arunachal Pradesh contained α-phellandrene,
eugenol, β-phellandrene, α-pinene, elixene, cis-caryophyllene, myrcene, and limo-
nene [57].
Williams et al. [58] reported high concentrations of proanthocyanidins and trans-­
cinnamaldehyde in C. verum extract. Cinnamomum verum dried leaves collected
from Delhi were reported to contain 1,2-trans-sabinene hydrate, (Z)-β-ocimene, and
germacrene A as major compounds and α-gurjunene, myrcene, α-pinene, and
β-sabinene as minor compounds. Trans-sabinene hydrate, (Z)-β-ocimene, and ger-
macrene A were the chemotypes reported [49]. Bark and twig of Cinnamomum
verum were reported to contain cinnamaldehyde and 2-methoxycinnamaldehyde
[59–61]. Alva et al. [62] isolated and identified potential anti-quorum sensing (QS)
compounds such as benzenamine, cyclohexyl-15-crown-5, N; N-diethyl-4-methyl-,
2-methyl-, and 2-propenoic acid; and oxybis(2,1-ethanediyloxy-2,1-ethanediyl)
from leaf ethanolic extract of C. verum against Pseudomonas aeruginosa based on
the in silico analysis.
Singh et al. [63] reported GC-MS analysis of C. zeylanicum leaf volatile oil and
oleoresin identified 19 and 25 components. About 13 components were identified
from the C. zeylanicum bark volatile oil, whereas its bark oleoresin showed the pres-
ence of 17 components. The major component was (E)-cinnamaldehyde followed
by d-cadinene. Jayaprakash et al. [47] reported that the volatile oil from C. zeylani-
cum fruit grown at Karnataka and Kerala consists of hydrocarbons and oxygenated
compounds, b-caryophyllene, and trans-cinnamyl acetate as major constituents.
Raina et al. [64] reported eugenol, linalool, and piperitone as major components of
leaf oil of Andaman. Cinnamomum zeylanicum leaf oil is used as a source of euge-
nol [65]. Cinnamomum zeylanicum was reported with high levels of eugenol and
cinnamaldehyde [66]. Duke [67] reported that C. zeylanicum bark contains volatile
oils of eugenol, trans-cinnamic acid, cinnamaldehyde, condensed tannins, phenolic
compounds, catechins, proanthocyanidins, monoterpenes and sesquiterpenes,
pinene, calcium-monoterpene oxalate, mucilage, gum, resin, and traces of coumarin.
656 S. Surendran and R. Ramasubbu

The GC-MS studies of C. zeylanicum essential oil clearly showed the presence
of 38 components which include monoterpenes, sesquiterpenes, aromatic alde-
hydes, and ketones. Cinnamaldehyde was the major compound, followed by benz-
aldehyde [68]. Cinnamomum zeylanicum bark essential oil possesses compounds
such as cinnamic acid, cinnamaldehyde, eugenol, benzoic acid, benzaldehyde, trit-
erpenes, monoterpenes, and sesquiterpenes [69]. Vangalapati et al. [70] reported
presence of chemical constituents in different parts of C. zeylanicum. The barks and
leaves contain cinnamaldehyde and eugenol, respectively. Roots and barks showed
the presence of camphor and trans-cinnamyl acetate and the fruits β-caryophyllene.
Buds showed the presence of terpene hydrocarbons, alpha-bergamotene, alpha-­
copaene, and oxygenated terpenoids. Flowers showed the presence of (E)-cinnamyl
acetate, trans-alphabergamotene, and caryophyllene oxide.
Jakhetia et al. [71] reported that C. zeylanicum contains cinnamic acid, cinnam-
aldehyde, cinnamate, trans-cinnamaldehyde, caryophyllene oxide, l-borneol,
l-­bornyl acetate, eugenol, b-caryophyllene, E-nerolidol, cinnamyl acetate, terpin-
olene, a-terpineol, a-cubebene, and alpha-thujene. Cinnamomum zeylanicum oil has
been reported to contain chemical constituents such as cinnamic acid, benzoic acid,
and benzaldehyde whose lipophilic part is responsible for its antimicrobial proper-
ties [72]. Cinnamomum zeylanicum bark essential oil contains cinnamyl acetate
[73]. Brari and Thakur [74] reported cinnamaldehyde and linalool from the essential
oil isolated from C. zeylanicum. The essential oil of C. zeylanicum bark was rich in
trans-cinnamaldehyde [75].
Cinnamomum zeylanicum bud volatile oil has been reported to contain δ-cadinene,
tetradecanol, α-humulene, α-copaene, α-bergamotene, and viridiflorene. Leaf oil
contains (E)-cinnamaldehyde, eugenol, β-caryophyllene, linalool, (E)-cinnamyl
acetate, and α-terpineol. Moreover, fruit stalks oil contain α-humulene, caryophyl-
lene, (E)-cinnamyl acetate, δ-cadinene, α-copaene, and (E)-τ-cadinol. Flower oil of
C. zeylanicum contain trans-α-bergamotene, caryophyllene oxide, tetradecanal,
α-cadinol, and globulol. Similar enantiomeric distributions have been reported for
C. camphora essential oil [76]. Mallavarapu et al. [77] isolated essential oil of
C. zeylanicum collected from Bangalore and Hyderabad and analyzed it by using
GC and GC-MS. Eugenol was reported as the main constituent along with 47 other
constituents. Both oil samples were different with respect to the quantities of lin-
alool, (3-caryophyllene, (E)-cinnamaldehyde, (E)-cinnamyl acetate, and benzyl
benzoate. The main phytocompounds of oil collected from Bangalore were
a-­phellandrene, eugenol, linalool, (E)-cinnamyl acetate (E)-cinnamaldehyde, and
P-caryophyllene, while those of oil collected from Hyderabad contained eugenyl
acetate, eugenol, benzyl benzoate, and linalool.
Mallavarapu and Ramesh [77] reported 49 constituents from fruit oil of C. zeyl-
anicum from Bangalore. The main constituents were a-pinene, P-caryophyllene,
G-cadinene, and a-muurolol. The phytocompounds of the oil under study were dif-
ferent from those of the earlier reports wherein (E)cinnamyl acetate and
P-caryophyllene were the main constituents. The oil has been reported to contain
phenyl propanoids, oxygenated monoterpenes, monoterpenes, and sesquiterpenes.
The main constituents of the oil were a-pinene, P-pinene, P-caryophyllene,
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff 657

a-­muurolene, y-cadinene, 3-cadinene, and a-muurolol. The oil was devoid of euge-
nol, E-cinnamaldehyde, benzyl benzoate, and camphor which are major constitu-
ents of the leaf, stem bark, and root oils of C. zeylanicum.
Senanayake et al. [78] reported that C. zeylanicum essential oil contained several
resinous compounds, such as cinnamic acid, cinnamaldehyde, and cinnamate. A
spicy flavor and a strong aroma of Cinnamomum were reported due to the presence
of cinnamaldehyde. Trans-cinnamaldehyde, terpinolene, cinnamyl acetate, eugenol,
caryophyllene oxide, L-borneol, b-caryophyllene, E-nerolidol, alpha-cubebene,
L-borneol acetate, alpha-terpineol, and alpha thujene were some of the essential oils
found in C. zeylanicum [63, 79, 80]. Aldehydes, esters, phenols, acids, diterpenes,
sesquiterpenes, monoterpenes, benzopyrones, hydrocarbon alcohols, and flavonoids
were the chemical substances found in C. zeylanicum. Aldehydes present in C. zey-
lanicum bark essential oil were methoxycinnamaldehyde, benzenepropanal, cinna-
maldehyde, vanillin, cuminaldehyde, benzaldehyde, hydrocinnamic,
2-methyl-3-phenyl-propanal, and citronellal. Alcohol groups present in C. zeylani-
cum were cinnamyl alcohol, α-terpineol, linalool, α-bisabolol, cinnamyl acetate
esters, cinnamaldehyde, methyl cinnamate, hydrocinnamyl acetate, benzyl benzo-
ate, and bornyl acetate [47, 81]. Brari and Thakur [74] reported cinnamaldehyde and
linalool from essential oil isolated from C. zeylanicum.
Kamalakannan et al. [82] isolated hymecromone and umbelliferone from etha-
nolic extract of C. cassia. Cinnamomum cassia contains volatile oils with cinnamic
acid, eugenol, cinnamyl alcohol, cinnamaldehyde, melilotic acid, δ-cadinene, phe-
nolic compounds, epicatechins, cinnamic aldehydes, monoterpenes, tannins, procy-
anidins, diterpenes, glycosides (cinnacassides A–Z), oxalate, sesquiterpenes
(pinene), and traces of coumarin [83]. Packiaraj et al. [84] reported major com-
pounds such as NDidehydrohexacarboxyl-2,4,5-trimethylpiperazine,
1,2,4-­triazoliumylide phenol, 3,5-dimethoxy acetate, and 4′-isopropylidene-bis-
(2-cyclohexyl) phenol. Coumarin (1,2-benzopyrone) content was reported with a
major difference between C. cassia and C. zeylanicum in their vegetative parts [85].
Tanaka et al. [86] isolated 3-(2-hydroxyphenyl)-propanoic acid and its
O-glucoside from the stem bark of C. cassia. Chemical compounds of C. cassia
were coumarin, (Z)-cinnamaldehyde, α-ylangene, and β-caryophyllene [87–89].
Barks and leaves of C. cassia contain cinnzeylanol, 19-dehydroxy-13-­
hydroxycinncassiol, (18R)-1-hydroxycinncassiol, (18S)-3-dehydroxycinncassiol
glucoside, (18S)-3-dehydroxy-8-hydroxycinncassiol, (18S)-cinncassiol, (18S)-3,5-­
didehydroxy-­ 1,8-dihydroxycinncassiol, and 2,3-dihydroxy-1-(4-hydroxy-3,5-
dimethoxyphenyl)-1-propanone [90, 91]. Leaves contain
(1R,2R)-4-[(3S)-3-hydroxybutyl]-3,3,5- trimethylcyclohex-4-ene-1,2-diol,
(3S,5R,6R,7E,9S)-3,5,6,9-tetrahydroxy-7-enemegastigmane, and (1R,2R,4S,6S)-4-
(2-hydroxypropan-2-yl)-1-methyl-7-oxabicyclo[4.1.0]heptan-2-ol dimethanol [90].
The twig of C. cassia was reported to contain certain chemical compounds such
as cinnamyl alcohol and 2-hydroxy-cinnamyl alcohol [61, 92], (+)-syringaresinol,
cinnamomulactone, 2-hydroxycinnamaldehyde [61, 91–93], cinnamic acid [92],
and phenethyl (E)-3-[4-methoxyphenyl]-2-propenoate [61]. Chemical constituents
reported in C. cassia leaves were 1-(3,4-dimethoxyphenyl)-1,2,3-propanetriol [90],
658 S. Surendran and R. Ramasubbu

(7S,8S)-syringoylglycerol [91], (+)-(1S,2S)-1-(3-methoxy-4-hydroxyphenyl)-1,2,3-­

propanetril-­2-O-β-D-glucopyranoside, n-butyl-β-D-fructofuranoside, tachioside
[89], (−)-4-epi-lyoniresinol [94].
Twigs of Cinnamomum cassia were reported to contain cinncassin A1, cinncas-
sin H, cinncassin I, cinncassin J, cinncassin K, cinncassin L, cinncassin M, cinna-
momoside A.9 [95], 5R-methyl-3-heptatriacontyl-2(5H)-furanone [96], cinncassin
A2, cinncassin A3, cinncassin A4, cinncassin A5, cinncassin A6, cinncassin A7,
cinncassin N, cinncassin O, cinncassin F [61, 91–93], icariside D, isotachioside
[97], 2-O-β-D-glucosyl-(1S)-phenylethylene glycol, and cinnamaldehyde [61].
Namomulactone was isolated from the C. cassia twigs together with nine known
compounds: cinnamaldehyde, trans-cinnamic acid, coumarin,
2-­hydroxycinnamaldehyde, 2-methoxycinnamaldehyde, benzoic acid, syringar-
esinol, 2-hydroxy-cinnamyl alcohol, and phenethyl (E)-3-[4-methoxyphenyl]-2-­
propenoate [62].
Several compounds were reported in C. camphora by various studies carried out
on different plant parts. Barks and leaves contain (7α, 7′α, 8α, 8′α)-3,7-hydroxy-4-­
methoxy-3′,4′- methylenedioxy lignane and (−)-medioresinol and trans-4,5-­
dimethoxy-­3-hydroxycinnamaldehyde [98]. Paulownin was also found in the bark
[99]. Twigs of C. camphora were reported to contain cinnacassin F [95].
(+)-Epipinoresinol was identified in leaves and barks [98]. Dimethylmatairesinol
and (7α,7′β,8α,8′α)-3-methoxy-4-hydroxy-3′,4′-methylenedioxy-7,9:7,9-­
diepoxylignane [98, 99] and trans-4,5-dimethoxy-3-hydroxycinnamaldehyde were
reported from C. camphora barks and leaves [98].
Singh et al. [37] reported 18 compounds from the C. glanduliferum essential oil
collected from Champawat (Uttarakhand). A high proportion of oil contain oxygen-
ated monoterpenes among which the predominant compounds were 1,8-cineole and
α-terpineol. Monoterpene hydrocarbons were present in C. glanduliferum.
1,8-­cineole, α-terpineol, germacrene D-4-ol, α-pinene, and α-thujene were the
major constituents. Chowdhury [100] reported the presence of 1,8- cineole, fol-
lowed by caryophyllene oxide, camphor, α-terpineol, and linalool. Leaf essential oil
composition of C. glanduliferum collected from Arunachal Pradesh was reported to
contain (E)-nerolidol, caryophyllene oxide, β-pinene, and linalool [101]. Prakash
et al. [102] reported chemical constituents such as germacrene D-4-ol, α-pinene,
α-terpineol, α-thujene, and 1,8-cineole from C. glanduliferum oil.
Kumar et al. [103] reported cinnamaldehyde, trans-cinnamyl acetate, ascabin,
hydrocinnamyl acetate, and beta-caryophyllene as the major constituents of
C. tamala leaves. Agrawal et al. [53] isolated essential oils from fresh aerial parts of
C. tamala collected from CIMAP, Pantnagar, Uttarakhand. Several chemical con-
stituents such as (E)-cinnamyl acetate, linalool, and (E)-cinnamaldehyde were iden-
tified. The stem barks and leaves of C. tamala collected from Mizoram showed the
presence of several chemical constituents. Methyl cinnamate was the major con-
stituent of stem bark oil. Trans-cinnamaldehyde, styrene, benzyl benzoate, and lin-
alool were the minor constituents being detected. Linalool and methyl cinnamate
were detected as the phytocompounds of leaf oil. Benzyl benzoate, α-pinene, hexa-
nol, β-pinene, and phellandrene were reported as the constituents of leaf oil [79].
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff 659

Nath et al. [32] carried out GC-MS analysis in C. tamala essential oil from Assam,
India. α-Linalool, α-pinene, and pinene were the major constituents, whereas cin-
namaldehyde and eugenol were the minor constituents.
Cinnamomum tamala leaves collected from Dehradun, Uttarakhand, contain cin-
namaldehyde, cis-linalool oxide, linalool, and cinnamyl acetate as the major con-
stituents. Benzaldehyde, 1,8-cineole, bornyl acetate, 3-phenyl propanal, and
p-cymene were the minor constituents [104]. Gulati et al. [105] reported linalool
and cinnamaldehyde from the two samples of C. tamala from the Kumaun region.
Cinnamaldehyde was reported as the main compound of C. tamala (Kubeczka and
Formacek 2002) [106–108]. Cinnamomum tamala oil samples were also reported to
contain cinnamic acid [109]. Showkat et al. [110] identified chemical constituents
such as β-caryophyllene, germacrene A, β-sabinene, α-pinene, myrcene, (Z)-β-­
ocimene, linalool, α-gurjunene, and trans-sabinene hydrate in C. tamala leaf essen-
tial oil. Leaf samples were detected with three flavonoid compounds: quercetin,
quercetin, and kaempferol [112]. Eugenol was the principal constituent in C. tamala
essential oil followed by eugenyl acetate and α-phellandrene [55]. Cinnamomum
tamala leaf volatile oil was reported to contain eugenol which is the major constitu-
ent [50, 112].
2,6,10-Trimethyl-12-oxatricyclo[7.3.0.0{1,6}]tridec-2-ene and hexahydropyri-
dine,4- [4,5-dimethoxyphenyl]-in were isolated from hexane extract, and three
compounds from dichloromethane extract, namely, 2,5-chloro-3β-­
hydroxy-6βnitro-5α-androstan-17-one, acetic acid,10,13-dimethyl-2-oxo-
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H cyclopenta
[a]phenanthren17-ylester, and 6á,19-CycloAndrost-4-ene-3,17-dione were reported
from extracts of C. tamala [113]. Heer et al. [114] reported 21 compounds from
fresh leaves of C. tamala essential oil collected from northwestern Himalaya by
GC-MS analysis. They consist of complex mixtures of monoterpenes, phenylpro-
panoids, and sesquiterpenes. Kumar et al. [103] reported that C. tamala leaves con-
tain several phytochemicals such as β-caryophyllene, trans-cinnamyl acetate,
eugenol, and cinnamaldehyde. Srivastava et al. [115] reported the GC-MS analysis
of C. camphora oil, and the major constituents were fenchone, camphene, a-­thujene,
L-limonene, and cisp-menthane. Camphor was found in C. camphora from
Pantnagar, Uttarakhand [53]
Ghalib et al. [116] reported C. iners from chloroform and alcoholic leaf extracts.
Nine components were detected as major components. Eicosanoic acid ethyl ester
and caryophyllene are the most prominent components of the chloroform extract.
Caryophyllene was the major compound of the alcohol extract. Udayaprakash et al.
[117] reported six compounds, i.e., pentadecanoic acid, 14-methyl-, methyl ester;
4-piperidineacetic acid, 10-octadecenoic acid, methyl ester; cyclopropanebutanoic
acid, 2-[[2-[[2-[(pentylcyclopropyl) methyl] cyclopropyl] methyl] cyclopropyl]
methyl]-, methyl ester; cyclopentaneundecanoic acid, methyl ester; 1-acetyl-5-­
ethyl2-[3-(2-hydroxyethyl)-1H-indol-2-yl]-a-methyl-methylester; and 3-pentyl-,
methyl ester, oxiraneundecanoic acid, found in the essential oil of leaves of C. iners
by GC-MS analysis.
660 S. Surendran and R. Ramasubbu

Baskaran and Ebbie [118] reported nine constituents including caryophyllene

oxide, terpinen-4-ol linalool, and benzyl benzoate which were the major constitu-
ents in the essential oil of C. chemungianum. Rameshkumar et al. [119] reported
β-selinene, caryophyllene oxide, longiborneol, tetradecanal, intermedeol, and
α-cyperone as major constituents of C. chemungianum essential oil.
Sriramavaratharajan and Murugan [120] reported a study on the essential oil of
C. chemungianum in which chemical constituents such as veratrole, ρ-cymen-7-ol,
germacrene B, longiborneol, and α-cyperone were not identified but had been
recorded from earlier studies. Several minor constituents present in the present
study were also not reported in the previous reports.
Five compounds, i.e., eugenol, isoobtusilactone, obtusilactone,
3,4-­methylenedioxy-5-methoxy cinnamyl alcohol, and myristicin, were detected in
C. subavenium roots [121]. Lai et al. [122] reported that C. subavenium barks con-
tain (±)-subaveniumin A and (±)-subaveniumin B. Huang et al. [123] reported
methyl cinnamate, methyl-trans-3-(3,4-dimethoxyphenyl)-3- propenoate,
3,4-­methylenedioxycinnamyl alcohol, 3,4-dimethoxycinnamyl alcohol, methyleu-
genol, safrole, carvacrol, thymol, 3,4-methylenedioxy, cinnamaldehyde, and
3,4-dimethoxy cinnamaldehyde in the C. subavenium bark. Both leaves and barks
of C. subavenium contain caryophyllene oxide and eugenol. Hao et al. [124]
reported 1α,6β-dihydroxy-5, 10-bis-epi-eudesm15-carboxaldehyde-6-O-β-D-­
glucopyranoside, and D-threo-guaiacylglycerol 7-O-β-D-glucopyranoside in the
barks of C. subavenium. Hao et al. [124] reported compounds such as wilsonol,
(3S,5R,6S,7E)-megasfigma-7-ene-3,5,6,9-tetrol, (4R)-p-menthama-1,2α,8-triol,
(3R,4R)-p-Menth-1-ene-3,4-diol 3-O-β-D-glucopyranosid, (3R,4S,6R)-p-menth-1-­
ene-3,6-diol 3-O-β-D-glucopyranoside, and asicariside B1 in the leaves of
C. subavenium.
Bakar et al. [125] reported that the barks of C. osmophloeum contain cinnamal-
dehyde and eugenol. Rao and Gan [126] have also reported that the leaves of
C. osmophloeum contain eugenol and cinnamaldehyde. Utchariyakiat et al. [127]
reported that its fruits contain trans-cinnamyl acetate, and caryophyllene. Barceloux
[129] has reported that its flowers contain trans-α-bergamotene, trans-cinnamyl
acetate, and caryophyllene oxide.
Leaf oil of C. cordatum contains chemical constituents such as methyl
(E)-cinnamate, terpinen-4-ol, linalool, α-terpineol, and methyl eugenol [66].
Camphor was the main constituent of the root bark oil, but unlike leaf and stem bark
oils, it does not have any commercial value. The main constituents found from bark
of root and stem were cinnamaldehyde and camphor [81]. Jantan et al. [128] identi-
fied 43 compounds from C. cordatum leaf essential oils with major constituents
such as phellandrene, benzyl benzoate, linalool, terpinen-4-ol, benzyl salicylate,
(E)-methyl cinnamate, and methyl eugenol. The essential oils obtained from the
bark of C. cordatum contain cinnamaldehyde, leaves contain eugenol, roots have
camphor, and buds show the presence of α-bergamotene and α-copaene. Flowers,
fruits, and fruit stalks contain trans-cinnamyl acetate [87].
Baruah and Nath [101] have reported phytocompounds of C. glaucescens essen-
tial oils isolated from leaf, panicle, and stem bark in Assam. Leaf oils showed the
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff 661

presence of α-phellandrene, α-farnesene, 1, 8-cineole, α-pinene, linalool, and

α-phellandrene (major compounds) and β-pinene, β-caryophyllene, and terpineol
(minor compounds). Essential oil composition of C. impressinervium was studied
with both wild and fresh cultivated leaves. Presence of eugenol and δ-3-carene was
detected in fresh wild leaves. Eugenol was detected in cultivated leaf samples and
the minor constituents of fresh wild leaves were limonene, α-pinene, and eugenol
acetate. Limonene, δ-3-carene (1.6%), and eugenol acetate were the minor constitu-
ents [129].
Baruah and Nath [130] reported that the essential oil compositions of C. cham-
pokianum leaves from Arunachal Pradesh were elemicin and methyl eugenol
(4.9%). Nath et al. [44] carried out chemical analysis of shade-dried leaves, root
bark, and stem bark of C. pauciflorum and detected the presence of cinnamaldehyde
in all the samples. Nath et al. [129] reported (E)-cinnamaldehyde from C. pauciflo-
rum leaves from Meghalaya. Shade-dried leaves of (E)-cinnamaldehyde and lin-
alool were the major and minor compounds, respectively, of C. pauciflorum leaves.
Hrideek et al. [131] reported chemical constituents of bark and leaf oil of C. mac-
rocarpum and C. riparium. The major constituents of C. riparium bark oil were
shikimole, eugenyl methyl ether, and delta cadinene, whereas leaf contains shiki-
mole and eugenyl methyl ether. The major compounds of C. macrocarpum bark oil
were cinnamyl acetate, 4-teroinol, benzyl benzoate, and linalool. Cinnamomum
macrocarpum leaf oil contains cinnamyl acetate, gamma terpinene, and azulene as
the major compounds. Sriramavaratharajan et al. [133] reported phytocompounds
of essential oil of C. camphora, and 1,8-cineole has been detected in the essential
oils of C. agasthyamalayanum. However, camphor was the dominant compound of
C. agasthyamalayanum. Pinene and terpineol were the two major constituents of
C. camphora, but these were identified as minor constituents of essential oils of C.
agasthyamalayanum.
Sriramavaratharajan et al. [133] reported leaf essential oils from C. perrottetii
collected from three distinct populations in the southern Western Ghats, which were
analyzed by GC-FID and GC-MS. A total of 56 volatile constituents representing
92.2–96.3% of the oils were identified. Variations in the chemical constituents of the
oils were found. α-Pinene, tau-cadinol, and α-cadinol were the three major com-
pounds present in all three samples. Tau-cadinol and α-cadinol were the character-
istic constituents of C. perrottetii leaf. Twig and leaf essential oils of C. osmophloeum
have been reported with tau-cadinol and α-cadinol as the major constituents (Cheng
et al.) [134].
Coumarin content was reported to be higher in C. cassia than in C. verum,
C. tamala, and C. camphora. Cinnamomum cassia bark was reported to have sev-
eral cinnamaldehyde derivatives synthesized from cinnamic acid, such as
2′-hydroxycinnamaldehyde [89]. Baruah and Nath [135] reported that panicle
essential oil of C. bejolghota from the Jorhat area of Assam contains (Z)-methyl
α-farnesene, isoeugenol, β-caryophyllene, linalool, α-phellandrene, 1–8-cineole,
α-pinene, β-pinene, and β-phellandrene. Stem bark oil was reported to have
β-caryophyllene, β-pinene, α-terpineol, linalool, (E)-cinnamaldehyde, p-cymene,
662 S. Surendran and R. Ramasubbu

α-pinene, l,8-cineole, (E)-methyl cinnamate, α-phellandrene, terpinen-4-ol, euge-

nol, and (Z)-methyl isoeugenol.
Eugenol, linalool, cinnamyl acetate, cinnamaldehyde, α-caryophyllene, and
eugenol acetate were reported from cinnamon. C. camphora contains predomi-
nately (E)-cinnamaldehyde, 1,8-cineole and camphor. C. fragrans contains
α-pinene, β-caryophyllene, β-pinenes, and 1,8-cineole. C. angustifolium contains
α-phellandrene, 1,8-cineole, p-cymene, β-caryophyllene, and α-pinene. C. altissi-
mum bark essential oil contains phenolic compounds such as linalool, limonene,
methyl eugenol, terpinen-4-ol, c-terpinene, a-terpineol, 1,8-cineole, and a-terpinene
[136, 137]. Active constituents of C. keralaense bark were flavonoids, cardiac gly-
cosides, anthraquinone, and saponins [138]. Sriramavaratharajana et al. [132]
reported main constituent of the EOs of C. camphora, 1,8-cineole, was not identi-
fied in the EOs of C. agasthyamalayanum. Camphor was the principal constituent
of C. agasthyamalayanum; however, in C. camphora the concentration was much
lower (Table 1).

3 Pharmacological Activity of Cinnamomum spp.

3.1 Antimicrobial Activity of Phytocompounds

of Cinnamomum spp.

Bullerman et al. [139] reported that the bark oil of C. zeylanicum inhibited fungal
growth and aflatoxin production due to the presence of eugenol and cinnamalde-
hyde. Montes-Belmont and Carvajal [140] reported fungitoxic properties against
fungi involved in respiratory tract mycoses such as Aspergillus niger, A. fumigatus,
A. nidulans, and A. flavus. Simic et al. [39] reported that C. zeylanicum oil has the
strongest antifungal activity due to the presence of trans-cinnamaldehyde as the
major component. A study has been reported that 80% of bacteria and fungi were
killed by cinnamaldehyde [141]. Choudhary et al. [142] reported the antimicrobial
activity of Cinnamomum cassia essential oil against several bacterial cultures.
About 99.4% of the organisms including Streptococcus oralis, Micrococcus roseus,
S. anginosus, S. sanguinis, S. intermedius, and Enterobacter aerogenes were inhib-
ited, but it was not effective against Salmonella Paratyphi B.
Biavati et al. [143] studied the antimicrobial effects of C. cassia aqueous infu-
sion and observed inhibition in the microbial strains such as Micrococcus roseus,
S. intermedius, S. anginosus, S. mutans, S. sanguis, S. oralis, S. morbillorum, S. sal-
ivarius, S. uberis, Klebsiella pneumonia, and Flavobacterium. Rameshkumar et al.
[144] reported that C. filipedicellatum essential oil showed moderate activity against
gram-positive and gram-negative bacteria such as Salmonella Typhi and
Staphylococcus aureus, and no inhibition was observed in Pseudomonas aerugi-
nosa. Dongmo et al. [145] studied the antifungal activity of C. zeylanicum essential
oil from Cameroon against some common fungi causing spoilage of stored food
Table 1 Chemical compounds reported in Cinnamomum spp
Sl. no Plant name Distribution Phytocompounds isolated Source of compound Reference
1. Cinnamomum India [Karnataka, Kerala, Linalool, (E)-caryophyllene (E)-cinnamyl acetate Petiole, terminal Essential oils Leela et al. [28]
malabatrum Tamil Nadu]; endemic bicyclogermacrene, benzyl benzoate, caryophyllene shoot, leaf, and shoot
(Burm.f.) J.Presl oxide, and humulene epoxide II
3,4′,5,7-Tetrahydroxyl flavones, Leaves Extract Agrawal et al. [22]
3,3′,4′,5,7-pentahydroxy flavones, kaempferol-3-­O-
sophoroside, and quercetin 3-O-rutin
Eugenol, β-caryophyllene, cinnamic aldehyde, Bark Essential oils Agrawal et al. [22]
benzaldehyde, camphor, cadinene, limonene, geraniol,
ocimene, γ-terpinene, eugenol acetate, benzyl
cinnamate, β-phellandrene, α-terpineol, and benzyl
acetate, cinnamaldehydes
Alkaloids, tannins, glycosides, triterpenoids, flavonoids, Leaf Extract Natarajan et al. [32]
and saponins
Cinnamic aldehyde, benzaldehyde, eugenol, camphor, Leaves Essential oil Agrawal et al. [22]
cadinene, α-terpineol, limonene, geraniol, eugenol
acetate, ocimene, β-caryophyllene, γ-terpinene,
β-phellandrene, benzyl cinnamate, and benzyl acetate
Cinnamaldehydes. kaempferol-3-O-sophoroside, Bark Essential oil Agrawal et al. [22]
3,4′,5,7-tetrahydroxyl flavones, 3,3′,4′,5,7-pentahydroxy
flavones, and quercetin 3-O-rutin
N-Didehydrohexacarboxyl-2,4,5-­trimethylpiperazine, Leaf Packiaraj et al. [85]
1,2,4-triazoliumylide phenol 3,5-dimethoxy acetate,
4′-isopropylidene-bis-(2-­cyclohexyl) phenol
Cinnamaldehydes, kaempferol-3-O-sophoroside, Bark Essential oil Agrawal et al. [22]
3,4′,5,7-tetrahydroxyl flavones, 3,3′,4′,5,7-pentahydroxy
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff

flavones, and quercetin 3-O-rutin

Cinnamic aldehyde, benzaldehyde, eugenol, camphor, Leaves Essential oil Agrawal et al. [28]
cadinene, α-terpineol, limonene, geraniol, eugenol
acetate, ocimene, β-caryophyllene, γ-terpinene,
β-phellandrene, benzyl cinnamate, and benzyl acetate
(continued)
663
Table 1 (continued)
664

Sl. no Plant name Distribution Phytocompounds isolated Source of compound Reference

2. Cinnamomum India [Assam, Karnataka, Linalool, geraniol, citronellol Leaf Essential oil Nath et al. [32]
sulphuratum Nees Kerala, Meghalaya, Tamil Geranial, neral, and geraniol Stem, leaf, and bark Essential oil Baruah et al. [33]
Nadu], Myanmar; leaf
700–2000 m
Linalool-type Bark and leaves Essential oil Nath et al. [32]
Methyl cinnamate-type – – Baruah et al. [35]
Cinnamaldehyde-type – – Baruah et al. [34]
Benzyl benzoate Leaf and stem bark Essential oil Rameshkumar and
Phenylethyl benzoate oils George [15]
Phenolic groups and triterpenoids – Crude methanol Maridass [13]
extract
α-Phellandrene, Z-β-ocimene, 1,1-dicyclopropyl-2- Leaf Essential oil Kumar et al. [36]
methyl-l-pentene, linalool, eugenol, β-phellandrene
β-caryophyllene, and benzyl benzoate
S. Surendran and R. Ramasubbu
Sl. no Plant name Distribution Phytocompounds isolated Source of compound Reference
3. Cinnamomum verum India [widely cultivated], Cinnamaldehyde Stem bark Essential oil Rameshkumar and
J.Presl Brazil, Cambodia, China, George [15]
Fiji, Myanmar, Philippines, (E)-Cinnamaldehyde, eugenol, (E)-cinnamyl acetate, Petiole Essential oil Rao et al. [38]
Seychelles, Taiwan, and linalool
Tanzania, Vietnam; also
cultivated in many other Trans-cinnamyl acetate, α-humulene, α-muurolene Flowers, buds, and Essential oil Mollenbeck et al. [40]
countries in Asia, native to fruit
Sri Lanka Cinnamaldehyde Leaves and bark Essential oil Variyar and
Bandyopadhyay [41]
Eugenol – Essential oil Mallavarapu et al. [42];
Rao et al. [43]
Benzyl benzoate Leaf and bark Essential oil Nath et al. [44]
Camphor Root and bark Essential oil Wijesekera et al. [45]
Linalool and (E)-cinnamyl acetate Tender twigs Essential oil Kaul et al. [46]
Linalool, β-caryophyllene, and (E)- cinnamyl acetate Pedicels of buds, Essential oil Kaul et al. [46]
flowers, and fruits Jayaprakasha et al. [47]
Trans-cinnamaldehyde, 4-vinyl benzoic acid, coumarin, Bark Methanolic Mariappan et al. [48]
(E)-3-(2-methoxyphenyl)-2-propenoic acid extract
α-Linalool, α-pinene, and α-pinene cinnamaldehyde and – Essential oil Nath et al. [32]
eugenol
1,2-Trans-sabinene hydrate, (Z)-β-ocimene, germacrene Dried leaves Essential oil Mir et al. [49]
A, α-gurjunene, myrcene, α-pinene, β-sabinene,
trans-sabinene hydrate, (Z)-β-ocimene, germacrene A
(continued)
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff
665
Table 1 (continued)
666

Sl. no Plant name Distribution Phytocompounds isolated Source of compound Reference

Eugenol and α-phellandrene, p-cymene, α-pinene, Fresh leaf Essential oils Baruah et al. [130]
1,8-cineole, eugenol acetate, benzaldehyde, linalool
α-Terpineol, p-cymene, 1,8-cineole, α-phellandrene, Stem bark Essential oils Baruah et al. [130]
terpin-4-ol, α-pinene, β-pinene, linalool, myrcene,
α-terpinene, caryophyllene
Eugenol, spathulenol, aromadendrene, viridiflorene, and Dried leaves Essential oils Kapoor et al. [50]
methyl eugenol
(E)-Cinnamaldehyde, linalool, (E)-cinnamyl acetate, Leaf Essential oils Joshi et al. [209]
β-pinene, and α-copaene
Linalool and (E)-cinnamaldehyde, 1,8-cineole, Fresh aerial parts Essential oil Agrawal et al. [53]
camphor, eugenol, (E)- cinnamaldehyde, (E)-cinnamyl
acetate, epicubenol
Methyl eugenol, eugenol, (E)-cinnamyl acetate, and – – Kumar et al. [54]
β-caryophyllene, ascabin, cinnamaldehyde
Cinnamaldehyde, cinnamyl acetate, and linalool Leaves Essential oil Lohani et al. [56]
Cinnamaldehyde, cis-linalool oxide, linalool, and Leaves Essential oil Mohan et al. [104]
cinnamyl acetate, benzaldehyde, 1,8-cineole, bornyl
acetate, 3-phenyl propanal, and p-cymene
α-Linalool, α-pinene, pinene, cinnamaldehyde, and Leaf Essential oil Nath et al. [32]
eugenol
Cinnamaldehyde, cinnamyl acetate, and linalool Leaves Essential oil Lohani et al. [56]
α-Phellandrene, eugenol, β-phellandrene, α-pinene, Leaves Essential oil Sankaran et al. [57]
elixene, cis-caryophyllene, myrcene, limonene
Proanthocyanidins and trans-cinnamaldehyde Bark Extract Williams et al. [58]
1,2-Trans-sabinene hydrate, (Z)-β-ocimene, germacrene – Essential oil Mir et al. [49]
A, α-gurjunene, myrcene, α-pinene, β-sabinene,
trans-sabinene hydrate, (Z)-β-ocimene, and germacrene
p-Cymene, α-pinene, 1,8-cineole, eugenol acetate, Leaf Essential oil Baruah et al. [130]
benzaldehyde, linalool, eugenol, and α-phellandrene
S. Surendran and R. Ramasubbu
Sl. no Plant name Distribution Phytocompounds isolated Source of compound Reference
α-Terpineol, p-cymene, 1,8-cineole, α-phellandrene, Stem bark Essential oil Baruah et al. [130]
terpin-4-ol, α-pinene, β-pinene, linalool, myrcene,
α-terpinene, caryophyllene
Eugenol, spathulenol, aromadendrene, viridiflorene, and Leaves Essential oil Kapoor et al. [50]
methyl eugenol
(E)-Cinnamaldehyde, linalool, (E)-cinnamyl acetate, – Essential oil Joshi et al. [51]
β-pinene, α-copaene, α-copaene
Cinnamyl acetate, linalool, and (Z)- cinnamaldehyde, Leaves Essential oil Chanotiya et al. [52]
camphene, α-pinene, 3- phenyl propanal, benzaldehyde,
bornyl acetate, (Z)-cinnamyl acetate, coumarin,
salicylaldehyde, and β-copaen-4α-ol
Linalool, (E)-cinnamaldehyde and camphor linalool, Aerial part Essential oil Agrawal et al. [53]
(E)-eugenol, (E)- cinnamaldehyde, (E)-cinnamyl
acetate, epicubenol
Methyl eugenol, eugenol, (E)-cinnamyl acetate, and Leaf Essential oil Kumar et al. [103]
β-caryophyllene (major constituents) and
cinnamaldehyde and ascabin (minor components)
Cinnamaldehyde, cinnamyl acetate, and linalool Leaves Essential oil Lohani et al. [56]
Cinnamaldehyde, cis-linalool oxide, linalool, and Leaves Essential oil Mohan et al. [104]
cinnamyl acetate benzaldehyde, 1,8-cineole, bornyl
acetate, 3-phenyl propanal, and p-cymene
Eugenol, eugenyl acetate, α-phellandrene β-elemene, Leaves Essential oil Rana et al. [55]
acetyl eugenol, and isoeugenol
Cinnamyl acetate, benzaldehyde β-pinene, 1,8-cineole, Leaves Essential oil Lohani et al. [56]
and caryophyllene oxide cinnamaldehyde and linalool
α-Phellandrene, eugenol, β-phellandrene, α-pinene, Leaves Essential oil Sankaran et al. [57]
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff

elixene, cis-caryophyllene, myrcene, limonene

Proanthocyanidins and trans-cinnamaldehyde – Extract Williams et al. [58]
α-Linalool, α-pinene, cinnamaldehyde, and eugenol Leaf Essential oil Nath et al. [32]
α-Pinene, β-pinene, α-linalool, 1,2-trans-sabinene Leaves Essential oil Mir et al. [49]
hydrate, germacrene A, myrcene, α-gurjunene,
β-sabinene (Z)-β-ocimene
667

(continued)
Table 1 (continued)
668

Sl. no Plant name Distribution Phytocompounds isolated Source of compound Reference

Eugenol, p-cymene, α-pinene, 1,8-cineole, acetate, Leaf and stem bark Essential oil Baruah et al. [130]
benzaldehyde, α-terpineol, terpin-4-ol, α-pinene,
b-pinene, linalool, myrcene, α-terpinene, caryophyllene,
terpineol, α-phellandrene
Cinnamaldehyde, 2-methoxycinnamaldehyde Bark and twig – Yan et al. [59]; Liu et al.
[60]; Kim et al. [61]
Benzenamine, cyclohexyl-15-crown-5, N, N-diethyl-4- Leaf Ethanolic extract Alva et al. [62]
methyl-, oxybis (2,1-ethanediyloxy-2,1-ethanediyl) and
2-methyl-, 2-propenoic acid
Eugenol Leaf Essential oil Singh et al. [63]
4. Cinnamomum India [widely cultivated], Oxygenated trans-cinnamyl acetate and b-caryophyllene Fruit Essential oil Jayaprakash et al. [47]
zeylanicum Linn. Brazil, Cambodia, China, Eugenol, linalool, and piperitone Leaf Essential oil Raina et al. [64]
Fiji, Myanmar, Philippines,
Seychelles, Taiwan, Eugenol Leaf Essential oil Reynolds [65]
Tanzania, Vietnam; also Eugenol, trans-cinnamic acid, cinnamaldehyde, Bark Essential oil Duke [67]
cultivated in many other condensed tannins, catechins, proanthocyanidins,
countries in Asia, native to phenolic compounds, gum, pinene, calcium-monoterpenes
Sri Lanka oxalate, resin, mucilage and traces of coumarin
Eugenol and cinnamaldehyde – – Jantan et al. [66]
Monoterpenes, ketones, sesquiterpenes, and aromatic – Essential oil Uma et al. [68]
aldehydes, cinnamaldehyde benzaldehyde
Cinnamic acid, cinnamaldehyde, eugenol, benzoic acid, Bark Essential oil Gupta et al. [69]
benzaldehyde, triterpenes, sesquiterpenes, and
monoterpenes
Cinnamaldehyde and eugenol Bark and leaves Essential oil Vangalapati et al. [70]
(E)-Cinnamyl acetate, trans-alpha-bergamotene, and Flowers Essential oil Vangalapati et al. [70]
caryophyllene oxide
Camphor Bark and root Essential oil Vangalapati et al. [70]
Trans-cinnamyl acetate and β-caryophyllene Fruit Essential oil Vangalapati et al. [70]
Terpene hydrocarbons, alpha-copaene, alpha- Buds Essential oil Vangalapati et al. [70]
S. Surendran and R. Ramasubbu

bergamotene, and oxygenated terpenoids

Sl. no Plant name Distribution Phytocompounds isolated Source of compound Reference
Cinnamic acid, benzoic acid, and benzaldehyde that is – Essential oil Ramos-Nino et al. [72]
lipophilic
Cinnamyl acetate Bark Essential oil Gupta et al. [73]
Cinnamaldehyde, linalool – Essential oil Brari and Thakur [74]
Trans-cinnamaldehyde Bark Essential oil Baratta et al. [75]
Tetradecanol, α-humulene, δ-cadinene, α-copaene, Bud Essential oil Pragadheesh et al. [76]
viridiflorene, and α-bergamotene
Contain (E)-cinnamaldehyde, eugenol, β-caryophyllene, Leaf Essential oil Pragadheesh et al. [76]
linalool, (E)-cinnamyl acetate, and α-terpineol
Caryophyllene oxide, tetradecanal, trans- Flower Essential oil Pragadheesh et al. [76]
α-bergamotene, α-cadinol, and globulol
α-Humulene, caryophyllene, (E)-τ-cadinol, Fruit stalks Essential oil Pragadheesh et al. [76]
(E)-cinnamyl acetate, δ-cadinene, α-copaene
Linalool, 3-caryophyllene, (E)-benzyl benzoate, – Essential oil Mallavarapu et al. [42]
cinnamaldehyde, and (E)- cinnamyl acetate
Cinnamic acid, cinnamaldehyde, cinnamate – Essential oil Senanayake et al. [78]
Terpinolene, cinnamyl acetate, trans-cinnamaldehyde, – Essential oil Singh et al. [63];
eugenol, caryophyllene oxide, L-borneol, Malsawmtluangi et al.
b-caryophyllene, E-nerolidol, alpha-cubebene, [79]; Jayaprakasha et al.
L-borneol acetate, alpha-terpineol, and alpha thujene [80]
Methoxycinnamaldehyde, benzenepropanal, – Essential oil Jayaprakasha et al. [47,
cinnamaldehyde, vanillin, cuminaldehyde, 81]
benzaldehyde, hydrocinnamic, 2-methyl-3-phenyl-
propanal, and citronellal; cinnamyl alcohol, α-terpineol,
linalool, and α-bisabolol; cinnamyl acetate esters,
diethyl acetal, cinnamaldehyde, methyl cinnamate,
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff

hydrocinnamyl acetate, benzyl benzoate, bornyl acetate

Cinnamaldehyde and linalool – Essential oil Brari and Thakur [74]
(continued)
669
Table 1 (continued)
670

Sl. no Plant name Distribution Phytocompounds isolated Source of compound Reference

5. Cinnamomum cassia Southern China, Southeast Hymecromone and umbelliferone – Ethanolic extract Kamalakannan et al. [82]
(L.) J.Presl Asia (India, Indonesia, Cinnamic acid, eugenol, cinnamyl alcohol, – Essential oil Liao et al. [83]
Laos, Malaysia, Thailand, cinnamaldehyde, melilotic acid, δ-cadinene, phenolic
and Vietnam) compounds, epicatechins, cinnamic aldehydes,
monoterpenes, tannins, procyanidins, diterpenes,
glycosides (cinnacassides A–Z), oxalate, sesquiterpenes
(pinene), and traces of coumarin
4′-Isopropylidene-bis-(2-cyclohexyl) phenol, Packiaraj et al. [84]
NDidehydrohexacarboxyl-2,4,5-trimethylpiperazine,
1,2,4-triazoliumylide phenol 3, 5-dimethoxy acetate
Coumarin (1, 2-benzopyrone) – – Archer [85]
O-Glucoside and 3-(2-hydroxyphenyl)- propanoic acid Root bark Essential oil Tanaka et al. [86]
Coumarin, (Z)-cinnamaldehyde, α-ylangene, and – – Mbaveng and Kuete [88];
β-caryophyllene Chericoni et al. [87];
Bansode [89]
Cinnzeylanol, 19-dehydroxy-13-hydroxycinncassiol, Bark and leaves – Zhou [90] Yang [91]
(18R)-1-hydroxycinncassiol, (18S)-3-
dehydroxycinncassiol glucoside, (18S)-3-dehydroxy-8-
hydroxycinncassiol (18S)-cinncassiol,
(18S)-3,5-didehydroxy-1,8-dihydroxycinncassiol,
2,3-dihydroxy-1-(4-hydroxy-3,5-dimethoxyphenyl)-1-
propanone
(1R,2R,4S,6S)-4-(2-Hydroxypropan-2-yl)-1-methyl-7- Leaves – Zhou [90]
oxabicyclo[4.1.0]heptan-2-ol dimethanol (1R,2R)-4-
[(3S)-3-Hydroxybutyl]-3,3,5-trimethylcyclohex-4-ene-
1,2-diol and
(3S,5R,6R,7E,9S)-3,5,6,9-tetrahydroxy-7-
enemegastigmane
S. Surendran and R. Ramasubbu
Sl. no Plant name Distribution Phytocompounds isolated Source of compound Reference
Cinnamyl alcohol 2-hydroxy-cinnamyl alcohol Twig – Kim et al. [61]; Chen [92]
(+)-Syringaresinol, cinnamomulactone, – – Chen [92]; Yang [91]; He
2-hydroxycinnamaldehyde et al. [93]
Kim et al. [61]
Cinnamic acid – – Chen [92]; Yan et al. [59]
Phenethyl (E)-3-[4-methoxyphenyl]-2- propenoate – – Kim et al. [61]
1-(3,4-Dimethoxyphenyl)-1,2,3-propanetriol Leaves – Zhou [90]
(7S,8S)-Syringoylglycerol – – Yang [91]
(−)-4-epi-Lyoniresinol Leaves – Zeng et al. [94]
n-Butyl-β-D-fructofuranoside, (+)-(1S,2S)-1-(3- – – Zhou [90]
Methoxy-4-hydroxyphenyl)- 1,2,3-propanetril-2-O-β-D-
glucopyroside, tachioside
Cinncassin A1, cinncassin J, cinncassin I, cinncassin L, Twig – Liu et al. [95]
cinncassin M, cinncassin K, cinnamomoside, and
cinncassin H
5R-Methyl-3-heptatriacontyl-2(5H)-furanone – – Li et al. [96]
Cinncassin A2, cinncassin A3, cinncassin A4, cinncassin – – Chen [92]; Yang [91] Kim
A5, cinncassin A6, cinncassin A7, cinncassin N, et al. [61] He et al. [93]
cinncassin O, cinncassin F
Icariside D, isotachioside – – Guo et al. [97]
Namomulactone, a new butyrolactone, syringaresinol, Twigs – Kim et al. [61]
cinnamaldehyde, coumarin, 2-hydroxycinnamaldehyde,
trans-cinnamic acid, 2-methoxycinnamaldehyde,
benzoic acid, phenethyl (E)-3-[4-methoxyphenyl]-2-
propenoate, 2-hydroxy-cinnamyl alcohol
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff

Cinnamaldehyde derivatives synthesized from cinnamic Bark – Bansode [89]

acid, such as 2′-hydroxycinnamaldehyde and coumarin
2-O-β-D glucosyl-(1S)-phenylethylene glycol, – – Kim et al. [61]; Yan et al.
cinnamaldehyde [59]
(continued)
671
Table 1 (continued)
672

Sl. no Plant name Distribution Phytocompounds isolated Source of compound Reference

6. Cinnamomum India [Andhra Pradesh, (7α, 7′α, 8α, 8′α)-3, 7-Hydroxy-4-methoxy-3′,4′- Bark and leaves – Feng [98]
camphora (L.) J. Andaman Islands, Assam, methylenedioxy lignane and (−)-medioresinol and
Presl Karnataka, Kerala, Nicobar trans-4,5-dimethoxy-3-hydroxycinnamaldehyde
Islands, Maharashtra, Trans-4,5-Dimethoxy-3-hydroxycinnamaldehyde, Bark and leaves – Feng [98]
Tamil Nadu, Tripura, West (+)-epipinoresinol
Bengal – widely
cultivated], China, Japan Dimethylmatairesinol and (7α, 7′β, 8α, – – Xu [99]; Feng [98]
(native), Korea, and 8′α)-3-Methoxy-4-hydroxy-3′,4′-methylenedioxy-
Vietnam and widely 7,9:7,9-diepoxylignane
cultivated all over the Fenchone, camphene, a-thujene, L-limonene, and – Essential oil Srivastava et al. [115]
world cisp-menthane
p-Cymene, camphor, a-pinene, alpha- humulene, – Essential oils Joshi et al. [51]
1,8-cineole, and camphene
Camphor – – Agrawal et al. [53]
Pinene and terpineol, 1,8-cineole – Essential oil Sriramavaratharajana
et al. [132]
1,8-cineole, (E)-cinnamaldehyde, and camphor – – Abdelwahab et al. [154];
Chalchat and Valade
[137]
S. Surendran and R. Ramasubbu
Sl. no Plant name Distribution Phytocompounds isolated Source of compound Reference
7. Cinnamomum India [Assam, Meghalaya, 1,8-Cineole and α-terpineol. Monoterpene hydrocarbons – Essential oil Singh et al. [37]
glanduliferum Tripura], Bangladesh, germacrene D-4-ol, α-pinene, and α-thujene
(Wall.) Meisn. Bhutan, China, Malaysia, 1,8-cineole, caryophyllene oxide, camphor, α-terpineol, – – Chowdhury [100]
Myanmar, Nepal, Tibet; linalool.
1500–2500 (−3000) m
(E)-Nerolidol, caryophyllene oxide, β-pinene, and Leaf Essential oil Baruah and nath et al.
linalool [101]
1,8-Cineole, α-terpineol, germacrene D-4-ol, α-pinene, – Essential oil Singh et al. [37]
and α-thujene
β-Caryophyllene, β-pinene, α-terpineol, Stem bark Oil Baruah and Nath [101]
(E)-cinnamaldehyde, p-cymene, linalool, α-pinene,
l,8-cineole, (E)-methyl cinnamate, α-phellandrene,
terpinen-4-ol, eugenol, and (Z)-methyl isoeugenol
Germacrene D-4-ol, α-pinene, α-terpineol, α-thujene, – Essential oil Prakash et al. [102]
and 1,8-cineole
8. Cinnamomum Ascabin, cinnamaldehyde, hydrocinnamyl acetate, Leaves Essential oil Kumar et al. [103]
tamala (Buch.- beta-caryophyllene, and trans-cinnamyl acetate
Ham.) T.Nees & (E)-Cinnamyl acetate, linalool, and (E)-cinnamaldehyde Fresh aerial parts Essential oils Agrawal et al. [53]
Eberm.
Methyl cinnamate Stem and bark Essential oils Malsawmtluangi et al. [79]
Trans-cinnamaldehyde, styrene, benzyl benzoate, and Leaf Essential oils Malsawmtluangi et al.
linalool and methyl cinnamate, α-pinene, β-pinene, [79]
hexanol, and phellandrene
Linalool and cinnamaldehyde – – Gulati et al. [105]
Cinnamaldehyde – – Gulati et al. [105];
Kubeczka and Formacek
[106]; Dighe et al. [107];
Seth et al. [108]
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff

(continued)
673
Table 1 (continued)
674

Sl. no Plant name Distribution Phytocompounds isolated Source of compound Reference

Cinnamic acid – Essential oil Husain et al. [109]
Germacrene A, β-sabinene, β-caryophyllene, α-pinene, Leaf Essential oil Showkat et al. [110]
myrcene, (Z)-β-ocimene, linalool, α-gurjunene, and
trans-sabinene hydrate
Flavonoid compounds: quercetin, quercetin, and Leaf – Prasad et al. [111]
kaempferol
Eugenol eugenyl acetate and α-phellandrene – Essential oil Rana et al. [55]
Eugenol Leaf Volatile oil Dighe et al. [107];
Kapoor et al. [50]
Two compounds: hexahydropyridine,4- – Hexane extract Khajapeer et al. [113]
[4,5-dimethoxyphenyl]-in and 2,6,10-trimethyl-12-
oxatricyclo[7.3.0.0{1,6}] tridec-2-ene
2,5-Chloro-3β-hydroxy-6βnitro-5α-androstan-17-one, – Dichloromethane Khajapeer et al. [113]
acetic acid,10,13-dimethyl-2-oxo- extract
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H
cyclopenta [a]phenanthren17-ylester and
6á,19-CycloAndrost-4-ene-3,17-dione
Mixtures of monoterpenes, phenylpropanoids, and Leaves Essential oil Heer et al. [114]
sesquiterpenes.
β-Caryophyllene, trans-cinnamyl acetate, eugenol, and Leaves – Kumar et al. [54]
cinnamaldehyde.
9. Cinnamomum iners India [Assam, Tripura], Eicosanoic acid ethyl ester and caryophyllene – Chloroform Ghalib et al. [116]
Reinw. ex Blume Bangladesh, Cambodia, extract
China, Jawa, Indonesia, caryophyllene – Alcohol extract Ghalib et al. [116]
Laos, Malaysia, Myanmar,
Philippines, Sri Lanka, Pentadecanoic acid, 14-methyl-, methyl ester; Leaves – Udayaprakash et al. [117]
Sumatra, Thailand, Tibet, 4-piperidineacetic acid, 10-octadecenoic acid,
Vietnam; 100–1000 m cyclopentaneundecanoic acid, methyl ester; methyl ester;
cyclopropanebutanoic acid, 2-[[2-[[2-[(pentylcyclopropyl)
methyl] cyclopropyl] methyl] cyclopropyl] methyl]-,
methyl ester; 1-acetyl-5-ethyl2-[3-(2-hydroxyethyl)-1H-
S. Surendran and R. Ramasubbu

indol-2-yl]-a-methyl-methylester; 3-pentyl-, methyl ester,

oxiraneundecanoic acid
Sl. no Plant name Distribution Phytocompounds isolated Source of compound Reference
10. Cinnamomum India [Kerala, Tamil Caryophyllene oxide, terpinen-4-ol linalool, and benzyl – Essential oil Baskaran and Ebbie [118]
chemungianum Nadu]; 800–1100 m; benzoate
M.Mohanan & endemic to the Western Found to have β-selinene, caryophyllene oxide, – Essential oil Rameshkumar et al. [119]
A.N.Henry Ghats longiborneol, tetradecanal, intermedeol, and α-cyperone
Veratrole, ρ-cymen-7-ol, germacrene B, longiborneol, – – Sriramavaratharajan and
and α-cyperone, viridiflorene Murugan [120]
11. Cinnamomum India [Assam, Manipur, α-Phellandrene, α-farnesene, 1,8-cineole, α-pinene, Leaf Essential oils Baruah and Nath [130]
glaucescens (Nees) Sikkim, West Bengal], linalool α-phellandrene b-pinene b-caryophyllene and
Hand.-Mazz. Bangladesh, Bhutan, Laos, terpineol
Myanmar, Nepal, Vietnam
12 Cinnamomum Distribution: India [Assam, Eugenol and δ-3-careen, limonene α- pinene, and Leaf Essential oil Nath and Baruah [129]
impressinervium West Bengal, Sikkim], eugenol acetate
Meisn. Bangladesh, Bhutan,
Myanmar, Nepal
13. Cinnamomum Distribution: India Elemicin and methyl eugenol Leaf Essential oil Baruah and Nath [101]
champokianum [Assam]; c. 83 m; endemic
Baruah & S.C.Nath
14. Cinnamomum Distribution: India [Assam, Cinnamaldehyde Shade-dried leaves, – Nath et al. [44]
pauciflorum Nees. Meghalaya, Mizoram], root bark, and stem
Bangladesh, China, bark
Myanmar, Nepal; (E)-Cinnamaldehyde and linalool Leaves – Baruah and Nath [101]
1000–1700 m
15. Cinnamomum India [Goa, Karnataka, Cinnamyl acetate, 4-teroinol, benzyl benzoate, and Bark Oil Hrideek et al. [131]
macrocarpum Kerala, Maharashtra, Tamil linalool
Hook.f. Nadu], Myanmar;
600–1000 m
(continued)
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff
675
Table 1 (continued)
676

Sl. no Plant name Distribution Phytocompounds isolated Source of compound Reference

16. Cinnamomum Distribution: India (Z)-Methyl α-farnesene, isoeugenol, β-caryophyllene, Panicle Essential oil Baruah and Nath [101]
bejolghota [Andaman Islands, linalool, α-phellandrene, 1,8-cineole, α-pinene,
(Buch.-Ham.) Sweet Arunachal Pradesh, Assam, β-phellandrene, and β-pinene
Himachal Pradesh,
Madhya Pradesh,
Meghalaya, Nicobar
Islands, Orissa, Punjab,
Sikkim, West Bengal,
Tamil Nadu (cultivated),
Tripura], Bangladesh,
Bhutan, Cambodia, China,
Laos, Myanmar, Nepal,
Thailand, Vietnam;
600–1800 m
17. Cinnamomum India [Kerala, Tamil α-Pinene, α-cadinol, and tau-cadinol Leaf Essential oil Sriramavaratharajan et al.
perrottetii Meisn. Nadu]; 1600–2100 m; [133]
endemic
18. Cinnamomum Distribution: India 1,8-cineole – Essential oils Sriramavaratharajan et al.
agasthyamalayanum [Kerala]; 800–1000 m; [132]
Robi, Sujanapal & endemic to the Western
Udayan Ghats
19. Cinnamomum Distribution: India Shikimole, eugenyl methyl ether, delta cadinene Bark Oil Hrideek et al. [131]
riparium Gamble [Karnataka, Kerala, Tamil
Nadu]; 250–1400 m;
endemic to the Western
Ghats
S. Surendran and R. Ramasubbu
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff 677

product. The inhibitory action of C. zeylanicum essential oil on Aspergillus flavus

and Fusarium moniliforme was determined on potato dextrose agar, and 500 ppm of
C. zeylanicum oil has inhibited the growth of A. flavus and Fusarium.
Ranasinghe et al. [146] reported that C. zeylanicum essential oil demonstrated
high fungicidal activity against Lasiodiplodia theobromae, Colletotrichum musae,
and Fusarium proliferatum. Shan et al. [147] studied the antibacterial activity, mini-
mum inhibitory concentration (MIC), and minimum bactericidal concentration
(MBC) of C. burmannii extract. Inhibitory effects of five common foodborne patho-
genic bacteria such as Listeria monocytogenes, Bacillus cereus, Escherichia coli,
Staphylococcus aureus, and Salmonella anatum were evaluated in C. burmannii.
Gende et al. [148] studied the inhibitory activity of C. zeylanicum essential oil
against three strains of Paenibacillus larvae of different geographical origins. Gupta
et al. [149] reported that cinnamon oil exhibits a wide zone of inhibition against
B. cereus (29.0 mm), followed by S. aureus with 20 mm. The inhibition was also
observed against P. aeruginosa, E. coli, and Klebsiella sp. Jantan et al. [66] reported
antimicrobial activity of eight Cinnamomum species such as C. mollissimum, C. zey-
lanicum, C. impressicostatum, C. microphyllum, C. rhyncophyllum, C. scortechinii,
C. pubescens, and C. cordatum. Six dermatophytes such as Trichophyton rubrum,
Microsporum canis, T. mentagrophytes, M. gypseum, M. audouinii, and T. ton-
surans, Aspergillus fumigates (filamentous fungi), and five strains of yeasts such as
C. glabrata, C. tropicalis, C. parapsilosis, Candida albicans, and Cryptococcus
neoformans were examined. The strong inhibition was observed on fungal growth
in the leaf oil of C. cordatum and bark and twig oils of C. impressicostatum and
C. pubescens.
Aneja et al. [150] assessed the antimicrobial potentiality of ethanol, acetone, and
methanol extracts of C. zeylanicum bark. The ethanolic, methanolic, and acetonic
bark extracts exhibited greater antimicrobial activities than the water extracts
against Streptococcus mutans, Staphylococcus aureus, Saccharomyces cerevisiae,
and Candida albicans. Lactobacillus acidophilus was found as resistant to all the
five extracts. The acetonic extract showed greater antimicrobial activity than the
alcoholic and water extracts. The strongest inhibition was observed in the acetonic
extract against C. albicans with inhibition zone of 29.30 mm and 12.5 mg/ml MIC
as compared to the standard antifungal drug amphotericin B that has showed zone
of inhibition of about 13 mm.
Goyal et al. [151] evaluated in vitro antibacterial activity of C. tamala stem bark
extract by agar well diffusion assay. Ethanol, ethyl acetate, and methanol showed
significant activity (11.26 mm to 20.77 mm) against all tested bacteria except
Escherichia coli. Ethyl acetate extract showed minimum activity (12 mm–15 mm)
against Staphylococcus aureus. Mishra et al. [152] carried out antifungal bioassay
of C. zeylanicum bark and leaf extracts by hanging drop technique against A. solani
and C. lunata. All the extracts showed 50 to 100% inhibition at 100 μg/ml concen-
tration. However, the treatment of the spores of the two fungal species with the
highest concentration (500 μg/ml) of bark and leaf extracts in all the solvents
showed 100% fungicidal activity as it completely arrested the germination of spores.
Abdelwahab et al. [153] reported antimicrobial activity of C. pubescens essential
oils and against methicillin-resistant Staphylococcus aureus. Methicillin-resistant
678 S. Surendran and R. Ramasubbu

Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Bacillus subtilis, and

Salmonella choleraesuis were tested against C. pubescens. Jantan et al. [66] reported
the antifungal activity of C. pubescens essential oil. Friedman et al. [154] reported
that cinnamaldehyde as the major constituent of C. pubescens (56.15%) was known
to exhibit antibacterial activity against Salmonella typhimurium and Escherichia
coli. Bouhdid et al. [155] studied the cellular damage induced by C. verum essential
oil in Staphylococcus aureus and Pseudomonas aeruginosa.
Rattanachaikunsopon and Phumkhachorn [156] examined antimicrobial activi-
ties against Streptococcus iniae. Cinnamon oil exhibited minimal inhibitory con-
centration (MIC) of 40 mg/ml and cinnamaldehyde exhibited MIC of 20 mg/ml
against S. iniae. There was no apparent mortality in fish fed on fish diets supple-
mented with 0.4% (w/w) of cinnamon oil and with 0.1% (w/w) of oxytetracycline
5 days prior to infection with S. iniae. Unlu et al. [157] reported that C. zeylanicum
bark essential oil was highly effective against gram-positive bacteria Staphylococcus,
Streptococcus, Enterococcus, and Pseudomonas aeruginosa.
Ababutain [158] reported that C. verum exhibited in vitro antimicrobial activity
against Staphylococcus aureus and Bacillus subtilis and Pseudomonas aeruginosa,
Escherichia coli, and Candida albicans (yeast) using hole-plate diffusion method.
Cinnamomum verum strongly inhibited the growth of B. subtilis and C. albicans
only. Staphylococcus aureus and Escherichia coli were found to be resistant.
Cinnamon extracts showed remarkable effect on B. subtilis and C. albicans at MIC
of 3.125–6.25 and 12.5–25 μg/ml, respectively. Jain et al. [159] reported the antimi-
crobial activity of methanolic extract of C. tamala against S. aureus, E. coli, P. aeru-
ginosa, Citrobacter braakii, Klebsiella pneumonia, Rhizopus stolonifer, and
Microsporum gypseum by disc diffusion method.
Shareef et al. [160] investigated essential oils of Cinnamomum sp. for their anti-
bacterial activity against six bacterial species including Escherichia coli,
Staphylococcus aureus, Klebsiella pneumonia, Pseudomonas aeruginosa, Brucella
sp. and Proteus sp. Prabuseenivasan et al. [161] recorded that Pseudomonas aerugi-
nosa was more sensitive to cinnamon essential oil, whereas Klebsiella pneumoniae
and Staphylococcus aureus were less sensitive to cinnamon essential oil. Babu et al.
[162] reported that Escherichia coli was found to be more sensitive to cinnamon
essential oil and Listeria monocytogenes was less sensitive to cinnamon essential oil.
Boniface et al. [163] evaluated antibacterial and antifungal activities of C. zeyl-
anicum essential oils. Minimum inhibitory concentration (MIC) and mycelial
growth inhibition were investigated on Candida albicans, Aspergillus ochraceus,
Aspergillus parasiticus, Penicillium digitatum, and Fusarium oxysporum. The oil
has showed significant properties against E. coli and S. aureus and fungicidal activi-
ties against C. albicans, Aspergillus ochraceus, Aspergillus parasiticus, Fusarium
oxysporum, and Penicillium digitatum. Mahmoud [164] carried out the antifungal
activity of C. zeylanicum bark extracts against Aspergillus niger and Penicillium
digitatum. Mohan et al. [104] examined antimicrobial activities of C. tamala essen-
tial oils against nine microbial strains by using broth micro-dilution method.
Cinnamomum tamala oil exhibited significant antifungal activity and satisfactory
antibacterial activity.
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff 679

Dhara and Tripathi [165] investigated the antimicrobial activity of cinnamon

essential oils and their bioactive compounds against pathogenic ESBL-producing
bacteria by disc diffusion assay. MIC of bioactive compound and their interaction
with ESBL proteins were determined by macro-broth dilution and molecular dock-
ing method. ESBL property was exhibited by Enterobacteriaceae, Escherichia coli,
and Klebsiella pneumoniae. Cinnamon oil exhibited antibacterial properties against
ESBL due to the presence of main bioactive compounds such as eugenol and cin-
namaldehyde. Herman et al. [166] studied the antimicrobial activity of essential oils
of C. zeylanicum against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus
aureus, and Candida albicans. Essentials oils showed higher inhibitory activity
against tested microorganism strain.
Yadav and Dubey [167] reported that C. tamala had fungicidal/fungistatic activity
and inhibited the growth of two ringworm fungi, Microsporum audouinii and
Trichophyton mentagrophytes. The minimum concentration at which C. tamala essen-
tial oils inhibited fungal growth in poisoned food was 500 ppm. Kapoor et al. [50]
reported that the volatile oil and oleoresins from C. tamala leaf were found to be effec-
tive against a number of fungi, but oleoresins were less effective. Complete fungal
growth inhibition by volatile oil has been reported from this study at a dose of 6 μL
against Aspergillus niger, A. solani, A. flavus, and Fusarium moniliforme by using the
inverted petri plate assay. Mishra et al. [168] reported the antibacterial effect of
C. tamala leaf against Staphylococcus aureus, Pseudomonas vulgaris, Streptococcus
pneumoniae, and E. coli. The minimum inhibitory concentration (MIC) of oil and
solvent extracts from C. tamala has varied between 2.40 and 0.60 mg/mL.
Elhag et al. [169] reported the antimicrobial activity of ethanolic, chloroform,
petroleum ether, and methanolic extracts of C. zeylanicum bark against Escherichia
coli and Pseudomonas aeruginosa (gram-negative bacteria, gram-positive bacteria
(Staphylococcus aureus and Bacillus subtilis)), Candida albicans, and Aspergillus
niger (fungal species). All extracts exhibited significant antimicrobial activity
against the tested organisms and the petroleum ether (PE). Antimicrobial activity
was most probably due to the presence of (E)-cinnamaldehyde, a known antimicro-
bial natural product and major compound of petroleum ether extract. Valizadeh
et al. [170] conducted an antimicrobial study on C. zeylanicum barks and leaves
against S. typhimurium, E. coli, and B. cereus by disk and agar well diffusion meth-
ods. The essential oil was effective on B. cereus in both methods with the highest
inhibition zone of 30 mm in the highest concentration. MIC of all Candida species
was 0.012%. The minimum fungicidal concentration of leaf extracts of C. dublini-
ensis, C. parapesilosis, C. albicans was recorded as 0.048% and 0.012% against
C. parapesilosis, C. albicans respectively. Hameed et al. [171] reported that C. zey-
lanicum was highly active against Aspergillus flavus with inhibition zone of
6.16 ± 0.42. The zone of inhibition of C. zeylanicum methanolic extract against
Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia
coli, and Klebsiella pneumonia ranged from 6.12 ± 0.52 to 0.39 ± 0.17 mm for all
treatments.
Hassan et al. [172] reported the antimicrobial activity of C. tamala leaf methano-
lic extract against six gram-negative strains, three gram-positive bacterial strains,
680 S. Surendran and R. Ramasubbu

and one fungal strain by agar well diffusion method. The extract showed variable
degree of inhibition zones except for dichloromethane, aqueous fraction, and crude
extract which were found to be completely inactive against Salmonella Typhi (a
gram-negative strain). Adarsh et al. [173] reported significant antimicrobial activity
of C. zeylanicum against Escherichia coli (gram-negative), Enterococcus faecalis
(gram-positive), and Salmonella Typhi (gram-positive) by agar diffusion method.
Naik et al. [174] assessed the antimicrobial activity of two cinnamon leaf oils and
extracts by disc diffusion assay and the minimum inhibitory concentration by two-
fold serial dilution method against E. coli, S. Typhi, S. aureus, B. cereus, and C. per-
fringens. Essential oils and extracts exhibited the highest zone of inhibition (ZOI)
against S. aureus and E. coli. Both oils and extracts showed minimum inhibitory
concentration in the range of 0.156 mg/ml to 5 mg/ml.
Cong et al. [175] demonstrated the antimicrobial activity of leaf essential oil
from C. longipaniculatum against Staphylococcus aureus, Bacillus subtilis, Sarcina
lutea, and Salmonella typhimurium. Chairunnisa et al. [176] reported that volatile
compounds such as α-pinene, α-terpineol, 1,8-cineole, and trans-cinnamaldehyde
from C. burmannii essential oil exhibit antibacterial activity against Escherichia
coli and Staphylococcus aureus. Aqueous extracts from C. camphora leaves exhibit
positive effect on Penicillium purpurogenum, Trichoderma harzianum, Aspergillus
fumigatus, Phanerochaete chrysosporium, and Gloeophyllum trabeum with concen-
trations of 5% and 10% found to be effective against Botryodiplodia theobromae
(Hu et al. 2017) [177].
Rangel et al. [178] reported the antifungal activity of C. zeylanicum leaf essential
oil against Candida spp. with MIC and MFC values ranging from 62.5 to 1000 μg/
mL. Cinnamomum cassia essential oil was reported to contain cinnamaldehyde,
cinnamic acid, and benzaldehyde as the major constituents and with remarkable
antibacterial activity against Escherichia coli, Staphylococcus hyicus,
Staphylococcus aureus, Propionibacterium acnes, and Pseudomonas aeruginosa
[179–181]. Lu et al. [182] reported that C. cassia acetone extract exhibited antifun-
gal activity against Alternaria alternata, Botrytis cinerea, Colletotrichum glycines,
Fusarium decemcellulare, and Alternaria solani with the half-maximal effective
concentration ranging from 45.68 mg/L to 105.09 mg/L.

3.2 Antioxidant Activity of Phytocompounds

of Cinnamomum spp.

Lin et al. [183] evaluated antioxidant activities of aqueous and ethanol extracts from
Cinnamomum cassia dry bark. At a concentration of 1.0 mg/mL, C. cassia ethanol
extracts exhibit greater inhibition than α-tocopherol. The same extract also showed
an excellent antioxidant activity in enzymatic and nonenzymatic liver tissue oxida-
tive systems. Ethanolic extract of C. cassia revealed the strongest antioxidant activ-
ity followed by α-tocopherol. The IC50 values of ethanolic extract of C. cassia
compared to α-tocopherol were found to be lower in thiobarbituric acid test
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff 681

(IC50 = 0.24 mg/mL vs 0.37 mg/mL), in xanthine oxidase inhibition test

(IC50 = 0.09 mg/mL vs 0.19 mg/mL), and in cytochrome c test (IC50 = 0.16 mg/
mL vs 0.27 mg/mL).
Mathew and Abraham [184] had reported the antioxidant activity of the metha-
nolic bark extract of C. verum. The scavenging activity was found to be increased
with increasing concentration of BHA and CBE up to 12.5 lg ml and then found as
stable with increasing concentration. The EC50 value of CBE was found to be
4.21 lg ml and that of BHA 5.79 lg ml, which was inversely related to the antioxi-
dant capacity. The hydroxyl radical scavenging activity was observed in a dose-
dependent manner in 15–250 lg ml range. The percentage inhibition of peroxidation
in linoleic acid system by various concentrations ranging from 25 to 200 lg ml was
found to be 81.8% to 93.3%. Mathew and Abraham [184] had reported the antioxi-
dant activity of the methanolic bark extract of C. verum (CLE) were studied and
compared to antioxidant compounds like Trolox, butylated hydroxyl anisole, gallic
acid, and ascorbic acid. The free radical scavenging activities were observed espe-
cially against DPPH radical and ABTS radical cation. They also exhibited hydroxyl
radical scavenging activity, reducing power, and metal ion chelating activity. The
peroxidation inhibiting activity of extract recorded using the linoleic acid emulsion
system showed good antioxidant activity.
Jayaprakasha et al. [185] evaluated the antioxidant activity of various extracts
from C. zeylanicum through in vitro model systems, such as β-carotene-linoleate
and 1,1-diphenyl-2-picryl-hydrazyl (DPPH). The order of activity of extract in dif-
ferent solvents were water > methanol > acetone > ethyl acetate using β-carotene/
linoleic acid system. Mancini-Filho et al. [186] reported that ether, aqueous extracts,
and methanol of C. zeylanicum inhibited the oxidative process in 68%, 87.5%, and
95.5%, respectively. Okawa et al. [187] reported that flavonoids isolated from cin-
namon have free radical scavenging activities and antioxidant properties.
Yang et al. [188] investigated the antioxidant activities of barks, buds, and leaves
of C. cassia extracted with ethanol and supercritical fluid extraction. For the anti-
oxidant activity comparison, IC50 values of the SFE and ethanol extracts in the
DPPH scavenging assay were 0.562–10.090 mg/mL and 0.072–0.208 mg/mL, and
the Trolox equivalent antioxidant capacity values were 6.789–58.335 mmole
Trolox/g and 133.039–335.779 mmole Trolox/g, respectively. Mustaffa et al. [11]
reported that methanolic extract of C. iners bark showed high effective scavenging
activity with IC50 value of 0.02 mg/mL. The antioxidant activity at maximum con-
centration (2.0 mgmL) was found to be 84.33%. Cinnamomum tamala was reported
with potential antioxidant activities in diabetic rats [55], while C. osmophloeum
showed significant in vitro and in vivo antioxidant activities under oxidative
stress [189].
Pandey and Chandra [190] evaluated the antioxidant activity of aqueous and
ethanol extracts of C. verum leaf galls. The ethanol extracts of leaf galls showed
high antioxidant and analgesic activity. The aqueous and ethanol extract possessed
equal capacity of antioxidants to inhibit free radicals (IC50 = 13.3 and 13.53 μg/ml)
but was less for ascorbic acid with IC50 = 9.96 μg/ml. Ethanol extract was more
effective in scavenging superoxide radicals compared to ascorbic acid. For
682 S. Surendran and R. Ramasubbu

analgesic activity, maximum time required for response against thermal stimuli was
observed in ethanol extract and maximum % of writhing inhibition (44.57%) when
compared to aqueous extract. Chua et al. [191] reported the antioxidant activity of
C. osmophloeum ethanolic extracts from the twigs of C. osmophloeum. BuOH frac-
tion exhibited the best performance and consequently, kaempferol-7-O-rhamnoside
was also isolated and its activity was confirmed.
Chakraborty and Das [192] evaluated the antihyperglycemic activity of C. tamala
leaf aqueous extracts. Quantification of antioxidants of the leaves – phenols, ascor-
bate, and carotenoids – revealed that C. tamala leaves had high antioxidants. Anis
et al. [193] investigated the antioxidant activity of extracts from C. iners wood. The
ethanol extract showed EC50 value of 14.96 μg/mL with the highest antioxidant
activity followed by chloroform extract with EC50 > 30 μg/mL. No activity was
observed in water extract. Park et al. [194] evaluated the antioxidant activity of
C. verum extract by supercritical fluid extracts and Marc methanol extracts. Higher
antioxidant activities were observed in DPPH and ABTS radical scavenging assay.
Srinivasa et al. [195] reported that C. aromaticum showed significant antioxidant
activity and was used as a natural antioxidant agent. Abeysekera et al. [196] reported
that C. zeylanicum ethanolic extracts of both leaf and bark had significantly high
antioxidant activity. Abdelwahab et al. [138] reported that C. altissimum bark extract
displayed antioxidant activities with IC50 value of 38.5 ± 4.72 μg/ml using DPPH
assay and 345.2 ± 14.8 (μM Fe (II)/g dry mass) using FRAP assay.
Salleh et al. [197] reported the antioxidant and anticholinesterase activity of
C. griffithii and C. macrocarpum essential oil. The bark oil of C. griffithii exhibits
IC50 value of 73.4 μg/mL on DPPH assay, while the leaf oil showed inhibition
value of 65.5 μg/mL. Cinnamomum macrocarpum bark oil exhibits inhibition val-
ues of 55.8% and 66.1% at 1 mg/mL concentration. Udayaprakash et al. [117] con-
ducted antioxidant studies on C. iners methanolic leaf extract. DPPH free radical
scavenging activity of methanolic leaf extract recorded an IC50 value at the concen-
tration of 15 g/ml. ABTS assay (99.36%) showed maximum inhibition followed by
TBA (95.39%) and FTC (81.37%). Brodowska et al. [198] carried out the antioxi-
dant activity of C. cassia essential oils. Lower IC50 value was observed in DPPH
and ABTS assay (IC50 = 42.03 μg/L and IC50 = 5.13 μg/L) for cinnamon extracts
and indicates higher radical scavenging activity. Extracts were found to be better
radical scavenger than essential oils with IC50 values of 64.51 μg/L (ABTS)
and147.23 μg/L (DPPH).
Valizadeh et al. [170] conducted an antioxidant study on C. zeylanicum barks and
leaves by DPPH assay. Free radical scavenging activity was found to be increased
by increasing C. zeylanicum essential oil concentration. The concentration of CEO
resulting in 50% inhibition of the free radical (IC50) was 79.54 μg/mL. Ervina et al.
[199] reported that the C. zeylanicum bark infusion showed the highest antioxidant
activity with an IC50 value of 3.03 followed by ethanolic extract and its water and
ethyl acetate fractions with IC50 values of 8.36, 8.89, and 13.51 μg/mL, respec-
tively. Fu et al. [200] reported antioxidative effect in diet-induced obese rats by seed
kernel oil of C. camphora. Liu et al. [201] reported that ferric scavenging activity
test on C. longipaniculatum leaves displayed a higher reducing activity of
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff 683

proanthocyanidins compared to vitamin C and BHT but lower than BHA by ferric
scavenging activity test. Potassium ferricyanide reduction method confirmed a
higher antioxidant activity than BHA (0.094 mg/mL), vitamin C (0.125 mg/mL),
and BHT (0.125 mg/mL) when the proanthocyanidin concentration was
0.156 mg/mL.
Liu et al. [202] evaluated the antioxidative activity of the flavonoids isolated
from C. camphora leaves. The flavonoids exhibited DPPH free radical scavenging
activity similar to the positive control of vitamin C with increasing concentration.
The reducing ability also increased significantly with the increase of concentration
and was very close to vitamin C, BHA, and BHT. Kallel et al. [203] reported high
cytotoxicity cell line effect in C. zeylanicum essential oil. In vitro cytotoxicity was
examined using an MTT assay against HeLa and Raji cell lines. The essential oil
inhibited the proliferation of HeLa and Raji cell lines and showed IC50 values of
0.57 μg/mL and 0.13 μg/mL. Priani et al. [204] reported that strong antioxidant
activity with IC50 value of 10.04 ± 0.08 ppm was observed in the bark of C. bur-
mannii. A peel-off mask which significantly exhibits potent antioxidant effects
(IC50 = 47.31 ± 1.47 ppm) was formulated. Ribeiro et al. [205] reported the antioxi-
dant activity of leaf and stem of C. zeylanicum by using DPPH method. The inhibi-
tion percentage for the leaves was 59.17 ± 0.11% and for the stem was 61.34 ± 0.11%.
Raksha et al. [206] conducted an antioxidant activity on C. tamala leaf extracts
by DPPH free radical assay and observed significant antioxidant activity. The
hydroalcoholic leaf extract at a 100 μm/ml concentration exhibited inhibition activ-
ity of about 96.99 ± 0.99%. Singh et al. [207] reported the antioxidant and antidia-
betic effect of C. cassia bark methanolic extracts. In acute toxicity testing, up to
2000 mg/kg methanolic extracts did not show any significant toxic signs; hence, the
antidiabetic activity was carried out at 125, 250, and 500 mg/kg dose levels. The
diabetic animals showed significant increases in the levels of total cholesterol (TC),
very-low-density lipoprotein, and TC/high-density lipoprotein radio compared with
that of normal control and also the extracts prevent STZ-induced hyperlipidemia. In
the histopathological analysis, sections from the liver, pancreas, and kidney of the
diabetic animals and the animals treated with MECC 500 mg/kg showed mid-to-­
moderate toxic effects.

3.3 Anti-inflammatory and Anticancer Activity

of Phytocompounds of Cinnamomum spp.

Chao et al. [208] evaluated the anti-inflammatory activity of C. osmophloeum leaf

essential oil and reported that the essential oil has higher potential to inhibit proIL-
1â protein expression induced by LPS-treated J774A.1 murine macrophage.
­
Essential oil clearly inhibited proIL-1â protein expression at a dosage of 60 μg/
mL. A dose of 60 μg/mL effectively inhibits IL-1â and IL-6 production but not for
TNF-R. Maridass and Ghanthikumar [138] carried out the anti-inflammatory activ-
ity of ethanol extracts of C. keralaense bark extract in albino rats using
684 S. Surendran and R. Ramasubbu

carrageenan-­induced experimental model of inflammation. The volume of inflam-

mation was significantly reduced by a maximum dose of 400 mg/kg. Joshi et al. [51]
investigated the anti-inflammatory activity of C. zeylanicum bark extract. Ethanol
extract of C. zeylanicum suppressed intracellular release of TNF in murine neutro-
phils as well as leukocytes in pleural fluid. The extract at 20 μg/ml concentration
inhibits TNF gene expression in LPS-stimulated human PBMCs.
Liao et al. [210] investigated the anti-inflammatory effects of different constitu-
ents of C. cassia such as cinnamic acid, cinnamic alcohol, cinnamic aldehyde, and
coumarin using lipopolysaccharide (LPS)-stimulated mouse macrophage and car-
rageenan (Carr)-induced mouse paw edema model. A significant concentration-­
dependent inhibition of nitric oxide (NO) and prostaglandin E2 (PGE2) tumor
necrosis factor (TNF-α) levels were detected when macrophages were treated with
cinnamic aldehyde together with LPS. After Carr injection, cinnamic aldehyde
attenuated myeloperoxidase (MPO) activity and the malondialdehyde (MDA) level
in the edema paw also decreases the NO, TNF-α, and PGE2 levels on the serum
level. Cinnamic aldehyde showed excellent anti-inflammatory activities.
Hossain et al. [211] evaluated the anti-inflammatory activity of C. tamala leaf
ethanolic extract using carrageenan- and histamine-induced rat paw edema test at
200 and 400 mg/kg body weight. At the dose of 400 mg/kg body weight, the extract
showed a significant anti-inflammatory activity both in the carrageenan- and
histamine-­induced edema test models in rats showing 60.84% and 59.48% reduc-
tion in the paw volume comparable (P < 0.01) to that produced by indomethacin
(63.63% and 66.01%) at 4 h. At 400 mg/kg body weight, the inhibition percentage
of edema paw volume was statistically significant (P < 0.05; P < 0.01). Ho et al.
(2013) [215] reported that cinnamon has potential therapeutic effect against neuro-
degenerative diseases and its potent anti-neuroinflammatory capacity.
Cinnamaldehyde had the greatest anti-neuroinflammatory capacity.
Han and Parker [212] reported that essential oil from C. zeylanicum bark showed
strong antiproliferative effects on skin cells and significantly inhibited the produc-
tion of several inflammatory biomarkers, including intercellular cell adhesion mol-
ecule-­ 1, monocyte chemoattractant protein-1, interferon-inducible T-cell alpha
chemoattractant, vascular cell adhesion molecule-1, interferon gamma-induced pro-
tein 10, and monokine induced by gamma interferon. Prajapati et al. [213] carried
out the anti-inflammatory activity of C. zeylanicum oil by using carrageenan-­
induced paw edema model. The highest anti-inflammatory activity (30.58%) was
observed at 3-hour of post-oral administration at the dose of 200 mg/kg. Budiastuti
et al. [214] conducted an anti-inflammatory activity on C. burmannii bark essential
oil using paw test in Wistar rats. A significant increase was observed in the inhibi-
tion of edema in the administration of CBOK compared to the negative control. A
number of inflammatory cells and TNF-α expression were also observed to be
decreased.
Du et al. [215] evaluated the anti-inflammatory activity of C. longepaniculatum
essential oil using three experimental models such as carrageenan-induced paw
edema in rat and acetic acid-induced vascular permeability and dimethyl benzene-­
induced ear edema in mice. The inflammation was significantly inhibited in the
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff 685

dose-dependent manner. A dose-dependent reduction of the connective tissue injury

and infiltration of inflammatory cell and paw thickness were observed. Bhagavathy
and Latha [216] studied the cytotoxic effect of C. verum ethanol extract tested with
HL60 leukemia cell lines. Cell lines were free from any kind of bacterial and fungal
contaminations. Plate 1 indicates dead cells and their cellular uptake of the dye
which appear as blue in color. In MTT assay cell death and cell viability of leukemia
cell line of anticancer activity was estimated. The results showed 84.1% cell viabil-
ity in the concentration of 1 mg/ml. The IC50 of cell viability was observed at the
concentration of 127 μg/ml of the ethanol extract. Al-Zereini et al. [217] reported
the cytotoxic activity of C. verum barks. The cytotoxic activity was evaluated
against the MDA-MB-231 breast cancer cell line. Both EOs showed cytotoxic activ-
ity against the breast cancer cell line with IC50 value of 0.14–0.46 μL/mL.

3.4 Wound Healing Activity of Phytocompounds

of Cinnamomum spp.

Kamath et al. [218] evaluated the wound healing activity of C. zeylanicum bark
ethanolic extract in Wistar rats. The extract at doses of 250 mg/kg and 500 mg/kg
body weight significantly enhance the wound breaking strength, of wound contrac-
tion and epithelialization period. In the dead space wound, the granulation tissue
weight, hydroxyproline content, and breaking strength were also increased by the
extract. Soni et al. [219] reported that active extract from ethanolic extract of
C. tamala leaves was responsible for the wound healing activity in diabetic Wistar
albino rats. Both the wound area and day of epithelialization were significantly
decreased in the excision wound model. Significantly higher tensile strength was
observed in the rats treated orally with ethanolic extract treated in incision wound
model. Weights of wet and dry granulation tissue also increase with increased
amounts of hydroxyproline, elastin, and collagen.
Narkhede et al. [220] reported the wound healing activity of C. zeylanicum and
C. tamala in Sprague Dawley rats. The time taken for complete epithelialization and
wound contraction was significantly less than the control. The mean tensile strength
was significantly greater after 16 days. Methanolic extract showed better granula-
tion tissues, better tensile strength, and early and complete epithelialization. Deepa
et al. [221] reported that the hydroalcoholic extract of C. nitidum stem bark showed
dose-dependent percentage wound healing. Significant wound contraction and high
degree of tensile strength were observed in treated animals as compared with the
control. Hydroxyproline level was found to be significantly increased in a dose-­
dependent manner.
Ahmadi et al. [222] evaluated the effects of an ointment prepared from C. verum
essential oil in infected wound model. Topical administration of C. verum remark-
ably shortened the inflammatory phase, increased fibroblast distribution and colla-
gen deposition, and accelerated the cellular proliferation, reepithelialization, and
keratin synthesis. The mRNA levels of IGF-1, FGF-2, and VEGF were remarkably
686 S. Surendran and R. Ramasubbu

higher in C. verum-treated groups (especially 2%) than in the control group. Topical
administration of C. verum increased the antioxidant power and reduced the MDA
content in comparison to control animals. C. verum accelerates wound healing by
upregulating the IGF-1, FGF-2, and VEGF expression and increasing cell prolifera-
tion, collagen synthesis, and reepithelialization ratio.
Kefayat et al. [223] reported cinnamon extracts were incorporated into the bacte-
rial cellulose membranes to prepare an all-natural wound dressing. The cinnamon
extract membrane maintains appropriate moisture content for an acceptable period
of time. Although the tensile strength and elongation at break values of the cinna-
mon extract were slightly lower than the BC membrane, they are still in ideal ranges.
The cinnamon extract membrane exhibits significantly more antibacterial effects
against Staphylococcus aureus and Escherichia coli, and they are also found to be
more biocompatible with L929 normal skin fibroblast cells than with the bacterial
cellulose and chitosan membranes.

4 Conclusion

Research on Cinnamomum genus promotes further development and utilization of

new drugs by revealing the presence of several bioactive compounds and their bio-
logical potentialities. The present review reported several chemical and clinical
studies carried out in 25 Indian species and also their major biological potentialities
such as antimicrobial, antioxidant, anti-inflammatory, wound healing, and antican-
cer potentialities. The Cinnamomum genus contains approximately 250 species, but
chemical studies are focused only on few species such as C. verum, C. tamala,
C. cassia, C. subavenium, C. camphora, C. kotoense, C. glanduliferum, etc. The
main studies on Cinnamomum are focused on essential oils. Major chemical com-
pounds reported in Cinnamomum are cinnamaldehydes, linalool, eugenol,
(E)-cinnamyl acetate, β-caryophyllene, benzyl benzoate, 1,8-cineole, and
α-terpineol. Only a few attempts were made to isolate the bioactive constituents;
hence, the research should be focused on widened isolation and evaluation of their
pharmacological potentialities both in vitro and in vivo. Deep and systematic stud-
ies are still required to explore this medicinally promising genus.

Acknowledgments Authors gratefully acknowledged the Science and Engineering Research

Board, Department of Science and Technology (SERB-DST), Government of India, for the finan-
cial support in their work (CRG/2019/001873).

References

1. Pitman NC, Jørgensen PM (2002) Estimating the size of the world’s threatened flora. Science
298(5595):989–989
2. Veeresham C (2012) Natural products derived from plants as a source of drugs. J Adv Pharm
Technol 3(4):200
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff 687

3. Seth SD, Sharma B (2004) Medicinal plants in India. Indian J Med Res 120(1):9
4. Fabricant DS, Farnsworth NR (2001) The value of plants used in traditional medicine for
drug discovery. Environ Health Perspect 109(suppl 1):69–75
5. Newman DJ, Cragg GM (2007) Natural products as sources of new drugs over the last 25
years. J Nat Prod 70(3):461–477
6. Kharwar RN, Maurya AL, Verma VC et al (2012) Diversity and antimicrobial activity of
endophytic fungal community isolated from medicinal plant Cinnamomum camphora. Proc
Natl Acad Sci India Sect B Biol Sci 82(4):557–565
7. Schmidt E, Jirovetz L, Buchbauer G et al (2006) Composition and antioxidant activities of
the essential oil of cinnamon (Cinnamomum zeylanicum Blume) leaves from Sri Lanka. J
Essent Oil-Bear Plants 9(2):170–182
8. Maridass M, Victor B (2008) Ethnobotanical uses of Cinnamomum species, Tamil Nadu,
India. Ethnobot Leafl 2008(1):18
9. Burkill H (1985) The useful plants of West Tropical Africa. Royal Botanic Garden
Kew, London
10. Wagner H, Fessler B, Geyer B et al (1986) 5-lipoxygenase-inhibitors from medicinal plants.
Planta Med 52(06):549–550
11. Mustaffa F, Indurkar J, Shah M et al (2013) Review on pharmacological activities of
Cinnamomum iners Reinw. ex Blume. Nat Prod Res 27(10):888–895
12. Pengelly A (2004) Constituents of medicinal plants. CABI Publishing, Cambridge, p 66
13. Maridass M (2008) Anti-inflammatory activity of the methanolic extract of Cinnamomum
sulphuratum barks. Ethnobot Leafl 2008(1):63
14. Maridass M (2009) Screening of antifungal activities of barks of Cinnamomum species. Thai
J Pharm Sci 33:137–143
15. Rameshkumar KB, George V (2006) Cinnamomum sulphuratum Nees – a benzyl benzoate-­
rich new chemotype from southern western ghats, India. J Essent Oil Res 18(5):521–522
16. Shivaprasad D (2015) Reproductive biology of Cinnamomum sulphuratum Nees. From wet
evergreen forest of Western Ghats in Karnataka. Proc Int Acad Ecol Environ Sci 5(1):7
17. Lemonica IP, Macedo AB (1994) Abortive and/or embryofetotoxic effect of Cinnamomum
zeylanicum leaf extracts in pregnant rats. Fitoterapia 65(5):431–434
18. Kubo M, Ma S, Wu J, Matsuda H (1996) Anti-inflammatory activities of 70% methanolic
extract from Cinnamomi Cortex. Biol Pharm Bull 19(8):1041–1045
19. Zhang C, Fan L, Fan S et al (2019) Cinnamomum cassia Presl: a review of its traditional uses,
phytochemistry, pharmacology and toxicology. Molecules 24(19):3473
20. Annegowda HV, Gooi TS, Awang SHH et al (2012) Evaluation of analgesic and antioxidant
potency of various. Int J Pharmacol 8(3):198–203
21. Kumar BH, Basheer S (2010) Antioxidant potential and antimicrobial activity of Cinnamomum
Malabathrum (Batka). Orient J Chem 26(4):1449
22. Agarwal SK, Chipa RC, Samantha Suresh KC (2013) Anticancer activity of Cinnamomum
Malabatrum against Dalton’s ascitic lymphoma. Int J Res Pharmacol Pharmacother
2:314–319
23. Kurokawa M, Kumeda CA, Yamamura J et al (1998) Antipyretic activity of cinnamyl deriva-
tives and related compounds in influenza virus-infected mice. Eur J Pharmacol 348(1):45–51
24. Kar A, Choudhary BK, Bandyopadhyay NG (1999) Preliminary studies on the inorganic
constituents of some indigenous hypoglycaemic herbs on oral glucose tolerance test. J
Ethnopharmacol 64(2):179–184
25. Hasler CM, Blumberg JB (1999) Phytochemicals: biochemistry and physiology. Introduction.
J Nutr 129(3):756S–757S
26. Costa MA, Zia ZQ, Davin LB, Lewis NG (1999) Chapter four: toward engineering the meta-
bolic pathways of cancer- preventing lignans in cereal grains and other crops. In: Romeo JT
(ed) Recent advances in phytochemistry, phytochemicals in human health protection, nutri-
tion, and plant defense, vol 33. Kluwer Academic/Plenum Publishers, New York, pp 67–87
27. Porrini M, Riso P (2008) Factors influencing the bioavailability of antioxidants in foods: a
critical appraisal. Nutr Metab Cardiovasc 18(10):647–650
688 S. Surendran and R. Ramasubbu

28. Leela NK, Vipin TM, Shafeekh KM et al (2009) Chemical composition of essential oils
from aerial parts of Cinnamomum malabatrum (Burman f.) & Presl. Bercht. Flavour Fragr J
24(1):13–16
29. Aravind R, Bindu AR, Bindu K, Alexeyena V (2014) GC-MS analysis of the bark essential
oil of Cinnamomum malabatrum (Burman. F) Blume. Res J Pharm Technol 7(7):754–759
30. Anil AM, Bency BJ, Helen PM, Rani DS (2018) Docking and in vitro studies on antioxidant,
antibacterial and cytotoxic properties of cinnamon (Cinnamomum malabathrum). Inter J Res
Analy Rev 5(5):66–72
31. Natarajan P, John S, Thangatirupati A, Kala R (2014) Antihyperlipidemic activity of alco-
holic extract of Cinnamomum malabatrum burm. On cholesterol diet induced rats. World J
Pharm Res 3(6):1599–1615
32. Nath SC, Hazarika AK, Baruah RN et al (1994) Major components of the leaf oil of
Cinnamomum sulphuratum Nees. J Essent Oil Res 6(1):77–78
33. Baruah A, Nath SC, Leclercq PA (1999) Leaf and stem bark oils of Cinnamomum sulphura-
tum Nees from Northeast India. J Essent Oil Res 11(2):194–196
34. Baruah A, Nath SC, Hazarika AK (2002) Essential oils of Cinnamomum sulphuratum Nees-A
new chemotype source of spice value from Northeast India. Indian Perfum 46:89–92
35. Baruah A, Nath SC, Hazarika AK (2001) Methyl cinnamate, the major component of the leaf
and stem bark oils of Cinnamomum sulphuratum Nees. Indian Perfum 45:39–41
36. Kumar KNS, Rajalekshmi M, Sangeetha B et al (2013) Chemical fingerprint of leaves of
Cinnamomum sulphuratum Nees growing in Kodagu, Karnataka. J Pharmacogn Phytochem
2:163–168
37. Singh C, Singh S, Pande C et al (2014) Chemical composition of the leaves essential oil
from Cinnamomum glanduliferum (Wall) Meissn from Uttarakhand, India. J Essent Oil Bear
Plants 17(5):927–930
38. Rao BR, Rajput DK, Bhattacharya AK (2007) Essential oil composition of petiole of
Cinnamomum verum Bercht. & Presl. J Spices Aromat Crops 16:38–41
39. Simic A, Sokovic MD, Ristic M et al (2004) The chemical composition of some Lauraceae
essential oils and their antifungal activities. Phytother Res 18:713–717
40. Mollenbeck S, Konig T, Schreier P et al (1997) Chemical composition and analysis of enan-
tiomers of essential oils from Madagascar. Flavour Fragr J 12:63–69
41. Variyar PS, Bandyopadhyay C (1989) On some chemical aspects of Cinnamomum zeylani-
cum. Pafai J 10(4):35–38
42. Mallavarapu GR, Ramesh S, Chandrasekhara RS et al (1995) Investigation of the essential oil
of cinnamon leaf grown at Bangalore and Hyderabad. Flavour Fragr J 10:239–242
43. Rao BRR, Rajput DK, Kaul PN et al (2006) Effect of short and long-term storage on essential
oil content and composition of cinnamon (Cinnamomum verum Bercht. & Presl.). J Spices
Aromat Crops 15:19–24
44. Nath SC, Pathak MG, Baruah A (1996) Benzyl benzoate, the major component of the leaf and
stem bark oil of Cinnamomum zeylanicum Blume. J Essent Oil Res 8:327–328
45. Wijesekera ROB, Jayawardene AL, Rajapakse LS (1974) Volatile constituents of leaf, stem
and root oils of cinnamon (Cinnamomum zeylanicum). J Sci Food Agric 25:1211–1220
46. Kaul PN, Bhattacharya AK, Rajeswara Rao BR et al (2003) Volatile constituents of essential
oils isolated from different parts of cinnamon (Cinnamomum zeylanicum Blume). J Sci Food
Agric 83:53–55
47. Jayaprakasha GK, Jaganmohan Rao L, Sakariah KK (1997) Chemical composition of the
volatile oil from the fruits of Cinnamomum zeylanicum Blume. Flavour Fragr J 12:331–333
48. Mariappan PM, Sabesan G, Koilpillai B et al (2013) Chemical characterisation and antifun-
gal activity of methanolic extract of Cinnamomum verum J. Presl bark against Malassezia
spp. Pharmacogn J 5(5):197–204
49. Mir SR, Ali M, Kapoor R (2004) Chemical composition of essential oil of Cinnamomum
tamala Nees et Eberm. leaves. Flavour Fragr J 19(2):112–114
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff 689

50. Kapoor IPS, Singh B, Singh G, Isidorov V, Szczepaniak L (2009) Chemistry, antimicrobial
and antioxidant potentials of Cinnamomum tamala Nees & Eberm.(Tejpat) essential oil and
oleoresins. Nat Prod Radiance 8(2):106–116
51. Joshi SC, Padalia RC, Bisht DS, Mathela CS (2009) Terpenoid diversity in the leaf essential
oils of Himalayan Lauraceae species. Chem Biodivers 6(9):1364–1373
52. Chanotiya CS, Yadav A (2010) Enantioenriched (3S)-(+)-linalool in the leaf oil of
Cinnamomum tamala Nees et Eberm. from Kumaon. J Essent Oil Res 22(6):593–596
53. Agarwal R, Pant AK, Prakash O (2012) Chemical composition and biological activities of
essential oils of Cinnamomum tamala, Cinnamomum zeylenicum and Cinnamomum cam-
phora growing in Uttarakhand. In: Chemistry of phytopotentials: health, energy and environ-
mental perspectives. Springer, Berlin/Heidelberg, pp 87–92
54. Kumar KN, Sangeetha B, Rajalekshmi M et al (2012) Chemoprofile of tvakpatra; leaves of
Cinnamomum verum JS Presl. Pharm J 4(34):26–30
55. Rana VS, Langoljam RD, Verdeguer M, Blázquez MA (2012) Chemical variability in the
essential oil of Cinnamomum tamala L. leaves from India. Nat Prod Res 26(14):1355–1357
56. Lohani H, Andola HC, Chauhan N et al (2012) Variability in volatile constituents of
Cinnamomum tamala leaf from Uttarakhand Himalaya. Asian Pac J Trop Biomed
2(2):S667–S669
57. Sankaran V, Chakraborty A, Jeyaprakash K et al (2015) Chemical analysis of leaf essential
oil of Cinnamomum tamala from Arunachal Pradesh, India. J Chem Pharm Sci 8(2):246–248
58. Williams AR, Ramsay A, Hansen TV, Ropiak HM (2015) Anthelmintic activity of trans-­
cinnamaldehyde and A-and B-type proanthocyanidins derived from cinnamon (Cinnamomum
verum). Sci Rep 5(1):1–2
59. Yan YM, Fang P, Yang MT et al (2015) Anti-diabetic nephropathy compounds from
Cinnamomum cassia. J Ethnopharmacol 165:141–147
60. Liu YH, Tsai KD, Yang SM et al (2017) Cinnamomum verum ingredient
2-­methoxycinnamaldehyde: a new antiproliferative drug targeting topoisomerase I and II in
human lung squamous cell carcinoma NCI-H520 cells. Eur J Cancer Prev 26(4):314–323
61. Kim GJ, Lee JY, Choi HG (2017) Cinnamomulactone, a new butyrolactone from the twigs
of Cinnamomum cassia and its inhibitory activity of matrix metalloproteinases. Arch Pharm
Res 40(3):304–310
62. Alva PP, Suresh S, Nanjappa DP et al (2021) Isolation and identification of quorum sens-
ing antagonist from Cinnamomum verum leaves against Pseudomonas aeruginosa. Life Sci
267:118878
63. Singh G, Maurya S, DeLampasona MP et al (2007) A comparison of chemical, antioxidant
and antimicrobial studies of cinnamon leaf and bark volatile oils, oleoresins and their con-
stituents. Food Chem Toxicol 45(9):1650–1661
64. Raina VK, Srivastava SK, Aggarwal KK et al (2001) Essential oil composition of Cinnamomum
zeylanicum Blume leaves from Little Andaman, India. Flavour Fragr J 16(5):374–376
65. Reynolds JEF (1993) Martindale, the extra pharmacopoeia, 13th edn. Info Access &
Distribution, Singapore
66. Jantan IB, Karim Moharam BA, Santhanam J, Jamal JA (2008) Correlation between chemi-
cal composition and antifungal activity of the essential oils of eight Cinnamomum. Species.
Pharm Biol 46(6):406–412
67. Duke JA (1985) CRC handbook of medicinal herbs. CRC Press, Boca Raton, p 677
68. Uma B, Prabhakar K, Rajendran S, Lakshmi Sarayu Y (2009) Studies on GC/MS spectro-
scopic analysis of some bioactive antimicrobial compounds from Cinnamomum zeylanicum.
J Med Plant Res 8(31):125–131
69. Gupta C, Garg AP, Uniyal RC et al (2008) Comparative analysis of the antimicrobial activity
of cinnamon oil and cinnamon extract on some food-borne microbes. Afr J Microbiol Res
2(9):247–251
70. Vangalapati M, Satya NS, Prakash DS et al (2012) A review on pharmacological activities
and clinical effects of cinnamon species. Res J Pharm Bio Chem Sci 3(1):653–663
690 S. Surendran and R. Ramasubbu

71. Jakhetia V, Patel R, Khatri P et al (2010) Cinnamon: a pharmacological review. J Adv Sci
Res 1(2):19–23
72. Ramos-Nino ME, Clifford MN, Adams MR (1996) Quantitative structure activity relation-
ship for the effect of benzoic acids, cinnamic acids and benzaldehydes on Listeria monocyto-
genes. J Appl Bacteriol 80(3):303–310
73. Gupta C, Garg AP, Uniyal RC, Kumari A (2008) Comparative analysis of the antimicrobial
activity of cinnamon oil and cinnamon extract on some food-borne microbes. Afr J Microbiol
Res 2(9):247–251
74. Brari J, Thakur DR (2015) Insecticidal efficacy of essential oil from Cinnamomum zeyl-
anicum Blume and its two major constituents against Callosobruchus maculatus (F.) and
Sitophilus oryzae (L.). J Agric Technol 11(6):1323–1336
75. Baratta MT, Dorman HJ, Deans SG et al (1998) Antimicrobial and antioxidant properties of
some commercial essential oils. Flavour Fragr J 13:235–244
76. Pragadheesh VS, Saroj A, Yadav A et al (2013) Chemical characterization and antifungal
activity of Cinnamomum camphora essential oil. Ind Crop Prod 49:628–633
77. Mallavarapu GR, Ramesh S (2000) Essential oil of the fruits of Cinnamomum zeylanicum
Blume. J Essent Oil Res 12(5):628–630
78. Senanayake UM, Lee TH, Wills RB (1978) Volatile constituents of cinnamon (Cinnamomum
zeylanicum) oils. J Agric Food Chem 26(4):822–824
79. Malsawmtluangi L, Nautiyal BP, Hazarika T et al (2016) Essential oil composition of bark
and leaves of Cinammoum verum Bertch & Presl from Mizoram, North East India. J Essent
Oil Res 28(6):551–556. https://doi.org/10.1080/10412905.2016.1167131
80. Jayaprakasha GK, Jagan Mohan Rao L et al (2003) Volatile constituents from Cinnamomum
zeylanicum fruit stalks and their antioxidant activities. J Agric Food Chem 51(15):4344–4348
81. Jayaprakasha GK, Rao LJ, Sakariah KK (2002) Chemical composition of volatile oil from
Cinnamomum zeylanicum buds. Z Naturforsch C 57(11–12):990–993
82. Kamalakannan K, Rayar A, Megala L (2016) Isolation of phytochemicals from the bark of
Cinnamomum cassia and antidiabetic study in alloxan induced diabetic rats. World J Pharm
Sci 4:143–149. ISSN (Print): 2321-3310; ISSN (Online): 2321-3086
83. Liao SG, Yuan T, Zhang C et al (2009) Cinnacassides A–E, five geranylphenylacetate glyco-
sides from Cinnamomum cassia. Tetrahedron 65(4):883–887
84. Packiaraj R, Jeyakumar S, Ayyappan N et al (2016) Antimicrobial and cytotoxic activities of
endophytic fungus Colletotrichum gloeosporioides isolated from endemic tree Cinnamomum
malabatrum. Stud Fungi 1(1):104–113
85. Archer AW (1988) Determination of cinnamaldehyde, coumarin and cinnamyl alcohol in cin-
namon and cassia by high-performance liquid chromatography. J Chromatogr A 447:272–276
86. Tanaka S, Yoon YH, Fukui H et al (1989) Antiulcerogenic compounds isolated from Chinese
cinnamon. Planta Med 55(03):245–248
87. Chericoni S, Prieto JM, Iacopini P et al (2005) In vitro activity of the essential oil of
Cinnamomum zeylanicum and eugenol in peroxynitrite-induced oxidative processes. J Agric
Food Chem 53(12):4762–4765
88. Mbaveng AT, Kuete V (2017) Cinnamon species. In: Medicinal spices and vegetables from
Africa. Academic Press, Amsterdam, pp 385–395
89. Bansode VJ (2012) A review on pharmacological activities of Cinnamomum cassia Blume.
Int J Green Pharm 6:102–108
90. Zhou L (2016) Studies on the chemical constituents and immunomodulatory activities of the
leaves of Cinnamomum cassia. Huazhong University of Science and Technology, Wuhan
91. Yang B, Liu S, Liu Y et al (2017) PAHs uptake and translocation in Cinnamomum camphora
leaves from Shanghai, China. Sci Total Environ 574:358–368
92. Chen BJ (2015) Research on chemical constituents of Cinnamomum cassia Presl and
Cinnamomum porrectum (Roxb.) Kosterm. M. S. dissertation, Shandong University of
Traditional Chinese Medicine
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff 691

93. He S, Zeng KW, Jiang Y, Tu PF (2016) Nitric oxide inhibitory constituents from the barks of
Cinnamomum cassia. Fitoterapia 112:153–160
94. Zeng JF, Zhu HC, Lu JW et al (2017) Two new geranylphenylacetate glycosides from the
barks of Cinnamomum cassia. Nat Prod Res 31(15):1812–1818
95. Liu X, Yang J, Fu J, Xie TG et al (2018) Phytochemical and chemotaxonomic studies on the
twigs of Cinnamomum cassia (Lauraceae). Biochem Syst Ecol 81:45–48
96. Li Z, Cai Z, Qian S, Chen M (2017) A new lactone from the twigs of Cinnamomum cassia.
Chem Nat Compd 53(2):234–236
97. Guo RL, Yin DZ, Zhou HF et al (2018) Chemical constituents from the immature buds of
Cinnamomum cassia (Lauraceae). Biochem Syst Ecol 78:102
98. Feng D (2016) Research on the chemical constituents of cinnamomum camphora. M. S. dis-
sertation, Shandong University of Traditional Chinese Medicine
99. Xu YW (2016) Research on chemical constituents of Cinnamomum chartophyllum H. W. Li.
M. S. dissertation, Shandong University of Traditional Chinese Medicine
100. Chowdhury AR (1999) Essential oil from Cinnamomum glanduliferum (Wall) Nees. Indian
Perfum 43(2):64–66
101. Baruah A, Nath SC (2006) Leaf essential oils of Cinnamomum glanduliferum (Wall) Meissn
and Cinnamomum glaucescens (Nees) Meissn. J Essent Oil Res 18(2):200–202
102. Prakash B, Singh P, Yadav S et al (2013) Safety profile assessment and efficacy of chemically
characterized Cinnamomum glaucescens essential oil against storage fungi, insect, aflatoxin
secretion and as antioxidant. Food Chem Toxicol 53:160–167
103. Kumar S, Vasudeva N, Sharma S (2012) GC-MS analysis and screening of antidiabetic, anti-
oxidant and hypolipidemic potential of Cinnamomum tamala oil in streptozotocin induced
diabetes mellitus in rats. Cardiovasc Diabetol 11(1):1–11
104. Mohan M, Haider SZ, Sharma A et al (2012) Antimicrobial activity and composition of the
volatiles of Cinnamomum tamala Nees. and Murraya koenigii (L.) Spreng. from Uttarakhand
(India). Asia Pac J Trop Dis 2:S324–S327
105. Gulati BC, Agarwal SG, Thappa RK et al (1977) Essential oil of Tejpat (Kumaon) from
Cinnamomum tamala. Indian Perfum 21:15–20
106. Kubeczka KH, Formacek V (2002) Essential oils analysis by capillary gas chromatography
and carbon-13 NMR spectroscopy, 2nd edn. John Wiley & Sons, New York
107. Dighe VV, Gursale AA, Sane RT et al (2005) Quantitative determination of eugenol from
Cinnamomum tamala nees and eberm. Leaf powder and polyherbal formulation using reverse
phase liquid chromatography. Chromatographia 61(9):443–446
108. Seth R, Mohan M, Singh P et al (2012) Chemical composition and antibacterial properties of
the essential oil and extracts of Lantana camara Linn. from Uttarakhand (India). Asian Pac J
Trop Biomed 2(3):S1407–S1411
109. Husain A, Virmani OP, Sharma A et al (1988) Major essential oil bearing plants of India.
Central Institute of Medicinal and Aromatic Plants (CIMAP), CSIR, Lucknow
110. Showkat RM, Ali M, Kapoor R (2004) Chemical composition of essential oil of Cinnamomum
tamala Nees & Eberm leaves. Flavour Fragr J.19:112–114
111. Prasad NK, Yang B, Dong X et al (2009) Flavonoid contents and antioxidant activities from
Cinnamomum species. Innov Food Sci Emerg Technol 10:627–632
112. Dighe VV, Gursale AA, Charegaonkar GA (2009) Quantitation of Eugenol, Cinnamaldehyde
and Isoeugenol from Cinnamomum tamala Nees and Eberm. leaf powder and Cinnamomum
zeylanicum Breyn stem bark powder by LC. Chromatographia 70(11):1759–1762
113. Khajapeer KV, Krishna PP, Baskaran RA (2015) GC MS and elemental analysis of
Cinnamomum tamala. Int J Pharm Pharm Sci 7:398–402
114. Heer A, Guleria S, Razdan VK (2017) Chemical composition, antioxidant and antimicrobial
activities and characterization of bioactive compounds from essential oil of Cinnamomum
tamala grown in north-western Himalaya. J Plant Biochem Biotechnol 26(2):191–198
692 S. Surendran and R. Ramasubbu

115. Srivastava B, Singh P, Shukla R, Dubey NK (2008) A novel combination of the essential oils
of Cinnamomum camphora and Alpinia galanga in checking aflatoxin B1 production by a
toxigenic strain of Aspergillus flavus. World J Microbiol Biotechnol 24(5):693–697
116. Ghalib RM, Hashim R, Sulaiman O et al (2012) Phytochemical analysis, cytotoxic activ-
ity and constituents–activity relationships of the leaves of Cinnamomum iners (Reinw. ex
Blume-Lauraceae). Nat Prod Res 26(22):2155–2158
117. Udayaprakash NK, Ranjithkumar M, Deepa S et al (2015) Antioxidant, free radical scav-
enging and GC–MS composition of Cinnamomum iners Reinw. ex Blume. Ind Crop Prod
69:175–179
118. Baskaran X, Ebbie MG (2008) Essential oil compounds and antibacterial activity of leaves
of Cinnamomum chemungianum Mohan et Henry (Lauraceae). Ethnobot Leafl 12:565–569
119. Rameshkumar KB, George V, Shiburaj S (2007) Chemical constituents and antibacterial
activity of the leaf oil of Cinnamomum chemungianum Mohan et Henry. J Essent Oil Res
19(1):98–100
120. Sriramavaratharajan V, Murugan R (2018) Cumin scented leaf essential oil of Cinnamomum
chemungianum: compositions and there in vitro antioxidant, α-amylase, α-glucosidase and
lipase inhibitory activities. Nat Prod Res 32(17):2081–2084
121. Chen CY, Wang HM, Chung SH et al (2010) Chemical constituents from the roots of
Cinnamomum subavenium. Chem Nat Compd 46(3):474–477
122. Lai Y, Liu T, Sa R et al (2015) Neolignans with a rare 2-oxaspiro [4.5] deca-6, 9-dien-8-one
motif from the stem bark of Cinnamomum subavenium. J Nat Prod 78(7):1740–1744
123. Huang GC, Kao CL, Yeh HC et al (2018) A new diphenyl ether from Cinnamomum subave-
nium. Chem Nat Compd 54(5):869–871
124. Hao X, Sun W, Ke C et al (2019) Anti-inflammatory activities of leaf oil from Cinnamomum
subavenium in vitro and in vivo. Biomed Res Int 2019:1
125. Bakar A, Yao PC, Ningrum V et al (2020) Beneficial biological activities of Cinnamomum
osmophloeum and its potential use in the alleviation of oral mucositis: a systematic review.
Biomedicine 8(1):3
126. Rao PV, Gan SH (2014) Cinnamon: a multifaceted medicinal plant. Evid Based Complement
Alternat Med 2014:1
127. Utchariyakiat I, Surassmo S, Jaturanpinyo M et al (2016) Efficacy of cinnamon bark oil
and cinnamaldehyde on anti-multidrug resistant Pseudomonas aeruginosa and the synergis-
tic effects in combination with other antimicrobial agents. BMC Complement Altern Med
16(1):1–7
128. Jantan IB, Ayop N, Hiong AB, Ahmad AS (2002) Chemical composition of the essential oils
of Cinnamomum cordatum Kosterm. Flavour Fragr J 17(3):212–214
129. Nath SC, Baruah AK (1994) Eugenol as the major component of the leaf oils of Cinnamomum
impressinervium Meissn. J Essent Oil Res 6(2):211–212
130. Baruah A, Nath SC (2007) Cinnamomum champokianum sp. nov. (Lauraceae) from Assam,
Northeastern India. Nord J Bot 25:281–285
131. Hrideek TK, Ginu J, Raghu AV et al (2016) Phytochemical profiling of bark and leaf volatile
oil of two wild Cinnamomum species from evergreen forests of Western Ghats. Plant Arch
16:266–274
132. Sriramavaratharajan V, Stephan J, Sudha V et al (2016) Leaf essential oil of Cinnamomum
agasthyamalayanum from the Western Ghats, India – a new source of camphor. Ind Crop
Prod 86:259–261
133. Sriramavaratharajan V, Sudha V, Murugan R (2016) Characterization of the leaf essential oils
of an endemic species Cinnamomum perrottetii from Western Ghats, India. Nat Prod Res
30(9):1085–1087
134. Cheng SS, Liu JY, Tsai KH et al (2004) Chemical composition and mosquito larvicidal activ-
ity of essential oils from leaves of different Cinnamomum osmophloeum provenances. J Agric
Food Chem 52(14):4395–4400
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff 693

135. Baruah A, Nath CS (2002) Panicle and bark oils of a variant of Cinnamomum beholghota
(Buch.-Ham.) Sweet from North East India. J Spices Aromat Crop 11(2):135–137
136. Abdelwahab SI, Mariod AA, Taha MME (2017) Chemical composition and antioxidant prop-
erties of the essential oil of Cinnamomum altissimum Kosterm (Lauraceae). Arab J Chem
10(1):131–135
137. Chalchat JC, Valade I (2000) Chemical composition of leaf oils of Cinnamomum from
Madagascar: C. zeylanicum Blume, C. camphora L., C. fragrans Baillon and C. angustifo-
lium. J Essent Oil Res 12(5):537–540
138. Maridass M, Ghanthikumar S (2008) Anti-inflammatory activity of Cinnamomum keralaense
bark extract. Pharmacologyonline 3:322–326
139. Bullerman LB, Lieu FY, Seier SA (1977) Inhibition of growth and aflatoxin production by
cinnamon and clove oils. Cinnamic aldehyde and eugenol. J Food Sci 42(4):1107–1109
140. Montes-Belmont R, Carvajal M (1998) Control of Aspergillus flavus in maize with plant
essential oils and their components. J Food Prot 61(5):616–619
141. McCann J (2003) Herbal Medicine Handbook, 2nd edn. Lippincott, Philadelphia
142. Chaudhry NMA, Tariq P (2006) Anti-microbial activity of Cinnamomum cassia against
diverse microbial flora with its nutritional and medicinal impacts. Pak J Bot 38(1):169
143. Biavati B, Franzoni S, Ghazvinizadeh H (1997) Antimicrobial and antioxidant properties of
plant essential oils. Essential oils. Basic and applied research. In: Proceedings of the 27th
international symposium on essential oils, Vienna, 8–3 September, pp 326–331
144. Rameshkumar KB, George V, Shiburaj S (2006) Chemical constituents and antimicro-
bial activity of the leaf oil of Cinnamomum filipedicellatum Kosterm. J Essent Oil Res
18(2):234–236
145. Dongmo PMJ, Tatsadjieu LN, Tchoumbougnang F et al (2007) Chemical composition, anti-
radical and antifungal activities of essential oil of the leaves of Cinnamomum zeylanicum
Blume from Cameroon. Nat Prod Commun 2(12):1934578X0700201219
146. Ranasinghe L, Jayawardena B, Abeywickrama K (2002) Fungicidal activity of essential
oils of Cinnamomum zeylanicum (L.) and Syzygium aromaticum (L.) Merr et LM Perry
against crown rot and anthracnose pathogens isolated from banana. Lett Appl Microbiol
35(3):208–211
147. Shan B, Cai YZ, Brooks JD, Corke H (2007) The in vitro antibacterial activity of dietary spice
and medicinal herb extracts. Int J Food Microbiol 117(1):112–119
148. Gende LB, Floris I, Fritz R et al (2008) Antimicrobial activity of cinnamon (Cinnamomum
zeylanicum) essential oil and its main components against Paenibacillus larvae from
Argentine. Bull Insectology 61(1):1
149. Gupta C, Garg AP, Uniyal RC et al (2008) Antimicrobial activity of some herbal oils against
common food-borne pathogens. Afr J Microbiol Res 2(10):258–261
150. Aneja KR, Joshi R, Sharma C (2009) Antimicrobial activity of Dalchini (Cinnamomum zeyl-
anicum bark) extracts on some dental caries pathogens. J Pharm Res 2(9):1387–1390
151. Goyal P, Chauhan A, Kaushik P (2009) Laboratory evaluation of crude extracts of
Cinnamomum tamala for potential antibacterial activity. Electron J Biol 5(4):75–79
152. Mishra AK, Mishra A, Kehri HK (2008) Inhibitory activity of Indian spice plant Cinnamomum
zeylanicum extracts against Alternaria solani and Curvularia lunata, the pathogenic dematia-
ceous moulds. Ann Clin Microbiol Antimicrob 8(1):1–7
153. Abdelwahab SI, Zaman FQ, Mariod AA (2010) Chemical composition, antioxidant and anti-
bacterial properties of the essential oils of Etlingera elatior and Cinnamomum pubescens
Kochummen. J Sci Food Agric 90(15):2682–2688
154. Friedman M, Kozukue N, Harden LA (2000) Cinnamaldehyde content in foods determined
by gas chromatography− mass spectrometry. J Agric Food Chem 48(11):5702–5709
155. Bouhdid S, Abrini J, Amensour M (2010) Functional and ultrastructural changes in
Pseudomonas aeruginosa and Staphylococcus aureus cells induced by Cinnamomum verum
essential oil. J Appl Microbiol 109(4):1139–1149
694 S. Surendran and R. Ramasubbu

156. Rattanachaikunsopon P, Phumkhachorn P (2010) Potential of cinnamon (Cinnamomum

verum) oil to control Streptococcus iniae infection in tilapia (Oreochromis niloticus). Fish
Sci 76(2):287–293
157. Unlu M, Ergene E, Unlu GV et al (2010) Composition, antimicrobial activity and in vitro
cytotoxicity of essential oil from Cinnamomum zeylanicum Blume (Lauraceae). Food Chem
Toxicol 48(11):3274–3280
158. Ababutain IM (2011) Antimicrobial activity of ethanolic extracts from some medicinal plant.
Aust J Basic Appl Sci 5(11):678–683
159. Jain A, Dubey M, Gupta A et al (2011) Antimicrobial activity of Cinnamomum tamala
(Tejpat) against some bacterial and fungal pathogens. J Pharm Res 4(11):3975–3977
160. Shareef AA (2011) Evaluation of antibacterial activity of essential oils of Cinnamomum sp.
and Boswellia sp. J Bas Res (Sci) 37(5):60–71
161. Prabuseenivasan S, Jayakumar M, Ignacimuthu S (2006) In vitro antibacterial activity of
some plant, essential oils. BMC Complement Altern Med 6(1):39
162. Babu AJ, Sundari AR, Indumathi J et al (2011) Study on the antimicrobial activity and mini-
mum inhibitory concentration of essential oils of spices. Vet World 4(7):311–316. https://doi.
org/10.5455/vetworld.4.311
163. Boniface Y, Philippe S, de Lima HR et al (2012) Chemical composition and antimicrobial
activities of Cinnamomum zeylanicum Blume dry leaves essential oil against food-borne
pathogens and adulterated microorganisms. Int Res J Biol Sci 1(6):18–25
164. Mahmoud SN (2012) Antifungal activity of Cinnamomum zeylanicum and Eucalyptus
microtheca crude extracts against food spoilage fungi. Euphrates J Agric Sci 4(3):26–39
165. Dhara L, Tripathi A (2013) Antimicrobial activity of eugenol and cinnamaldehyde against
extended spectrum beta lactamase producing enterobacteriaceae by in vitro and molecular
docking analysis. Eur J Integr Med 5(6):527–536
166. Herman A, Herman AP, Domagalska BW, Młynarczyk A (2013) Essential oils and herbal
extracts as antimicrobial agents in cosmetic emulsion. Indian J Microbiol 53(2):232–237
167. Yadav P, Dubey NK (1994) Screening of some essential oils against ringworm fungi. Indian
J Pharm Sci 56(6):227–230
168. Mishra AK, Singh BK, Pandey AK (2010) In vitro-antibacterial activity and phytochemical
profiles of Cinnamomum tamala (Tejpat) leaf extracts and oil. Rev Infect 1(3):134–139
169. Elhag DE, Osman Z, Omer H et al (2015) Chemical composition, antimicrobial activities
and TLC profile of different bark extracts of Cinnamomum zeylanicum. Pharm Innov 4(1,
Part A):33
170. Valizadeh S, Katiraee F, Mahmoudi R et al (2015) Biological properties of Cinnamomum
zeylanicum essential oil: phytochemical component, antioxidant and antimicrobial activities.
Int J Food Saf Nutr Public Health 6(3):174–184
171. Hameed IH, Altameme HJ, Mohammed GJ (2016) Evaluation of antifungal and antibacterial
activity and analysis of bioactive phytochemical compounds of Cinnamomum zeylanicum
(Cinnamon bark) using gas chromatography-mass spectrometry. Orient J Chem 32(4):1769
172. Hassan W, Zainab KSN, Noreen H et al (2016) Antimicrobial activity of Cinnamomum
tamala leaves. J Nutr Disord Ther 6(2):2161–0509
173. Adarsh A, Chettiyar B, Kanthesh B, Raghu N (2020) Phytochemical screening and antimi-
crobial activity of “Cinnamomum zeylanicum”. Int J Pharm Res Innov 13:22–33
174. Naik G, Haider SZ, Bhandari U et al (2021) Comparative analysis of in vitro antimicrobial
and antioxidant potential of Cinnamomum tamala extract and their essential oils of two dif-
ferent chemotypes. Agric Sci Dig A Res J 41(2):307–312
175. Cong Y, Zhang L, Zu YG (2016) Anti-inflammatory and antioxidant activities of Cinnamomum
longepaniculatum essential oil. Bull Bot Res 36:949–954
176. Chairunnisa, Tamhid HA, Nugraha AT 2017 Gas chromatography–mass spectrometry anal-
ysis and antibacterial activity of Cinnamomum burmannii essential oil to Staphylococcus
aureus and Escherichia coli by gaseous contact. In: AIP conference proceedings, vol 1823,
no 1. AIP Publishing LLC, Yogyakarta, Indonesia, p 020073
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff 695

177. Hu SH, Liu JL, Xu GQ (2017) Inhibitory activity of Cinnamomum camphora leaves extracts
on selected wood fungi and moulds. Forest Sci Technol 76–79
178. Rangel MDL, Aquino SGD, Lima JMD et al (2018) In vitro effect of Cinnamomum zeylani-
cum Blume essential oil on Candida spp. involved in oral infections. Evid Based Complement
Alternat Med 2018:1–13
179. Vaillancourt K, LeBel G, Yi L et al (2018) In vitro antibacterial activity of plant essential oils
against Staphylococcus hyicus and Staphylococcus aureus, the causative agents of exudative
epidermitis in pigs. Arch Microbiol 200(7):1001–1007
180. Li YR, Fu CS, Yang WJ et al (2018) Investigation of constituents from Cinnamomum cam-
phora (L.) J. Presl and evaluation of their anti-inflammatory properties in lipopolysaccharide-­
stimulated RAW 264.7 macrophages. J Ethnopharmacol 221:37–47
181. Song SY, Song SH, Bae MS et al (2019) Phytochemical constituents and the evaluation bio-
logical effect of Cinnamomum yabunikkei H. Ohba leaf. Molecules 24(1):81
182. Lu K, Wang QR, Huo X et al (2019) Composition analysis of acetone extract of Cinnamomum
cassia and its inhibition on 5 plant pathogens, Southwest China. J Agric Sci 32:798–802
183. Lin CC, Wu SJ, Chang CH et al (2003) Antioxidant activity of Cinnamomum cassia.
Phytother Res 17(7):726–730
184. Mathew S, Abraham TE (2006) In vitro antioxidant activity and scavenging effects of
Cinnamomum verum leaf extract assayed by different methodologies. Food Chem Toxicol
44(2):198–206
185. Jayaprakasha GK, Negi PS, Jena BS et al (2007) Antioxidant and antimutagenic activities of
Cinnamomum zeylanicum fruit extracts. J Food Compos Anal 20(3–4):330–336
186. Mancini-Filho J, Van-Koiij A, Mancini DA et al (1998) Antioxidant activity of cinnamon
(Cinnamomum Zeylanicum, Breyne) extracts. Boll Chim Farm 137(11):443–447
187. Okawa M, Kinjo J, Nohara T et al (2001) DPPH (1,1-diphenyl-2-picrylhydrazyl) radical
scavenging activity of flavonoids obtained from some medicinal plants. Biol Pharm Bull
24:1202–1205
188. Yang CH, Yang CS, Hwang ML et al (2012) Antimicrobial activity of various parts
of Cinnamomum cassia extracted with different extraction methods. J Food Biochem
36(6):690–698
189. Hsu FL, Li WH, Yu CW et al (2012) In vivo antioxidant activities of essential oils and their
constituents from leaves of the Taiwanese Cinnamomum osmophloeum. J Agric Food Chem
60(12):3092–3097
190. Pandey M, Chandra DR (2015) Evaluation of ethanol and aqueous extracts of Cinnamomum
verum leaf galls for potential antioxidant and analgesic activity. Indian J Pharm Sci 77(2):243
191. Chua MT, Tung YT, Chang ST (2008) Antioxidant activities of ethanolic extracts from the
twigs of Cinnamomum osmophloeum. Bioresour Technol 99(6):1918–1925
192. Chakraborty U, Das H (2010) Antidiabetic and antioxidant activities of Cinnamomum tamala
leaf extracts in STZ-treated diabetic rats. Glob J Biotechnol Biochem 5(1):12–18
193. Anis Z, Hashim R, Hasan Mehdi S et al (2012) Radical scavenging activity, total phenol con-
tent and antifungal activity of Cinnamomum iners wood. Iran J Energy Environ 3(5):74–78
194. Park SJ, Yu MH, Kim JE, Lee SP, Lee IS (2012) Comparison of antioxidant and antimicrobial
activities of supercritical fluid extracts and marc extracts from Cinnamomum verum. J Life
Sci 22(3):373–379
195. Srinivasa RK, Kumar KN, BVV, R.K. (2012) Microwave assisted extraction and evaluation
of in vitro antioxidant activity of Cinnamomum aromaticum. J Med Plants Res 6(3):439–448
196. Abeysekera WPKM, Premakumara GAS, Ratnasooriya WD (2013) In vitro antioxidant prop-
erties of leaf and bark extracts of ceylon cinnamon (Cinnamomum zeylanicum Blume). Trop
Agric Res 24(2):128–138
197. Salleh WMNH, Farediah A, Khong HY (2015) Antioxidant and anticholinesterase activi-
ties of essential oils of Cinnamomum griffithii and C. macrocarpum. Nat Prod Commun
10(8):1465–1468
696 S. Surendran and R. Ramasubbu

198. Brodowska KM, Brodowska AJ, Śmigielski K, Łodyga-Chruścińska E (2016) Antioxidant

profile of essential oils and extracts of cinnamon bark (Cinnamomum cassia). Eur J Biol Res
6(4):310–316
199. Ervina M, Nawu YE, Esar SY (2016) Comparison of in vitro antioxidant activity of infusion,
extract and fractions of Indonesian Cinnamon (Cinnamomum burmannii) bark. Int Food Res
J 23(3):1346
200. Fu J, Zeng C, Zeng Z, Wang B, Gong D (2016) Cinnamomum camphora seed kernel oil ame-
liorates oxidative stress and inflammation in diet-induced obese rats. J Food Sci 81:1295–1300
201. Liu Z, Mo K, Fei S, Zu Y, Yang L (2017) Efficient approach for the extraction of proantho-
cyanidins from Cinnamomum longepaniculatum leaves using ultrasonic irradiation and an
evaluation of their inhibition activity on digestive enzymes and antioxidant activity in vitro.
J Sep Sci 40(15):3100–3113
202. Liu Z, Kong L, Lu S, Zou Z (2019) Application of a combined homogenate and ultrasonic cav-
itation system for the efficient extraction of flavonoids from Cinnamomum camphora leaves
and evaluation of their antioxidant activity in vitro. J Anal Methods Chem 2019:4892635
203. Kallel I, Hadrich B, Gargouri B et al (2019) Optimization of cinnamon (Cinnamomum zeyl-
anicum Blume) essential oil extraction: evaluation of antioxidant and antiproliferative effects.
Evid Based Complement Alternat Med 2019:1
204. Priani SE, Mutiara R, Mulyanti D (2020) The development of antioxidant peel-off facial
masks from cinnamon bark extract (Cinnamomum burmannii). Pharmaciana 10(1):69–76
205. Ribeiro PRE, Montero IF, Saravia SAM et al (2020) Chemical composition and antioxidant
activity in the essential oil of Cinnamomum zeylanicum Nees with medicinal interest. J Med
Plants Res 14(7):326–330
206. Raksha R, Rajesh K, Preeti S et al (2021) Phytochemical screening and free radical scaveng-
ing activity of Cinnamomum tamala leaf extract. Intern J Zool Invest 7(2):376–386
207. Singh N, Rao AS, Nandal A et al (2021) Phytochemical and pharmacological review
of Cinnamomum verum J. Presl-a versatile spice used in food and nutrition. Food Chem
338:127773
208. Chao LK, Hua KF, Hsu HY et al (2005) Study on the Antiinflammatory activity of essential
oil from leaves of Cinnamomum osmophloeum. J Agric Food Chem 53(18):7274–7278
209. Joshi K, Awte S, Bhatnagar P (2010) Cinnamomum zeylanicum extract inhibits proinflamma-
tory cytokine TNF: in vitro and in vivo studies. Res Pharm Biotech 2(2):014–021
210. Liao JC, Deng JS, Chiu CS et al (2012) Anti-inflammatory activities of Cinnamomum cassia
constituents in vitro and in vivo. Evid Based Complement Alternat Med 2012:129152
211. Hossain MH, Jahan F, Howlader MSI et al (2012) Evaluation of antiinflammatory activity
and total flavonoids content of Manilkara zapota (linn.) bark. Int J Pharm Phytopharmacol
Res 2(1):35–39
212. Han X, Parker TL (2017) Antiinflammatory activity of cinnamon (Cinnamomum zeylanicum)
bark essential oil in a human skin disease model. Phytother Res 31(7):1034–1038
213. Prajapati JA, Humbal BR, Sadariya KA (2019) Determination of in-vivo anti-inflammatory
potential of Cinnamomum zeylanicum oil in female wistar rats. Pharm Innov J 8(7):544–547
214. Budiastuti B, Sukardiman S, Primaharinastiti R et al (2021) Anti-inflammatory activity of
cinnamon bark oil (Cinnamomum Burmannii (Nees & T. Nees) Blume) from Kerinci Regency
of Indonesia. ICEHHA, Flores
215. Du YH, Feng RZ, Li Q (2014) Anti-inflammatory activity of leaf essential oil from
Cinnamomum longepaniculatum (Gamble) N. Chao. Int J Clin Exp Med 7(12):5612
216. Bhagavathy S, Latha S (2015) Anticarcinogenic effects of Cinnamomum verum on HL60
leukemia cell lines. J Pharm Res 9(12):650–661
217. Al-Zereini WA, Al-Trawneh IN, Al-Qudah MA (2022) Essential oils from Elettaria cardamo-
mum (L.) Maton grains and Cinnamomum verum J. Presl barks: Chemical examination and
bioactivity studies. J Pharm Pharmacogn Res 10(1):173–185
218. Kamath JV, Rana AC, Chowdhury RA (2003) Pro-healing effect of Cinnamomum zeylanicum
bark. Phytother Res 17(8):970–972
Phytochemistry and Pharmacological Studies of Indian Cinnamomum Schaeff 697

219. Soni R (2013) Effect of ethanolic extract of Cinnamomum tamala leaves on wound healing
In Stz induced diabetes in rats. Asian J Pharm Clin Res 6:39–42
220. Narkhede N, Deo S, Inam F (2014) Comparative study of wound healing activity of various
spice and herbs in Rats. Int J Res Biosci Agric Tech 2(1):949–955
221. Deepa C, Srivastava R, Kumar Srivastava A et al (2016) Wound healing activity of hydro-­
alcoholic extract of Cinnamomum nitidum Blume (Lauraceae) in wistar albino rats. Curr Trad
Med 2(2):134–145
222. Ahmadi SG, Farahpour MR, Hamishehkar H (2019) Topical application of Cinnamon verum
essential oil accelerates infected wound healing process by increasing tissue antioxidant
capacity and keratin biosynthesis. Kaohsiung J Med Sci 35(11):686–694
223. Kefayat A, Hamidi Farahani R, Rafienia M (2021) Synthesis and characterization of cellu-
lose nanofibers/chitosan/cinnamon extract wound dressing with significant antibacterial and
wound healing properties. J Iran Chem Soc 19:1–12
Medicinal Properties and Population
Studies on Sarcostigma kleinii Wight &
Arn.

Silvy Mathew and Reshma Rajan

1 Introduction

India harbours about 15% (3000–3500) out of 20,000 medicinal plants of the world.
About 90% of these are found growing wild in different climatic regions of the
country. Among these medicinal plants, Sarcostigma kleinii is a perennial large
liana. Lianas are woody climbing vines that rely on other plants for support. They
encompass 25% of species diversity in tropical systems. There is a growing body of
evidence pointing to an increase in abundance of lianas in forests. Lianas diversity
and abundance has been shown to increase following disturbance in comparisons
between forest edges and interiors and between secondary and old growth forests.
By producing many rooting stems, lianas are able to rapidly colonize disturbed
areas, thereby increasing their chances of survival [1, 2].
MS Swaminathan foundation studies reveal that over 500 species of flowering
plants are under threat in the district, of which 300 are endemic to Western Ghats
and over 50 are critically endangered with many listed in Red Data Books. Among
them, Sarcostigma kleinii is a Rare, Endemic and Threatened (RET) species and
their study reveals that Sarcostigma kleinii is a rare Iiana. Once an important source
for oil for treating rheumatism, ulcers, leprosy and skin diseases and lighting tradi-
tional lamp. ­ (http://59.160.153.188/library/sites/default/files/25saving%2010%20
keystone%20plant%20species.pdf).

S. Mathew (*) · R. Rajan

Post Graduate Department of Botany, Vimala College (Autonomous), Thrissur, Kerala, India
Post Graduate Department of Botany, St.Thomas College (Autonomous),
Thrissur, Kerala, India

© The Author(s), under exclusive license to Springer Nature 699

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_27
700 S. Mathew and R. Rajan

2 Family Icacinaceae

The Icacinaceae are a family of flowering plants, consisting of trees, shrubs and
lianas, primarily of the tropics. The family was traditionally circumscribed quite
broadly, with around 55 genera totaling over 400 species. In 2001, however, this
circumscription was found to be polyphyletic, and the family was split into four
families in three different orders: Icacinaceae sensu stricto, Pennantiaceae (Apiales),
Stemonuraceae (Aquifoliales) and Cardiopteridaceae (also Aquifoliales).
Icacinaceae sensu stricto contains about 150 species, distributed into about 35 gen-
era [3]. Icacina senegalensis extracts have shown activity against malaria parasites
[4]. Nothapodytes nimmoniana shows antimicrobial activity and is traditionally
used as a remedy for malaria and has anti-inflammatory activities [5]. Rhaphiostylis
beninensis root possess anti-inflammatory activities.
Ramesha et al. [6] evaluated the production of an anticancerous alkaloid camp-
tothecin (CPT) and its derivatives, in 13 species of the family Icacinaceae, namely,
Apodytes dimidiata, Codiocarpus andamanicus, Gomphandra comosa, Gomphandra
coriacea, Gomphandra polymorpha, Gomphandra tetrandra, Iodes cirrhosa, Iodes
hookeriana, Miquelia dentata, Miquelia kleinii, Natsiatum herpeticum,
Pyrenacantha volubilis and Sarcostigma kleinii. His studies were the first reports of
CPT and its derivatives in these species and offer rich alternative plant sources for
the anticancer compound, CPT. The study is also supported by [7].
Also, Shweta et al. [8] isolated the same anticancer alkaloid CPT from Miquelia
dentata Bedd. (Icacinaceae). CPT, a quinoline alkaloid, is a potent inhibitor of
eukaryotic topoisomerase I, and together with its derivatives, CPT is the third larg-
est anticancer drug in the world market. This is the first report of production of CPT
by endophytic bacteria. The identity of the bacteria was ascertained by Gram stain-
ing and 16s rRNA sequencing. This potent eukaryotic topoisomerase inhibitor,
CPT, is also reported from Pyrenacantha volubilis (Icacinaceae) from the eastern
coast of peninsular India. They analysed the CPT and its derivatives using high-­
performance liquid chromatography (HPLC) coupled with electrospray mass spec-
trometry (ESI-MS) in all plant parts, such as twigs, leaves, roots, seedling, ripened
whole fruit, fruit coat, seed coat and cotyledons. Cotyledons and ripened whole
fruits contained the highest amount of CPT (1.35% and 0.60% dry weight,
respectively).

3 
Sarcostigma Kleinii

Taxonomical classification
• Kingdom: Plantae
Phylum: Magnoliophyta
Class: Magnoliopsida
Order: Celastrales
Medicinal Properties and Population Studies on Sarcostigma kleinii Wight & Arn. 701

Family: Icacinaceae
Genus: Sarcostigma
Species: Sarcostigma kleinii
Vernacular names
• English: Sarcostigma kleinii
Hindi: Mukhajali
Konkani, Marathi: Davabindu
Kannada: Puvanna
Tamil: Puvennai, Ota
Malayalam: Vellayodal, Erumathali, Odal, Vattodal,
Synonyms
• Chailletia edulis Kurz
• Sarcostigma edule Kurz
• Sarcostigma horsfieldii R.Br.
• Sarcostigma roxburghii Wall. ex Griff.
• Sarcostigma wallichii Baill.
Sarcostigma kleinii belongs to the family Icacinaceae. It is a wild edible plant tradi-
tionally used by the tribes in the Parambikulam Wildlife Sanctuary, Kerala, India
[9]. The plant’s bark and leaves are bitter, acrid, thermogenic, anthelmintic, diges-
tive, carminative, diuretic, anaphrodisiac, depurative, vulnerary and stomachic.
They are useful in vitiated conditions of vata, cephalalgia, gastropathy, anorexia,
flatulence, helminthiasis, strangury, indolent ulcers, leprosy, skin diseases, hysteria
and epilepsy. The oil is bitter, anaphrodisiac, anthelmintic, vulnerary and depura-
tive. It is useful in vitiated conditions of vata, helminthiasis, foul ulcers, leprosy and
skin diseases [10] (Fig. 1).
Sarcostigma kleinii is a much-branched vigorous climbing shrub with stems up
to 26 m long and up to 8 cm thick. Usually evergreen, the plant is sometimes leafless
when flowering. The plant is used as a source of food, medicine and oil. The oil is a
popular treatment for rheumatism in India. The fruit of this plant contains a thin
sweetish pulp surrounding the single seed. Leaves and young shoots of the plant can
be used in food by cutting into small pieces and cooked with salt and chilly, and
garnished with mustard seeds, curry leaves and onions in oil.

4 
Sarcostigma kleinii: Geographic Distribution

The Sarcostigma kleinii is also reported in many sacred groves of Kerala. It is avail-
able in E. Asia – southwest India, Andaman Islands, Myanmar, Vietnam, Malaya,
Indonesia. This plant is available in sacred groves. Sacred groves have been con-
served as sustainable biological resources. They serve as a valuable gene pool. They
are also considered as the first major effort to recognize and conserve biodiversity.
Since ancient period kavu has been recognized as the source of medicine, edibles
702 S. Mathew and R. Rajan

Fig. 1 Morphological features of Sarcostigma kleinii

Medicinal Properties and Population Studies on Sarcostigma kleinii Wight & Arn. 703

and other economically important plants for the natives. The notable medicinal spe-
cies include Anamirta cocculus, Curculigo orchioides, Cyclea peltata, Gloriosa
superba, Glycosmis pentaphylla, Ocimum spp., Phyllanthus amarus, Sarcostigma
kleinii, Scoparia dulcis and Tinospora cordifolia.
The habitat includes the Western Ghats, from Konkan southwards. It is a wild
edible plant traditionally used by the tribes in the Parambikulam Wildlife Sanctuary,
Kerala. They are usually found in Western Ghats at Low Altitudes. They are distrib-
uted widely in Maharashtra: Kolhapur, Karnataka: Chikmagalur and Coorg, Kerala:
all districts, and Tamil Nadu: Coimbatore, Kanniyakumari, Nilgiri and Tirunelveli
(http://eol.org/pages/5228816/overview).

5 Taxonomic Description of the Plant

They are woody climbers, branchlets and glabrous. Leaves are oblong-lanceolate,
apex acuminate, base rounded or obtuse; lateral nerves 8 pairs, reticulate; and peti-
ole 5–12 cm long. Flowers are 3–6 together, yellow; calyx cupular, 2 mm across, 5
toothed; petals 3–5 mm long, oblong, recurved; female flowers mostly from old
wood, ovary 1 celled, densely hairy; stigma sessile, discoid. Pistillode in male flow-
ers are conical. Fruits are drupe, orange-yellow in colour, glabrous [11] .

6 Phytochemical Constituents

In Table 1, preliminary screening of ethanolic extract was conducted to identify

various phytoconstituents as per the standard procedures to determine presence of
various phytoconstituents [11].
Camptothecin content based on HPLC analysis in Sarcostigma kleinii [6].
Scientists also isolated the β-sitosterol from the stems of Sarcostigma kleinii [12]
(Table 2).

Table 1 Preliminary phytochemical screening of Sarcostigma kleinii

Sl. Phytochemical
No constituents Reagents Inference
1 Alkaloids Dragendroff’s reagent, Mayer’s reagent Hager’s +
reagent
2 Carbohydrates Molish’s reagent, Fehling’s reagent +
3 Proteins and amino acids Biuret’s reagent, ninhydrin reagent −
4 Steroids and triterpenoids Leibermann-Burchard reagent, Salkowski test +
5 Glycosides Borntager’s reagent +
704 S. Mathew and R. Rajan

Table 2 Camptothecin content of Sarcostigma kleinii

Camptothecin
(% DW)
Species (V. No) Plant part Sample size Mean ± SD
Sarcostigma kleinii Leaf (H) 1 0.0042
(SK 1002) Leaf (F) 1 0.018
Stem bark (F) 1 0.0037
Fruit (F) 1 0.00036
H herbarium material, F fresh material

7 Medicinal Properties

Seed oil of Sarcostigma kleinii is used externally in rheumatism. Powdered bark is

given in rheumatism, neurological disorders and skin diseases. The oil from
Sarcostigma kleinii is used as an anaphrodisiac, anthelmintic, bitter, depurative and
vulnerary [9]. It is useful in vitiated conditions of vata, and for treating conditions
such as helminthiasis, foul ulcers, leprosy and skin diseases. The oil obtained from
the seeds is highly esteemed in India for the treatment of rheumatism. The bark and
leaves are acrid, anaphrodisiac, anthelmintic, carminative, bitter, depurative, diges-
tive, diuretic, stomachic, thermogenic and vulnerary. They are useful in the treat-
ment of vitiated conditions of vata and for conditions, such as cephalalgia,
gastropathy, anorexia, flatulence, helminthiasis, strangury, indolent ulcers, leprosy,
skin diseases, hysteria and epilepsy. Methanolic extracts of the leaf and bark have
shown high antioxidant activity. They can be considered as potential new sources of
natural antioxidants for food and nutraceutical products.
The plant’s bark and leaves are bitter, acrid, thermogenic, anthelmintic, diges-
tive, carminative, diuretic, anaphrodisiac, depurative, vulnerary and stomachic.
They are useful in vitiated conditions of vata, cephalalgia, gastropathy, anorexia,
flatulence, helminthiasis, strangury, indolent ulcers, leprosy, skin diseases, hysteria
and epilepsy. The oil is bitter, anaphrodisiac, anthelmintic, vulnerary and depura-
tive. It is useful in vitiated conditions of vata, helminthiasis, leprosy and skin dis-
eases [13].
Traditionally fruits of Sarcostigma kleinii are used in rheumatism, fatty oil of
seeds are considered as a cure for rheumatism and powdered bark mixed with honey
is also given in rheumatism, leprosy, hysteria and ulcers. Leaves boiled in oil also
used for rheumatism [14].

8 Phylogenetic Studies

Figure 2 explains the phylogenetic analysis of Icacinaceae members using ndhf

gene sequences. The sequences for Nothapodytes nimmoniana, Miquelia dentata,
Pyrenacantha volubilis and Sarcostigma kleinii marked were generated in the
Medicinal Properties and Population Studies on Sarcostigma kleinii Wight & Arn. 705

Fig. 2 Phylogenetic analysis of Icacinaceae members using ndhf gene sequences. (Copyright
accessed from Ramesha et al. [6])

present study. This study evaluated the phylogeny by using maximum likelihood
analysis of Icacinaceae members sensu stricto using RAxML analysis. In the figure,
values on the nodes indicate bootstrap support for the clades and the dotted lines
species are the members of Icacinaceae sensu lato as outgroup. Numbers before the
species name indicate the GenBank accession number.

9 Conclusion

Sarcostigma kleinii is an important ayurvedic plant with multiple remedies. The

whole parts of the plant are medicinally very important. Pharmacologically, it has
been evaluated for anthelmintic, antioxidant studies. However, further research on
this plant is needed to know the exact molecular mechanism and can lead to develop
safe therapeutic use in modern medicine.

References

1. Gentry AH (1991) The distribution and evolution of climbing plants. In: Putz FE, Mooney HA
(eds) The biology of vines. Cambridge University Press, Cambridge, pp 3–52
2. Ramachandran KK, Joseph GK (2001) Feeding ecology of Nilgiri langur (Trachypithecusjohnii)
in Silent Valley National Park, Kerala, India. pp 1155–1164
3. Karehed J (2001) Multiple origin of the tropical forest tree family Icacinaceae. Am J Bot
12:2259–2274
4. Sarr SO, Perrotey S, Fall I et al (2011) Icacina senegalensis (Icacinaceae), traditionally used
for the treatment of malaria, inhibits in vitro plasmodium falciparum growth without host cell
toxicity. Malar J 10:85. https://doi.org/10.1186/1475-­2875-­10-­85
706 S. Mathew and R. Rajan

5. Uma G, Balasubramaniam V, Jagathes KS (2016) Evaluation of antimicrobial activity of

Nothapodytes Nimmoniana Icacinaceae. World J Pharm Pharm Sci 2(6):5078–5083
6. Ramesha BT, Suma HK, Senthilkumar U, Priti V, Ravikanth G, Vasudeva R, Kumar TR,
Ganeshaiah KN, Shaanker RU (2013) New plant sources of the anti-cancer alkaloid, camptoth-
ecine from the Icacinaceae taxa, India. Phytomed Int J Phytother Phytopharm 20(6):521–527.
https://doi.org/10.1016/j.phymed.2012.12.003
7. Ramachandran A, Vasudeva R, Ravikanth G, Shaanker RU (2021) Variation in seedling vigour
and camptothecin content of Pyrenacantha volubilis Wight: insights for domestication. Genet
Resour Crop Evol 68(3):1061–1071
8. Shweta S, Bindu JH, Raghu J, Suma HK, Manjunatha BL, Kumara PM, Ravikanth G, Nataraja
KN, Ganeshaiah KN, Uma Shaanker R (2013) Isolation of endophytic bacteria producing the
anti-cancer alkaloid camptothecine from Miquelia dentata Bedd. (Icacinaceae). Phytomed Int
J Phytothera Phytopharm 20(10):913–917. https://doi.org/10.1016/j.phymed.2013.04.004
9. Yesodharan K, Sujana KA (2007a) Wild edible plants traditionally used by the tribes in the
Parambikulam wildlife sanctuary, Kerala, India. Nat Prod Radiance 6(1):74–80
10. Warrier PK, Nambiar VPK, Ramankutty C, Vasudevan NR (1996) Indian medicinal plants: a
compendium of 500 species, vol 5. Orient Longman Limited, Hyderabad, pp 76–79
11. Abraham E, Harindran J (2019) Pharmacognostic evaluation and formulation of shampoo
using Sarcostigma kleinii Wight & Arn leaves fam: Icacinaceae. Pharm Innov J 8(11):220–223
12. Karrer W (1958) Triterpene. In: Konstitution und Vorkommen der organischen Pflanzenstoffe.
Chemische Reihe (Lehrbücher und Monographien aus dem Gebiete der Exakten Wissenschaften),
vol 12. Birkhäuser, Basel, pp 769–843. https://doi.org/10.1007/978-­3-­0348-­6808-­2_23
13. Arunachalam K (2011) Phenolic content and antioxidant potential of Sarcostigma kleinii
Wight. & Arn. Taylor & Francis, pp 161–169
14. Vaidyaratnam TSV (1996) Indian medicinal plants: a compendium of 500 species, vol 5, 1st
edn. Orient Longman Ltd, Madras, pp 76–79
RETRACTED CHAPTER: The Utility
of Natural Mucilage from the Medicinal
Plant, ‘Patha’ (Cyclea peltata)
as an Alternative for Solidifying Agent
in Cell Growth Media

Anjana Krishnan, Jomy Joseph, and Sudha Kalyanikutty

The Editors have retracted this chapter because it has been published previously [1].
All authors agree with this retraction.
1. Krishnan, A., Joseph, J., Kalyanikutty, S. (2023). The Utility of Natural Mucilage
from the Medicinal Plant “Patha” (Cyclea peltata) as an Alternative for
Solidifying Agent in Cell Growth Media. In: Arunachalam, K., Yang, X.,
Puthanpura Sasidharan, S. (eds) Natural Product Experiments in Drug Discovery.
Springer Protocols Handbooks. Humana, New York, NY. https://doi.
org/10.1007/978-1-0716-2683-2_23

© The Author(s), under exclusive license to Springer Nature 707

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_28
Secondary Metabolites in Ophiorrhiza
brunonis Wight & Arn. (Rubiaceae):
A Lead Towards Its Anticancer Potential

S. N. Preethamol and John E. Thoppil

1 Introduction

About 80% of the world’s population depend upon plants or plant-based products
for food as well as health care needs as plants serve as rich source of nutrition and
safe medicines [1]. The medicinal properties of the plants can be ascribed to the
presence of various bioactive phytochemicals like phenols, flavonoids, tannins,
alkaloids and saponins [2]. The bioactive compounds that contribute to the thera-
peutic potential of the plants are actually produced by plants for their defensive
mechanism by various secondary biochemical pathways and are called secondary
metabolites [3]. They are reported to have pharmacological properties like anti-­
allergic, hypoglycaemic, antioxidant, antimicrobial and anticancer potentials [4–6].
Though they can exhibit individual therapeutic effect, secondary metabolites can
work synergistically with each other and enhance pharmacological action [1]. Thus,
the medicinal value of herbs or herbal products depends on the presence and quan-
tity of phytoconstituents in them which needs to be validated by scientific methods.
Ophiorrhiza L. is a species-rich genus of the family Rubiaceae found in the wet
tropical forests of South-East Asia, extending to Australia, New Guinea and Pacific
Islands [7]. The members are generally small, herbaceous or shrubby with several
healing properties. They have been used in traditional medication as snake bite anti-
tussive and analgesic and also for curing ulcers, leprosy, gastropathy and amenor-
rhoea [8]. Ophiorrhiza brunonis Wight &Arn. is one of the several species of the
genus used in the folklore medicine for the treatment of various ailments mentioned
above. The plant is usually grown in the evergreen forest of Kerala, Tamil Nadu and
Karnataka. It is an erect herb with branched stem which is woody at the base.
Flowers are white and pubescent externally. Capsules are glabrous and green.

S. N. Preethamol (*) · J. E. Thoppil

Cell and Molecular Biology Division, Department of Botany, University of Calicut,
Thenhipalam, Kerala, India

© The Author(s), under exclusive license to Springer Nature 727

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_29
728 S. N. Preethamol and J. E. Thoppil

Though the plant is used for curing various diseases in the conventional healing
practices, the phytocomponents responsible for its medicinal properties are not elu-
cidated completely. In this background, the present study was designed for the qual-
itative and quantitative analysis of the methanolic extract of the plant. For this,
preliminary phytochemical screening, quantification of the major bioactive phyto-
components and GC–MS analysis of the plant extract were done using standard
protocols.

2 Materials

2.1 Plant Materials Used

Fresh whole plant materials of O. brunonis were collected from Palakkad district of
Kerala in India. The collected plant materials were taxonomically authenticated by
Dr. M. Sabu (Professor, Department of Botany, University of Calicut, Kerala).

2.2 Chemicals Used

(1) 5% ferric chloride: 5 g FeCl3, 100 mL distilled water; (2) 10% lead acetate: 10 g
lead acetate, 100 mL distilled water; (3) Wagner’s reagent: 2 g iodine, 6 g potassium
iodide, 100 mL distilled water; (4) Hager’s reagent: Saturated picric acid solution;
(5) 1% lead acetate: 1 g lead acetate, 100 mL distilled water; (6) 1% hydrochloric
acid: 1 mL HCl, 100 mL distilled water; (7) 10% ferric chloride: 10 g FeCl3, 100 mL
distilled water; (8) 20% sodium hydroxide: 20 g NaOH, 100 mL distilled water; (9)
7% sodium carbonate: 7 g Na2CO3, 100 mL distilled water; (10) 5% sodium nitrate:
5 g Na2NO3, 100 mL distilled water; (11) Phosphate buffer (pH 4.7): 2 M sodium
phosphate, 0.2 M citric acid; (12) Bromocresol green solution; 69.8 mg BCG, 3 mL
2 N NaOH and 5 mL distilled water, make up to 1000 mL distilled water.

2.3 Equipments Used

Spectrophotometer (Elico SL 218, India), GC–MS (Shimadzu GCMS-QP-2010

plus system).
Secondary Metabolites in Ophiorrhiza brunonis Wight & Arn. (Rubiaceae)… 729

3 Methods

3.1 Preparation of the Extract

The plant materials were carefully washed and shade dried. Then chopped to small
pieces and powdered. 10 g of powder was Soxhlet extracted with 100 mL of 100%
methanol for 6 to 8 h at 40–50 °C. After cooling, the extract was filtered using
Whatman filter paper No.1 and concentrated at 60 °C. The final extract was then
stored in a dark bottle at 4 °C for further experiments.

3.2 Qualitative Phytochemical Analyses

The preliminary screening of the phytoconstituents in methanolic extract of the

plant was done using standard procedures as described below [9–14].

3.2.1 Test for Phenols

Ferric Chloride Test

A fraction of the extract was treated with a few drops of 5% ferric chloride solution.
Formation of deep blue or black colour precipitate indicates phenol content.

3.2.2 Test for Flavonoids

Lead Acetate Test

About 2 mL of the extract was treated with a few drops of 10% lead acetate solution.
The formation of a yellow coloured precipitate indicates the presence of flavonoids.

3.2.3 Test for Alkaloids

About 50 mg of the extract was dissolved in dilute hydrochloric acid and then fil-
tered. The filtrate thus obtained was used for the following tests.

Wagner’s Test

Few drops of Wagner’s reagent were added to a small amount of the filtrate.
Formation of a reddish-brown precipitate indicates the presence of alkaloids.
730 S. N. Preethamol and J. E. Thoppil

Hager’s Test

The filtrate was treated with a few drops of Hager’s reagent. Appearance of orange
or yellow coloured precipitate indicates alkaloid content.

3.2.4 Test for Phytosterols

Sulphuric Acid Test

1 mg of the extract was dissolved in 5 mL of chloroform. Few drops of concentrated

sulphuric acid were added to the solution by the sides of the test tube. Red upper
layer with sulphuric acid layer having a yellow-green fluorescence indicates the
presence of sterols.

3.2.5 Test for Terpenoids

Salkowski Test

To 2 mL of the test solution, 2 mL of chloroform was added and mixed well. Few
drops of concentrated sulphuric acid were added to form a layer. A reddish-brown
colouration at the interface of the solutions indicates the presence of terpenoids.

3.2.6 Test for Tannins

About 0.5 g of solvent-free extract was stirred with 10 mL of distilled water and
filtered. The filtrate was analysed for the presence of tannins.

Lead Acetate Test

To 5 mL of the filtrate, few drops of 1% lead acetate solution were added. Yellow
precipitate indicates the presence of tannins.

3.2.7 Test for Phlobatannins

Precipitation Test

2 mL of the extract was boiled with 1 mL of 1% hydrochloric acid. Appearance of

red precipitate indicates the presence of phlobatannins.
Secondary Metabolites in Ophiorrhiza brunonis Wight & Arn. (Rubiaceae)… 731

3.2.8 Test for Anthraquinones

Borntrager’s Test

50 mg of the extract was dissolved in 1 mL of 10% ferric chloride solution and 1 mL

of concentrated hydrochloric acid and then heated. The test solution was then cooled
and filtered. The filtrate was then added with equal volume of diethyl ether. This
solution was then extorted with strong ammonia. Development of pink or deep red
colour in the solution indicates the presence of anthraquinones.

3.2.9 Test for Coumarins

Ferric Chloride Test

1 mL of the sample solution was treated with 1 mL of ferric chloride solution.

Appearance of deep yellow colour is an indication of the presence of coumarins.

3.2.10 Test for Glycosides

Legal’s Test

50 mg of the extract was dissolved in pyridine. To the solution, a few drops of

sodium nitroprusside and 10% sodium hydroxide were added. Deep red colour indi-
cated glycoside contents.

3.3 Quantitative Estimation of Major Phytoconstituents

The estimation of the major bioactive phytoconstituents observed in the preliminary

screening was done as per the methodology described below.

3.3.1 Total Phenolic Content (TP)

The total phenol content of the extract was evaluated by following the methodology
of Oueslati et al. [15]. Stock concentration of the extract is prepared by dissolving
1 mg of the dried extract in 1 mL of methanol. From the stock, 0.1 mL of the extract
was taken in triplicates and mixed with 0.5 mL of distilled water and 0.125 mL of
1 N Folin-ciocalteu reagent and incubated for 5 min. After incubation, 1.25 mL of
7% sodium carbonate was added and the volume of the reaction mixture was made
up to 3 mL using distilled water. The reaction mixture was shaken well and incu-
bated in dark for another 90 min. After incubation, the absorbance of the solution
732 S. N. Preethamol and J. E. Thoppil

was measured against a blank at 760 nm. Gallic acid was the standard used. Phenolic
content of the extract was calculated from the calibration curve of the standard, and
the results were expressed as milligram of gallic acid equivalent per gram dry
weight (mg GAE/g DW) using regression equation.

3.3.2 Total Flavonoid Content (TF)

The quantity of the flavonoid in the extract was determined using the method of
Oueslati et al. [15], with slight modifications. From the stock concentration of 1 mg/
mL, 0.5 mL of the extract, taken in triplicates, was mixed with 0.5 mL of distilled
water and 0.3 mL of 5% sodium nitrate and incubated for 5 min at room tempera-
ture. After incubation, 0.3 mL of 10% AlCl3 was immediately added. Thorough
shaking was followed by the addition of 2 mL sodium hydroxide (1 M). The absor-
bance was then measured at 510 nm against a suitable blank. Quercetin was used as
the standard. The TF was calculated from the calibration curve of the standard using
regression equation and was expressed in milligram of quercetin equivalent per
gram dry weight (mg QE/g DW).

3.3.3 Total Terpenoid Content (TT)

Terpenoids in the extract were estimated as per Ghorai et al. [16], with slight modi-
fications. 0.2 mL of the extract (1 mg/mL), considered in triplicates, was mixed with
1.5 mL of chloroform and 1 mL of concentrated H2SO4. A yellow-green coloured
solution appeared and the chloroform layer was seen as separate layer. After sepa-
rating the chloroform layer, 2 mL of methanol was added to the residual mix which
dissolved the yellow-green solution. The absorbance of the final solution was mea-
sured against a blank at 538 nm. Linalool was the standard used. TT was calculated
from the calibration curve of linalool, and the results were expressed in milligram
of linalool equivalent per gram dry weight (mg LE/g DW).

3.3.4 Total Alkaloid Content (TA)

The total alkaloid content of the extract was quantified using the protocol suggested
by Shamsa et al. [17], with slight modifications. To 1 mL of the extract (1 mg/mL),
5 mL phosphate buffer (pH 4.7) and 5 mL bromocresol green solution (BCG) were
added. To this reaction mixture, serial addition of 1, 2, 3 and 4 mL of chloroform
was done and shaken well. The BCG layer was removed and the chloroform layer
containing the alkaloid was taken for reading absorbance against a blank at 470 nm.
Caffeine was used as the standard. The TA of the extract was calculated from the
calibration curve of the standard and was expressed in milligram of caffeine equiva-
lent per gram dry weight (mg CE/g DW). The samples were analysed in triplicates.
Secondary Metabolites in Ophiorrhiza brunonis Wight & Arn. (Rubiaceae)… 733

3.4 Gas Chromatography-Mass Spectrometry (GC–

MS) Analysis

The chemical composition of the plant extract was further analysed by GC–MS
analysis. Thermal Desorption system TD 20, fitted with WCOT column
(60 m × 0.25 mm × 0.25 m) coated with diethylene glycol was used for the analysis.
The carrier gas was helium with a flow rate of 1.21 mL/min. The column pressure
was 77.6 KPa. Injector and detector temperatures were kept at 260 °C. 6 μL of the
sample was injected and the split ratio of the column was 10:0. The parameters for
compound separation were linear temperature program of 70–260 °C at 3 °C/min
followed by 260 °C for 6 min, total run time 43 min. The MS parameters were elec-
tron ionization (EI) voltage of 70 eV, peak width of 2 s, mass range of 40–850 m/z
and detector voltage of 1.5 V.

3.5 Identification of Compounds

Compounds were recognised by comparing linear retention indices. The MS frag-

mentation patterns of the compounds were compared with compounds of known
composition, with the patterns presented in the spectral library of National Institute
of Standards and Technology (NIST) and also by literature survey. The compounds
were estimated on the basis of their particular GC peak areas.

3.6 Statistical Analysis

All the results were statistically analysed using the software SPSS Version 20. The
data were validated using one-way analysis of variance (ANOVA) and Duncan’s
multiple range tests and those with p < 0.05 were considered statistically significant.
The results were expressed as mean ± standard error (SE).

4 Results

4.1 Qualitative Phytochemical Analyses

The phytochemical analyses of the plant extract revealed the presence of phytocon-
stituents like phenols, flavonoids, sterols, terpenoids, tannins, alkaloids, anthraqui-
nones, coumarins and glycosides. Phlobatannin was found to be absent in the
extract.
734 S. N. Preethamol and J. E. Thoppil

4.2 Quantitative Estimation of Major Phytoconstituents

The TP content of the methanolic extract of O. brunonis was calculated from the
calibration curve of gallic acid and the result was observed to be 395.55 ± 0.51 mg
GAE/g DW. Also, the TF of the plant extract was calculated from the calibration
curve of quercetin and was found to be 309.83 ± 1.69 mg QE/g DW. The TT and TA
of the plant extract were calculated from the calibration curve of linalool and caf-
feine, and the results were observed to be 367.01 ± mg LE/g DW and
126.33 ± 1.36 CE/g DW, respectively.

4.3 Gas Chromatography-Mass Spectrometry (GC–

MS) Analysis

GC–MS analysis of the plant extract revealed the presence of 13 bioactive phyto-
components belonging to different classes of compounds. The list of these com-
pounds identified from the analysis is summarised in Table 1.
The major phytoconstituents identified in the extract were terpenoids (38.77%)
such as sesquiterpenoids like neophytadiene (11.72%) and humulane-1,6-dien-3-ol
(20.66%) and triterpenoids like squalene (6.39%). 14.91% of terpene alcohols like
phytol (10.97%) and solanesol (3.94%) were also found in the extract. Three types
of sterols namely, campesterol (2.66%), stigmasterol (5.27%) and gamma sitosterol
(9.35%) were also found. n-Hexadecanoic acid (15.77%) and tetradecanoic acid
(2.57%) were the fatty acids obtained. Alkane compounds and alkaloids were also
revealed in the analysis.

Table 1 Phytocompounds identified from the methanolic extract of Ophiorrhiza brunonis using
GC–MS analysis
Molecular
Retention time Name of the compound formula Class of the compound Peak area (%)
11.185 Dodecane C12H26 Alkane 2.07
11.496 Tetradecane C14H30 Alkane 2.71
16.382 Neophytadiene C20H38 Sesquiterpenoid 11.72
17.329 n- Hexadecanoic acid C16H32O2 Fatty acid 15.77
19.168 Phytol C20H40O Diterpene alcohol 10.97
20.112 Tetradecanoic acid C14H28O2 Fatty acid 2.57
22.536 1-Anliinoisoquinoline C15H12N2 Alkaloid 5.92
26.562 Squalene C30H50 Triterpenoid 6.39
30.662 Solanesol C45H74O Terpene alcohol 3.94
33.213 Campesterol C28H48O Sterol 2.66
33.695 Stigmasterol C29H48O Sterol 5.27
35.539 gamma-Sitosterol C29H50O Sterol 9.35
41.246 Humulane-1,6-dien-3-ol C15H26O Sesquiterpenoid 20.66
Secondary Metabolites in Ophiorrhiza brunonis Wight & Arn. (Rubiaceae)… 735

Thus, from the GC–MS analysis, six different classes of compounds like terpe-
noids (38.77%), fatty acids (18.34%), sterols (17.28%), terpene alcohols (14.91%),
alkaloids (5.92%) and alkanes (4.78%) were revealed.

5 Discussion

Secondary metabolites are bioactive compounds with specific physiological activi-

ties like antioxidant, anticancer and antimicrobial [18]. The medicinal properties of
any plant can be ascribed to the presence of various classes of secondary metabo-
lites. Hence, phytochemical analysis becomes very important to screen the phyto-
constituents that are responsible for the therapeutic activities of the plant [19].
Recent researches reveal that the therapeutic effects of the plant extracts against
diseases are due to the synergistic action of their phytoconstituents [20]. Reports
suggest that the compounds like phenols, flavonoids, terpenoids, sterols, tannins
and coumarins have medicinal properties [21]. In the present study, many phytocon-
stituents were revealed from the preliminary screening and bioactive secondary
metabolites like phenols, flavonoids, terpenoids and alkaloids were quantified and
the results were good. The observations suggest that the medicinal properties of the
plant, by which it is used in the folklore healing systems, is actually a combined
contribution of the bioactive secondary metabolites.
In the study, the quantities of the major metabolites revealed by the preliminary
screening were estimated. Phenols play an important role in antioxidant activity by
giving up hydrogen atoms from their hydroxyl groups to radicals and forming stable
phenoxy radicals [22]. Flavonoids are reported to exhibit anti-microbial, cytotoxic,
anti-inflammatory and anti-tumour activities [23]. Alkaloids help in plant survival by
providing protection against herbivores, insects and micro-organisms. In addition,
they act as allelopathic agents against other plants. Plants with alkaloid contents are
widely used as spices, drugs, dyes or poisons. Alkaloids also exert several pharma-
cological activities like anti-hypertensive effects, anti-malarial activity and anti-can-
cer activity [24]. Terpenoids are regarded as the most diverse group among secondary
metabolites with several therapeutic effects. The methanolic plant extract showed
significant quantities of phenols, flavonoids, terpenoids and alkaloid contents and
can probably explain the widespread use of the plant in traditional medicines.
GC–MS is an ideal technique for the qualitative and quantitative estimation of
volatile constituents [25]. From the analysis, it was observed that the major phyto-
components were terpenoids followed by fatty acids. The major compound recog-
nised was humulane-1,6-dien-3-ol (20.66%), which is a sesquiterpenoid with
several medicinal properties like anti-inflammatory, antibacterial, antiviral and anti-
tumour activities [26]. Squalene, is a triterpene with antioxidant, anticarcinogenic,
anti-allergic, immune stimulant, cholesterol-lowering and skin protection properties
[27]. Phytosterols are potent antioxidants that inhibit the production of reactive oxy-
gen species [20]. Bioactive phytosterols like campesterol, stigmasterol and gamma-
sitosterol were also revealed from the analysis. Fatty acids like n-­hexadecanoic acid
736 S. N. Preethamol and J. E. Thoppil

and tetradecanoic acid were also recognised. Two terpene alcohols, namely, solane-
sol and phytol were also identified. Solanesol exhibits antimicrobial, antitumour,
anti-inflammatory and anti-ulcer activities [28]. Phytol is a very good antinocicep-
tive and antioxidant agent, which is also involved in the production of vitamins E
and K [25]. Hence, the bioactivity of all the components could be contributing
towards the healing capacity of the plant extract.
From the results, it is clear that the plant extract has many compounds with anti-
cancer properties. The major compounds identified from the GC–MS analysis, like,
humulane-1,6-dien-3-ol, squalene and solanesol are reported to possess antitumour
potential. The cumulative effect of these compounds can enhance the medicinal
properties and are a very good lead towards the anticancer potential of the plant.

6 Conclusion

The present study on the methanolic extract of O. brunonis reveals the presence of
various highly bioactive secondary metabolites. The preliminary phytochemical
screening showed the presence of different classes of metabolites, indicating the
medicinal potential of the plant. The quantitative estimation of the major bioactive
compounds suggests that the plant has commendable quantity of secondary metabo-
lites. GC–MS analysis shows that the extract has many anticancer compounds like
humulane-1,6-dien-3-ol, squalene and solanesol. This shows that the plant can be a
good candidate for research in anticancer studies. Further, compounds with anti-­
inflammatory properties, antioxidant properties and antimicrobial properties were
also found. These compounds also add to the medicinal value of the plant. So the
healing efficacy of the plant might be the synergistic contribution of these com-
pounds, which probably substantiates its use in traditional medicines. The identifi-
cation of the secondary metabolites with antitumor efficacy by various analyses is a
lead toward its anticancer potential. More in vitro and in vivo trials will help to
explore more bioactive potentials of the plant as a medicine.

Acknowledgements The authors acknowledge the Forest Department of Kerala, India, for pro-
viding the permission for the collection of the plant specimens.
Conflicts of Interest The authors declare that they have no conflict of interest.

References

1. Meena AK, Bansal P, Kumar S (2009) Plants-herbal wealth as a potential source of ayurvedic
drugs. Asian J Tradit Med 4(4):152–170
2. Bajalan I, Zand M, Goodarzi M et al (2017) Antioxidant activity and total phenolic and fla-
vonoid content of the extract and chemical composition of the essential oil of Eremostachys
laciniata collected from Zagros. Asian Pac J Trop Biomed 7(2):144–146
Secondary Metabolites in Ophiorrhiza brunonis Wight & Arn. (Rubiaceae)… 737

3. Kennedy DO, Wightman EL (2011) Herbal extracts and phytochemicals: plant secondary
metabolites and the enhancement of human brain function. Adv Nutr 2(1):32–50
4. Katalinic V, Milos M, Kulisic T et al (2006) Screening of 70 medicinal plant extracts for anti-
oxidant capacity and total phenols. Food Chem 94(4):550–557
5. Mulabagal V, Tsay HS (2004) Plant cell cultures – an alternative and efficient source for the
production of biologically important secondary metabolites. Int J Appl Sci Eng 2(1):29–48
6. Borneo R, León AE, Aguirre A et al (2009) Antioxidant capacity of medicinal plants from the
Province of Córdoba (Argentina) and their in vitro testing in a model food system. Food Chem
112(3):664–670
7. Hareesh VS, Sabu M (2018) The genus Ophiorrhiza (Rubiaceae) in Andaman and Nicobar
Islands, India with a new species. Phytotaxa 383(3):259–272
8. Rajan R, Varghese SC, Kurup R et al (2013) Search for camptothecin-yielding Ophiorrhiza
species from southern Western Ghats in India: a HPTLC-densitometry study. Ind Crop Prod
43:472–476
9. Kumar GS, Jayaveera KN, Kumar CK et al (2007) Antimicrobial effects of Indian medicinal
plants against acne-inducing bacteria. Trop J Pharm Res 6(2):717–723
10. Trease GE, Evans WC (2002) Pharmacognosy, 3rd edn. Saunders Publishers, London
11. Siddiqui AA, Ali M (1997) Practical pharmaceutical chemistry. CBS Publishers and
Distributors, New Delhi, pp 126–131
12. Edeoga HO, Okwu DE, Mbaebie BO (2005) Phytochemical constituents of some Nigerian
medicinal plants. Afr J Biotechnol 4(7):685–688
13. Sofowara A (1993) Medicinal plants and traditional medicine in Africa. Spectrum Books
Ltd, Ibadan
14. Evans WC, Evans D (2002) Trease and Evans’ Pharmacognosy, 15th edn. Elsevier Health
Sciences, New York, pp 21–24
15. Oueslati S, Ksouri R, Falleh H et al (2012) Phenolic content, antioxidant, anti-­inflammatory
and anticancer activities of the edible halophyte Suaeda fruticosa Forssk. Food Chem
132(2):943–947
16. Ghorai N, Chakraborty S, Gucchait S, Saha SK, Biswas S (2012) Estimation of total terpe-
noids concentration in plant tissues using a monoterpene, linalool as standard agent. Protoc
Exch. https://doi.org/10.1038/protex.2012.05
17. Shamsa F, Monsef H, Ghamooshi R et al (2008) Spectrophotometric determination of total
alkaloids in some Iranian medicinal plants. Thai J Pharm Sci 32:17–20
18. Krishnaiah D, Devi T, Bono A et al (2009) Studies on phytochemical constituents of six
Malaysian medicinal plants. J Med Plant Res 3(2):67–72
19. Mungole AJ, Awati R, Chaturvedi A et al (2010) Preliminary phytochemical screening of
Ipomoea obscura (L): a hepatoprotective medicinal plant. Int J PharmTech Res 2(4):2307–2312
20. Oyebode OA, Erukainure OL, Ibej CU et al (2019) Phytochemical constituents, antioxidant
and antidiabetic activities of different extracts of the leaves, stem and root barks of Alstonia
boonei: an in vitro and in silico study. Bot Lett 166(4):444–456
21. Tayade AB, Dhar P, Sharma M et al (2013) Antioxidant capacities, phenolic contents, and GC/
MS analysis of Rhodiola imbricata Edgew. root extracts from Trans-Himalaya. J Food Sci
78(3):402–410
22. Sengul M, Yildiz H, Gungor N et al (2009) Total phenolic content, antioxidant and antimicro-
bial activities of some medicinal plants. Pak J Pharm Sci 22(1):102–106
23. Liu RH (2004) Potential synergy of phytochemicals in cancer prevention: mechanism of
action. J Nutr 134(12):3479–3485
24. Koche D, Shirsat R, Kawale M (2016) An overview of major classes of phytochemicals: their
types and role in disease prevention. Hislopia J 9:1–11
25. Arora S, Kumar G (2017) Gas Chromatography-Mass Spectrometry (GC-MS) determination
of bioactive constituents from the methanolic and ethyl acetate extract of Cenchrus setigerus
Vahl (Poaceae). Antiseptic 2:0–31
738 S. N. Preethamol and J. E. Thoppil

26. Jiao SG, Zhang RF, Li J et al (2018) Phytochemical and pharmacological progress on
humulane-­type sesquiterpenoids. China J Chin Mater Med 43(22):4380–4390
27. Reddy LH, Couvreur P (2009) Squalene: a natural triterpene for use in disease management
and therapy. Adv Drug Deliv Rev 61(15):1412–1426
28. Yan N, Liu Y, Zhang H et al (2017) Solanesol biosynthesis in plants. Molecules 22(4):510
Marine Macroalgae as a Treasure House
of Bioactive Compounds
and Nutraceuticals

Kajal Chakraborty

1 Introduction

Marine macroalgae (popularly called as seaweeds) were consumed by the coastal

communities since pre-historic times, particularly in the south-east Asian countries.
One of the prominent marine macroalgal species, Sargassum has been used in tradi-
tional Chinese medicine for more than 1000 years to treat different diseases.
Noticeably, the longer life expectancy of Japanese people was reported to be associ-
ated with their regular intake of marine macroalgae. Although the therapeutic uses
of macroalgae were found only in traditional medicines, lately during the 1990s,
with the discovery of bioactive compounds from these species further widened their
utilization in pharmaceutical industries. Interest in marine macroalgae-built bioac-
tive compounds and nutraceuticals as demonstrated by the scientific publications
and patents in the past decade have fittingly proven the potentials of bioactive com-
pounds from marine macroalgae to improve human well-being [1–6]. Marine mac-
roalgae establish an enormous congregation of species that preponderate the coastal
shelf areas and are every so often labeled as the “wonder herbs of the ocean” on
account of their pharmaceutical potential [7–9]. Although global utilization of
seaweeds/marine macroalgae constitutes the industrial applicaton, their bioactive
prospective is not completely explored, and biopharmaceutical industries are focus-
ing their thoughtfulness to discover and develop bioactive compounds and nutraceu-
ticals from the marine macroalgae. Among various species, brown marine
macroalgae (class Phaeophyceae) were instituted to be promising sources of bioac-
tive substances [6]. A total of 900 species of green seaweed, 1500 species of brown
seaweed and 4000 species of red seaweed are present worldwide. In 2018, global

K. Chakraborty (*)
Bioprospecting Section of Marine Biotechnology Division, Central Marine Fisheries
Research Institute, Cochin, Kerala, India
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 739

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_30
740 K. Chakraborty

production of marine macroalgae through mariculture (27.5% of all aquaculture)

was projected at about 32.4 million tons (wet weight), valued at 13.3 billion US$.
Various nutraceutical or functional food and pharmacophore leads from marine
macroalgae deliver numerous benefits for human health, and consequently, are valu-
able bioresources for the nutraceutical and pharmaceutical industries [10].

2 Diversity and Classification of Marine Macroalgae

Macroalgae are divided into three major classes based on different colors: green, red
and brown algae. Besides the colour other substantial differences are in their cell
wall composition, storage compounds, ultrastructure of mitosis, etc. [11]. Green
and red macroalgae were shaped by primary endosymbiosis, whereas brown algae
originated through secondary endosymbiosis [12]. The green algae belonging to the
class of Ulvophyceae are diverse with more than 900 marine originated species. A
common growth form of two widespread genera (Cladophora and Chaetomorpha)
are found as branched (or not) thin filaments. Sheets like form by two layers of cells
are typical characteristic of Ulva spp. of Ulva genus are popularly called sea lettuce
because of their appearance. A unique type of body organization of green algae is
known as siphonalean organization (or coenocytic organization). The best-known
example of siphonalean marine algae is represented by the genus Caulerpa [13]. The
phylum rhodophyta are the largest, and are classified under seven classes and thirt-­
three orders [14]. Several species of red algae have branched plantlike, small bushes
like shape. There are near about 1780 species of brown algae, currently classified as
Fucophyceae (or Phaeophyceae, which includes 17 orders) of the phylum
Ochrophyta. Brown algae are widespread in all seas of the world, but the abundance
and diversity is found cold waters. The order Laminariales (of brown algae) are
specified as one of the largest (in size) among the macroalgae and are labelled with
the word kelps.

3 Ethanapharmacology of Marine Macroalgae

As there is an increased trend towards utilizing natural drugs rather than synthetic
drugs, the knowledge about history of traditional medicine holds an important part
to develop drugs. Consistent with the World Health Organization (WHO), around
65% of the populace has been using herbal medicines for their primary health care
[15]. However, when compared to terrestrial plants use of marine macroalgae is not
much widespread. But there are several reports over Asian countries on the utility of
algae mainly as ingredients in the cuisine. Prior to 2000 BC itself Chinese medical
literature quoted the utilization of algae for food and medicine, whereas in Western
countries red algal products, such as carrageenan, agar were extensively used as
ingredients in food products. Marine macroalgae are commonly used by humans,
Marine Macroalgae as a Treasure House of Bioactive Compounds and Nutraceuticals 741

Table 1 Traditional medicinal uses of marine macroalgae

Traditional use References
Digestive system Diarrhea [18–21]
Dysentery
Enteritis
Hemorrhoids
Intestinal constipation
Jaundice
Endocrine system Thyroid goiter [20, 21]
Thyroid tumor
Respiratory system Bronchitis [18, 20, 22]
Cough
Throat irritation
Pulmonary problems
Resolves phlegm
Dispels heat
Urinary system Bladder snags [20]
Difficulty in urination
Diuretic

and have a great economic significance. The primary use of marine macroalgae as
food and medicine was reported as early as ~14,000 years ago. These were utilized
as a binder substance for fixation of lime [16]. Despite these, they have found uses
in conventional medicine for a number of ailments (Table 1). In Central American
countries, Gracilaria species of red seaweeds have reported to possess aphrodisiac
properties [17]. Powdered Gracilaria or agar were sold as appetite modulator and
digestive health promoter in some countries.

4 Marine Macroalgae as Valuable Bioresources

of Pharmacologically Active Metabolites and Functional
Food Products

Marine macroalgae or seaweed derived functional ingredients and structurally

diverse bioactive compounds have valuable pharmaceutical properties [1].
Marine macroalgae are valuable marine macro-flora, which are proved to have
wide-ranging commercial applications. In 2018, global production of marine mac-
roalgae through mariculture (27.5% of all aquaculture) was estimated at 32.4 mil-
lion tons (wet weight), valued at 13.3 billion US$ [23]. Marine macroalgae are the
sources for phycocolloids and also have applications as stabilizer, viscosifier, gell-
ing and emulsifying agents [24].
742 K. Chakraborty

The marine macroalgae contain a large assemblage of species that predominate in the coastal
shelf areas of Indian subcontinent

It is of note that marine life has advanced over a long period of time in austere
marine environmental situations. Remarkably, marine organisms display greater
occurrence of pharmaceutical potential, 1% vs. 0.1% (in preclinical screening) as
compared to those exhibited by the terrestrial counterparts [25], and there are
increasing reports of novel analogues of highly bioactive compounds over the
years [26].

Occurrences of marine natural products over the period from 1971 to 2015 (2)
Marine Macroalgae as a Treasure House of Bioactive Compounds and Nutraceuticals 743

A photo of seaweed harvest

Nutraceuticals have been demarcated as “concentrated, isolated, or purified” bio-

active molecules, and depict a characteristic juncture of pharmaceutical and func-
tional food products. Nutraceuticals are naturally originated pharmacologically
active leads(s), and for that reason, are anticipated to function as “Natural Drug.”
Efforts in this segment of marine macroalgal natural products have resulted an
archive of bioactive pharmacophores and nutraceutical products as immune boost-
ing agents and use against type-2 diabetes, arthritis, osteoporosis, hypertension,
dyslipidaemia and hypothyroidism [27].

Nutraceutical products from marine macroalgae

Marine macroalgae are consumed by the coastal communities since pre-historic

times, particularly in Japan and China [28], and also used up traditionally in
Indonesia, the Philippines, South Korea, North Korea and Malaysia [29]. Marine
macroalgae are used in the traditional Japanese cuisine “shojin ryori” [30, 31],
whereas Kombu, wakame and nori are integral part of the Japanese seaweed diet
[32]. Lately, consumption of marine macroalgae has gained wide attention in the
Americas and Europe because of their functional properties and introduction of
744 K. Chakraborty

Asian cuisine [33]. In India, Ulva, Gracilaria and Acanthophora are used in prepar-
ing food items with the coastal states of Kerala and Tamil Nadu [34–36]. Marine
macroalgae are deliberated as food supplement attributable to availability of valu-
able macro-nutrients and micro-nutrients and bioactive compounds. Nowadays,
marine macroalgae are considered as one of the major coastal resources that are
valuable to human consumption and environment in Asian, America and European
countries as ingredients in prepared foods. They are recognized for their richness in
various nutrients, such as minerals, dietary fibers and vitamins (cyanocobalamin)
other than polyunsaturated fatty acids and polyphenols [37]. The capability of
marine macroalgae to increase the storage stability of C20–22n-3 fatty acids was eval-
uated by analyzing the combined effect of organic fractions of Jania rubens, Hypnea
musciformis and Kappaphycus alvarezii [38, 39]. The potential use of seaweed spe-
cies such as Sargassum wightii, S. myriocystum, S. plagiophyllum, Caulerpa spp.,
Anthophycus longifolius, Spatoglossum asperum, Stoechospermum polypodioides,
Gracilaria corticata and Grateloupia indica as functional food supplements, have
been investigated. Sulphated polygalactans isolated from Gracilaria opuntia and
Kappaphycus alvarezii were evaluated for their potential to develop nutraceuticals.
The prebiotic activity of polysaccharide extracted from marine macroalgae
Sargassum wightii, Enteromorpha compressa, Acanthophora spicifera, etc. was
evaluated, for formulating functional food ingredients.

5 Therapeutic Applications of Marine Macroalgae

Phlorotannins, sulfated polysaccharides and polyphenols from the marine macroal-

gae have showed their bioactivities against propagation of cancer cells and produce
effects against anti-diabetic and anti-inflammatory responses [40–43]. Bioactive
components in marine macroalgae were acknowledged to moderate glucose-­
stimulated oxidative stress [44]. Among various abundantly available marine mac-
roalgal species, brown and red marine macroalgae (classes Phaeophyceae and
Rhodophyceae, respectively) were found to be the prospective sources of bioactive
substances [45–49].
During the year 1980–1995, marine macroalgae exhibited a landmark in pharma-
ceutical and functional food industries [50]. Many of the algae reported to have
anti-microbial, anti-inflammatory, anti-tumor, anti-oxidant, anti-hypertensive and
anti-coagulant, properties. The secondary metabolites obtained from marine mac-
roalgae exhibited a wide-stretching gamut of biological activities ranging from
insecticidal/algicidal to neurological activities in humans. High content of polyun-
saturated fatty acids, polyphenols, alkaloids, terpenes, pigments, vitamins, minerals
and insoluble and soluble dietary fibers accounts to its bioactivities. Apart from
these, marine polysaccharides, such as agar, alginate, carrageenan, fucoidan, ulvan,
laminarin and furcellaran from marine macroalgae are integral parts of a globally
thriving marine phycocolloid industry as it constitutes the most abundant source of
polysaccharides with promising biomedical applications [51]. They are also consid-
ered as potential renewable resource and known to be an enriched source of
Marine Macroalgae as a Treasure House of Bioactive Compounds and Nutraceuticals 745

bioactive metabolites. Therefore, it can be a very remarkable source of new natural

products with various biological properties, which could be used as functional
ingredients. Apart from direct consumption, many studies supported the health ben-
efits of marine macroalgae as supplementation with a regular diet. In addition to
benefits of regular consumption of marine macroalgae, the pharmacological proper-
ties of these have been widely recognized. As an example numerous studies have
reported innumerable counteractive effects of marine macroalgae against hyperten-
sion, obesity, inflammation and diabetes.

Number of publications on bioactive properties of marine macroalgae (in the middle of

1990–2020)

The number of publications in the areas of antioxidant compounds topped the list
followed by that of anti-inflammatory. The total number of publications in bioactive
compounds from marine macroalgae was deduced through google literature search
and online tools/database, such as MarinLit, Google Scholar, Science Direct,
Scifinder and PubMed. An increased number of publications in marine macroalgal
natural products acknowledged the importance of this class of marine flora.

6 Chemical Compounds from Marine Macroalgae

Despite several pharmacological activities labelled for marine macroalgae, these

were attributed to the specific compounds embedded in extracts as found by the
literature survey [52, 53] conducted on marine macroalgae from 1993 to 2020 using
Google Scholar, SciFinder and MarinLit database. Based on these data, compounds
belonging to distinct classes were reported. The prominent chemical classes reported
in marine macroalgae were terpenes, sterols, polyunsaturated fatty acids, polyketides,
polyphenols, polysaccharides and alkaloids.

6.1 Terpenoids

Terpenes are usually isolated from plants. Among diverse classes of drugs currently
utilized for infectious diseases and cancer treatments, around 23,000 molecules are
of terpenoid origin. Commercially available anti-malarial drug artemisnin and
746 K. Chakraborty

anti-cancer drug paclitaxel (taxol) are two fine examples in this regard. Marine mac-
roalgae are deliberated to be rich sources of terpenes, which have been isolated and
verified to possess several pharmacological potentials. According to the previous
reports, more than 1058 terpene molecules have been isolated and structurally char-
acterized only from marine macroalgae. Sargadiol-I, a terpenoid analogue, which
was isolated from Sargassum tortile, exhibited cytotoxic activity [54]. An anti-­
bacterial brominated chamigrane terpene was isolated from Laurencia majus-
cula [55].

Halogenated compounds with terpenoid moieties along with other small molecu-
lar bioactives were isolated and characterized from marine macroalgae [56–61] and
were classified into terpenoids, phenols/aromatics, indoles and non-terpenoid C15-­
acetogenins. Halogenated terpenoids, non-terpenoid acetogenins and indoles were
principally reported from red seaweed Laurencia, whereas the halogenated phenols
were isolated from Polysiphonia, Rhodomela and Symphyocladia [62]. Among the
halogenated compounds, halogenated terpenes and bromophenols displayed the
greater potential for new drug development [63].

6.2 Lipidic Compounds

During the previous decade, fatty acid profile of marine macroalgae has invited
much consideration by reason of their high lipid extract content of polyunsaturated
fatty acids (PUFAs) and steroids especially (18:3n-3), octadecatetranoic acid
(18:4n-3), arachidonic (20:4n-6) and eicosapentenoic acids (20:5n-3). Since marine
macroalgae are the sole organisms to synthesize long-chain PUFAs because of the
Marine Macroalgae as a Treasure House of Bioactive Compounds and Nutraceuticals 747

presence of specific enzymes, which are not in human, consumption of marine mac-
roalgae is highly favored. PUFAs are essential for brain development, many physi-
ological functions, signaling and regulation of transcription factors and in the
treatment of some autoimmune and cancer diseases. Red marine macroalgae were
found to contain more than 60 sterols and PUFAs and could be a sustainable source
of nutritive food. Besides, publications are not too short for their promising biologi-
cal activities, such as cytotoxicity, enzyme inhibitors, anti-inflammatory and anti-­
microbial. As seaweed contains a large number of fatty acids, it provides a potential
source of raw PUFAs [9] due to the reason that these compounds restore the perme-
ability barrier and prevent skin dehydration and dermatitis [64, 65]. Deficiency of
these fatty acids could lead to alopecia and eczema [66].

Br
OH H
O
OH
Br
HO
Sargadiol-I Chamigrane

6.3 Polysaccharides

Polysaccharides are the major components of marine macroalgae, and its content
ranges between 4% and 76% of their dry weight. The marine macroalgae with high-
est polysaccharide contents include Ascophyllum, Porphyra and Palmaria [67]. Red
algae contain unique sulfated galactans, such as carrageenans agarose and agar [68,
69]. The brown algae contain sulfated polysaccharides such as laminarin, alginate
and fucoidan [70–72]. The sulphated polysaccharides exhibit many valuable bio-
logical properties like anticoagulant, antiviral, antioxidant, anti-tumour, immuno-
modulating, anti-hyperlipidaemic and anti-hepatotoxic [73].

O
O
OCH3 H

H H
O HO

Fatty acid derivative Sterol analogue

Agar from red marine macroalgae

748 K. Chakraborty

Polysaccharide compounds isolated from marine macroalgae

Polysaccharides are used in cosmetics as a gelling agent, viscosity adjuster,

thickener and emulsifier polysaccharides hydrates the skin, thus potentially pro-
tecting it from wrinkles [74]. Alginate has extensive applications in drug delivery,
wound healing and also cell transplantation in tissue engineering by reason of their
structural resemblance with extracellular matrices of living tissues [75]. Seaweed
polysaccharide-based copolymers were synthesized, and drug release behaviour
was studied to ascertain its use as biomaterials. The potential of collagen-fucoidan
blend films, synthesized from Laminaria japonica, was evaluated for tissue regen-
erative properties. Fucoidan from brown marine macroalgae and carrageenan from
red marine macroalgae have prospective application in tissue engineering because
of their ability of inducing osteogenic and chondrogenic differentiation in stem
cells [76]. Ulvan-based polysaccharides in combination with poly (D-lactic acid)
could be used in wound healing and cartilage tissue engineering [77–79]. Due to
higher solubility in aqueous and organic solvents, and low viscosity, laminarin
could be used to develop hydrogels [80], other than cosmetic or therapeutic appli-
cations [81].
Marine Macroalgae as a Treasure House of Bioactive Compounds and Nutraceuticals 749

6.4 Polyketide Derivatives

Polyketides are secondary metabolites which either containing alternating carbonyl

or methylene groups or else compounds derived from precursors containing such
alternating groups. Many of the polyketides are medicinally active and are well
screened for their pharmacological potential. Of the total compounds isolated from
red algae, 12% occupies polyketides with a majority from the family Rhodomelaceae.
Isolaurenidificin and bromlaurenidificin were some of the major cytotoxic com-
pounds characterized [82].

HO H
H O
O

Br C O H
O H H
Br
O
R1 H
H H
Cl
Polyketide derivative
[Isolaurenidificin, R1 = OH; bromlaurenidificin R1 = Br] 12-Epoxyobtusallene-IV

6.5 Polyphenolic Compounds

Algal polyphenols otherwise ‘phlorotannins’ derives from phloroglucinol units (1,

3, 5-trihydroxybenzine) and constitutes a wide variety of heterogeneous group of
molecules possessing potential biological activities. Among the bioactives consti-
tuted in red algae, phenolic compounds occupies the second largest share involving
bromophenols, flavonoids and phenolic acids. Various bioactivities, such as anti-­
cancer, anti-bacterial, anti-oxidant, anti-fungal and anti-inflammatory, were associ-
ated with red algal polyphenols. Phenolic compounds are found in the marine
macroalgae [44, 83]. The most inimitable seaweed polyphenol compound is phloro-
tannins and other polyphenolic compounds include phenolic terpenoids, bromophe-
nols, mycosporine-like amino acids and flavonoids [84]. Phlorotannins, the most
important phenolic compound, is well known for applications such as anti-­
melanogenesis and anti-ageing [62, 85]. Among the marine macroalgae,
Laminariacea has the most abundant source of phlorotannins [86]. Phloroglucinol,
a phenolic derivative isolated from Sargassum wightii, S. tenerrimum and Turbinaria
conoides, was examined for biomedical properties. Phenolic compounds were
endowed with promising bioactivities, such as anti-inflammatory, anti-­
hyperglycemic, antimicrobial, antiviral, anti-allergic, antioxidant, hypertension,
neuroprotective and anti-cancer properties [87–90].
750 K. Chakraborty

R
R R

R R R R
R R
O
O O
R R
R R R
R
R

R = OAc
Polyphenolic compound from brown seaweed

Polyphenolic compound from brown seaweed

Classification of various classess of bioactive compounds from marine macroalgae

Marine Macroalgae as a Treasure House of Bioactive Compounds and Nutraceuticals 751

Various classes of bioactive compounds isolated from Gracilaria salicornia

Various classes of bioactive compounds isolated from Padina tetrastomatica [48, 91, 92]
752 K. Chakraborty

Various classes of bioactive compounds isolated from Turbinaria sp

Various classes of bioactive compounds isolated from Sargassum wightii [69, 72, 93–95]
Marine Macroalgae as a Treasure House of Bioactive Compounds and Nutraceuticals 753

7 Various Classes of Bioactive Compounds Isolated

from Turbinaria sp

7.1 Miscellaneous

Lectins are major seaweed-originated reversibly carbohydrate-binding bioactive

peptides [96], and owing to their specificity, lectins could bore to saccharides out-
side cell surfaces thus attenuating cell propagation [97, 98]. Lectins were reported
to possess antiviral, anti-cancer, antimicrobial, anti-inflammatory, anti-nociceptive
and acaricidal activities. Fucoxanthin is a xanthophyll carotenoid found in seaweed
lipids and is one of the most studied metabolites [99]. Fucoxanthin was reported to
possess various biological activities, such as anti-cancer, antioxidant, anti-obesity,
anti-inflammatory and neuroprotective properties [100]. Marine macroalgae are
either used as additives contributing to the organoleptic properties [101] because of
the presence of pigments, phenolics, polysaccharides, sterols, PUFA, etc. [92, 102,
103]. The fat-soluble vitamins (A, B, C, D and E) endow the marine macroalgae
with potential properties for use in skincare products [103]. Marine macroalgae
have amino acids, such as serine, arginine, alanine, histidine, proline, and tyrosine.
Porphyra and Palmaria have the maximum amount of arginine, which is considered
a natural moisturizing factor that can be used in cosmetic products) [103] (Table 2).

8 Nutraceuticals from Marine Macroalgae

Nutraceutical comprises of products such as vitamins and mineral supplements,

bioactive compounds, essential oils, anti-oxidant supplements and enzymes.
Nutraceuticals can be classified into functional foods, pharmaceuticals, medicinal
food, botanicals and dietary supplements based on their functional properties. The
actual mechanism of nutraceuticals involves several biological processes, such as
signal transduction pathways, antioxidant defenses, gene expression and preserva-
tion of mitochondrial integrity and cell proliferation [161]. As there is a notable
increment in global concern for health and nutrition availing natural ingredients, the
recent data’s on BBC Research on global nutraceuticals marked a growth rate of
285 billion dollars in 2021, and an estimated production of 336.1 billion dollars in
2023 (www.bccresearch.com). Thus, the present global situation urges to ponder
novel and efficient resources for the production of nutraceuticals with high value of
human benefit. According to the numbers presented in 2020 by FAO (Food and
Agriculture Organization), the world aquaculture production obtained 32.4 million
tonnes of marine macroalgae. Reports from FAO of the United Nations states about
the intensive cultivation of red seaweed species Porphyra, Kappaphycus alvarezii,
Eucheuma and Gracilaria reaching an annual cultivation of 18.5 thousand tonnes
754 K. Chakraborty

Table 2 Secondary metabolites of brown algae and its pharmacological potentials

Pharmacological
Terpenes/Terpenoids Algal species property References
Mediterraneone (meroditerpenoid) Cystoseira Anti-neoplastic [104]
mediterranea
Isoepitaondiol (meroditerpenoid) Stypopodium Insecticidal properties [105]
flabelliforme
Cyclozonarone (102) Dictyopteris Feeding-deterrent [106]
undulata activity
Chromenol derivatives Desmarestia Anthelmintic [107]
menziessi Cytotoxic
Stypoquinonic acid Stypopodium Tyrosine kinase [108]
zonale inhibitor
Methoxybifurcarenone Cystoseira Anti-fungal [109]
tamariscifolia Anti-bacterial
Sargassinone Sargassum Cytotoxic [110]
crispum
Hedaols A, B and C (bisnorditerpenes) Sargassum Cytotoxic [111]
hemiphyllum
Tetraprenyltoluquinol derivatives Cystoseira crinita Anti-oxidant [112]
Triprenyltoluquinol derivatives
Tetraprenyltoluquinone derivatives
(meroterpenoid)
Dictyone acetate Dictyota Cytotoxic [113]
3,4-epoxy 13-hydroxy pachydictyol A dichotoma
Dictyocrenulol Dictyota Insecticidal activity [114]
crenulata
Isopachydictyolal Dictyota Anti-viral [115]
4α-acetyldictyodial dichotoma
10-aetoxy-8,18-dihydroxy-2,6-­ Dictyota pfaffii Anti-viral [116]
dolabelladiene
(6R)-6-hydroxydichotoma-3,14-diene-­ Dictyota Anti-viral [117]
1,17-dial menstrualis
(6R)-6-acetoxidichotoma-3,14-diene-­
1,17-dial
Seven cadinane sesquiterpenes Dictyopteris Anti-cancer [118]
divaricata
Sargachromanols A-P Sargassum Anti-oxidant [119]
siliquastrum Inhibition of butyl
choline esterase
Four plastoquinones Sargassum Anti-oxidant [120]
micracanthum Cytotoxic
Atomarianones A, and B Taonia atomaria Cytotoxic [121]
Four hydroxylated quinones Taonia atomaria Anti-inflammatory [122]
2β,3α-epitaondiol Stypopodium Neurotoxic [123]
flabelliforme
Three bisnorsesquiterpenes Dictyopteris Anti-cancer [124]
divaricata
(continued)
Marine Macroalgae as a Treasure House of Bioactive Compounds and Nutraceuticals 755

Table 2 (continued)
Pharmacological
Terpenes/Terpenoids Algal species property References
Five sesquiterpenes Dictyopteris Anti-cancer [125]
Oplopane sesquiterpene divaricata
Perhydroazulene diterpene Dictyota Algicidal activity [126]
dichotoma
Two diterpenes Dictyota sp. Anti-tuberculosis [127]
Anti-malarial
Cytotoxic
Dolabellane diterpene Dictyota pfaffii Anti-fouling [128]
Seven meroditerpenoids and three Cystoseira Anti-fouling [129]
derivatives baccata Anti-bacterial
Four meroditerpenoids Halidrys Anti-fouling [130]
A chromene siliquosa
Seven dolabellanes Dilophus spiralis Anti-bacterial [131]
Amijiol acetate Dictyota Cytotoxic [132]
Dolabellatrienol dichotoma Protective against
Amijiol-7,10-diacetate DNA damage
Three meroterpenoids Sargassum Anti-oxidant [133]
siliquastrum
One dolabellane Dictyota pfaffii Anti-viral [116]
Sargachromanol Q Sargassum Cytotoxic [134]
Sargachromanol R siliquastrum
Seco-Taondiol Stypopodium Gastroprotective [135]
flabelliforme activity
Cystophloroketals A−E Cystoseira Anti-fouling [136]
tamariscifolia
Cadinan-4(15)-ene-1β,5α-diol Dictyopteris – [137]
Trans-3-norisocalamenen-4-ol divaricata
Bifurcatriol Bifurcaria Anti-protozoal activity [138]
bifurcata
Two dolastane diterpenes Canistrocarpus Cytotoxic [139]
cervicornis
Two xenicin diterpenoids Padina Anti-inflammatory [47]
Three xeniolide-type diterpenoids tetrastomatica
Three dolabellanes Padina Anti-diabetic [47]
Two dolastanes tetrastromatica
Sargilicixenicane Sargassum Anti-oxidant [95]
ilicifolium Anti-inflammatory
Two hydroperoxysterols Turbinaria ornata Cytotoxic [140]
3β,28ξ-dihydroxy-24-ethylcholesta- Sargassum Cytotoxic [141]
5,23Z-dien carpophyllum
2a-oxa-2- oxo-5α-hydroxy-3,4-dinor-­
24-ethylcholesta-24(28)-ene
Sulfoquinovosyldiacylglycerol Lobophora Anti-protozoal [142]
variegata
(continued)
756 K. Chakraborty

Table 2 (continued)
Pharmacological
Terpenes/Terpenoids Algal species property References
Cymatherelactone Cymathere Sodium channel [143]
cymatherols A-C methyl ester triplicata blocking
derivatives
Spiralisones A–D Zonaria spiralis Anti-bacterial [144]
Neurodegenrative
kinase inhibition
Dictyoptesterols A–C Dictyopteris PTP1Binhibitory [145]
undulata activity
Dictyopterisins A–J Dictyopteris PTP1Binhibitory [146]
undulata activity
Cytotoxic
Two polyketide lactones Sargassum Anti-oxidant [147]
wightii Anti-inflammatory
Eckstolonol Ecklonia Anti-oxidant [148]
stolonifera
Phloroglucinol derivative Eisenia bicyclis Anti-diabetic [149]
Phlorofucofuroeckol Eisenia arborea Anti-allergic [150]
Fucodiphlorethol G Ecklonia cava Anti-oxidant [151]
Diphlorethohydroxycarmalol Ishige okamurae Anti-diabetic [152]
Two phloroglucinols Fucus vesiculosus Anti-oxidant [153]
cytochromeP450
enzyme inhibition
Eckmaxol Ecklonia maxima Neuroprotective [154]
effects
Deoxylapachol Landsburgza Anti-fungal [155]
querciflia Cytotoxic
Diphlorethohydroxycarmalol Ishige okamurae Cytotoxic [156]
5′-Deoxy-5′-methylamino-adenosine Laminaria Growth stimulant [157]
japonica
Pheophytin a Sargassum Neurodiffrentiation [158]
fulvellum compound
Apo-9′-fucoxanthinone Cladostephus – [159]
Apo-13′-fucoxanthinoneloliolide spongiosus
Comosusols A–D Sporochnus Cytotoxic [160]
Comosone A comosus

produced in 2016. Carrageenan and agar from red seaweed are used as additives for
various products, such as water based gelling desserts, ice cream, cheeses, low-
calorie jellies, soy milk, flan puddings, dairy products, chocolate milk and processed
and canned meat, jellies, seasonings, beer sauces and other processed foods.
Gelidium, Gracilaria, Gelidiella and Pterocladiella are the species mostly used for
the extraction of gelatin which is a solidifying agent and an additive in confection
of pie fillings and toppings.
Marine Macroalgae as a Treasure House of Bioactive Compounds and Nutraceuticals 757

Marine macroalgae contain a large assemblage of species that predominate in the coastal
shelf areas of Indian subcontinent
Over the past few years, use of marine macroalgae to develop value-added com-
pounds and novel pharmacophores has attracted attention from pharmaceutical and
food industries. Nutraceutical products have been developed from marine macroal-
gae as green alternatives to synthetic drugs to combat rheumatic arthritic pains and
type-2 diabetes. Antihypercholesterolemic and antihypothyroidism nutraceuticals
were also developed from marine macroalgae to combat dyslipidaemia and hypo-
thyroid disorder. Lead molecules with action against angiotensin-converting
enzyme-I from marine macroalgae were isolated and added to a nutraceutical prod-
uct [40–42, 147, 162, 163].

9 Conclusions

Marine macroalgae are attaining tremendous attention due to the presence of bioac-
tive polysaccharides, terpenes, alkaloids, steroids, fatty acids, polyphenols and pig-
ments. These compounds are representatives of several biological properties such as
anti-oxidant, anti-inflammatory and anti-diabetic . From the nutritional point of
view, they are very rich in minerals, vitamins and soluble dietary fiber contents. Till
now, there are many species that remains unexplored and undoubtedly there opens
a wild field of research into the discovery and development of new natural product
based nutraceuticals and drugs. The diverse natural compounds from marine mac-
roalgae with unique medicinal activities has introduced algal products into pharma-
ceutical industry. Recent efforts to produce clearness in regulatory protocols in
connection with the nutraceutical products have also increased growth of this seg-
ment of marine microalgal research and their utilization to develop high-value com-
pounds and products for human health perspective. As a step towards upholding the
utilization of marine macroalgae, cohesive aquaculture of these species has been
commenced. The idea of utilization of marine macroalgae as sea vegetables via low-­
technology approach in third world countries is very approachable and practical. In
addition to this, development of functional food products also could provide oppor-
tunities to popularize the health benefits of marine macroalgae. Apart from agar and
carrageenan, a number of pharmaceutically important constituents can be isolated
from marine macroalgae which opens an alternative strategy to fulfill the market’s
demand for naturally derived compounds in food and medicines.
758 K. Chakraborty

Acknowledgements The author thanks the Director, Central Marine Fisheries Research Institute
for facilitating the research activities. This work was funded by the Indian Council of Agricultural
Research, New Delhi, India under Central Marine Fisheries Research Institute supported project
“Development of Bioactive Pharmacophores from Marine Organisms” (grant number MBT/
HLT/SUB23).

References

1. Kong DX, Jiang YY, Zhang HY (2010) Marine natural products as sources of novel scaffolds:
achievement and concern. Drug Discov Today 15(21–22):884–886. https://doi.org/10.1016/j.
drudis.2010.09.002
2. Blunt JW, Copp BR, Keyzers RA, Munro MH, Prinsep MR (2016) Marine natural products.
Nat Prod Rep 33(3):382–431. https://doi.org/10.1039/c5np00156k
3. Blunt JW, Carroll AR, Copp BR, Davis RA, Keyzers RA, Prinsep MR (2018) Marine natural
products. Nat Prod Rep 35(1):8–53. https://doi.org/10.1039/c7np00052a
4. Xie J, Zhang AH, Sun H, Yan GL, Wang XJ (2018) RSC Adv 8:812–824
5. Šimat V, Elabed N, Kulawik P, Ceylan Z, Jamroz E, Yazgan H, Čagalj M, Regenstein JM,
Özogul F (2020) Recent advances in marine-based nutraceuticals and their health benefits.
Mar Drugs 18(12):627. https://doi.org/10.3390/md18120627
6. Carroll AR, Copp BR, Davis RA, Keyzers RA, Prinsep MR (2021) Marine natural products.
Nat Prod Rep 38:362–413. https://doi.org/10.1039/D0NP00089B
7. Driggers EM, Hale SP, Lee J, Terrett NK (2008) The exploration of macrocycles for drug
discovery- an underexploited structural class. Nat Rev Drug Discov 7(7):608–624. https://
doi.org/10.1038/nrd2590
8. Faulkner DJ (2001) Marine natural products. Nat Prod Rep 18(1):1–49. https://doi.
org/10.1039/b006897g
9. Khotimchenko SV, Vaskovsky VE, Titlyanova TV (2002) Fatty acids of marine algae from the
Pacific coast of North California. Bot Mar 45:17–22. https://doi.org/10.1515/BOT.2002.003
10. Kishida R, Yamagishi K, Muraki I, Sata M, Tamakoshi A, Iso H, JACC study group (2020)
Frequency of seaweed intake and its association with cardiovascular disease mortality: the
jacc study. J Atheroscler Thromb 27(12):1340–1347. https://doi.org/10.5551/jat.53447
11. Rindi F, Pasella MM, Lee ME, Verbruggen H (2020) Phylogeography of the mediterranean
green seaweed Halimeda tuna (Ulvophyceae, Chlorophyta). J Phycol 56(4):1109–1113.
https://doi.org/10.1111/jpy.13006
12. Rindi F, Soler Vila A, Guiry M (2012) Taxonomy of marine macroalgae used as sources
of bioactive compounds. Mar Bioact Compd. https://doi.org/10.1007/978-­1-­4614-­1247-­2_1
13. Stam WT, Olsen JL, Zaleski SF, Murray SN, Brown KR, Walters LJ (2006) A forensic and
phylogenetic survey of Caulerpa species (Caulerpales, Chlorophyta) from the Florida coast,
local aquarium shops, and e-commerce: establishing a proactive baseline for early detection.
J Phycol 42(5):1113–1124. https://doi.org/10.1111/j.1529-­8817.2006.00271.x
14. Saunders GW, Hommersand MH (2004) Assessing red algal supraordinal diversity and tax-
onomy in the context of contemporary systematic data. Am J Bot 91(10):1494–1507. https://
doi.org/10.3732/ajb.91.10.1494
15. Fabricant DS, Farnsworth NR (2001) The value of plants used in traditional medicine for drug
discovery. Environ Health Perspect 109(1):69–75. https://doi.org/10.1289/ehp.01109s169
16. Chengkui Z, Tseng CK, Junfu Z, Chang CF (2004) Chinese seaweeds in herbal medicine.
Hydrobiologia 116-117:152–154. https://doi.org/10.1007/BF00027655
17. Featonby-Smith BC, Van Stade J (1983) The effect of seaweed concentrate on the growth of
tomato plants in nematode infested soil. Sci Hortic 20:137–147
18. Nadkarni AK, Nadkarni KM (1996) Nadkarni’s Indian materia medica: with Ayurvedic,
Unani- Tibbi, Siddha, allopathic, homeopathic, naturopathic & home remedies, appendices
& indexes, 3rd edn. Popular Prakashan, Mumbai
Marine Macroalgae as a Treasure House of Bioactive Compounds and Nutraceuticals 759

19. Fonnegra R, Jiménez SL (2007) Gracilaria (alga rodofícea), Plantas medicinales aprobadas
en Colombia, 2nd edn. Editoral Universidad de Antioquía, Medellín, pp 124–125
20. Anggadiredja JT (2009) Ethnobotany study of seaweed diversity and its utilization in
Warambadi, Panguhalodo areas of East Sumba district. Jurnal Teknologi Lingkungan:297–310.
https://doi.org/10.29122/jtl.v10i3.1476
21. Chengkui Z (1984) Phycological research in the development of the Chinese seaweed indus-
try. Hydrobiologia 116:7–18. https://doi.org/10.1007/BF00027633
22. Watt G (2014) A dictionary of the economic products of India, Gossypium to Linociera, vol
4. Cambridge University Press. https://doi.org/10.1017/CBO9781107239173
23. FAO (2020) The state of world fisheries and aquaculture. Rome, 244 p
24. Andrade PB, Barbosa M, Matos RP, Lopes G, Vinholes J, Mouga T, Valentão P (2013)
Valuable compounds in macroalgae extracts. Food Chem 138(2–3):1819–1828. https://doi.
org/10.1016/j.foodchem.2012.11.081
25. Munro MH, Blunt JW, Dumdei EJ, Hickford SJ, Lill RE, Li S, Battershill CN, Duckworth AR
(1999) The discovery and development of marine compounds with pharmaceutical potential.
J Biotechnol 70(1–3):15–25. https://doi.org/10.1016/s0168-­1656(99)00052-­8
26. Montaser R, Luesch H (2011) Marine natural products: a new wave of drugs? Future Med
Chem 3(12):1475–1489. https://doi.org/10.4155/fmc.11.118
27. Chakraborty K, Antony T (2021) First report of spiro-compounds from marine macroalga
Gracilaria salicornia: prospective natural anti-inflammatory agents attenuate 5-­lipoxygenase
and cyclooxygenase-2. Nat Prod Res 35(5):770–781. https://doi.org/10.1080/1478641
9.2019.1608545
28. McHugh DJ (2003) A guide to the seaweed industry. FAO Fisheries Technical Paper 441.
Food and Agriculture Organization of the United Nations, Rome
29. Ganesan AR, Tiwari U, Rajauria G (2019) Seaweed nutraceuticals and their therapeutic role
in disease prevention. Food Sci Human Wellness 8(3):252–263
30. Tsuji S (1980) Japanese cooking: a simple art. Kodansha America, Incorporated,
New York, 518 p
31. Fujii M (2005) The enlightened kitchen. Kodansha International, Tokyo, 107 p
32. Griffin J (2015) An investigative study into the beneficial use of seaweed in bread and the
broader food industry. Dissertation presented to Dublin Institute of Technology, School of
Culinary Arts and Food Technology in partial fulfillment of the requirements for the bach-
elor’s degree BSc (Hons) Baking and Pastry Arts Management, 132 p
33. Bocanegra A, Bastida S, Benedí J, Ródenas S, Sánchez-Muniz FJ (2009) Characteristics and
nutritional and cardiovascular-health properties of seaweeds. J Med Food 12(2):236–258.
https://doi.org/10.1089/jmf.2008.0151
34. Dhargakar VK (2014) Uses of seaweeds in the Indian diet for sustenance and well-being. Sci
Cult 80(7–8):192–202
35. Subba RPV, Ganesan K, Suresh KK (2009) Seaweeds: a survey of research and utiliza-
tion. In: Khattar JIS, Singh DP, Gurpreet Kaur IK (eds) Algal biology and biotechnology.
International Publishing House, Pvt. Ltd, New Delhi/Bangalore, pp 165–178
36. Subba RPV, Periyasamy C, Rama RK, Srinivasa RA (2016) Seaweed for human welfare.
Seaweed Res Util 38:1–12
37. FAO (2003) The state of world fisheries and aquaculture. Rome
38. Chakraborty K, Joseph D (2018) Effects of antioxidative substances from seaweed on quality
of refined liver oil of leafscale gulper shark, Centrophorus squamosus during an accelerated
stability study. Food Res Int 103:450–461. https://doi.org/10.1016/j.foodres.2017.10.018
39. Chakraborty K, Joseph D (2018) Effect of antioxidant compounds from seaweeds on storage
stability of C20-22 polyunsaturated fatty acid concentrate prepared from dogfish liver oil. Food
Chem 260:135–144. https://doi.org/10.1016/j.foodchem.2018.03.144
40. Chakraborty K et al (2010) A process to prepare antioxidant and anti-inflammatory con-
centrates from brown and red seaweeds and a product thereof. Indian Patent Grant number
294451 (2064/CHE/2010, granted on 16/03/2018)
41. Chakraborty K et al (2012) A product containing anti-inflammatory principles from brown
seaweeds and a process thereof. Indian Patent number 5199/CHE/2012
760 K. Chakraborty

42. Chakraborty K. (2015) A process to prepare antidiabetic concentrates from seaweeds and a
product thereof. Indian Patent Appl. no. 3366/DEL/2015
43. Chakraborty K. (2017) A process to prepare anti-dyslipidemic concentrate from seaweed and
a product thereof. Indian Patent Appl. no. 201711013741
44. Chakraborty K, Joseph D (2016) Antioxidant potential and phenolic compounds of brown
seaweeds Turbinaria conoides and Turbinaria ornata (class: Phaeophyceae). J Aquat Food
Prod Technol 25(8):1249–1265. https://doi.org/10.1080/10498850.2015.1054540
45. Chakraborty K et al (2020) A composition and antihypertensive product from marine algae.
Indian Patent Appl no. 202011011489
46. Makkar F, Chakraborty K (2018) Highly oxygenated antioxidative 2H-chromen deriva-
tive from the red seaweed Gracilaria opuntia with pro-inflammatory cyclooxygenase and
lipoxygenase inhibitory properties. Nat Prod Res 32(23):2756–2765. https://doi.org/10.108
0/14786419.2017.1378209
47. Antony T, Chakraborty K (2019) Xenicanes attenuate pro-inflammatory 5-lipoxygenase:
prospective natural anti-inflammatory leads from intertidal brown seaweed Padina tetrastro-
matica. Med Chem Res 28:591–607. https://doi.org/10.1007/s00044-­019-­02322-­8
48. Antony T, Chakraborty K (2020) First report of antioxidative 2H-chromenyl derivatives from
the intertidal red seaweed Gracilaria salicornia as potential anti-inflammatory agents. Nat
Prod Res 34(24):3470–3482. https://doi.org/10.1080/14786419.2019.1579807
49. Antony T, Chakraborty K, Joy M (2021) Antioxidative dolabellanes and dolastanes from
brown seaweed Padina tetrastromatica as dual inhibitors of starch digestive enzymes. Nat
Prod Res 35(4):614–626. https://doi.org/10.1080/14786419.2019.1591402
50. Pati MP, Sharma SD, Lakshman N, Panda CR (2016) Uses of seaweed and its applica-
tion to human welfare: a review. Int J Pharm Pharm Sci 8:12–20. https://doi.org/10.22159/
ijpps.2016v8i1012740
51. Bilal M, Iqbal HMN (2019) Marine seaweed polysaccharides-based engineered cues for the
modern biomedical sector. Mar Drugs 18(1):7. https://doi.org/10.3390/md18010007
52. Blunt JW, Copp BR, Keyzers RA, Munro MH, Prinsep MR (2014) Marine natural products.
Nat Prod Rep 31(2):160–258. https://doi.org/10.1039/c3np70117d
53. Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years
from 1981 to 2010. J Nat Prod 75(3):311–335. https://doi.org/10.1021/np200906s
54. Numata A, Kanbara S, Takahashi C, Fujiki R, Yoneda M, Usami Y, Fujita E (1992) A cytotoxic
principle of the brown alga Sargassum tortile and structures of chromenes. Phytochemistry
31(4):1209–1213. https://doi.org/10.1016/0031-­9422(92)80262-­D
55. Vairappan CS, Daitoh M, Suzuki M, Abe T, Masuda M (2001) Antibacterial halogenated
metabolites from the Malaysian Laurencia species. Phytochemistry 58(2):291–297. https://
doi.org/10.1016/s0031-­9422(01)00243-­6
56. Rocha DHA, Seca AML, Pinto DCGA (2018) Seaweed secondary metabolites: in vitro and
in vivo anticancer activity. Mar Drugs 16(11):410. https://doi.org/10.3390/md16110410
57. Makkar F, Chakraborty K (2018) Antioxidant and anti-inflammatory oxygenated meroterpe-
noids from the thalli of red seaweed Kappaphycus alvarezii. Med Chem Res 27(8):2016–2026.
https://doi.org/10.1007/s00044-­018-­2210-­0
58. Makkar F, Chakraborty K (2018) Antioxidative sulphated polygalactans from marine mac-
roalgae as angiotensin-I converting enzyme inhibitors. Nat Prod Res 32(17):2100–2106.
https://doi.org/10.1080/14786419.2017.1363756
59. Makkar F, Chakraborty K (2018) First report of dual cyclooxygenase-2 and 5-lipoxygenase
inhibitory halogen derivatives from the thallus of intertidal seaweed Kappaphycus alvarezii.
Med Chem Res 27:2331–2340. https://doi.org/10.1007/s00044-­018-­2239-­0
60. Makkar F, Chakraborty K (2018) Novel furanyl derivatives from the red seaweed Gracilaria
opuntia with pharmacological activities using different in vitro models. Med Chem Res
27:1245–1259. https://doi.org/10.1007/s00044-­018-­2144-­6
61. Makkar F, Chakraborty K (2018) Previously undescribed antioxidative azocinyl morpho-
linone alkaloid from red seaweed Gracilaria opuntia with anti-cyclooxygenase and lipox-
Marine Macroalgae as a Treasure House of Bioactive Compounds and Nutraceuticals 761

ygenase properties. Nat Prod Res 32(10):1150–1160. https://doi.org/10.1080/1478641

9.2017.1326041
62. Wang BG, Gloer JB, Ji NY, Zhao JC (2013) Halogenated organic molecules of Rhodomelaceae
origin: chemistry and biology. Chem Rev 113(5):3632–3685. https://doi.org/10.1021/
cr9002215
63. Rosa GP, Tavares WR, Sousa PMC, Pagès AK, Seca AML, Pinto DCGA (2019) Seaweed sec-
ondary metabolites with beneficial health effects: an overview of successes in in vivo studies
and clinical trials. Mar Drugs 18(1):8. https://doi.org/10.3390/md18010008
64. Servel MO, Claire C, Derrien A, Coiffard L, De Roeck-Holtzhauer Y (1994) Fatty acid com-
position of some marine microalgae. Phytochemistry 36(3):691–693
65. Mansour MP, Volkman JK, Holdsworth DG, Jackson AE, Blackburn SI (1999) Very-­
long-­chain (C28) highly unsaturated fatty acids in marine dinoflagellates. Phytochemistry
50:541–548. https://doi.org/10.1016/S0031-­9422(98)00564-­0
66. Agatonovic KS, Morton DW (2020) Cosmeceuticals derived from bioactive substances found
in marine algae. J Oceanogr 1:106. https://doi.org/10.4172/2332-­2632.1000106
67. Paniagua-Michel Jde J, Olmos-Soto J, Morales-Guerrero ER (2014) Algal and microbial
exopolysaccharides: new insights as biosurfactants and bioemulsifiers. Adv Food Nutr Res
73:221–257. https://doi.org/10.1016/B978-­0-­12-­800268-­1.00011-­1
68. Makkar F, Chakraborty K (2017) Antidiabetic and anti-inflammatory potential of sulphated
polygalactans from red seaweeds Kappaphycus alverizii and Gracilaria opuntia. Int J Food
Prop 20(6):1326–1337. https://doi.org/10.1080/10942912.2016.1209216
69. Maneesh A, Chakraborty K, Makkar F (2017) Pharmacological activities of brown seaweed
Sargassum wightii (family Sargassaceae) using different in vitro models. Int J Food Prop
20(4):931–945. https://doi.org/10.1080/10942912.2016.1189434
70. Maneesh A, Chakraborty K (2018) Pharmacological potential of sulfated polygalactopyranosyl-­
fucopyranan from the brown seaweed Sargassum wightii. J Appl Phycol 30:1971–1988.
https://doi.org/10.1007/s10811-­017-­1385-­y
71. Dobrinčić A, Balbino S, Zorić Z, Pedisić S, Bursać Kovačević D, Elez Garofulić I, Dragović-­
Uzelac V (2020) Advanced technologies for the extraction of marine brown algal polysac-
charides. Mar Drugs 18(3):168. https://doi.org/10.3390/md18030168
72. Chakraborty K, Maneesh A (2020) Marine-derived polygalactofucan and its β-2-deoxy-­
amino-substituted glucopyranan composite attenuate 3-hydroxy-3-methylglutaryl-CoA
reductase: prospective natural anti-dyslipidemic leads. Med Chem Res 29:281–300. https://
doi.org/10.1007/s00044-­019-­02482-­7
73. Wang L, Wang X, Wu H, Liu R (2014) Overview on biological activities and molecular char-
acteristics of sulfated polysaccharides from marine green algae in recent years. Mar Drugs
12(9):4984–5020. https://doi.org/10.3390/md12094984
74. Kanlayavattanakul M, Fungpaisalpong K, Pumcharoen M, Lourith N (2017) Preparation and
efficacy assessment of malva nut polysaccharide for skin hydrating products. Ann Pharm Fr
75(6):436–445. https://doi.org/10.1016/j.pharma.2017.03.003
75. Lee KY, Mooney DJ (2012) Alginate: properties and biomedical applications. Prog Polym
Sci 37(1):106–126. https://doi.org/10.1016/j.progpolymsci.2011.06.003
76. Venkatesan J, Lowe B, Anil S, Manivasagan P, Kheraif AAA, Kang KH, Kim SK (2015)
Seaweed polysaccharides and their potential biomedical applications. Starch-Stärke
67:381–390. https://doi.org/10.1002/star.201400127
77. Popa EG, Reis RL, Gomes ME (2015) Seaweed polysaccharide-based hydrogels used for the
regeneration of articular cartilage. Crit Rev Biotechnol 35(3):410–424. https://doi.org/10.310
9/07388551.2014.889079. PMID: 24646368
78. Alves A, Duarte ARC, Mano JF, Sousa RA, Reis RL (2012) PDLLA enriched with ulvan
particles as a novel 3D porous scaffold targeted for bone engineering. J Supercrit Fluids
65:32–38. https://doi.org/10.1016/j.supflu.2012.02.023
79. Madub K, Goonoo N, Gimié F, Ait Arsa I, Schönherr H, Bhaw-Luximon A (2021) Green
seaweeds ulvan-cellulose scaffolds enhance in vitro cell growth and in vivo angiogenesis
762 K. Chakraborty

for skin tissue engineering. Carbohydr Polym 251:117025. https://doi.org/10.1016/j.carb-

pol.2020.117025. Epub 2020 Sep 3. PMID: 33142585
80. Custódio CA, Reis RL, Mano JF (2016) Photo-cross-linked laminarin-based hydrogels for
biomedical applications. Biomacromolecules 17(5):1602–1609. https://doi.org/10.1021/acs.
biomac.5b01736
81. Ayoub A, Pereira JM, Rioux LE, Turgeon SL, Beaulieu M, Moulin VJ (2015) Role of seaweed
laminaran from Saccharina longicruris on matrix deposition during dermal tissue-engineered
production. Int J Biol Macromol 75:13–20. https://doi.org/10.1016/j.ijbiomac.2015.01.017
82. Bawakid NO, Alarif WM, Alburae NA, Alorfi HS, Al-Footy KO, Al-Lihaibi SS, Ghandourah
MA (2017) Isolaurenidificin and bromlaurenidificin: two new C15-acetogenins from the red
alga Laurencia obtusa. Molecules 22(5):807. https://doi.org/10.3390/molecules22050807
83. Chakraborty K. et al (2015) Anti-inflammatory principles in a preparation of brown sea-
weeds. Indian Patent Appl. no. 4254/DEL/2015 (Patent Grant number 333392)
84. Cotas J, Leandro A, Monteiro P, Pacheco D, Figueirinha A, Gonçalves AMM, da Silva GJ,
Pereira L (2020) Seaweed phenolics: from extraction to applications. Mar Drugs 18(8):384.
https://doi.org/10.3390/md18080384
85. Valenzuela NCD, Ortiz VA, Shelton LM, Edeza JM, López RJ, Flores VMA, Báez BJ (2017)
Residual biomasses and protein hydrolysates of three green microalgae species exhibit
antioxidant and anti-aging activity. J Appl Phycol 29:189–198. https://doi.org/10.1007/
s10811-­016-­0938-­9
86. Rengasamy KR, Mahomoodally MF, Aumeeruddy MZ, Zengin G, Xiao J, Kim DH (2020)
Bioactive compounds in seaweeds: an overview of their biological properties and safety.
Food Chem Toxicol 135:111013. https://doi.org/10.1016/j.fct.2019.111013
87. Gómez-Guzmán M, Rodríguez-Nogales A, Algieri F, Gálvez J (2018) Potential role of sea-
weed polyphenols in cardiovascular-associated disorders. Mar Drugs 16(8):250. https://doi.
org/10.3390/md16080250
88. Morán-Santibañez K, Peña-Hernández MA, Cruz-Suárez LE, Ricque-Marie D, Skouta R,
Vasquez AH, Rodríguez-Padilla C, Trejo-Avila LM (2018) Virucidal and synergistic activity
of polyphenol-rich extracts of seaweeds against measles virus. Viruses 10(9):465. https://doi.
org/10.3390/v10090465
89. Alghazeer R, Howell NK, El-Naili MB, Awayn N (2018) Anticancer and antioxidant activi-
ties of some algae from Western Libyan Coast. J Nat Sci Res 10(7):232–246. https://doi.
org/10.4236/ns.2018.107025
90. Olasehinde TA, Olaniran AO, Okoh AI (2019) Macroalgae as a valuable source of natu-
rally occurring bioactive compounds for the treatment of Alzheimer’s disease. Mar Drugs
17(11):609. https://doi.org/10.3390/md17110609
91. Chakraborty K et al (2019) A process to prepare an antimicrobial therapeutic concentrate
from seaweed-associated bacterium and a product thereof. Indian Patent Application No
201911032735
92. Antony T, Chakraborty K (2020) Anti-inflammatory polyether triterpenoids from the marine
macroalga Gracilaria salicornia: newly described natural leads attenuate pro-inflammatory
5-lipoxygenase and cyclooxygenase-2. Algal Res 47:101–791. https://doi.org/10.1016/j.
algal.2020.101791
93. Maneesh A, Chakraborty K (2017) Previously undescribed fridooleanenes and oxygen-
ated labdanes from the brown seaweed Sargassum wightii and their protein tyrosine
phosphatase-1B inhibitory activity. Phytochemistry 144:19–32. https://doi.org/10.1016/j.
phytochem.2017.08.011
94. Maneesh A, Chakraborty K (2018) Previously undescribed antioxidative O-heterocyclic
angiotensin converting enzyme inhibitors from the intertidal seaweed Sargassum wightii
as potential antihypertensives. Food Res Int 113:474–486. https://doi.org/10.1016/j.
foodres.2018.07.035
95. Chakraborty K, Dhara S (2020) First report of substituted 2H-pyranoids from brown sea-
weed Turbinaria conoides with antioxidant and anti-inflammatory activities. Nat Prod Res
34(24):3451–3461. https://doi.org/10.1080/14786419.2019.1578761
Marine Macroalgae as a Treasure House of Bioactive Compounds and Nutraceuticals 763

96. Hori K, Matsubara K, Miyazawa K (2000) Primary structures of two hemagglutinins from
the marine red alga, Hypnea japonica. Biochim Biophys Acta 1474(2):226–236. https://doi.
org/10.1016/s0304-­4165(00)00008-­8
97. Gauto DF, Di Lella S, Estrin DA, Monaco HL, Martí MA (2011) Structural basis for ligand
recognition in a mushroom lectin: solvent structure as specificity predictor. Carbohydr Res
346(7):939–948. https://doi.org/10.1016/j.carres.2011.02.016
98. Manning JC, Romero A, Habermann FA, García Caballero G, Kaltner H, Gabius HJ (2017)
Lectins: a primer for histochemists and cell biologists. Histochem Cell Biol 147(2):199–222.
https://doi.org/10.1007/s00418-­016-­1524-­6
99. Cardoso SM, Pereira OR, Seca AM, Pinto DC, Silva AM (2015) Seaweeds as preven-
tive agents for cardiovascular diseases: from nutrients to functional foods. Mar Drugs
13(11):6838–6865. https://doi.org/10.3390/md13116838
100. Kim SK, Pangestuti R (2011) Biological activities and potential health benefits of fucoxanthin
derived from marine brown algae. Adv Food Nutr Res 64:111–128. https://doi.org/10.1016/
B978-­0-­12-­387669-­0.00009-­0
101. Bedoux G, Hardouin K, Burlot AS, Bourgougnon N (2014) Bioactive components from sea-
weeds: cosmetic applications and future development. Adv Bot Res 71:345–378. https://doi.
org/10.1016/B978-­0-­12-­408062-­1.00012-­3
102. Pereira L (2018) Seaweeds as source of bioactive substances and skin care therapy – cos-
meceuticals, algotheraphy, and thalassotherapy. Cosmetics 5:68. https://doi.org/10.3390/
cosmetics5040068
103. Salehi B, Sharifi-Rad J, Seca AML, Pinto DCGA, Michalak I, Trincone A, Mishra AP,
Nigam M, Zam W, Martins N (2019) Current trends on seaweeds: looking at chemical com-
position, phytopharmacology, and cosmetic applications. Molecules 24(22):4182. https://doi.
org/10.3390/molecules24224182
104. Fadli M, Aracil JM, Jeanty G, Banaigs B, Francisco C (1991) Novel meroterpenoids from
Cystoseira mediterranea: use of the crown-gall bioassay as a primary screen for lipophilic
antineoplastic agents. J Nat Prod 54(1):261–264. https://doi.org/10.1021/np50073a029
105. Rovirosa J, Sepulveda M, Quezada E, San-Martin A (1992) Isoepitaondiol, a diterpenoid of
Stypopodium flabelliforme and the insecticidal activity of stypotriol, epitaondiol and deriva-
tives. Phytochemistry 31(8):2679–2681. https://doi.org/10.1016/0031-­9422(92)83610-­B
106. Kurata K, Taniguchi K, Suzuki M (1996) Cyclozonarone, a sesquiterpene-substituted
benzoquinone derivative from the brown alga Dictyopteris undulata. Phytochemistry
41(3):749–752. https://doi.org/10.1016/0031-­9422(95)00651-­6
107. Davyt D, Enz W, Manta E, Navarro G, Norte M (1997) New chromenols from
the brown alga Desmarestia menziesii. Nat Prod Rep 9(4):305–312. https://doi.
org/10.1080/10575639708043644
108. Wessels M, König GM, Wright AD (1999) A new tyrosine kinase inhibitor from the marine
brown alga Stypopodium zonale. J Nat Prod 62(6):927–930. https://doi.org/10.1021/
np990010h
109. Bennamara A, Abourriche A, Berrada M, Charrouf M, Chaib N, Boudouma M, Garneau
FX (1999) Methoxybifurcarenone: an antifungal and antibacterial meroditerpenoid from the
brown alga Cystoseira tamariscifolia. Phytochemistry 52(1):37–40. https://doi.org/10.1016/
s0031-­9422(99)00040-­0
110. Ayyad SE, Slama MO, MoKhtar AH, Anter AF (2001) Cytotoxic bicyclic diterpene from the
brown alga Sargassum crispum. Boll Chim Farm 140(3):155–159
111. Takada N, Watanabe R, Suenaga K, Yamada K, Uemura D (2001) Isolation and structures
of hedaols A, B, and C, new bisnorditerpenes from a Japanese brown alga. J Nat Prod
64(5):653–655. https://doi.org/10.1021/np0005661
112. Fisch KM, Böhm V, Wright AD, König GM (2003) Antioxidative meroterpenoids from the
brown alga Cystoseira crinita. J Nat Prod 66(7):968–975. https://doi.org/10.1021/np030082f
113. Gedara SR, Abdel-Halim OB, El-Sharkawy SH, Salama OM, Shier TW, Halim AF (2003)
Cytotoxic hydroazulene diterpenes from the brown alga Dictyota dichotoma. Z Naturforsch
C: Biosci 58(1–2):17–22. https://doi.org/10.1515/znc-­2003-­1-­203
764 K. Chakraborty

114. Soto H, Rovirosa J, San-Martin A (2003) A new diterpene from Dictyota crenulata. Z
Naturforsch B: J Chem Sci 58(8):795–798. https://doi.org/10.1515/znb-­2003-­0812
115. Siamopoulou P, Bimplakis A, Iliopoulou D, Vagias C, Cos P, Vanden Berghe D, Roussis
V (2004) Diterpenes from the brown algae Dictyota dichotoma and Dictyota linearis.
Phytochemistry 65(14):2025–2030. https://doi.org/10.1016/j.phytochem.2004.06.018
116. Barbosa JP, Pereira RC, Abrantes JL, Cirne dos Santos CC, Rebello MA, Frugulhetti IC,
Texeira VL (2004) In vitro antiviral diterpenes from the Brazilian brown alga Dictyota pfaffii.
Planta Med 70(9):856–860. https://doi.org/10.1055/s-­2004-­827235
117. Pereira HS, Leão-Ferreira LR, Moussatché N, Teixeira VL, Cavalcanti DN, Costa LJ, Diaz R,
Frugulhetti IC (2004) Antiviral activity of diterpenes isolated from the Brazilian marine alga
Dictyota menstrualis against human immunodeficiency virus type 1 (HIV-1). Antivir Res
64(1):69–76. https://doi.org/10.1016/j.antiviral.2004.06.006
118. Song FH, Fan X, Xu XL, Zhao JL, Han LJ, Shi JG (2004) A new sesquiterpene-substituted
benzoic acid from the brown alga Dictyopteris divaricata. Chin Chem Lett 15(3):316–318.
https://doi.org/10.1080/1028602032000169532
119. Jang KH, Lee BH, Choi BW, Lee HS, Shin J (2005) Chromenes from the brown alga
Sargassum siliquastrum. J Nat Prod 68(5):716–723
120. Mori J, Iwashima M, Wakasugi H, Saito H, Matsunaga T, Ogasawara M, Takahashi S, Suzuki
H, Hayashi T (2005) New plastoquinones isolated from the brown alga, Sargassum micra-
canthum. Chem Pharm Bull (Tokyo) 53(9):1159–1163. https://doi.org/10.1248/cpb.53.1159
121. Abatis D, Vagias C, Galanakis D, Norris JN, Moreau D, Roussakis C, Roussis V (2005)
Atomarianones A and B: two cytotoxic meroditerpenes from the brown alga Taonia atom-
aria. Tetrahedron Lett 46(49):8525–8529. https://doi.org/10.1016/j.tetlet.2005.10.007
122. Tziveleka LA, Abatis D, Paulus K, Bauer R, Vagias C, Roussis V (2005) Marine polyprenyl-
ated hydroquinones, quinones, and chromenols with inhibitory effects on leukotriene forma-
tion. Chem Biodivers 2(7):901–909. https://doi.org/10.1002/cbdv.200590066
123. Sabry OM, Andrews S, McPhail KL, Goeger DE, Yokochi A, LePage KT, Murray TF,
Gerwick WH (2005) Neurotoxic meroditerpenoids from the tropical marine brown alga
Stypopodium flabelliforme. J Nat Prod 68(7):1022–1030. https://doi.org/10.1021/np050051f
124. Song F, Xu X, Li S, Wang S, Zhao J, Cao P, Yang Y, Fan X, Shi J, He L, Lü Y (2005)
Norsesquiterpenes from the brown alga Dictyopteris divaricata. J Nat Prod 68(9):1309–1313.
https://doi.org/10.1021/np040227y
125. Song F, Fan X, Xu X, Zhao J, Yang Y, Shi J (2006) Cadinane sesquiterpenes from the
brown alga Dictyopteris divaricata. J Nat Prod 67(10):1644–1649. https://doi.org/10.1021/
np040099d
126. Kim JY, Alamsjah MA, Hamada A, Fujita Y, Ishibashi F (2006) Algicidal diterpenes from the
brown alga Dictyota dichotoma. Biosci Biotechnol Biochem 70(10):2571–2574. https://doi.
org/10.1271/bbb.60281
127. Jongaramruong J, Kongkam N (2007) Novel diterpenes with cytotoxic, anti-malarial and anti-­
tuberculosis activities from a brown alga Dictyota sp. J Asian Nat Prod Res 9(6–8):743–751.
https://doi.org/10.1080/10286020701189203
128. Barbosa J, Fleury B, Da Gama B, Teixeira V, Pereira R (2007) Natural products as antifou-
lants in the Brazilian brown alga Dictyota pfaffii (Phaeophyta, Dictyotales). Biochem Syst
Ecol 35:549–553. https://doi.org/10.1016/j.bse.2007.01.010
129. Mokrini R, Mesaoud MB, Daoudi M, Hellio C, Maréchal JP, El Hattab M, Ortalo-Magné
A, Piovetti L, Culioli G (2008) Meroditerpenoids and derivatives from the brown alga
Cystoseira baccata and their antifouling properties. J Nat Prod 71(11):1806–1811. https://
doi.org/10.1021/np8004216
130. Culioli G, Ortalo-Magné A, Valls R, Hellio C, Clare AS, Piovetti L (2008) Antifouling
activity of meroditerpenoids from the marine brown alga Halidrys siliquosa. J Nat Prod
71(7):1121–1126. https://doi.org/10.1021/np070110k
131. Ioannou E, Quesada A, Rahman MM, Gibbons S, Vagias C, Roussis V (2011) Dolabellanes
with antibacterial activity from the brown alga Dilophus spiralis. J Nat Prod 74(2):213–222.
https://doi.org/10.1021/np1006586
Marine Macroalgae as a Treasure House of Bioactive Compounds and Nutraceuticals 765

132. Ayyad SE, Makki MS, Al-Kayal NS, Basaif SA, El-Foty KO, Asiri AM, Alarif WM, Badria
FA (2011) Cytotoxic and protective DNA damage of three new diterpenoids from the brown
alga Dictoyota dichotoma. Eur J Med Chem 46(1):175–182. https://doi.org/10.1016/j.
ejmech.2010.10.033
133. Lee SH, Kang SM, Ko SC, Lee DH, Jeon YJ (2012) Octaphlorethol A, a novel phenolic com-
pound isolated from a brown alga, Ishige foliacea, increases glucose transporter 4-mediated
glucose uptake in skeletal muscle cells. Biochem Biophys Res Commun 420(3):576–581.
https://doi.org/10.1016/j.bbrc.2012.03.036
134. Lee JI, Park BJ, Kim H, Seo Y (2014) Isolation of two new meroterpenoids from
Sargassum siliquastrum. Bull Korean Chem Soc 35:2867–2869. https://doi.org/10.5012/
bkcs.2014.35.9.2867
135. Areche C, Benites J, Cornejo A, Ruiz LM, García-Beltrán O, Simirgiotis MJ, Sepúlveda
B (2015) Seco-taondiol, an unusual meroterpenoid from the Chilean seaweed Stypopodium
flabelliforme and its gastroprotective effect in mouse model. Mar Drugs 13(4):1726–1738.
https://doi.org/10.3390/md13041726
136. El Hattab M, Genta-Jouve G, Bouzidi N, Ortalo-Magné A, Hellio C, Maréchal JP, Piovetti L,
Thomas OP, Culioli G (2015) Cystophloroketals A-E, unusual phloroglucinol-meroterpenoid
hybrids from the brown alga Cystoseira tamariscifolia. J Nat Prod 78(7):1663–1670. https://
doi.org/10.1021/acs.jnatprod.5b00264
137. Ji NY, Song YP, Miao FP, Liang XR (2016) Three cadinane derivatives from the marine
brown alga Dictyopteris divaricata. Magn Reson Chem 54(1):88–90. https://doi.org/10.1002/
mrc.4319
138. Smyrniotopoulos V, Merten C, Kaiser M, Tasdemir D (2017) Bifurcatriol, a new antipro-
tozoal acyclic diterpene from the brown alga Bifurcaria bifurcata. Mar Drugs 15(8):245.
https://doi.org/10.3390/md15080245
139. Campbell S, Murray J, Delgoda R, Gallimore W (2017) Two new oxodolastane diterpenes
from the Jamaican macroalga Canistrocarpus cervicornis. Mar Drugs 15(6):150. https://doi.
org/10.3390/md15060150
140. Shen YC, Tsai PI, Fenical W, Hay ME (1992) Secondary metabolite chemistry of the
caribbean marine alga Sporochnus bolleanus: a basis for herbivore chemical defence.
Phytochemistry 32(1):71–75
141. Tang HF, Yang-Hua Y, Yao XS, Xu QZ, Zhang SY, Lin HW (2002) Bioactive steroids from
the brown alga Sargassum carpophyllum. J Asian Nat Prod Res 4(2):95–101. https://doi.
org/10.1080/10286020290027362
142. Cantillo-Ciau Z, Moo-Puc R, Quijano L, Freile-Pelegrín Y (2010) The tropical brown alga
Lobophora variegata: a source of antiprotozoal compounds. Mar Drugs 8(4):1292–1304.
https://doi.org/10.3390/md8041292
143. Choi H, Proteau PJ, Byrum T, Pereira AR, Gerwick WH (2012) Cymatherelactone and
cymatherols A-C, polycyclic oxylipins from the marine brown alga Cymathere triplicata.
Phytochemistry 73(1):134–141. https://doi.org/10.1016/j.phytochem.2011.09.014
144. Zhang H, Xiao X, Conte MM, Khalil Z, Capon RJ (2012) Spiralisones A-D: acylphloroglu-
cinol hemiketals from an Australian marine brown alga, Zonaria spiralis. Org Biomol Chem
10(48):9671–9676. https://doi.org/10.1039/c2ob26988k
145. Yang F, Zhang LW, Feng MT, Liu AH, Li J, Zhao TS, Lai XP, Wang B, Guo YW, Mao SC
(2018) Dictyoptesterols A-C, ∆22-24-oxo cholestane-type sterols with potent PTP1B inhibi-
tory activity from the brown alga Dictyopteris undulata Holmes. Fitoterapia 130:241–246.
https://doi.org/10.1016/j.fitote.2018.09.001
146. Feng MT, Wang T, Liu AH, Li J, Yao LG, Wang B, Guo YW, Mao SC (2018) PTP1B inhibi-
tory and cytotoxic C-24 epimers of Δ28-24-hydroxy stigmastane-type steroids from the brown
alga Dictyopteris undulata Holmes. Phytochemistry 146:25–35
147. Maneesh A, Chakraborty K (2017) Unprecedented antioxidative and anti-inflammatory aryl
polyketides from the brown seaweed Sargassum wightii. Food Res Int 100(1):640–649.
https://doi.org/10.1016/j.foodres.2017.07.006
766 K. Chakraborty

148. Kang HS, Chung HY, Jung JH, Son BW, Choi JS (2003) A new phlorotannin from the
brown alga Ecklonia stolonifera. Chem Pharm Bull (Tokyo) 51(8):1012–1014. https://doi.
org/10.1248/cpb.51.1012
149. Okada Y, Ishimaru A, Suzuki R, Okuyama T (2004) A new phloroglucinol derivative from the
brown alga Eisenia bicyclis: potential for the effective treatment of diabetic complications. J
Nat Prod 67(1):103–105. https://doi.org/10.1021/np030323j
150. Sugiura Y, Matsuda K, Yamada Y, Nishikawa M, Shioya K, Katsuzaki H, Imai K, Amano H
(2006) Isolation of a new anti-allergic phlorotannin, phlorofucofuroeckol-B, from an edible
brown alga, Eisenia arborea. Biosci Biotechnol Biochem 70(11):2807–2811. https://doi.
org/10.1271/bbb.60417
151. Ham YM, Baik JS, Hyun JW, Lee NH (2007) Isolation of a new phlorotannin, fucodiphlor-
ethol G, from a brown alga Ecklonia cava. Bull Korean Chem Soc 28(9):1595
152. Heo SJ, Hwang JY, Choi JI, Han JS, Kim HJ, Jeon YJ (2009) Diphlorethohydroxycarmalol
isolated from Ishige okamurae, a brown algae, a potent alpha-glucosidase and alpha-­
amylase inhibitor, alleviates postprandial hyperglycemia in diabetic mice. Eur J Pharmacol
615(1–3):252–256. https://doi.org/10.1016/j.ejphar.2009.05.017
153. Parys S, Kehraus S, Krick A, Glombitza KW, Carmeli S, Klimo K, Gerhäuser C, König GM
(2010) In vitro chemopreventive potential of fucophlorethols from the brown alga Fucus
vesiculosus L. by anti-oxidant activity and inhibition of selected cytochrome P450 enzymes.
Phytochemistry 71(2–3):221–229. https://doi.org/10.1016/j.phytochem.2009.10.020
154. Wang J, Zheng J, Huang C, Zhao J, Lin J, Zhou X, Naman CB, Wang N, Gerwick W, Wang
Q, Cui W, He S (2018) Eckmaxol, a Phlorotannin extracted from Ecklonia maxima, produces
anti-β-amyloid oligomer neuroprotective effects possibly via directly acting on glycogen
synthase kinase 3β. ACS Chem Neurosci 9. https://doi.org/10.1021/acschemneuro.7b00527
155. Perry NB, Blunt JW, Munro MH (1991) A cytotoxic and antifungal 1,4-naphthoquinone and
related compounds from a New Zealand brown algae, Landsburgia quercifolia. J Nat Prod
54(4):978–985. https://doi.org/10.1021/np50076a009
156. Toume K, Miyata M, Egawa K, Nose K, Hayashi M, Komiya K, Ishibashi M (2004) Isolation
of diphlorethohydroxycarmalol from a brown alga Ishige okamurae. J Nat Med 58(2):79–80
157. Kuwada K, Kuramoto M, Utamura M, Matsushita I, Ishii T (2006) Isolation and structural
elucidation of a growth stimulant for arbuscular mycorrhizal fungus from Laminaria japon-
ica Areschoug. J Appl Phycol 18(6):795–800. https://doi.org/10.1007/s10811-­006-­9095-­x
158. Ina A, Hayashi K, Nozaki H, Kamei Y (2007) Pheophytin a, a low molecular weight com-
pound found in the marine brown alga Sargassum fulvellum, promotes the differentiation of
PC12 cells. Int J Dev Neurosci 25(1):63–68. https://doi.org/10.1016/j.ijdevneu.2006.09.323
159. El Hattab M, Culioli G, Valls R, Richou M, Piovetti L (2008) Apo-fucoxanthinoids and loliolide
from the brown alga Cladostephus spongiosus f. verticillatus (Heterokonta, Sphacelariales).
Biochem Syst Ecol 36(5–6):447–451. https://doi.org/10.1016/j.bse.2007.08.016
160. Ovenden SP, Nielson JL, Liptrot CH, Willis RH, Wright AD, Motti CA, Tapiolas DM (2011)
Comosusols A-D and comosone A: cytotoxic compounds from the brown alga Sporochnus
comosus. J Nat Prod 74(4):739–743. https://doi.org/10.1021/np1008009
161. Subudhi S (2017) Bioprospecting for algal based nutraceuticals and high value added com-
pounds. J Pharm Pharm. https://doi.org/10.15436/2377-­1313.17.1651
162. Chakraborty K et al (2019) An oral drug delivery system and an anti-bacterial topical appli-
cant from seaweed based hydrogel and a process thereof. Indian patent Application No
201911018958
163. Chakraborty K. et al (2020) A composition and anti-osteoporotic product from seaweeds.
Indian patent Application No 202011009121
Plant Metabolites as New Leads to Herbal
Drug Discovery: Approaches
and Challenges

Kapish Kapoor, Priyal Jain, and Joohee Pradhan

1 Introduction

Traditional medicines and natural goods are quite important. For many years, natu-
ral compounds and derivatives have been recognised as a source of medicinal agents
and structural variety. Natural products have a wide range of multidimensional
chemical structures, and their efficacy as biological function modifiers has also
received a lot of attention.
Finding robust and viable lead candidates, which is nothing more than the pro-
cess flow from a screening of natural product to a novel isolate, is proving to be a
difficult scientific work that demands skill and experience. However, in addition to
their chemical structure diversity and biodiversity, modern technologies have trans-
formed natural product screening in the search for novel medications. The use of
these technologies presents a once-in-a-lifetime opportunity to reinstate natural
products as a significant source of drug discovery.

Kapish Kapoor, Priyal Jain, and Joohee Pradhan died before publication of this work was
completed.

K. Kapoor (*) · J. Pradhan (*)

Department of Pharmaceutical Sciences, MLSU, Udaipur, Rajasthan, India
e-mail: [email protected]
P. Jain
School of Pharmacy, Devi Ahilya Vishwavidyalaya, Indore, Madhya Pradesh, India

© The Author(s), under exclusive license to Springer Nature 767

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_31
768 K. Kapoor et al.

1.1 Drugs from Natural Sources

We have recently made progress in identifying a number of plant metabolites with

medicinal potential. The first research began with an unrelated biological process.
However, ethno pharmacology’s significance cannot be overlooked or indigenous
knowledge, as the majority of findings have been tied to. The lead supplied was the
catalyst for the discovery of therapeutic plant metabolites by the information we
inherited from our forefathers; for instance, the Indian snakeroot, Rauvolfia seper-
tine, was referenced in Ayurveda Shastra is thought to have antihypertensive proper-
ties. Researchers examine the metabolites once they have been screened. In that
particular plant, researchers discovered a compound called Reserpine. Similarly,
there are a number of plant metabolites that have been linked to cancer. Primary
source of plant material and medicinal uses are shown in Table 1.

2 Approaches of Development of Drug from Plant Species

The primary stage of chemical isolation entails identifying the specific plant species
that provide medical benefits. The essential components in that plant species that
are linked to druggability are screened out and separated in the secondary stage.
Chemistry, biology, biochemistry, pharmacology, and history are just a few of the
subjects covered. Andrographolide from Andrographispaniculata, Picroside from
Picrorrhizakurroa, Morphine from Papaversomniferum, and Berberine from
Berberisaristata are examples of successful ethnomedicinal approaches.
Several chemicals, such as L-Dopa and paclitaxel, have been effectively extracted
from plants, such as Mucunaprurita and Taxusbrevifolia, regardless of their ethno-
medical utility.
Strategies for drug development from natural source:

2.1 Identification of Candidate Plant Species

2.1.1 The Traditional Medical System’s Approach

The conventional approach makes advantage of the vast array of botanical sources
available as remedies. Being a common medical strategy, it differs from the ethno-
medicinal system in the following ways:
(a) It is generally acknowledged and used, as opposed to the ethnomedicinal sys-
tem, which is used by a small number of families within a community.
(b) Unlike ethnomedicinal approach, the pharmacological procedure is fully
defined and standardised.
(c) While ethnomedicine is a simply cumulative examination of therapy, the tradi-
tional approach includes an analytical relationship between experimental con-
clusions and human physiological character and pharmacological principles [13].
Plant Metabolites as New Leads to Herbal Drug Discovery: Approaches and Challenges 769

Table 1 Herbal drugs with active constituent, source, and synthetic analogues
Metabolite Botanical
S. No. Disease class Molecule source Synthetic analogues
1 Anti-cancer Alkaloid Catharanthus Catharanthus Navelbine (vinorelbine),
[1–3] roseus Oncovin (vincristine),
Velban (vinblastine)
Alkaloid Taxol Taxus brevifolia Docetaxel
Alkaloid Camptothecin Camptotheca Topotecan and
acuminata Irinotecan
Lignan Podophyllotoxin Podophyllum Teniposide
pelatum,
Podophyllum
emodi
2 Anti-­ Alkaloid Belladona Atropa Glycopyrrolate
cholinergic belladonna,
[4, 5] Datura metel,
Alkaloid Physotigmine Physostigma Phenserine
venenosum
Alkaloid Pilocarpine Pilocarpus N-methyl derivative
jaborandi containing (S)-3-ethyl
4-[(4,-imidazolyl)
methyl]-2 oxazolidinone
3 Anti-­ Alkaloid Reserpine Rauvolfia Reserpine methonitrate
hypertensive serpentine
[6]
4 Anti-malarial Alkaloid Cinchona Cinchona sp. Artemisinin
[4]
5 Anti-gout Alkaloid Colchicine Colchicum Desacetylmethyl
[7] autumnale colchicin
(colcimid) and
Demecolcin
6 Local Alkaloid Cocaine Erythroxylum R-pseudococaine,
Anaesthetic coca Salicylmethylecgonine,
[4, 8] Methylvanillylecgonine
7 Skeletal Alkaloid d-turbocurarine Strychnos –
muscle toxifera,
relaxant Chondodendron
[9]
8 Analgesics Alkaloid Opium Papaver –
[10] somniferum
9 Contraceptives Steroid Diosgenin Dioscorea spp. Diosgenone
[11]
10 Cardiotonic Steroid Digoxin Digitalis –
[4, 12] purpurea
770 K. Kapoor et al.

2.1.2 Ethno-Pharmacology Approach

This method is based on a comprehensive examination of indigenous pharmaceuti-

cals in order to produce better and novel biologically active chemical entities
(NCEs), which include observation, description, and experimental conclusions [14].

2.1.3 Zoo Pharmacology Approach

Plants with various health advantages have been identified as a result of close inves-
tigation of cow grazing patterns and behavioural patterns. Cattles attracted to a spe-
cific plant species were a sign that the plant possessed certain properties that were
good to the health and well-being of its users. In some parts of Southern America,
such cattle grazing habits led to the discovery of plant species belonging to the
Solanaceae family, which are high in vitamin D3 derivatives [13].

2.2 Screening of Compounds with Therapeutic Use

2.2.1 Parallel Approach

When the biological activity of a plant is well recognised, either through traditional
use or indigenous knowledge, this strategy is used. The major goal of this screening
procedure is to extract the specific component from the plant that is responsible for the
plant‘s biological activity or medical significance. The strategy is laid out in Fig. 1 [13].

Plant Extraction

100% Methanolic 100%Aquoues 50% aquoues

Extract extract methanolic

Biological Fractionation
evaluation

Most Active -Aqueous extract

Compound -Butanol extract
-Chloroform extract
-Hexane extract
Structural
characterisation

Druggabilty
Test

Fig. 1 Parallel approach

Plant Metabolites as New Leads to Herbal Drug Discovery: Approaches and Challenges 771

Plant
Extract Hexane Chloroform Ethyl Acetate Butanol Aqueous

BIOLOGICAL ASSAY

MOST ACTIVE FRACTION

COMPOUNDS

STRUCTURAL CHARACTERISATION

DRUGGABILITY TEST

Fig. 2 Step-by-step approach

2.2.2 Step-by-Step Approach

This method is an alternative to the parallel screening method. It’s frequently used
in ad hoc tactics or when the plant‘s specific biological activity is unknown. The
method is depicted in Fig. 2 as a flow diagram [13].

3 Techniques for Characterisation of Isolated Extract

3.1 High-Performance Liquid Chromatography

High-performance liquid chromatography (HPLC) is a versatile, robust, and widely

used technique for the isolation of natural products. Currently, this technique is
gaining popularity among various analytical techniques as the main choice for fin-
gerprinting study for the quality control of herbal plants. Natural products are fre-
quently isolated following the evaluation of a relatively crude extract in a biological
assay in order to fully characterise the active entity. Purification of the compound of
interest using HPLC is the process of separating or extracting the target compound
from other (possibly structurally related) compounds or contaminants. Each com-
pound should have a characteristic peak under certain chromatographic conditions.
Identification of compounds by HPLC is a crucial part of any HPLC assay. The
parameters of this assay should be such that a clean peak of the known sample is
observed from the chromatograph [15].
HPLC-guided characterisation of phenylpropanoid and phenolic constituents of
nutmeg kernel (Myristica fragrans) showed that the HPLC-guided procedure to nut-
meg kernel resulted in 12 known compounds which were isolated in various yields
772 K. Kapoor et al.

Table 2 Compounds characterised using HPLC

Sr. No Compound
1 Elemicin
O

O
O

2 Isoelemicin
O

O
O

3 3-(4-Allyl-2,6-Dimethoxyphenoxy)-2,3-Dihydro-5-Methoxy-2-Methylbenzofuran
O

O O
O

4 Myristicin
O

5 Surinamensin
O
O
O

O O
OH

6 Malabaricone
OH O
OCH3

OH
OH
7 5-Methoxylicarin A
OCH3

OH
O

O O

8 Methoxylicarin A
O
O

O
O
O O O

(continued)
Plant Metabolites as New Leads to Herbal Drug Discovery: Approaches and Challenges 773

Table 2 (continued)
Sr. No Compound
9 Licarin A
H

OH
O
O O

10 Malabaricone B
OH O
H

OH
OH

11 Licarine C
OCH3

OCH3
O

O O

12 5-Methoxylicarin B
OCH3

O
O
O
O

13 Licarin B
H

O
O
O
O

and were identified as elemicin, isoelemicin, myristicin, surinamensin, malabari-

cone C, 2-(3′-allyl-2′,6′-dimethoxy-phenyloxy)-1-acetoxy-(3,4-dimethoxyphenyl)-
propylester, methoxylicarin A, licarin A, malabaricone B, licarin C, 5′-methoxylicarin
B, and licarin B. Another isolated compound was identified as 2-(3′-allyl-2′,6′-
dimethoxy-phenyloxy)-1-methyl-5-methoxy-1,2-dihydrobenzofuran is being
reported for the first time in the literature [16] as shown in Table 2.

3.2 Gas Chromatography

Gas chromatography (GC) is used to analyse volatile compounds without their

decomposition. It is coupled with various other spectroscopic techniques such as
mass spectroscopy (GC–MS), HPLC, NMR which has speed up the process of dis-
covery of new molecules than ever before [17]. GC–MS analysis applied for the
identification of bioactive compounds from methanolic and ethyl acetate extracts
from A. nilgiricum leaves and methanol extract from A. nilgiricum rhizomes
774 K. Kapoor et al.

contained 25 bioactive compounds. These phytocompounds were analysed for

activities against bacterial, fungal, viral, antioxidant, and diabetic target protein [18].

3.3 Spectroscopic Techniques

Spectroscopy is the use of absorption, emission, or scattering of electromagnetic

radiation by atoms or molecules (or atomic or molecular ions) to qualitatively or
quantitatively study the atoms or molecules or to study the physical process of a
compound. The theory behind the spectroscopy is the interaction of radiation with
matter. It can cause redirection of the radiation and/or transitions between energy
levels of atoms or molecules. This transition could be absorption, emission, or scat-
tering [17].

3.3.1 Ultraviolet-Visible Spectroscopy

Uv-vis regions range from wavelengths 190 nm to 800 nm, and almost all organic
molecules are transparent under this region. Bioactive compounds can be analysed
through UV VIS spectrophotometer in isolated or in mixture form. Some of the
phytochemicals detected are total phenolic extract (280 nm), flavones (320 nm),
phenolic acids (360 nm), etc. [19].
Organic molecules contain certain functional groups known as chromophore
having valence electrons. These electrons of each functional group absorbs UV-vis
radiation at different wavelengths and thus a certain molecule have a number of
absorption band in absorption spectrum.These aborption bands corresponds to
structural groups within the molecule. 95%ethanol is the most suitable solvent used
because most classes of compounds solubilises in it. other solvents used are water,
ether, petroleum, hexane, and methanol [17].

3.3.2 Infrared Spectroscopy

Infrared spectroscopy used IR radiation are the most useful region that ranges
between 4000 and 670 cm−1. Only those molecules can absorb irradiation whose
vibrational changes within the molecule causes net change in the dipole moment.
Many functional groups can be identified by their characteristic vibration frequen-
cies. It has a role in structural elucidation where new compounds are identified in
plants [17]. The absorptions of each type of bond (NIH, CIH, OIH, CIX, CJO, CIO,
CIC, CJC, CKC, CKN, and so on) are regularly found only in certain small portions
of the vibrational infrared region. A small range of absorption can be defined for
each type of bond. Outside this range, absorptions are normally due to some other
type of bond [20]. Therefore, the structure of a bioactive compound can be deter-
mined by detecting the characteristic frequency absorption band for the functional
Plant Metabolites as New Leads to Herbal Drug Discovery: Approaches and Challenges 775

Table 3 Compounds characterised using FT-IR

OH OH
OH OH

HO O HO O
OH

OH OH
OH O OH O

QUERCETIN MYRICETIN

groups present in the compound in the IR spectrum. Further, Fourier transform

infrared spectroscopy (FTIR) provides a high-resolution analysis of chemical con-
stituents and elucidation of structure of the molecule [21].
The Fourier-transform infrared spectroscopy (FT-IR) Analysis of Vernonia
amygdalina Del. (Bitter leaf) Methanol Leaf Extract, it was found out that the meth-
anol extracts of the plant material contained 8 peaks based on the differences of
polarity. The identification of functional groups of OH, C−H and C=O confirmed
the presence of alcohol, alkanes and ester compounds in this plant specimen [22].
One such example of UV-FT-IR analysis coupled together has been carried out
for ethanolic extract of Terminalia bellirica seed. The UV analysis of ethanolic seed
extract of T. bellirica was recorded in the ranges of 273–292 nm. Various absorption
bands in UV spectra corresponded to chromophoric groups such as aldehydes, ter-
tiary amines, amide groups, ketone, and aromatic compounds; therefore, UV spec-
troscopy shows the presence of three types of flavonoids, viz. flavone, fisetin, and
quercetin. The FT-IR spectrum was recorded in the range 3360.49–628.01 cm−1 and
it revealed the presence of three types of flavonoids, viz. quercetin, NaQSA sodium
salts of Quercetin 5, sulphonic acid, and myricetin are presented in Table 3 [23].

3.3.3 Nuclear Magnetic Resonance

Nuclear magnetic resonance (NMR) is used to study magnetic properties of com-

monly available carbon and hydrogen nuclei. Studying 1H NMR, number of each of
the distinct types of hydrogen nuclei (protons) and nature of environment of each
type can be determined. The study of carbon nuclei through nuclear magnetic reso-
nance (NMR) spectroscopy is an important technique for determining the structures
of organic molecules. Using it together with proton NMR and infrared spectros-
copy, a complete structure of unknown compound is determined without ant labori-
ous process. Fourier transform-NMR (FT-NMR) instrumentation makes it possible
to obtain routine carbon spectra easily. Carbon spectra can be used to determine the
number of non-equivalent carbons and to identify the types of carbon atoms (methyl,
methylene, aromatic, carbonyl, and so on) that may be present in a compound. Thus,
carbon NMR provides direct information about the carbon skeleton of a molecule.
Some of the principles of proton NMR apply to the study of carbon NMR; however,
structural determination is generally easier with carbon-13 NMR spectra than with
proton NMR. The combination of IR and NMR data is often sufficient to determine
completely the structure of an unknown molecule [20].
776 K. Kapoor et al.

Table 4 Compounds characterised using NMR

S.no Compound S.no Compound
1 2-(P-Hydroxyphenyl) Ethyl Stearate 5 Ursolic acid
OH H

O O H

H H

HO

2 Sitosterol H
6 Siderol

H H

H H H H

HO HO

3 Stigmasterol 10 Xanthomicrol

OH

O
H OAc

HO CH2OH

4 Campesterol 11 Penduletin
OH OH

OCH3 H

H3CO H3CO

H3CO H3CO
H OCH3

OH O
OH O

NMR served as a powerful and a rapid tool both to navigate the targeted isolation
process of bioactive constituents and reveal the identity of bioactive components.1D
1
H NMR spectroscopy was applied in the crude extract to monitor the presence of
siderol and identify other secondary metabolites. Henceforth, a total of 11 com-
pounds were revealed from the chemical investigation of dichloromethane extract of
S. euboea aerial parts, including one fatty acid ester, 2-(p-hydroxyphenyl) ethyl
stearate; three phytosterols, namely sitosterol, stigmasterol, and campesterol; one
triterpenoid, ursolic acid; four diterpenoids, i.e. siderol, eubol, eubotriol,
7-­epicandicandiol; and two flavonoids, xanthomicrol and penduletin as depicted in
Table 4. Another example of NMR utilisation reported were the 1H NMR spectra of
Agave syrups and comparative sweeteners were obtained. 1H NMR data coupled to
multivariate methods such as principal component analysis (PCA) allowed the iden-
tification and classification of Agave syrups as well as differentiation with respect to
other sweeteners [24].

3.3.4 Mass Spectroscopy

The pharmaceutical industry uses mass spectrometry in all phases of the drug devel-
opment process, from lead compound discovery and structural analysis, to synthetic
development and combinatorial chemistry, and to pharmacokinetics and drug
Plant Metabolites as New Leads to Herbal Drug Discovery: Approaches and Challenges 777

metabolism [20]. Mass spectroscopy involves the bombardment of organic mole-

cules either with electrons or lasers, thereby converting them to highly energetic
charged species. Using this spectroscopic technique, the relative molecular mass of
fragmented ions can be determined along with the information about places of frag-
mentations that can be subsequently used to predict the molecular formula of the
bioactive compound. Thus, mass spectroscopy provides abundant information
required for structure determination. For example, for structural elucidation of phe-
nolic compounds, mass spectroscopy has been found a highly efficient analytic tool
with electrospray ionisation (ESI), a preferred way of generating charged species
from macromolecules (phenolic compounds) [16]. The use of GC–MS, LC–MS,
and capillary electrophoresis-mass spectroscopy has made the identification of nat-
ural product easier [17].
GC–MS analyses of fraction collected from the column chromatography of ace-
tone extract of Lawsonias inermis shows the presence of total 6 constituents, i.e.
hexacosane, octadecane, docosane, heptacosane methyl, octacosane, and tetraco-
sane [25]. GC–MS determined various bioactive compounds from panax species. It
is found that 646 ginsenosides were identified from stems and leaves of P. ginseng
using linear ion-trap/Orbitrap mass spectrometry. Totally 10 compounds from the
ethanolic leaves extract of Silybum marianum (L) were identified by gas-­
chromatography–mass spectrometry (GC–MS) analysis. From these results, it was
observed that the presence of (+)-2-bornanone, isobornyl thiocyanoacetate,
a-­santoline alcohol, dodecane, dodecane, 2,6,11-trimethyl-, hexadecane, d-­mannose,
undecanoic acid, 9-octadecanoic acid, and oleic acid is presented in Table 5 [26].

Table 5 Compounds characterised using mass spectroscopy

S.No Compound
1 Kaempferol
OH

HO O

OH

OH O

2 Caffeic acid
O

OH
HO

OH

3 Myricetin
OH

OH

HO O
OH

OH

OH O
778 K. Kapoor et al.

4 Case Study of Herbal Molecules Developed

as Anti-cancer Drugs

Secondary metabolites that cause pharmacological or toxicological effects in

humans and animals are known as bioactive substances or plant-derived chemicals.
Plant-derived metabolites are organic molecules that fall under the main category.
Metabolites and secondary metabolites are two types of metabolites. Glucose,
starch, and sugar are examples of primary metabolites. Polysaccharide, protein, lip-
ids, and nucleic acid are all essential for normal body function such as the human
body’s growth and development [27]. Aside from their primary function, these sec-
ondary metabolites are created exclusively by biosynthetic and metabolite path-
ways. They are found within plants and are linked to plant growth and development
and are thought to be the result of metabolic ‘side tracks’ in plant cells, rather than
required for the plant‘s day-to-day operations [28]. Secondary compounds such as
terpenoids, phenolic acids, lignans, tannins, flavonoids, quinones, coumarins, alka-
loids, catechins, and isocatechins have been discovered to play an important role in
the treatment of cancer due to their antioxidant, anti-inflammatory, antitumor, anti-
mutagenic, and anticarcinogenic activities [29, 30]. These metabolites are involved
in a variety of functions in plants, including cellular signalling, photosynthesis, and
biotic and abiotic stress. While flavonoids defend against free radicals produced
during photosynthesis [31], it was found that anthocyanins are the most powerful
antioxidants that prevent cancer caused by chemicals.
Plant-derived compounds have a long history of usage in cancer treatment, lead-
ing to the invention of numerous anticancer medicines [32]. Anticancer drugs
derived from plants have been used since the 1950s [33]. Vinca alkaloids (vinblas-
tine and vincristine) from Catharanthus roseus of the Apocynaceae family were
discovered and developed as the first anticancer drugs [21]. Since then, many plants
have been studied for their anticancer potential, and more than 3000 plant species
have been identified as anticancer plants [30]. The National Cancer Institute has
analysed roughly 114,000 extracts for anticancer potential after collecting 35,000
plant samples from 20 nations [34].
Natural chemicals derived from medicinal plants are thought to be excellent can-
didates for anticancer medication development [35]. Picrorhiza kurroa, Cedrus
deodara, Berberis aristata, Piper longum, Curcuma zedoaria, Cannabis sativa,
Oroxylum indicum, Chelidonium majus, Taxus baccata, Curcuma longa, Typhonium
flagelliforme, Phaleria macrocarpa, Taraxacum mongolicum, Brucea javanica,
Taraxacum mongoli [36, 37]. Plant-based chemicals have a lot of potential for can-
cer treatment and prevention because of their safety, low cost, and oral bioavailabil-
ity [38]. As a result, rigorous scientific screening and clinical trials are critical for
the development of better anticancer medications based on plant-derived chemicals
as presented in Table 6. Despite the fact that a large number of medicinal plants
include biochemical elements with anticancer effects, more research and testing is
needed to create and design anticancer medications [46]. As a result, recent scien-
tific discoveries and advances in clinical trials not only provide potential to produce
plant-based anticancer treatments but also provide numerous opportunity to
Plant Metabolites as New Leads to Herbal Drug Discovery: Approaches and Challenges 779

Table 6 Some phyto compounds having anti-cancer properties

S.No Plant species Compound Pharmacological actions
1 Terminalia chebula Tannins, Antioxidant,
[39] Shikimic acid compounds, Antidiabetic,
Triterpenoids, Renoprotective,
Ellagic acid Hepatoprotective
2 Catharanthus roseus Vinblastine and Anticancerous
[40] Vincristine
3 Zingiber officinale Mono-and sesquiterpenoids, Anticancerous,
[41] Zingerone and Hepatoprotective,
Gingerols Hypercholesterolemic,
Anti-atherosclerotic
4 Camptotheca acuminate Topotecan and Anticancer agents (ovarian
[42] Irinotecan and small cell lung cancer)
5 Curcuma longa Curcumin Anticancer,
[43] Hepatoprotective
6 Podophyllum peltatum Etoposide and Anticancer agents
[44] Teniposide
7 Withania somnifera Steroidal lactones, Chemo preventive,
[45] Withanolides, Anticancerous,
Notably withaferin A Memory enhancer and
Immunomodulatory

comprehend their mechanism of action, as well as their pharmacological and toxi-

cological impacts. Medicinal plants have long been recognised as a source of com-
pounds with therapeutic promise, and they continue to be a valuable resource for
finding new drug leads [47].

5 Challenges and a Plan to Overcome Them

As previously said, global flora has endowed humanity with several medicinal com-
pounds. What has been uncovered thus far is just the tip of the iceberg. Many more
have yet to be discovered; however, as explained in the following sections, several
obstacles stand in the way of more innovative medications being discovered from
plant sources.

5.1 Plant Extracts Are Incompatible with High-Throughput

Screening (HTS)

The incompatibility of crude plant extracts with the high-throughput screening

(HTS) technique is one of the primary problems in the development of new medici-
nal compounds. HTS is chosen since it allows us to use cell-free and cell-based
assay techniques. HTS is known for its great precision, repeatability, robustness,
780 K. Kapoor et al.

and ease of use in liquid systems. The test material must not be degraded, coagu-
lated, precipitated, or inert to undesirable chemical reactions in order to execute
HTS correctly. Plant metabolites or plant extracts, on the other hand, frequently fail
to meet any, if not all, of these characteristics. Plant samples, for example, are
extremely viscous; they tend to coagulate and, if left undisturbed, precipitate out of
the solution. As a result, maintaining homogeneity in the HTS system is difficult.
Another point to consider is that HTS observations and outcomes are frequently
fluorescence dependant. In general, plant samples now contain fluorescent particles
or fluorescence quenching chemicals, which contribute to HTS colorimetric end-
points being misled [48]. Apart from that, plant extracts contain a variety of highly
polarised and highly non-polarised chemicals, such as polyphenols and flavonoids,
which can interfere with the HTS test type reaction. Even chlorophyll falls into this
category [49]. In addition to organic components, inorganic substances such as
heavy metal salts, which plants have a tendency to acquire from the environment,
can induce false-positive or false-negative results in HTS [50].

5.2 Demand Factor

Plant-based raw materials for the creation of new medicinal compounds are in high
demand right now. The global demand for medicinal plants is increasing at a high
rate of almost 15–20% per year, with the Indian market valued at around $1 billion
each year [51].
However, the increased demand for medicinal plants has resulted in the over-­
harvesting of several plant species that contain medicinal plant components.
Taxusbaccata, for example, has been gathered in large quantities from Himalayan
wild forests in order to extract the taxol molecule, which is particularly successful in
the treatment of ovarian cancer. Plants such as Gloriosa superba (flame lily), Aconitum
heterophyllum, Arnebia benthamii, Dactylorhiza hatagirea, Megacarpoea polyandra,
and others have shown similar behaviour. They have been over-harvested and over-
used due to high demand and are now classified as endangered species. Certain
medicinal plants that are powerful against various diseases have been over-­collected
and exploited to the point where they are on the verge of extinction in the wild [52].
Aegle marmelos is a plant that can be used to treat 31 ailments. Hemidescus indicus,
on the other hand, is utilised to treat 34 different disorders. Because of the excessive
use of the target plants, they were quickly cut down, reducing their availability and
supply in the wild. Simultaneously, the genetic diversity of those locations was dis-
rupted, affecting the natural ecosystem and livelihoods of the residents [53].

5.3 Increasing Rarity

The continued overuse of beneficial plant species with strong therapeutic potential
resulted in population declines of those specific target species in their native areas.
This resulted in a significant loss of habitat and livelihood for those who rely on
Plant Metabolites as New Leads to Herbal Drug Discovery: Approaches and Challenges 781

them. The erosion of shared social practises for conserving and preserving natural
resources is the primary cause of danger. Weakening of customary laws due to vari-
ous powerful socio-economic forces, as well as several other threatening factors
such as habitat alteration, climatic changes, invasion of non-natives, overgrazing of
livestock, high-density population, genetic drift, interruption in land usage, patho-
gens, and predators, have limited the high availability and posed a threat to the
abundance of rare medicinal plant species in that geographical area [52].
In some circumstances, different species of the same genera can be used to treat
the same ailment; for example, different Swertia sp., such as Swertia augustifolia,
Swertia cordata, Swertia chirajyta, and others, can be used to cure malarial fever.
As a result, there is no undue stress on a particular Swertia sp. On the other side,
species like Rauvolfia serpentine are under a lot of stress because they do not have
any other load-sharing partners. As a result, the risk of extinction and hazard associ-
ated with increasing rarity is a serious concern for those species that have metabo-
lites that are not typically found in other species, as in the case of R. serpentine [54].

5.4 Threat of Extinction

When a plant is discovered to have medicinal properties, it is at risk of extinction

owing to over-exploitation of that plant species. This was clearly demonstrated in
the occurrence known as the ‘taxol supply crisis’ [55]. Taxol was discovered to have
amazing therapeutic efficacy against ovarian cancer at the time, and this discovery
resulted in a sudden and massive increase in demand for taxol. Taxol, on the other
hand, could only be obtained from the bark of the Western Yew (Taxus brevifolia L.)
at the time. The bark of the Western Yew was intensively gathered in an unsustain-
able manner to meet demand. As a result, the Western Yew population is on the
verge of extinction.
Although, later on, alternative access to taxol was discovered, and the problem of
long-term taxol supply was solved. This helps to save a specific plant species. This
is a regular occurrence for other therapeutic plants, as growing most of them is a
time consuming and unprofitable endeavour due to the short generation time [56].

5.5 Cultivation of Medical Crops

Rather than taking portions of an interesting plant from the forest, it would have
been preferable if those plants could be farmed. This will eliminate the threat of
extinction, as well as the biodiversity and forest preservation issues. However, there
is extremely little information about plant propagation (only 10%), and agrotech-
nology has only been created successfully for 1% of the plants [57]. As a result, it is
reasonable to believe that most medicinal plants cannot be adequately cultivated due
to a lack of knowledge. As a result, agro-technology development must be one of
the most important research fields. This invention would aid in meeting rising mar-
ket demand while maintaining product quality consistency [54].
782 K. Kapoor et al.

Agro-forestry may be another option, as it has been observed that the forest envi-
ronment aids in the growth of many medicinal plants and the production of certain
metabolites with therapeutic properties. The use of agroforestry can benefit us in the
following ways:
(a) In a multi-strata system, shade-tolerant medicinal plants can be used in the
lower strata, giving us the possibility to produce.
(b) As a secondary crop, short-cycle therapeutic plants can be grown.
(c) In agro-forestry, larger trees with medicinal advantages can give shade and
serve as boundary markers.
(d) Medicinal plants and food crops can be interplanted [53].
Although the investment in medicinal plant production is more than that of typical
food crops, the return is also lower. This is the primary reason why most farmers are
uninterested in growing medicinal plants. Several organisations are attempting to
cultivate several therapeutic plants that are uncommon or endangered. They
attempted to produce 20 endangered medicinal plant species from northern India,
but only 10 were successful, with Rheum emobi being the most economically effi-
cient [58, 59].

5.6 Bio-piracy

Overexploitation of medicinally helpful target plants has resulted in restricted

access to them through various legislative provisions that control access to those
beneficial plants, sharing of plant benefits, and various patent issues that are regu-
lated by the local administration of origin. The UN Convention on Biological
Diversity (CBD) was established in 1992 to preserve plant genetic biodiversity. Its
goals are to conserve natural biodiversity, make sustainable use of genetic resources,
and distribute and share the benefits derived from natural resources in a fair and
equitable manner. Since the CBD rules were adopted, governments and their repre-
sentatives have been more interested in researchers using the medicinally essential
source plant in plant-based drug development projects [60]. Many developing coun-
tries, on the other hand, were still convinced that the quest for therapeutic chemicals
from plant extracts would destroy their natural ecology. As a result, numerous gov-
ernments began to impose stringent requirements for getting authorisation to visit
the flora. Simultaneously, the pharmaceutical corporations were discouraged from
investing time and money in this effort because positive results were rare. For exam-
ple, the US National Cancer Institute undertook a two-decade inquiry on 12,000
species to obtain 114,000 plant extracts, from which just two chemicals – taxol and
camptothecin – were acceptable for use as therapeutic molecules. The Nagoya
Protocol was released in to remove such impediments and unfavourable situations.
It was then agreed upon by 50 countries and became effective in September of 2014.
The protocol stated fair and justified use and distribution of genetic resources while
Plant Metabolites as New Leads to Herbal Drug Discovery: Approaches and Challenges 783

adhering to criteria to avoid environmental devastation and biodiversity conserva-

tion [61].
There are further issues with plant-based drug discovery in addition to the ones
described above. One of these natural compounds has a complex structure. There
are further issues with plant-based drug discovery in addition to the ones described
above. One of these natural compounds has a complex structure. They are extremely
difficult, if not impossible, to synthesise because of their intricate architectures. One
of the major disadvantages of dealing with plant metabolites is that the plant‘s out-
put is modest and slow. A tiny sample is required to determine the druggability at
first. However, the plant sample will be required in ampoule quantity for characteri-
sation and other procedures. It can be difficult to collect so much plant sample
because the source of the plant sample and the test laboratory are frequently located
on separate continents.
Different policies surrounding biopiracy, biodiversity conservation, and intellec-
tual property rights (IPR) exacerbate the problem. As a result, many pharmaceutical
behemoths have ceased their screening programmes and work with plant metabo-
lites since the turn of the century. In academia and small start-up businesses, field
work is now fairly restricted [62].

6 Scenario Currently Now

Commentarial experiments yielded synthetic compounds. It is projected that the

rate of successful hits will rise. However, this is not the case in reality. At that time,
it was discovered that the number of approved drugs had reduced the specific period
of time [62]. This is due to the fact that multiple synthetic materials are yielding
positive results. HTS are not biocompatible or have negative effects when used to
treat disease effects. Some intriguing synthetic leads do not have the right proper-
ties. As a result, cyral centres have a lesseadaptability. Another noteworthy point
and justification for this was the fact that every pharmaceutical company created in
the same generation has a strategy that is essentially the same and produces the
same outcome. Because as a result of these factors, attention has recently refocused
on the vegetation.
Another factor for the increased acceptability of natural products derived from
plants or other biological systems as drugs is that natural compounds have under-
gone evolutionary optimisation. When natural products and synthetic chemicals
obtained by combinatorial techniques were compared, it was discovered that the
largest differences are the consequence of alterations made to improve the HTS’
efficiency. Molecules having a higher number of chiral centres, for example, are
difficult to synthesis and assay as optical isomers, and the method is also quite
expensive. Natural products, on the other hand, always have a higher number of
chiral centres, making them more suitable to biological use.
Combinatorial tests are intended to produce molecules with a lower molecular
weight, shorter chains, and fewer reactive groups, making them easier not only to
784 K. Kapoor et al.

regulate and monitor but also rendering them ineffective. Plant metabolites have
gained in relevance as a result of better understanding of these issues [63]. Another
key strategy is now being implemented. Researchers are choosing for semisynthetic
or mimicking natural metabolites rather than entirely natural or synthetic molecules
[64]. Scientists have identified favoured structures in some special compounds with
specialised structures that are relatively common plant metabolites, such as benzo-
diazepines [65], N-acylhydrazone [66], and indoles [67].
These privileged structures are now the subject of inquiry. They are creating new
compounds based on semisynthetic or entirely synthetic architectures. To some
extent, mimicking these specific structures also yields favourable benefits. Newman
[68, 69] explains the various ways for these approaches in detail.

7 Conclusion

There are immense opportunities to investigate the therapeutic and other biological
aspects of previously inaccessible natural items as there is a growing interest in
herbal medication development with minimal adverse effects. It is necessary to con-
centrate on visualisation and identification of underused herbal plants all over the
world in order to determine its utility. The emphasis is therefore placed on the ratio-
nal and scientific extraction, separation, and characterisation of phytochemicals,
which are a gift from nature. The exploitation of natural products for the benefit of
humanity and the development of novel leads for drug discovery are both unmet
needs. After obtaining the phytochemical, it can be used for further research via
QSAR studies, molecular modelling, and animal studies, followed by a clinical
study. The potential of natural products to treat various ailment, as promising drug
candidates remain an important approach towards novel drug discovery to the
researcher and pharmaceutical companies. Natural goods have complicated chemi-
cal structures that vary depending on the species, and when existing high-tech pro-
cedures are used, new pharmaceuticals can be discovered, benefiting the entire
planet. As a result, the globe is always provided with nature, and man is gifted with
brain, so let us use it to discover new entities that will be available to the general
public at a reasonable cost, and we will be glad to live on this planet. Natural prod-
ucts have also been and will continue to be valuable sources of novel pharmacologi-
cal molecules. According to references found in literature, natural plants were used
to make life possible or prolong it many years ago. No life on Earth is feasible in the
twenty-first century without herbal pharmaceuticals or items obtained via natural
herbal drug development.
We examined the ways researchers use to obtain plant metabolites with drug-
gability at the opening of this chapter. These methods are simple to use, but when
we consider the amount of plants that still need to be tested for medicinal purposes,
they can become a daunting process.
As a result, several protocols can be investigated. The main issue we have men-
tioned with plant metabolites is that they are frequently incompatible with modern
Plant Metabolites as New Leads to Herbal Drug Discovery: Approaches and Challenges 785

high-throughput screening techniques, making plant screening for medicinal appli-

cations a time-consuming process. Aside from this issue, there are also issues with
manufacturing time, such as collecting plant parts from the forest and then process-
ing them for a certain metabolite, which is a lengthy procedure.
It makes it extremely difficult to balance output with market demand. Biodiversity,
biopiracy, and the threat of extinction are all challenges that need to be addressed.
We also talked about agro-forestry and agro-cultivation, which are very popular in
India’s Northern Himalayan region. However, knowledge about medicinal plant
production protocols is nearly impossible to come by. As a result, considerable
research in this topic can be beneficial. Because of these factors, as well as some
legal and trade difficulties, many pharmaceutical companies stopped working with
plant metabolites in the early twenty-first century and instead chose synthetic com-
pounds generated by combinatorial assays.. But the outcome of this was unexpect-
edly because the majority of these synthetic compounds failed to display the
requisite bio-adaptability, they were deemed unsatisfactory. As a result, plant
metabolites have reclaimed their prominence. The recent popularity of Ayurvedic
products can be used to justify these claims.

References

1. Lee ON, Ak G, Zengin G, Cziáky Z, Jekő J, Rengasamy KRR et al (2020) Phytochemical com-
position, antioxidant capacity, and enzyme inhibitory activity in callus, Somaclonal variant,
and Normal green shoot tissues of Catharanthus roseus (L) G. Don. Molecules 25(21):4945
2. Rutterschmidt D, Kovács Z, Lorantfy L, Misek Z, Rajsch G (2015) Taxol purification with
centrifugal partition chromatography. Planta Med 81(16):PW_152
3. Wang X, Tanaka M, Krstin S, Peixoto HS, Moura CCM, Wink M (2016) Cytoskeletal inter-
ference – a new mode of action for the anticancer drugs camptothecin and topotecan. Eur J
Pharmacol 789:265–274
4. Balandrin MF, Kinghorn AD, Farnsworth NR (1993) Plant-derived natural products in drug
discovery and development. Human medicinal agents from plants, ACS symposium series,
534. American Chemical Society, pp 2–12
5. Zhan ZJ, Bian HL, Wang JW, Shan WG (2010) Synthesis of physostigmine analogues and
evaluation of their anticholinesterase activities. Bioorg Med Chem Lett 20(5):1532–1534
6. Landazuri P, Loango N, Restrepo B (2017) Medicinal plants used in the management hyper-
tension. J Anal Pharm Res 5
7. Kumar A, Singh B, Sharma PR, Bharate SB, Saxena AK, Mondhe DM (2016) A novel micro-
tubule depolymerizing colchicine analogue triggers apoptosis and autophagy in HCT-116
colon cancer cells. Cell Biochem Funct 34(2):69–81
8. Mcleod IK (2017) Local anesthetics. Medscape. Mechanism of action: hormones with intra-
cellular receptors
9. Waldman HJ (1994) Centrally acting skeletal muscle relaxants and associated drugs. J Pain
Symptom Manag 9(7):434–441
10. Fields A, Wiegand TJ (2014) Opium and the constituent opiates. In: Wexler P (ed) Encyclopedia
of toxicology, 3rd edn. Academic Press, Oxford, pp 698–701
11. Raymon LP (2013) Pharmacology and mechanism of action of drugs. In: Siegel JA, Saukko
PJ, Houck MM (eds) Encyclopedia of forensic sciences, 2nd edn. Academic Press, Waltham,
pp 210–217
786 K. Kapoor et al.

12. Woods KL (1986) The mode of action of cardiac glycosides. J Clin Hosp Pharm 11(1):11–13
13. Katiyar C, Gupta A, Kanjilal S, Katiyar S (2012) Drug discovery from plant sources: an inte-
grated approach. Ayu 33(1):10–19
14. Ganesan A (2008) The impact of natural products upon modern drug discovery. Curr Opin
Chem Biol 12(3):306–317
15. Sasidharan S, Chen Y, Dharmaraj S, Karupiah S, Lachimanan Y (2011) Extraction, isolation
and characterization of bioactive compounds from plants? Extracts. Afr J Tradit Complement
Altern Med 8:1–10
16. Chiu S, Wang T, Belski M, Abourashed EA (2016) HPLC-guided isolation, purification and
characterization of Phenylpropanoid and phenolic constituents of nutmeg kernel (Myristica
fragrans). Nat Prod Commun 11(4):1934578X1601100416
17. Shah B, Seth A (2012) Textbook of pharmacognosy and phytochemistry – E-book. Elsevier
Health Sciences
18. Konappa N, Udayashankar AC, Krishnamurthy S, Pradeep CK, Chowdappa S, Jogaiah S
(2020) GC–MS analysis of phytoconstituents from Amomum nilgiricum and molecular dock-
ing interactions of bioactive serverogenin acetate with target proteins. Sci Rep 10(1):16438
19. Sharma M, Kaushik P (2021) Vegetable phytochemicals: an update on extraction and analysis
techniques. Biocatal Agric Biotechnol 36:102149
20. Pavia D, Lampman G, Kriz G, Vyvyan J (2015) Introduction to spectroscopy. In: Pavia DL,
Lampman GM, Kriz GS, Vyvyan JR (eds) A small scale approach to organic laboratory tech-
niques. Cengage Learning
21. Rakhee MJ, Sharma RK, Misra K (2018) Chapter 9 – Characterization techniques for
herbal products. In: Misra K, Sharma P, Bhardwaj A (eds) Management of High Altitude
Pathophysiology. Academic Press, pp 171–202
22. Bashir RA (2020) Phytochemical screening and Fourier transformed infrared spectroscopy(FT-
­IR) analysis of Vernonia amygdalina del. Methanol Leaf Extract
23. Hazra K (2019) Phytochemical investigation of terminalia bellirica fruit inside. J Pharm Clin
Res 12(8):191–194
24. Velázquez Ríos IO, González-García G, Mellado-Mojica E, Veloz García RA, Dzul Cauich
JG, López MG et al (2019) Phytochemical profiles and classification of agave syrups using (1)
H-NMR and chemometrics. Food Sci Nutr 7(1):3–13
25. Barupal T, Meena M, Sharma K (2019) Inhibitory effects of leaf extract of Lawsonia inermis
on Curvularia lunata and characterization of novel inhibitory compounds by GC–MS analysis.
Biotechnol Rep 23:e00335
26. Padma MGS, Jayaseelan T, Azhagumadhavan S, Sasikala P, Senthilkumar S, Mani P (2019)
Phytochemical screening and GC–MS analysis of bioactive compounds present in ethanolic
leaves extract of Silybum marianum (L). JDDT [Internet] 9(1):85–89
27. Shakya A, Correspondence A (2016) Medicinal plants: future source of new drugs. Int J Herb
Med 4:59–64
28. Bernhoft A (2010) A brief review. In: Bernhoft A (ed) Bioactive compounds in plants—ben-
efits and risks for man and animals. The Norwegian Academy of Science and Letters, Oslo,
pp 11–17
29. Nema R, Khare S, Jain P, Pradhan A, Gupta A, Singh D (2013) Natural products potential and
scope for modern cancer research. Am J Plant Sci 4:1270–1277
30. Kaur R, Kapoor K, Kaur HP (2011) Plants as a source of anticancer agents. J Nat Prod Plant
Resour 1:119–124
31. Kumar S, Mishra A, Pandey AK (2013) Antioxidant mediated protective effect of Parthenium
hysterophorus against oxidative damage using in vitro models. BMC Complement Altern Med
13(1):120
32. Khazir J, Mir BA, Pilcher L, Riley DL (2014) Role of plants in anticancer drug discovery.
Phytochem Lett 7:173–181
33. Prakash O, Kumar A, Kumar P, Ajeet A (2013) Anticancer potential of plants and natural prod-
ucts: a review. Am J Pharmacol Sci 1(6):104–115
Plant Metabolites as New Leads to Herbal Drug Discovery: Approaches and Challenges 787

34. Cragg GM, Boyd MR, Cardellina JH 2nd, Newman DJ, Snader KM, McCloud TG (1994)
Ethnobotany and drug discovery: the experience of the US National Cancer Institute. Ciba
Found Symp 185:178–190; discussion 90-6
35. Rao PV, Nallappan D, Madhavi K, Rahman S, Jun Wei L, Gan SH (2016) Phytochemicals
and biogenic metallic nanoparticles as anticancer agents. Oxidative Med Cell Longev
2016:3685671
36. Greenwell M, Rahman PKSM (2015) Medicinal plants: their use in anticancer treatment. Int J
Pharm Sci Res 6(10):4103–4112
37. Lohani A, Verma A, Joshi H, Yadav N, Karki N (2014) Nanotechnology-based cosmeceuticals.
ISRN. Dermatology 2014:843687
38. Alonso-Castro AJ, Villarreal ML, Salazar-Olivo LA, Gomez-Sanchez M, Dominguez F,
Garcia-Carranca A (2011) Mexican medicinal plants used for cancer treatment: pharmacologi-
cal, phytochemical and ethnobotanical studies. J Ethnopharmacol 133(3):945–972
39. Jena J, Gupta AK (eds) (2012) Ricinus communis linn: a phytopharmacological review
40. Pashaei-Asl F, Pashaei-Asl R, Khodadadi K, Akbarzadeh A, Ebrahimie E, Pashaiasl M (2018)
Enhancement of anticancer activity by silibinin and paclitaxel combination on the ovarian
cancer. Artif Cells Nanomed Biotechnol 46(7):1483–1487
41. Umadevi M, Rajeswari R, Rahale CS, Selvavenkadesh S, Pushpa R, Kumar KPS,
Bhowmik D (2012) Traditional and medicinal uses of Withania Somnifera. Pharm Innov
1(9):102–110
42. Gajalakshmi S, Rajeswari D (2013) Pharmacological activities of Catharanthus roseus: A per-
spective review. Int J Pharm Biosci 4:431–439
43. Sharma V, Sarkar IN (2013) Bioinformatics opportunities for identification and study of
medicinal plants. Brief Bioinform 14(2):238–250
44. Akhtar MS, Swamy MK (2018) Anticancer plants: natural products and biotechnological
implements, vol 2. Springer, Singapore
45. Rathinamoorthy R, Thilagavathi G (2014) Terminalia chebula – review on pharmacological
and biochemical studies. Int J PharmTech Res 6:97–116
46. Raina H, Soni G, Jauhari N, Sharma N, Bharadvaja N (2014) Phytochemical importance of
medicinal plants as potential sources of anticancer agents. Turk J Bot 38:1027–1035
47. Song Y-H, Sun H, Zhang A, Yan G-L, Han Y, Wang X-J (eds) (2014) Plant-derived natural
products as leads to anti-cancer drugs
48. Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, Linder T, Wawrosch C, Uhrin P et al
(2015) Discovery and resupply of pharmacologically active plant-derived natural products: a
review. Biotechnol Adv 33(8):1582–1614
49. Zhou J, Du G, Chen J (2014) Novel fermentation processes for manufacturing plant natural
products. Curr Opin Biotechnol 25:17–23
50. Fernando DR, Marshall AT, Forster PI, Hoebee SE, Siegele R (2013) Multiple metal accumu-
lation within a manganese-specific genus. Am J Bot 100(4):690–700
51. Joshi K, Chavan P, Warude D, Patwardhan B (2004) Molecular markers in herbal drug technol-
ogy. Curr Sci 87(2):159–165
52. Kala CPFN, Dhar U (2005) Traditional uses and conservation of Timur (Zanthoxylum arma-
tum DC.) through social institutions in Uttaranchal Himalaya. India Conservat Soc 3:224–230
53. Rao MR, Palada MC, Becker BN (2004) Medicinal and aromatic plants in agroforestry sys-
tems. Agrofor Syst 61(1):107–122
54. Kala CP, Dhyani PP, Sajwan BS (2006) Developing the medicinal plants sector in northern
India: challenges and opportunities. J Ethnobiol Ethnomed 2(1):32
55. Cordell GA (2011) Sustainable medicines and global health care. Planta Med 77(11):1129–1138
56. Kingston DGI (2011) Modern natural products drug discovery and its relevance to biodiversity
conservation. J Nat Prod 74(3):496–511
57. Narula A, Kumar S, Bansal K., Srivastava P (2004) Biotechnological approaches towards
improvement of medicinal plants. In Plant biotechnology and molecular markers
58. Alam G, Peppelenbos L (2009) Cultivation of medicinal plants in Uttarakhand. Econ Polit
Wkly 99–104
788 K. Kapoor et al.

59. Ghayur MN, Gilani AH (2005) Gastrointestinal stimulatory and uterotonic activities of dietary
radish leaves extract are mediated through multiple pathways. Phytotherapy research: An
international journal devoted to pharmacological and toxicological evaluation of natural prod-
uct derivatives 19(9):750–755
60. Cragg GM, Katz F, Newman DJ, Rosenthal J (2012) The impact of the United Nations con-
vention on biological diversity on natural products research. Nat Prod Rep 29(12):1407–1423
61. Morrison C, Humphries F, Lawson C (2021) A regional review of genetic resource access and
benefit sharing – key issues and research gaps. Environ Policy Law 51:1–24
62. David B, Wolfender J-L, Dias DA (2015) The pharmaceutical industry and natural products:
historical status and new trends. Phytochem Rev 14(2):299–315
63. Koehn FE, Carter GT (2005) The evolving role of natural products in drug discovery. Nat Rev
Drug Discov 4(3):206–220
64. Newman DJ (2008) Natural products as leads to potential drugs: an old process or the new
Hope for drug discovery? J Med Chem 51(9):2589–2599
65. Evans BE, Rittle KE, Bock MG, DiPardo RM, Freidinger RM, Whitter WL et al (1988)
Methods for drug discovery: development of potent, selective, orally effective cholecystokinin
antagonists. J Med Chem 31(12):2235–2246
66. Duarte CD, Barreiro EJ, Fraga CA (2007) Privileged structures: a useful concept for the ratio-
nal design of new lead drug candidates. Mini Rev Med Chem 7(11):1108–1119
67. Mason JS, Morize I, Menard PR, Cheney DL, Hulme C, Labaudiniere RF (1999) New 4-point
pharmacophore method for molecular similarity and diversity applications: overview of the
method and applications, including a novel approach to the design of combinatorial libraries
containing privileged substructures. J Med Chem 42(17):3251–3264
68. Kinghorn AD, Chin Y-W, Swanson SM (2009) Discovery of natural product anticancer agents
from biodiverse organisms. Curr Opin Drug Discov Devel 12(2):189–196
69. Tsang CK, Qi H, Liu LF, Zheng XF (2007) Targeting mammalian target of rapamycin (mTOR)
for health and diseases. Drug Discov Today 12(3-4):112–124
Biochanin A Chemistry, Structural
Modifications, and Therapeutic
Applications: An Update

Mudasir Maqbool, Kitika Shenmar, Ansab Akther, Reyaz Hassan Mir,

Adil Farooq Wali, and Roohi Mohi-ud-din

1 Introduction to Natural Products

Potential drug leads have come primarily from natural sources. There has been a
drop in their use in drug discovery and development in recent years, although while
combinatorial chemistry provides a wide range of structures, natural products offer
a unique opportunity to identify new low-molecular weight lead molecules [1–7].
Since less than 10% of the global biodiversity has been investigated for biological
activity, there are many more useful natural lead compounds to be discovered. The
problem is in obtaining this natural chemical diversity [4]. There is an infinite sup-
ply of creative scaffolds for developing effective medications from natural

Adil Farooq Wali and Roohi Mohi-ud-din contributed equally with all other contributors.

M. Maqbool
Pharmacy Practice Division, Department of Pharmaceutical Sciences, University of Kashmir,
Srinagar, Kashmir, India
K. Shenmar · R. H. Mir
Pharmaceutical Chemistry Division, Chandigarh College of Pharmacy,
Landran, Punjab, India
A. Akther
School of Health Science, University of Petroleum and Energy Studies,
Uttarakhand, Dehradun, India
A. F. Wali (*)
Department of Pharmaceutical Chemistry, RAK College of Pharmaceutical Sciences, RAK
Medical and Health Science University, Ras Al Khaimah, UAE
e-mail: [email protected]
R. Mohi-ud-din (*)
Department of General Medicine, Sher-I-Kashmir Institute of Medical Sciences (SKIMS),
Srinagar, Jammu and Kashmir, India

© The Author(s), under exclusive license to Springer Nature 789

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_32
790 M. Maqbool et al.

ingredients to treat a wide variety of pathological conditions. Although new syn-

thetic chemistry-based techniques in NPs play a vital role in disease treatment and
prevention [8–11]. Numerous novel biomolecular mediators have been identified in
NPs, which have benefited human health by acting as beneficial therapies of option
[12–16]. Around 50% of anti-infective and anticancer medications produced from
natural products, such as silibinin, paclitaxel, and lovastatin, are inspired by nature.
75–80% of the world’s population still gets their medicine from plants, as per
WHO. Anticancer, anti-inflammatory, antimicrobial, and antioxidant properties are
just some of the pharmacological properties of NPs [17–24]. NPs are classified into
the following primary classes based on their structural similarity: polyphenols (tan-
nins, flavonoids, lignans), terpenoids, saponins, and alkaloids. Isoflavones, a class
of flavonoids, are phytoestrogens having a striking chemical resemblance to that of
17- β-estradiol. Isoflavones are mostly found in legumes, peanuts, soybeans, green
beans, and chickpeas. Isoflavone-rich diets have drawn the scientific community’s
attention due to their health benefits, which include osteoporosis, cancer prevention,
as well as cognitive function maintenance [25–28]. There are chemicals in plants
called phytoestrogens that resemble estrogens in molecular structure and size. Of
the several estrogenic drugs available today, plant flavonoid isoflavones are the most
extensively employed. Humans obtain isoflavones mostly from soy and soy prod-
ucts. Consumption of these foods has a variety of impacts on the body [29–31].
Observational studies have discovered that persons who consume a lot of isofla-
vones through a soy-rich diet had a lower chance of acquiring a variety of cancers,
especially prostate, breast, colon, stomach, and bladder cancer. Isoflavones are
regarded as chemopreventive and can be utilized to treat a variety of hormonal
abnormalities [32]. Phytoestrogens are classified into four major classes: isoflavo-
noids, flavonoids, stilbenoids, and lignans. Isoflavonoids are phenolic secondary
plant metabolites that are physiologically active. In addition, Isoflavones are made
up of pharmacologically active aglycones such as genistein and daidzein, as well as
their precursors biochanin A and formononetin, and glycosides such as genistin and
daidzin. Among them, Biochanin A has received considerable interest in recent
years due to its broad therapeutic potential [33, 34].

2 Natural Sources of Biochanin A

Biochanin A (5,7-dihydroxy-4′-methoxy-isoflavone, BCA) (Fig. 1) was initially

derived from the stems and leaves of Trifolium pretense L, a plant of the Leguminosae
family, more commonly referred to as the Fabaceae (Table 1). This plant is often
used to treat postmenopausal women’s difficulties and eczema, asthma coughs, and
eye ailments [35, 45, 46]. Furthermore, biochanin A was discovered from the
Traditional Chinese Medicine plant Astragalus membranaceus. Biochanin A is also
found in peanuts (Arachis hypogaea), Indian rosewood (Dalbergia sissoo), soy
(Glycine max), chickpea (Cicer arietinum), alfalfa sprouts (Medicago sativa), and
golden tree (Cassia fistula) [35, 39, 40, 47–53].
Biochanin A Chemistry, Structural Modifications, and Therapeutic Applications… 791

Fig. 1 Biochanin A HO O
(5,7-dihydroxy-4′- A C
methoxy-isoflavone, BCA)
B
OH O
O
(1)

Table 1 Natural sources of Biochanin A

Plant name Common name Part used References
Trifolium pretense Red clover Above ground parts, flower heads [35, 36]
Cicer arietinum Chickpea Seeds and sprout [35, 37]
Dalbergia paniculata Phansi Stem, bark, and leaves [35, 38]
Casia fistula Amaltas Fruit [35, 39]
Arachis hypogaea Peanut Peanut skin [35, 40, 41]
Astragalus membranaceus Goat’s horn Roots [35, 42]
Medicago sativa Alfalfa Leaves [35, 43, 44]

Biochanin A in the human gut is demethylated by the intestinal bacteria to genis-

tein, another bioactive isoflavone. Even though both the precursor and the product
have almost similar structures, they do not have the same in vivo and in vitro bio-
logical activities. BCA regulates multiple biological roles by acting as a competitive
substrate for some enzymes or by binding DNA and some other specific proteins.
Though in-depth evaluation of the complete bioactivity profile of BCA has still not
been carried out, it has shown estrogenic, anti-inflammatory activity, modulatory
action on glucose and lipid metabolism, and chemoprotective role in cancer and
neurological disorders along with various drug interaction effects. Commercially it
is already being sold as an active ingredient in many health supplements to ease
postmenopausal symptoms in women due to its estrogen-like action. Though its use
for putative health benefits is increasing day-by-day, the clinical trials data for its
role in alleviating postmenopausal symptoms and its action in endocrine-related
degenerative diseases, including endocrine-related cancer, are still trivial and con-
flicting [32, 54, 55].

3 Chemistry of Biochanin A

One of the oldest known natural chemical scaffolds showing many biological activi-
ties is isoflavones. BCA is an O-methylated isoflavone with molecular formula
(C16H12O5) and molecular weight 284.267. Due to the 2,3-double bond in the ring C,
the –OH present at position 7 in ring A and the position-4′ in ring B, the present
isoflavone exhibits multifaceted bioactivity. Various derivitizations in these posi-
tions of significance have underlined their importance in the structure-activity rela-
tionships [35]. Chemically, its structure resembles estrogen, and it is thought to act
792 M. Maqbool et al.

on ERα and ERβ subtypes of estrogen receptors (ERs). It shows both agonistic and
antagonistic action on these receptors with ERβ functioning as a tumor suppressor
by opposing the mitogenic action of ERα [7] Physically, it is a white crystalline
powder with a melting point of 210–213 °C and solubility of 1 mg/mL in ethanol,
30 mg/mL in DMSO and DMF and 0.0583 mg/mL in water. Due to its poor aqueous
solubility, it has limited oral absorptivity. Various attempts have been made to
improve BCA’s bioavailability and solubility by using liposomes, dispersion agents,
silver nanoparticles, and synthetic manipulation [5].

4 Structural Modifications of Biochanin A

In 2018, Gebreyohannes and Sherif synthesized genistein, BCA, and their analogs
(Fig. 2) to show the structure-activity relationship between the various substituents
present on rings A, B, and C and the DPPH (1,1-diphenyl-2-picrylhydrazyl) radical
scavenging activity. It was found that compound (2), which did not have any sub-
stituent on ring B, was the most potent analog exhibiting radical scavenging activity
of 86.95 ± 3.94% inhibition at 100 𝜇g/ml followed by genistein (84.89 ± 2.155). It
was postulated that whenever the –OH in ring B at position 4′ was masked by an
alkyl group, the compound became inactive. BCA backed this, and compound (3)
did not show any activity in the said assay. However, the study also showed that the
hydroxyl groups present at positions 5 and 7 of ring A played a bigger role in modu-
lating antioxidant activity as proven by moderate DDPH radical scavenging activity
of the other analogs (4) (74.77 ± 1.90), (5) (73.81 ± 1.61), (6) (76.36 ± 1.42) and (7)
(65.56 ± 1.15) [56].
Due to the isoflavone nucleus present in BCA, it also displays estrogenic activity.
However, to improve the poor oral bioavailability and aqueous solubility, Alexia
et al. synthesized ester and carbamate derivatives of BCA. All the 5 derivatives
synthesized along with BCA were tested for the estrogenic and antiproliferative

HO O
HO O HO O

OH O
OH O OH O
2 F NO2
3 4
HO O
HO O O O

OH O
CH3 OH O O O
5 Br Br
6 7

Fig. 2 Potent analogs of Biochanin A against radical scavenging activity

Biochanin A Chemistry, Structural Modifications, and Therapeutic Applications… 793

Fig. 3 Most potent H

carbamate analogs of N O O
H 3C H 2C
Biochanin A with 10 O
maximum estrogenic
activity OH O
O
8

O O
O O O
O

N N
N

N N
NH2

9 10 11

Fig. 4 Modified 3-phenylquinolone scaffold obtained from BCA modification

activities by using human breast and endometrial adenocarcinoma cells. The results
showed that compound (8) (Fig. 3) displayed the maximum receptor-binding affin-
ity (RBA) with the relative ERα- and ERβ-binding affinity of 0.06 ± 0.01 and
0.08 ± 0.02. It was found that (8) affects MCF-7 and Ishikawa cells by induction of
gene expression to a level similar to 17β-estradiol and BCA but, contrary to the
action of both of the latter, for suppression of cell proliferation as well. In addition,
(8) appeared to display higher stability than all the other derivatives synthesized and
BCA in both MCF-7 and Ishikawa cells. The authors concluded that compound (8)
offers a safer alternative for hormone replacement therapy as compared to BCA [55].
Nontuberculous mycobacteria (NTM) are omnipresent bacteria that usually
cause infections when acquired through water, soil, animals, or artificial water res-
ervoirs like swimming pools, etc. They are generally grouped under the
Mycobacterium avium complex (MAC) comprising of M. intracellulare and
M. avium and are responsible for NTM infections in various patient populations
such as immunocompromised group, HIV positive, and cystic fibrosis. It was found
that BCA was an efflux pump inhibitor (EPI) of M. smegmatis, a related NTM spe-
cies. To synthesize EPIs active against MAC infections, the structure of BCA was
modified based on the exhaustive computational study on EPIs available in the lit-
erature. It was found that by getting rid of the phenolic –OH in ring A of BCA, by
isosteric replacement of O with NH, and by replacing the 4′- methoxy group in ring
B with propyloxy substituent, excellent MAC EPIs were obtained. The work carried
out by Cochiti et al.in 2017 reported the compound (9 10 and 11) belonging to the
modified 3-phenylquinolone scaffold obtained from BCA modification (Fig. 4)
were able to reverse the resistance of the M. avium strains to all the antimycobacte-
rial drugs and EtBr, further increasing their antimicrobial efficacies to record highs.
794 M. Maqbool et al.

Compound (10) showed up to 40 to 96-fold reduction in the MIC value showing

better efficacy than the references included in the study too [57].
In a recently published work of Pan et al., it was shown that BCA behaves as a
potent sensitizer of temozolomide in glioblastoma. Resistance to the said drug is the
biggest cause of treatment failure in patients of this aggressive form of cancer. The
mechanism of action was tested both in vitro as well as in vivo and was proved to be
a result of BCA’s interaction with AMPK residues leading to autophagy inhibition.
The point of intervention was in the AMPK/ULK1 pathway, as revealed by the dock-
ing studies [58].
Liu et al. carried out a study in 2015 where they took the basic skeleton from the
chickpeas isoflavonoids and modified and recombined them to obtain new deriva-
tives, which showed considerable hypoglycemic effects. The three naturally occur-
ring isoflavonoids selected were genistein, BCA, and formononetin (12). The
modified derivatives (13, 14, 15, and 16) showed (Fig. 5) enhanced hypoglycemic
activity compared to parent compounds. Moreover, the combination of 13, 14, and
genistein and 13, 15, and genistein gave a better antidiabetic effect than all the other
combinations of derivatives, and parent compounds tested [12].

5 Pharmacological Activities of Biochanin A

5.1 Antihyperglycemic Effect

Pharmacological therapies for diabetes management have been linked to side effects
such as liver damage, lactic acidosis, diarrhea, and diminished responsiveness with
continuous use. Currently, the quest to discover natural substances capable of treat-
ing diabetes and other disorders has lasted decades, with biochanin A being men-
tioned as a possible candidate. In streptozotocin-induced diabetic rats, its
antihyperglycemic activity was examined. The scientists reported that after taking
biochanin A orally, normal plasma glucose, glycosylated hemoglobin, and insulin
levels were restored due to improved glycolytic enzyme activity [34, 49]. The
PPAR-α and PPAR-agonistic activities of natural compounds, such as BioA, further
supported their antidiabetic potential [34, 59].

5.2 Osteogenic Effect

Osteoporosis has been associated with an increase in adipogenesis in the bone mar-
row (osteoporosis due to age or menopause). There is evidence that isoflavones can
aid in the reduction of bone loss associated with aging or menopause [34, 60, 61].
Su et al. investigated the effects of biochanin A on osteoblast and adipocyte forma-
tion in a study using adipose-derived stem cells. Biochanin A was proven to reduce
adipocyte differentiation, PPAR-γ, and leptin and osteopontin mRNA expression,
Biochanin A Chemistry, Structural Modifications, and Therapeutic Applications… 795

HO O

Genistein+ BCA+
O
O
Formononetin (12)

HO O
HO O

SO3Na
OH O
OH O O
O

13 14

O COOCH 3
O O
O COOCH 3
H3COOC O
O
H3COOC OH
15
O

O
HO
O

O O O
O
Cr O

O O OH
HO

16
O

Fig. 5 Derivatives of Biochanin A with other isoflavonoids as antidiabetic agents

while osteogenic marker genes and osteocalcin expression were used to promote
alkaline phosphatase activity and mineralization. Additionally, transcription factor
2, osteoprotegerin, and Ras homolog family member A (Rho A) were activated.
This indicates that biochanin A promotes bone development [34, 62]. On the other
hand, biochanin A has been shown to prevent bone loss in ovariectomized rats at
796 M. Maqbool et al.

biologically relevant quantities of ≤1 μM in vivo. Biochanin A and matrix metal-

loproteinases (MMPs) are intimately related to the pathophysiology of osteoarthri-
tis, which motivated researchers to study biochanin A‘s protective effects on MMPs
in osteoarthritis [34, 59].

5.3 Gastroprotective Effect

Gastric ulceration is connected with oxidative stress and the formation of free radi-
cals. Preclinical studies indicate that flavonoids may protect against ethanol-induced
stomach ulcers by lowering excessive reactive oxygen species generation [34, 63].
Biochanin A has been shown to protect the stomach mucosa from damage caused by
ethanol in rats. In this study, enhanced nitric oxide and superoxide dismutase activ-
ity, decreased malondialdehyde levels, and, therefore, alleviated oxidative stress
[34, 64]. The gastroprotective activity of its derivative, genistein, was also revealed
in a study where it decreased indomethacin-induced gastropathy in rats by reducing
oxidative stress, decreasing inflammatory response, and repairing mucoprotective
functionality [34, 65].

5.4 Neuroprotective Activity

Many neurological disorders, viz. Alzheimer’s disorder and Parkinson’s disorder

are driven on by excessive oxidative stress. The activation of microglia, which
results in neuroinflammation, is another sign of neurodegeneration. Injection of
lipopolysaccharide in the substantia nigra is used as a Parkinson’s disease model
because it activates glial cells and causes dopaminergic neurons to degenerate [34,
66]. Studies have shown that biochanin A can protect neurons from
lipopolysaccharide-­induced neuronal injury by inhibiting the activity of microglia
and preventing dopaminergic neuronal injury in vivo and in vitro, respectively.
Additional benefits include reductions in interleukin 6, interleukin 1β, and TNF-α
and decreased generation of reactive oxygen species. These neurochemical changes
established biochanin A‘s protective impact in Parkinson’s syndrome [34, 67].
It has been found that rotenone, a commonly used pesticide, can cause selective
damage to dopaminergic neurons, resulting in clinical signs of Parkinson’s syn-
drome [34, 68]. Surprisingly, excessive neonatal iron supplementation can also
result in dopaminergic neuron degeneration, despite the fact that iron is required for
neural development in trace levels [34, 69]. The combined effects of iron and rote-
none on neurochemical and behavior changes in the rat brain were looked at, and it
was found that iron and rotenone co-treatment led to behavioral changes as well as
striatal dopamine depletion in rats. Biochanin A, which is found in plants, was
found to help improve the behavioral problems and dopamine depletion caused by
the co-treatment of iron and rotenone [34, 70].
Biochanin A Chemistry, Structural Modifications, and Therapeutic Applications… 797

Aluminum, another neurotoxic toxin that stimulates glial cells, also produces
neuroinflammation through NF-κB signaling, leading to the production of prosta-
glandins, tumor necrosis factor-α, and nitric oxide. Aluminum buildup results in an
amyloid beta deposition in the brain, leading to neurodegeneration [34, 71, 72].
Recently, a biochanin-rich chickpea extract was established. This biochanin A rich
extract showed a protective role in aluminum-induced molecular neurodegeneration
by inhibiting NF-κB signaling [34, 73]. Biochanin A has previously been demon-
strated to suppress the NF-κB activation pathway by suppressing the degradation of
IκB in various experimental models [34, 74]. In scopolamine-treated aged mice,
MDA levels increased and decreased dramatically, respectively, due to the antioxi-
dant properties of the drug [34, 75].
Increased glutamate levels in cerebral ischemia cause neurotoxicity and cell
death. It has been proven that drugs intended to mitigate neurotoxicity following an
ischemic stroke should target the glutamate oxaloacetate transaminase enzyme,
which is implicated in glutamate metabolism. In this context, biochanin A has been
shown to be a potent stimulator of glutamate oxaloacetate transaminase production
and activity in brain cells. It markedly boosted mRNA and protein expression of
glutamate oxaloacetate transaminase and safeguarded cells against glutamate-­
induced mortality [34, 76]. However, when the p75 neurotrophin death receptor
(p75NTR) is overexpressed, it has been linked to the death of neurons exacerbated
by peripheral neuropathy or spinal cord injury. Biochanin A, which blocks p38-­
MAPK, was very good at reducing ibuprofen-induced p75NTR expression and
increasing cell survival in vitro [34, 77].

5.5 Anticancer Activity of Biochanin A

The consumption of an isoflavone-rich diet and cancer prevalence have been

reported to be inversely related. A phytoestrogen and flavonoid Biochanin A have
widely been demonstrated to downregulate Akt/MAPK pathway. The Akt/MAPK
pathway can potentiate cellular proliferation and excessive growth, thereby impart-
ing the chances of different categories of cancers. Hence, in relevance to the involve-
ment of the Akt/MAPK pathway in several cellular changes such as cell
differentiation, proliferation, cellular growth and survival, biochanin A can poten-
tially possess antimitogenic and antitumorigenic activity by inducing apoptosis and
inhibiting cellular signaling invasion. Osteosarcoma, pancreatic cancer, hepatocel-
lular carcinoma, malignant melanoma [78], and more importantly, prostate and
breast cancer have been depicted to be attenuated by Biochanin A. It can attack
cyclin-dependent kinase (CDK) and reverse the cyclin accumulation by arresting
the cell cycle or preventing the intensity of metastasis [79]. The aromatase enzyme
responsible for estrogen synthesis can also be attenuated by biochanin A, thus mini-
mizing the chances of breast cancer severity [80]. Additionally, head and neck can-
cer benefit from biochanin A via regulation of the NF-κB pathway [81]. It can give
rise to putative advantages in dietary cancer prophylaxis as well. Besides, biochanin
798 M. Maqbool et al.

A has been proved to produce synergistic or potentiating effects against several

types of carcinomas when combined with other natural compounds. One of the
combination examples of biochanin A includes sorafenib, which downregulates
cyclin gene expression and arrests the G0/G1 phase of the cell cycle [82]. Therefore,
keeping in mind the various characteristics of biochanin A, it is a potential agent in
cancer research and chemotherapy.

5.6 Anti-inflammatory Activity of Biochanin A

Several reports have revealed that biochanin A can negatively target the NF-κB
pathway with further inhibition of proinflammatory cytokines release, as NF-κB is
actively engaged in cytokine production. The mechanism involved could be phos-
phorylation activation of Iκβα, which is the inhibitor of NF-κB. In addition, other
inflammatory pathways such as iNOS, P38 MAPK, and AFT-2 can also be regulated
by biochanin A through phosphorylation inhibition [83], thus, creating an anti-­
inflammatory and antiproliferative scenario as well [79]. Indirectly, the JAK-STAT
pathway of NF-κB can also be targeted by biochanin A, initiating an anti-­
inflammatory cascade [84]. Furthermore, biochanin A mediates the stoppage of
cytokine bombardment and other proinflammatory molecules such as TNF-α, IL-1β,
iNOS, and COX-2 through targeting microglial activation, thus declining cytokine
storm as microglia are often considered to be accountable for the cytokine-mediated
inflammatory cascade [67, 85]. In a previous study to treat an inflammatory condi-
tion, the total inflammatory cells such as neutrophils, eosinophils, and cytokines
were found to be suppressed by biochanin A [86]. This could further be the rationale
behind biochanin A-induced controlled inflammation. Therefore, inflammatory dis-
eases such as rheumatoid arthritis, gout, and asthma can be benefitted from bio-
chanin A. Furthermore, numerous neurodegenerative diseases like Alzheimer’s
disease, Parkinson’s diseases, Huntington’s chorea, amyotrophic lateral sclerosis,
and cerebral ischemia have extensively been characterized by neuroinflammation in
different brain regions, hence considering potent anti-inflammatory action of bio-
chanin A, it can be the possible moiety for the therapeutic interventions in theses
brain diseases.

5.7 Antimicrobial Activity of Biochanin A

Traditionally, natural products, including flavones, have been utilized to cure micro-
bial infections. First time in the year 1996, biochanin A was found to have antiviral
potential against herpesvirus 6 where it acted by downregulating the tyrosine kinase
phosphorylation [87]. Likewise, owing to the action of biochanin A on the NF-κB
transcription factor and regulation of Akt and ERK1/2 signaling molecules, it can
possess antimicrobial activity. In this context, biochanin A has been shown to
Biochanin A Chemistry, Structural Modifications, and Therapeutic Applications… 799

minimize the influenza H5N1-associated production of cytokines and viral nucleo-

protein, thereby creating their milder chances of multiplication [88]. Being a flavo-
noid, the biochanin A scavenges reactive oxygen species (ROS) produced by
microorganisms depicting its antioxidant potential [89]. In addition, biochanin A
also possesses antibacterial and anti-Leishmanial characteristics [90]. Due to the
activation of the MAPK/mTOR pathway by biochanin A, autophagy can be
enhanced. This phenomenon can result in the reduced existence of different patho-
gens [91]. These all processes can be the triggering points for eradication or dimin-
ished amount of pathogens like Salmonella, Chlamydia, Clostridia, etc. Despite
that, biochanin A has only a narrow spectrum of activity against viruses. Hence,
considering the future perspective, biochanin A gets one of the promising positions
in the treatment and halting of infectious diseases including COVID-19 because
SARS-CoV is a highly contagious virus and additionally inflammation is its one of
the core features [92].

5.8 Hepatoprotective Activity of Biochanin A

Since liver dysfunction and hepatoxicity can arise due to several factors, including
ROS and inflammation. Hence, the antioxidant and anti-inflammatory properties of
biochanin A can be the relieving criteria against liver damage [93]. In an animal
model, drug-induced hepatotoxicity was shown to be alleviated with the help of
biochanin A by modulating NF-κB/pAKT pathway. Bax3, caspase-3, and eNOS
activation were also found to be downregulated, keeping the liver cells apoptosis
minimal [94]. Other cascades like activated antioxidant molecule Nrf2/HO-1 and
inhibited inflammatory marker NLRP3 inflammasome has been demonstrated to be
initiated with the biochanin A treatment, thereby reducing the occurrence of acute
liver injury [95, 96]. Many chemically induced liver toxicity such as carbon tetra-
chloride, arsenic, lipopolysaccharide, and can be relieved when biochanin A was
administered as a hepatoprotective therapeutic agent. Here, the mechanisms
involved could be anti-inflammatory, antioxidant, and immunomodulatory actions
[93, 97]. In a nutshell, biochanin A can be either tested and used pre-clinically or
clinically for several liver pathogeneses.

6 Conclusion

Natural bioactive chemicals are currently gaining popularity due to their pharmaco-
logical potential. Biochanin A‘s anticancer and neuroprotective capabilities have
been intensively investigated in recent years. Biochanin A’s therapeutic role and
multimechanistic approach against many diseases have been disclosed in numerous
investigations. Biochanin A‘s anticancer, antioxidant, anti-inflammatory, antimicro-
bial, and neuroprotective activities have been discussed in this article. Despite the
800 M. Maqbool et al.

fact that it has been used in clinical trials for postmenopausal symptoms, more clini-
cal trials are needed to assess its efficacy and safety in other therapeutic uses.
Organic chemists could investigate the structure–activity connection of biochanin A
to create more bioavailable biochanin A derivative. Biochanin A toxicological pro-
filing, such as hepatotoxicity and nephrotoxicity, should also be investigated. It is
possible that biochanin A could serve as a unique and prospective lead isoflavone
for therapeutic development based on preliminary research. In addition, major
research efforts must be made to uncover the hidden potential and unknown mecha-
nisms of this dietary phytoestrogen.

References

1. Jan R, Shah AJ, Wani TU, Farooq S, Jachak SM, Masoodi MH (2021) Curry leaf: An insight
into its pharmacological activities, medicinal profile, and phytochemistry. 4:145–168
2. Mishra BB, Tiwari VK (2011) Natural products: an evolving role in future drug discovery. Eur
J Med Chem 46(10):4769–4807
3. Rey-Ladino J, Ross AG, Cripps AW, McManus DP, Quinn R (2011) Natural products and the
search for novel vaccine adjuvants. Vaccine 29(38):6464–6471
4. Cragg GM, Newman DJ (2005) Biodiversity: a continuing source of novel drug leads. Pure
Appl Chem 77(1):7–24
5. Haefner B (2003) Drugs from the deep: marine natural products as drug candidates. Drug
Discov Today 8(12):536–544
6. Butler MS (2004) The role of natural product chemistry in drug discovery. J Nat Prod
67(12):2141–2153
7. Mir RH, Wani TU, Jan R, Shah AJ, Sabreen S, Mir PA, Rasool S, Masoodi MH, Bhat ZA
(2022) Nigella sativa as a therapeutic candidate for arthritis and related disorders. In: Black
seeds (Nigella Sativa). Elsevier, pp 295–312
8. Veeresham C (2012) Natural products derived from plants as a source of drugs. J Adv Pharm
Technol Res 3(4):200
9. Mohi-Ud-Din R, Mir RH, Wani TU, Shah AJ, Mohi-Ud-Din I, Dar MA, Pottoo FH (2021)
Novel drug delivery system for curcumin: implementation to improve therapeutic efficacy
against neurological disorders. Comb Chem High Throughput Screen 25:607–615
10. Mohi-Ud-Din R, Mir RH, Wani TU, Shah AJ, Banday N, Pottoo FH (2021) Berberine in the
treatment of neurodegenerative diseases and nanotechnology enabled targeted delivery. Comb
Chem High Throughput Screen 25:616–633
11. Mohi-Ud-Din R, Mir RH, Mir PA, Farooq S, Raza SN, Raja WY, Masoodi MH, Singh IP, Bhat
ZA (2021) Ethnomedicinal uses, Phytochemistry and pharmacological aspects of the genus
Berberis Linn: a comprehensive review. Comb Chem High Throughput Screen 24(5):624–644
12. Hong J (2014) Natural product synthesis at the interface of chemistry and biology. Chemistry
(Weinheim an der Bergstrasse, Germany) 20(33):10204
13. Zafar M, Sarfraz I, Rasul A, Jabeen F, Samiullah K, Hussain G, Riaz A, Ali M (2018)
Tubeimoside-1, triterpenoid saponin, as a potential natural cancer killer. Nat Prod Commun
13(5):1934578X1801300530
14. Mohi-Ud-Din R, Mir RH, Shah AJ, Sabreen S, Wani TU, Masoodi MH, Akkol EK, Bhat ZA,
Khan H (2021) Plant-derived natural compounds for the treatment of amyotrophic lateral sclero-
sis: an update. Curr Neuropharmacol. https://doi.org/10.2174/1570159X19666210428120514
15. Shah AJ, Mir RH, Mohi-Ud-Din R, Pottoo FH, Masoodi MH, Bhat ZA (2021) Depression:
an insight into heterocyclic and cyclic hydrocarbon compounds inspired from natural sources.
Curr Neuropharmacol 19(11):2020–2037
Biochanin A Chemistry, Structural Modifications, and Therapeutic Applications… 801

16. Ahmad G, Hassan R, Dhiman N, Ali A (2021) Anti-inflammatory assessment of

3-Acetylmyricadiol in LPS-stimulated raw 264.7 macrophages. Comb Chem High Throughput
Screen 25:204–210
17. Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years
from 1981 to 2010. J Nat Prod 75(3):311–335
18. Banerjee P, Erehman J, Gohlke B-O, Wilhelm T, Preissner R, Dunkel M (2015) Super natural
II—a database of natural products. Nucleic Acids Res 43(D1):D935–D939
19. Rasul A, Millimouno FM, Ali Eltayb W, Ali M, Li J, Li X (2013) Pinocembrin: a novel natural
compound with versatile pharmacological and biological activities. Biomed Res Int 2013
20. Marucci C, Fumagalli G, Calogero F, Silvani A, Christodoulou MS, Martinet N, Passarella D
(2015) Natural products and cancer stem cells. Curr Pharm Des 21(38):5547–5557
21. Koeberle A, Werz O (2014) Multi-target approach for natural products in inflammation. Drug
Discov Today 19(12):1871–1882
22. López-Alarcón C, Denicola A (2013) Evaluating the antioxidant capacity of natural products:
a review on chemical and cellular-based assays. Anal Chim Acta 763:1–10
23. Strömstedt AA, Felth J, Bohlin L (2014) Bioassays in natural product research–strategies
and methods in the search for anti-inflammatory and antimicrobial activity. Phytochem Anal
25(1):13–28
24. Mir RH, Godavari G, Siddiqui NA, Ahmad B, Mothana RA, Ullah R, Almarfadi OM, Jachak
SM, Masoodi MH (2021) Development; therapy, design, synthesis, molecular modelling, and
biological evaluation of Oleanolic acid-Arylidene derivatives as potential anti-inflammatory
agents. Drug Des Devel Ther 15:385
25. Mujeeb F, Bajpai P, Pathak N (2014) Phytochemical evaluation, antimicrobial activity, and
determination of bioactive components from leaves of Aegle marmelos. Biomed Res Int 2014
26. Ko K-P (2014) Isoflavones: chemistry, analysis, functions and effects on health and cancer.
Asian Pac J Cancer Prev 15(17):7001–7010
27. Mir RH, Shah AJ, Mohi-Ud-Din R, Potoo FH, Dar M, Jachak SM, Masoodi MH (2021)
Natural anti-inflammatory compounds as drug candidates in Alzheimer’s disease. Curr Med
Chem 28:4799–4825
28. Mir RH, Sawhney G, Verma R, Ahmad B, Kumar P, Ranjana S, Bhagat A, Madishetti S, Ahmed
Z, Jachak SM (2020) Oreganum Vulgare: in-vitro assessment of cytotoxicity, molecular dock-
ing studies, antioxidant, and evaluation of anti-inflammatory activity in LPS stimulated RAW
264.7 cells. Med Chem 17(9):983–993
29. Heinonen S, Wähälä K, Adlercreutz H (1999) Identification of isoflavone metabolites dihy-
drodaidzein, dihydrogenistein, 6′-OH-O-dma, and cis-4-OH-equol in human urine by gas
chromatography–mass spectroscopy using authentic reference compounds. Anal Biochem
274(2):211–219
30. Vitale DC, Piazza C, Melilli B, Drago F, Salomone S (2013) Isoflavones: estrogenic activity,
biological effect and bioavailability. Eur J Drug Metab Pharmacokinet 38(1):15–25
31. Mir RH, Masoodi MH (2020) Anti-inflammatory plant polyphenolics and cellular action
mechanisms. Curr Bioact Compd 16(6):809–817
32. Yu C, Zhang P, Lou L, Wang Y (2019) Perspectives regarding the role of Biochanin A in
humans. Front Pharmacol 10:793
33. Ososki AL, Kennelly EJ (2003) Phytoestrogens: a review of the present state of research.
Phytother Res 17(8):845–869
34. Raheja S, Girdhar A, Lather V, Pandita D (2018) Biochanin A: a phytoestrogen with therapeu-
tic potential. Trends Food Sci Technol 79:55–66
35. Sarfraz A, Javeed M, Shah MA, Hussain G, Shafiq N, Sarfraz I, Riaz A, Sadiqa A, Zara R,
Zafar S (2020) Biochanin A: a novel bioactive multifunctional compound from nature. Sci
Total Environ 722:137907
36. Booth NL, Overk CR, Yao P, Totura S, Deng Y, Hedayat A, Bolton JL, Pauli GF, Farnsworth
NR (2006) Seasonal variation of red clover (Trifolium pratense L., Fabaceae) isoflavones and
estrogenic activity. J Agric Food Chem 54(4):1277–1282
802 M. Maqbool et al.

37. Lv Q, Yang Y, Zhao Y, Gu D, He D, Yili A, Ma Q, Cheng Z, Gao Y, Aisa HA (2009)

Comparative study on separation and purification of isoflavones from the seeds and sprouts
of chickpea by high-speed countercurrent chromatography. J Liq Chromatogr Relat Technol
32(19):2879–2892
38. Enas A, Sameh A, Ahmed S (2012) Phytochemical and biological studies on Isoflavonoids
from Dalbergia paniculata cultivated in Egypt. Pharmacologia 3:84–90
39. Sartorelli P, Carvalho CS, Reimão JQ, Ferreira MJP, Tempone AG (2009) Antiparasitic activity
of Biochanin A, an isolated isoflavone from fruits of Cassia fistula (Leguminosae). Parasitol
Res 104(2):311–314
40. Chukwumah YC, Walker LT, Verghese M, Ogutu S (2009) Effect of frequency and duration of
ultrasonication on the extraction efficiency of selected isoflavones and trans-resveratrol from
peanuts (Arachis hypogaea). Ultrason Sonochem 16(2):293–299
41. Chukwumah YC, Walker LT, Verghese M, Bokanga M, Ogutu S, Alphonse K (2007)
Comparison of extraction methods for the quantification of selected phytochemicals in peanuts
(Arachis hypogaea). J Agric Food Chem 55(2):285–290
42. Butkutė B, Dagilytė A, Benetis R, Padarauskas A, Cesevičienė J, Olšauskaitė V, Lemežienė
N (2018) Mineral and phytochemical profiles and antioxidant activity of herbal material from
two temperate Astragalus species. Biomed Res Int 2018
43. Deavours BE, Dixon RA (2005) Metabolic engineering of isoflavonoid biosynthesis in alfalfa.
Plant Physiol 138(4):2245–2259
44. Bora KS, Sharma A (2011) Phytochemical and pharmacological potential of Medicago sativa:
a review. Pharm Biol 49(2):211–220
45. Vlaisavljevic S, Kaurinovic B, Popovic M, Djurendic-Brenesel M, Vasiljevic B, Cvetkovic
D, Vasiljevic S (2014) Trifolium pratense L. as a potential natural antioxidant. Molecules
19(1):713–725
46. Kagan IA, Flythe MD (2012) Factors affecting the separation and bioactivity of red clover
(trifoliumpratense) extracts assayed against clostridium sticklandii, a ruminal hyper ammonia-­
producing bacterium. Nat Prod Commun 7(12):1934578X1200701217
47. Chen J, Ge B, Wang Y, Ye Y, Zeng S, Huang Z (2015) Biochanin A promotes proliferation that
involves a feedback loop of microRNA-375 and estrogen receptor alpha in breast cancer cells.
Cell Physiol Biochem 35(2):639–646
48. Chundi V, Challa SR, Garikapati DR, Juvva G, Jampani A, Pinnamaneni SH, Venigalla S (2016)
Biochanin-A attenuates neuropathic pain in diabetic rats. J Ayurveda Integr Med 7(4):231–237
49. Harini R, Ezhumalai M, Pugalendi KV (2012) Antihyperglycemic effect of Biochanin A, a soy
isoflavone, on streptozotocin-diabetic rats. Eur J Pharmacol 676(1–3):89–94
50. Zhang L, Li Q, Yang X, Xia Z (2012) Effects of sodium selenite and germination on the sprout-
ing of chickpeas (Cicer arietinum L.) and its content of selenium, formononetin and Biochanin
A in the sprouts. Biol Trace Elem Res 146(3):376–380
51. Khedgikar V, Gautam J, Kushwaha P, Kumar A, Nagar GK, Dixit P, Chillara R, Voruganti S,
Singh SP, Uddin W (2012) A standardized phytopreparation from an Indian medicinal plant
(Dalbergia sissoo) has antiresorptive and bone-forming effects on a postmenopausal osteopo-
rosis model of rat. Menopause 19(12):1336–1346
52. Ming X, Ding M, Zhai B, Xiao L, Piao T, Liu M (2015) Biochanin A inhibits lipopolysaccharide-­
induced inflammation in human umbilical vein endothelial cells. Life Sci 136:36–41
53. Lindner H (1976) Occurrence of anabolic agents in plants and their importance. Environ Qual
Saf Suppl 5:151–158
54. Moon YJ, Shin BS, An G, Morris ME (2008) Biochanin A inhibits breast cancer tumor growth
in a murine xenograft model. Pharm Res 25(9):2158–2163
55. Fokialakis N, Alexi X, Aligiannis N, Siriani D, Meligova AK, Pratsinis H, Mitakou S, Alexis
MN (2012) Ester and carbamate ester derivatives of Biochanin A: synthesis and in vitro evalu-
ation of estrogenic and antiproliferative activities. Bioorg Med Chem 20(9):2962–2970
56. Hamza Sherif S, Gebreyohannes BJ (2018) Synthesis, characterization, and antioxidant activi-
ties of genistein, Biochanin A, and their analogues. J Chem 2018
Biochanin A Chemistry, Structural Modifications, and Therapeutic Applications… 803

57. Cannalire R, Machado D, Felicetti T, Costa SS, Massari S, Manfroni G, Barreca ML, Tabarrini
O, Couto I, Viveiros MJ (2017) Natural isoflavone Biochanin A as a template for the design of
new and potent 3-phenylquinolone efflux inhibitors against Mycobacterium avium. Eur J Med
Chem 140:321–330
58. Dong Q, Wang D, Li L, Wang J, Li Q, Duan L, Yin H, Wang X, Liu Y, Yuan G (2022) Biochanin
A sensitizes glioblastoma to Temozolomide by inhibiting autophagy. Mol Neurobiol:1–11
59. Sundaresan A, Radhiga T, Deivasigamani B (2018) Biological activity of Biochanin A: a
review. Asian J Pharm Pharmacol 4(1):1–5
60. Atkinson C, Compston JE, Day NE, Dowsett M, Bingham SA (2004) The effects of phytoes-
trogen isoflavones on bone density in women: a double-blind, randomized, placebo-controlled
trial. Am J Clin Nutr 79(2):326–333
61. Kawakita S, Marotta F, Naito Y, Gumaste U, Jain S, Tsuchiya J, Minelli E (2009) Effect of an
isoflavones-containing red clover preparation and alkaline supplementation on bone metabo-
lism in ovariectomized rats. Clin Interv Aging 4:91
62. Su S-J, Yeh Y-T, Su S-H, Chang K-L, Shyu H-W, Chen K-M, Yeh H (2013) Biochanin A
promotes osteogenic but inhibits adipogenic differentiation: evidence with primary adipose-­
derived stem cells. Evid Based Complement Alternat Med 2013
63. Royer M, Diouf PN, Stevanovic T (2011) Polyphenol contents and radical scavenging capaci-
ties of red maple (Acer rubrum L.) extracts. Food Chem Toxicol 49(9):2180–2188
64. Hajrezaie M, Salehen N, Karimian H, Zahedifard M, Shams K, Batran RA, Majid NA, Khalifa
SA, Ali HM, El-Seedi H (2015) Biochanin A gastroprotective effects in ethanol-induced gas-
tric mucosal ulceration in rats. PLoS One 10(3):e0121529
65. Vivatvakin S, Werawatganon D, Somanawat K, Klaikeaw N, Siriviriyakul P (2017) Genistein-­
attenuated gastric injury on indomethacin-induced gastropathy in rats. Pharmacogn Mag
13(Suppl 2):S306
66. Duty S, Jenner P (2011) Animal models of Parkinson’s disease: a source of novel treatments
and clues to the cause of the disease. Br J Pharmacol 164(4):1357–1391
67. Wang J, Wu W-Y, Huang H, Li W-Z, Chen H-Q, Yin Y-Y (2016) Biochanin A protects against
lipopolysaccharide-induced damage of dopaminergic neurons both in vivo and in vitro via
inhibition of microglial activation. Neurotox Res 30(3):486–498
68. Sanders LH, Greenamyre JT (2013) Oxidative damage to macromolecules in human Parkinson
disease and the rotenone model. Free Radic Biol Med 62:111–120
69. Chen H, Wang X, Wang M, Yang L, Yan Z, Zhang Y, Liu Z (2015) Behavioral and neurochemi-
cal deficits in aging rats with increased neonatal iron intake: silibinin’s neuroprotection by
maintaining redox balance. Front Aging Neurosci 7:206
70. Yu L, Wang X, Chen H, Yan Z, Wang M, Li Y (2017) Neurochemical and behavior deficits
in rats with iron and rotenone co-treatment: role of redox imbalance and neuroprotection by
Biochanin A. Front Neurosci 11:657
71. Bondy SC (2014) Prolonged exposure to low levels of aluminum leads to changes associated
with brain aging and neurodegeneration. Toxicology 315:1–7
72. Salomone S, Caraci F, Leggio GM, Fedotova J, Drago F (2012) New pharmacological strat-
egies for treatment of Alzheimer’s disease: focus on disease modifying drugs. Br J Clin
Pharmacol 73(4):504–517
73. Wahby M, Mohammed D, Newairy A, Abdou H, Zaky A (2017) Aluminum-induced molecular
neurodegeneration: the protective role of genistein and chickpea extract. Food Chem Toxicol
107:57–67
74. Wu D-Q, Zhong H-M, Ding Q-H, Ba L (2014) Protective effects of Biochanin A on articular
cartilage: in vitro and in vivo studies. BMC Complement Altern Med 14(1):1–10
75. Biradar S, Joshi H, Chheda T (2014) Biochanin-A ameliorates behavioural and neurochemical
derangements in cognitive-deficit mice for the betterment of Alzheimer’s disease. Hum Exp
Toxicol 33(4):369–382
804 M. Maqbool et al.

76. Khanna S, Stewart R, Gnyawali S, Harris H, Balch M, Spieldenner J, Sen CK, Rink C (2017)
Phytoestrogen isoflavone intervention to engage the neuroprotective effect of glutamate oxalo-
acetate transaminase against stroke. FASEB J 31(10):4533–4544
77. Kalb R (2005) The protean actions of neurotrophins and their receptors on the life and death
of neurons. Trends Neurosci 28(1):5–11
78. Xiao P, Zheng B, Sun J, Yang J (2017) Biochanin A induces anticancer effects in SK-Mel-28
human malignant melanoma cells via induction of apoptosis, inhibition of cell invasion and
modulation of NF-κB and MAPK signaling pathways. Oncol Lett 14(5):5989–5993
79. Hsu Y-N, Shyu H-W, Hu T-W, Yeh J-P, Lin Y-W, Lee L-Y, Yeh Y-T, Dai H-Y, Perng D-S,
Su S-H (2018) Anti-proliferative activity of Biochanin A in human osteosarcoma cells via
mitochondrial-involved apoptosis. Food Chem Toxicol 112:194–204
80. Wang Y, Gho WM, Chan FL, Chen S, Leung LK (2008) The red clover (Trifolium pratense)
isoflavone Biochanin A inhibits aromatase activity and expression. Br J Nutr 99(2):303–310
81. Cho I-A, You S-J, Kang K-R, Kim S-G, Oh J-S, You J-S, Lee G-J, Seo Y-S, Kim DK, Kim
CS (2017) Biochanin-A induces apoptosis and suppresses migration in FaDu human pharynx
squamous carcinoma cells. Oncol Rep 38(5):2985–2992
82. Youssef MM, Tolba MF, Badawy NN, Liu AW, El-Ahwany E, Khalifa AE, Zada S, Abdel-­
Naim AB (2016) Novel combination of sorafenib and biochanin-A synergistically enhances
the anti-proliferative and pro-apoptotic effects on hepatocellular carcinoma cells. Sci Rep
6(1):1–12
83. Kole L, Giri B, Manna SK, Pal B, Ghosh S (2011) Biochanin-A, an isoflavon, showed anti-­
proliferative and anti-inflammatory activities through the inhibition of iNOS expression, p38-­
MAPK and ATF-2 phosphorylation and blocking NFκB nuclear translocation. Eur J Pharmacol
653(1–3):8–15
84. Basu A, Das AS, Borah PK, Duary RK, Mukhopadhyay R (2020) Biochanin A impedes STAT3
activation by upregulating p38δ MAPK phosphorylation in IL-6-stimulated macrophages.
Inflamm Res 69(11):1143–1156
85. Chen H-Q, Jin Z-Y, Li G-H (2007) Biochanin A protects dopaminergic neurons against
lipopolysaccharide-­induced damage through inhibition of microglia activation and proinflam-
matory factors generation. Neurosci Lett 417(2):112–117
86. Ko W-C, Lin L-H, Shen H-Y, Lai C-Y, Chen C-M, Shih C-H (2011) Biochanin A, a phytoes-
trogenic isoflavone with selective inhibition of phosphodiesterase 4, suppresses ovalbumin-­
induced airway hyperresponsiveness. Evid Based Complement Alternat Med 2011
87. Cirone M, Zompetta C, Tarasi D, Frati L, Faggioni A (1996) Infection of human T lymphoid
cells by human herpesvirus 6 is blocked by two unrelated protein tyrosine kinase inhibitors,
Biochanin A and herbimycin. AIDS Res Hum Retrovir 12(17):1629–1634
88. Sithisarn P, Michaelis M, Schubert-Zsilavecz M, Cinatl J Jr (2013) Differential antiviral and
anti-inflammatory mechanisms of the flavonoids Biochanin A and baicalein in H5N1 influenza
A virus-infected cells. Antivir Res 97(1):41–48
89. Michaelis M, Sithisarn P, Cinatl J Jr (2014) Effects of flavonoid-induced oxidative stress on
anti-H5N1 influenza a virus activity exerted by baicalein and Biochanin A. BMC Res Notes
7(1):1–6
90. Hanski L, Genina N, Uvell H, Malinovskaja K, Gylfe Å, Laaksonen T, Kolakovic R, Mäkilä
E, Salonen J, Hirvonen J (2014) Inhibitory activity of the isoflavone Biochanin A on intracel-
lular bacteria of genus chlamydia and initial development of a buccal formulation. PLoS One
9(12):e115115
91. Zhao X, Tang X, Guo N, An Y, Chen X, Shi C, Wang C, Li Y, Li S, Xu H (2018) Biochanin
A enhances the defense against salmonella enterica infection through ­AMPK/ULK1/mTOR-­
mediated autophagy and extracellular traps and reversing SPI-1-dependent macrophage (MΦ)
M2 polarization. Front Cell Infect Microbiol 8:318
92. Ross R, Conti P (2020) COVID-19 induced by SARS-CoV-2 causes Kawasaki-like disease
in children: role of pro-inflammatory and anti-inflammatory cytokines. J Biol Regul Homeost
Agents 34:767–773
Biochanin A Chemistry, Structural Modifications, and Therapeutic Applications… 805

93. Breikaa RM, Algandaby MM, El-Demerdash E, Abdel-Naim AB (2013) Biochanin A protects
against acute carbon tetrachloride-induced hepatotoxicity in rats. Biosci Biotechnol Biochem
77(5):909–916
94. Chaturvedi S, Malik MY, Azmi L, Shukla I, Naseem Z, Rao C, Agarwal NK (2018)
Formononetin and Biochanin A protects against ritonavir induced hepatotoxicity via modula-
tion of NfκB/pAkt signaling molecules. Life Sci 213:174–182
95. Breikaa RM, Algandaby MM, El-Demerdash E, Abdel-Naim AB (2013) Multimechanistic
antifibrotic effect of Biochanin A in rats: implications of proinflammatory and profibrogenic
mediators. PLoS One 8(7):e69276
96. Liu X, Wang T, Liu X, Cai L, Qi J, Zhang P, Li Y (2016) Biochanin A protects
lipopolysaccharide/D-galactosamine-induced acute liver injury in mice by activating the Nrf2
pathway and inhibiting NLRP3 inflammasome activation. Int Immunopharmacol 38:324–331
97. Jalaludeen AM, Ha WT, Lee R, Kim JH, Do JT, Park C, Heo YT, Lee WY, Song H (2016)
Biochanin A ameliorates arsenic-induced hepato-and hematotoxicity in rats. Molecules
21(1):69
Dietary Natural Polyphenols Against
Bacterial and Fungal Infections:
An Emerging Gravity in Health Care
and Food Industry

Biswajit Patra, Nibedita Das, Mohammad Zaki Shamim,

Tapan Kumar Mohanta, Bishwambhar Mishra, and Yugal Kishore Mohanta

1 Introduction

Polyphenols are naturally available plant composites and also the most significant
antioxidant for human beings. The gastrointestinal tract is the essential organ gave
to consume less calories segments, the eating routine might be viewed as one of the
fundamental variables in the usefulness, respectability and creation of digestive
microbiota [1]. In the gastrointestinal tract, numerous polyphenols remain unab-
sorbed in the digestive organ, where the gastrointestinal microbiota are generally
processed. While expecting essential jobs for progressing host prosperity, this
digestive well-being climate is introduced with the impact of outer impacts,

B. Patra
School of Life Sciences, Sambalpur University, Jyoti Vihar, Burla, Sambalpur, Odisha, India
N. Das
Department of Botany, University of Science and Technology Meghalaya, Techno City,
Baridua, Ri-Bhoi, Meghalaya, India
M. Z. Shamim
Department of Food Nutrition and Dietetics, Faculty of Sciences, Assam Down Town
University, Gandhinagar, Panikhaiti, Guwahati, Assam, India
T. K. Mohanta
Natural and Medical Sciences Research Centre, University of Nizwa, Nizwa, Oman
B. Mishra
Department of Biotechnology, Chaitanya Bharathi Institute of Technology (CBIT), Gandipet,
Hyderabad, Telangana, India
Y. K. Mohanta (*)
Nanobiotechnology and Translational Knowledge Laboratory, Department of Applied
Biology, University of Science and Technology Meghalaya, Techno City, Baridua, Ri-Bhoi,
Meghalaya, India
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 807

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_33
808 B. Patra et al.

including dietary patterns [2]. A couple procedures have been created to build dis-
solvability and transport across the gastrointestinal parcel and move it to designated
digestive districts to determine dietary polyphenols at the low bioavailability.
Dietary polyphenols are normal plant-based mixtures, including food sources, for
example, vegetables, grains, organic products, espresso, tea, wine, etc. [3].
Hydroxylated phenyl moieties characterize polyphenols as only a huge heteroge-
neous gathering of mixtures. Polyphenols are typically sorted into flavonoids and
non-flavonoids in view of their compound construction and intricacy (counting phe-
nolic rings and replacement gatherings). Human body sees polyphenols as xenobi-
otics, and their bioavailability is respectably poor [4]. Recently, more than 8000
polyphenols have been distinguished and are grouped by their carbon skeleton idea:
flavonoids, phenolic acids, lignans and stilbenes. The organization, just as the pro-
portion of various species that structure the digestive microbiome, is exceptionally
different inside the human populace, and every individual has their own interesting
profile of microbial species, which can measure up to a fingerprint [5]. The separa-
tion of stomach microbiota structure and profile is brought about by the impact of
various and different elements, like age, beginning, geological area, climate, dietary
propensities, probiotics, health and the utilization of anti-infection agents [6].
Commensal microbes produce bacteriocins that explicitly repress individuals from
the equivalent or comparable bacterial species (e.g. E. coli versus microorganism
enterohemorrhagic E. coli). Commensal microbes produce short-chain unsaturated
fats and cause pH decrease, subsequently forestalling the colonization by microor-
ganisms whose ideal pH for development is natural [7]. The extraordinary variety of
bacterial species shaping the stomach microbiota ensnares the huge number of qual-
ities which they contain and the huge metabolic limit of the gastrointestinal micro-
biome, which is roughly 100-crease more prominent than that of the human liver
[8]. Digestive microbes add to the breakdown of polysaccharides and polyphenols
just as partake in the synthesis of nutrients (B12, K).

1.1 Sources of Polyphenols

A few thousand composites having a polyphenol structure have been distinguished

in higher plants, and a few hundred are found in consumable plants. These atoms are
auxiliary metabolites of plants and are for the most part engaged with guard against
bright radiation or hostility by pathogens [9]. These mixtures might be ordered into
various gatherings as an element of the quantity of phenol rings that they contain
and of the underlying components that tight spot these rings to each other. In human
food sources, flavanones are found in tomatoes and certain sweet-smelling plants
like mint; however, they are available in high focuses just in citrus fruit [10]. The
primary aglycones are naringenin in grapefruit, hesperetin in oranges and eriodic-
tyol in lemons. Leafy foods, for example, tea and red wine, establish the principal
wellsprings of polyphenols. Certain polyphenols are originated in some plant items
(natural product, vegetables, oats, leguminous plants, organic product juices, wine,
Dietary Natural Polyphenols Against Bacterial and Fungal Infections: An Emerging… 809

tea, implantations and so forth), while others are explicit to specific food varieties
(flavanones in citrus organic product, isoflavones in soya and phloridzin in apples).
Much of the time, food varieties contain complex combinations of polyphenols,
which are regularly inadequately characterized [11]. Apples contain flavanol mono-
mers and oligomers, chlorogenic corrosive and little amounts of other hydroxycin-
namic acids, 2 glycosides of phloretin, a few quercetin glycosides and anthocyanins
and cyanidin 3-galactoside in the skin of specific varieties [12]. Apples are one of
the uncommon kinds of nourishment for which genuinely exact information on
polyphenol composition are accessible.

1.2 Role in Antimicrobial Activity

Flavours has large history of being utilized as normal food additives with people
medication. This is a direct result of antimicrobial impact which contains saponin,
alkaloids, flavonoids, anthocyanin, phenolic acids and tannins [13]. Rejuvenating
balm from polyphenols is enormous gatherings of organization with most grounded
antimicrobial impact. Many examination distributions detailing in various kinds of
plant arrangements can apply both positive and adverse consequence on organisms.
Taking into account that polyphenols have been demonstrated to build the develop-
ment of Akkermansia muciniphila, the valuable effect of polyphenols on human
well-being might result from other than cancer prevention activity [14]. Every one
of these explorations recommend that polyphenols arriving at the digestive organ
may not exclusively be catabolized to phenolic acids additionally impacts of gastro-
intestinal probiotic microorganisms. Taken together, polyphenols have all the ear-
marks of being ready to adjust stomach microecology and, by influencing the
absolute number of advantageous species in the stomach, may give positive stom-
ach health [15]. The impact of pure polyphenols and plant extract, just as the
strength of that effect on microscopic organisms, contrasts relying upon the sort of
both phenolic mixtures and microbial strain. The antibacterial movement of flavo-
noids might result from their capacity to frame complexes with proteins through
certain forces, for example, hydrogen holding and hydrophobic impact just as by
covalent bond formation [12]. Proteins adjusted by polyphenols restricting have a
certain amino acid obstructed and go through conformity advances, which can
cause changes in protein structure, hydrophobicity, dissolvability and isoelectric
point. In phenolic protein complexation, prompt changes in their physicochemical
and organic properties including the absorbability and use of food proteins as well
as digestive enzyme activities [14]. Quinones are recognized to composite irrevers-
ibly with nucleophilic amino acids in protein compounds, which prompts inactiva-
tion and loss of capacity in the proteins. They potentially associate with cell divider
polypeptides, layer-bound catalysts and surface-uncovered adhesins of pathogenic
bacteria [15]. The catalysts cysteine transpeptidases are utilized by Gram-positive
bacteria to show proteins in the surface of the cell glycoproteins, and they can con-
nect to proteins in the cross-span peptide of the cell divider. The inhibitory effect of
810 B. Patra et al.

polyphenols on the activity of the bacterial efflux siphon, which changes transport
through the cell divider and cytoplasmic layers are additionally considered.
Flavonoids can modulate the action of bacterial proteins, which are significant for
cell life [16]. The union of nucleic corrosive can be hindered by polyphenols like-
wise through topoisomerase restraint. Flavonoids are inhibitors of topoisomerases,
and it assumes a significant part in their antimycobacterial activity [17]. The signifi-
cant capacity of the cell wall is to give cell integrity and shape to act as an osmotic
obstruction. Gram-negative microbes were resistant for numerous antibacterial sub-
stances because of the hydrophilic surface of their external layer and related pro-
teins in the periplasmic space, which are equipped for separating numerous
atoms [18].

1.3 Potential Use in Food Industry

Protein-polysaccharide nanocarriers have been accounted for as being promising

for polyphenols encapsulation [19]. Dynamic parts tie to the protein part of the
nanocarrier by means of hydrogen holding and hydrophobic connections, while
polysaccharides add to the avoidance of enzymatic protein degradation in gastric
conditions. Some polyphenols are eugenol, catechins, quercetin, epigallocatechin-­
gallate, epigallocatechin, curcumin and polyphenols extracted from some edible
oils and teas [17]. Catechin associated with proline-rich proteins and phenolic ring
with prolines in β-casein. The components of exemplification empowering
polyphenol-­ nanocarrier collaborations incorporate ionic gelation, coacervation,
inclusion complexation, co-crystallization, liposome entrapment, freeze-drying,
nanoencapsulation, emulsion and yeast embodiment. These different mechanisms
can build the bioavailability of polyphenols to give strength during processing and
storage [18]. Polyphenol-rich nanoparticles can be utilized in food processing to
improve physicochemical qualities, flavour profile, food nutrient, functional proper-
ties and antimicrobial effect [19]. Polyphenols are an assorted plant metabolite,
utilized for protection may be unique. Other than varieties in synthetic properties,
the measures for establishing suitable strategies likewise required for encapsulation
properties [10]. Curcumin is a polyphenol present at the rhizomes of the Curcuma
longa L. plant. It serves as a specific yellow-orange regular shading for food and
strong effects on food flavour.

2 Sources of Dietary Polyphenols

Dietary polyphenols have become huge consideration among nutritionists, food

researchers and consumers because of their effect in human well-being. Recent
research supports a specificity for polyphenols in the counteraction of degenerative
sicknesses, especially malignant growths, cardiovascular illnesses and
Dietary Natural Polyphenols Against Bacterial and Fungal Infections: An Emerging… 811

neurodegenerative infections. Some data are accessible on the qualities and quanti-
ties of polyphenols that are consumed every day all throughout the world [12]. This
information has been acquired through examination of the principle of hydrolysis of
glycosides and esters in the food varieties. Utilization of these substances has been
assessed at 20–25 mg/d in the Denmark, Holland and United States. In Spain, the
complete utilization of catechins and proanthocyanin dimers has been assessed at
18–31 mg per day, and the primary sources are pears, apples, red wine and grapes.
Utilization of significant constituents might differ profoundly indicated by tea and
coffee consumption. A few people who drink a few cups each day might consume
as much as 500–800 mg hydroxycinnamic acids per day [13]. Regulation of cell
signalling pathways by polyphenols may help essentially to clarify the components
of the activities of polyphenol-rich compounds. Some studies have additionally
shown that different polyphenol subgroups might vary essentially in stability, bio-
availability and physiological capacities connected with human health [14].

2.1 Chemistry and Classification of Polyphenols

Large numbers of phenolic structures are presently known, and among them more
than 4000 flavonoids have been distinguished. Polyphenols also artificially por-
trayed as mixtures with phenolic constituents. This group natural products are
exceptionally varied and contains few sub-groups of phenolic components. Organic
products, vegetables and different sorts of food sources like chocolate, tea and wine
are rich source of polyphenols [15]. The variety and wide dissemination of polyphe-
nols in plants have prompted various approaches to arranging these normally hap-
pening compounds. Polyphenols have been grouped by their natural capacity, source
of origin and chemical construction. Phenolic acids are non-flavonoid polyphenolic
intensifies that can be additionally separated into two principle types, benzoic cor-
rosive and cinnamic corrosive [16]. Flavonoids have the common structure in which
the two C6 units of ring A and ring B are of phenolic characteristics. The fundamen-
tal designs of flavonoids are aglycones. In plants, the majority of these mixtures
exist as glycosides. Organic exercises of these mixtures, including cell reinforce-
ment action, rely upon both the underlying contrast and the glycosylation patterns
[18]. They are generally found in the leguminous group in plants. Since beans, espe-
cially soybean, are a significant eating regimen in many societies. Genistein and
daidzein are the two principle isoflavones found in soy [19]. Flavones and their
3-hydroxy subsidiaries flavonols including their glycosides methoxides of the rings
make the biggest subgroup among all polyphenols. The most well-known flavonol
aglycones, quercetin and kaempferol alone have not less than 279 and 347 unique
glycosidic blends, respectively [20]. Some flavanones have interesting substitution
designs, i.e. furanoflavanones, prenylated flavanones, pyranoflavanones and ben-
zylated flavanones, giving subordinates of this subgroup [21]. A notable flavanonol
is taxifolin from citrus organic products. Proanthocyanidins are generally viewed as
consolidated tannins. Anthocyanidins are the important parts of the red, blue and
812 B. Patra et al.

purple colours of most of bloom petals, vegetables and certain varieties of rice
grains. Anthocyanidins in plants mostly exist in glycosidic structures, which are
available as anthocyanins [22]. Delphinidin Cyanidin and Pelargonidin are the most
broadly found anthocyanidins with multiple monomeric anthocyanidins. Some
polyphenols may have N-containing utilitarian substituents. Two such gatherings of
polyphenolic amides are of importance for normal food source. Capsaicin are
accountable for the hotness of the chili peppers but found as cancer prevention agent
and mitigating properties and also oxidative protection context in cells [23]. The
phenolic acids, phenolic amides and flavonoids are a few non-flavonoid polyphe-
nols found in food varieties that are viewed as vital to human health. Among these,
resveratrol is interesting to the grapes and red wine and its subsidiaries are found in
berry organic products. In strawberries and in the skins of various berries nuts, these
ellagic acid derivatives are also available [24].

2.2 Microbial Sources

Diet assumes a prevailing part in tweaking the digestive microbiota. Large numbers
of these dietary substrates are prebiotics, which are specifically used by colonic
microorganisms giving medical advantages. The stomach microbiota is mostly
addressed by set of bacterial phyla, i.e. Actinobacteria, Firmicutes, Proteobacteria,
Verrucomicrobia and Bacteroidota [25]. High inter-individual variability, Firmicutes
is the biggest phylum in rodents with more than 250 genera. The phylum
Actinobacteria is less reliably distinguished as predominant and addresses a lower
rate of the absolute microscopic organisms. It incorporates the variety Bifidobacterium
from which numerous probiotics are collected [26]. Additionally, the phylum
Verrucomicrobia incorporates the variety Akkermansia spp., which is available in
low extent and is presently viewed as a next edge probiotic [27]. Other applicable
microorganisms considered as next-generation probiotics like A. muciniphila,
B. thetaiotaomicron and F. prausnitzii are interacting with the host immune system
and have been related with valuable impacts on the host [28].

2.3 Biosynthesis and Metabolic Engineering for Production

of Polyphenols

Phenolic acids like gallic and cinnamic acids are viewed as metabolites of the shiki-
mate pathway. Biosynthesis of complex polyphenols, like flavonoids, is connected
to plastid and mitochondrial determined intermediates and each expecting com-
modity to the cytoplasm where they are consolidated into discrete pieces of the
molecule [29]. The aromatic compound is considered to start from the amino acid
phenylalanine and its result of the shikimate pathway considered as three units of
Dietary Natural Polyphenols Against Bacterial and Fungal Infections: An Emerging… 813

malonyl-CoA. Phenylalanine smelling salts lyase is a critical protein of the phenyl-

propanoid pathway, which catalyses the change of phenylalanine to cinnamate
which then prompts the component structures [30]. The last moderate 4-coumaroyl-
CoA and three atoms of malonyl-CoA are then dense to yield the primary flavonoid
structure by the compound chalcone synthase. Chalcone is isomerized by chalcone
flavanone isomerase (CHI) to a flavanone [31]. This flavanone halfway is significant
in light of the fact that it is basically from all classes of flavonoids including their
subgroups. Chalcone isoflavones and coumestrols are significant through various
proteinaceous enzyme with isoflavone synthase.

3 Antimicrobial Activity of Polyphenols

Polyphenols that are not digested in the intestine arrive at the colon. The microflora
hydrolyses glycosides into aglycones and broadly processes the aglycones into dif-
ferent good smelling acids [32]. Aglycones are parted by the launch of the hetero-
cycle at various structure relying upon their compound construction. Flavanols
primarily produce hydroxy phenylacetic acids, flavones and flavanones fundamen-
tally produce hydroxyphenyl propionic acids and flavanols principally produce
phenylvalerolactones and hydroxyphenyl propionic acids [33]. These acids are
additionally processed to subsidiaries of benzoic corrosive. The microbial metabo-
lites are consumed and formed with glycine, glucuronic corrosive or sulphate. The
cleavage and metabolic pathways are grounded in creatures, and the impact of sub-
stance structure on debasement is known [34]. However, some limited research data
are available to recognize the new microbial composition and metabolite produc-
tion. Interindividual varieties and the impact of the microflora structure and of the
typical eating regimen on microbial metabolite creation must be assessed. Late
investigations have shown that plasma fixations and urinary discharge of microbial
metabolites in people can be higher than those of tissue systems related to polyphe-
nols. For example, wine polyphenols that are not effectively absorbed in urinary
excretion of microbial metabolism in human health [35].

3.1 Antibacterial Activity

Continuous foodborne infection flare-ups are one of the fundamental concerns of

the food and agro industries. This is the reason for the utilization of regular parts
that have been expanded, which prompts the enhancement of microbiological safety.
The components incorporated with antimicrobial movement into adequate nanocar-
riers can benefit control and the development of microbes with waste micro-­
organisms [27]. This has been reported that thymol follows up on Gram-positive
and negative bacterial microscopic organisms and emphatically affects the food fla-
vour. Yet it is inadequately dissolvable in water. After polyphenol adsorption,
814 B. Patra et al.

openings on the outer layer of the cell were seen, and even lysis was possible [28].
Other antimicrobial parts in the nano-encapsulated structures could be significantly
more productive against microorganisms. For instance, normal antimicrobials
showed better antimicrobial action when they were as nanosized particles.
β-Glucosidases are created because of glucoside-rich conditions by a few digestive
microbes like Blautia producta, Bifidobacterium spp., B. thetaiotaomicron, E. coli,
L. plantarum and Erysipelato clostridium ramosum [29]. Numerous lactic acid bac-
teria and some microscopic organisms (Streptococcus thermophilus, L. acidophilus,
Lactobacillus delbrueckii ssp. bulgaricus) are additionally ready to create
β-glucosidases [30]. Due to their well-being, these β-glucosidase-creating microor-
ganisms are utilized to build the bio accessibility of phenolic glucosides during
food aging.

3.2 Anti-candidal Activity

There has been a sharp ascent in the event of Candida diseases and related mortality
throughout the most recent couple of years because of the developing collection of
immunomodulated population. Limited accessible antifungal organisms, unwanted
side effects and toxicity represent a significant clinical test for the treatment of can-
didiasis [31]. However, components that got from regular sources displaying signifi-
cant antifungal properties are a promising hotspot for the advancement of novel
enemy of candidal treatment. Phenolic compounds disengaged from normal sources
have antifungal properties of interest [32]. Especially, phenolic acids have shown
promising in vitro and in vivo action against Candida species. Phenolic acid subor-
dinates separated from these sources, i.e. caffeic, gallic, benzoic, cinnamic, phenyl-
acetic acids and protocatechuic additionally have antifungal activity [33]. Therefore,
phenolic acids got from various normal sources have significant factor against
changeable MIC value of Candida species. Moreover, a potential impact on the
C. albicans has been displayed for caffeic acid subordinates which might interfere
1,3-β-glucan synthase. Some investigations have found metabolic pathways of phe-
nolic acids against Candida. In vitro immunoregulatory impact on monocytes
against C. albicans by cinnamic acid have eugenol inhibitory cell cycle at G1, S and
G2-M stages in C. albicans and subsequent instigates apoptosis [34]. Another phe-
nolic compound with association with curcumin additionally instigates apoptosis in
C. albicans, by expanding the responsive oxygen species (ROS) and acceptance of
CaMCA1 gene expression. In antifungal resistance, there are significant limits in
deficient spectrum range, less bioavailability with tolerance index, interaction with
different nanodrug medications, insufficient pharmacokinetic profile and extensive
poisonous effects [35]. Another review has shown that phenolic mixtures like thy-
mol and carvacrol fundamentally decline the articulation levels of harmfulness
qualities CDR1 and MDR1 in fluconazole-resistant C. albicans.
Dietary Natural Polyphenols Against Bacterial and Fungal Infections: An Emerging… 815

4 Polyphenolic Antibacterial for Food Preservation

Preservation is an extremely critical activity in the food industry [36]. Nanotechnology

assumes a significant part in exploration and development in bundling innovation,
shrewd and active dynamic packaging [35]. There is an emerging interest for the
improvement of new harmless to the ecosystem films for food packaging in light of
biomaterials [37]. This is particularly significant on account of cancer prevention
agents that as parts of packaging materials might give delayed time span of usability
to food items. Nano emulsions containing polyphenols have been utilized for mak-
ing organic product-based food preservation, which showed great antimicrobial and
physicomechanical properties as well as had a harmless to the ecosystem on account
of waste use from the food industry [38]. Gelatin and papaya puree with cinnamal-
dehyde nano emulsion palatable composite films could be harmless to the ecosys-
tem as well as eco-friendly antimicrobial packaging material for food applications.

4.1 Food Preservative Potential

Smart packaging and developing demand for natural food sources are driving a
emergent interest in natural antimicrobials and effective opposing impact against a
wide scope of undesirable microorganisms in foods [39]. Controlling microbial
development in food items has forever been a major concern for the various partners
in the agricultural food sector. Some research should be thought for ensuring both
food safety and food waste deduction. Therefore, this peculiarity of antimicrobial
resistance and the presence of antibiotics effect build ups in the environment have
drawn in much consideration from present day consumers [40]. Thus, the antimicro-
bials action that are powerful against both pathogenic and waste microorganisms is
crucial. The presence of alkyl bunches in the fragrant core generates phenoxyl
extremists answered to improve the antibacterial efficacy of phenolics and change
their dissemination proportion between aqueous and non-fluid stages, including
bacterial phases [41]. The capacity to enter the cell film and interact with cell com-
ponents incites irreversible harm to the cell wall and coagulation of the cell content,
influencing both membrane and intracellular catalysts. Polyphenol dependability is
an essential property for application in food systems and is a component of a few
variables, such as chemical structure, size, water dissolvability and polarity [42].
However, nourishment has become a key factor to human health and maximal
knowledge of the impacts of treatment processes in fundamental for maintaining the
function of plant biomolecules not just as food preservatives but also builds of nutri-
tional concentration. The capacity of polyphenols for quite under specific environ-
mental conditions with high temperature and light could genuinely influence their
synthetic and physical stabilities [43]. Different phytochemicals and cancer preven-
tion activities purposefully introduced to food nutritional system might assist with
balancing polyphenols. Vitamin C added to processed yellow fruits natural product
816 B. Patra et al.

applied a defensive effect on plant chemicals [44]. Eatable coatings give an obstruc-
tion to vaporous exchange as well as the transmission of dampness, flavours and
other soluble constituents of processed items when stored for long long.

4.2 Food Packaging Potential

There is a developing interest for the advancement of new environment friendly

films for food storing in light of biomaterials. Nanofilms contrasted with customary
food-packing films ought to have another aspect for the inactive and controlled
arrival of antimicrobial and other dynamic parts. Nano-emulsions containing poly-
phenols have been utilized for making organic product-based eatable products,
which showed potential antimicrobial and physico-mechanical properties.
Additionally, a harmless ecosystem aspect on account of waste use also applied
from the food industry [45].

4.3 Challenges in the Application to Food Industry

With the advantages of nanotechnology, the potential risk in food factory and their
application could be considered for health management. But the fact is there are no
proof on the health risk of polyphenol-stacked nanoparticles, the risk evaluation of
nanomaterials, nano silver, zinc oxide or silicon dioxide utilized for their exemplifi-
cation was reviewed [46]. The critical physicochemical properties of nanoparticles
that are answerable for toxicity including molecule size, surface coating and reac-
tivity, crystallography, total carrying capacities, surface coatings, combination and
readiness changes and sample purity [47]. The physicochemical properties of these
particles can establish a supportive effect on free radicals as well as cell death
inflammation. The biochemical movement of polyphenols is mostly connected with
their capacity to metals and free radical scavenge. However supportive oxidant con-
duct under specific conditions, prompting the arrangement of responsive oxygen
species that can harm lipids, DNA and other components [48]. Utilization of tea in
high dosages prompts an imbalance in the cancer prevention effect and favourable
to antioxidant activities of tea flavonoids, dietary iron absorption as well as intesti-
nal effect along with digestive enzyme from green tea. The decrease of gastrointes-
tinal assimilation of dietary iron and the precipitation of stomach related effect by
tannins from tea which has lipase action by polyphenols [49]. For the utilization of
phenolic compounds for food storage capacity, they must be stable until the termi-
nation of product which they were added [50]. Nonetheless, polyphenols are rela-
tively unstable when straight forwardly applied in food sources. The steadiness of
such compounds in food system can be credited to a progression of stabilities, phys-
iochemical compounds, colloidal and natural correlation with each other [51].
Dietary Natural Polyphenols Against Bacterial and Fungal Infections: An Emerging… 817

5 Conclusion and Future Perspectives

Progresses in in vitro experiment show the colonic fermentation to assist with

revealing the physiological effect, substrate inclinations and metabolites inter-
change of chief individuals from the stomach microbiota prompted by polyphenols
[52]. Recent investigations of bioactive phenolic metabolites produced from the
activity of bacterial enzymes can anticipate and permit unravelling organisms’
crosstalk, supporting the duplibiotic idea of dietary polyphenols in animals.
However, animal diet have different phytochemicals that could apply antimicrobial
and antioxidant impact on human stomach microbiota [53]. These collaborations
between the plant phytochemicals and the microbial composition can affect both
synthesis and significant antifungal properties against Candida [54]. Past examina-
tions have shown phenolic acid mixtures have significant anti-biofilm impacts and
inhibitory potential movement on morphogenesis and enzymatic reaction of
Candida species.

Acknowledgements: The authors would like to extend their sincere appreciation to their respec-
tive institutions for providing a suitable ambiance for developing this manuscript. Y.K.M. is highly
indebted and extends its sincere thanks to SERB-DST, Government of India for providing support
to his Nano-biotechnology and Translational Knowledge Laboratory through research Grant No.
SRG/2022/000641.

References

1. Ma B, Stepanov I, Hecht SS (2019) Recent studies on DNA adducts resulting from human
exposure to tobacco smoke. Toxics:7
2. Man S, Luo C, Yan M, Zhao G, Ma L, Gao W (2021) Treatment for liver cancer: from sorafenib
to natural products. Eur J Med Chem 224:113690
3. Sikiru AB, Arangasamy A, Egena SSA, Veerasamy S, Reddy IJ, Raghavendra B (2021)
Elucidation of the liver proteome in response to an antioxidant intake in rabbits. Egypt
Liver J:11
4. Izzo C, Annunziata M, Melara G, Sciorio R, Dallio M, Masarone M et al (2021) The
role of resveratrol in liver disease: a comprehensive review from in vitro to clinical trials.
Nutrients 13:1–23
5. Singh AK, Cabral C, Kumar R, Ganguly R, Rana HK, Gupta A et al (2019) Beneficial effects
of dietary polyphenols on gut microbiota and strategies to improve delivery efficiency.
Nutrients 11
6. Milinčić DD, Popović DA, Lević SM, Kostić A, Tešić ŽL, Nedović VA et al (2019) Application
of polyphenol-loaded nanoparticles in food industry. Nano 9
7. Protease S-M, Case T, Panagiotopoulos AA, Karakasiliotis I, Kotzampasi D, Dimitriou M et al
(2021) Natural polyphenols inhibit the dimerization of the SARS-CoV-2 main protease: the
case of Fortunellin and its structural analogs. Molecules 26:6068
8. Pascoalino LA, Reis FS, Prieto MA, Barreira JCM, Ferreira ICFR, Barros L (2021) Valorization
of bio-residues from the processing of main portuguese fruit crops: from discarded waste to
health promoting compounds. Molecules:26
9. Tringali C (2020) Special issue: from natural polyphenols to synthetic bioactive analogues.
Molecules 25:3–5
818 B. Patra et al.

10. Ben-Othman S, Jõudu I, Bhat R (2020) Bioactives from agri-food wastes: present insights and
future challenges. Molecules 25:510
11. Xie Y, Chen J, Xiao A, Liu L (2017) Antibacterial activity of polyphenols: structure-activity
relationship and influence of hyperglycemic condition. Molecules:22
12. López-Yerena A, Domínguez-López I, Vallverdú-Queralt A, Pérez M, Jáuregui O, Escribano-­
Ferrer E et al (2021) Metabolomics technologies for the identification and quantification of
dietary phenolic compound metabolites: an overview. Antioxidants. 10:1–25
13. de Falco B, Grauso L, Fiore A, Bochicchio R, Amato M, Lanzotti V (2021) Metabolomic
analysis and antioxidant activity of wild type and mutant chia (Salvia hispanica L.) stem and
flower grown under different irrigation regimes. J Sci Food Agric 101:6010–6019
14. Uriarte-fr G, Hern MM, Guti G, Santiago-ortiz MM, Morris-quevedo HJ, Meneses-mayo
M (2021) Pre-Hispanic foods oyster mushroom (Pleurotus ostreatus), Nopal (Opuntia ficus-­
indica) and Amaranth (Amaranthus sp.) functional cookies. J Fungi 7:911
15. Elejalde E, Villarán MC, Alonso RM (2021) Grape polyphenols supplementation for exercise-­
induced oxidative stress. J Int Soc Sports Nutr 18
16. Kumar A, Rani M, Mani S, Shah P, Singh DB, Kudapa H et al (2021) Nutritional significance
and antioxidant-mediated antiaging effects of finger millet: molecular insights and prospects.
Front Sustain Food Syst 5:1–17
17. Ofosu FK, Daliri EBM, Elahi F, Chelliah R, Lee BH, Oh DH (2020) New insights on the use
of polyphenols as natural preservatives and their emerging safety concerns. Front Sustain Food
Syst. https://doi.org/10.3389/fsufs.2020.525810
18. Cháirez-Ramírez MH, de la Cruz-López KG, García-Carrancá A (2021) Polyphenols as antitu-
mor agents targeting key players in cancer-driving signaling pathways. Front Pharmacol:1–25
19. Martinengo P, Arunachalam K, Shi C (2021) Polyphenolic antibacterials for food preservation:
review, challenges, and current applications. Foods 10:2469
20. Rodríguez-Daza MC, Pulido-Mateos EC, Lupien-Meilleur J, Guyonnet D, Desjardins Y, Roy
D (2021) Polyphenol-mediated gut microbiota modulation: toward prebiotics and further.
Front Nutr 8
21. Ray SK, Mukherjee S (2021) Evolving interplay between dietary polyphenols and gut micro-
biota—an emerging importance in healthcare. Front Nutr 8:1–18
22. Othman L, Sleiman A, Abdel-Massih RM (2019) Antimicrobial activity of polyphenols and
alkaloids in middle eastern plants. Front Microbiol 10
23. Bouarab-Chibane L, Forquet V, Lantéri P, Clément Y, Léonard-Akkari L, Oulahal N et al
(2019) Antibacterial properties of polyphenols: characterization and QSAR (quantitative
structure-activity relationship) models. Front Microbiol 10
24. Teodoro GR, Ellepola K, Seneviratne CJ, Koga-Ito CY (2015) Potential use of phenolic acids
as anti-Candida agents: a review. Front Microbiol 6:1–11
25. Delli Bovi AP, Marciano F, Mandato C, Siano MA, Savoia M, Vajro P (2021) Oxidative stress
in non-alcoholic fatty liver disease. An updated mini review. Front Med 8:1–14
26. Pérez-Jiménez J, Neveu V, Vos F, Scalbert A (2010) Identification of the 100 richest dietary
sources of polyphenols: an application of the phenol-explorer database. Eur J Clin Nutr
64:S112–S120
27. Tsao R (2010) Chemistry and biochemistry of dietary polyphenols. Nutrients 2:1231–1246
28. Bouarab Chibane L, Degraeve P, Ferhout H, Bouajila J, Oulahal N (2019) Plant antimicrobial
polyphenols as potential natural food preservatives. J Sci Food Agric 99
29. Stawarz-Janeczek M, Kryczyk-Poprawa A, Pytko-Polo J (2021) Antioxidant-rich natural raw
materials in the prevention and treatment of selected oral cavity and periodontal diseases.
Antioxidants 10:1–15
30. Makarewicz M, Drożdż I, Tarko T, Duda-Chodak A (2021) The interactions between polyphe-
nols and microorganisms, especially gut microbiota. Antioxidants 10:1–70
31. Romero C, Nardoia M, Arija I, Chamorro S (2021) Combining grape byproducts to maximise
biological activity of polyphenols in chickens. Animals 11:1–12
Dietary Natural Polyphenols Against Bacterial and Fungal Infections: An Emerging… 819

32. Cheng Y, Chen Y, Li J, Qu H, Zhao Y, Wen C et al (2019) Dietary β-sitosterol improves growth
performance, meat quality, antioxidant status, and mitochondrial biogenesis of breast muscle
in broilers. Animals 9
33. Taguri T, Tanaka T, Kouno I (2004) Antimicrobial activity of 10 different plant polyphenols
against bacteria causing food-borne disease. Biol Pharm Bull 27:1965–1969
34. de Silva OL, Garrett R, Monteiro MLG, Conte-Junior CA, Torres AG (2021) Pomegranate
(Punica granatum) peel fractions obtained by supercritical CO2 increase oxidative and colour
stability of bluefish (Pomatomus saltatrix) patties treated by UV-C irradiation. Food Chem
362:130159
35. Ekong MB, Iniodu CF (2021) Nutritional therapy can reduce the burden of depression man-
agement in low income countries: a review. IBRO Neurosci Rep 11:15–28
36. Kabra A, Sharma R, Hano C, Kabra R, Martins N, Singh BU (2019) Phytochemical composi-
tion, antioxidant, and antimicrobial attributes of different solvent extracts from myrica escu-
lenta buch.-ham. ex. d. Don leaves. Biomol Ther 9
37. Bracci L, Fabbri A, Del Cornò M, Conti L (2021) Dietary polyphenols: promising adjuvants
for colorectal cancer therapies. Cancers 13
38. Zhang W, Qi S, Xue X, Al Naggar Y, Wu L, Wang K (2021) Understanding the gastrointestinal
protective effects of polyphenols using foodomics-based approaches. Front Immunol 12:1–18
39. Drețcanu G, Iuhas CI, Diaconeasa Z (2021) The involvement of natural polyphenols in the
chemoprevention of cervical cancer. Int J Mol Sci 22
40. Tuli HS, Mittal S, Aggarwal D, Parashar G, Parashar NC, Upadhyay SK et al (2021) Path of
Silibinin from diet to medicine: a dietary polyphenolic flavonoid having potential anti-cancer
therapeutic significance. Semin Cancer Biol 73:196–218
41. Jantan I, Haque MA, Arshad L, Harikrishnan H, Septama AW, Mohamed-Hussein ZA (2021)
Dietary polyphenols suppress chronic inflammation by modulation of multiple inflammation-­
associated cell signaling pathways. J Nutr Biochem 93:108634
42. Jiang H, Zhang W, Li X, Xu Y, Cao J, Jiang W (2021) The anti-obesogenic effects of dietary
berry fruits: a review. Food Res Int 147:110539
43. Knezevic S, Ghafoor A, Mehri S, Barazi A, Dziura M, Trant JF et al (2021) Catechin and other
catechol-containing secondary metabolites: bacterial biotransformation and regulation of car-
bohydrate metabolism. PharmaNutrition 17:100273
44. Marhuenda J, Silvia P, Victoria-montesinos D (2021) A randomized, double-blind, placebo-­
controlled trial to determine the effectiveness of a polyphenolic extract (Hibiscus sabdariffa
and Lippia citriodora) for reducing blood pressure in prehypertensive and type 1 hypertensive
subjects. Molecules 26:1783
45. Płowuszyńska A, Gliszczyńska A (2021) Recent developments in therapeutic and nutraceuti-
cal applications of p-methoxycinnamic acid from plant origin. Molecules 26
46. Kowalska H, Kowalska J, Ignaczak A, Masiarz E, Domian E, Galus S et al (2021) Development
of a high-fibre multigrain bar technology with the addition of curly kale. Molecules 26:1–20
47. Augimeri G, Montalto FI, Giordano C, Barone I, Lanzino M, Catalano S et al (2021)
Nutraceuticals in the mediterranean diet: potential avenues for breast cancer treatment.
Nutrients 13
48. Vesely O, Baldovska S, Kolesarova A (2021) Enhancing bioavailability of nutraceutically used
resveratrol and other stilbenoids. Nutrients 13:1–15
49. Gomes MJC, Kolba N, Agarwal N, Kim D, Eshel A, Koren O et al (2021) Modifications in the
intestinal functionality, morphology and microbiome following intra-amniotic administration
(Gallus gallus) of grape (vitis vinifera) stilbenes (resveratrol and pterostilbene). Nutrients 13
50. Yamaguchi K, Itakura M, Kitazawa R, Lim SY, Nagata K, Shibata T et al (2021) Oxidative
deamination of lysine residues by polyphenols generates an equilibrium of aldehyde and
2-piperidinol products. J Biol Chem 297:101035
51. Scuto M, Trovato Salinaro A, Caligiuri I, Ontario ML, Greco V, Sciuto N et al (2021)
Redox modulation of vitagenes via plant polyphenols and vitamin D: novel insights for
820 B. Patra et al.

c­ hemoprevention and therapeutic interventions based on organoid technology. Mech Ageing

Dev 199:111551
52. Patra S, Pradhan B, Nayak R, Behera C, Das S, Patra SK et al (2021) Dietary polyphenols in
chemoprevention and synergistic effect in cancer: clinical evidences and molecular mecha-
nisms of action. Phytomedicine 90:153554
53. Liu XZ, Ju Y, Bao N, Luo YL, Huang LL, Cao NX et al (2021) Effects of polyphenol-rich
Aronia melanocarpa pomace feeding on growth performance, biochemical profile, and meat
quality in pigs at weaned and finishing stages. Livest Sci 252
54. Shang A, Li J, Zhou DD, Gan RY, Bin LH (2021) Molecular mechanisms underlying health
benefits of tea compounds. Free Radic Biol Med 172:181–200
Phyto-Constituents as Potential Leads
for the Development of Novel Antiepileptic
Drugs

Joohee Pradhan, Purnima Paliwal, Sunita Panchawat, Rohini Trivedi,

and Devshree Gayakwad

1 Introduction: Etiology, Symptoms, and Classification

of Epilepsy

Epilepsy is a CNS disorder, characterized by diffusely abnormal electroencephalo-

gram, that exhibits as seizures with consciousness loss with or without characteriz-
ing movements (convulsions), physical senses, or mental phenomenon [1]. It is well
elucidated as propensity to frequently occurring seizures. Epilepsy is obtained from
Greek and Latin word for seizure, which means to seize. Epilepsy influences each
sex whether it is male or female or individuals from all the age groups from child-
hood to the aging population. In the earliest times, epileptic attacks were believed to
be the outcome of supernatural power and evils or demons who require exorcism [2].

Purnima Paliwal, Sunita Panchawat, Rohini Trivedi and Devshree Gayakwad contributed equally
with all other contributors.

J. Pradhan (*) · S. Panchawat

Department of Pharmaceutical Sciences, Mohanlal Sukhadia University,
Udaipur, Rajasthan, India
e-mail: [email protected]
P. Paliwal
School of Pharmacy, Devi Ahilya Vishwavidyalaya, Indore, Madhya Pradesh, India
R. Trivedi
Department of Botany, Mohanlal Sukhadia University, Udaipur, Rajasthan, India
D. Gayakwad
Acropolis Institute of Pharmaceutical Education and Research,
Indore, Madhya Pradesh, India

© The Author(s), under exclusive license to Springer Nature 821

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_34
822 J. Pradhan et al.

In epilepsy, patient observes a behavioral change that lasts only for a short period
that may be due to signs or symptoms (such as cognizance loss, stiffening, jerking),
caused by concurrent activity of neuron in the brain. Seizure arousal can be local-
ized (which affects one hemisphere of the brain), generalized (which affects both
the hemispheres) and unrevealed arousal [3]. Despite the fact that the cause of epi-
lepsy in many patients is unknown, seizures can be the outcome of about any insult
that unsettles the brain function. It can be caused by both genetic factor (Idiopathic)
and acquired factor (Symptomatic) [4]. These insults comprise acquired causes;
some may be peripheral to injury/surgery on the head, brain (intracranial tumor),
tuberculoma, cysticercosis, cerebral ischemia, etc. Epilepsy was divided into three
types by the International League Against Epilepsy (ILAE) in year 1989: Idiopathic
in which recurring seizures without detectable abnormalities, Cryptogenic epilepsy
with cause, and Symptomatic epilepsies had a recognizable cause [5]. Idiopathic
epilepsies constitute 40% of the epilepsies worldwide [6]. Idiopathic epilepsies are
further divided into idiopathic generalized and partial epilepsy. Some idiopathic
epilepsies occur due to inheritance by mutations in genes that code for iron chan-
nels. In symptomatic epilepsies, there are some genetic disorders that are responsi-
ble for neuropathological and neurocutaneous diseases or changes at the molecular
level: such as Angelman syndrome and Rett syndrome [7].
Thus, epilepsies have been classified variously; major types are described
in Fig. 1.

Fig. 1 General classification of epilepsies [1]

Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs 823

2 Pharmacological Therapy of Epilepsy

The main aim of antiepileptic drug therapy is to improve quality of life by control-
ling seizures and diminishing drug toxicity. It has been observed that about two-­
thirds of epilepsy patients are cured with available antiepileptic drugs. Currently,
various first- and second-generation AEDs are in use as mentioned in Table 1, each
with its own limitations including side effects, tolerance, dependency, and extended
period toxicity [8]. The alternative path for the management of epilepsy can be by
the use of herbal sources and their active constituent having fewer side effects [9].

3 Worldwide Condition

Epilepsy influences 50 million individuals around the world. According to a survey,

it has been assessed that 4 out of 1000 people are detected with active epilepsy,
which means the patient needs treatment. Globally every 12 months, around 5 mil-
lion people are analyzed with epilepsy. In developed countries, around 49 per
100,000 people each year are diagnosed with epilepsy, and in other developing
countries, this number is approx. 139 per 100,000 people. This may be due to cera-
bral malaria or neurocysticercosis, which is the endemic condition in these places;
the increased incidence of injuries due to road traffic, birth injuries are the other
causes. Around 80% population with epilepsy are living in nations that have low or
middle revenue [10].

4 The Drug-Resistant Epilepsy

Despite the incessant development of antiepileptic drugs, there are until now more
than 30% of patients accompanied by drug-resistant epilepsy, which leads to unusual
growth in the occurrence of disease and impermanence of epilepsy. Mechanism of
drug-resistant epilepsy is overexpression of efflux transporter, e.g., P-glycoprotein,
and altered expression of voltage-gated ion channels [11]. The most usual category
of drug-resistant epilepsy is temporal lobe epilepsy, generally cured by surgical
operation. Surgical treatment technique intended for mesial temporal lobe epilepsy
is intricate, and in surgeries like this, the patient’s well-being is a menace.Recently,
new drug targets emerge moderately, inclusive of glutamate neurotransmitters and
Ca2+ channels [12–15], transient receptor potential vanilloid-type 1 (TRPV1), Na+
K+ 2Cl− co-transporter (NKCC), etc. [16]. Sen et al. also established the increased
expression of NKCC1 in medically resistant refractory human epilepsy with hip-
pocampal sclerosis and focal cortical dysplasia [17]. Due to side effects possessed
by currently available AEDs, herbal remedies play a divine role in epilepsy
824 J. Pradhan et al.

Table 1 Efficacy spectrum of currently available antiepileptic drugs

Generation
of AEDs AED Efficacy spectrum Comments
First Valproic acid For all type of May cause serious or life-threatening
generation seizures damage to the liver, especially in children
Benzodiazepines For all seizure Can instigate tonic seizures, principally
types after I.V. use in Lennox–Gastaut
syndrome (LGS), a type of epilepsy
Phenobarbital For nearly all Not effectual against absence seizures
seizure types
Primidone For nearly all No efficacy against absence seizures
seizure types
Carbamazepine Focal seizures and Can provoke or exacerbate absence
generalized tonic seizures and myoclonic seizures
clonic seizures
Phenytoin Focal seizures and Can instigate or exacerbate absence
generalized tonic seizures and myoclonic seizures
clonic seizures
Second Lamotrigine Nearly all seizure Can instigate or exacerbate myoclonic
generation types seizures. Its effective preeminently
documented against focal seizures,
generalized tonic clonic seizures, absence
seizures, and drop attacks associated with
LGS
Levetiracetam Nearly all seizure Effectual against tonic and atonic
types seizures. Not documented. Efficacy best
documented against focal seizures,
generalized tonic clonic seizures and
myoclonic seizures
Topiramate Nearly all seizure Efficacy against absence seizures not
types documented efficacy best documented
against focal seizures, generalized tonic–
clonic seizures, and drop attacks
associated with LGS
Zonisamide Nearly all seizure Efficacy against most generalized seizure
types types poorly documented
Oxcarbazepine Focal seizures and Can precipitate or aggravate absence
generalized tonic seizures and myoclonic seizures
clonic seizures
Perampanel Focal seizures and Can cause serious or life-threatening
generalized tonic changes in their mental health and
clonic seizures behavior
Vigabatrin Focal seizures and Shown to be particularly efficacious in
infantile spasm the treatment of infantile spasms
associated with tuberous sclerosis
complex can precipitate or aggravate
myoclonic seizures
(continued)
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs 825

Table 1 (continued)
Generation
of AEDs AED Efficacy spectrum Comments
Rufinamide Focal seizures, and Can cause loss of coordination and
drop attacks difficulty walking
associated with
LGS
Felbamate Focal seizures, and May cause a serious blood condition
drop attack or called aplastic anemia
assault associated
with LGS
Elisacarbazepine Focal seizures May precipitate or aggravate absence
acetate seizures and myoclonic seizures
Lacosamide Focal seizures May cause cardiac side effects
Pregabalin Focal seizures Can precipitate or aggravate myoclonic
seizures
Gabapentin Focal seizures Can precipitate or aggravate myoclonic
seizures
Tiagabine Focal seizures Can precipitate or aggravate absence
seizures and myoclonic seizures
Brivaracetam Focal seizures May cause clinically apparent drug
induced liver disease
Everolimus Seizures relate to Efficacy best documented against focal
tuberous sclerosis seizures associated with tuberous
complex only sclerosis complex
Stiripentol Seizures Only indicated for use in combination
associated with with clobazam and valproic acid against
Dravet syndrome tonic–clonic seizures associated with
only Dravet syndrome

management including drug-resistant epilepsy. In recent studies, cannabinoid, Kava

(Piper methysticum), Huperzine A, etc., show evidence for their anticonvulsant
activity [18].

5 Problems Associated with the Use of Existing AEDs

The long-term use of currently available first- and second-generation AEDs is lim-
ited due to their adverse effects, withdrawal symptoms, and deleterious interactions
with other drugs. Furthermore, some of the available antiepileptic drugs may even
potentiate certain type of seizures. Given the wide availability of effective agents,
the toxicity and pharmacokinetic profile of an AED have become major factors in
the selection process. The following section defines various problems associated
with the use of existing AEDs:
826 J. Pradhan et al.

5.1 Developmental Problem with Intrauterine

Antiepileptic Exposure

It has been divulged that women with epilepsy at the time of pregnancy with prena-
tal antiepileptic exposure have adverse effects in children. There are innumerable in
vitro evaluations that showed that antiepileptic drugs have an impact on neuronal
development [19]. Prenatal exposure to antiepileptic drugs with AEDs such as car-
bamazepine and valproate was found to exhibit adverse effects on verbal abilities.
During pregnancy or before birth, antiepileptics may produce growth-related com-
plications to the child. These types of developmental problems can be diagnosed by
the plasma nerve growth factor (NGF) level, which is the potential biomarker.
Periconceptional folate use may be important as a protective measure in at-risk
pregnancies [20].

5.2 Enzyme Induction with Antiepileptic Drugs

Several frequently prescribed AEDs inclusive of phenobarbital, phenytoin, and car-

bamazepine trigger the synthesis of a broad range of monooxygenase and conjugat-
ing enzymes. These drugs are eminent to bring down the duration and action of
numerous lipid- and non-lipid-soluble drugs, as well as anticoagulants, cytotoxic,
analgesics, antiretrovirals, glucocorticoids, statins, antihypertensives, oral contra-
ceptives, psychoactive drugs, immunosuppressants, and obviously, other AEDs. In
women having epilepsy, enzyme-inducing AEDs have been correlated with abnor-
malities in sex hormone profiles [21], antidepressant and antipsychotic medications
are metabolized by the cytochrome P450 (CYP) system, and consequent treatment
with an inducing AED could lower serum concentrations [22]. Numerous studies
indicate that consequent administration of enzyme-inducing AEDs accelerates the
metabolism of many classes of chemotherapeutic agents resulting in substantially
reduced exposure [23]. Enzyme-inducing AEDs increase the number of serologic
markers of vascular risk, particularly cholesterol [24]. Low homocysteine levels
were observed due to antiepileptic drugs. Therefore, phenytoin and carbamazepine
may have different effects on some serologic markers [25].

5.3 Liver Enzymes Affected by Antiepileptic Drug

Liver enzymes can entertain as markers of hepatocellular injury, e.g., aspartate ami-
notransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT),
and gamma-glutamyl transferase (GGT). However, those enzymes are exaggerated
in liver disease, the exaggeration also can be subordinate to enzyme induction unac-
companied by hepatic pathology [26]. In certain, antiepileptic drugs have numerous
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs 827

serious responses, as detected with carbamazepine (CBZ), valproic acid (VPA), and
phenytoin (PHT). However, to some extent relatively rare, when collated with dif-
ferent consistently known hepatotoxic drugs, the hepatotoxicity instigated by the
antiepileptic drug can cause death or an acute liver failure, which could critically
need liver transplantation. The hepatotoxicity instigated by antiepileptic drug hap-
pens either because of the production of reactive toxic metabolite/s or because of
induction of immune allergic reactions. Hepatotoxicity is analog with distinct clini-
cal indications of drug allergy (fever, rash, and eosinophilia). This reaction is char-
acteristic of CBZ and PHT. Additional idiosyncratic hepatotoxic reaction originates
from hepatotoxic metabolites because of abnormal metabolism. This reaction has
been observed with VPA [27].

5.4 Antiepileptic Drugs’ Effect on Growth

and Bone Metabolism

About 50% of patients with epilepsy who take AEDs are observed to have bone
deformities. Manifestation of patients with AED-related bone diseases comprises
bone pain, muscle weakness, and fractures, with little or no torment. These manifes-
tations do not appear until the first fracture occurs [28]. For measuring the levels of
bone mineral density (BMD), there is a technique that is known as Dual-energy
X-ray absorptiometry (DXA) [29]. Abnormal BMD values were observed in one-­
third to two-thirds of patients with epilepsy. However, it is understandable that
AEDs have an effect on bone metabolism and increased fractures are not clear, the
drug metabolism might play a dominant part in evolution of these adverse influ-
ences. Temazepam, a metabolite of diazepam via CYP3A4, was detected to be
increasing the possibility of fractures. Moreover, long-term use of CBZ may aug-
ment the danger of fracture and bone loss, instigate a status of reduction in bone and
mineral metabolism, increment in bone turnover, and diminution BMD. Continuing
use of VPA may upsurge the risks of bone damage [22]. TPM is also a carbonic
anhydrase inhibitor that might impede PTH-induced bone resorption, subsequent in
hypocalcemia. Juvenile rats treated with VB were observed to have reduced body
mass gain and repressed compact bone growth.

5.5 Visual Performance Affected by Antiepileptic Drugs

Visual disturbance in sufferers detected with epilepsy can be as a consequence of

additionally the ailment progression [30] or the anticonvulsant remedy prescribed to
treat the seizures. Visible problems such as simultaneous notion of snapshots, i.e.,
diplopia, nystagmus (rapid involuntary motion of eye), and blurred imaginative and
prescient genuinely are probably an early neurotoxic impairment of extended rem-
edy [14]. Listed underneath are the antiepileptic drugs, with their mechanism of
action and visible side consequences (Table 2).
828 J. Pradhan et al.

Table 2 AEDs with visual side effects and mechanism of action

Antiepileptic
drugs Mechanism of action Side effects
Acetazolamide Carbonic anhydrase Decreased IOP with increased ocular blood flow
inhibitor
Benzodiazepine GABA-mediated Blurred vision, Electroretinogram and Visual
AEDs inhibition via Evoked Potential (VEP) changes, maculopathy
benzodiazepine receptor
Carbamazepine Inhibition of voltage-­ Blurred vision, diplopia, abnormal color
(old) dependent Na+ channels perception, nystagmus, oscillopsia,
photosensitivity, altered VEPs
Ethosuximide Control of Ca2+ into Modulation of Na+, and Cl− conductance,
(old) nerve terminals dyskinesia, light sensitivity, myopia
Gabapentin GABA agonist Blurred vision, nystagmus, diplopia, visual
(new) Possible GABA electrophysiological changes
mechanism
Glutamate receptor
effect
Lamotrigine Reduced glutamate Blurred vision, diplopia, some visual
(new) release by inhibiting electrophysiological disturbances, nystagmus
voltage-sensitive Na+
channels
Levetiracetam Unknown mechanism Diplopia
(May selectively prevent
hyper synchronization)
Oxcarbazepine Blockage of Blurred vision and Diplopia
voltage-sensitive
Na+ channels
Phenytoin (old) Voltage-dependent Na+ Impairment of voluntary movement (dyskinesia),
channels inhibition rapid involuntary movement of eye (nystagmus),
paralysis of the muscle within or surrounding the
eye (ophthalmoplegia), blurred vision, disturbed
colour perception
Primidone Unknown mechanism Diplopia and nystagmus
associated to drug
metabolism
Sodium GABAergic inhibition Voltage dependent sodium channels altered VEPs,
valproate and cause abnormal color perception
Topiramate GABA Cl− channels Simultaneous perception of two images i.e.,
(new) potentiation, Carbonic diplopia and nearsightedness known as acute
anhydrase inhibitor myopia
Tiagabine (new) Inhibitor of GABA Blurred vision, rapid movement of eye,
reuptake simultaneous perception of two images
Vigabatrin (new) Inhibitor of Rapid involuntary movement of eye (nystagmus)
GABA-transaminase
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs 829

5.6 CNS Adverse Effects

These include the following:

5.6.1 Cognitive Effects

Cognitive impact characteristically comprises diminished attention, decision-­

making function, intellect, linguistic skills, reminiscence, and processing speed.
Phenobarbital and topiramate devour the utmost potential for those complications;
even still several AEDs may impair characteristics of cognizance. Psychological
impedance has been related to phenobarbital in investigation viewing enhancement
as soon as the drug is discontinued. Children exposed to phenobarbital have lesser
intellect scores than the ones taking valproate [31].

5.6.2 Psychiatric Effects

Depression and anxiety are common among people with epilepsy [32]. The behav-
ioral adverse impact can occur with levetiracetam and also with topiramate,
zonisamide, and phenobarbital. Irritability and aggression are the topmost appre-
hensions with levetiracetam, often seen shortly after subsequent initiation. Psychosis
is sporadic. It may be preexisting, peri-ictal, or could be due to enforced stabiliza-
tion of brain action. Mood disorders, particularly anxiety and depression, are com-
munal comorbidities in epilepsy that may or may not be accompanied by AED
therapy. Patients should be evaluated for mood disorder earlier and often throughout
treatment as chronic dysthymia and depression disturb reporting of adverse effects
and seizure severity, also affecting the complete quality of life [33].

5.7 General Medical Effects

Many AEDs have limited use because of the risk for rare but serious effects that may
result in death. The use of felbamate and vigabatrin is limited because of the risk for
aplastic anemia and visual field deficits, respectively [34]. However, phenytoin, the
most widely used AED in the USA, may also cause hepatic failure.

5.8 Hypersensitivity

Maculopapular outbreak on the chest, inside elbow, and knee parts results in hyper-
sensitivity, which shows that the drug must be stopped as soon as possible. The rash
may lead to hypersensitivity, which can be lethal (e.g., Stevens–Johnson syndrome),
830 J. Pradhan et al.

needing hospitalization [33–36]. Lamotrigine rashes are high starting dose and
rapid escalation, as well as young age and concurrent valproate [31]. The drug
should be discontinued if the patient develops a rash. In the main surveying study of
1890 outpatients with epilepsy, researchers evaluated the rates of rash related to 15
AEDs [37]. Primary evaluating non-AED analysts of rash, they equated rash rates
for separate AEDs. The maximum rash rates arose with phenytoin (5.9%), lamotrig-
ine, (4.8%), and carbamazepine (3.7%). The lowermost rash rates arisen with felb-
amate, primidone, topiramate (all<1%), levetiracetam (0.6%), gabapentin (0.3%),
and valproate (0.7%).

5.9 Paediatric Issues

The probable for hostile events in children is superior than in grownups as young
children have immature detoxification mechanisms and a superior inconsistency in
dosing owed to a broader range of body size and weight. Valproate has been con-
cerned with hepatic toxicity in children, though phenobarbital, phenytoin, carbam-
azepine, oxcarbazepine, and lamotrigine cause advanced occurrences of rash in
children than adults [38, 39]. Metabolic acidosis, Hyperthermia, Nephrolithiasis,
and oligohydrosis are several disorders caused by Topiramate and Zonisamide in
children and adults [38–41]. Though, noteworthy metabolic acidosis in children can
lead to growth retardation [42] Gingival hyperplasia, an adverse event seen in
patients of all ages who take phenytoin, arises much more frequently in develop-
mentally impaired patients and young children [43].

6 The Herbal Remedies for Epilepsy

Herbal medications are currently the greatest typical alternative to the allopathic
system of medication, which play a significant role in the treatment to control epi-
leptic seizures or complications caused by antiepileptic drugs. Nature is a wealthy
source of organic and chemical diversity. For decades, individuals with epilepsy are
using a diversity of botanicals and herbs, traditional schemes of medicine are preva-
lent in growing international countries, and up to 80% of the population depends on
traditional medicines for their prime healthcare requirements. Numerous plants
used for the remedy of epilepsy in exceptional structures of conventional medica-
tion have shown activity when tested on a contemporary day for the detection of
anticonvulsant activity. Herbal medicine is an area of complementary alternative
medicine that is readily amenable to empirical research [44, 45]. Numerous natural
drugs have impact on the central nervous system and are found to have antiepileptic
potential; some important ones, especially those studied during the last three
decades, are presented here along with their most important biologically active moi-
ety as reported in the literature (Table 3). The table also contains information about
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs 831

the method of evaluation of antiepileptic activity; abbreviations are provided as a

footnote to the table. For more details about the methods of evaluation, readers are
advised to refer to the cited literature [45].
The chemical constituents mentioned in the table can be studied in detail using
various computational methods and can be used for the design and development of
a novel, third-generation antiepileptic agent with the help of various computational
approaches described later in this chapter.

7 Molecular Targets for Antiepileptic Drugs

A thorough knowledge of recent advances in the physiology of ion channels and

other potential molecular targets, in conjunction with new information on the genet-
ics of idiopathic epilepsies, can be applied to the search for improved AEDs. The
following paragraphs contain a brief description of conventional and newly identi-
fied targets for AEDs available from the literature (Fig. 2); empirical screening of
which may successfully lead to the development of many useful AEDs, each with
unique properties and distinct clinical profiles.

7.1 Receptors as AED Targets

7.1.1 Voltage-Gated Ion Channels

The aberrant excitability associated with an epileptic discharge is necessarily medi-

ated by voltage-gated and ligand-gated ion channels and may even be the result of
defects in the function of these ion channels. Because of the crucial role played by
these ion channels in the physiology of all types of epilepsy, they are the important
AED targets.
Voltage-gated ion channels are superfamily of receptors, which are transmem-
brane proteins, comprising 143 genes. When there is voltage difference, these chan-
nels open up for response. This superfamily encompasses the S4 family in which the
pore-forming subunits are built on a motif of six transmembrane segments (S1–S6),
the fourth of which (S4) contains a voltage-sensing element (Fig. 3a–d).

Voltage-Gated Na+ Channels

Sodium channels (Fig.3a) are voltage-operated transmembraneous proteins that

become selectively permeable to sodium ions when the membrane depolarizes and
that are generally closed at resting states. They are functionally expressed from a
single family of nine genes encoding pore-forming α subunits; NaV1.1, NaV1.2,
NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.8, and NaV1.9. From the molecular
Table 3 List of herbal antiepileptic drugs along with their major active constituents and methods used to evaluate their antiepileptic potential
832

Name of the plant and Model used for

S. no family Active constituent Chemical structure evaluation Part of plant used
OH
1 Acanthus montanus 1. 2,6-bis(1,1-dimethyl-­ethyl)4-methyl phenol PTZ Whole plant
2. Allyl(2tetrahydro-­furylmethoxy)Dimethyl MIS
silane (1) STR
3. Sulfurous acid, cyclohexyl methyl hexyl ester (2) PIC
4. Alpha-Methyl-4-­methylmannoside O Si
O CH2

5. Hexadecenoic acid methyl ester (3)

O
6. 11-Octadecenoic acid methyl ester Si
O O

7. Docosane (4)
8. N, N-Dimethyl valeramide O OH

9. 2,6,10,15-Tetramethyl heptadecane OH
HO O
O

(5)
O

(6)
O

(7)
H3C
CH3

(8)
N

O
(9)
J. Pradhan et al.
 Name of the plant and Model used for
S. no family Active constituent Chemical structure evaluation Part of plant used
OH
O
2 Alchornea Laxiflora 10. Quercetin-7,4′-disulphate O PTZ Whole plant
S
O OH
O O O
(Euphorbiaceae) 11. Quercetin O
S MES
OH
OH (10)
12. Quercetin-3′,4′-disulphate STR
OH O
13. Quercetin-3,4′-diacetate OH PIS
OH
14. Rutin HO O
NMDA
15. Quercetrin OH (11)
OH O
OH
O
O
S
OH
HO O O
(12)
O
OH O O S O
OH
OH
OCOCH3
HO O (13)

OCOCH3
OH O
OH
HO OH

OH O
HO

O
HO O OH
O

O OH

HO
OH (14)
OH
HO
O
HO O OH
O

O OH
HO
OH (15)

3 Alpha Terpinol 16. ± α-Terpineol OH MES Alpha Terpinol as

(monoterpene) (16) PTZ emulsion
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs

(continued)
833
Table 3 (continued)
834

Name of the plant and Model used for

S. no family Active constituent Chemical structure evaluation Part of plant used
O H
O
HO
4 Bacopa monnierie 17. Bacoside A MES Leaves
O OH
HO H O
(Brahmi) 18. Bacoside B HO OH PTZ
O
H
HO (17) HO
(Scrophulariaceae) 19. Bacoside A3 OH
STR
20. Rosavin O O
H LPHE
HO
21. Quercetin
O OH
22. Apigenin H O
HO OH
O HO
H
23. Luteolin HO
(18) HO

24. 3,4-Dimethoxycinnamic acid OH

HO

H
HO HO O
H
HO HO O
O O H
HO O O
H
OH O O

HO (19)
OH
HO

OH
HO OH

O O OH
O OH
(20)
O
OH
OH
OH

HO O

(21)
OH
OH O
HO

O
OH
HO
O
(22)
HO
OH
O
OH
HO
O (23)
J. Pradhan et al.

O
O O
HO (24)
 Name of the plant and Model used for
S. no family Active constituent Chemical structure evaluation Part of plant used
5 Berberine 25. Berberine O N+ PTZ Berberine
O
(isoquinoline alkaloid) O
MES Hydrochloride solution
(25) O
KA

O
6 Carissa endulis 26. 3-O-acetyl chlorogenic acid OH
HO
(Apocynaceae) 27. Kaempferol 3-O-b-D glucopyranoside O OH
28. Quercetin 3-O-b-D glucopyranoside H3COCO OH O OH
29. Rhamnetin 3-O-b-D glucopyranoside (26)
R1
30. Isorhamnetin 3-O-b-D glucopyranoside
OH
31. Isorhamnetin 3-O-b-D
R1 O
glucopyranoside-(2″-1″)-rhamnopyranoside
32. Caredulis, 1- [1- [2-(2 hydroxypropoxy) OR3
propoxy] propane-2-­yloxy] propane-2-ol OH O
33. (+)-butyl-α-L-rhamnoside
R1 R2 R3

27 H OH Glu
28 OH OH Glu
29 OH OMe Glu
30 OMe OH Glu
31 OMe OH Glu (2-1) Rha
OH
O O
O O OH

(32)
O O
HO H
OH
HO H
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs

(33)

(continued)
835
Table 3 (continued)
836

Name of the plant and Model used for

S. no family Active constituent Chemical structure evaluation Part of plant used
7 Casimiroa endulis 34. Umbelliferon MES Leaves
O O OH
(Ruteacea) 35. Esculatin (34) PTZ
OH
36. Imperatorin
37. Xanthotoxol O O OH
(35)
O

O
O

(36) O

OH
O O O

(37)
OH
O
8 Cotyledon orbiculate 38. Cotyledoside C PTZ Whole plant
O
(Crassulaceae) 39. Orbicusides A O
PIC
O OH
40. Orbicusides B O BIC
O
O
41. Orbicusides C (38) NMDA
O
H
R2
OH

O O R1 O
O
O

R1 R2

39. O H
40. OH H
41. H OH
J. Pradhan et al.
 Name of the plant and Model used for
S. no family Active constituent Chemical structure evaluation Part of plant used
O
9 Cymbopogon 42. Citronellal (42) PTZ Essential oil from
winterians 43. Citronellol HO PIC leaves
(43)
44. Geraniol (44)
STR
HO

10 Delphinium 45. Denudatine OH MEZ Whole plant

denudetum 46. Delphinine PTZ
HO
47. β-sitosterol BIC
N
STR
(45) PIC

O O O
HO
O
O N
O O
(46)
O
HO

(47)

(continued)
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs
837
Table 3 (continued)
838

Name of the plant and Model used for

S. no family Active constituent Chemical structure evaluation Part of plant used
11 Erythrina velentina Erythrinane alkaloids- (48) PTZ Stem bark
O
and erythrina 48. Erythraline O N STR
mulungu (Fabaceae) 49. Erysopine O
HO
50. Erysovine
51. Erysodine N
HO O
(49)
52. Schelhammeridine
O
53. Erythramine
54. Erythratine N
HO O
(50)

HO

N
OO

(51)

O N
O

O
(52)

O
N O

O
(53)
OH

O
N O

(54) O
J. Pradhan et al.
 Name of the plant and Model used for
S. no family Active constituent Chemical structure evaluation Part of plant used
12 Ferula gummosa 55. Pinene MES Seed acetone extract
(Apiaceae) 56. α -thujene (55) PTZ

(56)

13 Ficus 57. Saponins N. A MES Methanol extract of

platyphylla(moraceae) PTZ stem bark
STR
14 Harpagophytum 58. Harpagoside HO
PTZ Secondary root aqueous
procubens 59. Kaempferol HO
BIC extract
O
(Pedaliaceae) 60. Luteolin PIC
HO O O
HO
OH
O

(58) OHOH
HO

O
OH
HO
O OH
(59)
HO
OH
O
OH
HO
(60)
O

(continued)
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs
839
Table 3 (continued)
840

Name of the plant and Model used for

S. no family Active constituent Chemical structure evaluation Part of plant used
15 Hyptis spicigera 61. Cineole PTZ Whole plant decoction
O
(Lamiaceae) 62. Caryophyllene (61) STR
63. α -pinene PIC
64. β -pinene
65. α –phellandrene (62)

(63)

(64)

(65)

16 Laurus nobilis 66. Eucalyptol PTZ Leaf essential oils

(Lauraceae) 67. Terpinyl acetate (66) MES
O
68. Methyleugenol
69. α- and β-pinenes O
O (67)
70. Lauric acid O

O
(68)
OH

(69)
O OH

(70)
J. Pradhan et al.
 Name of the plant and Model used for
S. no family Active constituent Chemical structure evaluation Part of plant used
HO
17 Leonotis leonurus 71. Apigenin PTZ Whole plant aqueous
O
(Lamiaceae) 72. Apigenin-8-C-β-glucoside OH BIC extract
HO (71)
73. Leonurine O PIC
OH NMDA
OH
HO OH
O
O OH
(72)
HO OH

O
O
HO
O N
O NH2
(73)
H2N
HO
18 Magnolia grandiflora 74. Magnolol MES Ethyl ether and
(Magnoliaceae) PTZ Hydroalcoholic extract
OH (74) of seed; bark

19 Micro glossa pyrifolia 75. Germacrene – D MES Leaf essential oil

(Asteraceae) PTZ
(75) PIC
INH
NMDA
STR
(continued)
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs
841
Table 3 (continued)
842

Name of the plant and Model used for

S. no family Active constituent Chemical structure evaluation Part of plant used
OH
20 Mimosa Pudica 76. 5,7,3′,4′-tetrahydroxyl-6-­C-beta-D- OH PTZ Leaf decoction
(Leguminosae) glucopyranosyl flavones HO O STR
O (76) NMDA
77. 7,8,3′,4′-tetrahydroxyl-6-­C-beta-D- HO
OH O
glucopyranosyl flavones HO OH PIC
OH
78. Mimosine OH
79. Tyrosine OH
OH
HO O
80. Mamimosinamine
O (77)
81. Mimosinicacid. HO
O
HO OH
OH
O HO O
N
HO NH2
(78)
H2N

HO O OH
(79)
O (80)
N
HO NH2
O (81)
O
N
HO OH
O
21 Nardostachys 82. Nardin H PTZ Ethanol extract of roots
OH
jatamansi 83. Pyranocoumarine MES
H (82)
(Valerianaceae) H

O O O
(83)

O
J. Pradhan et al.
 Name of the plant and Model used for
S. no family Active constituent Chemical structure evaluation Part of plant used
O O O
22 Piliostigma 84. Piliostigmol PTZ Whole plant decoction
HO OH
reticulatum 85. 6,8-di-C-­methylquercetin-3,30,7-­trimethyl OH O STR
(84)
(Caesalpiniaceae) ether R1 NMDA
86. 6,8-di-C-­methylquercetin-30-­­dimethyl ether O O O
R2
87. 30,6,8, -tri-C-­methylquercetin-3,7-­dimethyl OH OH
OH O R3
ether (85)

88. 6-C-methylquercetin-­3-methyl ether

89. 6,8-di-C-­methylkaempferol-3-­­methyl ether R1 R2 R3
90. 6-C-methylquercetin-­3,30,7-trimethyl ether 85 CH3 OCH3 OCH3
86 CH3 OH OCH3
87 CH3 OCH3 CH3
88 H OH OH
89 CH3 OH OH
90 H OCH3 OCH3

23 Pimpinella anisum 91. Trans-anethol O MES Fruit essential oil

(91)
(umbelliferae) 92. Eugenol HO PTZ
93. Methyl chavicol
O (92)
94. Anisaldehyde
O
95. Estragole (93)

O
(94) O

O
(95)

(continued)
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs
843
Table 3 (continued)
844

Name of the plant and Model used for

S. no family Active constituent Chemical structure evaluation Part of plant used
OH
24 Rhizome Pinelliae 96. Pedatisectine F OH NKTM Ethanol extract of tuber
N
(Araceae) 97. Hypoxanthine HO
OH
98. Erythriotal (96) N
N NH
99. Uridine
N O
NH
(97)
OH
HO
OH
HO
(98)
O
HO O NH
N O
HO
OH (99)

NH2
25 Sutherlandia 100. L-canavanine H2N N OH
PTZ Shoot aqueous extract
O
frutescens (Fabaceae) 101. Pinitol NH2 O
PIC
102. GABA (100) BIC
HO OH
103. Asparagines
O OH

HO OH
(101)
OH
O NH2

(102)
O
NH2
HO
NH2 O (103)
J. Pradhan et al.
 Name of the plant and Model used for
S. no family Active constituent Chemical structure evaluation Part of plant used
26 Taxus wallichiana 104. (E)-2-octen-1-ol OH PTZ Methanol leaf extract
(104)
105. n-pentacosane
106. Caryophyllene oxide
107. 1-octanol
108. Hexanoic acid
109. (Z)-3-hexenol (105)

O
(106)
OH
(107)
O

OH
(108)
OH

(109)

(continued)
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs
845
Table 3 (continued)
846

Name of the plant and Model used for

S. no family Active constituent Chemical structure evaluation Part of plant used
27 Voacanga Africana 110. Voacangine O O
H
PTZ Whole plant
(Apocynaceae) 111. Voacamine H N NMDA
112. Vobustine N O
STR
H (110)
113. Amataine PIC
114. Akuammidine
115. Tabersonine NHO
N
116. Coronaridine
O
HN
O N
(111)

O
HO
N N
HN N
O
O
O O
(112)
O H
O N

O N (113)

O
N O
O
N
O HO

N
N
H

(114)
J. Pradhan et al.
 Name of the plant and Model used for
S. no family Active constituent Chemical structure evaluation Part of plant used
- - - N - -

O N
O H (115)
N

NH (116)
O O

28 Withania somnifera 117. Withaferin A HO O OH

MEZ Alcoholic extract of
(Solanaceae) 118. Sitoindoside IX O O PTZ plant
119. Sitoindoside X O (117)
OH
HO OH
HO O
O O OH
O O
O (118)
O
OH O
HO

HO O
O

O
O (119)

O
O
OH

a
Abbreviations: PTZ Pentylenetetrazole, MES Maximal Electroshock, NMDA N-Methyl-D-Aspartate, INH Isonicotinic acid, PIC Picrotoxin, STR Strychnine,
LPHE Lithium-Pilocarpine Hypoxic Episode, KA Kainic Acid, BIC Bicuculine, NKTM Nikethamide, TLE Temporal Lobe Epilepsy, SE Status Epilepticus, IPI
Initial precipitating injury, AEDs Antiepileptic drugs, HLTE Hind limb tonic extension, PHT Phenytoin, PB Phenobarbitone, GABA Gamma Amino Butyric Acid
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs
847
848 J. Pradhan et al.

Fig. 2 Important molecular targets for AEDs

point of view, different types of sodium channels can be distinguished regarding

their main subunits, and several of which have been cloned. Overlying sites of the
voltage-gated sodium channel are attacked through channel-blocking AEDs
[46–48].

Voltage-Gated Ca+ Channels

Voltage-gated calcium channels (Fig. 3b) mediate calcium influx that both controls
neuronal excitability and regulates calcium-sensitive intracellular signaling path-
ways. From their closed/resting state, calcium channels open when the membrane
potential depolarizes to a threshold point, at which the inner voltage sensor moves
and the channel confirmation modified to an open-pore calcium-conducting state. In
these channels, ion conduction only takes place in open state. Voltage-gated calcium
channels are responsible for burst firing and rhythm generation. Their contribution
to neurons membrane potential is also noted. Their pharmacological classification is
as follows: High voltage-activated (HVA); L-type, N- type, R-type (responsible for
calcium entry and expressed in nerve terminals); P/Q, and low voltage-activated
(LVA); T-type (having voltage threshold, which is low, transient current generation,
burst firing pattern, and critical to pacemaker activity) [49]. The α1 subunits with
auxiliary subunits, which include β subunits (β1–β4), γ subunits (γ1–γ8), and α2–δ
subunits [50–52].
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs 849

Fig. 3 a. Voltage-gated sodium channel; b. Voltage-gated calcium channel; c. Voltage-gated potas-

sium channel; d. HCN channel. In voltage-gated Na+ and Ca2+ channels, four domains (referred to
as I–IV or D1–D4) are expressed as a single polypeptide arranged around a central pore that con-
ducts the ionic current. In voltage-gated K+ channels, the channel is a tetramer of four individual
subunits, each of which contains a single S1–S6 domain. In all of the voltage-gated channels, four
reentrant pore loops (P-loops) between the S5 and S6 segments form the external mouth of the
ion channel

Voltage-Gated K + Channels

For limiting excitability in neural cells, K + channels (Fig. 3c) are the main targets.
α-Subunit, which comprises the ion-conduction pore, selectivity filter, and gating
apparatus, and various auxiliary subunits that serve modulatory roles, is responsible
for the formation of voltage-gated potassium channel. The typical K+ channel is a
tetramer of individual subunits, each one of which is homologous to a domain of the
pore-forming α or α1 subunits of voltage-gated Na+ or Ca2+ channels. There is clear
evidence that voltage-gated K+ channels are valid molecular targets for AEDs.
850 J. Pradhan et al.

HCN Channels

The hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels are

Na+ permeable and K+ permeable. In cardiac cells and neurons, they participate in
pacemaker currents. The negative membrane potential hyperpolarization (−50 mV)
leads to channel opening [53]. In addition, they are also modulated by cAMP bind-
ing to a consensus cyclic nucleotide-binding domain in the carboxy terminus.
Binding of cAMP shifts the voltage dependence of activation to more positive
potentials; it can also lead to the direct opening of the channels (Fig. 3d).

Voltage-Gated Chloride Channels (ClC)

The mammalian ClC gene family encodes nine Cl channels with diverse functions
in plasma membranes and intracellular organelles. One of these channels, ClC-2, a
homodimeric channel found in neurons and glia, has been implicated in epilepsy
and thus may be an important target for AEDs.

7.1.2 Ligand-Gated Ion Channels

Also known as inotropic receptors, ligand-gated ion channels open up in response

to the binding of a chemical messenger. They fall into three major superfamilies,
namely: the cys-loop receptors (pentameric in structure, comprising the GABAA,
glycine, nicotinic-cholinergic, and 5-HT3 receptors), the glutamate ionotropic
receptors (comprising the AMPA, kainate, and NMDA receptors), and the ATP-­
gated channels as shown in Fig. 4a–c.

Fig. 4 Ligand-gated ion channel; a.: Membrane topology diagram of cys-loop receptors- GABA,
Ach, and Glycine receptor channels; b. Glutamate receptor channel; c. ATP-gated channels
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs 851

With reference to AED binding, GABAA, nicotinic-cholinergic, and the gluta-

mate ionotropic receptors (AMPA and NMDA receptors) are of special importance.
Binding of agonist to these receptors induces a conformational change that opens
the channel. The cys-loop receptors vary in their ion selectivity. GABAA and glycine
receptors are permeable to Cl− and HCO3−, whereas nicotinic cholinergic receptors
are permeable mainly to Na+ and K+, but also to Ca2+. The ionotropic glutamate
receptors are also cation-permeable, with significant variation in the extent of Ca2+
permeability.
The majority of known natural or synthetic convulsant compounds act via the
ligand-gated ion channels, with the greatest number and variety acting to diminish
GABA-mediated transmission either by direct action on GABAA receptors or by
other effects on GABAergic function.

GABAA Receptors

Gamma amino butyric acid (GABA) is the main inhibitory neurotransmitter in the
brain. Inhibitory neurons that make use of GABA as neurotransmitter are found
throughout the brain, but in any region they may comprise a wide range of morpho-
logical and functional types that participate in different circuits with principal neu-
rons. Chemical agents that impair GABAergic inhibition are powerful convulsants,
and therefore, an increase in activity of GABA is associated with anticonvulsant
action. GABAA receptors have a pentameric structure, in which around central Cl−
pore five subunits are arranged like spokes of a wheel. Nineteen distinct genes
encode 19 subunits (α1–6, β1–3, γ1–3, δ, ε, θ, π, ρ1–2). Each subunit has four trans-
membrane segments, with both the amino and carboxy termini located extracellu-
larly. These extracellular segments form the recognition sites (two per channel) for
GABA and also, in some channel types, the recognition site (one per channel) for
benzodiazepine-like allosteric modulators [54]. The emerging understanding of the
different roles of phasic and tonic inhibition in epileptic phenomena may suggest
improved approaches to targeting GABAA receptors for epilepsy therapy.

Nicotinic Cholinergic Receptors

These receptors respond to the acetylcholine neurotransmitter. Autosomal dominant

nocturnal frontal lobe epilepsy happens usually during sleep [55] and has been
related to mutations in nicotinic acetylcholine receptors [56], and thus, these recep-
tors may be regarded as a substabtial target for the search of new AEDs. Like other
members of the cys-loop receptors, nicotinic cholinergic receptors are also pentam-
eric structures. In mammals, the 16 subunits (α 1– α 7, α 9, α 10, β 1– β 4, δ, ε, and
γ), each of which has four transmembrane domains, are encoded by 16 distinct genes.
852 J. Pradhan et al.

Glycine Receptors

These receptors are comparable GABAA receptor functionally and structurally.

They are cys-loop ligand-gated Cl− channels. They play a critical inhibitory func-
tion in the spinal cord and brain stem. Several endogenous ligands including gly-
cine, taurine, or betaine are able to open glycine receptors. Though, Glycine
receptors lack a functional role in the forebrain, so they are unlikely to be a useful
AED target.

Ionotropic Glutamate Receptors

Ionotropic glutamate receptors are tetrameric structures (Fig. 4b), which encompass
three receptor families identified by the agonists that selectively activate them:
AMPA, kainate, and NMDA. Each of the families has a specific set of subunits: four
for the AMPA receptors, five for the kainite receptors, and seven for the NMDA
receptors [57]. These channels mediate most of the fast excitatory transmission in
the central nervous system and are thus involved in all brain functions. Their exces-
sive activation plays a large role in epileptic phenomena, including the paroxysmal
depolarization shift and seizure discharges.

NMDA Receptors
NMDA receptors are blocked in a voltage-dependent fashion by means of Mg2+,
such that the open channels are in large part impermeable to ion flow at negative
membrane potentials (near the resting potential), due to retention of Mg2+ in the
channel pore.

AMPA Receptors
AMPA receptors are composed of four kinds of subunits, designated GluR1–4
(alternatively GluR A–D), which intrigate to form tetramers. AMPA receptors serve
as the primary mediators of fast excitatory neurotransmission in the mammalian
central nervous system, and changes in their cellular expression underlie forms of
synaptic plasticity. AMPA receptor antagonists may have antiepileptogenic activity,
if only by virtue of their capability to powerfully suppress the seizures.

7.1.3 Acid-Sensing Ion Channels (ASICs)

Acid-sensing ion channels are a family of proton-gated cation channels related to the
epithelial Na+ channels, which have diverse functions in metazoan cells. Six isoforms
have been cloned; these are widely expressed as homomeric or heteromeric channels
in the central and peripheral nervous systems. ASICs in sensory neurons are believed
to be involved in nociception when injury or inflammation causes acidification. The
functional roles of ASICs in the brain are less well understood.
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs 853

7.1.4 G-Protein-Coupled Receptors (GPCRs)

GPCRs comprise the largest set of therapeutic drug targets for known medicinal
agents. All GPCRs have an extracellular N-terminal, an intracellular C-terminal,
and seven α-helical transmembrane sections (Fig. 5). They are separated into three
chief classes, out of them of relevant importance here are the metabotropic gluta-
mate receptors (mGluRs) and the GABAB receptors, which play important roles in
controlling excitability at glutamatergic and GABAergic synapses. Any peptide
neurotransmitters, such as neuropeptide Y, galanin, somatostatin, and the enkepha-
lins and endorphins, which act at GPCRs, are inclusive in epileptic phenomena.

Metabotropic Glutamate Receptors

The metabotropic glutamate receptors are a family of eight G-protein receptors that
are categorized into three groups defined by their sequence homology, second mes-
senger effects, and common pharmacology. There is little evidence to indicate that
genetic alterations of mGluRs play a role in the pathogenesis of epilepsy.

GABAB Receptors

GABAB receptors were originally recognized as the receptors facilitating the

bicuculline-­insensitive, Cl−-independent repressive effects of GABA and
baclofen on sympathetic ganglion neurons and presynaptic terminals [58–61].
GABAB receptors are expressed presynaptically at GABAergic and glutamater-
gic synapses, wherein they act to diminute neurotransmitter release by reducing
Ca2+ entry. GABAB receptors are also expressed postsynaptically at GABAergic

Fig. 5 Membrane topology of G-protein-coupled (metabotropic) receptors

854 J. Pradhan et al.

synapses, where they produce a late hyperpolarization in response to synapti-

cally released GABA by enhancing K+ permeability through GIRKs. The upreg-
ulation of both GABAB receptor protein in corticothalamic circuits may contribute
to the seizure phenotype, and thus, these may be important targets for newer
AED search.

7.2 Enzymes as AED Targets

Two enzymes, GABA-transaminase and carbonic anhydrase, are recognized AED

targets.

7.2.1 GABA-Transaminase

GABA released from synapse is transported into astrocytes and nerve terminals,
where it is either taken up into synaptic vesicles or metabolized by two mitochon-
drial enzymes, GABA-transaminase (4-aminobutyrate-2-oxoglutarate aminotrans-
ferase) and succinic semialdehyde dehydrogenase, to yield succinate, a tricarboxylic
acid cycle intermediate. It was shown that inhibitors of GABA-transaminase raise
brain GABA content and inhibit seizures in rodents. But at the same time, it is also
reported that chronic inhibition of GABA-transaminase has a risk of retinal damage,
and that is why the utility of GABA-transaminase as an AED target remains
uncertain.

7.2.2 Carbonic Anhydrase

Carbonic anhydrase (carbonate dehydratase) is an enzyme present in various iso-

forms in most of the tissues, including the blood and brain. By controlling the rate
of hydration of CO2 and dehydration of bicarbonate (HCO3−), it modulates intra-
cellular and extracellular pH. Specifically, carbonic anhydrase inhibition causes
extracellular acidification because of interference with H+ buffering. Neuronal
excitability is influenced by pH in various ways – most important in epilepsy is
modulation of the functional consequences of GABAA receptor activation, which
occurs through intraneuronal carbonic anhydrase VII. Many clinically used AEDs
today are found to inhibit carbonic anhydrase, but because of the problem of toler-
ance, it has not been considered a promising target for new AED development.
This situation may change if the propensity for tolerance can be overcome, per-
haps by selective targeting of isoforms with intracellular–extracellular or neuro-
nal–astrocytic specificity.
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs 855

8 Computational Approach Towards Development of New

AEDs from Herbal Sources

Computer-aided drug design (CADD) approaches are useful tools to interpret and
guide experiments to expedite the drug design process. CADD is of two types, viz.
structure-based Drug Design (SBDD) and ligand-based Drug Design (LBDD). In
structure-based, the structural knowledge of target is considered, and in ligand-­
based knowledge of known ligands with their bioactivity is considered. There are
different methods available for identifying new drugs, which include 3D-QSAR,
Docking studies, MD simulation studies, and ADME properties [62]. Figure 6
shows the CADD application for searching and investigating new drugs.

Fig. 6 Application of computer-aided drug design (CADD) for the design of new drug
856 J. Pradhan et al.

8.1 Structure-Based Drug Design (SBDD)

In SBDD, the knowledge acquired from the binding site of a 3D macromolecule

structure is used to design and evaluate ligands based on their predicted interactions
with the protein-binding site. Thus, identification of a valid drug target and the
acquisition of its structural information are the first vital steps in SBDD. This
includes:
(a) Binding site prediction or identification
(b) Docking and scoring
(c) Flexibility and solvent effects

8.2 Ligand-Based Drug Design (LBDD)

In cases where the 3D structure of the target protein is lacking, information taken
from a set of ligands active against a target (receptor or enzyme) can be used to
detect important structural and physicochemical properties (molecular descriptors)
responsible for the detected biological activity. Here, there is an assumption that
structurally similar compounds display similar biological responses and interaction
with the target. The compound set should encompass a wide range of concentrations
(at least four orders of magnitude) to generate a reliable ligand-based screening
model. Common ligand-based design techniques are:
(a) Quantitative structure–activity relationship (QSAR)
(b) Pharmacophore modeling
(c) Compound selection
(d) Specificity
Docking-Based Virtual Screening Molecular docking is used to predict the binding
mode of ligands within the binding site of target proteins. Various docking software
are available inclusive of Schrodinger, Autodock Vina, Molegro, etc., which differ
based on scoring function and conformational sampling. Docking calculation is
done to investigate the binding affinity between compounds and targets. Different
target proteins are downloaded from the Protein Data Bank.

MD Simulation MD simulation provides information about the internal motions of

the receptor–ligand complex with time. It is a widely used method to understand the
properties of the structure and the microscopic interaction between them. Different
MD simulation programs are available including Desmond. The conformation
gained afterward MD simulation is more stable than molecular docking
conformation.
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs 857

CADD comprises several stages:

(a) Target identification: In this stage, target associated with the specific disease is
identified.
(b) Target validation: In this stage, target role in disease phenotype is considered.
In this stage, the target is bound to a partner molecule to check its capability to
regulate the body’s biological functions.
(c) Lead identification: This stage necessitates the discovery of chemical entities
that have potency against biological targets, and it is assumed that the making
of such drug can cure disease.
(d) Lead optimization: In this stage, the lead compound properties and potency
improved through iterative cycles. For the development of safe and efficient
drugs, both in vivo and in vitro experiments are performed to select candidates.
For determining pharmacodynamic and pharmacokinetic property, structure–
activity relationship (SAR) is developed.
(e) Preclinical stage: This stage is inclusive of synthesis and formulation research
of the drug, involves drug synthesis and formulation research, for checking tox-
icity and potency in vivo animal studies conducted.
(f) Clinical trials: This stage is inclusive of three phases, which include investiga-
tion of properties such as its efficacy, adverse drug reaction, dosage, its safety,
and pharmacokinetic and pharmacological properties of the candidate drug on
human body.
For the development of new AEDs from herbal sources, one may consider to follow
several steps mentioned below:
1. Identify the target among various molecular targets for which the drug is to be
developed. A detailed understanding of the underlying cause of the disease is
required for this stage.
2. Validate the selected target to find out its capacity to regulate biological func-
tions in the body after binding to a partner molecule.
3. For lead identification, consider the library of phyto-constituents as mentioned in
the present chapter and identify the degree of potency and specificity against the
selected biological target with the help of Structure-Based Drug Design Studies.
4. Lead optimization to obtain a compound with more effectiveness, less toxicity,
increased absorption. Optimizing lead is inclusive of some techniques, which are
as follows: structural genomics, computational biology, molecular modeling.
5. Preclinical and Clinical trials to finally get a new drug candidate to the market.
Various phyto-constituents mentioned in this chapter can be subjected to
Computational studies including molecular docking, molecular dynamics simula-
tion, pharmacophore modeling, etc., to find out their binding mode with target pro-
teins, and thus can serve as a potential database for the development of new, safer,
and effective AEDs. A detailed description of these computational techniques is
beyond the scope of this chapter. Readers are suggested to refer to the books and
articles published specifically for this purpose.
858 J. Pradhan et al.

9 Conclusion and Perspective

Despite the scientific progress in understanding the pathophysiological processes

related to seizure initiation, amplification, and propagation in the brain, and despite
the large number of first- and second-generation AEDs available on the pharmaceu-
tical market, there are still approximately 30% of epilepsy patients that are inade-
quately treated with the current frontline antiepileptic drugs. For these patients, the
most appropriate therapeutic option is presumably the combined administration of
two or more AEDs – each having its own limitations and adverse effects that can
lead to treatment failure or reduce the patient’s quality of life. Thus, there is a need
for new, more effective and potential, third-generation anticonvulsant drugs for
intractable epilepsies. Besides, nature is a rich source of biological and chemical
diversity and a number of plants in the world have been used in traditional medicine
remedies, including anticonvulsant one. The present chapter gives an account of
medicinal plants showing anticonvulsant properties having chemically diverse
phyto-constituents responsible for the said effects. Over the past few decades,
researchers have focused on drug discovery from herbal medicines. An information
from the structural characterization of molecular targets, along with better under-
standing of their function, may allow for more selective targeting for AEDs. The
chemical structure of the chief bioactive constituents presented in this chapter may
provide a database for computer-aided drug design, which, by using various
approaches of drug discovery along with the knowledge of molecular targets for the
AEDs, may lead to novel, third-generation AEDs for the treatment of intractable
epilepsies.

References

1. Tripathi K (2018) Essential of medical pharmacology. Jaypee Brothers, Medical Publishers

Pvt. Limited, New Delhi
2. WHO (2005) Epilepsy: the disorder. Epilepsy Atlas, pp 15–28. http://www.who.int/mental_
health/neurology/Epilepsy_disorder_rev1.pdf
3. Devinsky O, Vezzani A, O’Brien TJ, Jette N, Scheffer IE, De Curtis M, Perucca P (2018)
Epilepsy. Nat Rev Dis Prim 4:18024
4. Berkovic FS, Mulley CJ, Scheffer EI, Petrou S (2006) Human epilepsies: interaction of
genetic and acquired factor. Trends Nuerosci 29(7):391–397. https://doi.org/10.1016/j.
tins.2006.05.009
5. Engle J Jr (1989) Commission on classification and terminology of the international league
against epilepsy, “Proposal for revised classification of epilepsies and epileptic syndromes”.
Epilepsia 30:389–399
6. Ciecka J (1982) Book reviews: book reviews. Rev Soc Econ 40(1):76–78. https://doi.
org/10.1080/00346768200000024
7. Sirven Joseph I (2015) Epilepsy: a spectrum disorder. Cold Spring Harb Perspect Med 5.
https://doi.org/10.1101/cshperspect.a022848
8. Perucca P, Scheffer IE, Kiley M (2018) The management of epilepsy in children and adult.
Med J Aust:226–233. https://doi.org/10.5694/mja17.00951
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs 859

9. Giridhar BN, Srinivasu CC, Raju PT, Lakshmana DN (2015) Estimation of trace elements
concentration in anti-epileptic medicinal plants by using EDXRF. Int J Sci Res (IJSR)
4(2):211–216. https://doi.org/10.21275/SUB15931
10. Beghi E (2019) The epidemiology of epilepsy. Neuroepidemiology:1–7. https://doi.
org/10.1159/000503831
11. Patrick K, Steven SC, Martin BJ (2011) Drug resistance epilepsy. Eng J Med:919–926. https://
doi.org/10.1056/NEJMra1004418
12. Rajakulendran S, Hanna MG (2016) The role of calcium channels in epilepsy. Cold Spring
Harb Perspect Med. https://doi.org/10.1101/cshperspect.a022723
13. Kohl M, Paulsen O (2010) The roles of GABAB receptor in cortical network activity. Adv
Pharmacol:205–229. https://doi.org/10.1016/S1054-­3589(10)58009-­8
14. Go T (2004) Carbamazepine-induced IgG1 and IgG2 deficiency associated with B cell matura-
tion defect. Seizure:187–190. https://doi.org/10.1016/S1059-­1311(03)00086-­4
15. Lasoń W, Chlebicka M, Rejdak K (2013) Research advances in basic mechanisms of sei-
zures and antiepileptic drug action. Pharmacol Rep:787–801. https://doi.org/10.1016/
S1734-­1140(13)71060-­0
16. Hass M, Forbush B III (2009) The Na-K-Cl cotrnasporte of secretory epithelia. Annu Rev
Physiol 62:15–34
17. Sen A, Martinian L, Nikolic M, Walker MC, Thom M, Sisodiya SM (2007) Increased NKCC1
expression in refractory human epilepsy. Epilepsy Res:220–227. https://doi.org/10.1016/j.
eplepsyres.2007.01.004
18. Arun SK, Ekta R, Abdul W, Satyendra RK (2015) Pharmacoresistant epilepsy: a current update
on non-conventional pharmacological and non-pharmacological interventions. J Epilepsy Res
5(1). https://doi.org/10.14581/jer.15001
19. Meador KJ, Gilliam FG, Kanner AM, Pellock JM (2001) Cognitive and behavioral effects
of antiepileptic drugs. Epilepsy Behav 2:SS1–SS17. https://doi.org/10.1006/ebeh.2001.0235
20. Karaya A, Burak O, Selçuk İ, Co M (2019) Epilepsy & behavior serum NGF levels may be
associated with intrauterine antiepileptic exposure-related developmental problems. Epilepsy
Behav:60–66. https://doi.org/10.1016/j.yebeh.2019.05.013
21. Dana-Haeri J, Oxley J, Richens A (1984) Pitutary responsiveness to gonadotrophin-releasing
and thyrotrophin-releasing hormone in epileptic patients reciving carbamazepine or phenytoin.
Clin Endocrinol:163–168. https://doi.org/10.1111/j.1365-­2265.1984.tb00071.x
22. Spina E, Perucca E (2002) Clinical significance of pharmacokinetic interactions between anti-
epileptic and psychotropic drugs. Epilepsia:37–44. https://doi.org/10.1046/j.1528-­1157.2002
.043s2037.x
23. Vecht JC, Wagner LG, Wilms BE (2003) Interaction between antiepilectic and chemotherapeu-
tic drugs. Lancet Neurol:404–409. https://doi.org/10.1016/S1474-­4422(03)00435-­6
24. Isojärvi JIT (1993) Serum lipid levels during carbamazepine medication. Arch Neurol:17–20.
https://doi.org/10.1001/archneur.1993.00540060030012
25. Mintzer S, Mattson RT (2009) Should enzyme-inducing antiepileptic drugs be considered
first-line agents. Epilepsia:42–50. https://doi.org/10.1111/j.1528-­1167.2009.02235.x
26. Ahmed SN, Siddiqi AZ (2006) Antiepileptic drugs and liver disease. Seizure:156–164. https://
doi.org/10.1016/j.seizure.2005.12.009
27. Arroyo S, Morena A (2001) Life-threatening adverse events of antiepileptic drugs. Epilepsy
Res:155–174. https://doi.org/10.1016/S09201211(01)00306-­0
28. Sheth RD (2004) Bone health in epilepsy. Lancet Neurol:516. https://doi.org/10.1016/
S1474-­4422(04)00848-­8
29. Musa A, Haluk S, Ercan M (2003) Evaluation of bone mineral density with dual x-ray absorp-
tiometry for osteoporosis in children with bladder augmentation. J Pediatr Surg:230–232.
https://doi.org/10.1053/jpsu.2003.50050
30. Ludwig B, Marsan CA (1975) Clinical ictal pattern in epileptic patients with occipital electro-
encephalographic foci. Neurology:463–471. https://doi.org/10.1212/wnl.25.5.463
860 J. Pradhan et al.

31. Hermann B, Meador JK, Gaillard DW, Cramer AJ (2010) Cognition across the lifes-
pan: antiepileptic drugs, epilepsy, or both? Epilepsy Behav:1–5. https://doi.org/10.1016/j.
yebeh.2009.10.019
32. Blumer D, Montouris G, Hermann B (1995) Psychiatric morbidity in seizure patients on
a neurodiagnostic monitoring unit. Neuropsychiatry Clin Neurosci:445–456. https://doi.
org/10.1176/jnp.7.4.445
33. Cramer JA, Mintzer S, Wheless J, Mattson RH (2010) Adverse effects of antiepileptic drugs:
a brief overview of important issues. Expert Rev Neurother:885–891. https://doi.org/10.1586/
ern.10.71
34. Besag Frank MC (2004) Behavioural effects of the newer antiepileptic drugs: an update.
Expert Opin Drug Saf:1–8. https://doi.org/10.1517/14740338.3.1.1
35. Parker WA, Shearee CA (1979) Phenytoin hepatotoxicity: a case report and review.
Neurology:175–178. https://doi.org/10.1212/wnl.29.2.175
36. Anderson GD (2002) Children versus adults: pharmacokinetic and adverse-effect differences.
Epilepsia:53–59. https://doi.org/10.1046/j.15281157.43.s.3.5.x
37. Arif H, Buchsbaum R, Weintraub D, Koyfman S, Salas-Humara C, Bazil CW, Resor SR,
Hirsch LJ (2007) Comparision and predictors of rash associated with 15 antiepileptic drugs.
Neurology:1701–1709. https://doi.org/10.1212/01.wnl.0000261917.83337.db
38. Perucca P, Gilliam GF (2012) Adverse effects of antiepileptic drugs. Lancet Neurol:792–802.
https://doi.org/10.1016/S1474-­4422(12)70153-­9
39. Fricke-Galindo I, Jung-cook H, Lerena A, Lopez-Lopez M (2018) Pharmacogenetics of
adverse reactions to antiepileptic drugs. Neurologia:165–176. https://doi.org/10.1016/j.
nrl.2015.03.005
40. Moore TJ, Weiss SR, Kaplan S Blaisdell CJ (2002) Reported adverse drug events in infants
and children under 2 years of age. Pediatrics:1–5. https://doi.org/10.1542/peds.110.5.e53
41. Mathis LL, Lyasu S (2007) Safety monitoring of drugs granted exclusivity under the best phar-
maceuticals for children act: what the FDA has learned. Clin Pharm Therap:133–134. https://
doi.org/10.1038/sj.clpt.6100285
42. McSherry E (1978) Acidosis and growth in nonuremic renal disease. Kidney Int:349–354.
https://doi.org/10.1038/ki.1978.135
43. Camfield P, Camfield C (2006) Monitoring for adverse effects of antiepileptic drugs.
Epilepsia:31–34. https://doi.org/10.1111/j.15281167.2006.00657.x
44. Liu W, Ge T, Pan Z, Leng Y, Lv J, Li B (2017) The effects of herbal medicine on epilepsy.
Oncotarget:48385–48397. https://doi.org/10.18632/oncotarget.16801
45. Pradhan J, Sunita P (2018) Herbal therapies for epilepsy: chemistry, biology and potential
applications of selected plants and compounds. Chem Biol Interface 8(4):205–224
46. Tripathi M, Reddy P, Rawat D (2014) Chemistry and biology interface. Chem Biol 4:1–22
47. Ragsdale D, McPhee J, Scheuer T, Catterall W (1994) Molecular determinants of state-­
dependent block of Na+ channels by local anesthetics. Science:1724–1728. https://doi.
org/10.1126/science.8085162
48. Ragsdale D, McPhee J, Scheuer T, Catterall W (1996) Common molecular determinants of
local anesthetic, antiarrhythmic, and anticonvulsant block of voltagegated Na+ channels. Proc
Natl Acad Sci:9270–9275. https://doi.org/10.1073/pnas.93.17.9270
49. Yarov-Yarovoy V, Brown J, Sharp EM, Clare JJ, Scheuer T, Catterall WA (2001) Molecular
determinants of voltage-dependent gating and binding of pore-blocking drugs in transmem-
brane segment IIIS6 of the Na+ channel alpha subunit. J Biol Chem:20–27. https://doi.
org/10.1074/jbc.M006992200
50. Drew CDM (2000) Instant pharmacology. Postgrad Med J 76(896):381–381a. https://doi.
org/10.1136/pmj.76.896.381a
51. Ffrench-Mullen JM, Barker JL, Rogawski MA (1993) Calcium current block by (−)-pen-
tobarbital, phenobarbital, and CHEB but not (+)-pentobarbital in acutely isolated hippo-
campal CA1 neurons: comparison with effects on GABA-activated Cl- current. J Neurosci
13(8):3211–3221. https://doi.org/10.1523/jneurosci.1308-­03211.1993
Phyto-Constituents as Potential Leads for the Development of Novel Antiepileptic Drugs 861

52. Stefani A, Spadoni F, Siniscalchi A, Bernardi G (1996) Lamotrigine inhibits Ca2+ currents
in cortical neurons: functional implications. Eur J Pharmacol 307:113–116. https://doi.
org/10.1016/0014-­2999(96)00265-­8
53. Pisani A, Bonsi P, Martella G, De Persis C, Costa C, Pisani F, Bernardi G, Calabresi P (2004)
Intracellular calcium increase in epileptiform activity. Epilepsia 45(7):719–728. https://doi.
org/10.1111/j.0013-­9580.2004.02204.x
54. Hainsworth HA, Nicolle MCL, Alexey P, Toni S, Andrew RD (2003) Actions of sipatrigine,
202W92 and lamotrigine on R-type and T-type Ca2+ channel currents. Eur J Pharmacol
467(1–3):77–80. https://doi.org/10.1016/S0014-­2999(03)01625-­X
55. Arias RL, Bowlby RM (2005) Pharmacological characterization of antiepileptic drugs and
experimental analgesics on low magnesium-induced hyperexcitability in rat hippocampal
slices. Brain Res 1047(2):233–244. https://doi.org/10.1016/j.brainres.2005.04.052
56. Monaghan EP, McAuley JW, Data JL (1999) Ganaxolone: a novel positive allosteric modu-
lator of the GABA(A) receptor complex for the treatment of epilepsy. Expert Opin Investig
Drugs 8(10):1663–1671. https://doi.org/10.1517/13543784.8.10.1663
57. Scheffer IE, Bhatia KP, Lopes-Cendes I, Fish DR, Marsden CD, Andermann E, Andermann
F, Desbiens R, Keene D, Cendes F, Manson JI, Constantinou JEC, Mclntosh A, Berkovic SF
(1995) Autosomal dominant nocturnal frontal lobe epilepsy. Brain 118(1):61–73. https://doi.
org/10.1093/brain/118.1.61
58. Steinlein OK, Mulley JC, Propping P, Wallace RH, Phillips HA, Sutherland GR, Scheffer
IE, Berkovic SF (1995) A missense mutation in the neuronal nicotinic acetylcholine receptor
α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet
11(2):201–203. https://doi.org/10.1038/ng1095-­201
59. Mayer ML, Armstrong N (2004) Structure and function of glutamate receptor ion channels.
Annu Rev Physiol 66(1):161–181. https://doi.org/10.1146/annurev.physiol.66.050802.084104
60. Bowery NG, Smart TG (2006) GABA and glycine as neurotransmitters: a brief history. Br J
Pharmacol 147:109–119. https://doi.org/10.1038/sj.bjp.0706443
61. Bowery NG, Hill DR, Hudson AL, Middlemiss DN, Shaw J, Turnbull M (1980) (−)Baclofen
decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA
receptor. Nature 283(5742):92–94. https://doi.org/10.1038/283092a0
62. Brogi S (2019) Computational approaches for drug discovery. Molecules 24(17):3061. https://
doi.org/10.3390/molecules24173061
Role of Polyphenols in Cardiovascular
Diseases

Hitesh Chopra, Shabana Bibi, Yugal Kishore Mohanta, Sony Kumari,

and Atif Amin Baig

1 Introduction

Polyphenols are naturally occurring compounds found in a broad range of foods and
beverages. Polyphenol concentrations in fresh fruit range between 200 and 300 mg
per 100 g. They contain a lot of polyphenols, which may be found in the goods
made from these fruits. In a serving of red wine, tea, or coffee, polyphenols may
vary from 100 to 200 mg. Chocolate and cocoa beans contain high levels of poly-
phenols [1–3].
Polyphenols, plant secondary metabolites, have two primary functions: UV pro-
tection and disease defense. Color, flavor, aroma, and oxidative stability are all
directly influenced by polyphenols. For cancer, cardiovascular disease, diabetes,
osteoporosis, and neurological illnesses, epidemiological studies and meta-analyses

H. Chopra
Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
S. Bibi
Department of Biosciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan
Y. K. Mohanta
Nano-biotechnology and Translational Knowledge Laboratory, Department of Applied
Biology, University of Science and Technology Meghalaya (USTM), Techno City, Baridua,
Ri-Bhoi, Meghalaya, India
e-mail: [email protected]
S. Kumari
Department of Applied Biology, University of Science and Technology Meghalaya,
Ri-Bhoi, India
A. A. Baig (*)
University Institute of Public Health, Faculty of Allied Health Sciences, The University of
Lahore, Lahore, Pakistan
Institute of Molecular Biology & Biotechnology, The University of Lahore, Lahore, Pakistan

© The Author(s), under exclusive license to Springer Nature 863

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_35
864 H. Chopra et al.

suggest that dietary polyphenols may be beneficial [4–17]. Polyphenols and other
dietary phenolics are increasingly studied for their potential health benefits. Food
polyphenols and their effects on health and sickness are the focus of this research
project. Phytochemicals are substances that plants make for their own benefit. The
phrase “essential nutrient” may describe non-essential plant components. Individual
nutrients’ impacts on health remain unknown, but the benefits of eating a diet rich
in fruits and vegetables have long been recognized by the general public. If you eat
a plant-based diet, the health benefits of specific phytochemicals are linked to those
of the foods that contain those phytochemicals [5–7, 9].
Polyphenols are secondary compounds found in plants. Flavonoids (flavonols,
flavones, flavanones, isoflavones, proanthocyanidins) and stilbenes and lignans are
molecules that make up phenolic acids (hydroxybenzoic and hydroxycinnamic
acids). Phenolic chemicals increase the flavor and nutritional value of fruits in vari-
ous ways [18–22]. The antioxidant characteristics of phenolic compounds might
help protect against LDL, platelet aggregation, and damage to red blood cells [23].
Antimutagens, anticarcinogens, antimicrobials, and clarifiers are all phenolics’
other properties [24–33]. These chemicals impact the color, astringency, and bitter-
ness of red wine [34, 35]. Fruit and vine stems and yeast metabolism may both
produce these by-products. Phenolics also serve as oxygen reservoirs and browning
substrates. Polyphenols’ biological properties are influenced by their bioavailabil-
ity. It is governed by their chemical structure as to how quickly they are absorbed in
the intestines. Green tea’s catechins and citrus fruits’ flavanones have a high bio-
availability [36]. An assessment of intestinal absorption may be made by looking at
the antioxidant capacity of plasma following polyphenol-rich food consumption.
Flavonoids’ plasma concentration decreases after they are ingested. Because plasma
albumin has a significant affinity for quercetin, it has a longer elimination half-life.
Antioxidants such as glycosylated flavonoids are found in abundance [37].
Cardiovascular disease is influenced by both environmental and hereditary factors.
Variables including physical activity, smoking, and a diet heavy in saturated fat
increase the prevalence of cardiovascular disease (CVD) [38]. As a result, it is dif-
ficult to pinpoint a single reason for many ailments in this population. There is
strong evidence that diets high in polyphenols, such as those found in tea and cocoa,
may improve cardiovascular health [39]. The consumption of flavanols, flavonols,
and flavones was associated with an increased risk of coronary heart disease (CHD)
[40–43]. Flavanones and anthocyanins reduced cardiovascular disease deaths [44–
47]. Those who drank three cups of tea a day reduced their risk of cardiovascular
disease by 11% [48].
Many people argue over which polyphenols are best for reducing heart disease.
Flavonoids, which are found in chocolate and soy, have lower cardiovascular dis-
ease risk [39]. Reduced blood pressure, increased endothelial function, and
decreased platelet adhesion have been linked to antioxidant effects on low-density
lipoprotein (LDL). A diet high in flavanols from cocoa may lessen the risk of car-
diovascular disease and hypertension [39]. Hypertension risk may be reduced by
Role of Polyphenols in Cardiovascular Diseases 865

drinking one cup of black tea daily [49]. Short-term tea consumption had no effect
in lowering blood pressure [50].
Endothelial cell bioavailability of nitric oxide may be influenced by polypheno-
lic chemicals, which impact an enzyme known as nitric oxide synthase [51, 52].
Polyphenols may cause endothelium-dependent relaxation [9]. Black tea and purple
grape juice have been shown to reduce platelet activation and aggregation [53–55].
Flavanols and flavonoids may be used to prevent vascular damage [56]. Polyphenols
have been shown to positively impact cardiovascular health via a wide range of
epidemiological studies (as shown in Fig. 1) [57]. Overall mortality risk was
inversely linked to polyphenol intake from diverse sources, such as red wine,
almonds, and olive oil, in the PREDIMED trial [58, 59]. Polyphenol intake was a
substantial risk factor for heart disease in the same study. A lot of factors must be
considered while analyzing observational data. It is possible that eating more
polyphenol-­rich plant foods and reducing your diet of animal foods will improve
your health. Polyphenol consumption estimates may be skewed by a recall, portion
size, and the likely polyphenol content of similar meals. In this kind of investiga-
tion, several variables might make it difficult to pinpoint the underlying reason. An
observational study is the first step in conducting controlled intervention research.
Clinical trials that include specific phenolic compounds and phenolic-rich extracts
or meals should be considered [58, 59].

Fig. 1 Uses of polyphenols in cardiovascular disorders

866 H. Chopra et al.

2 Risk Factors for CVD

2.1 Diabetes

Early vascular anomalies may be seen before diagnosis or be linked to pre-diabetic

phases; therefore, treating diabetes as a risk factor for CVD prevention is essential.
There is a negative impact on prognosis at glucose concentrations as low as
5.6 mmol/l (101 mg/dl) on fasting plasma glucose concentrations linearly and sig-
nificantly associated with cardiovascular disease risk [60]. This includes glucose
concentrations below the diabetes threshold. EpiDREAM data showed an increased
risk of cardiovascular illness in those with and without diabetes, those with impaired
fasting glucose or impaired glucose tolerance, and those newly diagnosed with dia-
betes (CVD) [61]. According to a study, 1 mmol/l increase in fasting plasma glucose
was linked to a 17% increase in cardiovascular events or death [61]. People with a
reduced risk of cardiovascular diseases (CVD), such as children and nonsmokers,
are vulnerable to hyperglycemia because of their increased risk of diabetes. 7
Diagnosis and treatment of dysglycemia as a long-term risk factor, such as treating
high cholesterol or high blood pressure, may be more effective in preventing cardio-
vascular disease than focusing on particular blood sugar levels. Diabetes and cardio-
vascular disease share many pathophysiological pathways. While hyperglycemia
directly influences atherosclerosis formation and progression, other pathophysio-
logic variables such as hyperinsulinemic, insulin-resistant, and dyslipidemic states
also play a role. Hyperinsulinemia, which activates several inflammatory signaling
pathways, may aggravate the cardiovascular disease, whereas dyslipidemia may
enhance mitochondrial malfunction and cell death due to mitochondrial dysfunction
[62, 63]. These activities damage the heart and circulatory system, resulting in
macro- and microvascular diseases.
Microvascular dysfunction and metabolic abnormalities accompany diabetes and
heart failure (HF) in the pathogenesis of heart failure, which goes beyond the simple
macrovascular effects of diabetes, such as cardiomyopathy. The heart is also affected
by diabetes and metabolic, structural, and functional changes. Diabetic cardiomy-
opathy is caused only by these changes in the heart, without any accompanying
cardiac problems (DMCMP). Obese and hypertensive women and men with left
ventricular hypertrophy and systolic dysfunction have been linked to the develop-
ment of diastolic dysfunction due to chronic high blood sugar and oxidative stress.
DMCMP may appear in various ways, including as a symptom [62, 63]. Early
DMCMP fibrosis and increased LV stiffness, which may lead to HF symptoms,
were not influenced by diabetes duration or metabolic control quality [64]. Because
of a lack of HF patients in clinical research, the prevalence of HF in diabetes is
overestimated at 19–26% [64]. Risk factors for diabetic heart failure (HF) that are
not directly linked to blood glucose levels are also related to the condition.
Sulfonylureas, insulin, metformin, and insulin detemir are all popular diabetes med-
ications. When it comes to estimating the risk of HF in diabetics, it seems that more
criteria beyond blood glucose levels should be taken into account. Diabetes patients
Role of Polyphenols in Cardiovascular Diseases 867

with type 2 diabetes who had intensive or regular glycaemic therapy had no change
in heart failure rates, according to a meta-analysis that included 37,229 individuals
[65]. A cohort study of 271,174 people with T2DM from the Swedish National
Diabetes Register and 1,355,870 matched controls found that 22 people under the
age of 55 with T2DM who had several risk factors (HbA1c, LDL-cholesterol, blood
pressure, albuminuria, and smoking) outside the target had the highest risk of hos-
pitalization for HF.
Hospitalization for heart failure was associated with atrial fibrillation, a high
BMI, and higher HbA1c and renal function [66]. Diabetes-related high blood pres-
sure (HDH) may cause a decreased or increased ejection fraction (HEF) (HFpEF).
In individuals with type 2 diabetes, HFpEF has overtaken HFrEF as the most fre-
quent form of ventricular dysfunction, and T2DM is becoming an increasingly
important role in the pathogenesis of LV dysfunction [63, 67].

2.2 Cholesterol

Due to inadequate delivery of oxygen, working muscles in heart develops acute

coronary syndrome (ACS), cardiomyopathy, or heart failure. There is an acute coro-
nary syndrome, which comprises unstable angina pectoris and sudden death [68].
When a plaque ruptures, a thrombus is generated. This is the first step in the throm-
bosis process. Plaque erosion may be the initial sign of acute coronary syndrome in
up to a quarter of patients. Atherothrombosis is also caused by activated macro-
phages and T lymphocytes, both inflammatory reactions. A patient’s cardiovascular
collateral reserve and occlusion level impact clinical outcomes [68].
Atherosclerotic plaques associated with acute coronary syndromes may be cate-
gorized based on their structural properties. Inflammatory cells proliferate, necrotic
cores are tiny, and smooth muscle is absent from susceptible plaque. Several factors
lead to a rise in plaque in the body, including high blood pressure, diabetes, high
LDL, low HDL, and a high ACE level. In contrast, individuals with minimal risk
factors have firm plaques with strong fibrous caps, weak necrotic cells, and a dense
extracellular matrix with little inflammatory material in them. Meta-analysis of
90,056 people showed that a reduction in LDL of 38.6 mg/dl resulted in a 20%
decrease in major cardiovascular events [69]. Statin treatment improved plaque sta-
bility and lowered mortality, acute coronary syndrome incidence, and recurrence of
coronary ischemia in MIRACLE [70]. According to the PROVE IT TIMI-22 clini-
cal study findings, atorvastatin was shown to be no more effective than high-dose
statins in lowering cardiovascular events [71]. All patients should be given large
doses of statins, regardless of their cholesterol levels, according to the 2017 ESC
STEMI recommendations. High dosages of statins and low LDL cholesterol levels
<70 mg/dL have been linked to decreased incidence of cardiovascular mortality in
individuals on evolocumab. Atherosclerosis is a common cause of peripheral arte-
rial disease in the lower limbs.
868 H. Chopra et al.

As a result, men who begin smoking at a young age are more likely to get the
disease [72]. The vast majority of peripheral artery disease-caused amputations
result from diabetes and smoking. Atherosclerosis causes the walls of blood vessels
to become thinner over time. Symptoms will begin to appear within a few months.
Fontaine and Rutherford are utilized to determine the severity of a patient’s illness
[73]. Studies have shown that the ankle-brachial index (ABI) is a risk factor for
coronary artery disease in patients with lower limb illnesses. In contrast, an abnor-
mally low ABI indicates a significant medical problem.
According to the 2017 European Society of Cardiology (ESC) recommenda-
tions, those with an initial LDL level of 70–135 mg/dL should have their cholesterol
lowered to 70 mg/dL or reduce their LDL levels by 50% [74]. Statin treatment has
been found to reduce overall and cardiovascular mortality in individuals with
peripheral arterial disease. There was a strong correlation between abdominal aortic
aneurysms and the presence of atherosclerotic cardiovascular disease. Patients with
abdominal aneurysms were typically discovered to have additional cardiovascular
problems. The risk of developing an aortic aneurysm increases with increasing age,
smoking, and having a male significant other [75]. While intimal atherosclerosis
and thrombosis are frequent, elastin fragmentation and persistent inflammation only
occur in aortic aneurysms.

2.3 Smoking

The risk of coronary heart disease (CHD) related to cigarette smoking may be quan-
tified using RR and excess risk [76]. Nonsmokers are more likely to die from coro-
nary heart disease (CHD) than smokers, according to the risk ratio (RR). To explain
the difference in illness rates between smokers and nonsmokers, the phrase “extra
risk” is employed.
Depending on the risk estimate you choose, your chance of developing coronary
heart disease (CHD) increases or decreases over time. The Cancer Prevention Study
II (CPS-II) data display the RRs and excess mortality rates by age group [76]. As the
RRs became older, they began to decrease rapidly (35–54 years old). According to
these new studies, tobacco-related heart attacks seem to be less prevalent among the
elderly. On the other hand, smokers’ mortality rates from coronary heart disease
(CHD) have been demonstrated to be inconsistent. People under the age of 35 are at
increased risk of coronary heart disease due to a lower mortality rate from CHD and
a higher incidence of coronary events among smokers. There was an increase in
smoking-related mortality from coronary heart disease (CHD) despite the RR
decreasing as people aged.
Role of Polyphenols in Cardiovascular Diseases 869

3 Phenolics in CVD

Increased platelet aggregation has been connected to the increased production of

PGs and TXA2, an extremely potent blood platelet activator through the thrombox-
ane receptor that functions as a proaggregator and vasoconstrictor mediator [77]. A
decrease in the production of TxA2 inhibits platelet aggregation and platelet plug
formation through COX inhibition. Platelet ARA pathway research has indicated
that PC may inhibit platelet aggregation in vitro. At low phenol concentrations, a
pomegranate PC-rich extract (POMx) has been demonstrated to have an antiplatelet
action, potentially blocking platelet aggregation [78]. In terms of ARA and collagen-­
induced platelet aggregation, POMx had the largest influence. PCs such as 8-­paradol,
daidzein, silychristineins, silybins, ginkgetin, apigenin, cycloheterophyllin, brous-
soflavonol F, quercetin, and hesperetin may be found in various plants (e.g., capers,
blueberries, radish, coriander, oregano, onion, asparagus, apples, tomato, cranber-
ries, lettuce, potato). These drugs greatly inhibit COX-1 [79–82]. Nurtjahja-­
Tjendraputra et al. investigated the COX-1 inhibitory effect of 8-paradol and
gingerol analogues [82]. 8-Paradol, not synthetic gingerol, produced the highest
COX-1 inhibitory impact (4 ± 1 M) (IC50 ± 20 M). Geranylgeraniol reduced ARA-­
induced TXB2 synthesis by 28.17%, 54.677%, and 80.44% at doses of 1, 10, and
100 nmol/mL, according to Calixto et al. Geranylgeraniol also inhibits PGE2 syn-
thesis regardless of the ARA dose [81]. This has an inhibition index of 49.1%,
69.6%, and 89.7% at these concentrations. According to these findings, PC seems to
be primarily focused on the COX-1 enzyme. According to Cheung et al., quercetin
and ginkgo biloba lowered COX-1 activity. Ginkgetin IC50 values varied from 100
to 200 mM. All COX-1 inhibitors crystallized with hydrogen bonds between Tyr
385 and Arg 120 [80]. Components like this encircled COX-1’s primary gate. Arg
120 and Tyr 355 of flavonoids’ phenolic oxygen create hydrogen bonds. Researchers
found that the 100 mM concentrations of COX-1 inhibitors daidzein and genistein
outperformed each other [79]. Daidzein was shown to have a 40% threshold impact.
Silybin, silychristin, and silydianin all inhibit COX-1; according to Bijak et al.,
Silychristin and silybin were the most potent inhibitors (IC50 35 and 60 mM,
respectively) [83]. In a computer simulation, both drugs inhibit COX-1’s active site.
Both PCs include tyrosine residues that interact with various enzymes [84].
Flurbiprofenum, a nonsteroid anti-inflammatory medication, has an 8.9 kcal/mol
binding mode to COX-1 active site entrance. COX-1 and COX-2 inhibition by phlo-
roglucinol is 45–74% and 49–72% at doses of 10–50 M (found in brown seaweed
but usually used as a synthetic drug). In animal studies, phloroglucinol (2.5 and
5 mol) decreased ex vivo platelet aggregation caused by ARA by 57–71% [85].
Another kind of PC is T-cell antagonists. Tectorigenin (from the lily Belamcanda
chinensis) is a competitive antagonist at the thromboxane receptor, much as acetyl-
salicylic acid or thromboxane synthases [86]. Certain PCs such as apigenin (parsley
and peppermint, as well as thyme), luteolin (oregano, peppermint), genistein, quer-
cetin, and carnosol (rosemary) may also be found in PCs [87]. Flavonoids with
double bonds in C2-C3 and keto groups in C4 can bind to TxA2 receptors. More
870 H. Chopra et al.

than ARA therapy, Ginsenoside Rk1 or Ajoene inhibited platelet formation of

12-12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) [88, 89].
The formation of AGEs has been linked to several non-communicable disorders
[90–93]. Consumption of glycated foodstuffs or in situ reactions due to normal
metabolism might lead to an increase in the buildup of AGE. Growth of the age an
increase in the protective systems, Glyoxalase I (AGE-R1 and Glyoxalase I), has
been shown to reduce insulin resistance, inflammation, and oxidative stress [94, 95].
High water content and moderate temperature are preferred in aging-reversing
dietary experiments. By Rodriguez et al., carboxymethyl-lysine levels in the blood
were reduced on a med diet (without alcohol) [96] (CML). Patients on medical diets
with or without coenzyme Q10 supplementation saw a reduction in serum CML
levels after 4 hours [97]. Boiling the turkey lowers the amount of malondialdehyde
(MDA) in an antioxidant-rich concentrate prepared from Chilean berries [98]. If
you consume 500 mL of water with a 250 g turkey burger, your postprandial MDA-­
triglycerides AUC decreases by 35% [98]. Subjects who consumed PC-cooked tur-
key (380 mg GAE) and berry concentrate drink (1.39 ± 0.05 mg GAE/g) in the
postprandial interval exhibited lower MDA and triglycerides. It has also been related
to cardiovascular disease (CVD) and a shorter lifespan in mammalian tissues
through the MDA-Lys adduct, which is formed when MDA reacts with amino acids
and proteins [99–101].
Possible interactions between PC and dicarbonyl and -unsaturated compounds
might decrease protein AGE formation [102, 103]. Canadian wild berries and tropi-
cal, medicinal herbs have anti-glycation capabilities because of their total PC con-
tent. One way PC extracts prevent AGE formation is by cell responses and the
elimination of reactive species directly. These antiglycation mechanisms, from gly-
oxalase 1 expression through proteasome and cathepsin D and L elimination, are
examples of prevention methods. The most efficient benzene rings were monohy-
droxylated, dihydroxylated, and trihydroxylated [92]. Flavonoids such as quercetin,
epicatechin, and anthocyanidines undergo metaglyoxal reactions [93, 104, 105].
The addition takes place in the A ring of the flavonoid. Stilbenes, which inhibit BSA
from glycating, have also been shown to be beneficial [106, 107]. An RCT in healthy
volunteers showed that it reduced plasma methylglyoxal by 16% after 4 weeks
[108]. Epicatechin and quercetin 3-glucoside increased plasma nmol/L
(2000 nmol/L) in healthy participants given the same dosages. Because quercetin
and epicatechin both have half-lives of 17 and 2 hours, these flavonoids may explain
the discrepancies in their effects [109]. When meals are cooked, the anti-glycating
activities of polyphenols (PC) need to be explored further because oxidation prod-
ucts may result in quinones that bind covalently to proteins [109].
Polyphenols may protect against the chemotherapy medication’s cardiotoxicity,
including arrhythmias, heart disease, and sudden death [110, 111]. Due to several
processes, these compounds are well recognized for their cardioprotective proper-
ties. These include suppressing ROS generation, mitochondrial dysfunction, apop-
tosis, and p53 activation inhibition. Researchers found evidence that
doxorubicin-induced cardiotoxicity was protected by kaempferol and resveratrol,
two flavonoid and phenolic compounds, but not cancer [112, 113]. There was no
Role of Polyphenols in Cardiovascular Diseases 871

denying that isorhamnetin was the most intriguing molecular entity discovered.
Doxorubicin’s antitumor efficacy was boosted, as well as its ability to protect
against cardiotoxicity [114, 115]. Centaurea borysthenica Gruner and Centaurea
daghestanica (Lipsky) Wagenitz have recently been studied for their phenolic con-
tent and cardioprotective effects [116]. Doxorubicin-exposed rat cardiomyocytes
were shown to be protected by both C. borysthenica, and C. daghestanica extracts.
In this investigation, C. daghestanica methanolic extracts had no effect on the effec-
tiveness of doxorubicin.
In addition, Alhaider’s team researched the cardioprotective properties of the
date palm, known in Arabic as Nakl (date). The total flavonoid, total phenolic, and
antioxidant capabilities of four date palm fruit extracts from eastern Saudi Arabia
were investigated using in vivo mice myocardial infarction models. Antioxidants
and heart-protective flavonoids found in fruit extracts have been linked to tissue
recovery after ischemia by mobilizing circulating progenitor cells from the bone
marrow to the site of myocardial infraction [117]. H9c2 cardiac cell lines were
exposed to oxidative stress, LDL oxidation, HMG-CoA reductase, angiotensin-­
converting enzyme regulation in vitro, and extract fractions of Syzygium cumini (L.)
Skeels seeds showed cardioprotective effects. Acids such as ellagic, cinnamic, feru-
lic, and quercetin make up the group of compounds. In experiments on H9c2 cardio-
myocytes, these fractions reduced oxidative stress, and molecular docking showed
a favorable link between phytochemical substances and enzymes essential for
avoiding cardiovascular disorders [118]. The heart-protective effects of Marrubium
vulgare L., an Iranian medicinal herb, were investigated in an in vivo Wistar rat
model. To determine the aqueous fraction of extract’s total phenolic and flavonoid
content, Langendroff analysis was utilised [119]. These two primary chemicals
from Aspalathus linearis (Burm.f.) R. Dahlgren may prevent myocardial infarction
caused by chronic hyperglycemia [120]. By opening the Ca2+-activated K+ channel
and activating protein kinase C, the isoflavone puerarin protects the heart against
damage caused by ischemia and reperfusion. In an in vivo rat model with cardiovas-
cular risk factors, Tian and his colleagues found that polyphenolic extracts from
apple peels were more cardioprotective than extracts from apple meat [121]. The
skin of an apple has more total flavonoids and total phenolics.
Human and animal studies have linked moderate alcohol use, especially red
wine, to an elevated risk of cardiovascular disease (CVD). Compared to those who
never drank at all, moderate alcohol intake may reduce the risk of death from heart
disease and other causes by 6–5 drinks per day in case–control studies and five
drinks per day in cohort studies [122]. It contains 14 grams of alcohol per serve.
Moderate use of alcohol offers more favorable effects than abstinence, but these
advantages are lost when consumption is excessive. Women benefit from a daily
alcohol intake of 3–30 grams, while males benefit from daily alcohol consumption
of 12–60 grams [123]. Rimm et al. found that drinking between 30 and 50 g of
alcohol per day may reduce the chance of having ischemic heart disease by 42%
[124]. Women in their 40 s and 50 s who consumed 5–24 g of alcohol per day low-
ered their risk for ischemic heart disease by 40% and total stroke by 40–50%,
872 H. Chopra et al.

according to Stampfer and colleagues [125]. Some epidemiological studies fail to

account for the effects of even modest drinking.
Alcohol usage has been linked to an elevated risk of cardiovascular disease for
more than half a century [46, 126]. St. Leger’s research in 1979 was the only one
that included red wine consumption; however, he did not identify the content of
alcohol in the wine. In 1992, Renaud et al. invented the French paradox [127].
Serum cholesterol levels were comparable to those in the United States and the
United Kingdom, but cardiovascular disease mortality was reduced, perhaps owing
to moderate red wine drinking. According to multiple studies, red wine consump-
tion has been linked with a lower risk of cardiovascular disease and all-cause mor-
tality since then [128–132]. There was a negative connection between cardiovascular
disease, stroke, and death in the Copenhagen Heart Study with wine intake but not
beer or spirits [133]. Another study by Grnbaek and colleagues found that wine
drinkers had 20% and 24% lower overall mortality rates than non-drinkers [134].
However, in most epidemiological investigations, wine outperformed other alco-
holic drinks, but not in case–control or prospective studies [134]. This meta-­analysis
could not determine that one form of alcoholic beverage was preferable to another
because of the wide variability in study design, consumption, and drink type.
Cardiovascular disease (CVD) risk may be reduced by drinking alcohol in modera-
tion [135].
According to Mostofsky et al., consuming alcohol has positive and negative
effects. Women who drank just one drink per day and often (three or more times per
week) had the lowest mortality risk [136] compared to women who abstained or
drank substantially more alcohol. Researchers found that the amount of alcohol
consumed per week that had the most negligible impact on health outcomes was
zero (95% confidence interval 0.0–0.8) standard drinks.
Natural chemical compounds studied against cardiovascular diseases worldwide
have been enlisted in Table 1.

4 Flavonoids

Egg yolk, red meat, and fish high in choline and betaine produce trimethylamine
N-oxide (TMAO). Proximal cecum and cecum anaerobic bacteria digest dietary
fibers with a bit of aid from the breakdown of protein and peptides to create them
[137]. Insulin sensitivity, glucose and fat metabolism are all affected by the pres-
ence of short-chain fatty acids (SCFAs). It has been established that SCFAs may
lower cardiovascular and metabolic disease risk factors [138]. TMAO and SCFA,
two bioactive chemicals generated by genetically modified organisms (GMOs), are
linked to chronic cardiovascular disease (CVD) [139, 140]. Thrombosis, hyperten-
sion, and heart failure have all been linked to alterations in the microbiota in the
human gut (as shown in Fig. 2) [142]. It has recently been demonstrated that GPCRs
may regulate blood pressure through activating GPRs, such as GPR3 and Olr78
(Olfr78). It is SCFAs that energize GPR41, GPR43, and Olfr78. GPR41 is an
Table 1 Natural chemical compounds studied against cardiovascular diseases worldwide

anthocyanidines Capsaicin Capsiate

Capsiconiate Cinnamic acid Dihydrocapsaicin

Role of Polyphenols in Cardiovascular Diseases

Dihydrocapsiate Dihydrocapsiconiate Doxorubicin

Ellagic acid Epicatechin eriodictyol

(continued)
873
Table 1 (continued)
874

Ferulic acid Hesperetin Homocapsaicin

Homodihydrocapsaicin Isorhamnetin Kaempferol

naringenin Nordihydrocapsaicin Nordihydrocapsiate

piperine Pterostilbene Puerarin

H. Chopra et al.
Role of Polyphenols in Cardiovascular Diseases 875

Stilbene

Trimethylamine oxide
resveratrol
Quercetin
876 H. Chopra et al.

Fig. 2 Cardiovascular disease and flavonoid metabolism are linked to gut bacteria. Ingesting cho-
line from dietary sources (such as cholesterol, phospholipids, and l-carnitine) allows the GM to
create TMA. Flavin monooxygenase is oxidized to generate TMAO in the liver, which subse-
quently enters the systemic circulation through the hepatic circulation. Foam cells and platelets
build when TMAO levels rise, disrupting cholesterol transport and encouraging the development
of atherosclerotic plaques. (Reproduced with permission from [141])

antagonistic ligand to Olfr78, which may trigger SCFAs and result in hypertension
[143, 144]. There’s no better place to start than in the gut when it comes to cancer.
SCFA stimulates GPR43 to offset the effects of Olfr78-mediated renin release
[145]. GPR41 and Olfr78 may have conflicting impacts on blood pressure control
following the propionate response [146, 147]. Vasoactive oxygen species generation
is decreased, monocyte chemoattractant protein levels fall, vascular leukocyte, neu-
trophil, and monocyte adhesion to the artery wall are reduced by angiotensin II
injection in aseptic mice.
Because of this, individuals with high plasma TMAO concentrations had a higher
risk of cardiovascular events throughout 3 years [148]. TMAO levels were reported
to be increased in mouse plaque and foam cells [149, 150]. TMAO improves angio-
tensin II’s pressor action on blood pressure (Ang II). As long as TMAO and Ang II
are administered simultaneously, the pressor effect may remain throughout the trial.
TMAO alone had little impact on rat blood pressure, but it increased the pressor
effect when combined with low-dose Ang II [151]. As angiopoietin-2 or angiopoi-
etin-­2 analogs are processed, TMAO may enhance the pressor activity of the recep-
tor proteins [152]. It was used to explore citrus flavonoids in a variety of cell types.
Hesperetin and naringenin both slowed the growth of apoB100 in HepG2 cells for
4 hours. If given to HepG2 cells, naringenin lowers the quantity of microsomal
transfer proteins and cholesterol acyltransferase that may be employed for lipopro-
tein formation [153–155].
Role of Polyphenols in Cardiovascular Diseases 877

To test this hypothesis, lemon peel polyphenols, such as eriodictyol and hesperi-
din, were added to a high-fat diet (HFD) in C57BL/6 mice [156]. In diabetic/dia-
betic mice (db/db), orange peel extract decreased liver fat and blood plasma levels.
In Wistar rats fed a high-cholesterol diet for 90 days, naringenin (50 mg/kg) was
shown to decrease plasma lipids and liver fat, as well as MMP gene expression and
macrophage infiltration indicators. Citrus flavonoid and tocotrienol intake reduced
total plasma cholesterol by 20–30%, LDL by 19–27%, and TG by 20–30% over
4 weeks (24–34%). For a year, people with moderate hypercholesterolemia were
shown to have lower total cholesterol, LDL cholesterol, and apoB. At 500 mg/day
for 24 weeks, individuals with hypertriglyceridemia had significant reductions in
their levels of both plasma triglycerides (TG) and apoB (apolipoprotein B). A big-
ger Japanese research found a link between frequent consumption of citrus fruits
(six to seven times weekly) and a lower risk of cardiovascular disease, especially
ischemic stroke (10,623 participants: 4147 men and 6476 women) [157]. There was
a decrease in fatty streak pattern and macrophage infiltration in rabbits fed with
naringin. Hypercholesterolemic rabbits’ endothelial cell ICAM-1 expression may
be reduced by naringin [158]. In rabbits with high plasma cholesterol, the antiath-
erogenic effects of naringin and naringenin may be due to their capacity to lower
aortic VCAM1 and MCP-1 expression. Dyslipidemia has been associated to abnor-
mally high apoB-containing lipoprotein levels [159]. To test this hypothesis, scien-
tists gave wild-type mice supplemental fat and naringin. Naringin may inhibit the
manufacture of apoB100 in HepG2 cells by activating a signalling cascade there
[160]. The antiatherogenic properties of naringenin were shown in Ldlr-/- mice
given a Western diet with 3% naringenin (w/w).
Flavones, a subtype of luteolin-rich flavonoids, work by signaling and activating
the cAMP/protein kinase A cascade, activating NO synthase, increasing endothelial
NO concentration [161]. This mechanism causes vasodilation, controlled by potas-
sium and calcium channels [162].
Inhibition of the renin-angiotensin-aldosterone system, improvement of endo-
thelial dysfunction, and regulation of smooth muscle contraction in vessels [163].
These methods work by activating NO-synthase 3, increasing plasma NO levels.
Endothelial function is improved by inhibiting endothelin-1 activity on smooth
muscle cells in arteries [164].
The antihypertensive impact of quercetin and kaempferol is reliant on NO pro-
duced in the endothelium, according to in vitro studies. Endothelial denudation sig-
nificantly reduced the vasodilator action of the two flavonols [165–167]. It may
activate potassium channels triggered by calcium and voltage-dependent potassium
channels, which is similar to quercetin’s vasodilatory impact in denuded endothe-
lium. The ability of naringenin to reduce blood pressure is attributable to both mem-
brane hyperpolarization and relaxing of vascular smooth muscle [168]. This
demonstrates naringenin’s therapeutic value in hypertension [169]. The second fla-
vanone, hesperetin, causes vasodilation through its active metabolite (hesperetin-­7-0-­
betaglucuronide) by boosting nitric oxide synthase adhesion and decreasing nitrous
oxide levels. Thus, NO levels rise in the plasma [170]. Vasodilation occurs when
intracellular calcium ions are reduced by inhibiting voltage-gated calcium channels
878 H. Chopra et al.

[171]. Many studies have indicated an inverse connection between flavonoid intake
and the incidence of acute myocardial infarction (AMI), and even problems after
AMI may be reduced by moderate red wine consumption [172]. Polyphenols (quer-
cetin, resveratrol) or diets rich in these chemicals (red wine or natural grape juice)
have been demonstrated to minimize cell suffering induced by myocardial ischemia
and improve contractile dysfunction after a heart attack. Following infarction, flavo-
noids protect myocardium cells by reducing oxidative stress and increasing NO
levels [172]. It has also been linked to a reduced risk of myocardial infarction in
young and middle-aged women [173].
In the case of brain ischemia, significant blood flow interruption causes meta-
bolic abnormalities. Local homeostatic disruptions (particularly ionic homeostasis,
acid–base balance) will trigger excessive production of excitatory amino acids.
These conditions enhance oxidative stress, causing neuronal death and tissue dam-
age. Flavonoids may help prevent ischemic strokes by lowering blood pressure,
increasing lipid oxidation, and improving endothelial function. Moreover, resvera-
trol may minimize the amount of injured tissue after ischemia in experimental mod-
els, presumably due to reduced lipid oxidation. Grape polyphenols may lower the
number of ischemia-affected neurons [174].

5 Stilbene in CVD

Since coronary heart disease mortality in southwest France was significantly

reduced despite high cholesterol consumption, saturated fat intake, and smoking,
the French paradox highlighted its cardioprotective capabilities [175]. French isch-
emic heart disease mortality rates were much lower than those in the United
Kingdom and the United States, according to the World Health Organization
(WHO). Heart health benefits were found despite having the same risk factors for
coronary heart disease, such as high blood pressure and BMI [176].
In a 1992 epidemiological study, Renaud explained the French paradox [127].
According to the latest research, those who drink wine are less likely to die from
coronary heart disease (CHD). For the French paradox, Renaud speculated that
wine’s ability to offset dairy fat consumption was responsible [127]. This is why
resveratrol, a red wine phenolic compound, caught the eye of biologists.
Angiogenesis, oxidative stress, cardiac hypertrophy, and ischemic-reperfusion dam-
age have all been shown to be improved by the use of stilbenoids. Stilobenoids that
have received the greatest attention include resveratrol, piceatannins, and gnetol.
When it comes to reducing CVD risk, resveratrol is beneficial [177]. However, res-
veratrol (2.5 mg/kg/day for 10 weeks) reduced wall stiffness in normal Wistar–
Kyoto rats. SHR rats treated with resveratrol had lower arterial compliance, perhaps
via reducing pro-growth ERK activation [178]. When administered to animals, res-
veratrol has an effect on blood pressure. Resveratrol has no effect on blood pressure
at low doses (2.5 mg/kg/day for 10 weeks), while it has a significant effect at high
doses (200 mg/kg/day for 4 weeks). In SHR, hydralazine (25 mg/kg/day) and
Role of Polyphenols in Cardiovascular Diseases 879

resveratrol (2.5 mg/kg/day) both decreased blood pressure more than either medica-
tion alone did [179]. Resveratrol might be used in combination with current drugs.
It was shown that resveratrol intake of 150 mg/day reduced blood pressure in indi-
viduals. Diastolic blood pressure is unaffected by resveratrol [180]. Pterostilbene’s
effect on blood pressure has been studied in a small number of human trials. There
were no significant differences in blood pressure between the two dosages of
Pterostilbene (125 mg twice a day vs. 50 mg twice a day) [181]. Resveratrol was
shown to inhibit platelet aggregation in animal and human studies [182, 183]. This
may be related to the COX-1 inhibitory effect of resveratrol (50 g/mL) on the ara-
chidonic acid pathway [184]. MAPK inhibition [185], nitric oxide/cGMP activation
[186], and phosphoinositide signaling inhibition [185] are further ways. Vascular
function, lipid accumulation, lipogenesis, and lipolysis gene regulation are all
affected by resveratrol [187, 188]. Resveratrol also lowers the apoptosis of endothe-
lial cells produced by oxidized LDL. Endothelial cells are similarly protected
against cell death by pterostilbene [189]. Pterostilbene activated AMPK and sup-
pressed mTOR in endothelial cells, resulting in cytoprotective autophagy [190].
Pterostilbene stimulated AMPK via the activation of CAMKK. TGF, TNF, IL-1, and
IL-6 have been shown to prevent atherosclerosis in mice by reducing pterostilbene’s
ability to inhibit cell proliferation and cell cycle progression in vascular smooth
muscle cells [191, 192]. Lipopolysaccharides, LDL cholesterol, and lipid peroxida-
tion in mice were reduced by piceatannol (15–45 mg/kg) [193, 194].
Cardiovascular disease has nitric oxide as an essential reactive nitrogen species
(RNS) in its pathogenesis. Although nitric oxide is a free radical because it lacks a
paired electron, this does not make it reactive. Oxidation of one of the guanidino
nitrogen atoms of L-arginine to L-citrulline in the presence of NADPH and O2 pro-
duces NO in the body [195]. It is produced by the endothelial NOS (eNOS) and is
essential for cardiovascular homeostasis (in endothelial cells, not in all cell types).
Low NO concentrations benefit the circulatory system by increasing blood flow, but
high NO concentrations have the opposite effect due to their reactive properties.
Treatment with resveratrol boosted eNOS mRNA expression in HUVEC and
HUVEC-derived EA.hy 926 cells [196]. eNOS protein expression and eNOS-­
derived NO production were increased after long-term resveratrol incubation.
Resveratrol’s cardiovascular effects may be attributed to increased eNOS expres-
sion and activity [197]. Resveratrol and quercetin decreased intracellular NO and
superoxide production in oxLDL, but not in HUVECs that had been exposed to
LDL [198].
Resveratrol is an antioxidant because of the aromatic groups in its structure.
2,2′-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), 1,1 diphenyl-2-­
picrylhydrazyl (DPPH), and the hydroxyl radical may be sequestered by resveratrol,
according to research [199]. Resveratrol has been shown to reduce oxidative-stress-­
induced apoptosis in PBMCs, RPE cells, rat pheochromacytoma cells, and mouse
3T3 fibroblasts, among others [200–202], because LDL oxidation is a key contribu-
tor to atherosclerosis, its antioxidant qualities may help prevent this illness.
Oxidation of LDL is prevented in vitro by resveratrol [203]. Reduced ROS produc-
tion and lipid peroxidation in atherosclerotic lesions have been shown by resveratrol
880 H. Chopra et al.

[204, 205]. According to researchers, resveratrol scavenges lipid peroxidation by

neutralizing lipid peroxyl or carbon-centered radicals [206]. There is an increase in
intracellular superoxide production with little doses of resveratrol [207].

6 Conclusion and Future Directions

Many foods contain polyphenols, which may protect against CVD and contribute to
a healthy diet via in vivo research. Getting a hold on the underlying processes is
difficult. This is exacerbated by the fact that many in vitro studies use low quantities
of polyphenols, which have little bioavailability and are rapidly transformed into
less harmful phenols, aldehides, and salicyates. For this reason, in vitro, antioxidant
capacity tests should not be used as a predictor of intra vivo antioxidant activity
because of their low bioavailability and rapid metabolism. Understanding the phar-
macological actions of dietary polyphenols on receptor, cell signaling, and gene
expression is becoming increasingly complex. In many cases, polyphenol metabolic
products may be just as powerful as their parent compounds, and the levels neces-
sary to activate these pathways are often orders of magnitude smaller than those
required for direct antioxidant activity.
When it comes to polyphenols, pharmacology has to return to its origins.
Polyphenols’ stability, absorption, distribution, and metabolism have been over-
looked in the design of in vitro tests to determine their mechanism of action.
Polyphenols and their metabolic products in cell culture need to be tested in animals
before being used in cell culture. As a result, persistent exposure to low concentra-
tions in live organisms cannot be modeled using a single big dosage. Each approach
exposes a diverse set of mechanisms, even if the end outcome (antioxidant protec-
tion, for instance) is the same.
It is important to understand the pharmacological mechanism by which polyphe-
nols have cardiovascular effects, not only for dietary advice but also for the develop-
ment of medications and nutraceuticals that target the same pathways as polyphenols.
An example of a semisynthetic drug, Diosmin, contains hesperidin as its active
component, widely used in Europe and the United States, particularly in the treat-
ment of vein ischemia [208, 209]. Rather than an antioxidant effect, diosmin has a
venous constriction way of action. Although polyphenols are capable of a wide
range of beneficial effects in humans, the first step in properly understanding their
pharmacological potential is to move away from the direct antioxidant notion.

References

1. Pandey KB, Rizvi SI (2009) Plant polyphenols as dietary antioxidants in human health and
disease. Oxidative Med Cell Longev 2:270–278
2. Ganesan K, Xu B (2017) A critical review on polyphenols and health benefits of black soy-
beans. Nutrients 9:455
Role of Polyphenols in Cardiovascular Diseases 881

3. Cory H, Passarelli S, Szeto J, Tamez M, Mattei J (2018) The role of polyphenols in human
health and food systems: a mini-review. Front Nutr 5:87
4. Edmands WMB, Ferrari P, Rothwell JA, Rinaldi S, Slimani N, Barupal DK, Biessy C, Jenab
M, Clavel-Chapelon F, Fagherazzi G et al (2015) Polyphenol metabolome in human urine
and its association with intake of polyphenol-rich foods across European countries. Am J
Clin Nutr 102. https://doi.org/10.3945/ajcn.114.101881
5. Gardener H, Caunca MR (2018) Mediterranean diet in preventing neurodegenerative dis-
eases. Curr Nutr Rep 7:10–20
6. ICW A, PCH H (2005) Polyphenols and disease risk in epidemiologic studies… Proceedings
of the 1st international conference on polyphenols and health held in Vichy, France, November
18–21, 2004. Am J Clin Nutr 81:317S–325S
7. Tresserra-Rimbau A, Rimm EB, Medina-Remón A, Martínez-González MA, de la Torre R,
Corella D, Salas-Salvadó J, Gómez-Gracia E, Lapetra J, Arós F et al (2014) Inverse association
between habitual polyphenol intake and incidence of cardiovascular events in the PREDIMED
study. Nutr Metab Cardiovasc Dis 24. https://doi.org/10.1016/j.numecd.2013.12.014
8. Vita JA (2005) Polyphenols and cardiovascular disease: effects on endothelial and platelet
function. Am J Clin Nutr 81:292S–297S
9. Yamagata K (2019) Polyphenols regulate endothelial functions and reduce the risk of cardio-
vascular disease. Curr Pharm Des 25. https://doi.org/10.2174/1381612825666190722100504
10. Arts ICW, Hollman PCH (2005) Polyphenols and disease risk in epidemiologic studies. Am
J Clin Nutr 81:317S–325S
11. Kocic B, Kitic D, Brankovic S (2013) Dietary flavonoid intake and colorectal cancer risk:
evidence from human population studies. J BUON 18:34
12. Hollman PCH, Katan MB (1997) Absorption, metabolism and health effects of dietary fla-
vonoids in man. Biomed Pharmacother 51. https://doi.org/10.1016/S0753-­3322(97)88045-­6
13. Khan J, Deb PK, Priya S, Medina KD, Devi R, Walode SG, Rudrapal M (2021) Dietary fla-
vonoids: cardioprotective potential with antioxidant effects and their pharmacokinetic, toxi-
cological and therapeutic concerns. Molecules 26:4021
14. Graf BA, Milbury PE, Blumberg JB (2005) Flavonols, flavones, flavanones, and human
health: epidemiological evidence. J Med Food 8:281–290
15. Beckman CH (2000) Phenolic-storing cells: keys to programmed cell death and periderm
formation in wilt disease resistance and in general defence responses in plants? Physiol Mol
Plant Pathol 57. https://doi.org/10.1006/pmpp.2000.0287
16. Spencer JPE, Abd El Mohsen MM, Minihane AM, Mathers JC (2008) Biomarkers of the
intake of dietary polyphenols: strengths, limitations and application in nutrition research. Br
J Nutr 99:12–22
17. Rodríguez-García C, Sánchez-Quesada C, Toledo E, Delgado-Rodríguez M, Gaforio JJ
(2019) Naturally lignan-rich foods: a dietary tool for health promotion? Molecules 24:917
18. Mutha RE, Tatiya AU, Surana SJ (2021) Flavonoids as natural phenolic compounds and
their role in therapeutics: an overview. Future J Pharm Sci 7. https://doi.org/10.1186/
s43094-­020-­00161-­8
19. Tungmunnithum D, Thongboonyou A, Pholboon A, Yangsabai A (2018) Flavonoids and
other phenolic compounds from medicinal plants for pharmaceutical and medical aspects: an
overview. Medicines 5. https://doi.org/10.3390/medicines5030093
20. Zhao J, Yang J, Xie Y (2019) Improvement strategies for the oral bioavailability of poorly
water-soluble flavonoids: an overview. Int J Pharm 570:118642
21. Kumar S, Pandey AK (2013) Chemistry and biological activities of flavonoids: an overview.
Sci World J 2013:162750
22. Panche AN, Diwan AD, Chandra SR (2016) Flavonoids: an overview. J Nutr Sci 5:e47
23. Amarowicz R, Pegg RB (2017) The potential protective effects of phenolic compounds
against low-density lipoprotein oxidation. Curr Pharm Des 23. https://doi.org/10.217
4/1381612823666170329142936
882 H. Chopra et al.

24. Bouarab Chibane L, Degraeve P, Ferhout H, Bouajila J, Oulahal N (2019) Plant antimicrobial
polyphenols as potential natural food preservatives. J Sci Food Agric 99:1457–1474
25. Leyva-Jimenez FJ, Lozano-Sanchez J, Borras-Linares I, de la Cadiz-Gurrea ML, Mahmoodi-­
Khaledi E (2019) Potential antimicrobial activity of honey phenolic compounds against gram
positive and gram negative bacteria. LWT 101. https://doi.org/10.1016/j.lwt.2018.11.015
26. Aguirre-Becerra H, Pineda-Nieto SA, García-Trejo JF, Guevara-González RG, Feregrino-­
Pérez AA, Álvarez-Mayorga BL, Rivera Pastrana DM (2020) Jacaranda flower (Jacaranda
mimosifolia) as an alternative for antioxidant and antimicrobial use. Heliyon 6. https://doi.
org/10.1016/j.heliyon.2020.e05802
27. Takó M, Kerekes EB, Zambrano C, Kotogán A, Papp T, Krisch J, Vágvölgyi C (2020) Plant
phenolics and phenolic-enriched extracts as antimicrobial agents against food-contaminating
microorganisms. Antioxidants 9:165
28. Mammadov R, Kaska A, Ozay C (2017) Phenolic composition, antioxidant and cyto-
toxic activities of Prospero autumnale. Indian J Pharm Sci 79. https://doi.org/10.4172/
pharmaceutical-­sciences.1000266
29. Yang CS, Landau JM, Huang MT, Newmark HL (2001) Inhibition of carcinogenesis by
dietary polyphenolic compounds. Annu Rev Nutr 21:386–406
30. Friedman MC (1997) Biochemistry, and dietary role of potato polyphenols. A review. J Agric
Food Chem 45:1523–1540
31. Olivas-Quintero S, López-Angulo G, Montes-Avila J, Díaz-Camacho SP, Vega-Aviña R,
López-Valenzuela JÁ, Salazar-Salas NY, Delgado-Vargas F (2017) Chemical composition
and biological activities of Helicteres vegae and Heliopsis sinaloensis. Pharm Biol 55. https://
doi.org/10.1080/13880209.2017.1306712
32. Chariyakornkul A, Punvittayagul C, Taya S, Wongpoomchai R (2019) Inhibitory effect of
purple rice husk extract on AFB1-induced micronucleus formation in rat liver through modu-
lation of xenobiotic metabolizing enzymes. BMC Complement Altern Med 19. https://doi.
org/10.1186/s12906-­019-­2647-­9
33. Mushtaq M, Sultana B, Anwar F, Batool S (2015) Antimutagenic and antioxidant potential of
aqueous and acidified methanol extracts from citrus limonum fruit residues. J Chil Chem Soc
60. https://doi.org/10.4067/S0717-­97072015000200025
34. Beaver C, Collins TS, Harbertson J (2020) Red wine phenolic compounds using ultraviolet –
visible spectra. Molecules 25:1–8
35. Fourie E, Aleixandre-Tudo JL, Mihnea M, du Toit W (2020) Partial least squares calibra-
tions and batch statistical process control to monitor phenolic extraction in red wine fermen-
tations under different maceration conditions. Food Control 115. https://doi.org/10.1016/j.
foodcont.2020.107303
36. Fang X, Azain M, Crowe-White K, Mumaw J, Grimes JA, Schmiedt C, Barletta M, Rayalam
S, Park HJ (2019) Effect of acute ingestion of green tea extract and lemon juice on oxidative
stress and lipid profile in pigs fed a high-fat diet. Antioxidants 8. https://doi.org/10.3390/
antiox8060195
37. Ahn-Jarvis JH, Parihar A, Doseff AI (2019) Dietary flavonoids for immunoregulation and
cancer: food design for targeting disease. Antioxidants 8:202
38. Buttar HS, Li T, Ravi N (2005) Prevention of cardiovascular diseases: role of exercise, dietary
interventions, obesity and smoking cessation. Exp Clin Cardiol 10:229–249
39. Katz DL, Doughty K, Ali A (2011) Cocoa and chocolate in human health and disease.
Antioxid Redox Signal 15:2779–2811
40. Huxley RR, Neil HAW (2003) The relation between dietary flavonol intake and coronary heart
disease mortality: a meta-analysis of prospective cohort studies. Eur J Clin Nutr 57:904–908
41. Lagiou P, Samoli E, Lagiou A, Tzonou A, Kalandidi A, Peterson J, Dwyer J, Trichpoulos D
(2004) Intake of specific flavonoid classes and coronary heart disease – a case-control study
in Greece. Eur J Clin Nutr 58. https://doi.org/10.1038/sj.ejcn.1602022
Role of Polyphenols in Cardiovascular Diseases 883

42. Rimm EB, Katan MB, Ascherio A, Stampfer MJ, Willett WC (1996) Relation between intake
of flavonoids and risk for coronary heart disease in male health professionals. Ann Intern
Med 125. https://doi.org/10.7326/0003-­4819-­125-­5-­199609010-­00005
43. Hirvonen T, Pietinen P, Virtanen M, Ovaskainen ML, Häkkinen S, Albanes D, Virtamo J
(2001) Intake of flavonols and flavones and risk of coronary heart disease in male smokers.
Epidemiology 12. https://doi.org/10.1097/00001648-­200101000-­00011
44. Bondonno NP, Dalgaard F, Kyrø C, Murray K, Bondonno CP, Lewis JR, Croft KD, Gislason
G, Scalbert A, Cassidy A et al (2019) Flavonoid intake is associated with lower mortal-
ity in the Danish diet cancer and health cohort. Nat Commun 10. https://doi.org/10.1038/
s41467-­019-­11622-­x
45. Peterson JJ, Dwyer JT, Jacques PF, McCullough ML (2012) Do flavonoids reduce cardiovas-
cular disease incidence or mortality in US and European populations? Nutr Rev 70:491–508
46. Kruger MJ, Davies N, Myburgh KH, Lecour S (2014) Proanthocyanidins, anthocyanins and
cardiovascular diseases. Food Res Int 59:41–52
47. Wallace TC (2011) Anthocyanins in cardiovascular disease. Adv Nutr 2:1–7
48. Gardner EJ, Ruxton CHS, Leeds AR (2007) Black tea – helpful or harmful? A review of the
evidence. Eur J Clin Nutr 61:3–18. https://doi.org/10.1038/SJ.EJCN.1602489
49. Li D, Wang R, Huang J, Cai Q, Yang CS, Wan X, Xie Z (2019) Effects and mechanisms of tea
regulating blood pressure: evidences and promises. Nutrients 11:E1115
50. Igho-Osagie E, Cara K, Wang D, Yao Q, Penkert LP, Cassidy A, Ferruzzi M, Jacques PF,
Johnson EJ, Chung M et al (2020) Short-term tea consumption is not associated with a reduc-
tion in blood lipids or pressure: a systematic review and meta-analysis of randomized con-
trolled trials. J Nutr 150. https://doi.org/10.1093/jn/nxaa295
51. Tuteja N, Chandra M, Tuteja R, Misra MK (2004) Nitric oxide as a unique bioactive signaling
messenger in physiology and pathophysiology. J Biomed Biotechnol 2004:227–237
52. Förstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart
J 33:829–837
53. Blumberg JB, Vita JA, Oliver Chen CY (2015) Concord grape juice polyphenols and car-
diovascular risk factors: dose-response relationships. Nutrients 7. https://doi.org/10.3390/
nu7125519
54. Duffy SJ, Vita JA, Holbrook M, Swerdloff PL, Keaney JF (2001) Effect of acute and chronic
tea consumption on platelet aggregation in patients with coronary artery disease. Arterioscler
Thromb Vasc Biol 21. https://doi.org/10.1161/01.ATV.21.6.1084
55. McEwen BJ (2014) The influence of diet and nutrients on platelet function. Semin Thromb
Hemost 40. https://doi.org/10.1055/s-­0034-­1365839
56. Rees A, Dodd GF, Spencer JPE (2018) The effects of flavonoids on cardiovascular health:
a review of human intervention trials and implications for cerebrovascular function.
Nutrients 10:1852
57. Peters U, Poole C, Arab L (2001) Does tea affect cardiovascular disease? A meta-analysis.
Am J Epidemiol 154. https://doi.org/10.1093/aje/154.6.495
58. Tresserra-Rimbau A, Rimm EB, Medina-Remón A, Martínez-González MA, López-­
Sabater MC, Covas MI, Corella D, Salas-Salvadó J, Gómez-Gracia E, Lapetra J et al (2014)
Polyphenol intake and mortality risk: a re-analysis of the PREDIMED trial. BMC Med 12.
https://doi.org/10.1186/1741-­7015-­12-­77
59. Tresserra-Rimbau A, Medina-Remón A, Pérez-Jiménez J, Martínez-González MA, Covas
MI, Corella D, Salas-Salvadó J, Gómez-Gracia E, Lapetra J, Arós F et al (2013) Dietary
intake and major food sources of polyphenols in a Spanish population at high cardiovascu-
lar risk: the PREDIMED study. Nutr Metab Cardiovasc Dis 23. https://doi.org/10.1016/j.
numecd.2012.10.008
60. Sarwar N, Gao P, Kondapally Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E,
Ingelsson E, Lawlor DA, Selvin E, Stampfer M et al (2010) Diabetes mellitus, fasting blood
glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102
884 H. Chopra et al.

prospective studies. Lancet (London, England) 375:2215–2222. https://doi.org/10.1016/

S0140-­6736(10)60484-­9
61. Anand SS, Dagenais GR, Mohan V, Diaz R, Probstfield J, Freeman R, Shaw J, Lanas F,
Avezum A, Budaj A et al (2012) Glucose levels are associated with cardiovascular disease and
death in an international cohort of normal glycaemic and dysglycaemic men and women: the
EpiDREAM cohort study. Eur J Prev Cardiol 19. https://doi.org/10.1177/1741826711409327
62. Low Wang CC, Hess CN, Hiatt WR, Goldfine AB (2016) Clinical update: cardiovascular
disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2
diabetes mellitus – mechanisms, management, and clinical considerations. Circulation 133.
https://doi.org/10.1161/CIRCULATIONAHA.116.022194
63. Paulus WJ, Dal Canto E (2018) Distinct myocardial targets for diabetes therapy in heart fail-
ure with preserved or reduced ejection fraction. JACC Heart Fail 6:1–7
64. Jia G, Hill MA, Sowers JR (2018) Diabetic cardiomyopathy: an update of mechanisms con-
tributing to this clinical entity. Circ Res 122:624–638
65. Castagno D, Baird-Gunning J, Jhund PS, Biondi-Zoccai G, MacDonald MR, Petrie MC,
Gaita F, McMurray JJV (2011) Intensive glycemic control has no impact on the risk of heart
failure in type 2 diabetic patients: evidence from a 37,229 patient meta-analysis. Am Heart J
162. https://doi.org/10.1016/j.ahj.2011.07.030
66. Rawshani A, Rawshani A, Franzén S, Sattar N, Eliasson B, Svensson A-M, Zethelius B,
Miftaraj M, McGuire DK, Rosengren A et al (2018) Risk factors, mortality, and cardiovas-
cular outcomes in patients with type 2 diabetes. N Engl J Med 379. https://doi.org/10.1056/
nejmoa1800256
67. Ernande L, Audureau E, Jellis CL, Bergerot C, Henegar C, Sawaki D, Czibik G, Volpi C,
Canoui-Poitrine F, Thibault H et al (2017) Clinical implications of echocardiographic phe-
notypes of patients with diabetes mellitus. J Am Coll Cardiol 70. https://doi.org/10.1016/j.
jacc.2017.07.792
68. Gach O, El Husseini Z, Lancellotti P (2018) Acute coronary syndrome. Rev Med Liege 73.
https://doi.org/10.29309/tpmj/2018.25.05.324
69. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T,
Peto R, Collins R, Simes R, Cholesterol Treatment Trialists’ (CTT) Collaborators (2005)
Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from
90 056 participants in 14 randomised trials of statins. Lancet 366. https://doi.org/10.1016/
S0140-­6736(05)67394-­1
70. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman
BR, Leslie S, Stern T (2001) Effects of atorvastatin on early recurrent ischemic events in
acute coronary syndromes the MIRACL study: a randomized controlled trial. J Am Med
Assoc 285. https://doi.org/10.1016/S1062-­1458(01)00368-­3
71. Mikhail N (2017) Effects of Evolocumab on cardiovascular events. Curr Cardiol Rev 13.
https://doi.org/10.2174/1573403x13666170918165713
72. Zieske AW, Takei H, Fallon KB, Strong JP (1999) Smoking and atherosclerosis in youth.
Atherosclerosis 144. https://doi.org/10.1016/S0021-­9150(98)00326-­8
73. Hardman RL, Jazaeri O, Yi J, Smith M, Gupta R (2014) Overview of classification systems
in peripheral artery disease. Semin Intervent Radiol 31:378–388
74. Soran H, Dent R, Durrington P (2017) Evidence-based goals in LDL-C reduction. Clin Res
Cardiol 106:237–248
75. Aune D, Schlesinger S, Norat T, Riboli E (2018) Tobacco smoking and the risk of abdominal
aortic aneurysm: a systematic review and meta-analysis of prospective studies. Sci Rep 8.
https://doi.org/10.1038/s41598-­018-­32100-­2
76. Jha P (2020) The hazards of smoking and the benefits of cessation: a critical summation
of the epidemiological evidence in high-income countries. elife 9. https://doi.org/10.7554/
ELIFE.49979
Role of Polyphenols in Cardiovascular Diseases 885

77. Warner TD, Nylander S, Whatling C (2011) Anti-platelet therapy: cyclo-oxygenase inhi-
bition and the use of aspirin with particular regard to dual anti-platelet therapy. Br J Clin
Pharmacol 72:619–633
78. Mattiello T, Trifirò E, Jotti GS, Pulcinelli FM (2009) Effects of pomegranate juice and extract
polyphenols on platelet function. J Med Food 12. https://doi.org/10.1089/jmf.2007.0640
79. Karlíčková J, Říha M, Filipský T, Macáková K, Hrdina R, Mladěnka P (2015) Antiplatelet
effects of flavonoids mediated by inhibition of arachidonic acid based pathway. Planta Med
82. https://doi.org/10.1055/s-­0035-­1557902
80. Wu CM, Wu SC, Chung WJ, Lin HC, Chen KT, Chen YC, Hsu MF, Yang JM, Wang JP, Lin
CN (2007) Antiplatelet effect and selective binding to cyclooxygenase (COX) by molecular
docking analysis of flavonoids and lignans. Int J Mol Sci 8. https://doi.org/10.3390/i8080830
81. Calixto NO, E Silva MCDC, Gayer CRM, Coelho MGP, Paes MC, Todeschini AR (2007)
Antiplatelet activity of geranylgeraniol isolated from Pterodon pubescens fruit oil is mediated
by inhibition of cyclooxygenase-1. Planta Med 73. https://doi.org/10.1055/s-­2007-­967177
82. Nurtjahja-Tjendraputra E, Ammit AJ, Roufogalis BD, Tran VH, Duke CC (2003) Effective
anti-platelet and COX-1 enzyme inhibitors from pungent constituents of ginger. Thromb Res
111. https://doi.org/10.1016/j.thromres.2003.09.009
83. Bijak M, Saluk-Bijak J (2017) Flavonolignans inhibit the arachidonic acid pathway in blood
platelets. BMC Complement Altern Med 17. https://doi.org/10.1186/s12906-­017-­1897-­7
84. Chang MC, Chang HH, Chan CP, Chou HY, Chang BE, Yeung SY, Wang TM, Jeng JH (2012)
Antiplatelet effect of phloroglucinol is related to inhibition of cyclooxygenase, reactive oxy-
gen species, ERK/p38 signaling and thromboxane A2 production. Toxicol Appl Pharmacol
263:287–295. https://doi.org/10.1016/J.TAAP.2012.06.021
85. Applová L, Karlíčková J, Říha M, Filipský T, Macáková K, Spilková J, Mladěnka P (2017)
The isoflavonoid tectorigenin has better antiplatelet potential than acetylsalicylic acid.
Phytomedicine 35. https://doi.org/10.1016/j.phymed.2017.08.023
86. Guerrero JA, Lozano ML, Castillo J, Benavente-García O, Vicente V, Rivera J (2005)
Flavonoids inhibit platelet function through binding to the thromboxane A2 receptor. J
Thromb Haemost 3. https://doi.org/10.1111/j.1538-­7836.2004.01099.x
87. Lee JJ, Jin YR, Lim Y, Hong JT, Kim TJ, Chung JH, Yun YP (2006) Antiplatelet activity of
carnosol is mediated by the inhibition of TXA2 receptor and cytosolic calcium mobilization.
Vasc Pharmacol 45. https://doi.org/10.1016/j.vph.2006.04.003
88. Srivastava KC, Tyagi OD (1993) Effects of a garlic-derived principle (ajoene) on aggregation
and arachidonic acid metabolism in human blood platelets. Prostaglandins Leukot Essent Fat
Acids 49. https://doi.org/10.1016/0952-­3278(93)90165-­S
89. Ju HK, Lee JG, Park MK, Park SJ, Lee CH, Park JH, Kwon SW (2012) Metabolomic
investigation of the anti-platelet aggregation activity of ginsenoside Rk1 reveals attenuated
12-HETE production. J Proteome Res 11. https://doi.org/10.1021/pr300454f
90. Hanssen NMJ, Wouters K, Huijberts MS, Gijbels MJ, Sluimer JC, Scheijen JLJM, Heeneman
S, Biessen EAL, Daemen MJAP, Brownlee M et al (2014) Higher levels of advanced gly-
cation endproducts in human carotid atherosclerotic plaques are associated with a rupture-­
prone phenotype. Eur Heart J 35. https://doi.org/10.1093/eurheartj/eht402
91. Rabbani N, Thornalley PJ (2018) Advanced glycation end products in the pathogenesis of
chronic kidney disease. Kidney Int 93:803–813
92. Lo CY, Hsiao WT, Chen XY (2011) Efficiency of trapping methylglyoxal by phenols and
phenolic acids. J Food Sci 76. https://doi.org/10.1111/j.1750-­3841.2011.02067.x
93. Totlani VM, Peterson DG (2006) Epicatechin carbonyl-trapping reactions in aqueous
Maillard systems: identification and structural elucidation. J Agric Food Chem 54. https://
doi.org/10.1021/jf061244r
94. Vlassara H, Cai W, Tripp E, Pyzik R, Yee K, Goldberg L, Tansman L, Chen X, Mani V,
Fayad ZA et al (2016) Oral AGE restriction ameliorates insulin resistance in obese individu-
als with the metabolic syndrome: a randomised controlled trial. Diabetologia 59. https://doi.
org/10.1007/s00125-­016-­4053-­x
886 H. Chopra et al.

95. Baye E, Kiriakova V, Uribarri J, Moran LJ, De Courten B (2017) Consumption of diets with
low advanced glycation end products improves cardiometabolic parameters: meta-analysis of
randomised controlled trials. Sci Rep 7. https://doi.org/10.1038/s41598-­017-­02268-­0
96. Rodríguez JM, Leiva Balich L, Concha MJ, Mizón C, Bunout Barnett D, Barrera Acevedo
G, Hirsch Birn S, Jiménez Jaime T, Henríquez S, Uribarri J et al (2015) Reduction of serum
advanced glycation end-products with a low calorie Mediterranean diet. Nutr Hosp 31.
https://doi.org/10.3305/nh.2015.31.6.8936
97. Lopez-Moreno J, Quintana-Navarro GM, Delgado-Lista J, Garcia-Rios A, Alcala-Diaz JF,
Gomez-Delgado F, Camargo A, Perez-Martinez P, Tinahones FJ, Striker GE et al (2018)
Mediterranean diet supplemented with coenzyme Q 10 modulates the postprandial metabo-
lism of advanced glycation end products in elderly men and women. J Gerontol A Biol Sci
Med Sci 73. https://doi.org/10.1093/gerona/glw214
98. Urquiaga I, Ávila F, Echeverria G, Perez D, Trejo S, Leighton F (2017) A Chilean berry concen-
trate protects against postprandial oxidative stress and increases plasma antioxidant activity
in healthy humans. Oxidative Med Cell Longev 2017. https://doi.org/10.1155/2017/8361493
99. Shao B, Pennathur S, Pagani I, Oda MN, Witztum JL, Oram JF, Heinecke JW (2010)
Modifying apolipoprotein A-I by malondialdehyde, but not by an array of other reactive
carbonyls, blocks cholesterol efflux by the ABCA1 pathway. J Biol Chem 285. https://doi.
org/10.1074/jbc.M110.118182
100. Pamplona R, Portero-Otín M, Riba D, Requena JR, Thorpe SR, López-Torres M, Barja G
(2000) Low fatty acid unsaturation: a mechanism for lowered lipoperoxidative modification
of tissue proteins in mammalian species with long life spans. J Gerontol A Biol Sci Med Sci
55. https://doi.org/10.1093/gerona/55.6.B286
101. Ruiz MC, Ayala V, Portero-Otín M, Requena JR, Barja G, Pamplona R (2005) Protein methi-
onine content and MDA-lysine adducts are inversely related to maximum life span in the
heart of mammals. Mech Ageing Dev 126. https://doi.org/10.1016/j.mad.2005.04.005
102. Ramkissoon JS, Mahomoodally MF, Ahmed N, Subratty AH (2013) Antioxidant and anti-­
glycation activities correlates with phenolic composition of tropical medicinal herbs. Asian
Pac J Trop Med 6. https://doi.org/10.1016/S1995-­7645(13)60097-­8
103. Harris CS, Cuerrier A, Lamont E, Haddad PS, Arnason JT, Bennett SAL, Johns T (2014)
Investigating wild berries as a dietary approach to reducing the formation of advanced glyca-
tion endproducts: chemical correlates of in vitro antiglycation activity. Plant Foods Hum Nutr
69. https://doi.org/10.1007/s11130-­014-­0403-­3
104. Kokkinidou S, Peterson DG (2013) Response surface methodology as optimization strategy
for reduction of reactive carbonyl species in foods by means of phenolic chemistry. Food
Funct 4. https://doi.org/10.1039/c3fo60032g
105. Li X, Zheng T, Sang S, Lv L (2014) Quercetin inhibits advanced glycation end product forma-
tion by trapping methylglyoxal and glyoxal. J Agric Food Chem 62. https://doi.org/10.1021/
jf504132x
106. Lv L, Shao XI, Wang L, Huang D, Ho CT, Sang S (2010) Stilbene glucoside from polygonum
multiflorum thunb.: a novel natural inhibitor of advanced glycation end product formation by
trapping of methylglyoxal. J Agric Food Chem 58. https://doi.org/10.1021/jf904122q
107. Shen Y, Xu Z, Sheng Z (2017) Ability of resveratrol to inhibit advanced glycation end product
formation and carbohydrate-hydrolyzing enzyme activity, and to conjugate methylglyoxal.
Food Chem 216. https://doi.org/10.1016/j.foodchem.2016.08.034
108. Van Den Eynde MDG, Geleijnse JM, Scheijen JLJM, Hanssen NMJ, Dower JI, Afman LA,
Stehouwer CDA, Hollman PCH, Schalkwijk CG (2018) Quercetin, but not epicatechin,
decreases plasma concentrations of methylglyoxal in adults in a randomized, double-blind,
placebo-controlled, crossover trial with pure flavonoids. J Nutr 148. https://doi.org/10.1093/
jn/nxy236
109. Dower JI, Geleijnse JM, Gijsbers L, Zock PL, Kromhout D, Hollman PCH (2015) Effects
of the pure flavonoids epicatechin and quercetin on vascular function and cardiometabolic
health: a randomized, double-blind, placebo-controlled, crossover trial. Am J Clin Nutr 101.
https://doi.org/10.3945/ajcn.114.098590
Role of Polyphenols in Cardiovascular Diseases 887

110. Zordoky BNM, Robertson IM, Dyck JRB (2014) Preclinical and clinical evidence for the role
of resveratrol in the treatment of cardiovascular diseases. Biochim Biophys Acta Mol basis
Dis 1852:1155–1177
111. Zhang N, Wei WY, Li LL, Hu C, Tang QZ (2018) Therapeutic potential of polyphenols in
cardiac fibrosis. Front Pharmacol 9:122
112. Han X, Gao S, Cheng Y, Sun Y, Liu W, Tang L, Ren D (2012) Protective effect of naringenin-­7-­
O-glucoside against oxidative stress induced by doxorubicin in H9c2 cardiomyocytes. Biosci
Trends 6. https://doi.org/10.5582/bst.2012.v6.1.19
113. Repo-Carrasco-Valencia R, Hellström JK, Pihlava JM, Mattila PH (2010) Flavonoids and
other phenolic compounds in Andean indigenous grains: Quinoa (Chenopodium quinoa),
kañiwa (Chenopodium pallidicaule) and kiwicha (Amaranthus caudatus). Food Chem 120.
https://doi.org/10.1016/j.foodchem.2009.09.087
114. Razavi-Azarkhiavi K, Iranshahy M, Sahebkar A, Shirani K, Karimi G (2016) The protective
role of phenolic compounds against doxorubicin-induced cardiotoxicity: a comprehensive
review. Nutr Cancer 68:892–917
115. Sun J, Sun G, Meng X, Wang H, Luo Y, Qin M, Ma B, Wang M, Cai D, Guo P et al (2013)
Isorhamnetin protects against doxorubicin-induced cardiotoxicity in vivo and in vitro. PLoS
One 8. https://doi.org/10.1371/journal.pone.0064526
116. Korga A, Józefczyk A, Zgórka G, Homa M, Ostrowska M, Burdan F, Dudka J (2017)
Evaluation of the phytochemical composition and protective activities of methanolic extracts
of Centaurea borysthenica and Centaurea daghestanica (Lipsky) Wagenitz on cardiomyocytes
treated with doxorubicin. Food Nutr Res 61. https://doi.org/10.1080/16546628.2017.134407
7
117. Alhaider IA, Mohamed ME, Ahmed KKM, Kumar AHS (2017) Date palm (Phoenix dac-
tylifera) fruits as a potential cardioprotective agent: the role of circulating progenitor cells.
Front Pharmacol 8:592. https://doi.org/10.3389/FPHAR.2017.00592/BIBTEX
118. Syama HP, Arya AD, Dhanya R, Nisha P, Sundaresan A, Jacob E, Jayamurthy P (2017)
Quantification of phenolics in Syzygium cumini seed and their modulatory role on tertiary
butyl-hydrogen peroxide-induced oxidative stress in H9c2 cell lines and key enzymes in car-
dioprotection. J Food Sci Technol 54. https://doi.org/10.1007/s13197-­017-­2651-­3
119. Garjani A, Tila D, Hamedeyazdan S, Vaez H, Rameshrad M, Pashaii M, Fathiazad F (2017)
An investigation on cardioprotective potential of Marrubium vulgare aqueous fraction against
ischaemia-reperfusion injury in isolated rat heart. Folia Morphol (Warsz) 76. https://doi.
org/10.5603/FM.a2017.0011
120. Dludla PV, Joubert E, Muller CJF, Louw J, Johnson R (2017) Hyperglycemia-induced oxida-
tive stress and heart disease-cardioprotective effects of rooibos flavonoids and phenylpyruvic
acid-2-O-β-D-glucoside. Nutr Metab 14:45
121. Tian J, Wu X, Zhang M, Zhou Z, Liu Y (2018) Comparative study on the effects of apple peel
polyphenols and apple flesh polyphenols on cardiovascular risk factors in mice. Clin Exp
Hypertens 40. https://doi.org/10.1080/10641963.2017.1313851
122. Piano MR (2017) Alcohol’s effects on the cardiovascular system. Alcohol Res 38:219–241
123. Wilsnack RW, Wilsnack SC, Kristjanson AF, Vogeltanz-Holm ND, Gmel G (2009) Gender
and alcohol consumption: patterns from the multinational GENACIS project. Addiction 104.
https://doi.org/10.1111/j.1360-­0443.2009.02696.x
124. Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ (1999) Moderate alcohol intake
and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic
factors. Br Med J 319. https://doi.org/10.1136/bmj.319.7224.1523
125. Thadhani R, Camargo CA, Stampfer MJ, Curhan GC, Willett WC, Rimm EB (2002)
Prospective study of moderate alcohol consumption and risk of hypertension in young
women. Arch Intern Med 162. https://doi.org/10.1001/archinte.162.5.569
126. Leger ASS, Cochrane AL, Moore F (1979) Factors associated with cardiac mortality in devel-
oped countries with particular reference to the consumption of wine. Lancet 313. https://doi.
org/10.1016/S0140-­6736(79)92765-­X
888 H. Chopra et al.

127. Renaud S, de Lorgeril M (1992) Wine, alcohol, platelets, and the French paradox for coro-
nary heart disease. Lancet 339. https://doi.org/10.1016/0140-­6736(92)91277-­F
128. Lippi G, Franchini M, Favaloro EJ, Targher G (2010) Moderate red wine consumption and
cardiovascular disease risk: beyond the French paradox. Semin Thromb Hemost 36:59–70
129. Haseeb S, Alexander B, Baranchuk A, Electrophysiology C (2017) Wine and cardiovascular
health a comprehensive review in depth. Circulation 136:1434–1448
130. Ditano-Vázquez P, Torres-Peña JD, Galeano-Valle F, Pérez-Caballero AI, Demelo-Rodríguez
P, Lopez-Miranda J, Katsiki N, Delgado-Lista J, Alvarez-Sala-Walther LA (2019) The fluid
aspect of the mediterranean diet in the prevention and management of cardiovascular disease
and diabetes: the role of polyphenol content in moderate consumption of wine and olive oil.
Nutrients 11:2833
131. Castaldo L, Narváez A, Izzo L, Graziani G, Gaspari A, Minno G, Di; Ritieni, A. (2019) Red
wine consumption and cardiovascular health. Molecules 24:3626
132. Hansen AS, Marckmann P, Dragsted LO, Finné Nielsen IL, Nielsen SE, Grønbæk M (2005)
Effect of red wine and red grape extract on blood lipids, haemostatic factors, and other risk
factors for cardiovascular disease. Eur J Clin Nutr 59. https://doi.org/10.1038/sj.ejcn.1602107
133. Truelsen T, Grønbæk M, Schnohr P, Boysen G (1998) Intake of beer, wine, and spirits and
risk of stroke: the Copenhagen City heart study. Stroke 29. https://doi.org/10.1161/01.
STR.29.12.2467
134. Gronbaek M, Becker U, Johansen D, Gottschau A, Schnohr P, Hein HO, Jensen G, Sorensen
TIA (2000) Type of alcohol consumed and mortality from all causes, coronary heart disease,
and cancer. Ann Intern Med 133. https://doi.org/10.7326/0003-­4819-­133-­6-­200009190-­00008
135. Klatsky AL (1999) Moderate drinking and reduced risk of heart disease. Alcohol Res Health
23:15–23
136. Mostofsky E, Mukamal KJ, Giovannucci EL, Stampfer MJ, Rimm EB (2016) Key findings
on alcohol consumption and a variety of health outcomes from the nurses’ health study. Am
J Public Health 106:1586–1591
137. Pingitore A, Chambers ES, Hill T, Maldonado IR, Liu B, Bewick G, Morrison DJ, Preston T,
Wallis GA, Tedford C et al (2017) The diet-derived short chain fatty acid propionate improves
beta-cell function in humans and stimulates insulin secretion from human islets in vitro.
Diabetes Obes Metab 19. https://doi.org/10.1111/dom.12811
138. Donohoe DR, Garge N, Zhang X, Sun W, O’Connell TM, Bunger MK, Bultman SJ (2011)
The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian
colon. Cell Metab 13. https://doi.org/10.1016/j.cmet.2011.02.018
139. Romano KA, Vivas EI, Amador-Noguez D, Rey FE (2015) Intestinal microbiota composition
modulates choline bioavailability from diet and accumulation of the proatherogenic metabo-
lite trimethylamine-N-oxide. MBio 6. https://doi.org/10.1128/mBio.02481-­14
140. Roberts AB, Gu X, Buffa JA, Hurd AG, Wang Z, Zhu W, Gupta N, Skye SM, Cody DB,
Levison BS et al (2018) Development of a gut microbe–targeted nonlethal therapeutic to
inhibit thrombosis potential. Nat Med 24. https://doi.org/10.1038/s41591-­018-­0128-­1
141. Li Q, Gao B, Siqin B, He Q, Zhang R, Meng X, Zhang N, Zhang N, Li M (2021) Gut micro-
biota: a novel regulator of cardiovascular disease and key factor in the therapeutic effects of
flavonoids. Front Pharmacol 12. https://doi.org/10.3389/fphar.2021.651926
142. Wilson Tang WH, Hazen SL (2017) The gut microbiome and its role in cardiovascular dis-
eases. Circulation 135. https://doi.org/10.1161/CIRCULATIONAHA.116.024251
143. Pluznick JL (2017) Microbial short-chain fatty acids and blood pressure regulation. Curr
Hypertens Rep 19:25
144. Natarajan N, Hori D, Flavahan S, Steppan J, Flavahan NA, Berkowitz DE, Pluznick
JL (2016) Microbial short chain fatty acid metabolites lower blood pressure via endo-
thelial G protein-coupled receptor 41. Physiol Genomics 48. https://doi.org/10.1152/
physiolgenomics.00089.2016
145. Chiou VL, Burotto M (2015) Pseudoprogression and immune-related response in solid
tumors. J Clin Oncol 33:3541–3543
Role of Polyphenols in Cardiovascular Diseases 889

146. Pluznick JL, Protzko RJ, Gevorgyan H, Peterlin Z, Sipos A, Han J, Brunet I, Wan LX, Rey F,
Wang T et al (2013) Olfactory receptor responding to gut microbiotaderived signals plays a
role in renin secretion and blood pressure regulation. Proc Natl Acad Sci U S A 110. https://
doi.org/10.1073/pnas.1215927110
147. Jia Q, Xie Y, Lu C, Zhang A, Lu Y, Lv S, Zhang J (2019) Endocrine organs of cardiovascular
diseases: gut microbiota. J Cell Mol Med 23:2314–2323
148. Tang TWH, Chen HC, Chen CY, Yen CYT, Lin CJ, Prajnamitra RP, Chen LL, Ruan
SC, Lin JH, Lin PJ et al (2019) Loss of gut microbiota alters immune system composi-
tion and cripples postinfarction cardiac repair. Circulation 139. https://doi.org/10.1161/
CIRCULATIONAHA.118.035235
149. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu
X, Chung YM et al (2011) Gut flora metabolism of phosphatidylcholine promotes cardiovas-
cular disease. Nature 472. https://doi.org/10.1038/nature09922
150. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L
et al (2013) Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes
atherosclerosis. Nat Med 19. https://doi.org/10.1038/nm.3145
151. Ufnal M, Jazwiec R, Dadlez M, Drapala A, Sikora M, Skrzypecki J (2014) Trimethylamine-­
N-­oxide: a carnitine-derived metabolite that prolongs the hypertensive effect of angiotensin
II in rats. Can J Cardiol 30. https://doi.org/10.1016/j.cjca.2014.09.010
152. Wu H, Kim M, Han J (2016) Icariin metabolism by human intestinal microflora. Molecules
21. https://doi.org/10.3390/molecules21091158
153. Borradaile NM, De Dreu LE, Huff MW (2003) Inhibition of net HepG2 cell apolipoprotein
B secretion by the citrus flavonoid naringenin involves activation of phosphatidylinositol
3-kinase, independent of insulin receptor substrate-1 phosphorylation. Diabetes 52. https://
doi.org/10.2337/diabetes.52.10.2554
154. Wilcox LJ, Borradaile NM, De Dreu LE, Huff MW (2001) Secretion of hepatocyte apoB is
inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of
ACAT2 and MTP. J Lipid Res 42. https://doi.org/10.1016/s0022-­2275(20)31634-­5
155. Mulvihill EE, Allister EM, Sutherland BG, Telford DE, Sawyez CG, Edwards JY, Markle
JM, Hegele RA, Huff MW (2009) Naringenin prevents dyslipidemia, apolipoprotein B over-
production, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resis-
tance. Diabetes 58. https://doi.org/10.2337/db09-­0634
156. Fukuchi Y, Hiramitsu M, Okada M, Hayashi S, Nabeno Y, Osawa T, Naito M (2008) Lemon
polyphenols suppress diet-induced obesity by up-regulation of mRNA levels of the enzymes
involved in β-oxidation in mouse white adipose tissue. J Clin Biochem Nutr 43. https://doi.
org/10.3164/jcbn.2008066
157. Yamada T, Hayasaka S, Shibata Y, Ojima T, Saegusa T, Gotoh T, Ishikawa S, Nakamura
Y, Kayaba K (2011) Frequency of citrus fruit intake is associated with the incidence of
cardiovascular disease: the Jichi Medical School cohort study. J Epidemiol 21. https://doi.
org/10.2188/jea.JE20100084
158. Choe SC, Kim HS, Jeong TS, Bok SH, Park YB (2001) Naringin has an antiatherogenic effect
with the inhibition of intercellular adhesion molecule-1 in hypercholesterolemic rabbits. J
Cardiovasc Pharmacol 38. https://doi.org/10.1097/00005344-­200112000-­00017
159. Vergès B (2015) Pathophysiology of diabetic dyslipidaemia: where are we? Diabetologia
58:886–899
160. Allister EM, Mulvihill EE, Barrett PHR, Edwards JY, Carter LP, Huff MW (2008) Inhibition
of apoB secretion from HepG2 cells by insulin is amplified by naringenin, independent of the
insulin receptor. J Lipid Res 49. https://doi.org/10.1194/jlr.M800297-­JLR200
161. Ciumărnean L, Milaciu MV, Runcan O, Vesa SC, Răchisan AL, Negrean V, Perné MG, Donca
VI, Alexescu TG, Para I et al (2020) The effects of flavonoids in cardiovascular diseases.
Molecules 25:4320
162. Scholz EP, Zitron E, Katus HA, Karle CA (2010) Cardiovascular ion channels as a molecular
target of flavonoids. Cardiovasc Ther 28:e46–e52
890 H. Chopra et al.

163. Pacurari M, Kafoury R, Tchounwou PB, Ndebele K (2014) The renin-angiotensin-­aldosterone

system in vascular inflammation and remodeling. Int J Inflamm 2014:689360
164. Sandoo A, Veldhuijzen van Zanten JJC, Metsios GS, Carroll D, Kitas GD (2015) The
endothelium and its role in regulating vascular tone. Open Cardiovasc Med J 4. https://doi.
org/10.2174/1874192401004010302
165. Olaleye MT, Crown OO, Akinmoladun AC, Akindahunsi AA (2014) Rutin and quercetin
show greater efficacy than nifedipin in ameliorating hemodynamic, redox, and metabolite
imbalances in sodium chloride-induced hypertensive rats. Hum Exp Toxicol 33. https://doi.
org/10.1177/0960327113504790
166. Calfío C, Huidobro-Toro JP (2019) Potent vasodilator and cellular antioxidant activity of
endemic patagonian calafate berries (berberis microphylla) with nutraceutical potential.
Molecules 24. https://doi.org/10.3390/molecules24152700
167. Abdallah HM, Hassan NA, El-Halawany AM, Mohamed GA, Safo MK, El-Bassossy HM
(2020) Major flavonoids from Psiadia punctulata produce vasodilation via activation of endo-
thelial dependent NO signaling. J Adv Res 24. https://doi.org/10.1016/j.jare.2020.01.002
168. Saponara S, Testai L, Iozzi D, Martinotti E, Martelli A, Chericoni S, Sgaragli G, Fusi F,
Calderone V (2006) (+/−)-Naringenin as large conductance Ca(2+)-activated K+ (BKCa)
channel opener in vascular smooth muscle cells. Br J Pharmacol 149:1013–1021. https://doi.
org/10.1038/SJ.BJP.0706951
169. Yang Y, Li PY, Cheng J, Mao L, Wen J, Tan XQ, Liu ZF, Zeng XR (2013) Function of BKCa
channels is reduced in human vascular smooth muscle cells from han chinese patients with
hypertension. Hypertension 61. https://doi.org/10.1161/HYPERTENSIONAHA.111.00211
170. Yamamoto M, Jokura H, Hashizume K, Ominami H, Shibuya Y, Suzuki A, Hase T,
Shimotoyodome A (2013) Hesperidin metabolite hesperetin-7-O-glucuronide, but not
hesperetin-3′-O-glucuronide, exerts hypotensive, vasodilatory, and anti-inflammatory activi-
ties. Food Funct 4:1346–1351. https://doi.org/10.1039/C3FO60030K
171. Liu Y, Niu L, Cui L, Hou X, Li J, Zhang X, Zhang M (2014) Hesperetin inhibits rat coronary
constriction by inhibiting Ca2+ influx and enhancing voltage-gated K+ channel currents of
the myocytes. Eur J Pharmacol 735. https://doi.org/10.1016/j.ejphar.2014.03.057
172. Vogel RA (2002) Alcohol, heart disease, and mortality: a review. Rev Cardiovasc Med 3:7–13
173. Cassidy A, Mukamal KJ, Liu L, Franz M, Eliassen AH, Rimm EB (2013) High anthocyanin
intake is associated with a reduced risk of myocardial infarction in young and middle-aged
women. Circulation 127. https://doi.org/10.1161/CIRCULATIONAHA.112.122408
174. Lin B (2012) Polyphenols and neuroprotection against ischemia and neurodegeneration. Mini
Rev Med Chem 11. https://doi.org/10.2174/13895575111091222
175. Ferrières J (2004) The French paradox: lessons for other countries. Heart 90:107–111
176. Artham SM, Lavie CJ, Milani RV, Ventura HO (2009) Obesity and hypertension, heart fail-
ure, and coronary heart disease – risk factor, paradox, and recommendations for weight loss.
Ochsner J 9:124–132
177. Magyar K, Halmosi R, Palfi A, Feher G, Czopf L, Fulop A, Battyany I, Sumegi B, Toth
K, Szabados E (2012) Cardioprotection by resveratrol: a human clinical trial in patients
with stable coronary artery disease. Clin Hemorheol Microcirc 50. https://doi.org/10.3233/
CH-­2011-­1424
178. Behbahani J, Thandapilly SJ, Louis XL, Huang Y, Shao Z, Kopilas MA, Wojciechowski P,
Netticadan T, Anderson HD (2010) Resveratrol and small artery compliance and r­ emodeling in
the spontaneously hypertensive rat. Am J Hypertens 23. https://doi.org/10.1038/ajh.2010.161
179. Thandapilly SJ, Louis XL, Behbahani J, Movahed A, Yu L, Fandrich R, Zhang S, Kardami
E, Anderson HD, Netticadan T (2013) Reduced hemodynamic load aids low-dose resvera-
trol in reversing cardiovascular defects in hypertensive rats. Hypertens Res 36. https://doi.
org/10.1038/hr.2013.55
180. Liu Y, Ma W, Zhang P, He S, Huang D (2015) Effect of resveratrol on blood pressure: a
meta-analysis of randomized controlled trials. Clin Nutr 34. https://doi.org/10.1016/j.
clnu.2014.03.009
Role of Polyphenols in Cardiovascular Diseases 891

181. Riche DM, Riche KD, Blackshear CT, McEwen CL, Sherman JJ, Wofford MR, Griswold
ME (2014) Pterostilbene on metabolic parameters: A randomized, double-blind,
and placebo-­ controlled trial. Evid Based Complement Altern Med 2014. https://doi.
org/10.1155/2014/459165
182. Olas B, Wachowicz B, Saluk-Juszczak J, Zieliński T (2002) Effect of resveratrol, a natural
polyphenolic compound, on platelet activation induced by endotoxin or thrombin. Thromb
Res 107. https://doi.org/10.1016/S0049-­3848(02)00273-­6
183. Stef G, Csiszar A, Lerea K, Ungvari Z, Veress G (2006) Resveratrol inhibits aggregation of
platelets from high-risk cardiac patients with aspirin resistance. J Cardiovasc Pharmacol 48.
https://doi.org/10.1097/01.fjc.0000238592.67191.ab
184. Zbikowska HM, Olas B, Wachowicz B, Krajewski T (1999) Response of blood platelets to
resveratrol. Platelets 10. https://doi.org/10.1080/09537109976103
185. Olas B, Wachowicz B, Holmsen H, Fukami MH (2005) Resveratrol inhibits polyphos-
phoinositide metabolism in activated platelets. Biochim Biophys Acta Biomembr 1714.
https://doi.org/10.1016/j.bbamem.2005.06.008
186. Shen MY, Hsiao G, Liu CL, Fong TH, Lin KH, Chou DS, Sheu JR (2007) Inhibitory mecha-
nisms of resveratrol in platelet activation: pivotal roles of p38 MAPK and NO/cyclic GMP. Br
J Haematol 139. https://doi.org/10.1111/j.1365-­2141.2007.06788.x
187. Ou HC, Chou FP, Sheen HM, Lin TM, Yang CH, Huey-Herng Sheu W (2006) Resveratrol, a
polyphenolic compound in red wine, protects against oxidized LDL-induced cytotoxicity in
endothelial cells. Clin Chim Acta 364. https://doi.org/10.1016/j.cccn.2005.06.018
188. Voloshyna I, Hai O, Littlefield MJ, Carsons S, Reiss AB (2013) Resveratrol mediates anti-­
atherogenic effects on cholesterol flux in human macrophages and endothelium via PPARγ
and adenosine. Eur J Pharmacol 698. https://doi.org/10.1016/j.ejphar.2012.08.024
189. Zhang L, Zhou GZ, Song W, Tan XR, Guo YQ, Zhou B, Jing H, Zhao SJ, Chen LK
(2012) Pterostilbene protects vascular endothelial cells against oxidized low-density
lipoprotein-­induced apoptosis in vitro and in vivo. Apoptosis 17. https://doi.org/10.1007/
s10495-­011-­0653-­6
190. Zhang L, Cui LQ, Zhou GZ, Jing HJ, Guo YQ, Sun WK (2013) Pterostilbene, a natural small-­
molecular compound, promotes cytoprotective macroautophagy in vascular endothelial cells.
J Nutr Biochem 24. https://doi.org/10.1016/j.jnutbio.2012.06.008
191. Zhang Y, Zhang Y (2016) Pterostilbene, a novel natural plant conduct, inhibits high fat-induced
atherosclerosis inflammation via NF-κB signaling pathway in toll-like receptor 5 (TLR5)
deficient mice. Biomed Pharmacother 81. https://doi.org/10.1016/j.biopha.2016.04.031
192. Park ES, Lim Y, Hong JT, Yoo HS, Lee CK, Pyo MY, Yun YP (2010) Pterostilbene, a natural
dimethylated analog of resveratrol, inhibits rat aortic vascular smooth muscle cell prolif-
eration by blocking Akt-dependent pathway. Vasc Pharmacol 53. https://doi.org/10.1016/j.
vph.2010.04.001
193. Llarena M, Andrade F, Hasnaoui M, Portillo MP, Pérez-Matute P, Arbones-Mainar JM,
Hijona E, Villanueva-Millán MJ, Aguirre L, Carpéné C et al (2016) Potential renoprotective
effects of piceatannol in ameliorating the early-stage nephropathy associated with obesity in
obese Zucker rats. J Physiol Biochem 72. https://doi.org/10.1007/s13105-­015-­0457-­1
194. Uchida-Maruki H, Inagaki H, Ito R, Kurita I, Sai M, Ito T (2015) Piceatannol lowers the blood
glucose level in diabetic mice. Biol Pharm Bull 38. https://doi.org/10.1248/bpb.b15-­00009
195. Palmer RM (1993) The L-arginine: nitric oxide pathway. Curr Opin Nephrol Hypertens
2:122–128
196. Wallerath T, Deckert G, Ternes T, Anderson H, Li H, Witte K, Förstermann U (2002)
Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and
activity of endothelial nitric oxide synthase. Circulation 106. https://doi.org/10.1161/01.
CIR.0000029925.18593.5C
197. Li H, Wallerath T, Förstermann U (2002) Physiological mechanisms regulating the expres-
sion of endothelial-type NO synthase. Nitric Oxide Biol Chem 7:132–147
892 H. Chopra et al.

198. Kostyuk VA, Potapovich AI, Suhan TO, De Luca C, Korkina LG (2011) Antioxidant and
signal modulation properties of plant polyphenols in controlling vascular inflammation. Eur
J Pharmacol 658. https://doi.org/10.1016/j.ejphar.2011.02.022
199. Soares DG, Andreazza AC, Salvador M (2003) Sequestering ability of butylated hydroxy-
toluene, propyl gallate, resveratrol, and vitamins C and E against ABTS, DPPH, and
hydroxyl free radicals in chemical and biological systems. J Agric Food Chem 51. https://
doi.org/10.1021/jf020864z
200. King RE, Kent KD, Bomser JA (2005) Resveratrol reduces oxidation and proliferation of
human retinal pigment epithelial cells via extracellular signal-regulated kinase inhibition.
Chem Biol Interact 151. https://doi.org/10.1016/j.cbi.2004.11.003
201. Chan CM, Huang CH, Li HJ, Hsiao CY, Su CC, Lee PL, Hung CF (2015) Protective effects
of resveratrol against UVA-induced damage in ARPE19 cells. Int J Mol Sci 16. https://doi.
org/10.3390/ijms16035789
202. Neal SE, Buehne KL, Besley NA, Yang P, Silinski P, Hong J, Ryde IT, Meyer JN, Jaffe GJ
(2020) Resveratrol protects against hydroquinone-induced oxidative threat in retinal pigment
epithelial cells. Investig Ophthalmol Vis Sci 61. https://doi.org/10.1167/iovs.61.4.32
203. Losa GA (2003) Resveratrol modulates apoptosis and oxidation in human blood mononu-
clear cells. Eur J Clin Investig 33. https://doi.org/10.1046/j.1365-­2362.2003.01219.x
204. Guo R, Su Y, Liu B, Li S, Zhou S, Xu Y (2014) Resveratrol suppresses oxidised low-density
lipoprotein-induced macrophage apoptosis through inhibition of intracellular reactive oxygen
species generation, lox-1, and the p38 MAPK pathway. Cell Physiol Biochem 34. https://doi.
org/10.1159/000363026
205. Olas B, Wachowicz B (2002) Resveratrol and vitamin C as antioxidants in blood platelets.
Thromb Res 106. https://doi.org/10.1016/S0049-­3848(02)00101-­9
206. Tadolini B, Juliano C, Piu L, Franconi F, Cabrini L (2000) Resveratrol inhibition of lipid
peroxidation. Free Radic Res 33. https://doi.org/10.1080/10715760000300661
207. Ahmad KA, Clement MV, Pervaiz S (2003) Pro-oxidant activity of low doses of resveratrol
inhibits hydrogen peroxide – induced apoptosis. Proc Ann N Y Acad Sci 1010:365–373
208. Amato C (1994) Advantage of a micronized flavonoidic fraction (Daflon 500 mg) in compari-
son with a nonmicronized diosmin. Proc Angiol 45:531–536
209. Maksimović ZV, Maksimović M, Jadranin D, Kuzmanović I, Andonović O (2008)
Medicamentous treatment of chronic venous insufficiency using semisynthetic diosmin – a
prospective study. Acta Chir Iugosl 55. https://doi.org/10.2298/ACI0804053M
Steam Distillation: Principle
and Applications for the Extraction
of Essential Oils from Plants

Alankar Shrivastava

1 Introduction

There are more than 250 known essential oils. Various nations produce different
types of essential oils. India positions second on the planet for trading essential oils
[1]. The essential oil is volatile, and concentrated lipophilic liquid compounds with
characteristic fragrance are obtained from the various plants. These are also known
as fragrant oils, aromatic oils, volatile oils, or ethereal oils. They are also named on
the name of plant through which they are extracted, e.g., clove oil obtained cloves
[2]. Essential oil products cannot be replaced by synthetic materials. Most of these
are quite stable in normal atmospheric conditions. The fresh extractives are usually
colorless but may darken upon aging due to oxidation. This may be the reason why
they are kept in amber-colored glass bottles in dry place in properly closed contain-
ers. The industrial production of essential oil industry involves plant cultivation and
distillation to obtain oil [3]. It creates jobs for rural people for supply of raw materi-
als and workers involved in processing of oils. Essential oils are extensively used
globally for fragrances, food flavoring, pharmaceuticals, and aromatherapy [4].
The concentrated natural plant components containing volatile fragrant com-
pounds are essential oils (EOs), otherwise called volatile oils. Most EOs are inferred
by steam distillation and have remarkable properties, which bring about different
opportunities for application, likewise in the present medical context [5]. Essential
oils are secondary metabolites organic molecules and of relatively low molecular
weight rarely including sulfur, nitrogen, bromine, and chlorine in their structure [6].
The global essential oil market size was valued at USD 18.6 billion in 2020 and is
expected to expand at a compound annual growth rate (CAGR) of 7.4% in terms of
revenue from 2021 to 2028 [7]. By and large, medicinal oils are included in a few
significant parts in generally high concentration (20–95%) and other parts present

A. Shrivastava (*)
Shri Rawatpura Sarkar Institute of Pharmacy, Kumhari, Durg, India

© The Author(s), under exclusive license to Springer Nature 893

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_36
894 A. Shrivastava

in trace levels, e.g., Origanum compactum oil contains carvacrol (30%) and thymol
(27%), and citrus peel oil contains d-limonene (>80%). They are obtained from
various parts of the aromatic plants, including flowers, leaves, fruits, buds, seeds,
rhizomes, barks, and roots. Essential oils have recently begun to receive much atten-
tion as possible sources of safe and natural alternative medicines [8]. Essential oils
are known to possess anticancer, antioxidant, and antimicrobial effects. They may
act as an alternative for synthetic preservatives in food items. Gram-negative organ-
isms are believed to be slightly less sensitive to essential oils than Gram-positive
bacteria [9]. The components such as carvacrol and isoeugenol in some essential
oils have proven anti-inflammatory activity [10]. Essential oils in air-spray form can
be used for purifying indoor air and are often safe to allergic and asthmatic patients
[11]. Some essential oils, e.g., clove, lavender, and eucalyptus oils were also found
effective against many fungal species isolated from environmental air samples [12].

2 Distillation

Techniques for the purification of chemicals have a place within the domain of parti-
tion science. Every method for separation of one component from others can be
used for purifying components. The significant general thought for the improve-
ment of purity of any component is the selection of materials for the construction of
apparatus in which purification tasks are to be performed. Distillation is one of the
well-known techniques usually performed in the initial stages of purification. This
can be combined with other processes, e.g., chromatography, if high-grade purifica-
tion is required [13].
Distillation is a commonly used process for separation of liquid mixtures into
pure components and is an important unit operation for running chemical, petro-
chemical, and related industries. The normal perception is that it will remain an
important operation in these industries in the future as well. Advances in distillation
procedures have been basic to expanding the way of life for mankind in the course
of the past few thousand years [14]. Distillation is the most established separation
process and the most broadly involved unit operation in industry. The technique can
be utilized for many different purposes (Also refer Fig. 1) [15].
Innovations in the field of distillation processes can promote sustained growth in
food and chemical industries [16]. The term distillation alludes to an overall class of
strategies used to isolate parts from a blend dependent on a distinction in their vola-
tilities [17, 18]. By and large, a distillation process involves heating the liquid mix-
ture to the vapor state so as to enable the selective condensation and partition of
desired component(s) [19, 20]. The thermodynamic equilibrium governs the degree
of partition while the pace of division is controlled by the mass exchange [21, 22].
The basic principle of separation is presented in Fig. 2.
Steam Distillation: Principle and Applications for the Extraction of Essential Oils… 895

Fig. 1 Various types of distillation methods

Fig. 2 Principle of distillation process

896 A. Shrivastava

3 Brief History

Traditional extraction advances to recuperate esteem added items from plant materi-
als incorporate solvent extraction, steam distillation, and acid and alkali extraction.
In these, steam distillation method is known for recovery of high-boiling-point vola-
tile oils from complex and inert components, solid or liquid, using superheated or
saturated steam for separation [22]. Although it is unknown exactly what was dis-
tilled, the finding of clay jars from Babylonia that resemble stills may be the first
proof of distillation. The carbon dating studies show that those pots were of second
millennium BC. Albeit the principal drawings of stills date from the Hellenistic
school of chemists (second century AD), from composed and archeological proof it
was presumably the Arab chemists who idealized the craft of distillation to a degree
important to get genuinely focused alcohol from a fermented beverage. The Arabs
turned into the world’s driving researchers and were quick to involve distilled alco-
hol in medication. The soonest piece of distillation device (from Iran) that has
endured is Islamic and is dated between the tenth and twelfth hundreds of years. In
the nineteenth century, the alcohol business extended extensively, particularly in
France. The distillation of alcoholic beverages was becoming inescapable all
through Europe and Asia. The earliest stills of the eastern Asians and Arabs were
relatively small earthenware or glass pot stills of the alembic type, but did not use
flowing water as a coolant. The initial distillation assembly soju, which is an exam-
ple of Korean traditional stills, was heated by fires by charcoal or wood and recently
(in bygone eras) by boiling water or steam. Later copper replaced the material uti-
lized for making stills because of its advantages such as durability, good thermal
conductivity, and malleability. To some extent, bronze was also used for the same
purpose. Copper stills could be made to a wide scope of shapes and sizes; they could
persevere through quite a long while of utilization, didn’t break when warmed
straightforwardly, and caused a more uniform pace of distillation, with minimal
charring. The additional advantage of copper stills is improved organoleptic proper-
ties of distilled spirits due to removal of volatile organosulfur compounds [23].
Throughout the long term, the method spread broadly, and the principal book
regarding the matter, Das kleine Distillierbuch, by Brunswig, appeared in 1500
[24]. In science, the synthetic course of steam distillation was first portrayed by
Avicenna (Ibn Sina, 980–1037, Persia, Afghanistan). The procedure was utilized to
deliver essential oils and alcohol; the former was basic to fragrance-based treatment
(aromatherapy). Another invention was condensing coil increases the effectiveness
of distillation of essential oils using steam distillation [25].
Before the tenth century, it was still generally accepted that most essential oils
had solid therapeutic properties. Therefore, most of the credit of improvement in
purification and recovery of essential oils using distillation technologies goes to
pharmacists [26]. Jean-Baptiste Cellier-Blumenthal invented the first continuously
working distillation column in France and patented it in 1813. The first steam distil-
lation was probably performed by Claude Dariot (1533–1594), who heated the ves-
sel part between bottom and head. The direct steam distillation, however, was
Steam Distillation: Principle and Applications for the Extraction of Essential Oils… 897

reported by the Chinese around seventh century, but the evidence is not conclu-
sive [27].

3.1 Steam Distillation

Steam distillation facilitates the separation of compounds that are steam volatile
below their normal boiling points. The water obtained in the receiver can be easily
removed from volatile portion. One of the examples is the separation of naphthalene
and nitrobenzene [28]. This method is traditionally used for the separation of essen-
tial oils from plants. The superheated or saturated steam is responsible for vaporiza-
tion or extraction of fragrant compounds from the raw material. The volatile
components absorb heat from steam and are transported along with water vapors.
The components reached to the condenser and formed organic layer above water in
the receiver. Overall, two products are obtained in this process: (1) hydrosol and (2)
volatile oil. The hydrosol consists of water and some hydrolyzed components of
plant forming the bottom layer. The volatile oil in the upper layer in the decanter can
be then easily separated [29].

3.2 Principle

As per the kind of contact between the network and the water as well as steam, there
are three variations of the steam distillation process: dry steam distillation (Fig. 3),
direct steam distillation (Fig. 4), and hydrodistillation (water distillation) (Fig. 5).

Fig. 3 Dry distillation method

898 A. Shrivastava

Fig. 4 Direct steam distillation

Fig. 5 Water hydrodistillation

In direct steam distillation, the matrix is upheld on a grid with perforations or

screen embedded somewhat over the lower part of the still. This plan doesn’t permit
direct contact with water, though the boiler can be inside or outside the still. The
low-pressure immersed steam streams up through the network, gathering the evapo-
rated components. In hydrodistillation, the matrix is in direct contact with the boil-
ing water either by drifting or by being totally submerged relying upon its density.
The boiler is inside the still, and fomentation might be important to forestall agglu-
tination. In dry steam refining, the matrix is upheld and steam moves through it. The
Steam Distillation: Principle and Applications for the Extraction of Essential Oils… 899

distinctions are because of the steam being created external to the still and super-
heated at moderate pressures [30]. In comparison with other extraction processes,
steam distillation presents some advantages:
• Products obtained are solvent-free
• Further separation steps are not required
• Possibility of large-scale production
• Cheap equipment and well-known technology
• Minimum loss of polar compounds by controlling the reflux
However, the problem associated with steam distillation is degradation of ther-
mally unstable components and/or hydrolysis reaction with water, long extraction
period (1–5 h), high-power requirement, polluted waste water discharge, and risk of
foam or emulsion formation [31].
The blend of immiscible liquids tends to boil when the total vapor pressure is
equivalent to the atmospheric pressure. The principle of steam distillation can be
explained by example of distillation of mixture of turpentine and water. The boiling
point of turpentine is about 160 °C, but the mixture with water boils at about
95.6 °C. The vapor pressure of combination of turpentine and water reaches to
atmospheric pressure at lower temperature. The vapor pressures of individual com-
ponents at this point are about 15.06 kPa (113 mmHg) and 101.31 kPa for water and
turpentine, respectively. Thus, using this principle, essential oils with high boiling
point may also be separated easily with less deterioration and loss [32]. Furthermore,
countercurrent stream of vapour and liquid in a distillation column expands mass
exchange effectiveness. Superheated steam is likewise frequently utilized [33, 34].

3.3 Microwave-Assisted Steam Distillation

Electromagnetic waves with frequency between 300 MHz and 300 GHz are called
microwaves. The combination of ionic conduction and dipole movement is respon-
sible for heating. The mechanism of working of microwave is out of scope of writ-
ing, readers may refer any literature (also refer Fig. 6) related to its working
mechanism. The advantages are better control, almost instantaneous heating and
less possibility of degradation of components. On the other hand, not all substances
can be heated using microwave and depends on the polarity of solvent, e.g., hexane
and chloroform (less polar) not produces heat. Overall, the efficiency of distillation
is increased by using microwave technology. There are many literatures published
based on this method. The solvent-free microwave-based distillation methods is
further extension [35].
In this process, distillation is carried out under normal pressure without solvent
by placing fresh leafy material in microwave reaction apparatus. The oil cells bursts
due to increase in inner tension when irradiated with microwaves and released oil
then distilled by moisture present in situ water from fresh leaves [36, 37]. A few
examples are extraction from Schisandra chinensis [38], Korean medicines [39],
orange peels [37], and Thymus mastichina [40].
900 A. Shrivastava

Fig. 6 Principle of working of microwave extraction

4 Future Aspects

There are few published research studies related to improvement of performance in

terms of saving energy or yield of essential oils. One of such published research is
Xio et al. [41], where it can save energy consumption and minimize loss of asarinin
and sesamin during extraction process from roots and rhizomes of Asarum het-
erotropoides var. mandshuricum (AHVM). According to the authors, microwave-­
assisted steam distillation with solvent extraction (MSDE) method was most
suitable in comparison to steam distillation (SD), conventional hydrodistillation
(HD), and microwave-assisted hydrodistillation (MHD).
In another study by Lainez-Cerón et al. [42], the effect of operating conditions
for the extraction of Eucalyptus EO by hydrodistillation on different performance
indicators was evaluated and compared to those obtained for systems that use direct
steam injection, HDS, and SD. The effect of the evaluated conditions on the extrac-
tion kinetics was described in terms of the parameters of two mathematical models.
It has shown how large amounts of steam delivered at low rate improve mass trans-
fer and extraction rate.
Microwave-assisted hydrodistillation (MAHD) and conventional hydrodistilla-
tion (HD) techniques were compared in the extraction of essential oils from
Amomum subulatum seeds [43]. The MAHD method gives good yield, more anti-
oxidant and antibacterial activity in EO obtained by HD method.
The studies mentioned above are just few of the reported in recent time. The
simple steam distillation methods are either solvent-free or less amount of solvent
for optimum yield of EOs. The analysis of components of EOs is generally per-
formed by using hyphenated techniques e.g., GC-MS, which is obvious due to its
capability of analysis at molecular level. The hyphenated techniques are costly and
require more skill analyst. The simple techniques such as GC-FID methods can also
be used for analysis in the case reference standards are available. The solvent-free
extraction procedures along with such methods can be performed for improved uti-
lization of green extraction procedures with economy as an advantage. Thus, the
segment needs to be explored for the researchers working in this field.
Steam Distillation: Principle and Applications for the Extraction of Essential Oils… 901

Acknowledgments The authors acknowledge the support given by KIET Group of Institution,
KIET School of Pharmacy, Ghaziabad.

Conflict of Interest None declared by author.

References

1. Chávez-González ML, Rodríguez-Herrera R, Aguilar CN (2016) Essential oils: a natural

alternative to combat antibiotics resistance. In: Kon K, Rai M (eds) Antibiotic resistance.
Academic, pp 227–237. https://doi.org/10.1016/B978-­0-­12-­803642-­6.00011-­3
2. Rassem HHA, Nour AH, Yunus RM (2016) Techniques for extraction of essential oils from
plants: a review. Aust J Basic Appl Sci 10(16):117–127
3. Mendes M, Pessoa F (2010) Spices, seasonings, and essential oils. https://doi.
org/10.1002/9780470622834.ch52
4. Attokaran M (2011) Essential oils. In: Attokaran M (ed) Natural food flavors and colorants.
https://doi.org/10.1002/9780470959152.ch4
5. Steflitsch W (2017) Aromatherapie: wann können ätherische Öle medizinisch eingesetzt
werden? [Aromatherapy: from traditional and scientific evidence into clinical practice]. Dtsch
Med Wochenschr 142(25):1936–1942. German. https://doi.org/10.1055/s-­0043-­116476
6. Reyes-Jurado F, Franco-Vega A, Ramírez-Corona N, Palou E, López-Malo A (2015) Essential
oils: antimicrobial activities, extraction methods, and their modeling. Food Eng Rev 7:275–297.
https://doi.org/10.1007/s12393-­014-­9099-­2
7. Essential oils market size, share & trends analysis report by product (orange, cornmint, euca-
lyptus), by application (medical, food & beverages, spa & relaxation), by sales channel, by
region, and segment forecasts, 2021–2028. Available online: https://www.grandviewresearch.
com/industry-­analysis/essential-­oils-­market#
8. Shaaban HAE, El-Ghorab AH, Shibamoto T (2012) Bioactivity of essential oils and their
volatile aroma components: review. J Essent Oil Res 24(2):203–212. https://doi.org/10.108
0/10412905.2012.659528
9. Seow YX, Yeo CR, Chung HL, Yuk H-G (2014) Plant essential oils as active antimicrobial
agents. Crit Rev Food Sci Nutr 54(5):625–644. https://doi.org/10.1080/10408398.2011.59950
4
10. Salud Pérez G, Miguel ZS, Lucina AG, Miguel RL (2011) Anti-inflammatory activity of some
essential oils. J Essent Oil Res 23(5):38–44. https://doi.org/10.1080/10412905.2011.9700480
11. Caimmi D, Neukirch C, Demoly P (2021) Essential oils: what is the clinical tolerance in asth-
matic patients? J Asthma. https://doi.org/10.1080/02770903.2021.1888975
12. Schroder T, Gaskin S, Ross K, Whiley H (2017) Antifungal activity of essential oils against
fungi isolated from air. Int J Occup Environ Health 23(3):181–186. https://doi.org/10.108
0/10773525.2018.1447320
13. Newman EJ (2005) Purification. In: Worsfold P, Townshend A, Poole C (eds) Encyclopedia of
analytical science, 2nd edn. Elsevier, Amsterdam, pp 103–104
14. Stichlmair J, Klein H, Rehfeldt S (2021) Distillation principles and practice, 2nd edn. Wiley,
Hoboken, p 1
15. Rico-RamOHrez V, Diwekar U (2000) Multicomponent distillation. In: Encyclopedia of sepa-
ration science. Academic, San Diego, p 1071
16. Cardoso-Ugarte GA, Juárez-Becerra GP, SosaMorales ME, López-Malo A (2013) Microwave-­
assisted extraction of essential oils from herbs. J Microw Power Electromagn Energy
47(1):63–72. https://doi.org/10.1080/08327823.2013.11689846
17. Lam KF, Sorensen E, Gavriilidis A (2013) Review on gas–liquid separations in microchannel
devices. Chem Eng Res Des 91:1941–1953
902 A. Shrivastava

18. Caven-Quantrill DJ, Buglass AJ (2006) Comparison of micro-scale simultaneous distillation–

extraction and stir bar sorptive extraction for the determination of volatile organic constituents
of grape juice. J Chromatogr A 1117:121–131
19. Kurt SK, Vural-Gursel I, Hessel V, Nigam KDP, Kockmann N (2016) Liquid-liquid extraction
system with microstructured coiled flow inverter and other capillary setups for single-stage
extraction applications. Chem Eng J 284:764–777
20. Gorak A, Schoenmakers H (2014) Distillation: operation and applications. Elsevier, Amsterdam
21. Heils R, Hu X, Liese A, Smirnova I (2016) In situ production and renewal of biocatalytic coat-
ings for use in enzymatic reactive distillation. Chem Eng J 306:992–1000
22. Curcio E, Drioli E (2005) Membrane distillation and related operations—a review. Sep Purif
Rev 34:35–86
23. Kockmann N (2017) History of distillation. In: Reference module in chemistry, molecular
sciences and chemical engineering. Elsevier. https://doi.org/10.1016/B978-­0-­12-­409547-­
2.14064-­8
24. Resetarits MR, Lockett MJ (2003) Distillation. In: Encyclopedia of physical science and tech-
nology, 3rd edn. Academic, San Diego, p 547
25. Schlosser Š (2011) Distillation—from bronze age till today. In: Markoš J (ed) Proceedings
of the 38th international conference of Slovak society of chemical engineering, Tatranské
Matliare, Slovakia, pp 1–12
26. Hernandez E (2000) Essential oils, distillation. In: Worsfold P, Townshend A, Poole CF (eds)
Encyclopedia of analytical science, vol 1, 2nd edn. Elsevier, Amsterdam, 2005, pp 2739–2744
27. Kockmann N (2014) History of distillation. Elsevier. https://doi.org/10.1016/B978-­0-­12-­
386547-­2.00001-­6
28. Roohinejad S, Koubaa M, Barba FJ, Leong SY, Khelfa A, Greiner R, Chemat F (2017) Extraction
methods of essential oils from herbs and spices. In: Hashemi SMB, Khaneghah AM, de Souza
Sant’Ana A (eds) Essential oils in food processing. https://doi.org/10.1002/9781119149392.ch2
29. Hay YO, Abril-Sierra MA, Sequeda-Castañeda LG, Bonnafous C, Raynaud C (2018)
Evaluation of combinations of essential oils and essential oils with hydrosols on antimicrobial
and antioxidant activities. J Pharm Pharmacogn Res 6(3):216–230
30. Attokaran M (2017) Methods of extraction of essential oils. In: Attokaran M (ed) Natural food
flavors and colorants. https://doi.org/10.1002/9781119114796.ch7
31. Chemat F (2010) Techniques for oil extraction. In: Sawamura M (ed) Citrus essential oils,
flavor and fragrance. Wiley, Hoboken, p 9
32. Subrahmanyam CVS, Thimmasetty J, Suresh S, Devi VK (2020) Pharmaceutical engineering,
unit operation II. Vallabh Prakashan, Delhi, p 225
33. Stichlmair J, Klein H, Rehfeldt S (2021) Distillation: principles and practice, 2nd edn. American
Institute of Chemical Engineers, Inc./Wiley. https://doi.org/10.1002/9781119414674
34. Božović M, Navarra A, Garzoli S, Pepi F, Ragno R (2017) Esential oils extraction: a 24-hour
steam distillation systematic methodology. Nat Prod Res 31(20):2387–2396. https://doi.org/1
0.1080/14786419.2017.1309534
35. Zhao C, Yang X, Tian H, Yang L (2020) An improved method to obtain essential oil, flavo-
nols and proanthocyanidins from fresh Cinnamomum japonicum Sieb. leaves using solvent-­
free microwave-assisted distillation followed by homogenate extraction. Arab J Chem
13(1):2041–2052. https://doi.org/10.1016/j.arabjc.2018.03.002
36. Sui X, Liu T, Ma C, Yang L, Zu Y, Zhang L, Wang H (2012) Microwave irradiation to pretreat
rosemary (Rosmarinus officinalis L.) for maintaining antioxidant content during storage and
to extract essential oil simultaneously. Food Chem 131:1399–1405
37. Boukroufa M, Boutekedjiret C, Petigny L, Rakotomanomana N, Chemat F (2015) Bio-refinery
of orange peels waste: a new concept based on integrated green and solvent free extraction
processes using ultrasound and microwave techniques to obtain essential oil, polyphenols and
pectin. Ultrason Sonochem 24:72–79
Steam Distillation: Principle and Applications for the Extraction of Essential Oils… 903

38. Ma C, Yang L, Zu Y, Liu T (2012) Optimization of conditions of solvent-free microwave

extraction and study on antioxidant capacity of essential oil from Schisandra chinensis (Turcz.)
Baill. Food Chem 134:2532–2539
39. Seo E, Kuete V, Kadioglu O, Krusche B, Schröder S, Greten HJ, Arend J, Lee I, Efferth T (2013)
Antiangiogenic activity and pharmacogenomics of medicinal plants from traditional Korean
medicine. Evid-Based Complement Alternat Med. https://doi.org/10.1155/2013/131306
40. Araujo ARTS, Périno S, Fernandez X, Cunha C, Rodrigues M, Ribeiro MP, Jordao L, Silva
LA, Rodilla J, Coutinho P et al (2021) Solvent-free microwave extraction of thymus masti-
china essential oil: influence on their chemical composition and on the antioxidant and antimi-
crobial activities. Pharmaceuticals 14:709. https://doi.org/10.3390/ph14080709
41. Xiao Y, Liu Z, Huiyan G, Yang F, Lin Z, Yang L (2021) Improved method to obtain essen-
tial oil, asarinin and sesamin from Asarum heterotropoides var. mandshuricum using
microwave-­assisted steam distillation followed by solvent extraction and antifungal activity
of essential oil against Fusarium spp. Ind Crops Prod 162:113295. https://doi.org/10.1016/j.
indcrop.2021.113295
42. Lainez-Cerón E, Jiménez-Munguía MT, López-Malo A, Ramírez-Corona N (2021) Effect of
process variables on heating profiles and extraction mechanisms during hydrodistillation of
eucalyptus essential oil. Heliyon 7(10):e08234. https://doi.org/10.1016/j.heliyon.2021.e08234
43. Mande P, Sekar N (2021) Comparative study of chemical composition, antibacterial and anti-
oxidant activity of essential oils isolated from the seeds of Amomum subulatum by using
microwave extraction and hydro-distillation methods. J Indian Chem Soc 98(11):100201.
https://doi.org/10.1016/j.jics.2021.100201
Key Factors Influencing Agrobacterium-
Mediated Transformation Efficiency
in Plants: A Case Study

Durga Prasad Barik

37.1 Introduction

Plants are the key to life on earth. They are, directly or indirectly, the primary source
of energy for all terrestrial animals; for instance, plants supply directly 90% of calo-
rific intake and 80% of the protein intake of man. Breeding of crop plants has been
carried out by man for thousands of years. It is, however, only over the last 50 years,
as a result of highly sophisticated breeding processes, combined with improved agri-
cultural methods and modern technology, that this has brought about a dramatic
increase in yield and quality of crops. Generally, though, these improved crop plants
are often susceptible to many diseases caused by fungi, insects, bacteria, nematodes,
and viruses. The tendency for crop plants to be threatened by many diseases and pests
compared to wild plant species is due mostly to the breeding programs, whereby
selection for characteristics such as yield takes priority over those for disease and
pest resistance. For many years this has been overcome by the use of pesticides, but
there is now increasing concern about the environmental safety of these chemicals,
which can persist in the food chain and may be toxic to plants and animals. Given that
pesticides have been largely successful only in the control of fungi and insects, and
offer little protection against viruses, viroids, and bacteria, it is now more urgent than
ever to find alternative methods of protecting crop plants from diseases [1].
Plant breeding has several other serious limitations for use as a tool to increase
disease resistance. There are only a limited number of plant species which are able
to cross-fertilize, thus restricting the transfer of potentially useful traits. Moreover,
having found useful traits, it is impossible to prevent the co-transfer of undesirable
ones, which can take many years to breed out again by back-crossing.

Durga Prasad Barik (*)

Department of Botany and Biotechnology [Supported by OHEPEE (HE-PTC-WB-02017)
and DST-FIST Program], Ravenshaw University, Cuttack, Odisha, India
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 905

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_37
906 D. P. Barik

How can genetic engineering be of use in the quest for new answers to the prob-
lems of providing plants with the ability to resist disease? The aim of crop plant
genetic engineering is to insert a gene (or genes) which improves an existing plant
variety whilst retaining the desirable genetic make-up of the original plant. The
main tool at the disposal of the scientist is the use of nature’s own genetic engineer,
Agrobacterium. Three different species of Agrobacterium are found, i.e., A. tumefa-
ciens, A. rhizogenes, and A. radiobacter of which A. radiobacter is an avirulent
strain and A. tumefaciens is found to be most effective.
The microbe Agrobacterium tumefaciens is harmful to plants and useful to scien-
tists for the same reason: It transfers DNA into plant genomes. Found in soil world-
wide, A. tumefaciens causes disease in plants by transferring its own DNA into plant
cells. But in the laboratory, the ability to move all sorts of genes into plants has
made the microbe the standard tool for investigating plant genetics and modifying
crops. The manipulation of this bacterium’s natural functions has allowed the biolo-
gist to transfer many foreign genes into plants.

37.2 Agrobacterium: A Natural Plant Genetic Engineer

Phytopathogenic gram-negative soil bacteria A. tumefaciens and A. rhizogenes

cause neoplastic diseases (crown gall or hairy root, respectively) in many dicotyle-
donous plant species. Agrobacterium tumefaciens infects plants at the crown, usu-
ally through a wound site, causing cancerous growths of proliferating plant cells
known as crown gall tumors. This disease in itself is ergonomically important and
affects most dicotyledonous plants causing millions of dollars’ worth of damage to
plants. In the 1940s, from experimental observations, it was concluded that a factor
is transmitted from the invading bacteria to the host plant cell. Further studies dem-
onstrated that the disease is actually the direct result of the transfer of a particular
DNA fragment (genes) from the bacterium to the plant cell. In addition to its chro-
mosomal DNA, Agrobacterium contains a much smaller circular DNA molecule
called a Ti (tumor-inducing) plasmodia, of which a small piece called the T-DNA
(transferred-DNA) is the factor transferred into plant cells. The T-DNA becomes
stably integrated into the plant’s chromosomes, from where it is able to perturb the
natural functions of the plant. The T-DNA encodes genes, which, when expressed,
bring about the production of new enzymes that are able to alter the hormone bal-
ance within the infected cell. This brings about de-differentiation and cell division,
leading to the proliferation of cells and the formation of tumors. This appears to be
of little benefit to the bacterium. However, other genes are also present in the T-DNA
which, when expressed, are able to synthesize novel compounds from naturally
occurring plant precursors. These novel compounds cannot be metabolized by the
plant but are a good source of nutrients for the bacterium (Fig. 1).
Crown gall disease affects hundreds of species, particularly fruits, nuts, and
ornamental plants such as roses. The disease recently caused severe damage and
economic losses among walnut tree growers in California. Once A. tumefaciens
Key Factors Influencing Agrobacterium-Mediated Transformation Efficiency in Plants... 907

Fig. 1 Agrobacterium tumefaciens in detail

infects a plant, the bacterium travels throughout the root system and can wipe out an
entire crop. The only option for farmers is to destroy the plants. The practice of
replacing the tumor-inducing genes with other DNA began in the 1970s and led to
the widespread use of the bacterium in research. The microbe is particularly well
suited for testing the functions of individual plant genes because bacterial DNA
disrupts the genome at the point of insertion.
“Agrobacterium can be used to insert a piece of DNA in the middle of a plant
gene, thus inactivating the gene,” says Derek W. Wood, who led part of the University
of Washington project. “We can then analyze the mutation to see what it does to the
plant.” This experiment has been done on a large scale. Many thousands of mutant
potato and alfalfa plants are available to plant researchers from institutions like the
University of Wisconsin in Madison. The microbe has also been used to create
transgenic crops, including new strains of corn and soybeans. Agrobacterium-
mediated gene transfer into a wide variety of crop species has already become a
realizable technique for plant improvement by transferring agronomically useful
genes such as insect resistance [2], virus resistance [3], resistance against bacterium
[4], and herbicide resistance [5, 6].
Agrobacterium tumefaciens genome has a very unusual structure. Some 5400
genes reside on four DNA elements—a circular chromosome, a linear chromosome,
and two smaller circular structures called plasmids. Many bacteria have circular
chromosomes and some have linear chromosomes, but Agrobacteria are the only
species known to have both structures together.

37.3 Ti Plasmid: Role and Importance

The discovery of the importance of the Ti plasmid in crown gall raised the next
obvious question, what is its role in tumor formation? The stable properties of tumor
tissue suggested that the plasmid, or some part of it, was stably maintained in the
plant cell. Thus, it became critical to demonstrate that plasmid DNA was, in fact,
actually present in tumor tissue. The Seattle group had previously searched for
908 D. P. Barik

bacterial DNA and then for the entire Ti plasmid in tumor tissue without success. At
this time, Southern hybridization was not yet developed. The laborious technique
they used was DNA renaturation kinetic analysis in which the rate of association of
a small amount of 32P-labeled single-stranded DNA (probe DNA) into a double-
stranded form is measured in the presence of a large amount of either tumor or
normal plant tissue DNA (driver DNA). If the tumor DNA contained DNA homolo-
gous to the probe, the tumor DNA would accelerate the association of the single-
stranded probe DNA. However, the drawback of this method is that it can detect
foreign DNA only if it constitutes a significant fraction of the labeled probe. Thus,
if only a few genes of the megaplasmid were present per tumor cell, they would not
be detected. Since the Seattle group did not detect the entire plasmid, they were bet-
ting that only a small part was in tumor cells. They mounted a brute force effort to
demonstrate this. Since it was likely that tumor tissue contained both transformed
and untransformed cells, as a first step, Milt Gordon went to George Melcher’s lab
in Germany where he cloned a tumor line. The renaturation kinetic analysis became
an assembly line operation, with different members of the lab playing specific roles.
As soon as the 32P-d CTP arrived, a nick translation reaction was initiated to label
the plasmid to its maximum specific activity. The labeled plasmid was then digested
with the restriction enzyme SmaI, which we had to purify since it was not commer-
cially available. The fragments were separated by preparative gel electrophoresis
and the 15 resolvable bands were electroeluted from the gel slices. Seventy-five
renaturation kinetic assays were set up with labeled probes and denatured driver
DNAs from either tumor or normal tissue. A total of 525 samples were taken around
the clock, and the percentage of single-stranded probe that had renatured to double-
stranded DNA at each time point was determined. These experiments gave the
hoped-for result. Two labeled bands renatured faster when incubated with tumor,
but not normal plant DNA. No other bands did. Thus, we concluded that a fragment
of the Ti plasmid was indeed present in tumor cells. The suspicions of many inves-
tigators had proven correct! DNA, and more specifically a fragment of the Ti plas-
mid, now named T-DNA for transferred-DNA, was the long-sought-after TIP.

37.4 T-DNA Transcription

Mike Thomashow in Seattle analyzed four cloned tumor lines, using restriction
enzymes and molecular hybridization techniques, to determine how T-DNA is
maintained in the host cell genome. Fortunately, by this time Southern hybridization
was a proven and reliable technique. Following digestion of tumor DNA with
restriction enzymes that cleaved within or outside the T-DNA and by determining
the sizes and numbers of the resulting T-DNA molecules by Southern hybridization,
he concluded (1) that the T-DNA is integrated into plant DNA, (2) that preferred
regions of the Ti plasmid serve as points of attachment to the plant DNA, and (3)
that the T-DNA can be linked to more than one site in plant DNA. Later studies by
Narendra Yadav in Mary-Dell Chilton’s group demonstrated that T-DNA is flanked
Key Factors Influencing Agrobacterium-Mediated Transformation Efficiency in Plants... 909

by 25-bp direct repeats. Presumably any DNA bounded by these sequences would
be transferred to the plant. Studies from several laboratories using Southern hybrid-
ization on fractionated cell components demonstrated that T-DNA is integrated only
into nuclear DNA.
The question of whether the integrated T-DNA is transcribed was quickly
answered by Martin Drummond working with Mary-Dell Chilton. They demon-
strated that RNA isolated from a cloned tumor line labeled with 32P in vivo hybrid-
ized to T-DNA. Interestingly, T-DNA is not transcribed in Agrobacterium.

37.5 Coding Properties of T-DNA

Although the T-DNA with its two flanking border sequences had now been identi-
fied, how it induced crown gall tumors and what other genes are important in plant
cell transformation awaited discovery. The Ghent, Leiden, and Seattle groups were
the primary contributors to this part of the story. In Ghent, Marcel Holsters led the
effort to determine the functional organization of the Ti plasmid of strain C58.
Using transposons Tn1 and Tn7, she isolated insertion and deletion mutants and
described their oncogenic and other biological properties. These studies, as well as
those from the two other groups, revealed that another region of the Ti plasmid
besides the T-DNA is essential for oncogenesis. Insertion of transposons in this
region, now termed the virulence or vir region, created an avirulent phenotype. They
also identified regions in the T-DNA and elsewhere on the plasmid that are not
essential for oncogenicity.
By mutagenizing the entire genome, Dave Garfinkel in Seattle uncovered a num-
ber of loci in the chromosome that are also important for virulence. They included
loci-encoding proteins required for binding of Agrobacterium to plant cells, a sugar-
binding protein required for maximum vir gene induction, and loci required for
sensing the acidic environment required for vir gene induction. Garfinkel also used
site-directed mutagenesis with Tn5 to develop a fine structure map of the T-DNA in
order to identify the function of genes responsible for tumor formation. He, together
with several colleagues in Seattle and Gert Ooms, a visiting graduate student from
Rob Schilperoort’s lab, isolated 75 Tn5 and 3 Tn3 insertions which identified four
genetic loci. Tms mutants (tumor morphology shooty) resulted in shoot prolifera-
tion in the tumor; tmr (tumor morphology rooty) resulted in root formation; and
insertions in tml (tumor morphology large) gave rise to unusually large tumors on
certain plants. Gert Ooms made similar observations independently. Later studies
showed that the “shooty” mutations resulted from insertions in two loci (iaaH and
iaaM) concerned with auxin synthesis and the “rooty” mutations contained an inser-
tion in a gene for cytokinin synthesis (ipt). Interestingly, no single insertion resulted
in avirulence. In later studies, Walt Ream showed that an avirulent phenotype
required simultaneous insertions in both genes coding for auxin and cytokinin
biosynthesis.
910 D. P. Barik

37.6 T-DNA Transfer and Integration

The process of transfer of T-DNA from Agrobacterium to the cells of the host plant
can be divided into a bacterial step and a plant cell step [7]. Once T-DNA was identi-
fied and characterized, attention turned to the question of how Agrobacterium trans-
fers T-DNA into plant cells. The vir region of the Ti plasmid is highly conserved in
octopine and nopaline strains and was surmised to be involved in the transfer pro-
cess. As a first step to constructing a fine structure map of this region, Scott Stachel
and Gyn An in Seattle constructed a Tn3 lacZ transposon which could randomly
generate gene fusions as well as serve as a reporter to study gene expression. They
identified six complementation groups in this region. In the course of these studies,
Stachel also observed that expression of the vir genes was enhanced significantly by
exudates of a variety of plant cell cultures. From Seattle, Stachel went to Ghent
where he and his collaborators then identified two phenolic compounds, acetosyrin-
gone (AS) and hydroxyacetosyringone (OH-AS) in plant exudates that induce the
vir genes [8].
Stachel was also an important player in elucidating the mechanism by which AS
induces the vir genes. He and Steve Winans in Seattle independently characterized
a two-component system, VirA/G, which controls expression of the vir regulon. AS
binds to the membrane-bound histidine kinase sensor protein VirA, which then acti-
vates the response regulator VirG, which in turn binds to upstream regions of each
of the vir operons and activates their transcription. This particular two-component
regulatory system was one of the very first to be described in any organism.
Stachel and Pat Zambryski also demonstrated that the addition of AS to
Agrobacterium results in the formation of a single-stranded, linear DNA molecule,
which they suggested is the intermediate in the transfer of T-DNA to plant cells.
They further suggested that this form of DNA, now termed the T-strand, resulted
from an endonucleolytic cleavage at the right and left borders of the T-DNA and
compared the transfer of this DNA to the transfer of single-stranded DNA in bacte-
rial conjugation.
The publication of Stachel et al. was quickly followed by a paper by Martin
Yanofsky et al. in Seattle which demonstrated that the virD operon encodes a site-
specific endonuclease that cleaves within each of the 25-bp direct repeats that flank
the T-DNA. Two proteins are required, Vir D1 and Vir D2. Once the Vir D2 protein
cleaves the DNA it remains covalently attached to the 5′ end of the T-strand, as first
demonstrated by Calvin Young et al. This protein likely serves as a pilot protein for
entry of the T-DNA into the plant cell nucleus. In support of this idea, Luis Herrera-
Estrella in Ghent demonstrated that the amino-terminal portion of the Vir D2 pro-
tein contains a nuclear localization signal. Another Vir protein Vir E2 was shown by
Barbara Hohn et al. in Basel, Switzerland, to be a single-stranded DNA-binding
protein which also has nuclear localization signals. This protein not only protects
the T-strand from degradation by plant nucleases but also helps direct the T-strand
into the plant cell nucleus (Fig. 2).
Key Factors Influencing Agrobacterium-Mediated Transformation Efficiency in Plants... 911

Fig. 2 Mechanism of T-DNA transfer

One of the most challenging questions of this interkingdom transfer of DNA is

how the T-DNA is transferred from bacteria to recipient cells. This problem is being
studied in numerous laboratories but the person who has made especially significant
contributions is Peter Christie at the University of Texas. The eleven open reading
frames of the vir B operon encode a trans envelope protein complex as well as the
T-pilus. The various proteins which make up this organelle provide the channel as
well as the energy for the transfer of the T-strand. Another protein, Vir D4, is a cou-
pling protein which recruits the effector proteins to the transenvelope protein com-
plex. Thus, it is likely that the transmembrane protein complex, the T-pilus, and the
coupling protein function as a single organelle to translocate the T-strand as well as
several other Vir proteins into host cells. This type IV secretion system (T4SS), first
identified as the conjugation apparatus in Escherichia coli, has now been identified
in many species of Gram-positive and Gram-negative bacteria; however,
Agrobacterium serves as the model system. The T4SS of Agrobacterium is unusual
in that both DNA and many Vir proteins are transferred. The Vir proteins, such as
VirE2, VirE3, and Vir F are transferred independently of DNA, but through the
same T4SS.
912 D. P. Barik

A more recent model for T-DNA integration based on “microhomology” has

been proposed [7] with the sequence of events to occur in the following order:
(i) The synapsis (association) between plant target DNA and T-DNA is initiated at
the 3′ end of the single-stranded T-DNA at a short region of homology
(microhomology).
(ii) The 5′ end of the single-stranded T-DNA is ligated to the 3′ end of the comple-
mentary plant cell DNA by means of the energy-rich phosphotyrosine bond.
(iii) Meanwhile, the 3′ end of the annealed single-stranded T-DNA is used as primer
to copy the plant DNA to which it will be ligated.
(iv) The upper strand of the plant DNA nicked at strategic points is extended by
repair replication to copy the T-DNA.
(v) The phosphotyrosine bond at the 5′ end of the T-DNA is replaced by a phos-
phodiester bond with the target DNA.
(vi) The T-DNA is covalently integrated in the host plant DNA.

37.7 Factors Influencing Agrobacterium

Transformation Efficiency

1. Collection and selection of explant types, i.e., cotyledonary node, epicotyl,

hypocotyl, leaf, internode, etc. (Figs. 3 and 4).
2. Selection of Agrobacterium strains with different plasmid construct for ex
LBA 4404 and EHA 105, each harboring the same plasmid construct pGUSINT
containing β-glucuronidase (GUS) intron gene (gus int) and the selectable
marker neomycin phosphotransferase gene (nptII).
3. Culture and maintenance of Agrobacterium strains with regular intervals.
4. Determination of phytotoxic levels of kanamycin, i.e., kanamycin (K4378,
Sigma, USA) (25, 50, 75, 100, 125, and 150 μg ml–1).
5. Selection of bactericidal antibiotics, i.e., sporidex (Ranbaxy, India), cefotax-
ime (Sigma, USA), and carbenicillin (Hi-Media, India).
6. Factors influencing transformation frequency: For the best transformation
efficiency, different factors were tested. These include bacterial growth phase at
different OD values at 600 nm (0.3, 0.4, 0.6, 0.8, and 1.0), wounding method
(glass wool, sterile sand, hand pricking), dilution of bacterial culture (25%, 50%,
75%, and 100%), infection time (5, 10, 15, and 20 min), pH of the co-cultivation
medium (5.5, 5.6, 5.7, 5.8, and 6.0), and co-cultivation period (1, 2, 3, 4, 5, and
6 days).
7. Selection of transformed shoots and transgenic plant production.
Key Factors Influencing Agrobacterium-Mediated Transformation Efficiency in Plants... 913

Fig. 3 A protocol for Agrobacterium-mediated transformation of Lathyrus sativus L.

37.8 Hijacking of Plant Signals and Structures

by Agrobacterium

Agrobacterium is a very clever organism in that it uses numerous plant metabolites

and cellular structures to further its own ends. We have already discussed how
Agrobacterium recognizes a wound site on a susceptible plant through the plant
metabolite AS which is involved in vir gene activation. Several other examples are
914 D. P. Barik

Fig. 4 A case study using Agrobacterium tumefaciens in legume plant, i.e., Lathyrus sativus L.

known. Once the T-DNA is transferred into the plant, the vir regulon no longer
needs to be expressed. Therefore, one of the products of T-DNA expression, indole
acetic acid (IAA), shuts down expression of the vir regulon by inhibiting the activa-
tion of the VirA/G regulatory system, thereby conserving carbon and energy. At
Key Factors Influencing Agrobacterium-Mediated Transformation Efficiency in Plants... 915

slightly higher concentrations, IAA kills the bacteria which may help explain the
long-standing observation that crown gall tumors often do not contain viable
bacteria.
Another product of transformed plant cells which plays an important role in the
biology of Agrobacterium are the opines. Studies from the laboratories of Stephen
Farrand, Steve Winans, Allen Kerr, and Max Tate demonstrated that certain opines
induce the synthesis of a signal molecule acyl homoserine lactone, which interacts
with a transcriptional activator to promote conjugal transfer of the Ti plasmid to
other agrobacteria.
Not only does Agrobacterium utilize extracellular plant signals in the infection
process, but it also hijacks cellular processes for the transport of the T-strand to the
nucleus. These pioneering studies have been carried out largely in the laboratories of
Stanton Gelvin, Vitaly Citovsky, and Tsvi Tzfira. The viscous cytoplasm with its
assemblage of membranous and nonmembranous structures most likely requires that
the T-strand be actively transported to the nucleus. Many DNA viruses use dynein
motor proteins of the host and the host microtubule system for their transport to the
nucleus. The available data suggest this may be true for the journey of the T-strand
to the nucleus also. Both Vir D2 and Vir E2 proteins with their nuclear localization
signals are important in nuclear import and both accumulate in the plant cell nucleus.
A number of other host proteins have been implicated in their interaction with the
T-strand but the roles they play in the transformation process are obscure.

37.9 Genetic Engineering of Plants

Soon after it was shown that T-DNA was integrated into the plant cell nucleus and
that the T-DNA was defined by its flanking border sequences, many laboratories
realized that Agrobacterium potentially might be a very useful vector for introduc-
ing any desired DNA into plants. This possibility was strengthened when Léon
Otten in Jeff Schell’s group demonstrated that opine genes were transferred in a
Mendelian fashion. Self-pollination of the transformed plant and crossing of trans-
formed and untransformed plants showed that this trait was transmitted through
pollen and eggs as a single dominant gene with the predicted Mendelian ratios.
Jean-Pierre Hernalsteens then inserted a Tn 7 transposon into an opine locus and
demonstrated that it was transferred to, and maintained in, tumor tissues induced by
this mutant strain. Since Tn5 had its own promoter, antibiotic resistance was not
expressed. However, this experiment did demonstrate that using the Ti plasmid as a
vector system for introducing DNA into plant cells was feasible.
The major technical problem in using the Ti plasmid as a gene vector is its large
size. This makes it impossible to employ a direct recombination strategy to insert
genes of interest into the T-DNA. Several indirect methods were developed in the
early 1980s for manipulating T-DNA but these were cumbersome and not easily
carried out. The problem was solved when two independent groups, one led by
Mary-Dell Chilton and the other by Rob Schilperoort, shrank the plasmid by
916 D. P. Barik

separating its two essential regions into two plasmids; the 25-bp borders flanking
the T-DNA between which genes of interest could be inserted and the vir region
which is necessary for the processing and transfer of the T-DNA. This binary vector
system is used in most laboratories today.
Two additional hurdles remained before plants could be routinely transformed in
an industrial setting with genes that create added value on the engineered plants.
First, plants had to be regenerated with the genes of interest stably maintained and
second, the introduced genes had to be expressed. The first problem was solved by
two independent groups Pat Zambryski et al. in Jeff Schell’s group and Andy Binns
et al. at the University of Pennsylvania. They both showed that the oncogenes of
T-DNA interfere with normal plant cell differentiation and that if they are removed,
transformed cells readily regenerate into normal plants. The second hurdle was
overcome when three independent groups (the Ghent group, a group from Monsanto
headed by Rob Fraley, and Chilton’s group) almost simultaneously reported on the
expression of foreign genes in transformed plants. All three groups used the nopal-
ine synthase promoter fused to an antibiotic resistance locus which resulted in anti-
biotic resistant tobacco transformants. These experiments opened up the age of
plant genetic engineering with the Monsanto Company leading the subsequent
industrial revolution in agriculture.
Although Agrobacterium has a very broad host range and tumors have been
detected on many dicotyledonous plants in Nature, the most important plants eco-
nomically worldwide are the monocots, which include the cereals. Since crown gall
tumors had never been observed in this group of plants, and initial efforts to trans-
form many of them in the laboratory were unsuccessful, many agrobiologists
believed that monocots were totally recalcitrant to Agrobacterium transformation.
However, a clever experiment performed in Barbara Hohn’s group, on the sugges-
tion of her virologist husband, clearly demonstrated in fact that Agrobacterium was
able to carry out the initial steps in maize transformation—the transfer of T-DNA
and expression of the transferred genes. These investigators introduced tandemly
repeated copies of the genome of maize streak virus between the T-DNA borders
and inoculated maize plants with Agrobacterium carrying this construct in a binary
vector. The inoculated leaves developed symptoms of maize streak viral disease!
Further experiments demonstrated that this viral infection, termed agroinfection,
requires the same Vir proteins as are required for tumor formation by wild-type
Agrobacterium. These results encouraged others to test a variety of strains of
Agrobacterium and different monocot tissues using a variety of reporter systems
and selective markers to look for T-DNA transfer and expression. In 1994, Hei and
his colleagues at the Japan Tobacco Company reported the efficient transformation
of rice. They studied a variety of tissues and several different strains of Agrobacterium,
screening for GUS color and selecting for hygromycin resistance. Of all the tissues
tested, scutellum callus gave the highest level of transformation and a “super-
binary” vector gave especially high transformation frequencies of various cultivars
of Japonica rice. High-frequency Agrobacterium transformation has now been
achieved for most cereal crops.
Key Factors Influencing Agrobacterium-Mediated Transformation Efficiency in Plants... 917

37.10 Expanded Host Range

Although Agrobacterium gene transfer and crown gall tumor formation in a wide
variety of plants is a common occurrence in nature, in the laboratory, Agrobacterium
can transfer DNA into a much broader group of eukaryotic cells. This was first dem-
onstrated by Paul Hooykaas and colleagues who reported that Agrobacterium carry-
ing a ura+ locus between T-DNA borders could transform a ura– strain of the yeast
Saccharomyces cerevisiae to prototrophy in medium that promoted vir gene induc-
tion. This group also showed that many other fungi could be transformed following
co-cultivation with Agrobacterium. Now, numerous algae, protozoa, and even Hela
cells have been stably transformed in the laboratory. These reports have opened up
a whole new use for Agrobacterium, allowing the genetic analysis of organisms that
previously were totally recalcitrant to such studies (Tables 1 and 2). A standard
protocol for Agrobacterium-mediated transformation of Lathyrus sativus is given in
Figs. 3 and 4.

37.11 T-DNA in Untransformed Plants

Agrobacterium is truly a natural genetic engineer, in that not only does it transform
plants to synthesize food (opines) for itself but its DNA can be found even in per-
fectly normal appearing, uninfected plants. In Seattle, Frank White and colleagues
reported that the T-DNA (rol) genes of A. rhizogenes can be readily detected in
uninfected Nicotiana glauca and many other species of tobacco. It seems most
likely that A. rhizogenes infected a Nicotiana plant millions of years ago to form
hairy root tumors which then regenerated into normal appearing plants which passed
down the conserved sequences to their progeny. This observation puts to rest the
idea that transgenic plants represent an unnatural phenomenon that only occurs in
the laboratory. One can safely bet that the finding of T-DNA in many species of
Nicotiana is not an isolated phenomenon limited to this plant.

37.12 Concluding Comments

Research on crown gall tumors began as a classic study in plant pathology aimed at
identifying the cause of a devastating plant disease with unusual symptoms. Studies
on Agrobacterium by investigators in laboratories around the world have revealed
new biological phenomena and practical applications far beyond what Smith and
Townsend could ever have imagined. On the one hand, Agrobacterium causes seri-
ous problems for growers of grapes, stone fruits, and ornamental plants. On the
other hand, it has provided an unusually exciting and rewarding experimental sys-
tem for those of us fortunate to have entered into its study. The study of
Table 1 Genetic transformation of tree species using Agrobacterium tumefaciens
918

Kanamycin
Infection and conc. for
co-cultivation selection (μg/ Gene
Species Strain Construct Explant details ml) expression Detection method References
Actinidia deliciosa LBA4404 pRokla-EG Leaf disc Infected with 50 nptII, Soybean PCR and Southern blot [9]
(kiwi fruit) nptII, soybean petiole, stem bacteria β-1,3 analysis, Northern blot
β-1,3 segment endonuclease and Western blot
endonuclease analysis
Carica papaya LBA4404 pB1121 (nptII, Petioles Just dipped and 50 gus, gus PCR and Southern blot [10]
(papaya) gus) from co-cultivated for analysis, Northern blot
multishoot 2 days and Western blot
analysis
Citrus aurantifolia EHA 105 p35SGUSINT Internodal Infected with 10 nptII, gus, npt, PRC and Southern blot [11]
(lime orange) (nptII, gus) segment bacterium for gus analysis, ELISA and
15–30 mins and histochemical enzyme
then assay
co-cultivated for
3 days
Citrus aurantium EHA 101 pGA482GG- Internode Explants 100 ctv-cp, gus, PCR and Southern bot [12]
(sour orange) CTVCP (gus, co-cultivated for ctv-cp analysis, Histochemical
ctv-cp) 1–3 days enzyme assay, Western
blot analysis
Citrus sinensis – EHA 105 p35SGUSINT Epicotyl Explants 100 nptII, gus, gus PCR and Southern blot [13]
Osbeck × (nptII, gus) incubated 15 min analysis, Northern blot
Poncirus trifolia in 15 ml bacterial and Western blot
(citrange) suspension, analysis, Histochemical
co-cultivated for enzyme assay
1, 3, 5 days
D. P. Barik
 Kanamycin
Infection and conc. for
co-cultivation selection (μg/ Gene
Species Strain Construct Explant details ml) expression Detection method References
Citrus sinensis LBA4404, p35SGUSINT Epicotyl Epicotyl 100 nptII, gus, gus PCR and Southern blot [14]
(Washington novel EHA 101, (nptII, gus) segments analysis, Northern blot
orange) EHA 105, C58 infected for and Western blot
10 min in analysis, histochemical
bacterial enzyme assay
suspension
(5 × 108 cfu/ml)
blotted dry,
co-cultivated for
2–3 days
Diospyros kaki LBA 4404, pB1121, Hypocotyl Segments of 100 nptII, gus, gus PCR and Southern blot [9]
(Japanese EHA 101 pSMAK251 hypocotyl analysis, Northern blot
persimmon) (nptII, gus) immersed in and Western blot
bacterial analysis, histochemical
suspension enzyme assay
approximately
(5 × 108 cfu/ml)
for 15 min and
then
co-cultivated for
3 days
Eucalyptus A6, LBA Each Leaf disc Co-cultivated for 9 nptII, gus, gus Southern blot analysis, [15]
camaldulensis 4404, GV containing petiole, stem 2 days in NPT II enzyme assay,
(eucalyptus) 3111, AGL1, nptII, gus segment bacterial histochemical enzyme
GV3850 suspension (109 assay
Key Factors Influencing Agrobacterium-Mediated Transformation Efficiency in Plants...

cells/ml) on
callusing
medium
919

(continued)
Table 1 (continued)
920

Kanamycin
Infection and conc. for
co-cultivation selection (μg/ Gene
Species Strain Construct Explant details ml) expression Detection method References
Hevea brasiliensis GV 2260 p35SGUSINT Callus Calli submerged 100 nptII, gus, Southern blot analysis, [16]
(rubber) (nptII, gus) in an overnight nptII, gus, gus histochemical enzyme
grown assay by Sudan III
Agrobacterium Staining (Jensen 1962)
suspension for
1 min and then
co-cultivated for
2 days
Larix C58 pPMP90, Somatic Bacterial 50 nptII PCR and Southern blot [17]
kaempferi × L. pMRKE70Km embryo suspension at OD analysis
decidua (hybrid (2 copies of 0.3
larix) nptII) (approximately
108 cfu/ml)
applied to
embryonal
masses kept on
proliferation
medium in dark
for 48 h
Malus domestica EHA 105 p35SGUSINT Internode Epicotyl 100 gus, gus Histochemical enzyme [18]
(royal gala apple) (nptII, gus) segments dipped assay
in overnight
grown bacterial
suspension
culture, a density
of 2 × 108 cfu/ml,
blotted dry,
D. P. Barik

co-cultivated for
48 h
 Kanamycin
Infection and conc. for
co-cultivation selection (μg/ Gene
Species Strain Construct Explant details ml) expression Detection method References
Malus domestica EHA 105 p35SGUSINT Leaf disc Wounded leaves 25 nptII, gus, PCR and Southern blot [19]
(Marshal (nptII, gus) petiole, stem co-cultivated in nptII, gus, gus analysis, ELISA and
Maclntosh apple) segment dark for 48 h NPT enzyme assay by
after infecting histochemical enzyme
with bacterial assay
suspension
Populusalba×grand- C58 pPMG85/587 Leaf 1–5 ml bacterial 50 nptII, aro A, Southern blot analysis
identata (populus (nptII, EPG segment broth culture nptII, aro A
hybrid NG 5339) synthase, aro infected for
A) 30 min and then
co-cultivated for
48–96 h
Prunus dulcis LBA 4404, p35SGUSINT Leaf Leaf wounded 15 nptII, gus, gus Southern blot analysis, [20]
(almond) EHA 101, (nptII, gus) from mid-rib NPT II enzyme assay
EHA 105, C58 dipped in and ELISA,
bacterial histochemical enzyme
suspension and assay
co-cultivated for
3–4 days
Pyrus communis EHA 101 pFM3002, Leaf Infected with 100 nptII, uid A, PCR and Southern blot [21]
(pear) pFAJ300 bacterial attacin E, analysis, Northern blot
(nptII, uid A, suspension attacin E and Western blot
attacin E) 5 × 107 cuf/ml analysis
Santalum album LBA4404, pKIW 105, Somatic Infected with 50 nptII, uid A, PCR and Southern blot [22]
(sandalwood) EHA 101 pIG121-Hm embryo bacterial nptII, uid A analysis, NPT II
Key Factors Influencing Agrobacterium-Mediated Transformation Efficiency in Plants...

(nptII, uid A) suspension and enzyme assay,

co-cultivated for histochemical enzyme
24 h assay
921
Table 2 Genetic transformation of grain legumes using Agrobacterium tumefaciens
922

Kanamycin
Infection and selection
Species Strain Construct Explant co-cultivation details (μgml−1) Gene detection and expression References
Cajanus cajan L. and LBA4404 pCAMBIA 1303 Different Infection for 30 min 50 uid A Histochemical GUS [23]
some grain legumes (uidA and gus) explants and co-cultivation for gus assay
48 h
Cajanus cajan (L.). GV2260 CaMV 35S Embryonic axis Co-cultivation for 12 h 50 nptII PCR analysis [24]
Millsp. (nptII) Southern analysis
Vr. Pusa 885
Cajanus cajan L. EHA105 pBin9GusInt Cotyledonary Infection for 20 min 50 nptII GUS-histochemical [25]
Millsp. (nptII and gusA) node and leaf and co-cultivation for gusA assay
explants 20 h
Cicer arietinum L. LBA4404 pBI 121 Embryo axis Infection for 20 min 50 nptII Histochemical GUS [26]
CaMV35S Co-cultivation for gus assay
(nptII and gus) 2–3 weeks Southern analysis
Cicer arietinum L. LBA4404 pBI 121 Embryo axis Cultured for 24 h on 50 nptII NPT II enzyme assay [27]
genotypes (uidA and nptII) SR medium prior to gus Histochemical GUS
ICCV-1 co-cultivation with assay
ICCV-6 bacteria Southern analysis
and Desi (local)
Cicer arietinum L. vr. A281 pKIW1105 Stem Co-cultivation for 80 nptII Histochemical GUS [28]
6153 and CM72 C58 p35SGUSINT Leaf 2 days gus assay
(nptII and gus)
Dalbergia sissoo EHA105 p35SGUSINT Cotyledonary Infection for 8–15 min 50 nptII GUS-histochemical [29]
(nptII and gus) node Co-cultivation for gus assay
Epicotyl 2–4 days
Galega orientalis Lam. LBA4404 pAC 4404 Node Co-cultivation for 100 nptII GUS-histochemical [30]
AGL1 (nptII and gus) Cotyledon 4 days gus assay
EHA105 pTiBo 542
MOG301 pEHA 105
pMOG 301
CaMv35S and gus
Glycine max EHA105 pTIT37SE Cotyledon NAI 50 nptII gus Histochemical GUS [31]
D. P. Barik

(L.) Merr. (nptII and gus) explant assay

Southern analysis
Glycine max EHA105 pBISNI Cotyledonary Infection for 3 h 50 nptII Histochemical GUS [32]
(L.) Merr. KYRT1 (nptII and gus) node Co-cultivation for 72 h gus assay
LBA4404
Glycine max EHA105 p35SGUSINT Cotyledon Infection for 2 s 50 gus Histochemical GUS [33]
(L.) Merr. (veco35 and gus) Co-cultivation for assay
cv. Jack, Chapman 3 days
Kunitz
Glycine max EHA105 or pPTN 101 Cotyledonary Infection for 30 min 50 bar Histochemical GUS [34]
(L.) Merr. EHA 101 pPTN 125 node Co-cultivation for gus assay
(bar and gus) 3 days Southern analysis
Herbicide tolerant
Lathyrus sativus L. LBA4404 pPCV 002-35S-GUS Somatic embryo Infection for 48 h 50 gus Histochemical GUS [35]
cv. P-24 (gus) Co-cultivation for assay
6 days
Medicago sativa L. A281 pGA 472 Somatic embryo Infection for 5–10 min 100 nptII gus NPT II enzyme assay [36]
cv. Zajecarska83 LBA4404 pB 121 I Co-cultivation for Histochemical GUS
(nptII and gus) 48–120 h assay
Southern analysis
Medicago sativa L. A208 Napoline strain Hypocotyl Co-cultivation for 25 gus Histochemical GUS [37]
A348 Octopine strain Stem 4 weeks assay
A281 Super virulant
A136 Avirulant
Pisum sativum L. AGL1 (nptII and bar) Immature Co- cultivation for NAI nptII bar PAT assay [38]
cv. Greenfeast & Rondo embryo axis 4 days Northern blot
Pisum sativum L. AGL1 pLN 27 Immature NAI 10 mg/ml nptII bar PCR-amplification [39]
(nptII and bar) cotyledon Phosphinot- Southern analysis
hricin
Vicia narbonensis EHA101 pGSGLUCI-2S Epicotyl NAI NAI nptII Histochemical GUS [40]
(nptII, gus and 2S gus assay
gene) 2s-gene Southern analysis
Vigna mungo (L.) Hepper LBA4404 Octopine type Primary leaf Co-cultivation for 50 nptII II assay [41]
Eha105 pTiAch 5 segment 2 days Southern analysis
Key Factors Influencing Agrobacterium-Mediated Transformation Efficiency in Plants...

Agropine type
pTiBo 542
Vigna unguiculata L. C58 pGV2260 Mature embryo NAI NAI gus GUS and DNA dot [42]
923

p35SGUSINT blot analysis

NAI no available information
924 D. P. Barik

Agrobacterium–plant interactions has led to many unanticipated pleasant surprises,

many of which were first observed in this system but now have been found to be
common in the biological world.
Many of the blockbuster discoveries on Agrobacterium–plant interaction have
been cited briefly in this narrative. However, much remains to be learned. The
chemical signaling between Agrobacterium and plants in the natural environment of
the plant’s rhizosphere has yet to be fully explored. In addition, the trafficking of the
T-strand from the inception of the transfer process to the plant cell nucleus provides
an area of fruitful research opportunities for interdisciplinary investigations. The
full potential of using Agrobacterium as a mutagen and a transfer system for genes
into an ever-expanding number of eukaryotic cells has yet to be realized. After
100 years, the tale of Agrobacterium is not yet finished.

References

1. Old RW, Primrose SB (1994) Gene transfer to plants. In: Carr NG (ed) Principles of gene
manipulation, an introduction to genetic engineering. Blackwell Scientific Publications,
Oxford, pp 268–301. Tinland B (1996) The integration of T-DNA into plant genomes. Trends
Plant Sci 1:178–184
2. Ananda KP, Sharma RP, Malik VS (1996) The insecticidal proteins of Bacillus thuringiensis.
Adv Appl Microbiol 41:1–43
3. Beachy RN, Loesch-Fries S, Tumer NE (1990) Coat protein-mediated resistance against virus
infection. Ann Rev Phytopathol 28:451–474
4. Diiring K, Porsch P, Flaudung M, Lorz H (1993) Transgenic potato plants resistant to the phy-
topathogenic bacterium Erwinia corotovora. Plant J 3:587–598
5. Mohapatra U, McCabe MS, Power JB, Schepers F, Vander Arend A, Davey MR (1999)
Expression of the bar gene confers herbicide resistance in transgenic lettuce. Transgenic
Res 8:33–44
6. Mohapatra U, McCabe MS, Power JB (2002) Agrobacterium-mediated transformation of let-
tuce for bialaphus resistance. In: Nandi SK, LMS P, Kumar A (eds) Proceedings of the national
seminar on role of plant tissue culture in bio-diversity conservation and economic develop-
ment. Gynodaya Prakashan, Nainital, pp 445–455.s
7. Tinland B (1996) The integration of T-DNA into plant genomes. Elsevier 1(6):178–184
8. Mondal TK, Bhattacharya A, Ahuja PS, Chand PK (2001) Transgenic tea [Camellia sinensis
(L.) O Kuntze cv. Kangrajat] plants obtained by Agrobacterium-mediated transformation of
somatic embryos. Plant Cell Rep 20:712–720
9. Nakamura Y, Sawada H, Kobayashi S, Nakajima I, Yoshikawa M (1999) Expression of soya-
bean M, ß-endogluconase cDNA and effect on disease tolerance in Kiwifruit Plants. Plant Cell
Reports 18:527–532
10. Yang J-S, Yu T-A, Cheng Y-H, Yeh S-D (1996) Transgenic Papaya plants from Agrobacterium-
mediated transformation of petioles of in vitro propagated multi-shoots. Plant Cell Reports
15:459–464
11. Pena L, Cervera M, Juarez J, Navarro A, Pina JA, Navarro L (1997) Genetic transformation
of lime (Citrus aurantifolia Swing.): factors affecting transformation and regeneration. Plant
Cell Reports 16:731–737
12. Gutierrez-E MA, Luth D, Moore GA (1997) Factors affecting Agrobacterium-mediated trans-
formation in citrus and production of sour orange (Citrus aurantium L) plants expressing the
coat protein gene of citrus tristeza virus. Plant Cell Reports 16:745–753
Key Factors Influencing Agrobacterium-Mediated Transformation Efficiency in Plants... 925

13. Cervera M, Pina JA, Juarez J, Navarro L, Pena L (1998) Agrobacterium – mediated trans-
formation of citrange: factors affecting transformation and regeneration. Plant Cell Reports
18:271–278
14. Bond JE, Roose ML (1998) Agrobacterium-mediated transformation of commercially impor-
tant citrus cultivar Washington novel orange. Plant Cell Reports 18:229–234
15. Mullins KV, Llewellyn DJ, Hartney VJ, Strauss S, Dennis ES (1997) Regeneration and trans-
formation of Eucalyptus camaldulensis. Plant Cell Reports 16:787–791
16. Arokiaraj P, Yeang HY, Cheong KF, Hamzah S, Jones H, Coomber S, Charlwood BV (1998)
CaMV 355 promoter directs ß glucuronidase expression in the laticiferous system of trans-
genic Hevea brasiliensis (rubber tree). Plant Cell Reports 17:621–625
17. Leeve V, Lelu MA, Jouanin L, Cornu D, Pilate G (1997) Agrobacterium tumifaciens – medi-
ated transformation of hybrid Larch (Larix Kaempferi × L. decidua) and transgenic plant
regeneration. Plant Cell Reports 16:680–685
18. Liu Q, Salih S, Hummerschlag F (1998) Etiolation of ‘Royal Gola’ apple (Malus × domestica
Borkh.) shoots promotes high-frequency shoot organogenesis and enhanced ß-glucuronidase
expression from stem internodes. Plant Cell Reports 18:32–36
19. Bolar JP, Norelli JL, Harman GE, Brown SK, Aldwinckle HS (1999) Expression of fungal
chitinolytic enzymes in transgenic apples confers high levels of resistance to scab. Plant bio-
technology and in vitro biology 36:465–468
20. Miguiel CM, Oliveira C (1999) Transgenic Almond (Prunus dulcis Mill.) plants obtained by
Agrobacteriun-mediated transformation of leaf explants. Plant Cell Rep 18:387–393
21. Reynoird JP, Mourgues F, Norelli J, Aldwinckle HS, Brisset MN, Chevreu E (1999) First
evidence for improved resistance to fire blight in transgenic pear expressing the attacin E gene
from Hyalophora cecropia. Plant Sci 149(1):23–31
22. Shiri V, Rao KS (1998) Introduction and expression of marker genes in sandalwood (Santalum
album L.) following Agrobacterium mediated transformation. Plant Sci 131(1):53–63
23. Shrivastava DK, Sanyal I, Singh BD, Amla DV (2001) Endogenous GUS-activities in Cajanus
cajan L. and some grain legumes: selective suppression for expression of GUS reporter gene.
J Plant Biol 28(3):243–250
24. Lawrence PK, Koundal KR (2000) Simple protocol for Agrobacterium tumefaciens- mediated
transformation of pigeonpea [Cajanus cajan (L.) Millsp.]. J Plant Biol 27(3):299–302
25. Singh ND, Sahoo L, Sonia, Jaireal PK (2002) In vitro shoot organogenesis and plant regen-
eration from cotyledonary node and leaf explants of pigeon pea (Cajanus cajan L. Millsp.).
Physiol Mol Biol Plants 8(1):113–140
26. Fontana GS, Santini L, Caretto S, Frugis G, Mariotti D (1993) Genetic transformation in the
grain legume Cicer arietinum L. (Chickpea). Plant Cell Rep 12:194–198
27. Kar S, Johnson TM, Nayak P, Sen SK (1996) Efficient transgenic plant regeneration through
Agrobacterium-mediated transformation of chickpea (Cicer arietinun L.). Plant Cell Rep
16:32–37
28. Husnain T, Malik T, Riazuddian S, Gordon MP (1997) Studies on expression of marker genes
in chickpea. Plant Cell Tiss Org Cult 49:7–16
29. Pradhan C (2000) Plant regeneration from tissue & cell cultures and Agrobacterium-mediated
genetic transformation of Dalbergia species. Ph.D thesis, Utkal University, Vanivihar,
Bhubaneswar
30. Collen AMC, Jarl CI (1999) Comparison of different methods for plant regeneration and trans-
formation of the legume Galega orientalis Lam. (goat’s rue). Plant Cell Rep 19:13–19
31. Hinchee MAW, Connor-Ward D, Christine AN, McDonald RE, Sato SJ, Gasser CS, Fischott
DA, Re DB, Fraley RT, Horsch RB (1998) Production of transgenic soybean plants using
Agrobacterium-mediated DNA transfer. Bio/Technology 6:912–922
32. Meurer CA, Dinkins RD, Collins GB (1998) Factors affecting soybean cotyledonary node
transformation. Plant Cell Rep 18:180–186
33. Santarem ER, Trick HN, Essig JS, Finer JJ (1998) Sonicated-assisted Agrobacterium-mediated
transformation of soybean immature cotyledons: optimization of transient expression. Plant
Cell Rep. 17:752–759
926 D. P. Barik

34. Zhang Z, Xing A, Staswick P, Clemente TE (1999) The use of glufosinate as a selective agent
in Agrobacterium mediated transformation of soyabean. Plant Cell Tiss & Org Cult 56:37–46
35. Barna KS, Mehta SL (1995) Genetic transformation and somatic embryogenesis in Lathyrus
sativus. J Plant Biochem Biotechnol 4:67–71
36. Ninkovic S, Miljus-Djukic J, Neskovic M (1995) Genetic transformation of alfalfa embryos
and their clonal propagation through repetitive somatic embryogenesis. Plant Cell Tiss Org
Cult 42:255–260
37. Samac DA (1995) Strain specificity in transformation of alfalfa by Agrobacterium tumefa-
ciens. Plant Cell Tiss Org Cult 43:272–177
38. Schroeder HE, Schotz AH, Wardley-Richardson T, Spencer D, Higgins TJV (1993)
Transformation and regeneration of two cultivars of pea (Pisum sativum L.). Plant Physiol
101:751–757
39. Grant JE, Cooper PA, McAra AE, Frew TJ (1995) Transformation of pea (Pisum sativum L.)
using immature cotyledons. Plant Cell Rep 15:245–258
40. Pickardt T, Meixner M, Schade V, Scheider O (1991) Transformation of Vicia narbonensis via
Agrobacterium-mediated gene transfer. Plant Cell Rep 9:535–538
41. Karthikeyan AS, Sarma KS, Veluthambi K (1996) Agrobacterium tumefaciens mediated trans-
formation of Vigna mungo (L.) Hepper. Plant Cell Rep 15:328–331
42. Penza R, Lurquin PF, Filippone E (1991) Gene transfer by co-cultivation of mature embryos
with Agrobacterium tumefaciens :application to cowpea (Vigna unguiculata Walp.). J Plant
Physiol 138:39–43
Evaluation of Medicinal Plant
with Reference to Its Substitute

T. V. Binu and C. B. Athira

1 Introduction

Ayurveda is believed to be the oldest treatise on medical system, which came into
existence in about 900 B.C. The word Ayurveda is derived from the Sanskrit words
Ayur “meaning life” and Veda “meaning science.” Thus, Ayurveda literally means
science of life. According to the Indian Hindu mythology, there are four Vedas writ-
ten by the Aryans – Rig Veda, Sam Veda, Yajur Veda, and Atharva Veda. Rig Veda is
the oldest among the four Vedas written later than 1500 B.C. The Ayurveda is said
to be an Upaveda (part) of Atharva Veda, whereas Charaka Samhita (1900 B.C.) is
the first recorded book fully devoted to the concept of practice of Ayurveda. It
describes 341 plants and plant products for use in medicine. The next Ayurvedic
literature that has special emphasis on surgery was Sushruta Samhita (600 B.C.).
Another important authority of Ayurveda was Vagbhata of Sindh, presently in
Pakistan, who practiced Ayurveda in around seventeenth century A.D. His work
Ashtanga Hridaya is considered unrivaled for the principles and practices of medi-
cine. Madhab Nicane (800–900 A.D.) was the next important milestone and is the
most famous work on diagnosis of diseases as per the Ayurvedic concept. Bhava
Mishra of Magadha is the first writer on Hindu medicine whose treatise, Bhava
Prakasha, written around 1550 is held in high esteem by modern Ayurvedic practi-
tioners for its description of approximately 470 medicinal plants.
Side by side with the systematic development of medicines in ancient India,
there was also organized medical help in the form of hospitals and dispensaries and
a certain measure of health propaganda. During the Buddhist period, monks trav-
eled all over the country not only preaching religion and philosophy and dispelling
ignorance but also alleviating human suffering, King Asoka, and his edicts are
famous. But even before Asoka’s time, evidence of organized medical care was seen

T. V. Binu (*) · C. B. Athira

Department of Botany, St Joseph’s College, Irinjalakuda, Thrissur, Kerala, India

© The Author(s), under exclusive license to Springer Nature 927

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_38
928 T. V. Binu and C. B. Athira

in Charaka Samhita. Vivid descriptions are found about the location, building, and
personnel and amenities of hospital, Aturalaya; a maternity home, Sutikargriha; a
nursery, sisugriha; and a pharmacy. It should be remembered that Ayurveda is not
the science of health. Healthful living, prevention of disease, and personal and
social hygiene all come under its ambit and not merely the cure of diseases.
Indian medicinal plants are the essence of Ayurveda and Ayurvedic treatments.
When used judicially and clocking with the basic principles, they produce miracu-
lous effects. Their role cannot be confined to merely treating diseases but they are
also used being of the human body. Hence, Ayurvedic drugs are rightly called the
elixirs of life. Ayurvedic herbs played an important role in Ayurvedic treatment,
from the ancient time to the modern time.
Ayurvedic medicinal plants are classified according to their properties such as
Rasa, Guna, Virya, and Vipaka. (This is one of the simplest and most important clas-
sification I narrate, but there have so many classifications.) This classification helps
us how to manage/work medicinal plants to cure diseases. Ayurveda states that viti-
ation/abnormal increase in vata, pitta and kapha are main cause of disease. Vitiation
is due to the increase or decrease of similar properties. All the Dravya/substance has
properties (Guna).Vata, pitta and kapha have considerable increases in related
Doshas, so proper identification of Ayurvedic medicinal plants is important in the
field of treatment. Medicinal plants used in South India and North India are differ-
ent, even though their Sanskrit names are similar. However, they show the same
actions. We classified Ayurvedic medicinal plants according to their synonyms
which give exact idea or colorful pictures about medicinal plants. In Ayurveda, the
morphology of medicinal plants is planned in the form of synonyms.
Antioxidants have imperative anticipatory roles, not merely on detrimental
changes in the aroma and dietetic eminence of food, although on tissue damage in an
assortment of human diseases. Free radicals are generated all the way through cus-
tomary metabolism of drugs, ecological chemicals, and xenobiotic as well as endog-
enous chemicals, particularly stress hormones (adrenalin and noradrenalin).
Accumulated substantiation suggests that ROS can be scavenged during chemopre-
vention utilizing innate antioxidant compounds present in foods and medicinal plants.
High-performance thin-layer chromatography (HPTLC) is a semiautomatic
instrumental TLC. HPTLC is different from conventional TLC due to smaller par-
ticles (<10 μm) of adsorbent and less thickness of the applied layer (<150 μm). But
the most striking difference is that it has an automatic sample applicator which is
able to apply sample in micro liter amounts, an automatic development chamber
provided with solvent reservoirs, and a densitometer/scanner which scans separated
bands by measurement of optical density. Hence, the process is more efficient due
to small particle size and no manual errors.
The automatic sample applicator of HPTLC applies sample in the form of bands;
hence, it gives better separation and resolution especially for components having Rf
values like isomers of curcumin. Simple spot application in TLC causes mixing of
close Rf value components and chromatogram has a tailing appearance. HPTLC
enables simultaneous analysis of many samples in less time with better analytical
precision and accuracy.
Evaluation of Medicinal Plant with Reference to Its Substitute 929

The qualitative analysis by physicochemical analysis such as loss on drying, total

ash, acid-insoluble ash, water-soluble extractive value, and alcohol-soluble extrac-
tive value of the formulation was done as per the standard methods.
The qualitative and quantitative analysis of herbal medicine is by phytochemical
analysis, physicochemical analysis, thin-layer chromatography (TLC), high-­
pressure thin-layer chromatography (HPTLC), and spectroscopy and also by pow-
der microscopic studies. The anatomical and morphological characters are also
considered for the identification of the medicinal plants. The quantitative analysis is
by phytochemical screening of the plant. It is an important step in the detection of
bioactive principles present in a particular medicinal plant and may lead to novel
drug discovery. Screening of the plants was performed using standard methods and
resulted in the detection of the presence of tannins, flavonoids, phenolics, saponins,
steroids, and glycosides. The presence of these phytochemicals can be correlated
with medicinal potential of these plants [1].
Medicinal plants have been identified and used throughout human history. Plants
produce many chemical compounds that have biological functions, including
defense against insects, fungi, and herbivorous mammals. At least 12,000 such com-
pounds have been isolated so far, a number estimated to be less than 10% of the
total. Chemical compounds in plants mediate their effect on the human body through
processes identical to those already well understood for the chemical compounds in
conventional drugs; thus, herbal medicines do not differ greatly from conventional
drugs in terms of how they work. This enables herbal medicines to have beneficial
pharmacology, but also gives them the same potential as conventional pharmaceuti-
cal drugs to cause harmful side effects. Moreover, plant material comes with a vari-
ety of compounds which may have undesired effects, though these can be reduced
by processing. The use of plants as medicines pre-dates written human history.
Ethnobotany, the study of traditional human uses of plants, is recognized as an
effective way to discover future medicines.
Valeriana wallichii (VW) popularly known as Indian valerian is one of the sig-
nificant plant species which belongs to the family Valerianaceae. It is native to India
(Himalayas). It is a reputed Ayurvedic herb and used in various formulations. It has
been used in the treatment of many diseases and has several activities including
anticonvulsant, antiparkinson, tranquillizing, hepatoprotective, neuroprotective,
hypotensive, and antidiabetic activity. This work is about the evaluation of the
Valeriana wallichii with reference to its substitute (Tables 1 and 2). The aims and
objectives of the study are listed below:
• To analyze two different medicinal plants, i.e., Valeriana wallichii and Valeriana
officinalis, based on their morphology, phytochemistry, and anatomical characters.
• To compare the macroscopical and microscopical characters of Valeriana wal-
lichii and Valeriana officinalis.
• To conduct physicochemical evaluation of Valeriana wallichii and Valeriana
officinalis.
• To compare the chromatographic profile of the two samples.
• Evaluation of the total phenolic content and antioxidant activity of Valeriana
wallichii and Valeriana officinalis.
930 T. V. Binu and C. B. Athira

Table 1 Phytochemical screening of Valeriana wallichii is given below

Phytochemical Ethanol extract Methanol extract
Alkaloids − −
Flavonoids ++ ++
Glycosides + +
Reducing sugar + +
Steroids − +
Terpenoids + +
Amino acids − −
Tannins +++ ++
Saponins − +
Presence, +; Absence, −

Table 2 Phytochemical screening of Valeriana officinalis is given below

Phytochemical Ethanol extract Methanol extract
Alkaloids _ _
Flavonoids ++ +
Glycosides + +
Reducing sugar + +
Steroids _ +
Terpenoids + +
Amino acids _ _
Tannins +++ +++
Saponins + +
Presence, +; Absence, −

2 Plant Description

Valeriana wallichii
2.1 

Botanical Name : Valeriana wallichii DC

Kingdom : Plantae
Division : Magnoliophyte
Class : Magnoliopsida
Order : Dipsacales
Family : Valerianaceae
Genus : Valeriana
Species : wallichii
Parts Used : Rhizome
Popular Names : Valerian Jatamansi, Taggar, Tagara, All-heal
Habitat : Temperate zone of Northwestern Himalayas up to an altitude of 3000 meters
Evaluation of Medicinal Plant with Reference to Its Substitute 931

2.2 Description

Indian valerian is an erect, perennial plant that grows to a height of 4 feet with pin-
nate, divided, and heart-shaped leaves. Pink or white flowers are found in clusters
on the leaf top. The roots are a hairy and spindly mass that is collected in the autumn
from two-year-old plants. The rhizomes are greenish-brown in color and hard and
tough internally. The herb is cultivated in Belgium, England, Eastern Europe,
France, Germany, the Netherlands, the Russian Federation, and the USA. The
medicinal plant is inhabitant to the Himalayas in Nagar, Minapin Glacier, and
Bultora Glacier in India. The herb is known as gilgiti valerian in Hindi and mushk
bala and risha wala in Urdu.

Valeriana officinalis
2.3 

Botanical Name : Valeriana officinalis L.

Kingdom : Plantae
Division : Magnoliophyte
Class : Magnoliopsida
Order : Dipsacales
Family : Caprifoliaceae
Genus : Valeriana
Species : officinalis
Parts Used : Root
Popular Names : Garden valerian, garden
Heliotrope Habitat : Terrestrial

2.4 Description

Valeriana officinalis, commonly called garden heliotrope, common valerian, or all-

heal, is a clumping perennial with scented leaves, stems, flowers, and roots. It is
native to Europe and Western Asia, but has escaped gardens and locally naturalized
in the northern USA and Canada. It typically grows in damp locations, but also can
be found in drier soils. It often naturalizes along roads or in fields. It typically grows
to 3–5′ (less frequently to 6′) tall, featuring a clump of deeply lobed basal foliage
from which rise tall, slender, sparsely-leaved stems topped in June–July by highly
fragrant, salver form, white to pale pink flowers in branched panicles (cymes to
2–4″ wide). Leaves are odd-pinnate, each leaf having seven to ten pairs (plus termi-
nal) of toothed, lance-shaped leaflets. Leaves are aromatic when bruised and the
roots are strong-smelling.
932 T. V. Binu and C. B. Athira

3 Review of Literature

Nature has been a source of medicinal agents since time immemorial. The impor-
tance of herbs in the management of human ailments cannot be overemphasized. It
is clear that the plant kingdom harbors an inexhaustible source of active ingredients
invaluable in the management of many intractable diseases. Furthermore, the active
components of herbal remedies have the advantage of being combined with many
other substances that appear to be inactive. However, these complementary compo-
nents give the plant as a whole safety and efficiency much superior to that of its
isolated and pure active components.
Plants are potent biochemists and have been components of phytomedicines
since time immemorial; man is able to obtain from them a variety of industrial
chemicals. Plant-based natural constituents can be derived from any part of the plant
like bark, roots, leaves, flowers, fruits, seeds, etc., i.e., any part of the plant may
contain active components.
For the success of primary healthcare, the activity and the use of suitable drugs
is one of the prerequisite plants have always been a source source of medicaments,
either in the form of traditional preparations or as pure active principles. These
plants which are used as medicine to treat and cure diseases are called medicinal
plants. According to World Health Organization (WHO), a medicinal plant in one or
more of its organ, contains substances that can be used for therapeutic purposes or
precursors for the synthesis of useful drugs.
People in India and China are known to have used plants in organized healthcare
regime for over 5000 years. European herbal medicines blossomed in the Greco-­
Roman era and remained in mainstream until six decades ago. The ancient civiliza-
tion of India, China, Greece, Arab, and other countries of the world developed their
own systems of medicine independent of each other but all of them were predomi-
nantly plant based. One of the oldest repositories of human knowledge, the Rig-
Veda (4500–4600 BC), mentioned the use of medicinal plants for the treatment of
diseases. In the long struggle to overcome the powerful forces of nature, human
beings have always turned to plants.
Nature has been a source of medicinal agents for thousands of years, and an
impressive number of modern drugs have been isolated from natural sources; many
of these isolations were based on the uses of the agents in traditional medicine. This
plant-based traditional medicine system continues to play an essential role in health-
care, with about 80% of the world’s habitants relying mainly on traditional medi-
cines for their primary healthcare.
Ayurvedic medicine is an ancient system of healthcare that is native to the Indian
subcontinent. It is presently used daily by millions of people in India, Nepal, and Sri
Lanka and indirectly through its being the major influence on Unani, Chinese, and
Tibetan medicine, in Tibet, and Pakistan too. The word Ayurveda is a tatpurusha
compound of the word ayus, which means life or life principles, and the word veda,
which refers to a system of knowledge. Thus, Ayurveda roughly translates as the
knowledge of life. According to Charaka Samhita, life itself is defined as the
Evaluation of Medicinal Plant with Reference to Its Substitute 933

combination of the body, sense organs, mind, and soul, the factor responsible for
preventing decay and death, which sustains the body over time and guides the pro-
cess of rebirth. According to this perspective, Ayurveda is concerned with measures
to protect ayus. This includes healthy living along with therapeutic measures that
relate to physical, mental, social, and spiritual harmony. Ayurveda is also one among
the few traditional systems of medicine to contain sophisticated system of surgery,
which is referred to as Salyachikitsa [2].
Herbs have been called part of nature’s pharmacy‖. Although their action can in
some ways be similar to modern drugs, herbal remedies are generally gentler and
safer. Many of the drugs used in conventional medicine are derived from herbs.
Herbalism uses the whole plant or whole parts of the plant, such as the leaves, the
flowers, or the roots. Using the whole plant helps in decreasing the side effects that
may occur when using isolated components. Herbs are plants that actually grown
fresh and purchased in dried form [3].

3.1 Valerianaceae

Valerian roots are acrid and bitter which are used as carminative and laxative and are
also used to treat blood diseases, burning sensation, cholera, skin diseases, throat
problems, and ulcers [4]. The use of extracts of the Valeriana roots and rhizomes for
sedation and to relieve sleep problems dates back to the eighteenth century [5], but
the exact composition of the preparations used was often not clear. According to
Suri et al. [6], its essential oil exhibited antimicrobial activity against pathogenic
bacteria and also exhibited potent antifungal activity against different human and
plant fungal pathogens.
In India, Valeriana has long been used in Ayurveda and Unani systems of medi-
cine, which describes its uses in skin diseases. Insanity, epilepsy, and snakebite are
considered to have remarkable sedative effects in nervous unrest, stress, and neural-
gia [4]. The plant is also used as cytotoxic. Roots of Valeriana wallichii are used as
an aphrodisiac and insecticide and to treat mental disorders [7].
In the search for the active substances of Valeriana, many compounds have been
isolated and identified during the last 120 years, but it is as yet uncertain which of
them are responsible for the recorded actions [8]. The most popular compounds, in
this connection, are the epoxy iridoids named valepotriates; their decomposition
products, the baldrinals; and the nonvolatile terpenoids grouped as valerenic acid
(VA) derivatives as well as some other members of the essential oil [8].
It is commonly known as Tagar which is an important ingredient of Ayurvedic
recipes for the treatment of nervous unrest and emotional problems. Besides, roots
provide commercially important essential oil used in perfumery. Morphologically,
it is a single species and is common in the Himalayan region (1220–2134 m) with
no subspecies or varieties. The investigations, however, revealed the existence of
chemically different forms (chemical races) within Valeriana wallichii DC on the
basis of chemical analysis of root extracts (essential oils and valepotriates)
934 T. V. Binu and C. B. Athira

responsible for the activity. Chemo type I is represented by maaliol (64.3%), while
type II possesses patchouli alcohol (40.2%) in their essential oils. Interestingly,
Charaka and Sushruta Samhita have also documented the existence of two types of
Tagar known as Pindtagar and Nata having medicinal properties [9]. It is a member
of the Valerianaceae family, consisting of about 200 species of Valeriana occurring
throughout the world [10] (Plate 1).
Valerian has been used as a medicinal herb since at least the time of ancient
Greece and Rome. Hippocrates described its properties, and Galen later prescribed
it as a remedy for insomnia. In medieval Sweden, it was sometimes placed in the
wedding clothes of the groom to ward off the “envy” of the elves. Sometimes people
put it in a tea. The Greek physician Dioscorides apparently recommended valerian
root to treat myriad disorders including heart palpitations, digestive problems, epi-
lepsy, and urinary tract infections. Valerian was recommended by Galen during the
second century as a treatment for insomnia. Valerian plants are as attractive as cat-
nip to cats, and it is rumored that the Pied Pipers secret to clearing the streets of
Hamlin was a store of valerian under his cloak. By the eighteenth century, valerian
was widely used as a sedative and to treat nervous disorders associated with a rest-
less digestive tract as well as the vapors in women. During World War I, valerian

Plate 1 Valeriana wallichii DC

Evaluation of Medicinal Plant with Reference to Its Substitute 935

was used to prevent and treat shell shock in frontline troops, and it was used during
World War II to help calm civilians subjected to air raids. Valerian was listed as a
sleep aid and anxiolytic in the US National Formulary until the 1940s. It fell into
disuse as more potent sedative-hypnotic pharmacologic agents became available.
Related species have been used in traditional Chinese medicine (TCM), Ayurvedic
medicine, and African herbal healing practices. Valeriana fauriei is used in tradi-
tional Chinese medicine and Japanese medicine as a sedative, a spasmolytic, and an
antidepressant. Valeriana capensis is used in African traditional medicine as a treat-
ment for epilepsy, hysteria, and nervous disorders. In the 1980s, valerian again
assumed a place of importance as a widely used nonprescription hypnotic and day-
time sedative, particularly in France, Belgium, Switzerland, Britain, Russia, and
Germany. Over 50 tons of valerians are sold each year in France alone. Adolescents
and young adults appear to be particularly attracted to valerian and other herbs that
affect the central nervous system. The German Commission E has given valerian
root a positive evaluation for use in states of restlessness. The European Scientific
Cooperative on Phytotherapy cites its indications as tenseness, restlessness, and irri-
tability with difficulty in falling asleep. Valeriana is used as medicine for insomnia,
anxiety, depression, menopausal symptoms, and stress and also used as sedative.
The unproven uses include absence of menstrual period, aches, acne, anorexia,
arthritis, etc. [11].
The genus Valeriana (family – Valerianaceae) comprises over 250 species, dis-
tributed throughout the world, and about 12 species are found in India [12]. The
genus is known for its popular name “valerian,” which is derived from the word
“valeo,” meaning to be strong, in the ninth century by Indian pharmacist and physi-
cian. In Latin, valerian is derived from the word “valere” which means to be well,
referring either to its aroma or its clinical effects. The genus is categorized as a
rasayana drug in traditional “Indian System of Medicine Ayurveda” and approved
as GRAS (generally recognized as safe) food ingredient in the USA [13].

Valeriana wallichii
3.2 

Roots are acrid and bitter which are used as carminative and laxative and are also
used to treat blood diseases, burning sensation, cholera, skin diseases, throat prob-
lems, and ulcers [4]. Its essential oil exhibited antimicrobial activity against patho-
genic bacteria and also exhibited potent antifungal activity against different human
and plant fungal pathogens [6].
In India, Valeriana has long been used in Ayurveda and Unani systems of medi-
cine, which describes its uses in skin diseases. Insanity, epilepsy, and snakebite are
considered to have remarkable sedative effects in nervous unrest, stress, and neural-
gia [4]. The plant is also used as cytotoxic. Roots of Valeriana wallichii are used as
an aphrodisiac and insecticide and to treat mental disorders [7]. Valeriana wallichii
(VW) or Indian valerian is one of the several valerian species indigenous to the
temperate Himalayas found in greater parts of India [14].
936 T. V. Binu and C. B. Athira

It is commonly known as Tagar which is an important ingredient of Ayurvedic

recipes for the treatment of nervous unrest and emotional problems. Besides, roots
provide commercially important essential oil used in perfumery. Morphologically,
it is a single species and is common in the Himalayan region (1220–2134 m) with
no subspecies or varieties. The investigations, however, revealed the existence of
chemically different forms (chemical races) within Valeriana wallichii DC on the
basis of chemical analysis of root extracts (essential oils and valepotriates) respon-
sible for the activity. Chemo type I is represented by maaliol (64.3%), while type II
possesses patchouli alcohol (40.2%) in their essential oils. Interestingly, Charaka
and Sushruta Samhita have also documented the existence of two types of Tagar
known as Pindtagar and Nata having medicinal properties. It is a member of the
Valerianaceae family, consisting of about 200 species of Valeriana occurring
throughout the world [10].
It is used in an assortment of pharmaceutical preparations for the cure of
migraine. The active constituents of Valeriana wallichii in the root are valerenic
acid, valerenol, valeranone, valtrate, and isovaltrate. The plant root occurs in short,
irregular pieces of about 5 cm long and 6–12 cm in diameters discernible with
oblique ridges along with bearing abundant, outstanding, spherical tubercles, to a
number of which beneath the surface, broad rootlets are attached. The upper surface
bears the remnants of leaves. The Valeriana wallichii rhizome is solid also tough
internally, it is greenish-brown in color along with the odor is effectively
valerianaceous.

Valeriana officinalis
3.3 

Its roots and rhizomes have been used in traditional Chinese medicine for their
sedative and antispasmodic properties [15]. Aroma: When dried properly, Valeriana
officinalis L., s.l. has only a very faint characteristic, valeric acid-like aroma which
becomes stronger as it ages. Improperly dried or old material possesses a strong and
characteristic odor due to the enzymatic hydrolysis of esters of valepotriates (isova-
leric acid and hydroxyvaleric acid). Taste: It tastes mildly sweet and camphoraceous
with a slightly bitter and spicy aftertaste [16, 17] (Plate 2).
When dried, the whole rhizome is up to 50 mm long and up to 30 mm in diam-
eter, obconical to cylindrical, with an elongated or compressed base. It has a yellow-
ish- brown to dark brown exterior with a circular stem and leaf scars. The rhizome
contains numerous thick, light to dark brown rootlets which are located around a
thin ligneous cord. The root is longitudinally wrinkled and approximately 100 mm
long and 1–3 mm in diameter, almost cylindrical, and almost the same color as the
rhizome. In longitudinal section, the pith exhibits a central cavity transverse by
septa. The solons are 20–50 mm long and pale yellowish gray in color with promi-
nent nodes separated by longitudinally striated internodes. It is commonly sliced in
half for ease of cleaning. The rootlets, which contain the majority of the essential
Evaluation of Medicinal Plant with Reference to Its Substitute 937

Plate 2 Valeriana officinalis L.

oil, are brittle and break in short, horny fractures and are whitish or yellowish
internally.
The major groups of constituents in this plant are valepotriates and sesquiter-
penes. It is not yet clearly understood which components of Valeriana officinalis are
responsible for the therapeutic properties [18]. The studies of the Chemical Analysis
and Biological Activity of the Essential Oils of Two Valerianaceous Species from
China: Nardostachys chinensis and Valeriana officinalis concluded that the isolated
essential oils could be used for future development of antimicrobial and antioxidant
agents [19].
Valeriana officinalis has been known as one of the highly effective sedatives and
restorative remedies for the nervous system. Early uses of valerian for its bitter and
aromatic qualities are reported. Related plants, spikenard derived from Nardostachys
jatamansi DC, are mentioned in the Bible. The Greek physician and pharmacist
Galen (131–201 AD) was probably the first to allude to the sedative qualities of
valerian, while the English doctor John Hill in the mid-eighteenth century first used
it therapeutically as a sedative. Valerian was chemically analyzed in the nineteenth
century and by the end of the century, the pharmaceutical texts included the uses of
valerian in a way almost as accepted today. Valerian has been prescribed and used
as the perfect herbal tranquilizer in World War I to treat soldiers suffering from
shell shock.
938 T. V. Binu and C. B. Athira

4 Phytochemistry

Qualitative phytochemical analysis of Valeriana wallichii was performed for alka-

loids, tannins, saponins, terpenoids, coumarins, and anthraquinones. The main con-
stituents of the essential oil present in the root and rhizome of Valeriana wallichii
are sesquiterpene hydrocarbon-santalene, ar-curcumene, and xanthorrhiza.
The plant Valeriana officinalis contains the following: alkaloids (0.01–0.05%),
valeranine, chatinine, alpha-methyl pyrrylketone, actinidine, skyanthine, and naph-
thyridyl methyl ketone; iridoid valepotriates (0.5–2.0%), valtrate, isovaltrate, didro-
valtrate, valerosidate, and others; volatile essential oil (0.2–02.8%), bornyl
isovalerate and bornyl acetate; valerenic, valeric, isovaleric, and acetoxyvalerenic
acids; valerenal, valeranone, and cryptofaurinol; and other monoterpenes and ses-
quiterpene; and lignans, hydroxypinoresinol.
Valerian contains over 150 chemical constituents; many are physiologically
active. There is substantial variation in the chemical constituents in plants from dif-
ferent sources, growing conditions, processing methods, and storage conditions.
Even in standardized plant extracts sold in Germany, there is some variation in the
amount of different chemical constituents that may account for clinical efficacy.
Despite these differences, the clinical effects appear to be remarkably consistent
across different preparations. Isovaleric acid is responsible for the herb’s unpleasant
aroma. Actinidine is a powerful attractant to cats, who will roll in valerian; catnip
contains similar chemical compounds. Valerian also seems to be one of several plant
species that concentrate chromium and are sometimes used to correct deficiencies
of this mineral in developing countries. The essential oil is also thought to contrib-
ute to valerian’s sedative effect [20].
The therapeutic potential of medicinal plants, as a source of phytochemicals, is
gaining momentum all over the globe. Among the phytochemicals, polyphenols are
largely being used in different health-related activities as the best antioxidants,
which are known to reduce the risk of several degenerative diseases including coro-
nary heart disease and cancer.
The most important bioactive groups of plants are alkaloids, terpenoids, tannins,
saponins, and phenolic compounds. Correlation between the phytoconstituents and
the bioactivity of plant is desirable to know for the synthesis of compounds with
specific activities to treat various health ailments and chronic disease as well [1, 21].
Valerian contains over 150 chemical constituents; many are physiologically
active. Active constituents of valerian: Iridoids valepotriates (0.5–2.0%) valtrates,
isovaltrate, didrovaltrate, valerosidate and others Volatile essential oil (0.2–02.8%):
bornyl isovalerate and bornyl acetate; valeric, isovaleric and acetoxyvalerenic acids;
valerenal, valeranone, cryptofaurinol; and monoterpenes and sesquiterpene,
Alkaloids (0.01–0.05%): valeranine, chatinine, alpha-methyl pyrrylketone, actini-
dine, skyanthine and naphthyridyl methyl ketone. Lignans: hydroxypinoresinol [11].
The phytochemical analysis of Valeriana wallichii rhizome detected the pres-
ence of terpenoids together with alkaloids saponins, tannins, and flavonoids in the
methanolic extract and alkaloids and saponins together with tannins in the aqueous
Evaluation of Medicinal Plant with Reference to Its Substitute 939

extract. Plant chemicals are regarded as secondary metabolites because the plants
that manufacture them may have little need for them. They are synthesized in all
parts of the plant body: barks, leaves, stems, root, flowers, fruits, seeds, etc., i.e., any
part of the plant body may contain active components.
The chemical components identified in the solvent extract of Valeriana wallichii
constitute cyclopentaneacetaldehyde, quinoline, aristolene, cyclohexane,
2,4-­diisopropenyl methvinyl, cyclopentane,1-(3-methylbutyl), tricyclo[5.1.0.0(2,4)
oct-5-ene-5-propanoic acid, ascorbic acid 2,6-dihexadecanoate, 9,12-­octadecadienoic
acid, pentadecanoic acid, 4-hexadecyl ester, and valeric acid as the major
constituents.
Preliminary phytochemical analysis confirmed presence of carbohydrate, phe-
nols, flavonoids, tannins, alkaloids, steroids, glycosides, phytosterols, and saponins.
Quantitative analysis showed presence of about 7.6% phenols, 1.3% flavonoids,
1.1% tannins, and 3.5% saponins. Spectroscopic study indicated that the isolated
compound is a phenolic compound: 3,4,5-trihydroxybenzoic acid.
The phytochemical screening of Valeriana wallichii revealed the presence of
flavonoids, reducing sugar, terpenoids, tannins, and phenolics. The therapeutic
action of the plant is due to the presence of major chemical constituent flavonoids.
This chemicals work with nutrients and fibers to form an integrated part of defense
system against various diseases and stress conditions. The result of preliminary
phytochemical analyses identifies the presence of different bioactive groups such as
terpenoids and phytosterols (in hexane extract), phenols and flavonoids (in ethyl
acetate), and phenols, flavonoids, and steroids (in ethanol extract) [22].
The Valeriana wallichii extract obtained was dried and used for qualitative anal-
ysis of different constituents like alkaloids, tannins, flavonoids, cardiac glycosides,
proteins, carbohydrate, reducing sugar, anthraquinone, and steroids in ethanolic
extract [23].
All plants produce chemical compounds as part of their normal metabolic activi-
ties. These phytochemicals are divided into (1) primary metabolites such as sugars
and fats, which are found in all plants, and (2) secondary metabolites, which are
found in a smaller range in plants, serving a more specific function. For example,
some secondary metabolites are toxins used to deter predation and others are phero-
mones used to attract insects for pollination. It is these secondary metabolites and
pigments that can have therapeutic actions in humans and can be refined to produce
drugs, for example, inulin from the roots of dahlias, quinine from the cinchona,
morphine and codeine from the poppy, and digoxin from the foxglove. Toxic plants
even have use in pharmaceutical development. Plants synthesize a bewildering vari-
ety of phytochemicals, but most are derivatives of a few biochemical motifs.
940 T. V. Binu and C. B. Athira

5 Total Phenol, Flavonoid, and Tannin Content

Total phenols in the methanolic extract of roots and aerial parts were determined by
the Folin-Ciocalteu colorimetric method described by Singleton and Rossi [24].
Rhizomes and roots contain cyclopentapyrans, acacetin-7-0-rutinosides, linarin-­
iso-­valerinate, and 4-methoxy-8-pentyl-1-naphthoic acid [21]. Flavonoids in the
methanolic extract of plant were determined by aluminum chloride colorimet-
ric method.
Two new flavone glycosides, acacetin 7-0-sophoroside and acacetin 7-0-(6-0-l-
rhamnopyranosyl)-sophoroside, were isolated from the rhizomes and roots of
Valeriana wallichii [25]. Total phenolic content of extracts was determined by the
Folin-Ciocalteu method [26].
A UV-Vis spectrometer (U-2001, Hitachi, Japan) is used for the quantification of
total phenols, when comparing with root samples of Valeriana wallichii from wild
individuals, a significantly higher (P < 0.05) total phenols (13.05 mg/g dry weight
gallic acid equivalent) [13].
The total phenols were determined calorimetrically by using the Folin-Ciocalteu
method; 2.5 ml of tenfold diluted Folin-Ciocalteu reagent, 2 ml of 7.5%sodium
carbonate, and 0.5 ml of phenolic extracts were mixed. After heating at 45 °C for
15 minutes, the absorbance was measured at 765 nm against a blank. The phenolic
content was expressed as gallic acid equivalents/g dry weight of sample [26]
(Table 3).

Table 3 HPTLC profiling of samples

HPTLC details of test solution
UV 366 nm
Lane Rf value Color of the band
Lane 1 – Valeriana officinalis 0.13 Gray
0.14 Gray
0.44 Green
0.62 Gray
0.66 Green
Lane 2 – Valeriana wallichii 0.12 Green
0.2 Brown
0.44 Green
0.46 Blue
0.44 Blue
Lane 3 – Lupeol (STD) 0.75 Green
Evaluation of Medicinal Plant with Reference to Its Substitute 941

6 Chromatographic Analysis

Valerenic acids and valepotriates are considered among the constituents responsible
for the sedative effect of roots and rhizomes of Valeriana species. Packed column
SFC/UV (p-SFC) was applied to the analysis of valerenic acids and valepotriates
extracted from the underground parts of Valeriana officinalis. The separation of
these compounds by p-SFC was optimized by varying the conditions (i.e., columns,
column coupling and stationary phase coupling, density programs, types of modi-
fiers, and modifier programs). A CN-stationary phase using supercritical carbon
dioxide modified with methanol/water (95:5) as mobile phase was successful in
separating both valerenic acids and valepotriates. The qualitative and quantitative
results of p-SFC are comparable to HPLC for both valerenic acids and valepotriates,
but analyses are faster with p-SFC than with HPLC [27].
India has rich wealth of important medicinal flora and its varied climate is ideally
suited for the cultivation of medicinal plants. The quality of the plant-derived medi-
cine is a matter of great concerns as the utilization of plant materials for cure of
infections and chronic human diseases is increasing. One of the major drawbacks in
the popularization of plant-based drugs is the inconsistent quality of the formulated
preparations. High-performance thin-layer chromatography, high-performance liq-
uid chromatography, chemical fingerprinting, and establishment of their library for
the commercially important medicinal and aromatic plant materials will help drug
industries and various institutions for the quality evaluation of their products to
complete in the world trade market of medicinal and aromatic plants. HPTLC and
HPLC are most commonly used modern tools for quality testing of raw materials
and finished products.
Modern thin-layer chromatography is a powerful, reliable, and cost-efficient
method for qualitative and quantitative analysis; HPTLC has a wide range of utility
in the field of plant-based products. In addition to qualitative detection, it provides
semiquantitative information on the main active constituents of plant preparations
[28]. Raaman [29] had made studies about the theoretical principles of chromatog-
raphy. High-performance thin-layer chromatography (HPTLC) is a sophisticated
and automated form of TLC, and HPTLC is the fastest of all chromatographic meth-
ods. HPTLC can analyze about 100 samples of five to ten different types per shift.
HPTLC is a visual technique, where the chromatogram is visible.
The FST and TST are widely used models of depression for screening new anti-
depressant drugs. Three extracts of Valeriana wallichii DC (Valerianaceae) rhizome
and fluoxetine were studied for antidepressant-like activity in two behavioral mod-
els, namely, the forced swim test (FST) and the tail suspension test (TST). It is sug-
gested that the antidepressant-like action of this herbal plant is not contingent upon
its terpenoid constituents.
TLC is a relatively cheap but powerful technique used to screen plant extracts for
the presence of different types of phenolic compounds. The relative position or Rf
values of the phenolic spots can be used as a first indication of phenolic compounds.
Plates can be sprayed with various reagents to detect the phenolic compounds. The
942 T. V. Binu and C. B. Athira

Fecl3- K3Fe (CN) 6 spray reveals all phenolics as blue spots. Rhodamine B spray is
used for polyphenols and flavanols by pink spot. Saturated KIO3 reveals gallic acid
and galloyl esters by brown or orange brown spots. One percent AlCl3 solution in
ethanol by yellow fluorescence reveals flavonoid and blue spot reveals phenolic
acids [30].
The pharmacological effects of Valeriana wallichii (VW) aqueous root extract
on sleep-wake profile and level of brain monoamines on Sprague-Dawley rats.
According to the study, it can be said that Valeriana wallichii water extract has a
sleep quality improving effect which may be dependent upon levels of monoamines
in the cortex and brainstem. It serves as an herbal therapeutic intervention to improve
sleep quality, i.e., increased deep sleep [31].
Gallo et al. [32] studied the pharmaceutical performance of the prepared
Valeriana officinalis dry extract through the design of tablets. The manufactured
tablets showed good compactability, friability, hardness, and disintegration time.
Those containing a disintegrate (Avicel PH 101) exhibited the best pharmaceutical
performance, having the lowest disintegration time of around 40 seconds.
Sung et al. [33] investigated the effect of valerian root extract and its major com-
ponent, valerenic acid, on memory function, cell proliferation, neuroblast differen-
tiation, serum corticosterone, and lipid peroxidation in adult and aged mice.
High-performance thin-layer chromatography fingerprint profiling was per-
formed to confirm the presence of various phytocompounds. The biomarker com-
pound was isolated by column chromatography method and characterized by
UV-visible, H 1-NMR, C 13-NMR, and mass spectroscopy methods.
Physicochemical analysis showed the presence of about 18% water-soluble com-
ponents and about 14% alcohol-soluble components .
Lovelyn and his co-workers studied the acute and chronic (90 days) oral toxicity
of Valeriana wallichii rhizome hydroethanolic extract in Swiss albino mice. From
this work, it could be concluded that Valeriana wallichii rhizome hydroethanolic
extract didn’t exhibit mortality, morbidity, or any other neurologic, hematologic, or
biochemical adverse effects apart from sedation which is the extension of their
known pharmacological activity, after single oral dose of 2000 mg/kg bw (14 days
of observation) or after once daily 200 mg/kg, 600 mg/kg, and 1800 mg/kg oral
treatments for 90 days in healthy adult Swiss albino mice [34].
The levels of valepotriates, dihydrovalepotriate, and acetyl-valepotriates from
Valeriana jatamansi Jones, Valeriana officinalis L., and Valeriana officinalis L. var.
latifolia Miq were obtained by using the reverse-phase high-performance liquid
chromatography (RP-HPLC) method. The highest levels were observed in Valeriana
Jatamansi Jones, followed by Valeriana officinalis L., and Valeriana officinalis
L. var. latifolia Miq. In addition, the content of iridoids varied significantly among
different parts and habitats.
The result of TLC of an alcoholic extract of Valeriana wallichii roots and its
extract was done in order to separate out compounds as possible. According to the
study, the Rf value of the given spot was found to be of 0.16, 0.48, and 0.84, respec-
tively, which come under the range of the Rf value of valerenic acid. The reported Rf
value for valerenic acid is 0.48.
Evaluation of Medicinal Plant with Reference to Its Substitute 943

UV and FTIR analysis of Valeriana wallichii root extract was carried out. The
result of FTIR analysis shows the identification of various functional groups present
in the extract. The absorption frequency of Valeriana wallichii root ethanolic extract
(C=S Stretching), C-O Stretching (Alcohols), C-O Stretching (Phenols), C=C
stretching (Aromatic), (N-H Bending), C=N stretching. The result of ultra-visible
spectrum detecting absorbance maxima of the phytochemical component present in
drug extract [23].
The GC-MS analysis of essential oils from cultivated Valeriana officinalis L. var.
latifolia Miq. identified six compounds, bornyl acetate (60.19%), (−)-acetic acid
Rhodomyrtus enol ester (3.87%), α-terpinyl acetate (1.55%), acetyl carene (1.68%),
α-selinene (26.07%), and (Z,E)-α-farnesene (1.56%), comprising 94.92% of the
total content. Cultivated Valeriana officinalis L. var. latifolia Miq. consisted of a
higher number of simple components, which was predominated by bornyl acetate
relative to that of wild Valeriana officinalis L.
Approximately 0.5–2.0% of Valeriana spp. consists of essential oils by gas
chromatography-­mass spectrometry (GC-MS) analysis, which varies with species,
climate, and growing environment. Valerian plants from high-altitude fertile and
sandy soil have significantly higher essential oil content and yield similar to that of
biennials compared to annuals. Valerian plants that produce a higher amount of
essential oil are cultivated between September and November, although the content
of essential oils decreases with longer periods of propagation.
A total of 150 compounds have been identified in the essential oils of valerian
plants, mainly including monoterpenes and sesquiterpenes. Most monoterpenes,
namely, borneol, bornyl acetate, and isobornyl acetate, exhibit various bioactivities.
Around 30 sesquiterpene have also been detected in the valerian essential oils.
These have been classified to be of the guaiane type and valerian type. Despite the
low contents of these essential oils, their biological activities have drawn the atten-
tion of researchers around the world.

7 Antioxidant Activity

Recent interest in antioxidants due to their involvement in the health benefit had led
to the development of a number of antioxidant capacity assays. Plants contain high
concentration of numerous redox active secondary metabolites or antioxidants, such
as ascorbic acid, carotenoids, glutathione, tocopherols, tocotrienols, and enzyme
with high antioxidant activity to help them protect against hazardous oxidative dam-
age. The simple definition of an antioxidant as described by Halliwell is a molecule
which, when present in small concentrations compared to that of an oxidizable sub-
strate, significantly delays or prevents the oxidation of the substrate‖ [35].
Shariq proposed that the hepatoprotective activity of the Valeriana wallichii
extracts could be due to its antioxidant activity [36]. The antioxidant activity of
methanolic extract could be attributed to the presence of rich amount of polyphenols
944 T. V. Binu and C. B. Athira

and flavonoids. Essential oil of Valeriana jatamansi roots showed moderate antioxi-
dant activity.
The antioxidant activity of essential oil and supercritical fluid extracts was evalu-
ated in DPPH radical, superoxide radical, and hydroxyl scavenging assays. The
reducing power of those oil and extracts was also studied. Essential oil and super-
critical fluid extracts gave comparable DPPH, superoxide radical scavenging, and
reducing power activity, and no much deviation among various activities was
observed. However, when we consider overall antioxidant assays, 200 bar extract of
valerian is the best among essential oils and extracts.
Antioxidants have imperative anticipatory roles, not merely on detrimental
changes in the aroma and dietetic eminence of food, although on tissue damage in
an assortment of human diseases. Cellular smashup or oxidative injury arising from
free radicals or reactive oxygen species (ROS) nowadays appears as the elementary
mechanism underlying a number of human beings with neurodegenerative disor-
ders, viral infections, diabetes, inflammation, and autoimmune pathologies along
with digestive system disorders. Free radicals are generated all the way through
customary metabolism of drugs, ecological chemicals, and xenobiotic as well as
endogenous chemicals, particularly stress hormones (adrenalin and noradrenalin).
Accumulated substantiation suggests that ROS can be scavenged during chemopre-
vention utilizing innate antioxidant compounds present in foods and medici-
nal plants.
The methanolic extract of Valeriana wallichii was used in the present study and
also screened for the presence of phytochemicals, viz., alkaloids, flavonoids, tan-
nins, saponins, glycosides, etc. and their effect on 2,2-diphenyl-1-picryl-hydraxyl
radical (DPPH) which was used to determine the free radical scavenging activity.

8 Anxiolytic Effects

The use of extracts of the Valeriana roots and rhizomes to cause sedation and relieve
sleep problems dates back to the eighteenth century [5]. The anxiolytic effect of
valerian root extract, valerenic acid, and concentrations of valerenic acid and GABA
isolated in extract using the elevated plus maze. This method has been often used by
researchers to test the anxiolytic properties of drugs and is an effective measure of
animal anxiety [37].
A promising approach to detect new active substances in Valeriana extracts con-
sists in searching for the presence of ligands for the principal brain receptors pre-
dominantly associated with anxiolytic, sedative, and/or sleep-enhancing properties
[38]. There is growing reason to believe that valerian root may be an effective alter-
native to the traditional anxiolytics, which often produce such aversive side effects
such as nausea, tremor, and addiction [39]. Marder et al. [38] reported the identifica-
tion in Valeriana officinalis of the flavone glycoside linarin (LN) and the discovery
that it has, like HN, sedative and sleep- enhancing properties that are potentiated by
Evaluation of Medicinal Plant with Reference to Its Substitute 945

simultaneous administration of valerenic acid (VA). These effects should be taken

into account when considering the pharmacological actions of Valeriana extracts.
Awad et al. [40] found that an ethanolic extract of Valeriana officinalis prompted
increased brain GABA levels and neurotransmission by stimulating glutamic acid
decarboxylase (GAD) in rat brains, as measured by an in vitro enzyme assay.
Murphy et al. [41] found that there was a significant reduction in anxious behav-
ior when valerian extract or valerenic acid exposed subjects were compared to the
ethanol control group. The evidence supports Valeriana officinalis as a potential
alternative to the traditional anxiolytics as measured by the elevated plus maze.

9 Materials and Methods

9.1 Plant Materials

Sample 1: Valeriana wallichii DC.

Sample 2: Valeriana officinalis L.

9.2 Methods

The present study was carried out in the Research and Development (R & D)
Department of Oushadhi. The description of the method used for the study is
detailed below.

9.2.1 Collection of Plant Materials

The plant materials used for this study consisting of dried rhizome of Valeriana wal-
lichii and Valeriana officinalis belonging to the family Valerianaceae were col-
lected from the Oushadhi premises. The rhizome was identified and authenticated
by a botanist of the Research and Development (R & D) Department of Oushadhi.

9.2.2 Processing of Plant Materials

The dried samples of Valeriana wallichii and Valeriana officinalis were stored in
airtight containers. A portion of the dried samples were pulverized into powder by
using a mixer grinder.
946 T. V. Binu and C. B. Athira

9.2.3 Preparation of Extracts

Alcoholic and methanolic extract was used for the study.

10 To Compare the Distinguishing Characteristics

of the Sample Macroscopical Analysis

The rhizomes of Valeriana wallichii and roots of Valeriana officinalis are examined
macroscopically. To compare the external characteristic features of the samples [42]:

10.1 Microscopical Analysis

10.1.1 Powder Microscopy

Procedure: Place the powered material on the slides. Add one to three drops of
glycerin-safranin mixture; if necessary stir with a fine-pointed needle to distribute
the testing agent evenly. Add a coverslip. Remove any excess liquid that may
exclude from under the coverslip by blotting around its edges gently with a filter
paper. Examine the slide under the microscope.

10.1.2 Anatomical Analysis [43]

Hand selection of rhizome and roots of Valeriana wallichii and Valeriana officinalis
were cut using a sharp blade. Thin transverse selections were stained in a safranin
and then fast green, passed through alcohol grades for dehydration, and then
mounted in a DPX. Observations were taken from these sections using light micro-
scope. Special identifying features of the plant parts were studied and identified.
And prepare the permanent sides of plant parts.
Procedure for permanent slide preparation:
I. Collect the plant material and wash the material.
II. Section the material using a new blade.
III. Stain the specimen using alcoholic safranin for 20 minutes.
IV. Pass the specimen through the alcoholic series for 5 minutes (50%, 70%, 75%,
80%, 90%, and 95%).
V. Dip the specimen in the following chemicals:
(a) Isopropyl (10 seconds)
(b) Fast green (1 seconds)
(c) Clave oil (3 minutes)
(d) Xylene (5 minutes)
Evaluation of Medicinal Plant with Reference to Its Substitute 947

VI. Mount the section using DPX (using a new slide and coverslip).
VII. Examine the slide under the microscope (Peter Gray, 1958).

10.2 Preliminary Phytochemical Analysis

All the extracts of Valeriana wallichii and Valeriana officinalis were subjected to
qualitative tests for the identification of various active constituents. The following
are the reagents used for the phytochemical screening:
1. Test for alkaloids
(a) A small portion of the extracts, viz., chloroform, ethyl acetate, and ethanol,
was stirred with few drops of dil. Hydrochloric acid and filtered. To the fil-
trate, Dragendorff’s reagent
(potassium bismuth iodide solution) was added and an orange brown pre-
cipitate indicates the presence of alkaloids.
(b) To the filtrate, Mayer’s reagent was added and a cream precipitate indicated
the presence of alkaloids.
(c) Measured 2 ml of various extract solutions was then mixed with dilute
hydrochloric acid and 0.1 ml of Wagner’s reagent. Formation of reddish-­
brown precipitate indicated the positive response for alkaloid.
2. Tests for flavonoids
To a portion of the various extracts, concentrated sulfuric acid was added. A
yellow coloration indicated the presence of flavonoids. The yellow coloration
disappeared on standing. Few drops of 1% aluminum chloride solution were
added to a portion of each fraction, and a yellow coloration indicated the pres-
ence of flavonoids.
3. Test for reducing sugars
Five ml of the extract is mixed with 5 ml of Fehling’s solution and boiled for
5 minutes. Formation of brick red-colored precipitate demonstrated the positive
test for reducing sugar.
4. Test for glycosides
To 1 ml of all the plant extracts, equal volume of Fehling’s solution A and B
was added. The mixture is heated in a water bath. Brick red coloration indicated
the presence of glycosides.
5. Test for steroids (Salkowski test)
Concentrated sulfuric acid was added to 10 mg of different extracts dissolved
in 1 ml of chloroform. A reddish-blue color exhibited by chloroform layer and
green fluorescence by the acid layer suggested presence of steroids.
6. Test for saponins
About 10 ml of the extract was mixed with 5 ml of distilled water and shaken
vigorously for a stable-persistent froth. The frothing was mixed with three drops
948 T. V. Binu and C. B. Athira

of olive oil and shaken vigorously and then observed for the formation of an
emulsion.
7. Test for terpenoids
About 5 ml of the extract was treated with 2 ml of chloroform and the concen-
trated sulfuric acid was carefully added to form a layer. A reddish-brown color-
ation of the interface indicates the presence of terpenoids.
8. Test for amino acid
Different extract solutions were treated with ninhydrin at the range of 4–8.
Development of a purple color indicated the positive response for amino acids.
9. Test for tannins and phenolic
(a) Around 5 ml of extract solutions was allowed to react with 1 ml of 5% ferric
chloride solution. Greenish-black coloration indicated the presence of
tannins.
(b) Approximately 5 ml of the extracts was treated with 1 ml of 10% aqueous
potassium dichromate solution. Formation of yellowish-brown precipitate
suggested the presence of tannins.
(c) Accurately 5 ml of the extracts was treated with 1 ml of 10% lead acetate
solution in water. Yellow color precipitation indicated presence of tannins.

10.3 Physicochemical Analysis

Physicochemical analysis such as loss on drying, total ash, acid-insoluble ash,

water-soluble extractive value, and alcohol-soluble extractive value of the formula-
tion was done as per the standard methods.
1. Determination of Total Ash Content
The total ash content of each sample was determined using an apparatus
called Muffle furnace. Incinerated 3 grams accurately weighed powder drug in a
crucible at temperature not exceeding 45 °C until free from carbon cooled and
weighed. Calculate the percentage total ash with reference to the air-dried drug.
2. Determination of Acid in Soluble Ash
Boil the ash obtained in the above method for 25 minutes, with 25 ml of dil.
HCl, collect the insoluble matter in a Gooch crucible or on an ashless filter paper,
wash with hot water, and ignite to constant weight. Calculated the percentage of
acid in soluble ash with reference to air-dried drug.
3. Determination of Water-Soluble Ash
Boil the ash for 5 minutes with 25 ml of water, collect the insoluble matter in
a Gooch crucible or on an ashless filter paper, wash with hot water, and ignite for
15 minutes, at temperature not exceeding 45 °C until free from carbon cooled
and weighed. Calculate the percentage of water-soluble ash with reference to the
air-dried drug.
Evaluation of Medicinal Plant with Reference to Its Substitute 949

4. Determination of Alcohol-Soluble Extractive Value

Macerate 5 grams of air-dried drug with 100 ml of chloroform 95% alcohol in
a closed flask for 24 hours, shaking frequently during 6 hours and allowed to
stand for 18 hours. Filter rapidly, taking precautions against loss of solvent,
evaporate 25 ml of the filtrate to dryness in a fared flat-bottomed shallow dish,
and dried at 105 °C to content weight and weighed. Calculate the percentage of
alcohol-soluble extractive value with reference to the air-dried drug.
5. Determination of Water-Soluble Extractive Value
Macerate 5 grams of the air-dried drug with 100 ml of chloroform water in a
conical flask for 24 hours, shaking frequently during 6 hours and allowing to
stand for 18 hours. Filter rapidly, taking precautions against loss of solvent,
evaporate 25 ml of the filtrate to dryness in a fared flat-bottomed shallow dish,
and dry at 105 °C, to constant weight and weighed. Calculate the percentage of
water-soluble extractive value with reference to the air-dried drug.
Proceed as directed for the determination of alcohol-soluble extractive value,
using chloroform water instead of ethanol. Calculate the percentage of water- solu-
ble extractive value, using the same equation.

11 Thin-Layer Chromatography (TLC) Profiling [23]

Thin-layer chromatography, or TLC, is a method for analyzing mixtures by separat-

ing the compounds in the mixture. TLC can be used to help determine the number
of components in a mixture, the identity of compounds, and the purity of a com-
pound. By observing the appearance of a product or the disappearance of a reactant,
it can also be used to monitor the progress of a reaction. TLC is a sensitive tech-
nique – microgram (0.000001 g) quantities can be analyzed by TLC and it takes
little time for an analysis (about 5–10 minutes). TLC consists of three steps – spot-
ting, development, and visualization. Spotting consists of using a micro pipet to
transfer a small amount of this dilute solution to one end of a TLC plate, in this case
a thin layer of powdered silica gel that has been coated onto a plastic sheet. The
spotting solvent quickly evaporates and leaves behind a small spot of the material.
Development consists of placing the bottom of the TLC plate into a shallow pool of
a development solvent, which then travels to the plate by capillary action.
Visualization of colored compounds is simple – the spots can be directly observed
after development.
TLC identification test and procedure:
Take 10 grams of coarsely powdered drug in 250 ml stoppered conical flask and
extract with 100 ml alcohol for 24 hours by maceration technique with occasional
shaking. Decant the extract and make up to 100 ml in volumetric flask. Take 25 ml
of extract from stock solution and dry on a water bath. Extract the dried marc with
petroleum ether at 60–80 °C (485) ml. Concentrate the pooled ether at 60–80 °C
extract to 5 ml.
950 T. V. Binu and C. B. Athira

1. Stationary phase : TLC preloaded with silica gel 60 F254 of 0.2 mm thickness.
2. Solvent system : Toluene/ethyl acetate/formic acid (5:4:1).
3. Volume of the test : 7 μl.
solution applied
4. Spotting TLC : Spotting on the TLC plate was done using a 1–2 cm capillary tube from
plates the bottom of the plate.
5. Developing the : After spotting, the plates were kept inside the chamber in ascendant
plate position. After developing, the plate was taken from the chamber and let
the solvent be vaporized.
6. Detection spot : For the detection of spot, a TLC apparatus is used. The plate kept in the
apparatus containing flow of UV rays and color was analyzed.
7. Calculation of RF : RF value was calculated by using formula: Rf=DSU/DSV; Where Rf is
value the retention factor DSU is the distance traveled by the solute DSV is the
distance traveled by the solvent.

12 High-Performance Thin-Layer
Chromatography (HPTLC)

12.1 Terpenoids

Sample name : Valeriana wallichii and Valeriana officinalis

Test sample : Lane 1 (5 micro liter) Valeriana officinalis, lane 2 (5 micro liter), Valeriana
wallichii, lane 3(4 micro liter) lupeol used as standard
Sample : Five grams of the sample + 50 ml methanol + reflux 30 minutes + filter +
preparation concentrated to 10 mL + injected to HPTLC stationary phase : Silica gel 60,
F254, HPTLC plates
Mobile phase : Toluene/chloroform/methanol (8:3:1)
Solvent front : 7 cm
Detection : UV366nm and visible light
Derivatization : Liebermann-Burchard reagent

13 Total Phenol Content [13]

Total phenols in the methanolic extract of root and aerial parts were determined by
the Folin-Ciocalteu colorimetric method described by Singleton and Rossi [24].
Methanolic extract (0.25 ml) diluted with distilled water (2.25 ml) was mixed with
the Folin-Ciocalteu reagent (0.25 ml) and allowed to stand for reaction for 5 min-
utes. This mixture was neutralized by 7% sodium carbonate (2.5 ml) and kept in
dark at room temperature for 90 minutes. The absorbance of resultant blue color
was measured at 765 nm using UV-Vis spectrophotometer. A UV-Vis spectropho-
tometer (U-2001, Hitachi, Japan) is used for the quantification of total phenols.
Samples were diluted with 80% (v/v) methanol to obtain 20–80% reduction in
absorbance at 734 nm with respect to blank. A standard curve of various
Evaluation of Medicinal Plant with Reference to Its Substitute 951

concentrations of ascorbic acid is prepared in 80% v/v methanol for the equivalent
quantification of antioxidant potential with respect to ascorbic acid. Results were
expressed in mM ascorbic acid equivalent (AAE)/100 g dry weight (DW).

14 DPPH Antioxidant Assay

DPPH radical scavenging assay – Method:

Principle:
The spectrophotometric assay uses the stable radical DPPH as a reagent.
The hydrogen atom or electron-donating abilities of the compounds and some
untainted of the compounds can be measured from bleaching of the purple-colored
methanol solution of 2.2-diphenyl-1-picrylhydrazyl (DPPH).
Reagents:
DPPH, ethanol, ascorbic acid.
Procedure:
1. Prepare the concentrations of standard solutions (ascorbic acid, BHA, etc.).
2. Prepare the plant extract solution in ethanol.
3. Prepare the 0.3 mm solution of DPPH in 100% ethanol. To 1 ml of this solution,
add 3 ml of the sample extract.
4. The same reaction mixture without the extract sample but with equivalent amount
of standard phosphate buffer should serve as control.
5. Shake the mixture and allow to stand at room temperature for 30 minutes.
6. Measure the absorbance of the reaction mixture at 517 nm. Determine the per-
centage scavenging activity at different concentrations.
7. The formula for % scavenging activity is 1-absorbance of test/absorbance con-
trol X 100.

15 Results

15.1 Macroscopical Analysis

15.1.1 
Valeriana wallichii DC

The roots are yellowish brown in color and are found in broken pieces, 5–6 cm
length, and 1–2 mm in width; fine lateral rootlets are also present. The fracture is
horny and the broken surface is yellow. The odor is aromatic and some plants are
pungent. The taste is camphoraceous and slightly bitter.
The rhizomes are yellowish to dull brownish in color; they are subcylindrical in
shape and consist of rhizomatous portion connected by short thick stolon formparts
(showed in plate). The rhizomatous portions are about 1–5 cm long and about
5–15 mm thick. They appear knotted due to the presence of many raised root scars,
952 T. V. Binu and C. B. Athira

chiefly on the sides and upon the lower surface, which together with the numerous
transverse grooves and ridges formed by the leaf scars gives a very rough surface to
those parts of the commercial drug. The fracture is horny and the broken surface is
yellow. The odor and taste resemble that of the root [Pharmacognosy of Indian Root
and Rhizome Drugs].

15.1.2 
Valeriana officinalis L

When dried, the whole rhizome is up to 50 mm long and up to 30 mm in diameter,

obconic to cylindrical, with an elongated or compressed base. It has a yellowish-­
brown to dark brown exterior with a circular stem and leaf scars. The rhizome con-
tains numerous thick, light to dark brown rootlets which are located around a thin
ligneous cord. The root is longitudinally wrinkled and approximately 100 mm long
and 1–3 mm in diameter, almost cylindrical, and almost the same color as the rhi-
zome (showed in Fig. 1). In longitudinal section, the pith exhibits a central cavity
transverses by septa. The stolons are 20–50 mm long and pale yellowish gray with
prominent nodes separated by longitudinally striated internodes. It is commonly.
sliced in half for ease of cleaning. The rootlets, which contain the majority of the
essential oil, are brittle and break in short, horny fractures and are whitish or yellow-
ish internally. Aroma: When dried properly, Valeriana officinalis L. s.l. has only a
very faint characteristic, valeric acid-like aroma which becomes stronger as it ages.
Improperly dried or old material possesses a strong and characteristic odor due to
the enzymatic hydrolysis of esters of the valepotriates (isovaleric acid and
hydroxyvaleric acid). Taste: It is mildly sweet and camphoraceous with a slightly
bitter and spicy aftertaste [16, 36, 44].

Fig. 1 Comparative evaluation of antioxidant activity of Valeriana wallichii and Valeriana

officinalis
Evaluation of Medicinal Plant with Reference to Its Substitute 953

15.2 Microscopical Analysis

15.2.1 Powder Microscopy

Valeriana wallichii DC

The powder from roots and rhizome is characterized by brown color. There is pres-
ence of starch, root hairs are slightly lignified, and cells of the cortical parenchyma
are axillary elongated. The length is about six to ten times the width (plate).

Valeriana officinalis L.

Examined under a microscope, starch grains are numerous, up to 20 μm in diameter,

mainly two to four compounds with cleft or radiate hilum, packed into parenchyma-
tous cells of the cortex and pith which are large elongated cells with slightly thick-
ened walls. Sclereids from the rhizome are small with thick walls, narrow branched
lumen, and numerous pits. Those from the base of the stem are larger with only
slightly thickened walls. Piliferous layer shows cicatrices or occasionally attached
unicellular root hairs and associated hypodermis of elongated cells, vessels with
reticulate thickening or bordered pits, fibers occasional and lignified with simple
pits (showed in Fig. 2), and lignified cells of tegumentary tissue from rhizome with

Fig. 2 Comparative evaluation of physicochemical parameters of Valeriana wallichii and

Valeriana officinalis
954 T. V. Binu and C. B. Athira

brown granular contents; fragments of the endodermis show sinuous walls. Calcium
oxalate is absent (Elizabeth Williamson [45]).

15.3 Anatomical Analysis

15.3.1 Valeriana wallichii DC

Roots The young roots are characterized by the absence of cork, while it is present
in mature roots. The root hairs present in young roots and very much in length from
20–24 and 12–10 micro in width. The exodermal layers turn red with the use of
Sudan III and the cells are suberized and lignified. The cortex consists of 32 layer
cells; the outer three to four layers just within the exoderm are mostly collenchyma-
tous without any intercellular space and somewhat smaller in size than the cells in
the middle part of the cortex. Excepting those immediately outside the endodermis,
which are about the same size as the collenchymatous cells but are parenchymatous
in nature and with small intercellular space. Starch is present in the cortex. The
endodermis consists of one layer of prominent cells. Some of the cell’s dimension
is 16–28 μ × 136–225 μ. The pericycle consists of one to three layers of parenchy-
matous cells, with a dimension of 20–30 μ × 90 μ. Some of the cells contain tannoid
substances. The xylem is tetrarch to polyarch, having up to radially arranged bun-
dles. Vessels have a dimension of 205 μ–255 μ × 20–36 μ. The primary root contains
a little pith at the center. The stellar structure varies with age of the plant.

15.3.2 Rhizome

It is characterized by the presence of cork and other secondary tissues and the pres-
ence of a large pith. The stoloniform parts are different in structure from the rhi-
zomatous parts, chiefly in having no roots. Secondary development is well marked
and the number of vascular bundles is greater than in the rhizomatous parts.

15.3.3 
Valeriana officinalis L.

The young roots are characterized by the absence of cork, while it is present in
mature roots. The root hairs are also present. The cortex consists of three to four
outer layers just.
within the exoderm which are mostly collenchymatous without any intercellular
space and somewhat smaller in size than the cells in the middle part of the cortex.
Starch is present in the cortex. Endodermis consists of one layer of prominent cells.
Some of the cells contain tannoid substance.
Evaluation of Medicinal Plant with Reference to Its Substitute 955

16 Phytochemical Evaluation

16.1 High-Pressure Thin-Layer Chromatography

(HPTLC) Profiling

The HPTLC analysis of the terpenoid content of Valeriana wallichii and Valeriana
officinalis is carried out by using lupeol as the standard. The RF value and color of
the band obtained at wavelength of 366 nm are given in Table 4.
After derivatization using the Liebermann-Burchard reagent, major bands may
be present such as triterpenes, steroids, saponins, and bitter principles. The
HPTLC sample profiling of lane 1 showed five spots. The RF values of lane 1
(Valeriana officinalis) which are 0.13, 0.41, 0.44, 0.62, and 0.66 are shown in
Plate 3. The RF values of lane 2 (Valeriana wallichii) which are 0.12, 0.2, 0.44,
0.46, and 0.44 are shown in Plate 3. The values showed variations. Lane 2 has
large variation with RF value of 0.2 of brown-colored band when compared to lane
1 and lane 3 (STD).

16.2 Evaluation of Antioxidant Activity

The two samples of Tagara were treated for their antioxidant activities. Among
them, Valeriana wallichii has the higher antioxidant activity with 97.85% for
414.8 ppm when compared to the antioxidant activity of Valeriana officinalis with
97.42% for 414.8 ppm. Table 5 showed the details about the antioxidant activities of
Tagara with its different species.

16.2.1 Properties (Fig. 3)

Data filtering: Savitzky-Golay 7 Baseline correction: Lowest slope peak threshold

min. slope
Peak threshold min. height: 10 AU peak threshold min. area: 50
Peak threshold max. Height: 990 AU Track start position: 5.0 mm
Track end position: 75.0 mm Display scaling Automatic All tracks at
WavelengthSc4

Table 4 Standard phenolic content

SL no. Standard Analyte 1 (mg/mL) Average absorbance, 765 nm
1 Std 0.2 20.00 0.545
2 Std 0.4 40.00 0.636
3 Std 0.6 60.00 1.128
4 Std 0.8 80.00 1.653
956 T. V. Binu and C. B. Athira

Plate 3 Powder
microscopy. (a) Valeriana
officinalis L., (b) Valeriana
wallichii DC

Table 5 Phenolic content of sample

SL no. Sample I D Analyte 1 (mg/Ml)
1 Sample 1 48.607
2 Sample 2 132.845
Evaluation of Medicinal Plant with Reference to Its Substitute 957

Fig. 3 Standard curve of gallic acid

17 Discussion

17.1 Comparative Evaluation of Valeriana wallichii

and Valeriana officinalis

17.1.1 Macroscopic Analysis

Valeriana wallichii and Valeriana officinalis showed variations in their morphologi-

cal characters and structures. Morphologically, they are in two different forms.
Valeriana wallichii is a rhizomatous form and Valeriana officinalis is an elongated
root form. The colors of the rhizomes and roots of Valeriana wallichii and Valeriana
officinalis are dark brown and yellow, respectively. We can distinguish them mor-
phologically (Plate 4).

17.1.2 Microscopic Analysis

The powdered forms of Valeriana wallichii and Valeriana officinalis are visually in
two different colors. A brownish color shows the Valeriana wallichii and a cream
white color shows the Valeriana officinalis. In Valeriana wallichii, starch is present,
root hairs are slightly lignified, and cells of the cortical parenchyma are elongated
axillary (Plate 5), whereas in Valeriana officinalis, vessels have reticulate thicken-
ing or bordered pits and fibers are occasional, lignified with simple pits (shown in
Plate 6), and lignified cells of tegumentary tissue from rhizome with brown granular
958 T. V. Binu and C. B. Athira

Plate 4 TLC profiling. (a) Valeriana wallichii DC, (b) Valeriana officinalis L.
Evaluation of Medicinal Plant with Reference to Its Substitute 959

Plate 5 Phytochemical
evaluation. (a) Valeriana
wallichii L., (b) Valeriana
officinalis L.
960 T. V. Binu and C. B. Athira

Plate 6 HPTLC profiling of samples

contents; fragments of endodermis show sinuous walls. Calcium oxalate is

absent [45].
The microscopical analysis in this study shows the starch granules, parenchyma-
tous cells, xylem fibers, etc. Both Valeriana wallichii with Valeriana officinalis have
similar vascular elements and presence of starch grains.

17.1.3 Phytochemical Analysis

The four extracts carried out revealed the following result:

Valeriana wallichii methanol extract: The methanol extract of Valeriana wallichii
revealed the presence of flavonoids, terpenoids, tannins, phenolic, glycosides,
reducing sugar, steroids, and saponins.
Valeriana wallichii ethanol extract: The ethanolic extract of Valeriana wallichii
revealed the presence of flavonoids, reducing sugar, terpenoids, tannins, pheno-
lic, and glycoside.
Evaluation of Medicinal Plant with Reference to Its Substitute 961

Valeriana officinalis methanol extract: The methanol extract of Valeriana officinalis

revealed the presence of flavonoids, terpenoids, tannins, phenolic, glycosides,
reducing sugar, steroids, and saponins.
Valeriana officinalis ethanol extract: The ethanol extract of Valeriana officinalis
revealed the presence of flavonoids, terpenoids, tannins, phenolic, glycosides,
reducing sugar, and saponins.
Depending on their role in plant metabolism, phytochemicals are classified as
primary or secondary constituents [46]. Primary constituents include the amino
acids common sugars, proteins, purines and pyrimidines of nucleic acids, chloro-
phyll, etc. Secondary constituents are the remaining plant chemicals such as alka-
loids, flavonoids, terpenes, lignans, curcumins, steroids, saponins, phenolics, and
glycosides. Flavonoids are the largest group of plant phenols. Flavonoids act as a
potent water-soluble antioxidant and free radical scavenger that prevents oxidative
cellular damage [47]. Flavonoids are reported to have antibacterial, anti-­
inflammatory, anticancer, antifungal, antiallergic, and diuretic properties [48].
Tannins possess amazing stringent properties and they bind to proline-rich proteins
and interfere with the protein synthesis [49]. Another class of natural products is the
terpenoids that have been derived from five-carbon isoprene units. These are natural
lipids that can be found in every class of living things and occupy the largest group
of natural products. Terpenes are widespread in nature, as constituents of essential
oils. One such classification is the monoterpenoids. By biochemical modifications
of monoterpenes, either oxidation or rearrangement produces the related monoter-
penoids. Monoterpenoids have two isoprene units. Monoterpenes may be of two
types, that is, linear (acyclic) or containing rings. Terpenoids had been used in the
prevention and treatment of several diseases [47]. The largest category of phyto-
chemicals and the most widely distributed in the plant kingdom are the phenolic
compounds. The three most important groups of dietary phenolics are flavonoids,
phenolic acids, and polyphenols. Phenolic compounds are a large and complex
group of chemical constituents present in plants. In the above-stated extracts, major-
ity of the phytoconstituents were revealed by the methanolic extract. Therefore,
methanolic extract can be selected for pharmacological studies. Methanolic extract
can be selected for the isolation of available active constituents because methanol,
being a bipolar solvent, possibly dissolves a wide range of phytoconstituents.
The methanolic extract of Valeriana wallichii shows the presence of the saponins
with other phytochemical constituents. Alkaloids are also absent in all extracts of
Valeriana wallichii and Valeriana officinalis in this study.
Flavonoid is a general name of a class of more than 6500 molecules based upon
a 15-carbon skeleton. The core structure is a 2-phenylbenzopyranone, in which the
three-carbon bridge between the phenyl groups is commonly cyclized with oxygen.
Therefore, flavonoids have been recognized as one of the largest and most wide-
spread groups of plant secondary metabolites, with marked antioxidant proper-
ties [50].
962 T. V. Binu and C. B. Athira

Flavonoids are efficient quenchers of singlet oxygen and could be valuable anti-
oxidants in systems under oxidative stress, particularly if a flavonoid-rich diet was
previously consumed [51].
It is well known that rutin, an active flavonoid compound, possesses potent anti-
oxidant properties against oxidative stress. Rutin (50 μm) blocked apoptosis in
human umbilical vein endothelial cells through decreasing reactive oxygen species,
increasing glutathione, restoring DeltaPsim, and protecting DNA damage.
The existence of flavonoid glycosides with sedative and sleeping-enhancing
properties in Valeriana demonstrates the existence of potentiating effects in its
extracts. The suspected presence of synergic effects in Valeriana [52] has been sub-
stantiated by these findings and brought to the fore for future clarification of the
mechanisms involved [53].
Glycosides are molecules in which a sugar is bound to a noncarbohydrate moi-
ety, usually a small organic molecule. Glycosides play numerous important roles in
living organisms. Many plants store chemicals in the form of inactive glycosides.
These can be activated by enzyme hydrolysis, which causes the sugar part to be
broken off, making the chemical available for use. Many such plant glycosides are
used as medications. In animals and humans, poisons are often bound to sugar mol-
ecules as part of their elimination from the body. An example is the cyanoglycosides
in cherry pits that release toxins only when bitten by an herbivore. The flavonoids
are present in all extract of Valeriana species. Hence, both of them have antioxidant
property and flavonoid can protect the DNA damage. Steroids are in the methanolic
extract of Valeriana officinalis. Steroids have anti-inflammatory property. Steroids
are used as the main treatment for certain inflammation of blood, inflammation of
muscles, etc. They may also be used selectively to treat inflammatory conditions
such as rheumatoid arthritis, lupus, or gout.
Terpenoids were important secondary metabolites, because they are used as anti-
microbial, antifungal, anti-parasitic, antihyperglycemic, and anti-inflammatory
agents. They have immunomodulatory properties. Valeriana wallichii and Valeriana
officinalis have high medicinal values due to the presence of various secondary
metabolites.

17.1.4 Physicochemical Analysis

The physicochemical parameters of Valeriana wallichii such as total ash content,

acid-insoluble ash, water-soluble ash, alcohol-soluble extractive and water-soluble
extractive values are shown in Table 6. According to the table, 8.26, 7.25, 6.96, 34,
and 21.09 are the total ash, acid-insoluble ash, water-soluble ash, alcohol-soluble
extractive, and water-soluble extractive values, respectively.
The physicochemical parameters of Valeriana officinalis such as total ash con-
tent, acid-insoluble ash, water-soluble ash, alcohol-soluble extractive, and water-­
soluble extractive values are shown in Table 7. According to the table, 4.8, 6.82,
Evaluation of Medicinal Plant with Reference to Its Substitute 963

Table 6 The ash value of Valeriana officinalis

SL no. Physicochemical parameters Values in percentage

1 Total ash 4.8
2 Acid-insoluble ash 6.82
3 Water-soluble ash 6.31
4 Alcohol-soluble extractive 33.2
5 Water-soluble extractive 20.65

Table 7 TLC profiling

Valeriana wallichii Valeriana officinalis

Rf value 0.51 Blue
Color of the band 0.27 Blue

Fig. 4 Densitogram of terpenoid

6.31, 33.2, and 21.3 are the total ash, acid-insoluble ash, water-soluble ash, alcohol-­
soluble extractive, and water-soluble extractive values, respectively.
The phytochemical parameters of Valeriana wallichii and Valeriana officinalis
show similarity in their values (Fig. 4). From this study, it shows that the physico-
chemical properties of Valeriana wallichii and Valeriana officinalis are similar.
964 T. V. Binu and C. B. Athira

17.1.5 Chromatographical Analysis

Thin-Layer Chromatography

In Valeriana wallichii, blue color bands were present at Rf value of 0.51. Blue color
bands are present at Rf value of 0.27 in Valeriana officinalis. Small variations in
their band length are present. Hence, the TLC system developed can be effectively
used for differentiating two varieties of Tagara. A number of blue bands are present
in both samples, which shows similarity of chemical components of both samples
(Plate 7 and Table 8).

Plate 7 Macroscopic analysis. (a) Valeriana wallichii DC, (b) Valeriana officinalis L.

Table 8 The ash values of Valeriana wallichii

SL no. Physicochemical parameters Values in percentage
1 Total ash 8.26
2 Acid-insoluble ash 7.25
3 Water-soluble ash 6.96
4 Alcohol-soluble extractive 34
5 Water-soluble extractive 21.09
Evaluation of Medicinal Plant with Reference to Its Substitute 965

HPTLC

Terpenes are a large and diverse class of organic compounds, produced by a variety
of plants, particularly conifers, which are often strong smelling and thus may have
had a protective function. They are the major components of resin and of turpentine
produced from resin (the name “terpene” is derived from the word “turpentine”).
Terpenes are major biosynthetic building blocks within nearly every living creature.
Steroids, for example, are derivatives of the triterpene squalene. When terpenes are
modified chemically, such as by oxidation or rearrangement of the carbon skeleton,
the resulting compounds are generally referred to as terpenoids. Terpenes and terpe-
noids are the primary constituents of the essential oils of many types of plants and
flowers. Essential oils are used widely as natural flavor additives for food, as fra-
grances in perfumery, and in traditional and alternative medicines such as aroma-
therapy. Synthetic variations and derivatives of natural terpenes and terpenoids also
greatly expand the variety of aromas used in perfumery and flavors used in food
additives. Vitamin A is an example of a terpene. The fragrance of rose and lavender
is due to monoterpenes. The carotenoids produce the red, yellow, and orange colors
of pumpkin, corn, and tomato, respectively.
Valeriana officinalis has more terpenoid content than Valeriana wallichii.
Valeriana officinalis shows Rf values of 0.13, 0.14, 0.44, 0.62, and 0.66 with color
bands of gray, gray, green, gray, and green, respectively. Valeriana wallichii shows
Rf values of 0.12, 0.2, 0.44, 0.46, and 0.44 with color bands of green, brown, green,
blue, and blue, respectively. Here lupeol is used as the standard with a wavelength
of 0.75 with green band. Valeriana officinalis shows nearest value to lupeol. Hence,
it contain more terpenoids than Valeriana wallichii.

18 Antioxidant Activity

The antioxidant activity of Valeriana officinalis (97.85) is slightly higher than

Valeriana wallichii (97.42%) (Table 9).
Antioxidants have imperative anticipatory roles, not merely on detrimental
changes in the aroma and dietetic eminence of food, although on tissue damage in
an assortment of human diseases. Cellular smashup or oxidative injury arising from
free radicals or reactive oxygen species (ROS) nowadays appears as an elementary
mechanism underlying a number of human beings with neurodegenerative disor-
ders, viral infections, diabetes, inflammation, and autoimmune pathologies along
with digestive system disorders. Free radicals are generated all the way through

Table 9 Antioxidant activities of Valeriana species

Concentration (ppm) Percentage (%)
Valeriana wallichii 414.8 97.42
Valeriana officinalis 414.8 97.85
966 T. V. Binu and C. B. Athira

Fig. 5 Standard curve of samples

customary metabolism of drugs, ecological chemicals, and xenobiotic as well as

endogenous chemicals, particularly stress hormones (adrenalin and noradrenalin).
Accumulated substantiation suggests that ROS can be scavenged during chemopre-
vention utilizing innate antioxidant compounds present in foods and medici-
nal plants.
It is revealed in the present study that the antioxidant activities of Valeriana wal-
lichii and Valeriana officinalis have slight difference in their concentration. So
based on the antioxidant property, they have the same biological functions (Fig. 5).

19 Summary

Phytochemical constituents of Valeriana wallichii and Valeriana officinalis were

known to show medicinal activity as well as physiological activity. Valeriana wal-
lichii and Valeriana officinalis have high medicinal values due to the presence of
various secondary metabolites. Both plant samples contained majority of the same
phytochemicals, and the further research should be carried out on the quantitative
study of plant which will be an interesting area for further study. Alkaloids are
absent in Valeriana wallichii and Valeriana officinalis. Certain diagnostic features
of morphology and anatomy have been found to be useful for correct identification
of both samples. Powder microscopical analysis helps in the identification of
Valeriana wallichii and Valeriana officinalis in powder form.
The phytochemical analysis showed the presence of various phytochemical con-
stituents like flavonoids, terpenoids, tannins, phenolics, and reducing sugars (glyco-
sides). The pharmacological activity of the medicinal plant Valeriana wallichii may
be due to the presence of these active constituents. These phytoconstituents are
Evaluation of Medicinal Plant with Reference to Its Substitute 967

merely responsible for the activity of the plant. The present study on the evaluation
of Valeriana wallichii for the preliminary phytochemical could be used as the diag-
nostic tool for the standardization of medicinal plant. Thus, our study may be an
important landmark in the correct identification of Valeriana wallichii.
The antioxidant activity and terpenoid content are greater in Valeriana officinalis
than in Valeriana wallichii. The chromatographic analysis, phytochemical analysis,
and physicochemical analysis show similarity in the chemical constituents and
compound of both species of Valeriana. Hence, it can be used as good substitute in
place of Valeriana wallichii.

References

1. Nandagoapalan V, Doss A, Marimuthu C (2016) Phytochemical analysis of some traditional

plants. Biosci Discov 7(1):17–20. ISSN: 2229-3469
2. Teresa B, Vincent S (2008) Encyclopedia Natura Medica (the grand reference on medicinal
& astral virtues of herbs and minerals), vol 1. Dominent Publishers and Distributers, New
Delhi, pp 3–19
3. Meena V, Sreesathya N, Surya PDV, Sumanjali A (2012) A review of pharmacological activi-
ties and clinical effects of cinnamon species. Res J Pharm Biol Chem Sci 3:653–663
4. Chopra RN, Nayar SL, Chopra IC (1986) Glossary of Indian medicinal plants. Council of
Scientific and Industrial Research, New Delhi
5. Madaus G (1976) Lehrbuch der biologischenHeilmittel. Georg Olms Verlag, Hidesheim,
pp 2770–2777
6. Suri S, Thind TS (1978) Antimicrobial activity of some essential oils. Ind Drug Pharmaceut
Indus 13:25–28
7. Gaur RD (1999) Flora of the District Garhwal North West Himalaya: with ethnobotanical
notes. Trans MEDIA, Srinagar
8. Houghton PJ (1999) The scientific basis for the reputed activity of Valerian. J Pharm Pharmacol
51:505–512
9. Mathela CS, Chanotiya CS, Sati S, Tiwari M, Sammal SS (2006) Chemical perspective of
Tagar an Ayurvedic drug. Indian J Tradit Knowl 5(4):474–477
10. Singh N, Ap G, Singh B, Kaul VK (2006) Quantification of valerenic acid in Valeriana jata-
mansi and Valeriana officinalis by HPTLC. Chromatographia 63:209–213
11. Jain UK, Patel A, Gupta N (2010) A comprehensive pharmacognostic report on valerian. Int J
Pharm Sci Res 1(7). ISSN: 0975-8232
12. Prakash V (1999) Indian Valerianaceae: a monograph on a medicinally important family.
Scientific Publishers, Jodhpur
13. Bhatt ID, Preeti Dauthal A, Rawat S, Gaira KS, Jugran A, Rawal RS, Dhar U (2011)
Characterization of essential oil composition, phenolic content, and antioxidant properties in
wild and planted individuals of Valeriana jatamansi Jones, 29 Dec 2011
14. Nadkarni KM (1918) Indian plants and drugs with their medicinal properties and uses, Indian
edn. Asiatic Publishing House, Delhi, pp 407–415
15. Lu A, Chen S (1986) Flora Reipublicae Popularis Sinicae. Science Press, Beijing; Tomus
73.2010:1(72)
16. Reynolds J (1993) Martindale the extra pharmacopoeia, 30th edn. The Pharmaceutical Press,
London. 2363 p
17. Steinegger E, Hansel R (1992) Textbook of pharmacognosy and phytopharmacology, 4th edn.
Springer-Verlag, Berlin. 804 p
968 T. V. Binu and C. B. Athira

18. Letchamo W, Ward W, Heard B, Heard D (2004) Essential oil of Valeriana officinalis L. cul-
tivars and their antimicrobial activity as influenced by harvesting time under commercial
organic cultivation. J Agric Food Chem 52. ISSN: 3915-3919
19. Zhou JW, Zhao J, Liu H, Liu Z, Wang J, Han J, Yu Z, Yang F (2010) Chemical analysis and bio-
logical activity of the essential oils of two valerianaceous species from China: Nardostachys
chinensis and Valeriana officinalis. Molecules 15:6411–6422
20. Kemper KJ (1999) Valerian (Valeriana officinalis). Longwood Herbal Task Force. http://www.
mcp.edu/herbal/default.htm, 15 Dec 1999
21. Pandey A, Shukla YN (1993) Naphthoic acid derivative from Valeriana wallichii.
Phytochemistry 32:135
22. Rajalakshmy MR, Geetha G (2016) Isolation and identification of 5-O-caffeoyl quinic acid
from Valeriana wallichii. Asian J Chem 28(3):572–574
23. Dhongade HJ, Sahu V, Sawarkar HA, Sahu P, Sahu R, Patel D, Kashyap P (2016) Isolation
and characterization of Valerinic acid from Valeriana wallichii (Valerinaceae). IJBPAS 5(6)
24. Singleton VL, Rossi JA (1965) Colorimetry of total phenolics with phosphomolybolic acid-­
phosphotunguntic and reagent. Am J Enol Viticult 16:144–158
25. Tang YP, Liu X, Biao Y (2003) Two new flavone glycosides from Valeriana jatamansi. J Asian
Nat Prod Res 5:257–261
26. Sayed A, Hossein G, Fereshteh M, Mehdi R (2012) Phenolic compounds and antioxidant
activity from saffron (Crocus sativus L.). Petal J Agr Sci 4:175–181
27. Bicchi, Binello A, Rubiolo P (2000) Packed column SFC/UV versus HPLC/UV analysis of
valerenic acids and valepotriates in extracts of Valeriana officinalis L. 11(3)
28. Ubadhyay A, Preeti S, Nayak M, Misra N, Afshankhan Dwivedi SK, Rao S (2006)
Standardisation techniques for medicinal and aromatic plants, 7–8
29. Raaman N (2006) Phytochemical techniques. New India Publishing Agency, New Delhi,
pp 19–77
30. Esmaeili N, Ebrahimzadeh H, Abdi K (2011) Determination of some phenolic compounds in
Crocus sativus L. corms and its antioxidant activities study. Pharmacogn Mag 7:74–80
31. Sahu S, Ray K, Yogendra Kumar MS, Gupta S, Kauser H, Kumar S, Mishra K, Panjwani U
(2012) Valeriana wallichii root extract improves sleep quality and modulates brain monoamine
level in rats. Phytomedicine 19:924–929
32. Gallo L, Ramírez-Rigo MV, Piña J, Palma S, Allemandi D, Bucalá V (2012) Valeriana offi-
cinalis dry plant extract for direct compression: preparation and characterization. Sci Pharm
80(4):1013–1026
33. Sung Min Nam A, Choi JH, Yoo DY, Kim W, Jung HY, Kim JW, Kang S-Y, Park J, Kim
D-W, Kim WJ, Yoon YS, Hwang IK (2013) Valeriana officinalis extract and its main compo-
nent, valerenic acid, ameliorate D-galactose-induced reductions in memory, cell proliferation,
and neuroblast differentiation by reducing corticosterone levels and lipid peroxidation. Exp
Gerontol 48:1369–1377
34. Joseph, Puthallath RE, Rao SN (2015) Acute and chronic toxicity study of Valeriana wallichii
rhizome hydro-ethanolic extract in Swiss albino mice. Asian J Med Sci 7(2)
35. Charles DJ (2013) Antioxidant properties of spices, herbs and other sources. Frontier Natural
Products Co-op, pp 509–516
36. Syed SN, Rizvi W, Kumar A, Khan AA, Moin S, Ahsan A (2014) A study to evaluate antioxi-
dant and hepatoprotective activity of aqueous extract of roots of Valeriana wallichii in CCl4
induced hepatotoxicity in rats. Int J Basic Clin Pharmacol 3(2):354–358
37. Pellow S, Chopin P, File S, Briley M (1985) Validation of open: closed arm entries in an
elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14(3):149–167
38. Marder M, Viola H, Wasowski C, Fernandez S, Medina JH, Paladini AC (2003) 6-
Methylapigenin and hesperidin: new valeriana flavonoids with activity on the CNS. Pharmacol
Biochem Behav 75:737–745
39. Stewart SH, Westra HA (2002) Benzodiazepine side-effects: from the bench to the clinic. Cur
Pharmaceut Des 8(1):1–3
Evaluation of Medicinal Plant with Reference to Its Substitute 969

40. Awad R, Levac D, Cybulska P, Merali Z, Trudeau VL, Arnason JT (2007) Effects of tradition-
ally used anxiolytic botanicals of enzymes of the g-aminobutyric acid (GABA) system. Can J
Phys Pharmacol 85(9):933–942. 5
41. Murphy K, Kubin ZJ, Shepherd JN, Ettinger RH (2010) Valeriana officinalis root extracts have
potent anxiolytic effects in laboratory rats. Phytomedicine 17:674–678
42. Neeraj T (2011) Quality standards of Indian medicinal plants. In: Medicinal plants unit. ICMR,
New Delhi, 9:96–98
43. Richa SS, Sharma ML (2014) Phytochemical investigation and anatomical study of three spe-
cies of Sida. Bio life 2(2):3–8
44. Graff A (1999) Valerian root. American Herbal Pharmacopoeia, p 2
45. Williamson E (1999) Valerian root (microscopy). American Herbal Pharmacopoeia, p 4
46. Wadood A, Ghufran M, Jamal SB, Naeem M, Khan A, Ghaffar R, Asnad (2013) Phytochemical
analysis of medicinal plants occurring in local area of Mardan. Biochem Analy Biochem
2(4):1000144
47. Yadav M, Chatterji S, Gupta SK, Watal G (2014) Preliminary phytochemical screening of six
medicinal plants used in traditional medicine. Int J Pharm Pharm Sci 6(5):539–542
48. Chic OI, Amom TT (2014) Phytochemical and antimicrobial evaluation of leaf-extracts of
Pterocarpus santalinoides. Euro J Med Plant 4(1):105–111
49. Radhika B, Murthy JVVSN, Grace DN (2013) Preliminary phytochemical analysis & antibac-
terial activity against clinical pathogens of medicinally important orchid Cymbidium aloifo-
lium (l.) sw. Int J Pharm Sci Res 4(10):3925–3931
50. Corradini E, Foglia P, Giansanti P, Gubbiotti R, Samperi R, Lagana A (2011) Flavonoids:
chemical properties and analytical methodologies of identification and quantitation in foods
and plants. Nat Prod Res 25:469–495
51. Morales J, Günther G, Zanocco AL, Lemp E (2012) Singlet oxygen reactions with flavonoids.
A theoretical – experimental study. PLoS One 7:e40548
52. Hobbs C (1989) Valerian: a literature review. Herbal Gram 21:19–34
53. Williamson EM (2001) Synergy and other interactions in phytomedicines. Phytomedicine
8:401–409
Biotechnology: Production of Natural
Bioactive Compounds from Leguminous
Plants and Disease Management

Shipra Jha and Bhawana Jain

1 Introduction

Malnutrition is a severe and common issue in public health. The size and severity of
the issue and the functionality of the weaknesses in both physiological and socio-­
economic terms need understanding and immediate intervention as a matter of
urgency [1, 2]. Having said that, the focus on their own narrow area of interest or
expertise, whether it is health care or food, discouraged development professionals
from using a truly holistic approach to dealing with the critical problem [3]. This
article is going to remedy this disparity and bring food-based practices back at the
forefront of conversation and facilitate its acceptance on a wider scale. In both
emerging and developed nations, micronutrient shortages occur and may be seen as
“secret hunger.” In developing nations, they occur in the sense of food poverty,
where total nutrition demands and food diversity prove to be the key problem.
Efforts to minimise micronutrient deficiency thus have to be made in the sense of a
projected 854 million population, 20 million under-five children subjected to
extreme malnutrition, and around one million kids die per year as a consequence of
malnutrition [4].
Iron deficiency is the most widespread micronutrient deficiency globally, which
affects the brain tissue. Iron deficiency anaemia is one of the six priority nutrition
measures for the Sustainable Development Targets. Malnutrition caused by a lack of
crucial mineral micronutrients such as iron (Fe) in their food is a major issue that
affects almost half of the world’s population. Also, in the absence of anaemia, iron
deficiency can cause fatigue and affect work efficiency [5]. Dietary iron absorption
is a dynamic mechanism that has received a lot of attention. Dietary iron is made up
of elemental iron as well as either haem or non-haem iron. The molecular processes

S. Jha (*) . B. Jain

Healthcare Department, Asia Pacific Institute of Management, New Delhi, India

© The Author(s), under exclusive license to Springer Nature 971

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_39
972 S. Jha and B. Jain

of absorption and bioavailability of these types vary significantly. Thus, both the
overall amount of iron and the form of iron in food are essential nutritionally [3].
Calcium blocks the synthesis of haem and non-haem iron during the initial iron
uptake into the enterocyte. Young women are particularly vulnerable to iron defi-
ciency as a result of menstrual and childbirth losses, according to the International
Journal of Science. The most important thing that raises a female’s risk of iron
deficiency is menstruation [6]. According to one report, even though volunteers ate
five portions of red meat and two portions of poultry per week, the recommended
dietary allowance (RDA) of iron for women was not easily met [7]. The reasons for
the variance among the Reference Dietary Intakes for iron and real iron consump-
tion have been proposed as a lack of availability, a lack of access to fresh foods, and
a lack of nutrition information and understanding.
The major reason for such high levels of malnutrition is insecurity and inade-
quate agricultural production. FAO is dedicated to alleviating the rising issue of
food poverty in the world, so that everybody will have access to healthy food [8].
This has been achieved by FAO by growing the provision of food-based services to
prevent starvation by enhanced intake of a sufficient and diverse diet. This illus-
trates the right to health, which means to ensure that everyone must have access to
a range of diets containing a variety of foods in order to have enough calories and
macronutrients [9].

1.1 Leguminous Seeds

Grain legumes are an excellent source of protein. Their exploitation is set to increase
as the world’s food needs increase. Furthermore, the positive benefits of legume
seed dietary consumption, which are the basis for several health statements, are cur-
rently being re-examined. Proteins and peptides are involved in the observed bio-
logical processes of legume plants, but their effects have not been fully revealed
[10–12]. Plant-based protein ingredients have gained prominence in the food indus-
try in recent years, as market habits have shifted away from the use of animal-­
derived proteins (e.g., casein, whey, and egg) in favour of dietary choices based on
religious, moral, or health reasons, cost, and availability [13]. In general, legumes
and cereals are high in protein, carbohydrates, fibre, vitamins, minerals, and photo-
chemical. They are often eaten together in the diet as supplementary protein sources,
with legumes being high in lysine but low in methionine and cysteine, while cereals
are the opposite [14].
Legumes and cereals are mostly used in their natural flour form because they are
less costly than purified products like starches or protein isolates and concentrates,
or chemically processed flours. There is an increasing trend in incorporating legume
flours into standard cereal and legume-based foods such as pizza, chips, tortilla, and
noodles and extruded snack products. This is leading to growth in modern pulse
products. Going forward, legumes also show excellent opportunities in frozen
dough foods either as added flour or as fillings. Pulses in view of their nutrient
Biotechnology: Production of Natural Bioactive Compounds from Leguminous 973

profile seem to be ideal for inclusion in designing snack foods, baby, and sports
foods [15, 16]. However, flours from different origins can behave differently and
have different effects on the nutrient composition of the product; thus, it is critical
to consider how these various flour ingredients react with one another [17]. Based
on their functionality and use, cereal and legume flours may be used. Soybean flour,
for example, is frequently added to foods to increase the protein content of the prod-
uct, while wheat flour comprises gluten, a protein that provides dough with the
special viscoelastic properties used for bread making. Water or oil-carrying capabil-
ity, solubility, foaming, and emulsion capacity/stability are all practical properties
of flour [18]. Because of the lack of uniform measurement protocols, variation in
raw material composition within the same form of crop seed due to genotype and/or
climate, and differences in seed processing technique, the functionality of legume
and cereal flours is difficult to compare in the literature (grinding, dehulling, and
defatting). Few researches have used both legumes and cereals in the same survey
in order to effectively and precisely to compare them [19].
In developed nations, legumes and cereals meet the majority of people’s energy
and protein needs. Even where the dietary iron content is sufficient, nutritional iron
deficiency is normal in these regions [20–22]. Iron bioavailability studies have
shown that most cereals, with the exception of highly processed wheat, absorb iron
poorly. Legumes contain more iron than cereals, but its bioavailability in humans
has not been thoroughly investigated. Recent studies show that soybeans and soy
protein materials have a poor level of iron absorption. However, since no clear com-
parisons of iron supply in soybeans and other legumes in humans have been
recorded, iron absorption from five widely consumed legumes was measured in
healthy volunteers [7].
Radio isotopic tests of iron absorption in human subjects were used to assess iron
bioavailability in a number of legumes. Soybeans, black beans, lentils, mung beans,
and split peas were made into soups and served to fasting subjects using the extrin-
sic tag system. The average percentage absorption ranged from 0.84% to 1.91%.
Absorption differences between means were not statistically important. According
to the findings, these five widely consumed legumes are all low in dietary iron
[23–24].

1.2 Bioactive Compounds in Legume Seeds

Legumes are well known for containing a variety of bioactive compounds, includ-
ing saponins, flavonoids, lectins, tannins, phytic acid, isoflavones, and others, which
contribute to their nutraceutical properties. The phenolics and flavonoid content of
highly pigmented and dark-coloured legume seeds is higher, which aids in antioxi-
dant function [25–27]. Legume seeds contain enzyme inhibitors such as alpha-­
amylase, beta-glycosidase, and gamma-aminobutyric acid (GABA), making them
useful as a nutraceutical molecule. Green legume seeds are also high in nutraceuti-
cals. Legume seeds are usually eaten after being processed to increase nutritional
bioavailability by inactivating trypsin, growth promoters, and hemagglutinins [9].
974 S. Jha and B. Jain

2 Nutritional and Antinutritional Components

of Legume Seeds

Legumes seeds contain a variety of nutritious and antinutritional ingredients, which

play an important role as a nutraceutical property [1].

2.1 Compounds Derived from Phenols

Phenolic compounds are used in legume seeds as antinutritional compounds, but

they may also serve as antioxidants due to their capacity to chelate metal ions, sup-
press lipid peroxidation, and scavenge free radicals. Tannins, phenolic acids, antho-
cyanins, and flavonoids are the most common phenolic compounds present in
legume seeds [28, 29]. Colour is given by polyphenolic compounds such as flavonol
glycoside, anthocyanins, and condensed tannins in legume seeds. Dark-coloured
and heavily pigmented plants, such as red kidney beans, have a high phenolic con-
tent. The phenolic content of legume seeds is strongly linked to their antioxidant
action. Legumes include phenolic compounds that have antibacterial, antiviral, anti-­
inflammatory, and antiallergenic properties. They have also been linked to a reduced
risk of cancer, heart disease, and diabetes [30]. According to a study of overall
phenolics versus antioxidant behaviours, fermented legume seeds have higher anti-
oxidant potential. The combination of antinutrient and biological antioxidant effects
found in legume seeds will aid in the enhancement of nutrient consumption, provid-
ing possible nutraceuticals for human health [19].

2.1.1 Tannins

Because of their ability to bind proteins, tannins aid in the elimination of poisons
from the intestine. Tannins also aid in oral hygiene by inhibiting the growth of bac-
teria that cause tooth decay [1].

2.1.2 Flavonoids

Flavonoids found in legume seeds function as antioxidants, preventing a variety of

diseases including cancer, cataracts, arteriosclerosis, inflammatory diseases, inflam-
mation, and ageing [31].
Biotechnology: Production of Natural Bioactive Compounds from Leguminous 975

2.1.3 Isoflavones

Isoflavones found in legume seeds function as an antioxidant, reducing the risk of a

variety of diseases including osteoporosis, cardiovascular disease, and cancer. It is
sometimes used to relieve the effects of menopause. The isoflavones daidzein and
genistein are natural phytoestrogens that can suppress LDL oxidation and thereby
lower the risk of atherosclerosis. Genistein and daidzein have anticancer properties.
Genistein inhibits platelet aggregation, leukotriene synthesis, DNA topoisomerase
II, angiogenesis, sex hormone bioavailability reduction, apoptosis induction, and
differentiation in cancer cells [32–34]. In B16 melanoma and HL-60 human leukae-
mia cells, daidzein causes differentiation. There is epidemiological evidence that
eating a lot of legume seeds lowers the chances of getting cancer [35].

2.1.4 Phytic Acid

As an antinutrient, phytic acid is used in legume plants. It is contained in legume

seeds as phosphate in the endosperm. Phytic acid acts as an anti-HIV agent by
inhibiting viral genome transcription [31]. Kidney stones are prevented by phytic
acid. It also aids in the prevention of cavities, plaque, and tartar in the teeth by
reducing calcium, fluoride, and phosphate solubilises and protecting the teeth from
demineralisation [36]. Phytic acid also aids in the prevention of heart disease and
diabetes mellitus. It also has anticarcinogenic and antioxidant effects [37].

2.1.5 Saponins

Saponins are secondary plant metabolites that may be steroidal or triterpenoid.

Triterpenoids are common saponins found in legume seeds. Saponins can play an
important anticancer function by reducing the formation of carcinogenic substances
in the colon [38]. They can also reduce the risk of cardiovascular disease. Saponins
can also stimulate the immune system by triggering the production of cytokines
including interleukins and interferon. Saponins can also have anti-inflammatory,
antifungal, antiparasitic, hypercholesterolemia, hypoglycaemia, immunomodula-
tory, and other beneficial effects [26, 27].

2.1.6 Lectin

C. cathartica’s lectin con C has a variety of applications, including blood grouping,

immunomodulation, and tissue marker. Con A stimulates immune cell responses in
the liver, resulting in tumour cell death. After binding to the mannose moiety, con A
exerts both autophagic and antihepatomic (immunomodulation) properties [39, 40].
Adenovirus microbeads bound to con A are an efficient method of supplying thera-
peutic transgenes for inflammatory bowel disease. Con A has also been shown to
976 S. Jha and B. Jain

induce mitosis while inhibiting lymphocyte cap and patch development due to anti-­
immunoglobulin. Con A exhibits similar behaviour to insulin in isolated fat
cells [19].

2.1.7 Protein

Pea, faba bean, and beans mature seeds produce 18–20% protein, while lupin and
soybean seeds contain 35–45% protein. The majority of the proteins present in
legume seeds are storage proteins with sedimentation coefficients of 7S and 11S
globulins. Some proteins in legume seeds have antifungal and antiviral function,
making them anti-HIV and antidiabetic. These proteins contain a number of impor-
tant amino acids that are good for human health [41]. The proteins found in Vigna
species have antifungal and antiviral properties. Ground bean lectin blocks polyga-
lacturonic acid’s hemagglutinating activity but not galacturonic acid or basic mono-
saccharides. It reduces the viability of hepatoma (HepG2), leukaemia (L1210), and
leukaemia (M1) cells while also inducing a mitogenic response in mouse spleno-
cytes. Since these proteins possess both of these features, they serve as an ideal
agent for the treatment of AIDS patients, with little adverse effects when compared
to pharmaceutical medications [42, 43].

2.1.8 Fibre

Legumes are a great source of fibre. Dietary fibre is derived from the part of plants
that is not digested by intestinal enzymes. Bacteria in the lower intestine can metab-
olise this and produce short-chain fatty acids. Fibre also lowers blood cholesterol
levels by binding with cholesterol in the human intestine. For diabetics, high-fibre
diets may increase serum lipoprotein levels, reduce blood pressure, and improve
blood glucose levels. Insoluble fibre increases the amount of waste content transient
time from the gastrointestinal tract [33].

2.1.9 Phytic Acid

Legumes’ phytic acid prevents colon cancer by iron chelation and inhibition of iron-­
related carcinogenesis initiation and progression. Furthermore, because of its ability
to increase the activation of natural killer cells, which is consistent with suppressed
tumour occurrence, it may have potential therapeutic application in cancer [11, 44].

2.1.10 Minerals and Vitamins

Soybean is a better source of vitamin B than cereals, but it lacks vitamin B12 and
C. Tocopherols, which are powerful natural antioxidants, are also found in soybean
oil. Soybean also contains 5% minerals. It has a high concentration of K, P, Ca, Mg,
Biotechnology: Production of Natural Bioactive Compounds from Leguminous 977

and Fe. Soy ferritin has a high concentration of iron. Minerals, such as copper, zinc,
magnesium, and manganese, serve as cofactors in certain enzymatic reactions.
Vitamins E and C are known to act as antioxidants and to prevent vitamin A oxida-
tion in the gastric intestinal tract. Vitamin E also protects against cancer by inhibit-
ing the formation of carcinogens from precursor compounds. Vitamin K, on the
other hand, serves a functional purpose in the liver by acting as a blood clotting
agent. Folic acid, a B vitamin, greatly decreases the risk of neural tube defects
(NTDs) such as spina bifida in newborns [37, 45].

2.1.11 Photochemical in Legumes

In addition to the health-promoting elements (fibres, proteins, resistant starch, and

minerals), legumes contain a plethora of photochemical with beneficial biological
activities. Several studies have shown that some polyphenols have strong protective
effects against a variety of pathological conditions, especially those caused by oxi-
dative stress, such as CVD and metabolic disorders. Cereals, legumes (beans and
pulses), oilseeds, bananas, spices, and some drinks are high in polyphenols [17].

2.1.12 Legume Fibres

Legumes are an excellent source of dietary fibre. Resistant starch, non-starch poly-
saccharides (cellulose, hemicelluloses, pectin, gums, and b-glucans), non-digestible
oligosaccharides, and lignin are examples of dietary fibres. Soluble fibre intake is
associated with lower serum total cholesterol (TC), LDL-C, and is inversely linked
to CHD mortality incidence. Dietary fibres can also help prevent obesity [46].

2.1.13 Antioxidant Activity

Because reactive oxygen species are commonly thought to be implicated in several

diseases such as cancer, diabetes, autoimmune disorders, multiple respiratory dis-
eases, and eye diseases, the antioxidant effects of food have been examined. Several
researchers have evaluated the antioxidant function of various dry beans.

2.1.14 Antinutritional Components (ANC)

Despite the possible nutritional and health-promoting properties of legume seeds,

the presence of antinutritional components (ANC) in them restricts their biological
importance and use as food. Bean seeds, such as chickpea, grain beans, lupin, and
peanut, contain a variety of antinutritional compounds that can be proteinous or
non-proteinous in nature. Some ANCs present in legume seeds are ubiquitous, such
as proteinase inhibitors, lectins, phytates, and polyphenols, while others are more
978 S. Jha and B. Jain

unique, such as some complex glycosides. Antinutrients in legume seeds are thought
to reduce protein and carbohydrate absorption. Since high temperatures during pro-
cessing inactivate the ANCs, the harmful effects of legume seeds are only found
after ingestion of raw and unprocessed seeds or flour. Most bean ANCs have an
impact on the digestive system, such as inhibiting digestive enzymes (e.g., protease
inhibitors), impairing hydrolytic functions and transport at the enterocyte site (lec-
tins), forming insoluble complexes (phytates, polyphenols), and increasing gas out-
put throughout the colon (beta-galactosides). The most well-known and widely used
protein inhibitors in legume seeds are trypsin inhibitors of both the Bowman-Birk
and Kunitz types, as well as amylase inhibitors present in chickpea. Most legumes,
such as kidney beans and grain beans, are also high in lectins. Legume seeds also
contain a variety of non-protein ANCs such as phenolic compounds, saponins, alka-
loids, phytates, and others that interfere with the biological use of their nutrients
[47]. Figure 1 shows benefits of phytochemicals.
Saponins have antimicrobial effects, which protect the body from fungi, bacteria,
and viruses. Simultaneously, they boost immune function by stimulating T-cell
development. They also act as antioxidants and scavengers of oxidative stress and it
is very useful in the management of coughs and the control of upper respiratory
soreness. Furthermore, plant-based saponins act as a natural heart tonic and have
been shown to prevent diabetes and fungi development [33].

Tannins have been shown to maintain functional and extreme haemostatic proper-
ties that aid in wound healing, improve irritated mucus membranes, and inhibit
bacterial growth, lowering blood pressure, lowering serum lipid levels, causing liver
necrosis, and modulating immune responses. This activity is accomplished by the
precipitation of proteins in bacteria, thus impeding the utility of proteins by bacteria
and, as a result, slowing protein production within the cells. The amount and type of
tannins used are important factors in these effects. Since tannins are also responsible
for a decrease in appetite, feed quality, and protein digestibility; foods high in tan-
nins are thought to be of poor nutritional value [48].

Phytochemicals Saponins Tannins

Flavonoids Steriod Terpinoid

Fig. 1 Benefits of phytochemical

Biotechnology: Production of Natural Bioactive Compounds from Leguminous 979

Flavonoids are important because they regulate and avoid tissue damage caused by
the presence of activated radical, or singlet oxygen organisms. Furthermore, flavo-
noids have a variety of biochemical properties. They function as vasodilators, reduce
swelling of body tissues, act as antioxidants and antimicrobial, and boost the
immune system’s efficacy [32].

Steroids are well-known essential cardiac stimulants. They have the ability to pro-
tect against mosquito and bacterial attacks. They are used in both cosmetics and
food, as herbal medicine to boost resilience. Because of their profound and efficient
inhibition of microbial growth, they are useful in conventional health services or
applications [40].

Terpenoids Terpenes, also known as terpenoids, are a class of organic compounds

released by plants. They have a heavy odour. The main distinction is that the body
consumes and utilises these substances in various ways. It also has anticancer, anti-
microbial, antifungal, antiviral, antihyperglycaemic, analgesic, anti-inflammatory,
and antiparasitic properties. Terpenes are also used to improve skin penetration and
to protect against inflammatory diseases [32].

Legume Plants with Potential Nutraceutical Properties

Bioactive compounds of leguminous plants have nutraceutical significance. A nutra-

ceutical is a food or component of a food that has medicinal or nutritional benefits,
such as disease prevention or treatment. Isolated nutrients, nutritional additives,
special diets, designer foods, natural medicines, packaged drinks, or processed
drinks are all examples. Several nutraceuticals present in legumes are among the top
200 on the American Nutraceutical Association’s list [7].

2.1.15 Soybean, Black (Glycine max L.)

It is a soybean variety with a black seed coat that has long been used as a tonic food
and substance in oriental medicine. Because of its active peptide compounds, tradi-
tional Chinese medicine theory suggests that black soybean is beneficial in the treat-
ment of diabetes, asthma, antiageing, cosmetology, blood circulation, and other
diseases [7].

2.1.16 Pigeon Pea

Meat, starch, calcium, manganese, crude fibre, fat, trace elements, and minerals are
all abundant in this legume food. Pigeon pea seeds are made up of 85% cotyledons,
14% seed coat, around 1% embryo, and a mixture of dietary nutrients. The majority
of the seed proteins are found in the foetus, while the majority of the carbohydrates
980 S. Jha and B. Jain

are found in the cotyledons. It is both nutritious and therapeutic in nature. When
scorched seeds are mixed with coffee, they can help with headaches and vertigo,
while fresh seeds can help with male urinary incontinence [17]. Immature beans, on
the other hand, are used to cure kidney problems. Pigeon pea seed husks have anti-
oxidant and antihyperglycemic action, making them a promising sustainable option
for the production of hyperglycaemic nutraceuticals.

2.1.17 Chickpeas (Cicer arietinum)

Chickpeas are in high demand all over the world due to their nutritious value.
Chickpea is an essential part in the diets of those who cannot afford animal proteins
in the semi-arid tropics. It is a great source in carbohydrates and protein, and the
quality of protein it contains is considered to be better than other pulses. Chickpeas
are low in cholesterol and high in calcium, dietary fibre (DF), vitamins, and miner-
als. Consumption of chickpeas has been shown to lower the incidence of chronic
diseases and improve health. Chickpea seed oil comprises a variety of sterols,
tocopherols, and tocotrienols. These phytosterols have been shown to have antibac-
terial, antiulcerative, antifungal, antitumor, and anti-inflammatory properties, as
well as a cholesterol-lowering impact [7].

2.1.18 Kidney Bean (Phaseolus sp.)

Phaseolus is the world’s most essential food legume for human consumption. Its
seedlings are mostly composed of carbohydrates and are a rich source of nitrogen
and protein. It also has several elements found in the human body like calcium,
magnesium, potassium, arsenic, copper, iron, zinc, manganese, and sulphur.
This legume contains a high concentration of bioactive ingredients such as
enzyme inhibitors, lectins, phenolics, phytates, and oligosaccharides all of which
play biochemical functions in humans and animals. Among them are the observed
biological processes include antioxidant potential and cholesterol reduction. As a
result of the elimination of low-density lipoproteins, Phaseolus has a defensive
function against cardiovascular problems. It has also demonstrated anticancer activ-
ity due to the antimutagenic and antiproliferative properties of its phenolics, lectins,
and protease inhibitors. It also has antiobesity and antidiabetic properties due to the
presence of resistant starch and α-amylase inhibitor [3].

Nutritional Value of Leguminous Plant

The nutritional value of legumes has been extensively researched. Legumes are high
in protein, fat, carbohydrates, nutrients, antioxidants, calcium, and water, as well as
being good source of thiamin (B1), beta-carotene (provitamin A), riboflavin (B2),
pyridoxine (B6), niacin, folic acid (folacin), pantothenic acid, ascorbic acid, and
Biotechnology: Production of Natural Bioactive Compounds from Leguminous 981

vitamins E and K. According to recent research, there are many ways to increase the
supply of nutritious nutrients through good cooking method collection [9]. The
most popular methods for cooking legumes, according to these reports, are steam-
ing, roasting, boiling, baking, sautéing, microwaving, and pressure-cooking. Aside
from that, the authors considered factors related to traditional domestic production,
such as washing, peeling, cutting, slicing, and soaking in their studies. Such infor-
mation has been researched for specific vegetables (broccoli, potato, and onion) and
legumes (beans and peas). Many studies have revealed major variations in cooking
techniques and investigated the effect of cooking on in vitro bile acid binding by
various vegetables. Bile acid binding has been found to lower cholesterol levels in
the blood, thus decreasing the risk of heart disease. In their first research, they dis-
covered that steam cooking increased bile acid binding in beets, eggplant, aspara-
gus, carrots, green beans, and cauliflower relative to uncooked vegetables. In their
subsequent research, the scientists achieved comparable results by steaming collard
greens, mustard greens, kale, Brussels sprouts, broccoli, green bell pepper, spinach,
and cabbage [17].
After 4 years, the writers revisited some of the same vegetables from the previ-
ous research, this time using different cooking methods (sautéing, heating, and
steaming). They concluded that sautéing has the highest health potential (binding
bile acids) for mustard greens, kale, broccoli, cabbage, and green bell pepper, while
steaming was the optimal option for collard greens.
It is difficult to forecast the effect and retention of certain vitamins without ade-
quate knowledge about the conditions and methods of food production, transporta-
tion, and handling, emphasising the critical need for further study in this area.
Flavour has been found to be the most critical of the key considerations that con-
sumers consider when choosing food for cooking at home (flavour, texture, nutri-
tion, cost, protection, and convenience). Preparing and cooking legumes and
vegetables to improve their flavour will increase their consumption, especially
among children.
Several experiments have been conducted since the early twentieth century to
explore the effect of preparation and cooking practices on the stability of nutrients
in food. The findings of these studies differ greatly, prompting consumers to wonder
about the best ways to prepare and cook foods so as to preserve their nutritional
qualities, especially in legumes and vegetables. Many other studies have examined
the effects of preparation and cooking on nutritional value and have shown that
legume growth conditions have a substantial effect on nutrient content [37], Table 1
shows protein content in leguminous seeds.

Table 1 Protein content (% in dry matter) in leguminous seeds (raw)

S. No Leguminous seed Protein content (%)
1 Peas 24–25
2 Lupin 33–63
3 Beans 19–24
4 Chickpea 15–28.4
982 S. Jha and B. Jain

Legumes are high in B-group vitamins including folate, thiamin, and riboflavin
but low in fat soluble vitamins and vitamin C. Folate is an important food that has
been linked to a lower risk of neural tube defects such as spina bifida in newborns.
Legumes are also high in zinc, iron, calcium, selenium, arsenic, copper, potassium,
magnesium, and chromium. These micronutrients play critical physiological roles
in bone health (calcium), enzyme activity and iron metabolism (copper), carbohy-
drate and lipid metabolism (chromium, zinc), protein synthesis, plasma membrane,
stabilisation (zinc). Haemoglobin synthesis iron and antioxidative activity. Legumes
are generally low in sodium, which is beneficial given the recent developments urg-
ing sodium reduction. While legumes have high iron contents, the iron’s bioavail-
ability is low, reducing the quality of legumes as a source of iron. However, as
legumes are eaten with vitamin C-rich foods, iron absorption is enhanced. As a
result, the high iron content will play a significant role in the prevention of anaemia,
especially in reproductive age or pregnant women [11, 42].
There is the largest incidence concentration of iron deficiency and iron defi-
ciency anaemia in low-income countries because of the persistent shortage of vital
nutrients. The WHO promotes iron supplementation policies for families with anae-
mia particularly since these communities do not have access to several bioavailable
sources of iron [45].
The key challenge of supplementation strategy is low rate of execution. In 2006,
a very substantial number of common negative impacts were diagnosed in individu-
als on iron supplementation, which culminated in questions about the protection of
iron supplements. These problems have been made clear by experiments and find-
ings. An expert group from the World Health Organization (WHO) believes that it
is the existence of highly absorbable supplementation, bypassing the developed sys-
tems for safely chaperoning iron and causing an abundance of non-transferrin-­
bound iron that undergirds the health hazards associated with iron supplements.
There is a controversy on whether iron distributed in foods is safer to the public than
supplements [45].
Several ways may be used to enhance nutritional iron values. In case of extreme
iron deficiency, nutrients may be given to some communities. In specific situations,
micronutrient pigments can be applied to packaged food products to enhance their
nutritious benefits.
The unhealthy eating habits making more people sick. The main reason behind
people’s sickness is their unhealthy eating habits. About every third citizen is ill
with different diseases. There is a rise in human and livestock disorders. The exis-
tence of multiple illnesses in human race is a topic that crops up in the minds of citi-
zens. The suggestion that doctors have technological instruments to diagnose illness
is insufficient and contested. Currently, physical and mental capacities are in
decline. Man is a social being, but the social ideals are weakening. This begs one the
doubt as to whether such circumstances are happening in our culture and it obvi-
ously is of considerable concern. The World Health Organization (WHO) suggests
that the consumption of fruit and vegetables was less than 20–50%. This is attrib-
uted to customer desires for items that are easy as opposed to those that are safer [50].
Biotechnology: Production of Natural Bioactive Compounds from Leguminous 983

Integrated food is more effective than food that is separated from whole food.
There are supplements for unnatural foods that have been discovered. Carotenoids
play a pivotal role in our well-being as these vitamins are effective in restoring harm
to our body’s liver, cells, and tissue. Likewise, the supplementation of vitamins A
and C will significantly influence radiation treatment and chemotherapy outcomes.
Salmonella resistance is being developed in humans and animals. Nowadays, citi-
zens are looking at alternative remedies like ayurvedic, herbal, and conventional
medications with great anticipation [51].
Iron deficiency is a prevalent problem. Here, the severity of the crisis and the
practical effect this is having on community demand steps to be enforced. The
methods for supporting the importance enhancement in order to address this issue
effectively. This section is an attempt to put food-based practices back in the middle
of the conversation and promote their acceptance at a higher stage [42]. Table 2
shows health benefits of pulses.
Vitamin and mineral shortages arise in both developed and emerging countries.
Primary efforts should be focused on micronutrient deficiency since an approximate
854 million people are undernourished, an approximate 20 million children under
the age of 5 are severely malnourished, and about 1 million children die suffering
from malnutrition per year.

Table 2 Health benefits of pulses

Bioactive
Scientific Health benefitsbeneficial constituents with
Pulses name health properties beneficial effects References
Soybean, Glycine Effective in treating diabetes, Dietary polyphenols Jeong et al. [24]
black max asthma, antiageing,
L. Merr cosmetology, blood
circulation, and other
diseases, also possess
antioxidant properties
Pigeon Cajanus Show antioxidant and Starch, calcium, Setya Ariviani
peas cajan antihyperglycaemic manganese, crude et al. [33]
properties, effective in fibre, fat, trace
headaches, vertigo, male elements, and
urinary incontinence, and minerals
kidney problem
Chickpeas Cicer Show antibacterial, Carbohydrates, Jukanti et al. [28]
arietinum antiulcerative, antifungal, calcium, dietary
L. antitumor, and anti-­ fibre, vitamins, and
inflammatory properties, minerals, sterols,
show cholesterol-lowering tocopherols, etc.
properties
Kidney Phaseolus Function against Phenolics, lectins, Wickramasinghe
beans vulgaris cardiovascular diseases phytates, resistant [38]
Decrease cholesterol level starch, protease
Possess antiobesity and inhibitors, etc.
antidiabetic properties
984 S. Jha and B. Jain

3 Biotechnological Approach: Production

of Bioactive Components

3.1 Iron Fortification of Food

The research study has concentrated primarily on food items, such as drinks, milk,
cereals, and condiments. The fortification of food items with iron means the incor-
poration of iron-containing components to the commodity formula (e.g., meat or its
derivatives). The choice of such components will be informed by a company’s most
valued product attributes, including flavour and colour [14].
Among the food legumes, lentils are an essential food crop that provides protein
as well as micronutrients to both human and animal diets. Legumes are one of the
least expensive forms of protein and micronutrients for vegetarian diets that are
deficient in animal products. The crop is a staple food in certain developed countries
where starvation is prevalent due to Fe deficiency. Biofortification, a genetic solu-
tion, or fortification, a food processing approach, has the potential to improve Fe
concentration and bioavailability. While research towards increasing Fe concentra-
tion and bioavailability by biofortification has begun, there has been little investiga-
tion into genetic strategies for increasing Fe bioavailability in legumes to date [52].
The aim of biofortification is growing the vitamins and other micronutrients in sta-
ple foods. Food fortification is the method of introducing beneficial micronutrients
to foods or drinks at their point of production. Iron fortification is much safer
method of supplying iron than supplement since it often provides many amounts of
servings at once. While iron supplements can increase amounts of body iron faster
than iron therapy, it is less risky.
Many experiments have investigated the efficacy of iron fortification. Despite
iron inclusion to different kinds of food since the early 1940s, its addition to pre-­
packaged food still creates technological challenge. The existence of iron induces
chemical disruption in food, triggering organic chemical modifications that some-
times are undesirable to the eater. With the aid of technological challenge, the indus-
try is making use the unsolvable, poorly soluble, or highly chelated iron substances,
but all of them have minimal chemical reactivity. That being said, chemical avail-
ability and solubility do not supply iron absorption. Iron carriers can provide a com-
bination of the assets required to execute this work. These carriers must be adapted
to the corresponding food commodity. This is an illustration that will demonstrate
several possibilities which apply to food. Iron can catalyse reactions with other
ingredients in food [9, 14].
There are other essential factors that affect the bioavailability of added iron.
Though non-haem iron is very well consumed by human body, haem iron is not as
well consumed. Besides the distinct absorption process of non-haem iron and haem
iron, there are interferences between the two. Polyphenols can obstruct the penetra-
tion of haem iron.
Meat-derived additives are found in numerous foods and beverages as fortifi-
cants. This may be a viable solution for certain categories but would not be suitable
Biotechnology: Production of Natural Bioactive Compounds from Leguminous 985

for more widely used products because of the concerns of market approval, pricing,
and supply.
Another type of iron is ferritin, which is a protein used by flora and fauna to
retain extra iron in their bodies. There has been a reported tendency of phytoferritin
as a nutritional fortificants. Folic acid has been available widely but needs to be
synthesised (beans, lentils, etc). Substances that resemble the action of ferritin have
recently demonstrated very high bioavailability. However, they can be challenging
to introduce into certain foods [11, 47].

3.2 Biofortification

By integrating conventional breeding methods with modern new technologies, bio-

fortification crops are able to mix characteristics of high-yield crops with high-iron
varieties. Biofortified crops may include micronutrients in the staple food of low-­
income nations. Particularly small quantities of micronutrients may improve human
health in the long run. There would be a major social effect of biofortified crops
since farmers will prefer those crops [14]. Biofortification is an attempt to raise the
iron content of cereal crops like wheat, rice, and millet and that of pulses like beans,
peas, and lentils. In this way, the concentration of iron in standard crop varieties is
comparatively small: about 50 ppm in pulses, 25 ppm in wheat, and less than 15 ppm
in rice. On the other side, certain specimens had greater incidences than others. The
bran that is extracted in wheat during milling phase contains much of the iron. Most
of the iron in the aleurone is possibly contained in very closely attached phytic acid
frameworks. The high degree of association between phytic acid and iron should
prevent bacterial growth in the gut. If these phytates can breakdown, phytates in the
gut are debatable [9].
When wheat flour extracted for making goods, iron content reduces further dur-
ing the processing of bran and presence of phytic acid. Iron-biofortified millet is
cultivated in India. It contains high iron content. Levels of iron in biofortified millet
are elevated rather than the seeds. The studies have shown that biofortified millet
can be effective towards iron deficiency [53]. Biofortified diet has strong iron con-
tent. Phytic acid is able to attach with iron found in beans, although much of the iron
is embedded in phytoferritin. Iron from ferritin has been found to be well absorbed.
Several researches reported about bioavailability of iron in biofortified beans, con-
sumed by developed nations. These experiments have concentrated on increasing
the amount of iron while neglecting iron’s effects on the body’s microbiome [51].
The targets for iron biofortification are exceedingly poor at present, much smaller
than those for iron supplementation. Extreme improvements to human biological
features could be possible by genetic modification but genetically engineered spe-
cies are grossly stigmatised.
986 S. Jha and B. Jain

4 Disease Management

Nutritional iron deficiency is a major source of anaemia worldwide. This means that
regular diet cannot meet the complete needs of iron in person. Nutritionists agree
that a balanced food community contains adequate nutrients to support health. It is
assumed that if individuals had an adequate supply of healthy food, they might sat-
isfy their dietary requirements. Despite developments in the sectors such as beef
processing and animal husbandry, there are still many instances of meat malnour-
ishment around the world. This suggests that ample food supply does not actually
contribute to appropriate intakes of vitamin and minerals [54]. Factors that induce
iron deficiency anaemia include low wages, overall low food consumption, poor
monotonous diet, and deficiency of micronutrients. A bad diet can lead to nutri-
tional loss and other detrimental consequences, which can be increased by becom-
ing naive about the importance of a diverse diet [55].
Micronutrient-poor food diets are also the major cause of micronutrient deficien-
cies. Due to technical advances, virtually every conventional food variety would be
adequate in order to meet peoples’ dietary requirements. There is need to preserve
and cultivate the right food to maintain balanced diets that support nutritious needs.
The most impacted demographic groups in need of better nutrition are typically
disadvantaged resource-poor peasant farmers and landholding workers who collect
food and fodder from the land and who also have little buying power. Those that is
who are physically weak, like pregnant and lactating mothers, younger kids and
famine-affected communities, who may fail to conform to a diet that is suitable in
quantity or consistency to have acceptable amounts of iron. All deprived and mar-
ginalised communities should get special care.
Frequent turnover of iron contributes to a chronic scarcity. It is one of the major
causes of iron deficiency anaemia in middle- to low-income countries, since they
produce high level of tannins and phytates which decrease the levels of iron.
Therefore, the measures taken to minimise or alleviate these consequences are
described below [6]. There are plenty of potato, fruit, and legume sources that need
to be immediately supported, along with “many leafy vegetables and legumes that
contain significant quantity of iron, with particular focus on growing the consump-
tion of animal commodities that are high in bioavailable iron and in iron absorption
enhancers.” Analysis in India indicated that anaemia was correlated with limited
meat intakes in children under 3 years of age [56].
Adding varied kinds of grains and tubers to a regular cereal or tuber diet will
dramatically improve the nutritional profile. Adding legumes will marginally
increase the iron balance of your diet. In that scenario, bioavailability of that iron
supply is poor. It is not necessary to reach the recommended amounts of iron con-
sumption without any beef, poultry, or fish. Adding 50 grams of meat improves the
person’s iron consumption “as well as the person’s bioavailable iron. The bioavail-
ability of iron (mg/1000 cal)” has been measured for each food portion in four sta-
ple intakes [57]. There should be ample food available to meet the varied human
needs. Many populations across the planet are unable to gain access to a range of
food that is high in micronutrient. A staple-based diet for a male must be varied
Biotechnology: Production of Natural Bioactive Compounds from Leguminous 987

which includes grains, fruits, and some meat. Obviously, this will not be feasible
with those citizens living in deprived neighbourhoods. Another way to protect hun-
ger is by dietary fortification and supplements [58].
The monotonous diets are often likely to be lacking in other essential nutrients
such as minerals and vitamin. People who follow those diets are likely to suffer
from a variety of nutritional deficiencies. By the intake of a larger range of plant
foods, including fruits and vegetables, humans can more easily attain the requisite
vitamins and minerals. A considerable number of “plant-based nutrients or photo-
chemical” can be consumed, and there is continuing research into the positive
impact of these nutrients. Eating a variety of foods has two benefits in terms of miti-
gating what is known as the double burden of malnutrition. Eating a range of kinds
of foods has double advantages in offsetting what is considered double pressure of
malnutrition [59].
High-fat foods have historically not been considered heart healthy; however,
research is increasing on the cardiovascular benefits of nuts as part of a low-fat and
cholesterol-rich diet. Clinical studies, which have directly researched on interaction
between almonds and blood, have shown that people who consume nuts decrease
cholesterol levels by 6–12%. A Life Sciences Research Office study of six clinical
treatments with walnuts reliably showed reductions in total and LDL cholesterol
that could reduce the incidence of cardiovascular disease [60].
In the late 1970s, researchers found that people in some regions of France who
drank red wine had fewer coronary disorders than other Western communities even
though their diet included large amounts of fat. This hypothesis emerged a sequence
of philosophical inquiries into the so-called “French Paradox” which were substan-
tiated by the conclusions of the ensuing studies. By one of the reports, high con-
sumption of one or more alcoholic drinks decreased the risk of heart attack [37, 61].
There is a chance that grape juice may provide advantages comparable to red
wine since both are high in phenolic antioxidants. Grape juice has been shown to
possess the capacity to suppress platelet aggregation [15]. Besides wine and coffee,
another liquid that includes polyphenols is chocolate. Flavonoids from cocoa help
reduce oxidative stress in LDL cholesterol. In a recent clinical study involving 23
participants, chocolate and cocoa powder was found to improve the oxidation of
low-density lipoprotein cholesterol by 8% against subjects eating a typical American
diet [61].
The important factors influencing iron absorption involve the body’s reserves of
iron (often known as the “pharmacodynamic variables”). As well, there are a range
of things often playing an important role in raising or diminishing the bioavailabil-
ity of iron, including haem (the protein inside red meat from cattle, fish, and poultry
blood) and non-haem iron (the newer iron supplements, such as ferrous sulphate
that are obtained from plant sources), the amount of cooking time and temperature,
and the existence of strengthening foods such as meat peptides and vitamin C (as
well as inhibiting foods such as phytic acid and calcium carbonate) [55].
Utilising both of these methods allows the optimal approach to avoid deficien-
cies. To decide the most suitable combination to end up addressing the bad social
nutrition, the condition study should therefore be performed on the extent,
988 S. Jha and B. Jain

frequency, and spread of social nutrition deficiency, food consumption patterns

including intake of micronutrients, and food preferences and behaviours of disad-
vantaged communities, especially socio-economic details to define the key barriers
and facilitators.
The most powerful method is likely to incorporate both enhanced production and
utilisation to encourage nutrient foods. The government has to take particular
account of marginal communities such as children and women who are pregnant.
Health-related prevention initiatives, dietary improvement and diversifying, and
food fortification including biofortification play a vital role in maintaining and
enhancing nutritional status of underprivileged communities. This approach includes
the supply of vitamin-enriched food. Food-based programmes provide health-related
advantages, including increased intakes of specific foods and overall lifestyles [59].
Government policy and legislation will decide which micronutrient-rich food
would be accessible and affordable. With comparatively limited expenditures in
agriculture, schooling, and public health, suffering from vitamin and mineral short-
ages may be removed. Modern and wild foods can be promoted since there is likeli-
hood that they produce large levels of micronutrients. A successful regulation that
prohibits urban gardening may have a major impact on micronutrient supply.
Stakeholders should consider the profitability of certain foods and their possible
health consequences when preparing a food-based solution [62].
A variety of strategies, initiatives, and services are needed to efficiently mitigate
nutritional problems. It contains following elements.
1. Increasing the total amount of food ingested for all most susceptible to deficien-
cies in addition to ensuring sufficient dietary consumption for all.
2. To consume safe balanced diet that contains micronutrient and animal products,
berries, and vegetables.
3. Regulate effects of inhibitory and enhancer molecules such as phytates and
vitamin C.
4. Refining, preservation, and process conditions that hold the micronutrients
adequately.
5. Therefore, nutrition education is critical.
6. Key issue are food quality and security with consequence for public health and
disease control which help to eliminate nutrient loss and optimise fruit and veg-
etable capacity as high value commodity.
7. Level of fortification is seven.

5 Conclusion

Worldwide public face various health issues, which can be prevented by enhancing
the quality of nutrients through their diet. Leguminous seeds are rich in proteins,
micronutrients, low-fat content and bioactive compounds includes dietary fibre,
phytosterols, oligosaccharides, and polyphenols. Leguminous seeds are main staple
food in various countries.
Biotechnology: Production of Natural Bioactive Compounds from Leguminous 989

Legumes and vegetables are used every day in our daily life as food. These super
foods are branded as of supreme nutritious supremacy. Legume seeds are a healthy
food for people all over the world since they contain higher quality proteins (around
20–40% protein) than cereals. Aside from protein, it contains sugars, fibre, amino
acids, micronutrients, and a variety of vitamins and minerals [63]. Legumes are also
well known for the presence of various bioactive compounds such as saponins, tan-
nins, flavonoids, Isoflavones, lectins, phytic acid, and so on, which are essential for
its nutraceutical property and provides beneficial effects on human health as well as
aids in the prevention or treatment of certain diseases such as cardiovascular dis-
ease, diabetes, digestive tract diseases, and so on. There are several other underuti-
lised food legume seeds that could be a source of nutraceutical food. The role of
legumes in human diet is projected to grow in the coming future in order to satisfy
the need for protein and other nutrients in the world’s population while also reduc-
ing the risk associated with animal food supply intake. Only little bit of vegetation
information is recorded and distributed, but it can be used without difficulty and
expense. There is also a long way to go for the curative uses of vegetables and only
a limited portion of the natural compounds in these plants have been recorded in the
existing database of medicinal herbs. Due to the advancement of the technology of
medicinal chemistry and pharmacology, there is a need for the identification of
more medicinal ingredients from foods. A great deal of health care providers wants
patients to consume lots of vegetables which are cultivated and grown at home and
for protein intake the best way to consume legume is in roasted form. We are so
naive of the essence and role of fruits and vegetables. It helps designing strategies,
resources, and policies to reduce the threat of food poisoning and promote its natu-
ral health benefits. Plants, including vegetables, as bioreactors for producing vac-
cines should also be explored to full potential for safeguarding human health and
animal welfare.
Iron deficiency anaemia and iron deficiency are also significant public health
issues. The global size and magnitude, together with the disruptive aspect of this
issue, demands immediate intervention to contain this crucial threat. With the
understanding that foods high in iron raise haemoglobin concentration and decrease
anaemia, a lot of attention is being put on iron fortification. This is also because
states, foreign organisations, and donors have found fortification and supplementa-
tion systems to be readily understood and efficient. However, you will find that in
fact this is not possible. Interest has now switched to nutritional methods that have
significant success for minimising anaemia. Health methods concentrate on opti-
mising the nutrition by growing the availability and intake of a sufficient and healthy
set of foods. Food-based interventions play a key function in combating iron and
other micronutrient shortages. There are many viable steps to be taken by foreign
organisations, states, line ministries of agriculture, health, education, industry and
the private sector, societies and households directly that will improve the use and
bioavailability of iron. These methods seek to fix many common nutritional issues
all at once. The simplest approach to solve this issue is food-based interventions.
Consumers have the ability to have healthier food options, wholesome products,
and a healthy farming system.
990 S. Jha and B. Jain

References

1. Balasundram N, Sundram K, Samman S (2006) Phenolic compounds in plants and agri-indus-

trial by-­products: antioxidant activity, occurrence, and potential uses. Food Chem 99:191–203
2. Singh B, Singh JP, Shevkani K, Singh N, Kaur A (2017) Bioactive constituents in pulses and
their health benefits. J Food Sci Technol 54:858–887
3. American Dietetic Association (1999) Position of the American Dietetic Association: func-
tional foods. J Am Diet Assoc 99:1278–1285
4. Cerutti AK, Bruun S, Donno D, Beccaro GL, Bounous G (2013) Environmental sustainability
of traditional foods: the case of ancient apple cultivars in Northern Italy assessed by multifunc-
tional LCA. J Clean Prod 52:245–252
5. Champ MMJ (2002) Non-nutrient bioactive substances of pulses. Brit J Nutr 88:307–319
6. Chávez-Santoscoy RA, Tovar AR, Serna-Saldivar SO, Torres N, Gutiérrez- Uribe JA (2014)
Conjugated and free sterols from black bean (Phaseolus vulgaris L.) seed coats as cholesterol
micelle disruptors and their effect on lipid metabolism and cholesterol transport in rat primary
hepatocytes. Genes Nutr 9:367
7. Arai S (1996) Studies on functional foods in Japan – state of the art. Biosci Biotechnol
Biochem 60:9–15
8. Chemat F, Vian MA, Cravotto G (2013) Green extraction of natural products: concept and
principles. Int J Mol Sci 13:8615–8627
9. Ashish Chaddha, Kim A (2015) Eagle Omega-3 Fatty Acids and Heart Health, Circulation
132:e350–e532
10. Cordell GA (2011) Phytochemistry and traditional medicine: a revolution in process.
Phytochem Lett 4:391–398
11. Cuadros-Rodríguez L, Ruiz-Samblás C, Valverde-Som L, Pérez-Castaño E, González-Casado
A (2016) Chromatographic fingerprinting: an innovative approach for food “identitation” and
food authentication: a tutorial. Anal Chim Acta 909:9–23
12. De Cassia da Silveira E, Sa R, Andrade LN, De Sousa DP (2013) A review on anti-­
inflammatsory activity of monoterpenes. Molecules 18:1227–1254
13. De Gennaro B, Notarnicola B, Roselli L, Tassielli G (2012) Innovative olive-growing models:
an environmental and economic assessment. J Clean Prod 28:70–80
14. Amarowicz R, Pegg RB (2008) Legumes as a source of natural antioxidants. Eur J Lipid sci
Tech 110:865–878
15. Donno D, Beccaro GL, Mellano MG, Cerutti AK, Bounous G (2015) Goji berry fruit (Lycium
spp.): antioxidant compound fingerprint and bioactivity evaluation. J Funct Foods 18(Part
B):1070–1085
16. Donno D, Boggia R, Zunin P, Cerutti AK, Guido M, Mellano MG, Prgomet Z, and Beccaro GL
(2015) Phytochemical fingerprint and chemo metrics for natural food preparation pattern rec-
ognition: an innovative technique in food supplement quality control. J Food Sci Technol 1–13
17. Anderson JW, Major AW (2002) Pulses and lipaemia, short- and long-term effect: potential in
the prevention of cardiovascular disease. Brit J Nutr 88:S263–S271
18. Ha YL, Grimm NK, Pariza MW (1987) Anticarcinogens from fried ground beef: heat-altered
derivatives of linoleic acid. Carcinogenesis 8:1881–1887
19. Amarowicz R, Estrella I, Hernández T, Robredo S, Troszyńska A, Kosińska A, Pegg RB (2010)
Free radical-scavenging capacity, antioxidant activity, and phenolic composition of green lentil
(Lens culinaris) Food Chem 121:705–711
20. Emahrungs, Umschau (2017) Legumes in human nutrition Nutrient content and protein quality
of pulses. 64:134–139
21. Shahidi F (2004) Functional Foods: Their Role in Health Promotion and Disease Prevention.
J Food Sci 69:R146–R149
22. Fabbri A, Crosby G (2016) A review of the impact of preparation and cooking on the nutri-
tional quality of vegetables and legumes. Int J Gastron Food Sci 3:2–11
Biotechnology: Production of Natural Bioactive Compounds from Leguminous 991

23. ILSI (1999) International Life Sciences Institute Safety assessment and potential health ben-
efits of food components based on selected scientific criteria. ILSI North America Technical
Committee on Food Components for Health Promotion. Crit Rev Food Sci Nutr 39:203–316
24. Jeong Ji Hee, Jo, Yu Na, Kim Hyeon Ju, Jin Dong Eun, Kim Dae-Ok, Heo Ho Jin (2014).
Black Soybean Extract Protects Against TMT-Induced Cognitive Defects in Mice. J Med Food
17:83–91
25. Kushi LH, Meyer KA, Jacobs DRJ (1999) Cereals, legumes, and chronic disease risk reduc-
tion: evidence from epidemiologic studies. Am J Clin Nutr 70:451S–458S
26. Lanza E, Hartman TJ, Albert PS, Shields R, Slattery M, Caan B, Paskett E, Iber F, Kikendall
JW, Lance P, Daston C (2006) High dry bean intake and reduced risk of advanced colorectal
adenoma recurrence among participants in the polyp prevention trial. J Nutr 136:1896–1903
27. Lin LZ, Harnly JM, Pastor-Corrales MS, Luthria DL (2008) The polyphenolic profiles of com-
mon bean (Phaseolus vulgaris L.) Food Chem 107:399–410
28. Jukanti AK, Gaur PM, Gowda CLL, Chibbar RN (2012). Nutritional quality and health ben-
efits of chickpea (Cicer arietinum L.): a review. Br J Nutr 108: S11–S26
29. Kalogeropoulos N, Chiou A, Ioannou M, Karathanos VT, Hassapidou M, Andrikopoulos NK
(2010) Nutritional evaluation and bioactive microconstituents (phytosterols, tocopherols,
polyphenols, triterpenic acids) in cooked dry legumes usually consumed in the Mediterranean
countries. Food Chem 121:682–690
30. Bukva M, Kapo D, Huseinbašić N, Gojak-Salimović S, Huremović J (2019) Iron content in
fruits, vegetables, herbs and spices samples marketed in Sarajevo, Bosnia and Herzegovina
Kem Ind 68:281–287
31. Madhujith T, Naczk M, Shahidi F (2004) Antioxidant activity of common beans (Phaseolus
vulgaris L.) J Food Lipids 11:220–233
32. Sayar S, Koksel H, Turhan M (2005) The effects of protein‐rich fraction and defatting on past-
ing behavior of chickpea starch. Starch‐Stärke 57:599–604
33. Ariviani S, Mudalifah I, Ishartani D, Fauza G (2020) Investigation on antioxidant activity,
protein, and whiteness degree of elicited cowpea sprouts flour prepared with various drying
technique. In AIP Conference Proceedings 2219(1):070003
34. Munirasu S, Ramasubramanian V, Arunkumar P. Effect of Probiotics diet on growth and
biochemical performance of freshwater fish Labeo rohita fingerlings. J Entomol Zool 5:
1374–1379
35. Donno D, Cerutti AK, Prgomet I, Mellano MG, Beccaro GL (2015) Foodomics for mulberry
fruit (Morus spp.): analytical fingerprint as antioxidants’ and health properties’ determination
tool. Food Res Int 69:179–188
36. López-Amorós ML, Hernández T, Estrela I (2006) Effect of germination on legume phenolic
compounds and their antioxidant activity. J Food Comp Anal 19:277–283
37. Bourn D and Prescott J (2002) A comparison of the nutritional value, sensory qualities and
food safety of organically and conventionally produced foods. Crit Rev Food Sci Nutr 42:1–34
38. Wickramasinghe S (1988) Nutritional anaemia. Clin Lab 10:117–134
39. Marinangeli CP, Jones PJ (2011). Whole and fractionated yellow pea flours reduce fasting
insulin and insulin resistance in hypercholesterolemia and overweight human subjects. Brit J
Nutr 105:110–117
40. Martı́nez-Navarrete N, Camacho M, Martı́nez-Lahuerta J, Martı́nez-Monzó J, Fito P (2002)
Iron deficiency and iron fortified foods—a review. Food Res Int 35:225–231
41. Salminen S, Bouley C, Boutron-Ruault MC, Cummings J, Franck A, Gibson GR, Isolauri E,
Moreau MC, Roberfroid M, Rowland I (1998) Functional food science and gastrointestinal
physiology and function. Br J Nutr 80:S147–S171
42. Boxall NS, Adak, GK, De Pinna E and Gillespie IA (2011) A Salmonella typhimurium Phage
Type (PT) U320 outbreak in England, 2008: Continuation of a trend involving ready-to-eat
products. Epidemiol Infect 139:1936–1944
43. Bucher HD, Hengstler P, Schindler C, Meiter G (2002). N-3 PUFA in coronary heart disease:
a meta-analysis of randomized controlled trials. Am J Med 112:298–304
992 S. Jha and B. Jain

44. Thompson B (2011) Combating micronutrient deficiencies: food-based approaches. ISBN

97818459371402011, 128. https://doi.org/10.1079/9781845937140.0000
45. Campos-Vega R, Oomah BD, Loarca-Piña G, Vergara-Castañeda HÁ (2013) Common beans
and their non-digestible fraction: cancer inhibitory activity—an overview. Foods 2:374–392
46. McBurney MI, Thompson LU (1987) Effect of human faecal inoculum on in vitro fermenta-
tion variables. Brit J Nutr 58:233–243
47. Bazzano LHJ, Ogden LG, Loria C, Vupputuri S, Myers L, Whelton PK (2001) Legume con-
sumption and risk of coronary heart disease in US men and women: NHANES I Epidemiologic
Follow-up Study. Arch Intern Med 161:2573–2578
48. Wehr E, Pilz S, Schweighofer N, Giuliani A, Kopera D, Pieber TR, Obermayer-Pietsch SB
(2009) Association of hypovitaminosis D with metabolic disturbances in polycystic ovary syn-
drome. Eur J Endocrinol 161:575–582
49. Bartnikowska E (2009) Biological activities of phytosterols with particular attention to their
effects on lipid metabolism. Pol J Food Nutr Sci 59:105–112
50. Beninger CW, Hosfield GL (2003) Antioxidant activity extracts, condensed tannin fractions,
and pure flavonoids from Phaseolus vulgaris L. seed coat color genotypes. J Agric Food Chem
51:7879–7883
51. Berrios JDJ, Morales P, Cámara M, Sánchez-Mata MC (2010) Carbohydrate composition of
raw and extruded pulse flours. Food Res Int 43:531–536
52. Bouic PJ (2001) The role of phytosterols and phytosterolins in immune modulation: a review
of the past 10 years. Curr Opin Clin Nutr Metab Care 4:471–475
53. Coothankandaswamy V, Liu Y, Mao SC, Morgan JB, Mandi F, Jekabsons MB, Nagle DG,
Zhou YD (2010) The alternative medicine pawpaw and its acetogenin constituents suppress
tumour angiogenesis via the HIF-1/VEGF pathway. J Nat Prod 73:956–961
54. Chaieb N, González JL, López-Mesas M, Bouslama M, Valiente M (2011) Polyphenols con-
tent and antioxidant capacity of thirteen faba bean (Vicia faba L.) genotypes cultivated in
Tunisia. Food Res Int 44:970–977
55. Donno D, Galizia D, Cerutti AK (2010) Fruit nutraceutical value in ancient apple cultivars
grown in Piedmont (Northern Italy). XXVIII International Horticultural Congress on Science
and Horticulture for People (IHC2010): International Symposium on Environmental, Edaphic,
and Genetic Factors Affecting Plants, Seeds and Turfgrass 940:131–138
56. Choung MG, Choi BR, An YN, Chu YH, Cho YS (2003) Anthocyanidin profile of Korean
cultivated kidney bean (Phaseolus vulgaris L.) J Agric Food Chem 51:7040–7043
57. Cheung PCK, Mehta BM (2015) Handbook of food chemistry. Springer, Berlin/
Heidelberg, Germany
58. Cerutti AK, Beccaro GL, Bruun S, Bosco S, Donno D, Notarnicola B, Bounous G (2014) LCA
application in the fruit sector: state of the art and recommendations for environmental declara-
tions of fruit products. J Clean Prod 73:125–135
59. Donno D, Cavanna M, Beccaro GL, Mellano MG, Torello-Marinoni D, Cerutti AK, Bounous
G (2013) Currants and strawberries as bioactive compound sources: determination of antioxi-
dant profiles with HPLC-DAD/MS. J Appl Bot Food Qual 86:1–10
60. Campos-Vega R, Loarca-Piña G, Oomah BD (2010) Minor components of pulses and their
potential impact on human health. Food Res Int 43:461–482
61. Cardador-Martinez A, Loarca-Pina G, Oomah BD (2002) Antioxidant activity in common
beans (Phaseolus vulgaris L.) J Agric Food Chem 50:6975–6980
62. Chung K, Wong T, Wei C, Huang Y, Lin Y (1998) Tannins and Human Health: A Review. Crit
Rev Food Sci Nutr 38:421–464
63. Zeisel S (1999) Regulation of “nutraceuticals.”. Science (Washington, DC) 285:1853–1855
Novel Eco-Friendly Method of Extraction
for Fixed Oils Using Solvent Action of Solid
Solubilizers

Pawan Mulani, Sweta S. Koka, Anirudh Padiyar, R. K. Maheshwari,

and G. N. Darwhekar

1 Introduction

Solubility is defined as the concentration of solute present in the saturated solution

at a certain temperature [1, 2]. In qualitative terms, it can be defined as the spontane-
ous interaction between two or more compounds to form a molecular dispersion [3].
A saturated solution is the one in which the solute is in equilibrium with the solvent
[4]. Solubility can be expressed as molarity, molality, normality, parts, percentage
volume fraction, mole fraction, % w/w, % w/v, and % v/v [4, 5]. The US
Pharmacopoeia and National Formulary define the solubility of a drug substance as
the number of millilitres of solvent required to dissolve 1 g of solute.

2 Techniques to Enhance the Solubility of Drug

There are several techniques which are employed to enhance the solubility of drug
as follows [5]:
1. pH alteration
2. Co-solvency [6]
3. Surface active agents [6]
4. Complexation [7]
5. Micellar solubilization

P. Mulani · S. S. Koka (*) · A. Padiyar · R. K. Maheshwari · G. N. Darwhekar

Acropolis Institute of Pharmaceutical Education and Research,
Indore, Madhya Pradesh, India
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 993

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_40
994 P. Mulani et al.

6. Hydrotropic solubilization
7. Mixed hydrotropic solubilization

2.1 Mixed Solvency Concept

A novel technique of solubility enhancement by use of mixed solvency concept has

been proposed. As per this concept, each and every substance has got solubilizing
property. The solubilities of large number of poorly water-soluble drugs have been
nicely improved using this concept. As per this statement, each substance is a solu-
bilizer. A concentrated aqueous solution containing various water-soluble sub-
stances may act as good solvent for poorly water-soluble drugs. Such concentrated
solutions may show synergistic or additive solubilizing actions of solubilizers pres-
ent in the solution for a particular solute [8–12].

2.1.1 Advantages of Mixed Solvency Concept

1. Each and every weaker solvent can be made a strong solvent for that solute by
proper selection of solubilizers.
2. Solid dispersions of poorly water-insoluble drugs may be developed using com-
bination of proper concentrations (in safe limits) of water-soluble solid excipi-
ents precluding the use of organic solvents (drawbacks of organic solvents
include pollution, high cost, and toxicity due to organic solvents) [8].
3. Mixed solvency can also be employed in titrimetric analysis.
4. Mixed solvency can also be employed in spectrophotometric analysis.

3 Extraction

Extraction is the first step to separate the desired natural products from the raw
materials. Extraction methods include solvent extraction, distillation method, press-
ing, and sublimation according to the extraction principle [13, 14]. Solvent extrac-
tion is the most widely used method. The extraction of natural products progresses
through the following stages:
1. The solvent penetrates into the solid matrix.
2. The solute dissolves in the solvent.
3. The solute is diffused out of the solid matrix.
4. The extracted solutes are collected.
Any factor enhancing the diffusivity and solubility in the above steps will facili-
tate the extraction. The properties of the extraction solvent, the particle size of the
raw materials, the solvent-to-solid ratio, and the extraction temperature.
Novel Eco-Friendly Method of Extraction for Fixed Oils Using Solvent Action of Solid… 995

The selection of the solvent is crucial for solvent extraction. Selectivity, solubil-
ity, cost, and safety should be considered in selection of solvents. Based on the law
of similarity and intermiscibility (like dissolves like), solvents with a polarity value
near to the polarity of the solute are likely to perform better and vice versa [14].
Generally, the finer the particle size is, the better result the extraction achieves.
The extraction efficiency will be enhanced by the small particle size due to the
enhanced penetration of solvents and diffusion of solutes.
The conventional extraction methods include the following:
1. Maceration
2. Percolation
3. Reflux extraction
Some modern extraction methods such as
1. Supercritical fluid extraction
2. Pressurized liquid extraction
3. Microwave-assisted extraction

3.1 Organic Solvents Used for Extraction

The evaporation of the organic solvents leads to isolation and concentration of ana-
lytes. Solvents suitable for the extraction should be less polar, highly volatile, and
have low viscosity. Organic solvents with low polarity such as hexane, dichloro-
methane, and diethyl ether are usually chosen as the organic extracting solvent [15].
The pollution and toxicity caused by most of the organic solvent are a big
challenge.

3.1.1 Drawbacks of Organic Solvents

Organic solvents have innumerous adverse effects caused by single exposure:

1. Dermatitis
2. Headache
3. Drowsiness
4. Eye irritation
They have long-term exposure which causes serious effects like:
1. Neurological disorders
2. Chronic renal failure
3. Liver damage
4. Necrosis
5. Mutagenesis disorder
996 P. Mulani et al.

4 Materials and Methods Used

Sesame oil and sesame seeds were purchased from local market. Sesame seeds were
powdered by means of home mixer. All other chemicals and solvents used were of
standard laboratory grade.

4.1 Procedure of Determination of Solubility of Sesame Oil

4.1.1 Approximate Solubility of Sesame Oil in Melted Thymol

(Temperature About 50 °C)

Melting point of thymol is 48 °C. One gram of thymol was taken in a test tube and
the test tube was dipped in a hot water bath to melt thymol, a clear colourless liquid
was obtained, 0.1 ml of sesame oil was transferred in test tube, and test tube was
shaken. Sesame oil was dissolved in melted thymol. Again, 0.1 ml of sesame oil was
transferred into the test tube. Same method was repeated. One millilitre of sesame
oil was easily dissolved by 1 g melted thymol (at about 50 °C) [8].

4.1.2 Approximate Solubility of Sesame Oil in Melted Menthol (at

About 45 °C)

Melting point of menthol is 45 °C. One gram of menthol was taken in a test tube and
the test tube was dipped in hot water bath to melt menthol, when a clear colourless
liquid (melted menthol) was obtained, 0.1 ml of sesame oil was transferred in a test
tube, and test tube was shaken. Sesame oil got dissolved in melted menthol. Again
0.1 ml of sesame oil was transferred in a test tube. Similarly, sesame oil was dis-
solved in melted menthol. One millilitre of sesame oil was dissolved by 1 g of
melted menthol (at about 45 °C). This indicates that even more quantity of sesame
oil may be dissolved in 1 g of melted menthol [8].

4.1.3 Approximate Solubility of Sesame Oil in a Solution Containing 50%

w/v Thymol in Ethanol

One millilitre of above solution was kept in a test tube. Sesame oil (0.1 ml) was
transferred in it and the test tube was shaken. Oil was completely dissolved in solu-
tion. Further, 0.1 ml sesame oil was transferred and the test tube was shaken. Again
oil was dissolved completely. Same procedure was repeated. It was found that 1 ml
solution was able to dissolve 1.4 ml of sesame oil. This study indicated that sesame
oil has very good solubility in 50% w/v solution [8].
Novel Eco-Friendly Method of Extraction for Fixed Oils Using Solvent Action of Solid… 997

4.1.4 Approximate Solubility of Sesame Oil in a Solution Containing 50%

w/v Menthol in Ethanol

One millilitre of above solution was kept in a test tube. Sesame oil (0.1 ml) was
transferred in it, and the test tube was shaken. Oil was completely dissolved in a
solution. Further, 0.1 ml sesame oil was transferred and the test tube was shaken.
Again oil was dissolved completely. Same procedure was repeated. It was found
that 1 ml solution was able to dissolve 0.8 ml of sesame oil. This study indicated that
sesame oil has quite good solubility in mentioned solution [9].

4.1.5 Approximate Solubility of Sesame Oil in a Solution Containing 25%

w/v Thymol and 25% w/v Menthol in Ethanol

One millilitre of above solution was taken in a test tube. Sesame oil was transferred
in it and the test tube was shaken. Oil was dissolved again. Same procedure was
repeated. It was found that 1 ml of solution was able to dissolve 0.9 ml of sesame
oil. Sesame oil has good solubility in the mentioned solution [9].

4.1.6 Approximate Solubility of Sesame Oil in a Eutectic Mixture

of Thymol and Menthol in 1:1 Ratio (M-T-1:1)

Thymol (25 g) and menthol (25 g) were triturated with the help of mortar pestle to
get clear colourless liquid (eutectic liquid). One millilitre of M:T-1:1 was kept in a
test tube and the test tube was shaken. Oil was completely dissolved. Further 0.1 ml
was taken and the test tube was shaken. Again oil was dissolved and the procedure
was repeated. It was found that 1 ml of eutectic liquid was able to dissolve 1 ml of
sesame oil. This study indicated that sesame oil has very good solubility in eutectic
mixture (M:T-1:1) [9].

4.2 Removability of Solids by Heating

(a) Thymol—One gram of thymol was kept on weighed stainless-steel plate and
exposed to about 80 °C in oven. It was found that all the thymol was removed
within 45 min.
(b) Menthol—One gram of menthol was kept on weighed stainless-steel plate and
exposed to about 80 °C in hot air oven. It was found that all menthol was
removed within 30 min.
(c) Removability of thymol from an oily solution containing thymol in sesame
oil—weight of a stainless-steel plate was noted. On this plate, an oily solution
containing 1 g thymol and 1 g sesame oil is transferred and again gross weight
998 P. Mulani et al.

is noted. Plate is exposed to about 80 °C in hot air oven. All menthol is removed
within 30 min.
Note: Sesame oil remains on the plate. It does not vaporize at this tempera-
ture (about 80 °C). Thus, we can employ melted thymol for the extraction of
sesame oil from powdered seeds.
(d) Removability of menthol from an oily solution containing menthol in sesame
oil—weight of a stainless-steel plate was noted. On this plate, an oily solution
containing 1 g menthol and 1 g sesame oil is transferred and again gross weight
is noted. Plate is exposed to about 80 °C in an oven. All menthol is removed in
about 30 min.
(e) Removability of thymol or menthol from other oily solutions (using stainless-­
steel plate method).
Same procedure (like method C) was used to observe the removability of
thymol and menthol from following oily solutions.
(i) Oily solution containing 1 ml of 50% w/v thymol in ethanolic solution and
1 g sesame oil.
(ii) Oily solution containing 1 ml of 50% w/v menthol in ethanol solution and
0.8 g of sesame oil.
(iii) Oily solution containing 1 ml of eutectic liquid (menthol: thymol 1:1) and
1 g of sesame oil.
(iv) Oily solution containing 1 ml of an ethanolic solution containing 25% w/v
thymol and 25% w/v menthol and 0.9 g of sesame oil.

4.3 Extraction Methods

4.3.1 Extraction of Sesame Oil from Powdered Sesame Seeds with Melted

Thymol (Temperature About 50 °C)

Powdered sesame seeds (5 g) were transferred in a 250-ml capacity beaker. Then,

15 g thymol was added. Beaker was kept on hot water bath to melt the thymol
(M.P.48 °C). When thymol got melted, the beaker was shaken for 30 min. During
this time, thymol was kept in melted condition with the help of hot water bath.
Melted thymol acted as solvent and dissolved the sesame oil of powdered sesame
seeds. After 30 min of shaking, the contents were strained through a Muslin cloth.
Strained liquid was transferred on a weighed stainless-steel plate. This plate was
kept in oven for removal of thymol at about 80 °C. About 1 h was required to get a
constant weight of plate together with extracted oil [13].
Yield of sesame oil was found to be 1.88 g.
Novel Eco-Friendly Method of Extraction for Fixed Oils Using Solvent Action of Solid… 999

4.3.2 Extraction of Sesame Oil from Powdered Sesame Seeds

with a Solution Containing 50% w/v Thymol in Ethanol

Powdered sesame seeds (3 g) were transferred in a beaker of 250-ml capacity. Then,

9 ml of 50% thymol in ethanol solution was transferred. The beaker was shaken for
30 min for extraction of sesame oil from powdered sesame seeds. After 30 min,
shaking the contents were transferred in centrifuge tubes and centrifugation was
carried out for 3 min at 12,000 rpm using Eppendorf centrifuge 5415. Then, decanted
clear liquid was kept on weighed stainless-steel plate and kept in an oven at about
80 °C for removal of thymol and ethanol. Constant weight of stainless-steel plate
together with extracted oil was obtained in about 1 h [13].
0.66 g of sesame oil was left on this stainless-steel plate. Pulp was nearly absent
in this case.

4.3.3 Extraction of Sesame Oil from Powdered Sesame Seeds with Melted

Menthol (Temperature About 45 °C)

Powdered sesame seeds (3 g) were transferred in a 250 ml capacity beaker. Then,

12 g menthol was added. Beaker was kept on hot water bath to melt the menthol
(M.P.44 °C). When menthol got melted, the beaker was shaken for 30 min. During
this time, the menthol was kept in melted condition with the help of water bath.
During these 30 min of shaking, melted menthol acted as a solvent and dissolved the
sesame oil powdered seeds. After 30 min, shaking the content was strained through
a muslin cloth. Strained liquid was transferred on a weighed stainless-steel plate.
This plate was kept in oven for removal of menthol at about 80 °C. About 1 h was
required to get a constant weight of stainless-steel plate together with extracted
oil [14].
Yield of sesame oil was found to be 1.40 g.

4.3.4 Extraction of Sesame Oil from Powdered Sesame Seeds

with a Solution Containing 50% w/v Menthol in Ethanol

Powdered sesame seeds (3 g) were transferred in a beaker of 250 ml capacity. Then,

9 ml of 50% w/v menthol in ethanol was transferred. The beaker was shaken for
30 min for extraction of sesame oil from powdered sesame seeds. After 30 min
shaking, the contents were transferred in centrifuge tubes and centrifugation was
carried out for 3 min at 12,000 rpm using Eppendorf Centrifuge 5415. Then,
decanted clear liquid was kept on weighed stainless-steel plate and kept in an oven
at about 80 °C for removal of menthol and ethanol. Constant weight of stainless-­
steel plate together with extracted oil was obtained in about 1 h [14].
0.81 g of sesame oil was left on this stainless-steel plate. Pulp was nearly absent.
1000 P. Mulani et al.

4.3.5 Extraction of Sesame Oil from Powdered Sesame Seeds

with a Solution Containing 25% w/v Thymol and 25% w/v Menthol
in Ethanol

Powdered sesame seeds (3 g) were transferred in a beaker of 250 ml capacity. Then,

9 ml of solution was transferred. The beaker was shaken for 30 min for extraction of
sesame oil from powdered sesame seeds. After 30 min shaking, the contents were
transferred in centrifuge tubes and centrifugation was carried out for 3 min at
12,000 rpm using Eppendorf Centrifuge 5415. Then, decanted clear liquid was kept
on stainless-steel plate and kept in an oven at about 80 °C for removal of thymol,
menthol, and ethanol. Constant weight of stainless-steel plate together with extracted
oil was obtained in about 1 h [14].
1.10 g sesame oil was left on this stainless-steel plate. Very little traces of pulp
were present.

4.3.6 Extraction of Sesame Oil from Powdered Sesame Seeds

with a Eutectic Liquid of Menthol and Thymol in 1:1 Ratio

Powdered sesame seeds (3 g) were transferred in a beaker of 250 ml capacity. Then,

9 ml of menthol: thymol-1:1 was transferred. The beaker was shaken for 30 min for
extraction of sesame oil from powdered sesame seeds. After 30 min shaking, con-
tents were transferred in centrifuge tubes and centrifugation was carried out for
3 min at 12,000 rpm using Eppendorf Centrifuge 5415. Then, decanted clear liquid
was kept on weighed stainless-steel plate and kept in an oven at about 80 °C for
removal of thymol and menthol. Constant weight of stainless-steel plate together
with extracted oil was obtained in about 1 h [15].
0.80 g sesame oil was left on this stainless-steel plate. Pulp was nearly absent.

4.3.7 Extraction of Sesame Oil from Powdered Sesame Seeds

with Hexane

The powdered sesame seeds (5 g) were transferred in a bottle of 100 ml capacity.

Then, 15 ml of hexane was transferred. The bottle was shaken for 30 min for extrac-
tion of sesame oil from powdered sesame seeds. After 30 min shaking, the contents
were filtered to get extract of sesame oil. Then, extract was kept on weighed
stainless-­steel plate and kept in an oven at about 80 °C for removal of hexane.
Constant weight of stainless-steel plate together with extracted oil was obtained in
about 30 min [15].
0.97 g sesame oil was left on this stainless-steel plate. Very minute traces of pulp
were present (Tables 1 and 2).
Novel Eco-Friendly Method of Extraction for Fixed Oils Using Solvent Action of Solid… 1001

Table 1 Results of approximate solubility studies

S. No Solvent Approximate solubility
1. Melted thymol (at about 50 ° C) More than 1 ml of sesame oil in 1 g melted thymol
2. Melted menthol (at about 45 °C) More than 1 ml sesame oil in 1 g melted menthol
3. 50% w/v thymol in ethanol 1.4 ml sesame oil in 1 ml of 50% w/v thymol in
ethanol
4. 50% w/v menthol in ethanol 0.8 ml of sesame oil in 1 ml of 50% w/v menthol in
ethanol
5. 25% w/v thymol 25% w/v 0.9 ml of sesame oil in 1 ml of 25% w/v thymol 25%
menthol in ethanol w/v menthol in ethanol
6. Eutectic liquid menthol: More than 1 ml of sesame oil in 1 ml of M:T-1:1
thymol-1:1

Table 2 Results of extraction studies using different techniques

S. No Solvent Yield of sesame oil
1. Melted thymol 37.6% w/w (with little pulp)
2. 50% w/v thymol in ethanol 22.0% w/w (pulp was nearly absent)
3. Melted menthol 33.3% w/w (with little pulp)
4. 50% w/v menthol in ethanol 27.0% w/w (pulp was nearly absent)
5. 25% w/v menthol 25% w/v thymol in ethanol 36.6% w/w (with traces of pulp)
6. Eutectic liquid M:T-1:1 26.6% w/w (pulp was nearly absent)
7. Hexane 32.3% w/w (with traces of pulp)

5 Result and Discussion

It gives approximate solubility of sesame oil in different solvents. Melted thymol

(temperature about 50 °C) shows very good solubility of sesame oil. More than 1 ml
of sesame oil gets dissolved in 1 g melted thymol, i.e., more than 50% solubility.
Similarly, more than 1 ml of sesame oil gets dissolved in 1 g melted menthol (tem-
perature about 45 °C), hence more than 50% solubility [8]. One millilitre of 50%
w/v thymol solution in ethanol dissolved 1.4 ml of sesame oil (about 58% w/v solu-
bility). One millilitre of 50% w/v menthol solution in ethanol dissolved 0.8 ml of
sesame oil (about 44% solubility). One millilitre of an ethanolic solution containing
25% thymol and 25% menthol dissolved 0.9 ml of sesame oil (about 47% solubility)
[9]. One millilitre of eutectic liquid menthol: thymol-1:1 dissolves more than 1 ml
of sesame oil, i.e., more than 50% solubility. All solvent systems show significant
solubilities for sesame oil. Removability studies show that thymol, menthol, and
ethanol can easily be removed at about 80 °C within 1 h. Based on all above consid-
erations, it was thought worthwhile to employ these solvent systems for extraction
of sesame oil from powdered sesame seeds [16, 17].
It shows the results of per cent yield of extracted sesame oil from powdered
sesame seeds employing different extraction methods. The observed values of per
cent yield of sesame oil are approximate values because some oil is left with marc,
some oil adheres to vessels, some oil adheres to cloth during straining, and some oil
adheres to the filter paper.
1002 P. Mulani et al.

6 Conclusion

In this work, it is nicely explained that the solubilizing properties of solids can be
employed for extraction of active constituents from various powders of plant mate-
rials giving eco-friendly methods. The use of toxic, pollution causing organic sol-
vents can be minimized. In the present work, the solvent power of ethanol was
improved using solids (menthol and thymol), so that ethanol (a safe class III sol-
vent) could be used to extract sesame oil. Literature survey revealed that hexane
(harmful solvent) is used with ethanol to extract sesame oil (ethanol is a weaker
solvent for sesame oil). Ethanol is a class III organic solvent. Class III organic sol-
vents are better than class II organic solvents (e.g., methanol, chloroform) from the
point of view of safety, pollution, etc.
Sometimes, because of poor solubility of active constituents in ethanol, we are
unable to use ethanol for extraction purpose and we use harmful organic solvents.
Ethanol can be made a strong solvent using menthol, thymol, etc., as reported in
this work.
Extraction with hexane was performed for comparison purpose only. Hexane is
largely employed for extraction of various oils. Also, in some of the extraction
methods, little amount of pulp was found together with extracted oil. This study is
to show that solids can nicely be employed for extraction of active constituent from
the herbal sources. Solids also possess solubilizing properties. Various harmful sol-
vents like hexane, cyclohexane, and chloroform have been employed for the extrac-
tion of various oils. In this study, traces of thymol or menthol left in the extracted oil
are not harmful. During removal of thymol or menthol from extracted portion, thy-
mol and menthol can be collected employing vacuum distillation, so that they can
be recycled. However, distillation shall require exposure to a much higher
temperature.

References

1. Martin A, Bustamanate P, Chun AHC (1994) Physical pharmacy. B. I. Waverly. Pvt Ltd,
New Delhi. pp 103–212. https://pharmabookbank.files.wordpress.com/2019/03/9.3.physical-
pharmacy.pdf
2. Aulton ME (2013) Pharmaceutics “The science of dosage form and design”. Churchill
Livingstone, New Delhi
3. Martin A (2011) “Solubility and distribution phenomena”, Physical pharmacy and pharmaceu-
tical sciences, 6th edn. Lippincott Williams and Wilkins, Philadelphia
4. United States Pharmacopoeia (2000) 24 National Formulary 19. United States Pharmacopoeial
Convention, Inc., pp 2231–2254
5. The United States Pharmacopoeia, USP 30-NF 25, 2007
6. Cooper JW, Gunn C (1985) General pharmacy. CBS Publisher and Distributors, Delhi,
pp 308–333
7. Remington JP (2006) Remington: the science and practice of pharmacy, 21st edn. Lippincott
Williams and Wilkins, Philadelphia, pp 773–774
Novel Eco-Friendly Method of Extraction for Fixed Oils Using Solvent Action of Solid… 1003

8. Maheshwari RK, Fouzdar A (2015) “Solid as solvent”—novel spectrophotometric analytical

technique for ornidazole tablets using solids (eutectic liquid of phenol and niacinamide) as
solubilizing agents. Indian Drugs 52:42–45
9. Maheshwari RK, Singh S, George P, Fouzdar A (2015) Solid as solvent—novel spectrophoto-
metric analytical technique for satranidazole tablets using solids(eutectic liquid of phenol and
niacinamide) as solubilizing agents. Int J Innov Res Pharm Sci 1:26–29
10. Maheshwari RK (2010) “Mixed solvency approach” Boon for solubilization of poorly water
soluble drugs. Asian J Pharm 4:60–63
11. Maheshwari RK (2014) “Solid as solvent”. Novel spectrophotometric analysis of satranidazole
tablets using phenol as a solvent. Indian Pharm XII:37–40
12. Soni LK, Solanki SS, Maheshwari RK (2014) Solubilization of poorly water soluble drug
using mixed solvency approach for aqueous injection. Br J Pharm Res 4(5):549–568
13. Kokate CK (1991) Practical pharmacognosy. Vallabh Prakashan, New Delhi, pp 107–111
14. Khandelwal KR (2002) “Practical pharmacognosy”—techniques and experiments, 9th edn.
Nirali Prakashan, Pune, p 82
15. Kokate CK, Purohit AP, Gokhale SB (2015) Pharmacognosy, 51st edn. Nirali Prakashan, Pune,
pp 23–27
16. Maheshwari RK (2010) Potentiation of solvent character by mixed solvency approach. A novel
concept of solubilization. J Pharm Res 3:411–413
17. Maheshwari RK, Mulani P, Baghel J (2019) Eco-friendly extraction using solids. J Drug Deliv
Ther 9(2):244–249
Conservation Attempts of Woody
Medicinal Plants of India
by Biotechnological Tools

Yasotha Jeyaram, Priya Prasannan, Arjun Pandian, and Ramasubbu Raju

1 Introduction

About 50% of plant species have been reported as endemic to the 34 global biodi-
versity hotspots; each hotspot contains 1500 endemic species [1]. The species with
compact populations are not considered to be vulnerable or endangered at present
but they are at risk and scattered within the restricted geographical regions and
moderately more extensive range [2]. Plants act as the best natural purifiers of the
environment and support an essential role in retaining the oxygen cycle, which is
essential for the survival of all forms of life and reducing carbon dioxides in the air
[3]. Ecologically, woody plants support windbreaks and shelterbelts and are used
for the protection of soil erosion, floods, and deserts [4]. The woody tree plants
reduced temperature in the environment through shade and by intercepting, absorb-
ing, and reflecting solar radiation, especially in warmer places [5]. Tree species are
houses of the majority of wild creatures including animals like insects, birds, small
mammals, and reptiles. The woody shrubs and trees on roadsides may protect the
travellers and curves, thus making a natural guide for safe driving. Woody trees
provide timber for the construction of buildings, agricultural implements, boat and
shipbuilding, matches and matchboxes, mathematical instruments, musical

Y. Jeyaram
Department of Botany, PRIST University, Thanjavur, Tamil Nadu, India
P. Prasannan · R. Raju (*)
Department of Biology, The Gandhigram Rural Institute (Deemed to Be University),
Gandhigram, Dindigul, Tamil Nadu, India
A. Pandian
Department of Botany, PRIST University, Thanjavur, Tamil Nadu, India
Division of Research and Innovation, Department of Biotechnology, Saveetha School of
Engineering, Saveetha Institute of Medical and Technical Sciences, Chennai, India

© The Author(s), under exclusive license to Springer Nature 1005

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_41
1006 Y. Jeyaram et al.

instruments, furniture and cabinetwork, pencil and pen holders, railway carriage
railway sleepers, packing cases and boxes, picture framing, etc. [4]. Moreover,
woody plants play an important role in the ecological balance and forest structure.
In India, people collect the barks, leaves, roots, and sometimes the whole plant
body. About 30% of the entire plant body was used for one-time purposes. In devel-
oped countries such as the United States, they contribute 25% of total drug produc-
tion whereas fast-developing countries such as China and India contribute 80%. The
main reason for decreasing the population rate of woody medicinal plants is the
introduction of alien species and anthropogenic further activities. Hamilton [6] doc-
umented that several hundreds of medicinal plants have been categorized under the
threatened category with extinction risk. Conservation of wild medicinal plants is
difficult through conventional methods such as layering budding, seed germination,
cuttings, and grafting. However, the availability of plant material is not sufficient to
propagate plantlets through conventional methods. To solve this problem, in vitro
propagation can be used and grown successfully.
The plant tissue culture technique is the most efficient technology for large-scale
plant multiplication through micropropagation. In recent years, it is imperative in
the area of plant propagation, secondary metabolites production, pathogen-free
plant production, production of high-yielding plants, and plant improvement.
Endangered and rare plant species have successfully propagated and conserved by
micropropagation. Tissue cultures were employed to preserve plant genetics,
develop more energetic plants, and rapid production of many uniform plants.

2 Effect of Various Sterilant on Various Explants of Shoot,

Node, Leaves, and Seeds

Explant surface sterilization was an essential and most perceptive step of plant tis-
sue culture. Surface sterilization has concerned with explants immersed into a suit-
able concentration of chemical sterilant or decontaminators for a particular time of
establishment in contamination-free culture. The axillary and apical bud of
Hildegardia populifolia, an endangered tree, was sterilized by using various steril-
ant at different time duration, Teepol was treated for 5 min and ethanol (70%) for
3 min, by mercuric chloride (0.1%) for 5 min, and finally cleaned with sterilized
distilled water for 4–5 times [7]. Hildegardia populifolia nodal explants were steril-
ized by 1% Bavistin for 30 min and washed with distilled water and 5% teepol for
15 min and mercuric chloride (0.1%) 3 min. The explants were washed using dis-
tilled water before culture [8]. Syzygium densiflorum explants from mother trees
were kept under running tap water (30 min) and Tween-80 (15 min), the earlier to
exterior sterilization. Further, explants were sterilized by mercuric chloride (0.1%)
for 5–10 min, subsequently rinsed with distilled water afterwards by 2% NaOCl for
5–10 min and ethanol (70%) for 5–10 min. The explants were rinsed with sterile
distilled water in a laminar airflow chamber [9]. Explants (leaf and stem) of
Conservation Attempts of Woody Medicinal Plants of India by Biotechnological Tools 1007

Nothapodytes foetida were washed in running tap water for 10 min and washed with
1–2 drops of Tween-10 followed sterile distilled water (3 times). The explant steril-
ization was attempted to submerge and shack explants in ethanol (70%) for 30 s and
rinsed with sterilized water (2 times). Surface sterilization was carried out with
mercuric chloride (0.1%) for 3 min in addition to sterile distilled water (3 times)
[10]. The in vitro-derived leaves of Zanthoxylum armatum were excised from the
40-day-old shoots by a sterile blade and soaked in a WPM liquid medium contain-
ing different concentrations of TDZ and shaken for different periods of 12, 24, and
36 h followed by cultured on a medium [11]. Shoot tip and nodal explants of
Gaultheria fragrantissima were washed by running tap water (10–15 min) then
treated with Bavistin (2 g−1) for 15–20 min and kept overnight at 25 °C with 70–80%
RH. The explants were again washed with tap water for 20–25 min followed by
4 g−1 Tata Master (15 min). The explants were treated with antibiotics plantomycin
(50 mg−1) and rifampicin (50 mg−1) for 20 min and washed with sterile water.
Further, the explants were sterilized with 0.1% of HgCl2 for 3 min and 100% of
Tween-80 (one to two drops) for 3 min, eventually sterilized in distilled water for
10 min (4–5 times) [12]. The shoot apex and tip explants of Elaeocarpus blascoi
were cleaned by running tap water (30 min) and then immersed in 10% of sodium
hypochlorite (5–8 min) with two or three drops of Teepol over again with sterile
distilled water (3 times). The explants were further treated with ethanol (70%) for
30 s, 0.05% HgCl2 and washed with sterile distilled water or 2–3 times and immersed
in the antimycotic solution for 5 min [13]. Leaf explants of Leptadenia reticulata
were initially treated with 0.1% Bavistin for 10–15 min and 0.1% of mercuric chlo-
ride for 3–4 min and washed by sterile distilled water (6–8 times) in a laminar air-
flow chamber [14]. Leptadenia reticulate nodal and apical shoots were
surface-sterilized by mercuric chloride (0.1%) for 4–5 min and immersed in ethyl
alcohol (90%) for 30–40 s, followed by washing with sterile water (6–7 times).
Then, explants were treated with additives such as adenine sulphate (25 mg−1), argi-
nine and citric acid, and ascorbic acid (50 mg−1) for 10–15 min [15]. Mature and
healthy seeds of Pterocarpus marsupium were sterilized in two stages. The first
stage was washed with running water for 10 min and sterilized by Bavistin (1%) for
5 min followed by rinsed with running tap water (8 min) and imbibed 24 h in dis-
tilled water. In the second step, the seeds were cleaned with HgCl2 (0.1%) for 4 min
and washed with distilled water (4 times) and cultured on nutrient media [16].
Young shoots of Rauvolfia serpentine were washed by using tap water for 30 min
and soaked in labolene (5%) for 5 min. Further, the explants were exteriorly steril-
ized by HgCl2 (0.1%) for 3 min and eventually washed with sterile water 4–5 times
[17]. Plant materials of Atropa acuminata were sterilized with Tween-20 (10 min)
and washed with tap water for 30 min. The nodal and shoot tip explants excised
from shoots were treated with 0.1% of Bavistin (10 min) and surface-sterilized with
HgCl2 (0.1%) for 4 min and rinsed with sterile distilled water 5 time [18]. Shoots of
Syzygium travancoricum were washed with 10% of Nocidet B-300 (wetting agent)
for 5 min and placed running tap water (30 min) and surface disinfected by 70%
ethanol (3 min) followed by HgCl2 (0.2%) for 5 min. Finally, explants were washed
with sterile distilled water (5–6 times) for 10 min [19]. The young leaves and seeds
1008 Y. Jeyaram et al.

of Berberis aristata were washed with tap water and immersed in Tween-20 (0.1%)
and agitated leaves (5–10 min) and seeds (15 min). The explants were treated with
fungicide such as Bavistin, carbendazim for leaves (20 min) and seeds (20 min) and
surface-sterilized by 0.1% of mercuric chloride for leaves (5 min) and seeds (7 min)
and washed with sterilized double-distilled water for (4–6 times) [20]. The healthy
seeds of Sterculia urens were washed with tap water and 5% of Tween-20 was addi-
tionally used with distilled water 3 times. Then, seeds were surface-sterilized with
mercuric chloride (0.5%) for 5–7 min followed by autoclaved distilled water 2–3
times [21]. Explants of Tylophora indica shoots were washed with running tap
water (30 min) and used 5% labolene to soak for 5 min. After that, 0.1% of HgCl2
(3 min) were used for sterilization and finally rinsed with sterile distilled water (4–5
times) [22]. The nodal and shoot tips of Garcinia travancorica were used as explants
and washed thoroughly with tap water for 15 min and washed with liquid detergent
several times. Explants were also sterilized with 1% Clorox for 15 min. Further,
explants were surface-sterilized by HgCl2 (0.01%) for 20 min and subsequently
washed with distilled water. Then, explants were surface-sterilized by ethanol
(70%) for 10 min and also rinsed with sterile distilled water 3 times [23].
5% Tween (10–15 min), 80% ethanol (30 s), and 0.1% HgCl2 (5 min) were
reported to be suitable for sterilizing the axillary bud and node of Ceropegia inter-
media [24]. The cotyledonary explant of Terminalia bellirica was washed with
lanolin soap solution followed by 0.1% HgCl2 for 15 min [25]. But at the same time,
nodal explants of Terminalia bellirica were treated with 20% Bavistin for 5–7 min
and followed by 0.1% HgCl2 for 7 min for in vitro culture [26]. Patel et al. [14]
reported to eradicate the microorganism from the leaf explants of Leptadenia reticu-
lata; it has washed with 0.1% Bavistin (10–15 min) and 0.1% HgCl2 (3–4 min).
Likewise, 0.1% Bavistin (20 min) 0.1% mercuric chloride (4 min) and 70% ethanol
were used for sterilizing the node of Nilgirianthus ciliates [27]. Surface sterilization
of explants Santalum album was effectively done by using Tween-80 (5 min) and
0.075% mercuric chloride (5–6 min) [28].
The nodal explants of Clerodendrum serratum were treated with 1% lanolin and
followed by 0.1% mercuric chloride was reported as effective to sterilize the
explants Couroupita guianensis [29]. Singh et al. [30] studied and recorded that leaf
of Meizotropis pellita was rinsed with two fungicides such as Bavistin 30 min and
0.1% Tween-20 for 5 min. Further, the explants were washed with 70% ethanol
(1 min) followed HgCl2 0.1% for 4 min. The individual concentrations of sodium
hypochlorite and calcium hypochlorite were effective for seed and node sterilization
[31, 32], whereas mercuric chloride has alone used to sterilize Decalepis hamiltonii
[33]. The application of Tween-20, 70% ethanol, and mercuric chloride was used to
eliminate the microorganism from the leaf explant [34]. The collected seeds of
Entada pursaetha were disinfected with Tween-20 (15 min), 70% ethanol, and
finally immersed in 0.1% HgCl2 for 10 min and also with distilled water [35].
Sharmila et al. [36] reported that various sterilization methods have been tested
for eliminating fungal contamination. Among these, Teepol solution (5–10 min),
10% Bavistin, and antibiotics such as ampicillin and rifampicin (15–20 min) fol-
lowed by 70% alcohol (30–60 s) and 0.1% mercuric chloride solution (3–7 min)
Conservation Attempts of Woody Medicinal Plants of India by Biotechnological Tools 1009

were considered as effective for leaf and stem explants. The leaf explant of Mahonia
leschenaultia was washed with 1% Labolene detergent for 10–20 min and 0.1%
HgCl2 for 5–10 min [37]. Similarly, Sahoo and Chand [38] studied the nodal portion
of Vitex negundo rinsed with 5% Laboline, 7% sodium hypochlorite (7–10 min),
and subsequently washed with 0.1% mercuric chloride for 8 min. Kumar et al. [39]
reported that Caesalpinia bonduc was soaked in sulphuric acid to break the seed
dormancy during the sterilization procedure seeds after that the explants were
washed with mercuric chloride solution.
The seeds of P. santalinus were treated with a combination of 50% HCl + 50
ethyl alcohol for 3 h and air-dried for 2 days before inoculation [40]. The axillary
bud segments, leaf, and nodal explants of Exacum wightianus were washed under
running tap water for 30 min. 0.1% Tween-20 (15 min) followed by 0.5% Bavistin
were used for sterilizing the explants. After subsequent washes with distilled water,
it was treated with 70% ethanol and finally sterilized with (0.1%) HgCl2 [41]. The
pods were soaked with distilled water for 24 h and washed with Tween-20 (15 min)
and followed by savlon antiseptic solution (0.06%). Further sterilization procedures
were carried out with 0.1% HgCl2 (20 min) followed by 70% ethanol (1 min) [42].
De-pulped seeds of Ilex khasiana were washed under running tap water for 10 min
soaked in 5% teepol for 5 min and treated with 70% ethanol (1 min) and finally
surface-sterilized with 15% sodium hypochlorite [43]. Lal and Singh [44] experi-
mented and recorded that the nodal explants of Celastrus paniculatus were washed
with teepol running tap water. Surface sterilization of nodal explants was success-
fully done under aseptic conditions using 0.1% HgCl2 for 3–5 min. Finally, the
nodal region was exposed to absolute alcohol and washed with sterilized distilled
water. The explant of Tylophora indica was soaked in 5% teepol solution for 5 min
followed by freshly prepared HgCl2 (for 3 min) [45, 46]. The nodal segments with
the axillary region of Gymnema sylvestre were surface-sterilized with Tween-20 for
3 min and 0.1% mercuric chloride (8 min) [47]. The seeds of G. sylvestre were dis-
infected with 0.5% HgCl2 containing laboline for 5 min [48]. The successfully ger-
minated 15-day-old seedlings of P. santalinus were collected and soaked in soap
solution to remove the contaminants and soil and the shoots were treated with 0.1%
mercuric chloride solution [49]. The sterilize nodal explants of Celastrus panicula-
tus in HgCl2 containing Tween-20 solutions (5 min) were washed with distilled
water. Further, the nodal explants were disinfected with 0.1% HgCl2 and washed
with double sterile distilled water [50]. Padmalatha and Prasad [51] documented
that the dried pods were soaked in boiling water (100 °C) overnight and treated with
5% sulphuric acid for 10 min. Seeds were further washed with 2% Bavistin for
30 min and nodes were exposed to 15 min by 70% ethanol and 0.1% HgCl2 were
used for disinfecting the pods and seeds.
Celastrus paniculatus nodal and internode explants were washed by running tap
water (30 min) followed by 25% NaOCl (10 min) and consequently washed with
autoclaved distilled water (4–5 times). The explants were further sterilized with
0.1% mercuric chloride (10 min) and washed 4–5 times by autoclaved double-­
distilled water and cultured on the medium [52]. The leaf and stem explants of
Rauwolfia tetraphylla washed running tap water (2 min) with Tween-20 (1 min)
1010 Y. Jeyaram et al.

followed by 60% ethanol (2 min) 0.1% mercuric chloride (HgCl2) (2 min) although
the stem and root explants were sterilized with 0.5% Bavistin (10 min), followed by
Tween-20 (2 min) and 0.1% mercuric chloride (4 min) [53]. The pods of Pterocarpus
marsupium were washed by running tap water (15 min) followed by 2% of Teepol
(10 min) and 5% of Tween-20 (4 min) and disinfected with 0.1% mercuric chloride
(HgCl2) for 6 min and cultured on medium [54]. The healthy seeds of Pterocarpus
santalinus were washed with 70% alcohol (1 min) and 0.1% HgCl2, followed by
0.1% sodium dodecyl sulphate (10 min) and washed by double sterile water for 5
times [55].

3 Effect on Various Media on In Vitro Shoot Multiplication

Plant tissue culture media provide essential components such as macro, micro, vita-
mins, hormones, and carbon source to the plant for their growth and development.
Lavanya et al. [7] reported axillary and apical buds were cultured on MS medium
fortified with different plant growth regulators (PGRs) to induce multiple shoots in
Hildegardia populifolia. Nodal explants inoculated in MS and WPM containing
PGRs were induced shoots [8]. The nodes of Syzygium densiflorum were cultured
on WPM with combinations of PGRs to develop multiple shoots and microshoots
were cultured on half-strength WPM to induce rooting [9]. The leaves and stem
explants of Nothapodytes foetida were induced somatic embryos on MS medium in
addition to PGRs and organic supplements [10]. In vitro raised aseptic leaf explants
of Zanthoxylum armatum were induced calli on WPM with PGRs [11]. Gaultheria
fragrantissima shoots tips and nodal explants cultured on WPM were induced mul-
tiple shoots. The nodal explants induced multiple shoots on MS medium supple-
mented with different concentrations of PGRs in Leptadenia reticulata, Syzygium
travancoricum, Sterculia urens, Tylophora indica, and Garcinia travancorica [15,
19, 21–23]. Syzygium travancoricum developed multiple shoots on both MS and
WPM [19], whereas nodal explants of Elaeocarpus blascoi and Rauvolfia serpen-
tina were induced multiple shoots on WPM [13, 17].
The leaf of Leptadenia reticulata has induced calli on MS medium with various
PGRs and the leaf calli of Leptadenia reticulate transfer to shooting MS medium to
induce multiple shoots [14]. Seeds of Pterocarpus marsupium were induced multi-
ple shoots on MS medium containing suitable PGRs and cotyledonary shoots were
induced roots when transferred to MS medium containing PGRs [16]. The in vitro
raised cotyledonary nodal explants of Pterocarpus marsupium were cultured on MS
medium [56]. The explants of Rhododendron wattii were cultured on WPM-induced
multiple shoots and microshoots were cultured on WPM with suitable rooting PGRs
which induced roots [57]. While microshoots of Rauvolfia serpentina induced root
on WPM [17], explants of shoot tips and nodal of Atropa acuminata were cultured
on MS medium fortified with PGRs and induced shoot proliferation and RT (Revised
tobacco) medium were used for shoot elongation rooting [18]. Leaf-derived callus
of Berberis aristata have induced multiple shoot on WPM [20]. Nodal explants of
Conservation Attempts of Woody Medicinal Plants of India by Biotechnological Tools 1011

Garcinia travancorica were initiated shoots on MS medium containing PGRs [23].

Ceropegia intermedia axillary bud and node to induce multiple shoots [24] and peti-
ole and leaf explants developed calli on MS medium with PGRs [62]. Terminalia
bellirica cotyledonary nodal explants induced shoot proliferation and multiple
shoots on MS medium [25]. Leptadenia reticulata leaf explants induced calli and
leaf-derived calli developed multiple shoots on MS with various concentrations of
PGRs. The microshoots were induced root on one-fourth strength of MS medium
[14]. The cotyledonary nodes of Sterculia urens cultured on MS medium to induced
multiple shoots [58]. The nodal explants of Nilgirianthus ciliates induced multiple
shoots on MS medium and the addition of PGRs and microshoots were developed
roots on half-strength MS medium [27]. The nodal explants of Santalum album
induced multiple shoots on MS medium and developed root from microshoots
which have cultured on quarter-strength MS basal medium [28]. Clerodendrum ser-
ratum nodal explants were induced the greatest shoot bud induction and multiple
shoots and microshoots induced root on MS medium [59]. Seeds of Couroupita
guianensis were germinated on MS medium containing PGRs and nodal explants
were cultured on MS medium with additional combinations of PGRs to induce mul-
tiple shoots. The roots were developed from microshoots cultured on half-strength
MS medium addition of PGRs [29]. Meizotropis pellita leaf explants have induced
calli and leaf-derived calli induced shoots were cultured on MS medium containing
different concentrations and combinations of PGRs. The roots were developed from
microshoots on MS medium [30]. The nodal explants of Commiphora wightii
showed shooting response on MS medium containing PGRs [60]. The nodal explants
of Pterocarpus marsupium have induced shoot on basal MS medium and multiple
shoots on MS medium containing PGRs [31] (Table 1).
The nodal explants of Decalepis arayalpathra and Vitex negundo were exhibited
growth response on MS medium [16, 38] whereas embryos cultured on MS Medium
influenced the growth of shoot formation. The bud and leaf explants of Decalepis
hamiltonii inoculated on MS medium showed a good culture response, and for fur-
ther growth, the medium was supplemented with PGRs. Most of the seed explants
were successfully germinated on MS medium and supplemented with plant growth
regulators [32, 39]. But in the case of Entada pursaetha, rooting has been initiated
on half-strength MS medium [35]. Likewise, some of the researchers studied and
reported that the leave explant was successfully grown on MS medium [34, 36, 37].
Anuradha and Pullaiah [40] documented that mesocotyl explants of Pterocarpus
santalinus were induced multiple shoots on B5 medium. In B5 medium shoot tip,
necrosis and leaf fall were observed whereas, on MS medium, these abnormalities
were recorded. Sita et al. [49] reported that shoot tips from seedlings were cultured
on B5 medium showed better shoot response. The different explants of E. wightia-
nus have shown callus induction on MS medium supplemented with various plant
growth regulators [41]. The cotyledonary explants of P. marsupium induced single
shoot on MS medium, and for better rooting, the plantlets were transferred to half-
and quarter-strength MS medium [42]. The seeds of Ilex khasiana cultured on MS
medium were failed to induced microshoots without hormones [43]. Some of the
researchers inoculated the nodal part in the MS medium that has failed to induce
Table 1 Conservation efforts of selected endemic and endangered woody medicinal plants of India
1012

S. No Name of the plant Explant Types of sterilant used Medium Conc. hormone Response Hardening (%) Restoration Reference
1. Hildegardia Axillary and Teepol (5 min), 70% MS BA and KIN Shoot Soil, sand, and 100% Lavanya et al.
populifolia apical bud ethanol (3 min), 0.1% (0.5–3 mg−1) with multiplication vermiculate [7]
(Malvaceae) mercuric chloride (5 min) GA3 (0.1–3 mg−1) (2:1:1) with MS
basal (¼ strength)
Nodal 1% Bavistin (30 min), 5% MS and BA, KIN and TDZ Shoot Garden 98.3% Upadhyay et al.
teepol (15 min), 0.1% WPM (0.5–10 μM) induction soil+manure (3:1) [8]
mercuric chloride (3 min) and soil rite,
vermicompost,
irrigated with MS
basal (¼ strength)
2. Syzygium Nodal Tween-80 (15 min), 0.1% WPM BAP (1.5 mg−1) with Shoot Sand and sterile 58.5% Ramasubbu
densiflorum mercuric chloride (5 min), IBA (1.5 mg−1) multiplication soil (1:1) sprayed and Divya [9]
(Myrtaceae) 2% NaOCl (5–10 min), distilled water
70% ethanol (5–10 min) with
Shoots Sterile distilled water Half- IBA (0.5 mg−1) Rooting micronutrients
strength and
WPM macronutrients
3. Nothapodytes Leaf and stem Washing in liquid detergent MS TDZ (0.5–3.0 mg−1) Somatic – – Khadke and
foetida (1–2 drops of Tween-10 in coconut water (20%) embryos Kuvalekar [10]
(Icacinaceae) distilled water), 70% (v/v) induction
ethanol (30 s), 0.1%
mercuric chloride (3 min)
4. Zanthoxylum Aseptic leaf Soaked in distilled water WPM TDZ (15 μM) and Calli induction Farmyard manure – Purohit et al.
armatum explants (24 h) combination of TDZ and soil (3:1) [11]
(Rutaceae) (6.0 μM) and NAA
(0.5 μM)
5. Gaultheria Shoot tips and 2.0 g−1 Bavistin (15– WPM TDZ (0.22 mg−1) Shoot 1:1:9 farmyard, – Bantawa et al.
fragrantissima nodal 20 min), 0.1% mercuric multiplication sand, and virgin [12]
(Ericaceae) chloride (3 min) with soil
Y. Jeyaram et al.

containing 1–2 drops of

100% (v/v) Tween-80
S. No Name of the plant Explant Types of sterilant used Medium Conc. hormone Response Hardening (%) Restoration Reference
6. Elaeocarpus Nodal 10% Sodium hypochlorite WPM TDZ (0.22 μM) Shoot Garden soil, – Siva et al. [13]
blascoi (5–8 min), 70% ethanol multiplication farmyard, and
(Elaeocarpaceae) (30 s), 0.05% mercuric river sand
chloride (5 min) mixture (1:2:1)
Regenerated Sterile distilled water WPM IBA (2 mg−1) Rooting
microshoots (half-
strength)
7. Leptadenia Leaf 0.1% (w/v) Bavistin MS 2,4-D (0.5 mg−1) and Callus Sand: FYM: Clay 95% Patel et al. [14]
reticulata (10–15 min) 0.1% HgCl2 BAP (0.5 mg−1) proliferation (3:1:1)
(Asclepiadaceae) (3–4 min)
Leaf-derived Sterile distilled water MS BAP (0.5 mg−1) and Shoot
calli NAA (0.1 mg−1) multiplication
Nodal 0.1% HgCl2 (3–4-5 min), MS IAA (0.6 μM) and Shoot Soil rite and 95% Arya et al. [15]
dipped in 90% ethyl alcohol BA (9 μM) multiplication sandy soil:
(30–40 s) farmyard manure:
soil rite (2:1:1)
8. Pterocarpus Seeds 1% Bavistin (5 min), seeds MS GA3 (0.50 μM) with Shoot Soil rite 86.7% Ahmad et al.
marsupium were kept in sterilized TDZ (0.50 μM) multiplication [16]
(Fabaceae) distilled water for
imbibition (24 h), 0.1%
HgCl2 (4 min)
Microshoots Sterile distilled water MS IBA (100 μM) Rooting
In vitro raised Sterile distilled water MS TDZ (0.4 μM) Shoot Soil and soil rite – Husain et al.
cotyledonary multiplication (1:1) [56]
nodal
9. Rhododendron In vitro raised Sterile distilled water WPM 2iP (39.36 μM) Shoot – – Mao et al. [57]
wattii (Ericaceae) nodal multiplication
Conservation Attempts of Woody Medicinal Plants of India by Biotechnological Tools

Microshoots Sterile distilled water WPM IBA (2.45 μM) Rooting

(continued)
1013
Table 1 (continued)
1014

S. No Name of the plant Explant Types of sterilant used Medium Conc. hormone Response Hardening (%) Restoration Reference
10. Rauvolfia Nodal 5% (v/v) detergent (5 min), WPM BA (5.0 μM) with Multiple shoot Garden soil 50 – Alatar et al.
serpentine 0.1% HgCl2 (3 min) NAA (1.0 μM) induction [17]
(Apocynaceae) Microshoots Sterile distilled water WPM NAA (1.0 μM) Rooting Soil rite 90
Microshoots Sterile distilled water RT medium IBA (1 mg−1) Rooting Vermiculite
11 Syzygium Nodal 70% ethanol (3 min) 0.2% MS and BA (17.7 μM) and Multiple shoot Sterilized sand 40% Anand et al.
travancoricum HgCl2 (5 min) WPM NAA (1.3 μM) induction and soil mixture [19]
(myrtaceae) (1:1)
12 Berberis aristata Young leaves 1% Tween-20 (5–10 min), WPM TDZ (0.5 μM) and Shoot Sterile soil and – Brijwal et al.
(Berberidaceae) (leaf-derived 0.5% Bavistin (20 min), BA (8.88 μM) with multiplication farmyard manure [20]
callus) 0.1% HgCl2 (5 min) NAA (2.68 μM) (3:1)
13. Sterculia urens Nodal 5% Tween-20 (10–15 min), MS TDZ (0.33 mg−1) Shoot Garden soil, 80% Dhiman et al.
(Sterculiaceae) 0.1% HgCl2 (5 min) multiplication organic manure, [21]
coco peat, and
vermiculite
(3:3:2:1)
14. Tylophora indica Nodal 5% detergent, labolene MS BA (2.5 μM), NAA Shoot Sterile garden 100% Faisal et al.
(Asclepiadaceae) (5 min), 0.1% HgCl2 (0.5 μM) and lAA multiplication soil, soil rite, or [22]
(3 min) (100 mg−1) vermiculite
15. Garcinia Nodal Shaking with 1% Clorox MS BAP (4.0 mg−1) Shoot Sterile soil and – Ramasubbu
travancorica (15 min), 0.01% HgCl initiation sand (1:1) et al. [23]
(Clusiaceae) (20 min), 70% ethanol MS BAP (4.0 mg−1) and Multiple
(10 min) NAA (1.0 mg−1) shoots and
shoot
elongation
Y. Jeyaram et al.
S. No Name of the plant Explant Types of sterilant used Medium Conc. hormone Response Hardening (%) Restoration Reference
16. Ceropegia Axillary bud 5% Tween (10–15 min), MS BA (6.66 μM) Multiple Peat moss and – Karuppusamy
intermedia and node 80% ethanol (30 s), 0.1% shoots garden soil(1:1) et al. [24]
(Asclepiadaceae) HgCl2 (5 min)
Petiole and – MS Vermicompost Calli induction – – Kashyap et al.
leaf explants extract and coelomic [62]
fluid in 3:1 ratio
17. Terminalia Cotyledonary Lanolin soap solution 0.1% MS BAP (2.0 mg−1) Shoot Soil rite and – Mehta et al.
bellirica nodal HgCl2 (15 min) BAP (3.5 mg−1) and proliferation sprayed with 1/4 [25]
(Combretaceae) KN (0.5 mg−1) multiple MS salt solution
shoots
Node 20% (v/v) Extran® (Merck, MS ½ MS + BA Shoot Organic manure – Dangi et al.
India) (5–7 min) 0.1% (8.8 μM) + NAA multiplication and garden soil [26]
HgCl2 (Merck, India) (2.6 μM) (1:1)
(7 min) IBA (2.5 μM) Rooting
18. Leptadenia Leaf 0.1% (w/v) Bavistin MS 2,4-D (0.5 mg−1) and Calli Sand, farm yard – Patel et al. [14]
reticulate (10–15 min) and 0.1% (w/v) BAP (0.5 mg−1) proliferation manure, and clay
(Asclepiadaceae) HgCl2 (3–4 min) (3:1:1)
Leaf-derived MS BAP (0.5 mg−1) and Multiple
calli NAA (0.1 mg−1) shoots
Microshoots One-fourth IBA (1.5 mg−1) and Rooting
strength 100 mg−1 Ascorbic
MS acid
19. Sterculia urens Cotyledonary – MS BAP (2.0 mg−1) Multiple Farmyard manure – Purohit and
Roxb. node shoots and soil (1:3) Dave [58]
(Sterculiaceae)
20. Nilgirianthus Nodal 0.1% (w/v) Bavistin MS BA (3 mg−1) and Multiple Vermicompost 100% survival Ramakrishnan
ciliatus (20 min) 0.1% mercuric IAA (0.1 mg−1) shoots and sand, rate et al. [27]
Conservation Attempts of Woody Medicinal Plants of India by Biotechnological Tools

(Acanthaceae) Microshoots chloride (HgCl2) (4 min) Half- IBA (1.0 mg−1) Rooting horticulture soil
and 70% ethanol strength (1:1:1)
MS
1015

(continued)
Table 1 (continued)
1016

S. No Name of the plant Explant Types of sterilant used Medium Conc. hormone Response Hardening (%) Restoration Reference
21. Santalum album Nodal Dipped in a CPT 0.1% MS NAA (0.53 μM), BA Multiple 40%, garden 100% Sanjaya et al.
(Santalaceae) (5 min) Tween-80, [5] (4.44 μM) shoots 50%, sieved sand, [28]
0.075% mercuric chloride and soil 10%)
[5, 6]
Microshoots – Quarter- IBA (98.4 μM) Rooting
strength
MS basal
22. Clerodendrum Nodal Laboline detergent 1% MS BAP (0.5 mg−1) Best shoot bud Sterilized – Upadhyay and
serratum (10 min) 0.1% mercuric induction and vermiculite Koche [59]
(Lamiaceae) chloride (10 min) multiplication
MS NAA (0.5 mg−1) Rooting
23. Couroupita Seeds Bavistin (7–8 min) 0.1% MS IBA (2.0 mg−1) Germination – 86% Shekhawat and
guianensis Nodal mercuric chloride (5–6 min) MS BAP (4.0 mg−1) Multiple Manokari [29]
(Lecythidaceae) alone and shoots
combinations of
BAP and KIN
(1.0 mg−1) + NAA
(0.5 mg−1) with
additives
Microshoots Distilled water ½ MS IBA (2.5 mg−1) Rooting
Y. Jeyaram et al.
S. No Name of the plant Explant Types of sterilant used Medium Conc. hormone Response Hardening (%) Restoration Reference
24. Meizotropis pellita Leaf Fungicide (Bavistin) 30 min MS 2–4, D (9.06 μM) Callus Sand and 55–65% Singh et al.
(Fabaceae) 0.1% Tween-20 (5 min). and 2–4, D induction and farmyard manure [30]
70% ethanol (1 min) and (9.06 μM) + 2-iP proliferation (3:1:1 ratio)
0.1% HgCl2 (4 min) (7.38 μM)
Leaf calli MS BA Shoot
(17.6 μM) + GA3 initiation
(1.0 μM)
Cotyledonary MS KN+ GA3 Multiple
node (4.6 μM + 1.0 μM) shoots
or BA (13.2,
17.6 μM) + GA3
(1.0 μM)
Microshoots MS IBA (4.9 μM) Rooting
25. Commiphora Node (with – MS BAP (2 mg−1) + GA3 Shoot – – Tejovathi et al.
wightii two nodes and (0.5 mg−1) response [60]
(Burseraceae) two
internodes)
26. Pterocarpus Nodal 10% sodium hypochlorite MS Without hormones Shoot Sand soil and 68% Tiwari et al.
marsupium (10 min) induction fame yard (1:1:1) [31]
(Fabaceae) MS IBA (0.2 mg−1) Multiple
shoots
Seeds 2% Teepol (10 min), 5% MS BA (3.0 mg−1) and Shoot Sterilized soil and 74% Tippani et al.
Tween-20 (4 min) and 0.1% IAA (0.5 mg−1) multiplication vermiculite (1:1) [54]
mercuric chloride (6 min)
Microshoots Distilled water ½ MS IBA (3.0 mg−1) Rooting
27. Decalepis Nodal – BA (2.0 mg−1) Shoot Not mentioned 85% Seeni and
arayalpathra proliferation Decruse [61]
Conservation Attempts of Woody Medicinal Plants of India by Biotechnological Tools

(Apocynaceae)
(continued)
1017
Table 1 (continued)
1018

S. No Name of the plant Explant Types of sterilant used Medium Conc. hormone Response Hardening (%) Restoration Reference
28. Calamus Embryo – MS TDZ (0.1 mg−1) Shoot – 90% Seeni and
nagabettai multiplication Decruse [61]
(Arecaceae)
29. Decalepis Buds and 0.1% HgCl2 (5 min) MS BA (1.5 mg1) + IAA Shoot Farmyard – Giridhar et al.
hamiltonii leaves (0.5 mg−1) multiplication manure, red soil [33]
(Apocynaceae) IBA (2.0 0.2 mg−1) Rooting and sand (1:1:1)
30. Citrus indica Seeds 5% Calcium hypochlorite MS TDZ (0.01 mg−1) Calli Mixture of garden – Laskar et al.
(Rutaceae) and NAA multiplication soil, leaf mould [32]
(90.1 mg−1) compost, and
BAP (0.5 mg−1), Shoot river sand (1:2:3)
TDZ (0.25 mg−1) multiplication
and NAA
(0.25 mg−1)
NAA (10 mg−1) Rooting
31. Vitex negundo Leaf 5% Tween-20 (10 min), MS IAA (0.3 mg−1) and Shoot Manure, soil, and Jawahar et al.
(Lamiaceae) 70% ethanol (10–15 s and BAP (0.3 mg−1) induction sand (1:1:1) [34]
0.1% mercuric chloride IBA (0.5 mg−1) Rooting
(2–3 min)
Nodes 5% Laboline, 7% sodium MS BA (2.0 mg−1) + GA3 Shooting Vermicompost 93% Sahoo and
hypochlorite (7–10 min), (0.4 mg−1) Chand [38]
and 0.1% mercuric IBA (1.0 mg−1) Rooting
chloride (8 min)
32. Entada pursaetha Seeds Tween-20 (15 min), 70% MS 5.0 mg−1BAP Shoot Garden soil 70% Vidya et al.
(Mimosae) ethanol and 0.1% HgCl2 organogenesis [35]
(10 min) 5.0 mg−1 NAA Rooting
Y. Jeyaram et al.
S. No Name of the plant Explant Types of sterilant used Medium Conc. hormone Response Hardening (%) Restoration Reference
33. Cayratia pedata Leave and Teepol (5–10 min) 10% MS BAP Calli – – Sharmila et al.
(Vitaceae) stem Bavistin (15–20 min), 70% (0.5 mg−1) + NAA formation [36]
alcohol (30–60 s) 0.1% (0.2 mg−1)
mercuric chloride solution
(3–7 min)
34. Mahonia Leave 1% Labolene detergent MS BA (1.0 mg−1) and Shoot Top soil and river 78.8 and 90.6 Radha et al.
leschenaultii (10–20 min), and 0.1% IAA (0.02 mg−1) formation sand (1:1) [37]
(Berberidaceae) HgCl2 (5–10 min) IBA (1.0 mg−1) Rooting
35. Caesalpinia Seeds Tween-20 (15 min), 70% MS BAP (17.57 μm) and Shooting – – Kumar et al.
bonduc ethanol (5 min), H2SO4 IBA (2.85 μm) [39]
(Ceasalpiniacae) (8 min) and 0.1% HgCl2 IBA (2.95 μm) Rooting
336. Pterocarpus Mesocotyl 50% HCL + 50 ethyl B5 BAP Shooting – – Anuradha and
santalinus explant alcohol (3 h) (3 mg−1) + NAA Pullaiah [40]
(Fabaceae) (1 mg−1)
IAA (0.1 mg−1), Rooting
NAA and IBA
Seeds 70% alcohol (1 min), 0.1% MS NAA + BAP + Kin Shoot Garden soil and 90% Arockiasamy
HgCl2, and 0.1% sodium (0.1 + 1.0+ 1.0 mg−1) multiplication sand (1:1) et al. [55]
dodecyl sulphate (10 min)
Microshoots Distilled water ¼ MS IAA 1.0 mg−1 Rooting
Nodal 2% Bavastin (15 min), 70% MS TDZ (1.0, 2.0 and Shoot Soil rite 20% Padmalatha
ethanol (2 min), and 0.1% 3.0 mg−1) multiplication and Prasad [51]
mercuric chloride (15 min)
Seed 2% Bavistin (30 min), 70% MS KIN (2.0 mg−1) and Shoot
ethanol (2 min) and 0.1% BA (1.0 mg−1) multiplication
mercuric chloride (12 min)
Microshoots Distilled water MS basal – Rooting
Conservation Attempts of Woody Medicinal Plants of India by Biotechnological Tools

(continued)
1019
Table 1 (continued)
1020

S. No Name of the plant Explant Types of sterilant used Medium Conc. hormone Response Hardening (%) Restoration Reference
37. Celastrus Internode 25% NaOCl (10 min), 0.1% MS BA (4.44 μM) Shoot buds Sand and 80% Rao and
paniculatus mercuric chloride (10 min) regeneration farmyard manure Purohit [52]
(Celastraceae) Microshoots Distilled water ¼ MS salts IBA (2.45 mM) Rooting (1:1)
Nodal 0.1% mercuric chloride and MS NAA (0.1 mg−1) and Shoot – – Martin et al.
Tween-20 (5 min) BA (1.5 mg−1) multiplication [50]
Nodal 0.1% mercuric chloride MS BAP (1.0 mg−1) Shoot Soil and sand 70% Lal and Singh
(3–5 min) and absolute multiplication mixture (3:1) [44]
alcohol
Microshoots Distilled water ½ MS NAA (0.5 mg−1) Rooting
38. Rauwolfia Leaf Tween-20 (1 min), 60% MS NAA (5.0 mg−1) Calli induction 2:1 ratio of sterile 86% Rohela et al.
tetraphylla ethanol (2 min), 0.1% garden soil and [53]
(Apocynaceae) mercuric chloride (2 min) sand
Stem and root 0.5% Bavistin (10 min), MS NAA (5.0 mg−1) Calli induction
Tween-20 (2 min), 0.1%
mercuric chloride (4 min)
Leaf and stem Distilled water MS TDZ (0.25 mg−1) Shoot
calluses and BAP (2 mg−1) multiplication
Microshoots Distilled water MS IAA (1.0 mg−1) and Rooting
IBA (1.0 mg−1)
Y. Jeyaram et al.
S. No Name of the plant Explant Types of sterilant used Medium Conc. hormone Response Hardening (%) Restoration Reference
39. Ilex khasiana Seeds 5% Teepol (10 min), 70% MS BA (8.88 μM) and Shoot Black soil: 70% Dang et al. [43]
(Aquifoliaceae) ethanol (1 min), and 15% Kn (4.64 μM) response vermiculite: sand
sodium hypochlorite (2:1:1)
(15 min)
Cotyledonary Distilled water MS
nodal
Leaf Distilled water MS 2,4-D (9.04 μM) and Callus
BA (2.32 μM) initiation
Leaf calli Distilled water MS BA (6.63 μM) Shoot bud
proliferation
Microshoots Distilled water ½ MS IBA (9.84 μM) Rooting
40. Tylophora indica Petiole 5% Teepol (5 min), 0.1% MS 2,4-D (10 μM) and Calli induction Sterile 100% Faisal et al.
(Asclepiadaceae) HgCl2 (3 min) TDZ (2.5 μM) vermiculite [45]
Friable callus Distilled water MS TDZ (2.5 μM) Shoot
multiplication
Microshoots Distilled water ½ MS IBA (0.5 μM) Rooting
Leaf 5% Teepol (5 min), 0.1% MS 2,4,5-T (10 μM) Calli induction Sterile – Faisal and Anis
HgCl (3 min) vermiculite [46]
Leaf calli Distilled water MS Kin (5 μM) Adventitious
shoots
Microshoots Distilled water ½ MS IBA (0.5 μM) Rooting
41. Gymnema Nodal Tween-20 (3 min), 0.1% MS 2,4-D (0.5 mg−1) Calli – – Gopi and
sylvestre R.Br mercuric chloride (8 min) Vatsala [47]
(Apocynaceae) In vitro Distilled water MS BA, KIN and NAA Shoot – – Komalavalli
axillary node (91.0, 0.5 and multiplication and Rao [48]
explants 0.1 mg−1)
Microshoots Distilled water ½ MS IBA (3 mg−1) Rooting
Conservation Attempts of Woody Medicinal Plants of India by Biotechnological Tools
1021
1022 Y. Jeyaram et al.

microshoots, which devoid of hormone [44, 48, 51]. Similarly, the petiole explant of
Tylophora indica showed callus induction and shoot multiplication on MS medium
[22]. The callogenesis of leaf explant of Tylophora indica has shown better response
on MS medium with various PGRs [46]. The cell suspension culture of Gymnema
sylvestre performed better response on MS medium [47]. Martin et al. [50] reported
that nodal explant of C. paniculatus achieved bud breakage and elongation in MS
medium without growth regulator.
Celastrus paniculatus internode explants were cultured on MS medium addition
of PGRs to initiate shoot buds. Microshoots were inoculated on one-fourth MS
medium supplemented with PGRs to induced roots [52]. The leaf, stem, and root of
Rauwolfia tetraphylla were cultured on MS medium addition of PGRs to induced
calli and in vitro-derived leaf and stem calluses were cultured on MS medium with
PGRs to induce multiple shoots although microshoots were cultured on MS medium
helped to develop roots [53]. The healthy seeds of Pterocarpus marsupium and
P. santalinus were inoculated on MS medium to develop multiple shoots and micro-
shoots on one-half and one-fourth MS strength medium to induced shoots and roots,
respectively [54, 55].

4 Effect on Various Hormones or PGRs

Plant growth regulators (PGRs) are natural organic compounds that have stimulated
or inhibited the specific enzymes or enzyme systems inside plant cells and facili-
tated to regulate plant metabolism. The nodal explants of Syzygium densiflorum
were cultured on WPM supplemented with IBA (1.5 mg−1) with BAP (1.5 mg−1) and
obtained 7.7 number of shoots per explants [9]. Nothapodytes foetida leaf and stem
explants induced maximum culture response (90%) of somatic embryo germination
and regeneration on MS medium addition of TDZ (0.5–3.0 mg−1) along with coco-
nut water (20%) [10]. In vitro regenerated leaves of Zanthoxylum armatum were
soaked in distilled water (24 h) and cultured on WPM containing TDZ (15 μM) and
NAA (0.5 μM) in which TDZ (6.0 μM) combination induced 90% of calli from
explants [11]. The shoots tips and nodal explants of Gaultheria fragrantissima
induced 35 shoots per explants from medium fortified with TDZ (0.22 mg−1) [12].
Similarly, TDZ induced multiple shoots in Elaeocarpus blascoi, Pterocarpus mar-
supium, and Sterculia urens [13, 21, 56]. The leaf explants of Leptadenia reticulata
induced calli on medium addition of 2,4-D (0.5 mg−1) and combinations of NAA
(1.0 mg−1) + BAP (0.5 mg−1) induced 48% more compact calli. The leaf-derived
calli developed a greater number of shoots [30] per explants with 8.62 cm of aver-
age length from medium containing BAP (0.5 mg−1) and NAA (0.1 mg−1) [14].
Leptadenia reticulata nodal explants induced [3, 4] multiple shoots on medium con-
taining IAA (0.6 μM) and BA (9 μM) [15]. Seeds of Pterocarpus marsupium were
developed maximum (23.0) number of shoots with 5.14 cm shoot length on medium
fortified with GA3 (0.50 μM) and TDZ (0.50 μM) [16]. The in vitro raised cotyle-
donary nodal explants of Pterocarpus marsupium induced highest [15] number of
Conservation Attempts of Woody Medicinal Plants of India by Biotechnological Tools 1023

shoots per explants were obtained from medium containing TDZ (0.4 μM) [56]. In
vitro raised Rhododendron wattii nodal explants were developed maximum (7.72)
no. of shoots along with highest shoot length (2.30 cm) from WPM addition of 2iP
(39.36 μM) [57]. Atropa acuminata shoot tips and nodal explants were induced
shoot proliferation 80% with average shoot number (5.8) on medium with IBA
(1 mg−1) and BAP (1 mg−1) [18]. The nodal explants of Syzygium travancoricum
were cultured on both MS and WPM containing combinations of PGRs BA
(17.7 μM) and NAA (1.3 μM) induced 25 shoots per explant [19]. The young leaf-­
derived callus of Berberis aristata induced multiple shoots (17.6–26.5) per callus
on medium containing combinations of PGRs TDZ (0.5 μM) and NAA (2.68 μM)
with BA (8.88 μM) [20]. Tylophora indica nodal explants showed a maximum (8.6)
number of shoots with 5.2 cm of average shoot length on medium containing NAA
(0.5 μM), BA (2.5 μM) [22]. The nodal explants of Garcinia travancorica were
inoculated on MS medium fortified with BAP (4.0 mg−1) have obtained 86% of
shoot initiation and combinations of NAA (1.0 mg−1) and BAP (4.0 mg−1) induced
2.8 shoots per node with an almost equal number of shoots (1.6) and shoot elonga-
tion [23]. The half-strength WPM containing IBA induced root on Syzygium densi-
florum and Elaeocarpus blascoi [9, 13] although WPM containing IAA and NAA
induced root on Rhododendron wattii and Rauvolfia serpentina [17, 57]. Microshoots
of Pterocarpus marsupium were induced root on full-strength MS medium with
IBA [16]. Ceropegia intermedia axillary bud and nodal explants have showed maxi-
mum (5.5) shootlets on MS medium containing BA (6.66 μM) [24] although petiole
and leaf explants of Ceropegia intermedia have induced calli on MS medium forti-
fied with PGRs [62]. The cotyledonary node of Terminalia bellirica showed best
shoot proliferation (80%) on MS medium containing BAP (2.0 mg−1), and a higher
number of shootlets [5] were obtained on MS medium containing combinations of
BAP (3.5 mg−1) and KN (0.5 mg−1) [25]. Leptadenia reticulata leaf explants induced
maximum calli on MS medium with BAP (1.0 mg−1) and 2,4-D (0.5 mg−1), respec-
tively. The leaf-derived calli have induced the highest number (30 per explants) of
shoots on BAP (0.5 mg−1) and NAA (0.1 mg−1) and microshoots cultured on one-­
fourth strength MS containing IBA (1.5 mg−1) with ascorbic acid (100 mg−1) exhib-
ited (81%) rooting [14]. The cotyledonary nodes of Sterculia urens induced 4.3
shoots on MS medium containing BAP (2.0 mg−1) [58]. Nilgirianthus ciliata nodal
explants induced higher shoots [24] on MS medium containing BA (3 mg−1) and
IAA (0.1 mg−1). The microshoots developed were exhibited 82% of rooting (14
number roots) on half-strength MS medium addition of IBA (1.0 mg−1) [27]. The
nodal explants of Santalum album showed maximum no. of shoots and shoot length
on MS medium with NAA (0.53 μM) and BA (4.44 μM) responded for a maximum
of 50% of roots from microshoots on quarter-strength MS with IBA (1230 μM)
[28]. The nodal explants of Clerodendrum serratum have developed higher shoot
induction and number of shoots with higher shoot length (5.2 cm) on MS medium
containing BAP (0.5 mg−1) and maximum [7] number of root were induced from the
microshoot on MS medium with NAA (0.5 mg−1) [59]. Couroupita guianensis seeds
were germinated (100%) on a medium containing IBA (2.0 mg−1) and nodal explants
induced multiple shoots (4.1 per explants) on a medium containing BAP (4.0 mg−1).
1024 Y. Jeyaram et al.

A maximum of 8.2 shoots were induced on combinations of BAP and KIN

(1.0 mg−1) + NAA (0.5 mg−1) with additives. The microshoots were induced root
(97%) on half-strength MS medium addition of IBA (2.5 mg−1) [29]. The leaf
explants of Meizotropis pellita induced calli on medium containing 2–4, D (9.06 μM)
and 2–4, D (9.06 μM) + 2-iP (7.38 μM). The cotyledonary node of Meizotropis pel-
lita induced multiple shoots (2.5 per explants) on medium containing KN+ GA3
(4.6 μM + 1.0 μM) or BA (13.2, 17.6 μM) + GA3 (1.0 μM) and microshoots induced
the highest 8.2 number of roots on medium with IBA (4.9 μM) [30]. The nodal
explants of Commiphora wightii exhibited best shootlet response (27%) on MS
medium combined with BAP (2 mg−1) + GA3 (0.5 mg−1) [60]. The nodal explants
of Pterocarpus marsupium induced 2.26 multiple shoots from MS medium with
IBA (0.2 mg−1) [31].
The nodal explant of Decalepis arayalpathra showed shoot proliferation on 2.0
BA mg−1 and produced mean no. of shootlets (1.0). The embryos of Calamus
nagabettai were effectively grown on 0.1 mg−1 TDZ induced medium and formed 5
no. of shoots [61]. In Decalepis hamiltonii, shoot multiplication was observed on
BA (1.5 mg−1) + IAA (0.5 mg−1) with 18 ± 1.2 shoots and 11.2 ± 0.4 cm shoot
length. For rooting, the medium was supplemented with IBA (2.0 mg−1) and
observed profuse rooting [33]. Laskar et al. [32] reported that seeds of Citrus indica
have induced calli formation on 0.01 mg−1 TDZ and 0.1 mg−1 NAA and the calli
were treated for shoot multiplication in supplemented with 0.5 mg−1 BAP, 0.25 mg−1
TDZ, and 0.25 mg−1 NAA. For rooting, the microshoots were treated with 1.0 mg−1
NAA. Similarly, the seeds of Entada pursaetha showed 95% of culture response on
5.0 mg−1 BAP and the highest shooting frequency was observed on the proximal
transverse division of cotyledon. The synergistic effect of BA (0.5 mg−1) + NAA
(0.5 mg−1) promoted shootlets 9.8 ± 1.23 with shoot length 12.8 ± 0.78 [35]. The
calli formation of Cayratia pedata was observed on BAP + NAA (0.2 mg−1) [36].
The leaf explant of Mahonia leschenaultii showed shoot multiplication on
1.0 mg−1 BA and 0.02 mg−1 IAA containing medium [37]. In Vitex negundo, maxi-
mum no. of shoots (17.39 ± 0.71) was observed in 0.3 mg/l IAA + 0.3 mg/l
BAP. Similarly, the highest no. of rooting frequency was observed on 0.5 mg/l IBA
[34]. Similar studies have been done in Vitex negundo [38]. The nodal explants
showed shoot multiplication on 2.0 mg−1 BA + 0.4 mg−1 GA3 and produced 2.0 + 0.4
mean no. of shoots. The optimal rooting was observed on 1.0 mg−1 IBA and about
94% of microshoots induced rooting. The maximum no. of shoots was observed on
Caesalpinia bonduc at 17.57 μmol BAP and 2.85 μmol IBA and 2.95 μmol IBA has
induced rooting calli [39].
The high frequency of shooting in (10–15 shoots) P. santalinus was observed on
B5 medium supplemented with 3 mg−1 BAP+ 1 mg−1 NAA induced. For better shoot-
ing, the medium was fructified with 15% coconut milk exhibited 85% response.
Half-strength MS medium was supplemented with 0.1 mg−1 IAA, NAA, and IBA in
each concentration which has shown 50% rooting [40]. The in vitro-grown callus was
induced shoots on (25 shoots) BA (2.0 mg−1) + NAA (0.5 mg−1) within the 2 weeks
of observation [41]. The nodal segments of I. khasiana induced maximum shoots
(10.2 ± 0.22) on 8.8 μm BA and 4.6 μm Kn. Similarly, the leaf disc initiate callus on
Conservation Attempts of Woody Medicinal Plants of India by Biotechnological Tools 1025

9.04 μm 2, 4-D, and 2.32 μm BA in combination. For rooting, the half-­strength MS

medium was supplemented with 9.84 μm IBA showed 93.3% of response with
5.56 ± 0.11 roots [43]. Lal and Singh [44] documented a maximum no of shoots
(8.9 ± 0.5) and 100% bud breakage 1.0 mg−1 BAP. The half-strength MS medium
induced 100% rooting on 0.5 mg−1 NAA. About 90% shoot multiplication of
Tylophora indica was achieved on MS medium supplemented with 2.5 mM TDZ and
0.5 mM IBA [45]. Similar studies were carried out in Tylophora indica, in which the
leaf callogenesis was observed on 5 μM Kinetin and at 0.5 μM IBA induced rooting
on half-strength MS medium [46]. Gopi and Vatsala [47] recorded maximum callus
formation on the MS medium supplemented with 0.5 mgl−1 2, 4-D and followed by
IAA, NAA, IBA at 2.5 mg−1. Similarly, cytokinin such as 2.5 mg−1 BA and 5.0 mg−1
Kn have also shown better callusing. The multiple shoot induction of Gymnema syl-
vestre was noted on the combination of 1.0 mg−1 BA and 0.1 mg−1 Kn with average
shoot no. 6.2 ± 0.07 and shooting frequency 76 ± 2.00. The medium was supple-
mented with different extracts, among these malt extract influences the shoot multi-
plication and prevents yellowing of leaves and also effectively prevents the callus
formation at the cut end of the explant. For rooting the shootlets formation, the half-
strength MS medium was supplemented with various auxins among which 3 mg−1
IBA showed a high frequency of rooting [48]. On single cytokinin treatment, 2–3
multiple shoots were induced in P. santalinus to increase the shooting frequency with
the combination of Kn and BA. The combination of 1 mg−1 Kn and BA produced 8
shoots within 4–6 weeks and at 5 mg−1 IBA showed optimum rooting [49]. For the
shoot elongation and multiplication, MS medium was supplemented with various
hormones either alone or combination established with 1.5 mg l−1 BA and 0.1 mg l−1
NAA with mean no. of shoots 5.0 ± 1.2. At the same time, ex vitro rooting with hard-
ening was performed [50]. The combination of BA and Kn (2.0 mg−1 + 1.0 mg−1)
have induced 19–20 shoots and rooting in P. santalinus [51].
Celastrus paniculatus internode explants showed a maximum number of (3.89)
shoot bud regeneration on medium supplemented with BA (4.44 μM) and one-­
fourth MS medium addition of IBA (2.45 mM) induced maximum (80%) rooting
[52]. The stem explants of Rauwolfia tetraphylla obtained a maximum of 412.8 mg
of fresh calli on MS medium supplemented with NAA (5.0 mg−1). In vitro-derived
stem calli has showed maximum of 20 shoot buds on MS medium addition of TDZ
(0.25 mg−1) and BAP (2 mg−1) and microshoots were cultured on MS medium with
IAA (1.0 mg−1) and IBA (1.0 mg−1) to induce rooting [53]. The seeds of Pterocarpus
marsupium were cultured on MS medium supplemented with BA (3.0 mg−1) and
IAA (0.5 mg−1) inducing a maximum of 17.3 [54]. The seeds of Pterocarpus santa-
linus showed the highest number of in vitro shoots (10.4) on MS medium supple-
mented with NAA + BAP + KIN (0.1 + 1.0 + 1.0 mg−1) and microshoots induced a
maximum of 76% of rooting on one-fourth MS medium with IAA 1.0 mg−1 [55].
1026 Y. Jeyaram et al.

5 Hardening

Hardening is one of the most important steps in plant tissue culture in which the
micropropagated plants were allowed to grow under controlled environmental con-
ditions. If the plants were immediately transferred to field conditions, they will get
shock from the outside environment. Due to the inconsistency of weather and
humidity, in vitro plantlets get so much stress from the outside environment. There
are so many factors that make it difficult for plants to acclimatize outside
environment.
Seeni and Decruse [61] have standardized the micropropagation protocol of
some of the rare, endangered, and threatened plants (Decalepis arayalpathra and
Calamus nagabettai). After rooting, invitro propagated plantlets were transferred to
pots containing vermiculite and kept in the greenhouse. About 73% of the rooted
plants were reported as survived and transferred to vermiculite-containing planting
medium [59]. The agar adhered from the root of Decalepis hamiltonii were removed
and planted into the soil of the pots, and the humidity was maintained at 60–70%
and allowed to grow for 2 months. The hardening mixture contained 1:1:1 ratio of
farmyard manure, red soil, and sand [33]. The in vitro-developed plantlets of Citrus
indica were hardened with the mixture of garden soil, leaf mould compost and river
sand (1:2:3) [32]. In vitro the rooted Rauvolfia serpentina plantlets were introduced
into different planting substratum with garden soil, soil rite, and vermiculite. After
the 4 weeks of observation, 30–54 plants were reported to survive in soil rite whereas
in vermiculite 51 plants and in garden soil 30 plants were recorded as survived [17].
The in vitro-developed shootlets of Terminalia bellirica were transferred to the
vermiculite-containing polybags [25]. The leaf of in vitro-grown plantlets was
expanded after 3 weeks of observation and transferred into the mist chamber. Patiel
et al. [63] recorded that at 15 °C temperature, the plantlets of Picrorhiza kurroa
were shown 100 ± 0.00a % survival rate on the sand. Where sprayed with Hoagland
solution in a regular 12-day interval, it exhibited better growth. The rooted plantlets
of Commiphora wightii were planted in vermiculite medium wetted with Hoagland’s
solution. On primary hardening, the rooted microshoots were planted into vermicu-
lite and maintained humidity [64].
Before the introduction of in vitro-grown P. marsupium to the soil, it was trans-
ferred to the culture tubes without sucrose. After that, plants were transferred to clay
pots and 70% of the plants were survived with a high degree of uniformity [56].
Similar studies have been done by Ahmad et al. [16] in P. marsupium, in which the
rooted microshoots were transferred to a potted medium containing soil rite. To
maintain the humidity, the microshoots were covered with transparent polybags and
supplemented 16/8 h of photoperiodism. The half-strength MS liquid was watered
for 20 days followed by tape water for alternative days. The acclimatized plants
were slowly transferred to a mixture of soil rite and garden soil containing medium.
The study conducted on the micropropagation of Oroxylum indicum using different
additives was exhibited better shootlets. The rooted plantlets were immersed in dis-
tilled water for 4 days and transplanted to the sand and soil mixtures [65].
Conservation Attempts of Woody Medicinal Plants of India by Biotechnological Tools 1027

Bantawa et al. [12] have treated the microshoots of Gaultheria fragrantissima

with 500 mg−1 IBA for 30 min before transplanting. The potting mixture containing
1:1:9 farmyard, sand, and virgin soil and supplemented with one-quarter strength of
WPM liquid medium for 7 days of interval. Different potting mixtures were tried for
the hardening procedure of shootlets hardened which vermiculite, garden soil and
cocopeat (1:2:3). After biotization with endophytes, plantlets showed better growth
response [21]. Similarly, this potting mixture was effectively used for the growth of
Garcinia xanthochymus [66].
The in vitro-grown plantlets of Decalepis arayalpathra were reintroduced to the
natural habit after rooting and observed the survival rate [67]. Husain et al. [56]
reported that prior to the introduction of in vitro-developed P. marsupium into the
soil, the shoots were allowed to culture without sucrose and transferred to clay pots
and 70% of the plants were survived. On in vitro and ex vitro rooting methods on
Leptadenia reticulata, it has shown that 95% of survival rates were observed under
greenhouse conditions. The ex vitro rooted plantlets were slowly adapted to low
humidity (50–55%) and high temperature (34–36 °C), high humidity (80–85%),
and low temperature (26–28 °C) [14].
The root of Zanthoxylum armatum was washed with Bavistin to eradicate fungal
contamination. The washed plantlets were introduced into the farmyard manure and
soil (3:1) and covered with polythene bags. After 1 week of observation, the plant-
lets were transferred to the garden soil and kept in the mist chamber [11]. The simi-
lar procedure has been done for the development of in vitro-developed Rhododendron
wattii with different potting mixture [57]. Purohit and Dave [58] have reported that
to avoid desiccation, it has directly transferred to the rooting medium. The plantlets
were easily adapted to the invitro hardening condition, mixture of sand and soil
rite (1:1).
Previous studies documented that ex vitro rooted plants were easily adapted to
external environments compared to micropropagated plants. In ex vitro conditions
low humidity high temperature and vice versa were maintained [29, 68]. Some of
the researchers have documented that vermicompost and soil rite as an effective
substratum to harden in vitro-grown plantlets [38, 69] whereas soil rite alone showed
a good growth response on the plantlets [70]. Similarly, in garden soil, a significant
plant growth response was observed [22, 35, 39]. The microshoots were hardened
and 80–82% of the plantlets were successfully hardened and placed under the mist
chamber [37]. Farmyard manure, sand, and soil (1:1:3) were also used for hardening
with humidity by 60% [30]. Siva et al. [13] studied the micropropagation protocol
for E. blascoi, after the completion of the rooting procedure, the plantlets were
slowly transferred to garden soil, farmyard, and river sand mixture (1:2:1). The
hardening medium of P. marsupium has reported to filled with farmyard manure,
sand, and soil in the ratio of 1:1:1. The plantlets were maintained in the greenhouse
with relative humidity 60 ± 5% and 30 ± 2 °C temperature [31]. The rooted explants
were planted in the mixture of sand: soil: peat moss and irrigated with one-fourth
MS salt solution [25]. The garden soil, sand, and vermiculite mixture has induced
the growth of Celastrus paniculatus during hardening [71].
1028 Y. Jeyaram et al.

The in vitro-grown plantlets were directly transferred to greenhouse conditions

and irrigated quarter-strength MS medium for 2 weeks. Then, plantlets were uncov-
ered and exposed to natural light and transferred to earthen pots containing garden
soil. About 70% of the plantlets were shown rooting on sand, black soil, and ver-
miculite mixture [43]. The rooted plantlets were maintained in high humidity condi-
tions and planted in soil and sand mixture for 15 days [40]. The regenerated plantlets
of C. paniculatus were successfully transferred to autoclaved sand and soil mixture
(3:1) and sprayed with MS medium [44]. The rooted plantlets showed 100% sur-
vival rate on garden soil [44]. In the first step, the regenerated plantlets were suc-
cessfully transferred to vermiculite-containing pots and maintained the humidity of
potted plantlets with polythene bags covered. The transferred plantlets were irri-
gated at every 3 days with half-strength MS medium without sucrose. After 2 weeks
of observation, plantlets were shifted to garden soil containing pots [46]. About 100
rooted plantlets with 6–5 fully expanded leaves and well-rooted plantlets transferred
to soil were observed with normal growth [48]. The hardened plantlets of P. santali-
nus were successfully transferred to a combination of soil and sand (1:1) and about
50% of the plants were survived. The rooted plantlets were transferred to test tubes
containing water and covered with parafilm. Similarly, the plantlets transferred to
the pots were covered with plastic covers to maintain the high humidity, and 60% of
the plants were survived [49]. Martin et al. [50] reported that the simultaneous ex
vitro rooting and hardening steps were done for the development of C. paniculatus.
Among the treatments at 100 mg l−1, each of IBA and NOA and 10 mg l−1 chloro-
genic acid-treated microshoots was planted into the sand- soil containing pots. After
5 weeks, root establishment was observed and the plantlets were transferred to a
coir-containing liquid medium. The plantlets were kept in a greenhouse and 98–99%
rooting was observed. Ramasubbu and Divya [9] reported that plantlets hardened in
sand soil (1:1) were sprayed with distilled water showed a better response. Rao and
Purohit [52] reported the in vitro regeneration of shootlets of Celastrus paniculatus
was transferred to polybags with sand and farmyard manure (1:1) and kept nursery
shade conditions to grow. The in vitro-developed plantlets of Rauwolfia tetraphylla
were transplanted into a plastic pot containing a 2:1 ratio of sterile garden soil and
sand [53]. In vitro rooted plantlets of Pterocarpus marsupium were transferred into
polybag containing a mixture of sterilized soil and vermiculite (1:1) [55].

6 Restoration to the Field

To enhance the plant growth and establishment, a successful acclimatization pro-

cess has been undertaken which decreases the percentage of dead and damage of the
plant [72]. According to Ahmed et al. [16] plantlets, that complete their acclimatiza-
tion process, showed an 86.7% survival rate without morphological changes. After
3 months of hardening, the plantlets of C. paniculatus were successfully introduced
into the field conditions and obtained 70% of survival rate [71]. Karuppusamy et al.
[24] described that the gradual exposure of plantlets to the field slowly balances the
Conservation Attempts of Woody Medicinal Plants of India by Biotechnological Tools 1029

humidity. Seventy-four healthy plantlets were planted into the field and regenerated
plantlets have not shown any morphological variance. The micropropagated plant-
lets of Nilgirianthus ciliates were planted into the campus of Alagappa University
and 100% of the survival rate was obtained [27]. Mao et al. [57] reported success-
fully acclimatized plantlets were reintroduced into the natural habitats and observed
growth of the plant. Sahoo and Chand [38] have also observed after 6 weeks of
observation of plantlets produces flowers and from this experiment reported that, all
the in vitro propagated plantlets of Santalum album showed 100% of survival rate
during field transfer [28]. The nursery-grown plantlets of Mahonia leschenaultia
were planted into Vattakanal shola forests at Palani hills showed 90.6% of survival
rate [37]. Some of the endogenous fungi treated with the root of Sterculia urens
showed high potency of survival rate in field conditions [21].
The fully developed plantlets of Celastrus paniculatus were successfully trans-
ferred to field condition and about 77% of the plantlets were survived [44].
Komalavalli and Rao [48] reported that about 80–85% of the hardened plantlets of
G. sylvestre were survived in field. The ex vitro rooted plantlets were directly intro-
duced in the field condition and showed normal growth [50]. The successfully hard-
ened plantlets of S. densiflorum were planted in the natural habitat of Megamalai
Wildlife Sanctuary and Kodaikanal Wildlife Sanctuary for the better survival rate.
After 2 months of observation, leaf senescence and slow vegetative growth were
observed [9]. At monsoon season, about 100 plantlets of Decalepis arayalpathra
were planted in Kallar and Aryankavu and about 280 plantlets of Calamus nagabet-
tai were reintroduced [61]. Celastrus paniculatus were successfully planted in field
conditions and obtained 80% of survival rate [52]. The in vitro-developed plantlets
of Rauwolfia tetraphylla were transplanted on the field and obtained 86% of sur-
vival rate [53]. The in vitro plantlets of Pterocarpus marsupium were successfully
transferred to the field with 74% survival rate [54]. The in vitro rooted plantlets
were successfully transformed on the field and obtained 90% of survival rate [55].

7 Conclusion

The present review investigates the importance of woody medicinal plants and their
mass propagation. Medicinal plants are prospective sources of therapeutic medi-
cines and have a considerable role in health systems for humans and animals and
maintaining proper health. They are disappearing under exploitation for their
medicinal, ornamental, perfumery uses. However, woody trees timbers are overex-
ploited for construction of the building, agricultural implements, boat and ship
building, musical instruments, and railway sleepers. Therefore, the rare and endan-
gered woody medicinal plants urgent need their conservation. In recent years, in
vitro culture techniques have been envisaged for germplasm conservation to ensure
the survival of endangered plant species and mass multiplication for commercial
and conservation purposes.
1030 Y. Jeyaram et al.

Acknowledgments Authors are gratefully acknowledged to Science and Engineering Research

Board, Department of Science and Technology (SERB-DST), Government of India, for the finan-
cial support in our work (CRG/2019/001873).

References

1. Myers N, Mittermeier RA, Mittermeier CG et al (2000) Biodiversity hotspots for conservation

priorities. Nature 403:853–858
2. Singh JS, Singh SP, Gupta SR (2006) Ecology, environment and resource conservation.
Anamaya Publishers, New Delhi
3. Chakraverty RK, Jain SK (1984) Beautiful trees and shrubs of Calcutta. Botanical Survey of
India, Calcutta
4. Seth MK (2003) Trees and their economic importance. Bot Rev 69(4):321–376
5. Schubert TH (1979) Trees for urban use in Puerto Rico and the Virgin Islands (No. 27).
Department of Agriculture, Forest Service, Southern Forest Experiment Station, Southern
Region, National Forest System
6. Hamilton AC (2004) Medicinal plants, conservation and livelihoods. Biodivers Conserv
13:1477–1517
7. Lavanya AR, Muthukrishnan S, Kumaresan V et al (2012) In vitro micropropagation of
Hildesgardia populifolia (Roxb.) Schott & Endl., endangered tree species from Eastern Ghats
of Tamil Nadu, India. J Agric Technol 8(5):1727–1744
8. Upadhyay A, Shahzad A, Ahmad Z (2020) In vitro propagation and assessment of genetic
uniformity along with chemical characterization in Hildegardia populifolia (Roxb.) Schott
& Endl.: a critically endangered medicinal tree. In Vitro Cell Dev Biol Plant 56(6):803–816
9. Ramasubbu R, Divya C (2020) Micropropagation of Syzygium densiflorum Wall. ex Wight &
arn.: an endemic and endangered semi-evergreen tree species of the Western Ghats, India. Tree
For People. https://doi.org/10.1016/j.tfp.2020.100037
10. Khadke S, Kuvalekar A (2013) Direct somatic embryogenesis and plant regeneration from leaf
and stem explants of Nothapodytes foetida: a critically endangered plant species. Int J Plant
Anim Environ Sci 3(1):257–264
11. Purohit S, Joshi K, Rawat V, Bhatt ID et al (2020) Efficient plant regeneration through cal-
lus in Zanthoxylum armatum DC: an endangered medicinal plant of the Indian Himalayan
region. Plant Biosyst Int J Deal All Aspects Plant Biol 154(3):288–294. https://doi.org/10.108
0/11263504.2019.1610107
12. Bantawa P, Da Silva JAT, Ghosh SK et al (2011) Determination of essential oil contents and
micropropagation of Gaultheria fragrantissima, an endangered woody aromatic plant of India.
J Hortic Sci Biotechnol 86(5):479–485
13. Siva SM, Priya TA, Balasubramanian P et al (2015) In vitro regeneration of an endangered
tree-Elaeocarpus blascoi Weibel.(Rudraksha) from Southern Western Ghats, Tamil Nadu,
India. Eur J Biotechnol Biosci 3(11):62–66
14. Patel AK, Agarwal T, Phulwaria M et al (2014) An efficient in vitro plant regeneration system
from leaf of mature plant of Leptadenia reticulata (Jeewanti): a life giving endangered woody
climber. Ind Crops Prod 52:499–505. https://doi.org/10.1016/j.indcrop.2013.11.025
15. Arya V, Shekhawat NS, Singh RP (2003) Micropropagation of Leptadenia reticulate-a medici-
nal plant. In Vitro Cell Dev Biol Plant 39(2):180–185
16. Ahmad A, Ahmad N, Anis M et al (2021) Gibberellic acid and thidiazuron promote microprop-
agation of an endangered woody tree (Pterocarpus marsupium Roxb.) using in vitro seedlings.
Plant Cell Tissue Organ Cult 144(2):449–462
17. Alatar AA (2012) High frequency shoot regeneration and plant establishment of Rauvolfia
serpentina: an endangered medicinal plant. J Med Plants Res 6:3324–3329. https://doi.
org/10.5897/jmpr12.111
Conservation Attempts of Woody Medicinal Plants of India by Biotechnological Tools 1031

18. Ahuja A, Sambyal M, Koul S (2002) In vitro propagation and conservation of Atropa acumi-
nata Royle ex Lindl-an indigenous threatened medicinal plant. J Plant Biochem Biotechnol
11(2):121–124
19. Anand A, Rao CS, Balakrishna P (1999) In vitro propagation of Syzygium travancoricum
Gamble–an endangered tree species. Plant Cell Tissue Organ Cult 56(1):59–63
20. Brijwal L, Pandey A, Tamta S (2015) In vitro propagation of the endangered species Berberis
aristata DC. via leaf-derived callus. In Vitro Cell Dev Biol Plant 51(6):637–647
21. Dhiman M, Sharma L, Singh A et al (2020) Ex situ conservation using in vitro methods of an
endangered plant Sterculia urens Roxb.: a high volume trade plant for Gum Karaya. Ind Crops
Prod 158:113015
22. Faisal M, Ahmad N, Anis M (2007) An efficient micropropagation system for Tylophora
indica: an endangered, medicinally important plant. Plant Biotechnol Rep 1(3):155–161
23. Ramasubbu R, Manikandan G, Sasikala N (2016) In vitro propagation of Garcinia travanco-
rica–an endemic and endangered tree species of Western Ghats, India. Indian J Trop Biodivers
24(1):64–69
24. Karuppusamy S, Kiranmai C, Aruna V et al (2009) In vitro conservation of Ceropegia interme-
dia-­an endemic plant of South India. Afr J Biotechnol 8(17):4052–4057
25. Mehta J, Sain M, Mathuriya BL et al (2012) Rapid micropropagation and callus induction of
Terminalia bellirica Roxb.-an endangered plant. Asian J Plant Sci Res 2(3):364–368
26. Dangi B, Khurana-Kaul V, Kothari SL et al (2014) Micropropagation of Terminalia bellirica
from nodal explants of mature tree and assessment of genetic fidelity using ISSR and RAPD
markers. Physiol Mol Biol Plants 20:509–516. https://doi.org/10.1007/s12298-­014-­0247-­1
27. Ramakrishnan R, Largia MJV, Satish L et al (2017) In vitro mass propagation and conservation
of Nilgirianthus ciliatus through nodal explants: a globally endangered, high trade medicinal
plant of Western Ghats. Plant Biosyst Int J Deal All Aspects Plant Biol 151(2):204–211
28. Sanjaya MB, Rathore TS, Rai VR (2006) Micropropagation of an endangered Indian sandal-
wood (Santalum album L.). J For Res 11:203–209. https://doi.org/10.1007/s10310-­006-­0207-­x
29. Shekhawat MS, Manokari M (2016) In vitro propagation, micromorphological studies and
ex vitro rooting of cannon ball tree (Couroupita guianensis aubl.): a multipurpose threatened
species. Physiol Mol Biol Plants 22(1):131–142. https://doi.org/10.1007/s12298-­015-­0335-­x
30. Singh L, Nailwal TK, Tewari L (2013) An in vitro approach for the conservation of Meizotropis
pellita: an endangered and endemic plant. Plant Am J Plant Sci 04:1233–1240. https://doi.
org/10.4236/ajps.2013.46151
31. Tiwari S, Shah P, Singh K (2004) In vitro propagation of Pterocarpus marsupium Roxb.: an
endangered medicinal tree. Indian J Biotechnol 3:422–425
32. Laskar MA, Hynniewta M, Rao CS (2009) In vitro propagation of Citrus indica Tanaka – an
endangered progenitor species. Indian J Biotechnol 8:311–316
33. Giridhar P, Rajasekaran T, Nagarajan S et al (2004) Production of 2-hydroxy-4-­
methoxybenzaldehyde in roots of tissue culture raised and acclimatized plants of Decalepis
hamiltonii Wight & Arn., an endangered shrub endemic to Southern India and evaluation of its
performance vis-a-vis plants from natural hab. Indian J Exp Biol 42:106–110
34. Jawahar M, Ravipaul S, Jeyaseelan M (2008) In vitro regeneration of Vitex negundo L. – a
multipurpose woody aromatic medicinal shrub. Plant Tissue Cult Biotechnol 18(1):37–42
35. Vidya SM, Krishna V, Manjunatha BK (2005) Micropropagation of Entada pursaetha DC – an
endangered medicinal plant of Western Ghats. Indian J Biotechnol 4:561–564
36. Sharmila S, Ramya E, Mownika S et al (2020) Micropropagation of an endangered and
endemic medicinal plant Cayratia pedata var. Glabra. Asian J Pharm Clin Res 13(6):191–196
37. Radha RK, Varghese AM, Seeni S (2013) Conservation through in vitro propagation and resto-
ration of Mahonia leschenaultii, an endemic tree of the Western Ghats. Sci Asia 39:219–229.
https://doi.org/10.2306/scienceasia1513-­1874.2013.39.219
38. Sahoo Y, Chand PK (1998) Micropropagation of Vitex negundo L., a woody aromatic medici-
nal shrub, through high-frequency axillary shoot proliferation. Plant Cell Rep 18:301–307.
https://doi.org/10.1007/s002990050576
1032 Y. Jeyaram et al.

39. Kumar SR, Krishna V, Pradeepa K et al (2012) Direct and indirect method of plant regenera-
tion from root explants of Caesalpinia bonduc (L.) Roxb.—a threatened medicinal plant of
Western Ghats. Indian. J Exp Biol 50:910–917
40. Anuradha M, Pullaiah T (1999) Propagation studies of red sanders (Pterocarpus santalinus
L.f.) in vitro – an endangered taxon of Andhra Pradesh, India. Taiwania 44:311–324
41. Baluprakash T, Arumugasamy K, Paulsamy S et al (2011) In vitro regeneration of Exacum
wightianum Arn. (Gentianaceae)-an endemic medicinal plant from the Nilgiris, Western
Ghats. J Appl Pharm Sci 1:167–171
42. Chand S, Singh AK (2004) In vitro shoot regeneration from cotyledonary node explants of a
multipurpose leguminous tree, Pterocarpus marsupium Roxb. In Vitro Cell Dev Biol-Plant
40:464–466. https://doi.org/10.1079/IVP2004548
43. Dang JC, Kumaria S, Kumar S et al (2011) Micropropagation of Ilex khasiana, a critically
endangered and endemic holly of Northeast India. AoB Plants 11:1–7. https://doi.org/10.1093/
aobpla/plr012
44. Lal D, Singh N (2010) Mass multiplication of Celastrus paniculatus Willd: an important medic-
inal plant under in vitro conditions via nodal segments. Int J Biodivers Conserv 2:140–145
45. Faisal M, Singh S, Anis M (2005) In vitro regeneration and plant establishment of Tylophora
indica (Burm. F.) Merrill: petiole callus culture. In Vitro Cell Dev Biol Plant 41:511–515.
https://doi.org/10.1079/IVP2005674
46. Faisal M, Anis M (2003) Rapid mass propagation of Tylophora indica Merrill via leaf callus
culture. Plant Cell Tissue Organ Cult 75:125–129. https://doi.org/10.1023/A:1025084203958
47. Gopi C, Vatsala TM (2006) In vitro studies on effects of plant growth regulators on cal-
lus and suspension culture biomass yield from Gymnema sylvestre R.Br. Afr J Biotechnol
5:1215–1219. https://doi.org/10.4314/ajb.v5i12.43029
48. Komalavalli N, Rao MV (2000) In vitro micropropagation of Gymnema sylvestre – a mul-
tipurpose medicinal plant. Plant Cell Tissue Organ Cult 61:97–105. https://doi.org/10.102
3/A:1006421228598
49. Sita GL, Sreenatha KS, Sujata S (1992) Plantlet production from shoot tip cultures of red
sandalwood (Pterocarpus santalinus L.). Curr Sci 62:532–535
50. Martin G, Geetha SP, Raja SS et al (2006) An efficient micropropagation system for
Celastrus paniculatus Willd.: a vulnerable medicinal plant. J For Res 11:461–465. https://doi.
org/10.1007/s10310-­006-­0237-­4
51. Padmalatha K, Prasad MNV (2008) In vitro plant regeneration of Pterocarpus santalinus Lf
(Red Sanders): an endangered medicinal plant and important timber tree. Tree Sci Biotechnol
2(1):1–6
52. Rao MS, Purohit SD (2006) In vitro shoot bud differentiation and plantlet regeneration in
Celastrus paniculatus Willd. Biol Plant 50(4):501–506
53. Rohela GK, Jogam P, Bylla P, Reuben C (2019) Indirect regeneration and assessment of
genetic fidelity of acclimated plantlets by SCoT, ISSR, and RAPD markers in Rauwolfia tetra-
phylla L.: an endangered medicinal plant. Bio Med Res Int 2019:1–14
54. Tippani R, Vemunoori AK, Yarra R et al (2013) Adventitious shoot regeneration from imma-
ture zygotic embryos of Indian Kino tree (Pterocarpus marsupium Roxb.) and genetic
integrity analysis of in vitro derived plants using ISSR markers. Hortic Environ Biotechnol
54(6):531–537
55. Arockiasamy S, Ignacimuthu S, Melchias G (2000) Influence of growth regulators and explant
type on in vitro shoot propagation and rooting of red sandal wood (Pterocarpus santalinus L.).
Indian J Exp Biol 38:1270–1273
56. Husain MK, Anis M, Shahzad A (2007) In vitro propagation of Indian Kino (Pterocarpus
marsupium Roxb.) using thidiazuron. In Vitro Cell Dev Biol Plant 43(1):59–64. https://doi.
org/10.1007/s11627-­006-­9011-­8
57. Mao AA, Vijayan D, Singha RN et al (2018) In vitro propagation of Rhododendron wattii
Cowan—a critically endangered and endemic plant from India. In Vitro Cell Dev Biol Plant
54(1):45–53. https://doi.org/10.1007/s11627-­017-­9869-­7
Conservation Attempts of Woody Medicinal Plants of India by Biotechnological Tools 1033

58. Purohit SD, Dave A (1996) Micropropagation of Sterculia urens Roxb.-an endangered tree
species. Plant Cell Rep 15(9):704–706
59. Upadhyay S, Koche V (2015) Comparison of different medium and establishment of an effi-
cient micropropagation technique of Clerodendrum serratum L. an endangered medicinal
plant. J Environ Sci Toxicol Food Technol 1(1):27–35
60. Tejovathi G, Goswami H, Bhadauria R (2011) In vitro propagation of endangered medicinal
plant-Commiphora wightii. Indian J Sci Technol 4(11):1537–1541
61. Seeni S, Decruse SW (2007) In vitro multiplication and restoration of selected rare, endan-
gered and threatened plants of India. Seed 600:83. In vitro multiplication and restoration of
selected RET plants of India. 3rd Global Botanic Gardens Congress
62. Kashyap S, Kapoor N, Kale RD (2016) Coscinium fenestratum: callus and suspension cell cul-
ture of the endangered medicinal plant using vermicompost extract and coelomic fluid as plant
tissue culture media. Am J Plant Sci 7(06):899–906. https://doi.org/10.4236/ajps.2016.76085
63. Patial V, Sharma M, Bhattacharya A (2017) Potential of thidiazuron in improved micropropa-
gation of Picrorhiza kurroa – an endangered medicinal herb of alpine Himalaya. Plant Biosyst
151:729–736. https://doi.org/10.1080/11263504.2016.1219417
64. Kant T, Tomar UK, Prajapati S et al (2010) In vitro propagation as a viable conservation strat-
egy for Commiphora wightii, an endangered medicinally important desert tree, India. Conserv
Evid 7:94–99
65. Bansal YK, Gokhale M (2012) Effect of Additives on Micropropagation of an Endangered
Medicinal Tree Oroxylum indicum L. Vent. Recent Adv Plant In Vitro Cult 183–196. https://
doi.org/10.5772/50743
66. Patil LM, Murthy HN, Dandin VS et al (2016) Micropropagation of yellow mangosteen: a
valuable endemic tree of India. J For Res 27(1):161–165
67. Gangaprasad A, Decruse SW, Seeni S et al (2005) Micropropagation and ecorestoration of
Decalepis arayalpathra (Joseph & Chandra.) Venter – an endemic and endangered ethnome-
dicinal plant of Western Ghats. Indian J Biotechnol 4:265–270
68. Rathore JS, Rathore V, Shekhawat NS et al (2004) Micropropagation of Woody Plants. Plant
Biotechnology and Molecular Markers. Anamaya Publishers, New Delhi, India, pp 195–205
69. Sharma S, Shahzad A, Ahmad A et al (2014) In vitro propagation and the acclimatization effect
on the synthesis of 2-hydroxy-4-methoxy benzaldehyde in Decalepis hamiltonii Wight and
Arn. Acta Physiol Plant 36:2331–2344. https://doi.org/10.1007/s11738-­014-­1606-­9
70. Dalal NV, Rai RV (2001) In vitro propagation of Ochreinauclea missionis (Wall. EX G. Don),
an ethnomedicinal endemic and threatened tree. In Vitro Cell Dev Biol Plant 37(6):820–823
71. Sharada M, Ahuja A, Kaul MK (2003) Regeneration of plantlets via callus cultures in Celastrus
paniculatus willd,-a rare endangered medicinal plant. J Plant Biochem Biotechnol 12:65–69.
https://doi.org/10.1007/BF03263163
72. Ahmed S (2018) Tissue culture studies on a medicinal plant of Capparidaceae under different
biochemical conditions. IJCRT 6(4):595–598
Conservation of Endangered Medicinal
Plants by In Vitro Propagation Methods

M. V. Lakshmi, S. Jeyaraj, and T. S. Swapna

1 Introduction

Medicinal herbs grow naturally all around us, and they have been used to treat ill-
ness and maintain health for centuries by different cultures all over the world. These
easily accessible and culturally significant traditional medicines are a vital source of
livelihood for indigenous and rural populations [1]. For decades, people have used
a wide variety of medicinal plants for their survival; mainly, they have been used in
the primary healthcare system since ancient times. Present-day medications based
on traditional knowledge are developed and preserved by different indigenous com-
munities around the globe. Medicinal plant species have received scientific and
commercial attention since they have immense potential in disease prevention and
curing various diseases. Explorations on plant wealth by various research teams
result in the identification of potential medicinal plants having the efficacy to be
used in the production of plant-based medicines. World Health Organization (WHO)
stated that 80% of developing countries rely on plant-based medicines to treat vari-
ous diseases. Since the usage of medicinal plants is growing rapidly with the
increasing demand for herbal drugs, natural health products, and secondary metabo-
lites [2, 3]. However, these natural resources are declining due to human interven-
tions like habitat destruction, pesticide usage, and overexploitation.
International Union for Conservation of Nature (IUCN) is an international orga-
nization devoted to studying the impact of human interventions on nature and pro-
tecting species and habitats for their survival. The Red List of threatened species
designed by IUCN has become the popular data source on the extinction risk of
species worldwide. Database from IUCN indicates that 50,000–80,000 flowering
plant species are widely used for medicinal purposes. About 15,000 species are
already threatened [4]. Traditional practitioners mainly obtain raw drugs from

M. V. Lakshmi (*) · S. Jeyaraj · T. S. Swapna

Department of Botany, University of Kerala, Thiruvananthapuram, Kerala, India

© The Author(s), under exclusive license to Springer Nature 1035

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_42
1036 M. V. Lakshmi et al.

plants, particularly IUCN’s rare, endangered, and threatened (RET) category. It is

believed that 25% of the estimated 250,000 species of vascular plants may become
extinct within the next 50 years [5, 6].
Moreover, poor seed germination, self-incompatibility, unavailability of polli-
nating agents, and lack of knowledge on the wealth of plants increased the risk of
extinction of medicinal plants worldwide. Such loss would be irreversible if we did
not take any conservation measures at the earliest. According to Cole et al. [7], the
loss of plant species is 100–1000 times higher than the expected extinction rate, and
for every 2 years, we are losing at least one potential plant having medicinal impor-
tance. Henceforth, the conservation of medicinal plants that are at the edge of
extinction is the prime concern since efforts are to be made to sustain plant wealth.
Here, in this chapter, the importance of endangered medicinal plants and their con-
servation strategies were discussed in detail.

2 Medicinal Plants: A Valuable Source of Herbal Products

Medicinal plants have many advantages; according to one estimate, each new plant-­
derived medication is worth $94 million to pharmaceutical corporations and $449
million to society [8]. Since, in recent years, medicinal herbs that exist in nature
have received more attention from the scientific community and in the commercial
trade. According to WHO, 2015 [9], around 60,000 plant species are used medici-
nally worldwide. India is one of the mega biodiversity-rich areas, with nearly 8000
species of medicinal plants belonging to 386 families and 2200 genera of flowering
plants are the primary source of raw drugs [10]. Previous studies signify that most
medicinal plants are flowering plants consisting of 33% trees, followed by herbs,
shrubs, climbers, and lower forms like algae, ferns, and fungi [10]. In recent times,
synthetic drugs have revolutionized health care worldwide, though the majority of
people still depend on herbal medicines to treat various diseases. According to
WHO, traditional medicine is the knowledge, skill, and practices mainly based on
beliefs, theories, and experiences of different indigenous peoples in preventing and
diagnosing physical and mental illness. The most common reasons for dependence
on traditional medicines are more affordable and least side effects than synthetic
medicines [11]. Similarly, the usage of traditional medicines increases when other
practices are ineffective in treating diseases.

3 Endangered Medicinal Plants and Their Conservation

Medicinal plants are inevitable since they have been used to prevent, diagnose, and
treat various life-threatening diseases from ancient times. Pharmaceutical industries
and traditional practitioners obtain raw drugs from the leaves, roots, whole plant,
bark, fruits, and seeds that are vital for plant survival and regeneration. However,
Conservation of Endangered Medicinal Plants by In Vitro Propagation Methods 1037

deforestation, illegal trading, over-grazing, climatic disasters, and destructive har-

vesting contribute to the shortage of medicinal plants, ultimately affecting their
existence on Earth. At the same time, rare and endangered medicinal plant species
are facing regeneration failure in nature due to low germination rate, malfunctioned
floral organs, and unfavorable climatic conditions.
In 2015, IUCN added 44 Indian medicinal plants in its Red List database, of
which 18 plants were categorized as vulnerable, 16 under endangered, and 10 as
critically endangered species (Table 1). A species classified as critically endangered
faces an extremely high risk of extinction in the wild. It means that the species
population has been reduced or will be reduced by 80% within three subsequent
generations. For wild species, it is the highest risk category assigned by the IUCN
Red List. Overexploitation of medicinal plant trees like Hippophae rhamnoides and
Juniperus communis for fuelwood, medicines, and fencing is the primary reason for
their reduction in population density in the entire Indian trans-Himalaya [12, 13].
Conservation of threatened medicinal plants can be attained through various sus-
tainable utilization practices, along with the development of appropriate regenera-
tion approaches. Similarly, the review on trade regulations and their implementation,
development of cultivation packages, sustainable collection practices, habitat man-
agement, surveys, and periodic assessment become a suitable approach for conserv-
ing endangered medicinal plants [14]. Among various biotechnological approaches,
micropropagation was efficient in the augmented production of valuable secondary
metabolites and conservation of a wide range of medicinal plants, including endan-
gered, rare, and threatened plant species [15]. Even though in vitro propagation has
a wide range of applications in plant research, many medicinal plants lack cost-­
effective methods for their effective utilization. Hence, efforts must be taken to
devise efficient protocols before they are commercialized.

4 In Vitro Propagation of Various Endangered Medicinal

Plants with Pharmacological Properties

The environmental concern for conserving medicinal plants has become an urgent
focus of discussion. It has been reported that 15,000 species of medicinal plants are
globally threatened due to the loss of habitat, overexploitation, invasive species, and
pollution [4]. The commercial exploitation of medicinal plants for the requirement
of various herbal products is increasing drastically without its restoration. Plants are
described as endangered when their exploitation exceeds 95% and are likely to
become extinct in the near future. The demand for these plant products is expanding
annually at the rate of 15–25% [16]. Therefore, the sustainable use and conservation
of the existing medicinal plant wealth have become a matter of urgency. The in situ
conservation of wild genetic plant diversity in its natural habitat is one of the practi-
cal and appropriate management strategies. Nevertheless, this onsite conservation
will be difficult for the plant species that do not develop viable seeds or too minute
1038 M. V. Lakshmi et al.

Table 1 Details on Indian medicinal plants listed in Red List Database [14]
Si. Vernacular
No. Botanical name name Endemic to Status Uses
1 Aconitum Gaping Himalayan region of CE It is a poisonous plant with
chasmanthum monkshood India and Pakistan over 60 alkaloids,
glycosides, sugars, and
elements in its tuber. Roots
are employed in a variety of
ayurvedic and homeopathic
compositions after they have
been mitigated.
2 Chlorophytum White gold India CE It is effective in alleviating
borivilianum carnal desires and treating
diabetes, arthritis, and natal
and post-natal problems
3 Gentiana Himalayan North Western CE Roots and rhizomes are used
kurroo Gentian Himalaya to treat cough, stomach ache,
and fever.
4 Gymnocladus Minkling Northeast India CE It is used to cure
assamicus dermatological disorders and
to get rid of leaches. The
plant parts are used in
ethno-­medicine due to its
anthelminthic properties
5 Lilium White lily Pakistan, CE Underground bulbs are used
polyphyllum Afghanistan, and medicinally as expectorant,
India. astringent, aphrodisiac,
antipyretic, and general
debility
6 Nardostachys Indian nard Mountain range of CE Rhizomes are used to treat
jatamansi Himalaya in Nepal, epilepsy
Bhutan, Myanmar,
Southwest China,
and India
7 Saussurea Indian Jammu Kashmir and CE Roots used as an antiseptic
costus costus Himachal Pradesh in and in treating bronchial
India asthma
8 Tribulus Rajasthan and CE The whole plant is used in
rajasthanensis Gujarat in India treating fever, sterility, and
skin problems
9 Valeriana High altitude region CE Treating the diseases of eye,
leschenaultia of southern-western blood, liver, hysteria,
Ghats hypochondriasis, nervous
unrest, and emotional stress
10 Commiphora Oleo gum Dry regions of CE Used to decrease cholesterol
wightii western India and synthesis in the liver
adjoining areas of
Pakistan
Conservation of Endangered Medicinal Plants by In Vitro Propagation Methods 1039

seeds. The lack of seeds, seed dormancy, non-viable seeds, and endophytic bacterial
and fungal contamination of plant materials are the major limitations in the conven-
tional propagation method of many plants [17].
Totipotency of a cell refers to its ability to develop into a whole organism. In
plant tissue culture system, the totipotent cells are grown in synthetic media, along
with different plant growth regulators (PGR). Previous studies demonstrated the
potential of in vitro culture in raising medicinal plants. The in vitro propagation
techniques are widely used for the production of disease-free plants, genetically
improved varieties, superior genotypes, and plants with enhanced secondary metab-
olite production. Plant tissue culture techniques were established at the end of the
1960s as a probable tool for the worthwhile production of plant secondary metabo-
lites [18]. These micropropagation techniques are highly suitable for endangered,
threatened, and rare species because of their increased coefficient of multiplication
and small demands on the number of initial plants and space [19]. The use of
explants such as apical shoots and axillary buds is better for the conservation of rare
and endangered species [20]. The contamination from different sources like bacteria
and fungi should be strictly avoided for fruitful cultures of plants. The standardiza-
tion of the better combinations of macro- and microelements, vitamins, amino
acids, growth regulators in plant tissue culture studies is the most significant step for
the regeneration of these plants. Many endangered plant species having high-quality
medicinal properties were successfully conserved through different micropropaga-
tion techniques. This is preferable for germplasm conservation to ensure the sur-
vival of endangered plant species, rapid mass propagation for large-scale
re-vegetation, and genetic manipulation studies under precisely controlled physical
and chemical conditions [21]. The integrated approach of these regeneration tech-
niques contributes effective, disease-free, and value-added herbal products for
future industries.

4.1 Seed Culture

Seed culture is an in vitro method for raising sterile seedlings. So far, only a few
medicinal plants have been raised through seed culture. In particular, seeds of
orchids are very minute and hard to germinate in in vivo conditions; hence, seed
culture was found to be an apt method for the regeneration of orchids.
Ethnopharmacological studies conducted in various orchids showed that they are
very significant in treating several diseases such as skin and infectious diseases,
problems concerning the digestive tract, respiratory and reproductive organs, against
tumors, for pain relief, and for lowering fever [22]. Successful establishment of tis-
sue culture protocol for an endangered wild plant species Saussurea esthonica was
achieved from seeds [23]. The optimal conditions for the seed germination and
in vitro seedling growth of Bambara groundnut (Vigna subterranea) based on dif-
ferent culture media compositions were developed by Kone et al. [24]. In vitro
propagation is a proper method to propagate the endangered medicinal orchid,
1040 M. V. Lakshmi et al.

Dendrobium lasianthera through mature seed culture [25]. The nutrient composi-
tion of culture media for orchids is a key factor in seedling growth [26]. Hesami
et al. [27] established a detailed protocol for in vitro seed germination and callus
formation of Ficus religiosa, an important indigenous medicinal woody plant.
Shatnawi et al. [28] successfully multiplied the microshoots derived from the
in vitro germinated seeds of Achillea millefolium and Moringa peregrina in the dif-
ferent concentrations of 6-benzyl amino purine (BA). The ex vitro and in vitro
plants extract of A. millefolium and M. peregrina showed antimicrobial activity
against the selected microorganism.

4.2 Embryo Culture

In embryo culture, embryos from seeds and ovules are allowed to grow in a nutrient-­
rich medium. The plantlets develop either directly from the embryo or indirectly
through callus formation. Strychnos potatorum is a medicinally important endan-
gered forest tree effective in treating gonorrhea, leukorrhea, gastropathy, bronchitis,
chronic diarrhea, dysentery, renal and vesicle calculi, diabetes, conjunctivitis, scle-
ritis, and ulcers [29]. Embryo culture was found to be an efficient way to conserve
this medicinally important species using zygotic embryos [30]. Similarly, the
zygotic embryo was used for the in vitro culture of an endangered tree species
Givotia rottleriformis [31] and Kelussia odoratissima [32]. An efficient, reproduc-
ible protocol for the regeneration of Oroxylum indicum, an endangered and medici-
nally important forest tree was also achieved through zygotic embryo culture [33].
In 2022, Kushalan et al. [34] regenerated Curculigo orchioides an endangered
medicinal plant, through somatic embryogenesis. C. orchioides is considered to
have aphrodisiac, immunostimulant, hepatoprotective, antioxidant, anticancer, and
antidiabetic activities [35].

4.3 Callus Culture

When a differentiated tissue produces a dedifferentiated mass of callus with no

regular form, it is called callus culture. Callus can be developed from any part of the
plant by adding hormones, particularly auxins, at certain concentrations [36]. Callus
culture is categorized into embryogenic and non-embryogenic cultures. Callus-­
mediated organogenesis is a widely used technique in biotechnology to conserve
medicinal plants. The conservation of endangered plant species continues to be a
factor in the encouragement of callus culture, and it becomes a rich source of many
therapeutic compounds [37]. The in vitro regeneration of Rauvolfia serpentina
through somatic callus culture was introduced by Mitra and Chaturvedi in 1970
Conservation of Endangered Medicinal Plants by In Vitro Propagation Methods 1041

[38]. An effective regeneration protocol for an endangered and potential medicinal

plant, Thymus persicus, was achieved via in vitro callus induction and indirect
organogenesis on MS medium supplemented with varying concentrations of NAA
and 2,4-D, alone or in combination with BAP and KN [39]. Likewise, an in vitro
propagation protocol of Zanthoxylum armatum through leaf explants (via callus)
with high shoot multiplication (10.4 shoots/callus piece) and 100% rooting was
developed by Purohit et al. in 2020 [40].

4.4 Shoot Tip/Apical Meristem Culture

The propagation through meristem culture has potent biotechnological applications

for the large-scale production of plants in a relatively short span of time with reduced
contamination [41]. The meristem-derived plants are virus-free and are more advan-
tageous from a practical and pharmaceutical view [42]. The apical meristem culture
studies conducted in an endangered plant species Curculigo orchioides, resulted in
the regeneration of multiple shoots, and an average of 125 plants were obtained
from a single meristem [43]. Curculigo latifolia is another potent medicinal herb
with anticancer [44] and antidiabetic properties [45] and has the ability to inhibit the
hepatitis B virus [46]. This was brought into cultivation by collecting seedlings
from the wild, resulting in its population decline [43]. As a result, in vitro plantlet
regeneration from shoot tip cultures was established by Babaei et al. [47] for its
effective production for future cultivation. Gentiana kurroo is a critically endan-
gered medicinal herb utilized as a bitter tonic, antiperiodic, expectorant, antibilious,
anthelmintic, anticancer, immunomodulatory, anti-inflammatory, and analgesic
agent. The rapid micropropagation of G. kurroo through apical meristem has been
developed by Kaushal et al. [48]. Recently (2020), Pe et al. [49] established an
effective in vitro propagation protocol through meristem culture to produce Hosta
X virus-free and genetically stable plants of an endangered species, H. capitata,
which is endemic to Korea.

4.5 Protoplast Culture

Protoplasts are cells without cell walls, widely used for the regeneration of plantlets.
Protoplast cultures are established by the removal of cell walls either by mechanical
or by enzymatic processes [50]. Protoplast culture and plant regeneration of medici-
nally important plant Tylophora indica were attained through callus regeneration
[51]. Gentiana straminea, an important medicinal plant in Chinese traditional medi-
cine, threatened due to the uncontrolled collection and poor seed germination [52].
Later, Shi et al. [53] developed an effective protocol for the regeneration of G. stra-
minea from its embryonic calli protoplasts.
1042 M. V. Lakshmi et al.

4.6 Bud Culture

Bud culture is a type of plant tissue culture technique widely used for raising plant-
lets either through stem node (single node culture) or axillary buds (axillary bud
culture). Kaur et al. [54] have standardized a quick method for the multiplication
and conservation of Inula racemose, an endangered medicinal plant that is widely
used in traditional medicine in India and Tibet. In addition to this, it is commonly
used in pharmaceutical industries for its antispasmodic, antiasthmatic, and digestive
properties. Dohling et al. [55] established an efficient protocol (axillary bud culture)
for the rapid and large-scale regeneration of Dendrobium longicornu, an endan-
gered and medicinally important epiphytic orchid seriously threaten due to overex-
ploitation and habitat destruction in Northeast India. Nilgirianthus ciliates, a
globally endangered aromatic slender shrub of the Western Ghats with extensive
applications in Ayurveda, was also regenerated through in vitro nodal culture [56].
Lately (2021), Khan et al. [57] developed a well-defined protocol for the large-scale
callus induction of Saussurea costus using four different explants (seeds, leaf, peti-
ole, and internodes) as well as micropropagation from auxiliary buds of S. costus. A
novel method, namely the nylon bag culture system, is considered useful in increas-
ing the growth and development of Jasminanthes tuyetanhiae, a precious medicinal
herb [58]. In order to increase the population of an endangered medicinal plant
Prunus africana, Komakech et al. [59] developed a protocol for micropropagation
using nodal segment explants due to its long flowering cycle and recalcitrant seeds.
P. africana is one of the most popular medicinal plants for treating many diseases,
including prostate cancer, benign prostatic hyperplasia, erectile dysfunction, uri-
nary tract disorders, skin lacerations, kidney disease, chest pain, stomach upset,
inflammation, and as an aphrodisiac.

4.7 Somatic Embryogenesis

Somatic embryogenesis is the development of a plant or somatic embryo from a

vegetative or somatic cell. There are two ways through which somatic embryogen-
esis may occur, such as direct and indirect embryogenesis. In vitro propagation
through somatic embryogenesis has been found successful in raising many medici-
nal plants [60–63]. It has been used to regenerate Centella asiatica and Aloe bar-
badensis [64, 65]. Phellodendron amurense is a medicinal plant that belongs to the
family Rutaceae. Though it is conventionally propagated by means of seeds, the
germination rate is meager [66]. In 2009, Azad et al. [67] established a plant regen-
eration protocol via somatic embryogenesis from hypocotyl and internodal explants
of P. amurense.
An effective in vitro propagation method was developed for the micropropaga-
tion of Psoralea corylifolia through somatic embryogenesis in cell suspension cul-
ture [68]. Rhizome explants were used for in vitro plantlet regeneration of
Conservation of Endangered Medicinal Plants by In Vitro Propagation Methods 1043

Podophyllum hexandrum, a critically endangered medicinal plant, through direct

organogenesis [69]. In 2017, Kumar et al. [70] successfully developed a promising
regeneration system for Hypoxis hemerocallidea, an important medicinal plant of
South African traditional medicinal system. Lately (2021), Viola canescens, an
important, threatened medicinal herb, was regenerated successfully through somatic
embryogenesis using leaf-derived calli [71].

5 Conclusion

The wild plant populations from which most medicinal plants are collected are
under threat since they gain more scientific and economic attention around the
globe. Due to human interventions, many medicinal plant species are at the brim of
extinction. Due to commercial exploitation, traditional remedies have occasionally
become unavailable to indigenous peoples who have relied on them for years or
millennia. The study and conservation of medicinal herbs are indispensable since
they have immense potential in curing various life-threatening diseases.
Approximately 15,000 medical plant species are already on the verge of extinction
worldwide. Experts predict that the Earth loses at least one key therapeutic candi-
date every 2 years. Hence, scientists and policymakers are proposing new proce-
dures and policies to safeguard our remaining medicinal treasures in the wild
through various Governmental and non-governmental organizations’ involvement.

References

1. Roberson E (2008) Nature’s pharmacy, our treasure chest: why we must conserve our natural
heritage. Centre for Biological Diversity. www.Biologicaldiversity.Org
2. Piet JH (1952) Logical presentation of the Saiva Siddhanta philosophy. Christian Literature
Society for India, Madras
3. Nalawade SM, Sagare AP, Lee CY, Kao CL, Tsay HS (2003) Studies on tissue culture of
Chinese medicinal plant resources in Taiwan and their sustainable utilization. Bot Bull Acad
Sin 44(2):79–98
4. Pimm S, Russell G, Gittleman J, Brooks T (1995) The future of biodiversity. Science 269:347
5. Raven PH (1987) The scope of plant conservation problem worldwide. In: Bramwell D,
Hamann O, Heywood V, Synge H (eds) Botanical gardens and the world conservation strategy.
Academic, London, pp 19–20
6. Schemske DW, Husband BC, Ruckelshaus MH, Goodwillie C, Parker IM, Bishop JG (1994)
Evaluating approaches to the conservation of rare and endangered plants. Ecology 75:584–606
7. Cole IB, Saxena PK, Murch SJ (2007) Medicinal biotechnology in the genus Scutellaria. In
Vitro Cell Dev Biol-Plant 43(4):318–327
8. Mendelsohn R, Balick MJ (1995) The value of undiscovered pharmaceuticals in tropical for-
ests. Econ Bot 49(2):223–228
9. Romanelli C, Cooper D, Campbell-Lendrum D, Maiero M, Karesh WB, Hunter D, Golden
CD (2015) Connecting global priorities: b­ iodiversity and human health: a state of knowledge
review. World Health Organistion/Secretariat of the UN Convention on Biological Diversity
1044 M. V. Lakshmi et al.

10. Gopi DK, Mattummal R, Narayana SKK, Parameswaran S (2018) IUCN red listed medicinal
plants of siddha. J Res Siddha Med 1(1):15
11. Benzie IF, Wachtel-Galor S (eds) (2011) Herbal medicine: biomolecular and clinical aspects,
2nd edn. CRC Press/Taylor & Francis, Boca Raton
12. Singh RP, Gupta MK (1990) Soil and vegetation study of Lahaul and Spiti cold desert of
Western Himalayas. Indian Forester 116(10):785–790
13. Fox JL, Nurbu C, Bhatt S, Chandola A (1994) Wildlife conservation and land-use changes in
the Transhimalayan region of Ladakh, India. Mt Res Dev 14:39–60
14. Dhyani A (2015) Critically endangered Indian medicinal plants. Heritage Amruth 11:42–45
15. Singh PR, Singh LJ (2021) In-vitro propagation for improvement of medicinal plants: a review.
J Pharmacogn Phytochem 10(1):1484–1489
16. Kala CP, Dhyani PP, Sajwan BS (2006) Developing the medicinal plants sector in northern
India: challenges and opportunities. J Ethnobiol Ethnomed 2(1):1–15
17. Ramakrishnan R, Periyasamy R, Lakkakula S, Subramani P, Arockiam SR, Manikandan R
(2017) In vitro propagation and conservation of useful endangered medicinal plants with anti-
cancer activity. J Mol Biol Biotechnol 2(3):8
18. Bourgaud F, Gravot A, Milesi S, Gontier E (2001) Production of plant secondary metabolites:
a historical perspective. Plant Sci 161(5):839–851
19. Oseni OM, Pande V, Nailwal TK (2018) A review on plant tissue culture, a technique for
propagation and conservation of endangered plant species. Int J Curr Microbiol App Sci
7(7):3778–3786
20. Chokheli VA, Dmitriev PA, Rajput VD, Bakulin SD, Azarov AS, Varduni TV, Stepanenko VV,
Tarigholizadeh S, Singh RK, Verma KK, Minkina TM (2020) Recent development in micro-
propagation techniques for rare plant species. Plants 9(12):1733
21. Sharma S, Thokchom R (2014) A review on endangered medicinal plants of India and their
conservation. J Crop Weed 10(2):205–218
22. Gutiérrez RM, Orchids P (2010) A review of uses in traditional medicine, its phytochemistry
and pharmacology. J Med Plants Res 4(8):592–638
23. Gailīte A, Kļaviņa D, Ievinsh G (2010) In vitro propagation of an endangered plant Saussurea
esthonica. Environ Expe Biol 8:43–48
24. Kone M, Koné T, Silué N, Soumahoro AB, Kouakou TH (2015) In vitro seeds germination and
seedling growth of Bambara groundnut (Vigna subterranea (L.) Verdc (Fabaceae)). Sci World
J 2015:595073
25. Utami ESW, Hariyanto S, Manuhara YSW (2017) In vitro propagation of the endangered
medicinal orchid, Dendrobium lasianthera through mature seed culture. Asian Pac J Trop
Biomed 7(5):406–410
26. An J, Kim PB, Park HB, Kim S, Park HJ, Lee CW et al (2021) Effects of different growth
media on in vitro seedling development of an endangered orchid species Sedirea japonica.
Plan Theory 10(6):1193
27. Hesami M, Daneshvar MH (2018) Indirect organogenesis through seedling-derived leaf
segments of Ficus religiosa- a multipurpose woody medicinal plant. J Crop Sci Biotechnol
21(2):129–136
28. Shatnawi M, Abubaker S, Odat N, Al-Tawaha AR, Majdalawi M (2021) Antimicrobial activity
and micropropagation of some rare and endangered plants of Jordan. J Ecol Eng 22(6):151
29. Yadav KN, Kadam PV, Patel JA, Patil MJ (2014) Strychnos potatorum: phytochemical and
pharmacological review. Pharmacogn Rev 8(15):61
30. Kagithoju S, Godishala V, Kairamkonda M, Nanna RS (2013) Embryo culture is an efficient
way to conserve a medicinally important endangered forest tree species Strychnos potatorum.
J For Res 24(2):279–283
31. Rambabu M, Upender M, Ujjwala D, Ugandhar T, Praveen M, Rama Swamy N (2006) In vitro
zygotic embryo culture of an endangered forest tree Givotia rottleriformis and factors affecting
its germination and seedling growth. In Vitro Cell Dev Biol-Plant 42(5):418–421
32. Askari-Khorasgani O, Mortazaeinezhad F, Otroshy M, Golparvar AR, Moeini A (2013) Direct
regeneration of an endangered medicinal plant Kelussia odoratissima. Int J Agric Crop Sci
5(17):1969
Conservation of Endangered Medicinal Plants by In Vitro Propagation Methods 1045

33. Talari S, Penchala S, Marka R, Rudroju S, Ramaswamy N (2013) Embryo culture an efficient
tool for conservation of an endangered medicinally important forest tree Oroxylum indicum
Kurz. Int J Biotechnol Res 3:45–52
34. Kushalan S, Yathisha UG, Khyahrii SA, Hegde S (2022) Phytochemical and antioxidant evalu-
ation of in vitro and in vivo propagated plants of Curculigo orchioides. In Vitro Cell Dev
Biol-Plant 11:1–10
35. Chauhan NS, Sharma V, Thakur M, Dixit VK (2010) Curculigo orchioides: the black gold with
numerous health benefits. J Chin Integr Med 8(7):613–623
36. Almemary A (2020) Callus induction and differentiation. Future Agric 3:5–9
37. Benjamin ED, Ishaku GA, Peingurta FA, Afolabi AS (2019) Callus culture for the production
of therapeutic compounds. Am J Plant Biol 4(4):76–84
38. Mitra GC, Chaturvedi HC (1970) Fruiting plants from in vitro grown leaf tissue of Rauvolfia
serpentina Benth. Curr Sci 39:128–129
39. Bakhtiar Z, Mirjalili MH, Sonboli A (2016) In vitro callus induction and micropropagation of
Thymus persicus (Lamiaceae), an endangered medicinal plant. Crop Breed Appl Biotechnol
16(1):48–54
40. Purohit S, Joshi K, Rawat V, Bhatt ID, Nandi SK (2020) Efficient plant regeneration through
callus in Zanthoxylum armatum DC: an endangered medicinal plant of the Indian Himalayan
region. Plant Biosyst Int J Deal All Aspects Plant Biol 154(3):288–294
41. Kumar N, Reddy MP (2011) In vitro plant propagation: a review. J Forest Environ Sci
27(2):61–72
42. Rout GR, Samantaray S, Das P (2000) In vitro manipulation and propagation of medicinal
plants. Biotechnol Adv 18(2):91–120
43. Wala BB, Jasrai YT (2003) Micropropagation of an endangered medicinal plant: Curculigo
orchioides Gaertn. Plant Tissue Culture 13(1):13–19
44. Ismail MF, Abdulla NP, Saleh GB, Ismail M (2010) Anthesis and flower visitors in Curculigo
latifolia Dryand. J Biol Life Sci 1:13–15
45. Kant R (2005) Sweet proteins–potential replacement for artificial low-calorie sweeteners. Nutr
J 4(1):1–6
46. Ali MF, Ratnam W, Heng LY (2007) Genetic effects of arsenic and heavy metals pollutants on
Curculigo latifolia Lumbah. J Biol Sci 7:1155–1162
47. Babaei N, Psyquay Abdullah NA, Saleh G, Lee Abdullah T (2014) An efficient in vitro plant-
let regeneration from shoot tip cultures of Curculigo latifolia, a medicinal plant. Sci World J
2014:275028
48. Kaushal S, Sidana A, Dev K (2014) In-vitro plant production through apical meristem culture
of Gentiana kurroo Royle. J Med Plants Stud 3(1):4–9
49. Pe PP, Naing AH, Soe MT, Kang H, Park KI, Kim CK (2020) Establishment of meristem cul-
ture for virus-free and genetically stable production of the endangered plant Hosta capitata.
Sci Hortic 272:109591
50. Bjowani SS, Rasdan MK (1983) Plant tissue culture: theory and practice. Developments in
crop science, Elsevier Science Publishers, Amsterdam, The Netherlands. 1–373
51. Thomas T, Isolation D (2009) Callus formation and plantlet regeneration from mesophyll pro-
toplasts of Tylophora indica (Burm. F.) Merrill: an important medicinal plant. In Vitro Cell
Dev Biol-Plant 45(5):591–598
52. Cai Y, Liu Y, Liu Z, Zhang F, Xiang F, Xia G (2009) High-frequency embryogenesis and
regeneration of plants with high content of gentiopicroside from the Chinese medicinal plant
Gentiana straminea maxim. In-Vitro Cell Dev Biol-Plant 45(6):730–739
53. Shi G, Yang L, He T (2016) Plant regeneration from protoplasts of Gentiana straminea maxim.
Open Life Sci 11(1):55–60
54. Kaur R, Kashyap A, Majeed S, Chauhan NS (2010) In vitro propagation and conservation of
Inula racemosa Hook. F. an endangered medicinal plant of temperate origin. J Adv Lab Res
Biol 1(1):67–70
1046 M. V. Lakshmi et al.

55. Dohling S, Kumaria S, Tandon P (2012) Multiple shoot induction from axillary bud cultures of
the medicinal orchid, Dendrobium longicornu. AoB Plants 2012:pls032
56. Rameshkumar R, Largia MJ, Satish L, Shilpha J, Ramesh M (2017) In-vitro mass propaga-
tion and conservation of Nilgirianthus ciliatus through nodal explants: a globally endangered,
high trade medicinal plant of Western Ghats. Plant Biosyst Int J Deal All Aspects Plant Biol
151(2):204–211
57. Khan A, Shah AH, Ali N (2021) In-vitro propagation and phytochemical profiling of a highly
medicinal and endemic plant species of the Himalayan region (Saussurea costus). Sci Rep
11(1):1–13
58. Nam NB, Trieu LN, Vu NT, Trung LH, Tra TTH, Tram LT, Dai PH, Tung HT, Nhut DT (2022)
Micropropagation of Jasminanthes tuyetanhiae: an endemic and valuable herb in Vietnam.
Plant Cell Tissue Organ Cult 148(1):35–44
59. Komakech R, Kim YG, Kim WJ, Omujal F, Yang S, Moon BC, Okello D, Rahmat E, Nambatya
Kyeyune G, Matsabisa MG, Kang Y (2020) A micropropagation protocol for the endangered
medicinal tree Prunus africana (Hook f.) Kalkman: genetic fidelity and physiological param-
eter assessment. Front Plant Sci 11:1871
60. Camper ND, Coker PS, Wedge DE, Keese RJ (1997) In-vitro culture of ginkgo. In-Vitro Cell
Dev Biol-Plant 33(2):125–127
61. Jayanthi M, Mandal PK (2001) Plant regeneration through somatic embryogenesis and RAPD
analysis of regenerated plants in Tylophora indica (Burm. f. Merrill.). In-Vitro Cell Dev Biol-­
Plant 37(5):576–580
62. Chand S, Sahrawat AK (2002) Somatic embryogenesis and plant regeneration from root seg-
ments of Psoralea corylifolia L., an endangered medicinally important plant. In-Vitro Cell
Dev Biol-Plant 38(1):33–38
63. Tawfik AA, Noga G (2002) Cumin regeneration from seedling derived embryogenic callus in
response to amended kinetin. Plant Cell Tissue Organ Cult 69(1):35–40
64. Joshee N, Biswas BK, Yadav AK (2007) Somatic embryogenesis and plant development in
Centella asiatica L., a highly prized medicinal plant of the tropics. Hortic Sci 42(3):633–637
65. Garro-Monge G, Gatica-Arias AM, Valdez-Melara M (2008) Somatic embryogenesis, plant
regeneration and acemannan detection in aloe (Aloe barbadensis Mill.). Agron Costarric 32:41
66. Chen, S-Y, Chien C-T, Baskin JM, and Baskin CC (2010) Storage behavior and changes in
concentrations of abscisic acid and gibberellins during dormancy break and germination in
seeds of Phellodendron amurense var. wilsonii (Rutaceae). Tree physiology 30(2):275–284
67. Azad MAK, Yokota S, Begum F, Yoshizawa N (2009) Plant regeneration through somatic
embryogenesis of a medicinal plant, Phellodendron amurense Rupr. In-Vitro Cell Dev Biol
Plant 45(4):441–449
68. Baskaran P, Jayabalan N (2009) In-vitro propagation of Psoralea corylifolia L. by somatic
embryogenesis in cell suspension culture. Acta Physiol Plant 31(6):1119–1127
69. Chakraborty A, Bhattacharya D, Ghanta S, Chattopadhyay S (2010) An efficient protocol for
in vitro regeneration of Podophyllum hexandrum, a critically endangered medicinal plant.
Indian J Biotechnol 09(2):217
70. Kumar V, Moyo M, Van Staden J (2017) Somatic embryogenesis in Hypoxis hemerocallidea:
an important African medicinal plant. S Afr J Bot 108:331–336
71. Khajuria AK, Hano C, Bisht NS (2021) Somatic embryogenesis and plant regeneration in
Viola canescens Wall. Ex. Roxb.: an endangered Himalayan herb. Plants 10(4):761
Application of Biotechnology to Produce
Plant-Derived Biologically Important
Compounds

Nadia Iqbal, Sidra Nisar Ahmed, Urooj Subhan, Nageen Arif,

Humaira Saleem, and Farah Deeba

1 Introduction

1.1 Plants as Source of Bioactive Compounds

Secondary metabolites from plants are rich source of bioactive substances that have
a variety of health benefits in both humans and animals. Several distinct phyto-
chemicals can be found in plant foods such as vegetables, fruits, grains, seeds, nuts,
and legumes. Current findings on phytochemical compounds have suggested that
they could be a crucial component of disease-fighting therapeutics and preventa-
tives. These sorts of foodstuffs which include such bioactive constituents are func-
tional foods and, if ingested in a constant and continuous way via meals, would
deliver desired beneficial health effects above their natural features. Furthermore,
individuals can also get fortified nutritional supplements that provide specific bioac-
tive phytoconstituents or a collection of bioactive components. Such nutritional
materials are usually given in higher amounts than it does in a typical diet or even
in a medicinal form in order to improve the health of individuals. Polyphenolic
compounds, terpenes, alkaloids, and saponins are the four more prevalent classes of
bioactive components derived from plants [1]. Based upon the overall optimal activ-
ity, biologically active compounds are generally classed as either primary or sec-
ondary [2]. Trees and shrubs synthesize hundreds of naturally occurring substances
based on physiological phase, tissue distribution (floral and non-floral leaves, fruits,
or bark), and ambient circumstances, including natural or anthropogenic stresses.
Such molecules might play a role in the cell’s fundamental biological mechanisms,

N. Iqbal (*) · U. Subhan · N. Arif · H. Saleem · F. Deeba

Department of Biochemistry and Biotechnology, The Women University, Multan, Pakistan
S. N. Ahmed
Department of Botany, The Women University, Multan, Pakistan

© The Author(s), under exclusive license to Springer Nature 1047

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_43
1048 N. Iqbal et al.

such as regulating cellular development and growth by serving either plant growth
factors, or pheromones [3]. Among those, the much more significant aspects include
polyamines, ethylene, gibberellins, brassinosteroids, cytokinins, abscisic acid, and
auxin. Nonetheless, their primary purpose is ecologically, particularly in terms of
protecting plants from predators, microorganisms, as well as fungus [4]. Plants
defend themselves against pathogenic infection via a variety of signal transduction
pathways, which are dependent upon physiological and biochemical characteristics
(selective or adaptive defences), and proactive modifications generated by infec-
tions (active and inducible defence). The benefits of bioactive compounds are pic-
turized in Fig. 1. Substances is also produced at small levels in response to certain
circumstances, such as terpenes, while transcription could be stimulated to create
excessive proportion in response to structural destruction and pathogenic infection.
Transcription factor compounds comprise phytoalexins, pathogen-related (PR) pro-
teins, glucanases, and chitinases, whereas passively and conventional defensive
chemicals comprise glucans, terpenoids, antimicrobial activity enzymes, antifeed-
ants, and enzyme inhibitors [5]. Glycosylated and concatenated versions of phyto-
chemicals implicated mostly in defensive response enable the plants to synthesize
as well as preserve metabolites in a non-toxic state. For eliminating autoallelopathy
and manufacture active forms fast but only when required, polymerization and par-
ticular distribution (for example, in extracellular environment or even other intracel-
lular organelles) potential options [6]. Across several plants, however, de novo

physiological targets that

are unique or even many

existing medications are

being improved

therapeutic plants:
maintenance of
traditional knowledge, Bioactive Alteration of cellular
novel antibacterial
confirmation of membranes anatomy and
medicinal herbs, compounds pharmaceutical research
physiology
conservation of
biodiversity

new therapeutic interfering with the

production motivation iterative metabolic process

In various microorganisms,
halting the creation and
a possible biologically
activities of Nucleic acids
active compound target::

Poor communications in
the Norla cell

cytoplasm components
thrombosis stimulation

Fig. 1 Benefits of bioactive compounds

Application of Biotechnology to Produce Plant-Derived Biologically Important… 1049

production of antifungal agents is indeed reported throughout the course of infec-

tion. Phytoalexins were comparable to intrinsic fungicidal poisons; however, they
are highly hydrophilic in nature. Plants could also create phytoecdysones, which
also have vertebrate physiological function and can affect or trigger early insect
metamorphosis. Ultimately, they might play a part in the development of symbiotic
relationships involving advantageous fungus and lichens [7]. Several methods are
available for extracting biologically active compounds: Traditional methods of
extraction include soxhlet, maceration, and water distillation. To limit its use of
chemicals as well as provide milder extraction efficiency, researchers have been
looking into using sonication, radiation, electrical currents, pressure changes, or
supercritical fluid extraction [7]. To get a pure extraction, often known as essential
essence, moisture residues could be eliminated (EO). Secondary metabolites are
categorized into three types based on their metabolic source: phenolics, terpenes,
and nitrogen-containing chemicals. The most important of these bioactive second-
ary chemicals in terms of antimicrobial and antiaflatoxin activities have been identi-
fied [8] (Table 1).

1.2 Commercially Important Plant Metabolites

From antiquity, herbs were used for therapeutic purposes all across the earth. Plants’
therapeutic properties are determined by their phytochemical constituents, particu-
larly secondary metabolites, that are excellent sources of high-value phytochemical
compounds. Bioactive compounds have complicated chemical characteristics and
thus are created in response to internal or external of stresses in order enable plants
to execute wide range of physiological activities. They are employed in a variety of
sectors, including pharmaceuticals, aesthetics, nutritional supplements, scents,
tastes, and colours. The widespread usage of such compounds in a variety of indus-
tries has prompted researchers to concentrate their efforts on improving synthesis
utilizing plant tissue culture (PTC) technologies and maximizing comparative
advantage in the production utilizing culture system [9]. PTC approaches, which are
not affected by climate or geographic factors, would allow for continuous, scalable,
cost-effective, and practical synthesis of secondary metabolites. The aim of this
systematic review is to evaluate the benefits of employing plant cell culture, the
dispersion of major bioactive molecules in land plants, various strategies involved
in production of secondary metabolites, as well as the industrial value of chosen
naturally occurring substances [10]. Herbs always have contributed immensely in
both clinical practice and research. Plant-based components are used by about 80%
of the worldwide people for essential nutrition and exercise [11, 12]. They are high
in phytonutrients, which provide a magical capacity to treat ailments and can be
employed in a variety of industries, including medicines, aesthetics, and nutritional
supplements. Due to various their cost-effectiveness, convenience, eco-friendliness,
and projected effectiveness equivalent to increased conventional pharmacological
agents, they are receiving greater attention among some of the increasing
1050 N. Iqbal et al.

Table 1 List of biologically active metabolites from plants and their uses
Name of
plant Biologically active metabolites Uses
Datura Tropane alkaloids like hyoscyamine Rheumatoid and arthritis
stramonium scopolamine and atropine discomfort relief, hallucinating
medication, autism and anxiety
treatment, potent mind-altering
drug, anti-inflammatory, and
antibiotic
Species of Ajmaline, α-solanine, ajmalicine, solasodine, Antidote for snake bites,
Rauwolfia serpentine and reserpine, β-carboline, naturally occurring tranquillizer,
reserpiline, alstonine, rescinnamine anxiety, sleeplessness, seizures,
and schizophrenic
Ephedra Proanthocyanidins include eucodelphinidin, Hunger suppressing,
leucopelargonine, leucoanthocyanidin, psychostimulants, asthmatic
lucenine, vicenin-1, and vicenin-2; ephedrine prophylactic, spine anaesthesia-­
alkaloids include 1-ephedrine, induced nasal congestion and
d-pseudoephedrine, norephedrine, hypotension, and urine discharge
norpseudoephedrine, methylephedrine, and
methylpseudoephedrine
norephedrine, norpseudoephedrine,
methylephedrine, and
methylpseudoephedrine; and flavonoids
include eucodelphinidin, leucopelargonine,
leucoanthocyanidin, lucenine, vicenin-1, and
vicenin-2
Ginkgo Ginkgo biloba is a type of plant that grows in Anti-inflammatory, antidiabetic,
biloba the United States. antihypertension,
Isorhamnetin, isorhamnetin, quercetin, antihypertension,
kaempferol bilobalide, ginsenoside, antihypertension,
ginkgolide A, B, C, quercetin, bilobalide, antihypertension, and malignancy
ginkgolide A, B, and C
Saussurea Flavonoids, phytosterols, triterpenoids, Anti-inflammatory,
medusa lignans, phenolics, gallic acid, syringin, antithrombotic, anticancer,
chlorogenic acid, ethyl gallate, rutin, immunosuppression,
isoquercitrin, gallic acid, syringin, antispasmodic, antibacterial,
chlorogenic acid, ethyl gallate, rutin, anticonvulsant, and antioxidative
isoquercitrin, and sesquiterpenoids
Thymus Rosmarinic acid, borneol, geraniol, carvacrol, Antibacterial, anti-HIV-1 action,
species thymol, α-terpineol carotenoids antispasmodic, neuroprotective,
antihypertensive,
hypocholesterolemic, strong
antioxidant ability, and flavor
enhancer ingredient
Stevia Essential oils, stevioside, steviol rebaudioside Diabetic treatment, coronary
rebaudiana heart disease, cancers, kidney
disorder, overweight, irritable
bowel syndrome treatment, and
periodontal disease treatment
(continued)
Application of Biotechnology to Produce Plant-Derived Biologically Important… 1051

Table 1 (continued)
Name of
plant Biologically active metabolites Uses
Maclura Isoflavones (scandenone and auriculasin), Cardiac activities, insecticidal,
pomifera prenylated isoflavones (osajin and pomiferin) synthetic dye, abrasive,
antimicrobial, and fungistatic
properties
Citrullus Saponins, steroids, alkaloids, and flavonoids Diabetic treatment, coronary
colocynthis heart disease, cancers, kidney
disorder, overweight, irritable
bowel syndrome treatment, and
periodontal disease treatment
Bacopa Triterpenoid saponins like bacosides Neural relaxant, memory
monnieri enhancer, anticonvulsant,
gastroprotective, free radical
scavenging
Commiphora Monoterpenoids, sesquiterpenoids, Infection, arthritis, rheumatism,
wightii diterpenoids, triterpenoids, steroids, overweight, and lipid metabolic
flavonoids, guggultetrols, and lignans are all abnormalities can all be treated
found in Commiphora wightii
Punica Pelletierine, ellagic acid, phenol, and Anticancer, antiheart illness,
granatum flavonoid are examples of flavonoid antidiabetes, and oral treatment,
compounds immune-modulating properties

population [13, 14]. As a result, pharmacodynamics, phytochemical constituents,

and agriculture have received the majority of study interest on medicinal herbs to
present. The growing demand for these kind of commodities has necessitated the
development of ways to increase output without affecting the wild population [10].
The preference of mainstream consumers for natural chemicals over synthesized
bioactive molecules contributes toward the utilization of bioactive molecules
derived from natural products. Numerous innovative nutritional and pharmacologi-
cal chemicals come from microalgae. Thus far, almost 15,000 new algae chemicals
have been discovered. Carotenoids, fatty acids, enzymes, peptides, toxins, and ste-
rols, for example, are pharmacologically active substances. Astaxanthin, cryptoxan-
thin, canthaxanthin, lutein, and zeaxanthin are significant algal carotenoids.
Numerous factors influence their formation, which includes nutritional supplemen-
tation, light, temperature, and pH. Methods have been proposed nonstop to improve
algae growing conditions in order to increase the efficiency and competitiveness of
these high-value combinations and make them more affordable to consumers.

1.3 Benefits of Using Plant Secondary Metabolites

Plant secondary metabolites (PSM) have been the subject of discussion in the
research world due to their supposed antiparasitic characteristics. Despite a long
history of indigenous medicinal awareness of the therapeutic and preventive
1052 N. Iqbal et al.

activities of plant secondary metabolites rich preparations, scientific proof of PSM’s

antiparasitic benefits is inconclusive. Some reasons of this dispute are discussed in
the opening section of this study, as well as the evidence presented on antiparasitic
properties of plants secondary metabolite. Plant secondary metabolites have anti-
parasitic effectiveness targeting parasitic worms. Increased plant secondary metab-
olites use can harm herbivore performance and survivability due to its antinutritional
characteristics. As a result, it is recommended that antiparasitic and antinutritional
activities of plant secondary metabolites be evaluated simultaneously. While evalu-
ating these features, relatively similar measurement, such as parasitized host effec-
tiveness, should be employed. The cost-benefit analysis indicates that parasitized
herbivores can advantage through long-term plant secondary metabolites ingestion
unless the antiparasitic advantages surpass the antinutritional factor costs.
Furthermore, parasitized animals may gain from plant secondary metabolite inges-
tion even if their performance is affected, as long as the latter is a positive effect.
Bioactive molecules provide protection against oxidative stress, wounds, ultraviolet
irradiation, and ozone, as well as allowing plants to respond to constant changes in
the external environment. Bioactive compounds are formed mostly from primary
metabolites including such amino acids and glucose(carbohydrates) that have
undergone addition of methyl group, hydroxylation, glycosylation, or oligomeriza-
tion [15]. Natural compounds, particularly phenylpropanoids and associated metab-
olites, appear to be rich source of antioxidants which actively neutralize reactive
oxygen species and reactive nitrogen species (ROS/RNS), according to growing
data. The maintenance of biological processes requires a delicate balance among
oxidative and antioxidative mechanisms. Increased reactive oxygen and nitrogen
species generation within organisms production of reactive oxygen species, cell
death, and programmed cell death or destruction [16]. Cellular injury is reduced
when reactive oxygen and nitrogen species are detoxified through enzymatic or
non-enzymatic defenders [17]. The antioxidant potential of 5 phenolics and flavo-
noids isolated from the persistent plant Ballota nigra (i.e., verbascoside, forsytho-
side, and caffeoyl malic acid) against superoxide, H2O2, chlorine oxide, and
hydroxide ions produced in cell-free mechanisms was evaluated [18]. Those phen-
ylpropanoids had powerful antioxidant properties comparable to N-acetyl cysteine,
a well-known scavenger because of its exceptional impact on human beings includ-
ing antitumor, free radical scavenging, antiviral, and anti-inflammatory compounds;
secondary bioactive molecules are becoming the subject of intense investigation
[19]. These chemicals, on the other hand, are mostly extracted from a variety of
plant lysates and cultured cells of plant at a high costs and productivity.
Pharmacologically manufacturing these compounds is both costly and difficult. As
a result, new, accurate, and cost-effective strategies for order to enhance the effi-
ciency of biologically active secondary metabolites are urgently needed [20].
Cyanobacteria have a number of characteristics that contribute to making them pal-
atable representatives for the biosynthetic pathways of secondary metabolites in
plants, including photosynthetic capacity, genetically engineered potential, as well
as the ability to thrive in extreme conditions. The capability of soil to promote the
survival of animals and plants behind and in front of earth, as well as ecological
Application of Biotechnology to Produce Plant-Derived Biologically Important… 1053

integrity, encompassing water and air, is described as soil health. Mechanical, bio-
chemical, and biological factors of soil are all interconnected. The physical and
chemical properties as well as the soil microbiology are influenced by physical
hierarchy, which in turn determines metabolic processes. Chemical qualities com-
prise cation-exchange capability, pH, saltiness, vitamins and nutrients, as well as
morphology, smoothness, permeability, and bulk density. Plant biodiversity is lost
as a result of agricultural practices that impair plant physiochemical complexity and
ground biodiversity [21]. The benefits of secondary metabolites to plants were
explained in Fig. 2.

1.4 Strategies for Improving Production or

Secondary Metabolites

Transgenesis (additionally called genetic transformation or genetic engineering) is

the most current step to increase genetic variability available in the crop. Transgenesis
targets to introduce, via special strategies, a particular gene (covered in a gene con-
struct) from a donor species into the genome of a host species. Organisms as a
consequence of transgenesis are usually referred to as genetically modified organ-
isms (GMOs). Transgenesis is getting used to introducing an extensive variety of
the latest agronomic, processing, and dietary developments into the main agricul-
tural and vegetable crops. In contrast to embryo rescue and protoplast fusion, trans-
genesis is not restricted through reproduction limitations. Genes can be transferred
from one realm into some other. Furthermore, only the particular gene construct is
introduced within the host organism. This offers excellent precision and rapidity to
the enhancement method. Transgenesis is a totally promising device for the devel-
opment of recent types with precise traits that are not present in the crop gene
pool [22].

Plant secondary
metabolites
involved in
protection against
parasites and fungal
infection

herbivores: Insects,
microbes/viruses: UV- protection and
molasses and competing plants attraction
bacteria and fungi N-storage
vertebrates

polinating insects,
inhibition of seed dispersing
Repellence, toxicity, growth inhibition
germination and animals, root nodule
growth inhibition and toxicity
growth of seedings bacteria and
adapted herbivores

Fig. 2 Benefits of using plants secondary metabolites

1054 N. Iqbal et al.

Numerous genome-editing tools including transcription activator-like effector

nucleases (TALENs), zinc-finger nucleases (ZFNs), and meganucleases (MNs)
have enabled plant scientists to control favored genes in crop vegetation. But these
strategies are costly and exhausting related to complicated techniques for successful
editing. Conversely, CRISPR/Cas9 is an entrancing, easy-to-design, fee-powerful,
and flexible tool for specific and efficient plant genome editing. In recent years, the
CRISPR/Cas9 system has emerged as an effective tool for targeted mutagenesis,
which includes single base substitution, multiplex gene editing, gene knockouts,
and regulation of gene transcription in plants. As a consequence, CRISPR/Cas9-­
primarily based genome editing has validated outstanding capacity for crop
improvement; however, regulation of genome-edited plants remains in its infancy.
Here, we considerably reviewed the supply of CRISPR/Cas9 genome-enhancing
tools for plant biotechnologists to target favored genes and its great applications in
crop breeding research. There are three kinds of modifications produced through
genome editing: type I involves altering some nucleotides, type II includes substi-
tute an allele with a pre-existing one, and type III permits for the insertion of latest
gene(s) in predetermined regions in the genome. Due to the fact maximum genome-­
modifying strategies can leave behind traces of DNA alterations obvious in a small
quantity of nucleotides, crops created by gene editing could avoid the stringent
regulation strategies generally related to GM crop improvement. For that reason,
many scientists consider plants improved with more specific gene editing strategies
could be more desirable to the public than transgenic plants. With genome editing
come the promise of recent plants being developed more rapidly with a very low
risk of off-target outcomes. It may be done in any laboratory with any crop, even
people who have complicated genomes and are not easily bred the use of traditional
techniques [23]. The various techniques and its applications are discussed in Table 2.
Classical Biotechnology and Current Next-Generation Sequencing (NGS)
techniques were correctly used to optimize plant-derived herbal products of bio-
medical importance. In advance, protein primarily based enhancing tools, viz. zinc-­
finger nucleases (ZFNs) and transcription activator-like endonucleases (TALENs)
have been popularized for transcriptional level genome manipulation. Clustered
often interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9)
endonuclease device is an effective, strong, and selective site-directed mutagenesis
method for RNA-guided genome-modifying. CRISPR/Cas9 genome-editing tool
employs designed guide-RNAs that identifies a three base-pair protospacer adjacent
motif (PAM) sequence occurring downstream of the target-DNA. The existing
review comprehensively complies the latest literature (2010–2020) retrieved from
scientific databases on the application of CRISPR/Cas9-enhancing tools as effective
genome-editing techniques in medicinal plants discussing the latest developments,
challenges, and future perspectives with notes on broader applicability of the tech-
nique in plants and lower organisms. In plants, CRISPR/Cas editing has been
applied effectively in terms of crop yield and stress tolerance. But very few medici-
nal plants were edited the use of CRISPR/Cas genome device due to the shortage of
entire genome and mRNA sequences and shortfall of appropriate transformation
and regeneration techniques. However, currently some of plant secondary metabolic
Application of Biotechnology to Produce Plant-Derived Biologically Important… 1055

Table 2 Different techniques and its applications

Different techniques Applications
Cluttered tissues Tissue clonal variability, mass production of plants in the lab,
regeneration of seedlings during planting
Nucleic acid isolation and Biotech, diagnostics, and molecular genetics
purification
DNA and RNA Determination of DNA and RNA size, recovery and purifying of
electrophoresis nucleotide sequences, study of PCR results in molecular diagnosis,
and fingerprinting
The use of markers Hereditary of plants and animals
(marker technology)
Protein purification and Commercialized items including enzymes, dietary proteins, and
isolation biopharmaceuticals are prepared using this method
PCR-based gene Diagnostics, criminology, and contagious disorders all benefit from
amplification gene amplification by PCR
Technology based on Food, drinks, fabrics, and cleansers are all products that use enzyme
enzymes technology
Protein electrophoresis Protein extraction and characterization by electrophoresis
Micropropagation Enables the generation of disease-free plants and the regeneration of
genetically manipulated cells
Genomic fingerprinting Criminology, medical diagnoses, maternity determination, and
archaeology all use genomic fingerprinting
Recombinant DNA Pharmaceuticals, biological and biomedical screening facilities,
agricultural biotech all use recombinant DNA

pathways (viz. alkaloid, terpenoid, flavonoids, phenolic, saponin, etc.) had been
engineered using CRISPR/Cas editing through knock-out, knock-in, point muta-
tion, fine-tuning of gene expression, and targeted mutagenesis. This genome-­
enhancing tool similarly extends its applicability by incorporating the tools of
artificial and systems biology, useful genomics, and NGS to produce genetically
engineered medicinal plants with advanced trends facilitating the production of
pharmaceuticals and nutraceuticals [24].
To resolve discrepancies in species identification and taxonomy, DNA-based
technologies such as PCR, RFLP, AFLP, RAPD, and genotyping may be used.
Biologically active compounds (alkaloids, flavonoids, terpenoids, etc.) can be pro-
duced in vitro using plant organ and tissue culture procedures under controlled con-
ditions. Recombinant DNA techniques can be utilized to manipulate metabolic
pathways and create protein medicines such as antibodies and hormones.
Bioinformatics and genomics, two new sciences, can be used to identify new drugs
using plant-based materials. Biotechnological strategies, we conclude, can improve
and strengthen medicinal plant research.
1056 N. Iqbal et al.

1.5 Approaches for Producing Bioactive Chemicals via

Genetic Engineering

Agricultural biotechnology continues to generate advantageous goods or services,

such as unique bioactive phytochemical compounds, flavones, and polyphenolic,
saponins, terpenoids, steroids, glycosides, tannins, volatile oils, and several others,
from plant cells, tissue samples, or organs cultured unbiased of environmental and
geographical factors under aseptic conditions. Medicines (pharmaceuticals), fla-
vors, fragrances (perfumes), pigments (dyes), herbicides and pesticides, aesthetics,
dietary supplements, and other bioactive molecules are all economically signifi-
cant [25].
For the generation of bioactive metabolites of secondary metabolic origin, many
approaches such as genetic alteration of plant life using A. tumefaciens rhizogenic,
hairy roots, and others may be used. Strategies based on recombinant DNA can be
employed to enhance metabolic processes and create protein medicines such as
immunoglobulin and hormones [26]. Bioinformatics and genetics can be used to
discover new drugs from plant-based compounds, and biotechnological methodolo-
gies can help to improve and expand indigenous medicinal research. Genetic bio-
technology studies and modifies nucleic acids and proteins in the lab for implications
in humans and livestock, farming, and the ecosystem [27].

1.6 Biotechnology and Bioactive Compound Production,

as Well as Molecular Biotechnology Techniques

Alkaloids, flavonoids, and other phenolic compounds, saponins, terpenoids, ste-

roids, glycosides, tannins, unstable oils, and other bioactive secondary metabolites
are all produced by plants. Tablets (prescribed medications), flavors, perfumes (fra-
grances), pigments (dyes), agrochemicals as well as cosmetics, food components,
and other uses for secondary bioactive compounds are among the most common.
Because in vitro production of these substances at a commercial level is challenging
due to sophisticated chemical compositions and complicated biochemical pro-
cesses, the majority of those metabolites are acquired from plant life. Biotechnology
provides a valuable tool for supplying required quantities of chemicals in an envi-
ronmentally responsible manner [28]. Callus, suspension, immobilized cells, and
differentiation cultures are the four most essential procedures used in this method.
Callus culture is the process of cultivating a disorderly mixture of cell from plant
plantlets on a semi-solid substrate that includes essential minerals and any hor-
mones needed to stimulate cell growth. When a callus is immersed in liquid nutrient
medium and developing cells as a dispersed cell subculture, suspension cultures are
formed. Suspension cultures are widely used in the research of pharmacological
bioactive compound synthesis by plant cells because of their rapid development.
Bioactive compounds have biotechnological importance because numerous of
them are economically valuable synthetic chemicals, certain of them seem to be
Application of Biotechnology to Produce Plant-Derived Biologically Important… 1057

harmful and must be removed from food, and they act as plant defenders against
insects, diseases, and foragers. The following is a summary of the various goals
achieved/achievable through the use of plant biotechnology: (1) synthesis of advan-
tageous biochemicals (massive-scale cell cultures), (2) through use of biomarkers
and genomic maps to aid traditional breeding efforts, (3) rapid clonal multiplication
(haphazard shoot/bulb/protocorm), (4) generation of haploids to develop homozy-
gous lines quickly (anther culture, ovary culture, interspecific hybridization), (5)
hybrid manufacturing that is hard to procure (embryo rescue, pollination), (6)
removal of the virus (thermotherapy, cryotherapy, or chemotherapy coupled with
meristem culture), (7) plants that reproduce vegetative propagation or that produce
refractory seeds must have their germplasm conserved (cryopreservation and DNA
clones), and (8) vegetational genetic modification (soma clonal variant, somatic
hybridization, and gene transfer).
Advantages of Tissue Cultures in Production of Useful Bioactive Compounds
In vitro propagation has become a dependable approach for mass synthesis of plant
material as the demand for innovative goods generated from plant life has risen.
These and a number of additional advantages of using plant cell culture for huge
quantity of critical bioactive chemicals at the industrial stage provide encourage-
ment for its application. The following are a few of the advantages:
(a) Plant-cultured cells are unaffected by environmental factors.
(b) Cellular cultures gain by synthesizing bioactive secondary metabolites and
going on walks in a controlled setting, regardless of climate or soil conditions.
(c) Production phases can be more geared, as they should be in accordance with
market demand.
(d) By utilizing defined cell strains, a higher level of product production and yield
could be preserved.
(e) Because our understanding of the biosynthesis pathways of popular phyto-
chemicals in plants and cultures is frequently still in its infancy, solutions that
are primarily centred on a cellular and microscopic level were required.
(f) These findings suggest that plant cellular cultures in vitro have the capacity to
produce secondary metabolites in industrial quantities.
(g) Cellular lifestyles will reduce strain on already overharvesting pharmaceutical
and other commercially important plant life. Use of in vitro propagation for the
synthesis of organic compounds and prescription medications has made huge
leaps forward in plant research.
(h) The increased use of herbal products for medical purposes, along with low
product yields and plant harvest supply concerns, has reignited interest in large-­
scale plant cellular culture technologies.
(i) The development of more modern molecular biology technologies for produc-
ing transgenic cultures and controlling the translation and regulation of biosyn-
thesis pathway is also likely to be a key step toward creating biological cultures
more widely applicable for secondary metabolite production.
(j) From mutant cellular lines, new synthesis methods may be discovered, poten-
tially leading to the development of novel products [28].
1058 N. Iqbal et al.

1.7 Current and Future Perspectives

Despite more focused efforts and intelligent techniques to enhance value to the
country’s herbal sector, the preferred production has not yet reached its maximum
potential. Despite this, the key challenging scenarios such as a lack of great research
documentation, monographs, uniformity in farming practices (excellent agricultural
practices, gap), good laboratory practice (GLP), and product enhancement and
commercialization persist. Furthermore, increased medicinal herb harvesting raises
concerns about plant extinction and deterioration of medicinal herb habitat, result-
ing in a shortage of plant raw materials, which could stymie efforts to achieve
excessive mass manufacture of secondary metabolites. Biotechnological pro-
grammes, in combination with plant tissue cultures, have been identified as an alter-
nate technique for scaling up secondary metabolite synthesis [29]. This includes
knowledge of naturally occurring substances and their biochemical functions, selec-
tion of the highest-yielding populations, specific genomic expression and regulating
enzyme management, and the use of cost-effective sterile bioreactors. A continuous
effort from the government, academia, and business to further nourish and sustain
the herbal sector is critical, leveraging the country’s wealth of plant species.
Certainly, the characteristics and dynamics of PSM-purposeful microbiome interac-
tions in maximum economic crops are still unknown. A few economically important
plants, such as ginger and garlic, can be used as models to study such interactions
and improve the synthesis of the ideal metabolites allicin and curcumin for com-
mercial purposes. Certainly, understanding the connection between economic crop
PSMs and useful microbiome can lead to stepped-forward agricultural practices that
enhance plant fitness and increase the yield of useful secondary metabolites [30, 31].

References

1. Zhao Y, Wu Y, Wang M (2015) Bioactive substances of plant origin. In: Cheung PCK, Mehta
BM (eds) Handbook of food chemistry. Springer Berlin Heidelberg, Berlin/Heidelberg,
pp 967–1008
2. Sharma M et al (2019) Metabolic engineering strategies for enhancing the production of
bio-active compounds from medicinal plants. In: Natural bio-active compounds. Springer,
Singapore, pp 287–316
3. Depuydt S et al (2016) How plant hormones and their interactions affect cell growth. In:
Molecular cell biology of the growth and differentiation of plant cells. CRC Press/Taylor &
Francis, Boca Raton, p 174
4. Mithöfer A, Maffei ME (2017) General mechanisms of plant defense and plant toxins. In:
Plant toxins. Springer, Dordrecht, pp 3–24
5. Walters D (2011) Plant defense: warding off attack by pathogens, herbivores and parasitic
plants. John Wiley & Sons. New York, United States.
6. Chaves Lobón N, de la Cruz IF, Gallego JCA (2019) Autotoxicity of diterpenes present in
leaves of Cistus ladanifer L. Plants 8(2):27
7. Ghasemzadeh A, Ghasemzadeh N (2011) Flavonoids and phenolic acids: role and biochemical
activity in plants and human. J Med Plant Res 5(31):6697–6703
Application of Biotechnology to Produce Plant-Derived Biologically Important… 1059

8. Giannenas I et al (2013) Essential oils and their applications in animal nutrition. Med Aromat
Plants 2:140. https://doi.org/10.4172/2167-­0412.1000140
9. Chandran H et al (2020) Plant tissue culture as a perpetual source for production of industrially
important bioactive compounds. Biotechnol Rep (Amsterdam, Netherlands) 26:e00450
10. Schulz V, Hänsel R, Tyler VE (2001) Rational phytotherapy: a physician’s guide to herbal
medicine. Psychology Press, London
11. Winter JM, Tang Y (2012) Synthetic biological approaches to natural product biosynthesis.
Curr Opin Biotechnol 23(5):736–743
12. Yuan H et al (2016) The traditional medicine and modern medicine from natural products.
Molecules 21(5):559
13. Nasri H et al (2014) New concepts in nutraceuticals as alternative for pharmaceuticals. Int J
Prev Med 5(12):1487
14. Atanasov AG et al (2015) Discovery and resupply of pharmacologically active plant-derived
natural products: a review. Biotechnol Adv 33(8):1582–1614
15. Crozier A et al (2006) Phenols, polyphenols and tannins: an overview. In: Crozier A, Clifford
MN, Ashihara H (eds) Plant secondary metabolites: Occurrence, structure and role in the
human diet. Wiley Online Library, John Wiley & Sons Publisher, Hoboken, New Jersey, pp
1–25. https://doi.org/10.1002/9780470988558.ch1
16. Douglas CJ (1996) Phenylpropanoid metabolism and lignin biosynthesis: from weeds to trees.
Trends Plant Sci 1(6):171–178
17. Eriksen NT (2008) The technology of microalgal culturing. Biotechnol Lett 30(9):1525–1536
18. Fraga CG et al (2010) Basic biochemical mechanisms behind the health benefits of polyphe-
nols. Mol Aspects Med 31(6):435–445
19. Gustafsson C (2009) Tools designed to regulate translational efficiency. In: Smolke C (ed) The
metabolic pathway engineering handbook: tools and applications. Boca Raton, FL, CRC Press,
678. http://dx.doi.org/10.1201/9781420077667.ch9
20. Jacobsen JH, Frigaard N-U (2014) Engineering of photosynthetic mannitol biosynthesis from
CO2 in a cyanobacterium. Metab Eng 21:60–70
21. National Research Council (2010) Toward sustainable agricultural systems in the 21st century.
National Academies Press, Washington, DC
22. Abdallah NA, Prakash CS, AG MH (2015) Genome editing for crop improvement: challenges
and opportunities. GM Crops Food 6(4):183–205. https://doi.org/10.1080/21645698.201
5.1129937. PMID: 26930114; PMCID: PMC5033222
23. Razzaq A, Saleem F, Kanwal M, Mustafa G, Yousaf S, Imran Arshad HM, Hameed MK,
Khan MS, Joyia FA (2019) Modern trends in plant genome editing: an inclusive review of
the CRISPR/Cas9 toolbox. Int J Mol Sci 20(16):4045. https://doi.org/10.3390/ijms20164045.
PMID: 31430902; PMCID: PMC6720679
24. Titanji VP, Ngwa AA, Ngemenya M (2007) Applications of biotechnology techniques to the
study of medicinal plants. Afr J Med Med Sci 36(Suppl):23–29
25. Atsmon J, Brill-Almon E, Nadri-Shay C (2015) Preclinical and first-in-human evaluation of
PRX-105, a PEGylated, plant-derived, recombinant human acetylcholinesterase-R. Toxicol
Appl Pharmacol 287:202–209
26. Karuppusamy S (2009) A review on trends in production of secondary metabolites from higher
plants by in vitro tissue, organ and cell cultures. J Med Plants Res 03:1222–1239
27. Alamgir ANM (2017) Therapeutic use of medicinal plants and their extracts. Pharmacognosy.
In: Rainsford KD (ed) Progress in drug research, vol 73. Springer, Cham, pp 403–426
28. Barker LR, Burton JR, Zieve PD (1995) Principles of ambulatory medicine. Williams &
Wilkins, Baltimore, pp 803–843
29. Schmidt TJ, Khalid SA, Romanha AJ, Alves TM, Biavatti MW, Brun R, Da Costa FB (2012)
The potential of secondary metabolites from plants as drugs or leads against protozoan
neglected diseases. Curr Med Chem 15:2176–2228
30. Pang EL, Loh H-S (2016) Current perspectives on dengue episode in Malaysia. Asian Pac J
Trop Med 9:395–401
31. O’Brien J, Wright GD (2011) An ecological perspective of microbial secondary metabolism.
Curr Opin Biotechnol 22:552–558
Appraisal of Medicinal Plants
for Pharmacological Properties

Mehmet Zeki Kocak and Mustafa Güven Kaysim

1 Introduction

1.1 Medicinal Plants: What Are the Major Concerns

and Differences from Other Crop and Non-crop Plants?

Generally, various plant species served as important natural resources in both tradi-
tional and modern medicine all over the world. The medicinal uses of plants and
herbal products have been known for thousands of years [1–3], and medicinal plants
have been playing an important role in the development of human culture since his-
tory as well as its in rural areas of advanced countries have been used as main source
of treatment of diseases [4–6]. In addition, it is considered a rich source of content
that can be used in drug development and synthesis [3, 7, 8]. Furthermore, these
plants are accepted as important food sources [9, 10]. Medicinal plants are used
especially as raw materials in the extraction of active substances used in the synthe-
sis of drugs for the treatment of different types of diseases [8, 11]. Natural products
play a key role as a source of pharmaceutical compounds, and many modern medi-
cines derived from traditional herbal medicines are used in modern pharmacother-
apy nowadays [12]. Furthermore, the phytochemical composition and health
benefits of many known medicinal plant species have not yet been fully investigated
but have a promising future [9, 12, 13]. Terrestrial (crop species and non-crop wild
species) plants provide a wide range of ecosystem support such as food and natural

M. Z. Kocak (*)
Department of Herbal and Animal Production, Vocational School of Technical Sciences, Igdir
University, Igdir, Turkey
e-mail: [email protected]
M. G. Kaysim
Department of Field Crops, Faculty of Agriculture, Igdir University, Igdir, Turkey

© The Author(s), under exclusive license to Springer Nature 1061

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_44
1062 M. Z. Kocak and M. G. Kaysim

drugs. Plants in the agricultural ecosystem can be divided into three distinct groups:
crop plants, non-target terrestrial plants, and non-crop plants in the off-crop area
which are not be affected by any plant conservation product treatments. In addition,
crop species are used as surrogates for non-cultivated non-crop plant species, since
they are easier to cultivate [14–16]. Notable therapeutic medicinal plants are poor
inputs for medicinal crop earnings. Recently, in addition to agroforestry systems,
single crops, intermediates, sequential crops, mixed crops, etc. are grown commer-
cially in different countries [17, 18]. The main disadvantages of cultivation of
medicinal plants include the following: (i) adverse weather conditions like drought,
flood, frost, and acidic heavy rain during germination, growth, and harvesting sea-
sons, (ii) viral and fungal diseases which spread rapidly among closely growing
plants of the same species, (iii) the attack of insects and rodents in the field; (iv)
extreme production cost, and (v) the required environmental conditions for cultiva-
tion of medicinal plants.

1.2 What Are the Major Families of Medicinal Plants?

Medicinal plants are used to meet health needs and combat various diseases since
humanity first started cultivating them. According to the World Health Organization
(WHO) reports, about 80% of the world’s population rely on medicinal plants for
their health needs [19]. Although all plants in nature are precious, considering their
intended use, medicinal plants have different functions to play in human life. In this
section, we will discuss some of the important medicinal plant families that are
frequently used for medicinal purposes, e.g., Fabaceae, Lamiaceae, Euphorbiaceae,
Apocynaceae, Malvaceae, Apiaceae, and Ranunculaceae families that consist of
many medicinal species [20, 21].
Fabaceae
Fabaceae is a large family of mostly herbaceous plants, including shrubs and trees.
Fabaceae consists of 720–730 genera and 19,500 species. Members of the Fabaceae
are dominant species in nearly every biome from deserts to tropical forests. Fabaceae
is divided into three subfamilies: Mimosoideae, Papilionoidea, and Caesalpinioideae
[22]. They have taproots. There are secondary roots that show veining around the
main roots. They fix the free nitrogen of the air by Rhizobium bacteria. The main
component found in many species of the Fabaceae family is alkaloids [19–21].
Arachis hypogaea, Glycine max, Lens culinaris, Phaseolus spp., and Medicago
sativa are well-known examples of this family [23, 24].
Lamiaceae
Lamiaceae is a family of flowering plants in the form of herbs, rarely trees, and
shrubs. Lamiaceae consist of 236–238 genera and 6500–7170 species. The most
distinctive features of this family of plants are they have a four-cornered body, annu-
lar (verticillate) leaf arrangement along the stem, and essential oils [25]. In addition
to some substances such as cellulose, pectin, and sugar, which are present in
Appraisal of Medicinal Plants for Pharmacological Properties 1063

medicines, there are also essences, the majority of which are formed by essential
oils, and it is known that these substances have important pharmacological effects
[20, 26]. The main component found in many species in Lamiaceae, which is rich in
essential oils, is terpenes [19, 21]. Some considerable members of Lamiaceae
include Lavandula angustifolia, Melissa officinalis L., Mentha arvensis L., Mentha
piperita L., Mentha spicata L., Rosmarinus officinalis L., Salvia officinalis L., and
Thymus vulgaris L. species [27].
Apiaceae
Apiaceae consists mostly of herbs and partly of shrubs and trees. Most Apiaceae are
annual, biennial, or perennial herbs consisting of 428–434 genera and 3500–3780
species [19, 23]. Its leaves are alternately arranged. In most genera, the leaves are
frequently aggregated toward the base. Its inflorescence is usually simple or com-
pound umbels. Umbelliferae, meaning “umbrella-bearers,” was the alternative term
used for Apiaceae because of its flowers that look like umbrellas. The main compo-
nent found in many species of Apiaceae, which is rich in essential oils, is coumarins
[21, 25]. Some prominent members of Apiaceae include Carum carvi L., Coriandrum
sativum L., Foeniculum vulgare, and Pimpinella anisum L. species [20, 27].
Apocynaceae
Apocynaceae is a family of flowering plants that also includes trees, shrubs, and
herbs. Apocynaceae consists of 380–415 genera and 4555–4700 species.
Apocynaceae has five subfamilies: Rauvolfioideae, Apocynoideae, Periplocoideae,
Secamonoideae, Asclepiadoideae [28]. Many of its species are tall trees found in
tropical rainforests, and most are from tropical and subtropical regions. Many of
these plants contain milky sap, and many species are poisonous when eaten [25].
Catharanthus roseus is one of the well-known species. The main component found
in many species in Apocynaceae, which is rich in alkaloids, is cardiac glycosides
[19, 21, 29].

1.3 Global Status of Medicinal Plants: All Are Wild-Collected,

Cultivated, or Both?

Since the day mankind existed, they collected plant and animal resources from
nature to meet their basic needs such as food, shelter and health. Even today, mil-
lions of people in many developing countries derive some of their income from the
plant and animal sources they collect. Valuable plants such as medicinal plants that
are low in the yield and high cost are still collected or cultivated in developed coun-
tries [30–32]. More than one-tenth of the plant species, about 80,000, are used for
medicinal purposes. 3000 of these plants are traded internationally. However, only
900 of them have been cultured and majority are harvested from the wild [33–35].
Despite such a small number of plant trade, the global medicinal plant export has
reached 2.6 million dollars according to the 2016 data [36]. Although nearly 70% of
1064 M. Z. Kocak and M. G. Kaysim

the medicinal plants used industrially have been cultivated, this ratio is the opposite
as a plant variety. To give an example, about 70% of the plants used for medicinal
purposes in India are found in tropical forest areas and the Himalayan region. While
20% of the known medicinal plants in China are used, only 2% of the medicinal
plants are cultivated. Nearly 150 plant species have been cultivated in Europe [35,
37, 38]. Considering the data, it is assumed that the cultivated medicinal plant is not
more than a few hundred species. However, it should be considered that the data on
medicinal and aromatic plants grown or collected from nature are very limited.
Cultivation is often preferred to protect endemic, rare, or endangered species and
genetic diversity and to combat pests and diseases [39–41]. In addition, it is of
course desirable to obtain a high-quality and high-yielding plant with little effort.
Therefore, considering all these reasons, producers prefer to cultivate the plant or
collect it from the wild, if possible.

1.4 Secondary Metabolites: Species-Specific

Remarkable Metabolites

Although there is no universal definition for secondary metabolites (SMs), we can

express it as follows. Unlike primary metabolites (such as carbohydrates, amino
acids, etc.), they are compounds that are not essential for the normal growth, devel-
opment, and reproduction of plants, but play a role in plant defense against environ-
mental damages [42–44] There are 2.14 million known SMs that are divided into
five main classes: terpenoids and steroids, fatty acid-derived substances and
polyketides, alkaloids, nonribosomal polypeptides, and enzyme cofactors [45].
Although some of these compounds are common in plants, they do not necessarily
have to exist in all plants. On the other hand, when it comes to medicinal plants
(especially for quantity and quality), secondary metabolites are the most needed
compounds [46, 47]. It is possible to identify medicinal plants by making use of the
species-specific secondary metabolites they contain. Lamiaceae species contain
aromatic compounds, while many members of Apiaceae contain essential oils.
Solanaceae and Papaveraceae species have alkaloids, while Sapindaceae species
have tannins. Liliaceae, Gramineae, and Juncaceae species contain flavonoids in
their leaves. Caryophylla family members such as Basellaceae, Molluginaceae,
Nyctaginaceae, and Phytolaccaceae are rich in betalains, a type of anthocyanin.
Terpenoids are commonly found in Apiaceae and gymnosperms [48]. Secondary
metabolites such as tannins, terpenoids, alkaloids, and flavonoids may exhibit anti-
microbial, antiparasitic, or antitumor properties [48, 49]. In addition, these second-
ary metabolites and the pharmacological activities of some medicinal plants are
given in Table 1.
Appraisal of Medicinal Plants for Pharmacological Properties 1065

Table 1 Secondary metabolites and pharmacological activity of some medicinal plants

Plants Secondary metabolites Activity References
Capsicum spp. Simple phenolics Circulatory stimulant [50]
Filipendula ulmaria Simple phenolics Anti-inflammatory [51]
Dryopteris filix-mas Simple phenolics Anti-inflammatory [52]
Vaccinium oxycoccos Tannins Urinary antiseptic [53]
Atropa belladonna Coumarins Anti-inflammatory [54]
Melilotus spp. Coumarins Anticancer [55]
Glycyrrhiza glabra Flavonoids Anti-inflammatory [56]
Calendula officinalis Flavonoids Anti-allergic [57]
Tilia cordata Flavonoids Antinociceptive [58]
Leonurus cardiaca Flavonoids Tumor promotion [57]
Polygala nyikensis Xanthones Antifungal [59]
Glycyrrhizae radix Saponins Antitussive [60]
Phytolacca americana Saponins Anti-inflammatory [61]
Bupleurum falcatum Saponins Antidepressant [62]
Catharanthus roseus Vinblastine Antitumor [63]
Datura stramonium Atropine Antiasthmatic [64]
Berberis vulgaris Berberine Antibacterial [65]
Nicotiana spp. Nicotine Parasympathomimetic [66]

1.5 Roles of Secondary Metabolites in Combating Diseases

Plants have the capacity to synthesize different organic molecules, known as sec-
ondary metabolites. Plant secondary metabolites (PSMs) play a role in plants’ adap-
tation to various environmental constraints and in ensuring the continued existence
of organisms in their ecosystems, but are not needed for organisms to live. In addi-
tion, these compounds differ between the same population of plants in respect of
their amounts and varieties. Secondary metabolites have defense functions against
both biotic and abiotic stresses [67–72]. Nevertheless, steroids and sterols, terpenes
and terpenoids, miscellaneous isoprenoids, volatile oils, resins, phenols and phenyl-
propanoids, glycosides, alkaloids (caffeine, ephedrine, nicotine, cocaine etc.), sapo-
nins, bitter principles, cardioactive compounds, etc., are significant classify of
secondary metabolites of plant origin [73–77]. Plant secondary metabolites (PSMs)
are important protectors against different diseases in plants and used as chemical
defense by plants against both biotic and abiotic stresses. In addition, they are used
as medicines, flavorings, fragrances, and insecticides [71, 78–80]. Ever since the
appearance of human civilization, plants have been one of the significant sources of
medicines. Plant secondary metabolites have been shown to play important roles in
the treatment of cancer and in reducing various in vitro and in vivo tumorigenic and
inflammatory factors [43, 75, 76, 81–83]. Medicinal plants have secondary metabo-
lites such as alkaloids, steroids, glycosides, or other known groups of compounds
which have remarkable pharmaceutical effects such anticancer, antidiabetic, antimi-
crobial, antimalarial, antidysenteric effects, as well as combat various types of dis-
eases [43, 76, 84, 85].
1066 M. Z. Kocak and M. G. Kaysim

1.6 Pharmacological Effects: Sensu Lato

Medicinal plants are a rich source of bioactive molecules that have numerous bio-
logical properties. These molecules mostly possess secondary metabolites such as
terpenes, alkaloids, and phenolic compounds of medicinal plants which have phar-
macological effects [86–89]. Furthermore, it is estimated that the plant kingdom
contains more than 200,000 secondary metabolites [46, 86]. The groups of plant
secondary metabolites include the following:
Terpenes
Terpenes are the largest and most diverse group of organic compounds produced
mostly by a variety of class of plant secondary compounds. The name “terpene” is
derived from the word “turpentine,” which in turn comes from the old French ter(e)
bintb, meaning “resin.” They are derived chemically from five-carbon isoprene
units that are assembled in different ways [90–93]. These compound contents in the
plants are mostly well-known for their anticancer effects and biological activities.
Some of the best known terpenes described as having anticancer molecules are car-
vone, carveol, isopulegol, eugenol, citral caryophyllene oxide, limonene, elemene,
and methotrexate, thymol, and carvacrol [91, 94–96]. Moreover, terpenes are abun-
dant in higher plants, conifers, citrus, and eucalyptus and are widely distributed in
the flowers, leaves, stems, and roots of these plants [95, 97, 98].
Alkaloids
Alkaloids are natural bioactive organic compounds that consist of one nitrogen
atom in the heterocyclic ring [99]. In addition, it is one of the largest groups of
amino acid-derived natural low-molecular-weight products [11] or all alkaloids
existing in nature [100]. Alkaloids can be discrete according to its fundamental
chemical structure into different types. The basic types of alkaloids are aromatics,
ephedras, carbolines, acridones, indoles, indolizidines, oxindoles, purines, pyrro-
loindoles, phenylethylamines, bisindoles, ergots, imidazoles, quinazolines, quino-
lines, piperidines, pyrrolizidines, manzamines, phenylisoquinolines, pyridines,
pyrrolidines, and simple tetrahydroisoquinolines [59, 101–103]. Apart from their
anticancer properties, these compounds have been found to have many important
bioactivities (such as anti-angiogenesis, autophagy, apoptosis, differentiation, cell
cycle stop, resistant chemoprevention, and anti-metastasis) in human and animal
health. In addition, alkaloids play an important role in increasing the susceptibility
of multidrug resistance (MDR) in human cancer cell lines [80, 91, 94, 104, 105].
Phenolics
Phenolics probably constitute the largest group of plant secondary metabolites
widely distributed in nature [91, 106]. These phenolics are pharmacologically valu-
able for to their anti-inflammatory activities such as quercetin or antihepatotoxic
properties such as silybin. According to structures or biosynthetic origin, phenolics
can be classified into tannins, coumarins, lignans, simple phenolics, flavonoids, stil-
benes, chromones, and xanthones [107, 108]. Phenolics and flavonoids, as are many
other important bioactive agents, have gained widespread interest because of their
Appraisal of Medicinal Plants for Pharmacological Properties 1067

antioxidant properties and healing properties [109]. In addition, natural phenolics

have produced different results on the inhibition of the proliferation of some cancer
cell lines, and many studies have demonstrated their anti-­inflammatory, antidia-
betic, antifungal, antiviral, antibacterial, antioxidant, skin protective effects as well
as their potential to be anticancer. Effect from UV and immunostimulating activities
[108, 110–113]. Phenolics play a considerable role in growth and reproduction by
protecting plants against pathogens. It has been recorded that after giving an elec-
tron or a hydrogen atom to free radicals, they are active by removing free radicals
and reactive oxygen species and, to a greater extent, have been described as having
effective biological activities [113–115].

1.7 Pharmacology

Many medicinal plants have long been confirmed as significant sources of therapeu-
tically active compounds. Herewith many research showed that a wide range of
medicinal plants exerted antioxidant, antimicrobial, analgesic, and anti-­inflammatory
activities [116–118]. Also, medicinal plants and their parts (leaves, roots, flowers,
seeds, and rhizomes) are used as fresh or dried, decoctions in powder form, tea, and
different extracts (water or alcohol extracts, juices, essential oils, tinctures, balsams,
resins) and used as part of medical treatments [118, 119].
Antioxidant
Antioxidants are free radical scavengers that help in delaying or preventing oxida-
tion. The vital concentration of free radicals or reactive oxygen species (ROS) in
living organisms is maintained by enzymatic antioxidants such as glutathione super-
oxide dismutase, peroxidase, catalase, glutathione reductase, and nonenzymatic
antioxidants such as glutathione, alpha-tocopherol, and ascorbic acid. Also, shown
that fruits rich in polyphenols exert both antioxidant [120, 121]. Many epidemio-
logical research have indicated a reverse relationship between antioxidants from
plant products and the ratio of diseases. Because medicinal plant antioxidants have
removed the free radicals [118, 122, 123], medicinal plants and their materials can
be important promising sources of antioxidants. Furthermore, many of its compo-
nents may contribute to its antioxidant and other protective properties. Among them
flavonoids, phenolic compounds, and vitamins show effective antioxidant activities
[124–127].
Antimicrobial
Medicinal plants are rich in varieties of secondary metabolites such as flavonoids,
phenolic compounds, alkaloids, and tannins which have been known in vitro to have
antimicrobial properties. Antimicrobial agents are particularly important in decreas-
ing the global effects of infectious diseases [128, 129]. In addition, increasing resis-
tance to traditional antibiotics by pathogenic microbes has made it inevitable to
search for new effective antimicrobial agents of plant origin. Initial examination of
plants for antimicrobial effects begins with the use of crude extracts that are water
1068 M. Z. Kocak and M. G. Kaysim

or alcohol. Antibacterial agents must meet the following conditions to ensure their
action against bacteria: (i) there must be a sensitive antibacterial purpose in the cell,
(ii) antibacterial agents should reach the target in sufficient quantity, and (iii) anti-
bacterial agents should be left to their natural state [130–133].
Anti-inflammatory
Phenolic and flavonoid compounds present in plants have showed important phar-
macological activities, such as anti-inflammatory effects through different mecha-
nisms [134]. Previous studies have shown that inflammation is mostly caused by
damage to living tissues by viral, bacterial, and fungal infections. The fundamental
purpose of inflammatory treatments is to destroy the harmful agents. Furthermore,
nonsteroidal anti-inflammatory drugs such as the isoform of the cyclooxygenase
enzyme (COX-1, COX-2) can reduce pain and inflammation by reducing prosta-
glandin production by inhibiting arachidonic acid metabolism [135]. Although non-
steroidal drugs have many side effects, there are plants (medicinal) that have no side
effects and have significant anti-inflammatory therapeutic effects [136–138].

1.8 Powerful Analysis of Relevant Studies: VOSviewer

Software for Reducing Dimension and Revealing Core
Points of the Medicinal Plant Studies

In the recent years, bibliometric analysis researches have been carried out in various
fields ranging from biology to agriculture and from management-economics to the
communication studies [139–142]. Herewith the bibliometric analysis, the relevant
former studies in certain and specified topics have been discussed and then recom-
mendations as “future outlook” are proposed for the readers. In addition to the con-
ventional bibliometric analysis, in the last decade, a great interest in uses of a
software named “VOSviewer” (developed by Leiden University; for more details,
please visit https://www.vosviewer.com/) has been addressed in innumerable topics
[143–146]. Along with the current chapter, VOSviewer-aided constructed visualiza-
tions were proposed. With the relevant visualizations, such as term analysis (Fig. 1),
keyword analysis (Fig. 2), core-hot keyword analysis (Fig. 3), and country analysis
(Fig. 4), we extracted and deduced some common themes according to the retrieved
data from Scopus, which was of reliable scientific databases [140]. Due to large data
in the relevant field, we used some limitations, viz., medicinal plants (in abstract,
title, keywords on Scopus). As expected, we had a great number of documents,
which were estimated to be about 700,000 but without any refinements. To be com-
patible with the book project, we specified our search using pharmacology, toxicol-
ogy, and pharmaceuticals and then we constructed the relevant figures, in this regard.
Term Analysis of the Documents
Of the analysis conducted, term analysis clearly revealed three major clusters. To
start with the red cluster, it might be “weird” to be “hot-spot” of the word “review.”
Appraisal of Medicinal Plants for Pharmacological Properties 1069

Fig. 1 Term analysis of the retrieved documents

Fig. 2 Keyword analysis of the retrieved documents

1070 M. Z. Kocak and M. G. Kaysim

Fig. 3 Core-hot keywords in “keyword analysis” of the extracted documents

When we have a quick number of document type, we observed that almost all of the
documents were “review papers” (equivalent to 20–20% of 2715 document num-
bers). The green cluster is based on biological activities, assays, and solvents of
extractions. Up to the best knowledge of the original researches, most reports of
herbal medicines are issued on biological activities, in particular antioxidant and
antimicrobial activities.
Keyword Analysis
In relation or comparison to the term analysis, regarding keyword analysis, a high
number of clusters were observed according to our inserted criteria. However, the
commonly and widely used words were “medicinal plants, natural products, anti-
oxidant activities, flavonoids, and cytotoxicity.” Of the metabolites available in
medicinal plants, secondary metabolites (rather than primary metabolites common
to all living organisms) are substantial in well-known activities of the plants. There
are about 100,000 elucidated compounds and flavonoids, a subgroup of secondary
metabolites, as well as hot-keyword of the current study, which are not only and
unique of the metabolites. Even being in a numerous reports, flavonoids are critical
in exerting the activities [147–152], and terpenoids, alkaloids, and other groups of
phenolics are furthermore significant and deserve to be investigated in detail.
Appraisal of Medicinal Plants for Pharmacological Properties 1071

Fig. 4 Country analysis of the extracted documents

Country Analysis
Corresponding to the country analysis, as expected from all fields, China, India, the
USA, Italy, Brazil, Iran, Germany, Turkey, and Pakistan were noted as the leading
countries in the field medicinal plants according to the number of documents pub-
lished on Scopus. It is significant to note that the number of documents does not
always reflect the quality. The number of documents is, in general, dependent on the
plant species distributed in the relevant region, number of experts in specific topics,
and most significantly laboratory infrastructure. We should also note that a low ratio
of the recorded plant species is assessed for medicinal purposes, being 50,000–80,000
plant species (equivalent to 20% of 400,000 plant species). In this regard, to an
extent, we could not generalize that the number of medicinal plants is directly linked
to the number of plant species. We should also address some issues on the export
and import of the species such as spice, supplementation, food additives, and drugs.
When we should have a quick look on the country-wise and value-wise export of
medicinal herbs (https://pib.gov.in/PressReleasePage.aspx?PRID=1594929), and
the USA, Germany, Vietnam, China, Italy, Pakistan, Bangladesh, the UK, Australia,
and France are the leading countries. As seen from the order of countries, we cannot
1072 M. Z. Kocak and M. G. Kaysim

deduce a common cause of disseminated number of documents and export value of

herbal medicines. As of the many cases, the medicinal plants also have multifaceted
and multidimensional issues.

2 Future of Medicinal Plants and Pharmacological Effects

Generally, medicinal plants and plant products have a promising future, as there are
about half a million of plant species in the world. However, the medical activities of
many of them have not yet been investigated and their medical activities may be
decisive in the treatment of current or future studies. In the same medicinal plant
species, different varieties can provide different amounts of flavonoid and phenolic
compounds as well as biological activities. Therefore, medicinal plant varieties
should be considered for future medical and pharmaceutical research studies.

3 Conclusions

To explore and advance these alternative choices for the use of phytochemical com-
pounds, investigation of medicinal plants along with intensive profiling research is
required. Targeted compounds should be used in biomedical and pharmaceutical
research consisting of in vitro, in vivo, and clinical trial steps to evaluate the safety,
efficacy, as well as side effects of the candidate compounds tested.

References

1. Adhikari PP, Paul SB (2018) History of Indian traditional medicine: a medical inheritance.
Asian J Pharm Clin Res 11:421–426
2. Johns T (2002) Plant genetic diversity and malnutrition: practical steps in the development of
a global strategy linking plant genetic resource conservation and nutrition. Afr J Food Nutr
Sci 3:98–100
3. Khazdair MR, Kianmehr M, Anaeigoudari A (2021) Effects of medicinal plants and flavo-
noids on Parkinson’s disease: a review on basic and clinical evidences. Adv Pharm Bull 11:224
4. Albuquerque UP, do Nascimento ALB, Chaves LS, Feitosa IS, de Moura JMB, Gonçalves P
H S, Júnior WSF. (2020) The chemical ecology approach to modern and early human use of
medicinal plants. Chemoecology 30:89–102
5. Dey A, Mukherjee A, Chaudhury M (2017) Alkaloids from apocynaceae: origin, pharmaco-
therapeutic properties, and structure-activity studies. Stud Nat Prod Chem 52:373–488
6. Hudha MN, Hamidah I, Permanasari A, Abdullah AG, Rachman I, Matsumoto T (2020) Low
Carbon Education: a review and bibliometric analysis. Eur J Educ Res 9:319–329
7. Ahad B, Shahri W, Rasool H, Reshi ZA, Rasool S, Hussain T (2021) Medicinal plants and
herbal drugs: an overview. In: Medicinal and aromatic plants: healthcare and industrial appli-
cations, p 1
8. Singh R (2015) Medicinal plants: a review. J Plant Sci 3:50–55
Appraisal of Medicinal Plants for Pharmacological Properties 1073

9. Oguntibeju OO (2018) Medicinal plants with anti-inflammatory activities from selected

countries and regions of Africa. J Inflamm Res 11:307
10. Rawat S, Andola H, Giri L, Dhyani P, Jugran A, Bhatt ID, Rawal RS (2014) Assessment of
nutritional and antioxidant potential of selected vitality strengthening Himalayan medicinal
plants. Int J Food Prop 17:703–712
11. Chakraborty S, Kumar P, Sanyal R, Mane AB, Prasanth DA, Patil MT, Dey A (2021)
Unravelling the regulatory role of miRNAs in secondary metabolite production in medicinal
crops. Plant Gene:100303
12. Máthé Á (2015) Botanical aspects of medicinal and aromatic plants. In: Máthé Á (ed)
Medicinal and aromatic plants of the world. Medicinal and aromatic plants of the world, vol
1. Springer, Dordrecht
13. Kumar A, Singh SK, Singh VK, Kant C, Singh AK, Tripathi V, Singh J (2021) An insight into
the molecular docking interactions of plant secondary metabolites with virulent factors caus-
ing common human diseases. S Afr J Bot
14. Costa TDSA, Vieira RF, Bizzo HR, Silveira D, Gimenes MA (2012) Secondary metabolites.
Embrapa agroindústria de alimentos-capítulo em livro científico. ALICE
15. Enyiukwu DN, Awurum AN, Ononuju CC, Nwaneri JA (2014) Significance of characteriza-
tion of secondary metabolites from extracts of higher plants in plant disease management. Int
J Adv Agric Res 2:8–28
16. Smith EA, Shields EJ, Nault BA (2017) Onion thrips colonization of onion fields bordering
crop and non-crop habitats in muck cropping systems. J Appl Entomol 141:574–582
17. Alamgir A (2017) Pharmacognostical botany: classification of medicinal and aromatic
plants (MAPs), botanical taxonomy, morphology, and anatomy of drug plants. Prog Drug
Res:177–293
18. He J, Yang B, Dong M, Wang Y (2018) Crossing the roof of the world: trade in medicinal
plants from Nepal to China. J Ethnopharmacol 224:100–110
19. Gao X, Wang W, Wei S, Li W (2009) Review of pharmacological effects of Glycyrrhiza
radix and its bioactive compounds. Zhongguo Zhong yao za zhi= Zhongguo zhongyao
zazhi=Zhongguo Zhong Yao Za Zhi 34:2695–2700
20. Lee B, Yun HY, Shim I, Lee H, Hahm DH (2012) Bupleurum falcatum prevents depression
and anxiety-like behaviors in rats exposed to repeated restraint stress. J Microbiol Biotechnol
22:422–430
21. Willis K(2017) State of the world’s plants
22. Narain N, Shanmugam S, de Souza Araújo AA (2019) Antioxidant, antimicrobial, analgesic,
anti-inflammatory and antipyretic effects of bioactive compounds from Passiflora species.
Med Plant:243–274
23. Chase MW, Christenhusz MJM, Fay MF, Byng JW, Judd WS, Soltis DE, Steven PF (2016)
An update of the angiosperm phylogeny group classification for the orders and families of
flowering plants: APG IV. Bot J Linn Soc 181:1–20
24. Tomlinson P (2016) Family: Fabaceae (Leguminosae). In: The botany of mangroves.
Cambridge University Press, Cambridge, pp 251–261
25. Simpson MG (2019) Diversity and classification of flowering plants: eudicots. Plant
Syst:285–466
26. Raja R (2021) Medicinally potential plants of Labiatae (Lamiaceae) family: an overview. J
Med Plant Res 6:203–213
27. Hamberger B, Hahlbrock K (2004) The 4-coumarate: CoA ligase gene family in Arabidopsis
thaliana comprises one rare, sinapate-activating and three commonly occurring isoenzymes.
Proc Natl Acad Sci 101:2209–2214
28. Bremer B, Bremer K, Chase MW, Reveal JL, Soltis DE, Soltis PS, Stevens PF, Anderberg
AA, Fay MF, Goldblatt P, Judd WS, Källersjö M, Kårehed J, Kron KA, Lundberg J, Nickrent
DL, Olmstead RG, Oxelman B, Pires JC, Zmarzty S (2003) An update of the angiosperm
phylogeny group classification for the orders and families of flowering plants: APG II. Bot J
Linn Soc 141:399–436
1074 M. Z. Kocak and M. G. Kaysim

29. Gulcin I, Beydemir S (2013) Phenolic compounds as antioxidants: carbonic anhydrase isoen-
zymes inhibitors. Mini Rev Med Chem 13:408–430
30. Astutik S, Pretzsch J, Ndzifon KJ (2019) Asian medicinal plants production and utilization
potentials: a review. Sustainability 11:5483
31. Hosseinzadeh S, Jafarikukhdan A, Hosseini A, Armand R (2015) The application of medicinal
plants in traditional and modern medicine: a review of Thymus vulgaris. Int J Clin Med 6:635
32. Vasisht K, Sharma N, Karan M (2016) Current perspective in the international trade of
medicinal plants materials: an update. Curr Pharm Des 22:4288–4336
33. Bentley R (2010) Medicinal plants. Domville-Fife Press, London, pp 23–46
34. Rao BR, Rajput DK (2010) Global scenario of medicinal plants. World 10500:I800
35. Schıppmann U, Leaman D, Cunnıngham AB (2006) Cultivation and wild collection of
medicinal and aromatic plants under sustainability aspects. In: Bogers RJ, Craker LE, Lange
D (eds) Med aromat plants. Springer, Dordrecht, p 17
36. World Bank (2018) Strategic segmentation analysis: Nepal. Medicinal and aromatic plants.
World Bank Group, Washington, DC, p 61
37. Demir İ (2020) An Ethnobotanical study of medicinal plants used in Hizan district (Bitlis-­
Turkey). YYÜ TAR BİL DERG 30:732–741
38. Zahra W, Rai SN, Birla H, Singh S, Sen Rathore AS, Dilnashin H, Keswani C, Singh SP
(2020) Economic importance of medicinal plants in Asian countries. In: Keswani C (ed)
Bioeconomy for sustainable development. Springer, Singapore, pp 359–377
39. Dar RA, Shahnawaz M, Qazi PH (2017) General overview of medicinal plants: a review. J
Phytopharm 6:349–351
40. Jurikova T, Skrovankova S, Mlcek J, Balla S, Snopek L (2018) Bioactive compounds,
antioxidant activity, and biological effects of european cranberry (Vaccinium oxycoccos).
Molecules 24:24
41. Vines G (2004) Herbal harvests with a future: towards sustainable sources for medicinal
plants. Plantlife International
42. Hassan I, Wan Ibrahim WN, Yusuf FM, Ahmad SA, Ahmad S (2020) Biochemical constituent
of ginkgo biloba (Seed) 80% methanol extract inhibits cholinesterase enzymes in javanese
medaka (Oryzias javanicus) model. J Toxicol
43. Kabera J, Semana E, Ally RM, Xin H (2014) Plant secondary metabolites: biosynthesis, clas-
sification, function and pharmacological properties. J Pharm Pharmacol 2:377–392
44. Stamp N (2003) Out of the quagmire of plant defense hypotheses. Q Rev Biol 78:23–55
45. Meng L, Wen KH, Brewin R, Wu Q (2020) Knowledge atlas on the relationship between
urban street space and residents’ health—A bibliometric analysis based on VOSviewer and
vitespace. Sustainability 12:2384
46. Böttger A, Vothknecht U, Bolle C, Wolf A (2018) Plant secondary metabolites and their gen-
eral function in plants. In: Lessons on caffeine, cannabis & co. Springer, Cham, pp 3–17
47. Martínez AL, González-Trujano ME, Aguirre-Hernández E, Moreno J, Soto-Hernández
M, López-Muñoz FJ (2009) Antinociceptive activity of Tilia americana var. mexicana
inflorescences and quercetin in the formalin test and in an arthritic pain model in rats.
Neuropharmacology 56:564–571
48. Alamgir ANM (2017) Cultivation of herbal drugs, biotechnology, and in vitro production
of secondary metabolites, high-value medicinal plants, herbal wealth, and herbal trade. In:
Therapeutic use of medicinal plants and their extracts, vol 1, pp 379–452
49. Hussein RA, El-Anssary AA (2019) Plants secondary metabolites: the key drivers of the
pharmacological actions of medicinal plants. Herb Med 1:13
50. Spiller F, Alves MK, Vieira SM, Carvalho TA, Leite CE, Lunardelli A, Poloni JA, Cunha FQ,
de Oliveira JR (2008) Anti-inflammatory effects of red pepper (Capsicum baccatum) on car-
rageenan and antigen-induced inflammation. J Pharm Pharmacol 60(4):473–478
51. Shilova IV, Krasnov EA, Korotkova EI et al (2006) Antioxidant properties of extracts from
the above-ground parts of Filipendula ulmaria. Pharm Chem J 40:660–662
Appraisal of Medicinal Plants for Pharmacological Properties 1075

52. Evans WC (2009) Pharmacognosy, 16th edn, Edinburgh/London/New York/Philadelphia/St

Louis/Sydney/Toronto
53. Kabel AM (2014) Free radicals and antioxidants: role of enzymes and nutrition. J Nutr
Health 2:35–38
54. Moukette BM, Pieme CA, Njimou JR, Biapa CPN, Marco B, Ngogang JY (2015) In vitro
antioxidant properties, free radicals scavenging activities of extracts and polyphenol compo-
sition of a non-timber forest product used as spice: Monodora myristica. Biol Res 48:1–17
55. Xu L, Wu Y, Zhao X, Zhang W (2015) The study on biological and pharmacological activity
of coumarins. AP3ER:135–138
56. Mahajan M, Kuiry R, Pal PK (2020) Understanding the consequence of environmental stress
for accumulation of secondary metabolites in medicinal and aromatic plants. J Appl Res Med
Aromat Plants 18:100255
57. Serafini M, Peluso I, Raguzzini A (2010) Flavonoids as anti-inflammatory agents. Proc Nutr
Soc 69(3):273–278
58. McMurry JE (2015) Organic chemistry with biological applications. In: Secondary metab-
olites: an introduction to natural products chemistry. Cengage Learning Ltd, Stamford,
pp 1016–1046
59. Susana J, Beatriz GM, Fabiana CM, Maria AD, Moacir GP (2011) Antifungal activity of five
species of Polygala. Braz J Microbiol 42:1065–1075
60. Ghorbanpour M, Hadian J, Nikabadi S, Varma A (2017) Importance of medicinal and aro-
matic plants in human life. In: Medicinal plants and environmental challenges. Springer,
Cham, pp 1–23
61. Kachmar MR, Naceiri Mrabti H, Bellahmar M, Ouahbi A, Haloui Z, El Badaoui K, Chakir S
(2021) Traditional knowledge of medicinal plants used in the Northeastern part of Morocco.
Evid-Based Complementary Altern Med
62. Lim TK (2015) Glycyrrhiza glabra. Edible medicinal and non-medicinal plants: volume 10,
modified stems, roots. Bulbs:354–457
63. Zhu J, Wang M, Wen W, Yu R (2015) Biosynthesis and regulation of terpenoid indole alka-
loids in Catharanthus roseus. Pharmacogn Rev 9:24–28
64. Soni P, Siddiqui AA, Dwivedi J, Soni V (2012) Pharmacological properties of Datura stra-
monium L. as a potential medicinal tree: an overview. Asian Pac J Trop Biomed 2:1002–1008
65. Kulak M, Ozkan A, Bindak RA (2019) Bibliometric analysis of the essential oil-bearing
plants exposed to the water stress: how long way we have come and how much further? Sci
Hortic 246:418–436
66. Ruan A, Gao Y, Fang C, Xu Y (2018) Isolation and characterization of a novel nicotinophilic
bacterium, Arthrobacter sp. aRF-1 and its metabolic pathway. Biotechnol Appl Biochem
65:848–856
67. Aguirre-Becerra H, Vazquez-Hernandez MC, de la OD S, Alvarado-Mariana A, Guevara-­
Gonzalez RG, Garcia-Trejo JF, Feregrino-Perez AA (2021) Role of stress and defense in
plant secondary metabolites production. In: Bioactive natural products for pharmaceutical
applications, pp 151–195
68. Ashraf MA, Iqbal M, Rasheed R, Hussain I, Riaz M, Arif MS (2018) Environmental stress
and secondary metabolites in plants: an overview. In: Plant metabolites and regulation under
environmental stress, pp 153–167
69. Celikcan F, Kocak MZ, Kulak M (2021) Vermicompost applications on growth, nutrition
uptake and secondary metabolites of Ocimum basilicum L. under water stress: a comprehen-
sive analysis. Ind Crops Prod 171:113973
70. Jain C, Khatana S, Vijayvergia R (2019) Bioactivity of secondary metabolites of various
plants: a review. Int J Pharm Sci 10:494–498
71. Makrane H, El Messaoudi M, Melhaoui A, El Mzibri M, Benbacer L, Aziz M (2018)
Cytotoxicity of the aqueous extract and organic fractions from Origanum majorana on human
breast cell line MDA-MB-231 and human colon cell line HT-29. Adv Pharmacol Sci
72. Perveen S, Al-Taweel A(Eds.). (2018) Terpenes and terpenoids. BoD–Books on Demand
1076 M. Z. Kocak and M. G. Kaysim

73. Alamgir ANM (2018) Secondary metabolites: secondary metabolic products consisting of
C and H; C, H, and O; N, S, and P elements; and O/N heterocycles. In: Therapeutic use of
medicinal plants and their extracts, vol 2, pp 165–309
74. Fakhri S, Moradi SZ, Ash-Rafzadeh A, Bishayee A (2021) Targeting cellular senescence in
cancer by plant secondary metabolites: a systematic review. Pharmacol Res:105961
75. Fernandez-Panchon MS, Villano D, Troncoso AM, Garcia-Parrilla MC (2008) Antioxidant
activity of phenolic compounds: from in vitro results to in vivo evidence. Crit Rev Food Sci
Nutr 48:649–671
76. Marrelli M (2021) Medicinal plants. Plants 10:1355
77. Seca AM, Pinto DC (2018) Plant secondary metabolites as anticancer agents: successes in
clinical trials and therapeutic application. Int J Mol Sci 19:263
78. Erhirhie EO, Emeghebo CN, Ilodigwe EE, Ajaghaku DL, Umeokoli BO, Eze PM, Ngwoke
KG, Chiedu OF (2019) Dryopteris filix-mas (L.) Schott ethanolic leaf extract and fractions
exhibited profound anti-inflammatory activity. Avicenna J Phytomedicine 9:396–409
79. Kumar M, Prakash S, Kumari N, Pundir A, Punia S, Saurabh V, Mekhemar M (2021)
Beneficial role of antioxidant secondary metabolites from medicinal plants in maintaining
oral health. Antioxidants 10:1061
80. Zaynab M, Fatima M, Abbas S, Sharif Y, Umair M, Zafar MH, Bahadar K (2018) Role of
secondary metabolites in plant defense against pathogens. Microb Pathog 124:198–202
81. Manandhar S, Luitel S, Dahal RK (2019) In vitro antimicrobial activity of some medicinal
plants against human pathogenic bacteria. J Trop Med
82. Scharf DH, Heinekamp T, Brakhage AA (2014) Human and plant fungal pathogens: the role
of secondary metabolites. PLoS Pathog 10:e1003859
83. Seca AM, Pinto DC (2019) Biological potential and medical use of secondary metabolites.
Medicines 6:66
84. Kyaw YMM, Bi Y, Oo TN, Yang X (2021) Traditional medicinal plants used by the mon
people in Myanmar. J Ethnopharmacol 265:113253
85. Wink M (2012) Medicinal plants: a source of anti-parasitic secondary metabolites. Molecules
17:12771–12791
86. Alzobaidi N, Quasimi H, Emad NA, Alhalmi A, Naqvi M (2021) Bioactive compounds and
traditional herbal medicine: promising approaches for the treatment of dementia. Degener
Neurol Neuromuscul Dis 11:1
87. Bhat SG (2021) Medicinal plants and its pharmacological values. In: Pharmacognosy-­
medicinal plants
88. Pagare S, Bhatia M, Tripathi N, Pagare S, Bansal YK (2015) Secondary metabolites of plants
and their role: overview. Curr Trends Biotechnol Pharm 9:293–304
89. Yang L, Yang C, Li C, Zhao Q, Liu L, Fang X, Chen XY (2016) Recent advances in biosyn-
thesis of bioactive compounds in traditional Chinese medicinal plants. Sci Bull 6:3–17
90. Bartwal A, Mall R, Lohani P, Guru SK, Arora S (2013) Role of secondary metabolites
and brassinosteroids in plant defense against environmental stresses. Plant Growth Regul
32:216–232
91. Irfan A, Imran M, Khalid M, Ullah MS, Khalid N, Assiri MA, Shahzad M (2021) Phenolic
and flavonoid contents in Malva sylvestris and exploration of active drugs as antioxidant
and anti-COVID19 by quantum chemical and molecular docking studies. J Saudi Chem Soc
25:101277
92. Patra JK, Kim ES, Oh K et al (2014) Antibacterial effect of crude extract and metabolites of
Phytolacca americana on pathogens responsible for periodontal inflammatory diseases and
dental caries. BMC Complement Altern Med 14:343
93. Tetali SD (2019) Terpenes and isoprenoids: a wealth of compounds for global use.
Planta 249:1–8
94. Bouyahya A, Belmehdi O, Benjouad A, El Hassani RA, Amzazi S, Dakka N, Bakri Y (2020)
Pharmacological properties and mechanism insights of moroccan anticancer medicinal
plants: what are the next steps? Ind Crops Prod 147:112198
Appraisal of Medicinal Plants for Pharmacological Properties 1077

95. Ng ZX, Koick YTT, Yong PH (2021) Comparative analyses on radical scavenging and cyto-
toxic activity of phenolic and flavonoid content from selected medicinal plants. Nat Prod Res
35:5271–5276
96. Theis N, Lerdau M (2003) The evolution of function in plant secondary metabolites. Int J
Plant Sci 164:S93–S102
97. Abdallah II, Quax WJ (2017) A glimpse into the biosynthesis of terpenoids. KnE Life
Sci:81–98
98. Trost BM, Min C (2020) Total synthesis of terpenes via palladium-catalysed cyclization strat-
egy. Nat Chem 12:568–573
99. Malekmohammad K, Rafieian-Kopaei M (2021) Mechanistic aspects of medicinal plants
and secondary metabolites against severe acute respiratory syndrome coronavirus 2 (SARS-­
CoV-­2). Curr Pharm Des
100. Dey P, Kundu A, Kumar A, Gupta M, Lee BM, Bhakta T, Kim HS (2020) Analysis of alka-
loids (indole alkaloids, isoquinoline alkaloids, tropane alkaloids). In: Recent advances in
natural products analysis, pp 505–567
101. Duan SC, Kwon SJ, Eom SH (2021) Effect of thermal processing on color, pheno-
lic compounds, and antioxidant activity of Faba bean (Vicia faba L.) leaves and seeds.
Antioxidants 10:1207
102. Munir N, Iqbal AS, Altaf I, Bashir R, Sharif N, Saleem F, Naz S (2014) Evaluation of anti-
oxidant and antimicrobial potential of two endangered plant species Atropa belladonna and
Matricaria chamomilla. Afr J Trad Comp Alter Med: AJTCAM 11:111–117
103. Šafratová M, Hošťálková A, Hulcová D, Breiterová K, Hrabcová V, Machado M, Cahlíková
L (2018) Alkaloids from Narcissus poeticus cv. Pink parasol of various structural types and
their biological activity. Arch Pharm Res 41:208–218
104. Jamshidi-Kia F, Lorigooini Z, Amini-Khoei H (2018) Medicinal plants: past history and
future perspective. J HerbMed Pharmacol:7
105. Twilley D, Lall N (2018) The role of natural products from plants in the development of
anticancer agents. Nat Prod Res:139–178
106. Christl H, Morilla J, Hoen T, Zumkier U (2019) Comparative assessment of the intrinsic
sensitivity of crop species and wild plant species to plant protection products and their active
substances and potential implications for the risk assessment: a literature review. Integr
Environ Assess Manag 15:176–189
107. Dajic-Stevanovic Z, Pljevljakusic D (2015) Challenges and decision making in cultivation of
medicinal and aromatic plants. Int J Med Aromat Plants. Springer, Dordrecht:145–164
108. Ulewicz-Magulska B, Wesolowski M (2019) Total phenolic contents and antioxidant poten-
tial of herbs used for medical and culinary purposes. Plant Foods Hum Nutr 74:61–67
109. Tungmunnithum D, Thongboonyou A, Pholboon A, Yangsabai A (2018) Flavonoids and
other phenolic compounds from medicinal plants for pharmaceutical and medical aspects:
an overview. Medicines 5:93
110. Ansari MA, Anurag A, Fatima Z, Hameed S (2013) Natural phenolic compounds: a potential
antifungal agent. Microbial pathogens and strategies for combating them. Sci Technol Educ
1:1189–1195
111. Keswani C, Mishra S, Sarma BK, Singh SP, Singh HB (2014) Unraveling the efficient appli-
cations of secondary metabolites of various Trichoderma spp. Appl Microbiol Biotechnol
98:533–544
112. Roleira FM, Varela CL, Costa SC, Tavares-da-Silva EJ (2018) Phenolic derivatives from
medicinal herbs and plant extracts: anticancer effects and synthetic approaches to modulate
biological activity. Stud Nat Prod Chem 57:115–156
113. Taslimi P, Gulçin İ (2017) Antidiabetic potential: in vitro inhibition effects of some natu-
ral phenolic compounds on α-glycosidase and α-amylase enzymes. J Biochem Mol Toxicol
31:e21956
114. Gurib-Fakim A (2006) Medicinal plants: traditions of yesterday and drugs of tomorrow. Mol
Aspects Med 27:1–93
1078 M. Z. Kocak and M. G. Kaysim

115. Pham-Huy LA, He H, Pham-Huy C (2008) Free radicals, antioxidants in disease and health.
Int J Biomed Sci: IJBS 4:89
116. Adebayo SA, Dzoyem JP, Shai LJ, Eloff JN (2015) The anti-inflammatory and antioxidant
activity of 25 plant species used traditionally to treat pain in southern African. BMC Complt
Altern Med 15:1–10
117. Akinyemi O, Oyewole SO, Jimoh KA (2018) Medicinal plants and sustainable human health:
a review. Hortic Int J 2:194–195
118. Škrovánková S, Mišurcová L, Machů L (2012) Antioxidant activity and protecting health
effects of common medicinal plants. Adv Food Nutr Res 67:75–139
119. Karakaya S, Koca M, Sytar O, Duman H (2020) The natural phenolic compounds and their
antioxidant and anticholinesterase potential of herb Leiotulus dasyanthus (K. Koch) Pimenov
& Ostr. Nat Prod Res 34:1303–1305
120. Boulmokh Y, Belguidoum K, Meddour F, Amira-Guebailia H (2021) Investigation of anti-
oxidant activity of epigallocatechin gallate and epicatechin as compared to resveratrol and
ascorbic acid: experimental and theoretical insights. Struct Chem:1–17
121. Ninkuu V, Zhang L, Yan J, Fu Z, Yang T, Zeng H (2021) Biochemistry of terpenes and recent
advances in plant protection. Int J Mol Sci 22:5710
122. Kabera JN, Semana E, Mussa AR, He X (2014) Plant secondary metabolites: biosynthesis,
classification, function and pharmacological properties. J Pharm Pharmacol 2:377–392
123. Nadon B, Jackson S (2020) The polyploid origins of crop genomes and their implications: a
case study in legumes. Adv Agron 159:275–313
124. Duffner A, Moser T, Candolfi MP (2020) Feasibility of assessing vegetative and genera-
tive endpoints of crop-and non-crop terrestrial plant species for non-target terrestrial plant
(NTTP) regulatory testing under greenhouse conditions. PloS One 15:e0230155
125. Frimpong EK, Asong JA, Aremu AO (2021) A review on medicinal plants used in the man-
agement of headache in Africa. Plants 10:2038
126. Tavallali H, Bahmanzadegan A, Rowshan V, Tavallali V (2021) Essential oil composition,
antioxidant activity, phenolic compounds, Total phenolic and flavonoid contents from pom-
ace of Citrus aurantifolia. JMPB 10:103–116
127. Traore KF, Kone KY, Ahi AP, Soro D, Assidjo NE, Fauconnier ML, Sindic M (2021) Phenolic
compounds characterisation and antioxidant activity of black plum (Vitex doniana) fruit pulp
and peel from Côte d’Ivoire. J Food Meas Charact 15:1281–1293
128. Manoharachary C, Nagaraju D (2016) Medicinal plants for human health and welfare. Ann
Phytomedicine 5:24–34
129. Mou Z, Zhao Y, Ye F, Shi Y, Kennelly EJ, Chen S, Zhao D (2021) Identification, biological
activities and biosynthetic pathway of dendrobium alkaloids. Front Pharmacol:12
130. Oualcadi Y, Aityoub A, Berrekhis F (2021) Investigation of different antioxidant capacity
measurements suitable for bioactive compounds applied to medicinal plants. J Food Meas
Charact 15:71–83
131. Romulo A, Zuhud EA, Rondevaldova J, Kokoska L (2018) Screening of in vitro antimicrobial
activity of plants used in traditional Indonesian medicine. Pharm Biol 56:287–293
132. Vatľák A, Kolesárová A, Vukovič N, Rovná K, Petrová J, Vimmerová V, Kačániová M (2021)
Antimicrobial activity of medicinal plants against different strains of bacteria. J Microbiol
Biotechnol Food Sci:174–176
133. Whangchai K, Shanmugam S, Van Le Q, Chau TP, Al-Kheraif AA, Brindhadevi K, Duc PA
(2021) Study of antimicrobial activity of Thespesia populnea-coated nanozirconium on cot-
ton gauze fabrics. Appl Nanosci:1–7
134. Puangpraphant S, Cuevas-Rodríguez EO, Oseguera-Toledo M (2022) Anti-inflammatory and
antioxidant phenolic compounds. In: Current advances for development of functional foods
modulating inflammation and oxidative stress. Academic Press, pp 165–180
135. Schultz F, Osuji OF, Wack B, Anywar G, Garbe LA (2021) Antiinflammatory medicinal
plants from the Ugandan greater mpigi region act as potent inhibitors in the COX-2/PGH2
pathway. Plants 10:351
Appraisal of Medicinal Plants for Pharmacological Properties 1079

136. Kuete V (2014) Health effects of alkaloids from african medicinal plants. In: Kuete V (ed)
Toxicological survey of African medicinal plants, pp 611–633
137. Osungunna MO (2021) Screening of medicinal plants for antimicrobial activity: pharmacog-
nosy and microbiological perspectives. J Microbiol Biotechnol:727–735
138. Ribeiro VP, Arruda C, Abd El-Salam M, Bastos JK (2018) Brazilian medicinal plants with
corroborated anti-inflammatory activities: a review. Pharm Biol 56:253–268
139. Büyükbaykal NG, İli B (2021) E-Spor kavramına yönelik araştırmaların bibliyometrik anal-
izi bibliometric analysis of researches for e-sport. UKSAD 6:572–583
140. Celik E, Durmus A, Adizel O, Uyar HN (2021) A bibliometric analysis: what do we know
about metals (loids) accumulation in wild birds? Environ Sci Pollut Res 28:10302–10334
141. Ritter MR, Silva TCD, Araújo EDL, Albuquerque UP (2015) Bibliometric analysis of ethno-
botanical research in Brazil (1988–2013). Acta Bot Brasilica 29:113–119
142. Yeung AWK, Heinrich M, Atanasov AG (2018) Ethnopharmacologya bibliometric analysis
of a field of research meandering between medicine and food science? Front Pharmacol 9:215
143. Hussein RA, El-Anssary AA (2019) Plants secondary metabolites: the key drivers of the
pharmacological actions of medicinal plants. J Herb Med 1:13
144. Kumar S (2017) Plant secondary metabolites (PSMs) of Brassicaceae and their role in plant
defense against insect herbivores – a review. J Appl Nat Sci 9:508–519
145. Mickymaray S (2019) Efficacy and mechanism of traditional medicinal plants and bioactive
compounds against clinically important pathogens. Antibiotics 8:257
146. Yu Y, Li Y, Zhang Z, Gu Z, Zhong H, Zha Q, Chen E (2020) A bibliometric analysis using
VOSviewer of publications on COVID-19. Ann Transl Med:8
147. Isah T (2019) Stress and defense responses in plant secondary metabolites production.
Biol Res 52
148. Khumalo GP, Van Wyk BE, Feng Y, Cock IE (2022) A review of the traditional use of
Southern African medicinal plants for the treatment of inflammation and inflammatory pain.
J Ethnopharmacol 283:114436
149. Quílez M, Ferreres F, López-Miranda S, Salazar E, Jordán MJ (2020) Seed oil from
Mediterranean aromatic and medicinal plants of the Lamiaceae family as a source of bioac-
tive components with nutritional. Antioxidants 9:510
150. Savych A, Milian I (2021) Total flavonoid content in the herbal mixture with antidiabetic
activity. PharmacologyonLine 2:68–75
151. Solnier J, Fladerer JP (2021) Flavonoids: a complementary approach to conventional therapy
of COVID-19? Phytochem Rev 20:773–795
152. Venkataramaiah C, Payani S, Priya BL, Pradeepkiran JA (2021) Therapeutic potentiality
of a new flavonoid against ketamine induced glutamatergic dysregulation in schizophrenia:
in vivo and in silico approach. Biomed Pharmacother 138:111453
Pharmacological Properties and Tissue
Culture Method of Endangered Medicinal
Plants

Yuhong Zheng, Xin Shi, and Li Fu

1 Introduction

China is one of the richest countries in the world in terms of plant species, with
more than 30,000 species of higher plants alone, accounting for about 10% of the
world’s species, including more than 11,000 species of medicinal plants. The 2020
edition of the Chinese Pharmacopoeia includes 602 species of medicinal origin
plants [1]. Only about half of these medicinal plant species have been propagated
and cultivated artificially, while the other half rely on the harvesting and processing
of wild resources for medicine. Due to long-term overharvesting and economic and
social development breaking the balance of the ecosystem, the wild resources of
some medicinal plants are becoming increasingly depleted. The Red Book of
Chinese Plants-Rare and Endangered Plants contains 168 species of medicinal
plants, accounting for 43.30% of all species, including 46 species of commonly
used traditional Chinese medicines and 19 species of bulk medicinal herbs (a total
of 27 origin plants) [2]. These rare and endangered medicinal plants share common
botanical characteristics, such as narrow distribution, slow growth rate, low fruit set,

Y. Zheng
Jiangsu Key Laboratory for the Research and Utilization of Plant Resources, Institute of
Botany, Jiangsu Province and Chinese Academy of Sciences (Nanjing Botanical Garden
Mem. Sun Yat-Sen), Nanjing, People’s Republic of China
X. Shi
Ningxia Institute of Quality Standards and Testing Technology for Agricultural Products,
Yinchuan, People’s Republic of China
L. Fu (*)
Key Laboratory of Novel Materials for Sensor of Zhejiang Province, College of Materials and
Environmental Engineering, Hangzhou Dianzi University,
Hangzhou, People’s Republic of China
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 1081

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_45
1082 Y. Zheng et al.

poor seed development, or difficulty in seed germination. These reasons cause their
natural populations to renew slowly and become rare and endangered. Therefore,
the development of artificial propagation techniques and population conservation
are prerequisites for the sustainable exploitation of such plants. This chapter will
provide an overview of the current status of research and conservation of propaga-
tion techniques for rare and endangered medicinal plants.
Among the methods of artificial propagation, seed propagation is undoubtedly the
easiest method. However, most of the rare and endangered medicinal plants have spe-
cial breeding systems and seed structures. They usually have long germination cycles
and low germination rates. Therefore, studying the biological properties and germina-
tion characteristics of seeds to improve the germination rate is the most important
research content and direction of seed propagation. Grafting propagation is only appli-
cable to woody rare and endangered medicinal plants, although the speed of seedling,
but the reproduction factor is not high. Its survival rate is greatly influenced by the age
of the scion and its affinity with the rootstock. Propagation by cuttings is suitable for all
woody and some herbaceous rare and endangered medicinal plants, with a larger repro-
duction factor but a longer seedling generation period. Its survival rate is influenced by
the season of cuttings, cutting substrate, age of the spike, and the type and concentra-
tion of rooting agent. Rapid propagation by tissue culture is a method applicable to all
cherished and endangered medicinal plants for rapid propagation. It has a high repro-
duction coefficient and fast reproduction rate and is especially suitable for rapid repro-
duction on a large scale and factory scale. It is the most intensively and extensively
studied method of rapid propagation of rare and endangered medicinal plants. However,
it is not easy to establish an efficient and stable technical system because the character-
istics of different species of plants themselves vary greatly.

2 Seed Propagation

Inefficient seed reproduction is one of the most direct causes of plant rarity and
endangerment. The main factors that make seed reproduction difficult are the fol-
lowing: (1) low fruit set due to special pollination methods; (2) long post-­maturation
period of seeds; (3) presence of seed germination inhibitors; and (4) difficulty in
germination due to special seed structure. In order to improve the ability of rare and
endangered plants to reproduce sexually, research has been conducted on their own
botanical characteristics.

2.1 Effect of Fruiting Rate on Seed Reproduction of Rare

and Endangered Plants

In the wild, orchids require specific pollinating insects to assist in pollination. Due
to the low number of pollinators or the special flower structure that cannot attract
pollinators, the Orchidaceae has only about 5% fruit set rate [3]. Combined with the
Pharmacological Properties and Tissue Culture Method of Endangered Medicinal Plants 1083

fact that the seed embryo of is Orchidaceae a multicellular primitive embryo body
and has no endosperm, most orchids have low seed germination rates [4–6]. Yagame
et al. [7] isolated symbiotic bacteria from Cremastra appendiculata that promote
seed germination, thus speculating that symbiotic germination may be the best way
to germinate seeds of Cremastra appendiculata. Unlike the orchids, the seeds of the
woody plant Magnolia officinalis varied in seed weight between 0.1 and 0.28 g in
different seed zones and in different orientation canopies [8–10]. Seed size was
found to be positively correlated with germination ability after grading seeds
according to single seed weight. The germination rate and average daily germina-
tion rate varied very much between grades. Differences in the contents of soluble
sugars, soluble proteins, and crude fats of the seeds of different grades during stor-
age also reached significant levels. Growth indicators such as mortality, seedling
height, and ground diameter of seedlings from large seeds were also significantly
better than those of small seeds.
The Tertiary relict Cercidiphyllum japonicum is a dioecious plant with a frag-
mented population distribution resulting in a low fruiting rate [11]. At the same
time, its seeds are small (only about 2.0 mm in width and 1.5 mm in length), which
also leads to low seed reproduction rate. Dosmann et al. [12, 13] chilling seeds at
3.5 °C for 8 d and placing them on a paper sprout bed at 25 °C in darkness or 15 h
of light increased their germination rate from 42% to 75%. A certain concentration
of gibberellin solution can also improve the germination rate of Cercidiphyllum
japonicum [14]. Ephedra sinica is a species in the Ephedraceae, with a long seed
development cycle, taking about 3 months from flowering to seed maturity. Although
it has a large number of flowers, but the flower defeat rate is high, and the flowers
and fruits are all easy to fall off, resulting in its low seed yield and poor quality [15,
16]. In addition, the thick and dense seed coat of Ephedra sinica hinders water
uptake during germination and reduces the rate of gas exchange. The presence of
germination-inhibiting substances within the seeds also contributes to the germina-
tion rate. Both the use of low-temperature lamination and treatment with gibberellin
significantly improved seed germination, resulting in 94% and 90% germination,
respectively, nearly three times higher than the control [17].

2.2 Effect of Breaking Dormancy on Plant Seed Reproduction

Seed dormancy is an adaptation acquired by plants during long-term evolution and

is an effective way to regulate the optimal timing and spatial distribution of seed
germination [18–22]. The seeds of many rare and endangered medicinal plants have
the phenomenon of dormancy, resulting in a low seedling rate and poor natural
renewal capacity of the population. It has been shown that the germination rate of
Rhodiola L. seeds in their natural state is only about 10%. The germination rate
could be increased after rinsing by running water, indicating the presence of germi-
nation inhibitors in Rhodiola L. seeds [23, 24]. Ferula sinkiangensis also has the
same characteristics. Nadjafi et al. [25] showed that daily rinsing under running
1084 Y. Zheng et al.

water coupled with refrigeration at 5 °C for 14 d was the most effective method to
break its dormancy, but the germination rate was only 26.1%. The seeds of the
genus Taxus have the phenomenon of after-ripening [26]. Germination inhibitors
are unevenly present in the lignified seed coat and are poorly permeable to water
and air [27, 28]. Therefore, the germination cycle is long in the natural state, usually
taking at least one year to germinate [29]. Panax ginseng is mainly propagated by
seeds, but the seeds have post-maturation characteristics and require long morpho-
logical and physiological maturation before germination. Some studies have shown
that gibberellin can promote Panax ginseng seed cleavage but not embryo growth
[30–32].

2.3 Effect of Germination Inhibitors on Plant

Seed Reproduction

Among the factors contributing to the long germination cycle of seeds of rare and
endangered medicinal plants, the widespread presence of germination inhibitors is
one of the most important factors. Such substances may be organic acids, alkaloids,
or some organic substances that release ammonia or cyanide upon decomposition.
They may be present in any part of the seed or fruit, and only when these inhibitory
substances are eliminated, can the seed germinate properly.
Rhodiola rosea substantially increased its germination rate either in 0–5 °C envi-
ronment or treated with 50–1000 mg/L gibberellin [33]. Low temperature and GA
relieved dormancy, thus promoting seed germination. The methanolic extract of
Rauvolfia yunnanensis seed kernels significantly reduced the germination rate of
Brassica campestris seeds, indicating the presence of germination inhibitors in the
seeds [34]. The germination rate of Rauvolfia yunnanensis seeds was significantly
increased up to more than 80% when the seeds were immersed at 28 °C for 24 h
under 200–2000 mg/L gibberellin. Both Cistanche deserticola and Cynomorium
songaricum are parasitic plants, and both have similar seed structures. The seed
embryo is a spherical protoembryo without differentiation of germ, radicle, and
cotyledons. The seeds contain the germination-inhibiting substance abscisic acid
[35–37]. Both seeds can be subjected to sufficient rainfall and can be showered with
germination-inhibiting material or finish post-maturing by lamination [37, 38]. Like
Cynomorium songaricum, Cistanche deserticola seed germination requires the pro-
duction of “shoot tubular organs” or “radicle-like structures” under the action of a
germination-stimulating substance released from the roots of the host plant. The end
of this structure expands to form primary suckers, which adhere to the surface of the
host root, then invade the host root, and connect with the vascular bundle of the host
plant to produce secondary suckers to complete the parasitic process [39–41]. In
their natural state, the chances of encountering host roots after the seeds of
Cynomorium songaricum and Cistanche deserticola mature are very small, which is
an important reason why these wild herbs are on the verge of depletion.
Pharmacological Properties and Tissue Culture Method of Endangered Medicinal Plants 1085

Sinopodophyllum hexandrum is a perennial herb in the family Berberaceae.

Although it has a fruit set rate of more than 87% and each fruit can contain up to 150
seeds, its seeds are dormant for up to 10 months under natural conditions [42]. In
addition, it is completely inactive if its seeds are stored at 4–6 °C for 1 year. On the
other hand, the dense seed coat and endosperm of its fruit also restrict the growth of
the radicle during germination, so the germination rate is not high under natural
conditions [43]. Therefore, a variety of intrinsic factors contribute to the endanger-
ment of Sinopodophyllum hexandrum. Both the seed coat and endosperm of Paeonia
rockii contain substances that inhibit seed germination and seedling growth in recip-
ient plants, and the seed coat is poorly permeable [44]. Both 300 mg/L gibberellin
or 40 °C warm water immersion significantly increased the germination rate, indi-
cating that these two methods increased the permeability of Paeonia rockii seed coat
and released the inhibition of seed germination by germination inhibitors [45].

3 Graft Propagation

The transfer of a part of a plant nutrient organ (branch, bud, scion, scion bud) to
another plant (rootstock) is to use interspecies affinity to make the scion and root-
stock heal at the formation layer of the union, so that the ducts and sieve tubes
interoperate and develop into a new individual. Therefore, the selection of scion and
rootstock is a key factor in the success of grafting. Compared with other asexual
propagation methods, grafting propagation has a low reproduction coefficient, but
the cycle of seedling establishment is short. Grafting is one of the most effective
methods of asexual propagation for woody plants that have difficulty cuttings
rooting.
Peng and Wang [46] developed a prediction model for the survival rate of
Eucommia ulmoides grafting using a quantitative regression method. The results
showed that the age and budding status of the mother plant were important factors
affecting the survival rate of Eucommia ulmoides grafting. Fan [47] found that the
thickness of the rootstock also had a significant effect on the growth of grafted
sprouting branches after grafting. Zhou et al. [48] found that with live seedlings of
Magnolia officinalis as rootstock, the survival rate of Magnolia officinalis popula-
tions from different sources differed significantly after grafting, as well as the
growth of branches and leaves after survival. In the grafting propagation of
Camptotheca acuminata, different sizes of scions had highly significant effects on
the survival rate of grafting and the growth of seedling height and diameter at breast
height of grafted seedlings [49]. For grafting of Torreya grandis, annual branches of
15 cm in length and 0.4 cm in diameter were selected, and the diameter of the scion
and rootstock were nearly equal [50]. The most suitable time for grafting is from
mid-February to early March to ensure a high survival rate. A study on grafting
seedlings of Taxus chinensis with 6-year-old rootstock and 1-year-old semi-woody
branches as scions found that when the scion was grafted in mid-February, the heal-
ing rate and tapping rate of the scion were highest. The tapping length was the
1086 Y. Zheng et al.

longest as well. The growth of the grafted seedlings was best when the scion was
grafted in mid-February and the buds were full and close to the interface. If the
3-year-old seedlings as rootstock, the scion with 1 leaf of the main tip of the reces-
sive axillary bud for the scion can promote the scion into bud early, improve the
survival rate of the main tip, and can form a complete crown shape. If you use
3-year-old seedlings and with a leaf of the main tip of the recessive axillary buds for
rootstock and scion, respectively, can promote the scion early into bud, improve the
survival rate of the main tip, and can form a complete crown shape [51].

4 Cutting Propagation

Propagation from cuttings is one of the most common ways of asexual propaga-
tion. The process involves intercepting a part of a plant’s nutritional organ, spray-
ing or dipping it in a certain concentration of rooting agent, and inserting it into a
loose and moist cultivation medium to make it root and branch and develop into a
complete plant. According to the source of the spike can also be divided into
branch cuttings, root cuttings, bud cuttings, and leaf cuttings. Compared with
other asexual propagation methods, the reproduction coefficient of cuttings is
high, fast, and easy to operate. The cuttings are generally semi-woody branches,
and the cuttings require a loose, water-holding medium. The season of cuttings
and the choice of rooting agent concentration are the most influential factors in
the survival rate of cuttings due to the great variation in the biological character-
istics of the plants themselves.
Chen et al. [52] showed that the most suitable period for cutting rooting of
Eucommia ulmoides cuttings in Beijing is from late May to mid-July. The survival
rate of 2-year-old young tree shoot for cutting can reach 60%, while the survival
rate of adult tree shoot for cutting is less than 20%. The rooting agents were effec-
tive in inducing adventitious root growth of the shoot. Among them, naphthale-
neacetic acid 50 μg/mL had the highest rooting rate. Both NAA and indolebutyric
acid promoted the rooting of Cercidiphyllum japonic shoot cuttings by combining
various indices such as rooting time, average root number, and root length [53].
IBA 100 mg/L + NAA 100 mg/L soaking the cuttings for 4 h was the most suitable
way to take cuttings. Since 2004, Fu et al. [54–59] conducted a systematic study
on the fast propagation technology of Taxus wallichiana var. mairei cuttings,
which involved the composition of cutting substrates, selection of spikes, types
and concentrations of rooting agents, the influence of factors such as cutting sea-
son on rooting, the management of light, fertilizer, pest control, and the construc-
tion of harvesting beds for cuttings. These works have laid the technical foundation
for the establishment of the rapid propagation technology system of cuttings of
Taxus wallichiana var. mairei. On this basis, Taxus cuspidata and Taxus × media
from the same genus have also achieved rapid reproduction of cuttings on a
large scale.
Pharmacological Properties and Tissue Culture Method of Endangered Medicinal Plants 1087

5 Tissue Culture Fast Propagation

Here, tissue culture is defined as the inoculation of a part of the plant body (i.e., the
explant, which can be a part or a whole organ), by aseptic manipulation, onto a
culture medium and cultivation in artificially controlled conditions to produce a
complete plant. Compared with other fast propagation methods, tissue culture
requires fewer plants, has a high reproduction coefficient, and is fast, which is the
main way to achieve large-scale fast propagation of rare and endangered plants.
According to whether to form healing tissue, group culture fast breeding can be
divided into two types: one is to induce exosomes to produce healing tissue and
proliferate, forming somatic embryos, and then differentiate from somatic embryos
to grow small plants (or direct differentiation of clumped shoots from healing tissue
after clumped shoot induction culture). This method of reproduction has the highest
reproduction coefficient and the fastest rate. The other type induces buds directly
from the explants without healing tissue induction and undergoes clumped bud
induction culture. Regardless of the route, the selection and sterilization of the
explants and the type and concentration of growth regulators used are crucial to the
success of fast breeding.
Chakraborty et al. [60] used Podophyllum hexandrum roots and rhizomes as
explants and Murashige-Skoog medium as the basic medium to induce clumped
shoots from the roots and rhizomes of Podophyllum hexandrum by adding cytokinin
KT and growth hormone 2,4-D, and eventually obtained sterile seedlings. Rajesh
et al. [61] inoculated the seed embryos of Podophyllum hexandrum onto MS medium
supplemented with 2,4-D (1.5 mg/L) and obtained embryonic healing tissue, which
was regulated by the addition of ABA to obtain a large number of somatic embryos.
After further differentiation and culture, the somatic embryos regenerated plantlets,
establishing a technical system for the regeneration of Peachy ginseng with seed
embryo explants. Tetrastigma hemsleyanum fast propagation can be carried out
using axillary buds, stem tips, and also young sprouted stem segments as explants
[62–64]. The low light is favorable for the sprouting of axillary buds [65–75]. The
reproduction factor of Dendrobium fimbriatum can be 5–7 times higher by using the
lateral buds and stem segments as explants, respectively, for group culture fast prop-
agation [76, 77]. The addition of certain concentrations of polyconazole and lantha-
num nitrate shortened the time of regenerative shoot differentiation of Dendrobium
fimbriatum test tube seedlings and increased the proliferation rate of histopatho-
genic seedlings. This treatment also promoted root differentiation, increased the
number of roots, and improved the rooting rate [78, 79].
The fast propagation of basal plant Anoectochilus roxburghii, Anoectochilus for-
mosanus, and Anoectochilus chapaensis of another group of medicinal plants of the
Orchidaceae has also been systematically studied [80–87]. They can be fastidiously
propagated by inducing clumped shoots from seeds after sterile germination. They
can also be used as explants with sprouted stem segments, stem tips, or stem pieces
about 2 mm thick to induce the production of adventitious shoots and thus obtain
clumped shoots for fast propagation.
1088 Y. Zheng et al.

6 Protection of Rare and Endangered Medicinal Plants

The conservation of rare and endangered plants is an important part of biodiversity

conservation. At present, the means of biodiversity conservation are mainly in situ
conservation and relocation conservation. Unlike other rare and endangered plants,
the conservation of rare and endangered medicinal plants can also be realized with
their in-depth exploitation and establishment of standardized production bases to
achieve the dual goals of conservation and promotion and application.

6.1 In Situ Conservation

In situ conservation refers to the protection of valuable ecosystems and wildlife and
their habitats by means of various types of nature reserves and national parks. This
approach is used to maintain the reproduction and evolution of organisms and the
flow of material and energy and ecological processes within the ecosystem. The
principle of in situ conservation is to achieve the conservation of endangered spe-
cies through the conservation of the ecological environment and the integrity of
biological taxa [88, 89]. It is the preferred measure for the conservation of rare and
endangered species. National parks are another form of protected area that first
originated in the United States and has since been adopted by most countries and
regions around the world [90]. The establishment of national parks is an important
element in the construction of Chinese ecological civilization system, which can
protect the originality and integrity of natural ecology and natural cultural heritage
[90, 91]. It provides stricter protection for important ecosystems, while providing
long-term protection for rare wildlife and plants [92–94]. As of 2020, China has
established 10 national park, including Sanjiangyuan, Hainan Tropical Rainforest,
and Shennongjia, with a total area of 222,900 square kilometers. The established
nature reserves and national parks have enabled the effective protection of almost all
rare and endangered species on the Red Book of Rare and Endangered Plants of
China, including rare and endangered medicinal plants.

6.2 Ex Situ Conservations

Ex situ conservation refers to the relocation of species whose survival and reproduc-
tion are seriously threatened due to the non-existence of living conditions and very
low numbers of species out of their original locations to zoos, botanical gardens, or
breeding centers for endangered plants and animals for conservation and manage-
ment [95, 96]. Ex situ conservation is a useful complement to in situ conservation
and is an important part of biodiversity conservation [97]. Ex situ conservation can
temporarily preserve and protect a certain number of populations for a short period
Pharmacological Properties and Tissue Culture Method of Endangered Medicinal Plants 1089

of time [98]. For rare and endangered medicinal plants, botanical gardens, arbore-
tums, or medicinal plant gardens are the ideal places for their ex situ conservation
[99, 100]. The construction level of Chinese botanical gardens and medicinal botan-
ical gardens is close to the level of developed countries. At present, there are 162
botanical gardens and arboretums in China, with a total area of 102,007 hectares.
These botanical and arboretum gardens protect 42.5% of the rare and endangered
plants in the Red Book of Rare and Endangered Plants of China.
At present, there is a contradiction in the development of Chinese herbal medi-
cine industry: On the one hand, there is a serious lack of raw materials for products
based on rare and endangered plants in the herbal medicine market [101–103]. On
the other hand, a lot of human and material resources are needed for the ex situ and
in situ conservation of rare and endangered medicinal plants. From the above review,
it is clear that the most important reason for the endangerment of rare and endan-
gered plants is that their own breeding systems are somehow defective [104, 105].
If we can strengthen the research of artificial propagation and supporting cultivation
technology of rare and endangered medicinal plants while protecting them in situ
and ex situ them, we can not only provide sufficient raw materials for herbs and
medicines, but also make rare and endangered medicinal plants protected or even
get out of the endangered status.

7 Conclusion

Beginning with the establishment of nature reserves in the 1950s to protect rare and
endangered medicinal plants in situ, research on rare and endangered medicinal
plants has been conducted in China for more than 70 years. Botanists have studied
the reproductive biology of many rare and endangered plants and have also estab-
lished a system of artificial breeding techniques for many rare and endangered
plants. The systematic study of the reproductive biology of orchids found that the
pollination of orchids is dominated by insect vectors, but some taxa lack sufficient
pollinators due to the low number of pollinating insects in their distribution sites or
the special flower structure and thus have low fruit set rates. In addition, the seed
embryos of some orchids are incompletely developed and have no endosperm, so
there is a long germination cycle due to the phenomenon of post-maturation. At the
same time, the supply of nutrients for seed germination is not guaranteed, resulting
in low germination rate. Besides, symbiotic fungi were also isolated from sme rare
and endangered orchid medicinal plants, and it is speculated that they may have
symbiotic germinahion. Based on the results of these |studies, targeted strategies
were developed to greatly improve the germination rate and reproduction ability of
rare and endangered medicinal plants of the orchid family and laid the foundation
for the development and utilization of rare and endangered medicinal plants of the
Orchidaceae. It should be noted, however, that there are many rare and endangered
plants whose reproductive biology and propagation methods have not been studied
systematically and thoroughly enough. Therefore, they have not been established a
1090 Y. Zheng et al.

proven artificial breeding system, such as the rare and endangered medicinal fern,
Cibotium barometz, is one of them. Therefore, we still have much work to do to
strengthen the research, protection, development, and utilization of rare medicinal
plant and animal resources and to promote the development of China’s traditional
Chinese medicine industry.

References

1. Xu X, Xu H, Shang Y, Zhu R, Hong X, Song Z, Yang Z (2021) Development of the general

chapters of the Chinese Pharmacopoeia 2020 edition: a review. J Pharm Anal 11:398
2. Qin H, Jin X, Zhao L (2020) Rare and endangered plants in China. In: Conservation and
reintroduction of rare and endangered plants in China. Springer, pp 21–31
3. Hossain MM, Sharma M, Pathak P (2013) In vitro propagation of Dendrobium aphyllum
(Orchidaceae)—seed germination to flowering. J Plant Biochem Biotechnol 22:157–167
4. Kananont N, Pichyangkura R, Chanprame S, Chadchawan S, Limpanavech P (2010) Chitosan
specificity for the in vitro seed germination of two Dendrobium orchids (Asparagales:
Orchidaceae). Sci Hortic 124:239–247
5. Thompson DI, Edwards TJ, van Staden J (2006) Evaluating asymbiotic seed culture methods
and establishing Disa (Orchidaceae) germinability in vitro: relationships, requirements and
first-time reports. Plant Growth Regul 49:269–284
6. Hosomi ST, Custódio CC, Seaton PT, Marks TR, Machado-Neto NB (2012) Improved assess-
ment of viability and germination of Cattleya (Orchidaceae) seeds following storage. Vitro
Cell. Dev. Biol.-Plant. 48:127–136
7. Yagame T, Funabiki E, Nagasawa E, Fukiharu T, Iwase K (2013) Identification and symbiotic
ability of Psathyrellaceae fungi isolated from a photosynthetic orchid, Cremastra appendicu-
lata (Orchidaceae). Am J Bot 100:1823–1830
8. Tan M, Yang Z, Yang X (2018) Study on seed germination and seedling growth of Houpo a
officinalis in different habitats. J Ecol Rural Environ 34:910–916
9. Xiao S, Xu Y, Zhiling Y (2012) Variation in seed and seedling traits among fifteen Chinese
provenances of Magnolia officinalis. Not Bot Horti Agrobot Cluj-Napoca 40:274–283
10. Zhou J, Kulkarni M, Huang L-Q, Guo L-P, Van Staden J (2012) Effects of temperature, light,
nutrients and smoke-water on seed germination and seedling growth of Astragalus mem-
branaceus, Panax notoginseng and Magnolia officinalis—highly traded Chinese medicinal
plants. South Afr J Bot 79:62–70
11. Kubo M, Sakio H, Shimano K, Ohno K (2004) Factors influencing seedling emergence and
survival in Cercidiphyllum japonicum. Folia Geobot 39:225–234
12. Dosmann MS, Iles JK, Widrlechner MP (2000) Stratification and light improve germination
of Katsura tree seed. HortTechnology 10:571–573
13. Dosmann MS, Iles JK (1997) Cold stratification improves germination of katsura tree.
HortScience 32:447F–448
14. Xue-long C, Fei W, Quan-ding D, Zuo-lin F, Hao Q (2017) Effect of temperature and hor-
mone of different provenance to Cercidiphyllum Japonicum Sieb. et Zucc. seed germination.
J Sichuan For Sci Technol 34:34–39
15. Xianjun W (2009) Study on physiological characteristics of seed germination of Ephedra
sinica. J Chin Med Mater 32:656–659
16. Ng JY, Marwaha A, Ans M (2021) The quality of information available about Ephedra sinica
on online vendor websites: the Canadian consumer experience. Complement Ther Med
57:102674
17. Limei S (2008) Effects of hormone treatments on the germination and seedling rate of
Ephedra sinica seeds. J Anhui Agric Sci 36:3512
Pharmacological Properties and Tissue Culture Method of Endangered Medicinal Plants 1091

18. Tasheva K, Kosturkova G (2012) The role of biotechnology for conservation and biologically
active substances production of Rhodiola rosea: endangered medicinal species. Sci World J
2012:274942. https://doi.org/10.1100/2012/274942
19. Karimi-Maleh H, Orooji Y, Karimi F, Alizadeh M, Baghayeri M, Rouhi J, Tajik S, Beitollahi
H, Agarwal S, Gupta VK (2021) A critical review on the use of potentiometric based biosen-
sors for biomarkers detection. Biosens Bioelectron 184:113252
20. Karimi-Maleh H, Khataee A, Karimi F, Baghayeri M, Fu L, Rouhi J, Karaman C, Karaman
O, Boukherroub R (2021) A green and sensitive guanine-based DNA biosensor for idaru-
bicin anticancer monitoring in biological samples: a simple and fast strategy for control of
health quality in chemotherapy procedure confirmed by docking investigation. Chemosphere
291:132928. https://doi.org/10.1016/j.chemosphere.2021.132928
21. Karimi-Maleh H, Karimi F, Fu L, Sanati AL, Alizadeh M, Karaman C, Orooji Y (2022)
Cyanazine herbicide monitoring as a hazardous substance by a DNA nanostructure biosen-
sor. J Hazard Mater 423:127058. https://doi.org/10.1016/j.jhazmat.2021.127058
22. Karimi-Maleh H, Ayati A, Davoodi R, Tanhaei B, Karimi F, Malekmohammadi S, Orooji
Y, Fu L, Sillanpää M (2021) Recent advances in using of chitosan-based adsorbents for
removal of pharmaceutical contaminants: a review. J Clean Prod 291:125880. https://doi.
org/10.1016/j.jclepro.2021.125880
23. Tasheva K, Kosturkova G (2010) Rhodiola rosea in vitro cultures peculiarities. Sci
Publications Univ Agron Sci Vet Med 2010b:103–112
24. Erst A, Yakubov V (2019) Regenerative in vitro capacity of rare species Rhodiola rosea
L. from various habitats. Contemp Probl Ecol 12:368–376
25. Nadjafi F, Bannayan M, Tabrizi L, Rastgoo M (2006) Seed germination and dormancy break-
ing techniques for Ferula gummosa and Teucrium polium. J Arid Environ 64:542–547
26. Bian F, Su J, Liu W, Li S (2018) Dormancy release and germination of Taxus yunnanensis
seeds during wet sand storage. Sci Rep 8:3205. https://doi.org/10.1038/s41598-­018-­21469-­9
27. Liu D, Yu HL, Li FL, Guo HH (2011) An analysis of dormancy and dormancy release in
Taxus chinensis var. mairei seeds. Seed Sci Technol 39:29–43. https://doi.org/10.15258/
sst.2011.39.1.04
28. Muñoz-Gutiérrez L, Vargas-Hernández JJ, López-Upton J, Soto-Hernández M (2009) Effect
of cutting age and substrate temperature on rooting of Taxus globosa. New For 38:187–196.
https://doi.org/10.1007/s11056-­009-­9139-­6
29. Iszkuło G, Boratyński A (2004) Interaction between canopy tree species and European yew
Taxus baccata (Taxaceae). Pol J Ecol 52:523–531
30. Hong CP, Kim J, Lee J, Yoo S, Bae W, Geem KR, Yu J, Jang I, Jo IH, Cho H (2021)
Gibberellin signaling promotes the secondary growth of storage roots in Panax ginseng. Int
J Mol Sci 22:8694
31. Lee J-W, Jo I-H, Kim J-U, Hong C-E, Kim Y-C, Kim D-H, Park Y-D (2018) Improvement
of seed dehiscence and germination in ginseng by stratification, gibberellin, and/or kinetin
treatments. Hortic Environ Biotechnol 59:293–301
32. Kim J, Shin W-R, Kim Y-H, Shim D, Ryu H (2021) Functional characterization of gibberellin
signaling-related genes in Panax ginseng. J. Plant Biotechnol. 48:148–155
33. Bilinska E, Buchwald W, Krajewska-Patan A (2010) Biology of germination of medicinal
plant seeds. Part XXIIa. Seeds of Rhodiola kirilowii (Regel.) Maxim from Crassulaceae fam-
ily. Herba Pol 56:7–13
34. Wang F, Cai C, Wen B (2011) Study on the characteristics of seed dormancy and germination
of Rauvolfia yunnanensis (Apocynaceae). Plant Divers Resour 33:229–234
35. Dong S, Zhang Y, Chen N, Li C, Gao H (2011) Study on characteristics of seeds dormancy
and germination of parasitic plant Cynomorium songaricum Rupr. Med. Plant. 2:1–12
36. Chen QL, Guo Y, Jiang Y, Tu P (2016) Mechanism of fluridone-induced seed germination of
Cistanche tubulosa. Pak J Bot 48:971–976
1092 Y. Zheng et al.

37. Wang J, Baskin JM, Baskin CC, Liu G, Yang X, Huang Z (2017) Seed dormancy and ger-
mination of the medicinal holoparasitic plant Cistanche deserticola from the cold desert of
Northwest China. Plant Physiol Biochem 115:279–285
38. Wenmei F, Geer S (2002) The comparison of the dynamic changes of endogenous hormones
between Cynomorium songaricum Rupr. and Avena chinensis Metag. during the germination
of their seeds. Acta Sci Nat Univ Neimonggol Nat Sci Ed 33:304–308
39. Yang Y, Yi X, Peng M, Zhou Y (2012) Stable carbon and nitrogen isotope signatures of root-­
holoparasitic Cynomorium songaricum and its hosts at the Tibetan plateau and the surround-
ing Gobi desert in China. Isot Environ Health Stud 48:483–493
40. Jiang Z-H, Tanaka T, Sakamoto M, Jiang T, Kouno I (2001) Studies on a medicinal para-
sitic plant: lignans from the stems of Cynomorium songaricum. Chem Pharm Bull (Tokyo)
49:1036–1038
41. Cui J-L, Vijayakumar V, Zhang G (2018) Partitioning of fungal endophyte assemblages
in root-parasitic plant Cynomorium songaricum and its host Nitraria tangutorum. Front
Microbiol 9:666
42. Badhwar R, Sharma H (1963) A note on the germination of Podophyllum seeds. Indian For
89:445–447
43. Nadeem M, Palni L, Purohit A, Pandey H, Nandi S (2000) Propagation and conservation
of Podophyllum hexandrum Royle: an important medicinal herb. Biol Conserv 92:121–129
44. Li Z, Qin G, He J, Cao X (2010) Comparative analysis of fatty acid composition in seed
kernel and coat of Paeonia rockii seeds. Seed 29:34–36
45. Zhang S, Tang H, Li W, Zhang R, He L (2020) Hypocotyl germination and cotyledon ana-
tomical structure of Paeonia rockii seeds by soaking with gibberellic acid and warm water.
Acta Bot Boreali-Occident Sin 40:442–453
46. Peng C, Wang P (1998) An analysis of the main elements in predicting the graft survival rate
of Eucommia ulmoides Oliv. J Hubei Inst Natl 6:24–26
47. Fan G (2008) A comparative study on the gratification and survival rates 40 clones of
Eucommia ulmoides. J Northwest For Univ 23:91–94
48. Zhou C, Tan M, Liu J, Cheng X (2019) Experimental study on the grafting and preservation
of the seed source of Magnolia officinalis. Jilin For Sci Technol 48:7–14
49. Su F, Lan J, Feng L (2012) Experimental study on Camptotheca acuminata Grafting. North
Hortic 19:62–65
50. Tang Z, Wu X (2008) Study on seedling technique for Chinese Torreya in Jingdezhen City.
Acta Agric Jiangxi 20:110–111
51. Yu M (2014) Grafting test of Taxus wallichiana var.mairei. J Fujian For Sci Technol 4:132–135
52. Chen Z, Zhang L (1998) Research on propagation technology of Eucommia cuttings. Chin
Herb Med 29:334–337
53. Mai M, Wang M, Shi D (2011) Study on twig cutting propagation techniques of Cercidiphyllum
japonicum. J. Fujian For. Sci. Technol. 38:102–106
54. Fu R, Huang Q, Liu A, Xu L, Huang X (2006) Studies on cutting propagation of Taxus chi-
nensis var. mairei VII. Comparison of photosynthesis physiological characteristics between
the seed seedlings and the cutting seedlings. Chin J Eco-Agric 14:62–63
55. Fu R, Sun X, Huang Q, Zhu J, Xu L (2005) Studies on the cutting propagation of Taxus
chinensis var.mairei.III .Effects of foliage fertilizer and transparency on growth of the cut
seedlings. Chin J Eco-Agric 13:175–177
56. Fu R, Xiaodong S, Qi H, Xueling H, Luxia X (2005) Studies on the cutting propagation of
Taxus chinensis var. mairei. IV. Effects of rooting powder on the rooting of the cutting. Chin
J Eco-Agric 13:178–180
57. Fu R, Zhu J, Huang Q, Lin Z, Huang J (2006) Studies on the cutting propagation of Taxus
chinensis var mairei V Occurrence and control of pests and diseases of the cuttage seedling
in greenhouse. Chin J Eco-Agric 14:193–195
Pharmacological Properties and Tissue Culture Method of Endangered Medicinal Plants 1093

58. Fu R, Zhu J, Liu S, Fang D, Ke Y (2006) Studies on cutting propagation of Taxus chinensis
var. mairei VII. Comparison of physiological metabolism between the seed seedlings and the
cutting seedlings. Chin J Eco-Agric 14:64–65
59. Fu S, Huang Q, Hu Z (2005) Studies on the cutting propagation of Taxus chinensis var.mairei
.I .Effects of medium, season and biological measures on the cutting propagation. Chin J
Eco-Agric 13:37–38
60. Chakraborty A, Bhattacharya D, Ghanta S, Chattopadhyay S (2010) An efficient protocol for
in vitro regeneration of Podophyllum hexandrum, a critically endangered medicinal plant.
Indian J Biotechnol 9:217–220
61. Rajesh M, Sivanandhan G, Jeyaraj M, Chackravarthy R, Manickavasagam M, Selvaraj N,
Ganapathi A (2014) An efficient in vitro system for somatic embryogenesis and podophyl-
lotoxin production in Podophyllum hexandrum Royle. Protoplasma 251:1231–1243
62. Du S, Xiang T, Song Y, Huang L, Sun Y, Han Y (2015) Transgenic hairy roots of Tetrastigma
hemsleyanum: induction, propagation, genetic characteristics and medicinal components.
Plant Cell Tissue Organ Cult PCTOC 122:373–382
63. Hu W, Zheng Y, Xia P, Liang Z (2021) The research progresses and future prospects
of Tetrastigma hemsleyanum Diels et Gilg: a valuable Chinese herbal medicine. J
Ethnopharmacol 271:113836
64. Peng X, Ji Q, Wu H, Li Y (2015) Slow-growth conservation and clonal fidelity of Tetrastigma
hemsleyanum microplants. Vitro Cell Dev Biol-Plant 51:463–470
65. Jiang W, Fu Y, Zhou X, Fu C (2011) High-frequency shoot regeneration of nodal explants
from Tetrastigma hemsleyanum Diels et Gilg: a valuable medicinal plant. Afr J Biotechnol
10:12177–12181
66. Xu L, Liu S, Bai Y, Ding H, Hu X, Wu X, Xu H, Zheng B (2018) Effects of light intensity
treatments on photosynthetic characteristics in Tetrastigma hemsleyanum. J Zhejiang AF
Univ 35:467–475
67. Zhou J, Zheng Y, Zhang J, Karimi-Maleh H, Xu Y, Zhou Q, Fu L, Wu W (2020) Characterization
of the electrochemical profiles of lycoris seeds for species identification and infrageneric
relationships. Anal Lett 53:2517–2528. https://doi.org/10.1080/00032719.2020.1746327
68. Wang Y, Pan B, Zhang M, Du X, Wu W, Fu L, Zhou W, Zheng Y (2020) Electrochemical
profile recording for pueraria variety identification. Anal Sci 36:20P079
69. Fu L, Su W, Chen F, Zhao S, Zhang H, Karimi-Maleh H, Yu A, Yu J, Lin C-T (2021) Early
sex determination of Ginkgo biloba based on the differences in the electrocatalytic perfor-
mance of extracted peroxidase. Bioelectrochemistry 140:107829. https://doi.org/10.1016/j.
bioelechem.2021.107829
70. Fu L, Wang A, Lyv F, Lai G, Zhang H, Yu J, Lin C-T, Yu A, Su W (2018) Electrochemical
antioxidant screening based on a chitosan hydrogel. Bioelectrochemistry 121:7–10. https://
doi.org/10.1016/j.bioelechem.2017.12.013
71. Fu L, Zheng Y, Zhang P, Zhang H, Wu M, Zhang H, Wang A, Su W, Chen F, Yu J, Cai
W, Lin C-T (2019) An electrochemical method for plant species determination and classi-
fication based on fingerprinting petal tissue. Bioelectrochemistry 129:199–205. https://doi.
org/10.1016/j.bioelechem.2019.06.001
72. Xu Y, Lu Y, Zhang P, Wang Y, Zheng Y, Fu L, Zhang H, Lin C-T, Yu A (2020) Infrageneric
phylogenetics investigation of Chimonanthus based on electroactive compound profiles.
Bioelectrochemistry 133:107455. https://doi.org/10.1016/j.bioelechem.2020.107455
73. Fan B, Wang Q, Wu W, Zhou Q, Li D, Xu Z, Fu L, Zhu J, Karimi-Maleh H, Lin C-T (2021)
Electrochemical fingerprint biosensor for natural indigo dye yielding plants analysis.
Biosensors 11:155. https://doi.org/10.3390/bios11050155
74. Fu L, Zhu J, Karimi-Maleh H (2021) An analytical method based on electrochemical sensor
for the assessment of insect infestation in flour. Biosensors 11:325. https://doi.org/10.3390/
bios11090325
1094 Y. Zheng et al.

75. Zheng Y, Wang D, Li X, Wang Z, Zhou Q, Fu L, Yin Y, Creech D (2021) Biometric iden-
tification of Taxodium spp. and their hybrid progenies by electrochemical fingerprints.
Biosensors 11:403
76. Tikendra L, Potshangbam AM, Dey A, Devi TR, Sahoo MR, Nongdam P (2021) RAPD,
ISSR, and SCoT markers based genetic stability assessment of micropropagated Dendrobium
fimbriatum Lindl. Var. oculatum Hk. f.-an important endangered orchid. Physiol Mol Biol
Plants 27:341–357
77. Roy J, Banerjee N (2003) Induction of callus and plant regeneration from shoot-tip explants
of Dendrobium fimbriatum Lindl. var. oculatum Hk. f. Sci Hortic 97:333–340
78. Da Silva JAT, Tsavkelova EA, Ng TB, Parthibhan S, Dobránszki J, Cardoso JC, Rao M, Zeng
S (2015) Asymbiotic in vitro seed propagation of Dendrobium. Plant Cell Rep 34:1685–1706
79. Luo J, Cheng Z, Long C (2006) Studies on the rapid propagation and in vitro storage of
Dendrobium candidum. Guihaia 26:69–73
80. Zhang A, Wang H, Shao Q, Xu M, Zhang W, Li M (2015) Large scale in vitro propagation of
Anoectochilus roxburghii for commercial application: pharmaceutically important and orna-
mental plant. Ind Crop Prod 70:158–162
81. Gam DT, Khoi PH, Ngoc PB, Linh LK, Hung NK, Anh PTL, Thu NT, Hien NTT, Khanh TD,
Ha CH (2020) LED lights promote growth and flavonoid accumulation of Anoectochilus rox-
burghii and are linked to the enhanced expression of several related genes. Plan Theory 9:1344
82. Lin X, Jiang X, Yang Z, Ma X, Yan X, Yang L (2018) Tissue culture rapid propagation and
transplantation techniques of Anoectochilus roxburghii (Wall) Lind. Med Plant 9:43–46
83. Ket N, Hahn E, Park S, Chakrabarty D, Paek K (2004) Micropropagation of an endangered
orchid Anoectochilus formosanus. Biol Plant 48:339–344
84. Zhang F, Lv Y, Dong H, Guo S (2010) Analysis of genetic stability through Intersimple
sequence repeats molecular markers in micropropagated plantlets of Anoectochilus formosa-
nus H AYATA, a medicinal plant. Biol Pharm Bull 33:384–388
85. Du X, Sun N, Hayashi J, Chen Y, Sugiura M, Shoyama Y (2003) Hepatoprotective and anti-
hyperliposis activities of in vitro cultured Anoectochilus formosanus. Phytother Res Int J
Devoted Pharmacol Toxicol Eval Nat Prod Deriv 17:30–33
86. Lv T, Teng R, Shao Q, Wang H, Zhang W, Li M, Zhang L (2015) DNA barcodes for the iden-
tification of Anoectochilus roxburghii and its adulterants. Planta 242:1167–1174
87. Dan Y, Yu X, Guo S-X, Meng Z (2012) Effects of forty-two strains of orchid mycorrhizal
fungi on growth of plantlets of Anoectochilus roxburghii. Afr J Microbiol Res 6:1411–1416
88. Ma J, Rong K, Cheng K (2012) Research and practice on biodiversity in situ conservation in
China: progress and prospect. Biodivers Sci 20:551–558
89. Heywood VH (2015) In situ conservation of plant species–an unattainable goal? Isr J Plant
Sci 63:211–231
90. Tan S, Zhong Y, Yang F, Gong X (2021) The impact of Nanshan National Park concession
policy on farmers’ income in China. Glob Ecol Conserv 31:e01804
91. Wu J, Wu G, Zheng T, Zhang X, Zhou K (2020) Value capture mechanisms, transaction
costs, and heritage conservation: a case study of Sanjiangyuan National Park. China Land
Use Policy 90:104246
92. Wang G, Innes JL, Wu SW, Krzyzanowski J, Yin Y, Dai S, Zhang X, Liu S (2012) National
park development in China: conservation or commercialization? Ambio 41:247–261
93. He S, Su Y, Wang L, Gallagher L, Cheng H (2018) Taking an ecosystem services approach for
a new national park system in China. Resour Conserv Recycl 137:136–144
94. Peng H, Zhang J, Lu L, Tang G, Yan B, Xiao X, Han Y (2017) Eco-efficiency and its determi-
nants at a tourism destination: a case study of Huangshan National Park. China Tour Manag
60:201–211
95. Volis S, Blecher M (2010) Quasi in situ: a bridge between ex situ and in situ conservation of
plants. Biodivers Conserv 19:2441–2454
96. Barazani O, Perevolotsky A, Hadas R (2008) A problem of the rich: prioritizing local plant
genetic resources for ex situ conservation in Israel. Biol Conserv 141:596–600
Pharmacological Properties and Tissue Culture Method of Endangered Medicinal Plants 1095

97. Perrino EV, Wagensommer RP (2021) Crop wild relatives (CWR) priority in Italy: distribu-
tion, ecology, in situ and ex situ conservation and expected actions. Sustainability 13:1682
98. Patel AK, Lodha D, Shekhawat NS (2020) An improved micropropagation protocol for the
ex situ conservation of Mitragyna parvifolia (Roxb.) Korth.(Rubiaceae): an endangered tree
of pharmaceutical importance. Vitro Cell. Dev. Biol.-Plant. 56:817–826
99. Grigoriadou K, Sarropoulou V, Krigas N, Maloupa E, Tsoktouridis G (2020) GIS-facilitated
effective propagation protocols of the endangered local endemic of crete Carlina diae (Rech.
f.) Meusel and A. Kástner (Asteraceae): serving ex situ conservation needs and its future
sustainable utilization as an ornamental. Plan Theory 9:1465
100. Thapa BB, Thakuri LS, Joshi PR, Chand K, Rajbahak S, Sah AK, Shrestha R, Paudel MR,
Park SY, Pant B (2020) Ex-situ conservation and cytotoxic activity assessment of native
medicinal orchid: Coelogyne stricta. J Plant Biotechnol 47:330–336
101. Wei X, Jiang M (2021) Meta-analysis of genetic representativeness of plant populations
under ex situ conservation in contrast to wild source populations. Conserv Biol 35:12–23
102. Ciocarlan N, Izverscaia T, Ghendov V (2018) Spontaneous medicinal plants research and
ex-situ conservation in the national botanical garden (institute), Republic of Moldova. Rev
Bot 16:50–56
103. Streczynski R, Clark H, Whelehan LM, Ang S-T, Hardstaff LK, Funnekotter B, Bunn E,
Offord CA, Sommerville KD, Mancera RL (2019) Current issues in plant cryopreserva-
tion and importance for ex situ conservation of threatened Australian native species. Aust J
Bot 67:1–15
104. Engels JM, Ebert AW (2021) A critical review of the current global ex situ conservation
system for plant agrobiodiversity. I. History of the development of the global system in
the context of the political/legal framework and its major conservation components. Plan
Theory 10:1557
105. Dostatny DF, Żurek G, Kapler A, Podyma W (2021) The ex situ conservation and potential
usage of crop wild relatives in Poland on the example of grasses. Agronomy 11:94
Natural Compounds with Pharmacological
Properties in Clinical Trials

Morvarid Noormohammadi and Farzad Shidfar

1 Introduction

Natural products serve as a repository for identifying novel leads that may be uti-
lized to treat various illnesses, including cancer, inflammation, and liver disease.
Natural chemicals or their derivatives have been the source of more than 50% of all
pharmaceutical drugs found to date [1]. Nowadays, medicinal plants have received
increased interest in both studies and clinical practice due to their minimal side
effects and availability. In most cases, herbal medications are utilized as a comple-
mentary and adjunct treatment for various conditions, such as type 2 diabetes mel-
litus (T2DM) or cardiovascular disease (CVD) [2]. This chapter introduces some
common types of these natural compounds and reviews clinical trials performed on
these natural compounds. The possible mechanisms for the observed impact are
then described.

2 Curcumin

Curcumin is a natural active phytochemical and one of the principal compounds

extracted from turmeric, the rhizome of Curcuma longa [3–5]. According to the
World Health Organization (WHO), curcumin can be used as a food additive in
0–3 mg/kg [6]. Curcumin has shown antioxidant, anti-inflammatory, anticancer, and
wound-healing properties according to in vitro and in vivo analysis [5, 7–15].
Several pharmacokinetic investigations of curcumin have shown that its

M. Noormohammadi · F. Shidfar (*)

Department of Nutrition, School of Public Health, Iran University of Medical Sciences,
Tehran, Iran
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 1097

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_46
1098 M. Noormohammadi and F. Shidfar

bioavailability is limited, owing to its instability, insufficient solubility and absorp-

tion, and quick metabolic clearance through reduction and conjugation in the exis-
tence of moderate temperature and illumination. Similarly, rat researches show that
curcumin‘s low absorption in humans is a primary obstacle to achieving enough
plasma levels with beneficial pharmacological effects. This bright-yellow natural
compound has great antioxidant potencies. In this way, curcumin may neutralize
lipid radicals in the cell membrane, earning it the title of “potent lipid-soluble anti-
oxidant.” Besides, curcumin has been shown to suppress lipid peroxidation and neu-
tralize reactive oxygen species (ROS, superoxide, peroxyl, and hydroxyl radicals
and RNS (reactive nitrogen species, nitric oxide, NO, and peroxynitrite) in the body.
According to studies, curcumin protects against oxidative stress [16]. Curcumin was
most often administered at doses ranging from 50 to 200 mg/kg body weight, higher
than in clinical studies. Later studies employed 1000 mg per day or 500 mg per day
for 8 weeks to get the desired results [17].
Curcumin supplementation in a dose of 1.5 g/day plus lifestyle adjustments for
12 weeks has not shown any superiority rather than lifestyle adjustments alone on
hepatic steatosis, liver enzymes, tumor necrosis-α (TNF-α), and inflammation in
individuals with nonalcoholic fatty liver disease (NAFLD) [18]. In a similar trial,
phospholipid curcumin intake in a dose of 250 mg per day for 2 months decreased
the grade of liver steatosis and aspartate aminotransferase (AST) in NAFLD
patients [19].
Turmeric has been used as a diabetic remedy for hundreds of years, and it con-
tinues to be used today. It has attracted scientific attention primarily because it
effectively controls blood glucose levels and hyperlipidemia in rodent studies and is
somewhat cost-effective and safe. Since then, curcumin has been examined in a few
human studies of T2DM patients to see whether it may help them with their difficul-
ties. In addition to insulin resistance, hyperglycemia, hyperlipidemia, and islet
apoptosis and necrosis, curcumin has been shown to benefit many other aspects of
diabetes, including inflammation. Furthermore, curcumin may be protective against
the negative consequences of diabetic condition. However, data from clinical stud-
ies of curcumin are only available in the treatment of diabetic nephropathy, micro-
angiopathy, and retinopathy, which are all conditions associated with diabetes [20].
In addition, in patients at high risk for T2DM, 180 mg per day curcumin supplemen-
tation for 12 weeks resulted in significantly lower circulating GSK-3β, islet amyloid
polypeptide, and insulin resistance [21].
Nano-micelle curcumin has more bioavailability compared to curcumin powder.
A recent clinical trial has shown the triglyceride-lowering potencies of 80 mg/day
nano-micelle curcumin supplementation in individuals with metabolic syndrome
for 12 weeks [22].
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women
of reproductive ages associated with an inflammatory condition, oxidative stress,
and hyperandrogenism [23]. Supplementation with 1.5 g/day curcumin divided into
three equal doses for 12 weeks has shown positive effects on oxidative stress in
women with PCOS by a significant increase in gene expression of peroxisome
proliferator-­activated receptor γ coactivator 1α (PGC1α) and glutathione peroxidase
Natural Compounds with Pharmacological Properties in Clinical Trials 1099

(Gpx) enzyme activity. It was also associated with beneficial potencies in hyperan-
drogenemia (by lowering Dehydroepiandrosterone) and hyperglycemia (by lower-
ing fasting plasma glucose) in these patients [24, 25]. Curcumin supplementation
with a lower dose, 500 mg per day for 12 weeks, resulted in weight loss, body mass
index (BMI) reduction, and glycemic control properties by reducing fasting glu-
cose, insulin, insulin resistance, and enhancing insulin sensitivity. After the inter-
vention, it was also associated with lower total cholesterol, low-density
lipoprotein-­cholesterol (LDL-chol), total cholesterol (total-chol) to high-density
lipoprotein-cholesterol (HDL-chol) ratio, and higher HDL-chol levels. Besides,
gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ)
and LDL receptor increased [26]. Glycemic control properties of curcumin by
reducing serum insulin are shown in another trial in a dose of 1000 mg per day
divided into two equal doses for 6 weeks [27].
Seven-week curcumin supplementation in the form of 80 mg nano-micelle cur-
cumin capsules two times per day may be helpful to prevent and even treat oral
mucositis severity and pain, a side effect of chemotherapy or radiotherapy in patients
with cancer who underwent chemotherapy with or without head and neck radio-
therapy [28].
In hemodialysis, which is associated with higher oxidative stress and inflamma-
tion, supplementation with 1 g/day curcumin for 12 weeks resulted in higher cata-
lase activity and preserved glutathione peroxidase activity. However, it did not
change malondialdehyde (MDA) and high-sensitive C-reactive protein (hs-CRP)
concentrations and glutathione reductase activity [29]. In a similar study in hemodi-
alysis patients, the anti-inflammatory of nano-curcumin supplementation for 3
months has been shown by lowering gene expression and concentrations of interleu-
kin 6 (IL-6) and TNF-α [30]. In kidney disease conditions, Gut dysbiosis and ure-
mic toxins production are also prevalent and associated with inflammation.
Curcumin supplementation in juice containing 2.5 gr turmeric three times weekly
for 3 months showed modulating effects by lowering p-CS, a uremic toxin [31].
In the intensive care unit (ICU) admitted critically ill patients with traumatic
brain injury, daily intake of 500 mg curcuminoids for seven days resulted in a sig-
nificant reduction of inflammatory markers IL-6, TNF-α, monocyte chemoattractant
protein-1 (MCP-1), and C-reactive protein (CRP) [32].
Intake of 400 mg per day curcumagalactomannosides for 6 weeks in individuals
with osteoarthritis had positive effects on pain and osteoarthritis symptoms com-
pared to glucosamine hydrochloride and chondroitin sulfate mixture [33].
Curcumin‘s anti-inflammatory benefits have been linked to a number of different
mechanisms, one of which is the inhibition of the nuclear factor kappa-light-chain-­
enhancer of activated B cells (NF-kb) [34].
Curcumin may affect lipid profile by inhibiting lipid synthesis via downregula-
tion of key enzymes, including β-hydroxy β-methylglutaryl-CoA (HMG-CoA)
reductase, sterol regulatory element-binding protein-1/2 (SREBP-1/2), and fatty
acid synthase (FAS) [35–37]. Curcumin enhances cholesterol 7alpha-hydroxylase
(CYP7a1) gene expression resulting in biliary lipid excretion [37]. Curcumin stimu-
lates the PPAR-γ activation [38]. Besides, by activating AMP-activated protein
1100 M. Noormohammadi and F. Shidfar

kinase (AMPK), curcumin stimulates lipid catabolism and regulates energy homeo-
stasis in cells [39]. By increasing lipoprotein lipase activity, curcumin reduces tri-
glyceride levels and dyslipidemia [40]. Also, curcumin reduces the amount of free
fatty acids in the blood, influences the absorption and transportation of cholesterol
through the digestive tract, and reduces the risk of lipid peroxidation [41]. As a
consequence of curcumin‘s ability to enhance the hemodynamic state of arteries
and boost nitric oxide synthase, it may reduce blood pressure [42].
Glycemic control properties of curcumin are shown to be via PPAR-γ activation,
increasing some glycolysis pathway enzyme activity (including hepatic glucoki-
nase) and decreasing some enzymes gluconeogenesis pathway activity (including
glucose-6-phosphatase and phosphoenolpyruvate carboxykinase) and also glucose
uptake stimulation by elevating gene expression of glucose transporter [20, 43, 44].
AMPK phosphorylation and activation as another role of curcumin on glucose
uptake increase. By enhancing mitogen-activated protein kinase kinase
(MEK)3/6-p38 and mitogen-activated protein kinase (MAPK) signaling pathways,
curcumin improves cellular glucose uptake by cells [45, 46]. Furthermore, curcumin
has been shown to ameliorate insulin resistance by boosting adiponectin levels and
reducing leptin levels [43, 44]. Besides, curcumin increases the production of
glucagon-­like peptide-1 (GLP-1) [47]. Additionally, curcumin may increase insulin
secretion by increasing B-cell activity [48]. Curcumin antioxidant properties are
another mechanism for reducing glucose intolerance [49].

3 Ginger

Zingiber officinale Roscoe (ginger) is an extensively utilized flavoring ingredient

and herbal medicine for hundreds of years in many cultures. Furthermore, ginger is
a common traditional cure for relieving prevalent health issues such as pain, nausea,
and vomiting, among other things. According to recent reports, more than 100
chemicals have purportedly been identified from ginger, including gingerol,
shogaols, zingiberene, zingerone, and other less common chemicals such as ter-
penes, vitamins, and minerals. Gingerols are believed to be the major constituents,
and they have been shown to have a variety of biological actions. A wide range of
biological activities, including antioxidant, antibacterial, and anti-­neuroinflammation,
have been investigated due to this, to mention a few examples. Because of ginger’s
potential pharmacological and physiological actions, there has been a substantial
rise in studies on ginger’s health-promoting effects [50].
Ginger supplements may enhance glucose and lipids metabolism factors in
T2DM. Supplementation with 2 g/day ginger powder for 12 weeks reduced fasting
plasma sugar, hemoglobin A1C (HbA1C), apo-lipoprotein B, apo-lipoprotein B/apo-­
lipoprotein A-I ratio, and MDA and increased apo-lipoprotein A-I, compared to
baseline and placebo group [51]. Besides, 3 gr/day ginger powder for 3 months
reduced glycemic indices (serum glucose, HbA1C, insulin, insulin resistance), hs-­
CRP, and MDA, while increased total antioxidant capacity (TAC) and
Natural Compounds with Pharmacological Properties in Clinical Trials 1101

paraoxonase-­1 (PON-1) activity in T2DM [52]. Ninety days of 1200 mg ginger

consumption in patients with T2DM decreased blood glucose and total choles-
terol [53].
In patients with rheumatoid arthritis (RA), a 12-week daily intake of 1.5 gr gin-
ger has shown inflammation-modulating effects via enhancement of forkhead box
P3 (FoxP3) gene expression. Besides, Retinoic acid receptor-related orphan nuclear
receptor gamma (RORγt) and T-box expressed in T cells (T-bet) genes expression
decreased after supplementation [54].
Ginger has anti-inflammatory properties that may prevent arachidonic acid
metabolism by inhibiting the cyclooxygenase and lipoxygenase pathways, which
results in a decrease in prostaglandin production. Ginger suppresses leukotriene
manufacture by inhibiting the 5-lipoxygenase pathway [55]. Ginger‘s antioxidant
properties have also been related to the presence of gingerols, which inhibit the
generation of ROS [56].
Zingiber officinale Roscoe has been shown to perform its glycemic control effect
by enhancing the activity of glycolytic enzymes (glucokinase, phosphofructoki-
nase, pyruvate kinase) [57]. It also includes 6-gingerol, tannins, polyphenolic com-
pounds, flavonoids, and triterpenoids that may have glycemic control effects [58].
By inhibiting α-glucosidase and α-amylase, gingerol is known to be helpful in dia-
betes conditions [59]. These effects were ascribed to gingerols’ ability to facilitate
insulin-independent glucose absorption by enhancing the translocation of the glu-
cose transporter type 4 (GLUT4) to the plasma membrane surface of muscle cells,
in conjunction with minor increases in overall GLUT4 protein expression [60].
Another mechanism by which ginger can lower blood glucose levels is by inhibiting
the hepatic phosphorylase enzyme, which prevents the breakdown of hepatic glyco-
gen stores. It can also increase the activity of enzymes that promote glycogen syn-
thesis, which can further lower blood glucose levels. The second potential impact is
inhibition of the activity of the hepatic “glucose 6-phosphatase” enzyme, which is
responsible for the conversion of glucose 6-phosphate to glucose and, as a result,
raises the amount of glucose in the bloodstream [61].

4 Sumac

Rhus coriaria L., often known as “sumac,” is a herb from the family Anacardiaceae
and the genus Rhus. Sumac has been used as a spice and herb throughout many
countries. A variety of biological activities, including antioxidant, hypoglycemic,
anti-inflammatory, cytotoxic, and anti-thrombin activity, are attributed to sumac.
Sumac‘s biological capabilities are attributed to the existence of several bioactive
Phyto-components such as phenolic acids (gallic acid) and flavonoids, which are
present in high concentrations (quercetin, kaempferol) [62].
Sumac‘s glycemic control properties have been documented in various in vitro
and in vivo animal and human investigations. Several polyphenols in sumac contain
insulin-like characteristics, and they have been shown to be favorable for enhancing
1102 M. Noormohammadi and F. Shidfar

insulin sensitivity and decreasing oxidative stress [62]. supplementation with sumac
powder 3 g/day after 3 months resulted in a significant decrease in serum glucose,
HbA1c, apoB, apoB/apoA-I ratio, and a significant increase in apoA-I and TAC In
T2DM patients [63]. In T2DM patients, 3 g/day sumac powder intake for 3 months
has shown a significant enhancement for PON1 activity and a significant decrease
in serum glucose, insulin, homeostatic model assessment of insulin resistance
(HOMA-IR), hs-CRP, and MDA [64].
In patients with NAFLD, sumac supplementation in combination with a low-­
calorie diet has shown benefits for liver function. In a 12-week supplementation
with 2 gr/day sumac, a trial has shown significantly lower hepatic fibrosis, alanine
transaminase (ALT), AST, fasting plasma glucose, serum insulin, HbA1c,
HOMA-IR, MDA, and hs-CRP, in the intervention group rather than the pla-
cebo [65].
The combination of sumac supplementation and a restricted-calorie diet has
shown to be favorable for obesity control. Restricted-calorie diet along with daily
intake of 3000 mg sumac in overweight or obese adult women with depression for
12 weeks was superior to restricted-calorie diet alone on weight loss, and anthropo-
metric measurements decrease including BMI, body fat, visceral fat, waist, and hip
circumference and MDA levels, an oxidative stress marker [66].
Sumac may have cardioprotective properties in patients with dyslipidemia. Four-­
week daily consumption of 1 gr sumac in patients with elevated total-chol and/or
triglycerides resulted in lower BMI, systolic blood pressure (SBP), diastolic blood
pressure (DBP), and total-chol [67]. In a similar study on patients with dyslipid-
emia, sumac supplementation for 6 weeks resulted in elevated HDL-chol and apo-­
lipoprotein A-1 [68].
Since no changes have been shown for insulin and GLUT-4 gene expression,
Rhus coriaria L. may act in its glycemic control effect by modulating insulin secre-
tion or function [69]. According to in vitro studies, Rhus coriaria L. may inhibit
α-amylase [70]. Phenolic acids and flavonoids, such as gallic acid, methyl gallate,
kaempferol, and quercetin in Rhus coriaria L., may have potencies for glycemic
control [71, 72]. Quercetin has also shown a favorable effect on glycemic control
and total-chol and LDL-chol lowering properties [73]. Flavonoids may enhance the
preservation of β-cell by antioxidant effects [74]. Rhus coriaria L. has several ingre-
dients with antioxidant activity, including tannin and gallic acids that are helpful in
ROS scavenging [75].

5 Lemon Balm

Melissa officinalis (MO), often known as lemon balm, is a plant from the mint fam-
ily Lamiaceae. MO is a rich source of active phytochemicals such as triterpenes,
flavonols, and phenolic acid, among other things. MO has been used as a remedy in
Asian traditional medicine, including rheumatoid arthritis, gastrointestinal
Natural Compounds with Pharmacological Properties in Clinical Trials 1103

problems, and neurological disorders, among others, even though several primary
studies are looking at the effects of MO in chronic cardiometabolic illnesses [2].
Melissa officinalis may have beneficial properties in lipid profile, glycemic con-
trol, and inflammation in T2DM. Supplementation with 700 mg/d Melissa officina-
lis for 12 weeks in patients with T2DM resulted in a significant lower fasting
glucose, HbA1c, triglycerides, hs-CRP, and SBP and a significant increase in beta
cell activity, HDL-chol [76]. It also had favorable effects in apo-lipoprotein A-I,
apo-lipoprotein B/ apo-lipoprotein A-I in patients with T2DM but did not show any
positive properties on intercellular adhesion molecule-1 (ICAM-1), AST and, alka-
line phosphatase (ALP) [77]. The toxic effects of M. officinalis extract on liver tis-
sue were shown at very high doses (0.450 and 1.350 g/kg). According to the findings
of this research, using 700 mg/day of a hydroalcoholic extract of M. officinalis in
individuals with T2DM is considered safe [77].
In patients with chronic stable angina, 3000 mg daily intake of Melissa officina-
lis for 8 weeks reduced triglycerides, total-chol, LDL-chol, MDA, and hs-CRP and
enhanced PON1 and HDL-chol [78].
Melissa officinalis has shown to be effective in lowering SBP and DBP [79]. It
may also effectively lower serum triglycerides in patients with T2DM and dyslipid-
emia [80] and LDL-chol and AST in individuals with borderline hyperlipid-
emia [81].
M. officinalis has been shown to perform its antidiabetic roles by enhancing glu-
cokinase activity and gene expression and reducing glucose-6-phosphatase and
phosphoenolpyruvate carboxykinase [82].
HMG-CoA reductase, sterol regulatory element-binding protein-1c (SREBP-1c),
acetyl CoA carboxylase 1 (ACC1), stearoyl CoA desaturase 1 (SCD1), and FAS are
among the genes that have been shown to be downregulated by M. officinalis. These
genes are involved in fatty acid production and may be responsible for the plant‘s
antihyperlipidemic actions [83]. M. officinalis is shown to activate the AMPK/ACC
pathway resulting in glucose control regulation and insulin resistance reduction in
adipocytes besides inhibition of fat accumulation in adipocyte tissue [84].

6 Cinnamon

Cinnamon is a plant related to the Lauraceae family [85]. It is a popular spice that
many civilizations around the globe have utilized for hundreds of years. In addition
to its culinary applications, cinnamon is considered a cure for respiratory, digestive,
and gynecological disorders in traditional Ayurveda medicine. It is possible to
employ almost every component of the cinnamon tree for medicinal or culinary
purposes, such as the bark, leaves, flowers, fruits, and roots. All sections of the plant
contain the same array of hydrocarbons in variable quantities, with primary ele-
ments such as cinnamaldehyde (bark), eugenol (leaf), and camphor (seed) being
found in varying amounts (root). Cinnamon has a broad range of therapeutic effects,
and this chemical diversity is probably responsible for the extensive range of
1104 M. Noormohammadi and F. Shidfar

benefits seen [86]. According to studies, cinnamon has favorable properties on gly-
cemic control, blood pressure, weight control, and lipid profile [85]. The active
component cinnamaldehyde has been proposed, which has been linked to cinna-
mon‘s blood glucose-lowering properties [87].
Several studies have examined the cinnamon effect on patients with diabetes.
Supplementation with 1000 mg cinnamon for 3 months in those with T2DM reduced
anthropometric indices including BMI, body fat, and visceral fat, had glycemic con-
trol properties by reducing fasting glucose, 2-hour postprandial glucose, HbA1C,
fasting insulin, and insulin resistance, and enhanced lipid profile including total-­
chol, LDL-chol, and HDL-chol especially in those with basal BMI ≥ 27 [88]. In
contrast, 3 gr of cinnamon consumption per day for 8 weeks did not significantly
affect glycemic control, advanced glycation end products (AGE), and antioxidant
status in adults with T2DM [89]. In adults with T2DM, 3000 mg cinnamon for 8
weeks did not enhance hs-CRP, TNF-α, IL-6, NF-kb, Sirtuin-1, and vascular adhe-
sion molecules, ICAM-1 and vascular cell adhesion molecule 1 (VCAM-1) [90,
91]. To compare different doses of cinnamon, another study showed that daily con-
sumption of 1, 3, or 6 g of cinnamon reduced serum glucose, triglyceride, LDL-­
chol, and total-chol in people with T2DM [92].
In patients with metabolic syndrome, daily 3 gr intake of cinnamon for 16 weeks
improved fasting blood glucose, glycosylated hemoglobin, blood pressure, anthro-
pometric indices, and lipid profile [93].
Supplementation with 1500 mg cinnamon in 3 equally divided doses in over-
weight or obese women with PCOS for 8 weeks led to weight loss, had glucose-­
lowering properties, and also decreased insulin and HOMA-IR. Besides,
supplementation reduced lipid markers, including total-chol and LDL-chol but
HDL-chol increased [94]. In a similar study, 1500 mg cinnamon in 3 equal divided
doses in women with PCOS for 12 weeks resulted in reduced fasting insulin,
HOMA-IR, and LDL [95].
In patients with NAFLD, daily consumption of 1.5 gr cinnamon for 12 weeks led
to a significant reduction in HOMA-IR, fasting glucose, total-chol, triglyceride,
ALT, AST, gamma glutamine transpeptidase (GGT), and hs-CRP. However, HDL
levels did not change [96].
In patients with migraine, daily consumption of 1800 mg cinnamon divided into
three equal doses for 2 months resulted in lower IL-6 and NO and reduced the fre-
quency, severity, and duration of headache [97].
Cinnamon contains anti-inflammatory effects [86, 98]. It is claimed that cinna-
mon contains certain narcotic, opioid, and anti-inflammatory substances such as
cinnamaldehyde, eugenol, and terpene. The anti-inflammatory feature has been
reported by cinnamaldehyde [99]. Cinnamaldehyde, the primary bioactive compo-
nent of cinnamon, may inhibit the synthesis of inflammatory cytokines such as IL-6,
IL-1beta, and TNF-α by inhibiting the expression of cyclooxygenase and nitric
oxide synthase [98, 100–103]. Several of cinnamon‘s constituents and metabolites
have been shown to modulate the release of inflammatory mediators [104, 105]. It
seems that cinnamon decreases NO’s metabolites, such as superoxide and peroxyni-
trite, which results in a reduction in the inflammation induced by NO, according to
Natural Compounds with Pharmacological Properties in Clinical Trials 1105

the research [98, 106, 107]. Terpene ingredients in cinnamon have been shown to
inhibit arachidonic acid metabolism and nitric oxide synthase enzyme [108].
Besides, Eugenol has been shown to be a potent inhibitor of arachidonic acid metab-
olism and antihistamine function resulting in the prohibition of inflammation [109].
Cinnamon may act as a scavenge for reactive carbonyl species resulting in the inhi-
bition of the generation of advanced glycation end products [110].
Cinnamon has been shown to have various benefits, including decreasing stom-
ach emptying, decreasing insulin levels, and increasing GLP-1 [111]. Cinnamon
extracts have shown to activate glycogen synthase, increase glucose absorption, and
inhibit glycogen synthase kinase-3 [112, 113]. Cinnamon extracts also stimulated
insulin receptor kinase and blocked dephosphorylation of the insulin receptor,
resulting in the insulin receptor being phosphorylated to its maximum level [113].
According to in vitro studies, stimulation of the insulin receptor by a water-soluble
polyphenol Type A polymer derived from cinnamon has been found to increase
insulin action by activating the insulin receptor. Methyl hydroxy chalcone polymer,
derived from cinnamon, is hypothesized to be responsible for a variety of biological
actions, including the reduction of insulin resistance [113–115].
Cinnamate, a phenolic substance found in cinnamon, has been shown to reduce
lipid peroxidation by increasing the activity of antioxidant enzymes in the liver [116].

7 Rheum Ribes

Rheum ribes is a plant that grows in the subtropical and temperate regions of the
world and is a member of the Polygonaceae family. Many active phytochemicals
and crude medicines may be found in this plant native to Asian nations. Flavonoids
(quercetin and catechin), anthocyanins (cyaniding), and stilbenes are among the
biologically active phytochemicals. The ethnomedicinal properties of Rheum ribes
include laxative, antioxidative, analgesic, antidiabetic, anti-mutagenic, cathartic,
anti-inflammatory, anticancer, antibacterial, hepatoprotective, antiplatelet, diarrhea,
measles, cholagogue, stomachic, smallpox, hemorrhoids, antiemetic, and antipsori-
atic properties [117].
Rheum ribes has been shown to have positive effects in diabetes conditions.
Following 6-week supplementation with Rheum ribes on extract improved insulin
sensitivity and oxidative markers, including malondialdehyde and high sensitivity
CRP in patients with T2DM [118].
Rheum ribes in the form of syrup may be helpful as a remedy on children with
Shigella caused dysentery diarrhea [119].
According to one study, Rheum ribes may have anti-depressive properties, which
observed this effect after a 6-week daily intake of 1200 mg Rheum ribes hydroalco-
holic extract in patients with major depressive disorder [120].
In diabetes conditions, Rheum ribes stalk extract has shown positive impacts on
serum lipid and glucose. Daily intake of 1200 mg Rheum ribes reduced fasting
1106 M. Noormohammadi and F. Shidfar

blood glucose, LDL-chol, and total-chol in patients with T2DM with hypercholes-
terolemia [121].
According to in vitro research, Rheum ribes might affect insulin secretion;
Because Ca2+ plays an important role in insulin exocytosis, the Rheum ribes extract
may function by elevating cytoplasmic Ca2+ via boosting the flow of extracellular
Ca2+ and intracellular Ca2+ [122].
The stem of the Rheum ribes contains large amounts of flavonoids, including
quercetin [121]. In addition, the rhizome of Rheum ribes contains stilbenes with
antioxidant activity [123]. Antioxidants effectively reduce oxidative stress disorders
by removing ROS [121]. Studies have indicated that aloe-emodin is the bioactive
component of Rheum ribes that significantly impacts the inflammatory state, most
likely via a decrease in pro-inflammatory cytokine production [124].

8 Urtica Dioica

Urtica dioica (Nettle), a member of the Urticaceae family, is well known for its
wide variety of biological activities and favorable benefits to human health. In addi-
tion to flavonoids, silicic acid, and butyric acid, potassium ions, nitrates and volatile
oil, histamine and serotonin, acetylcholine, formic acid, and leukotriene. This
plant’s anti-inflammatory, anti-hyperglycemic, anti-proliferative, immunomodula-
tory, diuretic, antiplatelet aggregation, anti-allergic, antimicrobial, antioxidant, anti-­
ulcer, and analgesic properties are among its many therapeutic benefits [125].
Urtica dioica leaf extract has inflammatory lowering properties in patients with
inflammatory bowel disease. Twelve-week daily supplementation with 1200 mg
Urtica dioica leaf extracts significantly reduced TNF-α and fecal calprotectin [126].
It also effectively lowers hs-CRP and platelet count and enhances antioxidant
defense by increasing superoxide dismutase enzyme (SOD) activity in these
patients [127].
Urtica dioica may have significant disease-managing results in men with benign
prostatic hyperplasia. According to a recent study, 12-week daily consumption of
450 mg Urtica dioica root extract has significant positive impacts on International
Prostate Symptoms Score, hs-CRP, and MDA and SOD activity [128].
In diabetes conditions, Urtica dioica has shown oxidative stress-lowering prop-
erties. Eight-week daily intake of 100 mg hydroalcoholic extract of Urtica dioica
significantly decreased IL-6 and hs-CRP [129] and increased TAC and SOD in
patients with T2DM [130]. Three-month supplementation with Urtica dioica leaf
extract in 500 mg capsule every 8 hours combined with anti-hyperglycemic medi-
cine significantly reduced fasting glucose, 2 hours postprandial glucose, and
HbA1c [131].
Several in vivo researches have looked at how Urtica dioica might influence
inflammatory and antioxidant markers in the body. CRP is generated in reaction to
Natural Compounds with Pharmacological Properties in Clinical Trials 1107

pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α and is a marker of

inflammation. Hs-CRP is a sensitive marker for systemic inflammation [127].
Caffeoylmalic acid, the primary phenolic component of Urtica dioica preparations,
inhibits cyclooxygenase-derived processes in a dose-dependent way while also hav-
ing a partial inhibitory impact on 5-lipoxygenase-catalyzed reactions. Caffeoylmalic
acid, in this way, prevents the generation of pro-inflammatory cytokines [132].
Urtica dioica may also limit the generation of cytokines by inhibiting NF-kb. In
addition to the numerous target genes of NF-kb, those encoding inflammatory and
chemotactic cytokines, such as IL-1, IL-2, IL-6, IL-8, and TNF-α, as well as pro-­
inflammatory enzymes such as inducible nitric oxide synthase and cyclooxygenase-
­2, are also targets of this transcription factor. In many inflammatory disorders, the
activation of the NF-kb is enhanced, resulting in overexpression of pro-­inflammatory
gene products [133]. The particular chemicals in Urtica dioica responsible for the
inhibitory effects on NF-kb have not been determined. However, suggestions
include flavonoids and carotenoids, present in Urtica dioica and have also been
examined for their anti-inflammatory properties [133, 134]. IDS 30 is another
extract from Urtica dioica, inhibiting cytokine production by suppressing NF-kb
activation [135].
The antioxidant properties of Urtica dioica might be beneficial in preventing
diabetic problems. Urtica Dioica seems to be safe, and it appears to have a positive
impact on glycemic control in people with advanced T2DM who need insulin.
Furthermore, Urtica dioica has been shown to boost the effectiveness of standard
oral anti-hyperglycemic medicines in controlling blood glucose levels. It seems that
the anti-hyperglycemic effectiveness of Urtica dioica is greater than that of tradi-
tional oral anti-hyperglycemic medications [131].

9 Conclusions

Nowadays, the consumption of several natural compounds and plants has increased
widely due to the observed health benefits. Cell culture, animal, and human studies
have introduced several natural compounds with extensive effects on various condi-
tions, including malignancies, infections, cardiometabolic risk factors like stroke,
myocardial infarction, dyslipidemia, insulin resistance, diabetes mellitus type 2,
and even weight management. However, it is essential to be sure of safety aspects
such as the physiological dose. It is necessary to receive these compounds in dosage
to observe the desired effects without side effects. The mechanisms by which these
compounds exert health-promoting effects have not been clearly understood and
studied. There is also a need for further studies to provide conclusive evidence of
the side effects. Besides, the safety of consuming these compounds in certain condi-
tions and diseases should also be noted. Considering all these conditions, it seems
that natural compounds can be used to provide health-supporting properties.
1108 M. Noormohammadi and F. Shidfar

References

1. Clark AM (1996) Natural products as a resource for new drugs. Pharm Res 13(8):1133–1141
2. Heshmati J, Morvaridzadeh M, Sepidarkish M, Fazelian S, Rahimlou M, Omidi A et al
(2020) Effects of Melissa officinalis (Lemon Balm) on cardio-metabolic outcomes: a system-
atic review and meta-analysis. Phytother Res 34(12):3113–3123
3. Lestari ML, Indrayanto G (2014) Curcumin. Profiles Drug Subst Excip Relat Methodol
39:113–204. https://doi.org/10.1016/b978-­0-­12-­800173-­8.00003-­9
4. Gupta SC, Kismali G, Aggarwal BB (2013) Curcumin, a component of turmeric: from farm
to pharmacy. Biofactors 39(1):2–13
5. Jabczyk M, Nowak J, Hudzik B, Zubelewicz-Szkodzińska B (2021) Curcumin in metabolic
health and disease. Nutrients 13(12):4440
6. Meeting JFWECoFA, Organization WH (2013) Evaluation of certain food additives and con-
taminants: seventy-seventh report of the joint FAO/WHO expert committee on food addi-
tives. World Health Organization
7. Alm-Eldeen AA, Mona MH, Shati AA, El-Mekkawy HI (2015) Synergistic effect of black
tea and curcumin in improving the hepatotoxicity induced by aflatoxin B1 in rats. Toxicol Ind
Health 31(12):1269–1280. https://doi.org/10.1177/0748233713491807
8. Dattani JJ, Rajput DK, Moid N, Highland HN, George LB, Desai KR (2010) Ameliorative
effect of curcumin on hepatotoxicity induced by chloroquine phosphate. Environ Toxicol
Pharmacol 30(2):103–109. https://doi.org/10.1016/j.etap.2010.04.001
9. Coban D, Milenkovic D, Chanet A, Khallou-Laschet J, Sabbe L, Palagani A et al (2012)
Dietary curcumin inhibits atherosclerosis by affecting the expression of genes involved in
leukocyte adhesion and transendothelial migration. Mol Nutr Food Res 56(8):1270–1281.
https://doi.org/10.1002/mnfr.201100818
10. Leclercq IA, Farrell GC, Sempoux C, dela Peña A, Horsmans Y. (2004) Curcumin inhibits
NF-kappaB activation and reduces the severity of experimental steatohepatitis in mice. J
Hepatol 41(6):926–934. https://doi.org/10.1016/j.jhep.2004.08.010
11. Kelany ME, Hakami TM, Omar AH (2017) Curcumin improves the metabolic syndrome
in high-fructose-diet-fed rats: role of TNF-α, NF-κB, and oxidative stress. Can J Physiol
Pharmacol 95(2):140–150. https://doi.org/10.1139/cjpp-­2016-­0152
12. Maithilikarpagaselvi N, Sridhar MG, Swaminathan RP, Zachariah B (2016) Curcumin pre-
vents inflammatory response, oxidative stress and insulin resistance in high fructose fed male
Wistar rats: potential role of serine kinases. Chem Biol Interact 244:187–194. https://doi.
org/10.1016/j.cbi.2015.12.012
13. Ramirez-Tortosa MC, Ramirez-Tortosa CL, Mesa MD, Granados S, Gil A, Quiles JL
(2009) Curcumin ameliorates rabbits’s steatohepatitis via respiratory chain, oxidative
stress, and TNF-alpha. Free Radic Biol Med 47(7):924–931. https://doi.org/10.1016/j.
freeradbiomed.2009.06.015
14. Cho JW, Lee KS, Kim CW (2007) Curcumin attenuates the expression of IL-1beta, IL-6, and
TNF-alpha as well as cyclin E in TNF-alpha-treated HaCaT cells; NF-kappaB and MAPKs
as potential upstream targets. Int J Mol Med 19(3):469–474
15. Sidhu GS, Singh AK, Thaloor D, Banaudha KK, Patnaik GK, Srimal RC et al (1998)
Enhancement of wound healing by curcumin in animals. Wound Repair Regen 6(2):167–177
16. Farzaei MH, Zobeiri M, Parvizi F, El-Senduny FF, Marmouzi I, Coy-Barrera E et al (2018)
Curcumin in liver diseases: a systematic review of the cellular mechanisms of oxidative stress
and clinical perspective. Nutrients 10(7):855
17. Saadati S, Hatami B, Yari Z, Shahrbaf MA, Eghtesad S, Mansour A et al (2019) The effects
of curcumin supplementation on liver enzymes, lipid profile, glucose homeostasis, and
hepatic steatosis and fibrosis in patients with non-alcoholic fatty liver disease. Eur J Clin
Nutr 73(3):441–449. https://doi.org/10.1038/s41430-­018-­0382-­9
Natural Compounds with Pharmacological Properties in Clinical Trials 1109

18. Saadati S, Sadeghi A, Mansour A, Yari Z, Poustchi H, Hedayati M et al (2019) Curcumin and
inflammation in non-alcoholic fatty liver disease: a randomized, placebo controlled clinical
trial. BMC Gastroenterol 19(1):133. https://doi.org/10.1186/s12876-­019-­1055-­4
19. Mirhafez SR, Azimi-Nezhad M, Dehabeh M, Hariri M, Naderan RD, Movahedi A et al
(2021) The effect of curcumin phytosome on the treatment of patients with non-alcoholic
fatty liver disease: a double-blind, randomized, placebo-controlled trial. Adv Exp Med Biol
1308:25–35. https://doi.org/10.1007/978-­3-­030-­64872-­5_3
20. Zhang D-w, Fu M, Gao S-H, Liu J-L. Curcumin and diabetes: a systematic review. Evid
Based Complement Alternat Med 2013;2013
21. Thota RN, Rosato JI, Dias CB, Burrows TL, Martins RN, Garg ML (2020) Dietary supple-
mentation with curcumin reduce circulating levels of glycogen synthase kinase-3β and islet
amyloid polypeptide in adults with high risk of type 2 diabetes and Alzheimer’s disease.
Nutrients 12(4). https://doi.org/10.3390/nu12041032
22. Bateni Z, Rahimi HR, Hedayati M, Afsharian S, Goudarzi R, Sohrab G (2021) The effects of
nano-curcumin supplementation on glycemic control, blood pressure, lipid profile, and insu-
lin resistance in patients with the metabolic syndrome: a randomized, double-blind clinical
trial. Phytother Res 35(7):3945–3953. https://doi.org/10.1002/ptr.7109
23. Mohammadi M (2019) Oxidative stress and polycystic ovary syndrome: a brief review. Int J
Prev Med 10:86
24. Heshmati J, Moini A, Sepidarkish M, Morvaridzadeh M, Salehi M, Palmowski A et al (2021)
Effects of curcumin supplementation on blood glucose, insulin resistance and androgens in
patients with polycystic ovary syndrome: a randomized double-blind placebo-controlled clin-
ical trial. Phytomedicine 80:153395. https://doi.org/10.1016/j.phymed.2020.153395
25. Heshmati J, Golab F, Morvaridzadeh M, Potter E, Akbari-Fakhrabadi M, Farsi F et al (2020)
The effects of curcumin supplementation on oxidative stress, Sirtuin-1 and peroxisome pro-
liferator activated receptor γ coactivator 1α gene expression in polycystic ovarian syndrome
(PCOS) patients: a randomized placebo-controlled clinical trial. Diabetes Metab Syndr
14(2):77–82. https://doi.org/10.1016/j.dsx.2020.01.002
26. Jamilian M, Foroozanfard F, Kavossian E, Aghadavod E, Shafabakhsh R, Hoseini A et al
(2020) Effects of curcumin on body weight, glycemic control and serum lipids in women
with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Clin
Nutr ESPEN 36:128–133. https://doi.org/10.1016/j.clnesp.2020.01.005
27. Sohaei S, Amani R, Tarrahi MJ, Ghasemi-Tehrani H (2019) The effects of curcumin supple-
mentation on glycemic status, lipid profile and hs-CRP levels in overweight/obese women
with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled clinical
trial. Complement Ther Med 47:102201. https://doi.org/10.1016/j.ctim.2019.102201
28. Kia SJ, Basirat M, Saedi HS, Arab SA (2021) Effects of nanomicelle curcumin capsules on
prevention and treatment of oral mucositis in patients under chemotherapy with or with-
out head and neck radiotherapy: a randomized clinical trial. BMC Complement Med Ther
21(1):232. https://doi.org/10.1186/s12906-­021-­03400-­4
29. Rodrigues HCN, Martins TFP, Santana N, Braga CC, Silva MAC, Cunha LCD et al (2021)
Antioxidant and anti-inflammatory response to curcumin supplementation in hemodi-
alysis patients: a randomized, double-blind, placebo-controlled clinical trial. Clin Nutr
ESPEN. 44:136–142. https://doi.org/10.1016/j.clnesp.2021.06.006
30. Vafadar-Afshar G, Rasmi Y, Yaghmaei P, Khadem-Ansari MH, Makhdoomi K, Rasouli
J (2021) The effects of nanocurcumin supplementation on inflammation in hemodialysis
patients: a randomized controlled trial. Hemodial Int 25(2):232–239. https://doi.org/10.1111/
hdi.12911
31. Salarolli RT, Alvarenga L, Cardozo L, Teixeira KTR, de SGML LJD et al (2021) Can curcumin
supplementation reduce plasma levels of gut-derived uremic toxins in hemodialysis patients?
A pilot randomized, double-blind, controlled study. Int Urol Nephrol 53(6):1231–1238.
https://doi.org/10.1007/s11255-­020-­02760-­z
1110 M. Noormohammadi and F. Shidfar

32. Zahedi H, Hosseinzadeh-Attar MJ, Shadnoush M, Sahebkar A, Barkhidarian B, Sadeghi O

et al (2021) Effects of curcuminoids on inflammatory and oxidative stress biomarkers and
clinical outcomes in critically ill patients: a randomized double-blind placebo-controlled
trial. Phytother Res 35(8):4605–4615. https://doi.org/10.1002/ptr.7179
33. Thomas JV, Smina TP, Khanna A, Kunnumakkara AB, Maliakel B, Mohanan R et al (2021)
Influence of a low-dose supplementation of curcumagalactomannoside complex (CurQfen)
in knee osteoarthritis: a randomized, open-labeled, active-controlled clinical trial. Phytother
Res 35(3):1443–1455
34. Eslamparast T, Poustchi H, Zamani F, Sharafkhah M, Malekzadeh R, Hekmatdoost A (2014)
Synbiotic supplementation in nonalcoholic fatty liver disease: a randomized, double-blind,
placebo-controlled pilot study. Am J Clin Nutr 99(3):535–542
35. Saberi-Karimian M, Parizadeh SMR, Ghayour-Mobarhan M, Salahshooh MM, Dizaji BF,
Safarian H et al (2018) Evaluation of the effects of curcumin in patients with metabolic syn-
drome. Comp Clin Pathol 27(3):555–563
36. Soni K, Kutian R (1992) Effect of oral curcumin administration on serum peroxides and cho-
lesterol levels in human volunteers. Indian J Physiol Phannacol 36(4):273–275
37. Panahi Y, Khalili N, Hosseini MS, Abbasinazari M, Sahebkar A (2014) Lipid-modifying
effects of adjunctive therapy with curcuminoids–piperine combination in patients with
metabolic syndrome: results of a randomized controlled trial. Complement Ther Med
22(5):851–857
38. Rahimi HR, Mohammadpour AH, Dastani M, Jaafari MR, Abnous K, Mobarhan MG et al
(2016) The effect of nano-curcumin on HbA1c, fasting blood glucose, and lipid profile in
diabetic subjects: a randomized clinical trial. Avicenna J Phytomed 6(5):567
39. Liu Z, Cui C, Xu P, Dang R, Cai H, Liao D et al (2017) Curcumin activates AMPK path-
way and regulates lipid metabolism in rats following prolonged clozapine exposure. Front
Neurosci 11:558
40. Jiménez-Osorio AS, Monroy A, Alavez S (2016) Curcumin and insulin resistance—molecu-
lar targets and clinical evidences. Biofactors 42(6):561–580
41. Panahi Y, Ahmadi Y, Teymouri M, Johnston TP, Sahebkar A (2018) Curcumin as a potential
candidate for treating hyperlipidemia: a review of cellular and metabolic mechanisms. J Cell
Physiol 233(1):141–152
42. Boonla O, Kukongviriyapan U, Pakdeechote P, Kukongviriyapan V, Pannangpetch P,
Prachaney P et al (2014) Curcumin improves endothelial dysfunction and vascular remodel-
ing in 2K-1C hypertensive rats by raising nitric oxide availability and reducing oxidative
stress. Nitric Oxide 42:44–53
43. Hodaei H, Adibian M, Nikpayam O, Hedayati M, Sohrab G (2019) The effect of curcumin
supplementation on anthropometric indices, insulin resistance and oxidative stress in patients
with type 2 diabetes: a randomized, double-blind clinical trial. Diabetol Metab Syndr
11(1):1–8
44. Seo KI, Choi MS, Jung UJ, Kim HJ, Yeo J, Jeon SM et al (2008) Effect of curcumin supple-
mentation on blood glucose, plasma insulin, and glucose homeostasis related enzyme activi-
ties in diabetic db/db mice. Mol Nutr Food Res 52(9):995–1004
45. Akbari A, Mobini GR, Agah S, Morvaridzadeh M, Omidi A, Potter E et al (2020) Coenzyme
Q10 supplementation and oxidative stress parameters: a systematic review and meta-analysis
of clinical trials. Eur J Clin Pharmacol:1–17
46. Kim JH, Park JM, Kim EK, Lee JO, Lee SK, Jung JH et al (2010) Curcumin stimulates
glucose uptake through AMPK-p38 MAPK pathways in L6 myotube cells. J Cell Physiol
223(3):771–778
47. Kato M, Nishikawa S, Ikehata A, Dochi K, Tani T, Takahashi T et al (2017) Curcumin
improves glucose tolerance via stimulation of glucagon-like peptide-1 secretion. Mol Nutr
Food Res 61(3):1600471
48. Tabrizi R, Vakili S, Lankarani KB, Akbari M, Mirhosseini N, Ghayour-Mobarhan M et al
(2018) The effects of curcumin on glycemic control and lipid profiles among patients with
Natural Compounds with Pharmacological Properties in Clinical Trials 1111

metabolic syndrome and related disorders: a systematic review and meta-analysis of random-
ized controlled trials. Curr Pharm Des 24(27):3184–3199
49. He H-J, Wang G-Y, Gao Y, Ling W-H, Yu Z-W, Jin T-R (2012) Curcumin attenuates Nrf2
signaling defect, oxidative stress in muscle and glucose intolerance in high fat diet-fed mice.
World J Diabetes 3(5):94
50. Anh NH, Kim SJ, Long NP, Min JE, Yoon YC, Lee EG et al (2020) Ginger on human health:
a comprehensive systematic review of 109 randomized controlled trials. Nutrients 12(1):157
51. Khandouzi N, Shidfar F, Rajab A, Rahideh T, Hosseini P, Mir TM (2015) The effects of gin-
ger on fasting blood sugar, hemoglobin a1c, apolipoprotein B, apolipoprotein a-I and malo-
ndialdehyde in type 2 diabetic patients. Iran J Pharm Res 14(1):131–140
52. Shidfar F, Rajab A, Rahideh T, Khandouzi N, Hosseini S, Shidfar S (2015) The effect of gin-
ger (Zingiber officinale) on glycemic markers in patients with type 2 diabetes. J Complement
Integr Med 12(2):165–170. https://doi.org/10.1515/jcim-­2014-­0021
53. Carvalho GCN, Lira-Neto JCG, Araújo MFM, Freitas R, Zanetti ML, Damasceno
MMC (2020) Effectiveness of ginger in reducing metabolic levels in people with dia-
betes: a randomized clinical trial. Rev Lat Am Enfermagem 28:e3369. https://doi.
org/10.1590/1518-­8345.3870.3369
54. Aryaeian N, Shahram F, Mahmoudi M, Tavakoli H, Yousefi B, Arablou T et al (2019) The
effect of ginger supplementation on some immunity and inflammation intermediate genes
expression in patients with active Rheumatoid Arthritis. Gene 698:179–185. https://doi.
org/10.1016/j.gene.2019.01.048
55. Mahluji S, Ostadrahimi A, Mobasseri M, Attari VE, Payahoo L (2013) Anti-inflammatory
effects of Zingiber officinale in type 2 diabetic patients. Adv Pharm Bull 3(2):273
56. Madkor HR, Mansour SW, Ramadan G (2011) Modulatory effects of garlic, ginger, turmeric
and their mixture on hyperglycaemia, dyslipidaemia and oxidative stress in streptozotocin-­
nicotinamide diabetic rats. Br J Nutr 105(8):1210–1217. https://doi.org/10.1017/
s0007114510004927
57. Abdulrazaq NB, Cho MM, Win NN, Zaman R, Rahman MT (2012) Beneficial effects of gin-
ger (Zingiber officinale) on carbohydrate metabolism in streptozotocin-induced diabetic rats.
Br J Nutr 108(7):1194–1201. https://doi.org/10.1017/s0007114511006635
58. Shanmugam K, Ramakrishana C, Mallikarjuna K, Reddy KS (2009) The impact of ginger
on kidney carbohydrate metabolic profiles in STZ induced diabetic rats. Asian J Exp Sci
23(1):127–134
59. Rani MP, Padmakumari KP, Sankarikutty B, Cherian OL, Nisha VM, Raghu KG (2011)
Inhibitory potential of ginger extracts against enzymes linked to type 2 diabetes, inflamma-
tion and induced oxidative stress. Int J Food Sci Nutr 62(2):106–110. https://doi.org/10.310
9/09637486.2010.515565
60. Li Y, Tran VH, Duke CC, Roufogalis BD (2012) Gingerols of Zingiber officinale enhance
glucose uptake by increasing cell surface GLUT4 in cultured L6 myotubes. Planta Med
78(14):1549–1555. https://doi.org/10.1055/s-­0032-­1315041
61. Zhang XF, Tan BK (2000) Effects of an ethanolic extract of Gynura procumbens on serum
glucose, cholesterol and triglyceride levels in normal and streptozotocin-induced diabetic
rats. Singap Med J 41(1):9–13
62. Mohit M, Nouri M, Samadi M, Nouri Y, Heidarzadeh-Esfahani N, Venkatakrishnan K et al
(2021) The effect of sumac (Rhus coriaria L.) supplementation on glycemic indices: a system-
atic review and meta-analysis of controlled clinical trials. Complement Ther Med 61:102766
63. Shidfar F, Rahideh ST, Rajab A, Khandozi N, Hosseini S, Shidfar S et al (2014) The effect of
sumac (Rhus coriaria L.)powder on serum glycemic status, ApoB, ApoA-I and total antioxi-
dant capacity in type 2 diabetic patients. Iran. J Pharm Res 13(4):1249–1255
64. Rahideh ST, Shidfar F, Khandozi N, Rajab A, Hosseini SP, Mirtaher SM (2014) The effect
of sumac (Rhus coriaria L.) powder on insulin resistance, malondialdehyde, high sensitive
C-reactive protein and paraoxonase 1 activity in type 2 diabetic patients. J Res Med Sci
19(10):933–938
1112 M. Noormohammadi and F. Shidfar

65. Kazemi S, Shidfar F, Ehsani S, Adibi P, Janani L, Eslami O (2020) The effects of sumac
(Rhus coriaria L.) powder supplementation in patients with non-alcoholic fatty liver dis-
ease: a randomized controlled trial. Complement Ther Clin Pract 41:101259. https://doi.
org/10.1016/j.ctcp.2020.101259
66. Hariri N, Darafshi Ghahroudi S, Jahangiri S, Borumandnia N, Narmaki E, Saidpour A (2020)
The beneficial effects of sumac (Rhus coriaria L.) supplementation along with restricted
calorie diet on anthropometric indices, oxidative stress, and inflammation in overweight or
obese women with depression: a randomized clinical trial. Phytother Res 34(11):3041–3051.
https://doi.org/10.1002/ptr.6737
67. Asgary S, Salehizadeh L, Keshvari M, Taheri M, Spence ND, Farvid MS et al (2018) Potential
cardioprotective effects of sumac capsule in patients with hyperlipidemia: a triple-blind ran-
domized, placebo-controlled crossover trial. J Am Coll Nutr 37(4):286–292. https://doi.org/1
0.1080/07315724.2017.1394237
68. Hajmohammadi Z, Heydari M, Nimrouzi M, Faridi P, Zibaeenezhad MJ, Omrani GR et al
(2018) Rhus coriaria L. increases serum apolipoprotein-A1 and high-density lipoprotein
cholesterol levels: a double-blind placebo-controlled randomized clinical trial. J Integr Med
16(1):45–50. https://doi.org/10.1016/j.joim.2017.12.007
69. Mohammadi S, Kouhsari SM, Feshani AM (2010) Antidiabetic properties of the ethanolic
extract of Rhus coriaria fruits in rats. Daru 18(4):270
70. Giancarlo S, Rosa LM, Nadjafi F, Francesco M (2006) Hypoglycaemic activity of two spices
extracts: Rhus coriaria L. and Bunium persicum Boiss. Nat Prod Res 20(9):882–886
71. Shabana MM, El Sayed AM, Yousif MF, El Sayed AM, Sleem AA (2011) Bioactive constitu-
ents from Harpephyllum caffrum Bernh. and Rhus coriaria L. Pharmacogn Mag 7(28):298
72. Sales PM, Souza PM, Simeoni LA, Magalhães PO, Silveira D (2012) α-Amylase inhibitors:
a review of raw material and isolated compounds from plant source. J Pharm Pharm Sci
15(1):141–183
73. IuN N, Avezov G (1992) The efficacy of quercetin in alloxan diabetes. Eksp Klin Farmakol
55(1):42–44
74. Song Y, Manson JE, Buring JE, Sesso HD, Liu S (2005) Associations of dietary flavonoids
with risk of type 2 diabetes, and markers of insulin resistance and systemic inflammation in
women: a prospective study and cross-sectional analysis. J Am Coll Nutr 24(5):376–384.
https://doi.org/10.1080/07315724.2005.10719488
75. Capcarova M, Slamecka J, Abbas K, Kolesarova A, Kalafova A, Valent M et al (2012) Effects
of dietary inclusion of Rhus coriaria on internal milieu of rabbits. J Anim Physiol Anim Nutr
96(3):459–465
76. Asadi A, Shidfar F, Safari M, Hosseini AF, Fallah Huseini H, Heidari I et al (2019) Efficacy of
Melissa officinalis L. (lemon balm) extract on glycemic control and cardiovascular risk fac-
tors in individuals with type 2 diabetes: a randomized, double-blind, clinical trial. Phytother
Res 33(3):651–659. https://doi.org/10.1002/ptr.6254
77. Asadi A, Shidfar F, Safari M, Malek M, Hosseini AF, Rezazadeh S et al (2018) Safety and
efficacy of Melissa officinalis (lemon balm) on ApoA-I, Apo B, lipid ratio and ICAM-1 in
type 2 diabetes patients: a randomized, double-blinded clinical trial. Complement Ther Med
40:83–88. https://doi.org/10.1016/j.ctim.2018.07.015
78. Javid AZ, Haybar H, Dehghan P, Haghighizadeh MH, Mohaghegh SM, Ravanbakhsh M
et al (2018) The effects of Melissa officinalis (lemon balm) in chronic stable angina on
serum biomarkers of oxidative stress, inflammation and lipid profile. Asia Pac J Clin Nutr
27(4):785–791. https://doi.org/10.6133/apjcn.022018.01
79. Shekarriz Z, Shorofi SA, Nabati M, Shabankhani B, Yousefi SS (2021) Effect of Melissa
officinalis on systolic and diastolic blood pressures in essential hypertension: a double-blind
crossover clinical trial. Phytother Res 35(12):6883–6892. https://doi.org/10.1002/ptr.7251
80. Nayebi N, Esteghamati A, Meysamie A, Khalili N, Kamalinejad M, Emtiazy M et al (2019)
The effects of a Melissa officinalis L. based product on metabolic parameters in patients with
Natural Compounds with Pharmacological Properties in Clinical Trials 1113

type 2 diabetes mellitus: a randomized double-blinded controlled clinical trial. J Complement

Integr Med 16(3). https://doi.org/10.1515/jcim-­2018-­0088
81. Jandaghi P, Noroozi M, Ardalani H, Alipour M (2016) Lemon balm: a promising herbal
therapy for patients with borderline hyperlipidemia-A randomized double-blind placebo-­
controlled clinical trial. Complement Ther Med 26:136–140. https://doi.org/10.1016/j.
ctim.2016.03.012
82. Chung MJ, Cho S-Y, Bhuiyan MJH, Kim KH, Lee S-J (2010) Anti-diabetic effects of lemon
balm (Melissa officinalis) essential oil on glucose-and lipid-regulating enzymes in type 2
diabetic mice. Br J Nutr 104(2):180–188
83. Jun H-j, Lee JH, Jia Y, Hoang M-H, Byun H, Kim KH et al (2012) Melissa officinalis essen-
tial oil reduces plasma triglycerides in human apolipoprotein E2 transgenic mice by inhib-
iting sterol regulatory element-binding protein-1c–dependent fatty acid synthesis. J Nutr
142(3):432–440
84. Yen H-F, Hsieh C-T, Hsieh T-J, Chang F-R, Wang C-K (2015) In vitro anti-diabetic effect and
chemical component analysis of 29 essential oils products. J Food Drug Anal 23(1):124–129
85. Yazdanpanah Z, Azadi-Yazdi M, Hooshmandi H, Ramezani-Jolfaie N, Salehi-Abargouei A
(2020) Effects of cinnamon supplementation on body weight and composition in adults: a sys-
tematic review and meta-analysis of controlled clinical trials. Phytother Res 34(3):448–463
86. Ranasinghe P, Pigera S, Premakumara GS, Galappaththy P, Constantine GR, Katulanda P
(2013) Medicinal properties of ‘true’ cinnamon (Cinnamomum zeylanicum): a systematic
review. BMC Complement Altern Med 13(1):1–10
87. Allen RW, Schwartzman E, Baker WL, Coleman CI, Phung OJ (2013) Cinnamon use in type
2 diabetes: an updated systematic review and meta-analysis. Ann Fam Med 11(5):452–459
88. Zare R, Nadjarzadeh A, Zarshenas MM, Shams M, Heydari M (2019) Efficacy of cinnamon
in patients with type II diabetes mellitus: a randomized controlled clinical trial. Clin Nutr
38(2):549–556. https://doi.org/10.1016/j.clnu.2018.03.003
89. Talaei B, Amouzegar A, Sahranavard S, Hedayati M, Mirmiran P, Azizi F (2017) Effects of
cinnamon consumption on glycemic indicators, advanced glycation end products, and anti-
oxidant status in type 2 diabetic patients. Nutrients 9(9). https://doi.org/10.3390/nu9090991
90. Davari M, Hashemi R, Mirmiran P, Hedayati M, Sahranavard S, Bahreini S et al (2020)
Effects of cinnamon supplementation on expression of systemic inflammation factors, NF-kB
and Sirtuin-1 (SIRT1) in type 2 diabetes: a randomized, double blind, and controlled clinical
trial. Nutr J 19(1):1. https://doi.org/10.1186/s12937-­019-­0518-­3
91. Mirmiran P, Davari M, Hashemi R, Hedayati M, Sahranavard S, Bahreini S et al (2019) A
randomized controlled trial to determining the effect of cinnamon on the plasma levels of
soluble forms of vascular adhesion molecules in type 2 diabetes mellitus. Eur J Clin Nutr
73(12):1605–1612. https://doi.org/10.1038/s41430-­019-­0523-­9
92. Khan A, Safdar M, Ali Khan MM, Khattak KN, Anderson RA (2003) Cinnamon improves
glucose and lipids of people with type 2 diabetes. Diabetes Care 26(12):3215–3218. https://
doi.org/10.2337/diacare.26.12.3215
93. Gupta Jain S, Puri S, Misra A, Gulati S, Mani K (2017) Effect of oral cinnamon intervention
on metabolic profile and body composition of Asian Indians with metabolic syndrome: a
randomized double -blind control trial. Lipids Health Dis 16(1):113. https://doi.org/10.1186/
s12944-­017-­0504-­8
94. Borzoei A, Rafraf M, Asghari-Jafarabadi M (2018) Cinnamon improves metabolic factors
without detectable effects on adiponectin in women with polycystic ovary syndrome. Asia
Pac J Clin Nutr 27(3):556–563. https://doi.org/10.6133/apjcn.062017.13
95. Hajimonfarednejad M, Nimrouzi M, Heydari M, Zarshenas MM, Raee MJ, Jahromi BN
(2018) Insulin resistance improvement by cinnamon powder in polycystic ovary syndrome:
a randomized double-blind placebo controlled clinical trial. Phytother Res 32(2):276–283.
https://doi.org/10.1002/ptr.5970
96. Askari F, Rashidkhani B, Hekmatdoost A (2014) Cinnamon may have therapeutic benefits
on lipid profile, liver enzymes, insulin resistance, and high-sensitivity C-reactive protein in
1114 M. Noormohammadi and F. Shidfar

nonalcoholic fatty liver disease patients. Nutr Res 34(2):143–148. https://doi.org/10.1016/j.

nutres.2013.11.005
97. Zareie A, Sahebkar A, Khorvash F, Bagherniya M, Hasanzadeh A, Askari G (2020) Effect
of cinnamon on migraine attacks and inflammatory markers: a randomized double-blind
placebo-controlled trial. Phytother Res 34(11):2945–2952. https://doi.org/10.1002/ptr.6721
98. Ho S-C, Chang K-S, Chang P-W (2013) Inhibition of neuroinflammation by cinnamon and
its main components. Food Chem 138(4):2275–2282
99. Penckofer S, Schwertz D, Florczak K (2002) Oxidative stress and cardiovascular disease in
type 2 diabetes: the role of antioxidants and pro-oxidants. J Cardiovasc Nurs 16(2):68–85
100. Lee J, Kim KA, Jeong S, Lee S, Park HJ, Kim NJ et al (2009) Anti-inflammatory, anti-­
nociceptive, and anti-psychiatric effects by the rhizomes of Alpinia officinarum on complete
Freund’s adjuvant-induced arthritis in rats. J Ethnopharmacol 126(2):258–264
101. Lee HJ, Hyun E-A, Yoon WJ, Kim BH, Rhee MH, Kang HK et al (2006) In vitro
anti-­
inflammatory and anti-oxidative effects of Cinnamomum camphora extracts. J
Ethnopharmacol 103(2):208–216
102. Liao B-C, Hsieh C-W, Liu Y-C, Tzeng T-T, Sun Y-W, Wung B-S (2008) Cinnamaldehyde
inhibits the tumor necrosis factor-α-induced expression of cell adhesion molecules in endo-
thelial cells by suppressing NF-κB activation: effects upon IκB and Nrf2. Toxicol Appl
Pharmacol 229(2):161–171
103. Liao Z, Wang J, Tan H, Wei L (2017) Cinnamon extracts exert intrapancreatic cytoprotection
against streptozotocin in vivo. Gene 627:519–523
104. Modi KK, Jana M, Mondal S, Pahan K (2015) Sodium benzoate, a metabolite of cinnamon
and a food additive, upregulates ciliary neurotrophic factor in astrocytes and oligodendro-
cytes. Neurochem Res 40(11):2333–2347
105. Mondal S, Pahan K (2015) Cinnamon ameliorates experimental allergic encephalomyeli-
tis in mice via regulatory T cells: implications for multiple sclerosis therapy. PLoS One
10(1):e0116566
106. Raffai G, Kim B, Park S, Khang G, Lee D, Vanhoutte PM (2014) Cinnamaldehyde and
cinnamaldehyde-­containing micelles induce relaxation of isolated porcine coronary arteries:
role of nitric oxide and calcium. Int J Nanomedicine 9:2557
107. Lee H-S, Kim B-S, Kim M-K (2002) Suppression effect of Cinnamomum cassia bark-derived
component on nitric oxide synthase. J Agric Food Chem 50(26):7700–7703
108. Lee SK, Hong C-H, Huh S-K, Kim S-S, Oh O-J, Min H-Y et al (2002) Suppressive effect
of natural sesquiterpenoids on inducible cyclooxygenase (COX-2) and nitric oxide synthase
(iNOS) activity in mouse macrophage cells. J Environ Pathol Toxicol Oncol 21(2)
109. Hsueh WA, Law RE (1998) Cardiovascular risk continuum: implications of insulin resistance
and diabetes. Am J Med 105(1):4S–14S
110. Peng X, Cheng K-W, Ma J, Chen B, Ho C-T, Lo C et al (2008) Cinnamon bark proanthocy-
anidins as reactive carbonyl scavengers to prevent the formation of advanced glycation end
products. J Agric Food Chem 56(6):1907–1911
111. Hlebowicz J, Hlebowicz A, Lindstedt S, Björgell O, Höglund P, Holst JJ et al (2009) Effects
of 1 and 3 g cinnamon on gastric emptying, satiety, and postprandial blood glucose, insulin,
glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and ghrelin concen-
trations in healthy subjects. Am J Clin Nutr 89(3):815–821
112. Imparl-Radosevich J, Deas S, Polansky M, Baedke D, Ingebrutsen T, Anderson R et al
(1998) Regulation of phosphorylase phosphatase (PTP-1) and insulin receptor kinase by
fractions from cinnamon: implications for cinnamon regulation of insulin signaling. Horm
Res 50(3):177–182
113. Jarvill-Taylor KJ, Anderson RA, Graves DJ (2001) A hydroxychalcone derived from cinna-
mon functions as a mimetic for insulin in 3T3-L1 adipocytes. J Am Coll Nutr 20(4):327–336
114. Anderson RA, Broadhurst CL, Polansky MM, Schmidt WF, Khan A, Flanagan VP et al
(2004) Isolation and characterization of polyphenol type-A polymers from cinnamon with
insulin-like biological activity. J Agric Food Chem 52(1):65–70
Natural Compounds with Pharmacological Properties in Clinical Trials 1115

115. Qin B, Nagasaki M, Ren M, Bajotto G, Oshida Y, Sato Y (2004) Cinnamon extract prevents
the insulin resistance induced by a high-fructose diet. Horm Metab Res 36(02):119–125
116. Lee J-S, Jeon S-M, Park E-M, Huh T-L, Kwon O-S, Lee M-K et al (2003) Cinnamate sup-
plementation enhances hepatic lipid metabolism and antioxidant defense systems in high
cholesterol-fed rats. J Med Food 6(3):183–191
117. Achakzai JK, Anwar Panezai M, Kakar MA, Kakar AM, Kakar S, Khan J et al (2019) In
vitro anticancer MCF-7, anti-inflammatory, and Brine Shrimp Lethality Assay (BSLA) and
GC-MS analysis of Whole Plant Butanol Fraction of Rheum ribes (WBFRR). Biomed Res
Int 2019:3264846. https://doi.org/10.1155/2019/3264846
118. Ghafouri A, Hosseini S, Shidfar S, Kamalinejad M, AghaHosseini F, Heydari I et al (2020)
The effect of Aqueous, Ethanolic extracts of Rheum ribes on insulin sensitivity, inflamma-
tion, oxidative stress in patients with type 2 diabetes mellitus: a randomized, double-blind,
placebo-controlled trial. J Herbal Medicine 24:100389
119. Khiveh A, Hashempur MH, Shakiba M, Lotfi MH, Shakeri A, Kazemeini S et al (2017)
Effects of rhubarb (Rheum ribes L.) syrup on dysenteric diarrhea in children: a randomized,
double-blind, placebo-controlled trial. J Integr Med 15(5):365–372
120. Sayyah M, Boostani H, Pakseresht S, Malayeri A (2009) Efficacy of hydroalcoholic extract
of Rheum ribes L. in treatment of major depressive disorder. J Med Plant Res 3(8):573–575
121. Fallah Huseini H, Heshmat R, Mohseni F, Jamshidi AH, Alavi S, Ahvasi M et al (2008)
The efficacy of rheum ribes L. stalk extract on lipid profile in hypercholesterolemic type II
diabetic patients: a randomized, double-blind, placebo-controlled, clinical trial. J Med Plant
7(27):92–97
122. Naqishbandi AM, Josefsen K, Pedersen ME, Jäger AK (2009) Hypoglycemic activity of Iraqi
Rheum ribes root extract. Pharm Biol 47(5):380–383
123. Matsuda H, Tomohiro N, Hiraba K, Harima S, Ko S, Matsuo K et al (2001) Study on anti-­
Oketsu activity of rhubarb II. Anti-allergic effects of stilbene components from Rhei undu-
lati Rhizoma (dried rhizome of Rheum undulatum cultivated in Korea). Biol Pharm Bull
24(3):264–267
124. Hu B, Zhang H, Meng X, Wang F, Wang P (2014) Aloe-emodin from rhubarb (Rheum rhabar-
barum) inhibits lipopolysaccharide-induced inflammatory responses in RAW264. 7 macro-
phages. J Ethnopharmacol 153(3):846–853
125. Ziaei R, Foshati S, Hadi A, Kermani MAH, Ghavami A, Clark CC et al (2020) The effect of
nettle (Urtica dioica) supplementation on the glycemic control of patients with type 2 diabe-
tes mellitus: a systematic review and meta-analysis. Phytother Res 34(2):282–294
126. Nematgorgani S, Agah S, Shidfar F, Janani L, Faghihi A, Hosseini S (2020) The effect of
Urtica Dioica leaf extract intake on serum TNF-α, stool calprotectin and erythrocyte sedimen-
tation rate in patients with inflammatory bowel disease: a double-blind, placebo-­controlled,
randomized, clinical trial. Mediterr J Nutr Metab 13(1):75–87
127. Nematgorgani S, Agah S, Shidfar F, Gohari M, Faghihi A (2017) Effects of Urtica dioica leaf
extract on inflammation, oxidative stress, ESR, blood cell count and quality of life in patients
with inflammatory bowel disease. Journal of Herbal Medicine 9:32–41
128. Akbar Karami A, Sheikhsoleimani M, Reza Memarzadeh M, Haddadi E, Bakhshpour M,
Mohammadi N et al (2020) Urtica Dioica root extract on clinical and biochemical parameters
in patients with benign prostatic hyperplasia, randomized controlled trial. Pak J Biol Sci
23(10):1338–1344. https://doi.org/10.3923/pjbs.2020.1338.1344
129. Namazi N, Esfanjani AT, Heshmati J, Bahrami A (2011) The effect of hydro alcoholic Nettle
(Urtica dioica) extracts on insulin sensitivity and some inflammatory indicators in patients
with type 2 diabetes: a randomized double-blind control trial. Pak J Biol Sci 14(15):775–779.
https://doi.org/10.3923/pjbs.2011.775.779
130. Namazi N, Tarighat A, Bahrami A (2012) The effect of hydro alcoholic nettle (Urtica dioica)
extract on oxidative stress in patients with type 2 diabetes: a randomized double-blind clinical
trial. Pak J Biol Sci 15(2):98–102. https://doi.org/10.3923/pjbs.2012.98.102
1116 M. Noormohammadi and F. Shidfar

131. Kianbakht S, Khalighi-Sigaroodi F, Dabaghian FH (2013) Improved glycemic control in

patients with advanced type 2 diabetes mellitus taking Urtica dioica leaf extract: a random-
ized double-blind placebo-controlled clinical trial. Clin Lab 59(9–10):1071–1076. https://
doi.org/10.7754/clin.lab.2012.121019
132. Obertreis B, Giller K, Teucher T, Behnke B, Schmitz H (1996) Anti-inflammatory effect
of Urtica dioica folia extract in comparison to caffeic malic acid. Arzneimittelforschung
46(1):52–56
133. Riehemann K, Behnke B, Schulze-Osthoff K (1999) Plant extracts from stinging nettle
(Urtica dioica), an antirheumatic remedy, inhibit the proinflammatory transcription factor
NF-κB. FEBS Lett 442(1):89–94
134. Rubin LP, Chan GM, Barrett-Reis BM, Fulton AB, Hansen R, Ashmeade T et al (2012) Effect
of carotenoid supplementation on plasma carotenoids, inflammation and visual development
in preterm infants. J Perinatol 32(6):418–424
135. Konrad A, Mähler M, Arni S, Flogerzi B, Klingelhöfer S, Seibold F (2005) Ameliorative
effect of IDS 30, a stinging nettle leaf extract, on chronic colitis. Int J Color Dis 20(1):9–17
Phytopharmacological Aspects
of the Genus Terminalia

Aswathi Pokkadath , Reshmi Chembrammal ,

and John Ernest Thoppil

Abbreviations

Caco-2 Cancer coli-2

COX-2 Cyclooxygenase 2
MCF-7 Michigan Cancer Foundation-7 (Breast cancer cell line)
NF-Kb Nuclear factor kappa light chain enhancer of activated B cells
OSCC Squamous cell carcinoma
Spp. Species
TNF-a Tumour necrosis factor α

1 Introduction

Medicinal plants have been making an important role in humans. They are a very
rich source of traditional medicines. Nowadays, these medicinal plants are abun-
dantly used for modern medicines. For various diseases, medicinal plants could
make their milestone in treatment. The secondary metabolites produced by the
medicinal plants are very surprising and it is responsible for various biological
activities. Awareness of medicinal plant usage is an upshot of the many years of
struggle against illnesses due to which man learned to follow drugs in barks, seeds,
fruit bodies and other plant parts [1].
Genus Terminalia belonging to the family Combretaceae is spread worldwide
with 250 species, mainly in South Asia, Australia and South Africa. Among these
about 50 species are used as food [2]. Several Terminalia species revealed

A. Pokkadath (*) · R. Chembrammal · J. E. Thoppil

Cell and Molecular Biology Division, Department of Botany, University of Calicut,
Malappuram, Kerala, India

© The Author(s), under exclusive license to Springer Nature 1117

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_47
1118 A. Pokkadath et al.

nutraceutical value with the number of healthy profits, including the treatment for
various ailments [3]. Fruits of T. bellirica (Gaertn.) Roxb. and T. chebula Retz. are
common in Triphala, which is the polyherbal preparation in Ayurvedic and Thai folk
medicine by its pharmacological applications [4]. Terminalia species exhibit world-
wide distribution. The ethnobotanical importance and its medicinal use are various.
The majority of the fruits, leaves and stem bark of different Terminalia spp. has
been used for the treatment of geriatric diseases, memory improvement, abdominal
and back pain, cough, and colds, conjunctivitis, diarrhoea, fever, headache, heart
disorders, inflammation, leprosy, pneumonia, sexually transmitted diseases, urinary
disorders, etc. [5–7].
Medicinal plants are rich sources of bioactive compounds. Terminalia species
exhibit various biological activities such as antibacterial, antifungal and antipara-
sitic. Additionally, the plant extract showed antidiabetic, anticancer and antioxidant
activity. Terminalia has high therapeutic potential and clinical approval owed by its
traditional applications. Various Terminalia species are used in the form of herbal
medicine to cure several diseases like headache, fever, pneumonia, flu, abdominal
and back pain, cough and cold, conjunctivitis, geriatric, cancer, to improve memory,
diarrhoea, heart disorder, leprosy, sexually transmitted diseases and urinary tract
disorders. Moreover, these plants possess significant bioactivities like antibacterial,
antifungal, anti-inflammatory, antiviral, antiretroviral, antioxidant and antiparasitic
activity [8].
The phytochemical study of Terminalia species revealed the presence of glyco-
sides, flavonoids, tannins, phenols, saponin, carbohydrates, proteins, etc. [9].
Moreover, pure compounds are also isolated from the Terminalia species [10].
Likewise, the bioactivity study on Terminalia species provides a surprising result in
the field of research. It has been found that the growth of airborne pathogens like
MDR Acinetobacter sp. and MDR Pseudomonas aeruginosa is reduced when they
were treated with Terminalia bellirica (Gaertn.) Roxb [11]. and Terminalia chebula
Retz [12]. fruit extracts. Also, some of the Terminalia species are used as an inevi-
table ingredient in traditional medicines for the treatment of Malaria [13]. The anti-
cancer activity of Terminalia species has been focused on cancer which is one of the
important human diseases caused by various activities. It is caused by uncontrolled
cell division and can easily spread from one organ to another. So, the anticancer
research on Terminalia species has become a milestone in anticancer therapy.
Furthermore, some chemotherapy agents that are presently used have plant origins.
So, the studies on searching new plant species that provide natural products having
potential anticancer activity are relevant. Current information obtained from the
Scopus and Web of Science databases (2010–2020) reveals the anticancer potential
of Terminalia species [8]. Reports revealed antiproliferative activity of aqueous
extracts of Terminalia chebula Retz. using human lung cancer, A and mouse lung
cancer LLC cell lines [14]. The extract can inhibit cell proliferation by inducing
apoptosis and cell cycle arrest by regulating the mitochondrial pathway. It was
mediated by the proteins of the Bcl-2 family and inducing the PARP cleavage as
well as promoting cytochrome c release into the cytoplasm. Similarly, the Terminalia
fruits have an inhibitory effect against Caco-2 cells (Human epithelial cell line).
Phytopharmacological Aspects of the Genus Terminalia 1119

However, only methanol and aqueous fruit extracts showed antiproliferative activity
on the HeLa cell line. Also, the ethanolic leaf extract of T. catappa L. from Taiwan
revealed antiproliferative effects on HeLa and SiHa cervical cancer cell lines [15].
The current investigation mainly aims to provide detailed information regarding the
phytopharmacological aspects of the taxa Terminalia.

2 Phytochemical Aspects

2.1 Major Classes of Compounds and Chemical Constituents

of Species of Terminalia

Phytochemicals are the major cause of biological activities. The bioactivities include
triterpenes, alkaloids and flavonoids [16]. Tannins and polyphenols are the other
active phytocompounds, which contribute to the bioactivity of Terminalia spp. [17].
Also, triterpenoids, flavonoids and aliphatic compounds have several bioactive
properties [18] (Fig. 1).
Terminalia chebula is commonly used for digestive problems and its fruits are
used for the treatment of acidity, heat burn, heart disease, constipation, ulcers, piles,
inflammation, dysentery and diarrhoea. Also, it can remove toxins from the body.
The major phytocomponents present in T. chebula are alkaloids, soluble phenols,
phlobatannins, reducing sugars, carbohydrates, glycosides, inulin, terpenoids, tan-
nins and saponins. But there is no flavonoid, naphthoquinone and starch [19].
T. chebula aqueous fruit extract has the immense availability of carbohydrates,
anthocyanins, phenols and oils [20] whereas the proteins were absent in it. The pres-
ence of steroids is determined by Prajapati et al. [21].
The presence of non-nutritive phytochemicals and the other secondary metabo-
lites may be the reason for the medicinal properties of the plant. The extracts of the
dried powder of the pericarp of the fruits of T. chebula in petroleum ether, chloro-
form, ethyl alcohol and water were tested for the presence of tannins, alkaloids,
steroids, triterpenoids, flavonoids, hydroxyanthraquinones, cardiac glycosides,
saponins, carbohydrates (glucose and fructose), proteins, amino acids, fixed oils and
fatty acids. Proteins, cardiac glycosides, fixed oils and fats were found to be absent
in all the extracts [22]. Tannin has a role in plant growth regulation. Similarly, flavo-
noids can provide health benefits through cell signalling pathways as well as anti-
oxidant potential.
Terminalia bellirica has surprising medicinal values and is used in Ayurveda to
eliminate all three doshas. The fruits are used for the treatment of anaemia, jaundice
and white leprosy whereas seeds are used to control vomiting and cure bronchitis.
Additionally, T. bellerica is used to destroy germs and eye diseases. The major phy-
tocomponents present in T. bellerica are alkaloids, soluble phenols, phlobatannins,
reducing sugars, carbohydrates, glycosides, inulin, terpenoids and tannins. But
saponins, flavonoids, naphthoquinone and starch were not found in T. bellerica [19].
1120 A. Pokkadath et al.

Phytochemistry

Terminalia paniculata

Pharmacology
Activities

 Anti-oxidant activity
 Anti-microbial activity
 Anti-proliferative activity
 Anti-inflammatory activity

Fig. 1 Relationship between the phytochemistry and pharmacological aspects of Terminalia

The fruits of T. bellerica extracted with petroleum ether, chloroform, ethyl acetate
and 20% aqueous methanol (hydroalcohol) revealed several biologically active phy-
tocompounds such as alkaloids, tannins, flavonoids, carbohydrates, glycosides,
saponins, steroids, free amino acids, fats, fixed oils and starch [23]. Among these
extracts, ethyl acetate and hydroalcoholic extracts were significantly higher in com-
position than the others. This indicates that the majority of the phytochemicals are
polar. Additionally, the phytochemical evaluation of ethyl acetate and hydroalco-
holic extracts was almost similar.
The plant extracts of T. bellerica possess phytochemical activities which are sig-
nificant for the therapeutic index. The ethanolic leaf and fruit extract of T. bellerica
revealed the presence of alkaloids, phenolics, tannins, carbohydrates, glycosides,
steroids, saponin and proteins. Proteins are detected in both leaves and fruit extract,
but the presence of free amino acids was not detected. Phenolics are the most com-
mon phytocompounds found in T. bellerica leaves and fruit extract. The fruit
Phytopharmacological Aspects of the Genus Terminalia 1121

extracts exhibit the prominent amount of phenolic content than the leaves extract.
Also, the fruits of T. bellerica are the major source of flavonoids [24].
Terminalia arjuna is an important cardiotonic plant in Ayurveda. The cardiopro-
tective activity of T. arjuna bark is an important ayurvedic remedy described in
many ancient Indian medicinal literatures like Charaka Samhita and Astanga
Hridayam. It has many therapeutic values and is used since ancient times by tribal
people to cure diarrhoea, tubercular cough, asthma, earache, cleansing sores, dysen-
tery, ulcers, syphilitic infection, sex stimulation, skin disorders, relieving excessive
menstrual bleeding, leucorrhoea, angina and heart disease [25]. Preliminary phyto-
chemical analysis revealed the biologically active compounds present in high con-
centrations like phytosterols, lactones, flavonoids, phenolic compounds, tannins and
glycosides [26]. The bark extract has plenty of arjunic acid, arjunolic acid, arjun-
genin acid, arjunglycesides and terminic acid, glycosides, flavonoids, tannins,
oligomeric proanthocyanidins, minerals, etc. Preliminary phytochemical analysis of
T. arjuna bark with different solvents including cold acetone and methanol revealed
the presence of tannin, alkaloid, triterpenoid, flavonoid, phytosteroids and saponins
[27]. T. arjuna plant encompasses flavonoids and glycosides. Among these, flavo-
noids like arjunic acid, arjunolic acid, arjungenin acid and arjunglucosides are
strong antioxidants that play an important role in antihyperglycemic and analgesic
activity. Amino acid and resins are not found in the bark of T. arjuna. The phyto-
components like triterpenoids, flavonoids, tannins and phytosteroids hold substan-
tial antioxidant, antihyperglycemic and cardioprotective potential [28, 29].
Triterpenoids have the same upshot as vitamin C. It can reduce myocardial abnor-
malities, as well as pathological changes in biochemical markers caused by cyclo-
sporine A. Saponins responsible for the inotropic effects of T. arjuna [27]. Major
classes of compounds identified in Terminalia species are enlisted in Table 1.
Phytochemical analysis of Terminalia arjuna by GC–MS analysis exhib-
ited five peaks with the presence of 13 compounds. All the 13 chemical com-
pounds are biologically very active and include decamethylcyclopentasiloxane,
benzoic acid, 2,5-bis(trimethylsiloxy)-, trimethylsilyl ester, anethole, dodeca-
methylcyclohexasiloxane, 2H-1,4-benzodiazepin-2-one 7-chloro-1,3- dihydro-5-
phenyl-1-(trimethylsilyl), silane, dimethyl(dimethyl(dimethyl(2-isopropylphenoxy)
silyloxy)silyloxy)(2-isopropylphenoxy)-, tetradecamethylcycloheptasiloxane,
3-isopropoxy-­1,1,1,7,7,7-hexamethyl-3,5,5-tris(trimethylsiloxy)tetrasiloxane,
3-butoxy-1,1,1,7,7,7-hexamethyl-3,5,5-tris(trimethylsiloxy)tetrasiloxane, 2,4-ditert-
butylphenol, globulol, cadinol, heptadecyl 3-chloropropanoate, palmitoleic acid,
methyl (9Z)-9-hexadecenoate, dipentyl phthalate, phthalic acid, butyl 8-chlorooctyl
ester, dibutyl phthalate, 8,14-seco-3,19-epoxyandrostane-8,14-dione and 17-ace-
toxy-3á-methoxy-4,4-dimethyl, 1-monolinoleoylglycerol trimethylsilyl ether,
8,14-Seco-3,19-epoxyandrostane-8,14-dione, 17-acetoxy-3á-methoxy-4,4-di-
methyl [30]. Moreover, GC–MS analysis of T. arjuna exhibits 25 compounds which
include phenolic derivatives, hydrocarbons, alcoholic compounds, flavonoids,
alkaloids, ketones, carbohydrates, fatty acid ester, alkene compounds and fatty
acids [31].
1122 A. Pokkadath et al.

Table 1 Major classes of compounds identified in Terminalia spp

Plant name Class of compounds
Terminalia sericea Triterpenes, alkaloids and flavonoids
[16]
Terminalia catappa Tannins, gallotannins, ellagitannins, cyanidin and flavonoids.
[61, 62] Hydrolysable tannins, punicallin, punicalagin, gallic acid, flavonoids and
C-glycosides
Terminalia Flavonoids, tannins, steroids, carbohydrates and terpenoids
schimperiana [57]
Terminalia Water-soluble phenolics, tannins, flavonoids and anthraquinones
grandiflora [10]
Terminalia Alkaloids, tannins, saponins, steroids, flavonoids, anthraquinones and
glaucescens [63] phlobatannins
Terminalia Glycosides, phenols, tannins, saponins and flavonoids
avicennioides [64]
Terminalia superba Saponins, cardenolides, triterpenes, flavonoids, steroids, phenolics and
[65] tannins
Terminalia Alkaloids, cyanogenic glycosides, anthraquinones, terpenoids, flavonoids,
macroptera [66] tannins and saponins
Terminalia Proteins, carbohydrates, reducing sugars, phenols, tannins, flavonoids,
paniculata [67] saponins, terpenoids, alkaloids, lignins, anthocyanins, steroids and
glycosides

Major terpenoid compounds reported in T. arjuna are b-sitosterol, carminic acid

terminoside A and arjunaphthanoloside. Out of these, terminoside A and arjunaph-
thanoloside have high therapeutic values. Terminoside A can inhibit the production
of nitric oxide and reduce the level of nitric oxide synthase in macrophages stimu-
lated by liposaccharides whereas arjunaphthanoloside possesses high antioxidant
potential. Likewise, flavonoids are another high-level class of compound reported in
the bark of Terminalia arjuna. The major flavonoid components are arjunolone,
bicalein, flavones, kaempferol, pelargonidin, quercetin and luteolin [8]. Additionally,
castalagin and terflavin are reported by Kuo et al. [32].
Fruits of T. ferdinandiana are a rich source of gallic acid and ellagic acid [33].
These two compounds possess high antioxidant potential. The fruits are a good
source of luteolin, vitamin E and vitamin E analogues. Hesperetin, glycosides,
kaempferol, luteolin and quercetin are the effective antioxidant agents found in
T. ferdinandiana fruit [34]. All the important chemical constituents of Terminalia
and its structures are mentioned in Table 2.
About 34 polyphenolic compounds were identified by the HR-LC/MS analysis
in the methanolic fruit extract of some Terminalia species. It includes hydrolysable
tannins like gallate esters, ellagic acid derivatives and glycosides, and various ella-
gitannins. Gallic acid and simple gallate esters are also reported in Terminalia spe-
cies. The total content of polyphenolic compounds present in the methanolic fruit
extracts of T. horrida was approximately seven times more than that of T. chebula.
Chebulic ellagitannins are one of the prominent compounds found in T. horrida.
Chebulagic acid and chebulinic acid are the characteristic compounds present in it.
Phytopharmacological Aspects of the Genus Terminalia 1123

Table 2 Common phytoconstituents of Terminalia spp. and their structures

Plant name Phytoconstituent Structure
T. arjuna Terflavin [32]

β-Sitosterol [68]

Palmitoleic acid [30]

Globulol [30]

T. ferdinandiana Hesperetin [34]

Gallic acid [33]

Ellagic acid [33]

Luteolin [34]

(continued)
1124 A. Pokkadath et al.

Table 2 (continued)
Plant name Phytoconstituent Structure
T. sericea Linoleic acid [69]

Anolignan B [70]

Lupeol [71]

Sericoside [72]

T. glaucescens Terminalin [73]

Friedelin [74]

T. chebula Ellagitannin [75]

Methyl gallate [35]

Chebulic acid [35]

Source of chemical structures is from PubChem

Phytopharmacological Aspects of the Genus Terminalia 1125

But the hydrolysis product of chebulinic acid and the di-O-galloyl analogue was
found to be very less in T. chebula [35].
The promising availability of these phytoconstituents might be the reason for the
attractive pharmacological activities of the Terminalia species.

3 Pharmacological Activities

The ability of phytoconstituents plays a significant role in the pharmacological

activity of a plant. So, they could make a milestone in the therapeutic field. Major
pharmacological activities of Terminalia plants are antioxidant activity, antimicro-
bial activity, antiproliferative activity, antidiabetic activity, anti-inflammatory activ-
ity, etc.

3.1 Antioxidant Activity

Biological systems always create destructive free radicals by various metabolic pro-
cesses. Antioxidant activity can suppress this issue by scavenging those free radi-
cals. Oxidation is an important process in living organisms for the necessity of
performing catabolism. Oxygen-centred free radicals and several reactive oxygen or
nitrogen species were formed inside the body by various activities and cause severe
diseases like atherosclerosis, diabetes, cancer, and cirrhosis [36]. Automobile
exhaust, radiation, air pollution, cigarette smoke, and pesticides are environmental
pollutants that may form the reasons to generate free radicals. Various reports
revealed that Terminalia species possess high antioxidant potential [37] (Fig. 2).
The fruit extract of T. paniculata has an appreciable ability to scavenge free radi-
cals. All the four different antioxidant assays such as DPPH, hydroxyl free radical
scavenging assay, nitric oxide free radical scavenging assay, and superoxide free
radical scavenging activity revealed a significant result on antioxidant efficiency.
All the assays possess dose-dependent activity. In DPPH assay, ascorbic acid was
used as the standard, which exhibit 20.399 μg/mL of IC50 value while the IC50
value of T. paniculata was 23.068 μg/mL which was almost similar to that of ascor-
bic acid. So, it means T. paniculata exhibits a significant antioxidant potential [38].
T. arjuna is a major source of natural antioxidants and it has been widely used in
ayurvedic and Yunani Systems of medicine [39, 40]. Reports revealed that the anti-
oxidant activity of T. arjuna extracts varied substantially and it depends on the
nature of solvents as well as raw materials for the extraction process. Methanolic
extract of plant parts was considered as the best one to exploit the potential antioxi-
dant components. Also, the leaves extract of T. arjuna was found to prevent oxida-
tion. So, this means T. arjuna is a potential source of antioxidant agents and that is
why has been used in food and pharmaceutical industries [41].
1126 A. Pokkadath et al.

Photosynthesis Stress

- .
O2 NO
.
OH .
NO2
ROS/RNS

H2O2
Instability in cell system
Antioxidants

Cell Death Survival

Fig. 2 Antioxidant activity

Phenolic compounds are the good scavengers of free radicals. It can deactivate
free radicals such as DPPH radicals. It is a stable free radical with maximum absorp-
tion at 517 nm (emax = 9660/M/cm). The reactions with DPPH and extract should
neutralize the free radicals which have been accredited by the presence of phenolic
antioxidants. Also, in T. chebula the presence of compounds such as ascorbic acid,
gallic acid and ellagic acid showed a significant reactivity with DPPH radicals.
Therefore, it has been clearly understood that phenolic constituents of the extract
are significantly responsible to react with DPPH free radicals. The extract of T. che-
bula is an excellent antioxidant agent to scavenge DPPH radicals so that it may
avoid the cellular organelle damage from radiations. Consequently, earlier reports
reveal its use as a radioprotector also [42].

3.2 Antimicrobial Activity

Antimicrobial potential is the ability of a plant to inhibit the growth of microbes.

The methanolic crude extract of the fruits of T. bellerica showed considerable anti-
microbial activity. Disc diffusion method against 9 pathogens identified the antimi-
crobial activity of T. bellerica. The aqueous fruit extract of T. bellerica at 4 mg
concentration revealed the zone of inhibition at 15.5–28.0 mm on Staphylococcus
aureus. Thus, T. bellerica is considered as one of the strongest plant species of
Phytopharmacological Aspects of the Genus Terminalia 1127

Terminalia to inhibit the growth of S. aureus [43]. T. macroptera is a medicinal plant

to cure various infectious diseases. The ethanolic extract of T. macroptera root and
its liquid–liquid partition fractions were checked for antimicrobial activity. The
twofold serial microdilution assay was used to perform the antimicrobial activity
against seven different bacterial strains and Candida albicans. Prominent results
were revealed on Shigella dysenteriae and Vibrio cholerae [44]. The minimum
inhibitory concentration (MIC) of the ethanolic extract of T. macroptera was per-
formed on 100 clinical strains such as Campylobacter sp., Escherichia coli,
Salmonella sp., Shigella sp. and Vibrio cholerae. Additionally, the antimicrobial
activity of the T. macroptera ethanol extract revealed a significant antimicrobial
activity against Pseudomonas aeruginosa, Salmonella typhimurium, Shigella dys-
enteriae, Staphylococcus aureus, Streptococcus faecalis, Vibrio cholerae except
Candida albicans and Escherichia coli [44].
The antibacterial activity was performed on the aqueous and methanolic extract
of T. catappa, which give a good result against the bacterial strains such as S. aureus,
Stictonaclia subflava, Bacillus cereus, Bacillus megaterium, Mariniluteicoccus fla-
vus, Enterococcus faecalis, Pseudomonas pseudoalcaligenes and Citrobacter freun-
dii [45].
The leaves and bark of T. arjuna possess significant antibacterial activity against
4 different bacteria. The acetonic leaf extract exhibited prominent antibacterial
activity against Staphylococcus aureus (28 mm), Proteus mirabilis (27.6 mm),
Acinetobacter sp. (16.6 mm) and Pseudomonas aeruginosa (16 mm). These reports
revealed that the acetonic leaf extract showed good antibacterial activity against
S. aureus whereas the bark extract revealed almost equal inhibition against Gram-­
negative bacteria except P. aeruginosa. Similarly, the aqueous extract of T. arjuna
bark possesses a good activity against S. aureus [46].

3.3 Antiproliferative Activity

Cancer is a large group of diseases that can start in any organ if the cells grow
uncontrollably. According to World Health Organization, it is a non-communicable
disease and the second leading cause of death and causes a big economic problem
for patients all over the world. So, the study about antiproliferative activity on plants
will provide relief to the medical field. Genus Terminalia exhibits high amount of
antioxidant agents which in turn are responsible for the therapeutic effects.
Furthermore, some of the plants of the genus Terminalia have been reported to
exhibit anticancer activities. Triphala is an ayurvedic medicine, which is the combi-
nation of Terminalia bellirica (Gawrtn.) Roxb. and Terminalia chebula (Retz.)
Lyons, together with Phyllanthus emblica. It has cytotoxic potential against thymic
lymphoma cells, human breast cancer cell lines, human prostate cancer cell lines
and human pancreatic cancer cell lines [47].
Antiproliferative activity of the aqueous extract of T. chebula was performed on
human lung cancer A and mouse lung cancer LLC cell lines. It was found to inhibit
1128 A. Pokkadath et al.

cell proliferation and promoted anticancer activity. The cell proliferation was
induced by the apoptosis and cell cycle arrest by regulating the mitochondrial path-
way mediated by proteins of the Bcl-2 family and inducing the PARP cleavage and
encouraging the cytochrome c release into the cytoplasm [14]. Similarly, the fruit
extracts of T. ferdinandiana are very effective on the Caco-2 cells. However, metha-
nolic and aqueous fruit extracts of T. ferdinandiana revealed antiproliferative activ-
ity on HeLa cells. The ethanolic leaf extract of T. catappa exhibits good
antiproliferative activity in HeLa and SiHa cervical cancer cell lines [15].
An isolated hydrolysable tannin compound casuarinin obtained from the bark of
T. arjuna proved antiproliferative activity in human breast cancer cell lines (MCF-7
cells). Casuarinin can inhibit the growth of MCF-7 by blocking cell cycle progres-
sion in the G0/G1 phase and promoting apoptosis. P53 gene makes a significant role
in apoptosis and cell cycle by DNA damage [48]. The activities of various cyclin-­
dependent kinases are inhibited by P21/WAFI. Also, it blocks the phosphorylation
of retinoblastoma (RB) protein and inhibits the G1-S phase transition [49]. When
the MCF-7 cells were treated with casuarinin, it had no effective changes in the
expression of P53 whereas the P21/WAFI level was improved by casuarinin treat-
ment. Moreover, the flow cytometric analysis revealed that casuarinin causes arrest
of MCF-7 cells in the G0/G1 phase. So, the inhibition of cell cycle progression will
increase the activity of P21/ WAFI protein expression. Therefore, the quantity of
P53 protein, as well as its phosphorylation state, can regulate the transcriptional
activity and play a crucial role in P53-mediated functions. Additionally, when the
MCF-7 cells were treated with caspase-8-inhibitor, the cell growth inhibition as
well as the apoptotic induction of casuarinin was found to be reduced. Thus, casua-
rinin is a promising chemopreventive agent to cure breast cancer [32].
T. bellerica has significant medicinal activity and hence it was used in Indian
traditional medicinal systems. The majority of it proves its antiproliferative activity.
T. bellerica extract is used to check the antiproliferative activity against oral squa-
mous cell carcinoma (OSCC). It is a head and neck cancer induced by the impact of
carcinogens as well as the epidemiological influences like tobacco chewing and
betel quid, diet and immunodeficiency caused by viral infections. It was revealed
that gallic acid in T. bellerica is an antioxidant agent which in turn scavenge the free
radicals. So, they inferred that the strong antioxidant potential of gallic acid in
T. bellerica extract could exhibit a significant antiproliferative activity. Also, the
potential activity of gallic acid in T. bellerica inhibits autophagy, which in turn
diminishes the fusion of autophagosome and lysosomes in OSCC. The inhibition of
autophagy improves the apoptosis in OSCC by T. bellerica extract. Furthermore,
T. bellerica fruit extract possesses antiproliferative activity on Shionogi 115, breast
cancer MCF–7, prostate cancer PC–3, DU–145, leukaemia HK–63, HOS–1, HSC–2
and HL–60 cells. Also, the T. bellerica extract could make effective inhibition on
Hep2, Cal33 and FaDu cells that depends on both time and concentration. Apoptotic
protein analysis by Western blot technique is explicated by the effects of T. bellerica
extract on Cal33 cells. Mitochondria help for the process of initiation and progres-
sion of apoptosis, by the expression of pro-apoptotic protein Bax and consecutive
Phytopharmacological Aspects of the Genus Terminalia 1129

decrease in the expression of anti-apoptotic Bcl2. The intrinsic apoptosis thus

occurred by the effect of an increased expression of Bax/Bcl2 [50].
T. bellirica extracts have also been established by the inhibitory effects against
human A549 lung cancer cell lines and HepG2 hepatocarcinoma cell lines [51]. The
synergistic effects of anticancer chemotherapeutics improve the cytotoxic effect of
cisplatin and doxorubicin towards the cancer cell lines. Similarly, T. ferdinandiana
Exell. is an Australian species and it has antiproliferative activity against the num-
ber of cancer cell lines [52]. The extract can activate caspase-7, caspase-9 and poly
ADP-ribose polymerase (PARP), which represents that apoptosis induction occurs
through an intrinsic pathway. The leaf extracts of another two Australian Terminalia
spp. (T. carpentariae and T. grandiflora) had also revealed the ability to inhibit the
proliferation of Caco2 and HeLa [53].
Terminalia spp. has high levels of antioxidants phytochemicals and some of the
species have antiproliferative activity. T. sericea leaf extracts exhibit antiprolifera-
tive activity on Caco2 and HeLa carcinoma cell proliferation. Methanolic and aque-
ous extracts of T. sericea leaves were selected to examine the antiproliferative
activity. The effective antioxidant agents of the T. sericea leaf extracts inhibit the
proliferation of Caco2 and HeLa cancer cell lines. These methanolic and aqueous
extracts with high antioxidant agents act as effective inhibitors for cell proliferation
with IC50 values of 120–1400 μg/mL. The aqueous leaf extract exhibited IC 50
values of 528 and 120 μg/mL against Caco2 and HeLa cells, respectively. But the
methanolic extract possesses a prominent antiproliferative activity on HeLa cells
with IC50 values of 1358 μg/mL. The extracts with lower antioxidant contents were
not found to inhibit the proliferation of cancer cells [47]. So, it can be concluded
that several plants of the genus Terminalia exhibit significant inhibition on the
growth of cancer cells.

3.4 Anti-inflammatory Activity

Many human diseases are caused by inflammation. New reports revealed that non-­
communicable diseases share common pathophysiological mechanisms, as well as
oxidative stress and inflammation, which makes the onset and development of these
diseases [54]. Terminalia species with reported anti-inflammatory activity in vitro
may be due to the presence of phytochemicals. There is an effective outcome
between the anti-inflammatory and the structural properties of phytochemicals that
have already been reported [55, 56].
The anti-inflammatory activity of T. coriacea was experimented in albino Wistar
rats using both acute and chronic models, carrageenan-induced paw oedema and
cotton pellet-induced granuloma, respectively. T. coriacea extract was examined
with different concentrations (125, 250 and 500 mg/kg) by oral uptake of the leaf
extract. All the concentrations showed an excellent anti-inflammatory activity in a
dose-dependent manner. Similarly, the anti-inflammatory studies using the ethano-
lic fruit extracts were performed at different concentrations like 50 to 500 mg/kg on
1130 A. Pokkadath et al.

carrageenan-induced inflammation in rats. The result obtained by this study revealed

that the increased inhibitory activity on carrageenan-induced lipid peroxidation in
rat liver is concentration-dependent. The highest inhibition was found to be (84.08%)
at 250 mg/kg [57]. Gallic acid is another important phytocompound seen in
Terminalia spp. It was found to inhibit COX-1 and COX-2 with IC50 values of
1.5 μM and 74 μM, respectively.
The ethyl acetate extract of the root bark of T. glaucescens produce triterpene
compounds. Twelve different triterpene compounds were isolated from it, i.e., ter-
miglaucescin; b-D-glucopyranosyl 2a, 3b, 6b trihydroxy-23-gallylean-12-en-­28-
oate; arjunglucoside I; sericoside; arjungenin; sericic acid; arjunetin; chebuloside II;
3,3′4-tri-O-methylellagic acid; 3,3′-di-O-methylellagic acid; b-sitosterol and stig-
masterol. The phytoconstituents have been revealed to possess promising anti-­
inflammatory activity by the albumin denaturation as well as the haemolysis
assays [58].
Polyphenolic compounds are the characteristic feature of T. muelleri. The
extracts showed a prominent anti-inflammatory activity in the carrageenan-induced
paw oedema in a dose-dependent manner [59]. T. phanerophlebia is an endemic
species found in Africa. The crude extract of T. phanerophlebia showed a prominent
inhibition of COX-2 (92.4%). It was obtained by the effect of cholestane triterpe-
noids like b-sitosterol, b-sitostenone and stigmast-4-ene-3,6-dione. These isolated
compounds had that the established COX-2 inhibitory activity might be the effect of
triterpenoid b-sitosterol [59].
In vitro anti-inflammatory studies were carried out on T. catappa in the aqueous
extract of the bark. The bark revealed a considerable antioxidant activity than the
fruit and wood. The results had revealed a dose-dependent activity on all the parts
of the plant [60]. Additionally, ethyl acetate extract from the aerial parts of T. bel-
lirica at concentrations of 100 and 300 mg/kg was orally applied to the male BALB/
cN mice following tetrachloride intoxication. Moreover, Terminalia spp. treatment
diminishes the expression of inflammatory mediators like NF-kB, COX-2
and TNF-a.

4 Conclusion

Reports revealed that the genus Terminalia possess plenty of phytochemicals with
tremendous biological activities. The major phytochemicals found in Terminalia
spp. are alkaloids, phenols, flavonoids, tannins, terpenoids, carbohydrates, glyco-
sides, phlobatannins etc. All these phytochemicals have various biological proper-
ties in several fields. Most of them have high therapeutic values. Some of them serve
as antioxidant agents. In conclusion, it can be inferred that Terminalia spp. exhibit
significant antimicrobial, anticancer and anti-inflammatory properties. Thus, the
genus Terminalia seems to possess an irreplaceable group of plant species that may
be used in the therapeutic field for future studies and medical treatment.
Phytopharmacological Aspects of the Genus Terminalia 1131

Acknowledgments The first author is grateful to University of Calicut (U. O. No. 12753/2019/
Admn) for providing the financial assistance. Second author acknowledges the financial grant sup-
ported by the Council of Scientific and Industrial Research (CSIR) in the form of Senior Research
Fellowship (09/043(0186)/2017-EMR-1).

References

1. Petrovska BB (2012) Historical review of medicinal plants’ usage. Pharmacogn Rev 6:1–5
2. Fan C, Dong Y, Xie Y et al (2015) Shikonin reduces TGF-b1-induced collagen production and
contraction in hypertrophic scar-derived human skin fibroblasts. Int J Mol Med 36:985–991
3. Cock I (2015) The medicinal properties and phytochemistry of plants of the genus Terminalia
(Combretaceae). Inflammopharmacology 23:203–229
4. Intharuksa A, Ando H, Miyake K et al (2016) Molecular analysis of Terminalia spp. distrib-
uted in Thailand and authentication of crude drugs from Terminalia plants. Biol Pharm Bull
39:492–501
5. Maulik SK, Katiyar CK (2010) Terminalia arjuna in cardiovascular diseases: making the tran-
sition from traditional to modern medicine in India. Curr Pharm Biotechnol 11:855–860
6. Maulik SK, Talwar KK (2012) Therapeutic potential of Terminalia arjuna in cardiovascular
disorders. Am J Cardiovasc Drugs 12:157–163
7. Afshari AR, Sadeghnia HR, Mollazadeh H (2016) A review on potential mechanisms of
Terminalia chebula in Alzheimer’s disease. Adv Pharmacol Sci, pp 1–15
8. Das G, Kim DY, Fan C et al (2020) Plants of the genus Terminalia: an insight on its biological
potentials, pre-clinical and clinical studies. Front Pharmacol 11:1–30
9. Abraham A, Mathew L, Samuel S (2014) Pharmacognostic studies of the fruits of Terminalia
bellirica (Gaertn.) Roxb. J Pharmacognosy Phytochem 3:45–52
10. Wright MH, Sirdaarta J, White A et al (2016) Bacillus anthracis growth inhibitory properties
of Australian Terminalia spp.: putative identification of low polarity volatile components by
GC-MS headspace analysis. Pharm J 8:281–289
11. Dharmaratne MPJ, Manoraj A, Thevanesam V et al (2018) Terminalia bellirica fruit extracts:
in-vitro antibacterial activity against selected multidrug-resistant bacteria, radical scavenging
activity and cytotoxicity study on BHK-21 cells. BMC Complement Altern Med 18:325–325
12. Sharma C, Aneja KR, Kasera R et al (2012) Antimicrobial potential of Terminalia chebula
Retz. Fruit extracts against ear pathogens. WJOHNS 2:8–13
13. Malterud KEJP (2017) Ethnopharmacology, chemistry and biological properties of four
Malian medicinal plants. Plan Theory 6:2–13
14. Wang M, Yang L, Ji M et al (2015) Aqueous extract of Terminalia chebula induces apoptosis
in lung cancer cells via a mechanism involving mitochondria-mediated pathways. Braz Arch
Biol Technol 58:208–215
15. Lee CY, Yang SF, Wang PH et al (2019) Antimetastatic effects of Terminalia catappa leaf
extracts on cervical cancer through the inhibition of matrix metalloprotein-9 and MAPK path-
way. Environ Toxicol 34:60–66
16. Mongalo N, Mcgaw L, Segapelo T et al (2016) Ethnobotany, phytochemistry, toxicology and
pharmacological properties of Terminalia sericea Burch. Ex DC. (Combretaceae)–a review. J
Ethnopharmacol 194:789–802
17. Li K, Diao Y, Zhang H et al (2011) Tannin extracts from immature fruits of Terminalia che-
bula Fructus Retz. Promote cutaneous wound healing in rats. BMC Complement Altern Med
11:86–86
18. Chang Z, Zhang Q, Liang W et al (2019) A comprehensive review of the structure elucidation
of tannins from Terminalia Linn. Evidence-Based Complement Altern Med 2019:1–26
1132 A. Pokkadath et al.

19. Sharma R, Raizada S, Gautam A et al (2018) Phytochemical and antibacterial analysis of

Terminalia chebula and Terminalia bellirica. GRCHFJ:131–137
20. Saikia P, Bora TJ (2018) Phytochemical analysis of Emblica officinalis and Terminalia chebula
fruits extracts in Assam. Ahead-Int J Rec Res Rev 1:23
21. Prajapati S, Bhardwaj A, Gupta P (2020) Anatomical and phytochemical standardization of
Terminalia chebula and Syzygium jambolanum: a highly used medicinal plant in India. Plant
Cell Biotechnol Mol 21:31–41
22. Roopalatha UC, Mala V (2013) The phytochemical screening of the pericarp of fruits of
Terminalia chebula Retz. Int J Pharm Bio Sci 4(3):P550–P559
23. Grover P, Singh SK, Bansal GK (2014) Phytochemical investigations and systematic explora-
tion of anticancer potential of leaves of Terminalia bellerica. Lap Lambert Publishing
24. Shikha K (2018) Molecular and Phytochemical characterization of Terminalia bellerica
from North Western region of Himalayas in Himachal Pradesh India. Dissertation, Shoolini
University of Biotechnology and Management Sciences
25. Moulisha B, Bi K, Tarun KK et al (2011) Evaluation of analgesic and anti-inflammatory activi-
ties of Terminalia arjuna leaf. J Phytology 3:33–38
26. Mandal S, Patra A, Samanta A et al (2013) Analysis of phytochemical profile of Terminalia
arjuna bark extract with antioxidative and antimicrobial properties. Asian Pac J Trop Biomed
3:960–966
27. Kumar C, Nehar KR (2013) Phytochemical properties, total antioxidant status of acetone and
methanol extract of Terminalia arjuna Roxb. Bark and its hypoglycemic effect on type-II dia-
betic albino rats. J Pharmacogn Phytochem 2:199–208
28. Ragavan B, Krishnakumari S (2006) Antidiabetic effect of T. arjuna bark extract in alloxan
induced diabetic rats. Indian J Clin Biochem 21:123–128
29. Khanna AK, Chander R, Kapoor NK (1996) Terminalia arjuna an ayurvedic cardiotonic regu-
lates lipid metabolism in hyperlipidaemic rats. Phytother Res 10:663–665
30. Gupta D, Kumar M (2017) Evaluation of in vitro antimicrobial potential and GC–MS analysis
of Camellia sinensis and Terminalia arjuna. Biotechnol Rep 13:19–25
31. Ramesh R, Dhanaraj TS (2015) GC–MS analysis of bioactive compounds in Terminalia
Arjuna root. Int J Multidiscip Res Dev 2:460–462
32. Kuo PL, Hsu YL, Lin TC et al (2005) Casuarinin from the bark of Terminalia arjuna induces
apoptosis and cell cycle arrest in human breast adenocarcinoma MCF-7 cells. Planta Med
71:237–243
33. Cunningham A, Garnett S, Gorman J et al (2009) Eco–enterprises and Terminalia ferdinandi-
ana: “best laid plans” and Australian policy lessons. Econ Bot 63:16–28
34. Konczak I, Zabaras D, Dunstan M et al (2010) Antioxidant capacity and hydrophilic phyto-
chemicals in commercially grown native Australian fruits. Food Chem 123:1048–1054
35. Pfundstein B, El Desouky SK, Hull WE et al (2010) Polyphenolic compounds in the fruits of
Egyptian medicinal plants (Terminalia bellerica, Terminalia chebula and Terminalia horrida):
characterization, quantitation and determination of antioxidant capacities. Phytochemistry
71:1132–1148
36. Halliwell B, Gutteridge JM (1995) The definition and measurement of antioxidants in biologi-
cal systems. Free Radic Biol Med 18:125–126
37. Li Y, Trush MA (1994) Reactive oxygen-dependent DNA damage resulting from the oxidation
of phenolic compounds by a copper-redox cycle mechanism. Cancer Res 54:1895–1898
38. Aswathi P, Thoppil JE (2020) Assessment of antioxidant potential and antigenotoxicity analy-
sis through hydrogen peroxide-induced oxidative stress in Terminalia paniculata Roth. AJPCR
13:106–110
39. Singh UP, Singh DP, Maurya S et al (2004) Investigation on the phenolics of some spices hav-
ing pharmaco-therapeutic properties. J Herb Pharmacotherapy 4:27–42
40. Prakash D, Suri S, Upadhyay G et al (2007) Total phenol, antioxidant and free radical scaveng-
ing activities of some medicinal plants. Int J Food Sci and Nut 58:18–28
Phytopharmacological Aspects of the Genus Terminalia 1133

41. Chatha SAS, Hussain AI, Asad R et al (2014) Bioactive components and antioxidant properties
of Terminalia arjuna L. extracts. J Food Process Technol 5:1–5
42. Naik GH, Priyadarsini KI, Naik DB et al (2004) Studies on the aqueous extract of Terminalia
chebula as a potent antioxidant and a probable radioprotector. Phytomedicine 11:530–538
43. Elizabeth KM (2005) Antimicrobial activity of Terminalia bellerica Indian J. Clin Biochem
20:150–153
44. Silva O, Duarte A, Pimentel M et al (1997) Antimicrobial activity of Terminalia macroptera
root. J Ethnopharmacol 57:203–207
45. Nair R, Chanda S (2008) Antimicrobial activity of Terminalia catappa, Manilkara zapota and
Piper betel leaf extract. Indian J Pharm Sci 70:390
46. Aneja KR, Sharma C, Joshi R (2012) Antimicrobial activity of Terminalia arjuna Wight &
Arn.: an ethnomedicinal plant against pathogens causing ear infection. Braz J Otorhinolaryngol
78:68–74
47. Gu B, Shalom J, Cock IE (2018) Anti-proliferative properties of Terminalia sericea burch. Ex
dc leaf extracts against Caco2 and HeLa cancer cell lines. Pharm J 10:408–415
48. May P, May E (1999) Twenty years of p53 research: structural and functional aspects of the
p53 protein. Oncogene 18:7621–7636
49. Harper JW, Adami GR, Wei N et al (1993) The p21 Cdk-interacting protein Cip1 is a potent
inhibitor of G1 cyclin-dependent kinases. Cell 75:805–816
50. Patra S, Panda PK, Naik PP et al (2020) Terminalia bellirica extract induces anticancer activity
through modulation of apoptosis and autophagy in oral squamous cell carcinoma. Food Chem
Toxicol 136:111073
51. Pinmai K, Chunlaratthanabhorn S, Ngamkitidechakul C (2008) Synergistic growth inhibitory
effects of Phyllanthus emblica and Terminalia bellerica extracts with conventional cytotoxic
agents: doxorubicin and cisplatin against human hepatocellular carcinoma and lung cancer
cells. World J Gastroenterol 14:1491–1497
52. Tan AC, Konczak I, Ramzan I (2011) Potential antioxidant, anti-inflammatory, and proapop-
totic anticancer activities of Kakadu plum and Illawarra plum polyphenolic fractions. Nutr
Cancer 63:1074–1084
53. Courtney R, Sirdaarta J, White A (2017) Inhibition of Caco-2 and HeLa proliferation by
Terminalia carpentariae C.T.White and Terminalia grandiflora Benth. Extracts: identification
of triterpenoid components. Pharm J 9:175–184
54. Camps J, Garcı́a-Heredia A (2014) Introduction: oxidation and inflammation, a molecular
link between non-communicable diseases. In: Oxidative Stress and Inflammation in non-­
communicable diseases-molecular mechanisms and perspectives in therapeutics, Switzerland
55. Gautam R, Jachak SM (2009) Recent developments in antiinflammatory natural products. Med
Res Rev 29:767–820
56. Lago JHG, Toledo-Arruda AC, Mernak M et al (2014) Structure-activity association of flavo-
noids in lung diseases. Molecules 19:3570–3595
57. Khan MSA, Khatoon N, Al-Sanea MM et al (2018) Methanolic extract of leathery murdah,
Terminalia coriacea (Roxb.) Wight and Arn. Leaves exhibits antiinflammatory activity in
acute and chronic models. Med Principles Pract 27:267–271
58. Dawe A, Talom B, Kapche G et al (2017) Termiglaucescin, a new polyhydroxy triterpene
glucoside from Terminalia glaucescens with antioxidant and antiinflammatory potential.
ZNCBDA 72:203–208
59. Nair JJ, Aremu AO, Van Staden J (2012) Antiinflammatory effects of Terminalia phanero-
phlebia (Combretaceae) and identification of the active constituent principles. South Afr J Bot
81:79–80
60. Venkatalakshmi P, Brindha P, Vellingiri V (2015) In vitro antioxidant and anti-inflammatory
studies on bark, wood and fruits of Terminalia catappa L. Int J Phytomed 7:246–253
61. Dwevedi A, Dwivedi R, Sharma YK (2016) Exploration of phytochemicals found in Terminalia
sp. and their antiretroviral activities. Pharmacognosy Rev 10:73–83
1134 A. Pokkadath et al.

62. Terças AG, Monteiro ADS, Moffa EB et al (2017) Phytochemical characterization of

Terminalia catappa Linn. Extracts and their antifungal activities against Candida spp. Front
Microbiol 8:595–595
63. Adebayo EA, Ishola OR (2009) Phytochemical and antimicrobial screening of crude extracts
from the root, stem bark, and leaves of Terminalia glaucescens. Afr J Pharmacy Pharmacol
3:217–221
64. Mann A, Yahaya Y, Banso A et al (2008) Phytochemical and antimicrobial activity of
Terminalia avicennioides extracts against some bacteria pathogens associated with patients
suffering from complicated respiratory tract diseases. J Med Plant Res 2:094–097
65. Bamisaye FA, Odutuga AA, Minari JB et al (2019) Phytochemical constituents and antid-
iarrhoeal effects of the aqueous extract of Terminalia superba leaves on Wistar rats. Afr J
Pharmacy Pharmacol 7:848–851
66. Akpovona AE, Onoagbe OI, Prohp TP (2016) Proximate and phytochemical analyses of
mature stem bark of Terminalia macroptera Guill. & Perr. JCSN 41:111–116
67. Savithramma N, Linga RM, Yugandhar P, Suvarnalatha DP (2013) Ethnomedicinal studies
of Tumburu Theertham: a sacred grove of Tirumala hills, Andhra Pradesh, India. J Ethnobiol
Traditional Med 120:547–556
68. Anjaneyulu A, Prasad AR (1982) Chemical examination of roots or Terminalia-arjuna – the
structures of arjunoside III and arjunoside IV, two new triterpenoid glycosides. Phytochemistry
21:2057–2060
69. Chivandi E, Davidson BC, Erlwanger KH (2013) Proximate, mineral, fibre, phytate phos-
phate, vitamin E, amino acids and fatty acid composition of Terminalia sericea. S Afr J Bot
88:96–100
70. Eldeen IMS, Elgorashi EE, Mulholland DA et al (2006) Anolignan B: a bioactive compound
from the roots of Terminalia sericea. J Ethnopharmacol 103:457–467
71. Nkobole N, Houghton PJ, Hussein A et al (2011) Antidiabetic activity of Terminalia sericea
Burch. Ex DC. Constituents. Nat Prod Commun 6:1585–1588
72. Mochizuki M, Hasegawa N (2006) Acceleration of lipid degradation by sericoside of
Terminalia sericea roots in fully differentiated 3T3-L2 cells. Phytother Res 20:1020–1021
73. Zareen S, Choudhary MI, Ngounou FN et al (2002) Terminalin A, a novel triterpenoid from
Terminalia glaucescens. Tetrahedron Lett 43:6233–6236
74. Rahman AU, Zareen S, Choudhary MI et al (2005) Some chemical constituents of Terminalia
glaucescens and their enzymes inhibition activity. Z Naturforsch B 60:347–350
75. Lee DY, Kim HW, Yang H et al (2017) Hydrolyzable tannins from the fruits of Terminalia
chebula Retz and their α-glucosidase inhibitory activities. Phytochemistry 137:109–116
Anticancer Potential of Plant-Derived
Compounds: An Overview of Their
Epigenetic Mode of Action

Priyanka Soni, Md. Sajid Ghufran, and Govinda Rao Duddukuri

Abbreviations

Akt Protein kinase B

Bcl-2 B-cell lymphoma
BMI-1 B cell-specific moloney murine leukemia virus integration site 1
DNMTs DNA methyltransferases
EGCG Epigallocatechin gallate
ERK Extracellular signal-regulated kinase
EZH2 Enhancer of Zeste homolog 2
HATs Histone acetyltransferases
HDACs Histone deacetylases
miRNAs microRNAs
PRC Polycomb repressive complexes
SUZ12 Suppressor of zeste 12 homolog
TET Ten eleven translocases
TSGs Tumor suppressor genes

P. Soni · G. R. Duddukuri (*)

Department of Biochemistry and Molecular Biology, School of Biological Sciences,
Central University of Kerala, Kasaragod, Kerala, India
Md. S. Ghufran
Department of Chemistry, Faculty of Natural and Computational Sciences,
Gambella University, Gambella, Federal Democratic Republic of Ethiopia

© The Author(s), under exclusive license to Springer Nature 1135

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_48
1136 P. Soni et al.

1 Introduction

Cancer is undoubtedly a serious, multifaceted devastating disease that represents

one of the most severe global health problems threatening human life in both devel-
oping and developed countries. The development of cancer is a slow and multistep
process which takes quite a long time to develop within an individual. Usually, a
healthy person’s body replenishes the damaged or worn-out cells by the systematic
process of cell division. But this orderly process gets disrupted when the cells begin
to divide uncontrollably, invading and interfering with the normal cellular functions
during the development of cancer. A normal cell gradually turns into a malignant
one through an escalating series of alterations. The process begins with the induc-
tion of a mutation in a critical gene resulting in the “initiation” of cancer [1]. The
irreversible initiation is later followed by the “promotion” stage where the initiated
cell attains further mutations to divide clonally, forming a detectable mass of benign
or preneoplastic cells or unique subclones. This leads to the final stage of carcino-
genesis named “progression” where the subclones multiply repeatedly over time
and develop the capacity to metastasize exhibiting augmented invasiveness and
variations in biological as well as morphological features. The progressed cancer
cells then metastasize throughout the body and become extremely heterogenous,
resilient to treatment and more likely to be fatal [2].
Literature suggests the involvement of inherited genetic mutations in 5–10% of
all cancers, whereas the majority (80–90%) of the cancer cases are elicited by mod-
ern lifestyle and environmental factors that may epigenetically alter normal cellular
growth, survival, and functioning [3]. Some specific patterns of environmental
exposures or gene alterations can make human populations either more vulnerable
or more resilient to cancer [4]. The chances of cancer development within an indi-
vidual depends on quite a few interrelating factors, for instance, how frequently and
how long he/she gets the exposure, whether he/she gets exposed to any other carci-
nogenic or harmful agents, his/ her lifestyle, dietary habits, age, gender, and genetic
factors [5]. The most arduous task for the scientific community is to spot the unique
combinations of the aforementioned factors that will aid in interpreting why one
particular individual will develop cancer and the other will not [6]. The latest
advancements within the area of cancer epigenetics have asserted the substantial
reprogramming of each single factor of the epigenetic machinery, including enzy-
matic covalent DNA modifications, posttranslational histone modifications, posi-
tioning of nucleosomes, and expression of microRNAs in the commencement and
progression of cancer [7].
The most recent figures for 2020 revealed the emergence of approximately 19.3
million cancer cases globally, including around 1.3 million cases from India. This
astounding data also showed an alarming 47% rise in the overall cases to be expected
by 2040 [8, 9]. It compels researchers to develop a proactive approach toward the
treatment of cancer using naturally derived compounds with minimal systemic side
effects. The use of plant-derived natural products, phytochemicals or plant extracts
may provide a promising platform for the development of potent anticancer drugs
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic... 1137

containing small-molecule inhibitors targeting epigenetic-modified enzymes and

thus may aid in therapy for cancer prevention [10]. Therefore, this chapter focuses
on the role of phytochemicals for their epigenetic modifying potential in the func-
tional regulation of tumorigenesis and contributes to technical support for science-
based applications of phytochemicals in anticancer therapeutics.

2 Epigenetic Mechanisms Involved in the Commencement

of Cancer

The term “epigenetics” proposed by Conrad Hal Waddington in the year 1942 is the
study of heritable changes during cell division which brings about the modifications
to the genome resulting in altered gene expression without changes to the underly-
ing DNA sequence [4, 11]. The diverse epigenetic modifications include self-rein-
forcing and distinctive mechanisms namely DNA methylation, histone modifications,
and RNA-mediated gene silencing, which may have everlasting effect on the expres-
sion of critical genes [7] Fig. 1. The epigenetic scaffold maintains the proper func-
tioning and survival of cells through certain epigenetic modulators that modify the
DNA as well as histone proteins within the nucleosome complex to render “ON” or
“OFF” signals to genes [11]. The most important epigenetic modulators and their
mode of action which can be exploited for the development of cancer therapeutics
are briefly discussed here.

2.1 DNA Methylation

DNA methylation is one of the primary epigenetic modifications which is mediated

and catalyzed by the DNA methyltransferases (DNMTs) that bring about the cova-
lent transfer of a methyl group to the C-5 position of the cytosine base in the cyto-
sine-guanine (CpG) dinucleotide generating 5-methyl cytosine (5mC) [12]. The
enzymes culpable for imparting the DNA methylation marks comprise DNMT1 as
the maintenance methyl transferase and DNMT3a, DNMT3b that arbitrates the de
novo methylation [13]. DNA methylation, one of the most extensively studied epi-
genetic mechanisms, is dynamically involved in regulating certain biological pro-
cesses such as heritable silencing of genes, gene expression, and stability of the
genome that largely constitutes the epigenome network [14]. It regulates and blocks
gene expression by suppressing the binding of transcription factors (TFs) to gene
promoters or making the DNA inaccessible to their transcription factors [15].
Aberrant hypermethylation of CpG islands (CGIs) is one of the most imperative
epigenetic characteristics of tumors and is associated with the silencing of genes
involved in cell cycle regulation, tumor cell invasion, and other events in which gene
inactivation leads to metastasis [16, 17]. On the other hand, the activation of
1138 P. Soni et al.

Fig. 1 Cellular epigenetic mechanisms involved in the initiation and commencement of cancer.
The development and progression of deadly cancer involves deregulation of the cell cycle, meth-
ylation of target genes by DNA methyltransferases, histone modifications (acetylation, phosphory-
lation, methylation, and ubiquitination) by histone modifiers and transcriptional repression of
tumor suppressor genes via polycomb repressive complexes

potential oncogenes occurs due to gene-specific hypomethylation within the pro-

moter. The overexpression of DNMTs is found in breast, lymphoma, colon, and
liver cancer cells [16, 18].
During carcinogenesis, abnormal hypermethylation of the tumor suppressor
genes (TSGs) augments the menace of the tumor, worsens the diagnosis in affected
individuals, and increases the resistance to cancer therapy. This is the reason for
relying on the transcriptional restoration of methylated CGIs in TSGs during the
stages of cancer therapy [19]. There are abundant plant-derived natural compounds
or plant extracts which play a substantial role in cancer therapeutics. Reports show
that curcumin possesses an ability to alter “cancer-specific” DNA methylation as it
revives the hypermethylated TSGs via downregulation of DNMT1 [18]. Modulation
of miR-29b upon curcumin exposure aids in balancing the DNA methylation-
demethylation equilibrium by regulating Ten Eleven Translocases (TET) and
DNMT levels. The DNMT1 activity is also impaired upon curcumin-mediated
upregulation of p21 and modulation of TFs like AP1 or SP1 [18, 20]. Another natu-
ral compound named genistein, resulted in global hypomethylation of DNA in a
time-dependent manner with a reduced expression of DNMT3a and 3b [21, 22]. A
polyphenol Epigallocatechin gallate (EGCG) is also reported to inverse the meth-
ylation status of TSG, thereby reactivating it by decreasing the expression of
DNMT1 in breast cancer cells [23]. The effectiveness of natural compounds in
maintaining the DNA methylation machinery is also witnessed in HepG2 cells
where quercetin-mediated decrease in the expression of DNMTs significantly
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic... 1139

increased the 5-methylated cytosine (5-mC) [24]. Aforementioned are only a few
natural compounds that have an exemplary role in mediating DNA methylation.
More details about the plant extracts and the other plant-derived compounds which
may play an inevitable role in cancer prevention targeting the methylation status or
DNMTs are enlisted in Tables 1 and 2.

2.2 Histone Modifications

Histone modifications are the major modifications which take place posttranslation-
ally causing inaccessibility of DNA to bind with their transcription factors leading
to transcriptional alterations [25]. Histone deacetylases (HDACs), responsible for
deacetylation, are a class of conserved enzymes which catalyze the removal of ace-
tyl groups from lysine side chain residues of histone tails and play an indispensable
role in the transcription of genes to regulate migration and cellular proliferation [11,
26]. Histone acetyltransferases (HATs) bring about the acetylation of histone tail in
which the positive charge over histone proteins is neutralized and, finally, RNA
polymerase gets recruited, enabling gene transcription. These two enzymes play a
leading role in the regulation of gene transcription, malignant transformation, and
progression in a widespread variety of tumors [27]. Class I and II HDACs are con-
sidered to be general oncoproteins that interact with substrates and regulate gene
expression to promote tumorigenesis and cancer development [14, 28]. The deacet-
ylation of HDAC3 and depletion of HDAC 10 affects the G2/M transitions through
the regulation of cyclin A [26].
Protein methyltransferases are also important for regulation of gene expression
epigenetically via methylation of target histones (H2AR3, H3R2, H3R8, and H4R3)
as well as nonhistones’ proteins and have been involved in playing crucial roles in
human diseases, including progression of cancer [29]. The predominant type of
epigenetic modification, methylation of lysine results in the repression or derepres-
sion of transcription depending on the position that is being methylated [30]. To be
concise, histone modifications are a segment of an intricate network and control
chromatin organization, transcription of genes, DNA repair, and replication [31].
The impairment in the regulation of these cellular processes and equilibrium loss
might lead to the development of diseases such as cancer [27].
It is the need of time to develop effective HDAC inhibitors (HDACi) from natural
sources that can limit tumor growth and restrict abnormal proliferation of cells
finally attenuating the tumor burden. There are some safe and efficacious plant-
derived compounds that impose epigenetic regulation in cancer cells. This is evident
when treatment with a polyphenol named resveratrol results in an augmentation in
the acetylation levels of histone H3 and H4 (H3K9ac, H3K14ac, H4K5ac, H4K12ac,
and H4K16ac) in renal carcinoma cells (RCC) [32]. A similar increase in acetyla-
tion at H3 and H4 histones with a higher HAT activity and lower HDAC activity was
observed in sulforaphane-treated A375 melanoma cells [33] and RKO colon cancer
cells [34]. Detailed information regarding the efficient natural plant extracts or
Table 1 Anticancer efficacy of various plant extracts against different cancer types
Cells used with IC50
1140

Name of the plant Family Parts used Extract Doses used Cancer type concentration Epigenetic modifications References
Acorus calamus (Sweet Acoraceae Plant Ethanol 0–1250 μg/ml Prostate LNCaP ↓ Proliferation [68]
flag) (923 μg/mL) ↑ Cleaved PARP
↓ VEGF mRNA
Adenosma bracteosum Plantaginaceae Aerial part Ethanol 0–100 μg/mL Lung NCI-H460 ↓ Proliferation [69]
(Bonati) Liver (4.57 ± 0.32 μg/mL) ↑ Caspase-3 activity
HepG2
(5.67 ± 0.09 μg/mL)
Aeluropus lagopoides Poaceace Leaves Hexane 0–100 μg/mL Liver HepG2 [70]
(Mangrove grass) Ethyl acetate (24.29 ± 0.85 μg/mL)
⦸ G0/G1 phase

HepG2
(11.22 ± 0.67 μg/mL)
Alcea rosea (Hollyhock) Malvaceae Seeds Ethyl acetate 0–100 μg/mL Colon HCT116 ↑ Cleaved PARP [71]
SW480 ↑ Bax expression
Balb/c mice Go/G1 phase arrest
↓ Cyclin D1, EZH2
↓ β-catenin, Ki-67
Allium sativum (Garlic) Amaryllidaceae Bulb – 0–50 μg/mL Kidney A498 S phase arrest [72]
Lung A549 ↑ p53, Bax, Cas3, Cas9
↓ Bcl-2
Alpinia nantoensis Zingiberaceae Rhizome Ethanol 0–200 μg/mL Breast MDA-MB-231 ↓ PI3K/AKT and Ras-ERK [73]
Leaves (28.13 ± 2.43 μg/mL) activation
MDA-MB-231 ↓ EGFR activation
(36.05 ± 3.74 μg/mL)
Alstonia scholaris Apocynaceae Leaves Alkaloid 0–25 g/ml Cervical Hela ↓ Cell viability [74]
(Blackboard tree) fraction (5.53 g/ml)
Andrographis Acanthaceae Leaves Methanol 0–300 μg Melanoma A375 and B16F10 ↓ Bcl-2, cyclin B1 [75]
nallamalayana ↑ BAD, BAX, Caspase-3
↑ p53, p21
Annona cherimola Annonaceae Leaves Ethanol 0–696 μg/mL Breast MDA-MB-231 ↑ DNA fragmentation [76]
(Cherimoya) 0–692 μg/mL Leukemia (390.2 μg/mL) ↑ p21 and Bax/Bcl-2 ratio [77]
Monomac-1 ↑ DNA fragmentation
P. Soni et al.

(333.4 μg/mL) ↓ Bcl-2

KG-1 ↑ Cleaved PARP, Bax
(254.5 μg/mL)
 Cells used with IC50
Name of the plant Family Parts used Extract Doses used Cancer type concentration Epigenetic modifications References
Apium graveolens Apiaceae Whole celery Ethanol 0–3000 μg/mL Prostate LNCaP ↓ Cell viability [78]
(Celery) (2840 μg/mL) ↑ Cleaved PARP
↓ VEGF expression
Artemisia vulgaris Asteraceae Leaves Methanol 150 mg/kg Liver Balb C mice ↑ Albumin levels [79]
(Mugwort) ↓ Levels of AST, ALT, LDH,
AFP, Y-GT, 5NT, G6PDH,
and bilirubin
Asparagus laricinus Asparagaceae Cladode Methanol 0–200 μg/mL Breast MCF7 cells ↑ Cell death [51]
(Bushveld asparagus) (97.6 μg/mL)
Atropa acuminata Solanaceae Leaves Aqueous 0–80 μg/mL Cervical Hela ↑ DNA damage [80]
(Indian belladonna) (5.418 μg/mL) ↑ Cell death
Berberis lyceum Berberidaceae Plant Ethanol 0–8 mg/mL HCC HepG2 cells ↑ Cell death [81]
(Indian barberry) (47 μg/mL) ↑ CDK1
↓ CDK5, CDK9, CDK10
Bergenia ciliata (Hairy Saxifragaceae Rhizome Methanol 150 mg/kg Liver Balb C mice ↑ Albumin levels [82]
bergenia) ↓ AST, ALT, LDH, AFP,
Y-GT, 5NT, G6PDH, and
bilirubin
Brucea javanica Simaroubaceae Seeds Ethanol 0–10.42 mg/ml Breast MDA-MB-231 ↓ Proliferation [83]
(Macassar kernels) (10.42 mg/ml)
Caesalpinia sappan Fabaceae Heart wood Methanol 0–450 μg/ml Breast MCF-7 ↓ Cell viability [84]
(Brazilwood)) Leaves Lung A549
Cajanus cajan (Pigeon Fabaceae Roots Ethanol 0–8 μM Ovarian A2780/Taxol [85]
pea) 0.5 mM/kg (1.23 ± 0.10 μM and pathway
⦸ PI3K/Akt/NF-κB

35.85 ± 1.23 μM)

BABL/c nude mice
Catharanthus Roseus Apocynaceae Leaves Methanol 0–1000 μg/ml Liver HepG2 ↑ Cell death [86]
(Madagascar Periwinkle) 0–100 μg/ml Breast (153.00 ± 0.6 μg/ml) ↓ Cell viability [87]
MCF7 Altered morphology
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic...

(18.67 μg/ml)
(continued)
1141
Table 1 (continued)
1142

Cells used with IC50

Name of the plant Family Parts used Extract Doses used Cancer type concentration Epigenetic modifications References
Ceiba Pentandra (Silk Bombacaceae Aerial parts Methanol 0–100 μg/ml Breast MCF-7 ↓ Cell viability [88]
cotton tree) (18.859 μg/mL)
Celastrus orbiculatus Celastraceae Stem DMSO 0–100 μg/ml Nasopharyngeal NPC cell line 5-8F ↓ Cell viability [45]
(Oriental bittersweet) ↓ EZH2 expression
Centella asiatica Apiaceae Leaves Aqueous 0–750 mg/kg Lung Mice ↓ Tumor nodules in [89]
(Indian pennywort) bronchioles and alveolar
septa
Chromolena odorata Asteraceae Leaves Methanol 0–700 μg/mL Colorectal HT-29 ↓ Cell viability [90]
(Siamweed)
Costus speciosus Costaceae Rhizome Hexane 0–8 μg/ml Prostate PC3 cells ↑ Caspase-9/-3 activity [91]
(Crepe-Ginger) (2.3 μg/mL) ↑ Cleaved PARP
↑ Bax/Bcl-2 ratio
G0/G1 and G2/M arrest
Cinnamomum Lauraceae Bark Methanol 0–15 μM Oral DU145 and LNCaP ↓ Proliferation [92]
tenuifolium (246 and 22.2 μM) ↑ DNA damage
↑ ROS generation
Citrullus colocynthis Cucurbitaceae Leaves Methanol 0–45 μg Breast MCF-7 Cell cycle arrest [93]
(Bitter cucumber) ↑ p21, p27, HUS1, ATM
↓ Cyclin A, E, CDK2
Citrullus colocynth Cucurbitaceae Fruit pulp Ethanol 250 μg/ml Breast MDA-MB-231, ↑ Cell death [94]
Acetone MCF-7, SiHa ↓ BCL2 and BCLXL
(142 ± 16, 105 ± 8.3, ↑ BAX and caspase 3
157 ± 4.3 μg/ml)
MDA-MB-231, formation
⦸ Colony and sphere

MCF-7, SiHa
(140 ± 0.8, 94 ± 6.4,
121 ± 4.6 μg/ml)
Clinacanthus Nutans Acanthaceae Leaves and Hexane 0–200 μg/mL A549, CNE1, HepG2 ↑ Cells in sub-G1 phase [95]
(Snake Grass) stems ↑ Caspases 8, 9, and 3/7
P. Soni et al.
 Cells used with IC50
Name of the plant Family Parts used Extract Doses used Cancer type concentration Epigenetic modifications References
Citrus limon (Lemon) Rutaceae Juice Aqueous – Breast MDA-MB-231 ↑ JAK1, JAK2, TYK2, IRF7, [96]
IRF3
↑ JAK/STAT pathway
Crataegus aronia Rosaceae Leaves Hydro- 0–300 μg/ml Lung A549 ↓ PARP-1, caspase-3, Bcl2 [97]
(Azarole) alcoholic ↑ Cells in sub G0 phase
Crotalaria verrucosa Papilionaceae Leaves Aqueous 0–100 μg/mL Cervical Hela ↑ Cell death [98]
(Blue rattlepod) Prostate (7.07 μg/mL) ↑ DNA damage
DU145 ↓ Cell invasion and migration
(6.30 μg/mL)
Cyclamen pseudibericum Primulaceae Tuber Petroleum 0–1000 μg/mL Lung A549 ↑ miRNA miR-200c [42]
ether and (41.64 ± 2.35 μg/mL) ↓ Epithelial-mesenchymal
ethanol transition
Curculigo orchioides Hypoxidaceae Rhizome Aqueous 0–300 μg/mL Liver HepG2 ↓ Bcl-2 expression [99]
(Kali musli) ethyl acetate Cervical (133.44 ± 1.1 μg/ml) ↑ Caspase-3 and Caspase-8
Breast HeLa
(136.50 ± 0.8 μg/ml)
MCF-7
(145.09 μg/ml)
Dendrobium venustum Orchidaceae Stem Methanol 0–100 μM Lung NCI-H460 ↓ Src-STAT3-c-Myc [100]
NCI-H292 pathways
Eclipta alba Asteraceae Plant Methanol 0–500 μg/ml Colon HCT-116 cells ↓ Colony formation and [101]
(False daisy) (179 ± 0.81 μg/ml) migration
Altered morphology
Elephantopus scaber Asteraceae Plant Ethanol 0–2000 μg/ml Breast T47D ↓ Cell viability [102]
(Elephant’s foot) (58.36 ± 2.38 μg/ml) Sub G1 phase arrest
Altered cell morphology
Fragaria vesca Rosaceae Leaves Ellagitanin- 0–10,000 μg/ HCC HepG2 G2/M phase arrest [103]
(Wild strawberry) enriched mL ↓ EDU incorporation
fraction ↓ FAS expression
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic...

(continued)
1143
Table 1 (continued)
1144

Cells used with IC50

Name of the plant Family Parts used Extract Doses used Cancer type concentration Epigenetic modifications References
Fritillaria imperialis Liliaceae Bulb Methanol 0–800 μg/ml HCC HepG2 ↓ Cell viability [104]
(Crown imperial) Colon (550 μg/mL) ↑ Apoptosis
HCT116
Glycine max (Black Fabaceae Leaves Enzyme – Liver HepG2 (0.24 mg/ml) ↑ Cytotoxic potential [105]
soyabean) hydrolysis Breast MCF7 (0.275 mg/ml) ↑ Binding energy of
Cervical HeLa (0.940 mg/ml) peptide-caspase-3 binding
Seeds Hexane 0–2 mg/ml Breast MCF-7 ↓ Growth rate [106]
MDA-MB-231 ↓ JMJD5 levels
Leaves Ethanol 0–500 μg/mL Colon HCT116 ↓ Colony formation and [107]
Lung (IC50 = 121 μg/mL) adhesion
H1299 ↓ Cell growth and migration
(IC50 = 95 μg/mL)
Glycyrrhiza glabra Fabaceae Root Aqueous 0–1 mg/mL Nasopharyngeal C666-1 ↓ Cell viability [108]
(Licorice) ↑ Caspase-3 and Caspase-9
Gymnema sylvestre Apocynaceae Leaves Aqueous 0–50 μg/mL Osteosarcoma MG63 cell ↑ Cytotoxic potential [109]
(Gurmar) (19.5 μg/mL)
Glycyrrhiza glabra Fabaceae Rhizome Chloroform 0–300 μg/mL Lung HepG2, HeLa ↑ Cell death [110]
(Licorice) Methanol Cervical (184.32, 156 μg/mL) ↑ Caspase-8, Caspase-3
HepG2, HeLa ↓ Bcl-2
(90.14, 181 μg/mL)
Gynostemma Cucurbitaceae Aerial parts Ethyl acetate 0–100 μg/mL Breast MDA-MB-453 ↓ Proliferation [111]
pentaphyllum (Jiaogulan) (38.02 ± 2.98 μg/mL) ↑ Apoptosis
Regulation of cell cycle
progression
Gynura divaricata Asteraceae Aerial parts Aqueous 0–1000 μg/mL Liver Huh7 cells ↓ Colony formation [112]
(Hepatitis grass) (573 μg/mL) ↓ Wnt/β-catenin signaling
Hibiscus rosa-sinesis Malvaceae Flower Aqueous 0–5 mg/ml Breast MCF-7 Induce apoptosis [113]
(China rose) MDA-MB-231
Hypoxis colchicifolia Hypoxidaceae Leaves Methanol 0–1000 μg/mL Breast MCF-7 ↑ Cytotoxic potential [114]
(African potato) (3.24 μg/mL)
P. Soni et al.
 Cells used with IC50
Name of the plant Family Parts used Extract Doses used Cancer type concentration Epigenetic modifications References
Imperata Cylindrica Poaceace Leaves Methanol 0–640 μg/ml Oral SCC-9 cells ↑ Caspase 3 and 8 [115]
(Cogon grass) (141 μg/ml)
Jatropha gossypifolia Euphorbiaceae Bark – 0–156 μg/ml HCC HepG2 ↑ Cytotoxicity [116]
(Bellyache bush) (3.2 μM)
Kaempferia parviflora Zingiberaceae Rhizome Ethanol 0–1 mg/ml Cervical HeLa ↓ Cell viability [117]
(Thai ginseng) (0.22 mg/mL)
signaling
⦸ MAPK and PI3K/AKT

Lawsonia inermis Lythraceae Leaves Ethanol 0–700 μg/ml Lung A549 (490 μg/ml) ↑ Chromatin condensation [118]
(Henna) Colon DLD1 (480 μg/ml) ↑ DNA fragmentation
Liver HepG2 (610 μg/ml)
Leucas aspera Lamiaceae Plant Methanol 0–0.25 mg/mL Prostate PC3 cells Changed cell morphology [119]
(Thumbai) ↑ Antimigratory effect
Linum usitatissumum Linaceae Seeds – 0–100 μM Leukemia KG-1 (60 μM) ↑ DNA fragmentation [120]
(Flax) Monomac-1 (90 μM)
Litchi chinensis Sapindaceae Seeds Aqueous 0–400 μg/mL Breast BT474 and ↓ Proliferation & migration [121]
(Litchi) MDA-MB-231 cells
Mangifera indica Anacardiaceae Fruit peel Hydro- 0–600 μg/mL Colon HCT116 [122]
⦸ EMT

(Mango) alcoholic Caco-2 Histone 2AX

⦸ Colony formation

phosphorylation
↑ p53 expression
Marsypopetalum Annonaceae Leaves Methanol 0–1000 μg/ml Cervical HepG2 ↑ DNA fragmentation [123]
modestum Liver (358.68 μg/ml) Cell cycle arrest
HeLa ↑ Cells in the SubG1 phase
(445.91 μg/ml)
Matricaria chamomilla Asteraceae Leaves Aqueous 0–100 μg/mL Lung A549 S phase arrest [124]
(German Chamomile) (62.82 μg/mL) ↓ Bcl-2
↑ Bax, Caspase 3 and 7
(continued)
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic...
1145
Table 1 (continued)
1146

Cells used with IC50

Name of the plant Family Parts used Extract Doses used Cancer type concentration Epigenetic modifications References
Moringa oleifera Moringaceae Leaves Methanol 0–640 μg/ml Prostate PC3 cells [125]
(Drumstick tree) ↑ Bax, Caspase 3
⦸ G0/G1 phase

↓ Bcl-2, GLI1, and SMO

Aqueous 0–1% Lung A549 cells Caspase activation [126]
PARP-1 cleavage
Morus nigra Moraceae Fruit Ethanol 0–100 μg/mL Colon HT29 cells ↓ Cell viability [127]
(Black mulberry) ↑ Bax/Bcl-2 levels
↓ p53 and Procaspase-3
DMSO 0–1000 μg/mL Prostate PC3 cells G1 phase arrest [128]
(370.1 ± 5.8 μg/mL) ↑ Caspase activity
Mucuna pruriens (Velvet Fabaceae Seeds Methanol 0–800 μg/mL Breast T47D, MCF-7 G1 phase arrest [129]
bean) (349.37 ± 0.12, ↓ JAK2/STAT5A/Cyclin D1
356.17 ± 0.45 μg/mL) signaling
Murraya koenigii (Curry Rutaceae Leaves Hexane 0–1000 μg/ml Cervical HeLa ↑ Cytotoxicity [130]
tree) Ethyl acetate (<1 μg/ml)
Leaves DCM 0–25 μM Oral OSCC CLS-354 cells ↑ ER stress [131]
Cell death via p38 MAPK
Myrmecodia platytyrea Rubiaceae Leaves Methanol 0–100 μg/ml Liver SK-Hep1 and Huh7 [132]
Becc
⦸ STAT3/ERK pathways

Myrmecodia pendans Rubiaceae Stem Methanol – Breast HCC-1954 (16 ppm) ↓ Cell migration [133]
(Ant plant) Cervical MCF7 cells (60 ppm)
Hela cells (13 ppm)
Tuber Methanol 0–100 ppm Colon Caco-2 (24 ppm) ↓ Proliferation [134]
HCT-116 (30 ppm) ↓ Colony formation
Myrmecodia tuberosa Rubiaceae Plant Ethanol 0–1000 μg/ml Oral KB cells ↑ Apoptosis [135]
(Ant plant) (215 μg/ml)
Nelumbo nucifera Nelumbonaceae Leaves Aqueous 0–4 mg/ml Breast MDA-MB-231 ↓ RhoA, Rac1, and Cdc42 [136]
(Indian lotus) 4 T-1
↓ PKCα activation
⦸ ERK/p38 signaling
P. Soni et al.
 Cells used with IC50
Name of the plant Family Parts used Extract Doses used Cancer type concentration Epigenetic modifications References
Nigella sativa Ranunculaceae Seeds PBS 0–400 μg/ml Breast MCF-7 ↑ Caspase 3 [137]
(Black cumin) (8.05 ± 0.22 μg/ml) ↓ Survivin
Ocimum sanctum Lamiaceae Leaves Aqueous 0–50 μg/ml Leukemia K562 cells ↑ Cytotoxicity [138]
(Holy basil) (30 μg/ml)
Piper longum (Long Piperaceae Leaves Aqueous 0–80 μg/mL Cervical HeLa ↑ Cytotoxicity [139]
pepper) (5.27 μg/mL) ↑ DNA fragmentation
Plectranthus amboinicus Lamiaceae Leaves Aqueous 0–50 μg/mL Oral KB cells ↓ Cell viability [140]
(Mexican mint) Phyllanthaceae TiO2 ↑ p53 generation blocking
Phyllanthus niruri (Gale nanoparticles the DNA synthesis
of the wind)
Polygonum cuspidatum Polygonaceae Root Ethanol 0–100 μM Liver Hep3B and HepG2 ↓ STAT3 signaling [141]
(Japanese knotweed) (IC50 = 3.69 ± 0.51 ~ Cell-cycle arrest at S and
20.36 ± 2.90 μM) G2/M phases
Polygonatum cyrtonema Asparagaceae Rhizome – 0–1100 μg/mL Cervical HeLa cells ↑ Caspase-3 activity [142]
Hua ↓ CDK1 and Cyclin B1
↑ Bcl - 2, FasL, and
Caspases-8, 9, 10
Premna serratifolia Lamiaceae Roots Aqueous 0–1000 μg/mL Liver HepG2 ↑ Apoptosis [143]
(Sarunai) ↓ Cell migration
Primula vulgaris Primulaceae Flower DMSO 0–270 μg/mL Cervical HeLa cells Cell cycle arrest at S phase [53]
(Primrose) (182.4 μg/mL)
Putranjiva roxburghii Putranjivaceae Seeds Aqueous 0–10 mg/mL Pancreatic PANC-1 ↑ Cytotoxicity [144]
(Lucky bean) Breast (0.36 mg/mL) ↑ Cell death
Colon MDA-MB 231 ↑ DNA fragmentation
(0.26 mg/mL)
HCT-116
(0.54 mg/mL)
Rhus tripartita Anacardiaceae Leaves Acetone 0–64 μg/ml Leukemia THP-1 cells [57]
(63.12 ± 3.24 μg/ml) ↑ Apoptosis
⦸ Cell cycle
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic...

(continued)
1147
Table 1 (continued)
1148

Cells used with IC50

Name of the plant Family Parts used Extract Doses used Cancer type concentration Epigenetic modifications References
Ricinus communis Euphorbiaceae Leaves Hexane 0–500 mg/ml Breast MCF-7 cells ↓ PIK3R3 [145]
(Castor bean)
Saussurea lappa (Indian Asteraceae Roots Ethanol 0-5 mg/mL Liver HepG2 (1.10 mg/mL) ↓ Cell viability [146]
Costus tree) Aqueous HepG2 (2.85 mg/mL) ↓ Colony forming potential
Hydro- HepG2 (3.5 mg/mL) ↑ Apoptosis
ethanolic
Schkuhria pinnata Asteraceae Leaves Acetone 0–1000 μg/ml Cervical HeLa ↑ Cytotoxic [147]
(Mexican marigold) ↑ Cell death
Senecio asperulus Asteraceae Roots DCM 0–200 μg/mL Breast MCF7 cells Cell cycle arrest at S and G2 [51]
(Moferefere) Prostate (69.15 μg/mL) phase
PC3 cells Cell cycle arrest at G2 and
(69.25 μg/mL) early (G2/M) phase
Seriphium plumosum Asteraceae Leaves Acetone 0–1000 μg/ml Cervical HeLa ↑ Cytotoxic [147]
(Silver stoebe) ↑ Cell death
Solanum nigrum Solanaceae Plant Ethyl acetate 0–200 μg/ml Hepatic HepG2 Antiproliferative activity [148]
(Black Nightshade) (7.89 μg/ml)
Aqueous 0–200 μg/ml Breast MDF-7 ↓ Cell viability [149]
↑ Caspase 3 level

Strobilanthes crispa Acanthaceae Stem Hexane 0–200 μg/ml Liver HepG-2 ↑ Cytotoxic [150]
⦸ EMT

(Pecah kaca) Breast (38.8 μg/ml) Caspase 8 activation

MDA-MB-231
(42.5 μg/ml)
Syzygium cumini Myrtaceae Fruit Chloroform 0–5 μg/ml Ovary PA-1 ↑ Cytotoxicity [151]
(Java Plum) (1.31–3.09 μg/ml) ↓ Migration
Ethanol 0–1000 μg Colon HT29 ↓ Cell viability [152]
(267.5 μg/ml) Altered Bax: Bcl-2
↓ Migration
Taraxacum officinale Asteraceae Roots Aqueous 500 mg/kg Breast Albino rats Regulate PI3K and Akt [58]
(Common Dandelion) pathway
P. Soni et al.
 Cells used with IC50
Name of the plant Family Parts used Extract Doses used Cancer type concentration Epigenetic modifications References
Thymus vulgaris Lamiaceae Dried Haulm – 0.1% and 1% Breast Sprague-Dawley rats ↓ Tumor volume [153]
(Garden thyme) Balb/c mice ↓ H3K4me3
↑ miR22, miR34a, miR210
↓ Promoter methylation of
ATM, PTEN
Toona cilliata (Mountain Meliaceae Leaves Acetone 0–1000 μg/ml Cervical HeLa ↑ Cytotoxic [147]
cedar) ↑ Cell death
Tulbaghia violacea Amaryllidaceae Leaves Methanol 0–20 μM Cervical HeLa, ME180 ↑ DNA fragmentation [154]
(Society Garlic) (15 μM) ↑ Caspase-3/7 activity
↑ p53 upregulation
↑ Bak and Bax
Uncaria tomentosa Rubiaceae Bark Ethanol 0–100 μg/mL Melanoma B16-BL6 [155]
(Cat’s claw) C57BL/6 mice
⦸ Cell growth

↓ Tumor weight
⦸ ERK-Akt signaling

↓ Ki-67 expression
Urtica dioica Urticaceae Leaves Methanol 0–100 μg/mL Lung H1299 ↓ Proliferation [156]
(Common Nettle) (52.3 μg/mL) G2/M phase arrest
A549 ↑ Cleaved PARP
(47.4 μg/mL) ↑ Death receptor DR5
Viola odorata (Sweet Violaceae Aerial parts Hydro- 0–1000 μg/ml Breast MCF7-derived ↓ Migration, colony [157]
violet) alcoholic mammospheres formation
(600 μg/mL) ↑ Caspase 3/7 and 8
SKBR3-derived ↓ Decreased size and depth
mammospheres of generated tumor in CAM
(400 μg/mL) of chicken embryo
Viscum articulatum Santalaceae Frozen plant Aqueous 0–150 μg/mL Leukemia Jurkat E6.1 [158]
(Leafless mistletoe) tissue (2.4 μg/ml) ↓ Bcl-2,
⦸ G2/M phase

THP1 ↑ Bax, Caspase-3, 8

(1.0 μg/ml) ↑ DNA fragmentation
(continued)
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic...
1149
Table 1 (continued)
1150

Cells used with IC50

Name of the plant Family Parts used Extract Doses used Cancer type concentration Epigenetic modifications References
Vitex Trifolia Lamiaceae Leaves Ethanol 0–80 μg/mL Cervical HeLa ↑ Cytotoxicity [159]
(Chastetree) Breast (7.6 to 16.9 μg/mL)
MCF-7
(12.1 μg/mL)
Walsura pinnata Hassk Meliaceae Bark DCM 0–400 μM – Zebra fish ↓ Bcl-2 and survivin [160]
↑ Bax, Caspase 9
Withania coagulans Solanaceae Leaves Aqueous 0–30 μg/mL Cervical SiHa ↑ Cytotoxic [161]
(Indian rennet) (13.74 μg/mL) Morphological alterations
Cell cycle arrest in S and
G2/M phase
Withania somnifera Solanaceae Leaves Methanol 0–320 μg/ml Liver HepG2 ↓ Bcl-2, [162]
(Ashwagandha) (153.8 μg/mL) ↑ Bax
Roots Tris buffer 0–200 μg/ml Breast MDA-MB-231 Cell cycle arrest at G2/M [163]
(92 μg/mL) ↑ Cleaved Caspase 3
Wrightia tinctoria Apocynaceae Leaves Methanol 0–100 μg/ml Cervical HeLa ↑ Cytotoxicity [164]
(Indigo plant) (76.1 μg/ml)
Bark Methanol 0–200 μg/ml Breast MDA-MB-231 Antiproliferative effect [165]
(88.9 ± 1.27 μg/ml) ↓ Colony formation
MCF-7 ↑ Apoptosis
(45.71 ± 7.74 μg/ml)
Xanthium strumarium Asteraceae Fruit Ethanol 0–500 μg/ml Liver Huh-7 and Hep3B ↑ Cleaved Caspase 3 and [59]
(Rough cocklebur) (100 μg/mL) PARP

signaling
⦸ PI3K/AKT/mTOR

Zea mays Poaceae Corn silk Methanol 0–1000 μg/ml Breast MCF-7 ↓ Cell viability [166]
(Maize) ↑ Apoptosis
↑ p53, Bax, Caspase-3, and
Caspase-9
↓ Bcl-2 genes
P. Soni et al.
 Cells used with IC50
Name of the plant Family Parts used Extract Doses used Cancer type concentration Epigenetic modifications References
Zingiber cassumunar Zingiberaceae Rhizome Chloroform 0–200 μg/ml Leukemia CEMss ↑ Cytotoxicity [167]
(Cassumunar ginger) Cervical (9.20 ± 0.02 μg/ml)
HeLa
(<15 μg/ml)
Zingiber officinale Zingiberaceae Rhizome Methanol 0–120 μM Cervical HeLa Cell cycle arrest at G0/G1 [168]
(Ginger) (29.19 μM) ↓ Cyclin A and Cyclin D1

Activate AMPK
⦸ PI3K/AKT

Ziziphus Jujube Rhamnaceae Dried fruit Powder 5% or 10% Colon C57BL/6 mice [169]
(Jujuba) w/w ↑ Bax
⦸ Tumor progression

Activation of NF-κB/IL-6/
JAK1/STAT3 signaling
Semi dried Aqueous (0–3 mg/ml) Cervical OV2008 ↓ Bcl-2 and ↑ Bax [170]
fruits Breast (1.2 ± 0.03 mg/ml) Bax/Bcl-2 ratio
MCF-7
(1.8 ± 0.08b mg/ml)
Abbreviations- ↑: Increases; ↓: Decreases; ⦸: Inhibit
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic...
1151
Table 2 Anticancer efficacy of plant-derived phytochemicals against different cancer types
1152

Name of the compound Modifications Cancer Cells and doses used Mode of action References
Curcumin DNA methylation Breast T47D and HCC-38 ↑ TET1 and DNMT3 [20]
[(1E,6E)-1,7-bis(4-hydroxy-3- (5 and 10 μM) Modulation of miR-29b
methoxyphenyl) Breast MCF-7 cells ↓ Proliferation [171]
hepta-1,6-diene-3,5-dione)] (20 μM) ↓ GSTP1 promoter methylation
Breast MDA-MB-361 ↓ Sp1 and DNMT1 [172]
BALB/c nu/nu mice ↑ DLC1 demethylation
↑ DLC1 expression
Histone modification Blood Myeloproliferative ↑ SOCS1 and SOCS3 levels [173]
neoplasm cells ↓ HDAC activity and HDAC8
(20 μM) expression

Brain Medulloblastoma cells [174]

⦸ JAK2/STAT5 signaling

(0–40 μM) ↓ HDAC 4 expression

⦸ G2/M phase

SCID mice ↓ Tumor growth

(1 mg/kg) ↑ Survival
miRNA regulation Colon SW480 cells ↓ Cell proliferation [175]
Female nude mice
(200 mg/kg) ↓ miR-130a
⦸ Wnt/β-catenin pathway

Schwannoma (arising from RT4 Schwannoma cells Activated PARP, Cas-3 and 9 [176]
peripheral nervous sheaths) (10 and 20 μM) ↓ miRNA 350, miRNA 17–2-3p, let
7e-3p, miRNA1224, miRNA
466b-1-3p, miRNA 18a-5p, and
miRNA 322-5p
↑ miRNA122-5p, miRNA 3473,
miRNA182, and miRNA344a-3p
Apoptosis via miRNA 344a-3p
P. Soni et al.
Name of the compound Modifications Cancer Cells and doses used Mode of action References
Epigallocatechin gallate DNA methylation Breast MCF-7 and MDA-MB-231 ↓ DNA methylation [23]
(EGCG) cells (20 μM) Reactivated expression of SCUBE2
[[(2R,3R)-5,7-dihydroxy-2- ↓ DNMT expression
(3,4,5-trihydroxyphenyl)-3,4- Esophageal ECa109 cells ↓ Cell viability [177]
dihydro-2H-chromen-3-yl] (0–200 mg/l) ↑ p16 mRNA and protein expression
3,4,5-trihydroxybenzoate] Induce apoptosis via demethylation
of p16
Histone modification Endothelial HMEC-1 and HUVECs ↑ H3K9/14 ac, H3ac [178]
(25–200 μM) ↑ H3K4me3 and H3K9me3
Affects expression of HDAC5 and 7,
p300, CREBP, LSD1 or KMT2A
Prostate LNCaP cells ↓ Acetylation of Androgen receptor [179]
(20 μM) (AR)
↓ Hormone responsiveness of AR
miRNA regulation Nasopharyngeal TW01 and TW06 cells Modulates miR-296 [180]
(0–80 μM)
↓ Cell migration and invasion
⦸ STAT3 signaling

Enhances anoikis resistance

Cervical HeLa ↓ miR-203 and miR-125b and [181]
C33A ↑ miR-210
SiHa ↑ miR-210, miR-203, miR125b
CaSki ↑ miR-210, miR-29, miR-125b
(0–100 μg/ml)
(continued)
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic...
1153
Table 2 (continued)
1154

Name of the compound Modifications Cancer Cells and doses used Mode of action References
Genistein DNA methylation Cervical HeLa ↓ Global DNA methylation levels [22]
[5,7-dihydroxy-3-(4- (50 μM) ↓ DNMT1, DNMT3B DNMT3A
hydroxyphenyl) chromen-4-one] ↓ TSGs promoter methylation
HCC HepG2 ↓ DNMT1 level [182]
(22 μM) ↑ Apoptosis
Prostate Norwegian patients ↑ NOTCH3and [183]
(30 mg) JAG1 mRNAs
↓ MYC and ↑ PTEN activity
Histone modification Cervical HeLa ↓ HDAC, HMT H3K9 Activity [22]
(50 μM) ↓ HDAC5, HDAC1, HDAC6
↑ SETD5, SETD7, SETD6
Prostate LNCaP and PC3 ↑ HAT activity [184]
(50 μM) ↑ acetylated histones 3, 4, 2H3K4,
3H3K4
miRNA regulation Lung H292 and A549 Regulates circ_0031250/miR-873-5p/ [185]
(80 μM) FOXM1 axis
Prostate LNCaP, 22RV1, and DU145 Demethylates promoter CpG sites [186]
cells closest to the miR-200c/miR-141 loci
(40 μM) ↑ miR-200c expression
Breast MDA-MB-435 and Hs578t ↓ miR-155 [187]
cells ↑ FOXO3, PTEN, casein kinase, and
(0–25 μM) p27

apoptosis
⦸ Cell viability and induces
P. Soni et al.
Name of the compound Modifications Cancer Cells and doses used Mode of action References
Resveratrol DNA methylation Lung A549 cells Demethylates the ZFP36 promoter [188]
[5-[(E)-2-(4-hydroxyphenyl) (0–100 μM) ↓ DNMT1 expression
ethenyl] benzene-1,3-diol] ↓ Cell proliferation
Breast MDA-MB-231 cells ↓ Promoter hypermethylation [189]
(100 μM) ↑ DNA hypomethylation
Hypomethylated 1459 and 1547
genes after 24 and 48 h
Histone modification Renal ACHN cells ↓ Cellular migration [32]
(0–62.5 μg/mL) ↑ acH3K9, acH3K14, cH4K12,
acH4K5, and acH4K16
Prostate DU145 and PC3M cells ↓ MTA2, MTA3, HDAC1, and [190]
(0–100 μM) HDAC2 levels
Deactivates MTA1/HDACs complex

miRNA regulation Pancreatic AsPC-1 and PANC-1 [191]

⦸ PI3K/Akt pathway

(0–20 μM) ↑ miR-200a, miR-200b, and

⦸ Cyclin D1 and Bcl-2

miR-200c
⦸ Epithelial-mesenchymal transition

Breast MCF-7 and MDA-MB-231 Modulates expression of miR- [192]

⦸ Shh pathway

cells 199a-5p, miR-125b-1-3p, miR-

(100 μM) 140-5p, and miR-20a-5p
↓ Bcl-2
Activated Caspase 8 and 9

(continued)
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic...
1155
Table 2 (continued)
1156

Name of the compound Modifications Cancer Cells and doses used Mode of action References
Sulforaphane DNA methylation Skin Female SKH-1 hairless Altered expression of Pik3cd, Matk, [193]
[1-isothiocyanato-4- mice (2 μmol) and Adm2
methylsulfinylbutane] Changes in promoter CpG
methylation status
↓ Tumor incidence and tumor number
Colon Caco-2 ↓ DNMT1 protein expression [194]
(10–30 μmol/l) ↓ Nrf2 promoter methylation
Activation of Nrf2
Cervical HeLa [195]
(2.5 μM) ↓ DNMT3B expression
⦸ DNMT activity

Reactivates RAR𝛽, CDH1, DAPK1,

and GSTP1 genes
Histone modification Skin A375 cells ↓ HDAC and ↑ HAT activity [33]
(2.5–50 μM) ↓ HDACs 4 and 6
↓ AcH3K9, AcH3K14, and
AcH3K27
↑ H3K9me2, H3K79me2,
H3K36me3, and H3K79me3
Cervical HeLa ↓ HDAC activity [195]
(2.5 μM) ↓ HDAC1 expression
miRNA regulation Pancreatic BxPC-3, PANC-1, and ↑ miR135b-5p expression [196]
AsPC-1 cells ↑ RASAL2 expression
(10 μM)
Colon RKO and HCT 116 cells ↓ Cell viability [34]
⦸ ERK signaling

(20 μM) G2/M Phase arrest

↓ miR-21, HDAC, and hTERT
P. Soni et al.
Name of the compound Modifications Cancer Cells and doses used Mode of action References
Quercetin DNA methylation HCC HepG2 cells ↓ DNMT1, DNMT3A and DNMT3B [24]
[2-(3,4-dihydroxyphenyl)-3,5,7- (0–1000 μg/mL ChiNH/Q) levels
trihydroxychromen-4-one] ↑ 5-methylcytosine (5-mC) levels
Cervical HeLa ↓ DNMT activity [197]
(25 and 50 μM) ↓ HMT H3K9 activity
↓ Methylation of CDH1, MLH1,
PTEN, SOC51
Leukemia HL60 and U937 cells ↓ DNMT1 and DNMT3a expression [198]
(50 μmol/L) Demethylation of BCL2L11
Histone modification Cervical HeLa ↓ HDAC activity [22]
(25 and 50 μM) ↓ HDAC5, 6, 7, 10, 11 expression
levels
Leukemia HL60 and U937 cells ↓ Class I HDACs [198]
(50 μmol/L) Accumulation of acetylated histone 3
and histone 4
miRNA regulation Pancreatic AsPC1 and PANC1 ↑ miR-200b-3p [199]
(50 μM)
proliferation
⦸ CSCs self-renewal and

Ovarian SKOV-3 and A2780 ↑ Cleaved Caspase-3 [200]

⦸ Notch signaling

(0–100 μm/ml) ↑ miR-145

↑ Apoptosis
Abbreviations- ↑: Increases; ↓: Decreases; ⦸: Inhibit
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic...
1157
1158 P. Soni et al.

phytochemicals and their epigenetic mode of action in cancer cells are summarized
in Tables 1 and 2.

2.3 Noncoding RNAs

Noncoding RNAs (ncRNAs) are a type of any functional and dynamic RNA mole-
cules that are not translated into protein. It is predicted that above 60% of the total
genome is transcribed into ncRNAs [35]. Based on their sizes, it can be divided into
several types of RNAs such as snoRNAs, microRNAs, piRNAs, exRNAs, scaRNAs,
endogenous siRNAs, snRNAs, and long noncoding RNAs which are involved in
various cellular processes [36, 37]. MicroRNAs (miRNAs) are a class of small func-
tional molecules with an approximate 22 nucleotide sequence that play substantial
regulatory role in many cellular processes, including induction in pluripotency, cel-
lular apoptosis, cellular proliferation, and DNA damage [38]. miRNAs typically
bind with a partial complementary sequence located on the 3’ untranslated region
(3’-UTR) of the corresponding target mRNA that negatively regulates gene expres-
sion which brings about translational repression or degradation of target mRNA
leading to inhibition or activation of downstream signaling pathways [39].
Several medicinal plants are reported to exert their anticancerous action by regu-
lating a varied range of miRNAs [40]. One such mode of action was shown when
polysaccharides from the roots of Astragalus membranaceus inhibited the JNK
pathway and induced apoptosis via upregulation of miR-133a in human osteosar-
coma MG63 cells [41]. Another study revealed the anticancer potential of Cyclamen
pseudibericum tuber extracts as it hindered the migration and invasion of lung car-
cinoma A549 cells and resulted in an increase in the expression of miR-200c [42].
Many other medicinal plants and phytochemicals are well known to exert their
potent anticancer activity by reversing the epigenetic modifications or altering the
signaling pathways overall, leading to a favorable preventive role in cancer therapy
and are listed in Tables 1 and 2.

2.4 Polycomb Group Proteins

Polycomb group (PcG) proteins are a group of chromatin modulators that comprises
two disparate polycomb repressive complexes (PRCs), namely PRC1 and PRC2,
which bind and act in a sequential manner and affect the chromatin structure of criti-
cal target genes [43]. Initially, the catalytic subunit of PRC2 complex named
Enhancer of zeste homolog 2 (EZH2) trimethylates the lysine 27 residue on histone
H3 (H3K27me3) which along with the suppressor of zeste 12 homolog (SUZ12)
and Embryonic Ectoderm Development (EED) further anchors the PRC1 complex
to the chromatin. Afterwards, the catalytic subunit of the PRC1 complex named
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic... 1159

RING1B ubiquitinates the lysine 119 residue on histone H2A (H2AK119Ub), mak-
ing a platform for its association with B cell-specific moloney murine leukemia
virus integration site 1 (BMI-1). This phenomenon eventually leads to the transcrip-
tional suppression of gene expression via the induction of chromatin compaction
[17, 43].
Several reports have shown the abnormal overexpression of EZH2 and BMI-1
often promotes the tumorigenesis of lung cancer, breast cancer, prostate, bladder,
oral squamous cell carcinoma, and colorectal cancer. EZH2 is associated with the
metastasis of lymph nodes and combative phenotype of breast cancers guided by the
epigenetic silencing complex PRC-2/EED-EZH2 [44].
With the alarming rise of varied cancer types, the scientific community is in an
urgent need to develop novel, cost-effective, and harmless naturally derived com-
pounds that will aid in the cancer therapy in affected individuals. Some reports show
the striking effects of potent plant extracts on PcG proteins, making them ideal
candidates to be used in cancer therapy. For instance, the use of stem extract from
Celastrus orbiculatus averted the proliferation and progression in human NPC cell
line 5-8F cells by inhibiting the EZH2 signaling pathway [45]. Exposure to a puri-
fied extract from white grape pomace exhibited its anticancer effect in a multidisci-
plinary manner. It reduced the expression levels of prosurvival factors, phosphorylated
Akt (p-Akt), and B-cell lymphoma 2 (Bcl-2) with an increment in the expression of
p73 in a dose-dependent manner in Jurkat cells. The extract also led to a noteworthy
reduction in the expression of PcG proteins EZH2 and BMI1 and decreased the
expression of HDACs that may further mediate its proapoptotic effect by skipping
the DNA repair machinery [46]. Many more studies which assert the mode of action
of diverse plant extracts in the prevention of cancer are mentioned in Tables 1 and 2.

2.5 Cell Cycle Regulator Molecules

In a rapidly dividing mammalian cells with a 24-h cycle, the G1 phase lasts just
about 11 h, the S phase lasts approximately 8 h, the G2 phase lasts nearly 4 h, and
the M phase lasts roughly 1 h. The cell cycle is regulated at three foremost cell cycle
checkpoints. The G1 checkpoint, also known as the restriction point, where the cells
are not allowed to progress into the S phase if the conditions are unfavorable. The
G2 checkpoint halts the entry of the cell into the mitotic phase (M-phase) if certain
conditions are not achieved as the G2 checkpoint ensures that all the genes have
been replicated and also the replicated DNA is not damaged. The M checkpoint,
also called the spindle checkpoint, is located near the end of the metaphase stage
which ensures all the sister chromatids are suitably attached to the spindle microtu-
bules [47]. In addition to the checkpoints, a close cooperation between cyclins,
cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CKIs) is
essential to ensure the orderly progression of the cell to the next phase of the cell
cycle [48].
1160 P. Soni et al.

The diverse members of the cyclin and CDK families have their extended star-
ring role linked to epigenetic regulation. The EZH2 phosphorylation at threonine
350 (Thr350) mediated by CDK1 and CDK2 positively regulates the methyltrans-
ferase activity of EZH2 and enhances suppression of target loci resulting into the
increased cell proliferation [49]. The CDK1 and CDK2 activity is at its peak during
the S-M phase transition of cell cycle. Therefore, enhanced methyltransferase activ-
ity of EZH2 during this period ensures that after S-phase, the repressive mark
H3K27me3 is integrated into newly synthesized histones and is inherited by daugh-
ter cells during M-phase [50].
Nearly 50% of the drugs used in cancer prevention as part of chemotherapy are
of plant origin. The present scenario of cancer emergence at an alarming rate
requires an outstanding approach toward the chemoprevention including cell cycle
regulators since the tumor cells proliferate abnormally via derestricting the cell
cycle control over checkpoints. A few studies have proposed the cytotoxic behavior
of several plant extracts toward malignant cancer cells. The methanol extract of
Asparagus laricinus brought cell death in prostate cancer cell line, PC3 and breast
cancer cell line, MCF7 through apoptosis. Cell death was also observed via cell
cycle arrest at S and G2 phase in MCF7 cells and mitotic (G2/M) phase arrest in
PC3 cells when treated with dichloromethane extracts of Senecio asperulus [51]. In
HepG2 cells, exposure to an aqueous methanol fraction of Calystegia soldanella
resulted in G0/G1 phase arrest in a dose-dependent manner with a reduction in the
expression of cyclin E, cyclin D1, and cell cycle inhibitor p21. This fraction also
decreased the expression of retinoblastoma (RB) and its downstream regulator E2F
(transcription factor) [52]. The cytotoxic effect of flower extract from Primula vul-
garis was observed in HeLa cells via induction of cell cycle arrest at S phase in a
concentration-dependent pattern [53]. A wide range of plant extracts and phyto-
chemicals posing an imperative control over the cell cycle progression in cancerous
cells are described in Tables 1 and 2.

2.6 Akt/PKB Signaling Pathway

The serine/threonine kinase Akt pathway, also well-known as protein kinase B

(PKB) pathway, is an essential node in cell signaling downstream of cytokines,
growth factors, and other cellular stimuli within all higher eukaryotic cells that pro-
mote growth and cell survival [54]. The key proteins involved in this pathway are
phosphatidylinositol 3-kinase (PI3K) and Protein Kinase B (Akt). The Akt/PKB sig-
naling pathway is highly controlled by multiple mechanisms which often involve
crosstalk with other signaling pathways [55]. Complications with PI3K-Akt path-
way regulation may lead to an upsurge in signaling activity and have been associated
with a variety of diseases such as cancer. The most important antagonist of PI3K
activity is phosphatase and tensin homolog (PTEN), a tumor suppressor which is
often lost or mutated in tumor cells. Akt possesses the ability to phosphorylate more
than 100 diverse ranges of substrates, leading to a wide variety of effects on cells [56].
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic... 1161

The inhibition of PI3K/Akt by plant-derived compounds has been considered as

a probable tactic to make progress in the field of cancer management and develop-
ing novel therapeutics. The development of novel, safe, and naturally derived anti-
cancer agents primarily aimed at the selective signaling pathways may play an
imperative role in the fight against deadly cancer types. In this context, a recent
study asserts the effectiveness of a polyphenol-rich Rhus tripartita leaf extract as an
anticancer agent in acute monocytic leukemia THP-1 cells as it induces cell cycle
arrest followed by apoptosis by regulation of the PI3K-Akt-mTOR signaling path-
way [57]. The root extracts of Taraxacum officinale (TOE) normalized the Pdk1 and
Akt1 mRNA abundance in breast cancer-induced albino rats [58]. Apart from this,
the ethanol extract from fruits of Xanthium strumarium inhibited the tumor growth
by upregulating cleaved caspase-3 expression in an ex vivo model (BALB/c mice).
It also resulted in the occlusion of the PI3K/AKT/mTOR pathway and suppressed
the cellular proliferation and invasion of Huh-7 and Hep3B cells [59]. A plethora of
reports have revealed the anticancer effects of quite a few plant extracts and phyto-
chemicals in cancer cells via regulation of signaling pathways (Akt/ERK/JAK-
STAT). The details regarding the effect of plant extracts on intracellular signaling in
cancer cells are enlisted in Tables 1 and 2.

3 Modern Approaches for Cancer Treatment: Challenges

and Future Implications

At present, the prime effective approach to combat cancer includes radiotherapy

(use of intense X-rays to terminate cancer cells), surgical abscission (removal of
tumor from the body), and chemotherapy (use of anticancer drugs) which all pos-
sess fatal side effects [60]. The standards for cancer treatment and prevention have
changed with constant progress in the field of molecular and tumor biology during
the past few years. To confront the multifaceted disease, the present era of biomedi-
cal research thrives in developing the area of cancer research into a dynamic and
interdisciplinary arena. Acquisition of new technologies for the molecular profiling
of cancer and revelation of prognostic molecular targets based on specific molecular
variations have steered the consequent evolution in cancer therapy and the concept
of precision oncology [61]. This approach aims to manage the personalized treat-
ment in individually affected patients, and intends to hit cancer-specific suscepti-
bilities that may potentially improve the quality of life in patients by reducing the
toxic effects expectantly. Overall accomplishment of precision oncology is
restrained due to the heterogeneity of tumors along with the resistance to therapeu-
tic drugs.
1162 P. Soni et al.

3.1 Epigenetic Cancer Profiling and Specificity of Epidrugs

Certain lifestyle factors and environmental exposures are reported to play an impor-
tant role in the onset of cancer. A point to be considered here is that it is almost
impossible to control or quantify these factors in a real-life scenario or to model
them in a particular lab setup [62]. This is the reason behind the late diagnosis of the
disease due to the late-stage presentation and continues to hinder the possibilities of
an effective therapy. Identifying the respective oncogene and the probable signaling
pathways associated with it seems to be crucial for the success of cancer therapy [63].
The most evident and possible strategy for cancer management is clinical devel-
opment of specific epigenetic or signaling pathway inhibitors for instance, PI3K
inhibitors, Akt inhibitors, DNMT inhibitors, HDACs inhibitors, and miRNA inhibi-
tors from natural products. In this case, discerning and targeting the particular pro-
teins within the intricate intracellular signaling and developing their inhibitors will
be a risky and complex task. Another concerning fact regarding the concept of tar-
geting DNMTs is lack of specificity since the inhibiting agents may not be precise
for a particular hypermethylated gene and can finally hypomethylate the whole
genome. This can be resolved by the epigenomic profiling of cancer which will
reveal the role of epigenetic alterations in the commencement and progression of
tumorigenesis, ultimately leading to the early detection and therapeutic intervention
via pharmacological targeting using specific anticancer drugs or plant-derived natu-
ral compounds [64]. Combination approaches along with patient selection strategies
will assist in intensifying the practical effectiveness of inhibitors to understand and
overcome drug resistance of chemotherapy or chemo drugs used nowadays.

3.2 Cancer Stem Cells (CSCs)

The term CSCs refers to the small subpopulations of tumorigenic cells that can
potentially initiate the development of tumor and may cause major reversions as
they are resistant to treatment. It is evident that they can be regenerated even under
the strong therapeutic pressure and reformed microenvironment [65]. Inference
from quite a few clinical data promises the selective targeting of CSCs as a probable
strategy for treating relapsed cancer with the aid of plant extracts and plant-derived
phytochemicals.

3.3 The Nutrient Strategy

Dietary modulation in nutrient intake may synchronously stimulate proliferative

tumor cells to traditional cancer remedies and shield normal healthy cells from their
complicacy in a selective manner. Literature affirms that resilient cancer cells can be
eliminated by consumption of nutrient-deprived diet and in the absence of
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic... 1163

nutrient-responsive factors for growth as they impose the glycolytic assets leading
to oxidative metabolism and restrict the glutathione peroxidase activity (GPX) with
low glutathione levels [66].
It is proposed to follow a 4-day diet cycle in a weekly manner and consume a
vegan ketogenic diet (lower protein and carbohydrate content with higher lipid con-
tent) ahead of each round of chemo/radiation therapy. This could potentially reorga-
nize the systemic metabolism and provide an unfavorable environment for cancer
cells. This diet with the aforementioned composition and period of treatment might
vary the membrane chemistry of cells with high peroxidation index (PUFA enrich-
ment), lessen the sulfur-dependent antioxidant activity, and compel a metabolic
shift in cancer cells to mitochondrial metabolism [67]. This shows the imperative
role of plants and plant-based products in cancer prevention and maintenance.

4 Conclusion

Unraveling the possible mechanisms behind an individual’s retort to anticancer

drugs, in-depth analysis of his/her genetic and epigenetic profile, exploring the sig-
naling pathways and specific hallmarks will direct the development of innovative
personalized combination therapeutic strategies to prolong the overall survival and
quality of life in affected individuals. The detailed knowledge regarding each
patient’s tumor biology serves to be one of the hectic tasks and can be the most
remarkably promising approach toward cancer therapy with enhanced health-care
consequences along with reduced health-care expenses Fig. 2.
We strongly advocate that personalized therapies can be executed successfully
with an overall association of biologists, drug delivery experts, and medical oncolo-
gists. To achieve optimal clinical benefit for a patient, it is essential to formulate an

Fig. 2 Schematic diagram representing the possible strategy that may aid in an effective can-
cer therapy
1164 P. Soni et al.

appropriate drug delivery system (DDS) that suitably administers the required med-
ication under the correct conditions and within the necessary timeframe, thus avoid-
ing any potential risks or adverse effects. Early detection of cancer involves both
screening and surveillance and serves to be a reliable approach to improve and
manage the fatal outcomes of the disease. The practice of using natural and plant-
based extracts or phytochemicals as epigenetic agents appears to be a more reassur-
ing system for cancer treatment in the upcoming era. Even though more
comprehensive in vitro and in vivo trials are mandatory to examine their efficacy
and mode of action for an advanced cancer therapy.

Conflict of Interest All authors declare that there is no conflict of interest.

References

1. Stewart BW (2019) Mechanisms of carcinogenesis: from initiation and promotion to the

hallmarks. In: Baan RA, Stewart BW, Straif K (eds) Tumour site concordance and mecha-
nisms of carcinogenesis. International Agency for Research on Cancer, Lyon (FR). (IARC
Scientific Publications, No. 165.) Chapter 11. Available from: https://www.ncbi.nlm.nih.gov/
books/NBK570326/
2. Compton C (2020) Cancer initiation, promotion, and progression and the acquisition
of key behavioral traits. In: Cancer: the enemy from within. Springer, Cham. https://doi.
org/10.1007/978-3-030-40651-6_2
3. Mbemi A, Khanna S, Njiki S et al (2020) Impact of gene-environment interactions on can-
cer development. Int J Environ Res Public Health 17(21):8089. https://doi.org/10.3390/
ijerph17218089
4. Nebbioso A, Tambaro FP, Dell’Aversana C et al (2018) Cancer epigenetics: moving forward.
PLoS Genet 14(6):e1007362. https://doi.org/10.1371/journal.pgen.1007362
5. Lewandowska AM, Rudzki M, Rudzki S et al (2019) Environmental risk factors for cancer –
review paper. Ann Agric Environ Med 26(1):1–7. https://doi.org/10.26444/aaem/94299
6. Elmore LW, Greer SF, Daniels EC et al (2021) Blueprint for cancer research: critical gaps and
opportunities. CA Cancer J Clin 71(2):107–139. https://doi.org/10.3322/caac.21652
7. Roberti A, Valdes AF, Torrecillas R et al (2019) Epigenetics in cancer therapy and nanomedi-
cine. Clin Epigenetics 11(1):81. https://doi.org/10.1186/s13148-019-0675-4
8. Ferlay J, Laversanne M, Ervik M et al (2020) Global cancer observatory: cancer tomor-
row. International Agency for Research on Cancer, Lyon. Available from: https://gco.iarc.fr/
tomorrow, accessed [10 January 2022]
9. Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN esti-
mates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J
Clin 71:209–249. https://doi.org/10.3322/caac.21660
10. Dehelean CA, Marcovici I, Soica C et al (2021) Plant-derived anticancer compounds as new
perspectives in drug discovery and alternative therapy. Molecules 26(4):1109. https://doi.
org/10.3390/molecules26041109
11. Cheng Y, He C, Wang M et al (2019) Targeting epigenetic regulators for cancer therapy:
mechanisms and advances in clinical trials. Signal Transduct Target Ther 4:62. https://doi.
org/10.1038/s41392-019-0095-0
12. Michalak EM, Burr ML, Bannister AJ et al (2019) The roles of DNA, RNA and histone meth-
ylation in ageing and cancer. Nat Rev Mol Cell Biol 20:573–589. https://doi.org/10.1038/
s41580-019-0143-1
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic... 1165

13. Søreide K (2017) Cancer epigenetics. In: Handbook of epigenetics. Elsevier, Amsterdam,
pp 519–534. https://doi.org/10.1016/b978-0-12-805388-1.00034-1
14. Soni P, Ghufran MS, Kanade SR (2018) Aflatoxin B1 induced multiple epigenetic modu-
lators in human epithelial cell lines. Toxicon 151:119–128. https://doi.org/10.1016/j.
toxicon.2018.07.011
15. Cao H, Wang L, Chen B et al (2016) DNA demethylation upregulated Nrf2 expression in
Alzheimer’s disease cellular model. Front Aging Neurosci 7:244. https://doi.org/10.3389/
fnagi.2015.00244
16. Zhang W, Xu J (2017) DNA methyltransferases and their roles in tumorigenesis. Biomark
Res 5:1. https://doi.org/10.1186/s40364-017-0081-z
17. Soni P, Ghufran MS, Olakkaran S et al (2021) Epigenetic alterations induced by aflatoxin B1:
an in vitro and in vivo approach with emphasis on enhancer of zeste homologue-2/p21 axis.
Sci Total Environ 762:143175. https://doi.org/10.1016/j.scitotenv.2020.143175
18. Fabianowska-Majewska K, Kaufman-Szymczyk A, Szymanska-Kolba A et al (2021)
Curcumin from turmeric rhizome: a potential modulator of DNA methylation machinery in
breast cancer inhibition. Nutrients 13(2):332. https://doi.org/10.3390/nu13020332
19. Zhang J, Yang C, Wu C et al (2020) DNA methyltransferases in cancer: biology, paradox,
aberrations, and targeted therapy. Cancers (Basel) 12(8):2123. https://doi.org/10.3390/
cancers12082123
20. Al-Yousef N, Shinwari Z, Al-Shahrani B et al (2020) Curcumin induces re-expression of
BRCA1 and suppression of γ synuclein by modulating DNA promoter methylation in breast
cancer cell lines. Oncol Rep 43(3):827–838. https://doi.org/10.3892/or.2020.7473
21. Sundaram MK, Ansari MZ, Al Mutery A et al (2018) Genistein induces alterations of epigen-
etic modulatory signatures in human cervical cancer cells. Anti Cancer Agents Med Chem
18(3):412–421. https://doi.org/10.2174/1871520617666170918142114
22. Sundaram MK, Unni S, Somvanshi P et al (2019) Genistein modulates signaling pathways
and targets several epigenetic markers in HeLa cells. Genes (Basel) 10(12):955. https://doi.
org/10.3390/genes10120955
23. Sheng J, Shi W, Guo H et al (2019) The inhibitory effect of (−)-epigallocatechin-3-gallate on
breast cancer progression via reducing SCUBE2 methylation and DNMT activity. Molecules
24(16):2899. https://doi.org/10.3390/molecules24162899
24. Abbaszadeh S, Rashidipour M, Khosravi P et al (2020) Biocompatibility, cytotoxicity, anti-
microbial and epigenetic effects of novel chitosan-based quercetin nanohydrogel in human
cancer cells. Int J Nanomed 15:5963–5975. https://doi.org/10.2147/IJN.S263013
25. Chappell G, Pogribny IP, Guyton KZ et al (2016) Epigenetic alterations induced by genotoxic
occupational and environmental human chemical carcinogens: a systematic literature review.
Mutat Res Rev Mutat Res 768:27–45. https://doi.org/10.1016/j.mrrev.2016.03.004
26. Li G, Tian Y, Zhu WG (2020) The roles of histone deacetylases and their inhibitors in cancer
therapy. Front Cell Dev Biol 8:576946. https://doi.org/10.3389/fcell.2020.576946
27. Pant K, Peixoto E, Richard S et al (2020) Role of histone deacetylases in carcinogenesis:
potential role in cholangiocarcinoma. Cell 9(3):780. https://doi.org/10.3390/cells9030780
28. Ceccacci E, Minucci S (2016) Inhibition of histone deacetylases in cancer therapy: lessons
from leukaemia. Br J Cancer 114:605–611. https://doi.org/10.1038/bjc.2016.36
29. Zhu F, Rui L (2019) PRMT5 in gene regulation and hematologic malignancies. Genes Dis
6(3):247–257. https://doi.org/10.1016/j.gendis.2019.06.002
30. Yao B, Christian KM, He C et al (2016) Epigenetic mechanisms in neurogenesis. Nat Rev
Neurosci 17(9):537–549. https://doi.org/10.1038/nrn.2016.70
31. Zhao S, Allis CD, Wang GG (2021) The language of chromatin modification in human can-
cers. Nat Rev Cancer 21:413–430. https://doi.org/10.1038/s41568-021-00357-x
32. Dai L, Chen L, Wang W et al (2020) Resveratrol inhibits ACHN cells via regulation of his-
tone acetylation. Pharm Biol 58(1):231–238. https://doi.org/10.1080/13880209.2020.173850
3
1166 P. Soni et al.

33. Mitsiogianni M, Trafalis DT, Franco R et al (2021) Sulforaphane and iberin are potent epi-
genetic modulators of histone acetylation and methylation in malignant melanoma. Eur J
Nutr 60:147–158. https://doi.org/10.1007/s00394-020-02227-y
34. Martin SL, Kala R, Tollefsbol TO (2018) Mechanisms for the inhibition of colon cancer
cells by sulforaphane through epigenetic modulation of microRNA-21 and human telomer-
ase reverse transcriptase (hTERT) down-regulation. Curr Cancer Drug Targets 18(1):97–106.
https://doi.org/10.2174/1568009617666170206104032
35. Zhang P, Wu W, Chen Q et al (2019) Non-coding RNAs and their integrated networks. J
Integr Bioinform 16(3):20190027. https://doi.org/10.1515/jib-2019-0027
36. Chen J, Xue Y (2016) Emerging roles of non-coding RNAs in epigenetic regulation. Sci
China Life Sci 59:227–235. https://doi.org/10.1007/s11427-016-5010-0
37. Zhu L, Zhang B, Dai Y et al (2017) A review: epigenetic mechanism in ochratoxin A toxicity
studies. Toxins (Basel) 9(4):113. https://doi.org/10.3390/toxins9040113
38. Mens MMJ, Ghanbari M (2018) Cell cycle regulation of stem cells by microRNAs. Stem Cell
Rev Rep 14:309–322. https://doi.org/10.1007/s12015-018-9808-y
39. O’Brien J, Hayder H, Zayed Y et al (2018) Overview of microRNA biogenesis, mechanisms
of actions, and circulation. Front Endocrinol (Lausanne) 9:402. https://doi.org/10.3389/
fendo.2018.00402
40. Shanmugapriya N, Sasidharan S (2020) MicroRNA deregulation and cancer and medici-
nal plants as microRNA regulator. Asian Pac J Trop Biomed 10:47–53. https://doi.
org/10.4103/2221-1691.275419
41. Chu Y, Fang Y, Chi J et al (2018) Astragalus polysaccharides decrease prolifera-
tion, migration, and invasion but increase apoptosis of human osteosarcoma cells by
up-regulation of microRNA-133a. Braz J Med Biol Res 51(12):e7665. https://doi.
org/10.1590/1414-431X20187665
42. Karagur ER, Ozay C, Mammadov R et al (2018) Anti-invasive effect of Cyclamen pseudi-
bericum extract on A549 non-small cell lung carcinoma cells via inhibition of ZEB1 medi-
ated by miR-200c. J Nat Med 72(3):686–693. https://doi.org/10.1007/s11418-018-1204-z
43. Yang Y, Li G (2020) Post-translational modifications of PRC2: signals directing its activity.
Epigenetics Chromatin 13:47. https://doi.org/10.1186/s13072-020-00369-1
44. Sun S, Yu F, Zhang L et al (2016) EZH2, an on-off valve in signal network of tumor cells. Cell
Signal 28(5):481–487. https://doi.org/10.1016/j.cellsig.2016.02.004
45. Wang X, Huang Y, Chen Y et al (2018) Efficacy of extracts of Celastrus orbiculatus in
suppressing migration and invasion by inhibiting the EZH2/ROCK1 signaling pathway in
human nasopharyngeal carcinoma. Oncol Lett 15(5):6695–6700. https://doi.org/10.3892/
ol.2018.8149
46. León-González AJ, Jara-Palacios MJ, Abbas M et al (2017) Role of epigenetic regulation on
the induction of apoptosis in Jurkat leukemia cells by white grape pomace rich in phenolic
compounds. Food Funct 8(11):4062–4069. https://doi.org/10.1039/c7fo00263g
47. Visconti R, Della Monica R, Grieco D (2016) Cell cycle checkpoint in cancer: a therapeuti-
cally targetable double-edged sword. J Exp Clin Cancer Res 35:153. https://doi.org/10.1186/
s13046-016-0433-9
48. Ding L, Cao J, Lin W et al (2020) The roles of cyclin-dependent kinases in cell-cycle progres-
sion and therapeutic strategies in human breast cancer. Int J Mol Sci 21(6):1960. https://doi.
org/10.3390/ijms21061960
49. Aleem E, Arceci RJ (2015) Targeting cell cycle regulators in hematologic malignancies.
Front Cell Dev Biol 3:16. https://doi.org/10.3389/fcell.2015.00016
50. Ma Y, Kanakousaki K, Buttitta L (2015) How the cell cycle impacts chromatin architecture
and influences cell fate. Front Genet 6:19. https://doi.org/10.3389/fgene.2015.00019
51. Mfengwana PH, Mashele SS, Manduna IT (2019) Cytotoxicity and cell cycle analysis of
Asparagus laricinus Burch. and Senecio asperulus DC. on breast and prostate cancer cell
lines. Heliyon 5(5):e01666. https://doi.org/10.1016/j.heliyon.2019.e01666
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic... 1167

52. Lee JI, Kim IH, Nam TJ (2017) Crude extract and solvent fractions of Calystegia soldanella
induce G1 and S phase arrest of the cell cycle in HepG2 cells. Int J Oncol 50(2):414–420.
https://doi.org/10.3892/ijo.2017.3836
53. Demir S, Turan I, Aliyazicioglu R et al (2018) Primula vulgaris extract induces cell cycle
arrest and apoptosis in human cervix cancer cells. J Pharm Anal 8(5):307–311. https://doi.
org/10.1016/j.jpha.2018.05.003
54. Asati V, Mahapatra DK, Bharti SK (2016) PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signal-
ing pathways inhibitors as anticancer agents: structural and pharmacological perspectives.
Eur J Med Chem 109:314–341. https://doi.org/10.1016/j.ejmech.2016.01.012
55. Manning BD, Toker A (2017) AKT/PKB signaling: navigating the network. Cell
169(3):381–405. https://doi.org/10.1016/j.cell.2017.04.001
56. Yang J, Nie J, Ma X et al (2019) Targeting PI3K in cancer: mechanisms and advances in clini-
cal trials. Mol Cancer 18:26. https://doi.org/10.1186/s12943-019-0954-x
57. Tlili H, Macovei A, Buonocore D et al (2021) The polyphenol/saponin-rich Rhus tripartita
extract has an apoptotic effect on THP-1 cells through the PI3K/AKT/mTOR signaling path-
way. BMC Complement Med Ther 21(1):153. https://doi.org/10.1186/s12906-021-03328-9
58. Nassan MA, Soliman MM, Ismail SA et al (2018) Effect of Taraxacum officinale
extract on PI3K/Akt pathway in DMBA-induced breast cancer in albino rats. Biosci Rep
38(6):BSR20180334. https://doi.org/10.1042/BSR20180334
59. Kim J, Jung KH, Ryu HW et al (2019) Apoptotic effects of Xanthium strumarium via PI3K/
AKT/mTOR pathway in hepatocellular carcinoma. Evid Based Complement Alternat Med
2019:2176701. https://doi.org/10.1155/2019/2176701
60. Pucci C, Martinelli C, Ciofani G (2019) Innovative approaches for cancer treatment: current
perspectives and new challenges. Ecancermedicalscience 13:961. https://doi.org/10.3332/
ecancer.2019.961
61. Malone ER, Oliva M, Sabatini PJB et al (2020) Molecular profiling for precision cancer
therapies. Genome Med 12(1):8. https://doi.org/10.1186/s13073-019-0703-1
62. Holleman GA, Hooge ITC, Kemner C et al (2020) The ‘real-world approach’ and its prob-
lems: a critique of the term ecological validity. Front Psychol 11:721. https://doi.org/10.3389/
fpsyg.2020.00721
63. Ankathil R (2019) The mechanisms and challenges of cancer chemotherapy resistance: a cur-
rent overview. Eur J Mol Clin Med 6(1):26–34. https://doi.org/10.5334/ejmcm.269
64. Lorscheider M, Gaudin A, Nakhlé J et al (2021) Challenges and opportunities in the deliv-
ery of cancer therapeutics: update on recent progress. Ther Deliv 12(1):55–76. https://doi.
org/10.4155/tde-2020-0079
65. Walcher L, Kistenmacher AK, Suo H et al (2020) Cancer stem cells-origins and biomark-
ers: perspectives for targeted personalized therapies. Front Immunol 11:1280. https://doi.
org/10.3389/fimmu.2020.01280
66. Salvadori G, Mirisola MG, Longo VD (2021) Intermittent and periodic fasting, hormones,
and cancer prevention. Cancers 13(18):4587. https://doi.org/10.3390/cancers13184587
67. Lettieri-Barbato D, Aquilano K (2018) Pushing the limits of cancer therapy: the nutrient
game. Front Oncol 8:148. https://doi.org/10.3389/fonc.2018.00148
68. Koca HB, Köken T, Özkurt M et al (2018) Effects of Acorus calamus plant extract on prostate
cancer cell culture. Anat J Bot 2(1):46–51. https://doi.org/10.30616/ajb.391985
69. Nguyen NH, Ta QTH, Pham QT et al (2020) Anticancer activity of novel plant extracts
and compounds from Adenosma bracteosum (Bonati) in human lung and liver cancer cells.
Molecules 25(12):2912. https://doi.org/10.3390/molecules25122912
70. Saleh KA, Albinhassan TH, Elbehairi SEI et al (2019) Cell cycle arrest in different cancer
cell lines (liver, breast, and colon) induces apoptosis under the influence of the chemical
content of Aeluropus lagopoides leaf extracts. Molecules 24(3):507. https://doi.org/10.3390/
molecules24030507
1168 P. Soni et al.

71. Ahmed I, Roy BC, Subramaniam D et al (2016) An ornamental plant targets epigenetic sig-
naling to block cancer stem cell-driven colon carcinogenesis. Carcinogenesis 37(4):385–396.
https://doi.org/10.1093/carcin/bgw009
72. Özkan İ, Koçak P, Yıldırım M et al (2021) Garlic (Allium sativum)-derived SEVs inhibit can-
cer cell proliferation and induce caspase-mediated apoptosis. Sci Rep 11:14773. https://doi.
org/10.1038/s41598-021-93876-4
73. Kuo CY, Weng TS, Kumar KJS et al (2019) Ethanol extracts of dietary herb, Alpinia
nantoensis, exhibit anticancer potential in human breast cancer cells. Integr Cancer Ther
18:1534735419866924. https://doi.org/10.1177/1534735419866924
74. Ahmad MS, Ahmad S, Ali A et al (2016) Anticarcinogenic and antimutagenic activity of
Alstonia scholaris on the albino mice bone marrow cells and peripheral human lympho-
cyte culture against methyl methane sulfonate induced genotoxicity. Adv Biomed Res 5:92.
https://doi.org/10.4103/2277-9175.183140
75. Purushotham G, Padma Y, Nabiha Y et al (2016) In vitro evaluation of anti-proliferative,
anti-inflammatory and pro-apoptotic activities of the methanolic extracts of Andrographis
nallamalayana Ellis on A375 and B16F10 melanoma cell lines. 3 Biotech 6(2):212. https://
doi.org/10.1007/s13205-016-0529-0
76. Younes M, Ammoury C, Haykal T et al (2020) The selective anti-proliferative and pro-apop-
totic effect of A. cherimola on MDA-MB-231 breast cancer cell line. BMC Complement Med
Ther 20(1):343. https://doi.org/10.1186/s12906-020-03120-1
77. Ammoury C, Younes M, El Khoury M et al (2019) The pro-apoptotic effect of a Terpene-rich
Annona cherimola leaf extract on leukemic cell lines. BMC Complement Altern Med 19:365.
https://doi.org/10.1186/s12906-019-2768-1
78. Köken T, Koca B, Özkurt M et al (2016) Apium graveolens extract inhibits cell proliferation
and expression of vascular endothelial growth factor and induces apoptosis in the human
prostatic carcinoma cell line LNCaP. J Med Food 19(12):1166–1171. https://doi.org/10.1089/
jmf.2016.0061
79. Ali S, Ejaz M, Dar KK et al (2020) Evaluation of chemopreventive and chemotherapeutic effect
of Artemisia vulgaris extract against diethylnitrosamine-induced hepatocellular carcinogen-
esis in Balb C mice. Braz J Biol 80(3):484–496. https://doi.org/10.1590/1519-6984.185979
80. Rajput S, Kumar D, Agrawal V (2020) Green synthesis of silver nanoparticles using Indian
Belladonna extract and their potential antioxidant, anti-inflammatory, anticancer and larvi-
cidal activities. Plant Cell Rep 39(7):921–939. https://doi.org/10.1007/s00299-020-02539-7
81. Mustafa K, Mohamed H, Shah AM et al (2020) In vitro anticancer potential of Berberis
lycium royle extracts against human hepatocarcinoma (HepG2) cells. Biomed Res Int
2020:8256809. https://doi.org/10.1155/2020/8256809
82. Dar KK, Ali S, Ejaz M et al (2019) In vivo induction of hepatocellular carcinoma by dieth-
ylnitrosoamine and pharmacological intervention in Balb C mice using Bergenia ciliata
extracts. Braz J Biol 79(4):629–638. https://doi.org/10.1590/1519-6984.186565
83. Chen X, Li S, Li D et al (2020) Ethanol extract of Brucea javanica seed inhibit triple-nega-
tive breast cancer by restraining autophagy via PI3K/Akt/mTOR pathway. Front Pharmacol
11:606. https://doi.org/10.3389/fphar.2020.00606
84. Naik Bukke A, Nazneen Hadi F, Babu KS et al (2018) In vitro studies data on anticancer
activity of Caesalpinia sappan L. heartwood and leaf extracts on MCF7 and A549 cell lines.
Data Brief 19:868–877. https://doi.org/10.1016/j.dib.2018.05.050
85. Sui M, Yang H, Guo M et al (2021) Cajanol sensitizes A2780/Taxol cells to paclitaxel by
inhibiting the PI3K/Akt/NF-κB signaling pathway. Front Pharmacol 12:783317. https://doi.
org/10.3389/fphar.2021.783317
86. Yumukjije C, Ndacyayisenga J (2019) Phytochemical analysis & in vitro anticancer activity
of methanol extract of Catharanthus Roseus leaves using HEPG2 cell line. IAETSD J Adv
Res Appl Sci vi(viii):2394–8442
87. Sudevan S, Paramasivam R, Sundar S et al (2017) Evaluation of metabolic compounds of
Catharanthus roseus and its anticancer activity. Eur J Pharm Med Res 4(9):282–290
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic... 1169

88. Abouelela ME, Orabi MAA, Abdelhamid RA et al (2018) Chemical and cytotoxic investiga-
tion of non-polar extract from Ceiba Pentandra (L.) Gaertn.: a study supported by computer
based screening. J Appl Pharm Sci 8(07):057–064. https://doi.org/10.7324/JAPS.2018.8710
89. Hamid IS, Rai Widjaja NM, Damayanti R (2016) Anticancer activity of Centella asiatica
leaves extract in benzo(a)pyrene-induced mice. Int J Pharmacogn Phytochem Res 8(1):80–84.
ISSN: 0975-4873
90. Adedapo AA, Oyagbemi AA, Fagbohun OA et al (2016) Evaluation of the anticancer prop-
erties of the methanol leaf extract of Chromolaena odorata on HT29 lung cancer cell line.
FASEB J 30:1193.6-1193.6. https://doi.org/10.1096/fasebj.30.1_supplement.1193.6
91. Elkady AI (2019) Targeting prostate cancer cell proliferation, stemness and metastatic poten-
tial using Costus speciosus-derived phytochemicals. Am J Transl Res 11(4):2550–2569
92. Chen CY, Yen CY, Wang HR et al (2016) Tenuifolide B from Cinnamomum tenuifolium
stem selectively inhibits proliferation of oral cancer cells via apoptosis, ROS generation,
mitochondrial depolarization, and DNA damage. Toxins (Basel) 8(11):319. https://doi.
org/10.3390/toxins8110319
93. Perveen S, Ashfaq H, Ambreen S et al (2021) Methanolic extract of Citrullus colocynthis sup-
presses growth and proliferation of breast cancer cells through regulation of cell cycle. Saudi
J Biol Sci 28(1):879–886. https://doi.org/10.1016/j.sjbs.2020.11.029
94. Chowdhury K, Sharma A, Kumar S et al (2017) Colocynth extracts prevent epithelial to mes-
enchymal transition and stemness of breast cancer cells. Front Pharmacol 8:593. https://doi.
org/10.3389/fphar.2017.00593
95. Ng PY, Chye SM, Ng CHH et al (2017) Clinacanthus nutans hexane extracts induce apopto-
sis through a caspase-dependent pathway in human cancer cell lines. Asian Pac J Cancer Prev
18(4):917–926. https://doi.org/10.22034/APJCP.2017.18.4.917
96. Mahmood N, Younas H, Zafar M et al (2021) Effects of plants extracts on the expression of
major genes of JAK/STAT pathway. Nucleosides Nucleotides Nucleic Acids 40(4):434–469.
https://doi.org/10.1080/15257770.2021.1896000
97. Omairi I, Kobeissy F, Nasreddine S (2020) Anti-oxidant, anti-hemolytic effects of Crataegus
aronia leaves and its anti- proliferative effect enhance cisplatin cytotoxicity in A549 human
lung cancer cell line. Asian Pac J Cancer Prev 21(10):2993–3003. https://doi.org/10.31557/
APJCP.2020.21.10.2993
98. Sana SS, Kumbhakar DV, Pasha A et al (2020) Crotalaria verrucosa leaf extract-mediated
synthesis of zinc oxide nanoparticles: assessment of antimicrobial and anticancer activity.
Molecules 25(21):4896. https://doi.org/10.3390/molecules25214896
99. Hejazi II, Khanam R, Mehdi SH et al (2018) Antioxidative and anti-proliferative potential of
Curculigo orchioides Gaertn in oxidative stress-induced cytotoxicity: in vitro, ex vivo and
in silico studies. Food Chem Toxicol 115:244–259. https://doi.org/10.1016/j.fct.2018.03.013
100. Bhummaphan N, Petpiroon N, Prakhongcheep O et al (2019) Lusianthridin targeting of
lung cancer stem cells via Src-STAT3 suppression. Phytomedicine 62:152932. https://doi.
org/10.1016/j.phymed.2019.152932
101. Nelson VK, Sahoo NK, Sahu M et al (2020) In vitro anticancer activity of Eclipta alba whole
plant extract on colon cancer cell HCT-116. BMC Complement Med Ther 20:355. https://doi.
org/10.1186/s12906-020-03118-9
102. Sulistyani N, Nurkhasanah N (2017) The cytotoxic effect of Elephantopus scaber Linn
extract against breast cancer (T47D) cells. International Pharmacy Conference. IOP Conf
Ser: Mater Sci Eng 259:012006. https://doi.org/10.1088/1757-899X/259/1/012006
103. Liberal J, Costa G, Carmo A et al (2019) Chemical characterization and cytotoxic potential
of an ellagitannin-enriched fraction from Fragaria vesca leaves. Arab J Chem 12:3652–3666.
https://doi.org/10.1016/J.ARABJC.2015.11.014
104. Kardan M, Yazdani Z, Morsaljahan Z et al (2019) Cytotoxic effect of methanolic extracts of
Fritillaria imperialis bulbs and Eryngium caucasicum leaves on hepatoma and colon cancer
cells. Asian Pac J Trop Biomed 9(8):353–358. https://doi.org/10.4103/2221-1691.262084
1170 P. Soni et al.

105. Chen Z, Li W, Santhanam RK et al (2019) Bioactive peptide with antioxidant and anticancer
activities from black soybean [Glycine max (L.) Merr.] byproduct: isolation, identification
and molecular docking study. Eur Food Res Technol 245:677–689. https://doi.org/10.1007/
s00217-018-3190-5
106. Wang Y, Liu L, Ji F et al (2018) Soybean (Glycine max) prevents the progression of breast
cancer cells by downregulating the level of histone demethylase JMJD5. J Cancer Res Ther
14(Supplement):S609–S615. https://doi.org/10.4103/0973-1482.187292
107. Kwak Y, Ju J (2017) Glycine max Merr. leaf extract possesses anti-oxidant properties,
decreases inflammatory mediator production in murine macrophages, and inhibits growth,
migration, and adhesion in human cancer cells. Food Sci Biotechnol 26(1):245–253. https://
doi.org/10.1007/s10068-017-0033-2
108. Zheng C, Han L, Wu S (2019) A metabolic investigation of anticancer effect of G. glabra
root extract on nasopharyngeal carcinoma cell line, C666-1. Mol Biol Rep 46(4):3857–3864.
https://doi.org/10.1007/s11033-019-04828-1
109. Packialakshmi B, Sowndriya SR (2019) Anti-cancer effect of Gymnema sylvestre leaf extract
against MG63, human osteosarcoma cell line - an in vitro analysis. Int J Curr Res Rev 11(11).
https://doi.org/10.31782/IJCRR.2019.11114
110. Hejazi II, Khanam R, Mehdi SH et al (2017) New insights into the antioxidant and apoptotic
potential of Glycyrrhiza glabra L. during hydrogen peroxide-mediated oxidative stress: an in
vitro and in silico evaluation. Biomed Pharmacother 94:265–279. https://doi.org/10.1016/j.
biopha.2017.06.108
111. Li Y, Huang J, Lin W et al (2016) In vitro anticancer activity of a nonpolar fraction from
Gynostemma pentaphyllum (Thunb.) Makino. Evid Based Complement Alternat Med
2016:6308649. https://doi.org/10.1155/2016/6308649
112. Yen CH, Lai CC, Shia TH et al (2018) Gynura divaricata attenuates tumor growth and
tumor relapse after cisplatin therapy in HCC xenograft model through suppression of cancer
stem cell growth and Wnt/β-catenin signalling. J Ethnopharmacol 213:366–375. https://doi.
org/10.1016/j.jep.2017.07.019
113. Nguyen C, Baskaran K, Pupulin A et al (2019) Hibiscus flower extract selectively induces
apoptosis in breast cancer cells and positively interacts with common chemotherapeutics.
BMC Complement Altern Med 19(1):98. https://doi.org/10.1186/s12906-019-2505-9
114. Moodley S, Dwarka D, Baijnath H et al (2021) In vitro anti-cancer, anti-hypertensive and
anti-hyperglycaemic effect of Hypoxis colchicifolia. J Nat Remedies 21(3). https://doi.
org/10.18311/jnr/2021/25315
115. Keshava R, Muniyappa N, Gope R (2020) Bioactivity-guided fractionation and elucida-
tion of anti-cancer properties of Imperata cylindrica leaf extracts. Asian Pac J Cancer Prev
21(3):707–714. https://doi.org/10.31557/APJCP.2020.21.3.707
116. Asep S, Hening H, Gema SP et al (2017) Anticancer activity of Jatrophone an isolated com-
pound from Jatropha gossypifolia plant against hepatocellular cancer cell hep G2 1886.
Biomed Pharmacol J 10(2). https://doi.org/10.13005/bpj/1154
117. Potikanond S, Sookkhee S, Na Takuathung M et al (2017) Kaempferia parviflora extract
exhibits anti-cancer activity against HeLa cervical cancer cells. Front Pharmacol 8:630.
https://doi.org/10.3389/fphar.2017.00630
118. Ishteyaque S, Mishra A, Mohapatra S et al (2020) In vitro: cytotoxicity, apoptosis and ame-
liorative potential of Lawsonia inermis extract in human lung, colon and liver cancer cell line.
Cancer Investig 38(8–9):476–485. https://doi.org/10.1080/07357907.2020.1811300
119. Mohan A, Nair SV, Lakshmanan VK (2017) Leucas aspera nanomedicine shows superior
toxicity and cell migration retarded in prostate cancer cells. Appl Biochem Biotechnol
181(4):1388–1400. https://doi.org/10.1007/s12010-016-2291-5
120. Tannous S, Haykal T, Dhaini J et al (2020) The anti-cancer effect of flaxseed lignan deriva-
tives on different acute myeloid leukemia cancer cells. Biomed Pharmacother 132:110884.
https://doi.org/10.1016/j.biopha.2020.110884
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic... 1171

121. Ma Y, Yan F, Wei W et al (2020) Litchi seed aqueous extracts play a role in suppression of
epithelial-mesenchymal transition, invasion and migration in breast cancer cells. Cell Cycle
19(3):317–325. https://doi.org/10.1080/15384101.2019.1710912
122. Lauricella M, Lo Galbo V, Cernigliaro C et al (2019) The anti-cancer effect of Mangifera
indica L. peel extract is associated to γH2AX-mediated apoptosis in colon cancer cells.
Antioxidants (Basel) 8(10):422. https://doi.org/10.3390/antiox8100422
123. Pumiputavon K, Chaowasku T, Saenjum C et al (2017) Cell cycle arrest and apoptosis induc-
tion by methanolic leaves extracts of four Annonaceae plants. BMC Complement Altern Med
17(1):294. https://doi.org/10.1186/s12906-017-1811-3
124. Dadashpour M, Firouzi-Amandi A, Pourhassan-Moghaddam M et al (2018) Biomimetic syn-
thesis of silver nanoparticles using Matricaria chamomilla extract and their potential antican-
cer activity against human lung cancer cells. Mater Sci Eng C Mater Biol Appl 92:902–912.
https://doi.org/10.1016/j.msec.2018.07.053
125. Khan F, Pandey P, Ahmad V et al (2020) Moringa oleifera methanolic leaves extract induces
apoptosis and G0/G1 cell cycle arrest via downregulation of Hedgehog Signaling Pathway
in human prostate PC-3 cancer cells. J Food Biochem 44(8):e13338. https://doi.org/10.1111/
jfbc.13338
126. Madi N, Dany M, Abdoun S et al (2016) Moringa oleifera’s nutritious aqueous leaf extract
has anticancerous effects by compromising mitochondrial viability in an ROS-dependent
manner. J Am Coll Nutr 35(7):604–613. https://doi.org/10.1080/07315724.2015.1080128
127. Erden Y (2021) Sour black mulberry (Morus nigra L.) causes cell death by decreasing mutant
p53 expression in HT-29 human colon cancer cells. Food. Bioscience 42:101113. https://doi.
org/10.1016/j.fbio.2021.101113
128. Turan I, Demir S, Kilinc K et al (2017) Antiproliferative and apoptotic effect of Morus
nigra extract on human prostate cancer cells. Saudi Pharm J 25(2):241–248. https://doi.
org/10.1016/j.jsps.2016.06.002
129. Sinha S, Sharma S, Vora J et al (2018) Mucuna pruriens (L.) DC chemo sensitizes human
breast cancer cells via downregulation of prolactin-mediated JAK2/STAT5A signaling. J
Ethnopharmacol 217:23–35. https://doi.org/10.1016/j.jep.2018.02.006
130. Aniqa A, Kaur S, Sadwal S (2021) A review of the anti-cancer potential of Murraya koenigii
(Curry Tree) and its active constituents. Nutr Cancer 74:12. https://doi.org/10.1080/0163558
1.2021.1882509
131. Utaipan T, Athipornchai A, Suksamrarn A et al (2017) Isomahanine induces endoplasmic
reticulum stress and simultaneously triggers p38 MAPK-mediated apoptosis and autophagy in
multidrug-resistant human oral squamous cell carcinoma cells. Oncol Rep 37(2):1243–1252.
https://doi.org/10.3892/or.2017.5352
132. Ju A, Cho YC, Kim BR et al (2018) Anticancer effects of methanol extract of Myrmecodia
platytyrea Becc. leaves against human hepatocellular carcinoma cells via inhibition of
ERK and STAT3 signaling pathways. Int J Oncol 52(1):201–210. https://doi.org/10.3892/
ijo.2017.4178
133. Bashari M, Yuniarti E, Putri T et al (2020) Inhibition capacity of the n-hexane fraction
of Myrmecodia pendens as a potential anti-cancer in breast and cervical cancer: in vitro
study. Indones J Cancer Chemoprevention 11(3):115–123. https://doi.org/10.14499/
indonesianjcanchemoprev11iss3pp115-123
134. Bashari MH, Hidayat S, Ruswandi YSR et al (2018) The n-hexane fraction of Myrmecodia
pendans inhibits cells survival and proliferation in colon cancer cell line. Int J Pharm Pharm
Sci 10(1):108. https://doi.org/10.22159/IJPPS.2018V10I1.21882
135. Yuletnawati SE, Meiyanto E, Agustina D (2016) High antitumor activity of ethanolic extracts
of papua’s ant nest plant (Myrmecodia tuberosa) on an oral carcinoma (KB) cell line. Int J Sci
Res 5:1619–1623. https://doi.org/10.21275/v5i1.nov1531391
136. Wu CH, Yang MY, Lee YJ et al (2017) Nelumbo nucifera leaf polyphenol extract inhibits
breast cancer cells metastasis in vitro and in vivo through PKCα targeting. J Funct Foods
37:480–490. https://doi.org/10.1016/j.jff.2017.08.021
1172 P. Soni et al.

137. Khurshid Y, Syed B, Simjee SU et al (2020) Antiproliferative and apoptotic effects of pro-
teins from black seeds (Nigella sativa) on human breast MCF-7 cancer cell line. BMC
Complement Med Ther 20:5. https://doi.org/10.1186/s12906-019-2804-1
138. Harsha M, Mohan Kumar KP, Kagathur S et al (2020) Effect of Ocimum sanctum extract
on leukemic cell lines: a preliminary in-vitro study. J Oral Maxillofac Pathol 24(1):93–98.
https://doi.org/10.4103/jomfp.JOMFP_181_19
139. Yadav R, Saini H, Kumar D et al (2019) Bioengineering of Piper longum L. extract-mediated
silver nanoparticles and their potential biomedical applications. Mater Sci Eng C Mater Biol
Appl 104:109984. https://doi.org/10.1016/j.msec.2019.109984
140. Maheswari P, Harish S, Ponnusamy S et al (2021) A novel strategy of nanosized herbal
Plectranthus amboinicus, Phyllanthus niruri and Euphorbia hirta treated TiO2 nanoparticles
for antibacterial and anticancer activities. Bioprocess Biosyst Eng 44(8):1593–1616. https://
doi.org/10.1007/s00449-020-02491-6
141. Li W, Zhang Q, Chen K et al (2019) 2-Ethoxystypandrone, a novel small-molecule STAT3
signaling inhibitor from Polygonum cuspidatum, inhibits cell growth and induces apoptosis
of HCC cells and HCC Cancer stem cells. BMC Complement Altern Med 19:38. https://doi.
org/10.1186/s12906-019-2440-9
142. Li L, Thakur K, Cao YY et al (2020) Anticancerous potential of polysaccharides sequentially
extracted from Polygonatum cyrtonema Hua in Human cervical cancer Hela cells. Int J Biol
Macromol 148:843–850. https://doi.org/10.1016/j.ijbiomac.2020.01.223
143. Singh C, Anand SK, Tiwari KN et al (2021) Phytochemical profiling and cytotoxic evaluation
of Premna serratifolia L against human liver cancer cell line. 3 Biotech 11(3):115. https://
doi.org/10.1007/s13205-021-02654-6
144. Balkrishna A, Sharma VK, Das SK et al (2020) Characterization and anti-cancerous effect of
Putranjiva roxburghii seed extract-mediated silver nanoparticles on human colon (HCT-116),
pancreatic (PANC-1) and breast (MDA-MB 231) cancer cell lines: a comparative study. Int J
Nanomedicine 15:573–585. https://doi.org/10.2147/IJN.S230244
145. Hajrah NH, Abdul WM, Al-Garni SM et al (2019) Gene expression profiling to elucidate
the pharmacological and toxicological effects of Ricinus communis L. leaf extract in mam-
malian cells. Biotechnol Biotechnol Equip 33(1):397–407. https://doi.org/10.1080/1310281
8.2019.1578691
146. Ansari S, Hasan K, Bhat S (2021) Anticancer, antioxidant, and hepatoprotective activity
of Saussurea lappa, C.B. clarke (qust) on human hepatoma cell line. J Cancer Res Ther
17(2):499–503. https://doi.org/10.4103/jcrt.JCRT_571_19
147. Ndlovu MJ, Bagla VP, Mokgotho MP et al (2021) Potential anticancer activity of Acetone
extracts of Toona cilliata, Seriphium plumosum and Schkuhria pinnata on HeLa cervical
cancer cells. Afr Health Sci 21(2):663–672. https://doi.org/10.4314/ahs.v21i2.23
148. Nawaz A, Jamal A, Arif A et al (2021) In vitro cytotoxic potential of Solanum nigrum
against human cancer cell lines. Saudi J Biol Sci 28(8):4786–4792. https://doi.org/10.1016/j.
sjbs.2021.05.004
149. Lai YJ, Tai CJ, Wang CW et al (2016) Anti-cancer activity of Solanum nigrum (AESN)
through suppression of mitochondrial function and epithelial-mesenchymal transition (EMT)
in breast cancer cells. Molecules 21(5):553. https://doi.org/10.3390/molecules21050553
150. Koh RY, Lim FP, Ling LSY et al (2017) Anticancer mechanisms of Strobilanthes crispa
Blume hexane extract on liver and breast cancer cell lines. Oncol Lett 14(4):4957–4964.
https://doi.org/10.3892/ol.2017.6821
151. Li L, Mangali S, Kour N et al (2021) Syzygium cumini (jamun) fruit-extracted phytochemicals
exert anti-proliferative effect on ovarian cancer cells. J Cancer Res Ther 17(6):1547–1551.
https://doi.org/10.4103/jcrt.JCRT_210_20
152. Khodavirdipour A, Zarean R, Safaralizadeh R (2021) Evaluation of the anti-cancer effect
of Syzygium cumini ethanolic extract on HT-29 colorectal cell line. J Gastrointest Cancer
52(2):575–581. https://doi.org/10.1007/s12029-020-00439-3
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic... 1173

153. Kubatka P, Uramova S, Kello M et al (2019) Anticancer activities of Thymus vulgaris L. in

experimental breast carcinoma in vivo and in vitro. Int J Mol Sci 20(7):1749. https://doi.
org/10.3390/ijms20071749
154. Motadi LR, Choene MS, Mthembu NN (2020) Anticancer properties of Tulbaghia violacea
regulate the expression of p53-dependent mechanisms in cancer cell lines. Sci Rep 10:12924.
https://doi.org/10.1038/s41598-020-69722-4
155. Zari A, Alfarteesh H, Buckner C et al (2021) Treatment with Uncaria tomentosa promotes
apoptosis in B16-BL6 mouse melanoma cells and inhibits the growth of B16-BL6 tumours.
Molecules 26(4):1066. https://doi.org/10.3390/molecules26041066
156. D’Abrosca B, Ciaramella V, Graziani V et al (2019) Urtica dioica L. inhibits proliferation and
enhances cisplatin cytotoxicity in NSCLC cells via Endoplasmic Reticulum-stress-mediated
apoptosis. Sci Rep 9:4986. https://doi.org/10.1038/s41598-019-41372-1
157. Yousefnia S, Naseri D, Seyed Forootan F et al (2020) Suppressive role of Viola odorata
extract on malignant characters of mammosphere-derived breast cancer stem cells. Clin
Transl Oncol 22:1619–1634. https://doi.org/10.1007/s12094-020-02307-9
158. Mishra R, Sharma S, Sharma RS et al (2018) Viscum articulatum Burm. f. aqueous extract
exerts antiproliferative effect and induces cell cycle arrest and apoptosis in leukemia cells. J
Ethnopharmacol 219:91–102. https://doi.org/10.1016/j.jep.2018.03.005
159. Winarno EK, Susanto, Winarno H (2020) Antiproliferative activity against cancer cell lines
of gamma irradiated “Legundi” (Vitex Trifolia L.) leaves and its chromatogram profiles.
In: International Conference on Science and Applied Science (ICSAS2020), vol 2296. AIP
Conference Proceedings, p 020068. https://doi.org/10.1063/5.0030628
160. Leong KH, Mahdzir MA, Din MF et al (2017) Induction of intrinsic apoptosis in leukaemia
stem cells and in vivo zebrafish model by betulonic acid isolated from Walsura pinnata Hassk
(Meliaceae). Phytomedicine 26:11–21. https://doi.org/10.1016/j.phymed.2016.12.018
161. Tripathi D, Modi A, Narayan G et al (2019) Green and cost-effective synthesis of silver
nanoparticles from endangered medicinal plant Withania coagulans and their poten-
tial biomedical properties. Mater Sci Eng C 100:152–164. https://doi.org/10.1016/j.
msec.2019.02.113
162. Venkatachalapathy D, Shivamallu C, Prasad SK et al (2021) Assessment of chemopreven-
tive potential of the plant extracts against liver cancer using HepG2 cell line. Molecules
26(15):4593. https://doi.org/10.3390/molecules26154593
163. Dar PA, Mir SA, Bhat JA et al (2019) An anti-cancerous protein fraction from Withania
somnifera induces ROS-dependent mitochondria-mediated apoptosis in human
MDA-MB-231 breast cancer cells. Int J Biol Macromol 135:77–87. https://doi.org/10.1016/j.
ijbiomac.2019.05.120
164. Dixit A, Jain AK, Tailang M (2017) An in-vitro evaluation of cytotoxic activity of Wrightia
tinctoria. Int J Pharm 7(4):14–18. ISSN 2249-1848
165. Fatima N, Ahmad MK, Ansari JA et al (2016) Anticancer, antioxidant potential and profiling
of polyphenolic compounds of Wrightia tinctoria Roxb(RBr) bark. J Adv Pharm Technol Res
7(4):159–165. https://doi.org/10.4103/2231-4040.191428
166. Al-Oqail MM, Al-Sheddi ES, Farshori NN et al (2019) Corn silk (Zea mays L.) induced apop-
tosis in human breast cancer (MCF-7) cells via the ROS-mediated mitochondrial pathway.
Oxidative Med Cell Longev 2019:9789241. https://doi.org/10.1155/2019/9789241
167. Zulkhairi AM, Aspollah SM, Lian EGC et al (2017) Phytochemicals and cytotoxic studies of
Zingiber cassumunar Roxb. J Trop Agric and Fd Sc 45(2):187–197. ISSN: 1394-9829
168. Zhang F, Thakur K, Hu F et al (2017) 10-Gingerol, a phytochemical derivative from “tongling
white ginger”, inhibits cervical cancer: insights into the molecular mechanism and inhibitory
targets. J Agric Food Chem 65(10):2089–2099. https://doi.org/10.1021/acs.jafc.7b00095
169. Periasamy S, Wu WH, Chien SP et al (2020) Dietary Ziziphus jujuba fruit attenuates coli-
tis-associated tumorigenesis: a pivotal role of the NF-κB/IL-6/JAK1/STAT3 pathway. Nutr
Cancer 72(1):120–132. https://doi.org/10.1080/01635581.2019.1615515
1174 P. Soni et al.

170. Abedini MR, Erfanian N, Nazem H et al (2016) Anti-proliferative and apoptotic effects of
Ziziphus Jujube on cervical and breast cancer cells. Avicenna J Phytomed 6(2):142–148
171. Kumar U, Sharma U, Rathi G (2017) Reversal of hypermethylation and reactivation of
glutathione S-transferase pi 1 gene by curcumin in breast cancer cell line. Tumour Biol
39(2):1010428317692258. https://doi.org/10.1177/1010428317692258
172. Liu Y, Zhou J, Hu Y et al (2017) Curcumin inhibits growth of human breast cancer cells
through demethylation of DLC1 promoter. Mol Cell Biochem 425(1–2):47–58. https://doi.
org/10.1007/s11010-016-2861-4
173. Chen CQ, Yu K, Yan QX et al (2013) Pure curcumin increases the expression of SOCS1 and
SOCS3 in myeloproliferative neoplasms through suppressing class I histone deacetylases.
Carcinogenesis 34(7):1442–1449. https://doi.org/10.1093/carcin/bgt070
174. Lee SJ, Krauthauser C, Maduskuie V et al (2011) Curcumin-induced HDAC inhibition and
attenuation of medulloblastoma growth in vitro and in vivo. BMC Cancer 11:144. https://doi.
org/10.1186/1471-2407-11-144
175. Dou H, Shen R, Tao J et al (2017) Curcumin suppresses the colon cancer proliferation by
inhibiting Wnt/β-catenin pathways via miR-130a. Front Pharmacol 8:877. Published 2017
Nov 24. https://doi.org/10.3389/fphar.2017.00877
176. Sohn EJ, Bak KM, Nam YK et al (2018) Upregulation of microRNA 344a-3p is involved in
curcumin-induced apoptosis in RT4 schwannoma cells. Cancer Cell Int 18:199. https://doi.
org/10.1186/s12935-018-0693-x
177. Meng J, Tong Q, Liu X et al (2017) Epigallocatechin-3-gallate inhibits growth and induces
apoptosis in esophageal cancer cells through the demethylation and reactivation of the p16
gene. Oncol Lett 14:1152–1156. https://doi.org/10.3892/ol.2017.6248
178. Ciesielski O, Biesiekierska M, Balcerczyk A (2020) Epigallocatechin-3-gallate (EGCG) alters
histone acetylation and methylation and impacts chromatin architecture profile in human
endothelial cells. Molecules 25(10):2326. https://doi.org/10.3390/molecules25102326
179. Lee YH, Kwak J, Choi HK et al (2012) EGCG suppresses prostate cancer cell growth modu-
lating acetylation of androgen receptor by anti-histone acetyltransferase activity. Int J Mol
Med 30(1):69–74. https://doi.org/10.3892/ijmm.2012.966
180. Lin CH, Wang HH, Chen TH et al (2020) Involvement of microRNA-296 in the inhibi-
tory effect of epigallocatechin gallate against the migratory properties of anoikis-resistant
nasopharyngeal carcinoma cells. Cancers (Basel) 12(4):973. https://doi.org/10.3390/
cancers12040973
181. Zhu Y, Huang Y, Liu M et al (2019) Epigallocatechin gallate inhibits cell growth and regu-
lates miRNA expression in cervical carcinoma cell lines infected with different high-risk
human papillomavirus subtypes. Exp Ther Med 17:1742–1748. https://doi.org/10.3892/
etm.2018.7131
182. Sanaei M, Kavoosi F, Roustazadeh A et al (2018) Effect of genistein in comparison with
trichostatin A on reactivation of DNMTs genes in hepatocellular carcinoma. J Clin Transl
Hepatol 6(2):141–146. https://doi.org/10.14218/JCTH.2018.00002
183. Bilir B, Sharma NV, Lee J et al (2017) Effects of genistein supplementation on genome-wide
DNA methylation and gene expression in patients with localized prostate cancer. Int J Oncol
51(1):223–234. https://doi.org/10.3892/ijo.2017.4017
184. Majid S, Dar AA, Shahryari V et al (2010) Genistein reverses hypermethylation and induces
active histone modifications in tumor suppressor gene B-Cell translocation gene 3 in prostate
cancer. Cancer 116(1):66–76. https://doi.org/10.1002/cncr.24662
185. Yu Y, Xing Y, Zhang Q et al (2021) Soy isoflavone genistein inhibits hsa_circ_0031250/
miR-873-5p/FOXM1 axis to suppress non-small-cell lung cancer progression. IUBMB Life
73(1):92–107. https://doi.org/10.1002/iub.2404
186. Lynch SM, O'Neill KM, McKenna MM et al (2016) Regulation of miR-200c and miR-141
by methylation in prostate cancer. Prostate 76(13):1146–1159. https://doi.org/10.1002/
pros.23201
Anticancer Potential of Plant-Derived Compounds: An Overview of Their Epigenetic... 1175

187. de la Parra C, Castillo-Pichardo L, Cruz-Collazo A et al (2016) Soy isoflavone genistein-

mediated downregulation of miR-155 contributes to the anticancer effects of genistein. Nutr
Cancer 68(1):154–164. https://doi.org/10.1080/01635581.2016.1115104
188. Fudhaili A, Yoon NA, Kang S et al (2019) Resveratrol epigenetically regulates the expression
of zinc finger protein 36 in non-small cell lung cancer cell lines. Oncol Rep 41(2):1377–1386.
https://doi.org/10.3892/or.2018.6898
189. Medina-Aguilar R, Pérez-Plasencia C, Marchat LA et al (2016) Methylation landscape
of human breast cancer cells in response to dietary compound resveratrol. PLoS One
11(6):e0157866. https://doi.org/10.1371/journal.pone.0157866
190. Dhar S, Kumar A, Li K et al (2015) Resveratrol regulates PTEN/Akt pathway through inhibi-
tion of MTA1/HDAC unit of the NuRD complex in prostate cancer. Biochim Biophys Acta,
Mol Cell Res 1853:265–275. https://doi.org/10.1016/j.bbamcr.2014.11.004
191. Fu J, Shrivastava A, Shrivastava SK et al (2019) Triacetyl resveratrol upregulates miRNA-200
and suppresses the Shh pathway in pancreatic cancer: a potential therapeutic agent. Int J
Oncol 54(4):1306–1316. https://doi.org/10.3892/ijo.2019.4700
192. Venkatadri R, Muni T, Iyer A et al (2016) Role of apoptosis-related miRNAs in resvera-
trol-induced breast cancer cell death. Cell Death Dis 7:e2104. https://doi.org/10.1038/
cddis.2016.6
193. Li S, Yang Y, Sargsyan D et al (2020) Epigenome, transcriptome, and protection by sul-
foraphane at different stages of UVB-induced skin carcinogenesis. Cancer Prev Res (Phila)
13(6):551–562. https://doi.org/10.1158/1940-6207.CAPR-19-0522
194. Zhou J, Wang M, Sun N et al (2019) Sulforaphane-induced epigenetic regulation of Nrf2
expression by DNA methyltransferase in human Caco-2 cells. Oncol Lett 18:2639–2647.
https://doi.org/10.3892/ol.2019.10569
195. Ali Khan M, Kedhari Sundaram M, Hamza A et al (2015) Sulforaphane reverses the expres-
sion of various tumor suppressor genes by targeting DNMT3B and HDAC1 in human
cervical cancer cells. Evid Based Complement Alternat Med 2015:412149. https://doi.
org/10.1155/2015/412149
196. Yin L, Xiao X, Georgikou C et al (2019) Sulforaphane induces miR135b-5p and its target
gene, RASAL2, thereby inhibiting the progression of pancreatic cancer. Mol Ther Oncolytics
14:74–81. https://doi.org/10.1016/j.omto.2019.03.011
197. Kedhari Sundaram M, Hussain A, Haque S et al (2019) Quercetin modifies 5'CpG pro-
moter methylation and reactivates various tumor suppressor genes by modulating epigenetic
marks in human cervical cancer cells. J Cell Biochem 120(10):18357–18369. https://doi.
org/10.1002/jcb.29147
198. Alvarez MC, Maso V, Torello CO et al (2018) The polyphenol quercetin induces cell death in
leukemia by targeting epigenetic regulators of pro-apoptotic genes. Clin Epigenetics 10:139.
https://doi.org/10.1186/s13148-018-0563-3
199. Nwaeburu CC, Abukiwan A, Zhao Z et al (2017) Quercetin-induced miR-200b-3p regulates
the mode of self-renewing divisions in pancreatic cancer. Mol Cancer 16:23. https://doi.
org/10.1186/s12943-017-0589-8
200. Zhou J, Gong J, Ding C et al (2015) Quercetin induces the apoptosis of human ovarian carci-
noma cells by upregulating the expression of microRNA-145. Mol Med Rep 12:3127–3131.
https://doi.org/10.3892/mmr.2015.3679
Treatment of Cancer Using Combination
of Herbal and Novel Drug Delivery System

Nikita Kale

1 Introduction

Nanotechnology and nanoengineering tend to generate significant scientific and

technological push on in diverse domain including medicine and physiology. In a
large sense, they can be expressed as the science and engineering elaborated in the
design, synthesis, characterization, and approach of materials and devices whose
minute functional organization in at slightest one dimension is on the nanometer
scale, ranging from a few to some hundred nanometers. Nanodevices are acceptable
to serve as customized, targeted drug delivery vehicles to convey large doses of
chemotherapeutic agents or therapeutic genes into poisonous cells while cautious
healthy cells [1]. The molding can assemble nanodevices or etching, top-down tech-
niques, or by gathering structures atom by atom or molecule by molecule, bottom-
­up techniques. We are now closer to capable to fully characterize the differences
between the normal and the tumor cell. Coupled with the use of microdissection
techniques, it is also possible to interrogate the genetic make-up of individual cell
types. The hope is that use of such technologies will accelerate the progress in iden-
tifying the differences between normal and tumor cells, which in turn will lead to
development of new therapies that will specifically target the cancer. The conclusive
goal of these strategies is to eliminate the tumor with restricted effect on normal
tissue [2].
The considerable immediate influence of nanotechnologies in cancer remedy is
in drug delivery. The therapeutic index of about all drugs presently being used can
be upgraded if they are more ably delivered to their biological targets across appro-
priate application of nanotechnologies. Some drugs that have earlier failed clinical
trials might also be reinvestigated using nanotechnological techniques. A number of
hurdles may be overcome with numerous novel approaches of nano drug delivery

N. Kale (*)
Faculty of Pharmacy, Oriental University, Indore, India

© The Author(s), under exclusive license to Springer Nature 1177

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_49
1178 N. Kale

[3]. If a successful compound has a short half-life in the circulation, its stability can
be increased enormously by encasing it within nanosized liposomes as a drug car-
rier. In the occurrence of central nervous system cancers, many drugs have strug-
gling in crossing the blood–brain barrier to strike the tumor. Drug-loaded
nanoparticles are able to perforate this barrier, and have been appear to greatly
increase therapeutic concentrations of anticancer drugs in brain tumors. The best
means to increase the usefulness and diminish the toxicity of a cancer drug is to
straight the drug to its target and conserve its concentration at the site for an ade-
quate time for therapeutic action to take consequences [4].

2 Applications of Nanotechnology

2.1 Classification of Nanoparticles

There are numerous approaches for categorization of nanomaterials. Nanoparticles

are categorized based on one, two, and three dimensions (Fig. 1).

2.1.1 One-Dimension Nanoparticles

One-dimensional system, like thin film or fabricated surfaces, has been used for
decagon in electronics, chemistry, and engineering. Fabrication of thin films (sizes
1–100 nm) or monolayer is now ordinary place with in the area of solar cells or
catalysis. These thin films are using in several technological applications, including
information storage systems, chemical and biological sensors, fiber-optic systems,
magneto-optic, and optical device [5].

Identification, security and logistics

Diagnostics
Biomedical nanodevice
Batteries with high Bio-nanosensors
energy-storage Biodetecion of pathogens

Disinfection

Drug screening
Advance
technologies NANOTECHNLOGY
medical imaging

Controlled
drug delivery
Drug targeting

Medical implants Nanomedicine

Tissue engineering
Nanocoating
Identification, security and logistics

Fig. 1 Applications of nanotechnology

Treatment of Cancer Using Combination of Herbal and Novel Drug Delivery System 1179

2.1.2 Two-Dimension Nanoparticles

Carbon Nanotubes (CNTs)

Carbon nanotubes are hexagonal network of carbon atoms, 1 nm in diameter and
100 nm in length, as a layer of graphite rotated up into cylinder. CNTs are of two
types, single-walled carbon nanotubes (SWCNTs) and multiwalled carbon nano-
tubes (MWCNTs). The minute dimensions of carbon nanotubes, mingled with their
wonderful physical, mechanical, and electrical properties, make them distinctive
materials [5]. They dispose metallic or semi conductive properties, depending on
how the carbon leaf is wound on as such. The present density that nanotubes can
carry is exceptionally high and can extend one billion amperes per square meter
producing it a superconductor. The mechanical strength of carbon nanotubes is sixty
times notable than the best steels. Carbon nanotubes have a great volume for molec-
ular absorption and contributing a three-dimensional configuration. Additionally,
they are chemically very stable [6].

2.1.3 Three-Dimension Nanoparticles

Fullerenes (Carbon 60)

Fullerenes are spherical cages carrying from 28 to along with 100 carbon atoms,
hold C60. This is a hollow ball composed of associated carbon pentagons and hexa-
gons, resembling a soccer ball. Fullerenes are grade of materials displaying distinc-
tive physical properties. They can be subjected to maximal pressure and recover
their original shape when the pressure is delivered. These molecules do not merge
with each other, thus giving them considerable potential for approach as lubricants
[7]. They have compelling electrical properties and it has been recommended to use
them in the electronic field, ranging from data depot to production of solar cells.
Fullerenes are contributing potential application in the wealthy area of nanoelec-
tronics. Afterwards fullerenes are vacant structures with dimensions alike to several
biological active molecules; they can be packed with divergent substances and find
probable medical application [8].

2.2 Polymeric Nanoparticles

Polymeric nanoparticles (PNPs) are shapes with a diameter fluctuating from 10 to

100 nm. The PNPs are acquired from synthetic polymers, such as poly- £- caprolac-
tone, polyacrylamide, and polyacrylate or natural polymers, e.g., albumin, DNA,
chitosan, gelatine. Based on in vivo behavior, PNPs may be assorted as biodegrad-
able, i.e., poly(L- lactide) (PLA), poly-glycoside (PGA), and nonbiodegradable,
e.g., polyurethane. PNPs are traditionally coated with nonionic surfactants in order
to diminish immunological interactions (e.g., opsonization or presentation PNPs to
CD8 T-lymphocytes) as well as intermolecular interactions between the surface
1180 N. Kale

chemical class of PNPs (e.g., van der Waals forces, hydrophobic interlinkage or
hydrogen bonding) [9].
Drugs can be crippled on PNPs surface after a polymerization reaction or can be
enclosed on PNP structure during a polymerization step. Furthermore, drugs may be
rescued by desorption, dispersal, or nanoparticle erosion in target tissue [10].
The application of biodegradable nanosystems for the enlargement of nanomedi-
cines is one of the most victorious ideas. Nanocarriers contained of biodegradable
polymers experience hydrolysis in the body, construct biodegradable metabolite
monomers, such as lactic acid and glycolic acid [11]. Negligible systemic toxicity
is correlated with using of PLGA for drug transportation or biomaterial applica-
tions. Such nanoparticles are biocompatible with tissue and cells. Drug-­
biodegradable polymeric nanocarrier combined used for drug delivery is secure in
blood, nontoxic, and nonthrombogenic [12].

3 Preparation of Nanoparticles

The belongings of PNPs have to be developed depending on the particular applica-

tion. In order to accomplish the properties of interest, the way of preparation plays
a crucial role. Thus, it is extremely advantageous to have preparation techniques at
hand to obtain PNPs with the desired properties for a particular application. Distinct
techniques like polymerization, preformed polymers or ionic gelation, etc., are
used. The selection of suitable method for the production of nanoparticles depends
on the physicochemical nature of the polymer and the drug to be packed. The key
manufacturing processes of nanoparticles from preformed polymer are described in
the following sections [13].

3.1 Emulsion-Solvent Evaporation Method

This is one of the most commonly used methods for the preparation of nanoparti-
cles. Solvent evaporation was the first technique developed to formulate PNPs from
a solvent. In this technique, polymer solutions are prepared in volatile solvents and
emulsions are formulated. In the past, dichloromethane and chloroform preformed
polymer were extensively used, but are now restored with ethyl acetate which has a
stronger toxicological profile [14]. The emulsion is transformed into a nanoparticle
suspension on evaporation of the solvent for the polymer, which is granted to diffuse
along the continuous phase of the emulsion. In the conventional methods, two main
strategies are being used for the formation of emulsions, the preparation of single-
emulsions, e.g., oil-in-water (o/w) or double-emulsions, e.g., (water-in-oil)-in-
water, (w/o)/w. These methods utilize high-speed homogenization or ultrasonication,
followed by evaporation of the solvent, either by continuous magnetic stirring at
room temperature traditional or under decrease pressure [15]. Subsequently, the
Treatment of Cancer Using Combination of Herbal and Novel Drug Delivery System 1181

solidified nanoparticles can be collected by ultracentrifugation and cleaned with

distilled water to separate additives such as surfactants. Ultimately, the product is
lyophilized. Lemoine repaired PLGA nanoparticles of about 200 nm by utilizing
dichloromethane 1.0% (w/v) as the solvent and PVA or Span 40 as the stabilizing
agent. Nanoparticles of PLGA with a classic particle size of 60–200 nm by utilizing
dichloromethane and acetone (8:2, v/v) as the solvent system and PVA as the stabi-
lizing agent [16] (Fig. 2).

3.2 Salting- Out Method

Salting-out ground on the detachment of a water mixable solvent from watery solu-
tion via a salting-out effect. Salting-out is based on the separation of a water mis-
cible solvent from aqueous solution via a salting-out effect. Polymer and drug are
initially diffused in a solvent which is eventually emulsified into an aqueous gel
carrying the salting-out agent (electrolytes, like magnesium chloride and calcium
chloride, or nonelectrolytes like sucrose) and a colloidal stabilizer like poly vinyl
pyrrolidone or hydroxyl ethyl cellulose [17]. This oil/water emulsion is diluted with
a sufficient volume of water or aqueous solution to increase the diffusion of solvent
into the aqueous phase, thus influencing the formation of nanospheres. Various
manufacturing parameters can be diversified including stirring rate, internal/exter-
nal phase ratio, concentration of polymers in the organic phase, variety of electro-
lyte concentration, and type of stabilizer in the aqueous phase. This technique used
in the preparation of PLA, poly (methacrylic) acids, and ethyl cellulose nanospheres
shows high productivity and is easily scaled up. Salting-out does not need an
increase of temperature and consequently may be functional when heat-sensitive
substances have to be prepared. The considerable disadvantages are absolute
application to lipophilic drug and the considerable nanoparticles washing steps [18]
(Fig. 3).

Fig. 2 Schematic representation of the solvent-evaporation technique

1182 N. Kale

Fig. 3 Schematic representation of the salting-out technique dialysis

3.3 Emulsion-Diffusion Method

This is another extensively used method to prepare nanoparticles. The encapsulat-

ing polymer is dissolved in a moderately water-miscible solvent (such as propylene
carbonate, benzyl alcohol), and soaked with water to ensure the starting thermody-
namic equilibrium of both liquids. Eventually, the polymer-water-soaked solvent
phase is emulsified in an aqueous solution containing stabilizer, major to solvent
diffusion to the outer side phase and the generation of nanospheres or nanocapsules,
according to the oil-to-polymer ratio. Finally, the solvent is break by evaporation or
filtration, according to its boiling point. This technique grants several advantages,
such as high encapsulation productivities (generally 70%), no need for homogeniza-
tion, high batch-to-batch reliability, ease of scale-up, clarity, and small size distribu-
tion [19]. Disadvantages are the high volumes of water to be removed from the
suspension and the ejaculation of water-soluble drug into the soaked-aqueous exter-
nal phase throughout emulsification, diminishing encapsulation efficiency. Several
drug-stacked nanoparticles were prepared by the technique, including mesotetra
(hydroxyphenyl) porphyrin-stacked PLGA (p- THPP) nanoparticles doxorubicin-­
loaded PLGA nanoparticles, and cyclosporine (cy-A-); loaded sodium glycolate
nanoparticles [20] (Fig. 4).

3.4 Solvent Displacement/Precipitation Method

Solvent displacement involves the precipitation of a preformed polymer from an

organic solution and the diffusion of the organic solvent in the aqueous medium in
the presence or absence of surfactant. Polymers, drug, and or lipophilic surfactant
Treatment of Cancer Using Combination of Herbal and Novel Drug Delivery System 1183

Fig. 4 Schematic representation of the emulsification/solvent diffusion technique

Fig. 5 Schematic representation of the nanoprecipitation technique. Surfactant is optional

are dissolved in a semipolar water-miscible solvent such as acetone or ethanol. The

solution is then poured or injected into an aqueous solution containing stabilizer
under magnetic stirring. Nanoparticles are formed instantaneously by the rapid sol-
vent diffusion [21].
The solvent is then removed from the suspensions under reduced pressure. The
rates of addition of the organic phase into the aqueous phase affect the particles size.
It was observed that a decrease in both particles size and drug entrapment occurs as
the rate of mixing of the two phase increases. Nanoprecipitation method is well
suited for most of the poorly soluble drugs. Nanospheres’ size, drug release, and
yield were shown to be effectively controlled by adjusting preparation parameters.
Adjusting polymer concentration in the organic phase was found to be useful in the
production of smaller sized nanospheres through restricted to a limited range of the
polymer to drug ratio [22] (Fig. 5).
1184 N. Kale

4 Characterization of Nanoparticles

Nanoparticles are mainly characterized by their size, morphology, and surface

charge, utilizing such latest microscopic techniques as scanning electron micros-
copy (SEM), transmission electron microscopy (TEM), and atomic force micros-
copy (AFM). The standard particle diameter, their size distribution, and charge
influence the physical stability and the in vivo distribution of the nanoparticles.
Electron microscopy techniques are very beneficial in establishing the general shape
of polymeric nanoparticles, which may regulate their toxicity. The surface charge of
the nanoparticles influences the physical stability and again solvable of the polymer
dispersal as well as the in vivo performance [23, 24].

4.1 Particle Size

Particle size distribution and morphology are the principal parameters of assuming
of nanoparticles. Morphology and size are dignified by electron microscopy. The
vital application of nanoparticles is in drug release and drug targeting. It has been
found that particle size affects the drug release. Minute particles offer enormous
surface area. As a result, most of the drug stacked onto them will be disclose to the
particle surface directing to fast drug release. On the conflicting, drugs slowly dif-
fuse core huge particles. As a drawback, minute particles tend to aggregate during
storage and transportation of nanoparticle dispersion. Hence, there is a compromise
between a small size and maximum stability of nanoparticles. Polymer degradation
can also be affected by the particle size. For instance, the degradation rate of poly
(lactic-co-glycolic acid) was found to increase with increasing particle size in vitro
[25–27].
There are several tools for determining nanoparticle size as discussed below:
(a) Dynamic Light Scattering (DLS)
Currently, the quick and most popular method of regulating particle size is
photon-correlation spectroscopy (PCS) or dynamic light scattering (DLS). DLS
is widely used to dictate the size of Brownian nanoparticles in colloidal suspen-
sions in the nano and submicron ranges. Shining monochromatic light (laser)
toward a solution of spherical particles in Brownian motion causes a Doppler
shift when the light strikes the moving particle, changing the wavelength of the
arriving light. This change is connected to the size of the particle [28]. It is fea-
sible to extract the size distribution and offer a description of the particle is
shifting in the medium, estimating the diffusion coefficient of the particle and
using the auto connection function. The photon correlation spectroscopy (PCS)
represents the most regularly used technique for correct estimation of the par-
ticle size and size distribution based on DLS [29].
Treatment of Cancer Using Combination of Herbal and Novel Drug Delivery System 1185

(b) Scanning Electron Microscopy

Scanning electron microscopy (SEM) is giving morphological investigation
with direct visualization. The techniques based on electron microscopy offer
numerous advantages in morphological and sizing analysis; although, they pro-
vide restricted information with respect to the size distribution and true popula-
tion average [30]. For SEM characterization, nanoparticles’ solution must be
first transformed into a dry powder, which is then climbed on a sample holder
accompanied by coating with a conductive metal, such as gold, utilizing a sput-
ter coater. The sample is then scrutinized with a fascinated fine beam of elec-
trons [31]. The surface characteristics of the sample are acquired from the
secondary electrons released from the sample surface. The nanoparticles must
be able to resist vacuum, and the electron beam can destruct the polymer. The
mean size acquired by SEM is close with results obtained by dynamic light
scattering. Besides, these techniques are time absorbing, costly and frequently
need complementary information regarding sizing distribution [32].
(c) Transmission Electron Microscope
TEM employs on divergent principle than SEM, yet it repeatedly brings
same type of data. The sample preparation for TEM is compound and time
compelling because of its demand to be ultra-thin for the electron transmit-
tance. The nanoparticles’ dispersion is placed onto hold up mesh or films. To
make nanoparticles stand up to the instrument vacuum and smooth handling,
they are secured using again a negative staining material, like phosphotungstic
acid or by-product, uranyl acetate, etc., or by plastic submerging. Surrogate
method is to reveal the sample to liquid nitrogen temperatures later embedding
in lucid ice. The surface characteristics of the sample are acquired when a beam
of electrons are circulated across an ultra-thin sample, interchange with the
sample as it proceeds through [33].
(d) Atomic Force Microscopy
Atomic force microscopy (AFM) provides ultra-high aspiration in particle
size measurement and is located on a physical scanning of samples at sub-­
micron extent using a probe tip of atomic scale. Instrument contributes a topo-
graphical map of sample located on forces connecting the tip and the sample
surface. Samples are commonly scrutinized in contact or noncontact way
depending on their properties. In contact manner, the topographical map is cre-
ated by tapping the probe on to the surface beyond the sample and probe hovers
over the directing surface in noncontact manner. The central advantage of AFM
is its capacity to image nonconducting samples without any specific treatment,
thus permitting imaging of graceful biological and polymeric nano and micro-
structures. AFM furnishes the most precise description of size and size distribu-
tion and needed no mathematical treatment. Moreover, particle size obtained by
AFM technique furnishes actual picture which helps acknowledge the effect of
numerous biological conditions [34].
1186 N. Kale

4.2 Surface Charge

The nature and toughness of the surface charge of nanoparticles are extremely
important as it investigates their interlinkage with the biological environment as
well as their electrostatic correlation with bioactive hybrid. The colloidal stability is
examined through zeta potential of nanoparticles. This potential is a divergent esti-
mate of the surface charge. It corresponds to potential variation between the exter-
nal Helmholtz plane and the surface of shear. The measurement of the zeta potential
grants for predictions about the storage stability of colloidal dispersion. High zeta
potential values, likewise positive or negative, must be accomplished in order to
certify stability and avoid accumulation of the particles. The level of surface hydro-
phobicity can then be forecasted from the ethics of zeta potential. The zeta potential
can also contribute information concerning the nature of material enclosed within
the nanocapsules or coated onto the surface [35].

4.3 Surface Hydrophobicity

Surface hydrophobicity can be estimated by several techniques like hydrophobic

interaction chromatography, biphasic partitioning, adsorption of probes, contact
angle measurements, etc. Freshly, numerous sophisticated analytical techniques are
announced in literature for surface analysis of nanoparticles. X-ray photon associa-
tion spectroscopy grants the recognition of particular chemical groups on the sur-
face of nanoparticles [36].

5 There are Numerous Features that Nanotechnology are

Researching for Cancer Treatment Grounds,
as Following [37]

1. Enlarging the effectiveness of drug delivery and diminishing side effects, con-
sequently toxicity
2. Particular targeting of the dynamic components in cell/tissues
3. Boosting the properties of pharmacologically vital drugs like stability, solubil-
ity, half-life, and tumor accumulation
4. Producing stimuli-responsive drug deliver
5. Enlarging the area of drugs enclosed/connected to biomacromolecules like pro-
teins, mRNA
6. Development of therapeutic efficiency by delivering numerous active agents to
a fixed targeted site in order to conquer hindrance such as drug resistance
7. Overcoming biological hurdle
8. Enhancing the sensitivity of diagnosis and describing of tumorous sites
Treatment of Cancer Using Combination of Herbal and Novel Drug Delivery System 1187

9. Associating anticancer active elements with imaging molecules in order to

accomplish a concurrent assessment of the in vivo efficacy of the drugs
10. Expanding new lane for the production of synthetic vaccines
11. Enhancing cancer diagnosis and imaging with phase out medical gadget

6 Nanotechnology and Targeted Drug Delivery

The greatest instant smash of nanotechnologies in cancer therapy is in drug distribu-

tion. The therapeutic index of almost all drugs currently being used can be enhanced
if they are more adeptly delivered to their biological targets across suitable applica-
tion of nanotechnologies. Some drugs that have earlier undergone clinical trials
might also be reinvestigated using nanotechnological procedure. A number of hin-
drances may be conquering with several novel utilization of nano drug delivery. For
example, many drugs are not very soluble, making it difficult to administer thera-
peutic doses. These blends can be “solubilized” by producing them into crystalline
nano suspensions that are balanced by surfactants, or by consolidating them with
organic or lipid nanoparticles that retain them in circulation for prolonged periods.
If a successful compound has a short half-life in the circulation, its stability can be
enhanced enormously by encasing it within nanosized liposomes as a drug carrier.
In the case of central nervous system cancers, countless drugs have strain in cross-
ing the blood–brain barrier to strike the tumor. This barrier can be breached by drug-
loaded nanoparticles, which have been shown to significantly boost the therapeutic
concentrations of anticancer medicines in brain tumors [38].
The best means to expand the potency and reduce the toxicity of a cancer drug is
to straight the drug to its target and continue its concentration at the site for an
adequate time for therapeutic activity to take outcome. For example, lipid cationic
nanoparticles to an integrin-targeting ligand were appeared to deliver genes scrupu-
lously to antigenic blood vessels in tumor-carrying mice. As the therapeutic seg-
ment of the nanocomplex, a mutant RAF gene was integrated to the particle for
transfection and apprehension in the tumor cells; apprehension of this mutant gene
was emerged to block angiogenesis in this model. The directed nanoparticle caused
apoptosis in the tumors and a sustained regression of established primary and meta-
static tumors. The efficiency of drug delivery to many parts of the body is directly
contrived by particle size. Nanostructure-mediated drug delivery, a key technology
for the realization of nanomedicine, has the potential to enhance drug bioavailabil-
ity, upgrade the timed release of drug molecules, and entitle correctness drug target-
ing. Nanoscale drug delivery systems can be accomplished within pulmonary
remedies, as gene delivery direction, and in stabilization of drug molecules that
would or else deteriorate very rapidly. Ancillary advantages of using targeted
nanoscale drug conveyor are diminished drug toxicity and more systemic drug dis-
tribution [38, 39].
1188 N. Kale

7 Mechanisms of Drug Release

The polymeric drug conveyor delivers the drug at the tissue site by any one of the
three common physicochemical mechanisms.
• By the swelling of the polymer nanoparticles by hydration accompanied by
release across diffusion
• By an enzymatic reaction arising in rupture or cleavage or debasement of the
polymer at site of delivery, thereby liberating the drug from the captured
inner core
• Segregation of the drug from the polymer and its adsorption/rescue from the
swelled nanoparticles [40]
Advantages of nanostructure-moderated drug delivery comprise the capacity to
deliver drug molecules directly into cells and the capacity to target tumors within
healthy tissue. Nanoscale drug delivery architectures are able to puncture tumors
due to the discontinuous, or “porous,” nature of the tumor microvasculature, which
usually contains pores ranging from 100 to 1000 nm in diameter. The microvascu-
lature of healthy tissue ranges by tissue type, but in most tissues comprising the
heart, brain, and lung, there are compact intercellular junctions less than 10 nm.
Through accurate control of the drug conveyor architecture, the liberate of the drug
can be adjusted to accomplish a wished kinetic profile. Three of the most ordinary
kinetic profiles are zero order, first order, and Higuchi [41, 42].
The delivery of most drugs is accomplished through oral administration or by
injection and follows first-order kinetics. The absolute release profile for most drugs
would observe a steady liberation rate so that the drug levels in the body remain
continuous while the drug is being administered. Further current transdermal drug
delivery process follows the Higuchi model. As shown eventually, nanostructured
polymeric and silica nanoparticles are being enlarged as drug carriers, which
accomplished near zero-order kinetics [43].

Zero order : Dt  D0  K 0t

First order : ln Dt  ln D0  K1t

=
Higuchi order : Dt D=
0 KHt1 / 2

where Dt is the amount of drug released at time t, D0 is the initial amount of drug
released, result of initial quick release,
k0 is the zero-order release constant,
k1 is the first-order release constant, and
kH is the Higuchi release constant.
Liposomes (phospholipid spheres of ~100 nm in diameter that are bi-layered in
shape) are outstanding carriers for a diversity of drugs and are being examined enor-
mously for use in gene remedy protocols and targeted drug delivery in cancer. With
Treatment of Cancer Using Combination of Herbal and Novel Drug Delivery System 1189

Fig. 6 Drug release profiles from zero-order, first-order, and Higuchi kinetics

present liposome technologies, it is not tough to transfect a cell for grounds of gene
therapy, but the therapeutic gene may be deteriorating if it is not able to traffic out
of the endosome [44]. To upgrade the efficacy of gene therapy, synthetic pH-­
sensitive histidylated oligolysine can be attached to a drug-liposome complex to
support in escaping from the endosome. This protocol was appeared to enhance the
transfection efficiency in recumbent and pancreatic cancer cell lines by 39 times,
and upraised the manner of the transgene in a human prostate cancer xenograft
model in athymic nude mice without increasing toxicity [45]. Nanoparticles attached
to chemotherapeutic drugs allow them to traverse the blood–brain barrier for brain
tumor treatment. In January 2005, a nanoparticle-based drug called Abraxane
(paclitaxel protein-bound particles, Abraxis Oncology) was approved by the Food
and Drug Administration for breast cancer treatment. Abraxane uses nanoscale par-
ticles of the natural protein albumin that can be delivered in the body without the use
of solvents [46, 47] (Fig. 6).

8 Nanomedicine and New Drug Therapies for Cancer

All drug molecules are, in essence, products of natural or synthetic nanoengineer-

ing. For example, the most widely used and effective drug, the common aspirin, is
only about 0.6 nm. On the “large” side are therapeutic monoclonal antibodies that
are approximately 30 nm in length. Many of the globular proteins, such as hemoglo-
bin, are 5 nm in diameter, and natural proteins of similar size may be used as a thera-
peutic. Double-stranded DNA in the nucleus is about 2.5 nm in width, but totals 2
meters in length in the mammalian cell, an astounding example of “Nano packing”
in a 2- to 5-μm diameter nucleus [48].
1190 N. Kale

Medicinal and structural chemists have been creating and manipulating nanome-
ter and sub nanometer-sized components of drugs for decades, and will continue to
do so into the fore salable future. The difference is that they will now be joined by
a wide variety of scientists from a number of disciplines normally not involved in
drug research [49].
A recent article written by physicists in Physical Review Letters [50], titled
“Electronic Structure and Bonding of Au on a Si Oh, not zero 2 Cluster: A Nano
bullet for Tumours,” is a good example of how research from diverse sources can
and should be brought to bear on the problem of cancer. Success in this endeavor,
however, will require a concerted effort to integrate and coordinate the research in
an approach that might now be described as “systems biology” [51, 52].

9 Requirements for an Effective and Safe Cancer Drug

There must be an adequate drug concentration in the body to allow for an effective
dose at the tumor site. The target must be strongly inhibited, with the target’s func-
tion essential for tumor cell viability. The drug must have a high differential toxicity
toward the tumor or a favorable therapeutic window [53].
Research in nanomedicine will be addressing all these points, and a few exam-
ples in the drug development arena will be given below.
Monoclonal antibodies will be an essential component of the new wave of cancer
treatments developed through nanotechnologies. They are being used as imaging
vehicles, for drug targeting, as drug carriers, and as the drug itself. There are nine or
more FDA-approved antibodies approved for clinical use in cancer, and many more
are being evaluated in clinical trials [54]. The mechanism of action of the antibodies
includes receptor ligand-binding competition; interference with receptor function;
antibody-dependent, cell-mediated cytotoxicity; complement-dependent cellular
cytotoxicity; or, perhaps, a combination of the above. This activity can also be com-
bined with toxins directed at the cancer cell to produce an even more efficacious
drug [55]. One of the holy grails of drug research is to be able to rationally design
and produce effective small-molecule inhibitors of protein function. Development
of many drugs will be the result of application of nanotechnologies that have been
in place for many years. For example, nuclear magnetic resonance and x-ray crystal
structures of target proteins and their ligands or substrates are being used as the
template for rational design of new drugs. The target may be enzymes or receptor–
ligand proteins [56]. Inhibitors of enzymatic activity are, in general, easier to design
than blockers of protein–protein interactions. As an example, the first successful
drug approved for the treatment of chronic myeloid leukemia (CML), Gleevec-, is
an inhibitor of the tyrosine kinase mutant, BCR-ABL [57] (Table 1).
In many patients, administration of the drug results in what appears to be com-
plete remission, but Gleevec-resistant leukemia often returns through mutations in
Treatment of Cancer Using Combination of Herbal and Novel Drug Delivery System 1191

Table 1 Various plants used for the treatment of cancer [64]

S.No. Name of Plant Family Active Constituents Predicted Mode of Action
1 Aglaia Meliaceae Bisamide alkaloids Bisamide alkaloids of the
roxburghiana leaves exhibit anticancer
Miq. Hiern activity (by inhibiting the
growth of vinblastine-­
resistant KB cells).
2 Bauhinia Caesalpiniaceae Octacosane, beta-­ Beta-amyrin exhibited
racemosa amyrin, and significant anticancer activity
Lamk betasitostero against Hep-G2 cancer with
IC50 values of 25 μM. The
anticancer effects were
attributed to induction of
apoptosis and G2/M cycle
arrest in a dose-dependent
manner. Moreover,
beta-amyrin could also
activate the p38 and JNK
signaling pathways.
3 Caesalpinia Caesalpiniaceae Flavonoid, Flavonoids have been shown
pulcherrima myricitroside to possess a wide variety of
Sw. anticancer effects: they
modulate reactive oxygen
species (ROS)-scavenging
enzyme activities, participate
in arresting the cell cycle,
induce apoptosis, autophagy,
and suppress cancer cell
proliferation and
invasiveness.
4 Cocculus Menispermaceae Bisbenzylisoquinoline Exert the anticancer activity
hirsutus alkaloids through enhanced ROS
(Linn.) Diels. generation, activation of
MAP kinases, followed by
induction of autophagy and
apoptotic cell death.
5 Corchorus Tiliaceae Cardenolides, The cardenolide glycoside
aestuans beta-sitosterol acovenoside A interferes
Linn. with epidermal growth factor
receptor trafficking in
nonsmall cell lung cancer
cells. Cardenolide glycosides
are natural compounds
known to inhibit the ion
pumping function of the
Na+/K + -ATPase in cellular
systems.
(continued)
1192 N. Kale

Table 1 (continued)
S.No. Name of Plant Family Active Constituents Predicted Mode of Action
6 Luffa Cucurbitaceae Pentacyclic triterpene, Induces apoptosis by using
cylindrica bryonolic acid the mitochondrial pathway
(Linn.)M. J. rather than through the cell
Roem. cycle in ovarian cancer cell
line MDAH-2774. Cell
invasion, migration, and
colony formation capacity in
ovarian cancer cells were
reduced. Cell death was
induced by increasing
oxidative stress process in
ovarian cancer cells.
7 Symplocos Symplocaceae. Betulinic, oleanolic, The ellagic acid in the
racemosa acetyl oleanolic, and MDA-MB-231 cells showed
Roxb. ellagic acids significant antiproliferative
effects with dose-dependent
pattern. The antiproliferative
effects in MCF-7 cells were
observed in only at a high
concentration. Ellagic acid
had no effect on the cell
cycle in both breast cancer
cells.
8 Camellia Theaceae Theophylline and At micromolar
sinensis theobromine, concentrations, kaempferol
(Linn.) quercetin, kaempferol effectively inhibits the
O. Kuntze. growth of breast cancer cell
lines (VM7Luc4E2, MDA-
MB-231, MCF-7)
9 Coix Gramineae; Palmitoleic and Trans-vaccenic acid inhibits
lacryma-jobi Poaceae vaccenic acids proliferation and induces
Linn. apoptosis of human
nasopharyngeal carcinoma
cells via a mitochondrial-­
mediated apoptosis pathway.
10 Crocus Iridaceae Crocin The administration of crocin
sativus Linn. leads to inhibition of cell
proliferation and also
induction of apoptosis in the
cancer cells. Crocin also
inhibits Nf-kB in
hepatocytes, suppresses S
and G2/M phases of the cell
cycle, induces apoptosis, and
down-regulates inflammation
in HepG2 cells.
(continued)
Treatment of Cancer Using Combination of Herbal and Novel Drug Delivery System 1193

Table 1 (continued)
S.No. Name of Plant Family Active Constituents Predicted Mode of Action
11 Heliotropium Boraginaceae Indicine-Noxide Phase II studies in all panel
indicum Linn. tumors are indicated,
especially colon carcinoma
and leukemias.
12 Linum Linaceae Secoisolariciresinol Has been shown to inhibit
usitatissimum diglycoside the growth of established
Linn. human breast tumors.
13 Pastinaca Umbelliferae; Coumarins Coumarin derivatives are
sativa Linn. Apiaceae ubiquitous in nature and can
readily interact with diverse
enzymes and receptors in
cancer cells via weak bond
interactions; hence, coumarin
is a highly privileged
pharmacophore for the
development of novel
anticancer agents.
14 Plumbago Plumbaginaceae Naphthoquinone The cytotoxicity of
zeylanica derivatives, plumbagin 1,4-naphthoquinones is
Linn. related to their electron-­
accepting capability, which
gives rise to ROS production
leading to DNA damage and
cancer cell apoptosis.
15 Solanum Solanaceae Beta-solamarine Induced apoptosis of these
trilobatum cells by PS externalization in
Linn. a dose-dependent manner
and increased sub-G1
fraction were observed.
Quenching of the expression
of tumor necrosis factor
receptors (TNFRs) during
the progress of human lung
carcinogenesis has been
previously reported.
16 Taxus baccata Taxaceae Diterpene amide Diterpenoid amides may be
Linn. useful in the apoptosis
induction of human leukemia
cancer cells.
17 Vinca rosea Apocynaceae Vincristine Vincristine is a
Linn. chemotherapy drug that
belongs to a group of drugs
called vinca alkaloids.
Vincristine works by
stopping the cancer cells
from separating into two new
cells. So, it stops the growth
of the cancer.
(continued)
1194 N. Kale

Table 1 (continued)
S.No. Name of Plant Family Active Constituents Predicted Mode of Action
18 Catharanthus Apocynaceae Vinblastine and The antitumor activity of
roseus (L.) Vincristine vinblastine is thought to be
G. Don. due primarily to inhibition of
mitosis at metaphase through
its interaction with tubulin.
Vinblastine binds to the
microtubular proteins of the
mitotic spindle, leading to
crystallization of the
microtubule and mitotic
arrest or cell death.
19 Lycopersicon Solanaceae N-nitrosomorpholin Decreased serum lycopene
esculentum concentrations are associated
Mill. with an increased risk of
prostate cancer.
20 Symphytum Boraginaceae Allantoin Allantoin can ameliorate
officinale cisplatin-induced neurotoxic
Linn. insults to neurons. It
therefore shows promise as
an adjuvant drug in cancer
treatment.

the active site. By careful study of the mutations and the structure of the kinase, new
small molecular inhibitors were designed that could block the mutant strains and
appear to be more efficacious than the original drug [58]. The two drugs are reported
to work synergistically, which will, hopefully, result in a complete cure of chronic
myeloid leukemia. Drugs derived from nucleic acids are beginning to make an
impact on the nanomedicine scene. Antisense technology exploits the use of oligo-
nucleotides in the range of 15 to 20 nucleotides to block the function of an RNA
target [59]. This technology has made rapid progress after experiencing initial dif-
ficulties in showing efficacy for in vivo models of disease. Ongoing clinical trials
using antisense drugs include prostate, breast, pancreatic, lung, colorectal, mela-
noma, and brain cancers [60].
A novel approach for this technology is to use oligonucleotides for sensitizing
tumor cells to chemotherapy. The oligonucleotides are being combined with nano-
liposomes to target and deliver the nucleic acids to the cancer cells and block pro-
duction of the alpha folate receptor [61]. This block was shown to decrease cell
survival of breast cancer cell lines, and sensitized a cell line by fivefold to doxoru-
bicin. This is a good example of how nanotechnologies can be used to increase the
effectiveness of existing drugs, facilitating the use of lower dosages to decrease
toxicity [62, 63].
Treatment of Cancer Using Combination of Herbal and Novel Drug Delivery System 1195

References

1. Hahens WI, Oomen AG, de Jong WH, Cassee FR (2007) What do we (need to) know about
the kinetic properties of nanoparticles in the body? Regulatory Toxicol Pharmacol 49:217–229
2. Couvreur P, Dubernet C, Puisieux F (1995) Controlled drug delivery with nano particles:current
possibilities and future trends. Eur J Pharm Biopharm 41:2–13
3. Suri SS, Fenniri H, Singh B (2007) Nanotechnology-based drug delivery systems. J Occup
Med Toxicol 2:16
4. Hett A (2004) Nanotechnology: small matters, many unknown
5. Lachman L, Lieberman HA, Kanig JL (1999) Theory and practice of industrial pharmacy, 3rd
edn. Pharmaceutical Industry, pp 26–30
6. Tomalia DA (2004) Birth of a new macromolecular architecture: Dendrimers as quantized
building blocks for nanoscale synthetic organic chemistry. Aldrichimica Acta. 37(2):39–57
7. Wiener EC, Brechbiel MW, Brothers H, Magin RL, Gansow OA, Tomalia DA (1994)
Dendrimer-based metal chelates: a new class of magnetic resonance imaging contrast agents.
Magn Reson Med 31:1–8
8. Li Y, Cheng Y, Xu T (2007) Design, synthesis and potent pharmaceutical applications of gly-
codendrimers: a mini review. Curr Drug Discov Technol 4:246–254
9. Fu HL, Cheng SX, Zhang XZ, Zhuo RX (2007) Dendrimers/DNA complexes encapsulated in
a water-soluble polymer and supported on fast degrading star poly (DL-Lactide) for localized
gene delivery. J Control Release 124:181–188
10. Cheng Y, Wang J, Rao T, he X., Xu T. (2008) Pharmaceutical Applications of Dendrimers:
promising nanocarriers for drug delivery. Front Biosci 13:1447–1471
11. Mecke A, Uppuluri S, Sassanella TM, Lee DK, Ramamoorthy A, Baker JR Jr (2004) Direct
observation of lipid bilayer disruption by poly (amidoamine) dendrimers. Chem Phys Lipids
132:3–14
12. Larson DR, Zipfel WR, Williams RM, Clark SW, Bruchez MP, Wise FW (2003) Water-soluble
quantum dots for multiphoton fluorescence imaging in vivo. Science 300:1434–1436
13. Ghosh PK (2000) Hydrophilic polymeric nanoparticles as drug carriers. Indian J Biochem
Biophys 37:273–282
14. Prasad Rao J, Geckeler KE Polymer nanoparticles: preparation techniques and size control
parameters, progress in polymer science G model. J Pharm Pharmaceut Sci 674
15. Reis CP, Neufeld RJ, Ribeiro AJ, Veiga F, Nanoencapsulation I (2006) Methods for prepara-
tion of drug-loaded polymeric nanoparticles. Nanomed Nanotechnol Biol Med 2:8–21
16. Lemoine D, Preat V (1998) Polymeric nanoparticles as delivery system for influenza virus
glycoproteins. J Control Release 54:15–27
17. Song CX, Labhasetwar V, Murphy H, Qu X, Humphrey WR, Shebuski RJ et al (1997)
Formulation and characterization of biodegradable nanoparticles for intravascular local drug
delivery. J Control Release 43:197–212
18. Catarina PR, Ronald JN, Antonio JR (2006) Nano capsulation 1. Method of preparation of
drug – loaded polymeric nanoparticles: nano technology. Biol Med 2:8–21
19. Allemann E, Gurny R, Doekler E (1993) Drug-loaded nanoparticles preparation methods and
drug targeting issues. Eur J Pharm Biopharm 39:173–191
20. Quintanar-Guerrero D, Allemann E, Fessi H, Doelker E (1998) Preparation techniques and
mechanism of formation of biodegradable nanoparticles from preformed polymers. Drug Dev
Ind Pharm 24:1113–1128
21. Jung T, Kamm W, Breitenbach A, Kaiserling E, Xiao JK, Kissel T (2000) Biodegradable nano
particles for oral delivery of peptides: is there a role for polymer to affect mucosal uptake? Eur
J Pharm Biopharm 50:147–160
22. Vargas A, Pegaz B, Devefve E, Konan-Kouakou Y, Lange N, Ballini JP (2004) Improved pho-
todynamic activity of porphyrin loaded into nano particles: an in vivo evaluation using chick
embryos. Int J Pharm 286:131–145
1196 N. Kale

23. Yoo HS, Oh JE, Lee KH, Park TG (1999) Biodegradable nanoparticles containing PLGA con-
jugates for sustained release. Pharm Res 16:1114–1118
24. El-Shabouri MH (2002) Positively charged nano particles for improving the oral bioavailabil-
ity of cyclosporine-a. Int J Pharm 249:101–108
25. Chorney M, DAneuberg H, Golomb G (2002) Lipophilic drug-loaded nanospheres by nano
precipitation: effect of the formulation variables on size, drug recovery and release kinetics. J
Control Releas E 83:389–400
26. Betancor L, Luckarift HR (2008) Trends Biotechnol 26:566
27. Venkatesan P, SreeJanardha Nan V, Muralidharan C, Valliappan K (2012) Improved HPLC
method with the aid of chemometric strategy: determination of loxoprofen in pharmaceutical
formulation. Acta Chim Slov 59:242–248
28. Venkatesan P, Manavalan R, Valliappan K Preparation and evaluation of sustained release
loxoprofen-loaded microspheres. J Basic Clin Pharm
29. De Assis DN, Mosqueira VC, Vilela JM, Andrade MS, Cardoso VN (2008) Release profiles
and morphological characterization by atomic force microscopy and photon correlation spec-
troscopy of 99 m technetium – fluconazole nanocapsules. Int J Pharm 349:152–160
30. Molpeceres J, Aberturas MR, Guzman M (2000) Biodegradable nanoparticles as a delivery
system for cyclosporine: preparation and characterization. J Microencapsul 17:599–614
31. Venkatesan P et al (2011) Int J Pharm Biomed Res (IJPBR) 2(3):107–117
32. Sathiya Sundar R, Murugesan A, Venkatesan P, Manavalan R (2010) Formulation development
and evaluation of carprofen microspheres. Int J Pharm Tech Res 2(3):1674–1676
33. Soppinath KS, Aminabhavi TM, Kulkurni AR, Rudzinski WE (2001) Biodegradable poly-
meric nanoparticles as drug delivery devices. J Control Release 70:1–20
34. Polakovic M, Gorner T, Gref R, Dellacherie E (1999) Lidocaine-loaded biodegradable nano-
spheres. II. Modelling of drug release. J Control Release. 60:169–177
35. Pangi Z, Beletsi A, Evangelatos K (2003) PEG-ylated nanoparticles for biological and phar-
maceutical application. Adv Drug Del Rev 24:403–419
36. Scholes PD, Coombes AG, Illum L, Davis SS, Wats JF, Ustariz C, Vert M, Davies MC (1999)
Detection and determination of surface levels of poloxamer and pva surfactant on biodegrad-
able nanospheres using SSIMS and XPS. J Control Release 59:261–278
37. Shi J, Kantoff PW, Wooster R, Farokhzad OC (2016) Cancer nanomedicine: Progress, chal-
lenges and opportunities. Nat Rev Cancer 17:20. [CrossRef] [PubMed]
38. Sahoo SK et al (2003) Nanotech approaches to drug delivery and imaging. Drug Discov Today
8:1112–1120
39. Vasir JK et al (2005) Nanosystems in drug targeting: opportunities and challenges. Curr
Nanosci 1:47–64
40. Kipp JE (2004) The role of solid nanoparticle technology in the parenteral delivery of poorly
water-soluble drugs. Int J Pharm 284:109–122
41. Rabinow BE (2004) Nanosuspensions in drug delivery. Nat Rev Drug Discov 3:785–796
42. Horn D, Rieger J (2001) Organic nanoparticles in the aqueous phase-theory, experiment, and
use. Angew Chem Int Ed 40:4330–4361
43. Torchilin VP (2005) Recent advances with liposomes as pharmaceutical carriers. Nat Rev
Drug Discov 4:145–160
44. Wissing SA, Kayser O, Muller RH (2004) Solid lipid nanoparticles for parenteral drug deliv-
ery. Adv Drug Deliv Rev 56:1257–1272
45. Koziara JM et al (2004) Paclitaxel nanoparticles for the potential treatment of brain tumors. J
Control Release 99:259–269
46. Steiniger SC et al (2004) Chemotherapy of glioblastoma in rats using doxorubicin-loaded
nanoparticles. Int J Cancer 109:759–767
47. Brannon-Peppas L, Blanchette JO (2004) Nanoparticle and targeted systems for cancer ther-
apy. Adv Drug Delivery Rev 56:1649–1659
48. Hood JD et al (2002) Tumor regression by targeted gene delivery to the neovasculature.
Science 296:2404–2407
Treatment of Cancer Using Combination of Herbal and Novel Drug Delivery System 1197

49. Whitesides GM (2003) The “Right” size in nanobiotechnology. Nat Biotechnol 21:1161–1165
50. Sun Q, Wang Q, Rao BK, Jena P (2004) Electronic structure and bonding of au on a SiO2
cluster: a nanobullet for tumors. Phys Rev Lett 93:186803/1–186,803/4
51. Hood L, Heath JR, Phelps ME, Lin B (2004) Systems biology and new technologies enable
predictive and preventative medicine. Science 306(2004):640–643
52. Hood L, Perlmutter RM (2004) The impact of systems approaches on biological problems in
drug discovery. Nat Biotechnol 22:1215–1217
53. Kamb A (2005) Opinion: what’s wrong with our cancer models? Nat Rev Drug Discov
4:161–165
54. Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevaci-
zumab, an Anti- VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391–400
55. Groner HC, Wels W (2004) Therapeutic antibodies. Curr Mol Med 4:539–547
56. Von Eschenbach AC (2004) A vision for the national cancer program in the United States. Nat.
Rev. Cancer 4:820–828
57. Arkin MR, Wells JA (2004) Small-molecule inhibitors of protein-protein interactions: pro-
gressing towards the dream. Nat Rev Drug Discov 3:301–317
58. Brooijmans N, Kuntz ID (2003) Molecular recognition and docking algorithms. Annu Rev
Biophys Biomol Struct 32:335–373
59. Card GL, Blasdel L, England BP, Zhang C, Suzuki Y, Gillette Y (2005) A family of phos-
phodiesterase inhibitors discovered by cocrystallography and scaffold-based drug design. Nat
Biotechnol 23:201–207
60. Erlanson DA, Wells JA, Braisted AC (2004) Tethering: fragment-based drug discovery. Annu
Rev Biophys Biomol Struct 33:199–223
61. Lipinski C, Hopkins A (2004) Navigating chemical space for biology and medicine. Nature
432:855–861
62. Rees DC, Congreve M, Murray CW, Carr R (2004) Fragment-based lead discovery. Nat Rev
Drug Discov 3:660–672
63. Shoichet BK (2004) Virtual screening of chemical libraries. Nature 432:862–865
64. Khare CP (2007) Indian Medicinal Plants, Khare CP ed, Published by Springer,
pp. 103,115,163,165,171 &179
Anti-inflammatory Potential of Lead
Compounds and Their Derivatives
from Medicinal Plants

Nisha Sam Nirmala, Navina Bala Krishnan, Vaishnavi Vivekanandan,

and Krishnaraj Thirugnanasambantham

1 Introduction

Since the late eighteenth century, the inflammatory process has been reported as one
of the most attractive areas of epidemiology and pharmacy. The word inflammation
is derived from the Latin word “Inflammatio” which is a complex cascade of reac-
tions organized by immune cells, molecular mediators, etc. that tend to respond to
injurious agents which can be chronic or acute. The five classic hallmark signs of
inflammation include heat, pain, redness, swelling, and loss of function [1].
Inflammation starts with an acute reaction and enters into prolonged or chronic
phase when left untreated (Fig. 1). Chronic inflammation can lead to various conse-
quences including arthritis [2], asthma [3], atherosclerosis [4], autoimmune dis-
eases [5], diabetes [6], and cancer [7].
Over a decade, inflammatory diseases seem to represent a chief cause of morbid-
ity [8]. Current therapy for inflammatory diseases is majorly confined to the usage
of steroidal and nonsteroidal anti-inflammatory agents. The chronic use of these
drugs is reported to in turn cause severe adverse effects on gastrointestinal, cardio-
vascular, renal functions [9, 10]. These adverse effects of available anti-­inflammatory
drugs lead to the need for mandatory knowledge on molecular mechanism behind
inflammation and explore drugs or bioactive compounds with mere or no toxicity.
Natural sources such as plants and their phytochemicals, microbes/animals, and
their bioactive elements are found to be promising sources of new anti-­inflammatory

N. S. Nirmala (*) · N. B. Krishnan · V. Vivekanandan

Department of Biotechnology, School of Electrical and Communication, Vel Tech Rangarajan
Dr Sagunthala R&D Institute of Science and Technology, Chennai, Tamilnadu, India
e-mail: [email protected]
K. Thirugnanasambantham
Pondicherry Centre for Biological Science and Educational Trust, Sundararaja Nagar,
Puducherry, Puducherry, India

© The Author(s), under exclusive license to Springer Nature 1199

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_50
1200 N. S. Nirmala et al.

Fig. 1 Schematic illustration of the inflammation types and its characteristics

agents. Herbal medicine, Phytomedicine, and Siddha medicine are recently gaining
momentum throughout the world due to the fact that they are safe, effective, and
cheaper than conventional modern medicines. Herbs and plants have been used to
treat human diseases since ancient times. According to Rig Veda which dates back
to 4500–1600 BC, medicinal plants were used to treat many human ailments [11].
In modern medicine, more than 200 compounds of plant origin have been commer-
cialized. Plant parts such as roots (Withania somnifera), leaves (Aegle marmelos),
fruits (Morinda citrifolia), etc. are employed as source of medicines [12, 13]. Some
of the important bioactive compounds of plants include alkaloids, flavonoids, tan-
nins, and phenolic compounds [14]. These bioactive compounds also hold antidia-
betic, antibacterial, antithrombotic, hypotensive, anti-inflammatory, and anti-cancer
potential. Although various in vitro and in vivo models for anti-inflammatory drug
development are available, systematic evaluation of phytoconstituents can facilitate
the identification and development of potential anti-inflammatory lead molecules
from natural sources. This chapter focuses on typical inflammatory diseases, its
molecular targets, NSAIDs in current usage, advantages of plant lead compounds
over NSAIDs with primary focus on the herbal plants, phytochemical classes, and
lead molecules with potent anti-inflammatory potential.

2 Inflammatory Diseases

Inflammatory diseases include an array of diseases that cause inflammation in dif-

ferent parts of the human body. These include inflammatory bowel disease, osteoar-
thritis, asthma, etc. and have become one of the most significant causes of death
across the world. Treatment for any inflammatory disease can vary from physical
therapy to medications and/or surgery.
Anti-inflammatory Potential of Lead Compounds and Their Derivatives from Medicinal… 1201

2.1 Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a worldwide idiopathic inflammatory disease

that involves chronic inflammation of the digestive tract or the gastrointestinal tract
by abnormal immune response to gut microflora or other inflammatory stimulators
[15]. Important diagnosis for IBD may include colonoscopy, computerized tomog-
raphy, MRI, capsule endoscopy, and balloon-assisted endoscopy. Though IBD is
multifactorial which may include genetics [16] host [17] and environmental factors
[18, 19], a universal cause is not found. IBD includes two chronic diseases such as
ulcerative colitis (UC) and Crohn’s disease (CD). It affects people of all ages,
including children and geriatric populations, impacting all aspects of life. UC is
characterized by mucosal inflammation or superficial erosions on the colonic wall
associated with bleeding [20] while CD results in transmural ulceration of any por-
tion of the gastrointestinal tract (GI) from mouth to rectum. UC appears to be
equally present in both genders [21] whereas CD is slightly more common in
females compared to males [15]. Bloody diarrhea is the main characteristic symp-
tom of UC. The classic hallmarks of CD include abdominal pain, watery diarrhea,
and weight loss [22, 23]. The onset of CD ranges from 15 to 30 years [24].

2.2 Dermal Inflammatory Disease

Dermal inflammatory diseases are one among the inflammatory diseases that occur
in the skin and other dermal tissues. This disease may occur at three levels viz.,
epidermis, dermis, and subcutaneous layer. According to Brinster Classification
[25], dermal or skin inflammatory diseases are of eight types viz., bullous, interface,
nodular and diffuse, spongiotic, vasculitis, perivascular, panniculitis, and psoriasi-
form. In bullous pemphigoid inflammation, the immune system produces antibodies
to the fibers that connect the epidermis and the dermis. These antibodies trigger
inflammation that produces the blisters and itching of bullous pemphigoid [26]. In
case of psoriasiform, the condition resembles the psoriasis [27].

2.3 Neural Inflammatory Disease

Neural inflammatory diseases are caused by inflammation in the nervous system or

neuronal cells of the body [28]. It can be due to a pile of conditions including infec-
tion, traumatic brain injury [29], toxic metabolites or autoimmunity [30].
Inflammation in neural disease could either be acute or chronic.
Acute neural inflammation usually follows injury to the central nervous system
immediately and is characterized by release of inflammatory molecules, endothelial
cell activation, platelet deposition, and tissue edema [31]. It is typically
1202 N. S. Nirmala et al.

characterized by rapid activation of microglia [32, 33]. Chronic neural inflamma-

tion is the sustained activation of glial cells and recruitment of other immune cells
into the brain. Chronic inflammations are typically associated with neurodegenera-
tive diseases. Common causes of chronic neuroinflammation include toxic metabo-
lites, autoimmunity, aging, microbes, viruses, traumatic brain injury [34], and spinal
cord injury [35]. Sustained chronic neural inflammation leads to neurodegenerative
diseases such as Alzheimer’s disease [36] and Parkinson’s disease [37].

2.4 Dental Inflammatory Disease

Based on the location of oral mucosa, dental inflammations are classified as glos-
sitis, stomatitis, gingivitis, periodontitis or cheilitis. If deeper structures are involved,
it might be a phlegmon or abscess [38]. Glossitis is mean soreness of the tongue, or
more usually inflammation with depapillation of the dorsal surface of the tongue
(loss of the lingual papillae) [39, 40]. It can be acute or chronic. The term Stomatitis
is derived from the Greek word stoma meaning “mouth” and the suffix -itis meaning
“inflammation.” It refers to any inflammatory process affecting the mucous mem-
branes of the mouth and lips, with or without oral ulceration [41].
In early stages of gingivitis, the gums become swollen, red, and may bleed. It is
considered the main cause of tooth loss for adults worldwide [42, 43]. Later or seri-
ous form of gingivitis is called as periodontitis, where the gums can pull away from
the tooth, bone can be lost, and the teeth may loosen or fall out. Cheilitis are inflam-
mation in lips and may be acute or chronic inflammation with chapped lips [44].

2.5 Renal Inflammatory Disease

Inflammation is intimately linked to renal disease as a complex interaction network

between renal parenchymal cells, macrophages, and dendritic cells, resulting in the
recruitment of circulating monocytes, lymphocytes, and neutrophils. Renal inflam-
matory disease that affects renal function includes glomerulonephritis, membrano-
proliferative glomerulonephritis (MPGN), IgA nephropathy (Berger’s disease),
interstitial nephritis, pyelonephritis, etc., and can be caused by infections, autoim-
mune disorders, and environmental toxins [45].
Glomerulonephritis is a glomerular disease wherein the internal kidney struc-
tures mainly glomeruli, the primary units of renal filtration become inflamed [46].
It causes blood cells to leak from the blood into the urine. Glomerulonephritis can
be proliferative or nonproliferative [47]. Interstitial nephritis is inflammation of a
type of kidney cell called renal interstitium [48, 49]. It can lead to acute renal failure
or kidney disease [50]. Blood in the urine, swelling, weight gain, nausea, and fever
are some symptoms of interstitial nephritis [51]. Pyelonephritis is a urinary tract
infection that is characterized by the entry of bowel organisms into the urinary tract
Anti-inflammatory Potential of Lead Compounds and Their Derivatives from Medicinal… 1203

predominantly by bacteria [52]. Symptoms include blood and pus in the urine, pain
during urination, pain in back and sides, and urgent or infrequent urination [53, 54].
Renal inflammation can affect other organs besides the kidneys as part of an autoim-
mune disorder. Lupus erythematosus is one of the well-known renal inflammatory
diseases [55].

2.6 Respiratory Inflammatory Disease

Respiratory inflammatory diseases occur in the respiratory tract of the human body
could be either acute or chronic. Infection with pneumonia and acute respiratory
distress syndrome (ARDS) are taken into account as acute, whereas chronic inflam-
mation is represented by asthma and chronic obstructive pulmonary disease (COPD)
[56]. Some well-known examples for respiratory inflammation include sinusitis,
pharyngitis, epiglottitis, laryngotracheitis, and bronchitis. Sinusitis is known as the
inflammation of mucosal membrane that lines the sinuses [57]. Bronchitis is identi-
fied by the inflammation of bronchi, the airways of lungs. Symptoms of respiratory
inflammatory diseases include coughing, production of sputum, chest pain, and
shortness of breath. Epiglottitis is a condition wherein inflammation and edema of
epiglottis and neighboring structures such as arytenoids, aryepiglottic folds, and
vallecula occur that blocks the entry of air into lungs [58]. It is frequently caused by
the bacteria Haemophilus influenzae type B (HIB) in children [59].

3 Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are antianalgesic, antipyretic, and

anti-inflammatory agent that are FDA-approved class of drugs. They are used as the
common medications against muscle pain, dysmenorrhea, arthritic conditions,
pyrexia, gout, migraines, and are used as an opioid-sparing agent in certain acute
trauma cases [60]. Important classes of NSAIDs drugs are illustrated in the
Fig. 2 below.

3.1 Mechanism of Action

NSAIDs act by inhibiting the cyclooxygenase enzymes COX-1 and COX-2, thereby
blocking the synthesis of prostaglandins. COX-1 is constitutively expressed in
healthy cells and it is responsible for maintaining mucosal barrier in the GI tract,
renal hemostasis, and platelet aggregation whereas, COX-2 is expressed only during
pain and inflammation [60].
1204 N. S. Nirmala et al.

Fig. 2 Classification of NSAIDs based on structure and mode of action

Fig. 3 Molecular mechanism of action of NSAIDs

Tissue damage leads to the release of various cytokines, hormones, and other
substances which in turn activate phospholipase A2 (Fig. 3). As a result, arachidonic
acid is released from membrane lipids. The two cyclooxygenase isoforms COX-1
and COX-2 are required to convert the arachidonic acid into unstable, prostaglandin
G2 (PGG2) which is further converted to a more stable form, prostaglandin H2
Anti-inflammatory Potential of Lead Compounds and Their Derivatives from Medicinal… 1205

(PGH2) and releases prostaglandin, prostacyclin, and thromboxane. The release of

these eicosanoids leads to the cause of pain, inflammation, vasodilation, platelet
aggregation, and an increase in temperature. Thus, the pain, fever, and inflammation
are gradually blocked or get decreased by the therapeutic action of NSAIDs target-
ing COX [60, 61].

3.2 NSAIDs in Current Use

NSAIDs are keystone in therapy against chronic and acute pain. NSAIDs have anti-­
inflammatory, analgesic, and antipyretic activity, available in the parenteral, topical,
intramuscular, and rectal forms. Generally, after a minor or major surgery or tooth
extraction, most of the patients will suffer from postoperative pain through the gen-
eration of prostaglandins. NSAIDs are used to reduce pain and inflammation alone
or in combination with opioids, local analgesics, and or adjuvants [61]. Some of the
ailments /disease with recommended NSAIDs are tabulated (Table 1).

3.3 Disadvantages of NSAIDs

NSAIDs show a ceiling effect where the increase of dose increases only the side
effects but not the therapeutic effect [61]. Continuous use of NSAIDs leads to the
inhibition of prostaglandins and destroys the GI mucosal barrier, which leads to GI
bleeding [68]. People with asthma are easily prone to adverse effects of NSAIDs.
Diclofenac causes the majority of the NSAIDs-related cardiovascular side effects
[60]. COX-2 inhibitor shows very less side effects when compared to nonselective
COX inhibitor. Some of the major side effects of NSAIDs and its pathophysiologi-
cal conditions are tabulated (Table 2).

Table 1 List of nonsteroidal anti-inflammatory drugs (NSAID) in current usage

Name of the
ailment/disease Recommended NSAIDs References
Postsurgical dental pain Ibuprofen, naproxen sodium, diclofenac [62]
Postoperative pain Ibuprofen, naproxen, ketorolac, diclofenac, piroxicam, [61]
celecoxib
Chronic gout Naproxen, indomethacin [63]
Rheumatoid arthritis Aspirin, ibuprofen, etodolac, naproxen, celecoxib [64]
Migraine Ibuprofen, naproxen sodium, diclofenac potassium, [65]
indomethacin, flurbiprofen
Osteoarthritis Diclofenac [66]
Covid Diclofenac sodium, ibuprofen, ketoprofen [67]
1206 N. S. Nirmala et al.

Table 2 List of major side effects of NSAIDs and its pathophysiological conditions
Side effects Pathophysiology condition References
Renal side effects Fluid-electrolyte disorders [60]
Renal papillary necrosis [68]
Acute renal dysfunction
Interstitial nephritis
Renal vasoconstriction
Reduced renal perfusion
Hyperkalemia
Sodium retention and edema
Gastrointestinal side effects Dyspepsia [69]
Heartburn [68]
Peptic ulcers
GI bleeding
Gastroduodenal ulcers
Cardiovascular side effects Myocardial infarction [60]
Thromboembolic events [68]
Atrial fibrillation
Heart stroke
Elevated blood pressure and Hardening of arteries [70]
hypertension Electrolyte imbalance
Hepatotoxic side effects Acute liver failure [71]
Others Urticaria, skin, and pulmonary [60]
infections

4 Anti-inflammatory Potential of Plants

In contrast to the synthetic drugs that are grievous to human beings and the environ-
ment, herbal drugs are the symbol of safety as they are free from side effects, eco-­
friendly, and locally available. Plants produce phytochemicals as secondary
metabolites to protect themselves from the both biotic and abiotic factors. Medicinal
plants with lead bioactive compounds play an important role in curing various dis-
eases [72]. Extraction of bioactive metabolites from plant material is the most
important step in testing its biological activity. When a whole extract is used,
chances are more for the synergistic effect between the active compounds in com-
parison to the isolation of each component [73]. The common anti-inflammatory
phytoconstituents found in herbal plants are steroids, flavonoids, alkaloids, poly-
phenols, glycosides, terpenoids, curcumins, Gamma-linolenic acid (GLA), linear
aliphatic alcohols, phenolic diterpenes, etc. Different mechanisms have been
explored for the anti-inflammatory potential of various herbal plants [74] (Fig. 4).
Plant secondary metabolites are produced by three biosynthetic pathways - shiki-
mate, acetate-malonate, and acetate-mevalonate pathway [75].
Anti-inflammatory Potential of Lead Compounds and Their Derivatives from Medicinal… 1207

Fig. 4 Mechanism of anti-inflammatory action by plant phenolics

4.1 Advantages of Plant Lead Compounds Over NSAIDS

The enormous structural diversity of natural products (NP) and their medicinal sig-
nificance has led researchers to predict that screening natural resources will gener-
ate new lead compounds [76]. Although NSAIDs are extensively used as medication,
high doses can lead to GI, renal or liver abnormalities [8, 77] and other side effects
on human health whereas plant leads are with less toxicity or at safe levels [78].
Recurrence of symptoms is another major problem related to NSAIDs which falls
under synthetic drugs [79] but NPs are efficient and have a wide spectrum specific-
ity toward curing the disease [78]. Various research findings have proven the state-
ment [80, 81]. Thus, plant lead compounds are safe, efficacious, cost-effective, and
biocompatible alternatives to treat inflammatory diseases [82, 83] (Fig. 5).
Chemicals of plant origin can also serve as a basis for later pharmacological chemi-
cal modification to provide for drugs of improved specificity or potency compared
to NSAIDs [78].

5 Medicinal Plants with Anti-inflammatory Potential

Medicinal plants are a huge repository of biologically active compounds and can be
used to treat various diseases either as a crude material or as a pure compound [84].
1208 N. S. Nirmala et al.

Fig. 5 Advantages of phytochemicals over anti-inflammatory drugs

Curcuma longa (Zingiberaceae)

5.1 

Curcuma longa synthesis, an antioxidative yellow-colored pigment named as cur-

cumin [85]. Curcumin exhibits its anti-inflammatory activity by inhibiting cyclo-
oxygenase −2 (COX), Lipoxygenase (LOX), inducible nitric oxide synthase
(iNOS). Experiments on the anti-inflammatory properties of curcumin suggested
that it is very effective in treating irritable bowel syndrome (IBS) and rheumatoid
arthritis (RA), and it acts as a reducing agent in kidney transplant surgery to delay
graft rejection [86].

Garcinia mangostana Linn. (Guttiferae)

5.2 

Mangosteen, xanthones, α- and γ-mangostins are major bioactive compounds that

were reported from Garcinia mangostana. These metabolites are found to inhibit
cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS) and attenuate
the release of prostaglandin E2 (PGE2) [84].
Anti-inflammatory Potential of Lead Compounds and Their Derivatives from Medicinal… 1209

Harpagophytum procumbens (Pedaliaceae)

5.3 

Harpagophytum procumbens is commonly known as Devil’s Claw and are rich in

iridoid glycosides, acetylated phenolic glycosides, and terpenoids. H. procumbens’
metabolites inhibit the cyclooxygenase-2 activity and further decrease the synthesis
of leukotrienes, nitric oxide, tumor necrosis factor-α (TNF-α), interleukin-1β
(IL-1β), IL-6, and PGE2. Since the extract of H. procumbens are reported to induce
gastric acidity in certain patients, it is not recommended for all [87].

Phyllanthus polyphyllus Linn. (Euphorbiaceae)

5.4 

Phyllanthus polyphyllus is a small shrub with one benzenoid and three aryl naph-
thalide lignans-based metabolites with medicinal importance. It inhibits the produc-
tion of NO and main proinflammatory cytokines such as TNFα, IL-12. It is useful in
the treatment of asthma, rheumatoid arthritis, and septic shock [84].

Rosa canina (Rosaceae)

5.5 

Rosa canina is a small European shrub and galactolipid, a main metabolite of

R. canina that was reported to inhibit the chemotaxis of neutrophils. Linoleic and
alpha-linolenic acids extracted from R. canina inhibited cyclooxygenase-1 (COX-1)
and cyclooxygenase-2 (COX-2) activities under in vitro condition [88].

Olea europaea (Oleaceae)

5.6 

The polyphenolic extract of olive leaves inhibited COX-2 and suppressed the pro-
duction of a proinflammatory cytokine such as IL-6 and IL-1β [89]. The extra virgin
olive oil decreases the postprandial inflammatory response by reducing postprandial
lipopolysaccharide levels and diminishes the risk of heart diseases [86].

Ambrosia psilostachya (Asteraceae)

5.7 

Cumanin, an ambrosanolides-type sesquiterpene from A. psilostachya was reported

to inhibit NO synthase and exhibited anti-inflammatory activity [90].
1210 N. S. Nirmala et al.

Salvia officinalis (Lamiaceae)

5.8 

Carnosol and carnosic acids are two phenolic diterpenes extracted from S. officina-
lis and were reported as anti-inflammatory metabolites. Both the phenolic diter-
penes directly interacted with microsomal PGE [2] synthase (mPGES)-1 and
suppressed prostaglandin G2 (PGE2) production [91].

Bischofia javanica (Phyllanthaceae)

5.9 

The methanolic leaf extract of B. javanica (MBJ) inhibited NO production, IL6,

IL -1β, TNF-α, and NF-κB and revealed anti-inflammatory activity of B. javan-
ica (Fig. 6). It also inhibits the MAPK pathway by inhibitory phosphorylation
of P38 and JNK. The common upstream kinase of NF-κB, P38, and JNK path-
ways is interleukin-­1 receptor-associated kinase-1 (TAK-1). Rapid phosphory-
lation, ubiquitination, and degradation of Interleukin-1 receptor-associated
kinase-1 (IRAK-1) are essential for phosphorylation of TAK1. MBJ inhibits the
degradation of IRAK-1, and increases its level, and blocks the mediators of
inflammation. It is used to treat tonsillitis, ulcers throughout Asia, Indonesia,
China, and Philippines [92].

Fig. 6 Molecular mechanism of action of methanolic leaf extract of Bischofia javanica (MBJ)
toward anti-inflammatory effect
Anti-inflammatory Potential of Lead Compounds and Their Derivatives from Medicinal… 1211

Caesalpinia digyna (Fabaceae)

5.10 

Bergenin, glutathione, and flavonoids are the phytocompounds of C.digyna.

Ethanolic and methanolic extracts of C. digyna were effective in inhibiting COX-1,
COX-2, and mPGES-1 [93].

Sphenocentrum jollyanum (Menispermaceae)

5.11 

The ethanolic leaf extract of S. jollyanum was rich in alkaloids, tannins, saponins,
flavonoids, and cardiac glycoside content. Further the ethanolic extract S. jollyanum
was reported to reduce carrageenan-induced paw edema, egg albumin-induced paw
edema, and xylene-induced ear edema in experimental mice [94].

Kigelia africana (Bignoniaceae)

5.12 

Roasted seeds, fruit infusion, fresh stem bark, and leaves of K. africana have been
reported to have potential therapeutic effect against inflammation [95].

Piper nigrum (Piperaceae)

5.13 

Nowadays Quorum sensing is emerging as the potential target for treating bacterial
infection which causes inflammation. Synthetic Coumaperine derivatives from
piper nigrum have been reported to inhibit Quorum sensing and block the NF-κB
pathway, which ultimately leads to the inhibition of inflammation [96].

Terminalia bellirica (Combretaceae)

5.14 

Tissue protein denaturation is commonly related to inflammation and arthritis. Ethyl

acetate and aqueous extract of T. bellirica contain ellagic acid which prevented tis-
sue protein denaturation, thereby acting as an anti-inflammatory agent [97].
1212 N. S. Nirmala et al.

6 Classes of Phytochemicals and Their Lead Compounds

6.1 Alkaloids

In plants, alkaloids are secondary metabolites produced in response to environmen-

tal modulations and biotic or abiotic stress that possesses significant biological
activities [98]. They play an important role in the plant defense against fungus,
bacteria, insects, and herbivorous [99]. Alkaloids represent an abundant resource for
drug discovery as they possess multiple physiological and pharmacological activi-
ties, such as analgesia, anti-inflammatory, antioxidant, antitumor, and antibacterial
effects [100]. Plant-derived alkaloids display a variety of anti-inflammatory activi-
ties that make them ideal as anti-inflammatory lead compounds. The main anti-­
inflammatory targets of alkaloids isolated from different plant sources include
iNOS, cytokines, COX-2, PGs, NF-kB, and MAPK. The alkaloids may act by sup-
pressing the activity of one or more of the above said targets to exhibit their thera-
peutic potential. Some of the alkaloids are reported to block inflammation at the
cellular level by acting on leukocytes, neutrophils, and endothelial cells. According
to the type of chemical structure, alkaloids are classified as indoles, carbazoles,
carbolines, quinolines, isoquinolines, pyrroles, piperidines, and purines [101]
(Table 3).

6.2 Terpenoids

Terpenoids are one of the most important families of natural compounds known for
their medicinal value. Terpenoids are the most widespread class of secondary
metabolites found in plants and lower invertebrates. Terpenoids are derived from
mevalonate through a common biosynthetic pathway and are named terpenoids,
terpenes or isoprenoids [136]. Most of the terpenes isolated from plant sources are
well-known inhibitors of NF-κB signaling, the major regulator in the pathogenesis
of inflammatory diseases and thus possessing anti-inflammatory applications [137].
Terpenoids are having 1, 2, 3, 4, 5, 6, and 8 isoprenoid C5 residues and are clas-
sified into hemi, mono, sesqui, di, sester, tri, and tetra terpenoids (carotenoids)
respectively [138]. The exact molecular target of the terpenoids remains unknown
as in the case of most plant extracts. Pharmaceutical studies with monoterpenoids
indicate that they may have some therapeutic potential whereas few studies indicate
the direct role of monoterpenoids in the inhibition of NF-kB signaling.
Sesquiterpenoids are known to be present in several traditional natural remedies.
Though several thousands of sesquiterpene structures have been characterized, ses-
quiterpene lactones are the ones which are most frequently found in natural formu-
lations. Physiologically active diterpenoids include varied classes like aphidicolin,
gibberellins, phorbols, taxanes, etc. They do not directly affect the NF-κB system,
although they can have indirect effects. Triterpenoids are the major substituent in
Anti-inflammatory Potential of Lead Compounds and Their Derivatives from Medicinal… 1213

Table 3 Summary of the various alkaloids reported from medicinal plants and their mode of anti-­
inflammatory action
Class of Mode of anti-­
alkaloid Lead compound(s) Plant species inflammatory action References
Indole Caulerpin Caulerpara Reduction of [102]
cemosa leukocyte cells in
number
Cassiaindoline Cassia alata Inhibition of [103]
anti-inflammatory
effect with edema
Strictosidine Uncaria Inhibition of NO [104]
rhynchophylla production
Geleganimine B Gelsemium Inhibition on the [105]
elegans Lipopolysaccharide-­
stimulated NO
production
Picrinine Alstonia Suppression of 5-LOX [106]
Vallesamine scholaris Dual inhibition on
COX-2 and 5-LOX
Scholaricine Inhibition on COX-2
Alsmaphorazine A Alstonia Inhibit the production [107]
pneumatophora of NO
Mitraphylline Uncaria Reduction in levels of [108]
tomentosa proinflammatory
cytokines
Evodiamine Evodia efructus Reduction in levels of [109]
proinflammatory
mediators
Suppression of
phosphorylation of
IκBα
Inhibition activation of
NF-κB
Carbazole Clausine D Clausena Reduction in the [110]
lansium production of
superoxide anion
Clauemarazole E Clausena Inhibition of NO [111]
emarginata production
Murrayakonine A Murraya Inhibition of [112]
Mukolidine koenigii proinflammatory
O-methyl murrayamine A cytokines (IL-6 and
TNF-α)
Girinimbine Murraya Reduction in the [113]
koenigii levels of NO, PGE2,
TNF-α, and IL-6 due
to the suppression of
COX-2 enzyme and
iNOS
(continued)
1214 N. S. Nirmala et al.

Table 3 (continued)
Class of Mode of anti-­
alkaloid Lead compound(s) Plant species inflammatory action References
β-Carboline 4-Methoxy-5-­ Picrasma Suppression in the [114]
hydroxycanthin-6-one quassioides production or [115]
expression of TNF-α,
NO, and iNOS
Dichotomide III, Stellaria Inhibition of [116]
dichotomide X, stellarine dichotoma and production of NO [117]
A, stellarine B, 1-acetyl-3-­ Neolitsea
methoxycarbonyl-b daibuensis
carboline, and
daibucarboline A
7-Methoxy-(9H-b-­ Eurycoma Reduction of [118]
carbolin-1-il)-1-propenoic longifolia production of NO,
(7-MCPA) PGE2, and IL-6, and
also suppression of
the expression of
iNOS and COX-2
Harmine Peganum Inhibition of NF-κB [119]
harmala L. transactivity
Quinoline Leucophyllidine Leuconotis Reduction in the [120]
eugenifolius production of NO and
the expression of
iNOS
Cryptolepine Cryptolepiss Inhibition of the NO [121]
anguinolenta production and the
level of NF-κB
Skimmianine Ruta graveolens Suppression of [122]
L. proinflammatory
cytokines production
and the antioxidant
effect
Evolitrine Acronychia Suppression of [123]
pedunculata proinflammatory
cytokines
Oleracimine Portulaca Inhibition of the [124]
oleracea expressions of COX-2
and iNOS
Antidesmone Ajuga Suppression of the [125]
decumbens excess production of
Thunb. proinflammatory
cytokines
Regulation of
MAPK- NFκB
signaling pathways
(continued)
Anti-inflammatory Potential of Lead Compounds and Their Derivatives from Medicinal… 1215

Table 3 (continued)
Class of Mode of anti-­
alkaloid Lead compound(s) Plant species inflammatory action References
Isoquinoline (+)-1-Hydroxy-­ Lycorisradiata Selective inhibition of [126]
ungeremine COX-2
(+)-N-methoxylcarbonyl-2-­
dimethyl-isocorydione
Palmatine Coptis japonica Inhibition of the [127]
production and
expression of ROS,
NO, matrix
metalloproteinase-9
(MMP-9), and iNOS
Columbamine Tinospora Inhibition on [128]
sagittata LPS-induced NO
production and
TNF-α-induced
NF-κB activation
Glaucine Glaucium Reduction in the [129]
flavum Crantz production of TNF-α
and IL-6 and
enhanced the
production of IL-10
Pseudo Coptisine Corydalis Inhibition of the [130]
turtschaninovii activation of NF-κB
by the suppression of
ERK and p38
phosphorylation
Norisoboldine Lindera Reduction in [131]
aggregata infiltration of
(Sims.) Kosterm inflammatory cells
Erythraline Erythrina Suppression of NO [132]
crista-galli L. production
Chelidonine Chelidonium Suppression of the [133]
majus production of
proinflammatory
mediators
Warifteine Cissampelos Reduction in [134]
sympodialis neutrophil cell
adhesion and
migration
Delavatine A Incarvillea Suppression in the [135]
delavayi release of
proinflammatory
mediators by
inhibiting gene
expression
1216 N. S. Nirmala et al.

Table 4 Summary of terpenoids reported from medicinal plants and their mode of anti-­
inflammatory action
Mechanism of
Class of the Lead anti-inflammatory
terpenoid compound(s) Plant species action References
Monoterpenoids Aucubin Aucuba japonica IκBα degradation [140]
Catalposide Catalpa ovata IκBα degradation [141]
Sesquiterpenoids Artemisolide Artemisia asiatica IKKβ inhibition on [142]
Cys-179
Nepalolide A Carpesium IκB phosphorylation [143]
nepalense
Diterpenoids Acanthoic Acanthopanax IκBα phosphorylation [144]
Acid Koreanum Nakai
Tanshinone Salvia IKKα /β and NIK [145]
IIA miltiorrhiza inhibition
Triterpenoids Avicins Acacia victoriae DNA binding [146, 147]
Betulinic acid Betula alba IKKα inhibition [148, 149]
Tetraterpenoids Lycopene Psidium guajava NF-κB translocation [150, 151]
β- carotene Momordica IκBα degradation, DNA [152, 153]
cochinchinensis binding

several Chinese herbal remedies, such as ginseng and Platycodon. Carotenoids are
powerful antioxidants which have therapeutic effects in several chronic illnesses,
such as cardiovascular disease and osteoporosis. In addition, they play major role
against inflammatory responses and cancer, suggesting their role in modulating
redox-sensitive signaling pathways, such as NF-κB signaling. Most terpenes are
known to have upstream targets common to both NF-κB signaling pathway and
MAPK pathway which ultimately lead to the suppression of inflammatory responses
[139]. Some of the examples of terpenoids showing potent anti-inflammatory poten-
tial have been listed (Table 4).

6.3 Polyphenols

Polyphenols include various bioactive phytochemicals that have pulled consider-

able attention toward biological applications [154]. Polyphenols exhibit its anti-­
inflammatory activity by modulating the changes in the activation of transcription
factors such as nuclear factor (NF)-κB, activator protein (AP)-1, peroxisome
proliferator-­activated receptors (PPARs), and nuclear factor erythroid 2-related fac-
tor 2 (Nrf2), where its DNA-binding capacity modulates various signal transduction
pathway such as mitogen-activated protein kinases (MAPKs), phosphatidylinositol
3-kinase (PI3K)/RAC-alpha serine/threonine-protein kinase (Akt), and ubiquitin-­
proteasome system. It also decreases the production inflammation mediators such
as nitric oxide (NO), adhesion molecules like intercellular adhesion molecule
Anti-inflammatory Potential of Lead Compounds and Their Derivatives from Medicinal… 1217

(ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and E-selectin, prostaglan-

din (PG) E2, PGI2, leukotriene (LT) B4, LTC4, and chemokines like chemokine
(C-X-C motif) ligand (CXCL) 8, chemokine (C-C motif) ligand 2 (CCL2), CCL3.
The cytokines produced by lymphocytes or monocytes may be proinflammatory
(IL-1β, IL-2, TNFα, Il-6, IL-8, IFN-γ, etc.) or anti-inflammatory effects (IL-10,
IL-4, TGFβ) and play important role in immune response homeostasis. Polyphenols
are reported to exhibit anti-inflammatory activity by balancing proinflammatory and
anti-inflammatory cytokines [155, 156].
Besides an anti-inflammatory molecule, polyphenols also possess antioxidant
properties. It acts through various mechanisms like suppression of reactive oxygen
species (ROS) either by inhibiting the enzymes involved in their production, scav-
enging of ROS, or upregulation of antioxidant defenses. Many epidemiological and
human studies have suggested that daily intake of polyphenols-rich diet can reduce
the incidences of carcinogenesis, cardiovascular disease, and neurological dis-
ease [157].
Flavonoids, a class of polyphenolic compounds having an anti-inflammatory
capacity by inhibiting the production of inflammatory mediators by modulating the
arachidonic acid pathway, inhibiting several enzymes such as ATPase, prostaglan-
din, cyclooxygenase, lipoxygenase, NADH oxidase, protein kinase, hydrolases,
peroxidases, tyrosinases, and phospholipases [158].
In an inflammatory process, flavonoids can act as reducers of free radical accu-
mulation or ROS scavengers, inhibitors of the activity of regulatory enzymes in the
inflammatory process, and immune cell modulators [159]. Some flavonoids, such as
quercetin, rutin, morin, hesperidin, catechin, genistein, cyanidin, etc. have been
demonstrated to exhibit anti-inflammatory functions during in vitro and in vivo
experiments [160]. Some of the examples of anti-inflammatory properties of poly-
phenolic compounds from medicinal plants are tabulated (Table 5).

7 Conclusion

Localization and elimination of harmful agents is the major aim of inflammation but
uncontrolled and chronic inflammatory responses lead to many inflammatory dis-
eases. The synthetic drugs such as NSAIDs widely used in the treatment of many
inflammatory diseases are having deleterious side effects in the gastrointestinal,
cardiovascular, and renal systems. Development of less toxic and more effective
anti-inflammatory agents is an ultimate but challenging task for a pharmaceutical
chemist. However, plant metabolites with diverse and potential lead compounds are
candidates for the design and discovery of new anti-inflammatory drugs. Application
of medicinal plants for the treatment of inflammatory diseases has been promising.
This chapter has provided a concise summary describing the potency of plant com-
pounds with anti-inflammatory activities and their possible molecular mechanisms
that would help researchers engaged in discovery of potential phytochemical lead
compounds with anti-inflammatory potential.
1218 N. S. Nirmala et al.

Table 5 Summary of the various polyphenols reported from medicinal plants and their mode of
anti-inflammatory action
Class of phenolic Mode of anti-­
compound Lead compound(s) Plant species inflammatory action References
Stilbenes Resveratrol Polygonum Reduction in the [161]
cuspidatum expression of TNF-α,
IL-6, c-Jun N -
terminal kinase
(JNK-1), IκB Kinase β
(IKKβ), NF-κ B,
C-reactive protein
(CRP), suppressor of
cytokine signaling 3
(SOCS-3)
Vaccinium Inhibit NF-κB and [162]
macrocarpon JAK-STAT signaling
pathways
Piceatannol Passiflora Suppression of TNF-α, [163]
edulis NF-Κb, iNOS, IL-6, NO
Pterostilbene Vaccinium Inhibit the production [164]
corymbosum of TNF-α, IL-1 β,
IL-4, COX-2, NF- κB
Lignans Arctigenin Arctium lappa Inhibition of NO, [165]
iNOS, IL-6, TNF-α
Secoisolariciresinol Linumusita Inhibition of NF- κB [166]
diglucoside (SDG) tissimum signaling pathway
Phenolic acid Curcumin Curcuma longa Inhibition of [167]
proinflammatory
signaling cascades,
such as the NF𝜅B-,
MAPK, COX, and
LOX-pathways.
Downregulation of
cytokines like TNF𝛼,
IL-1𝛽, and IL-6.
Blocking the
expression of cell
adhesion molecules
(e.g., ICAM-1)
Hydroxycinnamic Caffeic acid Rhodiola sacra Reduction in the level [168]
acid phenethyl ester of TNF-α, IL-1β,
(CAPE) NF-κB
Caffeic acid Allium sativum Inhibition of NF-κB [169]
and AP-1
p-coumaric acid Cornifructus Inhibition of NF- κB [170]
signaling pathway
Rosmarinic acid Blechnum Reduction in the level [171]
brasiliense of TNF-α, IL-1β
Chlorogenic acid Cymbopogo Inhibition of NF-κB [172]
ncitratus signaling pathway
Ferulic acid Triticum Inhibition of TNF-α, [173]
aestivum IL-6, and NO
(continued)
Anti-inflammatory Potential of Lead Compounds and Their Derivatives from Medicinal… 1219

Table 5 (continued)
Class of phenolic Mode of anti-­
compound Lead compound(s) Plant species inflammatory action References
Hydroxybenzoic Gallic acid Camellia Inhibition of 5-LOX [174]
acid (HBA) sinensis activity
Protocatechuic acid Eucommia Reduce the level of [175]
(PCA) ulmoides IL-2, IL-6, TNF-α
Phenolic Hydroxytyrosol Olea europaea Inhibition of iNOS, [176]
derivatives COX-2, NF-κB,
STAT-1α, Interferon
regulatory factors
(IRF-1)
Oleocanthal Olea europaea Inhibition of NO, [177]
Macrophage
inflammatory protein -
1α(MIP-1α), IL-1β,
TNF-α, IL-6
6-Shogaol Zingiber Inhibit the release of [178]
officinale NO, iNOS,
prostaglandin E2
(PGE2), IL-1β, TNF-α,
COX-2. Block the
signaling pathways
such as NF-κB,
MAPK.
Oleuropein Olea europaea Downregulation of [179]
cyclooxygenase
(COX)-2, microsomal
prostaglandin E
synthase-1 (mPGES-
1), MAPK, NF-κB
signaling pathways,
IL-6, and TNF-α
cytokines
Magnolol Magnolia Suppression of NO, [180]
officinalis iNOS, PGE2, NF-κB
Tannins Prodelphinidin-B4-3′- Camellia Inhibition of COX-2, [181]
O-gallate (PDG) sinensis iNOS, PGE2, NO,
NF-κB
Penta-O-galloyl- β-D-­ Paeonia Inhibition of IL-8, [182]
glucose suffruticosa NF-κB, TNF-α
Paeonia Inhibition of iNOS, [183]
lactiflora COX-2
Gallotannin 15 Euphorbia Inhibition of NO, [184]
(1,2,3,4,6-penta-O-­ species iNOS, NF-κB
galloyl-β-D-glucose)
Gallotannin 23
(1,2,6-tri-O-galloyl-β-­­
D-allose)
(continued)
1220 N. S. Nirmala et al.

Table 5 (continued)
Class of phenolic Mode of anti-­
compound Lead compound(s) Plant species inflammatory action References
Coumarins Osthole Cnidium Inhibit the production [185]
monnieri of NO, PGE2, TNF-α,
and IL-6. Suppressed
the activity of iNOS,
COX-2, NF-κB, and
p38 MAPK signaling
pathways
Scopoletin Canarium Inhibition of 5-LOX [186]
patentinervium activity
Daphnetin Daphne odora Inhibition of IL-1β, [187]
TNF-α, iNOS, and
COX-2, NO
6-isopentenyloxy-7-­ Gerbera Inhibition of NF-κB
methoxy coumarin serrata and signaling pathway
and Haplophyllum
8-isopentenyloxy7-­ pedicellatum
methoxy coumarin
Esculetin Fraxinus Suppression of [188]
rhynchophylla proinflammatory
cytokines (TNF-α,
IL-1β, IL-6) and
chemokine (CCL17)
through blocking of
NF-κB and STAT1
signaling pathway
Anthraquinones Chrysophanol Rheum Reduction in the levels [189]
palmatum of interleukin (IL)-4,
IL-5, and IL-13, tumor
necrosis factor
(TNF)-α, inducible
nitric oxide synthase,
and blocking of
NF-kB signaling
pathway
Emodin Aloe vera Suppression of IL-1β, [190]
IL-6, TNF-α, TLR4/
NF-κB signaling
pathway, vascular cell
adhesion molecule 1
(VCAM1), and
intercellular adhesion
molecule 1 (ICAM-1)
(continued)
Anti-inflammatory Potential of Lead Compounds and Their Derivatives from Medicinal… 1221

Table 5 (continued)
Class of phenolic Mode of anti-­
compound Lead compound(s) Plant species inflammatory action References
Flavonoids Homoplantaginin Salvia plebeia Suppression of TLR4 [191]
and NLRP3 signaling
Baicalin Scutellaria Inhibition of NLRP3 [192]
baicalensis inflammasome
Licoflavanone Glycyrrhiza Decreased [193]
glabra L. proinflammatory
cytokines
and COX-2/iNOS
expression levels
Apigenin Justicia Reduced the levels of [194]
gendarussa NF-κB, COX-2,
PGE2, IL-1β, and
TNF-α; elevated the
level of anti-
inflammatory
cytokine, IL-10
Kaempferol Portulaca Decreased the [195]
oleracea L. expression levels of
iNOS and COX-2
Barringoside I Barringtonia Inhibitory effects on [196]
racemosa LPS-induced NO
production

References

1. Dideberg V, Kristjansdottir G, Milani L, Libioulle C, Sigurdsson S, Louis E, Syvänen AC

(2007) An insertion–deletion polymorphism in the interferon regulatory factor 5 (IRF5) gene
confers risk of inflammatory bowel diseases. Hum Mol Genet 16(24):3008–3016
2. Harth M, Nielson WR (2019) Pain and affective distress in arthritis: relationship to immu-
nity and inflammation. Expert Rev Clin Immunol 15(5):541–552. https://doi.org/10.108
0/1744666X.2019.1573675
3. Barnes PJ (2017) Cellular and molecular mechanisms of asthma and COPD. Clin Sci (Lond)
131(13):1541–1558. https://doi.org/10.1042/CS20160487
4. Zhu Y, Xian X, Wang Z, Bi Y, Chen Q, Han X, Tang D, Chen R (2018) Research progress on
the relationship between atherosclerosis and inflammation. Biomol Ther 8(3):80. https://doi.
org/10.3390/biom8030080
5. Kirsch-Volders M, Bolognesi C, Ceppi M, Bruzzone M, Fenech M (2020) Micronuclei,
inflammation and auto-immune disease. Mutat Res Rev Mutat Res 786:108335. https://doi.
org/10.1016/j.mrrev.2020.108335
6. Karam BS, Chavez-Moreno A, Koh W, Akar JG, Akar FG (2017) Oxidative stress and inflam-
mation as central mediators of atrial fibrillation in obesity and diabetes. Cardiovasc Diabetol
16(1):120. https://doi.org/10.1186/s12933-­017-­0604-­9
7. Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G (2006) Inflammation and
cancer: how hot is the link? Biochem Pharmacol 72:1605–1621. https://doi.org/10.1016/j.
bcp.2006.06.029
1222 N. S. Nirmala et al.

8. Dewanjee S, Dua TK, Sahu R (2013) Potential anti-inflammatory effect of Leea macro-
phylla Roxb. leaves: a wild edible plant. Food Chem Toxicology 59:514–520. https://doi.
org/10.1016/j.fct.2013.06.038
9. Divya T, Latha P, Usha K, Anuja G, Suja S, Shyamal S, Shine V, Sini S, Shikha P,
Rajasekharan S (2009) Anti-inflammatory, analgesic and anti-lipid peroxidative properties of
Wattakakavolubilis (Linn. f.) Stapf. Indian J Nat Prod Resour 8:137–141
10. Sofidiya MO, Imeh E, Ezeani C, Aigbe FR, Akindele AJ (2014) Antinociceptive and anti-­
inflammatory activities of ethanolic extract of Alafia barteri. Rev Bras Farmacogn 24:348–354
11. Singh AG, Kumar A, Tewari DD (2012) An ethnobotanical survey of medicinal plants used in
Terai forest of western Nepal. J Ethnobiol Ethnomed 8(1):1–15
12. Ashutosh M, Kumar PD, Ranjan MM, Susil K, Ashutosh M (2009) Phytochemical screening
of Ichnocarpus Frutescens plant parts. Int J Pharmacogn Phytochem Res 1(1):5–7
13. Picchi V, Migliori C, Scalzo RL, Campanelli G, Ferrari V, Di Cesare LF (2012) Phytochemical
content in organic and conventionally grown Italian cauliflower. Food Chem 130(3):501–509
14. Dey PM (2012) Methods in plant biochemistry, Vol 1. Academic Press
15. McDowell PJ, Diver S, Yang F, Borg C, Busby J, Brown V, Grandison T (2021) The inflam-
matory profile of exacerbations in patients with severe refractory eosinophilic asthma receiv-
ing mepolizumab (the MEX study): a prospective observational study. Lancet Respir Med
9(10):1174–1184
16. Kaser A, Martínez-Naves E, Blumberg RS (2010) Endoplasmic reticulum stress: implications
for inflammatory bowel disease pathogenesis. Curr Opin Gastroenterol 26(4):318
17. Mirkov MU, Verstockt B, Cleynen I (2017) Genetics of inflammatory bowel disease: beyond
NOD2. Lancet Gastroenterol Hepatol 2(3):224–234
18. Ramos GP, Papadakis KA (2019) Mechanisms of disease: inflammatory bowel diseases. In:
Mayo Clinic proceedings, vol 94(1). Elsevier, pp 155–165
19. Guan Q (2019) A comprehensive review and update on the pathogenesis of inflammatory
bowel disease. J Immunol Res 1:7247238. https://doi.org/10.1155/2019/7247238
20. Grant RK, Jones GR, Plevris N, Lynch RW, Jenkinson PW, Lees CW, Arnott ID (2021)
The ACE (Albumin, CRP and Endoscopy) index in acute colitis: a simple clinical index on
admission that predicts outcome in patients with acute ulcerative colitis. Inflamm Bowel Dis
27(4):451–457
21. Langan RC, Gotsch PB, Krafczyk MA, Skillinge DD (2007) Ulcerative colitis: diagnosis and
treatment. Am Fam Physician 76(9):1323–1330
22. Ricanek P, Lunde LK, Frye SA, Støen M, Nygård S, Morth JP, Tønjum T (2015) Reduced
expression of aquaporins in human intestinal mucosa in early stage inflammatory bowel dis-
ease. Clin Exp Gastroenterol 8:49
23. Mekhjian HS, Switz DM, Watts HD, Deren JJ, Katon RM, Beman FM (1979) National
Cooperative Crohn’s disease study: factors determining recurrence of Crohn’s disease after
surgery. Gastroenterology 77(4):907–913
24. Mandal S, Barnett J, Brill SE, Brown JS, Denneny EK, Hare SS, Hurst JR (2021) ‘Long-­
COVID’: a cross-sectional study of persisting symptoms, biomarker and imaging abnormali-
ties following hospitalisation for COVID-19. Thorax 76(4):396–398
25. Brinster NK (2008) Dermatopathology for the surgical pathologist: a pattern based approach
to the diagnosis of inflammatory skin disorders (part I). Adv Anat Pathol 15(2):76–96
26. Rabinowitz LG, Esterly NB (1993) Inflammatory bullous diseases in children. Dermatol Clin
11(3):565–581
27. Smits T, Robles CA, van Erp PE, van de Kerkhof PC, Gerritsen MJP (2005) Correlation
between macroscopic fluorescence and protoporphyrin IX content in psoriasis and actinic
keratosis following application of aminolevulinic acid. J Investig Dermatol 125(4):833–839
28. Streit WJ, Mrak RE, Griffin WST (2004) Microglia and neuroinflammation: a pathological
perspective. J Neuroinflammation 1(1):1–4
29. Ebert SE, Jensen P, Ozenne B, Armand S, Svarer C, Stenbaek DS, Pinborg LH (2019)
Molecular imaging of neuroinflammation in patients after mild traumatic brain injury: a lon-
Anti-inflammatory Potential of Lead Compounds and Their Derivatives from Medicinal… 1223

gitudinal 123I-CLINDE single photon emission computed tomography study. Eur J Neurol
26(12):1426–1432
30. Mosley RL, Hutter-Saunders JA, Stone DK, Gendelman HE (2012) Inflammation and adap-
tive immunity in Parkinson’s disease. Cold Spring Harb Perspect Med 2(1):a009381
31. Mihaylova S, Killian A, Mayer K, Pullamsetti SS, Schermuly R, Rosengarten B (2012)
Effects of anti-inflammatory vagus nerve stimulation on the cerebral microcirculation in
endotoxinemic rats. J Neuroinflammation 9(1):1–11
32. Garden GA (2013) Epigenetics and the modulation of neuroinflammation. Neurotherapeutics
10(4):782–788
33. Streit WJ, Xue QS, Braak H, Del Tredici K (2014) Presence of severe neuroinflammation
does not intensify neurofibrillary degeneration in human brain. Glia 62(1):96–105
34. Mayer CL, Huber BR, Peskind E (2013) Traumatic brain injury, neuroinflammation, and
post-traumatic headaches. Headache 53(9):1523–1530
35. Wang Q, Liu Y, Zhou J (2015) Neuroinflammation in Parkinson’s disease and its potential as
therapeutic target. Transl Neurodegener 4(1):1–9
36. Meraz-Ríos MA, Toral-Rios D, Franco-Bocanegra D, Villeda-Hernández J, Campos-Peña V
(2013) Inflammatory process in Alzheimer’s disease. Front Integr Neurosci 7:59
37. Barnum CJ, Tansey MG (2012) Neuroinflammation and non-motor symptoms: the dark pas-
senger of Parkinson’s disease? Curr Neurol Neurosci Rep 12(4):350–358
38. Kösling S (2008) Encyclopedia of diagnostic imaging. Springer-Verlag, Berlin Heidelberg,
New York
39. Crispian S (2008) Oral and maxillofacial medicine: the basis of diagnosis and treatment, 2nd
edn. Churchill Livingstone, Edinburgh, p 356. ISBN 978-0443068188
40. Rogers K (ed) (2010) The digestive system, 1st edn. Britannica Educational Pub., in associa-
tion with Rosen Educational Services, New York, p 146. ISBN 978-1615301317
41. Stewart MG, Selesnick S (eds) (2010) “35”. Differential diagnosis in otolaryngology head
and neck surgery. Thieme, New York. ISBN 9781604062793
42. Baelum V, Lopez R (2004) Periodontal epidemiology: towards social science or molecular
biology? Community Dent Oral Epidemiol 32(4):239–249
43. Nicchio I, Cirelli T, Nepomuceno R et al (2021) Polymorphisms in genes of lipid metabolism
are associated with Type 2 diabetes mellitus and periodontitis, as comorbidities, and with the
subjects’ periodontal, glycemic, and lipid profiles. J Diabetes Res 2021:1049307. PMCID:
PMC8601849
44. Braun-Falco O (2000) Dermatology: with 281 tables, 2nd completely rev edn. Springer,
Berlin, p 1166. ISBN 9783540594529
45. Andrade-Oliveira V, Foresto-Neto O, Watanabe IKM, Zatz R, Câmara NOS (2019)
Inflammation in renal diseases: new and old players. Front Pharmacol 10:1192
46. Verma VK, Kumar A, Bhardwaj G, Kumar S, Kumar M, Chandan KK (2015) Anaesthesia for
chronic renal disease and renal transplant: an update. J Evol Med Dent Sci 4(19):3346–3365
47. Floege J (2013) Primary glomerulonephritis: a review of important recent discoveries. J
Kidney Res Clin Pract 32(3):103–110
48. Kitching AR (2002) Cytokines, T cells and proliferative glomerulonephritis. Nephrology
7(5):244–249
49. Lovisa S, LeBleu VS, Tampe B, Sugimoto H, Vadnagara K, Carstens JL, Kalluri R (2015)
Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in
renal fibrosis. Nat Med 21(9):998–1009
50. Caravaca-Fontán F, Shabaka A, Sánchez-Álamo B, de Lorenzo A, Díaz M, Blasco M,
Rodríguez E, Sierra-Carpio M, Malek Marín T, Urrestarazú A, Corona Cases C, Praga M,
Fernández-Juárez G (2020) Spanish Group for the Study of glomerular diseases (GLOSEN).
Recurrent acute interstitial nephritis: what lies beneath? Clin Kidney J 14(1):197–204.
https://doi.org/10.1093/ckj/sfaa018
51. Meyers CM (2014) “Chronic tubulointerstitial disease”, National Kidney Foundation primer on
kidney diseases. Elsevier, pp 390–396. https://doi.org/10.1016/b978-­1-­4557-­4617-­0.00045-­5.
ISBN 9781455746170
1224 N. S. Nirmala et al.

52. Duggal A, Koury G, Waraich KK (2011) Medical therapy in emphysematous pyelonephritis.

Infect Dis Clin Pract 19(2):124–125
53. Chivima B (2014) Pyelonephritis. Nursing standard (Royal College of Nursing (Great
Britain): 1987). 28(23):61. https://doi.org/10.7748/ns2014.02.28.23.61.s51
54. McKinney M (ed) (2011) Lippincott’s guide to infectious diseases. Lippincott Williams
& Wilkins
55. Parikh SV, Almaani S, Brodsky S, Rovin BH (2020) Update on lupus nephritis: core cur-
riculum 2020. Am J Kidney Dis 76(2):265–281. https://doi.org/10.1053/j.ajkd.2019.10.017
56. Moldoveanu B, Otmishi P, Jani P, Walker J, Sarmiento X, Guardiola J, Saad M, Yu J (2009)
Inflammatory mechanisms in the lung. J Inflamm Res 2:111
57. Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, Brook I, Kumar KA, Kramper M, Orlandi
RR, Palmer JN, Patel ZM, Peters A, Walsh SA, Corrigan MD (2015) Clinical practice
guideline (update): Adult Sinusitis Executive Summary. Otolaryngol Head Neck Surg
152(4):598–609. https://doi.org/10.1177/0194599815574247
58. Guerra AM, Waseem M (2022) Epiglottitis. [updated 2021 Nov 7]. In: StatPearls [internet].
StatPearls Publishing, Treasure Island (FL); 2022 Jan. Available from: https://www.ncbi.nlm.
nih.gov/books/NBK430960/
59. Dowdy R, Cornelius BW (2020) Medical management of epiglottitis. Anesth Prog
67(2):90–97. https://doi.org/10.2344/anpr-­66-­04-­08
60. Ghlichloo I, Gerriets V (2021) Nonsteroidal anti-inflammatory drugs (NSAIDs). May 12. In:
StatPearls [internet]. StatPearls Publishing, Treasure Island (FL); 2022 Jan. PMID: 31613522
61. Cosmo GD, Congedo E (2015) The use of NSAIDs in the postoperative period: advantage
and disadvantages. J Anesth Crit Care Open Access 3(4):00107. https://doi.org/10.15406/
jaccoa.2015.03.00107
62. Hersh EV, Moore PA, Grosser T, Polomano RC, Farrar JT, Saraghi M, Theken KN (2020)
Nonsteroidal anti-inflammatory drugs and opioids in postsurgical dental pain. J Dent Res
99(7):777–786
63. Sutaria S, Katbamna R, Underwood M (2006) Effectiveness of interventions for the treatment
of acute and prevention of recurrent gout – a systematic review. Rheumatology (Oxford)
45(11):1422–1431. https://doi.org/10.1093/rheumatology/kel071
64. Bullock J, Rizvi SA, Saleh AM, Ahmed SS, Do DP, Ansari RA, Ahmed J (2018) Rheumatoid
arthritis: a brief overview of the treatment. Med Princ Pract 27(6):501–507
65. Rothrock JF (2010) Non-steroidal anti-inflammatory drugs (NSAIDs) for acute migraine
treatment. Headache 50(10):1635–1636
66. Bariguian Revel F, Fayet M, Hagen M (2020) Topical diclofenac, an efficacious treatment for
osteoarthritis: a narrative review. Rheumatol Ther 7(2):217–236
67. Kelleni MT (2021) Early use of non-steroidal anti-inflammatory drugs in COVID-19
might reverse pathogenesis, prevent complications and improve clinical outcomes. Biomed
Pharmacother 133:110982
68. Wongrakpanich S, Susantitaphong P, Isaranuwatchai S, Chenbhanich J, Eiam-Ong S, Jaber
BL (2017) Dialysis therapy and conservative management of advanced chronic kidney dis-
ease in the elderly: a systematic review. Nephron 137(3):178–189
69. Fendrick AM, Greenberg BP (2009) A review of the benefits and risks of nonsteroidal anti-­
inflammatory drugs in the management of mild-to-moderate osteoarthritis. Osteopath Med
Prim Care 3(1):1–7
70. Harirforoosh S, Asghar W, Jamali F (2013) Adverse effects of nonsteroidal antiinflammatory
drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm
Sci 16(5):821–847
71. Bessone F, Hernandez N, Tagle M, Arrese M, Parana R, Méndez-Sánchez N, Silva M (2021)
Drug-induced liver injury: a management position paper from the Latin American Association
for Study of the liver. Ann Hepatol 24:100321
Anti-inflammatory Potential of Lead Compounds and Their Derivatives from Medicinal… 1225

72. Khumalo GP, Van Wyk BE, Feng Y, Cock IE (2022) A review of the traditional use of
Southern African medicinal plants for the treatment of inflammation and inflammatory pain.
J Ethnopharmacol 283:114436. https://doi.org/10.1016/j.jep.2021.114436
73. Azab A, Nassar A, Azab AN (2016) Anti-inflammatory activity of natural products. Molecules
21(10):13–21
74. Yatoo M, Gopalakrishnan A, Saxena A, Parray OR, Tufani NA, Chakraborty S, Iqbal H
(2018) Anti-inflammatory drugs and herbs with special emphasis on herbal medicines for
countering inflammatory diseases and disorders-a review. Recent Patents Inflamm Allergy
Drug Discov 12(1):39–58
75. Wills RB, Bone K, Morgan M (2000) Herbal products: active constituents, modes of action
and quality control. Nutr Res Rev 13(1):47–77
76. Khazir J, Mir BA, Mir SA, Cowan D (2013) Natural products as lead compounds in drug dis-
covery. J Asian Nat Prod Res 15(7):764–788. https://doi.org/10.1080/10286020.2013.798314
77. Qandil AM (2012) Prodrugs of nonsteroidal anti-inflammatory drugs (NSAIDs), more than
meets the eye: a critical review. Int J Mol Sci 13(12):17244–17274
78. Ahmad B, Friar EP, Vohra MS, Garrett MD, Serpell CJ, Fong IL, Wong EH (2020)
Mechanisms of action for the anti-obesogenic activities of phytochemicals. Phytochemistry
180:112513. https://doi.org/10.1016/j.phytochem.2020.112513
79. Jo WS, Yang KM, Choi YJ, Jeong CH, Ahn KJ, Nam BH, Lee SW, Seo SY, Jeong MH (2010)
In vitro and in vivo anti-inflammatory effects of pegmatite. Mol Cell Toxicol 6:195202.
https://doi.org/10.1007/s13273-­010-­0027-­0
80. Gomez-Flores R, Calderon CL, Scheibel LW, Tamez-Guerra P, Rodriguez-Padilla C, Tamez-­
Guerra R, Weber RJ (2000) Immunoenhancing properties of Plantago major leaf extract.
Phytother Res 14(8):617–622
81. Ray B, Chauhan NB, Lahiri DK (2011) The “aged garlic extract”: (AGE) and one of its
active ingredients S-allyl-L-cysteine (SAC) as potential preventive and therapeutic agents for
Alzheimer’s disease (AD). Curr Med Chem 18:330613
82. Anand U, Jacobo-Herrera N, Altemimi A, Lakhssassi N (2019) A comprehensive review on
medicinal plants as antimicrobial therapeutics: potential avenues of biocompatible drug dis-
covery. Meta 9(11):258
83. Uddin G, Rauf A, Siddiqui BS, Muhammad N, Khan A, Shah SUA, Rauf DA (2014)
Anti-nociceptive, anti-inflammatory and sedative activities of the extracts and chemical
constituents of Diospyros lotus L. Phytomedicine 21:954–959. https://doi.org/10.1016/j.
phymed.2014.03.001
84. Kumar S, Bajwa BS, Kuldeep S, Kalia AN (2013) Anti-inflammatory activity of herbal
plants: a review. Int J Adv Pharm Biol Chem 2(2):272–281
85. Wal P, Saraswat N, Pal RS, Wal A, Chaubey M (2019) A detailed insight of the anti-­
inflammatory effects of curcumin with the assessment of parameters, sources of ROS and
associated mechanisms. Open Med J 6(1):64
86. Ghasemian M, Owlia S, Owlia MB (2016) Review of anti-inflammatory herbal medicines.
Adv Pharmacol Sci 2016:9130979
87. Raditic DM, Bartges JW (2014) The role of chondroprotectants, nutraceuticals, and nutrition
in rehabilitation. In: Canine rehabilitation and physical therapy. WB Saunders, pp 254–276
88. Lattanzio F, Greco E, Carretta D, Cervellati R, Govoni P, Speroni E (2011) In vivo anti-­
inflammatory effect of Rosa canina L. extract. J Ethnopharmacol 137(1):880–885
89. Aissaoui Y, Boukhari Y, Mahi MA (2021) The anti-inflammatory effect of polyphenolics
olive leaf extracts Olea europaea L. Phytothérapie. https://doi.org/10.3166/phyto-­2021-­0251
90. Wiart, C. (2007). Ethnopharmacology of medicinal plants: Asia and the Pacific. Springer
Science & Business Media
91. Bauer J, Kuehnl S, Rollinger JM, Scherer O, Northoff H, Stuppner H, Koeberle A (2012)
Carnosol and carnosic acids from Salvia officinalis inhibit microsomal prostaglandin E2
synthase-­1. J Pharmacol Exp Ther 342(1):169–176
1226 N. S. Nirmala et al.

92. Lee S, Ha J, Park J, Kang E, Jeon SH, Han SB, Cho S (2021) Antioxidant and anti-­
inflammatory effects of Bischofia javanica (Blume) leaf methanol extracts through the regu-
lation of Nrf2 and TAK1. Antioxidants (Basel) 10(8):1295
93. Emon NU, Alam S, Rudra S, Al Haidar IK, Farhad M, Rana MEH, Ganguly A (2021)
Antipyretic activity of Caesalpinia digyna (Rottl.) leaves extract along with phytoconstit-
uent’s binding affinity to COX-1, COX-2, and mPGES-1 receptors: in vivo and in silico
approaches. Saudi J Biol Sci 28(9):5302–5309
94. Uka E, Ewere EG, Effiong GS (2021) Anti-inflammatory potential of ethanol leaf extract of
Sphenocentrum jollyanum in experimental mice. GSC Adv Res Rev 7(1):146–156
95. Nabatanzi AM, Nkadimeng S, Lall N, Kabasa JD, McGaw JL (2020) Ethnobotany, phyto-
chemistry and pharmacological activity of Kigelia africana (Lam.) Benth. (Bignoniaceae).
Plants 9(6):753
96. Kadosh Y, Muthuraman S, Yaniv K, Baruch Y, Gopas J, Kushmaro A, Kumar RS (2021)
Quorum sensing and NF-κB inhibition of synthetic coumaperine derivatives from piper
nigrum. Molecules 26(8):2293
97. Gupta A, Kumar R, Ganguly R, Singh AK, Rana HK, Pandey AK (2021) Antioxidant, anti-­
inflammatory and hepatoprotective activities of Terminalia bellirica and its bioactive com-
ponent ellagic acid against diclofenac induced oxidative stress and hepatotoxicity. Toxicol
Rep 8:44–52
98. Taha HS, El Bahr MK, Seif ENM (2009) In vitro studies on Egyptian Catharanthus roseus
(L.) G.Don. IV: manipulation of some amino acids as precursors for enhanced of indole alka-
loids production in suspension cultures. Aust J Basic Appl Sci 3(4):3137–3144
99. Seigler DS (1998) Pyrrolizidine, quinolizidine, and indolizidine alkaloids. In: Plant second-
ary metabolism. Springer, Boston, pp 546–567
100. Gautam R, Jachak SM (2009) Recent developments in anti-inflammatory natural products.
Med Res Rev 29(5):767–820
101. Bai R, Yao C, Zhong Z, Ge J, Bai Z, Ye X, Xie Y (2021) Discovery of natural anti-­inflammatory
alkaloids: potential leads for the drug discovery for the treatment of inflammation. Eur J Med
Chem 213:113–165
102. de Souza ET, de Lira DP, de Queiroz AC, da Silva DJC, de Aquino AB, Mella EAC, Lorenzo
VP, de Miranda GEC, de Araujo-Junior JX, de Oliveira Chaves MC, Barbosa-Filho JM, de
Athayde-Filho PF, de Oliveira Santos BV, Alexandre-Moreira MS (2009) The antinociceptive
and anti-inflammatory activities of caulerpin, a bisindole alkaloid isolated from seaweeds of
the genus Caulerpa. Mar Drugs 7:689–704
103. Villaseñor IM, Sanchez AC (2009) Cassiaindoline, a new analgesic and anti-­inflammatory
alkaloid from Cassia alata. Z Naturforsch C J Biosci 64(5–6):335–338. https://doi.
org/10.1515/znc-­2009-­5-­605
104. Ma B, Wu C, Yang J, Wang R, Kano Y, Yuan D (2009) Three new alkaloids from the leaves of
Uncaria rhynchophylla. Helv Chim Acta 92(8):1575–1585
105. Qu J, Fang L, Ren X, Liu Y, Yu S, Li L, Bao X, Zhang D, Li Y, Ma S (2013) Bisindole
alkaloids with neural anti-inflammatory activity from Gelsemium elegans. J Nat Prod
76(12):2203–2209
106. Shang J, Cai X, Feng T, Zhao Y, Wang J, Zhang L, Yan M, Luo X (2010) Pharmacological
evaluation of Alstonia scholaris: anti-inflammatory and analgesic effects. J Ethnopharmacol
129(2):174–181
107. Koyama K, Hirasawa Y, Nugroho A, Hosoya T, Hoe T, Chan K, Morita H (2010)
Alsmaphorazines A and B, novel indole alkaloids from Alstonia pneumatophora. Org Lett
12(18):4188–4191
108. Rojas-Duran R, González-Aspajo G, Ruiz-Martel C, Bourdy G, Doroteo-Ortega V, Alban-­
Castillo J, Robert G, Auberger P, Deharo E (2012) Anti-inflammatory activity of Mitraphylline
isolated from Uncaria tomentosa bark. J Ethnopharmacol 143(3):801–804
Anti-inflammatory Potential of Lead Compounds and Their Derivatives from Medicinal… 1227

109. Fan X, Zhu J, Sun Y, Luo L, Yan J, Yang X, Yu J, Tang W, Ma W, Liang H (2017) Evodiamine
inhibits Zymosan-induced inflammation in vitro and in vivo: inactivation of NF-κB by inhib-
iting IκBα phosphorylation. Inflammation 40(3):1012–1027
110. Shen D, Chan Y, Hwang T, Juang S, Huang S, Kuo P, Thang T, Lee E, Damu A, Wu T (2014)
Constituents of the roots of Clausena lansium and their potential anti-inflammatory activity.
J Nat Prod 77(5):1215–1223
111. Xia H, Ou Yang G, Li C, Yang J, Ma J, Zhang D, Li Y, Li L, Zhang D (2015) Clauemarazoles
A–G, seven carbazole alkaloids from the stems of Clausena emarginata. Fitoterapia 103:83–89
112. Nalli Y, Khajuria V, Gupta S, Arora P, Riyaz-Ul-Hassan S, Ahmed Z, Ali A (2018) Correction:
four new carbazole alkaloids from Murraya koenigii that display anti-inflammatory and anti-­
microbial activities. Org Biomol Chem 16(11):1994. https://doi.org/10.1039/c8ob90030b
113. Mohan S, Hobani Y, Shaheen E, Abou-Elhamd A, Abdelhaleem A, Alhazmi H, Abdelwahab
S (2020) Girinimbine from curry leaves promotes gastro protection against ethanol induced
peptic ulcers and improves healing via regulation of anti-inflammatory and antioxidant mech-
anisms. Food Funct 11(4):3493–3505
114. Fan H, Qi D, Yang M, Fang H, Liu K, Zhao F (2013) In vitro and in vivo anti-inflammatory
effects of 4-methoxy-5- hydroxycanthin-6-one, a natural alkaloid from Picrasma quassioides.
Phytomedicine 20(3–4):319–323. https://doi.org/10.1016/j.phymed.2012.11.016
115. Liu JF, Shao M, Zhai DW, Liu K, Wu LJ (2009) Protective effect of 4-methoxy-5-­
hydroxycanthin-6-one, a natural alkaloid, on dextran sulfate sodium-induced rat colitis.
Planta Med 75(2):142–145. https://doi.org/10.1055/s-­0028-­1088390
116. Chen YF, Kuo PC, Chan HH, Kuo IJ, Lin FW, Su CR, Yang ML, Li DT, Wu TS (2010)
β-carboline alkaloids from Stellaria dichotoma var. lanceolata and their anti-inflammatory
activity. J Nat Prod 73(12):1993–1998. https://doi.org/10.1021/np1003627
117. Wong SL, Chang HS, Wang GJ, Chiang MY, Huang HY, Chen CH, Tsai SC, Lin CH, Chen
IS (2011) Secondary metabolites from the roots of Neolitsea daibuensis and their anti-­
inflammatory activity. J Nat Prod 74(12):2489–2496. https://doi.org/10.1021/np100874f
118. Ngoc PB, Pham TB, Nguyen HD, Tran TT, Chu HH, Chau VM, Lee JH, Nguyen TD (2016)
A new anti-inflammatory β-carboline alkaloid from the hairy-root cultures of Eurycoma lon-
gifolia. Nat Prod Res 30(12):1360–1365. https://doi.org/10.1080/14786419.2015.1056187
119. Liu X, Li M, Tan S, Wang C, Fan S, Huang C (2017) Harmine is an inflammatory inhibitor
through the suppression of NF-κB signaling. Biochem Biophys Res Commun 489(3):332–338.
https://doi.org/10.1016/j.bbrc.2017.05.126
120. Deguchi J, Shoji T, Nugroho AE, Hirasawa Y, Hosoya T, Shirota O, Awang K, Hadi AH,
Morita H (2010) Eucophylline, a tetracyclic Vinylquinoline alkaloid from Leuconotis eugeni-
folius. J Nat Prod 73(10):1727–1729. https://doi.org/10.1021/np100458b
121. Olajide OA, Ajayi AM, Wright CW (2009) Anti-inflammatory properties of cryptolepine.
Phytother Res 23(10):1421–1425. https://doi.org/10.1002/ptr.2794
122. Ratheesh M, Sindhu G, Helen A (2013) Anti-inflammatory effect of quinoline alkaloid
skimmianine isolated from Ruta graveolens L. Inflamm Res 62(4):367–376. https://doi.
org/10.1007/s00011-­013-­0588-­1
123. Ratnayake W, Suresh TS, Abeysekera AM, Salim N, Chandrika UG (2019) Acute anti-­
inflammatory and anti-nociceptive activities of crude extracts, alkaloid fraction and evo-
litrine from Acronychia pedunculata leaves. J Ethnopharmacol 238:111827. https://doi.
org/10.1016/j.jep.2019.111827
124. Li CY, Meng YH, Ying ZM, Xu N, Hao D, Gao MZ, Zhang WJ, Xu L, Gao YC, Ying XX
(2016) Three novel alkaloids from Portulaca oleracea L. and their anti-inflammatory effects.
J Agric Food Chem 64(29):5837–5844. https://doi.org/10.1021/acs.jafc.6b02673
125. Lu X, Pu Y, Kong W, Tang X, Zhou J, Gou H, Song X, Zhou H, Gao N, Shen J (2017)
Antidesmone, a unique tetrahydroquinoline alkaloid, prevents acute lung injury via regulat-
ing MAPK and NF-κB activities. Int Immunopharmacol 45:34–42
1228 N. S. Nirmala et al.

126. Liu ZM, Huang XY, Cui MR, Zhang XD, Chen Z, Yang BS, Zhao XK (2015) Amaryllidaceae
alkaloids from the bulbs of Lycoris radiata with cytotoxic and anti-inflammatory activities.
Fitoterapia 101:188–193. https://doi.org/10.1016/j.fitote.2015.01.003
127. Jeon S, Kwon K, Shin S, Lee S, Rhee S, Han S, Lee J, Kim H, Cheong J, Ryu J, Min B, Ko K,
Shin C (2009) Inhibitory effects of Coptis japonica alkaloids on the LPS-induced activation
of BV2 microglial cells. Biomol Ther 17(1):70–78
128. Liu X, Hu Z, Shi Q, Zeng H, Shen Y, Jin H, Zhang W (2010) Anti-inflammatory and anti-­
nociceptive activities of compounds from Tinospora sagittata (Oliv.) Gagnep. Arch Pharm
Res 33(7):981–987. https://doi.org/10.1007/s12272-­010-­0702-­7
129. Remichkova M, Dimitrova P, Philipov S, Ivanovska N (2009) Toll-like receptor-mediated
anti-inflammatory action of glaucine and oxoglaucine. Fitoterapia 80(7):411–414
130. Yun KJ, Shin JS, Choi JH, Back NI, Chung HG, Lee KT (2009) Quaternary alkaloid, pseudo-
coptisine isolated from tubers of corydalis turtschaninovi inhibits LPS-induced nitric oxide,
PGE (2), and pro-inflammatory cytokines production via the down-regulation of NF-kappaB
in RAW 264.7 murine macrophage cells. Int Immunopharmacol 9(11):1323–1331. https://
doi.org/10.1016/j.intimp.2009.08.001
131. Luo Y, Liu M, Xia Y, Dai Y, Chou G, Wang Z (2010) Therapeutic effect of norisoboldine, an
alkaloid isolated from radix Linderae, on collagen-induced arthritis in mice. Phytomedicine
17(10):726–731. https://doi.org/10.1016/j.phymed.2010.01.013
132. Ozawa M, Kawamata S, Etoh T, Hayashi M, Komiyama K, Kishida A, Kuroda C, Ohsaki
A (2010) Structures of new Erythrinan alkaloids and nitric oxide production inhibitors
from Erythrina crista-galli. Chem Pharm Bull 58(8):1119–1122. https://doi.org/10.1248/
cpb.58.1119
133. Liao W, He X, Yi Z, Xiang W, Ding Y (2018) Chelidonine suppresses LPS-induced pro-
duction of inflammatory mediators through the inhibitory of the TLR4/NF-κB signaling
pathway in RAW264.7 macrophages. Biomed Pharmacother 107:1151–1159. https://doi.
org/10.1016/j.biopha.2018.08.094
134. Lima TF, Rocha JD, Guimarães-Costa AB, Barbosa-Filho JM, Decoté-Ricardo D, Saraiva
EM, Arruda LB, Piuvezam MR, Peçanha LM (2014) Warifteine, an alkaloid purified from
Cissampelos sympodialis, inhibits neutrophil migration in vitro and in vivo. J Immunol Res
2014:752923. https://doi.org/10.1155/2014/752923
135. Xie Q, Wu GZ, Yang N, Shen YH, Tang J, Zhang WD (2018) Delavatine A, an unusual iso-
quinoline alkaloid exerts anti-inflammation on LPS-induced proinflammatory cytokines pro-
duction by suppressing NF-κB activation in BV-2 microglia. Biochem Biophys Res Commun
502(2):202–208. https://doi.org/10.1016/j.bbrc.2018.05.144
136. Bouvier F, Rahier A, Camara B (2005) Biogenesis, molecular regulation and function of plant
isoprenoids. Prog Lipid Res 44(6):357–429. https://doi.org/10.1016/j.plipres.2005.09.003
137. Salminen A, Lehtonen M, Suuronen T, Kaarniranta K, Huuskonen J (2008) Terpenoids: natu-
ral inhibitors of NF-kappaB signaling with anti-inflammatory and anticancer potential. Cell
Mol Life Sci 65(19):2979–2999. https://doi.org/10.1007/s00018-­008-­8103-­5
138. de las Heras B, Hortelano S (2009) Molecular basis of the anti-inflammatory effects of terpenoids.
Inflamm Allergy Drug Targets 8(1):28–39. https://doi.org/10.2174/187152809787582534
139. Kawai T, Akira S (2007) Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med
13(11):460–469. https://doi.org/10.1016/j.molmed.2007.09.002
140. Jeong HJ, Koo HN, Na HJ, Kim MS, Hong SH, Eom JW, Kim KS, Shin TY, Kim HM (2002)
Inhibition of TNF-a and IL-6 production by aucubin through blockade of NF-kB activation
in RBL-2H3 mast cells. Cytokine 18:252–259
141. Kim SW, Choi SC, Choi EY, Kim KS, Oh JM, Lee HJ, Oh HM, Kim S, Oh BS, Kimm KC,
Lee MH, Seo GS et al (2004) Catalposide, a compound isolated from catalpa ovata, attenu-
ates induction of intestinal epithelial proinflammatory gene expression and reduces the sever-
ity of trinitrobenzene sulfonic acid-induced colitis in mice. Inflamm Bowel Dis 10:564–572
142. Kim BH, Lee JY, Seo JH, Lee HY, Ryu SY, Ahn BW, Lee CK, Hwang BY, Han SB, Kim
Y (2007) Artemisolide is a typical inhibitor of IkB kinase b targeting cysteine-179 residue
Anti-inflammatory Potential of Lead Compounds and Their Derivatives from Medicinal… 1229

and down-regulates NF-kB-dependent TNF-a expression in LPS-activated macrophages.

Biochem Biophys Res Commun 361:593–598
143. Wang CN, Shiao YJ, Lin YL, Chen CF (1999) Nepalolide A inhibits the expression of induc-
ible nitric oxide synthase by modulating the degradation of IkB-a and IkB-b in C6 glioma
cells and rat primary astrocytes. Br J Pharmacol 128:345–356
144. Chao TH, Lam T, Vong BG, Traves PG, Hortelano S, Chowdhury C, Bahjat FR, Lloyd GK,
Moldawer LL, Bosca L et al (2005) A new family of synthetic diterpenes that regulates cyto-
kine synthesis by inhibiting IkBa phosphorylation. Chembiochem 6:133–144
145. Jang SI, Kim HJ, Kim YJ, Jeong SI, You YO (2006) Tanshinone IIA inhibits LPS-induced
NF-kB activation in RAW 264.7 cells: possible involvement of the NIK-IKK, ERK1/2, p38
and JNK pathway. Eur J Pharmacol 542:1–7
146. Haridas V, Arntzen CJ, Gutterman JU (2001) Avicins, a family of triterpenoid saponins from
Acacia victoriae (Bentham), inhibit activation of nuclear factor-kB by inhibiting both its
nuclear localization and ability to bind DNA. Proc Natl Acad Sci U S A 98:11557–11562
147. Haridas V, Kim SO, Nishimura G, Hausladen A, Stamler JS, Gutterman JU (2005)
Avicinylation (thioesterification): a protein modification that can regulate the response of
oxidative and nitrosative stress. Proc Natl Acad Sci U S A 102:10088–10093
148. Alakurtti S, Mkel T, Koskimies S, Yli-Kauhaluoma J (2006) Pharmacological properties of
the ubiquitous natural product betulin. Eur J Pharm Sci 29:1–13
149. Takada Y, Aggarwal BB (2003) Betulinic acid suppresses carcinogen-induced NF-kB activa-
tion through inhibition of IkBa kinase and p65 phosphorylation: abrogation of cyclooxygen-
ase-­2 and matrix metalloprotease-9. J Immunol 171:3278–3286
150. Stefano DD, Maiuri MC, Simeon V, Grassia G, Soscia A, Cinelli MP, Carnuccio R (2007)
Lycopene, quercetin and tyrosol prevent macrophage activation induced by gliadin and IFN-­
g. Eur J Pharmacol 566:192–199
151. Huang CS, Fan YE, Lin CY, Hu ML (2007) Lycopene inhibits matrix metalloprotein-9
expression and down-regulates the binding activity of nuclear factor-kB and stimulatory
protein-­1. J Nutr Biochem 18:449–456
152. Bai SK, Lee SJ, Na HJ, Ha YG, Han JA, Lee H, Kwon YG, Chung CK, Kim YM (2005)
ß-Carotene inhibits inflammatory gene expression in lipopolysaccharide-stimulated macro-
phages by suppressing redox-based NF-kB activation. Exp Mol Med 37:323–334
153. Palozza P, Serini S, Torsello A, Nicuolo FD, Piccioni E, Ubaldi V, Pioli C, Wolf FI, Calviello
G (2003) ß-Carotene regulates NF-kB DNA-binding activity by a redox mechanism in human
leukemia and colon adenocarcinoma cells. J Nutr 133:381–388
154. Sobhani M, Farzaei MH, Kiani S, Khodarahmi R (2021) Immunomodulatory; anti-­
inflammatory/antioxidant effects of polyphenols: a comparative review on the parental com-
pounds and their metabolites. Food Rev Intl 37(8):759–811
155. Yahfoufi N, Alsadi N, Jambi M, Matar C (2018) The immunomodulatory and anti-­
inflammatory role of polyphenols. Nutrients 10(11):1618
156. Costa G, Francisco V, Lopes MC, Cruz MT, Batista MT (2012) Intracellular signaling path-
ways modulated by phenolic compounds: application for new anti-inflammatory drugs dis-
covery. Curr Med Chem 19(18):2876–2900
157. Hussain T, Tan B, Yin Y, Blachier F, Tossou MC, Rahu N (2016) Oxidative stress and inflam-
mation: what polyphenols can do for us? Oxidative Med Cell Longev 2016:7432797. https://
doi.org/10.1155/2016/7432797
158. Nunes C, Barreto Arantes M, Menezes de Faria Pereira S, Leandro da Cruz L, de Souza
Passos M, Pereira de Moraes L, Vieira I, Barros de Oliveira D (2020) Plants as sources of anti-­
inflammatory agents. Molecules (Basel, Switzerland) 25(16):3726. https://doi.org/10.3390/
molecules25163726
159. Maleki SJ, Crespo JF, Cabanillas B (2019) Anti-inflammatory effects of flavonoids. Food
Chem 299:125124. https://doi.org/10.1016/j.foodchem.2019.125124
160. Jucá MM, Cysne Filho F, de Almeida JC, Mesquita D, Barriga J, Dias K, Barbosa TM,
Vasconcelos LC, Leal L, Ribeiro JE, Vasconcelos S (2020) Flavonoids: biological activi-
1230 N. S. Nirmala et al.

ties and therapeutic potential. Nat Prod Res 34(5):692–705. https://doi.org/10.1080/1478641

9.2018.1493588
161. Ghanim H, Sia CL, Abuaysheh S, Korzeniewski K, Patnaik P, Marumganti A, Dandona P
(2010) An antiinflammatory and reactive oxygen species suppressive effects of an extract
of Polygonum cuspidatum containing resveratrol. J Clin Endocrinol Metabol 95(9):E1–E8
162. Thimóteo NSB, Iryioda TMV, Alfieri DF, Rego BEF, Scavuzzi BM, Fatel E, Dichi I (2019)
Cranberry juice decreases disease activity in women with rheumatoid arthritis. Nutrition
60:112–117
163. Yamamoto T, Li Y, Hanafusa Y, Yeh YS, Maruki-Uchida H, Kawakami S, Kawada T (2017)
Piceatannol exhibits anti-inflammatorynunes euphorbia species effects on macrophages
interacting with adipocytes. Food Sci Nutr 5(1):76–85
164. Li J, Deng R, Hua X, Zhang L, Lu F, Coursey TG, Li DQ (2016) Blueberry component
pterostilbene protects corneal epithelial cells from inflammation via anti-oxidative pathway.
Sci Rep 6(1):1–10
165. Zhao F, Wang L, Liu K (2009) In vitro anti-inflammatory effects of arctigenin, a lignan from
Arctium lappa L., through inhibition on iNOS pathway. J Ethnopharmacol 122(3):457–462
166. Bowers LW, Lineberger CG, Ford NA, Rossi EL, Punjala A, Camp KK, Hursting SD (2019)
The flaxseed lignan secoisolariciresinol diglucoside decreases local inflammation, sup-
presses NFκB signaling, and inhibits mammary tumor growth. Breast Cancer Res Treat
173(3):545–557
167. Fürst R, Zündorf I (2014) Plant-derived anti-inflammatory compounds: hopes and disap-
pointments regarding the translation of preclinical knowledge into clinical progress. Mediat
Inflamm 2014:146832. https://doi.org/10.1155/2014/146832
168. Jung WK, Lee DY, Kim JH, Choi I, Park SG, Seo SK, Choi IW (2008) Anti-inflammatory
activity of caffeic acid phenethyl ester (CAPE) extracted from Rhodiola sacra against
lipopolysaccharide-­induced inflammatory responses in mice. Process Biochem 43(7):783–787
169. Kim SR, Jung YR, An HJ, Kim DH, Jang EJ, Choi YJ, Chung HY (2013) Anti-wrinkle and
anti-inflammatory effects of active garlic components and the inhibition of MMPs via NF-κB
signaling. PLoS One 8(9):e73877
170. Yoon JH, Youn K, Ho CT, Karwe MV, Jeong WS, Jun M (2014) p-Coumaric acid and ursolic
acid from corni fructus attenuated β-Amyloid25–35-induced toxicity through regulation of
the NF-κB signaling pathway in PC12 cells. J Agric Food Chem 62(21):4911–4916
171. Fasolo JM, Vizuete AFK, Rico EP, Rambo RB, Toson NS, Santos E, Heriques AT (2021)
Anti-inflammatory effect of rosmarinic acid isolated from Blechnum brasiliense in adult
zebrafish brain. Comp Biochem Physiol C Toxicol Pharmacol 239:108874
172. Francisco V, Costa G, Figueirinha A, Marques C, Pereira P, Neves BM, Batista MT (2013)
Anti-inflammatory activity of Cymbopogon citratus leaves infusion via proteasome and
nuclear factor-κB pathway inhibition: contribution of chlorogenic acid. J Ethnopharmacol
148(1):126–134
173. Yin ZN, Wu WJ, Sun CZ, Liu HF, Chen WB, Zhan QP, Hui WU (2019) Antioxidant and anti-­
inflammatory capacity of ferulic acid released from wheat bran by solid-state fermentation of
aspergillus Niger. Biomed Environ Sci 32(1):11–21
174. Thitimuta S, Pithayanukul P, Nithitanakool S, Bavovada R, Leanpolchareanchai J,
Saparpakorn P (2017) Camellia sinensis L. extract and its potential beneficial effects in
antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase activities. Molecules
22(3):401
175. Hu R, He Z, Liu M, Tan J, Zhang H, Hou DX, Wu S (2020) Dietary protocatechuic acid
ameliorates inflammation and up-regulates intestinal tight junction proteins by modulating
gut microbiota in LPS-challenged piglets. J Anim Sci Biotechnol 11(1):1–12
176. Maiuri MC, De Stefano D, Di Meglio P, Irace C, Savarese M, Sacchi R, Carnuccio R (2005)
Hydroxytyrosol, a phenolic compound from virgin olive oil, prevents macrophage activation.
Naunyn Schmiedeberg’s Arch Pharmacol 371(6):457–465
Anti-inflammatory Potential of Lead Compounds and Their Derivatives from Medicinal… 1231

177. Scotece M, Gómez R, Conde J, Lopez V, Gómez-Reino JJ, Lago F, Gualillo O (2012) Further
evidence for the anti-inflammatory activity of oleocanthal: inhibition of MIP-1α and IL-6 in
J774 macrophages and in ATDC5 chondrocytes. Life Sci 91(23–24):1229–1235
178. Ha SK, Moon E, Ju MS, Kim DH, Ryu JH, Oh MS, Kim SY (2012) 6-Shogaol, a ginger prod-
uct, modulates neuroinflammation: a new approach to neuroprotection. Neuropharmacology
63(2):211–223
179. Castejón ML, Rosillo MÁ, Montoya T, González-Benjumea A, Fernández-Bolaños JM,
Alarcón-de-la-Lastra C (2017) Oleuropein down-regulated IL-1β-induced inflammation and
oxidative stress in human synovial fibroblast cell line SW982. Food Funct 8(5):1890–1898
180. Lu SH, Hsu WL, Chen TH, Chou TC (2015) Activation of Nrf2/HO-1 signaling path-
way involves the anti-inflammatory activity of magnolol in Porphyromonas gingivalis
lipopolysaccharide-­ stimulated mouse RAW 264.7 macrophages. Int Immunopharmacol
29(2):770–778
181. Hou DX, Luo D, Tanigawa S, Hashimoto F, Uto T, Masuzaki S, Sakata Y (2007) Prodelphinidin
B-4 3′-O-gallate, a tea polyphenol, is involved in the inhibition of COX-2 and iNOS via the
downregulation of TAK1-NF-κB pathway. Biochem Pharmacol 74(5):742–751
182. Oh GS, Pae HO, Cho BM, Lee HS, Kim IK, Yun YG, Chung HT (2004) Penta-O-galloyl-­
beta-D-glucose inhibits phorbol myristate acetate-induced interleukin-8 [correction of
intereukin-8] gene expression in human monocytic U937 cells through its inactivation of
nuclear factor-kappaB. Int Immunopharmacol 4(3):377–386
183. Lee SJ, Lee IS, Mar W (2003) Inhibition of inducible nitric oxide synthase and cyclooxygen-
ase-­2 activity by 1, 2, 3, 4, 6-penta-O-galloyl-β-D-glucose in murine macrophage cells. Arch
Pharm Res 26(10):832–839
184. Kim MS, Park SB, Suk K, Kim IK, Kim SY, Kim JA, Kim SH (2009) Gallotannin isolated
from euphorbia species, 1, 2, 6-tri-O-galloyl-β-D-allose, decreases nitric oxide production
through inhibition of nuclear factor-κ> B and downstream inducible nitric oxide synthase
expression in macrophages. Biol Pharm Bull 32(6):1053–1056
185. Fan H, Gao Z, Ji K, Li X, Wu J, Liu Y, Zhao F (2019) The in vitro and in vivo anti-­inflammatory
effect of osthole, the major natural coumarin from Cnidium monnieri (L.) Cuss, via the
blocking of the activation of the NF-κB and MAPK/p38 pathways. Phytomedicine 58:152864
186. Mogana R, Teng-Jin K, Wiart C (2013) Anti-inflammatory, anticholinesterase, and anti-
oxidant potential of scopoletin isolated from Canarium patentinervium Miq.(Burseraceae
Kunth). Evid Based Complement Alternat Med 2013:734824
187. Das S, Mandal S (2018) Current developments on anti-inflammatory natural medicines.
Asian J Pharm Clin Res 11(8):61
188. Jeong NH, Yang EJ, Jin M, Lee JY, Choi YA, Park PH, Kim SH (2018) Esculetin from
Fraxinus rhynchophylla attenuates atopic skin inflammation by inhibiting the expression of
inflammatory cytokines. Int Immunopharmacol 59:209–216
189. Song G, Zhang Y, Yu S, Lv W, Guan Z, Sun M, Wang J (2019) Chrysophanol attenuates
airway inflammation and remodeling through nuclear factor-kappa B signaling pathway in
asthma. Phytother Res 33(10):2702–2713
190. Chen Y, Feng B, Yuan Y, Hu J, Zhao W, Jiang H, Du Z (2020) Aloe emodin reduces car-
diac inflammation induced by a high-fat diet through the TLR4 signaling pathway. Mediat
Inflamm 2020:6318520. https://doi.org/10.1155/2020/6318520
191. He B, Zhang B, Wu F, Wang L, Shi X, Qin W, Lin Y, Ma S, Liang J (2016) Homoplantaginin
inhibits palmitic acid-induced endothelial cells inflammation by suppressing TLR4 and
NLRP3 inflammasome. J Cardiovasc Pharmacol 67(1):93–101. https://doi.org/10.1097/
FJC.0000000000000318
192. Liu X, Liu C (2017) Baicalin ameliorates chronic unpredictable mild stress-induced depres-
sive behavior: involving the inhibition of NLRP3 inflammasome activation in rat prefrontal
cortex. Int Immunopharmacol 48:30–34. https://doi.org/10.1016/j.intimp.2017.04.019
193. Frattaruolo L, Carullo G, Brindisi M, Mazzotta S, Bellissimo L, Rago V, Curcio R, Dolce
V, Aiello F, Cappello AR (2019) Antioxidant and anti-inflammatory activities of flavanones
1232 N. S. Nirmala et al.

from Glycyrrhiza glabra L. (licorice) leaf Phytocomplexes: identification of Licoflavanone as

a modulator of NF-kB/MAPK pathway. Antioxidants (Basel, Switzerland) 8(6):186. https://
doi.org/10.3390/antiox8060186
194. Kumar KS, Sabu V, Sindhu G, Rauf AA, Helen A (2018) Isolation, identification and char-
acterization of apigenin from Justicia gendarussa and its anti-inflammatory activity. Int
Immunopharmacol 59:157–167. https://doi.org/10.1016/j.intimp.2018.04.004
195. Miao L, Tao H, Peng Y, Wang S, Zhong Z, El-Seedi H, Dragan S, Zengin G, Cheang WS,
Wang Y, Xiao J (2019) The anti-inflammatory potential of Portulaca oleracea L. (purslane)
extract by partial suppression on NF-κB and MAPK activation. Food Chem 290:239–245.
https://doi.org/10.1016/j.foodchem.2019.04.005
196. Van Q, Vien LT, Hanh T, Huong P, Cuong NT, Thao NP, Thuan NH, Dang NH, Thanh NV,
Cuong NX, Nam NH, Kiem PV, Minh CV (2020) Acylated flavonoid glycosides from
Barringtonia racemosa. Nat Prod Res 34(9):1276–1281. https://doi.org/10.1080/1478641
9.2018.1560290
Alzheimer’s Disease Treatment Using
Natural Foods: A Overview

Tanima Bhattacharya, Debashrita Das, Hitesh Chopra, and Atif Amin Baig

1 Introduction

The term Alzheimer’s disease is named after Dr. Alois Alzheimer in 1906.
Alzheimer’s disease is a serious ailment of the brain that gradually progresses and
cannot be reversed back, slowly destroying thinking and memorizing skills. As a
result, the individual suffering from this disease finds it very difficult to perform
even the simplest of tasks. The symptoms of the disease usually vary from person to
person, but generally, they include having problems in language, unpredictable
behavior, and memory loss [1]. Individuals in the age group of the mid-60 s are most
likely to face the symptoms of Alzheimer’s disease. The majority of the elderly in
the clinic have evidence of neurofibrillary and vascular pathology [2]. Elderly

Tanima Bhattacharya and Debashrita Das contributed equally with all other contributors.

T. Bhattacharya
Department of Food and Nutrition, College of Human Ecology, Kyung Hee University,
Dongdaemun-gu Seoul, Republic of Korea
Nondestructive Bio-Sensing Laboratory, Department of Biosystems Machinery Engineering,
College of Agriculture and Life Science, Chungnam National University, Yuseong-Gu
Daejeon, Republic of Korea
D. Das
PRCS Technologies, Kolkata, West Bengal, India
H. Chopra
Chitkara College of Pharmacy, Chitkara University, Rajpura, Patiala, Punjab, India
A. A. Baig (*)
University Institute of Public Health, Faculty of Allied Health Sciences, The University of
Lahore, Lahore, Punjab, Pakistan
Institute of Molecular Biology & Biotechnology, The University of Lahore,
Lahore, Punjab, Pakistan

© The Author(s), under exclusive license to Springer Nature 1233

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_51
1234 T. Bhattacharya et al.

people having mild cognitive impairment are more prone to develop Alzheimer’s
disease. The prevalence of this disease globally is supposed to be as much as 24
million of which in the USA, the number of affected people are about 5.5 million.
In western societies, Alzheimer’s disease frequently causes dementia [3]. The grad-
ual loss in cognitive functioning, which includes remembering capacity, thinking
ability, and reasoning capacity, and loss of behavioral capabilities, which causes
hindrance to proper carrying out of the day-to-day activities, is known as dementia.
However, the rate at which Alzheimer’s disease will progress is variable and approx-
imately individuals suffering from Alzheimer’s disease survive for 3–11 years after
being diagnosed with the disease and some can even survive for as much as 20 years.
During the time of diagnosis of the disease, the extent of impairment can eventually
directly impact the life expectancy of the affected individual. The leading cause
behind the disease is the development of proteins like amyloid and tau abnormally
inside and around the cells of the brain, forming plaques and tangles within the cells.
Figure 1 represents the pathophysiology of Alzheimer’s disease with amyloid
precursor protein causing cognitive dysfunction in human beings [4]. Considering
the alarmingly increasing mortality rate from Alzheimer’s disease, it is essential to
consider the natural foods that can act as medicines and help prevent and treat the
occurrence of Alzheimer’s disease successfully [5]. According to current trends,
several researches are being done for foods helping properly treat the disease. Thus,

Fig. 1 Pathophysiology of Alzheimer’s disease

Alzheimer’s Disease Treatment Using Natural Foods: A Overview 1235

different studies related to this subject are critically evaluated and reviewed so that
a better view of the recent progression in this subject area can be obtained.

1.1 Foods as Medicine in Treating the Disease

Proper foods and nutritional support, including vitamins and curcumin, have a
prominent role in the survival of individuals suffering from Alzheimer’s disease.
Many studies have established a strong connection between nutrients and
Alzheimer’s disease, from which it can be known that the Mediterranean diet, vita-
mins, and curcumin are the three major role players in this regard. Swaminathan and
Jicha [6] suggest that approaching Alzheimer’s disease with proper nutrition can be
helpful in prevention, slowing down, or halting the usual progression of the occur-
rence of the disease.
Figure 2 represents how phyto-based drugs help prevent and treat the symptoms
and issues related to Alzheimer’s disease. It has been mentioned that plant flavo-
noids, vitamins, omega-3 fatty acids, metabolic substrates, antioxidants, and trace
minerals like dietary constituents can influence the cellular processes and pathways
connected with the neurodegeneration case of Alzheimer’s disease. In the following
section, certain specific foods acting as medicines in treating Alzheimer’s disease
will be extensively discussed, focusing on the recent research on this subject area.

Fig. 2 Mode of action of phyto-based drugs for the treatment of Alzheimer’s disease
1236 T. Bhattacharya et al.

Berries As per the opinion of Singh [7], berries containing plenty of nutritive and
bioactive substances have a vital role in preventing and providing therapeutic effects
for different neurodegenerative diseases like Alzheimer’s and Parkinson’s disease.
Berries, which include strawberry, grapes, blackberry, and blueberry, contain poly-
phenols that act as potent antioxidants as well as vitamins like B complex, A, C, and
E, which can help in delaying the occurrence of neurodegeneration along with
bringing about considerable improvement in the memory as well as cognitive activi-
ties of the frontal lobes present in the brain. The phytonutrients present in the berries
associate with the distinct signaling pathways, causing the folding of the proteins
and preventing neuroinflammation. Agarwal et al. [8] conducted a study in as many
as 925 patients aged between 58 and 98 years, and the connection between con-
sumption of strawberry and occurrence of Alzheimer’s-related dementia was evalu-
ated with the help of proportional hazard models. The study results found that
subjects who consumed a more significant number of strawberries experienced a
lower risk of dementia from Alzheimer’s. Vitamin C, anthocyanidins, flavonoids,
and pelargonidin were connected to lowering the risk of Alzheimer’s dementia.

Nuts Gorji et al. [9] conducted a study on the impact of nuts, especially almond,
hazelnut, and walnut, on acting against atrophy of brain and memory loss. The study
discussed the bioactive compounds present in these nuts and evaluated them as
effective supplements and natural foods acting as medicines in the treatment of
patients suffering from Alzheimer’s disease. It has also been found that these nuts
can essentially provide micro- and macronutrients along with essential phytochemi-
cals that can impact various pathways involved in the pathogenesis of Alzheimer’s
disease, including oxidative stress, tau phosphorylation, amyloidogenesis, and neu-
rogenesis. Similarly, in the literature of Chauhan and Chauhan [10], it has been
mentioned that walnuts contain different components showing antioxidant and anti-­
inflammatory features, which can help in the therapeutic treatment of Alzheimer’s
disease. Supplementation in the diet with walnuts can be essentially beneficial for
the improvement in cognitive functions as well as reducing the chances of faster
progression of Alzheimer’s disease.

Omega-3 Fatty Acids It has been experimentally proven that the intake of a diet
enriched in docosahexaenoic acid (DHA) can protect brain cells from cognitive
damage and neurodegenerative diseases like Alzheimer’s. Yet, there are signs from
other epidemiological studies suggesting an unpredictable relationship between
having omega-3 fatty acids in the diet and decreased risk of Alzheimer’s. The study
of Quinn et al. [11] found that the omega-3 fatty acids with shorter chains are more
effective than those with long chains in treating Alzheimer’s disease. On the other
hand, in Avallone et al.’s [12] study, omega-3 fatty acids have shown strong poten-
tial in having anti-inflammatory and metabolic features in managing neurodegen-
erative diseases like Alzheimer’s and Parkinson’s. It was found that treating such
patients with omega-3 fatty acids was safe and well tolerated when supplementation
is done at the early stages of the disorder.
Alzheimer’s Disease Treatment Using Natural Foods: A Overview 1237

Cruciferous Vegetables It has been evidenced in the manuscript of Manchali et al.

[13] about various studies demonstrating the positive effects of cruciferous vegeta-
bles in preventing Alzheimer’s disease. There are plenty of bioactive compounds
present in cruciferous vegetables that are of utmost effectiveness in preventing oxi-
dative stress, which has the maximum possibility to occur in Alzheimer’s disease. In
addition to this, there has also been evidence of clinical investigation that has sug-
gested that increasing the intake of cruciferous vegetables in diet can also help
lower the rate of occurrence of cognitive decline in the older age. Kim (2021) stud-
ied the impact of sulforaphane present in cruciferous vegetables on the protection of
brain health, including many neurodegenerative diseases like Alzheimer’s disease.
It is reported that sulforaphane works effectively against biomarkers of Alzheimer’s
disease, like oxidative stress, amyloid-β, and inflammation, thereby helping prevent
Alzheimer’s disease.

Spices In Mirmosayyeb et al.’s [14] article, the role of common spices like that of
pepper, cinnamon, turmeric, saffron, and zingiber toward prevention or halting of
neurodegenerative disease like Alzheimer’s has been discussed, which acts by sup-
pressing the inflammatory pathways involved in the disease and by exhibiting the
antioxidant activity and inhibition of acetylcholinesterase and aggregation of
amyloid-β. Mohanty (2017) studied the importance and function of Indian spices in
treating Alzheimer’s disease and evidenced that the phytochemicals present in
Indian spices can be a potential therapeutic agent for treating memory loss and
dementia related to Alzheimer’s disease. However, more studies are needed to help
in isolation, identification, and characterization of the bioactive compounds present
in the spices, which can help in the inhibition of cholinesterase activities and thereby
preventing the occurrence of Alzheimer’s [15].

Seeds The polyphenolic compounds present in grape seeds help in the prevention
and treatment of Alzheimer’s disease, and it is also safe, tolerable, bioactive, and
bioavailable. The polyphenolic compounds also help in interfering with the patho-
genesis of Alzheimer’s disease [16]. Biswas et al.’s [17] study assessed the cholin-
esterase inhibition potential of the extracts from the seed of Tamarindus indica, and
the results showed that the seed extracts have the moderate potential of inhibiting
acetylcholinesterase. However, it also suggested that further studies are needed to
identify molecules that may act as potent cholinesterase inhibitors in treating
Alzheimer’s disease.

2 Phyto-Based Drugs

There are five drugs approved for clinical use for the treatment of Alzheimer’s dis-
ease based on their properties of inhibiting cholinesterase, including tacrine, done-
pezil, and galantamine. But these drugs have been shown to have limited effectiveness
and are associated with other side effects to the body [18]. For this reason, the
1238 T. Bhattacharya et al.

Table 1 List of plants having medicinal value and their mode of action for treating
Alzheimer’s disease
Name of the Useful portion ofMode of action against Alzheimer’s
medicinal plant the plant disease References
Convolvulus Convolamine and Reduces biomarkers of Alzheimer’s Bihaqi et al.
pluricaulis convolvine disease in male Wister rats (2012) [21]
Glycyrrhiza Glycyrrhizin Relieves the inflammation of neurons Song et al.
glabra and memory deficiency as prompted by (2013) [22]
systemic treatment with
lipopolysaccharide in mice
Withania Withanamides Cleaves off beta-site amyloid precursor Mahrous et al.
somnifera and withanolides protein cleaving enzyme 1 (BACE1) or (2017) [23]
β-site amyloid precursor protein-cleaving
enzyme and acetylcholinesterase and
inhibits them
Nardostachys Valeranone and Improves memory and learning Karkada et al.
jatamansi nardosinone processes in mice (2012) [24]
Ficus carica Quercetin Causes induction of bioactivity of Khojah and
neurons and fights against Alzheimer’s Edrada-Ebel
disease related to oxidative stress (2017) [25]
Coriandrum Coumarin Proliferates glial cells, Liu et al.
sativum Suppresses Aβ42, and activates (2016) [26]
extracellular kinase regulated by signals

researchers are trying to find an alternative drug source that can be safe and effective
for the treatment of the disease. It has been seen in the literature of Ayaz et al. [19]
that curcumin can modulate inflammatory pathways involved in the central nervous
system, inhibit the aggregation of amyloid-β, as well as decrease the load of free
radicals in the body. For this reason, curcumin-based drugs can be essentially help-
ful to prevent or treat Alzheimer’s disease. Certain flavonoids like catechins and
myricetin help inhibit aggregation of amyloid-β and act as antioxidants, making
them a potent phyto-based drug for treating Alzheimer’s disease. Similarly, in the
study of Ovais et al. [20], certain important medicinal plants that have proper bioac-
tive substances and potentially act against Alzheimer’s disease have been exten-
sively highlighted. Among them, a few plants with their therapeutic properties
against Alzheimer’s have been discussed in Table 1.

3 Exploring Efficacy of Phyto-Based Drugs

Phyto-based drugs are essentially effective in treating Alzheimer’s disease and its
related symptoms. The study of Cacabelos et al. [27] suggests that plenty of phyto-
medicines exhibit promising outcomes in the therapeutic treatment of Alzheimer’s
disease. Along with customized nanomedicines, these phyto-based drugs could per-
form more effectively by efficiently delivering the bioactive compounds of the
Alzheimer’s Disease Treatment Using Natural Foods: A Overview 1239

medicines to the target sites in the body. Again, Girek and Szymański [18] discussed
the efficacy of tacrine that acts as the inhibitor of acetylcholinesterase, but it was
seen that there are several side effects of the drug. In this study, it was seen that the
side effects could be diminished if it is phyto-tacrine hybrid. It has also been high-
lighted that the phyto hybrids can exhibit anti-inflammatory and neuroprotective
effects, which certainly confirms the better efficacy of the phyto-based tacrine for
treating Alzheimer’s disease. D’Onofrio et al. [28] studied the role of phytochemi-
cals in the treatment of Alzheimer’s disease and concluded that the phytochemicals
can slow down the onset of Alzheimer’s disease by exhibiting anti-inflammatory,
anticholinergic, and antioxidant properties. In Karimi’s [29] manuscript, herbs like
Curcuma longa, Cyperus rotundus, and Thymus vulgaris have been shown to have
effective potential in the treatment of Alzheimer’s and these herbs could be later
produced as effective anti-Alzheimer’s drugs in the future. On the other hand, in the
manuscript of Ahmed and Gilani [30], the therapeutic potential of curcuminoid
mixture is believed to be more effective than that of curcumin alone in the treatment
of Alzheimer’s disease. From this, it can be stated that curcuminoids can be effec-
tively used for developing drugs derived from plant sources.
Figure 3 represents the various neuroprotective potential of different herbs and
their efficacy in performing antioxidant and anti-inflammatory functions in the body
[31]. The role of phytochemicals derived from various sources in treating
Alzheimer’s disease is described in Table 2.

Fig. 3 Neuroprotective action of different herbs

1240 T. Bhattacharya et al.

Table 2 List of phytochemicals derived from different sources playing a beneficial role in the
treatment of Alzheimer’s disease
Name of Derived Pharmacological
the plant Phytochemical from impact Benefits References
Curcuma Curcumin Phenol Activation of Protects Nam et al.
longa regulation of cyclic neuroinflammation (2014)
adenosine neuritogenesis and [32];
monophosphate exhibits Hoppe
(AMP) response antioxidant et al.
element binding features (2013)
mediated by protein [33]
kinase C/extracellular
receptor kinase
Galanthus Galantamine Alkaloid Inhibition of Anti-inflammation, Furukawa
Sp. acetylcholinesterase, antioxidant, and et al.
accumulation of neuroprotection (2014)
microglial cells, and [34]
enhancement of
antioxidant enzymes
Abies Ligraminol Terpenoid Inhibition of the Protects against Xia et al.
holophylla E4-O-β-d- production of nitric neurodegenerative (2012)
xyloside oxide and [35]
neuroinflammatory
diseases
Citrus Naringenin Phenol Activation of Neuroprotection, Raza et al.
paradisi; signaling of nuclear anti-inflammatory (2013)
citrus factor erythroid effects, and [36]; Lou
sinensis 2-related factor/ antioxidant et al.
antioxidant response activities (2014)
element, upregulation [37]
of the antioxidant
enzymes, reduction
of nitric oxide, and
signaling of
cytokines
Morus Quercetin Phenol Scavenges free Antioxidant Pany et al.
alba radical, and inhibits activities and (2014)
cyclooxygenase-2 anti-inflammatory [38]
and nuclear factor properties
kappa light chain
enhancer of activated
B-cells

In the review by Howes et al. [39], the efficacy of Chinese herbal medicines
derived from plants like Polygala tenuifolia for treating Alzheimer’s disease has
been discussed. All the scientific evidences regarding the herbal medicines used
traditionally for the effective treatment of Alzheimer’s disease help in the under-
standing that phyto-based drugs can essentially be used for relieving the symptoms
and exhibit pharmacological properties pertinent to Alzheimer’s disease.
Alzheimer’s Disease Treatment Using Natural Foods: A Overview 1241

4 Toxicity Issues

Although it is evident from the above discussion that the phyto-based drugs have a
strong potential to treat Alzheimer’s disease, it is also of utmost importance to have
an in-depth understanding of whether there is any kind of toxicity-related issues or
not. This is why Mehla et al. [40] assessed the efficacy of Indian medicinal herbs
and, at the same time, evaluated the toxicity of the phyto drugs. The extract of
Centella asiatica, which can help in supporting enhanced working memory and bet-
ter self-related mood, is found to have good tolerance in various studies [41]. No
such toxicity issues have been reported for this herb up to a value of 1 g/kg of dos-
age when given orally. On the other hand, Bacopa monnieri extract was evaluated to
be safe and tolerable in healthy male helpers when given single and multiple doses
daily for 4 weeks.
Similarly, Sanka et al. [42] studied a shift in the paradigm of using drugs to treat
Alzheimer’s disease owing to fatal side effects toward the usage of phyto-based
herbal medicines. It is reported that herbal medicines exhibit a variety of benefits
over that of other drugs by having a significantly less adverse impact on the body.
This is because, unlike other medications, even if there is slight overdosage of the
phyto-based medicine, it would not be a vital issue for the body. Thus, it makes the
fact well evident that no such studies are reporting the toxicity of the phyto-based
drugs for the treatment of Alzheimer’s disease. Koynova and Tenchov [43] summa-
rized the efficacy of the extracts derived from plant sources and the drugs derived
from them for the purpose of treatment and also prevention of Alzheimer’s disease.
It stated that the phyto-based drugs are nowadays very well accepted globally and
that multifactorial type of pathogenesis of Alzheimer’s disease needs drugs cover-
ing a wide range of activities. For this reason, as phyto-based drugs possess a vari-
ety of compounds performing many mechanisms, these are estimated to be
non-harmful and more effective than drugs having a simple and single target for
treating complex disorders like Alzheimer’s disease.

5 Past and Future Expectations

It is highly evident from the overall discussion that Alzheimer’s disease has com-
plex pathophysiology and the rapid rise in the Alzheimer’s cases demands the effec-
tive treatment of the disease. Although the disease has been studied widely, as
reported by Opare Asamoah Botchway [44], tacrine was the first drug approved to
be used by the US Food and Drug Administration, mainly targeting the memory and
thinking-related signs of the disease. But still, it was seen that the drug had specific
side effects that were limited to the dosage, which involved anxiety, dizziness,
insomnia, nausea, and diarrhea, being typical for the cholinergic stimulation. Also,
owing to its potential to damage the liver, this drug was discontinued, and, later on,
1242 T. Bhattacharya et al.

other medications like rivastigmine, memantine, donepezil, and galantamine were

approved to treat Alzheimer’s. These drugs also have been reported to have dose-­
limiting side effects, for which currently the researchers are mainly emphasizing on
the disease-modifying medications aiming to mainly slow down the progression of
Alzheimer’s disease. The currently researched medicines include solanezumab,
saracatinib, and pioglitazone, but these are reported to have temporal benefits. Thus,
the researchers are optimistic that there would be disease-modifying medicines that
can totally prevent the chain of Alzheimer’s disease in the future. Bondi et al. [45]
reported that the future expectations of Alzheimer’s treatment involve allowing vari-
ous biomarkers that can target the different pathologies for showing the presence of
specific pathologies. The genetic evaluation can help understand the assessment of
different disorders and help identify the deficit patterns reflecting the effect of vari-
ous pathologies on the syndrome of dementia related to Alzheimer’s. Bondi et al.
[45] demonstrated that neuroimaging biomarkers and neuropsychological assess-
ment can help explain the heterogeneous representation of early signs of Alzheimer’s
in the future. On the other hand, Edmonds et al. [46] found another innovative
approach of treating Alzheimer’s with phytochemicals whose efficacy can be
improved with targeted delivery by nanotechnology, thereby addressing the issues
of conventional therapies of Alzheimer’s.

6 Conclusion

The aging population of the developed and developing countries is increasing rap-
idly and therefore the frequency of occurrence of Alzheimer’s disease is likely to
almost double in every 20 years till the year 2040. Alzheimer’s disease will become
a public health burden in the upcoming years and be expensive. That is why it is
essential nowadays to focus on preventing and treatment of the Alzheimer’s disease
and not merely on the temporal relieving of the symptoms. Many studies suggest
that phyto-based drugs have a promising potential in curing Alzheimer’s disease
and slowing down the progression of its signs and symptoms.

Consent for Publication Not applicable.

Conflict of Interest The authors declare that there are no conflicts of interest, financial or otherwise.

Consent Statement/Ethical Approval Not required.

No funding was received.

Alzheimer’s Disease Treatment Using Natural Foods: A Overview 1243

References

1. Alzheimer’s Association (2016) 2016 alzheimer’s disease facts and figures includes a spe-
cial report on the personal financial impact of Alzheimer's on families. Alzheimer’s and
Dementia 12:459
2. Chertkow H, Feldman HH, Jacova C, Massoud F (2013) Definitions of dementia and pre-
dementia states in Alzheimer's disease and vascular cognitive impairment: consensus from
the Canadian conference on diagnosis of dementia. Alzheimers Res Ther 5:S2. https://doi.
org/10.1186/alzrt198
3. Mayeux R, Stern Y (2012) Epidemiology of Alzheimer disease. Cold Spring Harb Perspect
Med 2:a006239. https://doi.org/10.1101/cshperspect.a006239
4. Takahashi RH, Nagao T, Gouras GK (2017) Plaque formation and the intraneuronal accumula-
tion of β-amyloid in Alzheimer’s disease. Pathol Int 67:185. https://doi.org/10.1111/pin.12520
5. Botchway BOA, Moore MK, Akinleye FO, Iyer IC, Fang M (2018) Nutrition: review on the
possible treatment for Alzheimer’s disease. J Alzheimers Dis 61:867. https://doi.org/10.3233/
JAD-­170874
6. Swaminathan A, Jicha GA (2014) Nutrition and prevention of Alzheimer’s dementia. Front
Aging Neurosci 6:282. https://doi.org/10.3389/fnagi.2014.00282
7. Singh R (2018) Current Alzheimers management with berries fruits therapy. J Public Health
Nutr 1:17. https://doi.org/10.35841/public-­health-­nutrition.1.2.17-­24
8. Agarwal P, Holland TM, Wang Y, Bennett DA, Morris MC (2019) Association of strawber-
ries and anthocyanidin intake with alzheimer's dementia risk. Nutrients 11:3060. https://doi.
org/10.3390/nu11123060
9. Gorji N, Moeini R, Memariani Z (2018) Almond, hazelnut and walnut, three nuts for neuropro-
tection in Alzheimer's disease: a neuropharmacological review of their bioactive constituents.
Pharmacol Res 129:115–127. https://doi.org/10.1016/j.phrs.2017.12.003
10. Chauhan A, Chauhan V (2020) Beneficial effects of walnuts on cognition and brain health.
Nutrients. https://doi.org/10.3390/nu12020550
11. Quinn JF et al (2010) docosahexaenoic acid supplementation and cognitive decline in
Alzheimer disease: a randomized trial. JAMA J Am Med Assoc. https://doi.org/10.1001/
jama.2010.1510
12. Avallone R, Vitale G, Bertolotti M (2019) Omega-3 fatty acids and neurodegenerative dis-
eases: new evidence in clinical trials. Int J Mol Sci. https://doi.org/10.3390/ijms20174256
13. Manchali S, Chidambara Murthy KN, Patil BS (2012) Crucial facts about health benefits of
popular cruciferous vegetables. J Funct Foods. https://doi.org/10.1016/j.jff.2011.08.004
14. Mirmosayyeb O et al (2017) possible role of common spices as a preventive and therapeutic
agent for Alzheimer's disease. Int J Prev Med. https://doi.org/10.4103/2008-­7802.199640
15. Singhal A, Bangar O, Naithani V (2012) Medicinal plants with a potential to treat
Alzheimer and associated symptoms. Int J Nutr Pharmacol Neurol Dis Ther. https://doi.
org/10.4103/2231-­0738.95927
16. Pasinetti G (2010) Role of grape seed polyphenols in Alzheimer’s disease neuropathology.
Nutr Diet Suppl. https://doi.org/10.2147/nds.s6898
17. Biswas K et al (2017) Assessment of in-vitro cholinesterase inhibitory and thrombolytic poten-
tial of bark and seed extracts of Tamarindus indica (L.) relevant to the treatment of Alzheimer's
disease and clotting disorders. J Intercult Ethnopharmacol. https://doi.org/10.5455/
jice.20161229055750
18. Girek M, Szymański P (2019) Phyto-Tacrine hybrids as promising drugs to treat Alzheimer's
disease. Chemistry Select. https://doi.org/10.1002/slct.201803672
19. Ayaz M, Ullah F, Sadiq A, Kim MO, Ali T (2019) Editorial: natural products-based drugs:
potential therapeutics against Alzheimer's disease and other neurological disorders. Front
Pharmacol. https://doi.org/10.3389/fphar.2019.01417
1244 T. Bhattacharya et al.

20. Ovais M et al (2018) Phyto-therapeutic and Nanomedicinal approaches to cure Alzheimer’s

disease: present status and future opportunities. Front Aging Neurosci. https://doi.org/10.3389/
fnagi.2018.00284
21. Bihaqi S, Singh A, Tiwari M (2012) Supplementation of convolvulus pluricaulis attenuates
scopolamine-induced increased tau and amyloid precursor protein (AβPP) expression in rat
brain. Indian J Pharmacol. https://doi.org/10.4103/0253-­7613.100383
22. Song JH et al (2013) Glycyrrhizin alleviates neuroinflammation and memory deficit induced
by systemic lipopolysaccharide treatment in mice. Molecules. https://doi.org/10.3390/
molecules181215788
23. Mahrous RS, Ghareeb DA, Fathy HM, Abu EL Khair RM, Abdallah (2017) The protective
effect of Egyptian Withania somnifera against Alzeheimer's. Med Aromatic Plants. https://doi.
org/10.4172/2167-­0412.1000285
24. Karkada G, Shenoy KB, Halahalli H, Karanth KS (2012) Nardostachys jatamansi extract pre-
vents chronic restraint stress-induced learning and memory deficits in a radial arm maze task.
J Nat Sci Biol Med. https://doi.org/10.4103/0976-­9668.101879
25. Khojah H, Edrada-Ebel R (2017) P43 the isolation and purification of bioactive metabolites
from Ficus carica and their neuroprotective effects in Alzheimer's disease. Biochem Pharmacol.
https://doi.org/10.1016/j.bcp.2017.06.044
26. Liu QF et al (2016) Coriandrum sativum suppresses Aβ42-induced ROS increases, glial cell
proliferation, and ERK activation. Am J Chin Med
27. Cacabelos R et al (2016) novel therapeutic strategies for dementia. CNS Neurolog Disord
Drug Targets. https://doi.org/10.2174/1871527315666160202121548
28. D'Onofrio G et al (2016) Phytochemicals in the treatment of Alzheimer's disease: a systematic
review. Curr Drug Targets. https://doi.org/10.2174/1389450117666161102121553
29. Karimi E (2020) Alzheimer’s: Phytotherapy and the most important herbs in the treatment of
Alzheimer’s. Plant Biotechnology Persa. https://doi.org/10.29252/pbp.2.1.61
30. Ahmed T, Gilani AH (2014) Therapeutic potential of turmeric in Alzheimer’s disease: cur-
cumin or curcuminoids? Phytother Res. https://doi.org/10.1002/ptr.5030
31. Shal B, Ding W, Ali H, Kim YS, Khan S (2018) Anti-neuroinflammatory potential of natu-
ral products in attenuation of Alzheimer’s disease. Front Pharmacol. https://doi.org/10.3389/
fphar.2018.00548
32. Nam SM et al (2014) Effects of curcumin (Curcuma longa) on learning and spatial memory as
well as cell proliferation and neuroblast differentiation in adult and aged mice by upregulating
brain-derived neurotrophic factor and CREB signaling. J Med Food. https://doi.org/10.1089/
jmf.2013.2965
33. Hoppe JB et al (2013) Free and nanoencapsulated curcumin suppress β-amyloid-induced
cognitive impairments in rats: involvement of BDNF and Akt/GSK-3β signaling pathway.
Neurobiol Learn Mem. https://doi.org/10.1016/j.nlm.2013.08.001
34. Furukawa S, Yang L, Sameshima H (2014) Galantamine, an acetylcholinesterase inhibitor,
reduces brain damage induced by hypoxia-ischemia in newborn rats. Int J Dev Neurosci.
https://doi.org/10.1016/j.ijdevneu.2014.06.011
35. Xia JH et al (2012) Sesquiterpenoids and triterpenoids from Abies holophylla and their bioac-
tivities. Phytochemistry. https://doi.org/10.1016/j.phytochem.2011.11.011
36. Raza SS et al (2013) Neuroprotective effect of naringenin is mediated through suppression
of NF-κB signaling pathway in experimental stroke. Neuroscience. https://doi.org/10.1016/j.
neuroscience.2012.10.041
37. Lou H, Jing X, Wei X, Shi H, Ren D, Zhang X (2014) Naringenin protects against 6-OHDA-­
induced neurotoxicity via activation of the Nrf2/ARE signaling pathway. Neuropharmacology.
https://doi.org/10.1016/j.neuropharm.2013.11.026
38. Pany S, Pal A, Sahu PK (2014) Neuroprotective effect of quercetin in neurotoxicity induced
rats: role of neuroinflammation in neurodegeneration. Asian J Pharm Clin Res
39. Howes MJR, Fang R, Houghton PJ (2017) Effect of Chinese herbal medicine on Alzheimer’s
disease. Int Rev Neurobiol
Alzheimer’s Disease Treatment Using Natural Foods: A Overview 1245

40. Mehla J, Gupta P, Pahuja M, Diwan D, Diksha D (2020) Indian medicinal herbs and formula-
tions for Alzheimer’s disease, from traditional knowledge to scientific assessment. Brain Sci.
https://doi.org/10.3390/brainsci10120964
41. Puttarak P et al (2017) Effects of Centella asiatica (L.) Urb. On cognitive function and mood
related outcomes: a systematic review and meta-analysis. Sci Rep. https://doi.org/10.1038/
s41598-­017-­09823-­9
42. Sanka N, Santhipriya N, Nadendla RR (2018) An updated review on anti-Alzheimer’s herbal
drugs. Journal of Drug Delivery and Therapeutics. https://doi.org/10.22270/jddt.v8i6.2049
43. Koynova R, Tenchov B (2017) Natural product formulations for the prevention and treatment
of Alzheimer’s disease: a patent review. Recent Pat Drug Deliv Formul. https://doi.org/10.217
4/1872211312666171207152326
44. Botchway BOA (2017) Alzheimer’s disease – the past, the present and the future. Sci J Clin
Med. https://doi.org/10.11648/j.sjcm.20170601.11
45. Bondi MW, Edmonds EC, Salmon DP (2017) Alzheimer’s disease: past, present, and future. J
Int Neuropsychol Soc. https://doi.org/10.1017/S135561771700100X
46. Edmonds EC et al (2016) Heterogeneous cortical atrophy patterns in MCI not captured by con-
ventional diagnostic criteria. Neurology. https://doi.org/10.1212/WNL.0000000000003326
Natural Products Used in the Treatment
of Autoimmune Disorder

Anjali Saharan, Meenakshi Dhanawat, Chander Parkash Dora,

Rakesh Kumar Sindhu, and Inderjeet Verma

1 Introduction

Autoimmune illnesses are caused by deregulated immune responses, which attack

the body’s tissues instead of protecting the host from external pathogenic invaders.
Autoimmunity evolves by the complex combination of genetic and environmental
variables. Autoimmune inflammation and tissue damage are exacerbated by cell-­
mediated and/or antibody-mediated effector responses. These conditions either
have a strong impact on organs such as systemic autoimmunity or primarily focus
on one organ, that is, organ-specific autoimmunity [1]. Some of the autoimmune
disorders such as type 1 diabetes, rheumatoid arthritis (RA), systemic lupus erythe-
matosus, multiple sclerosis, Graves’ syndrome, psoriasis, and inflammatory bowel
syndrome (ulcerative colitis [UC]) are discussed below in detail.
It was explored that the prevalence of these diseases is much higher in developed
countries as compared to developing ones. These diseases were further carried out
for study as they have a prevalence rate of more than 2%. To monitor and control
severe medication in terms of allopathy, herbal medicines were used to counteract
the autoimmune disorder. The uncontrolled immune pathology may lead to various
serious disabilities/deformities along with loss of functioning of organs. As

A. Saharan
MM School of Pharmacy, Maharishi Markandeshwar University, Sadopur-Ambala, Haryana,
India
M. Dhanawat
Amity Institute of Pharmacy, Amity University Haryana, Gurugram, Haryana, India
C. Parkash Dora · R. K. Sindhu
Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
I. Verma (*)
M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be University),
Mullana-Ambala, Haryana, India

© The Author(s), under exclusive license to Springer Nature 1247

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_52
1248 A. Saharan et al.

autoimmune diseases are chronic, they will impart a negative impact on economic,
psychological, and social causes [2]. To counterbeat all these above-mentioned fac-
tors and to alleviate the side effects of the allopathic medicines, various herbal
plants were explored in terms of their usage in highly privileged autoimmune disor-
ders, which are discussed in detail ahead. To ensure safety, therapeutic agents and
treatment regimens should be obliged to prevent patients from autoimmunity. Plant
products contain a variety of bioactive compounds with therapeutic potential due to
which they are widely used in various ailments such as inflammatory diseases, auto-
immune diseases, infectious diseases, and cancer [3, 4]. Many autoimmune disor-
ders have common symptoms, such as skin rashes and exhaustion. Swelling and
redness, difficulty concentrating, numbness and tingling in the hands and feet, hair
loss, and skin rashes all lead to the diagnosis of immune response disorders [5].

2 Causes of Autoimmune Disease

All of these elements interact in the mosaic of autoimmune diseases, as mentioned.

The resulting three etiopathogenic factors [6] are involved in it, as shown in Fig. 1.
The exact etiological root cause behind any study is not explored yet but these
mentioned risk factors had a possible influence on the autoimmune disorder, as
discussed below.
Genetics Some autoimmune diseases are passed down through generations,
increased by mutations of genes, such as ankylosing spondylitis and other autoim-
mune illnesses, which have been linked to major histocompatibility complex
(MHC)-I or II [7].

Fig. 1 Etiopathogenic factors involved in autoimmune disease

Natural Products Used in the Treatment of Autoimmune Disorder 1249

Clones Autoreactive clones may be able to escape negative selection in the thy-
mus. It is possible that not all self-antigens are represented in the thymus, or that
some antigens are not processed and presented correctly [8].

Abnormal expression of class II antigens The expression of these antigens leads

to various serious disorders such as those of thyroid epithelial cells and salivary
gland [9].

Sex In lupus, an autoimmune disorder, a constant decline in the estrogen level has
been shown, which is used to enhance autoimmunity [10].

Exposure of hidden (sequestered) antigens or new epitopes Because some self-­

antigens are late-developing antigens (new epitopes) or are limited to specialized
organs, lymphoid cells may not be exposed to them during differentiation (seques-
tered antigens). Antigens released from these organs as a result of a traumatic injury
or surgery may trigger the immune system, causing an autoimmune illness to
develop—intracellular antigens (such as DNA and mitochondria); band-3″ protein
on senescent red blood cells (RBCs), eye lenses, and spermatozoa; and rheumatoid
factor are only a few examples [11].

Cross-reactivity with microorganisms (molecular mimicry) Certain pathogens

contain antigens that contain determinants that react with self-antigens in a cross-­
reactive manner, which results in the production of effector cells or antibodies
against tissue antigens, showing their immune response.

Viral involvement It was found that retroviral infection in Sjogren’s syndrome

(dry eye/dry mouth) and systemic lupus erythematosus were caused by viral infec-
tions [12].

3 Types of Autoimmune Disorders

The autoimmune disorders having more provenances are depicted in Fig. 2.

3.1 Type 1 Diabetes

Following cardiovascular illnesses and malignancies, autoimmune diseases are the

third most common type of illness in the developed world. Type 1 diabetes, often
known as autoimmune diabetes, affects ten million people around the world. This
condition is characterized by the death of pancreatic cells by autoimmunity, result-
ing in insulin insufficiency, hyperglycemia, and complications. Diabetes mellitus is
a metabolic ailment that primarily affects the body’s immune system and it kills the
1250 A. Saharan et al.

Fig. 2 Types of various autoimmune disorders

pancreatic cells by following the antigen–antibody reaction of T-cells, and autoanti-

bodies. Natural products and their derivative secondary metabolites having their
bioactive molecules are widely used due to their therapeutic immunomodulatory
action in diabetes [13]
Some majorly used herbal plants are discussed below in detail

3.1.1 
Emblica officinalis

It is also known as Indian gooseberry or amla and acts as an antioxidant; it is adap-

togenic, hepatoprotective, hypolipidemic, cytoprotective, and immunomodulatory
in nature. It produces one of the world-renowned natural product combinations
triphala (a polyherbal drug combination). It is widely used to promote longevity
and for the treatment of inflammatory and human immunodeficiency virus (HIV)
disease. It controls lymphocyte proliferation and interleukin (IL) production. It has
antioxidant potential due to the presence of vitamin C and tannins. Pectin was also
found, which is responsible for the reduction of serum cholesterol levels and main-
tenance of blood pressure. It has immunomodulatory properties due to the inhibi-
tion of interleukins and interferons [14].
Natural Products Used in the Treatment of Autoimmune Disorder 1251

3.1.2 
Momordica charantia

It is also known as bitter melon or bitter gourd, and is a climber plant that is well
known for its medicinal and nutraceuticals values. The pharmacological properties
exhibited by it are antimicrobial, anti-inflammatory, and antihelminthic. It was
found to contain saponin polypoid and alkaloid momo ricin. In vivo investigations
show that its chemical ingredients have an immunostimulatory impact, with the rise
in interferon and cell-mediated immunity mechanisms [15].

3.1.3 
Nigella sativa

N. sativa, commonly known as black seeds, is a dicotyledon fruit that exhibits vari-
ous therapeutic potentials such as antidiabetic, antihypertensive, anti-inflammatory,
and antihistaminic properties. It was found to escalate the antioxidant mechanism
that prevents lipid peroxidation in diabetes [16].

3.1.4 
Sida cordiflia

It is also known as flannel weed that has aphrodisiac and antidiabetic properties. It
was discovered that hypoglycemic impact of flannel by activating beta cells and
decreasing oxidative stress and free radical production [17].

3.1.5 
Psidium guajava

It is commonly known as guava and is an evergreen shrub or small tree. It mainly

contains vitamin C, tannins, and flavonoids such as quercetin, isoflavonoids, and
kaempferol, which exhibit antioxidant, antihyperglycemic, and analgesic actions [18].

3.1.6 
Gymnema sylvestre

It is commonly known as gymnema and used in the management of various diseases

such as obesity, diabetes, cancer, hepatotoxicity, and hyperlipidemia. The prime
constituents found in it are gymnemic acids and gymnema saponins, which help
control fasting sugar [19].

3.1.7 
Azadirachta indica

It is commonly known as neem and is well known for its number for therapeutic
benefits. It contains various phytoconstituents such as nimbin, nimbinin, and nimbi-
dinin, which impart its properties as a stimulant, antioxidant, and as a contraceptive.
1252 A. Saharan et al.

Experimental studies reveal that it is used for the production of gamma interferon
and it also stimulates cell-mediated immunostimulant activity [20].

3.1.8 
Allium sativum

It is commonly known as garlic and is used as a digestant and carminative. It is also

used to treat diseases like atherosclerosis and headache. It also has antimicrobial,
antifungal, antilipidemic, antithrombotic, and antidiabetic properties. It prevents the
formation of peroxidase, which helps suppress diabetes [21].

3.1.9 
Tinospora cordifolia

It is commonly known as guduchi. It exhibits various medicinal properties like anti-

oxidant, immunomodulatory, antidiabetic, anti-inflammatory, and antiarthritic. It is
used as an antidiabetic as it minimizes oxidative stress and it also has immuno-
modulatory effects by enhancing phagocytic activity [22].

3.1.10 
Trigonella foenum-graecum L.

It is commonly known as fenugreek. The main constituents found in it are diosgenin

and 4-hydroxyisoleucine. It has been shown to have hypoglycemic and antidyslip-
idemic effects.
Hypoglycemic impact of diosgenin is due the renewal of pancreatic β-cells and
stimulation of insulin secretion. 4-Hydroxyisoleucine has shown antidiabetic poten-
tial via stimulation of glucose-dependent insulin secretion and improves insulin
resistance by promoting mitochondrial in muscle and/or liver. Fenugreek seeds are
also a rich source of fiber. The soluble dietary fiber fraction of fenugreek (i.e., galac-
tomannan) has been shown to enhance glycemic control [23, 24].

3.1.11 
Panax ginseng

It is commonly known as ginseng and contains polysaccharides, polyacetylenes,

and ginsenosides. Ginseng and ginsenosides have been found to lower blood glu-
cose, increase insulin sensitivity, and regulate lipid metabolism by activating the
peroxisome proliferator-activated receptors (PPARs) that regulate glucose and lipid
metabolism, as well as the transcription of proteins involved in glucose and fatty
acid uptake. Ginsenosides activate the AMP-activated protein kinase (AMPK) path-
way, resulting in anticarcinogenic, immunomodulatory, anti-inflammatory, antial-
lergic, antiatherosclerotic, antihypertensive, and antidiabetic actions, as well as in
reduction of hepatic gluconeogenesis and steatosis [25].
Natural Products Used in the Treatment of Autoimmune Disorder 1253

3.1.12 
Cinnamomum cassia

It is commonly known as cinnamon. They are found to contain procyanidin that

shows hypoglycemic effects by enhancing lipid accumulation in adipose tissue and
insulin concentrations in the blood and pancreas [26].

3.1.13 
Plantago ovata

It is commonly known as psyllium. The main phytoconstituents found in it are poly-

saccharides such as psyllium heteroxylans. It acts as an antidiabetic by retarding
glucose flow to the small intestine or by delayed gastric emptying, which shows
hypoglycemic effects as a result [27].

3.1.14 
Zingiber officinale

It is commonly known as ginger. It contains phytoconstituents such gingerols,

shogaols, paradols, and zingiberene, which have antioxidative, glycemic and lipid-­
lowering, immunomodulatory, anti-inflammatory, and antiapoptosis properties.
Gingerols, shogaols, and diarylheptanoids, which block the activities of cyclooxy-
genase (COX), inducible nitric oxide synthase (NOS), and lipoxygenase, reduce
prostaglandin synthesis, and interfere with cytokine signaling, which are thought to
be responsible for ginger’s anti-inflammatory properties [28].

3.2 Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by high-grade

inflammation that causes joint destruction, deformities, impaired quality of life, and
premature mortality due to increased cardiovascular risk [29–32]. With the help of
early diagnosis and effective treatment, deformity of the joints can be prevented
[33]. Therapy of RA has evolved considerably since the use of willow bark in the
eighteenth century to the present armamentarium of synthetic disease-modifying
antirheumatic drugs (DMARDs), biologic DMARDs (bDMARDs), and targeted
synthetic DMARDs (tsDMARDs). Methotrexate (MTX) is the widely used gold-­
standard drug in the treatment of RA. However, MTX alone is not always appropri-
ate because of inadequate efficacy, and approximately 10–30% of RA patients
discontinue it because of toxicity [34, 35]. Biologic DMARDs (bDMARDs) are
efficacious in the treatment of RA; however, bDMARDs have major limitations:
parenteral administration, risk of infection, neutralizing antibodies, and prohibitive
cost [36, 37]. Targeted synthetic DMARDs (tofacitinib, nilotinib, and iguratimod)
are expensive, cardiovascular (CV) protection not demonstrated, and have an
1254 A. Saharan et al.

increased risk of herpes zoster and vascular events like deep vein thrombosis (DVT)
and pulmonary thromboembolism [38].

4 Natural Products Used in the Treatment

of Rheumatoid Arthritis

Due to the limitation of synthetic and biologic DMARDs, nowadays several RA

patients have started to turn to natural and herbal bioactive agents to relieve the
symptoms of RA and its characteristics [39]. Approximately 36% of the US popula-
tion uses complementary and alternative medicine to relieve the symptoms. A sum-
mary of significant natural compounds in the treatment of arthritis is presented below.

Curcuma longa
4.1 

Curcumin is a well-studied natural compound in rheumatoid arthritis. It has potent

anti-inflammatory properties and is derived from turmeric (Curcuma longa). A
recent experimental study has found that curcumin has the potential to reduce and
treat pro-inflammatory cytokines, and improve disease activity and histopathology
scores as compared to methotrexate in adjuvant-induced Levis rats [40]. Curcumin
has the potential to inhibit the suppression of the nuclear factor-kappa B (NF-κB)
signaling [41]. Curcumin also inhibits the cyclooxygenase and lipoxygenase path-
ways and leads to the suppression of inflammatory mediator [42]. A recent random-
ized control study including 24 RA patients has demonstrated that 250 mg curcumin
twice a day for 12 weeks significantly improved American College of Rhematology
(ACR) 20 criteria, Western Ontario and McMaster Universities Arthritis Index
(WOMAC) index, and Visual Analogue Scale (VAS) pain score [43].

Tripterygium wilfordii
4.2 

Triptolide, a diterpene triepoxide, is a bioactive natural compound isolated from

Tripterygium wilfordii Hook F (TwHF), which is used to treat inflammatory arthritis
and other autoimmune diseases [44]. In recent years, various studies have been
published emphasizing the value of triptolide in the treatment of inflammatory dis-
orders [45]. Triptolide has the potential to induce T-cell apoptosis mediated through
phosphorylation of Signal transducer and activator of transcription 3 (STAT3) and
also attenuates the NF-κB activity. In collagen-induced arthritis, experimental study
has shown that triptolide can protect bone deformity by targeting Receptor activator
Natural Products Used in the Treatment of Autoimmune Disorder 1255

of nuclear factor kappa-Β ligand (RANKL)-mediated Extracellular signal-regulated

kinase/Akt signaling pathway or PI3K-Akt signaling pathway (ERK/Akt) [46, 47].

4.2.1 Alkaloids

Alkaloids are obtained from various natural resources and they have a variety of
pharmacological activities that contribute to the management of RA [48]. Various
research studies have shown that alkaloid compounds such as sinomenine, piper-
longumine, Withania somnifera (ashwagandha), Nigella sativa, koumine
(Gelsemium elegans), berberine, oxymatrine, and trikatu prevent arthritis progres-
sion via various pathways such as T-cell proliferation, reactive oxygen species
(ROS), and downregulation of various pro-inflammatory cytokines (tumor necrosis
factor [TNF]-α, IL-6, IL-12, and NF-kB). A recent double-blind study that included
120 RA patients demonstrated that sinomenine (120 mg twice daily) taken in com-
bination with MTX for 24 weeks significantly improved inflammation in arthritic
patients [49]. Withania somnifera has also the potential to suppress NF-kB signal-
ing, pro-inflammatory cytokines, and TNF-α and to reduce RANKL levels essential
for differentiation of osteoclast. An experimental animal study has found that allyl-
isopropylacetamide (AIA) Wistar rats treated with ashwagandha (1000 mg kg/day)
for 8 days showed significantly reduced bone destruction. It might be due to the
result of inhibition of inflammatory mediators and modulating the biochemical pro-
cesses associated with rheumatoid arthritis [50].

4.2.2 Phenolic Compounds

Various studies have shown the potential of phenolic compounds like flavonoids,
resveratrol, emodin, rosmarinic acid, and mangiferin in the treatment of arthritis.
These natural compounds have the properties to modulate both the action and the
production of inflammatory mediators via inhibition of NF-kB signaling. Flavonoids,
isolated from the citrus fruits, especially bergamot juice, have the potential to treat
arthritis. A recent clinical study involving RA patients has found that pomegranate
extract (250 mg twice a day) taken for 8 weeks, resulted in a significant reduction in
disease activity measures compared to indomethacin [51].

4.2.3 Quercetin

Quercetin is a naturally occurring flavonoid that is widely found in fruits, herbs, and
vegetables. Several recent experimental studies have demonstrated that quercetin
has the potential to treat rheumatoid arthritis by reducing cyclooxygenase and
lipoxygenase expressions and modulating the activation of the NF-kB signaling
pathway [52]. A study reported that, through a double-blind placebo-controlled
1256 A. Saharan et al.

study that included 50 RA females treated with quercetin (500 mg/day) for 8 weeks,
demonstrated that quercetin significantly improved early morning stiffness, pain,
and disease activity scores in 28 joints and reduced TNF-α levels compared to pla-
cebo [53].

4.2.4 Psoriasis

Psoriasis is a disease condition accomplished by the abnormal growth of skin cells

and their growth multiplicity is very high without any need. The newly formed cells
cause inflamed red patches with an appearance as silver-white scales of plaque on
the skin. It was found that 30% of persons suffering from psoriasis had swelling,
stiffness, and pain in their joints [54]. Some of the herbal species that had a positive
impact on it are explored below.

Glycyrrhiza glabra
4.3 

It is commonly known as liquorice. The therapeutic moiety mainly found in it is

glycyrrhizin. It is a glycoconjugate triterpene extracted from the roots of the
liquorice which have been widely used to treat allergic diseases by suppressing the
tumor necrosis factor. It also inhibits monocyte adhesion cells and hinders mitogen-­
activated protein kinase (MAPK) signaling pathways [54].

Calendula officinalis L.
4.4 

It was reported that Calendula officinalis flowers contain various bioactive com-
pounds such as terpenoids, carotenoids, flavonoids, and polyunsaturated fatty acids.
The presence of these moieties showed anti-inflammatory activities in various skin
disorders [55].

Annona squamosa
4.5 

It is also known as sugar apple. The chemical constituents found in it are quamo-
cenin, annotemoyin, reticulatain, and squamocin, shown to have antioxidant and
anti-inflammatory properties, which proves its effectiveness for various skin disor-
ders [56, 57].
Natural Products Used in the Treatment of Autoimmune Disorder 1257

Melaleuca alternifolia
4.6 

It is also known as the tea tree. The leaves contain various oil glands and are rich in
aromatic oil containing terpinolene and cineole, which are mainly used in the treat-
ment of acne, dandruff, and cold sores. It was used to produce allergic dermatitis
with sensitization to the sesquiterpenoid fraction [58].

Momordica charantia
4.7 

Momordica charantia is commonly called bitter melon or ampalaya. It contains

active constituents such as momordicoside, monordicophenoide, dihydrophaseic
acid, glucopyranoside, guanosine adenosine, uracil, and cytosine. These compounds
were found to be effective against various bacterial infections and against a variety
of skin conditions like psoriasis, acne, and wounds [59].

Silybum marianum
4.8 

They are commonly known as milk thistle seeds that contain phytoconstituents such
as silibinin (silybin), silychristin, and silydianin, which trigger an outbreak of pso-
riasis; it was found that it inhibits human T-cell activation, which occurs in psoria-
sis [60].

4.8.1 Graves’ Disease

This is the most prominent disease characterized mainly by altering the function of
the thyroid gland by stimulating the overproduction of hormones. Thyroid hor-
mones are used to regulate the body’s energy consumption and help in metabolism.
Some of the herbal moieties such as isoflavonoids, rosmarinic acid, blue flag, gug-
gul, selenium, iodide, and vitamin D3 supplements have profound effects on thyroid
hormones and the hypothalamus [61]. Some of the herbal plants tabulated in Table 1
have a positive effect on thyroid functioning.

5 Inflammatory Bowel Disease

Crohn’s disease (CD) and ulcerative colitis (UC) are examples of inflammatory
bowel disease (IBD), which is a category of chronic illnesses defined by gastroin-
testinal tract inflammation [64]. Several anti-inflammatory medications including
1258 A. Saharan et al.

Table 1 Natural products used in the treatment of Graves’ disease

S. Biological
no. source Active constituents Mechanism of action References
1. Commiphora Gallic acid, quercetin,Increases iodine uptake by the Ng et al.
wightii and guggulsterones E thyroid gland, enzymes involved in [61]
and Z thyroid hormone production, and
tissue oxygen intake
2. Glycine max Genistein and daidzein Inhibits thyroperoxidase that Bhardwaj
catalyzes iodination and thyroid et al. [62]
hormone biosynthesis
3. Allium cepa Allyl alcohol and Inhibits thyroid function Chee et al.
methyl disulfide [63]
4. Melissa Flavonoids, rosmarinic Inhibits thyroid stimulating Mannaa
officinalis acid, gallic acid, and hormone (TSH) receptor binding, et al. [64]
phenolic compounds which causes decreased production
of T3 and T4 in the thyroid gland

6-mercaptopurine, 5-aminosalicylic acid (5-ASA), steroids, and Non-steroidal anti-­

inflammatory drugs (NSAIDs) are commonly used to treat IBD. However, these
drugs showed severe adverse effects, and most therapies are ineffective. Thus, it is
crucial to identify newer and safer medications that are effective in the treatment
and prevention of IBD. Various natural derivatives have been shown to safely sup-
press pro-inflammatory pathways and control IBD by inhibiting the expression of
pro-inflammatory cytokines (e.g., tumor necrosis factor [TNF]-α), intercellular
adhesion molecule, pro-inflammatory mediators (e.g., inducible nitric oxide syn-
thase [iNOS] and cyclooxygenase-2 [COX-2]), and master transcription factors
(e.g., nuclear factor-kappa B) [65].
Some natural derivatives that have shown anti-inflammatory activities are resve-
ratrol from Polygonum cuspidatum, berberine and berberrubine from Berberis vul-
garis, catechins from Camellia sinensis, 14-O-acetylcholine from Aconitum
laciniatum, capnoidine from Corydalis dubia, zedoarondiol from Curcuma
heyneana, bromelain from Ananas comosus, and other pigmented fruits and vegeta-
bles [66]. A few examples of natural products used in the treatment of inflammatory
bowel disease are described in Table 2.

5.1 Multiple Sclerosis

Multiple sclerosis is a neurological autoimmune disease characterized by inflamma-

tion, demyelination, and axonal damage. Multiple sclerosis drugs do not enhance
myelin sheath healing directly. As a result, several studies have attempted to pro-
mote demyelination to gain greater therapeutic outcomes. Natural products offer the
unique benefit of protecting and rebuilding the neurological system, in addition to
Natural Products Used in the Treatment of Autoimmune Disorder 1259

Table 2 Natural products used in the treatment of inflammatory bowel diseases

S. Biological Active
no. source constituents Mechanism of action References
1. Ananas Bromelain Reduces mRNA expression of Verma et al.
comosus pro-inflammatory cytokines interleukin [67]
(IL)-8 and tumor necrosis factor
(TNF)-α
2. Panax Ginsenosides Inhibits inflammatory cytokines and Wang et al.
quinquefolius restores microbiome inhibited [68]
by azoxymethane/dextran sodium
sulfate (AOM/DSS)
3. Penicillium Pyrenocine A Inhibits nitrite production and the Toledo et al.
paxillin synthesis of pro-inflammatory [69]
cytokines and Prostaglandin E2 (PGE2)
4. Styrax Styraxosides A Inhibits the expression of nitric oxide Yun et al.
japonica synthase (NOS) and cyclooxygenase-2 [70]
(COX-2); mRNA expression levels of
NOS and COX-2, TNF-α, and IL-1;
and inhibits the nuclear factor-kappa B
(NF-kB) pathway’s DNA-binding
capacity
5. Euphorbia Euphol Reduces the expression of NOS2, Dutra et al.
tirucalli Vascular endothelial growth factor [71]
(VEGF), and Ki67 in colonic tissues;
inhibits the levels and expression of
IL-1, chemokine (C-X-C motif) ligand
1 (CXCL1)/KC, Monocyte
chemoattractant protein-1 (MCP-1),
Macrophage Inflammatory Protein-1
(MIP-2), TNF-α, and IL-6 in colonic
tissue
6. Cinnamomum trans- Significant reduction of the Schink et al.
verum Cinnamaldehyde Lipopolysaccharides (LPS)-dependent [72]; Yu
and p-cymene IL-8 secretion et al. [73]

alleviating clinical symptoms [74] (Table 3). Natural products used in the treatment
of multiple sclerosis has been depicted in Table 3.

6 Conclusion

Autoimmune diseases occurs because of the body’s natural defenses the immune
system - attack the body’s own healthy tissue. Establishing proper balance through
the use of above natural products, and lifestyle changes may thus offer a safe and
effective alternative to traditional treatment and bring new hope to patients who are
suffering from the autoimmune diseases. Chemical compounds isolated from
1260 A. Saharan et al.

Table 3 Natural products used in the treatment of multiple sclerosis

S.
no. Biological source Active constituents Mechanism of action References
1 Isodon eriocalyx Eriocalyxin B Inhibits Janus kinase/signal Giacoppo et al.
transducer and activator of [75]
transcription (Jak/STAT)
and NF-κB signaling
pathways
2 Scutellaria Baicalein ↓ (TNF-α, IL-1β) Hashimoto et al.
baicalensis [76]
3 Cnidium monnieri Osthole ↓ (interferon-gamma - Hashimoto et al.
IFN-γ, IL-17) [76]
4 Astragalus Astragaloside IV ↑ Glucocorticoid pathway Hanisch and
membranaceus Kettenmann [77]
5 Glycyrrhiza inflata 18β-Glycyrrhetinic ↓ Mitogen-activated protein Liu et al. [78]
acid kinase (MAPK) pathway

various plants have the potential to treat diabetes, rheumatoid arthritis, psoriasis,
inflammatory bowel disease, multiple sclerosis, and ulcerative colitis. There are
thousands of texts and monographs available on herbal remedies, but a majority of
medicines are not envisaged in research due to lack of knowledge. The present lit-
erature summarized the therapeutic and medicinal benefits of various natural
compounds.

References

1. Chaplin DD (2010) Overview of the immune response. J Allergy Clin Immunol 125(2):3–23
2. Missoum H, Alami M, Bachir F et al (2019) Prevalence of autoimmune diseases and clini-
cal significance of autoantibody profile: data from National Institute of Hygiene in Rabat,
Morocco. Hum Immunol 80(7):523–532
3. Ho LJ, Lai JH (2004) Chinese herbs as immunomodulators and potential disease-modifying
antirheumatic drugs in autoimmune disorders. Curr Drug Metab 5(2):181–192
4. Srivastava S, Singh D, Patel S et al (2017) Role of enzymatic free radical scavengers in man-
agement of oxidative stress in autoimmune disorders. Int J Biol Macromol 101:502–517
5. Baizabal-Carvallo JF, Jankovic J (2015) Stiff-person syndrome: insights into a complex auto-
immune disorder. J Neurol Neurosurg Psychiatry 86(8):840–848
6. Marrack P, Kappler J, Kotzin BL (2001) Autoimmune disease: why and where it occurs. Nat
Med 7(8):899–905
7. Cooper GS, Stroehla BC (2003) The epidemiology of autoimmune diseases. Autoimmun Rev
2(3):119–125
8. Inshaw JR, Cutler AJ, Burren OS et al (2018) Approaches and advances in the genetic causes
of autoimmune disease and their implications. Nat Immunol 19(7):674–684
9. Asano M, Toda M, Sakaguchi N et al (1996) Autoimmune disease as a consequence of devel-
opmental abnormality of a T cell subpopulation. J Exp Med 184(2):387–396
10. Bruserud O, Oftedal BE, Wolff AB et al (2016) AIRE-mutations and autoimmune disease.
Curr Opin Immunol 43:8–15
Natural Products Used in the Treatment of Autoimmune Disorder 1261

11. Sakaguchi S, Sakaguchi N (1989) Organ-specific autoimmune disease induced in mice by

elimination of T cell subsets. V. Neonatal administration of cyclosporin A causes autoimmune
disease. J Immunol Res 142(2):471–480
12. Goris A, Liston A (2012) The immunogenetic architecture of autoimmune disease. Cold
Spring Harb Perspect 4(3):007260
13. Eyre S, Hinks A, Bowes J et al (2010) Overlapping genetic susceptibility variants between
three autoimmune disorders: rheumatoid arthritis, type 1 diabetes and coeliac disease. Arthritis
Res Ther 12(5):1–6
14. Khan KH (2009) Roles of Emblica officinalis in medicine-a review. Bot Res Int 2(4):218–228
15. Srivastava VK, Nath P (1972) Inheritance of some qualitative characters in Momordicacharantia
L. Indian J Hortic 29(3):319–321
16. Ali BH, Blunden G (2003) Pharmacological and toxicological properties of Nigella sativa.
Phytother Res 17(4):299–305
17. Jain A, Choubey S, Singour PK et al (2011) Sidacordifolia (Linn)–an overview. J Appl Pharm
Sci 1(2):23–31
18. Oh WK, Lee CH, Lee MS et al (2005) Antidiabetic effects of extracts from sidiumguajava. J
Ethnopharmacol 96(3):411–415
19. Persaud SJ, Al-Majed H, Raman A et al (1999) Gymnemasylvestre stimulates insulin release
in vitro by increased membrane permeability. J Endocrinol 163(2):207–212
20. Biswas K, Chattopadhyay I, Banerjee RK et al (2002) Biological activities and medicinal
properties of neem (Azadirachtaindica). Curr Sci 10:1336–1345
21. Augusti KT (1996) Therapeutic values of onion (Allium cepa L.) and garlic (Allium sativum
L.). Indian J Exp Biol 34(7):634–640
22. Manjrekar PN, Jolly CI, Narayanan S (2000) Comparative studies of the immunomodulatory
activity of Tinosporacordifolia and Tinosporasinensis. Fitoterapia 71(3):254–257
23. Zia T, Hasnain SN, Hasan SK (2001) Evaluation of the oral hypoglycaemic effect of
Trigonellafoenum-graecum L. (methi) in normal mice. J Ethnopharmacol 75(3):191–195
24. Kanetkar P, Singhal R, Kamat M (2007) Gymnemasylvestre: a memoir. Clin Biochem Nutr
41(2):77–81
25. Kim DH (2012) Chemical diversity of Panax ginseng, Panaxquinquifolium, and
Panaxnotoginseng. J Ginseng Res 36(1):1
26. Verspohl EJ, Bauer K, Neddermann E (2005) Antidiabetic effect of Cinnamomum cassia and
Cinnamomumzeylanicum in vivo and in vitro. Phytother Res 19(3):203–206
27. Fischer MH, Yu N, Gray GR et al (2004) The gel-forming polysaccharide of psyllium husk
(PlantagoovataForsk). Carbohydr Res 339(11):2009–2017
28. Mascolo N, Jain R, Jain SC et al (1989) Ethnopharmacologic investigation of ginger
(Zingiberofficinale). J Ethnopharmacol 27(2):129–140
29. Calabro A, Caterino AL, Elefante E et al (2016) One year in review 2016: novelties in the treat-
ment of rheumatoid arthritis. Clin Exp Rheumatol 34(3):357–372
30. Strand V, Singh JA (2017) Evaluation and management of the patient with suspected inflam-
matory spine disease. Mayo Clin Proc 92(4):555–564
31. Hintenberger R, Falkinger A, Danninger K et al (2018) Cardiovascular disease in patients with
autoinflammatory syndromes. Rheumatol Int 8:37–50
32. Gonzalez-Gay MA, Gonzalez-Juanatey C, Martin J (2005) Rheumatoid arthritis: a disease
associated with accelerated atherogenesis. Semin Arthritis Rheum 35:8–17
33. Aletaha D, Smolen JS (2018) Diagnosis and management of rheumatoid arthritis. JAMA
320:1360–1372
34. Aggarwal P, Naik S, Mishra KP et al (2006) Correlation between methotrexate efficacy & tox-
icity with C677T polymorphism of the methylenetetrahydrofolate gene in rheumatoid arthritis
patients on folate supplementation. Indian J Med Res 124(5):521–526
35. Schiff MH, Whelton A (2000) Renal toxicity associated with disease-modifying antirheumatic
drugs used for the treatment of rheumatoid arthritis. Semin Arthritis Rheum 30:196–208
1262 A. Saharan et al.

36. Oldsworth EA, Donaghy B, Fox KM et al (2021) Biologic and targeted synthetic DMARD uti-
lization in the United States: Adelphi Real World disease specific programme for rheumatoid
arthritis. Rheumatol Ther 8(4):1637–1649
37. Ruderman EM (2012) Overview of safety of non-biologic and biologic DMARDs.
Rheumatology 51:37–43
38. Scott IC, Hider SL, Scott DL (2018) Thromboembolism with Janus Kinase (JAK) inhibitors
for rheumatoid arthritis: how real is the risk. Drug Saf 41(7):645–653
39. Prager N, Bickett K, French N (2002) A randomized, double-blind, placebo-controlled trial to
determine the effectiveness of botanically derived inhibitors of 5-α-reductase in the treatment
of androgenetic alopecia. Altern Complement Med 8(2):143–152
40. Zheng Z, Sun Y, Liu Z (2015) The effect of curcumin and its nanoformulation on adjuvant-­
induced arthritis in rats. Drug Des Dev Ther 9:4931–4942
41. Tong KK, Yang D, Chan EY et al (1999) Downregulation of lymphocyte activity and human
synovial fibroblast growth in rheumatoid arthritis by triptolide. Drug Dev Res 47:144–153
42. Kapoor B, Gupta R, Gupta M (2012) Natural products in the treatment of rheumatoid arthritis.
Int J Green Pharm 11:356–363
43. Jeyakodi S, Nai A, Divya K et al (2021) Safety and efficacy of biosolve curcumin in active
rheumatoid arthritis: a randomized double-blind placebo-controlled clinical study. Am J
Phytomed Clin Ther 9(2):5
44. Zhu W, Li Y, Zhao J et al (2022) The mechanism of triptolide in the treatment of connective
tissue disease-related interstitial lung disease based on network pharmacology and molecular
docking. Ann Med 54(1):541–552
45. Chen SR, Dai Y, Zhao J et al (2018) A mechanistic overview of triptolide and celastrol, natural
products from Tripterygiumwilfordii Hook F. Front Pharmacol 9:104
46. Fan D, Guo Q, Shen J et al (2018) The effect of triptolide in rheumatoid arthritis: from basic
research towards clinical translation. Int J Mol Sci 19(2):376
47. Gong Y, Huang X, Wang D et al (2017) Triptolide protects bone against destruction by tar-
geting RANKL-mediated ERK/AKT signalling pathway in the collagen-induced rheumatoid
arthritis. Biomed Res 28:4111–4116
48. Santiago LÂM, Neto RNM, Ataíde ACS et al (2021) Flavonoids, alkaloids and saponinsare
these plant-derived compounds an alternative to the treatment of rheumatoid arthritis, A litera-
ture review. Clin Phytoscience 7(1):1–10
49. Huang R, Pan H d, Wu J et al (2019) Comparison of combination therapy with methotrexate
and sinomenine or leflunomide for active rheumatoid arthritis: a randomized controlled clini-
cal trial. Phytomedicine 57:403–410
50. Sultana F, Neog MK, Rasool MK (2017) Withaferin-A, a steroidal lactone encapsulated man-
nose decorated liposomes ameliorates rheumatoid arthritis by intriguing the macrophage repo-
larization in adjuvant-induced arthritic rats. Colloids Surf B: Biointerfaces 155:349–365
51. Skoczyńska M, Swierkot J (2018) The role of diet in rheumatoid arthritis. Reumatologia
56(4):259–267
52. Shen P, Lin W, Deng X et al (2021) Potential implications of quercetin in autoimmune dis-
eases. Front Immunol 23(12):199. https://doi.org/10.3389/fimmu.2021.689044
53. Javadi F, Ahmadzadeh A, Eghtesadi S et al (2017) The effect of quercetin on inflammatory
factors and clinical symptoms in women with rheumatoid arthritis: a double-blind, randomized
controlled trial. J Am Coll Nutr 36(1):9–15
54. Marino A, Paterniti I, Cordaro M et al (2015) Role of natural antioxidants and potential use of
bergamot in treating rheumatoid arthritis. Pharma Nutrition 3(2):53–59
55. Raut AS, Prabhu RH, Patravale VB (2013) Psoriasis clinical implications and treatment: a
review. Crit Rev Ther Drug Carrier Syst 30(3):183–216
56. Chandrasekar R, Sivagami B (2016) Alternative treatment for psoriasis-a review. Int J Res
5(4):2188–2197
57. Bhoir SS, Vishwapathi V, Singh KK (2019) Antipsoriatic potential of Annonasquamosa seed
oil: an in vitro and in vivo evaluation. Int J Phytomedicine 54:265–277
Natural Products Used in the Treatment of Autoimmune Disorder 1263

58. Pazyar N, Yaghoobi R (2012) Tea tree oil as a novel antipsoriasis weapon. Skin Pharmacol
Physiol 25(3):162–163
59. Sharma S, Sharma R, Goyal K et al (2021) Potential of herbal treatment of Psoriasis: a laconic
review. Asian J Res Pharm Sci 11(1):51–57
60. Daniyal M, Akram M, Zainab R et al (2019) Progress and prospects in the management of
psoriasis and developments in phyto-therapeutic modalities. Dermatol Ther 32(3):e12866
61. Ng CM, Judy PS, Shek CC et al (2012) Hyperthyroidism caused by a Grave disease that is not
Graves’ disease. Am J Med 125(3):e3–e4
62. Bhardwaj M, Kumar A, Tripathi S (2013) Commiphorawightii down regulates HMG CoA
reductase in hyperlipidemic rats. Int J Appl Pharm Sci 4:441–447
63. Chee PP, Fober KA, Slightom JL (1989) Transformation of soybean (Glycine max) by infect-
ing germinating seeds with Agrobacterium tumefaciens. Plant Physiol 91(3):1212–1218
64. Mannaa FA, Abdel-Wahhab KG, Hassan LK et al (2021) Influence of Melissa officinalis meth-
anolic extract on hyperthyroidism in a rat model. Egypt Pharm J 20(2):134
65. Yeshi K, Ruscher R, Hunter L (2020) Revisiting inflammatory bowel disease: pathology, treat-
ments, challenges and emerging therapeutics including drug leads from natural products. J
Clin Med 9(5):1273
66. Hossen I, Hua W, Ting L et al (2020) Phytochemicals and inflammatory bowel disease: a
review. Crit Rev Food Sci Nutr 60(8):1321–1345
67. Verma N, Meena NK, Majumdar I et al (2017) Role of bromelain as herbal anti-inflammatory
compound using in vitro and in vivo model of colitis. J Autoimmun 3:1–8
68. Wang CZ, Yu C, Wen XD et al (2016) American ginseng attenuates colitis-associated colon
carcinogenesis in mice: impact on gut microbiota and metabolomics. Cancer Prev Res
9(10):803–811
69. Toledo TR, Dejani NN, Monnazzi LG (2014) Potent anti-inflammatory activity of pyreno-
cine A isolated from the marine-derived fungus Penicilliumpaxilli Ma (G) K. Mediat Inflamm
2014:767061
70. Yun KJ, Min BS, Kim JY et al (2007) Styraxoside A isolated from the stem bark of Styrax
japonica inhibits lipopolysaccharide-induced expression of inducible nitric oxide synthase and
cyclooxygenase-2 in RAW 264.7 cells by suppressing nuclear factor-kappa B activation. Biol
Pharm Bull 30:139–144
71. Dutra RC, Claudino RF, Bento AF et al (2011) Preventive and therapeutic euphol treatment
attenuates experimental colitis in mice. PLoS One 6:27122
72. Schink A, Naumoska K, Kitanovski Z et al (2018) Anti-inflammatory effects of cinnamon
extract and identification of active compounds influencing the TLR2 and TLR4 signaling path-
ways. Food Funct 9:5950–5964
73. Yu S, Liu M, Hu K (2019) Natural products: potential therapeutic agents in multiple sclerosis.
Int Immunopharmacol 67:87–97
74. Selmaj I, Mycko MP, Raine CS et al (2017) The role of exosomes in CNS inflammation and
their involvement in multiple sclerosis. J Neuroimmunol 306:1–10
75. Giacoppo S, Pollastro F, Grassi G et al (2017) Target regulation of PI3K/Akt/mTOR pathway
by cannabidiol in treatment of experimental multiple sclerosis. Fitoterapia 116:77–84
76. Hashimoto M, Yamamoto S, Iwasa K et al (2017) The flavonoid Baicalein attenuates cuprizone-­
induced demyelination via suppression of neuroinflammation. Brain Res Bull 135:47–52
77. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the
normal and pathologic brain. Nat Neurosci 10(11):1387–1394
78. Liu HS, Shi HL, Huang F et al (2016) Astragaloside IV inhibits microglia activation via glu-
cocorticoid receptor mediated signaling pathway. Sci Rep 6(1):1–4
Strategies to Improve Antimicrobial
Activity of Natural Products: Approaches
and Challenges

Cristina M. Pérez Zamora, Carola A. Torres, and Ana M. Gonzalez

1 Introduction

The plants possess a variety of bioactive compounds, which have an array of bio-
logical activities. Many synthetic drugs have their origin from some plant-based
compounds. Most spices and herbs exert antimicrobial activity against different
microorganisms (bacteria, yeasts, and molds) and can be used as food preservatives
[1]. Besides, some plants have antimicrobial effects against human and plant patho-
gens. In the last decades, plant-based antimicrobials have received considerable
attention, because plants produce secondary metabolites in abundance, known to
possess antimicrobial activity [2]. Some of these metabolites are carbohydrates,
alkaloids, tannins, steroids, terpenoids, flavonoids, and so on [3].
But they still have numerous limitations for being used as antimicrobials [4]. The
emergence of drug-resistant and multidrug-resistant (MDR) organisms has become a

Cristina M. Pérez Zamora and Carola A. Torres contributed equally with all other contributors.

C. M. Pérez Zamora (*)

Universidad Nacional del Chaco Austral (UNCAUS), Presidencia Roque Sáenz Peña,
Chaco, Argentina
Consejo Nacional de Investigaciones Científicas y Técincas (CONICET),
Buenos Aires, Argentina
e-mail: [email protected]
C. A. Torres (*)
Instituto de Investigaciones en Procesos Tecnológicos Avanzados (INIPTA),
Sáenz Peña, Chaco, Argentina
Universidad Nacional del Chaco Austral, Sáenz Peña, Chaco, Argentina
e-mail: [email protected]
A. M. Gonzalez
Instituto de Botánica del Nordeste (IBONE-CONICET), Corrientes, Argentina

© The Author(s), under exclusive license to Springer Nature 1265

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_53
1266 C. M. Pérez Zamora et al.

global health concern affecting the diagnosis, treatment, and prevention of infections. As
just one example, the coronavirus disease-2019 (COVID-19) pandemic is causing
numerous bacterial and fungal infections in vulnerable patients hospitalized in intensive
care units (ICUs) [5]. Predictions for the year 2050 estimate that 300 million deaths will
result from this problem, with a loss of USD 100 billion to the global economy [6]. In
parallel with increasing rates of resistance to conventional antibiotics is the slowdown in
the development of new antimicrobials by the pharmaceutical industry, which has
aggravated the situation, leaving medical professionals with no alternatives for treating
patients battling life-threatening infections. Several studies have been published in
recent years on the subject of microbial resistance and the search for new therapeutic
options [7]. One method to resolve the threat of the development of drug resistance is to
use plant-based antimicrobials or their combination with synthetic antimicrobials [8, 9].
On the other hand, essential oils (EOs) from different traditionally used plants
are becoming increasingly important in the formulation of new products, mainly as
food preservatives against fungal and aflatoxin contamination [10, 11]. Different
technological treatments facilitate the utilization of natural bioactive compounds at
lower doses with improved antimicrobial effects.
This chapter aims to describe the advances made in recent years to improve the
antimicrobial activity of natural products derived from plants, mainly against clini-
cal pathogens and food contaminants. The field of application of these findings, the
main results obtained, and the difficulties and perspectives will also be discussed.

2 Antimicrobial Combinations

The combination of antibiotic drugs with extracts or compounds derived from

medicinal plants [12], recently denominated as “hybrid combination” therapy, has
been pointed out as one of the viable strategies to overcome antimicrobial resistance
[13]. The hybrid combination of herbs and drugs could be able to present increased
pharmacological activity (which can affect not just a single but various targets) and
simultaneously minimize the toxic side effects of synthetic drugs [13].
Many scientists have tried to establish synergistic combinations of plant-based
compounds with standard antibiotics. The following sections will describe how, in
recent years, several studies have been conducted on the combination of whole plant
extracts, bioactive fractions, essential oils, or natural products isolated from plants,
combined with each other or with synthetic antimicrobials, with promising results.

2.1 Plant Extracts or Bioactive Fractions

Here are several possibilities of combinations to consider: (1) plant extracts and
commercial antimicrobials, (2) plant extracts with each other or with natural prod-
ucts, (3) different fractions instead of the whole extract and commercial antimicro-
bials, and (4) fractions with other natural products.
Strategies to Improve Antimicrobial Activity of Natural Products: Approaches… 1267

Studies with plant extracts and commercial antimicrobials have been conducted
in different parts of the world [14–49]. In all cases, synergism was reported in some
or all combinations with antibiotics. The extraction methods and solvents used vary
according to the authors consulted. This is to be expected due to the variability of
chemical compounds present in the plant, which have an affinity for solvents of dif-
ferent polarity. Variability also occurs depending on the plant organ used. In most
cases, the checkerboard technique, fractional inhibitory concentration index (FICI)
calculation, and time-kill assay are used to determine the type of antibacterial inter-
action [14–46]. Disk diffusion technique is also mentioned, but much less frequently
[47–49]. The antibiotics most commonly used were gentamicin, chloramphenicol,
and ciprofloxacin [14–38]. Nevertheless, if the group of antimicrobials is taken into
account, aminoglycosides head the ranking with gentamicin, streptomycin, and
amikacin. They are closely followed by the group of beta-lactam antibiotics: ampi-
cillin, penicillin G, and imipenem. Regarding the microorganisms used, the most
common point was that the bacterial pathogens were selected according to the
World Health Organization (WHO) priority pathogen list: ESKAPE [14–44, 46, 48,
49]. This is an acronym for the group of bacteria, encompassing both Gram-positive
and Gram-negative species, made up of Enterococcus faecium, Staphylococcus
aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aerugi-
nosa, and Enterobacter species. These bacteria are common causes of life-­
threatening nosocomial infections among critically ill and immunocompromised
individuals and are characterized by potential drug resistance mechanisms. As
regards antifungal activity, combinations of the extracts with fluconazole were most
frequent, followed by nystatin and amphotericin B [24, 36–38, 41, 45]. The ATCC
strains or clinical isolates of Candida albicans were the most commonly used fun-
gal agents [24, 28, 36, 37, 41, 45].
In addition, works with combinations of plant extracts with each other or with
natural products like terpenes or phenolic compounds were also found [50–58].
Here again, the checkerboard method appears most frequently as a technique to
determine interactions [50–55]. However, the disk diffusion method is also used in
some works [56–58]. In all cases, a potentiation of the antimicrobial effect was
observed when the extracts were combined. Interestingly, not only studies against
ESKAPE group bacteria were found, but also potential applications against oral
pathogens and food contaminants. In fact, Abdulbaqi et al. [50] demonstrated that
the combination between green tea and aqueous extracts of Salvadora persica
exhibited synergistic antiplaque activity, and could be used as an active agent to
produce oral health care products. On the other hand, Chung et al. [51] showed that
the high citric acid content of citrus fruit extracts (CFEs) is likely to contribute to
the strong synergistic effect with essential oil components (EOCs), such as carva-
crol and thymol. This study provides new insight into the utility of CFEs with EOCs
to improve not only the microbiological safety of food products containing CFEs
but also their applicability as a natural antibacterial complex.
On the other hand, several authors report promising results when using different
fractions instead of the whole extract [41, 59–68]. For example, Liu et al. [59], who
worked with an ethyl acetate fraction from Pithecellobium clypearia (S20b) and
1268 C. M. Pérez Zamora et al.

antibiotics, demonstrated a synergistic effect on multidrug-resistant (MDR)

Acinetobacter baumannii and Pseudomonas aeruginosa. The transmission electron
microscopy results confirmed that S20b could damage the bacterial cell wall.
Moreover, the effects of S20b on the reversion resistance of A. baumannii and
P. aeruginosa against the corresponding antibacterial agents could possibly be asso-
ciated with the increase in bacterial membrane permeability. In addition, a recent
paper showed a total synergism effect in the hybrid combinations of alkaloid-­
enriched fraction (ERAF) obtained from Erythroxylum revolutum leaves + gentami-
cin, ERAF + norfloxacin, and ERAF + erythromycin against MDR S. aureus strain,
with a significant minimum inhibitory concentration (MIC) reduction of 84.7%,
75.0%, and 89.85%, respectively [60]. In most cases, the checkerboard technique
and FICI calculation are used to determine the type of antibacterial interaction. The
most frequently used antibiotics are again gentamicin and chloramphenicol, now
joined by erythromycin [60–65]. Regarding the microorganisms used, the most
common was the use of clinical isolates of methicillin-resistant S. aureus (MRSA)
and MDR Escherichia coli, other enterobacteria, and P. aeruginosa [41, 59–65].
Here again, clinical isolates of Candida albicans were the most commonly used
fungal agents [41, 65, 66].
Besides, combinations between fractions and other natural products like poly-
phenolic compounds were found. Noteworthy is the work of Sánchez-Chávez [67],
who conducted a bioguided assay of hexane extract from Trixis angustifolia to
detect an active fraction (AF) against Mycobacterium tuberculosis and a major fla-
vone (pebrellin) with no antimycobacterial activity. A subsequent combination anti-
microbial assay showed a synergistic antimycobacterial effect of AF in combination
with pebrellin; the results of the synergistic activity suggest that the antimycobacte-
rial activity found in T. angustifolia is due to the combined action of diverse metab-
olites present in the plant. Carvalho et al. [68] investigated the antimicrobial activity
of ethyl acetate fraction (EtOAc) from roots of Cochlospermum regium together
with some constituents previously isolated and commercially available (tannin and
gallic acid). Checkerboard assay showed that the combination of EtOAc fraction
with tannin results in a synergic effect against K. pneumoniae ATCC 43816,
S. aureus ATCC 29213, Candida krusei ATCC 34135, Candida glabrata ATCC
2001, and C. albicans ATCC 10231, thus highlighting the pharmacological use of
C. regium as a tannin-enriched extract for the treatment of infectious diseases.

2.2 Essential Oils (EOs)

In this topic there is a plethora of articles to consider [12, 49, 69–95]. Some authors
evaluate the antibacterial and antibiotic-modifying activity of EOs, alone and com-
bined. Here again, the combination with commercial antibiotics showed a synergis-
tic effect.
More recently, Freitas et al. [69] evaluated the antibacterial and antibiotic-­
modifying activity of the essential oil (EO) obtained from Baccharis reticulata and
Strategies to Improve Antimicrobial Activity of Natural Products: Approaches… 1269

the compound α-pinene against Pseudomonas aeruginosa and other MDR bacteria.
The essential oil (EO) potentiated norfloxacin and gentamicin against all strains
evaluated. Also, α-pinene increased the activity of norfloxacin against E. coli, as
well as potentiated the activity of norfloxacin and gentamicin against S. aureus. The
antimicrobial activity of this EO is mainly attributed to the presence of terpenes,
especially of the sesquiterpenes group. In summary, when the combinations of EO
with antibiotics were analyzed, it was found that the most used antibiotics were
ciprofloxacin and gentamicin [49, 69–85]. Regarding antifungals, fluconazole and
amphotericin B were the most used [76–79, 84–88]. When analyzing the microor-
ganisms employed, the most frequently used bacteria were clinical isolates of
MRSA, and MDR Klebsiella pneumoniae, Escherichia coli, Pseudomonas aerugi-
nosa, and Acinetobacter baumannii. Clinical isolates and ATCC strains of Candida
albicans and Candida parapsilosis led the ranking of fungi evaluated.
Similar to the previous cases, several studies with combinations of EO with other
natural products were also found [96–105]. Some of these combinations have appli-
cations in food. Clemente et al. [97] evaluated the effects of cinnamon and mustard
EOs against nine food-borne bacteria. The combinatorial assays demonstrated in
most cases an additive effect. In addition, synergies for Pseudomonas putida and
E. coli OI57:H7 were shown. Therefore, introducing them in combination could be
a great way to make a natural-active packaging. More recently, Ayari et al. [100]
demonstrated that the combination of oregano and thyme EOs showed a synergistic
effect against Bacillus cereus and Paenibacillus amylolyticus bacteria. Therefore,
the authors consider that this mixture has potential application as a food preserva-
tive. On the other hand, Kim et al. [104] proved that combinations of cinnamon bark
and lemongrass EOs, cinnamon bark and thyme thymol EOs, and lemongrass and
thyme thymol EOs showed synergistic activities on Listeria monocytogenes. Once
again, the antilisterial activity was evaluated by Iseppi et al. [101]. However, this
time EOs were combined with one bacteriocin previously isolated from seafood.
This study suggests that the combination of natural compounds such as Thymus
vulgaris and Salvia officinalis EOs and bacLp17 (bacteriocin) may be a useful
approach to the control of planktonic and sessile cells of L. monocytogenes in sea-
food products.

2.3 Natural Products or Isolated Compounds

A major limitation of working with plant extracts is the laborious isolation and
identification of bioactive metabolites. Nevertheless, research has been conducted
on antimicrobial interactions with metabolites isolated from plants or their deriva-
tives as well as with commercially available natural products [106–125]. Gentamicin
and ciprofloxacin were the most commonly used antibiotics in the combinations
[106–119], while the microdilution broth and checkerboard technique were used to
evaluate interactions. The most analyzed chemical compounds belong to the group
1270 C. M. Pérez Zamora et al.

of polyphenols, especially flavonoids, chalcones, catechins, and some phenolic

acids. Work was also found with alkaloids and terpenes as well as with lectin-type
plant proteins [123, 124]. In most of the studies, antimicrobial synergism was found
against clinical isolates of MDR bacteria and fungi.
The association of flavonoid luteolin and antibiotics was evaluated by several
authors. Synergism between gentamicin and luteolin on S. aureus and an additive
effect on E. coli was demonstrated by Bustos et al. [111]. Similarly, Torres et al.
[112] showed that the combination of luteolin and ampicillin had potent antibacterial
activities on MDR bacteria. The anti-MRSA synergism of prenyl flavonoids with 11
antibacterial agents and the reversal of MRSA resistance to aminoglycosides (espe-
cially amikacin) were reported by Zuo et al. [113]. More recently, the combination
of the flavonoid kaempferol 7-O-β-D-(6″-O-cumaroyl)-glucopyranoside isolated
from Croton piauhiensis with gentamicin presented synergistic effects against
S. aureus and E. coli. Amikacin also showed synergistic effects against these bacteria
[117]. Quercetin exhibited bactericidal and synergistic activity with meropenem on
carbapenem-resistant enterobacteria. The effective bactericidal activity of quercetin–
meropenem combination might have been achieved through alteration of blaVIM,
ompC expression and cellular morphology of bacteria [125].
The study by Usjkak et al. [116] with different chalcones demonstrated several
synergistic interactions with antibiotics (meropenem, amikacin, and ciprofloxacin),
as well as a notable reduction in expression of all investigated virulence factors. An
important mechanism of bacterial resistance is the presence of proteins from efflux
pumps in their membranes. It is known that the efflux pump is one of the main
causes of drug resistance. Recent work of Siqueira et al. [118] evaluated the effects
of two aminophenyl chalcones on the inhibition of the efflux pump of S. aureus and
showed a synergistic effect with norfloxacin and ciprofloxacin. The effect of one of
them is particularly notable against the S. aureus K2068 (MepA overexpresser)
strain. The authors suggest that this chalcone may contribute to the prevention or
treatment of infectious diseases caused by MDR S. aureus [118].
Strong synergistic relation was found against pathogens in the combination of
epigallocatechin gallate (EGCG) with gentamicin. The purified EGCG compound of
green tea has a great synergistic effect against MDR pathogens [115]. Checkerboard
and time-killing assays showed synergism between EGCG and meropenem (or car-
benicillin). EGCG significantly increased the effect of 1-[1-naphthylmethyl] pipera-
zine (efflux pump inhibitor) but was unrelated to β-lactamase production in
A. baumannii, suggesting EGCG may be associated with inhibition of efflux pumps.
This would suggest that EGCG–antibiotic combinations could provide an alternative
approach to treat A. baumannii infections, regardless of antibiotic resistance [121].
In the study by Gomes et al. [110], commercial catechin showed synergistic action
on S. aureus when it was combined with norfloxacin and gentamicin increasing anti-
biotic activity. In the same study, it was observed that the combination of catechin
with imipenem, tetracycline and erythromycin exhibited a synergistic effect on
E. coli. This synergism may be due to the ease of penetration into the bacterial cell
since catechin can alter membrane permeability and facilitate the action of
Strategies to Improve Antimicrobial Activity of Natural Products: Approaches… 1271

antibiotics at their internal sites of action. Catechin, like many lipophilic flavonoids,
can also cause rupture of the plasma membrane of the microorganism [110].
Lima et al. [108] evaluated the antibacterial, antifungal, and modulatory antibi-
otic activities of gallic acid, caffeic acid, and pyrogallol. The caffeic acid was the
best, potentiating the antibacterial effect over the three groups of bacteria studied.
Regarding potentiation of the effect of fluconazole, a synergistic effect was observed
only when assayed against Candida tropicalis, with all substances.
Regarding terpenes, a synergistic action of borneol associated with ciprofloxacin
against E. coli enterotoxigenic serotypes was noted [119]. In addition, synergistic
activity of borneol with other natural products against Candida albicans was dem-
onstrated [127].
Embelin, bioactive principle of Embelia ribes, exhibited a synergistic effect with
the antifungal drug ketoconazole against four different Malassezia spp. [122]. One
study conducted by Wan et al. [126] showed that cinnamic aldehyde, isolated from
Cinnamomum cassia, and pyrazinamide clearly act synergistically against
Mycobacterium tuberculosis in the murine model. Scanning electron microscopy
showed that M. tuberculosis cells swelled, collapsed, and ruptured after treatment
with sub-inhibitory concentration of phytocompound. This implies that the antimy-
cobacterial mechanism might be associated with the disruption of the cell wall.
In summary, the antibiotics most frequently used in combinations with natural
products were aminoglycosides, followed by beta-lactams and quinolones.
Antibiotics of the aminoglycosides class act in the inhibition of protein synthesis
such that bacterial resistance mechanisms mainly involve the activation of efflux
and target modification systems [128]. Thus, the synergistic effects that are gener-
ally obtained by the association of natural products with antibiotics are related to an
increase in the influx of the drug, which alters the permeability of the cell mem-
brane, favoring the penetration of antibiotics and potentializing its effect [129].

3 Encapsulation of Bioactive Molecules

Another strategy to enhance the antimicrobial effect of plant-derived products is

encapsulation. Natural antimicrobials are particle-loaded by different encapsulation
techniques. This tool is used mainly to provide protection, natural stabilization, and
controlled release of bioactive metabolites [130, 131]. According to the size of the
particles, can be distinguished the microparticles (diameter between 1 and 5000 μm)
[131, 132] and nanoparticles (diameter between 1 and 100 nm) [133].
Encapsulation of bioactive compounds also improves antimicrobial activity. This
is caused by the subcellular size of the particles, which reduces mass transfer resis-
tances, thereby increasing passive cellular uptake mechanisms and bioefficacy
[131]. Within natural products, the largest number of studies on encapsulation of
bioactive extracts or compounds is concentrated in EOs, mainly for application in
food products as food preservatives [10, 130, 134–161]. A minority of publications
present studies on other types of plant extracts or isolated compounds, with different
1272 C. M. Pérez Zamora et al.

applications, like human health [162–172], agriculture [140, 173], and antimicro-
bial activity about inert surfaces [174].
According to the material and encapsulation technique used, three main types of
nanosystems can be distinguished [175]: (1) polymeric type nanosystems (matrix
type, shell core type, nanofibers, nanotube), (2) lipid-based nanosystems (solid
nanoparticles, nanoliposomes, nanoemulsions), and (3) cyclodextrin (CD) com-
plexes. Also, a combination of these techniques can be used to obtain products or
more active materials.
The coordinative complexation of polyphenolic compounds with metal ions is
another possible alternative in the search to enhance antimicrobial activities [176,
177]. The combinations can take a wide variety of different forms, such as gels,
nanoparticles, films, and emulsions.
There are literature reviews for several nanoencapsulation techniques [175, 178–
180]. This section will not review the technological aspects of the different method-
ologies but will present a summary of the natural extracts or pure natural compounds
that have been nanoencapsulated and whose antimicrobial effect was improved.

3.1 Polymeric and Lipid-Based Nanosystems

In polymeric nanosystems, polymers such as chitosan (CS), gums, alginate, poly(ɛ-­

caprolactone) (PCL), poly(lactic-co-glycolic acid) (PLGA), polyethylene glycol,
methylcellulose, ethylcellulose, starch, cellulose, gelatin, and pectin are used [139,
175, 178]. In general, biocompatible polymers, whether synthetic or natural, are
preferred.
In the reviewed literature, the most used polymer for the encapsulation of natural
products is low molecular weight chitosan. This polymer can be very useful for the
development of new antimicrobial products because chitosan has antimicrobial
activity per se. Its biological activity can be improved when it is combined with
another bioactive substance. Usually, a synergism between natural products and
chitosan is observed. The natural products investigated are EOs, aqueous and
ethanolic/methanolic extracts, and polyphenolic compounds (isolated from herbal
extract or pure compounds commercially available).
Once again, the investigations were focused mainly on clinically relevant bacte-
ria, such as S. aureus, E. coli, K. pneumoniae, and P. aeruginosa. Also, oral patho-
gens such as Streptococcus sobrinus and Streptococcus mutans were tested. As
regards human pathogenic fungi, the most studied genus was Aspergillus.
Regarding potential food application, food-borne pathogens more studied were
Aspergillus sp., Bacillus sp., E. coli, Lactobacillus sp., Listeria sp., Penicillium sp.,
P. aeruginosa, S. aureus, and Salmonella typhimurium.
Generally, techniques employed to evaluate the antimicrobial activity were: disk/
well agar diffusion, broth dilution/microdilution, time-kill assay, AATCC-147 par-
allel streak, and standard dynamic shake flask, micro-atmosphere method.
Strategies to Improve Antimicrobial Activity of Natural Products: Approaches… 1273

3.1.1 Nanosystems with EOs

Nanosystems with EOs are the most widely studied, and, as reflected in the discus-
sion of this section, most of the time, the antimicrobial action of the EO is enhanced
after encapsulation.
In a study carried out by Barrera-Ruiz et al. [181], cinnamon (Cinnamomum
zeylanicum), thyme (Thymus vulgaris), and Schinus molle EOs encapsulated in chi-
tosan nanoparticles had a higher antimicrobial effect than the chitosan and EOs
alone on Staphylococcus aureus ATCC 25923, Enterococcus sp., Escherichia coli
ATCC 25922, and carbapenemase-producing Pseudomonas aeruginosa and
Klebsiella pneumoniae (BLEE +). Furthermore, chitosan nanoparticles loaded with
thyme EO, incorporated into burgers, significantly reduced the count of
Enterobacteriaceae, S. aureus, and fungi, compared to free EO [161]. In contrast,
when Vafani et al. [182] developed thyme oil-loaded chitosan-gelatin nanofibers
and tested against Clostridium perfringens, significant differences were not observed
in the antimicrobial activity as compared with free thyme oil. These different results
can be affected by the type of the formulation (nanoparticle or nanofiber), bacterial
strains used, the composition of thyme oil, and experimental conditions. Also,
Eucalyptus staigeriana EO nanoencapsulated using cashew gum (CG) presented
synergistic antimicrobial activity against L. monocytogenes and Salmonella enter-
itidis [183].
On the other hand, cinnamon EO encapsulated into chitosan nanoparticles pre-
sented improved antibacterial activity compared to free EO against Pseudomonas
fluorescens, Erwinia carotovora, and E. coli [184]. In another study, when cinna-
mon EO was nanoencapsulated by using chitosan and whey protein isolate, the
antibacterial activity slightly decreased against E. coli, Pseudomonas fragi,
S. aureus, and Shewanella putrefaciens [185]. In addition, the encapsulation
enhanced the antibacterial power of Cyperus articulatus rhizome EO against
S. aureus ATCC6538 and E. coli ATCC 8739 [186], as well as EO from nettle
(Urtica dioica) against B. cereus, E. coli, L. monocytogenes, S. aureus, and
Salmonella typhi [148].
The clove EO encapsulated with chitosan showed an inhibitory activity enhanced
on E. coli, L. monocytogenes, S. aureus, and S. typhi [187]. Similarly, Lee et al.
[188] demonstrated that clove EO with chitosan and poly-c-glutamic acid had syn-
ergistic and additive effects against Streptococcus sobrinus and S. mutans, respec-
tively, before nanoencapsulation (in solution). However, after nanoencapsulation,
they displayed synergistic activity against both strains [188]. In addition, clove-oil-­
loaded chitosan nanoparticles and gelatin electrospun nanofibers were evaluated
against E. coli O157:H7 biofilms on cucumbers [153]. The results show a signifi-
cant eradication effect on E. coli O157:H7 biofilms, and satisfactory antibiofilm
effect on cucumber during four days of storage at 4 °C and 12 °C.
Zabihi et al. [189] evaluated the antibacterial activity of the Allium sativum EO
and its nanoliposomal form; the sub-inhibitory concentrations (50% and 75%) had
a significantly higher inhibitory effect on Shiga toxin-2 titer (produced by E. coli
O157:H7) than its free EO.
1274 C. M. Pérez Zamora et al.

When Thymus capitatus EO was incorporated at a nanoemulsion (NE) oil-in-­

water, the antimicrobial activity against Gram-positive and Gram-negative bacteria
was significantly improved compared to free EO [160, 190] and was more efficient
than streptomycin (positive control). The minimum bactericidal concentration
(MBC) of free T. capitatus EO–NE was reduced to 0.4 mg/mL [190]. This finding
is really useful, because the free EO had an MBC upper than 3 mg/mL, and concen-
trations over this value are considered inadequate for applications in food. On the
other hand, the Thymus daenensis EO nanoemulsion reduced the MIC values against
ten MDR Acinetobacter baumannii isolates about the middle of MIC of free EO. In
addition, the nanoemulsion had considerable antibiofilm activity [191].
In vitro studies showed that nanoemulsification of Origanum vulgare EO
increased its antifungal activity. However, when nanoemulsion was applied to
Minas Padrão cheese, the observed antifungal effect was not good. Nanoemulsions
with higher concentrations of EO were needed to achieve inhibition [152]. In addi-
tion, Moraes-Levison et al. [155] evaluated O. vulgare EO nanoemulsions, which
did not significantly improve their antimicrobial action against E. coli and S. aureus.
Lavandula x intermedia EO nanoemulsion had 20% better antimicrobial activity
than free EO against E. coli and B. cereus. [192]. A similar effect was reported by
Gholipourkanani et al. [193] for nanoemulsions with EO from Origanum vulgare,
Eucalyptus globulus, Melaleuca alternifolia, and Lavandula angustifolia against fish
pathogens (Aeromonas hydrophila, Streptococcus iniae, and Photobacterium dam-
selae subspecies damselae), with MIC and MBC values lower than tetracycline.
Antimicrobial activities of oregano, thyme, and clove leave EO showed better
antibacterial activity against E. coli ATCC 29922, S. typhimurium ATCC 14028, and
S. aureus ATCC 25923 after the nanoencapsulation. The MIC values were decreased
by 27–60%, and oregano EO was the most active [194]. Minthostachys verticillata
EO nanoemulsion increased inhibitory activity from 46% (free EO) to 58% for
S. aureus ATCC 29213. The nanoemulsified EO decreased 3.53 log CFU/mL at 3 h
and 4.07 CFU/mL after 24 h [195, 196].
Nanoparticles of chitosan with EO from Illicium verum fruits exhibited enhanced
antifungal potency against Aspergillus flavus, Aspergillus sydowii, Aspergillus sul-
phureus, Aspergillus fumigatus, Aspergillus versicolor, Aspergillus niger,
Aspergillus terreus, Trichoderma viride, Rhizopus nigricans, and Penicillium pur-
purogenum. Also, the nanoparticles generated an inhibition of the production of
aflatoxins at a lower concentration than the free EO [10]. In addition, improved
antifungal and antiaflatoxin effects after encapsulation were described in several
papers [11, 140]. Moreover, the encapsulated Monarda citriodora EO showed a
preservative effect on seven different functional food samples (seeds), for spoilage
caused by fungal and aflatoxin B1 contamination [140].
The research by Izadi et al. [197] showed that chitosan nanoparticles with Carum
copticum EO and those with Peganum harmala seed extracts (PE), used alone and
in combination, completely inhibited the growth of Alternaria alternata. The MIC
values were at 500 and 750 ppm Carum copticum EO and PE nanoparticle, respec-
tively. When they were together encapsulated, the MIC decreased to 100 ppm.
Strategies to Improve Antimicrobial Activity of Natural Products: Approaches… 1275

Alderees et al. [135] studied the anti-yeast activity of oil-in-water encapsulated

nanoemulsion containing individual or a combination of the three EO of Tasmanian
pepper leaf (Tasmannia lanceolata), lemon myrtle (Backhousia citriodora), and
anise myrtle (Syzygium anisatum) against weak-acid-resistant Zygosaccharomyces
bailii in clear apple juice stored at 25 °C for 28 days. There was a synergistic effect
between Tasmanian pepper and anise myrtle. They caused a significant reduction in
microbial counts at day 0 from 2.1 to 2.9 log CFU/mL and caused a total elimination
(inactivation) of yeast cells at day 4 and continued to show no signs of growth until
the last day of the experiment (day 28). When Nirmal et al. [198] evaluated nano-
emulsioned Lemon myrtle and Anise myrtle EOs, only the first showed enhanced
antibacterial activity against S. aureus, L. monocytogenes, and E. coli compared to
EO alone (p < 0.05). Anise myrtle alone and nanoemulsioned was not active against
strains tested.
Encapsulation of Hyssopus officinalis EO into chitosan-pea protein isolate nano-
complex increased the efficiency of antifungal power against Botrytis cinerea. The
treatment with the nanocomplex postponed the spoilage process in strawberry fruits
on the eighth day, and it was able to reduce disease severity after nine days of stor-
age [187].
Hadian et al. [156] produced a nanogel with chitosan (CS) and benzoic acid
(BA), and they used it to encapsulate rosemary (Rosmarinus officinalis) EO (REO).
Their potential synergistic effects in the elimination of Salmonella typhimurium in
beef cutlets were evaluated during 12 days of storage at 4 °C. The results revealed
that 2 mg nanoencapsulated REO coating caused an immediate reduction in
S. typhimurium population (3.3 log CFU/g) on day 1 and continued to inhibit during
the 12 days of the study. In addition, nanoencapsulation of rosemary EO with chito-
san and γ-poly glutamic significantly increased the antimicrobial activity against
Bacillus subtilis, both in in vitro test and in model food (ready-to-drink barley tea
beverage) [136]. Also, multiple lipid nanoparticles loaded with rosemary EO had
six times more antibacterial activity than the pure EO [199].
Pepper fragrant EO into mesoporous silica particles exhibited antimicrobial
activity against food-borne bacteria (E. coli, Salmonella enterica, S. aureus, and
L. monocytogenes). The activity was better at 48 h than at 24 h, and exhibited sus-
tained release, prolonging the antibacterial activity over a period of time [200].
The inhibitory activity of Zataria multiflora EO against E. coli O157:H7 was
improved after incorporation into nanoliposomes (MIC decreased 50%).
Furthermore, sub-inhibitory concentrations of liposomal EO (50% and 75% of
MIC) had a significantly higher inhibitory effect on Shiga toxin-2 titers [201]. In the
same form, encapsulation of cinnamaldehyde in polydiacetylene and
N-hydroxysuccinimide liposomes improved its antibacterial activity, because that
caused a rapid reduction of E. coli and B. cereus to undetectable levels within 8 h of
incubation [158]. When Salvia officinalis EO was nanoemulsioned, its antibacterial
activity was improved only against S. aureus ATCC 25238 and Streptococcus pneu-
moniae PTCC 1240, but not against Haemophilus influenza PTCC 1623 and
Pseudomonas aeruginosa PTCC 1430 [191].
1276 C. M. Pérez Zamora et al.

Da Cunha et al. [202] enveloped the surface of silver catfish (Rhamdia quelen),
infected with Aeromonas hydrophila, with nanocapsules containing 3.6% of
Origanum majorana EO. The antimicrobial effects of these nanocapsules were sim-
ilar to those of the pure/free form but used 50 times less EO. All fish submitted to
daily baths with EO or nanocapsules loaded with EO showed significantly higher
survival rates than the control fish, and survival rates were similar to those treated
with the positive control (Maxflor®).

3.1.2 Nanosystems with Aqueous or Alcoholic Extracts

The number of works on nanosystems including plant extracts compared to those

containing EO was lower [203–209]. However, most of them are noted for the
potentiation of the antimicrobial effect of the extract after encapsulation.
Several works with potential applications in food can be mentioned. For exam-
ple, nanoparticles containing the acetonic extract of Compomanesia xanthocarpa
fruits showed activity against Listeria innocua while the free extract was not active
[203]. On the other hand, it was demonstrated that nanoliposome-encapsulated
extract of bay leaf (Laurus nobilis) can delay bacterial spoilage in the minced meat
treated with 1500 ppm of the nanoextract, and stored in the refrigerator (4 ± 1 °C).
Bacterial growth was not observed from day 4 for S. aureus and from day 8 for
E. coli over 16 days [154]. Nanocapsules of Melia azedarach leaf extract with chi-
tosan showed a significantly improved antibacterial activity against S. typhimurium
and Lactobacillus acidophilus with respect to the free extracts. The inhibition halos
obtained were upper than the control (tetracycline). In contrast, for E. coli, the halo
value was similar to the free extract, and they were lower than the control [205]. The
hydrolate (waste from EO obtention) of Lavandula x intermedia was not active but
showed antibacterial activity when it was nanoemulsified [192].
On the other hand, Triphala Churna (TC), a traditional Ayurvedic medicine rich
in polyphenols and vitamin C, when encapsulated with starch exhibited enhanced
antibacterial activity against Salmonella typhi and Shigella dysenteriae, and antib-
iofilm activity against MRSA ATCC 33591 and clinical strain S. aureus [206].
Besides the above-mentioned uses, the capsules can be applied to a wide variety
of surfaces to which they impart antimicrobial properties. Several studies showed
the viability of impregnation of fabrics, managing to encapsulate natural antimicro-
bials in different types of fabrics and with an antimicrobial effect preserved after
several washes [207]. This finding could have potential use in the health field, due
to the fact that they would have antimicrobial properties, and would improve differ-
ent characteristics. In this sense, medical-grade cotton fabrics were functionally
finished with chitosan nanoparticles loaded with methanolic extract of Cassia
angustifolia and Tamarindus indica by Chandrase et al. [208]. The modified fabrics
were evaluated on Escherichia coli and Staphylococcus aureus (isolated from the
wound dressing fabric materials of a diabetic foot) by AATCC-147 parallel streak
method. The results showed that the nanocomposite fabric was able to retain the
antibacterial activity even after ten industrial washes, with halos value 29.6 mm for
Strategies to Improve Antimicrobial Activity of Natural Products: Approaches… 1277

E. coli and 30.4 for S. aureus, thereby providing long-term durability of the nano-
composite finished fabric. In addition, bamboo and cotton fabrics were impregnated
with bovine albumin nanocapsules containing ethanolic extracts of three plants:
Terminalia chebula fruits, Rosmarinus officinalis leaves, and Opuntia littoralis
leaves [209]. The results showed inhibition halos of 42 and 44 mm for E. coli and
S. aureus, respectively. This activity was maintained after 30 washes, decreasing to
32 and 33 mm the zone of inhibition.

3.1.3 Nanosystems with Natural Products

Similar to the previous cases, these nanosystems find potential applications in

human health and in the food industry. The antibacterial effect of the natural product
is again enhanced after encapsulation.
A mixture of terpenes extracted from Melaleuca alternifolia and D-limonene
was incorporated as a nanoemulsion in juices of orange and pear, demonstrating a
significant reduction of Lactobacillus delbrueckii [146]. Also, thymol nanoemul-
sion has shown significantly improved activity against L. monocytogenes in milk
with different fat levels, compared to free crystals [210].
Sousa Tavares et al. [211] found that antimicrobial properties of ellagic acid
(EA) have been enhanced 43.3% and 31.6% for S. aureus (ATCC 6538P) and
P. aeruginosa (ATCC 9027), respectively, due to nanoencapsulation with zein, a
corn protein. Fusidic acid formulated as lipid-core nanocapsule uncoated and coated
with chitosan showed inhibitory activity approximately 64-folds higher than free
fusidic acid against S. aureus ATCC 25923, Enterococcus faecalis ATCC 29212,
and MDR S. epidermidis strain [170].
On the other hand, an antibacterial synergistic effect was observed when eugenol
was combined with a low amount of lysozyme into casein nanoparticles against
S. aureus and Bacillus sp. The MIC values decreased 3.75- to 4.16-fold, and MBC
decreased 2.92- to 1.70-fold [212].
These nanosystems also find application in agriculture as shown in the work of
Olouch et al. [213]. In this study, thymol and eugenol, when loaded into chitosan
nanoparticles, showed growth inhibition of 92–94% on Ralstonia solanacearum (a
bacterial wilt-causing pathogen in potatoes). The MIC values of biomolecules nano-
encapsulated were reduced sevenfold and sixfold compared to the MIC of free thy-
mol and eugenol, respectively. Thus, this result has shown promising potential as a
bactericide alternative for the managing of this soil-borne phytopathogen.
In addition, nanocapsules or nanoparticles can be used as a final form to be
applied into, or can be included after, another formulation as a film or a fabric, or
used to produce nanometric fibers. Hence, nanotechnology contributes to products
and materials functionalized with improved antimicrobial activity. Films containing
nanoparticles with silymarin extracted from milk thistle improved activity against
Staphylococcus aureus and Bacillus subtilis, compared to films with free silymarin
[214]. In another study, thymol-loaded liquid smoke chitosan-based nanofibers
were used to coat sea bass (Dicentrarchus labrax) fillets in order to delay the growth
1278 C. M. Pérez Zamora et al.

of microbials during storage (seven days) at 6 ± 1 °C. On the third day of cold stor-
age, fillets had the lowest total mesophilic aerobic bacteria and yeast and mold dur-
ing the storage period. Hence, this nanofiber could extend the shelf life of fish for
three days at 0 °C [215].

3.2 Cyclodextrin Inclusion Complexes

The cyclodextrins are a group of natural cyclic oligosaccharides obtained from

starch, with six, seven, or eight glucose residues linked by glycosidic bonds [1–4] in
a cylinder-shaped structure. In the hydrophobic cavity, they are capable of enclosing
highly hydrophobic molecules in a molecular proportion and constitute a true
molecular encapsulation [216, 217]. This is a strategy used to improve the biologi-
cal properties of bioactive molecules and there are many studies about it, as
described in the review by Suvarna et al. [218].
Cyclodextrins have the potential to be used as nanocarriers as they are capable of
forming complexes with several nonpolar molecules. The formed cyclodextrin
inclusion complexes (ICs) can be in solution or included in biopolymers, gels, nano-
fibers, and films, among others. For encapsulation and development of inclusion
complexes with molecules, natural and modified types of cyclodextrins can be
applied [219].
The study conducted by Ozdemir et al. [220] demonstrated that the method
employed to obtain the cyclodextrin (CD) complexes affects the final antimicrobial
activity. Also, the type of cyclodextrins employed is significant for this purpose.
Several studies have demonstrated that the antibacterial activity of EO entrapped
into CD was modified according to the type of CD used. Probably, this effect was
related to the capacity for releasing the molecule or extracts entrapped. For exam-
ple, this effect was observed by Silva et al. [221] who incorporated coriander EO in
dextrin-derived nanosponges (NS) to create a stable controlled release system. In
this work, NS with alpha-cyclodextrins (α-CDs) was the most effective against all
strains tested (E. coli O157:H7 CECT 5947, Yersinia enterocolitica CECT 500,
Brochothrix thermosphacta CECT 847, L. monocytogenes CECT 911,
Campylobacter jejuni ATCC 33560, Campylobacter coli ATCC 33559, C. jejuni
930/12 and C. coli 22/08).
In this section, we summarized natural products that were complexed with cyclo-
dextrins for improving their antimicrobial activity.
The antibacterial activity of Rosmarinus officinalis EO complexes β-cyclοdextrin
(β-CD) and two chemically modified β-CD matrices, hydroxypropyl-β-cyclodextrin
(HP-β-CD) and methyl-β-cyclodextrin (Me-β-CD), was tested against S. aureus
ATCC 25923 and E. coli by micro-atmosphere method. On day 1, the free EO
exhibited more than 50% growth inhibition, whereas all complexes could not reduce
bacterial growth at the same level as the control. But the inhibitory activity was
increased over the days, reaching maximum values at three days. Toward the end of
the study, the antibacterial activity of the cyclodextrin complexes was higher than
Strategies to Improve Antimicrobial Activity of Natural Products: Approaches… 1279

that of the free EO. This effect can be related to the capacity to release the active
compound over time [222].
In another work, the antimicrobial capacity of thymol and carvacrol against
E. coli and S. aureus was improved by forming complexes in hydroxypropyl-β-­
cyclodextrins compared to free EO [223]. Also, when clove oil and thymol were
encapsulated with HP-α-CD, HP-β-CD, and HP-γ-CD, they showed significant
inhibition against E. coli O157:H7 Sakai and S. aureus compared to free clove oil
and thymol [224].
When the lavender EO was encapsulated into hydroxypropyl-β-cyclodextrin, its
antimicrobial activity increased approximately threefold against E. coli, Candida
albicans, and S. aureus [225].
Cyclodextrins can be incorporated in different matrices to improve or provide
desired properties to a composite material. On this line, films formed with different
cyclodextrins impregnated with EO of clove have shown promising antimicrobial
activity, especially against Gram-positive and Gram-negative bacteria [134]. Castro
et al. [226] developed films employing nanocrystals of cellulose chemically modi-
fied with β-cyclodextrin and hydroxypropyl-β-cyclodextrin, with a selective carva-
crol loading capacity. The antibacterial activities against Bacillus subtilis were
promising.
D-limonene (L) is a natural phenolic compound with high antioxidant and anti-
microbial activity. According to most papers, limonene incorporated in β-cyclodextrin
nanosponges (CD–NS) showed higher antibacterial activity than free limonene,
when tested against Escherichia coli, Shigella flexneri, Staphylococcus aureus, and
Enterococcus sp. [227].
In addition, this beneficial effect can be used not just by health or food applica-
tions. An in vitro study carried out by Matei et al. [173] shows that inclusion com-
plexes obtained with deep eutectic solvent and polyphenols such as gallic acid,
silymarin, ferulic acid, and curcumin have promising antifungal activity against
Phytophthora cinnamomi, a phytopathogenic fungus that causes a negative eco-
nomic and environmental impact. Cai et al. [228] complexed allyl isothiocyanate (a
compound obtained from cruciferous vegetables) with two types of cyclodextrins,
methyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin, and demonstrated that
complexes can suppress the attack of brown and white rot fungi (Gloeophyllum
trabeum and Trametes versicolor) on wood, and help maintain the original appear-
ance of wood.
Curcumin encapsulated within hydroxypropyl-β-cyclodextrin load in a hydrogel
matrix demonstrated significant antimicrobial activity against S. aureus [165].
Subsequently, silver nanoparticles (AgNP) using an aqueous solution of
curcumin:hydroxypropyl-β-cyclodextrin were developed by Gupta et al. [167].
These nanoparticles presented significant antibacterial activity against
Gluconacetobacter xylinus ATCC 23770, Pseudomonas aeruginosa NCIMB 8295,
and S. aureus NCIMB 6571.
When complexes of hinokitiol (HT) with α-cyclodextrin, β-cyclodextrin, or
γ-cyclodextrin were evaluated against Bacillus subtilis, Staphylococcus aureus,
Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Aspergillus
1280 C. M. Pérez Zamora et al.

brasiliensis, antimicrobial activity of complex increased about fourfold compared

to that of HT alone [229].
Besides, the antibacterial activity of ellagic acid against clinical pathogens was
improved by mean development of complexes with cyclodextrins [230].
In contrast with most of the reports, a study published by Danciu et al. [231]
shows that the complexation of rutin with β-cyclodextrin (β-CD), hydroxylpropyl-­
β-­cyclodextrin (HP-β-CD), and randomly methylated β-cyclodextrin (RAMEB)
does not produce an improvement in antibacterial activity against a wide variety of
bacteria.

3.3 Natural Products Combined with Metals

Metallogels are gels that contain interactions binding metal and can magnify the
properties of the metal complexes [232]. Anh et al. [163] developed antibacterial
metallogels including tannic acid (TA), with pH- and H2O2-responsive properties, as
dressings for infected wounds, with different degrees of activity against S. epider-
midis, MRSA, and E. coli.
Nanoparticles of CuO using aqueous extract of Catha edulis leaf showed good
antibacterial activity against S. typhimurium [133]. A similar effect was observed
when nanoparticles of CuO were developed by using several plant extracts, such as
Acalypha indica [233], Phyllanthus amarus [234], Terminalia arjuna [235], Malva
sylvestris [236], and Gloriosa superba [237]. Also, ZnO nanoparticles with Bauhinia
tomentosa leaf extract showed improved inhibitory activity against P. aeruginosa
and E. coli [238].
At the same time, Jain et al. [239] synthesized silver nanoparticles using leaf
extracts of tulsi (Ocimum sanctum) with enhanced antibacterial properties against
E. coli.
On the other hand, an aqueous extract of saffron (Crocus sativus) wastages was
combined with silver nanoparticles (AgNP). They were tested against E. coli ATCC
25922, P. aeruginosa ATCC 27583, K. pneumoniae ATCC 9997, S. aureus ATCC
29213, B. subtilis ATCC 6633, and Shigella flexneri ATCC 12022. The unloaded
nanoparticles and free extract were not active against the microorganisms tested, but
the loaded AgNP was active with a relevant MIC value (250 μg/mL) for most of the
tested microorganisms [240].
Zinc silibinin complex [Zn(sil)(H2O)2] and mixed ligand zinc complexes such
as Zn(silibinin)(phenanthroline) [Zn(sil)(phen)] and Zn(silibinin)(neocuproine)
[Zn(sil)(neo)] have been synthesized by Vimalraj et al. [169], and demonstrated
good antibacterial activity against E. coli and S. aureus strains. The complexes
showed significant growth inhibition at 5 ug/mL against both strains compared to
control. Furthermore, the microbial inhibition produced by the complexes was bet-
ter than that produced by silibinin alone.
Strategies to Improve Antimicrobial Activity of Natural Products: Approaches… 1281

4 Benefits and Limitations of the Strategies Employed

for Improving Antibacterial Activity

The eradication of several pathogenic drug-resistant “Superbug” became difficult

especially in chronic infections due to antibiotic resistance. But the emergence of
antimicrobial resistance is a concern not just in the field of health. Therefore,
researchers around the world seek to improve the antimicrobial action of several
substances for application in processed and nonprocessed foods of different types,
fish farms, agriculture, veterinary, as well as health, among others.
Presented data in this chapter summarize much of the research carried out in
recent years for the development of new antimicrobial strategies or improvement of
antimicrobial potency based on natural products.
Regarding the combination of antimicrobials, in several of the articles analyzed,
plant extracts or phytocompounds did not show activity when used alone but were
effective in enhancing the effect of antibiotics. They have considerable synergic
effects, positively altering the effect of antibiotics and constituting an important
alternative to combating the increase of microbial resistance. It is important to men-
tion that most of the time, plant-derived antimicrobials usually possess a lower
potency than conventional antimicrobials, possibly due to interactions between the
phytochemicals present. The ability of plant active substances to increase the effec-
tiveness of an antibiotic is reflected in the modification or blocking of the resistance
mechanism.
Since the extracts are complex mixtures containing different compounds, one of
the main challenges is to identify which compound(s) is/are responsible for the
synergistic interaction with the antibiotic(s), and further studies to address this
drawback should be undertaken in the future. Besides, the phenomenon of syner-
gism can occur between polymers and natural products. In many studies, chitosan
and natural products have shown antimicrobial activity when tested alone, but when
nanoparticles are formed with both, the minimum inhibitory/bactericidal concentra-
tion significantly decreases, employing lower quantities of bioactive compounds.
This leads to thinking that the antibacterial activity of the components is not only
enhanced by the nano size but also that there is a synergistic action of the compo-
nents. Moreover, the antimicrobial activity of nanocapsules is affected by the prepa-
ration process.
On the other hand, nanotechnology offers alternatives to improve the bioactivity
of antimicrobial agents, with a wide variety of applications, such as incorporation to
the matrix or food coatings, protection of grains against fungal infections, drug
development, impregnation of fabrics with antimicrobial nanoparticles, and many
more. But, the main inconvenience for implementing this kind of treatment on prod-
ucts named above is the cost.
Moreover, the complexation with cyclodextrins also offers the advantage of
requiring lower concentrations of natural products to achieve the same level of inhi-
bition than uncomplexed or unencapsulated forms.
1282 C. M. Pérez Zamora et al.

Though the action of plant-based antimicrobial is reported to be nonspecific,

most reports suggest that the mode of action is by altering the membrane permeabil-
ity and/or altering the pH and efflux transporter proteins. Delivery systems, such as
nanocapsules, can be directed to bacteria-infected cells and are promising alterna-
tives, as they protect natural products from degradation, control release, increase
susceptibility of target microbes and improve bioavailability of the natural product.
Although the results presented are encouraging, because most studies report
improved antimicrobial activity in in vitro tests, we are far from having alternative
antimicrobials more effective than those currently available. It has been seen in
some research that products/substances with good results in in vitro tests do not
have the same effect when applied in vivo. Therefore, there is a need for the inves-
tigations to progress to new stages of investigation with in vivo tests that can dem-
onstrate useful efficacy against infections. However, evidence shows that natural
products play an important role in the development of new antimicrobial agents.

References

1. Gottardi D, Bukvicki D, Prasad S, Tyagi AK (2016) Beneficial effects of spices in food pres-
ervation and safety. Front Microbiol 7:1394. https://doi.org/10.3389/fmicb.2016.01394
2. Aminzare M, Abbasi Z, Amiri E, Hashemi M, Raeisi M, Mousavi N, Hassanzadazar H (2017)
Colibacillosis phytotherapy: an overview on the most important world medicinal plants effec-
tive on Escherichia coli. J Pharm Sci 9(5):629
3. Paiva PM, Gomes FS, Napoleão TH, Sá RA, Correia MTS, Coelho LCBB (2010)
Antimicrobial activity of secondary metabolites and lectins from plants. In: Méndez-Vilas A
(ed) Current research, technology and education topics in applied microbiology and micro-
bial biotechnology. Formatex Research Center, Badajoz
4. Kongkham B, Prabakaran D, Puttaswamy H (2020) Opportunities and challenges in managing
antibiotic resistance in bacteria using plant secondary metabolites. Fitoterapia 147:104762.
https://doi.org/10.1016/j.fitote.2020.104762
5. Gangneux JP, Bougnoux ME, Dannaoui E, Cornet M, Zahar JR (2020) Invasive fungal dis-
eases during COVID-19: we should be prepared. J Mycol Med 30(2):100971. https://doi.
org/10.1016/j.mycmed.2020.100971
6. Dadgostar P (2019) Antimicrobial resistance: implications and costs. Infect Drug Resist
12:3903–3910. https://doi.org/10.2147/IDR.S234610
7. Fatima H, Goel N, Sinha R, Khare SK (2021) Recent strategies for inhibiting multidrug-­
resistant and β-lactamase producing bacteria: a review. Colloids Surf B Biointerfaces
205:111901. https://doi.org/10.1016/j.colsurfb.2021.111901
8. Alibi S, Crespo D, Navas J (2021) Plant-derivatives small molecules with antibacterial activ-
ity. Antibiotics 10(3):231. https://doi.org/10.3390/antibiotics10030231
9. Álvarez-Martínez FJ, Barrajón-Catalán E, Herranz-López M, Micol V (2021) Antibacterial
plant compounds, extracts and essential oils: an updated review on their effects and
putative mechanisms of action. Phytomedicine 90:153626. https://doi.org/10.1016/j.
phymed.2021.153626
10. Dwivedy AK, Singh VK, Prakash B, Dubey NK (2018) Nanoencapsulated Illicium verum
Hook. f. essential oil as an effective novel plant-based preservative against aflatoxin B1
production and free radical generation. Food Chem Toxicol 111:102–113. https://doi.
org/10.1016/j.fct.2017.11.007
Strategies to Improve Antimicrobial Activity of Natural Products: Approaches… 1283

11. Kumar A, Singh PP, Gupta V, Prakash B (2020) Assessing the antifungal and aflatoxin B1
inhibitory efficacy of nanoencapsulated antifungal formulation based on combination of
Ocimum spp. essential oils. Int J Food Microbiol 330:108766. https://doi.org/10.1016/j.
ijfoodmicro.2020.108766
12. Lahmar A, Bedoui A, Mokdad-Bzeouich I, Dhaouifi Z, Kalboussi Z, Cheraif I, Ghedira K,
Chekir-Ghedira L (2017) Reversal of resistance in bacteria underlies synergistic effect of
essential oils with conventional antibiotics. Microb Pathog 106:50–59
13. Wagner H, Efferth T (2017) Introduction: novel hybrid combinations containing synthetic or
antibiotic drugs with plant-derived phenolic or terpenoid compounds. Phytomedicine 37:1–3.
https://doi.org/10.1016/j.phymed.2017.10.020
14. Cushri S, Siriyong T, Na-Phatthalung P, Voravuthikunchai SP (2014) Synergistic effects
of ethnomedicinal plants of Apocynaceae family and antibiotics against clinical isolates
of Acinetobacter baumannii. Asian Pac J Trop Med 7(6):456–461. https://doi.org/10.1016/
S1995-­7645(14)60074-­2
15. Choi J-G, Choi J-Y, Mun S-H, Kang O-H, Bharaj P, Shin D-W, Kwon D-Y (2015)
Antimicrobial activity and synergism of Sami-Hyanglyun-Hwan with ciprofloxacin against
methicillin-resistant Staphylococcus aureus. Asian Pac J Trop Med 8(7):538–542. https://doi.
org/10.1016/j.apjtm.2015.06.010
16. De Aquino PEA, Pereira NLF, Figueredo FG, Ferreira SS, Leandro LMG, Souza JCCO et al
(2015) The association between drugs and herbal products: in vitro enhancement of the anti-
biotic activity by extracts of dry floral buttons of Egletes viscosa L. (macela). Eur J Integr
Med 7(3):258–262. https://doi.org/10.1016/j.eujim.2015.03.001
17. Ahumada-Santos YP, Soto-Sotomayor ME, Báez-Flores ME, Díaz-Camacho SP, López-­
Angulo G, Eslava-Campos CA, Delgado-Vargas F (2016) Antibacterial synergism of
Echeveria subrigida (BL Rob & Seaton) and commercial antibiotics against multidrug resis-
tant Escherichia coli and Staphylococcus aureus. Eur J Integr Med 8(5):638–644. https://doi.
org/10.1016/j.eujim.2016.08.160
18. Cristo JS, Matias EF, Figueredo FG, Santos JF, Pereira NL, Junior JG et al (2016) HPLC pro-
file and antibiotic-modifying activity of Azadirachta indica A. Juss, (Meliaceae). Ind Crop
Prod 94:903–908. https://doi.org/10.1016/j.indcrop.2016.10.001
19. Mahomoodally MF, Dilmohamed S (2016) Antibacterial and antibiotic potentiating activ-
ity of Vangueria madagascariensis leaves and ripe fruit pericarp against human pathogenic
clinical bacterial isolates. J Tradit Complement Med 6(4):399–403. https://doi.org/10.1016/j.
jtcme.2015.09.002
20. Morais-Braga MFB, Sales DL, dos Santos SF, Chaves TP, Bitu VDCN, Avilez WMT et al
(2016) Psidium guajava L. and Psidium brownianum Mart ex DC. potentiate the effect of anti-
biotics against Gram-positive and Gram-negative bacteria. Eur J Integr Med 8(5):683–687.
https://doi.org/10.1016/j.eujim.2016.07.001
21. Taukoorah U, Lall N, Mahomoodally F (2016) Piper betle L. (betel quid) shows bacterio-
static, additive, and synergistic antimicrobial action when combined with conventional anti-
biotics. S Afr J Bot 105:133–140. https://doi.org/10.1016/j.sajb.2016.01.006
22. Akinyele TA, Igbinosa EO, Akinpelu DA, Okoh AI (2017) In vitro assessment of the syn-
ergism between extracts of Cocos nucifera husk and some standard antibiotics. Asian Pac J
Trop Biomed 7(4):306–313. https://doi.org/10.1016/j.apjtb.2016.12.022
23. Alves Ribeiro D, Soares Damasceno S, Augusti Boligon A, Alencar de Menezes IR, de
Almeida Souza MM, Martins da Costa JG (2017) Chemical profile and antimicrobial activ-
ity of Secondatia floribunda A. DC (Apocynaceae). Asian Pac J Trop Biomed 7(8):739–749.
https://doi.org/10.1016/j.apjtb.2017.07.009
24. Costa AR, de Lima SJ, Lima KRR, Rocha MI, Barros LM, da Costa JGM et al (2017)
Rhaphiodon echinus (Nees & Mart.) Schauer: chemical, toxicological activity and increased
antibiotic activity of antifungal drug activity and antibacterial. Microb Pathog 107:280–286.
https://doi.org/10.1016/j.micpath.2017.04.001
1284 C. M. Pérez Zamora et al.

25. de Sousa SZ, Macêdo NS, de Freitas TS, da Silva ARP, dos Santos JFS, Morais-Braga
MFB et al (2017) Antibacterial enhancement of antibiotic activity by Enterolobium contor-
tisiliquum (Vell.) Morong. Asian Pac J Trop Biomed 7(10):945–949. https://doi.org/10.1016/j.
apjtb.2017.09.006
26. Torres CA, Nuñez MB, Isla MI, Castro MP, González AM, Zampini IC (2017) Antibacterial
synergism of extracts from climbers belonging to Bignoniaceae family and commercial
antibiotics against multi-resistant bacteria. J Herb Med 8:24–30. https://doi.org/10.1016/j.
hermed.2017.02.002
27. Alayande KA, Pohl CH, Ashafa AOT (2018) Significance of combination therapy between
Euclea crispa (Thunb.) (leaf and stem bark) extracts and standard antibiotics against drug
resistant bacteria. S Afr J Bot 118:203–208. https://doi.org/10.1016/j.sajb.2018.07.025
28. Seebaluck-Sandoram R, Lall N, Fibrich B, Van Staden AB, Mahomoodally F (2018) Antibiotic-­
potentiating activity, phytochemical profile, and cytotoxicity of Acalypha integrifolia Willd.
(Euphorbiaceae). J Herb Med 11:53–59. https://doi.org/10.1016/j.hermed.2017.03.005
29. Siebra ALA, Oliveira LR, Martins AO, Siebra DC, Albuquerque RS, Lemos ICS et al
(2018) Potentiation of antibiotic activity by Passiflora cincinnata Mast. front of strains
Staphylococcus aureus and Escherichia coli. Saudi J Biol Sci 25(1):37–43. https://doi.
org/10.1016/j.sjbs.2016.01.019
30. Vambe M, Aremu AO, Chukwujekwu JC, Finnie JF, Van Staden J (2018) Antibacterial
screening, synergy studies and phenolic content of seven South African medicinal plants
against drug-sensitive and-resistant microbial strains. S Afr J Bot 114:250–259. https://doi.
org/10.1016/j.sajb.2017.11.011
31. Wang N, Chen H, Xiong L, Liu X, Li X, An Q, Wang W (2018) Phytochemical profile of
ethanolic extracts of Chimonanthus salicifolius S. Y Hu leaves and its antimicrobial and
antibiotic-mediating activity. Ind Crops Prod 125:328–334. https://doi.org/10.1016/j.
indcrop.2018.09.021
32. Aelenei P, Luca SV, Horhogea CE, Rimbu CM, Dimitriu G, Macovei I et al (2019) Morus alba
leaf extract: metabolite profiling and interactions with antibiotics against Staphylococcus spp.
including MRSA. Phytochem Lett 31:217–224. https://doi.org/10.1016/j.phytol.2019.04.006
33. Andrade JC, Silva ARP, Santos ATL, Freitas MA, Carneiro JNP, Gonçalo MIP et al (2019)
UPLC-MS-ESI-QTOF characterization and evaluation of the antibacterial and modulatory
antibiotic activity of Ziziphus joazeiro Mart. aqueous extracts. S Afr J Bot 123:105–112.
https://doi.org/10.1016/j.sajb.2019.02.001
34. Blonck B, Cock IE (2019) Interactive antimicrobial and toxicity profiles of Pittosporum
angustifolium Lodd. extracts with conventional antimicrobials. J Integr Med 17:261–272.
https://doi.org/10.1016/j.joim.2019.03.006
35. Ilanko P, McDonnell PA, van Vuuren S, Cock IE (2019) Interactive antibacterial profile of
Moringa oleifera Lam. extracts and conventional antibiotics against bacterial triggers of some
autoimmune inflammatory diseases. S Afr J Bot 124:420–435. https://doi.org/10.1016/j.
sajb.2019.04.008
36. Omokhua AG, Ondua M, van Staden J, McGaw LJ (2019) Synergistic activity of extracts
of three South African alien invasive weeds combined with conventional antibiotics against
selected opportunistic pathogens. S Afr J Bot 124:251–257. https://doi.org/10.1016/j.
sajb.2019.05.023
37. Rolta R, Sharma A, Sourirajan A, Mallikarjunan PK, Dev K (2021) Combination between
antibacterial and antifungal antibiotics with phytocompounds of Artemisia annua L: a
strategy to control drug resistance pathogens. J Ethnopharmacol 266:113420. https://doi.
org/10.1016/j.jep.2020.113420
38. Rodrigues FC, dos Santos ATL, da Cruz RP, Almeida-Bezerra JW, Coutinho HDM, Ribeiro
PRV et al (2022) Antimicrobial activity, modulatory effect and phytochemical analysis of
Sida galheirensis Ulbr. (Malvaceae). S Afr J Bot 147:286–293. https://doi.org/10.1016/j.
sajb.2022.01.021
Strategies to Improve Antimicrobial Activity of Natural Products: Approaches… 1285

39. Djouahri A, Saka B, Boudarene L, Benseradj F, Aberrane S, Aitmoussa S et al (2014) In

vitro synergistic/antagonistic antibacterial and anti-inflammatory effect of various extracts/
essential oils from cones of Tetraclinis articulata (Vahl) Masters with antibiotic and anti-­
inflammatory agents. Ind Crop Prod 56:60–66. https://doi.org/10.1016/j.indcrop.2014.02.035
40. Sahu MC, Patnaik R, Padhy RN (2014) In vitro combinational efficacy of ceftriaxone and leaf
extract of Combretum albidum G. Don against multidrug-resistant Pseudomonas aeruginosa
and host-toxicity testing with lymphocytes from human cord blood. J Acute Med 4:26–37.
https://doi.org/10.1016/j.jacme.2014.01.004
41. Costa GM, Endo EH, Cortez DAG, Nakamura TU, Nakamura CV, Dias Filho BP (2016)
Antimicrobial effects of Piper hispidum extract, fractions and chalcones against Candida
albicans and Staphylococcus aureus. J Mycol Med 26(3):217–226. https://doi.org/10.1016/j.
mycmed.2016.03.002
42. Thakur P, Chawla R, Goel R, Narula A, Arora R, Sharma RK (2016) Augmenting the
potency of third-line antibiotics with Berberis aristata: in vitro synergistic activity against
carbapenem-­resistant Escherichia coli. J Glob Antimicrob Resist 6:10–16. https://doi.
org/10.1016/j.jgar.2016.01.015
43. Endo EH, Costa GM, Makimori RY, Ueda-Nakamura T, Nakamura CV, Dias Filho BP (2018)
Anti-biofilm activity of Rosmarinus officinalis, Punica granatum and Tetradenia riparia
against methicillin-resistant Staphylococcus aureus (MRSA) and synergic interaction with
penicillin. J Herb Med 14:48–54. https://doi.org/10.1016/j.hermed.2018.07.001
44. Teethaisong Y, Pimchan T, Srisawat R, Hobbs G, Eumkeb G (2018) Boesenbergia rotunda
(L.) Mansf. extract potentiates the antibacterial activity of some β-lactams against β-lactam-­
resistant staphylococci. J Glob Antimicrob Resist 12:207–213. https://doi.org/10.1016/j.
jgar.2017.10.019
45. Zaidi KU, Shah F, Parmar R, Thawani V (2018) Anticandidal synergistic activity of Ocimum
sanctum and fluconazole of azole resistance strains of clinical isolates. J Mycol Med
28(2):289–293. https://doi.org/10.1016/j.mycmed.2018.04.004
46. Mahomoodally MF, Ugurlu A, Llorent-Martínez EJ, Nagamootoo M, Picot-Allain MCN,
Baloglu MC et al (2020) Syzgium coriaceum Bosser & J. Guého—an endemic plant potenti-
ates conventional antibiotics, inhibits clinical enzymes and induces apoptosis in breast cancer
cells. Ind Crops Prod 143:111948. https://doi.org/10.1016/j.indcrop.2019.111948
47. Mandal S, Mandal MD, Pal NK (2012) Enhancing chloramphenicol and trimethoprim
in vitro activity by Ocimum sanctum Linn. (Lamiaceae) leaf extract against Salmonella
enterica serovar Typhi. Asian Pac J Trop Med 5(3):220–224. https://doi.org/10.1016/
S1995-­7645(12)60028-­5
48. Dias-Souza MV, Dos Santos RM, Cerávolo IP, Cosenza G, Marçal PHF (2018) Euterpe olera-
cea pulp extract: chemical analyses, antibiofilm activity against Staphylococcus aureus, cyto-
toxicity and interference on the activity of antimicrobial drugs. Microb Pathog 114:29–35.
https://doi.org/10.1016/j.micpath.2017.11.006
49. AlAhadeb JI (2021) New combination of drugs to combat Escherichia coli DSM1103
QCDSM by reducing antibiotic ciprofloxacin standard dose using response surface method-
ology. J Infect Public Health 14(12):1815–1821. https://doi.org/10.1016/j.jiph.2021.10.029
50. Abdulbaqi HR, Himratul-Aznita WH, Baharuddin NA (2016) Anti-plaque effect of a syner-
gistic combination of green tea and Salvadora persica L. against primary colonizers of dental
plaque. Arch Oral Biol 70:117–124. https://doi.org/10.1016/j.archoralbio.2016.06.011
51. Chung D, Cho TJ, Rhee MS (2018) Citrus fruit extracts with carvacrol and thymol eliminated
7-log acid-adapted Escherichia coli O157: H7, Salmonella typhimurium, and Listeria mono-
cytogenes: a potential of effective natural antibacterial agents. Food Res Int 107:578–588.
https://doi.org/10.1016/j.foodres.2018.03.011
52. Penduka D, Mthembu W, Cele KH, Mosa RA, Zobolo AM, Opoku AR (2018) Extracts of
Ansellia africana and Platycarpha glomerata exhibit antibacterial activities against some
respiratory tract, skin and soft tissue infections implicated bacteria. S Afr J Bot 116:116–122.
https://doi.org/10.1016/j.sajb.2018.02.403
1286 C. M. Pérez Zamora et al.

53. Maheshwari M, Althubiani AS, Abulreesh HH, Qais FA, Khan MS, Ahmad I (2019) Bioactive
extracts of Carum copticum L. enhances efficacy of ciprofloxacin against MDR enteric bacte-
ria. Saudi J Biol Sci 26(7):1848–1855. https://doi.org/10.1016/j.sjbs.2017.12.008
54. Moreno MA, Zampini IC, Isla MI (2020) Antifungal, anti-inflammatory and antioxi-
dant activity of bi-herbal mixtures with medicinal plants from Argentinean highlands. J
Ethnopharmacol 253:112642. https://doi.org/10.1016/j.jep.2020.112642
55. Quirino A, Morelli P, Capua G, Arena G, Matera G, Liberto MC, Focà A (2020) Synergistic
and antagonistic effects of Citrus bergamia distilled extract and its major components on drug
resistant clinical isolates. Nat Prod Res 34(11):1626–1629. https://doi.org/10.1080/1478641
9.2018.1522631
56. Islam R, Rahman MS, Hossain R, Nahar N, Hossin B, Ahad A, Rahman SM (2015)
Antibacterial activity of combined medicinal plants extract against multiple drug resistant
strains. Asian Pac J Trop Med 5:S151–S154. https://doi.org/10.1016/S2222-­1808(15)60878-­7
57. Chakraborty S, Afaq N, Singh N, Majumdar S (2018) Antimicrobial activity of
Cannabis sativa, Thuja orientalis and Psidium guajava leaf extracts against methicillin-­
resistant Staphylococcus aureus. J Integr Med 16(5):350–357. https://doi.org/10.1016/j.
joim.2018.07.005
58. Archana H, Bose VG (2022) Evaluation of phytoconstituents from selected medicinal plants
and its synergistic antimicrobial activity. Chemosphere 287:132276. https://doi.org/10.1016/j.
chemosphere.2021.132276
59. Liu C, Huang H, Zhou Q, Liu B, Wang Y, Li P et al (2019) Antibacterial and antibiotic
synergistic activities of the extract from Pithecellobium clypearia against clinically impor-
tant multidrug-resistant gram-negative bacteria. Eur J Integr Med 32:100999. https://doi.
org/10.1016/j.eujim.2019.100999
60. Barbosa MF, Miranda PH, Souza CA, Ramos CS, Melo AL, Rocha JE et al (2021) Effect
of hybrid combinations of Erythroxylum revolutum Mart. leaf ethanolic extract or alkaloid-­
enriched fraction with antibiotic drugs against multidrug-resistant bacteria strains.
Phytomedicine Plus 1(4):100105. https://doi.org/10.1016/j.phyplu.2021.100105
61. Lavor AKL, Matias EF, Alves EF, Santos BS, Figueredo FG, Lima LF et al (2014) Association
between drugs and herbal products: in vitro enhancement of the antibiotic activity by frac-
tions from leaves of Croton campestris A. (Euphorbiaceae). Eur J Integr Med 6(3):301–306.
https://doi.org/10.1016/j.eujim.2014.03.002
62. Matias EFF, Alves EF, do Nascimento Silva MK, de Alencar Carvalho VR, Medeiros CR, dos
Santos FAV et al (2015) Phytochemical characterization by HPLC and evaluation of antibac-
terial and aminoglycoside resistance-modifying activity of chloroform fractions of Cordia
verbenacea DC leaf extracts. Eur J Integr Med 7(3):251–257. https://doi.org/10.1016/j.
eujim.2015.03.007
63. da Silva JB, de Bessa ME, Mayorga OAS, Andrade VT, da Costa YFG, de Freitas Mendes R
et al (2018) A promising antibiotic, synergistic and antibiofilm effects of Vernonia conden-
sata Baker (Asteraceae) on Staphylococcus aureus. Microb Pathog 123:385–392. https://doi.
org/10.1016/j.micpath.2018.07.031
64. Demgne OMF, Damen F, Fankam AG, Guefack MGF, Wamba BE, Nayim P et al (2021)
Botanicals and phytochemicals from the bark of Hypericum roeperianum (Hypericaceae) had
strong antibacterial activity and showed synergistic effects with antibiotics against multidrug-­
resistant bacteria expressing active efflux pumps. J Ethnopharmacol 277:114257. https://doi.
org/10.1016/j.jep.2021.114257
65. Rolta R, Kumar V, Sourirajan A, Upadhyay NK, Dev K (2020) Bioassay guided fractionation
of rhizome extract of Rheum emodi wall as bio-availability enhancer of antibiotics against
bacterial and fungal pathogens. J Ethnopharmacol 257:112867. https://doi.org/10.1016/j.
jep.2020.112867
66. Dantas-Medeiros R, Zanatta AC, de Souza LBFC, Fernandes JM, Amorim-Carmo B, Torres-­
Rêgo M et al (2021) Antifungal and antibiofilm activities of b-type oligomeric procyani-
dins from commiphora leptophloeos used alone or in combination with fluconazole against
Candida spp. Front Microbiol 27. https://doi.org/10.3389/fmicb.2021.613155
Strategies to Improve Antimicrobial Activity of Natural Products: Approaches… 1287

67. Sánchez-Chávez AC, Salazar-Gómez A, Zepeda-Vallejo LG, Hernández de Jesús MDL,

Quintos-Escalante M, Vargas-Díaz ME, Luna-Herrera J (2017) Trixis angustifolia hexanic
extract displays synergistic antibacterial activity against M. tuberculosis. Nat Prod Res
33(10):1477–1481. https://doi.org/10.1080/14786419.2017.1416381
68. Carvalho RS, Carollo CA, De Magalhães JC, Palumbo JMC, Boaretto AG, e Sá IN et al
(2018) Antibacterial and antifungal activities of phenolic compound-enriched ethyl acetate
fraction from Cochlospermum regium (mart. Et. Schr.) Pilger roots: mechanisms of action and
synergism with tannin and gallic acid. S Afr J Bot 114:181–187. https://doi.org/10.1016/j.
sajb.2017.11.010
69. Freitas PR, de Araújo ACJ, dos Santos Barbosa CR, Muniz DF, da Silva ACA, Rocha JE
et al (2020) GC-MS-FID and potentiation of the antibiotic activity of the essential oil of
Baccharis reticulata (ruiz & pav.) pers. and α-pinene. Ind Crop Prod 145:112106. https://doi.
org/10.1016/j.indcrop.2020.112106Get
70. Aleksic V, Mimica-Dukic N, Simin N, Nedeljkovic NS, Knezevic P (2014) Synergistic effect
of Myrtus communis L. essential oils and conventional antibiotics against multi-drug resis-
tant Acinetobacter baumannii wound isolates. Phytomedicine 21(12):1666–1674. https://doi.
org/10.1016/j.phymed.2014.08.013
71. Pereira V, Dias C, Vasconcelos MC, Rosa E, Saavedra MJ (2014) Antibacterial activity and
synergistic effects between Eucalyptus globulus leaf residues (essential oils and extracts) and
antibiotics against several isolates of respiratory tract infections (Pseudomonas aeruginosa).
Ind Crop Prod 52:1–7. https://doi.org/10.1016/j.indcrop.2013.09.032
72. de Aguiar UN, de Lima SG, dos Santos RM, Citó AMDGL, Sousa AJP, Silva RM et al (2015)
Chemical composition and modulation of antibiotic activity of essential oil of Lantana
caatingensis M. (Verbenaceae). Ind Crop Prod 74:165–170. https://doi.org/10.1016/j.
indcrop.2015.04.011
73. Aumeeruddy-Elalfi Z, Gurib-Fakim A, Mahomoodally MF (2016) Chemical composition,
antimicrobial and antibiotic potentiating activity of essential oils from 10 tropical medicinal
plants from Mauritius. J Herb Med 6(2):88–95. https://doi.org/10.1016/j.hermed.2016.02.002
74. Knezevic P, Aleksic V, Simin N, Svircev E, Petrovic A, Mimica-Dukic N (2016) Antimicrobial
activity of Eucalyptus camaldulensis essential oils and their interactions with conventional
antimicrobial agents against multi-drug resistant Acinetobacter baumannii. J Ethnopharmacol
178:125–136. https://doi.org/10.1016/j.jep.2015.12.008
75. Boonyanugomol W, Kraisriwattana K, Rukseree K, Boonsam K, Narachai P (2017) In
vitro synergistic antibacterial activity of the essential oil from Zingiber cassumunar Roxb
against extensively drug-resistant Acinetobacter baumannii strains. J Infect Public Health
10(5):586–592. https://doi.org/10.1016/j.jiph.2017.01.008
76. Dra LA, Brahim MAS, Boualy B, Aghraz A, Barakate M, Oubaassine S et al (2017) Chemical
composition, antioxidant and evidence antimicrobial synergistic effects of Periploca lae-
vigata essential oil with conventional antibiotics. Ind Crop Prod 109:746–752. https://doi.
org/10.1016/j.indcrop.2017.09.028
77. Elhidar N, Nafis A, Kasrati A, Goehler A, Bohnert JA, Abbad A et al (2019) Chemical com-
position, antimicrobial activities and synergistic effects of essential oil from Senecio anteu-
phorbium, a Moroccan endemic plant. Ind Crop Prod 130:310–315. https://doi.org/10.1016/j.
indcrop.2018.12.097
78. Nafis A, Kasrati A, Jamali CA, Mezrioui N, Setzer W, Abbad A, Hassani L (2019) Antioxidant
activity and evidence for synergism of Cannabis sativa (L.) essential oil with antimicrobial
standards. Ind Crop Prod 137:396–400. https://doi.org/10.1016/j.indcrop.2019.05.032
79. Soulaimani B, Nafis A, Kasrati A, Rochdi A, Mezrioui NE, Abbad A, Hassani L (2019)
Chemical composition, antimicrobial activity and synergistic potential of essential oil from
endemic Lavandula maroccana (Mill.). S Afr J Bot 125:202–206. https://doi.org/10.1016/j.
sajb.2019.07.030
80. Vitanza L, Maccelli A, Marazzato M, Scazzocchio F, Comanducci A, Fornarini S et al (2019)
Satureja montana L. essential oil and its antimicrobial activity alone or in combination with
gentamicin. Microb Pathog 126:323–331. https://doi.org/10.1016/j.micpath.2018.11.025
1288 C. M. Pérez Zamora et al.

81. Dumlupinar B, Karatoprak GŞ, Celik DD, Gürer ÜS, Demirci B, Gürbüz B et al (2020)
Synergic potential of Pelargonium endlicherianum Fenzl. Essential oil and antibiotic combi-
nations against Klebsiella pneumoniae. S Afr J Bot 135:117–126. https://doi.org/10.1016/j.
sajb.2020.08.022
82. Jugreet BS, Mahomoodally MF (2020) Essential oils from 9 exotic and endemic medicinal
plants from Mauritius shows in vitro antibacterial and antibiotic potentiating activities. S Afr
J Bot 132:355–362. https://doi.org/10.1016/j.sajb.2020.05.001
83. Jugreet BS, Mahomoodally MF (2021) Reprint of: essential oils from 9 exotic and endemic
medicinal plants from Mauritius show in vitro antibacterial and antibiotic potentiating activi-
ties. S Afr J Bot 140:478–485. https://doi.org/10.1016/j.sajb.2021.07.005
84. Braga AL, da Cruz RP, Carneiro JNP, dos Santos ATL, Sales DL, Bezerra CF et al (2021)
Piper regnellii (Miq.) C. DC.: chemical composition, antimicrobial effects, and modulation of
antimicrobial resistance. S Afr J Bot 142:495–501. https://doi.org/10.1016/j.sajb.2021.07.017
85. Brahim MAS, Fadli M, Hassani L, Boulay B, Markouk M, Bekkouche K et al (2015)
Chenopodium ambrosioides var. ambrosioides used in Moroccan traditional medicine can
enhance the antimicrobial activity of conventional antibiotics. Ind Crop Prod 71:37–43.
https://doi.org/10.1016/j.indcrop.2015.03.067
86. Göger G, Demirci B, Ilgın S, Demirci F (2018) Antimicrobial and toxicity profiles evaluation
of the Chamomile (Matricaria recutita L.) essential oil combination with standard antimi-
crobial agents. Ind Crop Prod 120:279–285. https://doi.org/10.1016/j.indcrop.2018.04.024
87. Khoury M, El Beyrouthy M, Ouaini N, Eparvier V, Stien D (2019) Hirtellina lobelii
DC. essential oil, its constituents, its combination with antimicrobial drugs and its mode of
action. Fitoterapia 133:130–136. https://doi.org/10.1016/j.fitote.2019.01.001
88. Jafri H, Ahmad I (2020) Thymus vulgaris essential oil and thymol inhibit biofilms and
interact synergistically with antifungal drugs against drug resistant strains of Candida
albicans and Candida tropicalis. J Mycol Med 30(1):100911. https://doi.org/10.1016/j.
mycmed.2019.100911
89. Barreto HM, de Lima IS, Coelho KMRN, Osório LR, de Almeida MR, dos Santos BHC et al
(2014) Effect of Lippia origanoides HBK essential oil in the resistance to aminoglycosides
in methicillin resistant Staphylococcus aureus. Eur J Integr Med 6(5):560–564. https://doi.
org/10.1016/j.eujim.2014.03.011
90. Kasrati A, Jamali CA, Fadli M, Bekkouche K, Hassani L, Wohlmuth H et al (2014)
Antioxidative activity and synergistic effect of Thymus saturejoides Coss. essential oils
with cefixime against selected food-borne bacteria. Ind Crop Prod 61:338–344. https://doi.
org/10.1016/j.indcrop.2014.07.024
91. Aguiar JJ, Sousa CP, Araruna MK, Silva MK, Portelo AC, Lopes JC (2015) Antibacterial and
modifying-antibiotic activities of the essential oils of Ocimum gratissimum L. and Plectranthus
amboinicus L. Eur J Integr Med 7(2):151–156. https://doi.org/10.1016/j.eujim.2014.10.005
92. Sienkiewicz M, Łysakowska M, Kowalczyk E, Szymańska G, Kochan E, Krukowska J et al
(2017) The ability of selected plant essential oils to enhance the action of recommended anti-
biotics against pathogenic wound bacteria. Burns 43(2):310–317. https://doi.org/10.1016/j.
burns.2016.08.032
93. Salem N, Kefi S, Tabben O, Ayed A, Jallouli S, Feres N et al (2018) Variation in chemical
composition of Eucalyptus globulus essential oil under phenological stages and evidence syn-
ergism with antimicrobial standards. Ind Crop Prod 124:115–125. https://doi.org/10.1016/j.
indcrop.2018.07.051
94. Sharma K, Guleria S, Razdan VK, Babu V (2020) Synergistic antioxidant and antimicrobial
activities of essential oils of some selected medicinal plants in combination and with synthetic
compounds. Ind Crop Prod 154:112569. https://doi.org/10.1016/j.indcrop.2020.112569
95. Rocha RR, Matos MNC, Guerrero JAP, Cavalcante RMB, Melo RS, Azevedo ÁMA et al
(2021) Comparative study of the chemical composition, antibacterial activity and synergic
effects of the essential oils of Croton tetradenius baill. and C. pulegiodorus baill. Against
Staphylococcus aureus isolates. Microb Pathog 156:104934. https://doi.org/10.1016/j.
micpath.2021.104934
Strategies to Improve Antimicrobial Activity of Natural Products: Approaches… 1289

96. Goldbeck JC, do Nascimento JE, Jacob RG, Fiorentini ÂM, da Silva WP (2014) Bioactivity
of essential oils from Eucalyptus globulus and Eucalyptus urograndis against planktonic cells
and biofilms of Streptococcus mutans. Ind Crop Prod 60:304–309. https://doi.org/10.1016/j.
indcrop.2014.05.030
97. Clemente I, Aznar M, Silva F, Nerín C (2016) Antimicrobial properties and mode of action of
mustard and cinnamon essential oils and their combination against foodborne bacteria. Innov
Food Sci Emerg Technol 36:26–33. https://doi.org/10.1016/j.ifset.2016.05.013
98. Veras HN, Rodrigues FF, Botelho MA, Menezes IR, Coutinho HD, Costa JG (2017)
Enhancement of aminoglycosides and β-lactams antibiotic activity by essential oil of Lippia
sidoides Cham. and the thymol. Arab J Chem 10:S2790–S2795. https://doi.org/10.1016/j.
arabjc.2013.10.030
99. Vázquez-Sánchez D, Galvão JA, Mazine MR, Gloria EM, Oetterer M (2018) Control of
Staphylococcus aureus biofilms by the application of single and combined treatments
based in plant essential oils. Int J Food Microbiol 286:128–138. https://doi.org/10.1016/j.
ijfoodmicro.2018.08.007
100. Ayari S, Shankar S, Follett P, Hossain F, Lacroix M (2020) Potential synergistic antimi-
crobial efficiency of binary combinations of essential oils against Bacillus cereus and
Paenibacillus amylolyticus - Part A. Microb Pathog 141:104008. https://doi.org/10.1016/j.
micpath.2020.104008
101. Iseppi R, Camellini S, Sabia C, Messi P (2020) Combined antimicrobial use of essential oils
and bacteriocin bacLP17 as seafood biopreservative to control Listeria monocytogenes both
in planktonic and in sessile forms. Res Microbiol 171(8):351–356. https://doi.org/10.1016/j.
resmic.2020.07.002
102. Ngo-Mback MNL, Babii C, Dongmo PJ, Toghueo MK, Stefan M, Boyom FF (2020)
Anticandidal and synergistic effect of essential oil fractions from three aromatic plants used
in Cameroon. J Mycol Med 30(2):100940. https://doi.org/10.1016/j.mycmed.2020.100940
103. Chraibi M, Fadil M, Farah A, Lebrazi S, Fikri-Benbrahim K (2021) Antimicrobial com-
bined action of Mentha pulegium, Ormenis mixta and Mentha piperita essential oils against
S. aureus, E. coli and C. tropicalis: application of mixture design methodology. LWT
145:111352. https://doi.org/10.1016/j.lwt.2021.111352
104. Kim J, Kim H, Beuchat LR, Ryu JH (2021) Synergistic antimicrobial activities of plant essen-
tial oils against Listeria monocytogenes in organic tomato juice. Food Control 125:108000.
https://doi.org/10.1016/j.foodcont.2021.108000
105. Soulaimani B, El Hidar N, El Fakir SB, Mezrioui N, Hassani L, Abbad A (2021) Combined
antibacterial activity of essential oils extracted from Lavandula maroccana (Murb.), Thymus
pallidus Batt. and Rosmarinus officinalis L. against antibiotic-resistant Gram-negative bacte-
ria. Eur J Integr Med 43:101312. https://doi.org/10.1016/j.eujim.2021.101312
106. Subramaniam S, Keerthiraja M, Sivasubramanian A (2014) Synergistic antibacterial action of
β-sitosterol-D-glucopyranoside isolated from Desmostachya bipinnata leaves with antibiot-
ics against common human pathogens. Rev Bras Farmacogn 24(1):44–50. https://doi.org/1
0.1590/0102-­695X20142413348
107. Albano M, Alves FCB, Andrade BFMT, Barbosa LN, Pereira AFM, de Souza MDLR et al
(2016) Antibacterial and anti-staphylococcal enterotoxin activities of phenolic compounds.
Innov Food Sci Emerg Technol 38:83–90. https://doi.org/10.1016/j.ifset.2016.09.003
108. Lima VN, Oliveira-Tintino CD, Santos ES, Morais LP, Tintino SR, Freitas TS et al (2016)
Antimicrobial and enhancement of the antibiotic activity by phenolic compounds: gal-
lic acid, caffeic acid and pyrogallol. Microb Pathog 99:56–61. https://doi.org/10.1016/j.
micpath.2016.08.004
109. Zuo GY, Wang CJ, Han J, Li YQ, Wang GC (2016) Synergism of coumarins from
the Chinese drug Zanthoxylum nitidum with antibacterial agents against methicillin-­
resistant Staphylococcus aureus (MRSA). Phytomedicine 23(14):1814–1820. https://doi.
org/10.1016/j.phymed.2016.11.001
1290 C. M. Pérez Zamora et al.

110. Gomes FMS, da Cunha XJ, Dos Santos JFS, de Matos YMLS, Tintino SR, de Freitas
TS, Coutinho HDM (2018) Evaluation of antibacterial and modifying action of catechin
antibiotics in resistant strains. Microb Pathog 115:175–178. https://doi.org/10.1016/j.
micpath.2017.12.058
111. Bustos PS, Deza-Ponzio R, Páez PL, Cabrera JL, Virgolini MB, Ortega MG (2018) Flavonoids
as protective agents against oxidative stress induced by gentamicin in systemic circula-
tion. Potent protective activity and microbial synergism of luteolin. Food Chem Toxicol
118:294–302. https://doi.org/10.1016/j.fct.2018.05.030
112. Torres CA, Sturla MA, Romero AM, Judis MA (2019) Bioguided isolation of antimicrobial
polyphenols from Cuspidaria convoluta leaves and their synergistic effect with antibiotics.
Asian Pac J Trop Biomed. https://doi.org/10.4103/2221-­1691.269525
113. Zuo GY, Yang CX, Han J, Li YQ, Wang GC (2018) Synergism of prenylflavonoids from
Morus alba root bark against clinical MRSA isolates. Phytomedicine 39:93–99. https://doi.
org/10.1016/j.phymed.2017.12.023
114. Bhattacharya S, Sen D, Bhattacharjee C (2019) In vitro antibacterial effect analysis of sta-
bilized PEGylated allicin-containing extract from Allium sativum in conjugation with other
antibiotics. Process Biochem 87:221–231. https://doi.org/10.1016/j.procbio.2019.09.025
115. Parvez MAK, Saha K, Rahman J, Munmun RA, Rahman MA, Dey SK et al (2019)
Antibacterial activities of green tea crude extracts and synergistic effects of epigallocat-
echingallate (EGCG) with gentamicin against MDR pathogens. Heliyon 5(7). https://doi.
org/10.1016/j.heliyon.2019.e02126
116. Ušjak D, Ivković B, Božić DD, Bošković L, Milenković M (2019) Antimicrobial activity of
novel chalcones and modulation of virulence factors in hospital strains of Acinetobacter bau-
mannii and Pseudomonas aeruginosa. Microb Pathog 131:186–196. https://doi.org/10.1016/j.
micpath.2019.04.015
117. Cruz BG, Dos Santos HS, Bandeira PN, Rodrigues THS, Matos MGC, Nascimento MF et al
(2020) Evaluation of antibacterial and enhancement of antibiotic action by the flavonoid
kaempferol 7-O-β-D-(6″-O-cumaroyl)-glucopyranoside isolated from Croton piauhiensis
müll. Microb Pathog 143. https://doi.org/10.1016/j.micpath.2020.104144
118. Siqueira MMR, Freire PDTC, Cruz BG, de Freitas TS, Bandeira PN, Dos Santos HS et al
(2021) Aminophenyl chalcones potentiating antibiotic activity and inhibiting bacterial efflux
pump. Eur J Pharm Sci 158. https://doi.org/10.1016/j.ejps.2020.105695
119. Leite-Sampaio NF, Gondim CNF, de Souza CES, Coutinho HD (2022) Antibiotic potentiat-
ing action of α-PINENE and borneol against EPEC and ETEC sorotypes. Microb Pathog 162.
https://doi.org/10.1016/j.micpath.2021.105371
120. Cabral V, Luo X, Junqueira E, Costa SS, Mulhovo S, Duarte A et al (2015) Enhancing activity
of antibiotics against Staphylococcus aureus: zanthoxylum capense constituents and deriva-
tives. Phytomedicine 22(4):469–476. https://doi.org/10.1016/j.phymed.2015.02.003
121. Lee S, Al Razqan GS, Kwon DH (2017) Antibacterial activity of epigallocatechin-3-gallate
(EGCG) and its synergism with β-lactam antibiotics sensitizing carbapenem-associated
multidrug resistant clinical isolates of Acinetobacter baumannii. Phytomedicine 24:49–55.
https://doi.org/10.1016/j.phymed.2016.11.007
122. Sivasankar C, Gayathri S, Bhaskar JP, Krishnan V, Pandian SK (2017) Evaluation of selected
Indian medicinal plants for antagonistic potential against Malassezia spp. and the synergistic
effect of embelin in combination with ketoconazole. Microb Pathog 110:66–72. https://doi.
org/10.1016/j.micpath.2017.06.026
123. Ferreira GRS, de Santana BJ, Procopio TF, de Lima Santos ND, de Lima BJRC, Coelho
LCBB et al (2018) Antimicrobial potential of Alpinia purpurata lectin (ApuL): growth
inhibitory action, synergistic effects in combination with antibiotics, and antibiofilm activity.
Microb Pathog 124:152–162. https://doi.org/10.1016/j.micpath.2018.08.027
124. da Silva PM, da Silva BR, de Oliveira Silva JN, de Moura MC, Soares T, Feitosa APS
et al (2019) Punica granatum sarcotesta lectin (PgTeL) has antibacterial activity and syn-
ergistic effects with antibiotics against β-lactamase-producing Escherichia coli. Int J Biol
135:931–939. https://doi.org/10.1016/j.ijbiomac.2019.06.011
Strategies to Improve Antimicrobial Activity of Natural Products: Approaches… 1291

125. Pal A, Tripathi A (2020) Demonstration of bactericidal and synergistic activity of quercetin
with meropenem among pathogenic carbapenem resistant Escherichia coli and Klebsiella
pneumoniae. Microb Pathog 143:104120. https://doi.org/10.1016/j.micpath.2020.104120
126. Wan CJ, Zhang Y, Liu CX, Yang ZC (2022) Cinnamic aldehyde, isolated from Cinnamomum
cassia, alone and in combination with pyrazinamide against Mycobacterium tuberculosis
in vitro and in vivo. S Afr J Bot 144:200–205. https://doi.org/10.1016/j.sajb.2021.08.009
127. Liu Y, Zhao Y, Guo DL, Liu WW, Liu YX (2017) Synergistic antimicrobial activity of ber-
berine hydrochloride, baicalein and borneol against Candida albicans. Chin Herb Med
9(4):353–357. https://doi.org/10.1016/S1674-­6384(17)60115-­1
128. Shakil S, Khan R, Zarrilli R, Khan AU (2008) Aminoglycosides versus bacteria–a description
of the action, resistance mechanism, and nosocomial battleground. J Biomed Sci 15(1):5–14.
https://doi.org/10.1007/s11373-­007-­9194-­y
129. Cushnie TT, Lamb AJ (2011) Recent advances in understanding the antibacterial properties of
flavonoids. Int J Antimicrob 38(2):99–107. https://doi.org/10.1016/j.ijantimicag.2011.02.014
130. Delshadi R, Bahrami A, Assadpour E, Williams L, Jafari SM (2021) Nano/microencapsulated
natural antimicrobials to control the spoilage microorganisms and pathogens in different food
products. Food Control 128:108180. https://doi.org/10.1016/j.foodcont.2021.108180
131. Gupta S, Variyar PS (2016) Nanoencapsulation of essential oils for sustained release: appli-
cation as therapeutics and antimicrobials. In: Grumezescu AM (ed) Nanotechnology in
the Agri-Food Industry, Encapsulations. Academic Press. Elsevier. Pages 641–672, ISBN
9780128043073. https://doi.org/10.1016/B978-0-12-804307-3.00015-6
132. Bilia AR, Guccione C, Isacchi B, Righeschi C, Firenzuoli F, Bergonzi MC (2014) Essential
oils loaded in nanosystems: a developing strategy for a successful therapeutic approach.
Evid-Based Complement Altern Med. https://doi.org/10.1155/2014/651593
133. Gebremedhn K, Kahsay MH, Aklilu M (2019) Green synthesis of CuO nanoparticles using
leaf extract of catha edulis and its antibacterial activity. J Pharm Pharmacol 7(7):327–342.
https://doi.org/10.17265/2328-­2150/2019.06.007
134. Adel AM, Ibrahim AA, El-Shafei AM, Al-Shemy MT (2019) Inclusion complex of clove
oil with chitosan/β-cyclodextrin citrate/oxidized nanocellulose biocomposite for active food
packaging. Food Packag Shelf Life 20. https://doi.org/10.1016/j.fpsl.2019.100307
135. Alderees F, Akter S, Mereddy R, Sultanbawa Y (2021) Antimicrobial activity of nanoencap-
sulated essential oils of Tasmannia lanceolata, Backhousia citriodora and Syzygium anisa-
tum against weak-acid resistant Zygosaccharomyces bailii in clear apple juice. Beverages
7(3):67. https://doi.org/10.3390/beverages7030067
136. Lee KH, Lee JS, Kim ES, Lee HG (2019) Preparation, characterization, and food applica-
tion of rosemary extract-loaded antimicrobial nanoparticle dispersions. LWT 101:138–144.
https://doi.org/10.1016/j.lwt.2018.10.072
137. Yadav A, Kujur A, Kumar A, Singh PP, Prakash B, Dubey NK (2019) Assessing the preser-
vative efficacy of nanoencapsulated mace essential oil against food borne molds, aflatoxin
B1 contamination, and free radical generation. LWT 108:429–436. https://doi.org/10.1016/j.
lwt.2019.03.075
138. Ribeiro-Santos R, Andrade M, Sanches-Silva A (2017) Application of encapsulated essential
oils as antimicrobial agents in food packaging. Curr Opin Food Sci 14:78–84. https://doi.
org/10.1016/j.cofs.2017.01.012
139. Chaudhari AK, Dwivedy AK, Singh VK, Das S, Singh A, Dubey NK (2019) Essential oils
and their bioactive compounds as green preservatives against fungal and mycotoxin contami-
nation of food commodities with special reference to their nanoencapsulation. Environ Sci
Pollut Res 26(25):25414–25431. https://doi.org/10.1007/s11356-­019-­05932-­2
140. Singh A, Chaudhari AK, Das S, Dubey NK (2020) Nanoencapsulated Monarda citrio-
dora Cerv. ex Lag. essential oil as potential antifungal and antiaflatoxigenic agent against
deterioration of stored functional foods. J Food Sci Technol 57(8):2863–2876. https://doi.
org/10.1007/s13197-­020-­04318-­4
1292 C. M. Pérez Zamora et al.

141. Zanetti M, Carniel TK, Dalcanton F, dos Anjos RS, Riella HG, de Araújo PH et al (2018)
Use of encapsulated natural compounds as antimicrobial additives in food packaging: a brief
review. Trends Food Sci Technol 81:51–60. https://doi.org/10.1016/j.tifs.2018.09.003
142. Zhang H, Li X, Kang H (2019) Chitosan coatings incorporated with free or nano-­encapsulated
Paulownia Tomentosa essential oil to improve shelf-life of ready-to-cook pork chops. LWT
116:108580. https://doi.org/10.1016/j.lwt.2019.108580
143. Sarvinehbaghi MB, Ahmadi M, Shiran M, Azizkhani M (2021) Antioxidant and antimicrobial
activity of red onion (Allium cepa, L.) extract nanoencapsulated in native seed gums coating
and its effect on shelf-life extension of beef fillet. J Food Meas Charact 15(5):4771–4780.
https://doi.org/10.1007/s11694-­021-­00985-­9
144. Bahrami A, Delshadi R, Assadpour E, Jafari SM, Williams L (2020) Antimicrobial-loaded
nanocarriers for food packaging applications. Adv Colloid Interf Sci 278:102140. https://doi.
org/10.1016/j.cis.2020.102140
145. Liao W, Badri W, Dumas E, Ghnimi S, Elaïssari A, Saurel R, Gharsallaoui A (2021)
Nanoencapsulation of essential oils as natural food antimicrobial agents: an overview. Appl
Sci 11(13):5778. https://doi.org/10.3390/app11135778
146. Donsì F, Annunziata M, Sessa M, Ferrari G (2011) Nanoencapsulation of essential oils to
enhance their antimicrobial activity in foods. LWT - Food Sci Technol 44(9):1908–1914.
https://doi.org/10.1016/j.lwt.2011.03.003
147. Prakash B, Kujur A, Yadav A, Kumar A, Singh PP, Dubey NK (2018) Nanoencapsulation: an
efficient technology to boost the antimicrobial potential of plant essential oils in food system.
Food Control 89:1–11
148. Bagheri R, Ariaii P, Motamedzadegan A (2021) Characterization, antioxidant and antibacte-
rial activities of chitosan nanoparticles loaded with nettle essential oil. J Food Meas Charact
15(2):1395–1402. https://doi.org/10.1007/s11694-­020-­00738-­0
149. Lu N, Liu Y (2020) Structural, physicochemical, and functional (antioxidant-antimicrobial)
properties of 2-O-methyl-β-cyclodextrin inclusion with hexahydro-β-acids in chitosan films.
Colloids Surf B Biointerfaces 191:111002. https://doi.org/10.1016/j.colsurfb.2020.111002
150. Cui H, Wang Y, Li C, Chen X, Lin L (2021) Antibacterial efficacy of Satureja montana
L. essential oil encapsulated in methyl-β-cyclodextrin/soy soluble polysaccharide hydro-
gel and its assessment as meat preservative. LWT 152:112427. https://doi.org/10.1016/j.
lwt.2021.112427
151. Huang H, Huang C, Yin C, Khan MR, Zhao H, Xu Y et al (2020) Preparation and character-
ization of β-cyclodextrin–oregano essential oil microcapsule and its effect on storage behav-
ior of purple yam. J Sci Food Agric 100(13):4849–4857. https://doi.org/10.1002/jsfa.10545
152. Bedoya-Serna CM, Dacanal GC, Fernandes AM, Pinho SC (2018) Antifungal activity of
nanoemulsions encapsulating oregano (Origanum vulgare) essential oil: in vitro study and
application in Minas Padrão cheese. Braz J Microbiol 49:929–935. https://doi.org/10.1016/j.
bjm.2018.05.004
153. Cui H, Bai M, Rashed MM, Lin L (2018) The antibacterial activity of clove oil/chitosan
nanoparticles embedded gelatin nanofibers against Escherichia coli O157: H7 biofilms on
cucumber. Int J Food Microbiol 266:69–78. https://doi.org/10.1016/j.ijfoodmicro.2017.11.019
154. Tometri SS, Ahmady M, Ariaii P, Soltani MS (2020) Extraction and encapsulation of Laurus
nobilis leaf extract with nano-liposome and its effect on oxidative, microbial, bacterial and
sensory properties of minced beef. J Food Meas Charact 14(6):3333–3344. https://doi.
org/10.1007/s11694-­020-­00578-­y
155. Moraes-Lovison M, Marostegan LF, Peres MS, Menezes IF, Ghiraldi M, Rodrigues RA et al
(2017) Nanoemulsions encapsulating oregano essential oil: production, stability, antibacte-
rial activity and incorporation in chicken pâté. LWT 77:233–240. https://doi.org/10.1016/j.
lwt.2016.11.061
156. Hadian M, Rajaei A, Mohsenifar A, Tabatabaei M (2017) Encapsulation of Rosmarinus offi-
cinalis essential oils in chitosan-benzoic acid nanogel with enhanced antibacterial activity in
beef cutlet against Salmonella typhimurium during refrigerated storage. LWT 84:394–401.
https://doi.org/10.1016/j.lwt.2017.05.075
Strategies to Improve Antimicrobial Activity of Natural Products: Approaches… 1293

157. Sotelo-Boyás ME, Correa-Pacheco ZN, Bautista-Baños S, Corona-Rangel ML (2017)

Physicochemical characterization of chitosan nanoparticles and nanocapsules incorporated
with lime essential oil and their antibacterial activity against food-borne pathogens. LWT
77:15–20. https://doi.org/10.1016/j.lwt.2016.11.022
158. Makwana S, Choudhary R, Dogra N, Kohli P, Haddock J (2014) Nanoencapsulation and
immobilization of cinnamaldehyde for developing antimicrobial food packaging material.
LWT - Food Sci Technol 57(2):470–476. https://doi.org/10.1016/j.lwt.2014.01.043
159. Zhang H, Liang Y, Li X, Kang H (2020) Effect of chitosan-gelatin coating containing nano-­
encapsulated tarragon essential oil on the preservation of pork slices. Meat Sci 166. https://
doi.org/10.1016/j.meatsci.2020.108137
160. Jemaa MB, Falleh H, Serairi R, Neves MA, Snoussi M, Isoda H et al (2018) Nanoencapsulated
Thymus capitatus essential oil as natural preservative. Innov Food Sci Emerg Technol
45:92–97. https://doi.org/10.1016/j.ifset.2017.08.017
161. Ghaderi-Ghahfarokhi M, Barzegar M, Sahari MA, Azizi MH (2016) Nanoencapsulation
approach to improve antimicrobial and antioxidant activity of thyme essential oil in beef
burgers during refrigerated storage. Food Bioprocess Technol 9(7):1187–1201. https://doi.
org/10.1007/s11947-­016-­1708-­z
162. Kiti K, Suwantong O (2020) Bilayer wound dressing based on sodium alginate incorporated
with curcumin-β-cyclodextrin inclusion complex/chitosan hydrogel. Int J Biol Macromol
164:4113–4124. https://doi.org/10.1016/j.ijbiomac.2020.09.013
163. Anh HTP, Huang CM, Huang CJ (2019) Intelligent metal-phenolic metallogels as dressings
for infected wounds. Sci Rep 9(1):1–10. https://doi.org/10.1038/s41598-­019-­47978-­9
164. Moradi S, Barati A, Tonelli AE, Hamedi H (2020) Chitosan-based hydrogels loading with
thyme oil cyclodextrin inclusion compounds: from preparation to characterization. Eur
Polym J 122. https://doi.org/10.1016/j.eurpolymj.2019.109303
165. Gupta A, Keddie DJ, Kannappan V, Gibson H, Khalil IR, Kowalczuk M et al (2019)
Production and characterisation of bacterial cellulose hydrogels loaded with curcumin
encapsulated in cyclodextrins as wound dressings. Eur Polym J 118:437–450. https://doi.
org/10.1016/j.eurpolymj.2019.06.018
166. Pinho E, Calhelha RC, Ferreira IC, Soares G (2019) Cotton-hydrogel composite for improved
wound healing: antimicrobial activity and anti-inflammatory evaluation—Part 2. Polym Adv
Technol 30(4):863–871. https://doi.org/10.1002/pat.4519
167. Gupta A, Briffa SM, Swingler S, Gibson H, Kannappan V, Adamus G et al (2020) Synthesis
of silver nanoparticles using curcumin-cyclodextrins loaded into bacterial cellulose-based
hydrogels for wound dressing applications. Biomacromolecules 21(5):1802–1811. https://
doi.org/10.1021/acs.biomac.9b01724
168. Adamczak A, Ożarowski M, Karpiński TM (2020) Antibacterial activity of some flavonoids
and organic acids widely distributed in plants. J Clin Med 9(1):109. https://doi.org/10.1021/
acs.biomac.9b01724
169. Vimalraj S, Rajalakshmi S, Saravanan S, Preeth DR, Vasanthi RL, Shairam M, Chatterjee S
(2018) Synthesis and characterization of zinc-silibinin complexes: a potential bioactive com-
pound with angiogenic, and antibacterial activity for bone tissue engineering. Colloids Surf
B Biointerfaces 167:134–143. https://doi.org/10.1016/j.colsurfb.2018.04.007
170. Cé R, Pacheco BZ, Ciocheta TM, Barbosa FS, de Alves CSA, Dallemole DR et al (2021)
Antibacterial activity against Gram-positive bacteria using fusidic acid-loaded lipid-core nano-
capsules. React Funct Polym 162. https://doi.org/10.1016/j.reactfunctpolym.2021.104876
171. Chen Y, Lu Y, Lee RJ, Xiang G (2020) Nano encapsulated curcumin: and its potential for
biomedical applications. Int J Nanomedicine 15. https://doi.org/10.2147/IJN.S210320
172. Pontes-Quero GM, Esteban-Rubio S, Pérez Cano J, Aguilar MR, Vázquez-Lasa B (2021)
Oregano essential oil micro-and nanoencapsulation with bioactive properties for biotechno-
logical and biomedical applications. Front Bioeng Biotechnol 602. https://doi.org/10.3389/
fbioe.2021.703684
1294 C. M. Pérez Zamora et al.

173. Matei PM, Martín-Gil J, Michaela Iacomi B, Pérez-Lebeña E, Barrio-Arredondo MT,

Martín-Ramos P (2018) Silver nanoparticles and polyphenol inclusion compounds compos-
ites for Phytophthora cinnamomi mycelial growth inhibition. Antibiotics 7(3):76. https://doi.
org/10.3390/antibiotics7030076
174. Romano I, Granata G, Poli A, Finore I, Napoli E, Geraci C (2020) Inhibition of bacterial
growth on marble stone of 18th century by treatment of nanoencapsulated essential oils. Int
Biodeterior Biodegradation 148. https://doi.org/10.1016/j.ibiod.2020.104909
175. Paredes AJ, Asensio CM, Llabot JM, Allemandi DA, Palma SD (2016) Nanoencapsulation in
the food industry: manufacture, applications and characterization. Nano 1(1):56–79
176. Kasprzak MM, Erxleben A, Ochocki J (2015) Properties and applications of flavonoid metal
complexes. RSC Adv 5(57):45853–45877. https://doi.org/10.1039/C5RA05069C
177. Samsonowicz M, Regulska E, Kalinowska M (2017) Hydroxyflavone metal complexes-­
molecular structure, antioxidant activity and biological effects. Chem Biol Interact
273:245–256
178. Pandit J, Aqil M, Sultana Y (2016) Nanoencapsulation technology to control release and
enhance bioactivity of essential oils. In: Grumezescu AM (ed) Nanotechnology in the
Agri-Food Industry, Encapsulations. Academic Press. Elsevier. Pages 597–640, ISBN
9780128043073. https://doi.org/10.1016/B978-0-12-804307-3.00014-4
179. Rezaei A, Fathi M, Jafari SM (2019) Nanoencapsulation of hydrophobic and low-soluble
food bioactive compounds within different nanocarriers. Food Hydrocoll 88:146–162.
https://doi.org/10.1016/j.foodhyd.2018.10.003
180. Jafari SM (2017) An overview of nanoencapsulation techniques and their classification. Adv
Food Nutr Res 2017:1–34. https://doi.org/10.1016/B978-­0-­12-­809436-­5.00001-­X
181. Barrera-Ruiz DG, Cuestas-Rosas GC, Sánchez-Mariñez RI, Álvarez-Ainza ML, Moreno-­
Ibarra GM, López-Meneses AK et al (2020) Antibacterial activity of essential oils encap-
sulated in chitosan nanoparticles. Food Sci Technol 40:568–573. https://doi.org/10.1590/
fst.34519
182. Vafania B, Fathi M, Soleimanian-Zad S (2019) Nanoencapsulation of thyme essential
oil in chitosan-gelatin nanofibers by nozzle-less electrospinning and their application to
reduce nitrite in sausages. Food Bioprod Process 116:240–248. https://doi.org/10.1016/j.
fbp.2019.06.001
183. Herculano ED, de Paula HC, de Figueiredo EA, Dias FG, Pereira VDA (2015) Physicochemical
and antimicrobial properties of nanoencapsulated Eucalyptus staigeriana essential oil. LWT -
Food Sci Technol 61(2):484–491. https://doi.org/10.1016/j.lwt.2014.12.001
184. Mohammadi A, Hosseini SM, Hashemi M (2020) Emerging chitosan nanoparticles loading-­
system boosted the antibacterial activity of Cinnamomum zeylanicum essential oil. Ind Crop
Prod 155. https://doi.org/10.1016/j.indcrop.2020.112824
185. Yang K, Liu A, Hu A, Li J, Zen Z, Liu Y et al (2021) Preparation and characterization of cin-
namon essential oil nanocapsules and comparison of volatile components and antibacterial
ability of cinnamon essential oil before and after encapsulation. Food Control 123. https://
doi.org/10.1016/j.foodcont.2020.107783
186. Kavaz D, Idris M, Onyebuchi C (2019) Physiochemical characterization, antioxidative, anti-
cancer cells proliferation and food pathogens antibacterial activity of chitosan nanoparticles
loaded with Cyperus articulatus rhizome essential oils. Int J Biol Macromol 123:837–845
187. Hadidi M, Pouramin S, Adinepour F, Haghani S, Jafari SM (2020) Chitosan nanoparticles
loaded with clove essential oil: characterization, antioxidant and antibacterial activities.
Carbohydr Polym 236. https://doi.org/10.1016/j.carbpol.2020.116075
188. Lee JS, Choi YS, Lee HG (2020) Synergistic antimicrobial properties of nanoencapsulated
clove oil and thymol against oral bacteria. Food Sci Biotechnol 29(11):1597–1604. https://
doi.org/10.1007/s10068-­020-­00803-­w
189. Zabihi A, Akhondzadeh Basti A, Amoabediny G, Tabatabaee Bafroee AS, Khanjari A,
Tavakkoly Bazzaz J (2019) The inhibitory effect of garlic (Allium sativum L.) essential oil
nanoliposomes on Shiga-toxin 2 expression in Escherichia coli O157: H7. Food Health J
2(1):6–11. https://doi.org/10.1016/j.ijbiomac.2018.11.177
Strategies to Improve Antimicrobial Activity of Natural Products: Approaches… 1295

190. Jemaa MB, Falleh H, Serairi R, Neves MA, Snoussi M, Isoda H, Ksouri R (2018)
Nanoencapsulated Thymus capitatus essential oil as natural preservative. Innov Food Sci
Emerg Technol 45:92–97. https://doi.org/10.1016/j.ifset.2017.08.017
191. Moghimi R, Aliahmadi A, Rafati H, Abtahi HR, Amini S, Feizabadi MM (2018) Antibacterial
and anti-biofilm activity of nanoemulsion of Thymus daenensis oil against multi-drug
resistant Acinetobacter baumannii. J Mol Liq 265:765–770. https://doi.org/10.1016/j.
molliq.2018.07.023
192. Garzoli S, Petralito S, Ovidi E, Turchetti G, Masci VL, Tiezzi A et al (2020) Lavandula x
intermedia essential oil and hydrolate: evaluation of chemical composition and antibacte-
rial activity before and after formulation in nanoemulsion. Ind Crop Prod 145. https://doi.
org/10.1016/j.indcrop.2019.112068
193. Gholipourkanani H, Buller N, Lymbery A (2019) In vitro antibacterial activity of four nano-­
encapsulated herbal essential oils against three bacterial fish pathogens. Aquac 50(3):871–875.
https://doi.org/10.1111/are.13959
194. Ruiz-Gonzalez N, Lopez-Malo A, Palou E, Ramirez-Corona N, Jimenez-Munguia MT
(2019) Antimicrobial activity and physicochemical characterization of oregano, thyme and
clove leave essential oils, nonencapsulated and nanoencapsulated, using emulsification. Appl
Food Biotechnol 6(4):237–246. https://doi.org/10.22037/afb.v6i4.25541
195. Cecchini ME, Paoloni C, Campra N, Picco N, Grosso MC, Perez MS et al (2021)
Nanoemulsion of Minthostachys verticillata essential oil. In-vitro evaluation of its antibacte-
rial activity. Heliyon 7(1). https://doi.org/10.1016/j.heliyon.2021.e05896
196. Upadhyay N, Singh VK, Dwivedy AK, Chaudhari AK, Dubey NK (2021) Assessment of
nanoencapsulated Cananga odorata essential oil in chitosan nanopolymer as a green approach
to boost the antifungal, antioxidant and in situ efficacy. Int J Biol Macromol 171:480–490.
https://doi.org/10.1016/j.ijbiomac.2021.01.024
197. Izadi M, Jorf SAM, Nikkhah M, Moradi S (2021) Antifungal activity of hydrocolloid nano
encapsulated Carum copticum essential oil and Peganum harmala extract on the patho-
genic fungi Alternaria alternata. Physiol Mol Plant Pathol 116. https://doi.org/10.1016/j.
pmpp.2021.101714
198. Nirmal NP, Mereddy R, Li L, Sultanbawa Y (2018) Formulation, characterisation and anti-
bacterial activity of lemon myrtle and anise myrtle essential oil in water nanoemulsion. Food
Chem 254:1–7. https://doi.org/10.1016/j.foodchem.2018.01.173
199. Rayhane BK, Rojo SR, Gaspar F, Leila CG (2019) Preparation of rosemary essential oil-­
loaded multiple lipid nanoparticles (ROMLNs) and evaluation of their antibacterial activity.
Abstract presented in at NanoSpain Conf 2019, Barcelona, Spain, 28–31 March 2019
200. Jin L, Teng J, Hu L, Lan X, Xu Y, Sheng J et al (2019) Pepper fragrant essential oil (PFEO)
and functionalized MCM-41 nanoparticles: formation, characterization, and bactericidal
activity. J Sci Food Agric 99(11):5168–5175. https://doi.org/10.1002/jsfa.9776
201. Khatibi SA, Misaghi A, Moosavy MH, Akhondzadeh Basti A, Mohamadian S, Khanjari A
(2018) Effect of nanoliposomes containing Zataria multiflora Boiss. essential oil on gene
expression of Shiga toxin 2 in Escherichia coli O157: H7. J Appl Microbiol 124(2):389–397.
https://doi.org/10.1111/jam.13641
202. da Cunha JA, de Ávila SC, Fausto VP, de Melo LDW, Henneman B, Frizzo CP et al (2018)
The antibacterial and physiological effects of pure and nanoencapsulated Origanum majo-
rana essential oil on fish infected with Aeromonas hydrophila. Microb Pathog 124:116–121.
https://doi.org/10.1016/j.micpath.2018.08.040
203. Oliveira DA, Angonese M, Ferreira SR, Gomes CL (2017) Nanoencapsulation of pas-
sion fruit by-products extracts for enhanced antimicrobial activity. Food Bioprod Process
104:137–146. https://doi.org/10.1016/j.fbp.2017.05.009
204. Pereira MC, Hill LE, Zambiazi RC, Mertens-Talcott S, Talcott S, Gomes CL (2015)
Nanoencapsulation of hydrophobic phytochemicals using poly (dl-lactide-co-­ glycolide)
(PLGA) for antioxidant and antimicrobial delivery applications: Guabiroba fruit
(Campomanesia xanthocarpa O. Berg) study. LWT 63(1):100–107. https://doi.org/10.1016/j.
lwt.2015.03.062
1296 C. M. Pérez Zamora et al.

205. Masjid NAS, Martien R, Dono ND (2019) In Vitro antibacterial activity of Mindi (Melia aze-
darach Linn.) leaf extract with nanoencapsulation technology. IOP Conf Ser: Earth Environ
Sci 387(1):012069. IOP Publishing
206. Nallasamy P, Ramalingam T, Nooruddin T, Shanmuganathan R, Arivalagan P, Natarajan S
(2020) Polyherbal drug loaded starch nanoparticles as promising drug delivery system: anti-
microbial, antibiofilm and neuroprotective studies. Process Biochem 92:355–364. https://doi.
org/10.1016/j.procbio.2020.01.026
207. Srivastava J, Chandra H, Nautiyal AR, Kalra SJS (2014) Antimicrobial resistance (AMR)
and plant-derived antimicrobials (PDAms) as an alternative drug line to control infections.
Biotech 4:451–460. https://doi.org/10.1007/s13205-­013-­0180-­y
208. Chandrasekar S, Vijayakumar S, Rajendran R (2020) Functional finishing of health care cot-
ton for enhanced efficiency of antibacterial activity by chitosan and herbal nanocomposites.
Acta Ecol Sin 40(6):473–477. https://doi.org/10.1016/j.chnaes.2020.08.004
209. Banupriya J, Maheshwari V (2019) A study on antibacterial property of herbal-biopolymer
nanoencapsulate treated fabric. J Drug Deliv Ther 9(4):433–437. https://doi.org/10.22270/
jddt.v9i4.3204
210. Pan K, Chen H, Davidson PM, Zhong Q (2014) Thymol nanoencapsulated by sodium casein-
ate: physical and antilisterial properties. J Agric Food Chem 62(7):1649–1657. https://doi.
org/10.1021/jf4055402
211. de Souza TW, Pena GR, Martin-Pastor M, de Sousa FFO (2021) Design and characterization
of ellagic acid-loaded zein nanoparticles and their effect on the antioxidant and antibacterial
activities. J Mol Liq 341. https://doi.org/10.1016/j.molliq.2021.116915
212. Wang Y, Xue Y, Bi Q, Qin D, Du Q, Jin P (2021) Enhanced antibacterial activity of eugenol-­
entrapped casein nanoparticles amended with lysozyme against gram-positive pathogens.
Food Chem 360:130036. https://doi.org/10.1016/j.foodchem.2021.130036
213. Oluoch G, Matiru V, Mamati EG, Nyongesa M (2021) Nanoencapsulation of thymol and
eugenol with chitosan nanoparticles and the effect against Ralstonia solanacearum. Adv
Microbiol 11(12):723–739. https://doi.org/10.4236/aim.2021.1112052
214. Lee JS, Kim ES, Lee HG (2017) Improving the water solubility and antimicrobial activity
of silymarin by nanoencapsulation. Colloids Surf B Biointerfaces 154:171–177. https://doi.
org/10.1016/j.colsurfb.2017.03.004
215. Ceylan Z, Sengor GFU, Yilmaz MT (2018) Nanoencapsulation of liquid smoke/thymol com-
bination in chitosan nanofibers to delay microbiological spoilage of sea bass (Dicentrarchus
labrax) fillets. J Food Eng 229:43–49. https://doi.org/10.1016/j.jfoodeng.2017.11.038
216. Zarzycki PK, Głód BK (2016) Cyclodextrins-based nanocomplexes for encapsulation of
bioactive compounds in food, cosmetics, and pharmaceutical products: principles of supra-
molecular complexes formation, their influence on the antioxidative properties of target
chemicals, and recent advances in selected industrial applications. In: Grumezescu AM (ed)
Encapsulations. Academic Press, Elsevier
217. Kfoury M, Auezova L, Greige-Gerges H, Fourmentin S (2019) Encapsulation in cyclodex-
trins to widen the applications of essential oils. Environ Chem Lett 17(1):129–143. https://
doi.org/10.1007/s10311-­018-­0783-­y
218. Suvarna V, Gujar P, Murahari M (2017) Complexation of phytochemicals with cyclodex-
trin derivatives–an insight. Biomed Pharmacother 88:1122–1144. https://doi.org/10.1016/j.
biopha.2017.01.157
219. Saffarionpour S (2019) Nanoencapsulation of hydrophobic food flavor ingredients and their
cyclodextrin inclusion complexes. Food Bioprocess Technol 12(7):1157–1173. https://doi.
org/10.1007/s11947-­019-­02285-­z
220. Ozdemir N, Pola CC, Teixeira BN, Hill LE, Bayrak A, Gomes CL (2018) Preparation of
black pepper oleoresin inclusion complexes based on beta-cyclodextrin for antioxidant and
antimicrobial delivery applications using kneading and freeze drying methods: a comparative
study. LWT 91:439–445. https://doi.org/10.1016/j.lwt.2018.01.046
Strategies to Improve Antimicrobial Activity of Natural Products: Approaches… 1297

221. Silva F, Caldera F, Trotta F, Nerín C, Domingues FC (2019) Encapsulation of coriander

essential oil in cyclodextrin nanosponges: a new strategy to promote its use in controlled-­
release active packaging. Innov Food Sci Emerg Technol 56. https://doi.org/10.1016/j.
ifset.2019.102177
222. Halahlah A, Kavetsou E, Pitterou I, Grigorakis S, Loupassaki S, Tziveleka LA et al (2021)
Synthesis and characterization of inclusion complexes of rosemary essential oil with various
β-cyclodextrins and evaluation of their antibacterial activity against Staphylococcus aureus. J
Drug Deliv Sci Technol 65. https://doi.org/10.1016/j.jddst.2021.102660
223. Rodríguez-López MI, Mercader-Ros MT, Pellicer JA, Gómez-López VM, Martínez-Romero
D, Núñez-Delicado E, Gabaldón JA (2020) Evaluation of monoterpene-cyclodextrin com-
plexes as bacterial growth effective hurdles. Food Control 108. https://doi.org/10.1016/j.
foodcont.2019.106814
224. López-Miranda S, Berdejo D, Pagán E, García-Gonzalo D, Pagán R (2021) Modified cyclo-
dextrin type and dehydration methods exert a significant effect on the antimicrobial activ-
ity of encapsulated carvacrol and thymol. J Sci Food Agric 101(9):3827–3835. https://doi.
org/10.1002/jsfa.11017
225. Yuan C, Wang Y, Liu Y, Cui B (2019) Physicochemical characterization and antibacterial activ-
ity assessment of lavender essential oil encapsulated in hydroxypropyl-beta-­cyclodextrin. Ind
Crop Prod 130:104–110. https://doi.org/10.1016/j.indcrop.2018.12.067
226. Castro DO, Tabary N, Martel B, Gandini A, Belgacem N, Bras J (2016) Effect of different car-
boxylic acids in cyclodextrin functionalization of cellulose nanocrystals for prolonged release
of carvacrol. Mater Sci Eng C 69:1018–1025. https://doi.org/10.1016/j.msec.2016.08.014
227. Salehi O, Sami M, Rezaei A (2021) Limonene loaded cyclodextrin nanosponge: prepara-
tion, characterization, antibacterial activity and controlled release. Food Biosci 42. https://
doi.org/10.1016/j.fbio.2021.101193
228. Cai L, Jeremic D, Lim H, Kim Y (2019) β-Cyclodextrins as sustained-release carri-
ers for natural wood preservatives. Ind Crop Prod 130:42–48. https://doi.org/10.1016/j.
indcrop.2018.12.061
229. Inoue Y, Suzuki R, Murata I, Nomura H, Isshiki Y, Kanamoto I (2020) Evaluation of antibac-
terial activity expression of the hinokitiol/cyclodextrin complex against bacteria. Acs Omega
5(42):27180–27187. https://doi.org/10.1021/acsomega.0c03222
230. Savic IM, Jocic E, Nikolic VD, Popsavin MM, Rakic SJ, Savic-Gajic IM (2019) The effect
of complexation with cyclodextrins on the antioxidant and antimicrobial activity of ellagic
acid. Pharm Dev Technol 24(4):410–418. https://doi.org/10.1080/10837450.2018.1502318
231. Danciu C, Pinzaru IA, Dehelean CA, Hancianu M, Zupko I, Navolan D et al (2018)
Antiproliferative and antimicrobial properties of pure and encapsulated rutin. Farmacia
66(2):302–308
232. Reyes-Arellano A (2008) Geles moleculares y organogelantes. TIP Revista Especializada en
Ciencias Químico-Biológicas 11(2):101–104
233. Sivaraj R, Rahman PK, Rajiv P, Narendhran S, Venckatesh R (2014) Biosynthesis and charac-
terization of Acalypha indica mediated copper oxide nanoparticles and evaluation of its anti-
microbial and anticancer activity. Spectrochim Acta A Mol Biomol Spectrosc 129:255–258.
https://doi.org/10.1016/j.saa.2014.03.027
234. Acharyulu NPS, Dubey RS, Swaminadham V, Kollu P, Kalyani RL, Pammi SVN (2014)
Green synthesis of CuO nanoparticles using Phyllanthus amarus leaf extract and their anti-
bacterial activity against multidrug resistance bacteria. Int J Eng Res 3(4):639–641
235. Yallappa S, Manjanna J, Sindhe MA, Satyanarayan ND, Pramod SN, Nagaraja K (2013)
Microwave assisted rapid synthesis and biological evaluation of stable copper nanoparticles
using T. arjuna bark extract. Spectrochim Acta A 110:108–115. https://doi.org/10.1016/j.
saa.2013.03.005
236. Awwad AM, Albiss BA, Salem NM (2015) Antibacterial activity of synthesized copper oxide
nanoparticles using Malva sylvestris leaf extract. SMU Med J 2(1):91–101
1298 C. M. Pérez Zamora et al.

237. Naika HR, Lingaraju K, Manjunath K, Kumar D, Nagaraju G, Suresh D, Nagabhushana H

(2015) Green synthesis of CuO nanoparticles using Gloriosa superba L. extract and their
antibacterial activity. JTUSCI 9(1):7–12. https://doi.org/10.1016/j.jtusci.2014.04.006
238. Sharmila G, Muthukumaran C, Sandiya K, Santhiya S, Pradeep RS, Kumar NM et al
(2018) Biosynthesis, characterization, and antibacterial activity of zinc oxide nanoparticles
derived from Bauhinia tomentosa leaf extract. JNC 8(3):293–299. https://doi.org/10.1007/
s40097-­018-­0271-­8
239. Jain S, Mehata MS (2017) Medicinal plant leaf extract and pure flavonoid mediated green
synthesis of silver nanoparticles and their enhanced antibacterial property. Sci Rep 7(1):1–13.
https://doi.org/10.1038/s41598-­017-­15724-­8
240. Bagherzade G, Tavakoli MM, Namaei MH (2017) Green synthesis of silver nanoparticles
using aqueous extract of saffron (Crocus sativus L.) wastages and its antibacterial activ-
ity against six bacteria. Asian Pac J Trop Biomed 7(3):227–233. https://doi.org/10.1016/j.
apjtb.2016.12.014
Plants with Immunomodulatory Potential
Described in Ayurveda

Sinimol Peethambaran Thekkekkoottumughath

Abbreviations

CD Cluster of differentiation
DNA Deoxyribonucleic acid
DTH Delayed-type hypersensitivity
HBD-2 Human beta-defensin-2
IL Interleukin
INF Interferon
iNOS Inducible nitric oxide synthase
L-DOPA Levodopa and l-3,4-dihydroxyphenylalanine
LFA-1-ICAM 
Lymphocyte function-associated antigen -1- Intercellular
Adhesion Molecule
LPS Lipopolysaccharide
SRBC Sheep red blood cell
Th Helper T cells
THC Delta-9-tetrahydrocannabinol
TNF Tumor necrosis factor
WBC White blood cell

1 Introduction

About three-quarters of global population depend upon herbal traditional remedies

for health care management as per the World Health Organization. In some way or
the other, traditional medicine, also referred to as herbal or indigenous or natural
medicine, existed in civilizations of various countries: Ayurveda (India), Chinese,
Unani, Tibb (South Asia), Egyptian, Western, Arabian, Greek, and Kampo (Japan)

S. P. Thekkekkoottumughath (*)
Regional Ayurveda Research Institute Thiruvananthapuram, Kerala, Under Central Council
for Research in Ayurvedic Sciences (CCRAS), Ministry of AYUSH, New Delhi, India

© The Author(s), under exclusive license to Springer Nature 1299

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_54
1300 S. P. Thekkekkoottumughath

[1]. Extensive research activities are being carried out all over the world for the vari-
ous therapeutic potential and medicinal values of traditional remedies by the
researchers and experts who bear the responsibility of keeping the traditional sys-
tems of medicine alive.
New epidemics are evolving like the present coronavirus disease-2019
(COVID-19). The novel coronavirus (nCoV) spillover event has emerged as a pub-
lic health emergency of international concern. This is the third instance of the emer-
gence of a novel coronavirus, after severe acute respiratory syndrome (SARS) in
2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 in
the past two decades. The repeated emergence and global scale of transmission,
significant number of deaths, infection and mortality of care providers and health
care workers, and higher risk of death in vulnerable groups have been the major
causes of concern. If we have a strong immune system, we may not get afflicted by
the disease or even if we get afflicted, the manifestation of symptoms may be
delayed or occur with mild symptoms [2].
Most of the immunomodulatory drugs prescribed in conventional medicine are
reported to have various side effects like increasing the risk of infections, reactiva-
tion of latent tuberculosis, medullar suppression, gastric irritation, pancreatitis,
hepatitis, dizziness, fever, rash, alopecia, nausea, diarrhea, fatigue, elevated trans-
aminase levels, hypertension, nephropathy, convulsions, hyperkalemia, neurotoxic-
ity, hirsutism, epilepsy, headache, paresthesia, and gingival hyperplasia [3].
Ayurveda is one of the most renowned and time-tested traditional system of med-
icine, with nil or minimal side effects and has flourished from ages till date. In
future also, this system will continue to serve the humanity with unique description
of the relationship of human body constitution and function to nature and the ele-
ments of the universe that act in coordination and affect the living beings. A lot of
plants with immunomodulatory potential have been described in various Ayurvedic
classical textbooks. Different plant-based principles have been isolated from such
plants with potential immunomodulatory activities. The aim of this review is to
bring to light such plants and researches done on them. The research papers were
selected from the most pertinent databases for the biomedical sciences.

2 Immunity and Immunomodulators

Natural defense system of body against various infectious diseases is termed as

immunity. Immunization, previous infection, and some external stimuli are the fac-
tors that trigger immunity. As a part of immune response, specific cells and media-
tors respond in a coordinated way when a foreign particle is identified [4].
Immune system is broadly classified into two broad categories: innate immune
system (nonspecific immune system) and adaptive immune system (acquired or
specific immune system) [5].
By means of producing pathogen (antigen)-specific T cells and B cells through a
gene rearrangement process, adaptive immunity is acquired by human body. Active
Plants with Immunomodulatory Potential Described in Ayurveda 1301

immunity is the adaptive immune reaction that develops in weeks/months and may
last throughout whole life as a result of exposure to antigen. Active immunity may
be acquired or natural. Antigen-specific reactions by B- and T lymphocytes are
involved in adaptive immunity. The strong phagocytic action of myeloid cells and
cytotoxic T lymphocytes is enhanced by helper T-cell-1 (Th1) lymphocytes. They
produce interleukin (IL)-2, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ.
Th2 lymphocytes produce IL-4, IL-5, and IL-10 and are classified by B cell facili-
tated production of antibodies. As a result of binding with antibodies, microorgan-
isms or toxins are neutralized. Additionally, through activation of complement
proteins, antibodies opsonize various pathogens, immobilize bacteria, and trigger
destruction of microorganisms by phagocytes [6].
Innate immunity includes chemical, microbiological, and physical barriers.
Macrophages, monocytes, cytokines, acute phase proteins, neutrophils, and com-
plement system are the main mediators of immune system that deliver quick defense
for body. Host recognizes various distinct moieties expressed by pathogens known
as pathogen-associated molecular patterns (PAMPs) to detect presence of a patho-
gen. They are recognized by the germline-encoded host sensors known as pattern
recognition receptors (PRRs). After that, an array of immune responses are quickly
triggered through induction of different chemokines, type I interferons, and cyto-
kines. Pattern recognition receptor families such as retinoic-acid-inducible gene I
(RIG-I)-like receptors, DNA receptors (cytosolic sensors for DNA), nucleotide-­
binding oligomerization domain-like receptors (NOD-like receptors), and toll-like
receptors have a significant part in defense mechanism of the host [7].
Macrophages and antigen-presenting cells that play significant roles in secretion
of cytokines, antigen presentation, processing, antibody-dependent cell-mediated
cytotoxicity, nitric oxide (NO) production, and phagocytosis are included in all
phases of nonspecific immunity. Naive and memory B cells and naive T cells are
activated by dendritic cells. The effectors of innate immunity including natural
killer (NK) cells are regulated, which govern specific and natural immune responses
by producing granulocyte–macrophage colony-stimulating factor (GM-CSF), tumor
necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) during diverse phases of dif-
ferentiation of dendritic cells [8].
Complement system is the tertiary important element of natural immunity and is
the main effector of humoral immunity among all the physiological systems of host
defense mechanism [9].
Immunomodulators These are biological or synthetic substances that can stimu-
late, suppress, or modulate any aspect of the immune system including both adap-
tive and innate arms of the immune system. The imbalance of immune responses
may cause a plethora of morbidities, such as AIDS, allergy, autoimmune diseases,
and immunosuppression, in spite of the high adeptness and specificity of the immune
system [10, 11]. Immunomodulators have been developed as recent researches from
epidemiological studies provide evidence of a rise in immunological diseases. They
are capable of stimulating or suppressing the immune response in immune-system-­
mediated diseases. Immunostimulatory drugs have been developed for managing
1302 S. P. Thekkekkoottumughath

AIDS, infection, immunodeficiency, and cancer. Immunosuppressive drugs are used

for inhibiting the immune response in various immune-mediated diseases like auto-
immune disorders or in the case of organ transplantation [12].
Nonspecific alterations are produced in the host response by most immunomodu-
lators in previous clinical practice. Consequently, recent focus has shifted to the
development of selective immunomodulators, directed only against anomalous
immune response [13].

3 Classification and Mechanism of Action

of Immunomodulators [14]

I. Immunosuppressants
(a) Category: Inhibitors of lymphocyte gene expression
Mechanism of action: Reduce leukocyte extravasation and proinflamma-
tory cytokine expression
Example: Glucocorticoids [15, 16]
(b) Category: Inhibitors of lymphocyte signaling
Mechanism of action: Antigen-triggered signal transduction constrain in
T cells and reduced expression of lymphokines and antiapoptotic proteins
Example: Cyclosporine [16, 17]
(c) Category: Inhibitors of lymphocyte signaling
Mechanism of action: By inhibition of calcineurin, T-cell activation
Example: Tacrolimus [18, 19]
(d) Category: Inhibitors of lymphocyte signaling
Mechanism of action: Downregulate T-cell growth factor receptor and
IL-2 and inhibit activation and proliferation of T lymphocyte
Example: Sirolimus [20, 21]
(e) Category: Cytotoxic agents
Mechanism of action: Inhibit new synthesis of purine, which results in
inhibition of proliferation of lymphocytes
Examples: Azathioprine; azathioprine sodium [20]
(f) Category: Cytotoxic agents
Mechanism of action: Inhibit new synthesis of guanine by the inhibition
of inosine monophosphate dehydrogenase
Example: Mycophenolate mofetil [22, 23]
(g) Category: Alkylating agent
Mechanism of action: By cross linking in the strands of DNA, averts
protein synthesis and cell division
Example: Cyclophosphamide [24]
(h) Category: Cytokine inhibitors
Mechanism of action: Bind and inhibit TNF-α to bind with its receptors
Examples: Etanercept, infliximab, adalimumab, anakinra, daclizumab,
and basiliximab [25–27]
Plants with Immunomodulatory Potential Described in Ayurveda 1303

(i) Category: Antibodies against specific immune cell molecules

Mechanism of action: By inducing cytotoxicity, reduce circulating
lymphocytes
Example: Antithymocyte globulin [28]
(j) Category: Antibodies against specific immune cell molecules
Mechanism of action: By producing internalization of the T-cell receptor,
prevent antigen recognition
Example: Muromonab [20, 29, 30]
(k) Category: Intercellular adhesion molecule inhibitors
Mechanism of action: By inhibiting lymphocyte function-associated
antigen-1 (LFA-1)/cognate ligand intercellular adhesion molecule (ICAM)
(LFA-1/ICAM) interaction, inhibit T-lymphocyte adhesion and trafficking
Example: Efalizumab [31]
II. Immunostimulants
(a) Category: Imidazothiazole derivative
Mechanism of action: Restoration of the suppressed immune function of
B- and T cells, monocytes, and macrophages
Example: Levamisole [32]
(b) Category: Recombinant cytokines
Mechanism of action: Inhibit cell proliferation and stimulate activities of
immune cells like increased phagocytosis and cytotoxicity of T cells
Examples: Aldesleukin, interferon alpha, interferon gamma [20, 33]
(c) Category: Hormonal analog
Mechanism of action: It induces lymphocyte proliferation and enhances
production of cytokines (i.e., IL-1, IL-2, and IFN-γ)
Example: Isoprinosine [34]

4 Concept of Immunity and Immunomodulators

in Ayurveda

The concept of immunity is explained in Ayurveda by means of various terms like

Vyadhikshamatva, Ojas, and Bala. Vyadhikshamatva (immunity) is the resisting
power of the body, which reacts to arrest the progress, occurrence, or reoccurrence
of diseases. However, the concept of Vyadhikshamatva is not merely immunity
against a specific infectious agent or disease like the concept of modern medicine.
Rather, it implies a resistance against the loss of the integrity, proportion, and inter-
relationship among the individual’s bioenergies and tissues. This homeostasis
among the supporting elements of the mind and body is known as health [35].
Ojas is the essence of all bodily tissues and the seat of strength/immunity. In
Ayurveda, Ojas has been considered vital in the defense mechanism of the body. In
conditions like diabetes mellitus and malnutrition, where loss of Ojas is a constant
feature, people are known to be susceptible to various other interrelated and
1304 S. P. Thekkekkoottumughath

degenerative diseases or recurrent infections. Therefore, any deficiency or alteration

in the quantity and quality of Ojas may lead to one or the other immunocompro-
mised disorders or syndromes [36].
Bala (vitality) is attainable from three sources: constitutional strength, which
comes from the parents and is inherited; temporal strength, which depends on the
time of day, season, and age (strength is greater in the early morning, spring, and
youth than in evening, summer, and old age); and acquired strength, in which dis-
ease can be defended against through proper exercise, diet, usage of Rasayanas
(Ayurvedic rejuvenators), etc. [37].

4.1 Immunomodulators

Immunomodulation described in Ayurvedic science integrates all the therapeutic

interventions aimed at modifying the immune response. Ayurveda has brilliantly
detailed about the daily routine to be followed right from waking up in the morning
till going to bed [38]. Moreover, dietary and lifestyle patterns that should be adopted
in different seasons mentioned in Ayurveda are also detailed [39].
Besides these, one should undergo Panchakarma procedures, which are the five
purificatory procedures in specific intervals, mentioned in Ayurveda. All these will
help to stimulate immune system as per Ayurveda. Furthermore, one comprehensive
discipline termed Rasayana, for rejuvenation of body and stimulation of immune
system, is also detailed in this science. It incorporates specific use of food articles,
herbs, herbomineral formulations, lifestyle, and self-discipline with social decorum
for achieving the optimum status of tissues such that our body is least affected by
disease-causing factors. Thus, Rasayana is a way to prevent diseases and retard
aging process [40].
Some special preparations used for Rasayana therapy are Chyavanaprasha,
Amalaki Rasayana, Haritaki Rasayana, Pippali Rasayana, Vidanga Rasayana,
Shilajitu Rasayana, Brahma Rasayana, and Lohashilajitu Rasayana. In this review,
single herbs described in Ayurveda, which possess immunomodulatory potential,
are discussed in detail.

4.2 Plants Described in Ayurveda with Scientifically

Established Immunomodulatory Potential

1. Ocimum sanctum Linn. (Family: Labiatae)

Parts used: Whole plant
Chemical constituents: Essential oils such as eugenol, carvacrol, derivatives
of ursolic acid, apigenin, flavonoids, and anthocyanins [41]
Plants with Immunomodulatory Potential Described in Ayurveda 1305

Significant increase in the levels of IFN-γ and percentages of T helper cells

and NK cells was observed after 4 weeks with ethanolic extract of Tulsi
leaves in a clinical study, which clearly showed its immunomodulatory
effect [42].
2. Morus alba Linn. (Family: Moraceae)
Parts used: Fruits, leaves, and bark
Chemical constituents: Flavonoids and anthocyanins
Results obtained from mice lethality test, indirect hemagglutination test, and
serum immunoglobulin levels showed that methanolic extract affected
humoral immunity. Significant increase in the neutrophil adhesion, carbon
clearance, and a reduction in cyclophosphamide-induced neutropenia, show-
ing its effect in cell-mediated immunity [43].
3. Aloe vera Tourn. ex Linn. (Family: Liliaceae)
Part used: Gel from leaves
Chemical constituent: Anthraquinone glycosides
Due to activation of macrophages, Acemannan (primary polysaccharide
obtained from Aloe vera gel) incubated on special type of mouse macro-
phage cell line, RAW 264.7, for 24 h caused immunostimulation [44, 45].
4. Andrographis paniculata Nees (Family: Acanthaceae)
Part used: Leaves
Chemical constituent: Diterpenes
Standardized Andrographis paniculata extract increased IFN-γ, IL-4, T
cells, and T helper cells, and decreased IL-2 at day 30 in a clinical study
done on healthy adults [46].
5. Asparagus racemosus Wild. (Liliaceae)
Part used: Roots
Chemical constituents: Saponins and sitosterols
In sheep red blood cell (SRBC)-sensitized animals, treatment with aqueous
root extract resulted in significant increase in cluster of differentiation
(CD)3+ and CD4/CD8+ percentages suggesting its effect on T-cell activa-
tion. Mixed Th1/Th2 adjuvant activity was also evident from upregulation of
Th1 (IL-2, IFN-γ) and Th2 (IL-4) cytokines. Higher delayed-type hypersen-
sitivity (DTH) responses and antibody titers were also seen proportionate to
this. Significant action was observed on activated lymphocytes [47].
6. Murraya koenigii (L.) Spreng. (Family: Rutaceae)
Part used: Leaves
Chemical constituents: Coumarin, carbazole alkaloids, and glucoside
The leaf extracts of the plant had certain effects to regulate mice immunol-
ogy related to oxidative stress metabolism. Moreover, aqueous extract
showed better response than methanolic extract. Interleukin (IL)-2, 4, 10,
and tumor necrosis factor alpha (TNF-α) expression was observed [48].
1306 S. P. Thekkekkoottumughath

7. Couroupita guianensis Aubl. (Family: Lecythidaceae)

Parts used: Fruits and flowers
Chemical constituents: Steroids, flavonoids, and phenolics
Aqueous and methanolic extract showed immunostimulation in vitro and in
vivo. An increase in phagocytic index and in DTH was observed [49].
8. Tinospora cordifolia Miers. (Family: Menispermaceae)
Part used: Stem
Important chemical constituents: Alkaloidal constituents such as berberine
and tinosporic acid
Seven immunomodulatory active compounds belonging to different classes
such as 11-hydroxymustakone, N-methyl-2-pyrrolidone, N-formylannonain,
cordifolioside A, magnoflorine, tinocordiside, and syringin, possessing
immunomodulatory activity, were isolated from Tinospora cordifolia in a
study. With an increase in percentage phagocytosis and nitric oxide (NO)
and reactive oxygen species (ROS) generation, ethyl acetate, water frac-
tions, and hot water extract showed significant immunomodulatory activ-
ity [50].
9. Lagenaria siceraria Mol. (Family: Cucurbitaceae)
Parts used: Leaves and fruit
Important chemical constituents: Cucurbitacin and beta-glycosidase
Purified saponin mixture isolated from fruits inhibited delayed-type hyper-
sensitivity response and increased hemagglutination antibody titer and car-
bon clearance significantly in a dose-dependent manner, thus demonstrating
the immunomodulatory activity [51].
10. Terminalia arjuna Roxb. (Family: Combretaceae)
Parts used: Leaves and bark
Important chemical constituents: Flavonoids, oligomeric proanthocyani-
dins, and tannins
Aqueous and alcoholic extract of the plant exhibited immunomodulation by
increasing the secondary immune response as evidenced by an increase in
anti-SRBC antibody titer [52].
11. Bauhinia variegata L. (Family: Fabaceae)
Part used: Bark
Important chemical constituents: Flavonoids, beta-sitosterol, and lupeol
Increase in hemagglutination antibody titer, macrophage stimulatory activ-
ity, and neutrophil adhesion is exhibited by ethanolic extract [53].
12. Sida cordifolia L. (Family: Malvaceae)
Parts used: Roots and seeds
Important chemical constituents: Ephedrine and pseudoephedrine
Plants with Immunomodulatory Potential Described in Ayurveda 1307

Production of T-cell precursor and passive influences on cytokine produc-

tion were stimulated by S. cordifolia [54].
13. Gymnema sylvestre (Retz.) R.Br. ex Sm. (Family: Asclepiadaceae)
Part used: Leaves
Important chemical constituent: Sapogenins
Methanolic extract of leaves showed remarkable enhancement in macro-
phage reactivity, proliferation of lymphocytes and NO, and ROS generation
in macrophages in dose-dependent manner. Gymnemic acid in leaves stimu-
lates both myeloid and lymphoid components of immune system [55].
14. Cordia superba Cham. (Family: Boraginaceae)
Part used: Leaves
Important chemical constituent: Alpha-amyrin
By the stimulation of NO, IFN-γ, and lipopolysaccharide, methanolic extract
of leaves exhibited a significant immunomodulation [56].
15. Picrorhiza scrophulariiflora Pennell. (Family: Scrophulariaceae)
Part used: Roots
Important chemical constituents: Iridoid glycosides and amphicoside
Aqueous and ethanolic extract of the root has the ability to modulate humoral
immune responses by acting on release of mediators of hypersensitivity
reactions, antibody production, and tissue responses to mediators in the tar-
get organs. Ethanolic extract was more potent than aqueous extract [57].
16. Cissampelos pareira Linn. (Family: Menispermiaceae)
Part used: Roots
Important chemical constituent: Hayatine alkaloids
Aqueous and ethanolic extract of the roots stimulates immune system and
affects humoral immunity as shown by its effect on the indirect hemaggluti-
nation test and serum immunoglobulin levels. It also affects cell-mediated
immunity [58].
17. Abutilon indicum Linn. (Family: Malvaceae)
Parts used: Whole plant
Important chemical constituents: Flavonoids and triterpenoids
Aqueous and ethanolic extract stimulates immune system and affects
humoral immunity, which is evident from its effect on the indirect hemag-
glutination test and serum immunoglobulin levels. It also affects cell-­
mediated immunity, showing significant increase in carbon clearance and
neutrophil adhesion [59].
18. Chlorophytum borivilianum Santapau & R.R. Fern. (Asparagaceae)
Part used: Roots
Important chemical constituent: Sapogenins
1308 S. P. Thekkekkoottumughath

After treatment with ethanolic extracts, increase in in vivo phagocytosis by

carbon clearance method, DTH, and percentage neutrophil adhesion was
observed, proving its immunomodulatory potential [60].
19. Nyctanthes arbor-tristis L. (Family: Oleaceae)
Parts used: Leaves and seeds
Important chemical constituent: Iridoid glucosides
Cell-mediated and humoral immunostimulant activity of aqueous extract of
flowers seemed to be mediated through proliferation of spleen cells and
increased production of cytokines like IL-2 and IL-6 [61].
20. Acacia catechu (L.f.) Willd. (Leguminosae)
Part used: Heartwood
Important chemical constituents: Flavonoids and quercetin
Treatment with extracts of heartwood increased the number of antibody-­
producing cells in the spleen, increased IL-10 production, decreased DTH,
increased phagocytic response by peritoneal macrophages on treatment, and
inhibited the release of TNF-α and the production of NO in mice [62].
21. Boswellia serrata Roxb. ex Colebr. (Family: Burseraceae)
Part used: Gum resin
Important chemical constituents: Triterpenes and ursanes
Extracts from the gum resin of Boswellia serrata and constituents like
boswellic acids affect the immune mechanism in different ways. Among the
various boswellic acids, acetyl-11-keto-beta-boswellic acid and 11-keto-­
beta-boswellic acid (KBA) were observed to be active. They increase phago-
cytosis of macrophages, inhibit activation of nuclear factor-kappa B
(NF-κB), produce a downregulation of TNF-α, and decrease IFN-γ, IL-1,
IL-2, IL-4, and IL-6. Inhibition of the conversion of C3 into C3a and C3b is
responsible for suppressions of the classic way of the complement sys-
tem [63].
22. Hibiscus rosa-sinensis L. (Family: Malvaceae)
Part used: Flowers
Important chemical constituent: Cyclopropanoids
Aqueous extract of H. rosa-sinensis has immunomodulatory activity, evi-
dent from increase in the number of plaque-forming cells, antibody titer,
DTH response, and level of serum IL-1α, and decrease in the concentration
of IL-2 in treated mice [64].
23. Cleome gynandra L. (Family: Cleomaceae)
Parts used: Leaf, seeds, and roots
Important chemical constituents: Hexacosanol and kaempferol
Plants with Immunomodulatory Potential Described in Ayurveda 1309

Ethanolic extract significantly inhibited immune system in dose-dependent

manner whereas aqueous extract exhibited mild immunosuppressive
effect [65].
24. Randia dumetorum (Retz.) Lam. (Family: Rubiaceae)
Part used: Fruit
Important chemical constituents: Saponins and triterpenes
Chloroform, petroleum ether, and methanolic extract caused increase in
DTH response, and thus exhibited immunomodulatory activity [66].
25. Allium sativum L. (Family: Amaryllidaceae)
Part used: Fruit
Important chemical constituents: Alliin and diallyl disulfide
Garlic appears to stimulate cell types such as dendritic cells, macrophages,
lymphocytes, natural killer cells, and eosinophils, by mechanisms including
phagocytosis, modulation of cytokine secretion, production of immunoglob-
ulin, and macrophage activation [67].
26. Boerhaavia diffusa L. (Family: Apiaceae)
Parts used: Whole plant
Important chemical constituents: Punarnavine and punarnavoside
Both in the presence and absence of specific mitogens in vitro and in vivo,
intraperitoneal administration of punarnavine increased total white blood
cell (WBC) count, bone marrow cellularity, number of alpha-esterase posi-
tive cells, circulating antibody titer, and number of plaque-forming cells in
the spleen; caused proliferation of splenocytes, thymocytes, and bone mar-
row cells; and significantly reduced the lipopolysaccharide (LPS)-induced
elevated levels of TNF-α, IL-1β, and IL-6 in mice [68].
27. Camellia sinensis (L.) Kuntze (Family: Theaceae)
Part used: Leaves
Important chemical constituent: Punarnavine
Extract has the ability of immunomodulation in infection by Candida albi-
cans through expression augmentation of human beta-defensin-2 (HBD-2),
IL-8, and IL-17A [69].
28. Cannabis sativa L. (Cannabaceae)
Parts used: Whole plant
Important chemical constituents: Delta-9-tetrahydrocannabinol (THC) and
cannabidiol
Defective immunological functions including deficiency of WBC blastogen-
esis to mitogens are observed in marijuana smokers. THC produced suppres-
sion of antibody formation, decreased cytokine production, enhanced the
production of IL-1, TNF-α, and IL-6, and suppressed IL-2, natural killer cell
activity, and interferon in mice [70].
1310 S. P. Thekkekkoottumughath

29. Centella asiatica (L.) Urb. (Family: Umbelliferae)

Parts used: Whole plant
Important chemical constituent: Triterpenoid saponins
Aqueous extract significantly increased production of IL-2 and TNF-α in
human peripheral blood mononuclear cells. But ethanol extract inhibited
human peripheral blood mononuclear cell mitogenesis and the production of
IL-2 and TNF-α [71].
30. Eclipta prostrata (L.) L. (Family: Compositae)
Parts used: Whole plant
Important chemical constituent: Triterpenoid glucoside
Methanolic extract increased phagocytic index and antibody titer signifi-
cantly [72].
31. Evolvulus alsinoides (L.) L. (Family: Convolvulaceae)
Parts used: Whole plant
Important chemical constituent: Alkaloids
Ethanolic extract showed increase in the phagocytic index in carbon clear-
ance test, dose-dependent increase in the neutrophil adhesion to the nylon
fibers, protection against immunosuppression induced by cyclophospha-
mide, and circulating serum immunoglobulins in hemagglutinating antibody
titer test, and has the ability to modulate both humoral and cell-mediated
immunity [73].
32. Clitoria ternatea L. (Family: Leguminosae)
Parts used: Leaves, roots, and flowers
Important chemical constituents: Flavonoid and phenolic compounds
The total white blood cells (WBCs), red blood cells (RBCs), T cells, and B
cells were significantly increased in animals treated with it, but monocytes
and eosinophils were decreased [74].
33. Moringa oleifera Lam. (Family: Moringaceae)
Part used: Leaves
Important chemical constituents: Vitamins A, B, and C, carotenoids, and
saponins
Methanolic leaf extract of M. oleifera caused increase in WBC, lymphocyte,
and neutrophil counts; neutrophil adhesion; and mean hemagglutination
antibody titer to sheep red blood cells, thus having a significant immunos-
timulatory effect on both the cell-mediated and humoral immune systems in
the Wistar albino rats [75].
34. Piper longum L. (Family: Piperaceae)
Part used: Fruits
Important Chemical constituent: Alkaloids
Plants with Immunomodulatory Potential Described in Ayurveda 1311

Total WBC count, number of plaque-forming cells, bone marrow cellularity,

and number of alpha-esterase positive cells were enhanced significantly with
the administration of Piper longum extract and piperine [76].
35. Tribulus terrestris L. (Family: Zygophyllaceae)
Part used: Fruits
Important chemical constituents: Steroidal saponins, flavonoids, alkaloids,
and glycosides
Immunomodulatory activity of Tribulus terrestris L. was evaluated by using
immunological studies like humoral antibody titer, phagocytic test,
­drug-­induced myelosuppression test, carbon clearance test, delayed-type
hypersensitivity response, and T-cell population (rosette and e-rosette for-
mation) test, and the results showed that it has potent immunomodulatory
activity [77].
36. Withania somnifera (L.) Dunal (Family: Solanaceae)
Part used: Roots
Important chemical constituents: Alkaloids, steroidal lactones, and saponins
Administration of an extract was found to enhance the total WBC count,
bone marrow cellularity, alpha-esterase positive cell number, and phagocytic
activity of peritoneal macrophages. Treatment along with the antigen pro-
duced an increase in the circulating antibody titer and the number of plaque-­
forming cells in the spleen. Delayed-type hypersensitivity reaction in mice
was inhibited [78].
37. Semecarpus anacardium L.f (Family: Anacardiaceae)
Part used: Fruit
Important chemical constituents: Biflavonoids, phenolic compounds, and
bhilawanols
On treatment with nut milk extract, alterations in the cell-mediated and
humoral immunity were significantly reverted to near-normal levels [79].
38. Glycyrrhiza glabra L. (Family: Leguminosae)
Part used: Roots
Important chemical constituents: Glycyrrhizin, glycyrrhetic acid, and
isoliquiritin
Glycyrrhiza herbal tinctures, when studied on humans, stimulated immune
cells. It was quantified by CD69 expression on CD8 and CD4 cells. This
activation took place within 24 h of ingestion and continued for at least
7 days [80].
39. Justicia adhatoda L. (Family: Acanthaceae)
Part used: Leaves
Important chemical constituents: Vasicine, vasicol, and vasicinone
1312 S. P. Thekkekkoottumughath

Methanolic extract of leaves increased the percentage neutrophil adhesion,

inhibited DTH reactiveness, and promoted phagocytic activity in rats [81].
40. Aegle marmelos (L.) Correa (Family: Rutaceae)
Parts used: Stem bark and fruits
Important chemical constituents: Aegeline and marmeline
Alcoholic extract stimulates immune system by acting through cellular and
humoral immunity [82].
41. Anacyclus pyrethrum (L.) Lag. (Family: Compositae)
Parts used: Root
Important chemical constituents: Alkaloids, triterpenes, and flavonoids
Petroleum ether extract of roots stimulated cellular and humoral immu-
nity [83].
42. Carica papaya L. (Family: Caricaceae)
Parts used: Leaves and fruit
Important chemical constituents: Alkaloids, carpaine, and pseudocarpaine
Enhanced phagocytic activity of peritoneal macrophages was correlated
with T helper 1 cytokine response, when treated with alcoholic extract of
fruit pulp and seed. Interferon-gamma increased the phagocytosis [84].
43. Cassia occidentalis L. (Family: Fabaceae)
Parts used: Aerial parts and seeds
Important chemical constituents: Alkaloids, flavonoids, tannins, and
phlobatannins
Isolated rhein suppressed functional responses of the T- and B-cell lympho-
proliferation in spleen cells [85].
44. Cocculus hirustus (L.) Diels (Family: Menispermaceae)
Parts used: Whole plant
Important chemical constituents: Flavonoids rutin and liquiritin
In cyclophosphamide-induced immunosuppressed animals, methanolic
extract showed enhanced specific and nonspecific activity on various
immune models [86].
45. Curcuma longa L. (Family: Zingiberaceae)
Part used: Rhizome
Important chemical constituents: Curcumin and demethoxycurcumin
Lyophilized turmeric reduced weight of spleen, proportion of CD4−, CD8+
T cells, and phagocytic activity [87].
46. Cynodon dactylon (L.) Pers. (Family: Poaceae)
Parts used: Whole plant, including root
Important chemical constituents: Triterpenoids, arundoin, and friedelin
Plants with Immunomodulatory Potential Described in Ayurveda 1313

Fresh juice increased humoral antibody response, antibody titer in the hem-
agglutination antibody assay, and plaque-forming cell assay [88].
47. Nigella sativa L. (Family: Ranunculaceae)
Part used: Seeds
Important chemical constituents: Nigellidine and α-hederin
The proliferative capacity of splenocytes and T-lymphocytes were enhanced
and IFN-γ secretion from splenocytes was suppressed when treated with
aqueous extract of Nigella sativa [89].
48. Phyllanthus emblica L. (Family: Phyllanthaceae)
Part used: Fruits
Important chemical constituents: Polyphenols and vitamin C
B- and T-lymphocytes were stimulated and interleukin production was
restored by alcoholic extract of fruits [90].
49. Solanum nigrum L. (Family: Solanaceae)
Part used: Seeds
Important chemical constituents: Glycoalkaloids, glycoproteins, and
polysaccharides
Isolated polysaccharides of Solanum nigrum seeds showed significant incre-
ment in the percentage of CD4+ T-lymphocyte and a decrease in the percent-
age of CD8+ T-lymphocyte of peripheral blood of tumor-bearing mice [91].
50. Valeriana wallichii DC. (Family: Valerianaceae)
Part used: Roots
Important chemical constituents: Pyridine alkaloids, some organic acids,
and terpenes
Alcoholic root extract inhibited hepatitis C virus (HCV) by binding with
HCV nonstructural B (NS5B) protein [92].
51. Vitex negundo L. (Family: Verbanaceae)
Parts used: Roots and leaves
Important chemical constituents: Negundoside, agnuside, and vitegnoside
Phagocytic cells such as macrophages and neutrophils were activated by
hydroalcoholic extract of leaves of V. negundo [93].
52. Zingiber officinale Roscoe (Family: Zingiberaceae)
Part used: Rhizome
Important chemical constituents: 6-Gingerol, 6-shogaol, and 6-paradol
Cell-mediated immune response and nonspecific proliferation of
T-­lymphocyte were affected by volatile oil of Zingiber officinale [94].
1314 S. P. Thekkekkoottumughath

53. Achyranthes aspera L. (Family: Amaranthaceae)

Part used: Root
Important chemical constituents: Saponins, alkaloids, and oleanolic acid
Cytokine-based immunomodulatory role was exhibited by polyphenolic
compounds of hydroalcoholic extract [95].
54. Alstonia scholaris (L.) R.Br. (Family: Apocynaceae)
Part used: Bark
Important chemical constituents: Alkaloids, phenols, and saponins
Aqueous extract enhanced phagocytic activity [96].
55. Azadirachta indica A. Juss. (Family: Meliaceae)
Part used: Leaves
Important chemical constituents: Tetranortriterpenoids and azadirone
Against Newcastle disease virus antigen, dried powdered leaves signifi-
cantly enhanced the antibody titers [97].
56. Berberis aristata DC. (Family: Berberidaceae)
Part used: Bark
Important chemical constituents: Isoquinoline alkaloids and
isothiocyanates
Suppressed viral-infection-induced upregulation of toll-like receptor 7
(TLR-7) signaling pathway was inhibited by isolated berberine [98].
57. Bergenia ciliata (Haw.) Sternb. (Family: Saxifragaceae)
Part used: Stem
Important chemical constituents: Flavonoids and phenolic compounds
Expression of CD69 on lymphocytes was stimulated by alcoholic extract [99].
58. Cassia fistula L. (Family: Leguminosae)
Part used: Bark
Important chemical constituents: Anthraquinones, flavonoids, and alkaloid
Antibody titer against Salmonella typhimurium “O” antigen and skin thick-
ness in 2,4-dinitrochlorobenzene-sensitized albino rats were increased by
hydroalcoholic extract of C. fistula [100].
59. Cinnamomum verum J.Presl. (Family: Lauraceae)
Part used: Bark
Important chemical constituents: Cinnamaldehyde and linalool
Phagocytic index in carbon clearance test, serum immunoglobulin levels,
neutrophil adhesion, and antibody titer values were increased by bark sus-
pension [101].
Plants with Immunomodulatory Potential Described in Ayurveda 1315

60. Cyperus rotundus L. (Family: Cyperaceae)

Part used: Rhizome
Important chemical constituents: α-Copaene, cyperene, and valerenal
Aqueous, alcoholic, ethyl acetate, and total oligomer flavonoid (TOF)
extracts of C. rotundus influence humoral-mediated immunity by stimulat-
ing B- and T-cell proliferation [102].
61. Illicium verum Hook.f. (Family: Schisandraceae)
Part used: Fruit
Important chemical constituents: Lectins, myrcene, and α-phellandrene
limonene
Immunomodulatory action by stimulating phagocytic function was exhib-
ited by lectins isolated from Illicium verum [103].
62. Mentha × piperita L. (Family: Lamiaceae)
Part used: Leaves
Important chemical constituents: Menthol and menthone
Hydrodistillate fractions of M. piperita affect the functional responses of
human polymorphonuclear leukocytes and peripheral blood mononuclear
cells [104].
63. Momordica charantia L. (Family: Cucurbitaceae)
Parts used: Leaves, fruits, and seed
Important chemical constituents: Triterpene, steroid, and alkaloid
Exposure of neutrophils and macrophages stimulates both their capacity to
ingest foreign particles and their intracellular killing activities when treated
with alcohol and diethyl ether extract [105].
64. Ocimum basilicum L. (Family: Lamiaceae)
Part used: Leaves
Important chemical constituents: Linalool, 1,8-cineol, and eugenol
Hydroalcoholic extract of leaves decreased bronchoalveolar lavage fluid lev-
els of IgE and phospholipase A2, but increased IFN-γ/IL-4 ratio [106].
65. Phyllanthus amarus Schumach. and Thonn. (Family: Phyllanthaceae)
Parts used: Whole plant
Important chemical constituents: Flavonoids, alkaloids, and terpenoids
Inhibitory action on both phagocytic and CD18 expressions of phagocytes
was exhibited by alcoholic extract of aerial parts [107].
66. Piper nigrum L. (Family: Piperaceae)
Part used: Fruits
Important chemical constituents: Piperine, piperic acid, and
piperlonguminine
1316 S. P. Thekkekkoottumughath

Aqueous extract of Piper nigrum promotes the proliferative signaling path-

ways in splenocytes and enhances murine spleen cell proliferation [108].
67. Pongamia pinnata (L.) Pierre (Family: Leguminosae)
Part used: Seeds
Important chemical constituents: Flavonoids, polyunsaturated fatty acids,
and alkaloids
For immune cell-signaling events needed for continued recruitment of neu-
trophils/other cells, isolated oil impact was seen [109].
68. Punica granatum L. (Family: Lythraceae)
Parts used: Fruits and peels
Important chemical constituents: Flavonoids and alkaloids
Significant reduction in nitric oxide levels, TNF-α levels, inducible nitric
oxide synthase (iNOS), and NF-κB expression was observed when treated
with aqueous extract [110].
69. Santalum album L. (Family: Santalaceae)
Part used: Heartwood
Important chemical constituents: Sesquiterpenic alcohols
Aqueous extract of Santalum album inhibited CD14 monocyte, cell prolif-
eration, and production of nitric oxide [111].
70. Saussurea costus (Falc.) Lipsch. (Family: Compositae)
Part used: Roots
Important chemical constituents: Sesquiterpenes, triterpenes, and flavonoids
Suppressive effect on the expression of the hepatitis B surface antigen in
Hep3B cells was exhibited by costunolide and dehydrocostus lactone [112].
71. Sphaeranthus indicus L. (Family: Compositae)
Parts used: Leaves and flowers
Important chemical constituents: Methyl chavicol, d-cadinene, and α-ionone
Increased hemagglutination antibody titer phagocytic activity, and delayed-­
type hypersensitivity was observed when treated with petroleum ether
extract from the flower heads of S. indicus [113].
72. Syzygium aromaticum (L.) Merr. and L.M. Perry (Family: Myrtaceae)
Part used: Flower buds
Important chemical constituents: Carvacrol, thymol, and eugenol
Alcoholic and aqueous extract exhibited suppressive effects on macrophages
and inhibited IL-1β, IL-6, and IL-10 in mouse. Essential oil increased leuco-
cyte count and DTH response in mice [114].
Plants with Immunomodulatory Potential Described in Ayurveda 1317

73. Terminalia chebula Retz. (Family: Combretaceae)

Part used: Fruits
Important chemical constituents: Flavonoids and tannins
In mice, aqueous extract exhibited increase in humoral antibody titer and
DTH [115].
74. Ziziphus jujuba Mill. (Family: Rhamnaceae)
Part used: Fruits
Important chemical constituents: Triterpenoids, sterols, and flavonoids
Aqueous extract increased thymus and spleen indices, T-lymphocyte prolif-
eration, hemolytic activity, and natural killer cell activity [116].
75. Datura metel L. (Family: Solanaceae)
Parts used: Leaves, fruits, and seeds
Important chemical constituents: Isofraxidin, scopatone, and daturadiol
Oil stimulated the proliferation of human peripheral blood mononuclear
cells; secretion of IL-2, IFN-γ, and TNF-α; induced the expression of CD56,
CD3, and CD8; and stimulated intracellular granulysin levels in the immune
cells [117].
76. Elettaria cardamomum (L.) Maton (Family: Zingiberaceae)
Part used: Fruits
Important chemical constituents: 1,8-Cineole, α-terpinyl acetate, and
sabinene
As a proof for immunomodulator activity, essential oil overlapped with vari-
ous canonical signaling pathways [118].
77. Hedychium spicatum Sm. (Family: Zingiberaceae)
Part used: Rhizome
Important chemical constituents: Sitosterol and its glucosides
Alcoholic extract increased neutrophil count, phagocytosis, and leucocyte
count [119].
78. Inula racemosa Hook.f. (Family: Compositae)
Part used: Root
Important chemical constituents: Inulin and alantolactone
Polysaccharide fraction of aqueous extract showed immunomodulatory
action by stimulating function of phagocytes [120].
79. Lepidium sativum L. (Family: Brassicaceae)
Part used: Whole plant, and seed
Important chemical constituents: Cardiac glycoside, alkaloids, and phenolic
flavonoids
Protein extract of Lepidium sativum alters Con-A-induced prolifera-
tion [121].
1318 S. P. Thekkekkoottumughath

80. Mucuna pruriens (L.) DC. (Family: Fabaceae)

Part used: Seed
Important chemical constituents: levodopa and l-3,4-dihydroxyphenylala-
nine (L-DOPA) and beta-sitosterol
M. pruriens modulate components of immune system like TNF-α, IL-1β,
IL-6, IFN-l, iNOS, and IL-2 [122].
81. Sesamum indicum L. (Family: Pedaliaceae)
Part used: Seed
Important chemical constituents: Unsaturated fatty acids and glycerol
Essential oil suppresses cellular immunity with the domination of Th2
responses and also acts on macrophages and proinflammatory functions of
dendritic cells [123].

5 Discussion

In this era of emerging pandemics like COVID-19, promising drugs to combat them
have to be discovered on an emergency basis. Antibody reagents, natural adjuvants,
and synthetic agents are used as immunomodulators in conventional medicine.
However, there are serious limitations in prescribing these medicines due to side
effects like increased risk of infection and generalized effect all over the immune
system. Consequently, there was increased usage of herbal plants, which are consid-
ered to be less toxic with fewer side effects, to treat diseases of immune system [124].
A lot of plants with immunomodulatory potential acting on various components
of immune system have been described in various Ayurvedic classical textbooks.
Different plant-based principles have been isolated from such plants with potential
immunomodulatory activity. These herbs seem to act through immunosuppressant,
immunostimulant, or immunoadjuvant activities by affecting the effector arm of the
immune response [125].
Main mechanisms of immunomodulation activity so far understood are via
immunostimulatory effect on peritoneal macrophages; cellular immune function
enhancement and nonspecific cellular immune system effect; increased nonspecific
immunity mediators; stimulation of phagocytosis; macrophage activation; lym-
phoid cell stimulation; increase in antigen-specific immunoglobulin production,
circulating total WBC count, interleukin-2, number of natural killer cells, reducing
chemotherapy-induced leukopenia, and increasing [126].
The herbal mixture preparations of Ayurveda may be acting on immune system
due to their phytochemicals with immunomodulatory properties, probably acting
synergistically [1].
From the above review it is evident that there are a lot of medicinal plants that
exert immunomodulatory activity in various experimental models. Various in vivo
and in vitro screening methods were employed to ascertain their pharmacological
Plants with Immunomodulatory Potential Described in Ayurveda 1319

activity. Some medicinal plants were observed to stimulate the immune response
(e.g., Ocimum sanctum, Tinospora cordifolia), while some suppress the immune
system (Cannabis sativa). Various secondary metabolites like sterols, alkaloids, fla-
vonoids, glycosides, saponins, and coumarins exhibit a wide range of immunomod-
ulating activity.

6 Conclusion

Herbal plants or extracts having immunomodulatory activity when administered

along with vaccines may be helpful in obtaining higher protective antibodies against
different infections. It is anticipated that policymakers from the Ayurvedic systems
of medicines may reframe public health policies on the basis of evidences generated
from experimental studies done on various plants on their immunomodulatory
potential. Collaborative studies at the national and global levels may be proposed.
Further researches may be conducted by research organizations on emergency basis,
as this may result in the development of lead molecule against COVID-19.

References

1. Kumar D, Arya V, Kaur R et al (2011) A review of immunomodulators in the Indian traditional

health care system. J Microbiol Immunol Infect 45(3):165–184. https://doi.org/10.1016/j.
jmii.2011.09.030
2. Sinimol TP, Emy SS, Soumya MC (2020) Immunomodulation in Ayurveda w.s.r. to its sig-
nificance in preventing infections like Covid 2019. Int J Ayurveda Pharma Res 8(7):75
3. Martinez AB, Mattila R, Font RG et al (2013) Immunomodulatory drugs: oral and systemic
adverse effects. Med Oral Patol Oral Cir Bucal 19(1):e24–e31. https://doi.org/10.4317/
medoral.19087
4. Baxter D (2007) Active and passive immunity, vaccine types, excipients and licensing. Occup
Med 57:552–556. https://doi.org/10.1093/occmed/kqm110
5. Vesely MD, Kershaw MH, Schreiber RD et al (2011) Natural innate and adap-
tive immunity to cancer. Annu Rev Immunol 29:235–271. https://doi.org/10.1146/
annurev-­immunol-­031210-­101324
6. Spellberg B, Edwards JE (2001) Type 1/Type 2 immunity in infectious diseases. Clin Infect
Dis 32:76–102. https://doi.org/10.1086/317537
7. Parkin J, Cohen B (2001) An overview of the immune system. Lancet 357:1777–1789.
https://doi.org/10.1016/S0140-­6736(00)04904-­7
8. Moradali MF, Mostafavi H, Ghods S et al (2007) Immunomodulating and anticancer agents
in the realm of macromycetes fungi (macrofungi). Int Immunopharmacol 7:701–724. https://
doi.org/10.1016/j.intimp.2007.01.008
9. Oh SR, Kinjo J, Shii Y et al (2000) Effects of triterpenoids from Pueraria lobata on immu-
nohemolysis: beta-D-glucuronic acid plays an active role in anticomplementary activity
in vitro. Planta Med 66:506–510. https://doi.org/10.1055/s-­2000-­8614
10. Oberbarnscheidt MH, Lakkis FG (2014) Innate allorecognition. Immunol Rev 258:145–149.
https://doi.org/10.1111/imr.12153
1320 S. P. Thekkekkoottumughath

11. Lerner A, Jeremias P, Matthias T (2016) The world incidence and prevalence of autoimmune
diseases is increasing. Int J Celiac Dis 3:151–155. https://doi.org/10.12691/ijcd-­3-­4-­8
12. Catanzaro M, Corsini E, Rosini M et al (2018) Immunomodulators inspired by nature: a
review on curcumin and echinacea. Molecules 23(11):2778. https://doi.org/10.3390/
molecules23112778
13. Dham SK (2017) Immunomodulation. Med J Armed Forces India 51(3):149–150. https://doi.
org/10.1016/S0377-­1237(17)30954-­1
14. Jantan I, Ahmad W, Bukhari SNA (2015) Plant-derived immunomodulators: an insight on
their preclinical evaluation and clinical trials. Front Plant Sci 6:655. https://doi.org/10.3389/
fpls.2015.00655
15. Golan DE (2008) Principles of pharmacology. The pathophysiologic basic of drug therapy.
Lippincott Williams & Wilkins, Pennsylvania, pp 795–809
16. Jain S (2008) Handbook of pharmacology. Pars Publication, London
17. Tortora GJ, Derrickson BP (2008) Principles of anatomy and physiology. Wiley, Hoboken
18. Singhal KC (2007) Essentials of pharmacotherapeutics. CBS Publishers, New Delhi
19. Sengupta PR (2009) Medical pharmacology. CBS Publishers, New Delhi
20. Katzung GB, Trevor JA (2009) Basic and clinical pharmacology. Lange Medical Books/
McGraw Hill, New York
21. Gilman’s G (2008) Manual of pharmacology and therapeutics. Professor of Pharmacology &
Medicine University of California, San Diego LaJolla
22. Rang HP, Dale MM (2007) Rang and Dale pharmacology. Churchill Livingestone, Edinburgh
23. Richard AH, Pamela CC (2009) Lippincott’s illustrated reviews: pharmacology. Wolters
Kluwer, New Delhi
24. Mythili M, Nair S, Gunasekaran S (2004) Effect of cyclophosphamide pretreatment on hema-
tological indices of Indian Bonnet monkeys. Indian J Pharmacol 36:175
25. Keane J, Gershon S, Wise RP et al (2001) Tuberculosis associated with infliximab, a
tumor necrosis factor alpha-neutralizing agent. N Engl J Med. https://doi.org/10.1056/
NEJMoa011110
26. Baudouin V, Crusiaux A, Haddad E et al (2003) Anaphylactic shock caused by immunoglobu-
lin E sensitization after retreatment with the chimeric anti-interleukin-2 receptor monoclonal
antibody basiliximab. Transplantation. https://doi.org/10.1097/01.TP.0000073809.65502.8F
27. Bartelds GM, Krieckaert CL, Nurmohamed MT et al (2011) Development of antidrug anti-
bodies against adalimumab and association with disease activity and treatment failure during
long-term follow-up. JAMA. https://doi.org/10.1001/jama.2011.406
28. Hansel TT, Kropshofer H, Singer T et al (2010) The safety and side effects of monoclonal
antibodies. Nat Rev Drug Discov. https://doi.org/10.1038/nrd3003
29. Sgro C (1995) Side-effects of a monoclonal antibody, muromonab CD3/orthoclone OKT3:
bibliographic review. Toxicology. https://doi.org/10.1016/0300-­483X(95)03123-­W
30. Liu L, Li Y (2014) The unexpected side effects and safety of therapeutic monoclonal antibod-
ies. Drugs Today. https://doi.org/10.1358/dot.2014.50.1.2076506
31. Berger JR, Houff SA, Major EO (2009) Monoclonal antibodies and progressive multifocal
leukoencephalopathy. MAbs. https://doi.org/10.4161/mabs.1.6.9884
32. Auffenberg C, Rosenthal LJ, Dresner N (2013) Levamisole: a common cocaine adulterant with
life-threatening side effects. Psychosomatics. https://doi.org/10.1016/j.psym.2013.02.012
33. Strayer DR, Carter WA (2012) Recombinant and natural human interferons: analysis of the
incidence and clinical impact of neutralizing antibodies. J Interferon Cytokine Res. https://
doi.org/10.1089/jir.2011.0069
34. Campoli-Richards D, Sorkin E, Heel R (1986) Inosine Pranobex. Drugs. https://doi.
org/10.2165/00003495-­198632050-­00001
35. Charak (2007) Deerghanjeevitheeya Adhyaya. In: Sharma RK, Bhagwan D (eds) Charaka
Samhita, 1st edn. Chaukhamba Sanskrit Series office, Varanasi
36. Vagbhata (2005) Doshadivijnaneeya. In: Srikanthamurthy KR (ed) Ashtanga Samgraha, 2nd
edn. Chaukhamba Orientalia, Varanasi
Plants with Immunomodulatory Potential Described in Ayurveda 1321

37. Charak (2008) Tisreshaniya. In: Shastri SN (ed) Charak Samhita. Chukhambha Bharty
Academy, Varanasi
38. Vagbhata (2005) Dinacharya. In: Srikanthamurthy KR (ed) Ashtanga Samgraha, 2nd edn.
Chaukhamba Orientalia, Varanasi
39. Vagbhata (2005) Ritucharya. In: Srikanthamurthy KR (ed) Ashtanga Samgraha, 2nd edn.
Chaukhamba Orientalia, Varanasi
40. Goyal M (2018) Rasayana in perspective of present scenario. Ayu 39:63–64. https://doi.
org/10.4103/ayu.AYU_300_18
41. Nadkarni KM, Nadkarni AK (2005) Indian materia medica. Popular Prakashan, Mumbai
42. Mondal S, Varma S, Bamola VD (2011) Double-blinded randomized controlled trial for
immunomodulatory effects of Tulsi (Ocimum sanctum Linn.) leaf extract on healthy volun-
teers. J Ethnopharmacol. https://doi.org/10.1016/j.jep.2011.05.012
43. Bharani SER, Asad M, Dhamanigi SS et al (2010) Immunomodulatory activity of methanolic
extract of Morus alba linn. (mulberry) leaves. Pak J Pharm Sci 23(1):63–68
44. Cooper JC, Turcasso N (1999) Immunostimulatory effects of b-1,3 glucan and acemannan.
JANA 2:5–11
45. Im SA, Lee YR, Lee YH et al (2010) In vivo evidence of the immunomodulatory activ-
ity of orally administered Aloe vera gel. Arch Pharm Res. https://doi.org/10.1007/
s12272-­010-­0315-­1
46. Rajanna M, Bharathi B, Shivakumar BR (2021) Immunomodulatory effects of Andrographis
paniculata extract in healthy adults – an open-label study. J Ayurveda Integr Med. https://doi.
org/10.1016/j.jaim.2021.06.004
47. Gautham M, Saha S, Bani S et al (2009) Immunomodulatory activity of Asparagus rac-
emosus on systemic Th1/Th2 immunity: implications for immunoadjuvant potential. J
Ethnopharmacol. https://doi.org/10.1016/j.jep.2008.10.028
48. Paul S, Bandyopadhyay TK, Bhattacharya A (2011) Immunomodulatory effect of leaf extract
of Murraya koenigii in diabetic mice. Immunopharmacol Immunotoxicol. https://doi.org/1
0.3109/08923973.2011.561354
49. Pradhan D, Panda PK, Tripathy G (2009) Evaluation of immunomodulatory activity of meth-
anolic extract of Couroupita guianensis Aubl flowers in rat. NPR 8(1):37–42
50. Sharma U, Bala M, Kumar M et al (2012) Immunomodulatory active compounds from
Tinospora cordifolia. J Ethnopharmacol. https://doi.org/10.1016/j.jep.2012.03.027
51. Deshpande JR, Choudhary AA, Mirsha MR et al (2008) Benefical effects of Lagenaria sicer-
aria Mol. Fruit epicarp in animal models. Indian J Exp Biol 46:234–242
52. Halder S, Bharal N, Mediratta PK et al (2009) Antiinflammatory, Immunomodulatory and
anti-nociceptic activity of Terminalia arjuna Roxb. Bark powder in mice and rats. Indian J
Exp Biol 47:577–583
53. Ghaisas MM, Saikh SA, Deshpande AD (2009) Evaluation of immunomodulatory
activity of ethanolic extract of stem bark of Bauhinia variegata L. IJGP. https://doi.
org/10.4103/0973-­8258.49379
54. Tekade SH, Mode SG, Waghmare SP (2008) Effect of Asparagus racemosus, Sida cordifolia
and levamisole on immunological parameters in experimentally induced immunosuppressed
broilers. Vet World 1(2):49–50
55. Singh VK, Dwivedi P, Chaudhary BR et al (2015) Immunomodulatory effect of Gymnema syl-
vestre (R.Br.) leaf extract: an in vitro study in Rat model. PLoS One. https://doi.org/10.1371/
journal.pone.0139631
56. Costa JFO, David JPL, David JM et al (2008) Immunomodulatory activity of extracts
from Cordia superba Cham. and Cordia rufescens A. DC. (Boraginaceae), plant spe-
cies native from Brazilian semiarid. Rev Bras Farmaacogn. https://doi.org/10.1590/
S0102-­695X2008000100004
57. Hussain A, Shadma W, Maksood A et al (2013) Protective effects of Picrorhiza kurroa on
cyclophosphamide-induced immunosuppression in mice. Protective effects of Picrorhiza
kurroa on cyclophosphamide-induced immunosuppression in mice. Pharmacogn Res. https://
doi.org/10.4103/0974-­8490.105646
1322 S. P. Thekkekkoottumughath

58. Bafna A, Mishra S (2009) Antioxidant and immunomodulatory activity of the alkaloidal frac-
tion of Cissampelos pareira Linn. Sci Pharm. https://doi.org/10.3797/scipharm.0904-­16
59. Dashputre NL, Naikwade NS (2010) Immunomodulatory activity of Abutilon indicum Linn.
on albino mice. IJPSR 1(3):178–184
60. Thakur M, Bhargava S, Dixit VK (2006) Immunomodulatory activity of Chlorophytum boriv-
ilianum Sant. F. Evid Based Complement Alternat Med. https://doi.org/10.1093/ecam/nel094
61. Bharshiv CK, Garg SK, Bhatia AK (2016) Immunomodulatory activity of aqueous extract
of Nyctanthes arbor-tristis flowers with particular reference to splenocytes proliferation and
cytokines induction. Indian J Pharmacol. https://doi.org/10.4103/0253-­7613.186210
62. Sunil MA, Sunitha VS, Radhakrishnan EK et al (2019) Immunomodulatory activities of
Acacia catechu, a traditional thirst quencher of South India. J Ayurveda Integr Med. https://
doi.org/10.1016/j.jaim.2017.10.010
63. Ammon HPT (2010) Modulation of the immune system by Boswellia serrata extracts and
boswellic acids. Phytomedicine. https://doi.org/10.1016/j.phymed.2010.03.003
64. Mishra N, Tandon V, Gupta R (2012) Immunomodulation by Hibiscus rosa-sinensis: effect
on the humoral and cellular immune response of Mus musculus. Pak J Biol Sci. https://doi.
org/10.3923/pjbs.2012.277.283
65. Kori ML, Gaur M, Dixit VK (2009) Investigation of immunomodulatory potential of Cleome
gynandra Linn. Asian J Pharm Clin Res 2(1):35–39
66. Satpute KL, Jadhav MM, Karodi RS et al (2009) Immunomodulatory activity of fruits of
Randia dumetorum Lamk. JPP 1(3):36–40
67. Arreola R, Fabian SQ, Lopez-Roa RI et al (2015) Immunomodulation and anti-inflammatory
effects of garlic compounds. J Immunol Res. https://doi.org/10.1155/2015/401630
68. Manu KA, Kuttan G (2009) Immunomodulatory activities of Punarnavine, an alka-
loid from Boerhaavia diffusa. Immunopharmacol Immunotoxicol. https://doi.
org/10.1080/08923970802702036
69. Rahayu RP, Prasetyo RA, Purwanto DA et al (2018) The immunomodulatory effect of
green tea (Camellia sinensis) leaves extract on immunocompromised Wistar rats infected by
Candida albicans. Vet World. https://doi.org/10.14202/vetworld.2018.765-­770
70. Friedman H, Klein TW, Newton C et al (1995) Marijuana, receptors and immunomodulation.
Adv Exp Med Biol. https://doi.org/10.1007/978-­1-­4615-­1951-­5_15
71. Punturee K, Wild CP, Kasinrerk W et al (2005) Immunomodulatory activities of Centella
asiatica and Rhinacanthus nasutus extracts. Asian Pac J Cancer Prev 6(3):396–400
72. Jayathirtha MG, Mishra SH (2004) Preliminary immunomodulatory activities of
methanol extracts of Eclipta alba and Centella asiatica. Phytomedicine. https://doi.
org/10.1078/0944711041495236
73. Srinivasan R (2019) Evaluation of immunomodulatory activity of the ethanolic extract of
Evolvulus alsinoides. Int J Pharmacol Toxicol Sci 9(2):32–38
74. Kshirsagar S, Thakur AS, Kshirsagar J (2015) Immunomodulatory and antioxidative prop-
erties of Clitoria ternatea. Int J Plant Sci. https://doi.org/10.15740/HAS/IJPS/10.2/158-­162
75. Nfambi J, Bbosa GS, Sembajwe LF et al (2015) Immunomodulatory activity of methano-
lic leaf extract of Moringa oleifera in Wistar albino rats. J Basic Clin Physiol Pharmacol
26(6):603–611. https://doi.org/10.1515/jbcpp-­2014-­0104
76. Sunila ES, Kuttan G (2004) Immunomodulatory and antitumor activity of Piper longum Linn
and piperine. J Ethnopharmacol. https://doi.org/10.1016/j.jep.2003.10.016
77. Mallaiah GK, Raju PK, Thirupathi K et al (2016) Evaluation of immunomodulatory activity
of Tribulus terrestris in animal model. Int J Pharm Biol Sci 6(2):171–177
78. Davis L, Kuttan G (2000) Immunomodulatory activity of Withania somnifera. J
Ethnopharmacol. https://doi.org/10.1016/s0378-­8741(99)00206-­8
79. Ramprasath VR, Shanthi P, Sachdanandam P (2006) Immunomodulatory and anti-­
inflammatory effects of Semecarpus anacardium LINN. Nut milk extract in experimental
inflammatory conditions. Biol Pharm Bull. https://doi.org/10.1248/bpb.29.693
Plants with Immunomodulatory Potential Described in Ayurveda 1323

80. Brush J, Mendenhall E, Guggenheim A et al (2006) The effect of Echinacea purpurea,

Astragalus membranaceus and Glycyrrhiza glabra on CD69 expression and immune cell acti-
vation in humans. Phytother Res. https://doi.org/10.1002/ptr.1938
81. Vinothapooshan G, Sundar K (2011) Immunomodulatory activity of various extracts of
Adhatoda vasica Linnexperimental rats. Afr J Pharm Pharmacol. https://doi.org/10.5897/
AJPP10.126
82. Patel P, Asdaq SMB (2010) Immunomodulatory activity of methanolic fruit extract of Aegle
marmelos in experimental animals. Saudi Pharm J. https://doi.org/10.1016/j.jsps.2010.05.006
83. Sharma V, Thakur M, Chauhan NS et al (2010) Immunomodulatory activity of petroleum ether
extract of Anacyclus pyrethrum. Pharm Biol. https://doi.org/10.3109/13880201003730642
84. Amin AH, Bughdadi FA, Abo-Zaid MA et al (2019) Immunomodulatory effect of papaya
(Carica papaya) pulp and seed extracts as a potential natural treatment for bacterial stress. J
Food Biochem. https://doi.org/10.1111/jfbc.13050
85. Panigrahi GK, Yadav A, Mandal P et al (2016) Immunomodulatory potential of Rhein, an
anthraquinone moiety of Cassia occidentalis seeds. Toxicol Lett. https://doi.org/10.1016/j.
toxlet.2016.01.006
86. Mallik A, Nayak S (2014) Comparative study of methanolic and aqueous extracts of Cocculus
hirsutus leaves on specific and nonspecific immune responses. Int J Phytomed 6(2):316
87. Kim YM, Lee JA, Kim JC et al (2014) Dietary turmeric presents mild immune suppressing
and anti-inflammatory effects. J Prev Vet Med. https://doi.org/10.13041/jpvm.2014.38.1.7
88. Mangathayaru K, Umadevi M, Reddy CU (2009) Evaluation of the immunomodulatory and
DNA protective activities of the shoots of Cynodon dactylon. J Ethnopharmacol. https://doi.
org/10.1016/j.jep.2009.02.036
89. Majdalawieh AF, Hmaidan R, Carr RI (2010) Nigella sativa modulates splenocyte prolif-
eration, Th1/Th2 cytokine profile, macrophage function and NK anti-tumor activity. J
Ethnopharmacol. https://doi.org/10.1016/j.jep.2010.06.030
90. Sai Ram M, Neetu D, Yogesh B et al (2002) Cyto-protective and immunomodulating prop-
erties of Amla (Emblica officinalis) on lymphocytes: an in-vitro study. J Ethnopharmacol.
https://doi.org/10.1016/S0378-­8741(01)00421-­4
91. Li J, Li QW, Gao DW et al (2009) Antitumor and immunomodulating effects of polysac-
charides isolated from Solanum nigrum Linne. Phyther Res. https://doi.org/10.1002/ptr.2769
92. Ganta KK, Mandal A, Debnath S et al (2017) AntiHCV activity from semi-purified methano-
lic root extracts of valeriana wallichii. Phytother Res. https://doi.org/10.1002/ptr.5765
93. Lad H, Joshi A, Dixit D et al (2016) Antioxidant, genoprotective and immunomodulatory
potential of Vitex negundo leaves in experimental arthritis. Orient Pharm Exp Med. https://
doi.org/10.1007/s13596-­016-­0234-­x
94. Zhou HL, Deng YM, Xie QM (2006) The modulatory effects of the volatile oil of ginger on
the cellular immune response in vitro and in vivo in mice. J Ethnopharmacol. https://doi.
org/10.1016/j.jep.2005.10.022
95. Narayan C, Kumar A (2014) Antineoplastic and immunomodulatory effect of polyphenolic
components of Achyranthes aspera (PCA) extract on urethane induced lung cancer in vivo.
Mol Biol Rep. https://doi.org/10.1007/s11033-­013-­2850-­6
96. Iwo MI, Soemardji AA, Retnoningrum DS et al (2000) Immunostimulating effect of Pule
(Alstonia scholaris L. R.Br., Apocynaceae) bark extracts. Clin Hemorheol Microcirculation
23(2–4):177–183
97. Sadekar RD, Kolte AY, Barmase BS et al (1998) Immunopotentiating effects of Azadirachta
indica (Neem) dry leaves powder in broilers, naturally infected with IBD virus. Indian J Exp
Biol 36(11):1151–1153
98. Yan YQ, Fu YJ, Wu S et al (2018) Antiinfluenza activity of berberine improves prognosis by
reducing viral replication in mice. Phyther Res. https://doi.org/10.1002/ptr.6196
99. Tumova L, Endrychova H, Vokurkova D (2018) Immunostimulant activity of Bergenia
extracts. Pharmacogn Mag. https://doi.org/10.4103/pm.pm_423_17
1324 S. P. Thekkekkoottumughath

100. Laxmi V (2015) Investigating the immunomodulatory effect of Cassia fistula on albino rats.
Adv Pharm Ethnomed. https://doi.org/10.14737/journal.ape/2015/3.1.1.5
101. Niphade SR, Asad M, Chandrakala GK et al (2009) Immunomodulatory activity of
Cinnamomum zeylanicum bark. Pharm Biol. https://doi.org/10.3109/13880200903019234
102. Soumaya KJ, Dhekra M, Fadwa CG et al (2013) Pharmacological, antioxidant, genotoxic
studies and modulation of rat splenocyte functions by Cyperus rotundus extracts. BMC
Complement Altern Med. https://doi.org/10.1186/1472-­6882-­13-­28
103. Bouadi H, Necib Y, Bahi A (2015) Immunomodulatory activity of lectins extracted from
illicium Verum. Int J Pharm Sci Rev Res 31(1):129–131
104. Cosentino M, Bombelli R, Conti A et al (2009) Antioxidant properties and in vitro immuno-
modulatory effects of peppermint (Mentha x piperita l.) essential oils in human leukocytes. J
Pharm Sci Res 1(3):33–43
105. Mahamat O, Flora H, Tume C et al (2020) Immunomodulatory activity of momordica charan-
tia L. (Cucurbitaceae) leaf diethyl ether and methanol extracts on Salmonella typhi -infected
mice and LPS-induced phagocytic activities of macrophages and neutrophils. Evid Based
Complement Altern Med. https://doi.org/10.1155/2020/5248346
106. Eftekhar N, Moghimi A, Mohammadian RN et al (2019b) Immunomodulatory and anti-­
inflammatory effects of hydroethanolic extract of Ocimum basilicum leaves and its effect on
lung pathological changes in an ovalbumin-induced rat model of asthma. BMC Complement
Altern Med. https://doi.org/10.1186/s12906-­019-­2765-­4
107. Jantan I, Ilangkovan MY, Mohamad HF (2014) Correlation between the major components
of Phyllanthus amarus and Phyllanthus urinaria and their inhibitory effects on phagocytic
activity of human neutrophils. BMC Complement Altern Med. https://doi.org/10.1186/1472-­
6882-­14-­429
108. Majdalawieh AF, Carr RI (2010) In vitro investigation of the potential immunomodulatory
and anti-cancer activities of black pepper (Piper nigrum) and cardamom (Elettaria cardamo-
mum). J Med Food. https://doi.org/10.1089/jmf.2009.1131
109. Muniandy K, Gothai S, Badran KMH et al (2018) Suppression of proinflammatory cyto-
kines and mediators in LPS-Induced RAW 264.7 macrophages by stem extract of alter-
nanthera sessilis via the inhibition of the NF-κB pathway. J Immunol Res. https://doi.
org/10.1155/2018/3430684
110. Labsi M, Khelifi L, Mezioug D et al (2016) Antihydatic and immunomodulatory effects of
Punica granatum peel aqueous extract in a murine model of echinococcosis. Asian Pac J Trop
Med. https://doi.org/10.1016/j.apjtm.2016.01.038
111. Gupta A, Chaphalkar SR (2016) Immunopharmacological screening of aqueous root extract
of Santalum album. J Herb Med Pharmacol 5(1):7–11
112. Chen HC, Chou CK, Lee SD et al (1995) Active compounds from Saussurea lappa Clarks that
suppress hepatitis B virus surface antigen gene expression in human hepatoma cells. Antivir
Res. https://doi.org/10.1016/0166-­3542(94)00083-­K
113. Bafna AR, MishraSH (2007) Immunomodulatory activity of petroleum ether extract of
flower heads of Sphaeranthus indicus linn. J Herb Pharmacother. https://doi.org/10.1300/
J157v07n01_03
114. Carrasco FR, Schmidt G, Romero AL et al (2009) Immunomodulatory activity of zingiber
officinale Roscoe, salvia officinalis L. and syzygium aromaticum L essential oils: evidence
for humor- and cell-mediated responses. J Pharm Pharmacol. https://doi.org/10.1211/
jpp/61.07.0017
115. Shivaprasad HN, Kharya MD, Rana AC et al (2006) Preliminary immunomodula-
tory activities of the aqueous extract of Terminalia chebula. Pharm Biol. https://doi.
org/10.1080/13880200500530542
116. Yu ZP, Xu DD, Lu LF et al (2016) Immunomodulatory effect of a formula developed from
American ginseng and Chinese jujube extracts in mice. J Zhejiang Univ Sci B. https://doi.
org/10.1631/jzus.B1500170
Plants with Immunomodulatory Potential Described in Ayurveda 1325

117. Chandan G, Kumar C, Verma K et al (2020) Datura stramonium essential oil composi-
tion and it’s immunostimulatory potential against colon cancer cells. 3 Biotech. https://doi.
org/10.1007/s13205-­020-­02438-­4
118. Han X, Parker TL (2017) Cardamom (Elettaria cardamomum) essential oil significantly
inhibits vascular cell adhesion molecule 1 and impacts genomewide gene expression in
human dermal fibroblasts. Cogent Med. https://doi.org/10.1080/2331205x.2017.1308066
119. Uttara J, Mishra SH (2009) Preliminary evaluation of immunomodulatory and antistress
activity of methanol extract of Hedychium spicatum. Pharmacologyonline 1:1057–1071
120. Mishra A, Thakur M, Alok S (2016) Evaluation of immunomodulatory activity of polysac-
chride fraction of Inula racemosa, Bombax ceiba and Allium sativum. Int J Pharm Sci Res.
https://doi.org/10.13040/IJPSR.0975-­8232
121. Daoudi A, Aarab L, Abdel-Sattar E (2013) Screening of immunomodulatory activity of total
and protein extracts of some Moroccan medicinal plants. Toxicol Ind Health. https://doi.
org/10.1177/0748233711430972
122. Rai SN, Birla H, Zahra W et al (2017) Immunomodulation of Parkinson’s disease using
Mucuna pruriens (Mp). J Chem Neuroanat. https://doi.org/10.1016/j.jchemneu.2017.06.005
123. Khorrami S, Daneshmandi S, Mosayebi G (2018) Sesame seeds essential oil and Sesamol
modulate the pro-inflammatory function of macrophages and dendritic cells and promote Th2
response. Med J Islam Repub Iran. https://doi.org/10.14196/mjiri.32.98
124. Sawant C, Joshi N, Reddy S et al (2014) Immunomodulatory medicinal plants of India: a
review. Int J Pharmacol Toxicol 4(2):109–115
125. Chulet R, Pradhan P (2010) A review on rasayana. Phcog Rev 3(6):229–e234
126. Wagner H (1984) In: Hikino H, Farnsworth NR (eds) Economic and medicinal plant research,
vol 1. Academic Press, London, pp 113–e153
Plant-Derived Drugs for Alzheimer’s
Disease and Other Neurological Disorders

B. Sumithra, Sanjeeb Kumar Mandal, Bishwambhar Mishra,

K. V. S. S. N. Mounika, J. Caleb Joel Raj, and C. V. S. Aishwarya

1 Introduction

Dementia often begins with the gradual loss of intellectual functions of the brain,
such as memory, thinking, decision-making, learning capacity, attention, language,
and visuo-spatial functions. Dementia is not specific to any disease but is rather
caused by many neurological diseases including Alzheimer’s disease (AD) vascular
body dementia, Lewy body dementia, and Parkinson’s disease [1, 2]. Alzheimer’s
disease is a neurodegenerative disease that causes nerve cell death and is the world-
wide leading cause of dementia among 60–80% of patients. It is chronic, slowly
progressive with late onset majorly associated with elderly people over the age of
65. The early signs associated are dementia, cognitive decline, and anxiety that
decline the quality of daily living. Over time, these signs grow and become progres-
sively more severe affecting the person’s social and behavioral activities that lead to
depressive feelings and finally death [3–5]. According to Alzheimer’s Association,
50 million people globally are affected by Alzheimer’s disease (AD) which is
expected to triple by 2050 and increase to 150 million [6, 7]. Even the reported AD
and dementia-related deaths are increasing globally due to many factors including
growing population, aging, and increase in average lifetime. The death rate increased
by more than 145% between 2000 and 2019 in the US population alone, thus creat-
ing a huge socio-economic burden on the healthcare system and society at large
[3, 8, 9].

B. Sumithra (*) · S. K. Mandal · B. Mishra · K. V. S. S. N. Mounika · J. C. Joel Raj ·

C. V. S. Aishwarya
Department of Biotechnology, Chaitanya Bharathi Institute of Technology, Hyderabad,
Telangana, India
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 1327

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_55
1328 B. Sumithra et al.

2 Etiology of Alzheimer’s Disease

The pathophysiological process of Alzheimers Disease (AD) is complex and mul-

tifactorial, with synaptic dysfunction of nerve cells as early events that lead to
nerve cell death, tissue loss and finally brain atrophy wherein regions of the brain
shrink and lose volume, which is severely seen in the hippocampus and cerebral
cortex [3]. The major hallmarks of the AD brain are excessive deposition of amy-
loid plaques (amyloid-beta (Aβ) peptides) and highly phosphorylated tau proteins
(tau tangles). Abnormal accumulation of Aβ oligomers and neurofibrillary tangles
of phosphorylated tau proteins at the synaptic sites are highly neurotoxic that
interrupt several synoptical signaling. Along with other processes such as oxida-
tive stress, mitochondrial damage, generation of free radicals and inflammation,
these aggregated proteins contribute to synaptic dysfunction and eventually lead to
neuronal and synaptic degeneration. Another earliest pathological event is the defi-
ciency of the vital neurotransmitter, acetylcholine (ACh). In Alzheimer’s condi-
tion, the two primary cholinesterases (ChEs), acetylcholinesterase (AChE) and
butyrylcholinesterase (BuChE), in the nervous system have increased activity,
resulting in scarcity of ACh levels and ultimately inhibiting neurotransmission [3,
10–12]. The underlying mechanism causing AD pathogenesis (Aβ, NFTs, and syn-
aptic loss) is still unknown [9]. Thus, in the current scenario, the inhibitors of
acetylcholinesterase (AChE), clearance of aggregated proteins, neuron protection
and regeneration, Anti-­inflammatory, antioxidant activities are major targets for
the development of drugs. Furthermore, genetic, environmental factors, and life-
style are also proven to impact AD development to a great extent [12, 13].
Despite the research, treatment for this 100-year-old Alzheimer’s disease has
several challenges and remained untreatable [13]. Although the treatment strategies
evolved in the last decade, there is no effective drug approved for the complete
treatment of AD, besides only balancing the symptoms. Several synthetic drugs
failed in clinical trials due to their limited efficacy and are also associated with
severe side effects [11–13]. Currently, these results demand effective and safe phar-
macotherapies from natural sources. Herbal medicine has played an important role
in the treatment of neurological disorders and offers an alternative option. The
polypharmacology concept of “multifunctional drugs (MTDs): one-compound
multiple-targets” has gained attention in developing drugs for neurodegenerative
diseases such as Parkinson’s and Alzheimer’s diseases. Considering this approach,
the natural compound is of special interest for MTDS, as the safety and pharmaco-
kinetics of synthetic multifunctional anti-AD drugs have several limitations [10,
14]. Several studies reported the potential of phytochemicals with significant anti-
AD activity [10, 11, 15]. This chapter summarizes the most effective plants and
their compounds against Alzheimer’s disease and other neurological impairments
in the following section.
Plant-Derived Drugs for Alzheimer’s Disease and Other Neurological Disorders 1329

3 Medicinal Plants Effective for Alzheimer’s Disease

and Other Neurological Disorders

Withania somnifera
3.1 

Withania somnifera, also known as “Ashwagandha,” is a perennial shrub native

across India and belongs to the plant family Solanaceae or the nightshade family
[16]. It is a nervine tonic, libido stimulant, and stress reliever used widely in
Ayurveda to aid the system to acclimatize to stress. Because of its nootropic prop-
erty, it enhances the cognitive behavior of the human brain [17]. It works as a hypo-
glycemic and hypolipidemic adaptogen. It has demonstrated anti-platelet
aggregatory, anti-inflammatory, anxiolytic (anti-anxiety), neuroprotective proper-
ties and anticonvulsive [18]. Withanolides are the major medicinal constituent of
W. somnifera. Dehydrowithanolide-R, Withanolides A-Y, withanone, withasomidi-
enone, withasomniferin-A, withasomniferols A-C, withaferin A and ergostane-type
steroidal lactones are among the therapeutic chemical components in ashwagandha.
The β-sitosterol, phytosterols, sitoindosides, and alkaloids are other compo-
nents [19].
Withania somnifera extract comprises a diverse variety of phytochemicals such
as steroidal lactones, steroids, flavonoids, salts, alkaloids, and nitrogen-containing
compounds. The plant has been shown to contain over 40 withanolides, 12 alka-
loids, and sitoindosides. However, withanolides are primarily responsible for phar-
macological actions [18]. These extracts possess various properties which can help
treat AD. A few of those properties are discussed next.

3.1.1 Neuroprotective Property

Ashwagandha has been demonstrated to have free radical scavenging and antioxi-
dant properties and also the ability to help maintain a robust immunity. Free radicals
created during the onset and course of Alzheimer’s disease have been demonstrated
to be scavenged by a subset of these components. Furthermore, these compounds
prevent amyloid-induced cell death in PC-12 cells and rat neural cells. Studies sug-
gest that prominent Withanamide A and Withanamide C [20] (Fig. 1a, b) extracted
from the fruits of somnifera plant protect PC-12 cells against amyloid peptide-­
induced cell toxicity. Withanamides A and Withanamides C cohere to the β-amyloid
and suppress fibril formation [21].

3.1.2 Antioxidant Property

Various experiments were conducted on W. somnifera and the extract obtained from
it proved its effectiveness in the treatment of AD and its related neurological dys-
functions [22]. One such study reveals that WS extract shields SK-N-SH cells
1330 B. Sumithra et al.

Fig. 1 Major
Withanamides of Withania
somnifera: (a) structure of
Withanamide A (WA) and
(b) structure of
Withanamide C (WC)

(neuroblastoma cell line) from toxicity caused by Aβ peptide and acrolein and it was
also able to lower the levels of ROS which in turn reduces the oxidative stress in
SK-N-SH cells [23].

3.1.3 Acetylcholinesterase (AChE) Inhibitory Activity

The cholinergic supposition of Alzheimer’s disease suggested the degradation of

cholinergic neural cells in the forebrain and the significant decline of neurotrans-
mission in the cerebral cortex and other areas are greatly responsible for the decline
in cognitive function in patients with the disease. AChE is an important factor of
cholinergic synaptic transmission and is involved in the fast hydrolysis of the neu-
rotransmitter acetylcholine, which leads to the cessation of nerve impulses [23]. The
reduction of this AChE activity promotes neuroprotection in patients suffering from
AD. By using various models, it has been proved that the WS extract’s AChE activ-
ity is significantly reduced in a dose-dependent manner [16].

3.1.4 Neuro-regenerative Property

Both axons and dendrites were significantly regenerated by a methanol extract of

ashwagandha, in addition to reconstructing synapses in neural cells [24]. This aque-
ous preparation of W. somnifera was observed to boost cholinergic activity in rats,
including increases in the content of acetylcholine and AChE activity, which might
help to explain the cognition-improvement and memory-increasing effects [16]
(Fig. 2).
The fundamental hindrance to the active ingredients withanolide A of Withania
somnifera penetrating the blood-brain barrier (BBB). The main withanolides have
not been reported to cross the BBB. However, withanamides (bioactive compounds
from the fruit of Withania somnifera) have been proven to cross the BBB following
intraperitoneal injection [17].
Plant-Derived Drugs for Alzheimer’s Disease and Other Neurological Disorders 1331

Fig. 2 Effects caused by the activity of W. somnifera somnifera extracts

From this, we can demonstrate that the Withania somnifera extracts have promis-
ing pharmacological potential. It exhibits various properties, that is, neuroprotec-
tion, neuroregeneration, AChE inhibitory activity, and antioxidant activity, which
are key segments that have to be considered in producing a potential pharmacologi-
cal effect against Alzheimer’s activity.

3.1.5 
Withania somnifera and Other Neurodegenerative Diseases

In addition to Alzheimer’s disease, W. somnifera can potentially be used in treating

other neural diseases like Parkinson’s disease and Huntington’s disease (Fig. 3). In
Huntington’s disease, Huntington’s protein mutation has been found to produce
neural dysfunctions and cell disintegrating processes, including transcriptional defi-
ciencies, excitotoxicity, oxidative stress, inflammation, mitochondrial dysfunction,
and apoptosis. The extracts of W. somnifera have been shown to regulate the func-
tions of mitochondria of the neural crest cells and control the behavioral changes. It
increases the antioxidant mechanism which protects the ganglia tissue against the
reactive oxygen species.
In Parkinson’s disease, the extracts of W. somnifera induce anti-inflammatory
and antioxidant action which in turn increases the expression of dopamine receptors
and prevents the fall of dopamine in the vicinity of the neural crest cells.
1332 B. Sumithra et al.

Fig. 3 Potential effects of W. sominifera are proven in different neurological disorders

Centella asiatica (Gotu Kola)

3.2 

Centella asiatica is an annual herb of the Apiaceae family. It is one of the most
significant revitalizing flora for the cells of CNS in Ayurveda, and it is said to be
capable of boosting intellect, vitality, and memory. Triterpenes, asiaticoside, vella-
rin, asiatic acid, adecassoside, glycosides, madecassic acid, sapogenins, and centel-
loside are among the bioactive substances found in it [16]. Centella asiatica is
believed to enhance levels of the neurotrophic factor BDNF (brain-derived neuro-
trophic factor) by activating MAP kinases (mitogen-activated protein kinase) [25]
(Fig. 4). It is also renowned for its potential to enhance the healing of wounds in
addition to its cognitive boosting properties. Centella asiatica blocks enzymes that
disintegrate collagen while enhancing collagen production in preclinical trials,
resulting in a faster wound healing rate [26]. Various in vivo and in-vitro experi-
ments were conducted on gotu kola and numerous animal models were made to
know about the working mechanisms of various extracts of C. asiatica. Some of the
properties were thoroughly explained using animal models [27]. A few of them are
mentioned in Fig. 5.

3.2.1 Neuroprotective property

As we know, amyloid plaques and amyloid accumulation in the cerebrovascular

system are pathological markers of Alzheimer’s disease [28]. Centella asiatica con-
tains several components, the best researched of which being Asiatic acid in pre-
clinical models. Asiatic acid has antioxidant and neuroprotective properties and
crosses the blood-brain barrier [29]. It has been claimed to have stimulatory-nervine
Plant-Derived Drugs for Alzheimer’s Disease and Other Neurological Disorders 1333

Fig. 4 Mechanism of action of Centella asiatica extracts

Fig. 5 Pharmacological effects of Centella asiatica

tonic, rejuvenate, sedative, anxiolytic, and intelligence-promoting properties on the

CNS [30]. Centella asiatica leaf extract was also shown to affect the shape of hip-
pocampal CA3 and amygdala neuronal dendritic arborization in newborn rats in a
1334 B. Sumithra et al.

study. The pre-and post-colchicine Cornu Ammonis (CA) therapy boosted cogni-
tion, lowered malondialdehyde and nitrite concentrations, improved GSH levels,
and boosted glutathione-S-transferase, catalase, and SOD activities [31].

3.2.2 Antioxidant Property

Oxidative stress (OS) seems to be a key event in AD’s etiology. At the same time,
aggregated Ab-induced oxidative stress is a trigger in AD’s progression. Superoxide
is considered to be the main ROS in the human body and it can be produced by the
action of aggregated Ab1e40 on mitochondria which induces the activity of SOD
(superoxide dismutase). The extracts of CA have been shown to significantly reduce
this SOD activity and at the same time reverse the inhibition produced by SOD in
neural cells. The only drawback to this activity is that the extracts work in a dose-­
dependent manner. These extracts also can moderate the activity of the enzyme
catalase which helps in the hydrolysis of peroxide (H2O2) into water and oxygen
based on cellular requirements. The data obtained from the experiment conducted
on mice model for Alzheimer’s disease have suggested that the extracts of Centella
might increase GR and GPx activity (antioxidant enzymes which help in the break-
down of ROS) in differentiated PC12 (for neurotoxicity) and IMR32 cells (neuro-
blastoma cell lines), reducing oxidative stress in these cells [32]. Glutathione is one
of the most common non-peptide intracellular thiols in cells, which is essential for
cellular oxidative metabolism. It would be assumed that raising glutathione levels
would lower ROS levels and oppose apoptotic signals [30].

3.2.3 Acetylcholinesterase (AChE) Inhibitory Activity

Hyperphosphorylation of tau protein, Aβ accumulation, and surging levels of ace-

tylcholinesterase (AChE) activity are the most common factors in the pathophysiol-
ogy of AD. Raw extract of Centella asiatica (RECA) was found to reduce AChE,
inflammation, and OS activities in both in-vivo (Sprague Dawley rats) and in vitro
(SH-SY5Y and RAW 264.7 cells). RECA has a higher percentage of glycosides
than aglycones, with madecassoside being the most abundant, trailed by asiatico-
side. RECA therapy of SH-SY5Y showed a concentration-dependent reduction in
AChE levels and productivity as well as an increase in the concentrations of acetyl-
choline (neurotransmitter), which in turn improves synaptic communications [30].

Evodia rutaecarpa benthem

3.3 

Evodia rutaecarpa Benthem, one of the most common species used in primitive
Chinese medicine, is a fruit of the genus Evodia that is used to cure headaches,
stomach discomfort, postpartum bleeding, diarrhea, physiological alterations
Plant-Derived Drugs for Alzheimer’s Disease and Other Neurological Disorders 1335

caused by stress, inflammation, hypertension, and cancer and amenorrhea. It was

recently reported to be a promising medication for controlling and preventing the
onset and progression of Alzheimer’s disease [33]. The components extracted from
this species possibly possess antioxidant activity, antimutagenic and immunomodu-
latory activity and anti-AD and anti-inflammatory properties. Second, anticancer,
anti-obesity, antinomic, antinociceptive, and antimetastatic properties are all pres-
ent. These findings are extremely promising in terms of treating neurodegenerative
diseases [34]. In vitro, the extracts obtained had a substantial inhibitory impact on
acetylcholinesterase, and in vivo, they had an anti-amnesic effect [35]. Out of all the
components extracted, three components have shown a reliable and efficient effect
on treating Alzheimer’s disease. They are evodiamine (Evo), berberine (BRB), and
dihydroevodiamine (DHED) [33, 35, 36] (Fig. 6a–c).

Salvia officinalis
3.4 

Salvia officinalis, commonly called Sage, is a part of the Lamiaceae/Labiatae plant

family. Sage is a rounded perennial shrub that is native to the Mediterranean and
Middle Eastern regions but is now found all over the world. Salvia is the family’s
biggest genus, with around 900 species. The aerial parts of the shrub, owing to their
flavoring and seasonal properties, have often been used in the preparation of a wide
variety of food products and traditional medicine. Ulcers, seizures, inflammation
ulcers, paralysis, rheumatism, dizziness, gout, diarrhea, dizziness, and

Fig. 6 Structures of effective phytochemicals of Evodia rutaecarpa Bentham: structure of (a)

berberine (BRB), (b) dihydroevodiamine (DHED), and (c) evodiamine (Evo)
1336 B. Sumithra et al.

hyperglycemia are all the conditions wherein S. officinalis has often been used to
provide the right treatment in the domain of folk medicine. This plant has been the
subject of intensive research in the past few years, intending to document its classic
usage and identify undiscovered biological effects. It has been found to have several
biological effects such as anticancer [37], antinociceptive, antioxidant, anti-­
inflammatory [38], antimicrobial [39], antidementia, and antimutagenic properties
so far [40].
The most important phytochemical components extracted from the various plant
parts such as leaves, roots, stems, and flowers include carbohydrates and fatty acids;
steroids; mono, di, tri and sesquiterpenoids and certain phenolic compounds,
namely, tannins and flavonoids [41–43]. The majority of these were extracted from
the aqueous extract, butanol fraction, alcoholic extract, or ethanoic extract of
the plant.
The severe loss of the functioning of cholinergic neurons is a key characteristic
of AD. Salvia officinalis has cholinergic properties; that is, it can mimic the action
of acetylcholine which is a neurotransmitter. In various research, it has, therefore,
been shown to have the potential to act as a source of innovative treatment for
AD. The research was conducted to assess the efficacy and the dependency of a
Salvia officinalis extract in individuals aged between 65 and 80 years with AD rang-
ing from a very mild to a serious condition of the disease for 4 months using a fixed
dosage of 60 drops/day. It was a placebo-controlled trial carried out in three differ-
ent centers in Iran. As a result of these, the extract from S. officinalis performed
better in terms of cognitive functions than the placebo-controlled group. No signifi-
cant variations in side effects between the two groups were noticed and in the S. offi-
cinalis extract group, the agitation of patients was overcome, which however
requires further confirmation. Thus, it was shown that a four-month therapy with a
hydroalcoholic extract enhanced cognitive functioning, according to Akhondzadeh
et al.’s randomized controlled experiment [44].
When looking at the mechanism, a possible interaction with the cholinergic sys-
tem has been hypothesized as one of the processes responsible for S. officinalis
cognitive and memory-enhancing effects. In research conducted on animals, the
ethanolic extract of the leaves used showed an increased memory retention capacity
in rats. Its interaction with nicotinic and muscarinic cholinergic systems was the
major factor responsible for the entire process of memory retention [45]. The essen-
tial oil (EO) from the S. officinalis leaf extract was found to have an intriguing
antioxidant activity with an IC50 value of 8.31 ± 0.55 mg/L. The inhibitory potency
of EO against the three enzymes 5-lipoxygenase (5-LOX), acetylcholinesterase
(AChE) and xanthine oxidase (XOD) was investigated for the first time in Tunisia.
The result was that the investigated enzymes AChE (IC50 = 38.71 ± 2.09 mg/L),
5-LOX (IC50 = 36.15 ± 1.27 mg/L) and XOD (IP (percent) = 36.89 ± 1.83 at a final
concentration of 50 mg/L in the well) were all completely inhibited by S. officinalis
EO [46].
The leaves were also shown to have fungistatic, virustatic, and antibacterial bio-
logical activities, among others. In healthy mice, the hydroalcoholic extract of
S. officinalis and rosmarinic acid (Fig. 7a), one of its main flavonoids, improved
Plant-Derived Drugs for Alzheimer’s Disease and Other Neurological Disorders 1337

Fig. 7 Chemical structures of potential compounds of Salvia officinalis: (a) rosmarinic acid and
(b) ursolic acid

cognition and delayed diabetes-induced impairments [47]. It also exhibits behavior

by which the beta-amyloid (Aβ) fibril aggregation is stimulated and the Aβ develop-
ment from Aβ1–40 and Aβ1–42 is brought to a halt in a dose-dependent approach.
It also has the potential to compromise the integrity of Aβ fibrils [48]. Ursolic acid
(Fig. 7b), another component abundantly found in S. officinalis, effectively sup-
presses AChE activity in vitro [49], thus suggesting that it might be beneficial to
treat AD patients owing to its neurons-protecting action from the influence of oxida-
tive stress and the ability to improve memory by inhibition of the AChE activ-
ity [50].
In conclusion, it can be stated that the S. officinalis L. extract can potentially
serve as a propitious therapeutic strategy in dealing with Alzheimer’s disease and
AD-related dementia [51].

Rehmannia glutinosa
3.5 

The generation of H2O2 and other reactive oxygen species is linked to neurodegen-
erative diseases. Catalpol (Fig. 8), an iridoid glycoside found in the root of the
Rehmannia glutinosa plant, protects cells and mice from a variety of harmful stim-
uli [52]. Increased levels of reactive oxygen species (ROS) at the intracellular level
produce oxidative stress, which is thought to be a typical cause of the death of
neurons [53]. The balance between ROS formation and anti-oxidative activities may
be disrupted as a result of aging and many neurodegenerative diseases such as
Alzheimer’s disease and Parkinson’s disease [54].
Glutathione is a powerful antioxidant that protects cells from a variety of reactive
oxygen species (ROS). Several linked enzymes confer various tasks for glutathione
in live cells, in addition to the direct elimination of ROS by glutathione. In the
metabolism of glutathione and the defense against ROS, astrocytes in the brain play
a key role [55]. At the cellular level, astrocytes use two antioxidant mechanisms that
can rapidly inactivate H2O2 to limit the risk of radical generation from peroxides.
Reduced glutathione (GSH) acts as an electron donor in a glutathione
1338 B. Sumithra et al.

Fig. 8 Chemical structure of catalpol, an active compound of Rehmannia glutinosa

peroxidase-catalyzed process to reduce H2O2 to water. This process produces oxi-

dized glutathione (GSSG), which is a glutathione reductase substrate. Glutathione
reductase is in charge of cellular glutathione redox cycling, which is necessary for
the detoxification of endogenous peroxides [56].
Astrocytes, the central nervous system’s resident immune cells, have been
linked to the maintenance and support of neurons. However, astrocytes can be trig-
gered in response to inflammation, damage or disease in the brain, and activated
astrocytes produce a variety of inflammatory mediators, including nitric oxide
(NO), tumor necrosis factor-a (TNF-a), and reactive oxygen species (ROS) [57]. In
comparison to neurons, astrocytes are found in greater numbers in the brain. They
are likely players in information processing and play an important role in brain
homeostasis. Catalpol pretreatment could reduce cell viability and cytotoxic
effects in a concentration-­dependent manner. Catalpol was found to protect astro-
cytes against H2O2, suggesting that it could be a potential protective agent.
Catalpol reduced intracellular ROS production, increased intracellular gluta-
thione levels and successfully corrected the H2O2-induced decrease in glutathione
redox cycling enzyme activity. Pretreatment with Catalpol, in particular, signifi-
cantly increased glutathione reductase and glutathione peroxidase activity [58].
Catalpol’s protection could be related to its ability to suppress ROS generation
and cell death caused by H2O2, as well as its ability to increase glutathione mecha-
nism cycling, including glutathione content and antioxidant enzyme activity. As a
result, Catalpol could be a promising therapy option for a variety of neurodegen-
erative illnesses linked to oxidative stress [59].

Gastrodia elata
3.6 

Gastrodia elata (GE) Blume (Orchidaceae) has been utilized in eastern countries
for ages as a traditional herbal anticonvulsant. Vertigo, tetanus, and general paraly-
sis are all treated with GE as an analgesic and sedative. Some of the key ingredi-
ents are gastrodin, vanillin, and hydroxybenzaldehyde. Organic acids, glucose,
Plant-Derived Drugs for Alzheimer’s Disease and Other Neurological Disorders 1339

Fig. 9 Chemical structure

of gastrodin, an active
compound of Gastrodia
elata

hydroxybenzaldehyde, phenolic compounds, and 4-(hydroxymethyl) phenol are

among the other ingredients [60] (Fig. 9).
When tested on transgenic mice with epileptic seizures, an antioxidant and anti-
convulsive effect was shown by vanillyl alcohol. Gastrodin is known to boost GABA
levels by suppressing the GABA shunt. In a PTZ-induced seizure, glutamate-­
induced apoptosis in neurons is prevented by methanol extracts of Gastrodia elata,
and the levels of GABA dropped significantly and glutamate levels were increased.
It also showed free radical scavenging and antioxidant properties, as well as inhibit-
ing kainate binding to glutamate receptors in kainate-induced seizures [61].
Excitotoxin and neuronal cell injury caused a dip in the levels of GABA and a
rise in glutamic acid and its salts after brief global brain ischemia, which was miti-
gated by GE’s & ether fraction or methanol extracts (EF & ME). The GABA was
shown to reduce lipid peroxidation in the order 4-(hydroxymethyl)phenol >
4-(hydroxymethyl)-2-methoxyphenol > phenolic aldehyde > 4-­hydroxybenzaldehyde.
The reduction of lipid peroxidation by ferrous ammonium sulphate [62] and mela-
tonin at lowering H2O2 or Fe2+-induced lipid peroxidation was also in this order of
potency. Indeed, of the key compounds in GE’s EFME, 4-(hydroxymethyl)phenol
shows the maximum anti-oxidative effect, even more active than melatonin.
The antioxidant action of hydroxy benzyl alcohol was previously demonstrated
to protect against ischemic brain injury. Melatonin prevents the formation of free
radicals and the oxidation of lipids. Melatonin is also said to have the ability to
prevent the Fenton process, which causes oxidative stress in a variety of metals,
including ferrous ions. The high antioxidant properties of GE and its primary ingre-
dients could be useful in treating lipid peroxidation-related neurological illness [63].

Cinnamomi cortex (CC)

3.7 

The dried bark of Cinnamomum cassia is known as Cinnamomi cortex (CC), and it
has been used to treat several potentially fatal ailments in traditional south Asian
medicine. Cinnamomi cortex possesses glucose and lipid metabolism improvement,
neuroprotection, anti-inflammatory, antioxidant, anticancer and other pharmaco-
logical properties [64].
At specific concentrations, three samples of cinnamon tannin demonstrate sig-
nificant scavenging capacity against hydroxyl and 2,2-diphenyl-1-picrylhydrazyl
(DPPH) radicals. The clearance rates of 2-diphenyl1-picrylhydrazyl radicals are
1340 B. Sumithra et al.

90.98%, 90.48%, and 89.38%, respectively, with the concentration of ethyl ethano-
ate extract, resin purification extract and crude extract about 0.04 mg/mL–1. In all
three samples, the hydroxyl radical clearance rates exceeded 65% and rose dose-­
dependently range from 0.1 to 0.6 mg/mL–1. In the future, Cinnamomi cortex tannin
could be employed as a natural antioxidant [65].
The therapeutic efficacy of Cinnamomi cortex extract on neurodegenerative dis-
eases like Alzheimer’s disease (AD) induced Drosophila and transgenic mice has
been studied. According to the researchers, the lifetime of Drosophila induced with
AD was extended, the motor capability was restored and the harmful Ab oligomer
present in its central nervous system was destroyed. After ingesting the Cinnamomi
cortex extract, transgenic mice had fewer 56 kDa Ab oligomers and plaques, as well
as improved cognitive performance. According to the findings, CC extract protects
PC12 cells from toxicity by reducing the synthesis of hazardous Ab oligomers. CC
could be developed into an easy-to-use Alzheimer’s disease prevention and treat-
ment medicine. For the first time, Jana et al. discovered the mechanism through
which sodium benzoate; one of Cinnamomi cortex plant metabolite for neurodegen-
erative diseases [66].
When tested on mice, sodium benzoate raised neurotrophic factors derived from
the brain and neurotrophin-3 levels in the central nervous system via the PKA-­
CREB pathway. These data show that CC could be utilized to treat neurodegenera-
tive illnesses as a main or secondary treatment. The Procyanidin type-a trimer
(trimer 1), (E)-3-phenylprop-2-enal and chromen-2-one extracted from Cinnamomi
cortex aqueous extract inhibited the swelling of the glial cell caused by deprivation
of glucose and oxygen, according to Panickar et al. [67]. Trimer 1 reduced nerve
cell swelling after ischemia injury by inhibiting the oxygen-free radical content and
circulation of calcium. It also reduced glutamate excitotoxicity by halting the reduc-
tion in glutamate uptake. The researchers concluded that CC could be utilized to
treat ischemia and other neurological issues [68].

4 Conclusions

For decades, numerous studies have been conducted to tackle different terrible neu-
rological conditions. Although a few medications are currently available for the
treatment of Alzheimer’s disease, synthetic drugs have several limitations. To date,
numerous drug candidates have been widely used in animal research and AD
patients, but no significant medication has been able to effectively cure the clinical
manifestations. Natural products, which involve the use of herbal drugs, could be a
viable cornerstone on which treatment procedures can be streamlined. It is undeni-
able that the demand for such medical therapy is growing. Medicinal plant-derived
biomolecules will help accelerate the development of new forms of treatment for
AD. Combining different plant remedies with potential neuroprotective effects as
MTDs could be useful in treating neurological disorders including Alzheimer’s dis-
ease. When these medications are used together, they start to improve drug efficacy
Plant-Derived Drugs for Alzheimer’s Disease and Other Neurological Disorders 1341

and patient adherence to therapy. In this chapter, numerous plants and various phy-
tochemicals and their potential applications for the treatment of neurodegenerative
disorders including Alzheimer’s disease are discussed.
It is also important to adopt a holistic approach that includes herbal medicinal
plants in our diet as well as trying to live in a collaborative environment that encour-
ages social, mental and spiritual activities, thereby reducing stress, which is a risk
factor for Alzheimer’s disease. Foreseeing the recent progress, we anticipate that the
intersection of medicinal plants will lead to successful therapeutic solutions for the
treatment of Alzheimer’s disease in near future.

References

1. Arvanitakis Z, Shah RC, Bennett DA (2019) Diagnosis and management of dementia: review.
JAMA 322(16):1589–1599. https://doi.org/10.1001/jama.2019.4782
2. https://www.who.int/news-­room/fact-­sheets/detail/dementia
3. Breijyeh Z, Karaman R (2020) Comprehensive review on Alzheimer’s disease: causes
and treatment. Molecules (Basel, Switzerland) 25(24):5789. https://doi.org/10.3390/
molecules25245789
4. Piau A, Nourhashémi F, Hein C, Caillaud C, Vellas B (2011) Progress in the development of
new drugs in Alzheimer;s disease. J Nutr Health Aging 15(1):45–57. https://doi.org/10.1007/
s12603-­011-­0012-­x
5. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ,
Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS,
Ghetti B, Klunk WE, McDade E, Martins RN et al (2012) Clinical and biomarker changes
in dominantly inherited Alzheimer’s disease. N Engl J Med 367(9):795–804. https://doi.
org/10.1056/NEJMoa1202753
6. Yiannopoulou KG, Papageorgiou SG (2020) Current and future treatments in Alzheimer dis-
ease: an update. J Cent Nerv Syst Dis 12. https://doi.org/10.1177/1179573520907397
7. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, Brayne C, Burns A,
Cohen-Mansfield J, Cooper C, Costafreda SG, Dias A, Fox N, Gitlin LN, Howard R, Kales
HC, Kivimäki M, Larson EB, Ogunniyi A, Orgeta V, Mukadam N (2020) Dementia preven-
tion, intervention, and care: 2020 report of the Lancet commission. Lancet (London, England)
396(10248):413–446. https://doi.org/10.1016/S0140-­6736(20)30367-­6
8. (2021) 2021 Alzheimer’s disease facts and figures. Alzheimers Dement 17(3):327–406. https://
doi.org/10.1002/alz.12328
9. GBD 2019 Dementia Forecasting Collaborators (2022) Estimation of the global prevalence
of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden
of Disease Study 2019. Lancet Public Health 7(2):e105–e125. https://doi.org/10.1016/
S2468-­2667(21)00249-­8
10. Ayaz M, Ullah F, Sadiq A, Kim MO, Ali T (2019) Editorial: natural products-based drugs:
potential therapeutics against Alzheimer’s disease and other neurological disorders. Front
Pharmacol 10:1417. https://doi.org/10.3389/fphar.2019.01417
11. Ovais M, Zia N, Ahmad I, Khalil AT, Raza A, Ayaz M, Sadiq A, Ullah F, Shinwari ZK
(2018) Phyto-therapeutic and nanomedicinal approaches to cure Alzheimer’s disease: pres-
ent status and future opportunities. Front Aging Neurosci 10:284. https://doi.org/10.3389/
fnagi.2018.00284
12. Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, Van der Flier
WM (2016) Alzheimer’s disease. Lancet (London, England) 388(10043):505–517. https://doi.
org/10.1016/S0140-­6736(15)01124-­1
1342 B. Sumithra et al.

13. DeTure MA, Dickson DW (2019) The neuropathological diagnosis of Alzheimer’s disease.
Mol Neurodegener 14(1):32. https://doi.org/10.1186/s13024-­019-­0333-­5
14. Makhoba XH, Viegas C Jr, Mosa RA, Viegas FPD, Pooe OJ (2020) Potential impact of the
multi-target drug approach in the treatment of some complex diseases. Drug Des Devel Ther
14:3235–3249. https://doi.org/10.2147/DDDT.S257494
15. Shal B, Ding W, Ali H, Kim YS, Khan S (2018) Anti-neuroinflammatory potential of nat-
ural products in attenuation of Alzheimer’s disease. Front Pharmacol 9:548. https://doi.
org/10.3389/fphar.2018.00548
16. Rao RV, Descamps O, John V, Bredesen DE (2012) Ayurvedic medicinal plants for Alzheimer’s
disease: a review. Alzheimers Res Ther 4(3):22. https://doi.org/10.1186/alzrt125
17. Sehgal N, Gupta A, Valli RK, Joshi SD, Mills JT, Hamel E, Khanna P, Jain SC, Thakur
SS, Ravindranath V (2012) Withania somnifera reverses Alzheimer’s disease pathology by
enhancing low-density lipoprotein receptor-related protein in liver. Proc Natl Acad Sci U S A
109(9):3510–3515. https://doi.org/10.1073/pnas.1112209109
18. Dar NJ, Ahmad M (2020) Neurodegenerative diseases and Withania somnifera (L.): an update.
J Ethnopharmacol 256:112769. https://doi.org/10.1016/j.jep.2020.112769
19. Halim MA, Rosli IM, Jaafar SSM, Ooi HM, Leong PW, Shamsuddin S, Najimudin N,
Azzam G (2020) Withania somnifera showed neuroprotective effect and increase longevity in
Drosophila Alzheimer’s disease model. BioRxiv. https://doi.org/10.1101/2020.04.27.063107
20. Kurapati KR, Atluri VS, Samikkannu T, Nair MP (2013) Ashwagandha (Withania som-
nifera) reverses β-amyloid1-42 induced toxicity in human neuronal cells: implications in
HIV-associated neurocognitive disorders (HAND). PLoS One 8(10):e77624. https://doi.
org/10.1371/journal.pone.0077624
21. Jayaprakasam B, Padmanabhan K, Nair MG (2010) Withanamides in Withania somnifera fruit
protect PC-12 cells from beta-amyloid responsible for Alzheimer’s disease. Phytother Res:
PTR 24(6):859–863. https://doi.org/10.1002/ptr.3033
22. Gregory J, Vengalasetti YV, Bredesen DE, Rao RV (2021) Neuroprotective herbs for the
management of Alzheimer’s disease. Biomol Ther 11(4):543. https://doi.org/10.3390/
biom11040543
23. Singh M, Ramassamy C (2017) In vitro screening of neuroprotective activity of Indian medici-
nal plant Withania somnifera. J Nutr Sci 6:e54. https://doi.org/10.1017/jns.2017.48
24. Konar A, Gupta R, Shukla RK, Maloney B, Khanna VK, Wadhwa R, Lahiri DK, Thakur MK
(2019) M1 muscarinic receptor is a key target of neuroprotection, neuroregeneration and
memory recovery by i-Extract from Withania somnifera. Sci Rep 9(1):13990. https://doi.
org/10.1038/s41598-­019-­48238-­6
25. Chiroma SM, Baharuldin M, Mat Taib CN, Amom Z, Jagadeesan S, Ilham Adenan M, Mahdi
O, Moklas M (2019) Centella asiatica protects d-Galactose/AlCl3 mediated Alzheimer’s
disease-like Rats via PP2A/GSK-3β signaling pathway in their Hippocampus. Int J Mol Sci
20(8):1871. https://doi.org/10.3390/ijms20081871
26. Cai A, Xiao L, Zhou Y-P, Zhang Z-G, Yang Q-W (2020) Effect of Evodia rutaecarpa (Juss)
Benth extract on Alzheimer disease in mice. Trop J Pharm Res 19:823–828. https://doi.
org/10.4314/tjpr.v19i4.21
27. Soumyanath A, Zhong YP, Henson E, Wadsworth T, Bishop J, Gold BG, Quinn JF (2012)
Centella asiatica extract improves behavioral deficits in a mouse model of Alzheimer’s disease:
investigation of a possible mechanism of action. Int J Alzheimers Dis 2012:381974. https://
doi.org/10.1155/2012/381974
28. Dhanasekaran M, Holcomb LA, Hitt AR, Tharakan B, Porter JW, Young KA, Manyam BV
(2009) Centella asiatica extract selectively decreases amyloid beta levels in hippocampus of
Alzheimer’s disease animal model. Phytother Res: PTR 23(1):14–19. https://doi.org/10.1002/
ptr.2405
29. Centella asiatica (Gotu kola): cognitive vitality. https://www.alzdiscovery.org/cognitive-vital-
ity/ratings/centella-asiatica (Accessed on 15.02.2022)
Plant-Derived Drugs for Alzheimer’s Disease and Other Neurological Disorders 1343

30. Hafiz ZZ, Amin M, Johari James RM, Teh LK, Salleh MZ, Adenan MI (2020) Inhibitory
effects of raw-extract centella asiatica (RECA) on acetylcholinesterase, inflammations, and
oxidative stress activities via in vitro and in vivo. Molecules (Basel, Switzerland) 25(4):892.
https://doi.org/10.3390/molecules25040892
31. Kumar A, Dogra S, Prakash A (2009) Neuroprotective effects of Centella asiatica against
intracerebroventricular colchicine-induced cognitive impairment and oxidative stress. Int J
Alzheimers Dis 2009:972178. https://doi.org/10.4061/2009/972178
32. Chen CL, Tsai WH, Chen CJ, Pan TM (2015) Centella asiatica extract protects against amyloid
β1-40-induced neurotoxicity in neuronal cells by activating the antioxidative defence system. J
Tradit Complement Med 6(4):362–369. https://doi.org/10.1016/j.jtcme.2015.07.002
33. Fang Z, Tang Y, Ying J, Tang C, Wang Q (2020) Traditional Chinese medicine for anti-­
Alzheimer’s disease: berberine and evodiamine from Evodia rutaecarpa. Chin Med 15:82.
https://doi.org/10.1186/s13020-­020-­00359-­1
34. Cooper EL, Ma MJ (2017) Alzheimer disease: clues from traditional and complementary med-
icine. J Tradit Complement Med 7(4):380–385. https://doi.org/10.1016/j.jtcme.2016.12.003
35. Park CH, Kim SH, Choi W, Lee YJ, Kim JS, Kang SS, Suh YH (1996) Novel anticholines-
terase and antiamnesic activities of dehydroevodiamine, a constituent of Evodia rutaecarpa.
Planta Med 62(5):405–409. https://doi.org/10.1055/s-­2006-­957926
36. Zhang Y, Wang J, Wang C, Li Z, Liu X, Zhang J, Lu J, Wang D (2018) Pharmacological basis
for the use of evodiamine in Alzheimer’s disease: antioxidation and antiapoptosis. Int J Mol
Sci 19(5):1527. https://doi.org/10.3390/ijms19051527
37. Russo A, Formisano C, Rigano D, Senatore F, Delfine S, Cardile V, Rosselli S, Bruno M (2013)
Chemical composition and anticancer activity of essential oils of Mediterranean sage (Salvia
officinalis L.) grown in different environmental conditions. Food Chem Toxicol 55:42–47.
https://doi.org/10.1016/j.fct.2012.12.036
38. Wang M, Shao Y, Li J, Zhu N, Rangarajan M, LaVoie EJ, Ho CT (1999) Antioxidative phenolic
glycosides from sage (Salvia officinalis). J Nat Prod 62(3):454–456. https://doi.org/10.1021/
np980436g
39. Veličković DT, Ranđelović NV, Ristić MS, Veličković AS, Šmelcerović AA (2003) Chemical
constituents and antimicrobial activity of the ethanol extracts obtained from the flower, leaf
and stem of Salvia officinalis L. J Serb Chem Soc 68(1):17–24. https://doi.org/10.2298/
JSC0301017V
40. Ghorbani A, Esmaeilizadeh M (2017) Pharmacological properties of Salvia officinalis
and its components. J Tradit Complement Med 7(4):433–440. https://doi.org/10.1016/j.
jtcme.2016.12.014
41. Capek P, Hríbalová V (2004) Water-soluble polysaccharides from Salvia officinalis L. possess-
ing immunomodulatory activity. Phytochemistry 65(13):1983–1992. https://doi.org/10.1016/j.
phytochem.2004.05.020
42. Hayouni E, Chraief I, Abedrabba M, Bouix M, Leveau JY, Mohammed H, Hamdi M (2008)
Tunisian Salvia officinalis L. and Schinus molle L. essential oils: their chemical compositions
and their preservative effects against Salmonella inoculated in minced beef meat. Int J Food
Microbiol 125(3):242–251. https://doi.org/10.1016/j.ijfoodmicro.2008.04.005
43. Mitić-Ćulafić D, Vuković-Gačić BS, Knežević-Vukčević JB, Stanković S, Simić DM (2005)
Comparative study on the antibacterial activity of volatiles from sage (Salvia officinalis L.).
Arch Biol Sci 57(3):173–178. https://doi.org/10.2298/ABS0503173M
44. Akhondzadeh S, Noroozian M, Mohammadi M, Ohadinia S, Jamshidi AH, Khani M (2003)
Salvia officinalis extract in the treatment of patients with mild to moderate Alzheimer’s dis-
ease: a double blind, randomized and placebo-controlled trial. J Clin Pharm Ther 28(1):53–59.
https://doi.org/10.1046/j.1365-­2710.2003.00463.x
45. Eidi M, Eidi A, Bahar M (2006) Effects of Salvia officinalis L (sage) leaves on memory reten-
tion and its interaction with the cholinergic system in rats. Nutrition (Burbank, Los Angeles
County, Calif.) 22(3):321–326. https://doi.org/10.1016/j.nut.2005.06.010
1344 B. Sumithra et al.

46. El Euch SK, Hassine DB, Cazaux S, Bouzouita N, Bouajila J (2019) Salvia officinalis essential
oil: chemical analysis and evaluation of anti-enzymatic and antioxidant bioactivities. S Afr J
Bot 120:253–260. https://doi.org/10.1016/j.sajb.2018.07.010
47. Hasanein P, Felehgari Z, Emamjomeh A (2016) Preventive effects of Salvia officinalis L. against
learning and memory deficit induced by diabetes in rats: possible hypoglycaemic and antioxi-
dant mechanisms. Neurosci Lett 622:72–77. https://doi.org/10.1016/j.neulet.2016.04.045
48. Porat Y, Abramowitz A, Gazit E (2006) Inhibition of amyloid fibril formation by polyphenols:
structural similarity and aromatic interactions as a common inhibition mechanism. Chem Biol
Drug Des 67(1):27–37. https://doi.org/10.1111/j.1747-­0285.2005.00318.x
49. Chung YK, Heo HJ, Kim EK, Kim HK, Huh TL, Lim Y, Kim SK, Shin DH (2001) Inhibitory
effect of ursolic acid purified from Origanum majorana L on the acetylcholinesterase. Mol
Cells 11(2):137–143. PMID: 11355692
50. Lin HQ, Ho MT, Lau LS, Wong KK, Shaw PC, Wan DC (2008) Anti-acetylcholinesterase
activities of traditional Chinese medicine for treating Alzheimer’s disease. Chem Biol Interact
175(1–3):352–354. https://doi.org/10.1016/j.cbi.2008.05.030
51. Wu TY, Chen CP, Jinn TR (2011) Traditional Chinese medicines and Alzheimer’s disease.
Taiwan J Obstet Gynecol 50(2):131–135. https://doi.org/10.1016/j.tjog.2011.04.004
52. Jiang B, Shen RF, Bi J, Tian XS, Hinchliffe T, Xia Y (2015) Catalpol: a potential therapeutic
for neurodegenerative diseases. Curr Med Chem 22(10):1278–1291. https://doi.org/10.217
4/0929867322666150114151720
53. Choi K, Kim J, Kim GW, Choi C (2009) Oxidative stress-induced necrotic cell death via
mitochondira-dependent burst of reactive oxygen species. Curr Neurovasc Res 6(4):213–222.
https://doi.org/10.2174/156720209789630375
54. Liu Z, Zhou T, Ziegler AC, Dimitrion P, Zuo L (2017) Oxidative stress in neurodegenerative
diseases: from molecular mechanisms to clinical applications. Oxidative Med Cell Longev
2017:2525967. https://doi.org/10.1155/2017/2525967
55. Hossain MA, Piyatida P, da Silva JAT, Fujita M (2012) Molecular mechanism of heavy
metal toxicity and tolerance in plants: central role of glutathione in detoxification of reactive
oxygen species and methylglyoxal and in heavy metal chelation. J Bot 2012:37. https://doi.
org/10.1155/2012/872875
56. Forman HJ, Fukuto JM, Torres M (2004) Redox signaling: thiol chemistry defines which reac-
tive oxygen and nitrogen species can act as second messengers. Am J Physiol Cell Physiol
287(2):C246–C256. https://doi.org/10.1152/ajpcell.00516.2003
57. Farina C, Aloisi F, Meinl E (2007) Astrocytes are active players in cerebral innate immunity.
Trends Immunol 28(3):138–145. https://doi.org/10.1016/j.it.2007.01.005
58. Cacabelos R, Torrellas C, Carrera I, Cacabelos P, Corzo L, Fernández-Novoa L, Tellado I,
Carril JC, Aliev G (2016) Novel therapeutic strategies for dementia. CNS Neurol Disord Drug
Targets 15(2):141–241. https://doi.org/10.2174/1871527315666160202121548
59. Yang C, Shi Z, You L, Du Y, Ni J, Yan D (2020) Neuroprotective effect of catalpol via anti-­
oxidative, anti-inflammatory, and anti-apoptotic mechanisms. Front Pharmacol 11:690. https://
doi.org/10.3389/fphar.2020.00690
60. Teoh ES (2016) Galeola to gymadenia. In: Medicinal orchids of Asia. Springer, Cham,
pp 375–440. https://doi.org/10.1007/978-­3-­319-­24274-­3
61. Jang JH, Son Y, Kang SS, Bae CS, Kim JC, Kim SH, Shin T, Moon C (2015)
Neuropharmacological potential of Gastrodia elata Blume and its components. Evid Based
Complement Alternat Med 2015:309261. https://doi.org/10.1155/2015/309261
62. Han YJ, Je JH, Kim SH, Ahn SM, Kim HN, Kim YR, Choi YW, Shin HK, Choi BT (2014)
Gastrodia elata shows neuroprotective effects via activation of PI3K signaling against oxidative
glutamate toxicity in HT22 cells. Am J Chin Med 42(4):1007–1019. https://doi.org/10.1142/
S0192415X14500633
63. Azam F (2010) Therapeutic potential of free radical scavengers in neurological disorders.
Handbook of free radicals: formation, types and effects. Nova Publishers, New York, pp 57–97
Plant-Derived Drugs for Alzheimer’s Disease and Other Neurological Disorders 1345

64. Dorri M, Hashemitabar S, Hosseinzadeh H (2018) Cinnamon (Cinnamomum zeylanicum) as

an antidote or a protective agent against natural or chemical toxicities: a review. Drug Chem
Toxicol 41(3):338–351. https://doi.org/10.1080/01480545.2017.1417995
65. Liu S, Yang L, Zheng S, Hou A, Man W, Zhang J, Wang S, Wang X, Yu H, Jiang H (2021) A
review: the botany, ethnopharmacology, phytochemistry, pharmacology of Cinnamomi cortex.
RSC Adv 11(44):27461–27497. https://doi.org/10.1039/D1RA04965H
66. Deshpande P, Gogia N, Singh A (2019) Exploring the efficacy of natural products
in alleviating Alzheimer’s disease. Neural Regen Res 14(8):1321–1329. https://doi.
org/10.4103/1673-­5374.253509
67. Panickar KS, Polansky MM, Graves DJ, Urban JF Jr, Anderson RA (2012) A procyanidin
type A trimer from cinnamon extract attenuates glial cell swelling and the reduction in glu-
tamate uptake following ischemia-like injury in vitro. Neuroscience 202:87–98. https://doi.
org/10.1016/j.neuroscience.2011.11.051
68. Modi KK, Jana M, Mondal S, Pahan K (2015) Sodium benzoate, a metabolite of cinnamon
and a food additive, upregulates ciliary neurotrophic factor in astrocytes and oligodendrocytes.
Neurochem Res 40(11):2333–2347. https://doi.org/10.1007/s11064-­015-­1723-­x
Properties and Mechanism
of Antimicrobial Agents
from Plant-­Derived Essential Oils

Afroze Naveed Basha, Ramya Subramanian, Kandeepan Chithan,

Gopinath Gurulingam Vincent, Karthigeyan Murugesan,
Ananthavalli Ramachandran, Sivakumar Pethanan, Mani Panagal,
Chella Perumal Palanisamy, and Ramaraj Jayakumararaj

1 Introduction

Essential oils (EOs), secreted by plants, are primarily meant for various physiologi-
cal, ecological and defence activities. They belong to various classes, that is, iso-
lates of fatty acids, isoprenoids and phenolic complexes, and can be secreted by
various organs of plants. The EO market globally has been predicted to grow at a
compound annual growth rate (CAGR) of ~8–10% and will reach a staggering fig-
ure in excess of USD ten billion in the next 5 years or so. Essential oil contents in
different plant species are influenced by genetic and climatic conditions; the same
plant species show different constituents in different ecoclimatic areas. Plants from
tropical climates possess highly effective antimicrobial components that can be

A. N. Basha · K. Chithan
PG Department of Zoology, Arulmigu Palaniandavar College of Arts & Culture, Palani, Tamil
Nadu, India
R. Subramanian
The Thavaram Trust, Madurai, Tamil Nadu, India
G. G. Vincent · K. Murugesan · A. Ramachandran · S. Pethanan
Department of Zoology, Arumugam Pillai Seethai Ammal College, Tiruppathur, Tamil Nadu,
India
M. Panagal
Department of Biotechnology, Annai College of Arts and Science, Kumbakonam, Tamil
Nadu, India
C. P. Palanisamy (*)
State Key Laboratory of Biobased Materials and Green Paper Making, School of Food
Science and Engineering, Qilu University of Technology, Shandong Academy of Sciences,
Jinan, Shandong, China
R. Jayakumararaj (*)
Department of Botany, Government Arts College, Madurai, Tamil Nadu, India

© The Author(s), under exclusive license to Springer Nature 1347

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_56
1348 A. N. Basha et al.

used to combat diseases of tropical climates. Chemotypic and genotypic variabili-

ties in plants, indicating the presence of some environment specific bio-molecules
with high medicinal value have been considered better than antibiotics for disease
control.
Besides, EOs from different plant species have shown importance in food and
cosmetics. These have been used as medicine since ancient times due to their struc-
ture–activity relationship. EOs are aromatic oily liquids obtained from flowers,
buds, seeds, leaves, twigs, barks, woods and roots of various plants. The term
‘essential’ is derived from ‘essence’, which means smell or taste and relates to the
property of these substances providing specific flavours [8]. These are complex
mixtures of different organic compounds, which possess the diverse antimicrobial
potential and are distributed throughout the plant kingdom occurring in about 60
angiosperm families [7].
The families are Lamiaceae, Rutaceae, Geraniaceae, Apiaceae, Aspetaceae,
Lauraceae, Fabaceae and Poaceae [32]. EOs are used for other purposes including
flavouring, perfuming, food preservation, alternative medicine and natural therapy
[51]. EOs target microbial strains both in vivo and in vitro and possess anticancer
and antioxidant properties [5, 41]. EOs can be isolated as single or in combination
without any change in their chemical composition and are obtained by distillation of
leaves, fruits, flowers, stem, flower bud or peel and roots [10]. These are also
obtained by fractionation or rectification and steam distillation.

1.1 Lectins and Polypeptides

Lectins and peptides are positively charged biomolecules with disulphide bonds and
inhibit microbial growth. Both work upon microbial membranes and form ion chan-
nels competitively and inhibit microbial proteins and bind with polysaccharide
receptors [31]. Thionin, a peptide commonly isolated from barley and wheat, con-
tains 47 amino acid residues [39]. It is highly toxic to yeast and Gram-positive
bacteria [16]. Another peptide Febatin isolated from faba beans contains 47 amino
acid residues, structurally similar to thionin and effective against Escherichia coli,
Pseudomonas aeruginosa and Enterococcus hirae. Few plant species contain phen-
ylpropanoids as EO constituents, which are made up of a chain of three carbons
bound to an aromatic ring of six carbons and are mainly derived from phenylala-
nine [61].

1.2 Alkaloids

Another group of plant-derived heterocyclic nitrogen compounds are alkaloids,

mostly used in medicine (Fig. 1). Morphine, an alkaloid, isolated from the opium
poppy Papaver somniferum is used for the treatment of bacterial and viral diseases
and codeine and heroin are its derivatives [11]. Diterpenoids (alkaloids), commonly
Properties and Mechanism of Antimicrobial Agents from Plant-Derived Essential Oils 1349

Fig. 1 Some of potential alkaloids from medicinal plants

isolated from the plants of the buttercup family, have shown antimicrobial proper-
ties [44]. Solamargine, a glycoloid from the berries of Solanum khasianum, is useful
against HIV infection [38]. Some alkaloids have microbiocidal effects and are
active against Giardia, Entamoeba species and diarrhoea [20]. Berberine (an alka-
loid) is potentially used against trypanosomes [18].

1.3 Phenolic Compounds

Phenolic compounds are highly active phytochemicals with immense antimicrobial

potential. These chemicals possess a single phenolic ring; cinnamic acid and caffeic
acid are the most commonly occurring phenolic compounds in plants and possess
potent antimicrobial activity [30]. Terragon and thyme are also effective against
microorganisms [2]. Hydroxylated phenols exhibit activity against microorganisms.
These are highly oxidized phenols which inhibit enzyme activity in microbes.
Eugenol, a polyphenol isolated from olive oil, is a potent antibacterial and antifun-
gal agent [45].

1.4 Quinones

Quinones are highly reactive aromatic compounds with two ketone substitutions.
These are formed before the melanin synthesis pathway in the skin and are ubiqui-
tous. Quinones appear after roughing reaction during fruit/vegetable chopping/
1350 A. N. Basha et al.

cutting [57]. Ubiquinone, known as a coenzyme, is an oxidation reduction com-

pound and helps in electron transport chain. Vitamin K is a derivative of quinone
and possesses antihemorrhagic activity due to its oxidation [53]. Quinones form
complexes with nucleophilic amino acids and exhibit antimicrobial activity.
Antianthraquinones isolated from Cassia italica were highly active against Bacillus
anthracis, Cornybacterium pseudo apothecium, Pseudomonas aeruginosa and
pseudomalliae. Hypercicum, an anthraquinone from Hypericum perforatum, works
as antidepressant [11].

1.5 Flavonoids, Flavones and Flavanols

Flavonoids occur as C6-C3 units linked to an aromatic ring. These are hydroxylated
phenolic substances, synthesized in plants in response to microbial infection.
Flavonoids are highly active against viruses (Fig. 2). These are phenolic structures,
which contain a carboxyl group. Flavonoids are formed after the addition of a
3-hydroxyl group. Glycyrrhizin, chrysin and swertifracheside are active against
HIV viruses [46]. Quercetin, a flavonoid compound, was effective against HSV-1,
Poliovirus-1 and Parainfluenza virus 3, while naringin, hesperetin and catechin
were less effective than quercetin. Galangin from Helichrysum aureointens was
effective against HSV-1 viruses and Gram-positive bacteria. Alpinumisoflavone is
effective against schistosomal infection. The mode of action of both flavones and
flavonoids is membrane disruption and enzymatic bindings, which depends on
hydroxylation due to the presence of hydroxyl groups on their rings [60].

Fig. 2 Some of active flavonoids from medicinal plants

Properties and Mechanism of Antimicrobial Agents from Plant-Derived Essential Oils 1351

1.6 Tannins

Tannin is a group of polymeric phenolic substances used for the tanning of leather
and the precipitation of gelatin. These possess astringent properties and are present
in wood, bark, leaves, fruits and roots. These are very strong antimicrobial agents.
Tannins act by penetration through the membrane, adhesion, competitive inhibition
of enzymes and binding to cellular envelops. Tannins inhibit the growth of larvae,
affect moulting in insects and are inhibitors of reverse transcriptase enzyme. There
are two categories of tannins, hydrolyzable (gallic acid) and condensed (proantho-
cyanidins) [21].

1.7 Coumarins

Coumarins are formed by the fusion of benzene and pyrene rings and show diverse
biological activity (anti-inflammatory, antithrombic and vasodilatory). Warfarin is
taken as an oral anticoagulant and used as a potential rodenticide. Coumarins also
show antiviral properties and are found effective against Candidiasis [19].

1.8 Terpenoids

Terpenoids are the most diversified group of secondary plant metabolites, derived
from a basic structure of five carbons (C5H8) commonly known as isoprenoid unit.
Terpenoids are classified on the basis of isoprenoid units found in the skeleton.
These are phenylpropanoids that interact with the cell membrane and accumulate in
the lipidic bilayer of bacteria [34] isolated diterpenoids from Sagittaria pygmaea.
Terpenoids or terpenes are active against bacteria, viruses and protozoa, while trit-
erpenoids like betulinic acid significantly inhibit the growth of the HIV virus. The
ethanol-soluble fractions of purple clove yield terpenoids, which show excellent
activity against Bacillus subtilis, Staphylococcus aureus and Gram-negative bacte-
ria as well as Candida albicans. Tricholorbdat-A, diterpenoid, directly inhibits
Helicobacter pylori activity [11].

2 Mechanism of Action of PEOs

Essential oils are highly potent phytochemicals, with high antimicrobial potential in
comparison to synthetic drugs as proved by low MIC values obtained in vitro.
Further, these natural products can stop genetic transformation in microbes. These
phytochemicals are active against more than one microbial strain while antibiotics
1352 A. N. Basha et al.

are not. These are either water or buffer soluble, show the least residual effect in the
body and do not show molecular catalysis and cross-reactivity [47]. These phyto-
chemicals possess mixed functional groups and are too complex in their structure;
therefore, microbes cannot develop resistance easily. EOs are multicomponent plant
products and contain different chemical groups such as pinene, camphor, limonene,
linalool, pyrogallol and chamaecynone [55].
All such components show diverse action mechanisms. EOs in eukaryotic cells
act as prooxidants, affect cell membrane permeability and inhibit the function of
cell organelles such as mitochondria. An important characteristic of EOs and their
components is their binding with lipids of bacterial cell membranes and mitochon-
drial cell structures making them more permeable to water [28]. Phenolic com-
pounds contain a hydroxyl group which acts as a transmembrane carrier of
monovalent cations and protons. This system works well for ionophore antibiotics
but not for aromatic compounds such as methanol. Phenols due to a selection of
high acidity and dislocated electron system release protons from the hydroxyl
group [59].
Undissociated covalent ions diffuse out, come across the cytoplasmic membrane
and dissociate to release proton in microbial cells, while terpenoids and phenylpro-
panoids interact with the bacterial cell membranes [13]. This activity may be due to
the hydrophobic nature of cyclic hydrocarbons which allows them to interact with
the bacterial cell membrane and occupy space between fatty acid chains and accu-
mulate in the lipid bilayer. This interaction leads to some important conformational
changes in the membrane structure, affecting their stability and resulting in the
expansion and formation of pore and fluidification of bacterial cells [22].
Thus, bacterial cells face leakage of ions across the cell membrane and lose
transmembrane ionic gradient very fast. Bacterial cells, however, restore the ionic
disturbances and counterbalance by using ionic pumps that check the cell death but
take a large portion of energy and make cell growth very slow [12]. Phenolic com-
ponents of EOs also interact with chemical groups of proteins and enzymes, and
most do so with protein through hydrogen bridges and ionic or hydrophobic interac-
tions while non-phenolic compounds interact with other functional groups [25].
Cinnamaldehyde, a natural constituent of Cinnamon, activates bacterial nucleic
acids and proteins by alkylation or formation of cross bridges. It also inhibits RNA,
DNA and protein synthesis in bacterial cells. It is also possible that EOs might
coagulate some cell constituents and cause denaturation by ionic release. The sulf-
hydryl groups in active components of EOs may interact more favourable against
the bacterial cells. Thus, garlic oil is more suitable than any other EO to kill both
Gram-negative and Gram-positive bacteria. A few chemical groups such as ketone,
aldehyde and acid may also interact in a better way with bacterial cells and their
components and show high antimicrobial activity but their major mode of action is
unknown [15].
Few oil components in combination with others might show synergistic effects
against microbes. Oxidized phenolic compounds were more toxic to bacterial cells.
Flavonoids lacking hydroxyl group very effectively disrupted the microbial mem-
brane. However, more hydroxylated phenolic compounds act on the membrane
Properties and Mechanism of Antimicrobial Agents from Plant-Derived Essential Oils 1353

surface due to the presence of the hydroxyl group. Flavonoids are highly effective
antimicrobial substances and inhibit the growth of a variety of microorganisms.
These form complexes with extracellular and soluble bacterial proteins and also
bind to bacterial cell walls. Catechins are flavonoids that inhibit the growth of Vibrio
cholerae, Streptococcus and Shigella. Flavonoids were also found inhibitory to a
number of viruses. The mechanism of action of terpenoids is not well understood
but it is believed to be involved in membrane disruption due to their lipophilic activ-
ity [50].
Capsaicin, a terpenoid, has a wide range of biological activities in humans affect-
ing the neural and digestive systems. Gram-positive bacteria possess a thick proteo-
glycan layer which does not respond to EOs. Gram-negative bacteria inhibit the
membrane disruption action of many EOs and show increased resistance against
drugs. Klebsiella pneumoniae was most resistant to many EOs but least resistant to
oregano Gram-negative K. pneumoniae possess an innate defence which prevents
entry of EO and does not allow access to the fragile inner membrane [23].

3 Antimicrobial Agents from Essential Oils

Essential oils from higher and aromatic plants have shown growth inhibitory poten-
tial against microbes due to the presence of certain secondary metabolites. People
in different parts of the world traditionally use EOs (Table 1) and their components
for various microbial infections related to skin, fever, gut and respiratory tract [26].
Clove, rosemary and lavender oils have shown strong antibacterial and antifungal
properties. Cinnamon oil possesses anti-diabetic and anti-inflammatory activity,
while lemon and peppermint show anticancer activity. EOs from Carum carvi,
Coriandrum sativum and Foeniculum vulgare effectively work against various
pathogenic bacteria [49].
A large number of EOs have been found effective against Gram-positive and
Gram-negative bacteria. Oil from Melaleuca alternifolia showed activity against
E. coli, S. aureus and skin pathogens. Few EOs and their major constituents were
found effective in the gaseous state against Haemophilus influenzae, Streptococcus
pneumoniae, S. pyrogens and Staphylococcus aureus [24]. Plant EOs (PEOs) have
been used traditionally for the eradication of respiratory tract infection and as ethi-
cal medicines by the tribals. These have also been used in inhalation therapy for
chronic bronchitis, sinusitis and respiratory tract mycoses. In aromatherapy, inhaled
EO vapours augment the output of respiratory tract fluid and maintain the ventila-
tion and drainage of the sinuses [9].
Essential oils also restore tracheal choking and reduce the intensity of asthma
attacks. EO from Mentha species shows antimicrobial and antioxidant activity [41],
due to the presence of free radical scavenging capacity (RSC). EOs from three spe-
cies M. aquatica, M. longifolia and M piperita exhibited strong activity against
E. coli strains. EOs from Hypericum scabrum and Hypericum scarboides showed
broad-spectrum antimicrobial activity against disease pathogens at a concentration
1354 A. N. Basha et al.

Table 1 Some EOs from medicinal plants against pathogenic microorganisms

EOs from Extraction
S. No. Medicinal plants plant parts methods Microorganisms References
1. Carum carvi L. Seeds Simple steam Bacillus cereus, [3]
distillation Bacillus subtilis,
Bacillus megaterium,
Staphylococcus aureus,
E. coli,
Pseudomonas sp.,
Salmonella typhi,
Salmonella paratyphi,
Shigella dysenteriae,
Vibrio cholerae
2. Coriandrum Whole Stream E. coli, [54]
sativum L. plant distillation Klebsiella pneumoniae,
Salmonella typhimurium,
Pseudomonas
aeruginosa,
Acinetobacter
baumannii,
B. cereus,
Staphylococcus aureus,
Enterococcus faecalis,
S. aureus SA08,
S. aureus isolates
(MRSA 10/08 and MRSA
12/08)
3. Foeniculum Dried Hydrodistillation Candida albicans, [49]
vulgare L. aerial Saccharomyces
parts and cerevisae,
fruits Staphylococcus aureus,
Listeria monocytogenes,
Bacillus cereus,
Salmonella sp.
4. Melaleuca Leaves Steam distillation Lactobacillus spp., [9]
alternifolia L. and Micrococcus luteus,
terminal Peptostreptococcus
branches anaerobius,
Porphyromonas
endodentalis,
P. gingivalis,
Prevotella spp.,
Prevotella intermedia,
Propionibacterium
acnes,
Proteus vulgaris,
Pseudomonas
aeruginosa,
Staphylococcus aureus
(continued)
Properties and Mechanism of Antimicrobial Agents from Plant-Derived Essential Oils 1355

Table 1 (continued)
EOs from Extraction
S. No. Medicinal plants plant parts methods Microorganisms References
5. Mentha Aerial Hydrodistillation E. coli, [43]
aquatica L. parts Salmonella enteritidis,
Salmonella typhi,
Micrococcus flavus,
Staphylococcus aureus,
Staphylococcus
epidermis,
Bacillus subtilis
6. Mentha Aerial Hydrodistillation E. coli, [43]
longifolia L. parts Salmonella enteritidis,
Salmonella typhi,
Micrococcus flavus,
Staphylococcus aureus,
Staphylococcus
epidermis,
Bacillus subtilis
7. Mentha piperita Aerial Hydrodistillation E. coli, [43]
L. parts Salmonella enteritidis,
Salmonella typhi,
Micrococcus flavus,
Staphylococcus aureus,
Staphylococcus
epidermis,
Bacillus subtilis
8. Hypericum Stems, Hydrodistillation E. coli, [4]
scabrum L. flowers Bacillus brevis,
and leaves Bacillus cereus,
Streptococcus pyogenes,
Pseudomonas
aeruginosa,
Staphylococcus aureus,
Candida albicans
9. Hypericum Stems, Hydrodistillation E. coli, [4]
scabroides flowers Bacillus brevis,
Robson & and leaves Bacillus cereus,
Poulter. Streptococcus pyogenes,
Pseudomonas
aeruginosa,
Staphylococcus aureus,
Candida albicans
10. Hypericum Stems, Hydrodistillation E. coli, [4]
triquetrifolium flowers Bacillus brevis,
Turra. and leaves Bacillus cereus,
Streptococcus pyogenes,
Pseudomonas
aeruginosa,
Staphylococcus aureus,
Candida albicans
(continued)
1356 A. N. Basha et al.

Table 1 (continued)
EOs from Extraction
S. No. Medicinal plants plant parts methods Microorganisms References
11. Sida cordifolia Fresh Steam distillation Staphyllococus aureus, [36]
L. leaves Staphyllococus
epidermidis, Candida
guilliermondii and
Trichosporon inkin
12. Hedychium Fresh Hydrodistillation Staphylococcus aureus, [14]
venustum rhizomes Bacillus cereus,
B. subtilis,
Serratia marcescens,
Pseudomonas
fluorescens,
P. aeruginosa,
Klebsiella pneumoniae,
Proteus vulgaris,
Escherichia coli,
Salmonella typhi
13. Hedychium Fresh Hydrodistillation Staphylococcus aureus, [14]
spicatum var. rhizomes Bacillus cereus,
acuminatum B. subtilis,
Serratia marcescens,
Pseudomonas
fluorescens,
P. aeruginosa,
Klebsiella pneumoniae,
Proteus vulgaris,
Escherichia coli,
Salmonella typhi
14. Hedychium Fresh Hydrodistillation Staphylococcus aureus, [14]
coronarium rhizomes Bacillus cereus,
B. subtilis,
Serratia marcescens,
Pseudomonas
fluorescens,
P. aeruginosa,
Klebsiella pneumoniae,
Proteus vulgaris,
Escherichia coli,
Salmonella typhi
15 Hedychium Fresh Hydrodistillation Staphylococcus aureus, [14]
flavescens rhizomes Bacillus cereus,
B. subtilis,
Serratia marcescens,
Pseudomonas
fluorescens,
P. aeruginosa,
Klebsiella pneumoniae,
Proteus vulgaris,
Escherichia coli,
Salmonella typhi
Properties and Mechanism of Antimicrobial Agents from Plant-Derived Essential Oils 1357

of 80 μL/mL. EO from Lippia sidoides contained carvacrol and thymol which were
effective against oral pathogens [4, 43].
Oils of Lemon and lime leaves were effective against infectious bacterial strains.
PEOs from Sida cordifolia (Malvaceae) contain volatile constituents active against
S. aureus, S. epidermidis, C. guilliermondii and Trichosporon inkin. PEOs from
Sida cordifolia are commonly used for the treatment of rheumatism, inflammation,
asthma and nasal congestion and were found effective against S. aureus and S. epi-
dermiditis at 8% (v/v) dose. Sesame seed oil from Sesame radiatum and Sesamum
indicum is used for wound healing; seeds are used as the staple food by local popu-
lation in Nigeria. It is cultivated by local farmers for obtaining seed oil [36].
EOs from the rhizome of Hedychium species possess bactericidal and fungicidal
activity. Oil is also used for the treatment of stomach ailments and infections. Oil of
H. coronarium is used for the treatment of swelling and inflammation in tumour.
Oils from H. spicatum, H. coronarium, H. acuminatum, H. gardenarium and
H. aurantiacum possess antimicrobial activity. Rhizome oils from H. coronarium
and H. spicatum var. acuminatum were active against S. aureus (MTCC 96), Bacillus
cereus (MTCC 430), B. subtilis (MTCC 491), Serratia marcescens (MTCC-97),
Pseudomonas fluorescens (MTCC 103), Salmonella typhi (MTCC-733) and
Candida albicans (MTCC 227). Day jasmine, Cestrum diurnum (Solanaceae),
Citrus nastudaidai and Hayata peel oil were highly effective against pathogenic
bacteria and proved to be strong antimicrobial agents [14].
Eugenol, a well-characterized oil constituent found in clove oil, was highly bac-
teriostatic and fungistatic. Olive oil shows bactericidal activity against harmful
intestinal microbiota (Clostridium perfringens and E. coli); it is also active against
beneficial microorganisms, Lactobacillus and Bifidobacterium bifidum. The antimi-
crobial compounds in olive oil are hydroxytyrosol, vanillic acid, p-coumaric acid,
ferulic acid and vanillin, which are highly effective against Listeria monocytogenes,
S. aureus, Salmonella enterica and Yersinia species. Juniper berry oil possesses
broad-spectrum pharmacological activities against bacterial and fungal strains. Its
strongest fungicidal activity was recorded against Candida species. EOs from the
leaves of Toddalia asiatica, Solidago microglossa and Cassia alata have shown
inhibitory activity against Gram-negative and Gram-positive bacteria [42].
Garlic is traditionally used as a natural medicine for the treatment of various
diseases. Its oil and powder were effective against bacterial pathogens by virtue of
systemic distribution in the small intestine. Garlic and its compounds are safer than
antibiotics in eradicating the infection caused by Helicobacter pylori. Aqueous gar-
lic extracts with omeprazole showed a synergistic effect against Helicobacter pylori.
Most of the commercial garlic preparations, available in the market, contain garlic
oil (GO) and allicin. Allicin derivatives allyl and methyl sulphide showed very high
antimicrobial potential and were effective against stomach cancer. Its diallyl com-
pounds were effective against H. pylori. Chile peppers contain provitamins A, E and
several B and are used in flavouring food materials. Its constituent capsaicin (terpe-
noid) showed biological activity against disease-causing pathogens in humans. It is
used as an analgesic and shows bactericidal activity against H. pylori [29].
1358 A. N. Basha et al.

Diterpenes from spices act as broad-spectrum antibacterial and antifungal agents.

A terpenoid from the ethanolic fraction of purple prairie clover has strong activity
against B. subtilis, S. aureus, Gram-negative bacteria and Candida albicans. Juniper
EO (Juniperus communis) (L) has shown strong activity against Gram-positive and
Gram-negative bacteria and Candida spp. (MIC from 0.78% to 2% v/v). EOs from
different Mentha species, that is, M. longifolia (L.), M. aquatica and M. piperita
(L.), exhibited strong activity against E. coli. Mixtures of cinnamon and clove oil
were growth inhibitory to food spoilage microorganisms, such as Aspergillus flavus,
Penicillium roqueforti, Mucor plumbus, Eurotium spp., Debarrycomyes hanseni,
Pichia faciens, Zygosaccharomyces rouxii, Candida lipolytica, S. aureus and
Pedicoccus hatiophillus [48].
Similar activity was found in Trigonella foenum-graecum and Cleome viscosa
seeds. EOs from Hypericum scabrum, H. scabroides and H. triquetrifolium exhib-
ited broad-spectrum antibacterial activity; the MIC value was 80 μL/
mL. Dracocephalum foetidum EO exhibited strong activity against methicillin-­
resistant S. aureus (MRSA) at a low concentration [33]. EOs from Thymus vulgaris
and Origanum vulgare were highly active against Listeria monocytogenes, S. aureus,
E. coli, Pseudomonas aeruginosa and Salmonella enteritidis at a low dose of
0.017–0.26 μL/cm3 [35]. MID values of horseradish (Armoracia rusticana) were
0.0083 μl/cm3 and of garlic oil (Allium sativum) 0.0083–0.53 μl/cm3 against the
above strains. Sida cordifolia showed inhibitory activity against S. aureus, S. epi-
dermidis, Candida guilliermondii and Trichosporon inkin. Olive oil shows activity
against Clostridium perfringens, E. coli, L. acidophilus and Bifidobacterium bifi-
dum [27].
EOs from M. piperita and M. aquatica have shown low MIC and MFC (4 μL/
mL) values against Trichophyton tonsurans and Candida albicans. α-Terpineol
(20.8%) from Tagetes minuta was active against bacteria and fungi. Oleoresin from
Piper cubeba has shown activity against Aspergillus flavus. Antimicrobial activity
was reported in tea tree, clove, rosemary, peppermint, bay basil and fennel EOs and
almond. Besides, wintergreen, eucalyptus, clove and sage EOs have toxic and irri-
tant properties [40].
EOs from leaves and flowers of Inula viscosa (Asteraceae) [6], Artemisia veloto-
rum, Lavandula augustifolia and Ocimum gratissimum have shown antifungal
activity and are currently in use as popular therapeutic medicines. Linalool from
Lippia alba exhibited high antimicrobial activity. The major chemotypes were dis-
tinguished for lemon peel oils: limonene, limonene/gamma-terpinene, linalyl ace-
tate/limonene and sabinene/linalool, gamma have shown strong antimicrobial
activity. The characteristic aromatic compounds of Citrus natsudaidai EO contain
myrcene, linalool, alpha-pinene, beta-pinene, limonene, nonanal, gamma-terpinene,
germacrene D and perillyl alcohol.
Essential oils isolated from the leaves and flowers of Eucalyptus (Myrtaceae)
and Inula viscosa (Asteraceae) have shown antifungal activity. EOs isolated from
many plant species possess antibacterial and antifungal activities. Volatile constitu-
ents isolated from leaves of Chamaecyparis formosensis (Matsum) contain (85%) α
pinene, which inhibits the growth of wood decay fungi, Laetiporus sulphureus and
Properties and Mechanism of Antimicrobial Agents from Plant-Derived Essential Oils 1359

Trametes versicolor at a concentration of 50 and 100 μg/mL. Chamaecynone

showed an antifungal index of 88.2% and 67.3% for Laetiporus sulphureus at 50 μg/
mL concentration [1].
EOs from Callicarpa americana were also antifungal [58]. Gurjnene is a major
antifungal constituent of the EO of Calea clematidea. Copaene, mytenol, germa-
cene-­D and α-murold have also shown strong antibacterial activity. EOs from
Thymus pulegoides, T. pulgaris and T. zygis have shown activity against Candida,
Aspergillus and dermatophytes. T. pulegiodes EO also showed MIC values ranging
from 0.04 to 0.33 mg/mL against the above fungi. EOs from Origanum vulgare,
Hirtum, Mentha spicata, Lavandula angustifolia, Salira fruticosa and Origanum
virens were active against human pathogenic fungi. Lippia sidosoides was active
against Candida spp. and Microsporum canis [17]. MICs ranged from 4 to 70 mg/
mL against M. canis and MFCs from 9 to 150 mg/mL, MICs against Candida spp.
ranged from 620 to 2500 mg/mL. Main constituents of L. sidosoides EO were thy-
mol (59.65%), E-caryophyllene (10.60%) and p-cymene (9.08%).
The essentiao oli (EO) from Salvia spinosa L was found effective against
Candida albicans and Aspergillus niger. S. spinosa had cineol, α-ocimene, ger-
macrene, butyl tiopene and trans caryophyllene it’s constituent. Similar activity was
reported in S. spinosa, S. cryptantha, S. multicaulis and S. tomentosa [56].
Artimesia arborescence EOs showed cytotoxicity against HSV-1 and HSV-2
viruses at 2.4 and 4.1 μg/mL. This plant is also used for the treatment of malaria,
hepatitis, cancer, inflammation and fungal and bacterial infections. Methanolic
extract of A. cardifolia inhibits HIV-1 protease activity. It contains tripcoumaroyl-
spermidine [37]. Sandalwood oil (S. album) also works against HSV-1 and HSV-2.
Tea tree oil (Melaleuca alternifolia) was effective against the TMV virus at a low
concentration, while Eucalyptus oil (Eucalyptus gliovulus), Manuka oil
(Leptospermum scoparium) and Peppermint oil were very effective against Herpes
simplex virus-1 and 2. Thyme PBNPs were effective against HSV type 1 and ginger
(Ginger officinalis) and Santolina (Santolina insularis) were active against N HSV
viruses. EO from Houttuynia cordata was active against HSV-1, influenza and
human immunodeficiency virus. Flavones were inhibitors of HIV-1 proteinase,
while lectins and tannins worked against the HIV-1 virus. Maprounea africana acts
as a potent inhibitor of HIV-1 RT. Artemisia arborescens showed virucidal effects
as determined by plaque reduction assay. Besides this plant, EOs have also shown
antiviral activity against HSV-1 [52].

4 Future Perspectives and Conclusion

Viral epidemic is a global concern, mandating an urgent need for antivirals. Some
viral diseases can be cured by antiviral drugs, but others still don’t have any vac-
cines/drugs. Most of the approved antiviral drugs are associated with side effects.
This eventually drives the need for the development of plant-based antivirals. Plants
contain a variety of phytochemicals like flavonoids, terpenoids, lignins, alkaloids
1360 A. N. Basha et al.

and coumarins that possess antioxidant activities and help inhibit the viral genome.
Various plant-derived products have been well studied against viruses like herpes
virus, human immunodeficiency virus (HIV), influenza and hepatitis virus. More
recently, Coronavirus disease (COVID-19) caused by a newly identified coronavi-
rus has become pandemic and affected the world’s population severely. However,
there are still less explored phytochemicals for the inhibition of HIV that causes
AIDS. In this chapter, an extensive investigation has been made on the applications
of EOs to control opportunistic infections (OIs) that occur due to bacterial and fun-
gal pathogens in HIV/AIDS patients. In recent years, there has been an increasing
interest in the use of plant-based natural products due to aspects concerning the
safety of synthetic compounds.
In addition to inducing resistance, antibiotics are sometimes associated with
opposing effects such as hypersensitivity, immune suppression and allergic reac-
tions. Therefore, there is a need to develop alternative antimicrobial drugs for the
treatment of OIs. At this point in time, investigations on plants used in traditional
medicines as potential sources of novel antimicrobial compounds gain due
prominence.

References

1. Assarch MH, Jaimand K, Rezaee MB (2007) Chemical composition of the essential oils of six
Eucalyptus species (Myrtacea) from South West of Iran. J Essent Oil Res 6:469–473
2. Bakhtiarizade M, Souri MK (2019) Beneficial effects of rosemary, thyme and tarragon essen-
tial oils on postharvest decay of Valencia oranges. Chem Biol Technol Agric 6:9
3. Begum J, Bhuiyan MNI, Chowdhury JU, Hoque MN, Anwar MN (2008) Antimicrobial activ-
ity of essential oil from seeds of Carum carvi and its composition. Bangladesh J Microbiol
25(2):85–89
4. Botelho MA, Nogueira NA, Bastos GM, Fonseca SG, Lemos TL, Matos FJ, Montenegro D,
Heukelbach J, Rao VS, Brito GA (2007) Antimicrobial activity of the essential oil from Lippia
sidoides, carvacrol and thymol against oral pathogens. Braz J Med Biol Res 40(3):349–356
5. Burt SA, Vlielander R, Haagsman HP, Veldhuizen EJ (2005) Increase in activity of essential
oil components carvacrol and thymol against Escherichia coli O157: H7 by addition of food
stabilizers. J Food Prot 68:919–926
6. Cafarchia C, De-Laurentis N, Milillo MA, Losacco V, Puccini V (2002) Antifungal activ-
ity of essential oils from leaves and flower of Inula viscosa (Asteraceae) by Apulian region.
Parasitologia 44:153–156
7. Calsam Ouattra B, Simard RE, Holley RA, Pictte GJP, Begin A (1997) Antibacterial activ-
ity of selected fatty acids and essential oil against six meat spoilage organism. Int J Food
Microorganism 37:155–162
8. Calsamiglia S, Busquet M, Cardozo PW, Castillejos L, Ferret A (2007) Invited review: essen-
tial oils as modifiers of rumen microbial fermentation. J Dairy Sci 90(6):2580–2585
9. Carson CF, Mee BJ, Riley TV (2002) Mechanism of action of Melaleuca alternifolia (tea tree)
oil on Staphylococcus aureus determined by time-kill, lysis, leakage, and salt tolerance and
electron microscopy. AAC 46(6):1914–1920
10. Cosentino S, Barra A, Pisano B, Cabizza M, Pirisi FM, Palmas F (2003) Composition and
antimicrobial properties of Sardinian Juniperus essential oils against food borne pathogens and
spoilage microorganisms. J Food Prot 66(7):1288–1291
Properties and Mechanism of Antimicrobial Agents from Plant-Derived Essential Oils 1361

11. Cowan MM (1999) Plant products as antimicrobial agents. Clin Microbiol Rev 12:564–582
12. Cox SD, Mann CM, Markam JL (2001) Interaction between components of the essential oil of
Melaleuca alternifolia. J Appl Microbiol 91:492–497
13. Dorman HJ, Deans SG (2000) Antimicrobial agents from plants: antibacterial activity of plant
volatile oils. J Appl Microbiol 88(2):308–316
14. Faleiro ML, Miguel MG, Ladeiro F, Vanancio F, Tavarses R, Brito JC, Figueiredo AC, Barrosa
JG, Pedro LG (2003) Antimicrobial activity of essential oils isolated from Portuguese endemic
species of Thymus. Lett Appl Microbiol 36:35–40
15. Feldberg RS, Chang SC, Kotik AN, Nadler M, Neuwirth Z, Sundstrom DC, Thompson NH
(1988) In vitro mechanism of inhibition of bacterial cell growth by allicin. Antimicrob Agent
Chemother 32(12):1763–1768
16. Fernandez MA, Garcia MD, Saenz MT (1996) Antibacterial activity of the phenolic acids frac-
tions of Scrophularia frutescens and Scrophularia sambucifolia. J Ethnopharmacol 53(1):11–14
17. Fontenelle ROS, Morias SM, Brito EHS, Kerntopt MR, Brilhante RSN, Cordeiro RA, Tome
AR, Queiroz MGR, Nascimento NRF, Sidrim JJC, Rocha MEG (2007) Chemical composi-
tion, toxicological aspects and antifungal activity of essential oil from Lippia sidoides Cham.
J Antimicrob Chemother 59:934–940
18. Freiburghaus F, Kaminsky R, Nkunya MHH, Brun R (1996) Evaluation of African medicinal
trypanocidal activity. J Ethano Pharmacol 55:1–11
19. Garg SS, Gupta J, Sharma S, Sahu D (2020) An insight into the therapeutic applications of
coumarin compounds and their mechanisms of action. Eur J Pharm Sci 152:105424
20. Ghoshal S, Krishna-Prasad BN, Lakshmi V (1996) Antiamoebic activity of Piper longum fruits
against Entamoeba histolytica in vitro and in vivo. J Ethanopharmacol 50:167–170
21. Girard M, Bee G (2020) Invited review: Tannins as a potential alternative to antibiotics to
prevent coliform diarrhea in weaned pigs. Animal 14(1):95–107
22. Griffin SG, Wyllie SG, Markham JL, Leach DN (1999) The role of structure and molecu-
lar properties of terpenoids in determining their antimicrobial activity. Flavour Fragrance J
14(5):322–332
23. Gustafson E, Cox SD, Liew SY, Wyllie SG, John R, Warmington J (2001) The bacterial mul-
tiple antibiotic resistant (Mar) phenotype leads to increased tolerance to tea tree oil. Pathology
33(2):211–215
24. Inouye S, Takizawa T, Yamaguchi H (2001) Antibacterial activity of essential oils and their
major constituents against respiratory tract pathogens by gaseous contact. J Antimicrob
Chemotherap 47(5):565–573
25. Juven BJ, Kanner J, Schved F, Weisslowicz H (1994) Factors that interact with the antibacterial
action of thyme essential oil and its active constituents. J Appl Bacteriol 76:626–631
26. Karaman S, Digrak M, Ravid U, Ilcim A (2001) Antibacterial and antifungal activity of the
essential oils of Thymus revolutus Celak from Turkey. J Ethnopharmacol 76(2):183–186
27. Kizil G, Toker Z, Ozen HC, Aytekin C (2004) The antimicrobial activity of essential oils of
Hypericum scabrum, Hypericum scabroides and Hypericum triquetrifolium. Phytother Res
18(4):339–341
28. Knobloch K, Weigand H, Weis N, Schwar HM, Vigenschow H (1986) Action of terpenoids
on energy metabolism. In: Progress in essential oil research: 16th international symposium on
essential oils. De Gruyter, Berlin, pp 429–445
29. Koch HP (1996) Biopharmaceutics of garlic’s effective compounds. In: Koch HP, Lawson P,
Lawson LD (eds) Garlic the science and therapeutic application of Allivum sativum. Williams
and Wilkins, Baltimore, pp 213–220
30. Kumar N, Goe N (2019) Phenolic acids: natural versatile molecules with promising therapeu-
tic applications. Biotechnol Rep (Amst) 24:e00370
31. Kurpe SR, Grishin SY, Surin AK, Panfilov AV, Slizen MV, Chowdhury SD, Galzitskaya OV
(2020) Antimicrobial and amyloidogenic activity of peptides. Can antimicrobial peptides be
used against SARS-CoV-2? Int J Mol Sci 21(24):9552
32. Lawless J (1995) The illustrated encyclopodia of essential oils. UK Elements Book Ltd,
Shafesbury, pp 1–47
1362 A. N. Basha et al.

33. Lee SB, Cha KH, Kim SN, Altantsetseg S, Shatar S, Sarangerel O, Nho CH (2007) The antimi-
crobial activity of essential oil from Dracocephalum foetidum against pathogenic microorgan-
isms. Microbiol 45(1):53–57
34. Liu XT, Pan Q, Shi Y, Williams ID, Sung HH, Zhang Q, Liang JY, Ip NY, Min ZD (2006)
Entrosane and labdane diterpenoides from Sagittaria and their antibacterial activity against
three oral pathogens. J Nat Prod 69(2):255–260
35. Lopez P, Sanchez C, Batlle R, Nerin C (2005) Solid and vapor-phase antimicrobial activities
of essential oils: susceptibility of selected food borne bacterial and fungal strains. J Agric Food
Chem 53(17):6939–6946
36. Lota M, de Rocca Serra D, Tomi F, Jacquemond C, Casanova J (2001) Volatiles components of
peel and leaf oils of lemon and lime species. Biochem Syst Ecol 29:77–104
37. Ma CM, Nakamura N, Hattori M (2001) Inhibitroy effect on HIV-1 protease of tri-­
pcoumaroylspermidine from Artemesia caruifolia and amides. Chem Pharm Bull (Yokyo)
49:915–917
38. McMohan JB, Currens MJ, Gulakowki RJ, Buckheit RWJ, Lackman SC, Michellamine B
(1995) A novel plant alkaloid inhibits human immuno deficiency virus-induce distinct mecha-
nisms. Antimicrob Agents Chemother 39:484–488
39. Méndez J, Blanco L, Lazaro JM, Salas M (1994) Primer-terminus stabilization at the psi 29
DNA polymerase active site mutational analysis of conserved motif TX2GR. J Biol Chem
269(47):30030–30038
40. Mimica-Dukić N, Božin B, Soković M, Mihajlović B, Matavulj M (2003) Antimicrobial and
antioxidant activities of three Mentha species essential oils. Planta Med 69(05):413–419
41. Mimica-Dukic N, Bozin B, Sokovic M, Simin N (2004) Antimicrobial and antioxidant activi-
ties of Melissa officinalis L (Lamiaceae) essential oil. J Agri Food Chem 52(9):2485–2489
42. Morel AF, Dias GO, Poro C, Simionatto E, Stuker CZ, Dalcol II (2006) Antimicrobial activity
of extractives of Solidago microglossa. Fitoterapia 77(6):453–458
43. Oliveira DR, Leitao GG, Santos SS, Bizzo HR, Lopes D, Alviano CS, Alviano DS, Leitao
SG (2006) Ethnopharmacological study of two Lippia species from Oriximiná, Brazil. J
Ethnopharmacol 108(1):103–108
44. Omulokoli E, Khan B, Chhabra SC (1997) Antiplasmodial activity of four Kenyan medicinal
plants. J Ethanopharmacol 56:133–137
45. Othman L, Sleiman A, Abdel-Massih RM (2019) Antimicrobial activity of polyphenols and
alkaloids in middle eastern plants. Front Microbiol 10:911
46. Parhi B, Bharatiya D, Swain SK (2020) Application of quercetin flavonoid based hybrid nano-
composites: a review. Saudi Pharm J 28(12):1719–1732
47. Patra AK (2012) An overview of antimicrobial properties of different classes of phytochemi-
cals. Diet Phytochem Microb:1–32
48. Pepeljnjak S, Kosalec I, Kalodera Z, Blazevic N (2005) Antimicrobial activity of Juniper berry
essential oil (Juniperus communis L, Cupressaceae). Acta Pharma 55:417–422
49. Prabuseenivasan S, Jayakumar M, Ignacimuthu S (2006) In vitro antibacterial activity of some
plant essential oils. BMC Comp Altern Med 6(1):39–45
50. Reuter HD, Koch JP, Lawson L (1996) Therapeutic effects and application of garlic and its
preparations. In: Koch HP, Lawson LD (eds) Garlic: the science and therapeutic application of
Allium sativum L and related species. William Wilkins, Baltimore, pp 135–212
51. Reynolds JEF (1996) Martindale- the extra pharmacopoeia 31st Ed. Royal Pharmaceautical
Society of Great Britian, London
52. Saddi M, Sanna CA, Chisu F, Casu L, Bonsignore L, De-Logu A (2007) Antiherpevirus activ-
ity of Artemisia arborescens essential oil and inhibiton of lateral diffusion in Vero cells. Ann
Clin Micro Antimicrob 6:10–16
53. Saini R (2011) Coenzyme Q10: the essential nutrient. J Pharm Bioallied Sci 3(3):466–467
54. Silva F, Ferreira S, Queiroz JA, Domingues FC (2011) Coriander (Coriandrum sativum L.)
essential oil: its antibacterial activity and mode of action evaluated by flow cytometry. J Med
Microbiol 60:1479–1486
Properties and Mechanism of Antimicrobial Agents from Plant-Derived Essential Oils 1363

55. Soković M, Glamočlija J, Marin PD, Brkić D, Griensven LJLD (2010) Antibacterial effects of
the essential oils of commonly consumed medicinal herbs using an in vitro model. Molecules
15(11):7532–7546
56. Sourmaghi MHS, Amin G, Samadi N, Hemmati F, Sarkhail P (2006) Chemical composition
and antimicrobial activity of essential oil of Salvia spinosa L. Asian J Plant Sci 5(4):654–656
57. Sugumaran M (2016) Reactivities of Quinone Methides versus o-Quinones in Catecholamine
metabolism and Eumelanin biosynthesis. Int J Mol Sci 17(9):1576
58. Tellez MR, Dayan FE, Schrader KK, Wedge DE, Duke SO (2000) Composition of some
biological activities of the essential oils of Callicarpa americana. J Agric Food Chem
48(7):3008–3012
59. Ultee A, Bennik MH, Moezelaar RJ (2002) The phenolic hydroxyl group of carvacrol is essen-
tial for action against the food-borne pathogen Bacillus cereus. AEM 68(4):1561–1568
60. Upadhyay RK (2010) Essential oils: anti-microbial, antihelminthic, antiviral, anticancer and
anti-insect properties. J Appl Biosci 36(1):1–22
61. Upadhyay RK (2011) Plant natural products: their pharmaceutical potential against disease
and drug resistant microbial pathogens. J Pharm Res 4(4):1179–1185
Nanotechnological Modus Operandi
for the Delivery of Cytotoxic
Phytochemicals

Thomson Alex, Alankar Shrivastava, Damanpreet Kaur Lang,

Rakhi Khabiya, Sweta S. Koka, and Yasmin Sultana

1 Introduction

Cancer is becoming a major health concern day by day and is spreading both in
developing as well-developed countries. The emergence of drug resistance to cyto-
toxic agents has made it difficult to control the spread of this disease [1]. Apart from
chemotherapeutical approaches, the management of cancer involves radiation ther-
apy and surgical interventions. The currently available chemotherapeutic drugs for
cancer treatment include anti-tubulin drugs like taxanes, numerous molecular tar-
geting drugs, DNA interactive drugs such as doxorubicin (Fig. 1) and antimetabo-
lites like methotrexate [2]. The utmost drawback of these cytotoxic agents is the
emergence of resistance and variable toxic effects in patients. Traditional Indian and
Chinese medicine has listed out various medicinal plants that have anti-cancer
action and are being evaluated alongside the modern medicine system. Side effects
that occur from the usage of synthetic chemotherapeutic agents such as hair loss,
lowering of the immune response, increased susceptibility to opportunistic infec-
tions, cardiac toxicity, neurological and gastrointestinal disturbances can be mini-
mized by direct delivery of plant-based cytotoxic agents at the tumour site [2].

T. Alex · Y. Sultana (*)

Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia
Hamdard, New Delhi, India
e-mail: [email protected]
A. Shrivastava (*)
KIET Group of Institution, KIET Group of Pharmacy, Ghaziabad, Uttar Pradesh, India
D. K. Lang
Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
R. Khabiya · S. S. Koka
Acropolis Institute of Pharmaceutical Education and Research,
Indore, Madhya Pradesh, India

© The Author(s), under exclusive license to Springer Nature 1365

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_57
1366 T. Alex et al.

Various phytochemicals from plant origin (Table 1) have proved to reduce cell pro-
liferation, slow down the rate of metastases, induction of apoptosis and inhibition of
angiogenesis [10, 11]. Paclitaxel (Fig. 1), a taxane diterpene, is extracted from
Taxus brevifolia Nutt. and is actively used in the treatment of a variety of cancers
[12]. The site-specificity can be enhanced by site targeting as well as various side
effects and poor drug delivery can be reduced by appointing nanotechnological drug
delivery approaches. The conventional drug delivery approaches do not render the
chemotherapeutic agent to distinguish between normal and cancerous cells, nano-
technology engineers the drug to only interact and bind with cancer cells, thus
reducing the chances of organ damage [13]. Using nanotechnology, the cancer cells
can be actively or passively targeted. In active targeting, a targeting agent is attached
to the nanoparticle and it works via antibody/antigen or ligand/receptor interaction
[14, 15]. The vectors that are used for active targeting include synthetic, natural and
lipid polymers. For enhanced half-life, the nanomaterial is coated with hydrophilic
polymer to prevent washout and increased time in the bloodstream. The coating

Fig. 1 Chemical structure of various phytochemicals discussed in the text

Nanotechnological Modus Operandi for the Delivery of Cytotoxic Phytochemicals 1367

Fig. 1 (continued)

even repels the plasma proteins leading to the prevention of opsonized [16]. The
most common hydrophilic polymers that are employed in cancer targeting include
poloxamine, polyethylene glycol, polysaccharide and poloxamer [17]. Passive tar-
geting of the cancer cells can be through the leaky blood vessels in the endothelial
cells, the delivery system can pass through the formed pores which are usually in
the range of 100–780 nm [18]. The lymphatic drainage is also faulty at the tumour
site, helping in the retention and accumulation of nanoparticles, which prolong the
drug action [19]. Nanotechnology has already transformed cancer treatment in
numerous ways and is fundamentally altering the treatment plan. It has had a sig-
nificant influence on selective cancer cell recognition, targeted drug administration
and overcoming the limits of traditional chemotherapies. The properties of
1368 T. Alex et al.

Table 1 Various natural anticancer phytochemicals derived from plant origin

Anticancer
phytochemical Source Action References
Vincristine Catharanthus Anti-tumour action, apoptotic action [3]
roseus
Vindesine Catharanthus Cell cycle arrest, microtubule [3]
roseus destabilizer
Vinblastine Catharanthus Cell cycle arrest, apoptotic action, [3]
roseus microtubule formation inhibitor
Vinorelbine Catharanthus Pro-apoptotic, cell cycle arrest, [3]
roseus anti-tumour action
Vinflunine Catharanthus Cell cycle arrest, apoptotic action, [3]
roseus microtubule formation inhibitor
Paclitaxel Taxus brevifolia Mitosis blocker, apoptotic inducer, [4]
spindle formation disruptor
Noscapine Papaver Tumour growth inhibitor, [5]
somniferum antiproliferative
Roscovitine Raphanus sativus Inhibits progression of cell cycle and [6]
cyclin dependent kinases
Epigallacotechin-3-­ Green tea Anti-proliferative, antioxidant, kinase [3]
gallate inhibitor
Flavopiridol Dysoxylum Growth inhibitor, anti-inflammatory, [7]
binectariferum immunomodulator
Pomiferin Maclura pomifera Antioxidant, pro-apoptotic [8]
Epipodophyllotoxin Podophyllum Cell cycle arrest, pro-apoptotic [6]
peltatum
Sulphoraphane Brassica Anti-proliferative, cancer growth [9]
inhibitor

nanoparticles are due to their specific shape, surface characteristic features and size.
The nanoparticles which range in the size of 10–100 nm are mostly considered in
cancer treatment and can effectively deliver cytotoxic agents as well as achieve the
enhanced permeability and retention effect. Nanoparticles that are in the size range
of 100 nm can be easily targeted by the phagocytes and the ones which range
between 1 and 2 nm can be easily cleared out by the kidneys. The nanoparticles
based on their composition can be divided into organic nanoparticles (Polymer,
Liposome-based nanoparticles, Dendrimers), inorganic nanoparticles (Gold, Silver,
Silica, Magnetic nanoparticles, Carbon nanotubes, Quantum dots) and hybrid
nanoparticles (Cell membrane coated nanoparticle, Organic-inorganic, Lipid-­
polymer nanoparticle) [20].
Efforts are being put forward to synthesize nanocarriers using eco-friendly tech-
niques to produce nontoxic and environmentally safe biomaterial. The nanoparticles
synthesized using green nanotechnology have good stability with suitable dimen-
sions [21]. The conventional synthesis method using chemical and physical meth-
ods has led to generation of toxic by-products which are environmentally hazardous.
The yield might be greater with conventional techniques but these methods are cost-
lier and complicated [22]. Green synthesis involves production of nanoparticles
Nanotechnological Modus Operandi for the Delivery of Cytotoxic Phytochemicals 1369

using plants, microbes and their by-products such as lipids and proteins. This tech-
nique uses a bottom-up approach which uses a stabilizing and reducing agent and
has three main steps: choosing an appropriate solvent medium, choosing a reducing
agent which is environmentally benign and eco-friendly and the last step is use of
nontoxic capping agent for a stabilized nanoparticle [23]. The magnetic nanoparti-
cles are synthesized by using a nanoemulsion mixture consisting of sodium hydrox-
ide and iron sucrose. In a study conducted by Kuang et al. used green synthesis
technique to produce magnetic nanoparticles, utilizing the extracts from oolong,
black and green tea [24]. Tripathi et al. synthesized carbon nanotubes using green
leaves extract from rose, Kaner, walnut, neem and garden grass [25]. Alippilakkotte
et al. synthesized polylactic acid/silver nanofibres using extracts from the fruit of
Momordica charantia [26].
In this chapter, we would be highlighting various nanoparticles that have been
studied and thus, can be employed to deliver cytotoxic phytochemicals in different
types of cancers.

2 Liposome

The size of liposomes ranges between 10 nm and 2500 nm and they are made up of
phospholipids. The final shape of liposomes depends upon the molar concentration,
ion concentration of the medium and temperature of the medium [27]. On the basis
of size, liposomes can be classified into multi-lamellar (1.5 um), oligo-lamellar
(1–1.5 um), uni-lamellar (100–250 nm) and small uni-lamellar (20–100 nm). The
main benefit of liposomal formulation is the sustained drug release pattern which
lowers down the requirement of dependency on injectable drugs. Moreover, the
half-life of the drug is also scaled up and it remains in the body for longer time,
when given in the form of liposomes [28, 29]. Liposomes can be administered by
oral route as well as intravenous route, for local administrations, liposomes are
injected via intraperitoneal, subcutaneous, intramuscular and intradermal route
[30]. The mechanism of action of liposomes on cancer cells is their ability to accu-
mulate at the tumour site after which they are up taken by cancer cells and release
free drug [31]. The anticancer effect of curcumin (Fig. 1), which is derived from
Curcuma longa, is being tested out on a variety of cancers such as prostate, liver and
breast cancers. This phytochemical works by interfering with the translation of
Bcl-xl protein and in regulation of apoptosis by having an effect on the release of
cytochrome and reactive oxygen species as well as affecting the cell cycle by regu-
lation of molecular factors like cyclin [32]. Forming liposomes of curcumin will
lead to improvement in the pharmacodynamic and pharmacokinetic profile of this
drug, reduction in dose required to show anti-cancer effect as compared with free
curcumin [33]. Another well-established anticancer agent, paclitaxel, which is
extracted from Taxus brevifolia, is utilized in various cancers such as gastric, breast,
ovarian and non-small cell lung cancer [34, 35]. It leads to cell death in cancer cells
by enhancing the polymerization of protein tubulin during the cell division, further
1370 T. Alex et al.

Table 2 Various liposomes and their usage in encapsulating cytotoxic phytochemicals

Cytotoxic Type of
Type of liposome phytochemical cancer Observations References
Conventional Daunorubicin Myeloid Enhanced drug levels on [39]
liposome leukaemia cancer site and clinical
efficacy
Conventional Daunorubicin Breast Clinically acceptable [40]
liposome cancer tolerability and safety
profile was established
Multifunctional Daunorubicin Brain Enhanced daunorubicin [41]
targeting liposome tumour uptake by glioma cells
Modified liposomes Paclitaxel Skin cancer Suppression of tumour [42]
growth
Conventional Paclitaxel Lung cancer Enhanced drug levels in the [43]
liposome lymph nodes

stabilizing the microtubules, causing disruption in the stability and finally causing
cell death [36]. Its cytotoxic action reduces due to its poor water solubility and high
lipophilicity; when non-aqueous base vehicle is added, the formulation causes
hypertensive reactions. Paclitaxel liposomes having mitochondrial targeting action
can be formulated by mixing cholesterol, d-α-tocopheryl polyethylene glycol 1000
succinate-triphenylphosphine conjugate and egg phosphatidylcholine in the molar
ratio of 3.5:8.5:88 respectively. In lung cancer, the above-formulated paclitaxel
liposomes showed apoptosis in drug-resistant cancer cells via stimulation of pro-­
apoptotic proteins such as Bid and Bax and suppression of anti-apoptotic protein
Bcl-2 [34]. Daunorubicin (Fig. 1), which is extracted from Streptomyces peucetius,
works by concentrating inside the mammary adenocarcinoma cells and murine lym-
phosarcoma cells. The uptake of this agent gets enhanced between 2.5 and 20 times
when formulated as a liposomal drug delivery system, in comparison to free dauno-
rubicin [37, 38]. Different types of liposomes that have been studied to carry cyto-
toxic phytochemicals are discussed in Table 2.

3 Carbon Nanotubes

Carbon nanotubes (CNTs), also known as tubular fullerenes [44], were first discov-
ered in 1991 by Japanese scientist Iijima [45]. CNTs are arising as novel nanomate-
rials for different biomedical applications and successfully developed to deliver
different medicinal agents and biomolecules to targeted sites. The lower cytotoxic-
ity and biocompatibility depend on dose, testing system, size, duration and surface
functionalization. The potential drawback of these systems is high cytotoxicity, lim-
iting their applications in different biological systems and humans. However, the
solubility and biocompatibility improvement for reducing cytotoxicity may be per-
formed by functionalization of CNTs [46]. CNTs and their connected materials
have numerous trademark properties and applications, settling on them an
Nanotechnological Modus Operandi for the Delivery of Cytotoxic Phytochemicals 1371

appropriate decision in the biomedical field, for example, drug release, gene ther-
apy, drug release and tissue engineering [47]. CNTs may have a length-to-diameter
ratio greater than 1,000,000 [48]. In CNTs, the medicinal components can be
entrapped in rolled graphene (with SP2 hybridization) sheets because of which it
gains more extensive length, high surface area and narrow diameter. The surface
modifications, e.g. attaching oxygen containing groups over the surface signifi-
cantly contribution in ligand targeting [49]. The ‘single-walled carbon nanotubes
(SWCNTs)’ and ‘multi-wall carbon nanotubes (MWCNTs)’ are contemplated to be
folded graphene sheets with lengths going from ~50 to 1000 nm and widths of ~5 to
20 nm [50]. Recently, attempts were made by researchers to extent the applicability
of CNTs for diagnosis, drug targeting and viral protein detection for fighting against
for different types of viral infections including corona virus and HIV [51]. Various
properties result from the development of carbon molecules in graphene chambers.
CNTs are tremendous round and hollow huge particle comprising of a hexagonal
arrangement of sp2 hybridized carbon atoms (C-C distance 1.4 Ǻ) [52]. The
researchers have found significant increase in efficiency in the perspective of tar-
geted tumour accumulation by functionalized SWNTs with targeting ligands RGD
peptide or antibodies [53]. The research published by Li et al. [54] describes
SWCNT system of curcumin, a polyphenolic anti-cancerous compound with poor
bioavailability. Polyvinylpyrrolidone and phosphatidylcholine were used for sur-
face modification increasing the concentration (18×) of curcumin in blood in mice.
The coating also increases the stability of curcumin and improving the shortfall of
drug resistance. The overall result indicates increase in uptake of curcumin in
human prostate cancerous PC-3 cells with promising inhibition of tumour growth.

4 Magnetic Nanoparticles (MNPS)

The rundown of advantages and utilizations of nanotechnology develops quickly. A

nanoscale material, e.g. magnetic nanoparticles (MNPs), with novel magnetic prop-
erties, have been generally utilized in various fields such as energy, biomedical,
environment and engineering applications. The MNPs have turned into an area of
intensive examination because of their expected application in biomedicine, cataly-
sis, horticulture and climate [55]. There is as yet a pressing need to foster novel
nanomaterials that can meet the prerequisites of arising disease theranostics appli-
cations. In this specific situation, MNPs offer interesting physicochemical proper-
ties and very attractive qualities, which make them ideal possibility for hyperthermia
treatment cancer [56]. The always expanding biomedical utilization of MNPs infers
expanding request in their adaptable and high-throughput creation, with finely tuned
and all-around controlled attributes [57]. MNPs is ‘a category of nanoparticles in
the size range of 1–100 nm reacts to an applied magnetic field [58]’. Magnetism is
a ‘kind of specific interaction, which experiences extreme changes at the nanoscale
system [59]’. They have enormous explicit surface regions, and can convey an
assortment of little atoms, proteins, RNA and so on [60]. The types and properties
of MNPs are given in Table 3.
1372 T. Alex et al.

Table 3 Types and properties of MNPs

S
No Classification Type Properties References
1 Silica-coated magnetic Magnetic Chemically inert, [61–63]
nanoparticles nanomaterials magnetic properties,
wrapped in non-toxicity, high thermal
nano-silica stability
(nSiO2)
2 Lipid-coated magnetic Nano-scale iron Good biocompatibility, [64]
nanoparticles/vesicle-type oxide targeting, specificity, high
magnetic nanoparticles phospholipid drug holding capacity
(Subclass: (1) Hydrophilic, (2) complex
Hydrophobic and, (3)
3 Polymer-coated magnetic – Properties depends on [65]
nanoparticle core nanoparticles and the
functionalization of the
polymer shell
4 Superparamagnetic iron oxide Mainly including Superparamagnetic [66]
nanoparticles (SPIONs) Fe3O4 and Fe2O3,

The nSiO2 microspheres after inhalation can cross blood–lung barrier and enters
into blood circulation possibly producing similar to systemic administration. These
can also be administered through injections or percutaneous permeation [67]. At the
point when magnetic particles are encircled by phospholipid bilayers, a colloidal
construction is shaped, which is generally depicted as ‘magnetic liposomes’. The
interior pit of this kind of liposome is totally involved by iron oxide particles [68].
MNPs are inclined to agglomeration because of high surface energy and huge
explicit surface area, making it hard to consistently scatter in polymers, which
incredibly restricts their exploration and application. Along these lines, polymer
change is a viable method for working on this peculiarity [69]. In the study of Tousi
et al. [70], the anticancerous activity of Eupatorin (Fig. 1), a natural methoxyfla-
vone, when encapsulated in ‘Fe3O4@mPEG-b-PLGA’ nanoparticles, was found to
be increased in prostate cancer cell lines as compared to free molecule. The research-
ers used oleic acid for stabilization of Fe3O4 nanoparticles were with the ‘mPEG-b-­
PLGA’ polymer for increasing cell uptake and its biocompatibility. The ‘poly
(lactic-co-glycolic) acid (PLGA)’ was used because of its biocompatibility and
releasing nontoxic monomers and oligomers, glycolic and lactic acid. The study
also found the formulation decreasing the necrosis and improved apoptosis which
may be an alternative for treating drug resistant cancer. In another publication, inhi-
bition activity against MCF-7 breast cancer cells and KB nasopharyngeal cancer
cells was observed using folate-grafted curcumin-loaded magnetic nanoparticles
reported by Montazerabadi et al. [71]. Upon alteration of magnetic field, the MNPs
can generate localized heat which are used to mediate cancer hyperthermia [72].
Montazerabadi et al. claim that problems associated with curcumin like low water
solubility, very poor bioavailability, rapid systemic elimination and metabolism
may be overcome by using their developed nanoparticles [71].
Nanotechnological Modus Operandi for the Delivery of Cytotoxic Phytochemicals 1373

5 Micelles

These are amphiphilic surfactant drug delivery system which shows the property of
aggregation by forming spherical vesicles when getting in contact with water. The
hydrophobic drugs can be incorporated into the inner nucleus of micelle which is
also hydrophobic. The basic structure of a micelle is a hydrophobic tail and a hydro-
philic head. The tail is composed of long chain fatty acids and the molecular weight
is greater as compared to other nanoparticle delivery system which makes it an ideal
choice for tissue targeting in case of solid tumours [73]. In a study conducted by Qiu
et al. synthesized polymeric micelles carrying luteolin (Fig. 1) and tested them on
C-26 colon cancer cell line. In rats the comparison was drawn between the formu-
lated preparation and free luteolin, it was noted that the luteolin polymeric micelles
lead to enhanced cytotoxic and bioavailability of the drug [74]. In another synthesis
study carried out by Dong et al. encapsulated honokiol (Fig. 1) in a star-shaped
polymeric micelle composed of poly(3-caprolactone) and monomethoxy
poly(ethylene glycol) via dissolution ultrasonic technique and tested the cytotoxic
profile on murine colon carcinoma CT26 cell lines. It was concluded that the poly-
meric micelles showed dose-related cytotoxic on the cancer cell lines [75]. The
honokiol micelles were even synthesized by Wei et al. which were composed of
copolymer poly(3-caprolactone)-poly(ethylene glycol)-poly(3-caprolactone) and
was tested in human lung adenocarcinoma cell line A549. The antiproliferative
action of the micelles were enhanced as compared to the free drug when tested in
the A549 cell lines [76]. Guo X formulated polymeric micelles composed of resve-
ratrol (Fig. 1) and semi-synthetic drug docetaxel (Fig. 1) for the treatment of drug-­
resistant breast cancer. For their formulation, they used methoxyl poly(ethylene
glycol)-poly(d,l-lactide) copolymer and were tested against MCF-7 breast cancer
cell lines. Prolonged drug release was observed with increased cytotoxicity as com-
pared to free drug [77].

6 Dendrimers

Dendrimers are hyperbranched, nano-sized molecules with radially symmetrical

structure. Variety of size and shapes can be achieved by making alternative layers of
polar and non-polar compounds. They act as a drug delivery vehicle due to their
water solubility, encapsulation ability and monodispersity property. Addition of
charged molecules or hydrophilic groups on the outer shell can make dendrimers
water soluble [78]. In a study conducted by Malar et al. formulated capsaicin (Fig. 1)
dendrosomal nano formulation via esterification process and tested them in vitro on
Hep2, MCF-7 and VERO cancer cell lines. Clinically effective cytotoxic concentra-
tion was attained by the formulated novel preparation [79]. In another synthesis
study conducted by Sharma et al. developed dendrimers of polyamidoamine and
gallic acid by employing Tomalia’s divergent growth method and they were tested on
breast cancer cell line MCF-7. It was noted that the formulated dendrimers showed
1374 T. Alex et al.

Table 4 Summarization of cytotoxic phytochemicals that have been effectively encapsulated in a

dendrimer
Cytotoxic
Type of dendrimer phytochemical Observation References
Poly(amidoamines)- Camptothecin In vivo and in vitro studies were [81]
Camptothecin PEGylated carried on HT-29 human colon
poly(L-lysine) cancer cell line and C26 murine
colon cancer cell lines which
indicated the effectiveness of the
formulated preparation
Polyester based Paclitaxel The effectiveness of the novel drug [82]
delivery system was confirmed on
C929 murine fibroblast model
Poly(ethylene glycol) based Lamellarin D Antiproliferative action was [83]
dendrimer (Fig. 1) confirmed using MDA-MB-231
Breast cancer cell, HT-29 colon
cancer cell line and A-549 Lung
cancer
Poly(amidoamines) Genistein Stability studies were carried and [84]
(Fig. 1) the formulation passed all the
stability tests
Partial acetylated Daunorubicin In vitro cytotoxic studies were [85]
poly(amidoamines)-FA carried on KB human carcinoma
cells
Poly(amidoamines) Curcumin Showed cytotoxic effects in [86]
neurotumours as compared to free
curcumin

increased cytotoxic profile on the breast cancer cell lines [80]. Various types of den-
drimers that are used to carry plant-based anticancer drug are discussed in Table 4.

7 Solid Lipid Nanoparticles

These are colloidal drug carriers and were developed as an alternative to previous
drug delivery agents such as polymeric nanoparticles, liposomes and emulsions.
These are next generation of submicron-sized lipid emulsion in which the oil, called
as liquid lipid, has been replaced by solid lipid. These nanocarriers have increased
surface area, enhanced drug loading capacity and are smaller in size [87]. These are
made from using the biodegradable polymers that have low acidity and toxicity, as
majority of the cytotoxic compounds are lipophilic and thus, they can be incorpo-
rated into this drug delivery system, making oral administration possible for cyto-
toxic drug [88]. In a study conducted by Serpe et al. formulated paclitaxel solid lipid
nanoparticles which showed similar cytotoxic profile as compared to drug present
in free solution. The efficacy of the developed formulation was tested on breast
cancer murine model and it was noted that the animals which received solid lipid
nanoparticles containing paclitaxel had reduced tumour size [89]. Solid lipid
Nanotechnological Modus Operandi for the Delivery of Cytotoxic Phytochemicals 1375

nanoparticles containing hyaluronic acid (Fig. 1) and paclitaxel were synthesized

by Shen et al. The aim of adding hyaluronic acid in this preparation was to enhance
the cytotoxic profile of paclitaxel. Initially, the paclitaxel-solid lipid nanoparticles
were prepared using film ultrasonic method and later on they were coated with hyal-
uronic acid. The novel drug delivery approach was tested on melanoma cell line
B16F10. The formulation enabled paclitaxel to impart cytotoxic effect at lower con-
centration as compared to free drug [90].

8 Exosomes

These are extracellular vesicles with a diameter of 30–150 nm and are secreted by B
cells, macrophages, T cells, dendritic cells, endothelial cells, epithelial cells and
endothelial cells. Exosomes are employed as a drug delivery agent in cancer research
because they have low immunogenicity, biocompatibility and biodistribution [91].
Different studies have highlighted that paclitaxel exosomes can amplify the clinical
effectiveness of exosomes. A study was conducted in which exosomes were extracted
from milk and were equipped with paclitaxel for testing them against xenografts of
human lung tumour. The prepared novel drug delivery system showed less immune
system toxicity in comparison to free drug [92]. Exosomes extracted from U-87 cell
line have the capability of passing the blood–brain barrier and they can be equipped
with paclitaxel to target glioblastoma multiforme [93]. It was noted from various
studies that the stability and bioavailability curcumin was by using exosomes as its
carrier. These exosomes were tested in GL26 brain tumour model and were given
via the intranasal route. The effect was reduction in inflammation, delayed in tumour
growth and mitigation of the brain endothelial cells [94]. In case of pancreatic can-
cer cells, the curcumin-exosome complex reduced the proliferation of cancer and
caused induction of apoptosis [95, 96]. Celastrol (Fig. 1), a plant-based triterpenoid,
has shown apoptosis activity against multidrug-resistant oral cancer cells from vin-
cristine (Fig. 1) via the JNK1/2 signalling pathway [97]. It was complexed with the
milk-derived exosomes and were tested in vitro against lung cancer. These were
proved to be stable, having oral delivery and low systemic toxicity [98]. Certain
agents such as docosahexaenoic acid (Fig. 1) can enhance the secretion of exosomes
and raise the small RNA levels for inhibition of pro-­angiogenesis mRNAs which
lead to suppression of cancer angiogenesis in case of breast cancer [99].

9 Polymeric Nanoparticles

These range in the size between 10 nm and 1000 nm and have beneficial properties
such as enhanced therapeutic effect of the encapsulated drug, site specificity and
route of administration. These are mostly used in ophthalmic and oral administration
due to increased bioavailability and reduced side effects [100]. In cytotoxic drug
delivery, polymeric nanoparticles provide a barrier between the anti-cancer drug and
1376 T. Alex et al.

Table 5 Different cytotoxic phytochemicals that are formulated as polymeric nanoparticle

Type of
Carrier drug Type of polymer cancer References
Paclitaxel Poly(lactic Breast [103]
acid)−poly(ethylene glycol)–maleimide cancer
Doxorubicin-­ D-α-Tocopherol polyethylene glycol Breast [104]
metformin (Fig. 1) succinate- Poly-(d,l-lactic-co-glycolic acid) cancer
Doxorubicin– Monomethoxy (polyethylene glycol)-b-P Breast [105]
curcumin (D,l-lactic-co-glycolic acid)-b-P (l-glutamic cancer
acid)
Paclitaxel Polyethyleneimine- Polylactic acid Lung [106]
cancer
Camptothecin Poly(ε-caprolactone)- poly(ethylene glycol) Glioma [107]
Doxorubicin– Poly(alkyl cyanoacrylate) Different [108]
cyclosporin A (Fig. 1) cancers
Paclitaxel Lip-Bovine serum albumin Different [109]
cancers

the healthy cells, thus reducing the toxicity profile of the carrier drug [101]. Bisht
et al. prepared polymeric nanoparticles carrying curcumin and they were composed
of crosslinked copolymers of N-vinyl-2-pyrrolidone, poly(ethylene glycol) monoac-
rylate and N-isopropylacrylamide. This nanodrug delivery system showed effective-
ness against human pancreatic tumour cell line and it induced apoptosis, regulated
levels of proinflammatory cytokines and blocks the activation of nuclear factor
kappa B [102]. Various plant-based cytotoxic drugs that have been formulated as a
polymeric nanoparticle drug delivery system are discussed in Table 5.

10 Nanofibres

This novel drug delivery system is synthesized using electrospinning technique, and
the formulated nanofibres are biodegradable as well as biocompatible. Nanofibres
have high surface area to mass ratio and low density [110]. Exceptional anti-cancer
activity was achieved in breast cancer model where camptothecin (Fig. 1) was com-
plexed with peptide amphiphile nanofibres [111]. To establish the efficacy of camp-
tothecin in lung cancer, nanofibres loaded with DNA were used to carry the molecule
and showed effective drug loading effect [112]. Vashisth et al. developed
poly(lactide-co-glycolide)–polycaprolactone biodegradable nanofibres carrying
quercetin (Fig. 1) and tested them for their efficacy on human hepatocellular cancer
cells. The novel preparation showed sustained release of quercetin along with
enhanced diffusion and aqueous permeability. The drug-releasing pattern initially
was a blast released, followed by slow release kinetics [113]. In another study con-
ducted by Gajanan et al., incorporated Emblica officinalis into the nanofibres made
up of polycaprolactone. The prepared formulation showed antiproliferative action
on human breast cancer cell lines [114]. Different types of nanofibres that are used
for carrying plant-based cytotoxic drugs are discussed in Table 6.
Nanotechnological Modus Operandi for the Delivery of Cytotoxic Phytochemicals 1377

Table 6 Various nanofibres that can be employed to encapsulate cytotoxic phytochemicals

Cytotoxic Type of
Type of nanofibre phytochemical cancer References
Poly (ε-caprolactone) Camptothecin C2C12 cell [115]
line
Polyethylene glycol Camptothecin Ovarian [116]
cancer
Breast
cancer
Chitosan Curcumin Breast [117]
cancer
Sodium alginate-chitosan Quercetin Colon [118]
cancer
Polycaprolactone/Polyethylene oxide/ Quercetin Breast [119]
Poly-lactic acid/poly (lactic-co-glycolic) acid cancer
Cellulose acetate/polyethylene glycol Quercetin Melanoma [120]

Table 7 FDA-approved nanocarriers for cytotoxic phytochemicals

Clinical
Trade Cytotoxic Route of Type of Type of trial Clinical trial
name phytochemical administration nanocarrier cancer status identifier
Onivyde® Irinotecan Intravenous Liposome Non-small FDA NCT00702182
(Fig. 1) cell lung approved NCT01494506
cancer
Pancreatic
cancer
Breast
cancer
Marqibo® Vincristine Intravenous Liposome Leukaemia FDA NCT00145041
approved NCT00495079
NCT01026220
Doxil® Doxorubicin Intravenous Liposome Ovarian FDA NCT00727961
cancer approved

11 Clinical Studies of Various Nanocarriers Containing

Cytotoxic Phytochemicals

In past two decades, it has been well established that nanocarriers are equipped with
advantages such as protecting the cytotoxic phytochemical from potential degrada-
tion, enhanced pharmacokinetic profile of the active drug and greater drug absorp-
tion at tumour site. The accumulation of nanoparticles at the tumour site is due to
the enhanced permeability effect [121]. The various nanocarriers that have been
approved by FDA in past are discussed in Table 7 and nanocarriers that are undergo-
ing clinical trials are discussed in Table 8 [122].
Table 8 Clinical trial status of various nanocarriers carrying cytotoxic phytochemicals
1378

Cytotoxic Route of Type of Clinical trial

Trade name phytochemical administration nanocarrier Type of cancer Clinical trial status identifier
Lipusu® Paclitaxel Intravenous Liposome Non-small cell lung cancer Phase 4 NCT02142790
Ovarian cancer NCT02996214
Breast cancer
Genexol-PM/ Paclitaxel Intravenous Micelle Non-small cell lung cancer Phase 4 NCT00912639
IG-001/ Breast cancer NCT03618758
Cynviloq Gastric cancer
Pancreatic cancer
Ovarian cancer
NK105 Paclitaxel Intravenous Micelle Colon cancer Phase 3 NCT01644890
Gastric cancer
Breast cancer
NK012 Irinotecan Intravenous Micelle Triple negative breast cancer Phase 2 and Phase NCT00951613
Small cell lung cancer 1(refractory solid tumour) NCT00951054
Refractory solid tumour NCT00542958
SYP-0709 Docetaxel Intravenous Polymeric Advanced solid cancer Phase 1 NCT02274610
Nanoparticles NCT01103791
CRLX101 Camptothecin Intravenous Polymeric Non-small cell lung cancer Phase 2 NCT01380769
(NLG207) nanoparticles Rectal cancer NCT02010567
Metastatic gastroesophageal cancer NCT01612546
NANOXEL Docetaxel Intravenous Micelle Bladder cancer Phase 3 NCT03585673
Head and neck squamous cell NCT02982395
carcinoma NCT02639858
Oesophageal cancer
L9-NC Camptothecin Intravenous Liposome Ewing’s sarcoma Phase 2 NCT00492141
Endometrial cancer NCT00249990
Lipocurc™ Curcumin Intravenous Liposome Solid tumours Phase 2 NCT02138955
LE-DT Docetaxel Intravenous Liposome Solid tumours Phase 2 NCT01151384
T. Alex et al.
Nanotechnological Modus Operandi for the Delivery of Cytotoxic Phytochemicals 1379

12 Conclusion

Systemic toxicities and drug resistance are the major problems associated with the
synthetic and semi-synthetic anticancer drugs. Nowadays, due to new extraction
and separation techniques and availability of high sophisticated machines, various
potent anticancer molecules are being extracted from plants. However, these phyto-
chemicals have short half-life, nonselective biodistribution, poor water solubility,
most of the agents are hydrophobic with low bioavailability which leads to hin-
drance in their clinical application. To subdue these effects, various nanocarriers
such as liposomes, dendrimers, micelles, magnetic nanoparticles, carbon nanotubes,
exosomes, polymeric nanoparticles, nanofibre and solid lipid nanoparticles can be
used to encapsulate the plant-based cytotoxic agents. The systemic toxicity is
reduced along with enhanced pharmacological activity and bioavailability.

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer sta-
tistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in
185 countries. CA Cancer J Clin 68(6):394–424
2. Nussbaumer S, Bonnabry P, Veuthey JL, Fleury-Souverain S (2011) Analysis of anticancer
drugs: a review. Talanta 85(5):2265–2289
3. Amin A, Gali-Muhtasib H, Ocker M, Schneider-Stock R (2009) Overview of major classes of
plant-derived anticancer drugs. Int J Biomed Sci 5(1):1
4. Che E, Gao Y, Wan L, Zhang Y, Han N, Bai J, Li J, Sha Z, Wang S (2015) Paclitaxel/gelatin
coated magnetic mesoporous silica nanoparticles: preparation and antitumor efficacy in vivo.
Microporous Mesoporous Mater 204:226–234
5. Singh A, Menéndez-Perdomo IM, Facchini PJ (2019) Benzylisoquinoline alkaloid biosyn-
thesis in opium poppy: an update. Phytochem Rev 18(6):1457–1482
6. Shah U, Shah R, Acharya S, Acharya N (2013) Novel anticancer agents from plant sources.
Chin J Nat Med 11(1):16–23
7. Cragg GM, Newman DJ (2005) Plants as a source of anti-cancer agents. J Ethnopharmacol
100(1–2):72–79
8. Son IH, Chung IM, Lee SI, Yang HD, Moon HI (2007) Pomiferin, histone deacetylase inhibitor
isolated from the fruits of Maclura pomifera. Bioorganic Med Chem Lett 17(17):4753–4755
9. Cornblatt BS, Ye L, Dinkova-Kostova AT, Erb M, Fahey JW, Singh NK, Chen MS, Stierer T,
Garrett-Mayer E, Argani P, Davidson NE (2007) Preclinical and clinical evaluation of sul-
foraphane for chemoprevention in the breast. Carcinogenesis 28(7):1485–1490
10. Hadjzadeh M, Tavakol Afshari J, Ghorbani A, Shakeri MT (2006) The effects of aque-
ous extract of garlic (Allium sativum L.) on laryngeal cancer cells (Hep-2) and L929 cells
in vitro. J Med Plants 5(18):41–48
11. Sadeghnia HR, Ghorbani Hesari T, Mortazavian SM, Mousavi SH, Tayarani-Najaran Z,
Ghorbani A (2014) Viola tricolor induces apoptosis in cancer cells and exhibits antiangio-
genic activity on chicken chorioallantoic membrane. Biomed Res Int 2014:625792
12. Sharifi-Rad J, Quispe C, Patra JK, Singh YD, Panda MK, Das G, Adetunji CO, Michael
OS, Sytar O, Polito L, Živković J (2021) Paclitaxel: application in modern oncology and
nanomedicine-based cancer therapy. Oxi Med Cell Longev 2021:3687700
1380 T. Alex et al.

13. Mousa SA, Bharali DJ (2011) Nanotechnology-based detection and targeted therapy in can-
cer: nano-bio paradigms and applications. Cancers 3(3):2888–2903
14. Nie S, Xing Y, Kim GJ, Simons JW (2007) Nanotechnology applications in cancer. Annu Rev
Biomed Eng 9:257–288
15. Cho K, Wang XU, Nie S, Shin DM (2008) Therapeutic nanoparticles for drug delivery in
cancer. Clin Cancer Res 14(5):1310–1316
16. Nikitin MP, Zelepukin IV, Shipunova VO, Sokolov IL, Deyev SM, Nikitin PI (2020)
Enhancement of the blood-circulation time and performance of nanomedicines via the forced
clearance of erythrocytes. Nat Biomed Eng 4(7):717–731
17. Ahmed A, Sarwar S, Hu Y, Munir MU, Nisar MF, Ikram F, Asif A, Rahman SU, Chaudhry
AA, Rehman IU (2021) Surface-modified polymeric nanoparticles for drug delivery to cancer
cells. Expert Opin Drug Deliv 18(1):1–24
18. Jain RK, Stylianopoulos T (2010) Delivering nanomedicine to solid tumors. Nat Rev Clin
Oncol 7(11):653–664
19. Ding Y, Xu Y, Yang W, Niu P, Li X, Chen Y, Li Z, Liu Y, An Y, Liu Y, Shen W (2020)
Investigating the EPR effect of nanomedicines in human renal tumors via ex vivo perfusion
strategy. Nano Today 35:100970
20. Yao Y, Zhou Y, Liu L, Xu Y, Chen Q, Wang Y, Wu S, Deng Y, Zhang J, Shao A (2020)
Nanoparticle-based drug delivery in cancer therapy and its role in overcoming drug resis-
tance. Front Mol Biosci 7:193
21. Ingale AG, Chaudhari AN (2013) Biogenic synthesis of nanoparticles and potential applica-
tions: an eco-friendly approach. J Nanomed Nanotechol 4(165):1–7
22. Chauhan RP, Gupta C, Prakash D (2012) Methodological advancements in green nano-
technology and their applications in biological synthesis of herbal nanoparticles. Int J
Bioassays 01:6–10
23. Parveen K, Banse V, Ledwani L (2016) Green synthesis of nanoparticles: their advantages
and disadvantages. In: AIP conference proceedings, vol 1724(1). AIP Publishing LLC,
Melville, New York, United States. pp 020048
24. Kuang Y, Wang Q, Chen Z, Megharaj M, Naidu R (2013) Heterogeneous Fenton-like oxida-
tion of monochlorobenzene using green synthesis of iron nanoparticles. J Colloid Interface
Sci 410:67–73
25. Tripathi N, Pavelyev V, Islam SS (2017) Synthesis of carbon nanotubes using green plant
extract as catalyst: unconventional concept and its realization. Appl Nanosci 7(8):557–566
26. Alippilakkotte S, Kumar S, Sreejith L (2017) Fabrication of PLA/Ag nanofibers by green
synthesis method using Momordica charantia fruit extract for wound dressing applications.
Colloids Surf A Physicochem Eng Asp 529:771–782
27. Frolov VA, Shnyrova AV, Zimmerberg J (2011) Lipid polymorphisms and membrane shape.
Cold Spring Harb Perspect Biol 3(11):a004747
28. Drummond DC, Meyer O, Hong K, Kirpotin DB, Papahadjopoulos D (1999) Optimizing
liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev
51(4):691–744
29. Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer
chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent
smancs. Cancer Res 46(12 Part 1):6387–6392
30. Oussoren C, Eling WM, Crommelin DJ, Storm G, Zuidema J (1998) The influence of the
route of administration and liposome composition on the potential of liposomes to protect tis-
sue against local toxicity of two antitumor drugs. Biochim Biophys Acta (BBA)-Biomembr
1369(1):159–172
31. Sawant RR, Torchilin VP (2010) Liposomes as ‘smart’pharmaceutical nanocarriers. Soft
Matter 6(17):4026–4044
32. Feng T, Wei Y, Lee RJ, Zhao L (2017) Liposomal curcumin and its application in cancer. Int
J Nanomedicine 12:6027
Nanotechnological Modus Operandi for the Delivery of Cytotoxic Phytochemicals 1381

33. Li PM, Li YL, Liu B, Wang WJ, Wang YZ, Li Z (2014) Curcumin inhibits MHCC97H liver
cancer cells by activating ROS/TLR-4/caspase signaling pathway. Asian Pac J Cancer Prev
15(5):2329–2334
34. Zhou J, Zhao WY, Ma X, Ju RJ, Li XY, Li N, Sun MG, Shi JF, Zhang CX, Lu WL (2013) The
anticancer efficacy of paclitaxel liposomes modified with mitochondrial targeting conjugate
in resistant lung cancer. Biomaterials 34(14):3626–3638
35. Xu X, Wang L, Xu HQ, Huang XE, Qian YD, Xiang J (2013) Clinical comparison between
paclitaxel liposome (Lipusu®) and paclitaxel for treatment of patients with metastatic gastric
cancer. Asian Pac J Cancer Prev 14(4):2591–2594
36. Surapaneni MS, Das SK, Das NG (2012) Designing Paclitaxel drug delivery systems aimed
at improved patient outcomes: current status and challenges. Int Sch Res Notices 2012:1–15
37. Forssen EA, Coulter DM, Proffitt RT (1992) Selective in vivo localization of daunorubicin
small unilamellar vesicles in solid tumors. Cancer Res 52(12):3255–3261
38. Klein K, Kaspers GL (2013) A review of liposomal daunorubicin in the treatment of acute
leukemia. Oncol Hematol Rev 9(2):142–148
39. Feldman EJ, Lancet JE, Kolitz JE, Ritchie EK, Roboz GJ, List AF, Allen SL, Asatiani E,
Mayer LD, Swenson C, Louie AC (2011) First-in-man study of CPX-351: a liposomal car-
rier containing cytarabine and daunorubicin in a fixed 5: 1 molar ratio for the treatment of
relapsed and refractory acute myeloid leukemia. J Clin Oncol 29(8):979
40. O’Byrne KJ, Thomas AL, Sharma RA, DeCatris M, Shields F, Beare S, Steward WP (2002)
A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast
cancer. Br J Cancer 87(1):15–20
41. Li XT, Ju RJ, Li XY, Zeng F, Shi JF, Liu L, Zhang CX, Sun MG, Lou JN, Lu WL (2014)
Multifunctional targeting daunorubicin plus quinacrine liposomes, modified by wheat germ
agglutinin and tamoxifen, for treating brain glioma and glioma stem cells. Oncotarget
5(15):6497
42. Du R, Zhong T, Zhang WQ, Song P, Song WD, Zhao Y, Wang C, Tang YQ, Zhang X, Zhang
Q (2014) Antitumor effect of iRGD-modified liposomes containing conjugated linoleic acid–
paclitaxel (CLA-PTX) on B16-F10 melanoma. Int J Nanomedicine 9:3091
43. Hu L, Liang G, Yuliang W, Bingjing Z, Xiangdong Z, Rufu X (2013) Assessing the effective-
ness and safety of liposomal paclitaxel in combination with cisplatin as first-line chemother-
apy for patients with advanced NSCLC with regional lymph-node metastasis: study protocol
for a randomized controlled trial (PLC-GC trial). Trials 14(1):1–7
44. Ibrahim KS (2013) Carbon nanotubes-properties and applications: a review. Carbon Lett
14(3):131–144
45. Patel J, Parikh S, Patel S, Patel R, Patel P (2021) Carbon nanotube (CNTs): structure, syn-
thesis, purification, functionalisation, pharmacology, toxicology, biodegradation and appli-
cation as nanomedicine and biosensor: carbon nanotube (CNTs). J Pharm Sci Med Res
1(02):017–044
46. Vardharajula S, Ali SZ, Tiwari PM, Eroğlu E, Vig K, Dennis VA, Singh SR (2012)
Functionalized carbon nanotubes: biomedical applications. Int J Nanomedicine 7:5361–5374
47. Thakur A, Bharti R, Sharma R (2021) Carbon nanotubes: types, synthesis, cytotoxicity and
applications in biomedical. Mater Today Proceed 50:2256–2268
48. Rahamathulla M, Bhosale RR, Osmani RAM, Mahima KC, Johnson AP, Hani U, Ghazwani
M, Begum MY, Alshehri S, Ghoneim MM, Shakeel F, Gangadharappa HV (2021) Carbon
nanotubes: current perspectives on diverse applications in targeted drug delivery and thera-
pies. Materials (Basel) 14(21):6707
49. Son KH, Hong JH, Lee JW (2016) Carbon nanotubes as cancer therapeutic carriers and medi-
ators. Int J Nanomedicine 11:5163–5185
50. Rashid MH, Ralph SF (2017) Carbon nanotube membranes: synthesis, properties, and future
filtration applications. Nanomaterials (Basel) 7(5):99
51. Varghese R, Salvi S, Sood P, Karsiya J, Kumar D (2022) Carbon nanotubes in COVID-19: a
critical review and prospects. Colloid Interface Sci Commun 46:100544
1382 T. Alex et al.

52. Kushwaha SK, Ghoshal S, Rai AK, Singh S (2013) Carbon nanotubes as a novel drug deliv-
ery system for anticancer therapy: a review. Braz J Pharm Sci 49(4):629–643
53. Liu Z, Chen K, Davis C, Sherlock S, Cao Q, Chen X, Dai H (2008) Drug delivery with carbon
nanotubes for in vivo cancer treatment. Cancer Res 68(16):6652–6660
54. Li H, Zhang N, Hao Y, Wang Y, Jia S, Zhang H (2019) Enhancement of curcumin antitumor
efficacy and further photothermal ablation of tumor growth by single-walled carbon nano-
tubes delivery system in vivo. Drug Deliv 26(1):1017–1026
55. Ali A, Shah T, Ullah R, Zhou P, Guo M, Ovais M, Tan Z, Rui Y (2021) Review on recent
progress in magnetic nanoparticles: synthesis, characterization, and diverse applications.
Front Chem 9:629054
56. Liu Y, Guo Z, Li F, Xiao Y, Zhang Y, Bu T, Jia P, Zhe T, Wang L (2019) Multifunctional
magnetic copper ferrite nanoparticles as fenton-like reaction and near-infrared photothermal
agents for synergetic antibacterial therapy. ACS Appl Mater Interfaces 11(35):31649–31660
57. Chmykhalo V, Belanova A, Belousova M, Butova V, Makarenko Y, Khrenkova V, Soldatov
A, Zolotukhin P (2021) Microbial-based magnetic nanoparticles production: a mini-review.
Integr Biol (Camb) 13(4):98–107
58. Malar GCG, Seenuvasan M, Kumar KS, Kumar MA (2021) Instrumental methods in sur-
face property analysis of magnetic nanoparticles. In: Kumar RP, Bharathiraja B (eds)
Nanomaterials. Academic Press, Cambridge, Massachusetts, United States, pp 691–697
59. Alonso J, Barandiarán JM, Fernández Barquín L, García-Arribas A (2018) Magnetic nanopar-
ticles, synthesis, properties, and applications. In: El-Gendy AA, Barandiarán JM, Hadimani
RL (eds) Micro and nano technologies, magnetic nanostructured materials. Elsevier, pp 1–40
60. Li X, Li W, Wang M, Liao Z (2021) Magnetic nanoparticles for cancer theranostics: advances
and prospects. J Control Release 335:437–448
61. Iler KR (1979) The chemistry of silica. Solubility, polymerization, colloid and surface prop-
erties and biochemistry of silica. Wiley, Chichester
62. Do Kim K, Kim SS, Choa YH, Kim HT (2007) Formation and surface modification of Fe3O4
nanoparticles by co-precipitation and sol-gel method. J Ind Eng Chem 13(7):1137–1141
63. Jafarzadeh M, Soleimani E, Sepahvand H, Adnan R (2015) Synthesis and characterization
of fluconazole-functionalized magnetic nanoparticles as a catalyst for the synthesis of 3-aryl
and 3-amino-imidazo [1, 2-a] pyridines. RSC Adv 5(53):42744–42753
64. Oliveira RR, Carrião MS, Pacheco MT, Branquinho LC, de Souza ALR, Bakuzis AF, Lima
EM (2018) Triggered release of paclitaxel from magnetic solid lipid nanoparticles by mag-
netic hyperthermia. Mater Sci Eng C Mater Biol Appl 92:547–553
65. Altenschmidt L, Sánchez-Paradinas S, Lübkemann F, Zámbó D, Abdelmonem AM,
Bradtmüller H, Masood A, Morales I, de la Presa P, Knebel A, García-Tuñón MAG, Pelaz
B, Hindricks KDJ, Behrens P, Parak WJ, Bigall NC (2021) Aerogelation of polymer-coated
photoluminescent, plasmonic, and magnetic nanoparticles for biosensing applications. ACS
Appl Nano Mater 4(7):6678–6688
66. Talluri S, Malla RR (2019) Superparamagnetic iron oxide nanoparticles (SPIONs) for diag-
nosis and treatment of breast, ovarian and cervical cancers. Curr Drug Metab 20(12):942–945
67. Hou H, Wang C, Nan K, Freeman WR, Sailor MJ, Cheng L (2016) Controlled release of
dexamethasone from an intravitreal delivery system using porous silicon dioxide. Invest
Ophthalmol Vis Sci 57(2):557–566. https://doi.org/10.1167/iovs.15-­18559
68. Diksha RI (2012) Synthesis, surface modification, characterization, and biomedical in vitro
applications of organically modified silica (ORMOSIL) nanoparticles. Methods Mol Biol
906:365–379
69. Zhang M, Qiao J, Qi L (2018) Dual-functional polymer-modified magnetic nanoparticles for
isolation of lysozyme. Anal Chim Acta 1035:70–76
70. Tousi MS, Sepehri H, Khoee S, Farimani MM, Delphi L, Mansourizadeh F (2021) Evaluation
of apoptotic effects of mPEG-b-PLGA coated iron oxide nanoparticles as a eupatorin carrier
on DU-145 and LNCaP human prostate cancer cell lines. J Pharm Anal 11(1):108–121
Nanotechnological Modus Operandi for the Delivery of Cytotoxic Phytochemicals 1383

71. Montazerabadi A, Beik J, Irajirad R, Attaran N, Khaledi S, Ghaznavi H, Shakeri-Zadeh A

(2019) Folate-modified and curcumin-loaded dendritic magnetite nanocarriers for the tar-
geted thermo-chemotherapy of cancer cells. Artif Cells Nanomed Biotechnol 47(1):330–340
72. Beik J, Abed Z, Ghoreishi FS, Hosseini-Nami S, Mehrzadi S, Shakeri-Zadeh A, Kamrava
SK (2016) Nanotechnology in hyperthermia cancer therapy: from fundamental principles to
advanced applications. J Control Release 235:205–221
73. Lu Y, Park K (2013) Polymeric micelles and alternative nanonized delivery vehicles for
poorly soluble drugs. Int J Pharm 453(1):198–214
74. Qiu JF, Gao X, Wang BL, Wei XW, Gou ML, Men K, Liu XY, Guo G, Qian ZY, Huang
MJ (2013) Preparation and characterization of monomethoxy poly (ethylene glycol)-
poly (ε-caprolactone) micelles for the solubilization and in vivo delivery of luteolin. Int J
Nanomedicine 8:3061
75. Dong P, Wang X, Gu Y, Wang Y, Wang Y, Gong C, Luo F, Guo G, Zhao X, Wei Y, Qian Z (2010)
Self-assembled biodegradable micelles based on star-shaped PCL-b-PEG copolymers for
chemotherapeutic drug delivery. Colloids Surf A Physicochem Eng Asp 358(1–3):128–134
76. Wei X, Gong C, Shi S, Fu S, Men K, Zeng S, Zheng X, Gou M, Chen L, Qiu L, Qian Z
(2009) Self-assembled honokiol-loaded micelles based on poly (ɛ-caprolactone)-poly (ethyl-
ene glycol)-poly (ɛ-caprolactone) copolymer. Int J Pharma 369(1–2):170–175
77. Guo X, Zhao Z, Chen D, Qiao M, Wan F, Cun D, Sun Y, Yang M (2019) Co-delivery of resve-
ratrol and docetaxel via polymeric micelles to improve the treatment of drug-resistant tumors.
Asian J Pharm Sci 14(1):78–85
78. Abdel-Rahman MA, Al-Abd AM (2013) Thermoresponsive dendrimers based on oligoethyl-
ene glycols: design, synthesis and cytotoxic activity against MCF-7 breast cancer cells. Eur
J Med Chem 69:848–854
79. Malar CG (2015) Dendrosomal capsaicin nanoformulation for the invitro anticancer effect on
HEp 2 and MCF-7 cell lines. Int J Appl Bioeng 9(2)
80. Sharma A, Gautam SP, Gupta AK (2011) Surface modified dendrimers: synthesis and charac-
terization for cancer targeted drug delivery. Bioorg Med Chem 19(11):3341–3346
81. Cheng Y, Li M, Xu T (2008) Potential of poly (amidoamine) dendrimers as drug carriers of
camptothecin based on encapsulation studies. Eur J Med Chem 43(8):1791–1795
82. He H, Li Y, Jia XR, Du J, Ying X, Lu WL, Lou JN, Wei Y (2011) PEGylated Poly (ami-
doamine) dendrimer-based dual-targeting carrier for treating brain tumors. Biomaterials
32(2):478–487
83. Pla D, Martí M, Farrera-Sinfreu J, Pulido D, Francesch A, Calvo P, Cuevas C, Royo M,
Aligué R, Albericio F, Alvarez M (2009) Lamellarin D bioconjugates II: synthesis and cel-
lular internalization of dendrimer and nuclear location signal derivatives. Bioconjug Chem
20(6):1112–1121
84. Abderrezak A, Bourassa P, Mandeville JS, Sedaghat-Herati R, Tajmir-Riahi HA (2012)
Dendrimers bind antioxidant polyphenols and cisplatin drug. PLoS One 7(3):e33102
85. Yue Y, Eun JS, Lee MK, Seo SY (2012) Synthesis and characterization of G5 PAMAM den-
drimer containing daunorubicin for targeting cancer cells. Arch Pharm Res 35(2):343–349
86. Raja KS, Balambika R, Dolai S, Shi W (2009) The concept of a green drug, curcumin and it’s
derivatives as a model system. Mini Rev Org Chem 6(2):152–158
87. Mukherjee S, Ray S, Thakur RS (2009) Solid lipid nanoparticles: a modern formulation
approach in drug delivery system. Indian J Pharm Sci 71(4):349
88. Wei T, Chen C, Liu J, Liu C, Posocco P, Liu X, Cheng Q, Huo S, Liang Z, Fermeglia M, Pricl
S (2015) Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer to
combat cancer drug resistance. Proc Natl Acad Sci 112(10):2978–2983
89. Serpe L, Catalano MG, Cavalli R, Ugazio E, Bosco O, Canaparo R, Muntoni E, Frairia R,
Gasco MR, Eandi M, Zara GP (2004) Cytotoxicity of anticancer drugs incorporated in solid
lipid nanoparticles on HT-29 colorectal cancer cell line. Eur J Pharm Biopharm 58(3):673–680
90. Shen H, Shi S, Zhang Z, Gong T, Sun X (2015) Coating solid lipid nanoparticles with hyal-
uronic acid enhances antitumor activity against melanoma stem-like cells. Theranostics
5(7):755
1384 T. Alex et al.

91. Bang C, Thum T (2012) Exosomes: new players in cell–cell communication. Int J Biochem
Cell Biol 44(11):2060–2064
92. Agrawal AK, Aqil F, Jeyabalan J, Spencer WA, Beck J, Gachuki BW, Alhakeem SS, Oben
K, Munagala R, Bondada S, Gupta RC (2017) Milk-derived exosomes for oral delivery of
paclitaxel. Nanomedicine 13(5):1627–1636
93. Salarpour S, Forootanfar H, Pournamdari M, Ahmadi-Zeidabadi M, Esmaeeli M, Pardakhty
A (2019) Paclitaxel incorporated exosomes derived from glioblastoma cells: comparative
study of two loading techniques. DARU J Pharm Sci 27(2):533–539
94. Zhuang X, Xiang X, Grizzle W, Sun D, Zhang S, Axtell RC, Ju S, Mu J, Zhang L, Steinman
L, Miller D (2011) Treatment of brain inflammatory diseases by delivering exosome encapsu-
lated anti-inflammatory drugs from the nasal region to the brain. Mol Ther 19(10):1769–1779
95. Osterman CJ, Lynch JC, Leaf P, Gonda A, Ferguson Bennit HR, Griffiths D, Wall NR (2015)
Curcumin modulates pancreatic adenocarcinoma cell-derived exosomal function. PLoS One
10(7):e0132845
96. Wei H, Chen J, Wang S, Fu F, Zhu X, Wu C, Liu Z, Zhong G, Lin J (2019) A nanodrug con-
sisting of doxorubicin and exosome derived from mesenchymal stem cells for osteosarcoma
treatment in vitro. Int J Nanomedicine 14:8603
97. Lin FZ, Wang SC, Hsi YT, Lo YS, Lin CC, Chuang YC, Lin SH, Hsieh MJ, Chen MK (2019)
Celastrol induces vincristine multidrug resistance oral cancer cell apoptosis by targeting
JNK1/2 signaling pathway. Phytomedicine 54:1–8
98. Aqil F, Kausar H, Agrawal AK, Jeyabalan J, Kyakulaga AH, Munagala R, Gupta R (2016)
Exosomal formulation enhances therapeutic response of celastrol against lung cancer. Exp
Mol Pathol 101(1):12–21
99. Hannafon BN, Carpenter KJ, Berry WL, Janknecht R, Dooley WC, Ding WQ (2015)
Exosome-mediated microRNA signaling from breast cancer cells is altered by the anti-­
angiogenesis agent docosahexaenoic acid (DHA). Mol Cancer 14(1):1–3
100. Schaffazick SR, Guterres SS, Freitas LD, Pohlmann AR (2003) Caracterização e estabilidade
físico-química de sistemas poliméricos nanoparticulados para administração de fármacos.
Química nova 26:726–737
101. Brewer E, Coleman J, Lowman A (2011) Emerging technologies of polymeric nanoparticles
in cancer drug delivery. J Nanomater 2011:1–10
102. Bisht S, Feldmann G, Soni S, Ravi R, Karikar C, Maitra A, Maitra A (2007) Polymeric
nanoparticle-encapsulated curcumin (“nanocurcumin”): a novel strategy for human cancer
therapy. J Nanobiotech 5(1):1–8
103. Khanna V, Kalscheuer S, Kirtane A, Zhang W, Panyam J (2019) Perlecan-targeted nanopar-
ticles for drug delivery to triple-negative breast cancer. Future Drug Discov 1(1):FDD8
104. Shafiei-Irannejad V, Samadi N, Salehi R, Yousefi B, Rahimi M, Akbarzadeh A, Zarghami N
(2018) Reversion of multidrug resistance by co-encapsulation of doxorubicin and metformin
in poly (lactide-co-glycolide)-d-α-tocopheryl polyethylene glycol 1000 succinate nanopar-
ticles. Pharma Res 35(6):1–3
105. Yuan JD, ZhuGe DL, Tong MQ, Lin MT, Xu XF, Tang X, Zhao YZ, Xu HL (2018) pH-­
sensitive polymeric nanoparticles of mPEG-PLGA-PGlu with hybrid core for simultaneous
encapsulation of curcumin and doxorubicin to kill the heterogeneous tumour cells in breast
cancer. Artif Cells Nanomed Biotechnol 46(sup1):302–313
106. Jin M, Jin G, Kang L, Chen L, Gao Z, Huang W (2018) Smart polymeric nanoparticles
with pH-responsive and PEG-detachable properties for co-delivering paclitaxel and survivin
siRNA to enhance antitumor outcomes. Int J Nano 13:2405
107. Çırpanlı Y, Allard E, Passirani C, Bilensoy E, Lemaire L, Çalış S, Benoit JP (2011)
Antitumoral activity of camptothecin-loaded nanoparticles in 9L rat glioma model. Int J
Pharma 403(1–2):201–206
108. Soma CE, Dubernet C, Bentolila D, Benita S, Couvreur P (2000) Reversion of multidrug
resistance by co-encapsulation of doxorubicin and cyclosporin A in polyalkylcyanoacrylate
nanoparticles. Biomaterials 21(1):1–7
Nanotechnological Modus Operandi for the Delivery of Cytotoxic Phytochemicals 1385

109. Zhao Y, Cai C, Liu M, Zhao Y, Pei W, Chu X, Zhang H, Wang Z, Han J (2019) An organic
solvent-free technology for the fabrication of albumin-based paclitaxel nanoparticles for
effective cancer therapy. Colloids Surf B: Biointerfaces 183:110394
110. Yu Y, Kong L, Li L, Li N, Yan P (2015) Antitumor activity of doxorubicin-loaded carbon
nanotubes incorporated poly (lactic-co-glycolic acid) electrospun composite nanofibers.
Nanoscale Res Lett 10(1):1–9
111. Soukasene S, Toft DJ, Moyer TJ, Lu H, Lee HK, Standley SM, Cryns VL, Stupp SI (2011)
Antitumor activity of peptide amphiphile nanofiber-encapsulated camptothecin. ACS Nano
5(11):9113–9121
112. Baig MM, Lai WF, Ashraf S, Saleem A, Akhtar MF, Mikrani R, Naveed M, Siddique F,
Taleb A, Mudassir J, Khan GJ (2020) The integrin facilitated internalization of fibronectin-­
functionalized camptothecin-loaded DNA-nanofibers for high-efficiency anticancer effects.
Drug Deliv Transl Res 10(5):1381–1392
113. Vashisth P, Singh RP, Pruthi V (2016) A controlled release system for quercetin from biode-
gradable poly (lactide-co-glycolide)–polycaprolactone nanofibers and its in vitro antitumor
activity. J Bioact Compat Polym 31(3):260–272
114. Arbade GK, Kumar V, Tripathi V, Menon A, Bose S, Patro TU (2019) Emblica officinalis-­
loaded poly (ε-caprolactone) electrospun nanofiber scaffold as potential antibacterial and
anticancer deployable patch. New J Chem 43(19):7427–7440
115. Amna T, Barakat NA, Hassan MS, Khil MS, Kim HY (2013) Camptothecin loaded poly
(ε-caprolactone) nanofibers via one-step electrospinning and their cytotoxicity impact.
Colloids Surf A Physicochem Eng Asp 431:1–8
116. Zhou Z, Piao Y, Hao L, Wang G, Zhou Z, Shen Y (2019) Acidity-responsive shell-­
sheddable camptothecin-based nanofibers for carrier-free cancer drug delivery. Nanoscale
11(34):15907–15916
117. Sedghi R, Shaabani A, Mohammadi Z, Samadi FY, Isaei E (2017) Biocompatible electro-
spinning chitosan nanofibers: a novel delivery system with superior local cancer therapy.
Carbohydr Polym 159:1
118. Wen P, Hu TG, Li L, Zong MH, Wu H (2018) A colon-specific delivery system for quer-
cetin with enhanced cancer prevention based on co-axial electrospinning. Food Funct
9(11):5999–6009
119. Eskitoros-Togay ŞM, Bulbul YE, Dilsiz N (2018) Quercetin-loaded and unloaded electro-
spun membranes: synthesis, characterization and in vitro release study. J Drug Deliv Sci
Technol 47:22–30
120. Stoyanova N, Spasova M, Manolova N, Rashkov I, Georgieva A, Toshkova R (2020)
Antioxidant and antitumor activities of novel quercetin-loaded electrospun cellulose acetate/
polyethylene glycol fibrous materials. Antioxidants 9(3):232
121. Vieira DB, Gamarra LF (2016) Advances in the use of nanocarriers for cancer diagnosis and
treatment. Einstein (Sao Paulo) 14:99–103
122. ClinicalTrials.gov. https://clinicaltrials.gov/. Accessed 03 Feb 2022
Plant-Based Green Nanoparticles
in Cancer Diagnosis and Chemotherapy

Arun John and Rinu Elizabeth Roy

1 Introduction

‘There is plenty of room at the bottom’ is a famous dialogue in a speech delivered

by Richard A. Feynman, father of nanotechnology, at the meeting of American
Physical Society on December 29, 1959, at California Institute of Technology
(CalTech). Because of its widespread applications and unexpected properties, intro-
duction of this scientific branch was a great achievement in the science endower,
and the trivial name nanotechnology was coined by Norio Taniguchi, a Japanese
scientist, after one decade in 1969 [1]. After another ten decades, from 1981 modern
nanotechnology explored along with the development of atomic level or nano-level
observation tools like scanning tunnelling microscopy (STM) and transition elec-
tron microscopy (TEM). Nanotechnology can be defined as a branch of science,
engineering and technology based on nanoscale particles, which is in the size range
1–100 nm. It is an interdisciplinary area across all scientific fields such as chemistry,
physics, biology, medicinal science, material science and engineering [1].
When the bulk material was converted to nanomaterial, there is a drastic change
in the physical and chemical properties. Its modified electronic, biochemical and
optical properties are due to the quantum size effect and increase in the band gap
between conduction and valence band. Its magic mechanical, catalytical and ther-
mal properties are due to increase in the surface area to volume ratio. Many of the
nanomaterials show anti-bacterial and anti-fungal properties which are attributed to
the anti-microbial characteristics through exceedingly large surface area with
respect to its size and compactable size to cell wall pores. Extraordinary

A. John (*)
St. Thomas College, Kozhencherry, Kerala, India
R. E. Roy
Christian College, Alappuzha, Kerala, India

© The Author(s), under exclusive license to Springer Nature 1387

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_58
1388 A. John and R. E. Roy

biochemical and optical properties of some nanomaterials help in rapid and sensi-
tive detection of cancer cells and tumours [2]. Nanoparticles act as selective drug
delivery vehicles, deliver medicines like chemotherapy directly to the tumours.
Even though the nanoparticles are in the 1–100 nm size range these can also be
classified on the basis of the nanostructure dimensions as zero-dimensional (0D),
one-dimensional (1D), two-dimensional (2D) and three-dimensional (3D) nanoma-
terials. Zero-dimensional nanomaterials are nanoparticles that have nanodimension
in all the three dimensions, for example, quantum dots, metal nanoparticles, carbon
dots and fullerenes. One-dimensional nanoparticles is in nano range in two dimen-
sions and out of nanoscale in the remaining one dimension; example, nanotubes and
nanowires [3]. In two-dimensional nanoparticles, they are nanoscale in one dimen-
sions and out of nano in two dimensions; for example, nanosheets and graphene.
Three-dimensional nanomaterials are composites or aggregates of different nano-
structures and are out of nanoscale in all the three dimensions.
Discovery of nanotechnology and its development is a milestone in cancer ther-
apy, especially in the diagnosis and drug delivery system, and it is an emerging
interdisciplinary branch. Nanoparticles are initially designed to carry small hydro-
phobic molecules, later which was also used for the delivery of antibodies, DNA,
peptides, imaging agents and other chemicals for treatments especially in the cancer
detection and treatment. In traditional drug delivery systems, oral ingestion and
intravascular injections are used for the chemo-distribution throughout the body by
the help of blood circulation systems. Efficiency of this systems are very less, since
a small part of the drugs is reached in the targeted area. Targeted drug delivery is
considered the main remedy to this problem, which helps in the complete delivery
of medicine in the targeted spot and reduces side effects [4].
Jatzkewitz was the first scientist in 1953 to develop a polymer-based drug deliv-
ery system. In 1960, Bangham et al. developed a liposomal-based drug delivery
system. Later in 1972, Scheffel et al. synthesized one micron sized human serum
albumin particles, which is used for human serum albumin micropore-based
albumin-­bound paclitaxel (Abraxane) as drug delivery system [5, 6]. Liposomal
doxorubicin (Doxil) was the first Food and Drug Administration (FDA)-approved
nanodrug for the treatment of Kaposi’s sarcoma in AIDS patients [7]. In this method,
Doxil was delivered at tumour sites through passive targeting which is also used for
drug delivery in multiple myelomas and ovarian cancers [8]. Myocet and
DaunoXome are non-pegylated liposomal doxorubicin and former is approved by
Canada and European countries for the treatment of breast cancer and later was
approved by the FDA for the first-line treatment of advanced AIDS-related Kaposi’s
sarcoma. In 2012, FDA approved Marqibo (vincristine sulphate liposome injection)
for the treatment of Philadelphia chromosome negative (Ph− acute lymphoblastic
leukaemia (ALL) [9].
There are different types of cancer treatments using nanoparticles – antibody-­
based targeting, aptamer-based targeting and ligand-based targeting. These mecha-
nisms are schematically represented in Fig. 1. Antibody-based targeting is a
well-established method for nuclear nanomedicine-based diagnostic and
Plant-Based Green Nanoparticles in Cancer Diagnosis and Chemotherapy 1389

Fig. 1 Schematic diagram of different mechanisms the cancer therapy on cells using nanoparticles

therapeutic purposes. Human epidermal growth factor receptor 2 is another method

and it is overexpressed in approximately 25% of invasive breast cancer. In ligand-­
based targeting, a number of targeting moieties have been used to functionalize the
surface of nanoparticles including short amino acid polymers, as well as small mol-
ecules (such as folic acid) and peptides (such as transferrin).

2 Gold Nanoparticles (AUNPS): Plant-Based Synthesis

and Cancer Treatment

Gold nanoparticles are considered promising nanoparticles for imaging and treat-
ment owing to their ease of green synthesis and functionalization, biocompatibil-
ity, as well as non-toxicity. AuNPs are cancer in vivo therapist and diagnostic
agents. These nanoparticles are radiation enhancers, laser therapy enhancers, con-
trast agents and radiofrequency thermotherapy enhancers [10]. During the radio-
therapy treatment using AuNPs, higher dose was received by cancerous cells than
the normal cells. Gold is biocompatible, non-toxic nanoparticles with potential
biocompatibility and the LD50 of this material is about 3.2 g (Au) per kg of body
weight [11].
1390 A. John and R. E. Roy

2.1 Gold Nanoparticles in Sensors for Probing and Imaging

Tumour Cells

AuNPs are wonderful candidates for sensing application in probing and imaging
tumour cells due to their ability to interact strongly with visible light. When exposed
to light, AuNP absorbs and scatters visible light because electrons in AuNP get
excited to a state of collective oscillation through surface plasmon resonance (SPR).
In the cancer imaging applications, AuNPs are targeted and accumulated in the
tumours and can be visualized in the region and cells under study through their
amazing optical scattering properties. Here, AuNPs can be detected by using phase
contrast optical microscopy, dark field microscopy, photothermal imaging, photo-
acoustic imaging, etc. Because of high atomic weight, AuNPs are used as a visual-
izing labelling agent and immunostaining at the ultrastructural level using
transmission electron microscopy [12]. It can be demonstrated that antibody-­
conjugated AuNP can be located at the receptors present on the plasma membrane
of cells (Fig. 2).

Fig. 2 Schematic diagram for imaging cancer cells with receptors on the surface with the help of
antibody-conjugated gold nano particles
Plant-Based Green Nanoparticles in Cancer Diagnosis and Chemotherapy 1391

2.2 Gold Nanoparticles As a Drug Delivery Vehicle Targeted

to Cancer Cells

One of the main functions of AuNPs in the cancer treatment as a drug delivery
vehicle is in the selective delivery of medicines in the site. Sze, charge and surface
properties of the nanoparticles have affected the uptake of AuNPs into cells and
their subsequent intracellular fate. The nature of covalent/non-covalent interactions
in drug-AuNP conjugate structure and the means of drug release following intro-
duction of the drug-AuNP complexes to cells give an effective drug delivery strat-
egy. The usage of AuNP as a drug delivery agent is critical to monitor any toxic
effects of residual materials in the cell after delivery AND an ideal model is a bio-
degradable nanoparticle vector whose lifespan is limited to the therapeutic window
[13]. The non-toxic profile and biocompatibility make AuNP as an amazing drug
delivery vehicle in cells.
In the cancer treatment field, AuNPs are currently being used as AuNP of various
shapes and sizes are absorbed by cancer cells either through a ligand–receptor spe-
cific interaction or non-specific means. In actual practice, AuNPs are coupled with
drug molecule and an appropriate ligand which directed them only to tumour cells.
Conjugation of AuNP to polyethylene glycol (PEG), and the conjugation of AuNPs
with specific antibodies that bind unique biomarkers expressed on tumour cells are
two main methods described by Chen et al. [14]. Modified AuNPs being taken up
by cancer cells are shown in Fig. 3.

Fig. 3 Schematic diagram of drug delivery system, AuNPs conjugated with anti-cancer drugs and
ligands coupled with the receptors on the surface of tumour cells
1392 A. John and R. E. Roy

Conjugation with PEG modifies the properties of AuNPs, prevents AuNP aggre-
gation and lengthens their retention time in blood. This modification also facilitates
the specific accumulation of AuNPs in tumour cells over healthy cells since the
elevated permeability of poorly differentiated blood vessels around tumours follow-
ing angiogenesis as well as the decreased clearance rate caused by the deficit of
functional lymphatic vessels in tumours [15].

2.3 Gold Nanoparticle as Computed Tomography Contrast

Agent in Detection of Cancer

In cancer detection, AuNPs are focused on the study of its application as X-ray
contrast agents. Iodine-based compounds, currently used in computed tomography
(CT) contrast agents, have several limitations such as including short imaging times
due to rapid renal clearance, renal toxicity and the need for catheterization in many
cases. When compared with iodine compounds, AuNPs are permitting longer imag-
ing time since they stay in the blood for a longer time than iodine agents.
Tissue distinguishability between different types of tissues based on computed
thermography (CT) depends on difference in degree of X-ray attenuation, where
attenuation coefficient is a function of the atomic number and electron density of the
contrast agents. AuNPs have more advantages over iodine-based contrast agents
because the atomic number and electron density of gold (79 and 19.32 g/cm3, respec-
tively) are much higher than those of the currently used iodine (53 and 4.9 g/cm3).
Therefore, when compared with the iodine compounds, AuNPs have higher absorp-
tion and better contrast can be achieved with lower X-ray dose. AuNPs are also used
for the enhanced detection of blood vessels. In 1970s, Dr. Judah Folkman of the
Harvard Medical School suggested that the cancer growth and metastasis depend on
angiogenesis for nutrients and oxygen and we can fight against cancer by inhibiting
new blood vessel formation [16]. In an advanced study, Chien et al. injected AuNPs
(1.9 nm in diameter) intravenously and recorded images over time with a standard
mammography unit. In this study, cancer tumours and kidney were seen with unusual
clarity and high spatial resolution. AuNPs are highly efficient and the smallest mea-
sured blood vessel lumen diameters were 3–5 μm. Computed thermography contrast
agent can be developed using antibiofouling polymer-coated AuNPs, gadolinium-
coated AuNPs, PEG-coated nanoparticles and antibody-coated nanoparticles.

2.4 Plant-Based Green Synthesis of Gold Nanoparticle

Application of AuNPs in biomedical applications especially in cancer imaging and

treatment is a very active research area in recent years. Green synthetic routes are
most acceptable method for the preparation of biocompatible AuNP for
Plant-Based Green Nanoparticles in Cancer Diagnosis and Chemotherapy 1393

biochemical uses. AuNPs can be easily synthesized using AuNPs using common
stabilizing agents such as sodium citrate, transferrin and cetyltrimethylammonium
bromide, while common species used for functionalization include various amines,
oligonucleotides, peptides, antibodies and lipids. Selection of different plants, algae,
bacteria and fungi as reducing agents and stabilizing agents for the size selective
biocompatible gold nanoparticle synthesis is a highly studied area [17]. For exam-
ple, AuNPs with particle-size distributions in the range of 2–12 nm were synthe-
sized by Raveendran et al. using glucose as a reducing agent and starch as a
protective agent. Huang et al. used Bayberry’s tannin extract simultaneously as
reducing and protective agents for the synthesize of AuNPs with an average size of
2 nm. Sharma et al. reported a synthetic root for AuNP preparation from the tea leaf
extract. Different concentration of the tea leaf extract could be used to control the
size of synthesized nanoparticles. Suman et al. [18] used extract from Morinda citri-
folia roots at room temperature for the synthesize of 8–17 nm sized AuNPs.
10 g of leaf, fruit or any other plant part is weighed and washed thoroughly four
times using double distilled water. This clean plant parts were cut into small pieces
and put into a blade blender with 30 mL of double distilled water until a homoge-
neous fluid was obtained. The plant extract was then diluted to 50 mL using distilled
water and larger particles in the extract can be removed through centrifugation for
2 min, followed by filtering through a 0.45 μm filter and the extracts were kept fro-
zen at −18 °C until used. In the green method of AuNP synthesis, consumable plant
parts with high antioxidant content were employed to ensure biocompatibility.
AuNPs could be synthesized by mixing 10 mL of the gold ion solution (1.0 mg
HAuCl4) with 0.75 mL of plant extract. Deep purple/red solution will be formed
within a few seconds, which is the indication of AuNP formation [19]. By changing
the time, temperature and pH, AuNP with varying size and shape can be synthesized
from plant extract (Fig. 4).

Fig. 4 Different steps in the synthesis of gold nanoparticle using plant extract
1394 A. John and R. E. Roy

3 Silver Nanoparticle: Green Synthesis

and Cancer Treatment

In recent years, nanoparticles of relatively noble metals such as gold, silver, copper
and palladium have drawn immense attention due to the wide range of new applica-
tions in various interdisciplinary areas including biochemical, medicinal, industrial
fields. Particularly, silver nanoparticles (AgNPs) have significant interest in medical
applications such as cancer imaging, cancer treatment, anti-bacterial agents without
toxic effects and industrial applications such as inkjet links containing well uniform
dispersions of nanosized silver particles that are useful for producing electronic
circuits [20]. For the proper utilization of AgNP for various applications, it requires
that the particles must be of nanosize and they must be produced easily as well as at
low cost and time consumption (Fig. 5).

3.1 Silver Nanoparticle in Different Cancer Diagnosis

and Treatments

In the ancient years, silver was used as an anti-inflammatory and anti-bacterial agent.
The most widely used silver compounds in biomedical application is silver sulphadi-
azine that is now replaced by the nanosilver. Green-synthesized AgNP is used in

Fig. 5 Green synthetic route for silver nanoparticle synthesis from plant extract
Plant-Based Green Nanoparticles in Cancer Diagnosis and Chemotherapy 1395

healthy pertaining commercial product improving aspects along with sustainable

properties. In the green method, plants are widely used as reducing and caping agents
for AgNP synthesis. Other biological materials such as microorganisms are also used
in the green synthesis of AgNPs. Aqueous stem bark extract of Moringa oleifera and
gum powder aqueous extract of gum powder aqueous extract were used in the AgNP
synthesis that triggered intracellular ROS production leading to DNA damage ulti-
mately causing apoptotic HeLa cells death in cervical cancer [19].
AgNPs can also be synthesized using marine algae, Ecklonia cava extract and by
using culture supernatant of Trichoderma harzianum fungus in the treatment of cer-
vical cancer of apoptotic and necrotic cells. AgNPs were also synthesized using
E. cava marine algae extract which replaces the highest IC50 value followed by
using benzoin gum powder extract. An anti-cancer compound extracted from
E. cava enhances the anti-cancer activity of green-synthesized AgNP from the
marine algae E. cava, that can be used for cancer treatment of almost all types of
cancers [21]. AgNPs synthesized from Adenium obesum leaf extract were used to
induce the apoptosis and autophagy via DNA damage and ROS generation in human
breast cancer cells (MCF-7 cell lines). AgNPs synthesized from aqueous extract of
flowers of Cassia fistula used in different cancer therapies inducing apoptosis in
human breast cancer cells as observed by acridine orange/ethidium bromide stain-
ing. Green-synthesized AgNP from aqueous root hair extract of Phoenix dactylifera
caused cancer cell death by arresting cell cycle at sub-G1 and S phase and are bio-
compatible with the healthy cells [22]. AgNP can also be synthesized from galacto-
mannan, the compound isolated from the aqueous extract from the fruit of Punica
granatum was used for induced cell death in lung cancer (A549 cell line) [23], colon
cancer (HCT116 cell line) and liver cancer cells (HepG2 cell line) while the toxicity
was significantly less in the mouse fibroblast cell (3T3-L1 cell line) [24] and here
the cell death was induced by activation of apoptotic pathways. AgNP synthesized
from aqueous peel extract of Dimocarpus longan was cytotoxic towards lung cancer
cells (H1299 cell line) [25], prostate cancer cells (VCaP cell line), and pancreatic
cancer cells (BxPC-3 cell line) [26].

3.2 Plant-Mediated Green Synthesis of Silver Nanoparticles

Biogenic synthesis of AgNPs is known for many researchers from long time.
Biogenic synthetic routes have several advantages over traditional chemical or
physical ones, since they are eco-friendly. Biological approach for synthesizing
AgNPs is being increasingly considered over the past few decades. This method is
a green technology aimed at minimizing the negative environmental impact. It had
been known that the synthesis of AgNPs using the chemical approach requires three
main ingredients; a silver salt, a reducing agent and the stabilizer which are replaced
using molecules obtained from living organisms such as plants, bacteria, fungi,
yeast and algae in biological approach [27, 28]. Plant extracts are eco-friendly
reducing agents used for the synthesis of AgNPs and are discussed below:
1396 A. John and R. E. Roy

20 g of fresh leaves or plant parts were collected and washed with distilled water
to remove all the unwanted dust particles, dried and the leaves were cut into small
pieces. The weighed leaves were transferred into a clean beaker containing 200 mL
of distilled water. It is boiled for 30 min. Then the extract was cooled and filtered
using Whatmann No. 1 and stored at 4 °C.
5 mL of plant extract was then added to 10 mL of 1 M (0.016 g) AgNO3 solution.
Shake well and keep the extract for 24 h in dark condition. The colour changes from
pale green to reddish brown indicating the formation of AgNPs.

4 Copper Nanoparticles (CuNPs) in Cancer Therapy

and Green Synthetic Routes

CuNPs showed excellent anti-cancer activity and exhibited a dose-dependent deg-

radation of DNA molecules through oxygen generation. CuNPs are also used as an
antibiotic, anti-microbial and anti-fungal agent when added to plastics, coatings
and textiles. CuNPs with efficient delivery characteristics are also used as diet
supplements. CuNP exhibits strong absorption in near-infrared region, exhibits
highly efficient light-to-heat transformation under near-infrared laser irradiation
and is used in selective thermal destruction of tumours. They also display fluores-
cence signal and capability for optical imaging. CuNPs serve as a carrier vehicle
for drug delivery and image-guided cancer therapy. Dry black bean (Phaseolus
vulgaris) plant extract was used for the synthesis of CuNPs and was found to be
cytotoxic to cervical cancer [29]. An activation of apoptotic pathways cellular
death was observed by intracellular ROS. Growth inhibition of the cells was also
analysed by colony-forming assay.

4.1 Copper Nanoparticles (CuNPs) in Cancer Therapy

A terpenoid (Cantharadin) extracted from Tamarindus indica was found to be an

anti-cancer compound. Hence, CuNPs synthesized from the extract of T. indica was
very effective in cancer treatment. CuNPs synthesized using aqueous leaf extract of
Olea europaea, showed cytotoxicity towards breast cancer (AMJ-13) and ovarian
cancer (SKOV-3) cells [30]. Green CuNPs from Azadirachta indica, Hibiscus rosa-­
sinensis, Murraya koenigii, Moringa oleifera and T. indica showed cytotoxicity
towards breast cancer cells (MCF-7). Green CuNPs synthesized from O. europaea
leaf extract showed the highest anti-cancer potential against AMJ-13 breast cancer
cells [31]. Due to the presence of anti-cancer compound hydroxytyrosol – a phenyl-
ethanoid, nanoparticle from the O. europaea showed higher anti-cancer potential.
CuNPs synthesized from aqueous leaf extract of Ficus religiosa was found to be
cytotoxic to lung cancer cells.
Plant-Based Green Nanoparticles in Cancer Diagnosis and Chemotherapy 1397

4.2 Green Synthesis of Copper Nanoparticle

Researchers now focus on the environmentally friendly synthetic method employ-

ing plant leaves, fruits, bark, and floral extracts. Aqueous leaf extracts of Azadirachta
indica, Hibiscus rosa-sinensis, Murraya koenigii, Moringa oleifera, and Tamarindus
indica can be used to create eco-friendly green synthetic CuNPs [30]. In this regard,
many plants were used for synthesizing, for example, the Syzygium aromaticum
(dried flower buds), Ocimum sanctum (leaf) [31], Magnolia kobus (leaf), Lawsonia
inermis (leaves), Nerium oleander (leaf), Euphorbia esula L (leaves), Vitis vinifera
(leaf) [32], Gloriosa superba L. (flower), Aloe vera (leaf) and citrus fruits and the
synthetic routes are as described below [33, 34] (Figs. 6 and 7).
200 g of fresh citrus fruits were washed in double distilled water and its fruit
juice was separated. It is diluted to 100 mL using double distilled water. The content
was transferred into a 250 mL beaker and heated for 10 min at 80 °C. Afterwards,
the solution was filtered using Whatman No. 40 filter paper to obtain citrus lemon
fruit aqueous extract. The clear filtrate was kept in a refrigerator for the experimen-
tal work. 100 mL of the extract was mixed with 4 g of copper sulphate pentahydrate
under magnetic stirring for 4 h at room temperature. After 4 h, blue coloured copper
sulphate solution changed into a brown colour indicating the formation of CuNP
through the reduction of copper ions from Cu (II) ions to Cu metal. The synthesized
copper nanoparticle solution was then centrifuged at 3000 rpm for 10 min to get a
clear solution and the synthesized nanoparticle can be characterized using
UV-Visible spectroscopy, FT-IR, SEM and XRD analysis.

Fig. 6 Steps in silver nanoparticle synthesis and characterization using plant extract
1398 A. John and R. E. Roy

Fig. 7 Green synthetic route for the synthesis of green copper nanoparticle from plant extract

5 Polymeric Nanoparticles (PNPS)

Polymer-based nanoparticles are emerging systems that are used in preclinical stud-
ies and as promising delivery agents. Polymers serve as a structural engineer for the
preparation of multifunctional nanoparticles with suitable size, shape and surface
functionalization. The excellent pharmacokinetic properties of polymeric nanopar-
ticles make them an ideal candidate for drug delivery applications. It is reported that
for the initiation, propagation and regeneration of cancers, the cancer stem cells
(CSCs) play a major role. Hence, recent studies report the functionalization of CSCs
on to the exterior or interior of the PNPs for the successful elimination of CSCs.
Polymeric drug-loaded nanoparticles are the best delivery systems developed so
far because of their excellent pharmacokinetic behaviour, size of particles, rate of
drug loading, surface charge and chemistry, speed of degradation etc., need to be
included [35–37]. Surface functionalization of PNPs makes the suitable as an effi-
cient drug vehicle by effectively accumulating the loaded drugs in cancer cells with-
out harming the healthy cells [36].
Some of the polymers in recent research, selectively used for CSC therapy,
include poly (D, L-lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), poly
(ethylene glycol) (PEG), chitosan (CS) and hyaluronic acid (HA) [37].
Plant-Based Green Nanoparticles in Cancer Diagnosis and Chemotherapy 1399

5.1 Poly (Lactide-CO-Glycolide) [PLGA]

The excellent biodegradability and biocompatibility makes PLGA suitable for

CSCs therapy as an efficient drug-loaded PNP [38–40]. Double emulsion method is
applied for the synthesis of PLGA nanoparticles, and the release of the drug to can-
cer cells along with their thermal response is triggered under acidic pH. Muntmadugu
et al. used PLGA decorated using salinomycin (SLM) and paclitaxel (PTX) to
destroy CSCs and normal cancer cells [41]. Further, Swaminathan et al. synthesized
PLGA nanoparticles which were found to be efficient in reducing the breast CSC
population with enhancement in their therapeutic efficacy. Smart PLGA nanoparti-
cles were also prepared by functionalizing its surface using HA and PF127 for tar-
geted cancer therapy applications.

5.2 Hyaluronic Acid (HA)

The anionic HA is a glycosaminoglycan, found dispersed in the connective, epithe-

lial and neural tissues and is known for its excellent properties like non-­
immunogenicity and biocompatibility. Hence, its surface is being decorated using a
wide variety of drugs specially for cancer treatment [42, 43]. Studies on functional-
ized HA using 5.2 g cholesterol (CHA) efficiently served as a template for selected
drugs in the CSCs therapy through an eco-friendly covalent connection. Several
bioconjugates of HA using paclitaxel and siRNA were developed selectively for
ovarian cancers and were found effective in destroying the gene activity both in
vitro and in vivo [43, 44]. Nevertheless, these HA nanoparticle-based drug delivery
systems were found to be defective in cancer treatment since after administration of
the drug it was found to accumulate in the liver. A solution to this problem was
addressed by decorating the surface of HA nanoparticles using poly(ethylene) gly-
col and the results showed that the presence of nanoparticles was significantly
reduced in the liver [45].

5.3 Poly(Ethylene Glycol) (PEG)

The highly hydrophilic PEG with exceptional solubility, free mobility, non-toxicity
and non-immunogenicity finds a wide application in the biomedical field. Shen
et al. used poly(ethylene glycol)-block-poly(d,l-lactide) (PEG-b-PLA) nanoparti-
cles into highly non-polar botezomib used in clinical applications. The drug-loaded
PEG-b-PLA nanoparticles selectively destroyed CSCs thus increasing the applica-
bility of bortezomib in breast cancer therapy [46]. Studies were also carried on
diblock copolymer nanoparticles of PEG and surface modified polycarbonates
(PAC) synthesized using ring opening polymerization which improved the efficacy
1400 A. John and R. E. Roy

of anti-cancer drugs. Ke et al. incorporated PEG-b-PLA nanoparticles into

Doxorubicin (DOX) which enhanced its anti-cancer capability and reduced their
toxicity [47]. Intelligent PEG-peptide-poly (+caprolactone) nanoparticle drug deliv-
ery system was developed to study the effects of CSCs and non-stem cancerous
cells and also to reduce the growth of tumours.

5.4 Polylactic Acid (PLA)

The biodegradable polymer, PLA has been effectively used as a polymeric drug-­
loaded nanoparticle delivery system in the treatment of lung cancer stem cells [48].
The PLA nanoparticles were embedded in docetaxel (DTX) and the results proved
remarkable anti-metastatic act of this dug-loaded nanoparticle system in both in
vitro and in vivo experiments. A similar drug-loaded nanoparticle system based on
PLA nanoparticles was also developed [49] using the method of emulsion solvent
evaporation which could effectively inhibit the growth of tumours and also improved
its anti-metastatic capability in the treatment of cancer [50]. Another drug delivery
system based on PLA nanoparticles encapsulated in quercetin (Qt) was developed
by Pandey et al. for the treatment of breast cancer cells [51]. A new system of PLA
nanoparticles grafted on to cellulose was developed to act on betulinic drug [CE-g-­
PLL/BA] which could successfully suppress the growth of tumours with few side
effects than BA alone [52].

5.5 Chitosan

The natural biodegradable and biocompatible polysaccharide, chitosan which is

obtained from chitin has wide biomedical applications [53]. Chauhan et al. have
done a detailed study on the targeting ability of chitosan nanoparticles which is used
to destroy the CSCs. 20 nm-sized chitosan nanoparticles were synthesized and were
selectively delivered into the cancerous cells to kill the CSCs. A mechanistic
approach was also proposed in the study where the drug-loaded chitosan nanopar-
ticles will be simultaneously released and diffused into the cytosol and then gets
build up in the nuclei of the tumour cells to destroy CSCs. Chitosan-based poly-
meric nanoparticles were developed to reduce the toxic behaviour of the drug and to
modify it by functionalizing using polyethylene glycol (PEG) and peptides [54].
Another important application of chitosan-based nanoparticles is in cell recogni-
tion, wherein doxorubicin-decorated nanoparticles were developed to target the
CSCs [55].
Thus to conclude, a variety of polymeric nanoparticles were developed as an
efficient drug-loaded system by using a number of drugs to selectively identify and
destroy CSCs in cancer therapy via a controlled release of drugs.
Plant-Based Green Nanoparticles in Cancer Diagnosis and Chemotherapy 1401

6 Conclusion

This chapter gives a comprehensive idea about activated and regulated molecular
pathways of different green-synthesized nanoparticles that are causing cancer cell
imaging and death. Optimal drug delivery strategy is based on receptor-based active
selective targeting of nanoparticles. Tumour-based nano-delivery vehicles are
employed for early cancer detection, therapy and post-therapeutic follow-up. Mode
of action and intensity of different green-synthesized nanoparticles vary from one
form of cancer to the other, which depends on the nanoparticle material, size and
shape of the particle, selection of plant precursor etc. Apart from the properties of
green plant-mediated nanoparticles, the cellular response is also crucial. ROSs can
be considered as a precursor molecule of cell death because they are the initiator
molecule in apoptotic, autophagic and necroptotic pathways. In nano-therapy, the
main objective is to utilize nanoparticles for the in vivo targeted selective killing of
cancer cells with no or minimal side effects.
This area is an emerging research field, in which the development of effective,
less toxic, biocompatible, selective drug delivery systems is most important in the
cancer cell identification and treatment. The potential of green-synthesized plant
genic nanoparticle in therapeutic in vitro systems has been explored, while 3D
tumour model studies and clinical trials remain unexplored.

References

1. Khanna SC, Speiser P (1969) Epoxy resin beads as a pharmaceutical dosage form I: methods
of preparation. J Pharm 58:1114–1117
2. Speiser P, Khanna SC (1970) Perlpolymerisate, eine neue perorale Darreichungsform und ihre
Beeinflussung durch Arzneistoffe. Prapar Pharm 6:1–4
3. Hasan S (2015) A review on nanoparticles : their synthesis and types biosynthesis mechanism.
Res J Recent Sci 4:9–11
4. Korbekandi H, Iravani S (2012) In: Hashim AA (ed) Silver nanoparticles, the delivery of
nanoparticles; ISBN: 978-953-51-0615-9.
5. Machado S, Pacheco JG, Nouws HPA, Albergaria JT, Delerue-Matos C (2015) Characterization
of green zero-valent iron nanoparticles produced with tree leaf extracts. Sci Total Environ
533:76–81
6. Kreuter J (1983) Evaluation of nanoparticles as drug delivery systems I: preparation methods.
Pharm Acta Helv 58:196–209
7. Kommareddy S, Tiwari SB, Amiji MM (2005) Long-circulating polymeric nanovectors for
tumor-selective gene delivery. Technol Cancer Res Treat 4:615–625
8. El-Sayed MA (2001) Some interesting properties of metals confined in time and nanometer
space of different shapes. Acc Chem Res 34(4):257–264
9. Link S, El-Sayed MA (1999) Spectral properties and relaxation dynamics of surface plas-
mon electronic oscillations in gold and silver nanodots and nanorods. J Phys Chem B
103(40):8410–8426
10. Link S, El-Sayed MA (2000) Shape and size dependence of radiative, non-radiative and pho-
tothermal properties of gold nanocrystals. Int Rev Phys Chem 19(3):409–453
11. Weissleder R (2001) A clearer vision for in vivo imaging. Nat Biotechnol 19(4):316–317
1402 A. John and R. E. Roy

12. Huang XH, El-Sayed IH, Qian W, El-Sayed MA (2006) Cancer cell imaging and photothermal
therapy in the near-infrared region by using gold nanorods. J Am Chem Soc 128(6):2115–2120
13. Boisselier E, Astruc D (2009) Gold nanoparticles in nanomedicine: preparations, imaging,
diagnostics, therapies and toxicity. Chem Soc Rev 38:1759–1782
14. Chen YS, Hung YC, Liau I, Huang GS (2009) Assessment of the in vivo toxicity of gold
nanoparticles. Nanoscale Res Lett 4:858–864
15. Cho W, Cho M, Jeong J, Choi M, Cho H, Han B et al (2009) Acute toxicity and pharmacokinet-
ics of 13 nm-sized PEG-coated gold nanoparticles. Toxicol Appl Pharmacol 236:16–24
16. Kim C, Ghosh P, Rotello V (2009) Multimodal drug delivery using gold nanoparticles.
Nanoscale 1:61–67
17. Kumar KM, Mandal BK, Sinha M, Krishnakumar V (2012) Terminalia chebula mediated
green and rapid synthesis of gold nanoparticles. Spectrochim Acta A Mol Biomol Spectrosc
86:490–494
18. Suman TY, Radhika Rajasree SR, Ramkumar R, Rajthilak C, Perumal P (2014) The green syn-
thesis of gold nanoparticles using an aqueous root extract of Morinda citrifolia L. Spectrochim
Acta A Mol Biomol Spectrosc 118:11–16
19. Shankar SS, Ahmad A, Pasricha R, Sastry M (2003) Bioreduction of chloroaurate ions by
geranium leaves and its endophytic fungus yields gold nanoparticles of different shapes. J
Mater Chem 13(7):1822–1826
20. He Y, Du Z, Ma S, Cheng S, Jiang S, Liu Y, Li D, Huang H, Zhang K, Zheng X (2016)
Biosynthesis, antibacterial activity and anticancer effects against prostate cancer (PC-3) cells
of silver NPs using Dimocarpus Longan Lour. peel extract. Nanoscale Res Lett 11(1):300
21. Priyadharshini RI, Prasannaraj G, Geetha N, Venkatachalam P (2014) Microwave-mediated
extracellular synthesis of metallic silver and zinc oxide NPs using macro-algae (Gracilaria
edulis) extracts and its anticancer activity against human PC3 cell lines. Appl Biochem
Biotechnol 174(8):2777–2790
22. Netala VR, Bethu MS, Pushpalatha B, Baki VB, Aishwarya S, Rao JV, Tartte V (2016)
Biogenesis of silver NPs using endophytic fungus Pestalotiopsis microspora and evaluation of
their antioxidant and anticancer activities. Int J Nanomedicine 11:5683
23. Padinjarathil H, Joseph MM, Unnikrishnan BS, Preethi GU, Shiji R, Archana MG, Maya
S, Syama HP, Sreelekha TT (2018) Galactomannan endowed biogenic silver NPs exposed
enhanced cancer cytotoxicity with excellent biocompatibility. Int J Biol Macromol
118:1174–1182
24. Farah MA, Ali MA, Chen SM, Li Y, Al-Hemaid FM, Abou-Tarboush FM, Al-Anazi KM,
Lee J (2016) Silver NPs synthesized from Adenium obesum leaf extract induced DNA dam-
age, apoptosis and autophagy via generation of reactive oxygen species. Colloids Surf B
Biointerfaces 141:158–169
25. Remya RR, Rajasree SR, Aranganathan L, Suman TY (2015) An investigation on cytotoxic
effect of bioactive AgNPs synthesized using Cassia fistula flower extract on breast cancer cell
MCF-7. Biotechnol Rep 8:110–115
26. Jeyaraj M, Sathishkumar G, Sivanandhan G, Mubarak Ali D, Rajesh M, Arun R, Kapildev G,
Manickavasagam M, Thajuddin N, Premkumar K, Ganapathi A (2013) Biogenic silver NPs for
cancer treatment: an experimental report. Colloids Surf B Biointerfaces 106:86–92
27. Jiang H, Manolache S, Wong ACL, Denes FS (2004) Plasma enhanced deposition of silver
nanoparticles onto polymer and metal surfaces for the generation of antimicrobial characteris-
tics. J Appl Polym Sci 93:1411–1422
28. Chandran SP, Chaudhary M, Pasricha R, Ahmad A, Sastry M (2006) Synthesis of gold nano-
triangles and silver nanoparticles using Aloe vera plant extract. Biotechnol Prog 22:577–583
29. Krishnaraj C, Muthukumaran P, Ramachandran R, Balakumaran MD, Kalaichelvn PT (2014)
Acalypha indica Linn: biogenic synthesis of silver and gold NPs and their cytotoxic effects
against MDA-MB-231, human breast cancer cells. Biotechnol Rep 4:42–49
Plant-Based Green Nanoparticles in Cancer Diagnosis and Chemotherapy 1403

30. Nagajyothi PC, Muthuraman P, Sreekanth TV, Kim DH, Shim J (2015) Green synthesis:
in vitro anticancer activity of copper oxide NPs against human cervical carcinoma cells. Arab
J Chem 10(2):215–225
31. Shirisha R, Varalakshmi KN (2017) Tamarindus indica bark extract and its bioactive fraction
induce apoptosis in HeLa and PA-1 cells. Indian J Pharm Sci 78(6):725–731
32. Sulaiman GM, Tawfeeq AT, Jaaffer MD (2018) Biogenic synthesis of copper oxide NPs using
olea europaea leaf extract and evaluation of their toxicity activities: an in vivo and in vitro
study. Biotechnol Prog 34(1):218–230
33. Abboud Y, Saffaj T, Chagraoui A, El Bouari A, Brouzi K, Tanane O, Ihssane B (2014)
Biosynthesis, characterization and antimicrobial activity of copper oxide nanoparticles
(CONPs) produced using brown alga extract (Bifurcaria bifurcata). Appl Nanosci 4:571–576
34. Angrasan JKVM, Subbaiya R (2014) Biosynthesis of copper nanoparticles by Vitis vinifera
leaf aqueous extract and its antibacterial activity. Int J Curr Microbiol App Sci 3(9):768–774
35. Vinogradov S, Wei X (2012) Cancer stem cells and drug resistance: the potential of nanomedi-
cine. Nanomedicine 7:597–615. https://doi.org/10.2217/nnm.12.22
36. Fonseca AC, Ferreira P, Cordeiro RA, Mendonça PV, Góis JR, Gil MH et al (2013) Drug
delivery systems for predictive medicine: polymers as tools for advanced applications. In:
Mozaffari MS (ed) New strategies to advance pre/diabetes care: integrative approach by
PPPM. Springer, Dordrecht
37. Fonseca AC, Serra AC, Coelho JFJ (2014) Bioabsorbable polymers in cancer therapy: latest
developments. EPMA J 6:1–18. https://doi.org/10.1186/s13167-­015-­0045-­z
38. Chaubal M (2002) Polylactides/glycolides-excipients for injectable drug delivery and beyond.
Drug Deliv Technol 2:34–36
39. Astete CE, Sabliov CM (2006) Synthesis and characterization of plga nanoparticles. J Biomater
Sci Polym Ed 17:247–289. https://doi.org/10.1163/156856206775997322
40. Biondi M, Ungaro F, Quaglia F, Netti PA (2008) Controlled drug delivery in tissue engineer-
ing. Adv Drug Deliv Rev 60:229–242. https://doi.org/10.1016/j.addr.2007.08.038
41. Muntimadugu E, Kumar R, Saladi S, Rafeeqi TA, Khan W (2016) Cd44targeted chemother-
apy for co-eradication of breast cancer stem cells and cancercells using polymeric nanopar-
ticles of salinomycin and paclitaxel. Colloids Surf B Biointerfaces 143:532–546. https://doi.
org/10.1016/j.colsurfb.2016.03.075
42. Luo Y, Ziebell MR, Prestwich GD (2000) A hyaluronic acid-taxolantitumor bioconjugate tar-
geted to cancer cells. Biomacromolecules 1:208–218. https://doi.org/10.1021/bm000283n
43. Prestwich GD (2011) Hyaluronic acid-based clinical biomaterials derived for cell and molecule
delivery in regenerative medicine. J Control Release 155:193–199. https://doi.org/10.1016/j.
jconrel.2011.04.007
44. Banzato A, Bobisse S, Rondina M, Renier D, Bettella F, Esposito G et al (2008) A paclitaxel-­
hyaluronan bioconjugate targeting ovarian cancer affords a potent in vivo therapeutic activity.
Clin Cancer Res 14:3598–3606. https://doi.org/10.1158/1078-­0432.CCR-­07-­2019
45. Choi KY, Chung H, Min KH, Hong YY, Kim K, Park JH et al (2009) Self-assembled hyal-
uronic acid nanoparticles for active tumor targeting. Biomaterials 31:106–114. https://doi.
org/10.1016/j.biomaterials.2009.09.030
46. Choi KY, Min KH, Yoon HY, Kim K, Park JH, Kwon IC et al (2011) PEGylation of hyaluronic
acid nanoparticles improves tumor targetability in vivo. Biomaterials 32:1880–1889. https://
doi.org/10.1016/j.biomaterials.2010.11.010
47. Shen S, Du XJ, Liu J, Sun R, Zhu YH, Wang J (2015) Delivery of bortezomib with nanopar-
ticles for basal-like triple-negative breast cancer therapy. J Control Release 208:14–24. https://
doi.org/10.1016/j.jconrel.2014.12.043
48. Ke XY, Ng VWL, Gao SJ, Tong YW, Hedrick JL, Yang YY (2014) Co-delivery of thioridazine
and doxorubicin using polymeric micelles for targeting both cancer cells and cancer stem cells.
Biomaterials 35:1096–1108. https://doi.org/10.1016/j.biomaterials.2013.10.049
1404 A. John and R. E. Roy

49. Yang N, Jiang Y, Zhang H, Sun B, Hou C, Zheng J et al (2015) Active targeting docetaxel-PLA
nanoparticles eradicate circulating lung cancer stem like cells and inhibit liver metastasis. Mol
Pharm 12:232–239. https://doi.org/10.1021/mp500568z
50. Liang Z, Yang N, Jiang Y, Hou C, Zheng J, Shi J et al (2015) Targeting docetaxel-pla nanopar-
ticles simultaneously inhibit tumor growth and liver metastases of small cell lung cancer. Int J
Pharm 494:337–345. https://doi.org/10.1016/j.ijpharm.2015.08.042
51. Pandey SK, Patel DK, Thakur R, Mishra DP, Maiti P, Haldar C (2015) Anti-cancer evaluation
of quercetin embedded pla nanoparticles synthesized by emulsified nanoprecipitation. Int J
Biol Macromol 75:521–529. https://doi.org/10.1016/j.ijbiomac.2015.02.011
52. Dai L, Yang T, He J, Deng L, Liu J, Wang L et al (2014) Cellulosegraft- poly(l-lactic acid)
nanoparticles for efficient delivery of anti-cancer drugs. J Mater Chem B 2:6749–6757. https://
doi.org/10.1039/C4TB00956H
53. Senel S, Mcclure SJ (2004) Potential applications of chitosan in veterinary medicine. Adv
Drug Deliv Rev 56:1467–1480. https://doi.org/10.1016/j.addr
54. Nascimento AV, Singh A, Bousbaa H, Ferreira D, Sarmento B, Amiji MM (2015)
Combinatorial-designed epidermal growth factor receptortargeted chitosan nanoparticles for
encapsulation and delivery of lipid-modified platinum derivatives in wild-type and resistant
non-small-cell lung cancer cells. Mol Pharm 12:4466–4477. https://doi.org/10.1021/acs.
molpharmaceut.5b00642
55. Rao W, Wang H, Han J, Zhao S, Dumbleton J, Agarwal P et al (2015) Chitosan-decorated
doxorubicin-encapsulated nanoparticle targets and eliminates tumor reinitiating cancer stem-­
like cells. ACS Nano 9:5725–5740. https://doi.org/10.1021/nn506928p
Use of Plant-Derived Nanoparticles
in Cancer Therapy

R. Sai Nandhini, S. Kalpana Shree, Phalguni Maity, G. S. Madhumathi,

Anindita Bhar, and Jeyanthi Palanivelu

1 Use of Plant Resources in Cancer

Therapy: Anticancer Phytochemical

Antineoplastic phytochemicals may be commonly extracted from edible plants,

including medicinal plants, vegetables and fruits. The abundance and easy avail-
ability of plants make it phytochemicals to be used in different studies. In addition,
phytochemicals found in these edible sources are usually safe for human consump-
tion, even beneficial for normal body function jobs. This means that they show less
or no toxic effects in normal human organs and cells when used in the correspond-
ing physical concentration. Further research on pharmacological properties of the
anti-cancer components of nature showed that they usually do not reflect only living
organisms such as anti-inflammation, antioxidation and immuno-modulation, but
also direct more cancer-related demonstration procedures and methods [1]. Their
anti-cancer bioactivities include stimulating apoptosis, anti-growth and anti-­
metastatic activities, working alone or in combination killing cancer cells. In short,
phytochemicals can work in many ways to fight cancer. Once bioactive phytochemi-
cals are identified, it is often used as a structural basis modification or as a leading
chemical to synthesise new compounds based on structure–function relationships,
physicochemical features and pharmacodynamics for their development along with
bioavailability and reduction of their toxins for continuous improvement [2]. A vari-
ety of novel phytochemicals have been found to have antineoplastic activity. They
are currently in clinical trials or clinical use for the treatment of cancer and show
promising clinical practice. Genistein, 5,7-dihydroxy-3-(4-hydroxyphenyl) chro-
men-4-one, belongs to a group of chemicals called flavones. It is found mainly in

R. S. Nandhini · S. Kalpana Shree · P. Maity · G. S. Madhumathi · A. Bhar · J. Palanivelu (*)

Department of Biotechnology, Vel Tech Rangarajan Dr. Sagunthala R & D Institute of
Science and Technology, Chennai, Tamil Nadu, India
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature 1405

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_59
1406 R. S. Nandhini et al.

leguminous plants, which include soybeans, lupine and fava beans. Studies show
that genistein exhibits a number of beneficial biological effects: heart disease, dia-
betes, neuropathy, osteoporosis, inflammatory diseases and cancer. In the last
decade, a few cancer-­related clinical trials on genistein, including colorectal, pros-
tate, pancreatic, breast and kidney cancer, have been diagnosed worldwide.
Meanwhile, the inhibition of the effects of genistein on different types of cancer and
subcutaneous pathways are under investigation. Like phytoestrogen, genistein can
competitively bind to oestrogen receptors (ERs) and affects oestrogen-dependent
cancer (Fig. 1).
Hwang et al, reported that genistein inhibits the growth of ovarian cancer cells
(BG-1) by suppressing both ER and insulin-like growth factor-1 receptor (IGF-1R)
signalling methods [3]. Genistein also presses proliferation and secretion of MCF-7
and 3T3-L1 breast cancer cells by reducing regulation of ERα expression [4]. In
addition, genistein induces apoptosis by inhibiting the nuclear factor-kappa B (NF-­
κB) pathway in LoVo and HT-29 human colon cancer cells [5] and T-cell leukaemia

Fig. 1 Plant resources containing nanoparticles used in cancer therapy

Use of Plant-Derived Nanoparticles in Cancer Therapy 1407

cells [6]. In addition, genistein is active ATM/P53-dependent mechanisms in colon

cancer cells (HCT-116 and SW-480) [7]. Genistein has been identified as a tyrosine
kinase inhibitor and antiangiogenic agent as well.
A DNA topoisomerase II inhibitor, contributes to cancer therapy by its antineo-
plastic activity. Recently, there are reports of the regulatory effect of genistein on
microRNA in cancer cells. Speeches of onco-miR-1260b in prostate cancer cells [8]
and kidney cancer cells [9] are reduced by genistein. On the other hand, genistein
controls the expression of tumour-suppressors miR-34a and miR-574-3p [10] pros-
tate cancer. Overall, these bioactivities of genistein result in the inhibition of cancer
cell growth.
Lycopene is a carotenoid found in red fruits and vegetables, such as red carrot,
watermelon, grapefruit, papaya and especially tomatoes. Because of polyunsatu-
rated hydrocarbon chain with 13 double bonds, 11 of them combined, lycopene is
very lipophilic and shows strong antioxidant activities. It can prevent oxidative
DNA damage and types of active oxygen (ROS) generation. This may have implica-
tions because of its chemopreventive activities against cancer [11]. Lycopene has
shown therapeutic activity in breast cancer [12], leukaemia [13], ACTH-pituitary
adenoma [14] and prostate cancer [15]. Holzapfel et al. report that the effectiveness
of lycopene against prostate cancer is due to its ability to detect multiple steps and
signal mechanisms in cancer development [16]. In a study by Yang et al. the growth
of androgen-independent prostate tumour (PC3 cells) was severely inhibited there-
after by lycopene treatment in the model of mice xenograft. At the same time, lyco-
pene also suppressed the tumour cell proliferation by increasing the expression of
increased cell nuclear antigen, reducing angiogenesis by lowering VEGF plasma
levels and inhibiting IGF-1 signalling by elevating plasma IGF-binding protein
level 3 [17]. An example of an anti-cancer phytochemical currently used clinically
is paclitaxel, which is mitotic. The inhibitor was first discovered in the Pacific’s reef,
Taxusbrevifolia in 1962, that paclitaxel strengthens cellular microtubules, thereby
preventing cell division. For now, it is FDA approved as an anti-cancer drug for
many types of cancer, including breast, lung and cervical cancer. At the time, its
semi-synthetic analogue, docetaxel, was developed by Pierre Potier. It has been
shown to have twice as much power as the parent compound, paclitaxel, because of
its effect on the centrosome of the mitotic spindle. It encourages and stabilizes the
assembly of microtubules, and prevents its disintegration, thereby causing a signifi-
cant decrease in free tubulin, preventing the division of mitotic cells and ultimately
preventing the proliferation of cancer cells. In the meantime, it is widely used in the
treatment of advanced and/or metastatic cancers of the breast, stomach, prostate and
lungs. Another mitotic inhibitor, vincristine, is a vinca alkaloid extracted from
Catharanthus roseus. It binds mitosis to metaphase by binding to tubulin dimers. It
has since been approved by the FDA as an anti- cancer drug in 1963 and is widely
used in the treatment of various types of cancer.
The tumour-fighting mechanisms of natural chemical phytochemicals are very
complex and require caution. In short, plant compounds can trigger apoptosis of
cancer cells, promote cell adhesion, prevent the proliferation of cancer cells and
direct the expression of cancer- related cells.
1408 R. S. Nandhini et al.

Fig. 2 Few naturally available anticancer phytochemicals

Phytochemicals can also act as suppressors of oncogenes, cancer cell invasion

and metastasis inhibitors, as well as growth factor controls. Many natural com-
pounds have been studied in the epidemiology, preclinical and early clinical stages.
Although there are many challenges, phytochemicals continue to be the best source
of chemotherapy novel medicines (Figs. 2 and 3).

2 Principal Steps in the Process of Nanoparticle Biosynthesis

2.1 Nano-based Drug Delivery

Nanotechnology has been shown to help the success of cancer drug development.
Several phytochemical nanoparticles are commercially available. Compared to free
phytochemicals, phytochemical nanoparticles show not only an increase in drug
solubility but also other benefits.
Changes in pharmacokinetics and distribution of phytochemicals due to the com-
position of nanoparticles can lead to improving the therapeutic index of these
Use of Plant-Derived Nanoparticles in Cancer Therapy 1409

Fig. 3 Flowchart of extraction technique to get biosynthesised nanoparticles

phytochemicals in reducing toxins and increasing efficiency. For example, conju-

gating phytochemicals as well as antibodies to form antibodies–drug conjugates
(ADCs) can produce potent cytotoxic phytochemicals selectively in cancer cells.
These conjugates are about the size of a nanometre. Definition of ADCs to the
tumour against other organs leads to a wide-ranging cytotoxic treatment win-
dow [18].
Improved permeability and retention (EPR) effect are the key to identifying a
tumour by nanovehicles. Many hardy plants are associated with a structure that has
a unique vascular structure lymphatic drainage dysfunction. EPR effect makes mac-
romolecules and nanocarriers “leaky” especially from the blood vessels around the
tumour [19]. In the meantime, lymphatic drainage dysfunction in the abscesses
1410 R. S. Nandhini et al.

allows them to focus on the area of cancer cells. The effect of EPR is not present in
normal muscles. The most important factors that influence the impact of EPR were
the size and consistency of biocompatibility. The minimum size of the EPR result is
cell size greater than 40 kDa (macromolecules) or particle size greater than 5 nm
(nanocarrier) (Fig. 3) [20]. It takes a lot of rotation time to give enough time for
delivery of the drug through the EPR effect. Many phytochemicals are low-weight
agents with rapid approval in vivo and widespread distribution in normal organs and
tissues [21]. MDR is one of the main causes of the failure of phytochemicals in
cancer. Using nanovehicles, the delivery of phytochemicals is a new strategy to
overcome MDR.
Modification of facial nanocarriers can improve the delivery of phytochemicals
and defeat drug resistance by altering biophysical interactions between nanocarriers
and cancer cell membrane lipids and increase the delivery of phytochemicals to
target tissues [22]. Chemical modification of phytochemicals and recruitment of
drug delivery systems are widely used for the delivery of phytochemicals. For chem-
ical repair, we focus on selected drug candidates who have been tested in clinical
trials or who have the ability to enter the clinic temptations. With the delivery pro-
grams of the phytochemical component, we will focus on the former FDA approved
(Fig. 4).

3 Nanoparticles

Nanoparticles are particles at a size of 10–1000 μm, non-embedded drugs or cov-

ered at the top [23]. Based on the materials used to make them, they can be divided
into biodegradable high molecular weight polymer nanoparticles and natural poly-
mer nanoparticles [24]. The former includes poly (lactic-co-glycolic acid (PLGA)
nanoparticles and polylactic acid (PLA) nanoparticles etc. The latter include albu-
min nanoparticles, gelatine cellulose nanoparticles and chitosan nanoparticles, etc.
Abraxane (nanoparticle’s formulations for paclitaxel) is the only FDA-approved
nanoparticle drug. Abraxane is made up of human serum albumin. Abraxane
nanoparticles are about 130 nm wide and have a loading capacity of about 10%
paclitaxel [25].
Paclitaxel loading of nanoparticles is achieved using advanced high-pressure
homogenisation technology by American Bioscience. In Abraxane, albumin is ille-
gally bound and retained by paclitaxel [26, 27]. Compared to other commercial
nanocarriers, Abraxane has unique advantages over its pharmacokinetic and drug
distribution. Abraxane does not depend solely on the effect of EPR for the delivery
of paclitaxel in cancer cells. Abraxane binds to gp60, a 6 kDa high-density glyco-
protein receptor albumin affinity, and albumin fluid phase entry for tumour endothe-
lium in the subendothelial area. Then, SPARC (secreted protein, acid and rich in
cysteine), an extracellular matrix glycoprotein highly exposed to a variety of can-
cers with a high concentration of gp60, also improves its plant placement (Fig. 4)
[28–30]. Phase I Abraxane® clinical trials in 19 patients with metastatic breast
Use of Plant-Derived Nanoparticles in Cancer Therapy 1411

Fig. 4 Current nanomedicines available for the treatment of cancer

cancer were performed at M. D. Anderson Cancer Centre, Texas, USA. This study
focuses on the toxicity profile, magnitude tolerated dose (MTD), as well as the
pharmacokinetics properties of Abraxane. The schedule was administered every
3 weeks using Abraxane dosage pump from 135 to 375 mg/m2. The results showed
that Abraxane was well tolerated, producing only neuropathy in three patients, sto-
matitis in two patients, and external keratopathy in two patients with doses of
1412 R. S. Nandhini et al.

ABI-007 at 375 mg/m2. They concluded that the Mett of Abraxane was 300 mg/m2.
The plasma AUC of Abraxane was higher than that of Taxol if 260 mg/m2 of
Abraxane was injected for 30 min i.e., 175 mg/m2 of Taxol injected as 3 h. Abraxane
provided an example of albumin nanoparticles that will be used in clinical practice
[31, 32]. Currently, Abraxane progresses to Phase II/III clinical trials for metastatic
breast cancer patients with i.e., dose at 260 mg/m2 in 3-week cycles compared to the
standard paclitaxel system, taken at 175 mg/m2. Compared to Taxol, Abraxane indi-
cated that patients’ response rates were significantly higher (19% vs 33%, respec-
tively) and much longer length of plant growth period (16.9 weeks vs 23.0,
respectively) [32, 33].

3.1 Silver Nanoparticles

Plant-based silver nanoparticles have been repeatedly tested against various human
cancer cell lines like breast cells, liver cells and colon cells. While compared to
other routine physical and chemical approaches in the treatment of this lethal dis-
ease, green synthesis of silver nanoparticles by implementing the abilities of various
secondary metabolites from plants has been proven to be more efficient, ecofriendly,
cost-friendly and safer [34].
For example, using the bark and leaf extracts from the tree Ziziphus xylopyrus
which is very common in the Indian sub-continent, biofabrication of silver nanopar-
ticles (AgNPs) was possible. Not only the Zizipus tree but also several other com-
mon plants and trees like hibiscus, polyalthia, papaya, Ocimum, Coriandrum and
Ficus are employed in the biosynthesis of silver nanoparticles [35].
Green synthesis of nanoparticles over synthetic nanoparticles has paved way to
overcome some serious problems like aggregation of nanoparticles, toxicity and
non-compatibility, which offers advantages like stability, faster reduction rate
and so on.

Benefits of
using green
nanoparticles

dna, reduced
reduced improved faster improved
mitrochondrial compatibility
toxicity stability reduction rate apoptosis
damage complications

Many research studies have proved that silver nanoparticles have beneficial toxic
mechanisms, which are capable of causing DNA and mitochondrial damage and
inducing apoptosis (programmed cell death) in cancer cells. For instance, green
synthesis of the plant Datura inoxia, activities like cell cycle arrest, decreased DNA
synthesis and apoptosis were recorded in cancer cells [36].
Use of Plant-Derived Nanoparticles in Cancer Therapy 1413

Interestingly enough, not just terrestrial plants but even marine corals were
reported to show anti-cancer properties when used to synthesise silver nanoparti-
cles. For example, extracts from the soft coral Cladiella pachyclados were used in
producing bioactive silver nanoparticles. This coral possesses a compound called
eunicellin, a diterpenoid that has a great potential against breast cancer [37].
This compound, when used to synthesise AgNPs or using silver nanoparticles as
drug carriers, showed anti-inflammatory potential almost equal to the commonly
used cancer drug Doxorubicin; in fact, it was able to express high selectivity
comparatively.
The experiment showed that silver nanoparticles synthesised using the extracts
from the mint plant as a stabilising agent exhibited a significant potential against the
HCT116 human cancer cell line [36]. This analysis showed that plant-mediated
AgNPs were capable of suspending cell division and minimising the further prolif-
eration of cancer cells.
AgNPs have proved themselves very useful in the manufacture of nanodrugs.
They use a mechanobiological and microenvironmental mechanism to cause apop-
totic cell death in carcinogenic cells with the aid of ROS-mediated pathways. For
example the chemotherapeutic drug—fructose coated angstrom silver has been
reported to inhibit osteosarcoma cells (a malignant bone cancer), pancreatic and
lung cancer cells. Further experiments showed the drug to be capable of inhibiting
tumour growth, improving survival rate and attenuating osteolysis in osteosarcoma-­
bearing mice [38].
Therefore, green-synthesised silver nanoparticles are being extensively studied
by researchers worldwide to be implemented in the cure of cancer effective imme-
diately, which could be a significant breakthrough, given its properties and eco-
friendly nature.

3.2 Nanodiamonds

Nanodiamonds are carbon nanoparticles with truncated octahedral architecture that

are about 2–8 nm in diameter and can deliver a wide range of therapeutics, includ-
ing small molecules, proteins and nucleic acids, making them very adaptable in the
field of anticancer research [39].
Superior properties of nanodiamonds like hardness, high thermal conductivity,
chemical stability and resistance to harsh environments have made them very com-
patible with several biotechnological and medical applications [40]. While com-
pared to other nanocarbons that are synthesised from carbon blacks or fullerenes,
nanodiamonds were confirmed to express comparatively less toxicity [41]. Thus,
they are widely used in delivering drugs due to their biocompatible properties.
For instance, a popular drug widely used in cancer therapy is Doxorubicin [42].
It is a small-molecule drug that aids in cell death or apoptosis. This drug slows down
or stops the growth of cancer cells by blocking an enzyme called topoisomerase 2.
Without this enzyme, cancer cells cannot grow or divide. While working on the 4T1
1414 R. S. Nandhini et al.

breast cancer cells in mice, the nanodiamond mediated doxorubicin delivery system
was well able to cease the generation of lung metastasis [43]. Thus, with the help of
nanodiamonds, the drug was able to be successfully delivered in several lab tri-
als which the researchers have speculated using Nano diamonds as intercellular
carriers of plant metabolites, like the plant metabolites quercetin and citropten are
intensely being studied for their pro-apoptotic and redox properties [42].
Quercetin is a natural pigment (flavonoid) that is available in most common
fruits, grains and vegetables and is nowadays taken as a dietary supplement. Due to
its high level of free radicals, the flavonoid promotes inflammation in human cells
which is a very important anti- cancer activity.
Citropten or 5,7-dimethoxycoumarin is a metabolite (coumarin) extracted from
a plant called Peleaanisata and several natural oils and citrus fruits which is known
for inducing melanogenesis [44].
Extensive studies have been carried out to assess whether these plant metabolites
were able to show improved antiproliferative and inflammatory effects when
adsorbed on nanodiamonds.
It was speculated that the bioactivities of these plant metabolites were modifiable
through their interaction with nanodiamonds.
When tests were performed on the HeLa cell line, it was evident that the conju-
gates were able to first penetrate the cell compartment, next, the intracellular spaces,
following the areas near the nuclear region successfully.
On the whole, based on the experiments performed on the HeLa and B16F10 cell
lines, it was clear that the nanodiamonds heightened the cell growth inhibitory prop-
erties of the two plant metabolites quercetin and citropten, making it an effective
agent against cancer [39].

3.2.1 
In Silico Studies of Plant Nanoparticles in Cancer Therapy

In silico studies are a very crucial step in the process of drug design. These are
computer-aided analyses that are carried out in order to know several properties like
the binding affinity which are very important in order to design an approvable drug.

4 Liposomes

Liposomes, with a diameter of 20–1200 nm, contain a water-repellent inner layer as

well external phospholipids. Hydrophilic drugs can be injected into the aqueous
core while hydrophobic drugs can be embedded or advertised externally with low
phospholipids. Liposomes can improve in vivo biocompatibility as well as the phar-
macokinetics of drugs and their properties can be improved by simply changing the
composition of bilayer parts [45].
Marqibo (liposomal formulations of vincristine, FDA approved) and Lipusu
(liposomal formulations for PTX, approved by China Food and Drug Administration)
only 2 liposomal phytochemical products entered the medical field applications.
Use of Plant-Derived Nanoparticles in Cancer Therapy 1415

Marqibo is made of a combination of sphingomyelin: cholesterol in the 57.4:

42.6 mol average [46].
Liposomes are approximately 100 nm in size and drug loading is done with a
remote-control loading. In preclinical studies, following an injection of 2.0 mg/m2
in mice, Marqibo showed higher AUC (63,438 vs 806 ng.h/ml) and lower permit (32
vs 2488 mL/h/m2) and volume (383 vs 113,513 mL/m2) for distribution compared
to Vincristine. Similar pharmacokinetic profiles have been demonstrated in mice
and dogs. These data show that Marqibo has half times the long cycle of system
rotation throughout three types. Of the 11 different cancer indications studied,
Marqibo was found to be present as more effective than vincristine at 8 [47–49].
In clinical studies, Marqibo was used for leukaemia. There are 65 patients in the
Phase II case. Marqibo dose of 2.25 mg/m2 once a week is associated with 63%
degree of neuropathy, 20% paraesthesia and no third-degree peripheral motor events
neuropathy. In contrast, vincristine injected into 1.4 mg/m2 every 21-day injection
is the same associated with 92% neuropathy, 78% paraesthesia and 16% grade 3
motor weakness. Marqibo has proven the highest accessible volume for each indi-
vidual and collection of vincristine compared to other vincristine products [50].
Lipusu is designed to eliminate the need for complex material pre-treatment and
side effects associated with Taxol car. This construction is repaired with egg PC and
cholesterol [51].
A study of preclinical acute poisonity was made available by mice comparing
Lipusu and Taxol. The results showed that Lipusu has the potential to more than
double LD50 (69.8 vs 33.0 mg/kg). In mice, Lipusu led to 1.5 times higher concen-
trations within the tumour tissue compared to Taxol 24 h after treatment. In the
Phase I study, a complete comparable safety profile has been reported with Lipusu
compared to Taxol®, the results show that Lipusu has twice as much MTD (375 mg/
m2 vs 175 mg/m2) [52].

5 Micelle

Micelles automatically assemble themselves when the concentration of the surfac-

tant exceeds its sensitivity micelle concentration (CMC). Compared to other nano-
carriers, micelles are smaller in size (10–400 nm). Micelles, especially polymeric
micelles, are gaining popularity as drug delivery carriers of phytochemicals [53].
Genexol-PM (Paclitaxel formulations, in Korea), polymeric micelle, is a product
that has entered the clinic. Genexol-PM is prepared using a solid distribution pro-
cess installation of paclitaxel in diblock monomethoxy poly (ethylene glycol)-
block-poly (D, L-lactide) (mPEG-PDLLA) is a polymer. The micelles are about
24 nm wide and are almost identical 16% w/w paclitaxel loading [54]. In this
micelle structure, a hydrophilic block (PDLLA group) forms a micellar corona and
the hydrophobic block (PEG group) forms the core. The PDLA team provides
hydrophobic interaction with paclitaxel resulting in high drug and spherical stable
loading core, the PEG group provides a polymer coating that can prevent the bind-
ing of plasma proteins and increase circulation time in plasma. In a pre-clinical
1416 R. S. Nandhini et al.

study, Genexol-PM showed strong inhibition of tumour growth and higher MTD
than-Taxol®. A few of the Genexol-PM clinical trials have been in operation or in
place completed, with indications including non- small cell lung cancer, metastatic
breast cancer and pancreatic cancer [55]. In the first phase of clinical trials,
Genexol-PM showed MTD 2.3 times higher than Taxol® in humans [56]. In addi-
tional clinical research, Genexol-PM has shown better performance than Taxol
when used alone and as part of a combined treatment. However, it is interesting that
Genexol-PM showed a very low T 1/2 (12 h vs 20 h) and AUC 11.58 compared to
Taxol®, possibly due to Genexol-PM faster approval and better access to cancer.

6 
Cladiella pachyclados

C. pachyclados is a marine soft coral that exhibits several anti-cancer properties

when silver nanoparticles were synthesised using its extract eunicellin. King
AbdulAziz University in Saudi Arabia conducted several experiments in order to
record the anti-cancer activities of the combination mentioned above.
The extracts recovered from the coral lying in the red sea were subjected to chemi-
cal profiling with the help of LC-HRESIMS (liquid chromatography-high-­resolution
electrospray ionisation mass spectrometry). Several other molecular-­level analyses of
the silver nanoparticles were performed using UV spectroscopy, XRD, FTIR, TEM,
and SEM, and an anti-proliferative assay was carried out [37]. By the aid of
SwissADME, an online software which is a web tool that allows to evaluate of phar-
macokinetics and drug-likeness of molecules [57] was used to analyse the drug-like
characteristics and ADME profiles (adsorption, distribution, metabolism and excre-
tion) of gastrointestinal absorption, blood-brain barrier, solubility and bioavailability
were studied. These compounds were subjected to inverse docking in order to assign
the potential protein targets using the PDB (protein data bank) and target platforms.
The divide and conquer strategy was implied in order to run a large number of dock-
ing experiments in less time consumption. Binding affinity score was set to −7 kcal/
mol to select the best targets. 26 targets were obtained for the human breast cancer cell
proteins. From the experiment, it was observed that the coral extract eunicellin deliv-
ered via AgNPs showed a significant level of antiproliferative activity and cytotoxicity
towards breast cancer cells almost as same as the common cancer drug doxorubicin.
(IC50 = 71.85 ± 3.57 μg/mL) [37].

MCF7 (SI) MDA – MB – 231 (SI) MCF10a

CE 24.32 ± 0.52 c
9.55 ± 0.53 (7.52)
b
71.85 ± 0.5c
(2.95)
AgNPs 5.62 ± 0.26b (7.34) 1.72 ± 0.14a (24) 41.29 ± 0.44b
Doxorubicin 2.61 ± 0.03a (7.7) 1.5 ± 0.26a (13.4) 20.09 ± 0.72a
Selectivity index (SI) = IC50 of tested material in a normal cell line/IC50 of the material in
cancer cell line
IC50 is the concentration required to kill 50% of the cell population
The letters a, b and c indicate the differences from repeated experiments n = 3
Use of Plant-Derived Nanoparticles in Cancer Therapy 1417

Out of the 26 compounds that were tested with the aid of inverse molecular dock-
ing, only six were found to show binding orientations inside the corresponding
binding sites. They also were reported to have the highest dG values, proving that
they could be used as potential binders for several BC proteins [37].

7 Flavonoids

As we discussed the usage of flavonoids like the quercetin in the treatment of can-
cer, there are many other such flavonoids which possess beneficial anti-cancer prop-
erties. For example, MYRICETIN is one of the plants derived flavonoids which
contains a lot of strong anticancer properties. This compound that is obtained from
common plants and fruits is also one of the major constituents of several food and
beverages [58]. Myricetin is proven to exhibit cytotoxic activity towards a huge
number of human cancer cell lines.
Research studies show that the biosynthesis of Myr-Au NPs resulted in spherical-­
shaped particles of size less than 50 nm [59].
mTOR is the mammalian target of rapamycin which is a kinase molecule that
regulates protein synthesis. A theoretical network analysis was carried out by the
Kyoto Encyclopedia of Genes and Genomes (KEGG) database with the help of a
software called Cytoscape 3.7.1 to understand the role of different genes in the
mTOR signalling mechanism. The observation of the said analysis is shown below
[59] (Table 1).
Molecular docking of myricetin (Myr) guided in understanding the X-ray crystal
structure of human mTOR kinase enzyme obtained from the RCSB-PDB (Research
Collaboratory for Structural Bioinformatics-Protein Data Bank).
The GLIDE program (v.11, Schrödinger, LLC, New York, 2016) was utilised in
extra precision (XP) docking mode with the Glidescore and E-model scoring func-
tions to perform the molecular docking analysis of myricetin for the mTOR gene.
MTT assay that is a colorimetric assay performed for assessing the cell meta-
bolic activity was done, and ROS generation studies were carried out and the values
were compared using SPSS (v. 20.0, SPSS Inc., Chicago, IL, USA).
In this analysis of Myr-AuNPs, extra precision GLIDE docking procedure was
done by removing the inhibitor compound with the human mTOR receptor. The
docking result of myrecitin was found to be −7.79 kcal mol−1, and its interactions

Table 1 The observation of a The measured value of degree 20

said analysis to understand
Closeness 0.007686
the role of different genes in
mTOR signalling mechanism Eccentricity 0.267857
Eigen vector 0.74402
Radiality 18.74074
Stress 6948
1418 R. S. Nandhini et al.

were confirmed with ALA 1708, ARG 1709, LYS 1710, ILE 1711 and ASP 1712 of
chain B, thereby proving a good binding activity of Myrecitin with human mTOR
kinase. The molecular docking studies in mTOR kinase were understood to show a
strong binding affinity with IC50 value = 13 μg mL–1. After staining, the cells treated
with myr-AuNPs showed a good proportion of dead cells, thereby showing an
anticancer activity [59].

8 Chitosan

Jatropha pelargoniifolia is a very famous medicinal shrub which is common in

Africa, Ethiopia and in some regions of the Arabian Peninsula [60]. The plant has
several therapeutic activities that make it very unique in research projects.
A recent phytochemical analysis of the plant has shown the presence of certain
bioactive compounds like tannins, coumarins and flavonoids which can be exploited
against cancer.
Chitosan is one of the important compounds extracted from the plant whose
composition is poly [-(1,4)-2-amino-2-deoxy-D-glucopyranose]. Chitosan is popu-
lar for being the second most abundant biopolymer next to cellulose. It has several
beneficial properties like biocompatibility, mucoadhesiveness and
biodegradability.
By combining the constituents of Jatropha with bacterial DNA gyrase B and the
kinase domain of human topo isomerase II a, a molecular docking analysis was
performed with the aid of the software Autodock 4.2.
From the Chemdraw ultra 12.0 software, the suitable ligand structures which
were bound to their respective proteins were downloaded and selected as a positive
control. With the aid of a universal force field, the ligand energies were minimised.
Further, with the help of the Lamarck Genetic algorithm model and Solis and
Wets local search method, a molecular docking experiment was performed for a
total of 2,500,000 energy calculations for each docking run. By using one way
ANOVA, a statistical analysis was done with graph pad prism 9.0 software [48].

9 Pro-haloacetate NPs

PDK or pyruvate dehydrogenase kinase is a mitochondrial enzyme which plays a

major role in reversing the suppression of mitochondria-dependent apoptosis. If the
suppression activity does not take place, the cell death process is disturbed and
might later become a lead cause of cancer. In order for cancer to progress, the
apoptosis process must be inhibited [49].
Inhibition of the PDK enzyme results in decreased tumour growth and angiogen-
esis in a variety of cancers with high selectivity. This indicates the importance of
Use of Plant-Derived Nanoparticles in Cancer Therapy 1419

reversing the mitochondrial suppression with metabolic modulating drugs like PDK
inhibitors. Recent molecular modelling studies show that the haloacetic acids are
capable of selective recognition of certain PDK isoforms allowing us to recognise
better haloacetate drug candidates. The quantitative docking energy data from the
molecular recognition analysis indicated that MCA (mono chloroacetate) was a
comparable PDK binder while DBA (di bromo acetate) showed a slightly weaker
binding than the DCA [49]. For further process of molecular modelling, the above-­
mentioned haloacetates were prepared with the help of SKETCH module. The fol-
lowing requirements was set up to carry out the procedure, followed by the
results [49].

Gradient convergence – 0.05 kcal/mol

NB cutoff – 8.00
Dielectric constant – 1.00
Docking protocol – induced fit
Score function – London dG
Active site – L53, Y80, S83, I111, R112, H115, S153, R154, I157, R158, I161 [49]

DBA DCA MCA

− 3.463(KJ mol−1) − 4.104 (KJ mol−1) − 4.121 (KJ Mol−1)

As a result of these analyses, we can interpret that PDK-modulating haloacetic

acids in pro-drugs can be used for inhibition of PDK in order to reverse the suppres-
sion of before mentioned apoptosis.

10 Plants and Bioactive Component-Based Nanoparticles

With the growing necessity day by day to develop environment and economy-­
friendly approaches in the cure of the deadly disease cancer, the utilisation of plant
nanoparticles has indeed offered a huge helping hand in this deed, given its numer-
ous advantages over several other existing techniques.
Employment of plants in the field of medicine especially in curing diseases is not
new in our civilisation. Taking this under consideration, the aid of green synthesis
of nanoparticles or simply green nanoparticles has improved not just the methods
but, ecofriendly and very achievable methods of treating cancer in multitudes.
Nowadays, synthesising nanoparticles with the aid of plants is a majorly dis-
cussed topic due to their unbelievably advantageous properties and safe nature.
Using commonly available plants, several nanoparticles have been synthesised suc-
cessfully. Few examples are given in Tables 2 and 3 [97].
1420 R. S. Nandhini et al.

Table 2 List of various common plants from where different nanoparticles have been synthesised
Plant Nanoparticle synthesised Size (nm)
Aloe vera Au & Ag 50–350
Curcuma longa Pd 10–15
Eucalyptus macrocarpa Au Ag 20–100
10–100
Mangifera indica Ag 20
Psidium guajava Au 25–30
Caria papaya Ag 15
Citrus sinensis Ag 35

11 Drug Release Nanosystem

Auxemma oncocalyx is a medicinal tree native to northeast Brazil. This tree is

known to have several medicinal properties including antisepsis and antitumor
activity which makes it very applicable as a part of traditional medicine in parts of
Brazil till date [98].
Oncocalyxone A or simply Onco A, a meroterpenoid quinone, is a secondary
metabolite extracted from the heartwood of the above-mentioned tree which pos-
sesses several pharmacological benefits like anti-platelet, anti-inflammatory, anal-
gesic, antioxidant and more importantly several antitumor properties which help in
fighting cancer [99, 100].
Several researches have shown that onco A is cytotoxic to human leukaemia cells
and other cancer cell lines during the cell phases G1, G1/S and S. While exposed,
the compound is capable of inhibiting DNA synthesis and cell division in the carci-
nogenic cells [98, 101].

Onco A was reported to show anti-proliferative activities on various cancer cell

lines of the lungs, ovarian, rectal and leukemic cancer resulting in intense anti-­
cancer research worldwide. In spite of its medicinal properties, during clinical trials,
unfortunately, the compound began to express certain toxicological side effects on
vital organs like the lungs, kidneys and heart [100].
Use of Plant-Derived Nanoparticles in Cancer Therapy 1421

Table 3 List of the phytochemicals used in drug delivery system

Type Advantages Limitations References
Nanoparticles Fairly simple to prepare. Huge use of polyvinyl [61–72]
Targeted and drug delivery. alcohol as a detergent-
Excellent size and size distribution issues with toxicity.
management. Limited targeting abilities.
Small drug doses.
Less toxicity.
Solid lipid Possibility of drug targeting and Particle growth. [73–76]
nanoparticles controlled drug release. Gelation tendency is
Incorporation of hydrophilic drugs unpredictable.
and lipophilic. Sometimes burst release.
There is no biotoxicity of the carrier.
Organic solvents are avoided.
Liposomes Improvement and control over Sterilisation. [77–82]
pharmacodynamics and Short shelf life
pharmacokinetics.
Toxicity is decreased.
Liposomes can be made target
selective.
Carbon High stability in vivo is obtained dueBecause of the insolubility [83–85]
nanotubes to their mechanical properties. of as-produced materials,
Large surface area is available for functionalisation is
multiple fictionalisation. essential to make the
Low costs are associated with bulk substance physiologically
production. acceptable.
A strong proclivity for
aggregation.
Micelles Very small size. Polymer synthesis is [86–91]
Structural stability is high. difficult.
Huge amount of drug loading. Immature drug-­
Water solubility is high. incorporating technology.
Less toxicity. Slow extravasation.
Dendrimers Due to strict control during the Complex, multistep [92–96]
synthesis, they have lower procedures are involved in
polydispersity index the processing and
As the density of the branches grows, synthesis of dendrimer-­
the outermost branches form spheres based nanoparticles.
around a lower-density core and the Trouble related to
outer surface density decreases, biodistribution.
leaving most of the area hollow
toward the core, thus increasing drug
impact

Following this, further researches theorised that the use of nanosystems can
reduce those toxic side effects by a great proportion with the help of Fucoidan, a
polysaccharide extracted from brown algae and certain marine invertebrates [102].
This compound is used widely in the green synthesis of nanoparticles using AEP
method aiding in a few advantageous biological activities like anti-inflammatory,
anticoagulant and antitumor activities as well as low toxicity [103].
1422 R. S. Nandhini et al.

Fucoidan is also claimed to show additional beneficial properties like improved

antitumor activity of certain chemotherapeutic drugs when used in combination and
induced cell growth inhibition and commencement of apoptosis in the breast cancer
cell lines [104].
Experiments were performed to analyse the release kinetics of OncoA from the
fucoidan-coated nanoparticles in vitro using dialysis technique with different solu-
tions in order to stimulate the pH of the gastrointestinal tract. Using HPLC-UV
technology, the released Onco A was quantified. Likewise, stability tests, biocom-
patibility tests, cytotoxicity tests and blood compatibility tests were vigorously car-
ried out in labs, which conveniently gave satisfying results proving fucoidan was
successfully able to deliver Onco A.
To conclude, with the implementation of fucoidan-coated nanoparticles possess-
ing OncoA prepared by AEP method, researchers were successfully able to gain
minimal toxicity residues and good compatibility with human blood, paving way
for further studies [103].

12 Polyphenol Nanoformulations for Cancer Therapy

12.1 Coumarins

Coumarins are polyphenols with appetite-suppressing structures that prevent ani-

mals from eating plants. It can also be used in the medicine of lymphedema. It may
also cause bleeding, which is their well-known feature. Fabaceae, Lamiaceae, and
Rosaceae are some among the natural sources of coumarins. These phytochemicals
have shown anticancer properties in several ways. 4-Methyl-7-hydroxycoumarin is
a synthetic coumarin made by methylation nanoparticles of umbelliferone
(7-hydroxycoumarin). 4-Methyl-7- hydroxy coumarin has shown anticancer effects
on cell melanoma A culture by increasing cell apoptosis, DNA fragmentation, cas-
pase-­3 and p53 (tumour suppressor factor) and decreased cell function. Farnesiferol
C is another coumarin extracted from plant species such as Ferula asafoetida.
Dendrosomal nanoformulation of farnesiferol C is indicated antineoplastic
activity by reducing cell proliferation in iAGS gastric cell line. Bax’s speech (an
antiapoptotic marker) and Bcl-2 (proapoptotic factor) were changed to increase
Bax/Bcl-2 levels due to treatment with dendrosomal farnesiferol C.

12.2 Flavonoids

Flavonoids are a group of sub-polyphenols classes, such as chalcones, flavones,

isoflavones, flavanones, flavonols and anthocyanins. Many pharmacological effects
flavonoids reported, such as antioxidant, anti-inflammatory, immunomodulatory
Use of Plant-Derived Nanoparticles in Cancer Therapy 1423

and antineoplastic activities. Flavonoids can be extracted from high plants. They
can be found in yellow, orange, or red and so on is widely available as colourful
fruits and vegetables in human food: Apiaceae (parsley), Ericaceae (berries),
Rutaceae (orange fruit), Rosaceae (apple) and a famous sweet product of Theobroma
cacao, that is, black chocolate. Flavonoids have shown antineoplastic properties
work in several subjects.

12.3 Diarylheptanoid (Curcumin)

Curcumin is a major diarylheptanoid polyphenolic structure extracted from tur-

meric (Curcuma longa) rhizome and has many biological and pharmacological
properties such as antioxidant, anti-inflammatory and anticarcinogenic functions. It
has been thoroughly researched in the field of cancer treatment drugs.

References

1. Wang ZB, Jiang H, Xia YG, Yang BY, Kuang HX (2012) α-Glucosidase inhibitory constitu-
ents from Acanthopanax senticosus harm leaves. Molecules 17(6):6269–6276
2. Chin WW, Parmentier J, Widzinski M, Tan EH, Gokhale R (2014) A brief literature and
patent review of nanosuspensions to a final drug product. J Pharm Sci 103(10):2980–2999.
https://doi.org/10.1002/jps.24098. Epub 2014 Aug 6. PMID: 25099918
3. Hwang KA, Park MA, Kang NH, Yi BR, Hyun SH, Jeung EB, Choi KC (2013) Anticancer
effect of genistein on BG-1 ovarian cancer growth induced by 17 β- estradiol or bisphenol A
via the suppression of the crosstalk between estrogen receptor alpha and insulin-like growth
factor-1 receptor signaling pathways. Toxicol Appl Pharmacol 272(3):637–646
4. Choi EJ, Jung JY, Kim GH (2014) Genistein inhibits the proliferation and differentiation of
MCF-7 and 3T3-L1 cells via the regulation of ERα expression and induction of apoptosis.
Exp Ther Med 8(2):454–458
5. Luo Y, Wang SX, Zhou ZQ, Wang Z, Zhang YG, Zhang Y, Zhao P (2014) Apoptotic effect
of genistein on human colon cancer cells via inhibiting the nuclear factor- kappa B (NF-κB)
pathway. Tumour Biol 35(11):11483–11488
6. Yamasaki M, Mine Y, Nishimura M, Fujita S, Sakakibara Y, Suiko M, Morishita K, Nishiyama
K (2013) Genistein induces apoptotic cell death associated with inhibition of the NF-κB
pathway in adult T-cell leukaemia cells. Cell Bio Int 37(7):742–747. https://doi.org/10.1002/
cbin.10101. Epub 2013 Apr 18. PMID: 23526666
7. Zhang Z, Wang CZ, Du GJ, Qi LW, Calway T, He TC et al (2013) Genistein induces G2/M
cell cycle arrest and apoptosis via ATM/p53-dependent pathway in human colon cancer cells.
Int J Oncol 43(1):289–296
8. Hirata H, Hinoda Y, Shahryari V, Deng G, Tanaka Y, Tabatabai ZL, Dahiya R (2014) Genistein
downregulates onco-miR-1260b and upregulates sFRP1 and Smad4 via demethylation and
histone modification in prostate cancer cells. Br J Cancer 110(6):1645–1654
9. Hirata H, Ueno K, Nakajima K, Tabatabai ZL, Hinoda Y, Ishii N, Dahiya R (2013) Genistein
downregulates onco-miR-1260b and inhibits Wnt-signalling in renal cancer cells. Br J Cancer
108(10):2070–2078
10. Chiyomaru T, Yamamura S, Fukuhara S, Hidaka H, Majid S, Saini S et al (2013) Genistein
up-regulates tumour suppressor microRNA-574-3p in prostate cancer. PLoS One 8(3):e58929
1424 R. S. Nandhini et al.

11. Trejo-Solís C, Pedraza-Chaverrí J, Torres-Ramos M, Jiménez-Farfán D, Cruz Salgado A,

Serrano-García N et al (2013) Multiple molecular and cellular mechanisms of action of
lycopene in cancer inhibition. Evid Based Complement Altern Med 2013:1–17, page 45:47.
http://dx.doi.org/10.1155/2013/705121
12. Uppala PT, Dissmore T, Lau BH, Andacht T, Rajaram S (2013) Selective inhibition of
cell proliferation by lycopene in MCF-7 breast cancer cells in vitro: a proteomic analysis.
Phytother Res 27(4):595–601. https://doi.org/10.1002/ptr.4764. Epub 2012 Jun 21. PMID:
22718574
13. Gharib A, Faezizadeh Z (2014) In vitro anti-telomerase activity of novel lycopene- loaded
nanospheres in the human leukaemia cell line K562. Pharmacogn Mag 10(Suppl 1):S157
14. Haddad NF, Teodoro AJ, Leite de Oliveira F, Soares N, de Mattos RM, Hecht F et al (2013)
Lycopene and beta-carotene induce growth inhibition and proapoptotic effects on ACTH-­
secreting pituitary adenoma cells. PLoS One 8(5):e62773
15. Elgass S, Cooper A, Chopra M (2014) Lycopene treatment of prostate cancer cell lines inhib-
its adhesion and migration properties of the cells. Int J Med Sci 11(9):948
16. Holzapfel NP, Holzapfel BM, Champ S, Feldthusen J, Clements J, Hutmacher DW (2013)
The potential role of lycopene for the prevention and therapy of prostate cancer: from
molecular mechanisms to clinical evidence. Int J Mol Sci 14(7):14620–14646. https://doi.
org/10.3390/ijms140714620. PMID: 23857058; PMCID: PMC3742263
17. Yang CM, Yen YT, Huang CS, Hu ML (2011) Growth inhibitory efficacy of lycopene and
β-carotene against androgen-independent prostate tumor cells xenografted in nude mice. Mol
Nutr Food Res 55(4):606–612
18. Chari RV, Miller ML, Widdison WC (2014) Antibody–drug conjugates: an emerging concept
in cancer therapy. Angew Chem Int Ed 53(15):3796–3827
19. Maeda H, Nakamura H, Fang J (2013) The EPR effect for macromolecular drug delivery to
solid tumours: improvement of tumour uptake, lowering of systemic toxicity, and distinct
tumour imaging in vivo. Adv Drug Deliv Rev 65(1):71–79
20. Fang J, Nakamura H, Maeda H (2011) The EPR effect: unique features of tumour blood ves-
sels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv
Drug Deliv Rev 63(3):136–151
21. Bertrand N, Wu J, Xu X, Kamaly N, Farokhzad OC (2014) Cancer nanotechnology: the
impact of passive and active targeting in the era of modern cancer biology. Adv Drug Deliv
Rev 66:2–25
22. Patel NR, Pattni BS, Abouzeid AH, Torchilin VP (2013) Nanopreparations to overcome mul-
tidrug resistance in cancer. Adv Drug Deliv Rev 65(13–14):1748–1762
23. Alexis F, Rhee JW, Richie JP, Radovic-Moreno AF, Langer R, Farokhzad OC (2008) New
frontiers in nanotechnology for cancer treatment. In: Urologic oncology: seminars and origi-
nal investigations, 26(1):74–85, page 56:58. Elsevier, New York, United States of America.
Urologic Oncology: Seminars and Original Investigations. https://doi.org/10.1016/j.
urolonc.2007.03.017
24. Liang Y, Li Y, Wang H, Zhou J, Wang J, Regier T, Dai H (2011) Co3O4 nanocrystals on
graphene as a synergistic catalyst for oxygen reduction reaction. Nat Mater 10(10):780–786
25. Stinchcombe TE (2007) Nanoparticle albumin-bound paclitaxel: a novel Cremphor- EL®-
free formulation of paclitaxel. Nanomedicine 2(4). https://doi.org/10.2217/17435889.2.4.415
26. Miele E, Spinelli GP, Miele E, Tomao F, Tomao S (2009) Albumin-bound formulation of
paclitaxel (Abraxane® ABI-007) in the treatment of breast cancer. Int J Nanomedicine 4:99
27. Singh K, Sai Nandhini R, Palanivelu J (2021) Nanosponges: in perspective to therapeutic
medicine. In: Nanotechnology in medicine. Springer, Cham, pp 87–104
28. Kratz F, Elsadek B (2012) Clinical impact of serum proteins on drug delivery. J Control
Release 161(2):429–445
29. Petrelli F, Borgonovo K, Barni S (2010) Targeted delivery for breast cancer therapy: the his-
tory of nanoparticle-albumin-bound paclitaxel. Expert Opin Pharmacother 11(8):1413–1432
Use of Plant-Derived Nanoparticles in Cancer Therapy 1425

30. Reddy LH, Bazile D (2014) Drug delivery design for intravenous route with integrated physi-
cochemistry, pharmacokinetics and pharmacodynamics: illustration with the case of taxane
therapeutics. Adv Drug Deliv Rev 71:34–57
31. Ibrahim NK, Desai N, Legha S, Soon-Shiong P, Theriault RL, Rivera E et al (2002) Phase I
and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle
formulation of paclitaxel. Clin Cancer Res 8(5):1038–1044
32. US Food and Drug Administration (2012) ABRAXANE® for injectable suspension (pacli-
taxel protein-bound particles for injectable suspension) (albumin-bound)
33. Roy U, Chakravarty G, Zu Bentrup KH, Mondal D (2009) Montelukast is a potent and dura-
ble inhibitor of multidrug resistance protein 2-mediated efflux of taxol and saquinavir. Biol
Pharm Bull 32(12):2002–2009
34. Javed B, Ikram M, Farooq F, Sultana T, Mashwani ZUR, Raja NI (2021) Biogenesis of sil-
ver nanoparticles to treat cancer, diabetes, and microbial infections: a mechanistic overview.
Appl Microbiol Biotechnol 105(6):2261–2275
35. Prakash NU, Bhuvaneswari S, Nandhini RS, Azeez NA, Al-Arfaj AA, Munusamy MA (2015)
Floral synthesis of silver nanoparticles using Stenolobium stans L. Asian J Chem 27(11):4089
36. Yesilot S, Aydin C (2019) Silver nanoparticles; a new hope in cancer therapy? East J Med
24(1):111–116
37. Alhadrami HA, Alkhatabi H, Abduljabbar FH, Abdelmohsen UR, Sayed AM (2021) Anticancer
potential of green synthesized silver nanoparticles of the soft coral c­ ladiellapachyclados sup-
ported by network pharmacology and in silico analyses. Pharmaceutics 13(11):1846
38. Hu XK, Rao SS, Tan YJ, Yin H, Luo MJ, Wang ZX et al (2020) Fructose-coated Angstrom
silver inhibits osteosarcoma growth and metastasis via promoting ROS-dependent apoptosis
through the alteration of glucose metabolism by inhibiting PDK. Theranostics 10(17):7710
39. Mengesha AE, Youan BC (2013) Nanodiamonds for drug delivery systems. In: Diamond-­
based materials for biomedical applications. Woodhead Publishing, Elsevier, Sawston,
Cambridge, UK, pages 186–205
40. Mochalin VN, Shenderova O, Ho D, Gogotsi Y (2012) The properties and applications of
nanodiamonds. Nat Nanotechnol 7(1):11–23
41. Horie M, Komaba LK, Kato H, Nakamura A, Yamamoto K, Endoh S et al (2012) Evaluation
of cellular influences induced by stable nanodiamond dispersion; the cellular influences of
nanodiamond are small. Diam Relat Mater 24:15–24
42. Gwak R, Lee GJ, Kim H, Lee MK, Rhee CK, Dae-Ro C et al (2015) Efficient doxorubicin
delivery using deaggregated and carboxylatednanodiamonds for cancer cell therapy. Nanosci
Nanotechnol Lett 7(9):723–728
43. Xiao J, Duan X, Yin Q, Zhang Z, Yu H, Li Y (2013) Nanodiamonds-mediated doxorubicin
nuclear delivery to inhibit lung metastasis of breast cancer. Biomaterials 34(37):9648–9656
44. National Center for Biotechnology Information (2022) PubChem compound summary for
CID 2775, Citropten. Retrieved February 25, 2022 from https://pubchem.ncbi.nlm.nih.gov/
compound/Citropten
45. Hofheinz RD, Gnad-Vogt SU, Beyer U, Hochhaus A (2005) Liposomal encapsulated anti-­
cancer drugs. Anti-Cancer Drugs 16(7):691–707
46. Silverman JA, Deitcher SR (2013) Marqibo(vincristine sulfate liposome injection) improves
the pharmacokinetics and pharmacodynamics of vincristine. Cancer Chemother Pharmacol
71(3):555–564
47. Castle MC, Mead JAR (1978) Investigations of the metabolic fate of tritiated vincristine in
the rat by high-pressure liquid chromatography. Biochem Pharmacol 27(1):37–44
48. Krishna R, Webb MS, Onge GS, Mayer LD (2001) Liposomal and nonliposomal drug phar-
macokinetics after administration of liposome-encapsulated vincristine and their contribution
to drug tissue distribution properties. J Pharmacol Exp Ther 298(3):1206–1212
49. Webb MS, Harasym TO, Masin D, Bally MB, Mayer LD (1995) Sphingomyelin-cholesterol
liposomes significantly enhance the pharmacokinetic and therapeutic properties of vincris-
tine in murine and human tumour models. Br J Cancer 72(4):896–904
1426 R. S. Nandhini et al.

50. Hagemeister F, Rodriguez MA, Deitcher SR, Younes A, Fayad L, Goy A, Cabanillas F (2013)
Long term results of a phase 2 study of vincristine sulfate liposome injection (M arqibo)
substituted for non-liposomal vincristine in cyclophosphamide, doxorubicin, vincristine,
prednisone with or without rituximab for patients with untreated aggressive non-H odgkin
lymphomas. Br J Haematol 162(5):631–638
51. Ye L, He J, Hu Z, Dong Q, Wang H, Fu F, Tian J (2013) Antitumor effect and toxicity of
Lipusu in rat ovarian cancer xenografts. Food Chem Toxicol 52:200–206
52. Xu X, Wang L, Xu HQ, Huang XE, Qian YD, Xiang J (2013) Clinical comparison between
paclitaxel liposome (Lipusu) and paclitaxel for treatment of patients with metastatic gastric
cancer. Asian Pac J Cancer Prev 14(4):2591–2594
53. Cabral H, Kataoka K (2014) Progress of drug-loaded polymeric micelles into clinical studies.
J Control Release 190:465–476
54. Kim SC, Kim DW, Shim YH, Bang JS, Oh HS, Kim SW, Seo MH (2001) In vivo evalua-
tion of polymeric micellar paclitaxel formulation: toxicity and efficacy. J Control Release
72(1–3):191–202
55. Lee KS, Chung HC, Im SA, Park YH, Kim CS, Kim SB et al (2008) Multicenter phase II trial
of Genexol-PM, a Cremophor-free, polymeric micelle formulation of paclitaxel, in patients
with metastatic breast cancer. Breast Cancer Res Treat 108(2):241–250
56. Kim TY, Kim DW, Chung JY, Shin SG, Kim SC, Heo DS, Kim NK, Bang YJ (2004) Phase I
and pharmacokinetic study of Genexol-PM, a cremophor-free, polymeric micelle-formulated
paclitaxel, in patients with advanced malignancies. Clin Cancer Res 10(11):3708–3716.
https://doi.org/10.1158/1078-­0432.CCR-­03-­0655. PMID: 15173077
57. DeLano WL (2002) Pymol: an open-source molecular graphics tool. CCP4 Newsl Protein
Crystallogr 40(1):82–92
58. Semwal DK, Semwal RB, Combrinck S, Viljoen A (2016) Myricetin: a dietary molecule with
diverse biological activities. Nutrients 8(2):90
59. Mohan UP, Sriram B, Panneerselvam T, Devaraj S, Mubarak Ali D, Parasuraman P et al
(2020) Utilization of plant-derived Myricetin molecule coupled with ultrasound for the syn-
thesis of gold nanoparticles against breast cancer. Naunyn Schmiedeberg’s Arch Pharmacol
393(10):1963–1976
60. Fern K (2018) Tropical plants database, Ken Fern. tropical. theferns. info
61. Gu FX, Karnik R, Wang AZ, Alexis F, Levy-Nissenbaum E (2007) Targeted nanoparticles for
cancer treatment. Nano Today 2:14–21
62. Cho K, Wang X, Nie S, Chen Z, Shin DM (2008) Therapeutic nanoparticles. Clin Cancer Res
14(5):1310–1316
63. Mishra B, Patel BB, Tiwari S (2009) Colloidal nanocarriers: a review on formulation technol-
ogy, types and applications toward targeted drug delivery. Nanomedicine: NBM 1:17
64. Lim KJ, Bisht S, Bar EE, Maitra A, Eberhart CG (2011) A polymeric nanoparticle formula-
tion of curcumin inhibits growth, clonogenicity and stem-like fraction in malignant brain
tumors. Cancer Biol Ther 11(5):464–473
65. Zu Y, Wang D, Zhao X, Jiang R, Zhang Q, Zhao D et al (2011) A novel preparation method
for camptothecin (CPT) loaded folic acid conjugated dextran tumor- targeted nanoparticles.
Int J Mol Sci 12(7):4237–4249
66. Pimple S, Manjappa AS, Ukawala M, Murthy RSR (2012) PLGA nanoparticles loaded with
etoposide and quercetin dihydrate individually: in vitro cell line study to ensure advantage of
combination therapy. Cancer Nanotechnol 3(1):25–36
67. Siu YS, Li L, Leung MF, Lee KLD, Li P (2012) Polyethylenimine-based amphiphilic core–
shell nanoparticles: study of gene delivery and intracellular trafficking. Biointerphases 7(1):16
68. Tang X, Cai S, Zhang R, Liu P, Chen H, Zheng Y, Sun L (2013) Paclitaxel- loaded nanopar-
ticles of star-shaped cholic acid-core PLA-TPGS copolymer for breast cancer treatment.
Nanoscale Res Lett 8(1):1–12
69. Sundar VD, Dhanaraju MD, Sathyamoorthy N (2014) Fabrication and characterization of
etoposide loaded magnetic polymeric microparticles. Int J Drug Deliv 6(1):24
Use of Plant-Derived Nanoparticles in Cancer Therapy 1427

70. Han FY, Thurecht KJ, Whittaker AK, Smith MT (2016) Bioerodable PLGA- based micropar-
ticles for producing sustained-release drug formulations and strategies for improving drug
loading. Front Pharmacol 7:185
71. Yang A, Liu Z, Yan B, Zhou M, Xiong X (2016) Preparation of camptothecin- loaded target-
ing nanoparticles and their antitumor effects on hepatocellular carcinoma cell line H22. Drug
Deliv 23(5):1699–1706
72. Zhou H, Liu X, Wu F, Zhang J, Wu Z, Yin H, Shi H (2016) Preparation, characterization,
and antitumor evaluation of electrospun resveratrol loaded nanofibers. J Nanomaterials 2016
73. Wong HL, Bendayan R, Rauth AM, Li Y, Wu XY (2007) Chemotherapy with anticancer
drugs encapsulated in solid lipid nanoparticles. Adv Drug Deliv Rev 59(6):491–504
74. Ekambaram P, Sathali AAH, Priyanka K (2012) Solid lipid nanoparticles: a review. Sci Rev
Chem Commun 2(1):80–102
75. Yassin AEB, Albekairy A, Alkatheri A, Sharma RK (2013) Anticancer- loaded solid lipid
nanoparticles: high potential advancement in chemotherapy. Digest J Nanomater Biostruct
(DJNB) 8(2):905–916
76. Abd-Allah FI, Dawaba HM, Samy AM, Nutan MT (2014) Application of solvent injection
method to develop stable, sustained release solid lipid nanoparticles of curcumin. Int J Dev
Res 4:2734–2742
77. Chadha R, Kapoor VK, Thakur D, Kaur R, Arora P, Jain DVS (2008) Drug carrier systems for
anticancer agents: a review. J Sci Ind Res 67:185–197
78. Narayanan NK, Nargi D, Randolph C, Narayanan BA (2009) Liposome encapsulation of cur-
cumin and resveratrol in combination reduces prostate cancer incidence in PTEN knockout
mice. Int J Cancer 125(1):1–8
79. Ramana LN, Sharma S, Sethuraman S, Ranga U, Krishnan UM (2012) Investigation on the
stability of saquinavir loaded liposomes: implication on stealth, release characteristics and
cytotoxicity. Int J Pharm 431(1–2):120–129
80. Venegas B, Zhu W, Haloupek NB, Lee J, Zellhart E, Sugár IP, Kiani MF, Chong PL (2012)
Cholesterol superlattice modulates CA4P release from liposomes and CA4P cytotoxic-
ity on mammary cancer cells. Biophys J 102(9):2086–2094. https://doi.org/10.1016/j.
bpj.2012.03.063. PMID: 22824272; PMCID: PMC3341537
81. Shah SM, Goel PN, Jain AS, Pathak PO, Padhye SG, Govindarajan S, Ghosh SS, Chaudhari
PR, Gude RP, Gopal V, Nagarsenker MS (2014) Liposomes for targeting hepatocellular carci-
noma: use of conjugated arabinogalactan as targeting ligand. Int J Pharm 477(1–2):128–139.
https://doi.org/10.1016/j.ijpharm.2014.10.014. Epub 2014 Oct 11. PMID: 25311181
82. Mehrabi M, Esmaeilpour P, Akbarzadeh A, Saffari Z, Farahnak M, Farhangi A, Chiani M
(2016) Efficacy of pegylated liposomal etoposide nanoparticles on breast cancer cell lines.
Turk J Med Sci 46(2):567–571
83. Li R, Wu RA, Zhao L, Hu Z, Guo S, Pan X, Zou H (2011) Folate and iron difunctional-
ized multiwall carbon nanotubes as dual-targeted drug nanocarrier to cancer cells. Carbon
49(5):1797–1805
84. Tian Z, Shi Y, Yin M, Shen H, Jia N (2011) Functionalized multiwalled carbon nanotubes-­
anticancer drug carriers: synthesis, targeting ability and antitumor activity. Nano Biomed
Eng 3(3)
85. Popov VN (2004) Carbon nanotubes: properties and application. Mater Sci Eng R: Rep
43(3):61–102
86. Nakanishi T, Fukushima S, Okamoto K, Suzuki M, Matsumura Y, Yokoyama M et al (2001)
Development of the polymer micelle carrier system for doxorubicin. J Control Release
74(1–3):295–302
87. Husseini GA, Pitt WG (2008) Micelles and nanoparticles for ultrasonic drug and gene deliv-
ery. Adv Drug Deliv Rev 60(10):1137–1152
88. Maeda H, Bharate GY, Daruwalla J (2009) Polymeric drugs for efficient tumor targeted drug
delivery based on EPR effect. Eur J Pharm Biopharm 71(3):409
1428 R. S. Nandhini et al.

89. Mourya VK, Inamdar N, Nawale RB, Kulthe SS (2011) Polymeric micelles: general consid-
erations and their applications. Indian J Pharm Educ Res 45(2):128–138
90. Wang C, Feng L, Yang X, Wang F, Lu W (2013) Folic acid-conjugated liposomal vincristine
for multidrug resistant cancer therapy. Asian J Pharm Sci 8(2):118–127
91. Kore G, Kolate A, Nej A, Misra A (2014) Polymeric micelle as multifunctional pharmaceuti-
cal carriers. J Nanosci Nanotechnol 14(1):288–307. https://doi.org/10.1166/jnn.2014.9021
92. Naha PC, Davoren M, Lyng FM, Byrne HJ (2010) Reactive oxygen species (ROS) induced
cytokine production and cytotoxicity of PAMAM dendrimers in J774A. 1 cells. Toxicol Appl
Pharmacol 246(1–2):91–99
93. Abdel-Rahman MA, Al-Abd AM (2013) Thermoresponsive dendrimers based on oligoethyl-
ene glycols: design, synthesis and cytotoxic activity against MCF-7 breast cancer cells. Eur
J Med Chem 69:848–854
94. Baig T, Nayak J, Dwivedi V, Singh A, Srivastava A, Tripathi PK (2015) A review about den-
drimers: synthesis, types, characterization and applications. Int J Adv Pharm Biol Chem
4(1):44–59
95. Malar CG (2015) Dendrosomal capsaicin nanoformulation for the invitro anticancer effect on
HEp 2 and MCF-7 cell lines. Int J Appl Bioeng 9(2)
96. Yang Q, Yang Y, Li L, Sun W, Zhu X, Huang Y (2015) Polymeric nanomedicine for tumor-­
targeted combination therapy to elicit synergistic genotoxicity against prostate cancer. ACS
Appl Mater Interfaces 7(12):6661–6673
97. Kuppusamy P, Yusoff MM, Maniam GP, Govindan N (2016) Biosynthesis of metallic
nanoparticles using plant derivatives and their new avenues in pharmacological applications–
an updated report. Saudi Pharma J 24(4):473–484
98. Melo ISVD, Santos AFD, Lemos TLGD, Goulart MOF, Santana AEG (2015) Oncocalyxone
A functions as an anti-glycation agent in vitro. PLoS One 10(6):e0131222
99. Barreto AC, Santiago VR, Freire RM, Mazzetto SE, Denardin JC, Mele G et al (2013)
Magnetic nanosystem for cancer therapy using oncocalyxone a, an antitomour secondary
metabolite isolated from a Brazilian plant. Int J Mol Sci 14(9):18269–18283
100. Cavalcanti IDL, Ximenes RM, Pessoa ODL, Magalhães NSS, de Britto Lira-Nogueira MC
(2021) Fucoidan-coated PIBCA nanoparticles containing oncocalyxone A: activity against
metastatic breast cancer cells. J Drug Deliv Sci Technol 65:102698
101. Pessoa C, Vieira FMAC, Lemos TG, Moraes MO, Lima PDL, Rabenhorst SHB et al (2003)
Oncocalyxone A from Auxemmaoncocalyx lacks genotoxic activity in phytohemagglutinin-­
stimulated lymphocytes. Teratog Carcinog Mutagen 23(S1):215–220
102. Sbardelotto AB (2013) Estudo do mecanismo de citotóxicidade da oncocalixona-A emleuce-
miapromiolocíticahumana–linhagem HL-60
103. Lira MCB, Santos-Magalhães NS, Nicolas V, Marsaud V, Silva MPC, Ponchel G, Vauthier C
(2011) Cytotoxicity and cellular uptake of newly synthesized fucoidan-coated nanoparticles.
Eur J Pharm Biopharm 79(1):162–170
104. Zhang Z, Teruya K, Yoshida T, Eto H, Shirahata S (2013) Fucoidan extract enhances the anti-­
cancer activity of chemotherapeutic agents in MDA-MB-231 and MCF-7 breast cancer cells.
Mar Drugs 11(1):81–98
The Global Concern for Cancer
Emergence and Its Prevention:
A Systematic Unveiling of the Present
Scenario

Md. Sajid Ghufran, Priyanka Soni, and Govinda Rao Duddukuri

1 Introduction

Cancer is a major public health issue and the leading cause of death globally,
accounting for about 10.0 million cancer deaths worldwide in 2020 [1–3]. It remains
the second leading cause of morbidity and mortality after cardiovascular disease
around the globe, and predominantly all cancer cases have their roots in lifestyle
and environment. The lifestyle factors comprising diet, obesity, cigarette smoking,
alcohol consumption, stress, physical inactivity and continuous exposure of human
beings to certain infections type, carcinogenic agents, ionizing radiations, and envi-
ronmental contaminants or toxicants [4–6]. Even though the world is paying good
attention to control the spread of infectious diseases, the growing burden of cancer
is being ignored in developing and least developed countries, where survival rates
are often less than half and there is also a lack of willingness and preparation among
the governing authorities to combat cancer [7, 8]. Over 100 different forms of can-
cer exist that influence all communities worldwide; however, there are marked vari-
ations in the types and pervasiveness of cancers among groups. Scientific data
suggests that new cancer cases are constantly being reported and a 47% rise from
2020 is expected in the global cancer burden, which is likely to be 28.4 million
cases by 2040 [9]. Although the total burden of cancer remains highest in rich
income civilizations, less developed and developing economies are reducing the gap
very quickly. As developing nations succeed in attaining lifestyles similar to those

M. S. Ghufran (*)
Department of Chemistry, Faculty of Natural and Computational Sciences, Gambella
University, Gambella, Federal Democratic Republic of Ethiopia
e-mail: [email protected]
P. Soni · G. R. Duddukuri
Department of Biochemistry and Molecular Biology, School of Biological Sciences, Central
University of Kerala, Tejaswini Hills, Kasargod, Kerala, India

© The Author(s), under exclusive license to Springer Nature 1429

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_60
1430 M. S. Ghufran et al.

of advanced nations, the risk of encountering cancer rates is getting much higher,
specifically breast, uterus, colon, and prostate cancer [10]. About one-third of deaths
from cancer are caused by obesity, high body mass index, low intake of fruits and
vegetables, use of tobacco, excessive alcohol consumption, and lack of physical
activity [11]. Certain types of infections that causes cancer such as human papillo-
mavirus (HPV) and hepatitis are accountable for 30% of the total cancer cases in
low- and lower-middle-income countries (LMICs) [12]. Cancer has a great impact
on the country’s economy and continues to grow. For example, in 2010, the total
annual financial cost of cancer was estimated at 1.16 trillion US dollars [13]. The
increasing prevalence of cancer as a foremost reason of death partially discloses the
significant decline in mortality rates of coronary heart disease and stroke in com-
parison to cancer in various countries [14]. Overall, the incidence of cancer and
mortality is growing fast around the globe, which reveals the growth and aging of
the population together as well as changes in the frequency and distribution of the
primary risk factors. Many of them are associated with social and economic devel-
opment [15, 16]. In this chapter, we summarized the available data to explain the
severity of the global cancer burden. We have accessed the GLOBOCAN 2020 data-
base created by the International Agency for Research on Cancer (IARC) to evalu-
ate the morbidity and mortality of cancer in different geographical regions of
the world.

2 Understanding the Burden of Cancer

in a Global Perspective

Noncommunicable diseases are by far the foremost cause of death worldwide,

accountable for 71% of total deaths in the year 2016 [17]. Out of the 15.2 million
premature deaths, 4.5 million (29.7%) deaths occurred due to cancer and is the first
or second primary cause of untimely death in 134 out of 183 countries in the world
[2]. Cancer is responsible for one in six deaths worldwide. The reason behind the
continuous upsurge in the cancer incidence and mortality is due to epidemiological
and demographic transitions and life expectancy [3, 18]. The urgency of the chal-
lenge due to non-communicable disease led to implementation of the Sustainable
Development Goals (SDGs) and their target 3.4, which determines to ensure the
achievement of a one-third decline in premature mortality from non-communicable
diseases by the year 2030 [19]. According to a WHO report, one in five people will
be affected by cancer before attaining the age of 75 [20].
Cancer is a serious public health challenge in all people irrespective of the social
status and the wealth of the individual and there has been an inequitable and uneven
retort seen in its global response [20, 21]. According to the assessments of the
International Agency for Research on Cancer (IARC), it is a major civic health issue
and the leading cause of death globally, accounting for 19.3 million new cancer
cases and about 10.0 million cancer deaths declared worldwide in the year 2020 and
The Global Concern for Cancer Emergence and Its Prevention: A Systematic Unveiling… 1431

over 47% global cancer burden estimated for the next 20 years [2, 20]. Breast cancer
has overtaken lung cancer as the most commonly recognized cancer in women.
Global comprehensive data on multiple forms of cancer in 2020 is shown in Table 1.
The top five most common new cases of cancer reported in 2020 across the world

Table 1 Estimated worldwide number of cases in terms of incidence, mortality, and prevalence by
cancer site in both men and women in 2020
Estimated new cases in Estimated deaths in 5-year prevalent cases
Types of cancer 2020 2020 (all ages)
Breast 2,261,419 684,996 7,790,717
Lung 2,206,771 1,796,144 2,604,791
Prostate 1,414,259 375,304 4,956,901
Colorectum 1,880,725 915,880 5,111,957
Stomach 1,089,103 768,793 1,805,968
Liver 905,677 830,180 994,539
Cervix uteri 604,127 341,831 1,495,211
Esophagus 604,100 544,076 668,388
Thyroid 586,202 43,646 1,984,927
Bladder 573,278 212,536 1,720,625
Non-Hodgkin 544,352 259,793 1,544,488
lymphoma
Pancreas 495,773 466,003 379,958
Leukemia 474,519 311,594 1,340,506
Kidney 431,288 179,368 1,207,547
Corpus uteri 417,367 97,370 1,415,213
Lip, oral cavity 377,713 177,757 959,248
Melanoma (skin) 324,635 57,043 1,092,818
Ovary 313,959 207,252 823,315
Brain, CNS 308,102 251,329 837,152
Larynx 184,615 99,840 518,380
Multiple myeloma 176,404 117,077 450,579
Nasopharynx 133,354 80,008 382,507
Gallbladder 115,949 84,695 137,466
Oropharynx 98,412 48,143 258,543
Hypopharynx 84,254 38,599 132,717
Hodgkin lymphoma 83,087 23,376 281,112
Testis 74,458 9334 296,686
Salivary glands 53,583 22,778 160,292
Anus 50,865 19,293 141,378
Vulva 45,240 17,427 135,892
Penis 36,068 13,211 102,157
Kaposi sarcoma 34,270 15,086 82,033
Mesothelioma 30,870 26,278 37,047
Vagina 17,908 7995 44,613
Data source: GLOBOCAN 2020
Abbreviation: CNS central nervous system
1432 M. S. Ghufran et al.

were breast (2.26 million cases), lung (2.21 million), prostate (1.41 million), colon
(1.15 million), and cancer of the stomach (1.09 million). Figure 1 shows the global
distribution of the top 10 cancer types for the estimated number of cancer incidence
and mortality in men and women in 2020. The most common reason for deaths from
cancer in 2020 were reported for the lungs (1.80 million), followed by colon and
rectum (0.93 million), liver (0.83 million), stomach (0.77 million), and breast (0.68
million) [9, 22]. The data summarized in Table 2 provides the status and trends in
organ-based cancer incidence and mortality cases in India for the year 2020. The top
five new cancer cases reported were cancer of the female breast, lip, oral cavity,

Fig. 1 Distribution of cancer incidence and mortality in the world for the top 10 most common
cancers in 2020. (a) Both sexes, (b) females, and (c) males. The area of the pie diagram represents
the proportion of the total number of cancer cases or deaths. (Data Source: GLOBOCAN 2020.
https://gco.iarc.fr/today/home)
The Global Concern for Cancer Emergence and Its Prevention: A Systematic Unveiling… 1433

Table 2 Estimated number of cases in India in terms of incidence, mortality, and prevalence,
based on site of cancer, in both men and women in the year 2020
Estimated new cases in Estimated deaths in 5-year prevalent cases
Types of cancer 2020 2020 (all ages)
Breast 178,361 90,408 459,271
Lip oral cavity 135,929 75,290 300,413
Cervix uteri 123,907 77,348 283,842
Lung 72,510 66,279 80,817
Esophagus 63,180 58,342 68,607
Stomach 60,222 53,253 81,270
Leukemia 48,419 35,392 127,493
Ovary 45,701 32,077 103,716
Non-Hodgkin 35,828 20,390 88,272
lymphoma
Liver 34,743 33,793 38,602
Larynx 34,687 21,660 82,087
Prostate 34,540 16,783 67,909
Colorectum 59,906 35,385 128,320
Brain, CNS 31,460 26,656 74,398
Hypopharynx 28,489 11,443 39,750
Bladder 21,096 11,154 49,257
Oropharynx 20,617 12,703 44,398
Thyroid 20,432 4895 55,248
Gallbladder 19,570 14,736 25,138
Kidney 16,861 9897 39,150
Corpus uteri 16,413 6385 43,484
Multiple myeloma 14,641 12,556 30,640
Pancreas 12,642 12,153 11,928
Penis 10,677 4760 26,280
Hodgkin lymphoma 9221 3513 24,928
Salivary glands 7850 5127 20,448
Nasopharynx 5697 4148 14,196
Vagina 5518 2723 12,315
Anus 5452 2776 12,278
Testis 4681 1252 14,812
Melanoma (skin) 3916 2296 9637
Vulva 3447 1694 8928
Mesothelioma 1709 1543 2223
Kaposi sarcoma 66 43 156
Data source: GLOBOCAN 2020
Abbreviation: CNS central nervous system

cervix uteri, lung, and esophagus. Figure 2 depicts the percentage distribution of the
top 10 cancer types in 2020 for the estimated number of cancer incidence and mor-
tality rates in men and women in India.
Reports suggests that in 2018, approximately 18.1 million people across the
world were suffering from cancer, and 9.6 million people died from the disease. By
1434 M. S. Ghufran et al.

Fig. 2 Distribution of cancer incidence and mortality in India for the top 10 most common cancers
in 2020. (a) Both sexes, (b) females, and (c) males. The area of the pie diagram represents the
proportion of the total number of cancer cases or deaths. (Data Source: GLOBOCAN 2020. https://
gco.iarc.fr/today/home)

the year 2040, these numbers will become twofold to nearby 29–37 million new
cases of cancer, with the highest upsurge and incidence of over two-thirds of the
world’s cancer in LMICs [20]. Among adults aged between 30 and 69 years, cancer
is the main reason for roughly 30% of all premature deaths from non-communicable
diseases (NCDs). In the year 2018, lung cancer (11.6% of total cases) was most
commonly detected cancer followed by female breast and colorectal cancer with
11.6% and 10.2% of all reported cases, respectively. The leading cause of death was
lung cancer (18.4% of total deaths) followed by colorectal and stomach cancers
with reported deaths of 9.2% and 8.2%, respectively [20]. The 10 most common
The Global Concern for Cancer Emergence and Its Prevention: A Systematic Unveiling… 1435

cancers namely lung, breast, colorectum, prostate, stomach, liver, esophagus, cervix
uteri, thyroid, and bladder were accountable for 60–70% of cancer incidence and
death [20]. The data provided in Table 3 shows incidence and mortality in the year
2020 based on age standardized rates and cumulative risk for various cancer cases
in different regions of the world.

2.1 Increasing Scale and Profile of Cancer Globally

Substantial global diversity among major cancer types is because of variances in life
expectancy and exposure to risk factors [18]. For the majority of cancer types, the
age-standardized rates (ASR) are higher in countries with a higher human develop-
ment index (HDI); however, in countries with low HDI some cancers namely naso-
pharyngeal cancer, cervical cancer, and Kaposi sarcoma are more common [2, 23].
Recent trends in the rates of major cancer acquired from high-quality cancer regis-
try data in nations based on the Human Development Index suggest that increasing
age-standardized rates contribute to two-fifths and aging of the population with
increased life expectancy contributes three-fifths of the future burden of cancer [24].
In absolute terminologies, the cancer burden is highest in countries with high and
very high Human Development Indexes (HDIs); however, the rises will be propor-
tionally more in terms of relative aspect in countries with low and medium HDIs
[3]. Particularly, in nations with low or medium HDI, the expected rise in the annual
number of new cancer patients in the coming decades is a clear sign of immediate
and good investment in control of cancer. Cancer cases in children are less com-
monly recognized, resulting in significant global dissimilarity. Worldwide, more
than 0.3 million children are diagnosed with cancer each year, and the frequency is
likely to rise with control of competing reasons of death, such as communicable
diseases [25].

2.2 Current Trends and Future Burden in Cancer Incidence

There has been an epidemiological transition in the past 60 years, as the mortality
from contagious diseases has declined and the burden of non-communicable dis-
eases, including cancer, has augmented [20]. This epidemiological shift is due to the
discovery of antibiotics, improvements in sanitation and the development of vac-
cines. The trends in cancer type with implications of strategies to control cancer are
strongly affected by changes in prevalence and the risk factor distribution. For
instance, the various effects of the smoking epidemic on the occurrence of lung
cancer are associated with the prevalence of tobacco usage in nations with high and
lower HDIs [26]. Likewise, the incidence of cancers associated with the infection,
1436 M. S. Ghufran et al.

Table 3 Global incidence and mortality rates (age-standardized rate, cumulative risk) for different
cancer cases in both sexes in the year 2020
Incidence Mortality
Both sexes Both sexes
Cumulative Cumulative
Age-­ risk ages Age-­ risk ages
World standardized 0–74 years standardized 0–74 years
region New cases rate (World) (%) Deaths rate (world) (%)
Eastern 331,233 130.2 13.6 222,189 92.1 9.91
Africa
Middle 106,467 111.1 11.7 71,570 78.4 8.4
Africa
Northern 307,507 141.9 14.61 191,081 89.9 9.21
Africa
Southern 116,391 202.4 20.0 61,659 109.0 11.5
Africa
Western 247,611 111.5 11.7 164,930 78.8 8.44
Africa
Caribbean 113,280 191.7 19.72 65,954 102.7 10.44
Central 261,646 140.2 14.3 126,071 66.0 6.91
America
South 1,095,348 201.4 20.24 521,389 91.5 9.5
America
Northern 2,556,862 360.7 33.93 699,274 87.1 9.22
America
Eastern 6,008,355 217.2 21.91 3,617,104 123.2 13.1
Asia
China 4,568,754 204.8 21.0 3,002,899 129.4 13.9
South-­ 1,100,037 152.1 15.62 689,093 95.4 10.1
Eastern
Asia
South-­ 1,951,843 102.5 10.93 1,258,683 67.0 7.41
Central
Asia
India 1,324,413 97.5 10.45 851,678 63.2 7.1
Western 443,475 175.8 18.31 244,551 98.6 10.6
Asia
Central and 1,314,193 246.1 25.5 695,828 118.9 13.4
Eastern
Europe
Western 1,424,394 325.0 31.24 559,671 103.3 10.85
Europe
Southern 953,048 279.2 27.4 423,090 98.9 10.52
Europe
Northern 706,808 316.5 30.5 276,642 99.8 10.3
Europe
(continued)
The Global Concern for Cancer Emergence and Its Prevention: A Systematic Unveiling… 1437

Table 3 (continued)
Incidence Mortality
Both sexes Both sexes
Cumulative Cumulative
Age-­ risk ages Age-­ risk ages
World standardized 0–74 years standardized 0–74 years
region New cases rate (World) (%) Deaths rate (world) (%)
Australia/ 235,955 447.6 40.43 58,744 85.8 8.55
New
Zealand
Melanesia 15,658 195.9 20.0 9022 120.7 12.6
Polynesia 1668 230.0 24.0 927 127.0 13.93
Micronesia 1010 180.6 18.85 661 118.1 12.7
Low HDI 650,423 115.7 12.1 439,852 82.7 8.8
Medium 2,326,749 108.5 11.52 1,513,219 71.5 7.9
HDI
High HDI 7,371,321 190.5 19.53 4,521,833 113.7 12.23
Very high 8,934,818 295.3 28.93 3,478,767 98.7 10.4
HDI
World 19,292,789 201.0 20.44 9,958,133 100.7 10.7
Low 447,703 121.2 12.5 308,783 87.5 9.2
income
Low middle 3,099,791 115.2 12.3 1,982,660 74.9 8.2
income
Upper 7,894,392 197.2 20.2 4,771,627 115.2 12.4
middle
income
High 7,841,425 309.7 30.1 2,890,601 94.8 9.9
income
Data source: GLOBOCAN 2020
Abbreviations: CNS central nervous system, HDI human development index

for example liver, cervix, and cancer of the stomach, has reduced significantly in the
last three decades in nations with very high HDIs, but they are common in countries
with low and medium HDIs [20, 27]. Trends in death rates are also a function of
changes in survival and occurrence that are linked to the ability of the health system
to manage cancer, including previous screening and access to effective treatment.
There are two clear findings from the studies on the chances of survival of cancer:
(i) investing in cancer management can improve survival and (ii) survival trends
vary by country and region [27].
1438 M. S. Ghufran et al.

2.3 Impact of Socioeconomic Status on Health

and Cancer Incidence

Health determinants such as economic status, biological factors, physical and social
environments have a significant impact on cancer incidence and its outcomes. For
instance, in countries with higher HDIs, use of tobacco is more prevalent in groups
with low socioeconomic status, ensuing in 60–90% higher degrees of cancers asso-
ciated with tobacco [12, 28]. Environmental factors also play a major role in the
socioeconomic disparity of cancer. The prevalence of many common cancers asso-
ciated with infection such as cancers of the liver (hepatitis B and C viruses), cervix
(Human papillomavirus), and stomach (Helicobacter pylori), is higher in the most
underprivileged groups both at the national and sub-national level with larger over-
all proportion of cancers associated with infection in lower socio-economic groups
and low-income nations [12, 28]. People living with HIV also have a higher risk of
developing many types of cancer, specifically those associated with AIDS (invasive
cervical cancer, non-Hodgkin lymphomas and Kaposi sarcoma) and transmissible
agents (liver cancer associated to hepatitis B and C viruses, Hodgkin lymphoma
linked to Epstein-Barr viruses and anal cancer caused by Human papillomavirus)
[29, 30]. By means of better treatment and a projected rise in people’s life expec-
tancy living with HIV/AIDS, more investment in clinical trials will be needed to
detect the best effective control strategies for cancer prevention.
Death from cancer is closely associated with the cancer stage at the time of diag-
nosis and the quality of treatment being given. The deprived groups participate less
in the screening programs and often experience geographical and economic barriers
which result in very late diagnoses and significant variances in outcomes [31–33].
Even if cancer is detected at an initial stage, these groups are more likely to get poor
quality care or fail to complete treatment or, in case of poor prognosis of cancers, be
transitioned to non-palliative care [34–36].

3 Factors Behind the Emergence of Cancer

Cancer is a disease where normal cells are transformed into abnormal tumor cells in
a multistage process that typically develops from a precancerous lesion into a malig-
nant tumor. These alterations are the consequence of the interaction between genetic
factors of the individuals and different classes of external agents or environmental
factors or cancer-causing agents (Fig. 3). The contribution of environmental and
genetic factors toward the risk of cancer emergence is 90–95% and 5–10%, respec-
tively. These risk factors as mentioned by the WHO [22, 37] includes:
• Physical carcinogenic agents, such as exposure to electromagnetic fields, ioniz-
ing and ultraviolet radiation.
The Global Concern for Cancer Emergence and Its Prevention: A Systematic Unveiling… 1439

Fig. 3 Schematic representation showing the influence of environmental and genetic factors in the
emergence of cancer. Cancer is a disorder of altered cell differentiation and growth, arises due to
the consequence of the interaction between genetic factors of individuals and different classes of
environmental factors. The contribution of environmental and genetic factors towards the risk of
cancer emergence is 90–95% and 5–10%, respectively

• Chemical carcinogenic agents, namely components of tobacco smoke, asbestos,

arsenic (a contaminant of drinking water), diethylstilbestrol, tamoxifen, and
exposure to heavy metals and certain environmental contaminants.
• Biological carcinogenic agents, such as diet and physical activity, food contami-
nants (mycotoxins) and infections resulting from certain bacteria, viruses, or
parasites.

3.1 Physical Factors

3.1.1 Ionizing Radiation

Ionizing radiation is one of the commonly listed potential carcinogens and its low
dose has enough energy to damage the DNA and may induce tumors in all organs of
the body. Individuals are more likely to get an increased dose of radiation exposure
during diagnostic imaging, medical treatment and therapeutic reasons or during
educational and scientific research in academia, which ultimately leads to the risk of
developing cancer [38, 39]. Most solid cancers and leukemia are associated with
radiation exposure which depends upon the dose and number of exposures. In gen-
eral, the risk of developing cancer as a result of a single low-dose exposure of 0.1
gray (Gy) was estimated to be approximately 1%. The estimates of individuals
1440 M. S. Ghufran et al.

exposed at a young age are large; for instance, the lifetime risk of individuals
exposed at age 10 would be about 2% [38]. Studies have found that the percentage
of all cancers caused by radiation is 2–3%, and children exposed to X-rays often
develop leukemia, liver, and bone cancer [40, 41]. Ionizing radiation can also stimu-
late neoplasia in the case of penetrating irradiation of the bladder, chest, and thyroid
gland. Radiation therapy in childhood stimulates tumorigenesis in the digestive tract
and the risk of developing malignant gastrointestinal tumors [41].

3.1.2 Exposure to Electromagnetic Fields

People in developed countries are regularly under exposure to low-frequency elec-

tromagnetic fields generated by power transmission lines and home appliances and
their long-term exposure has been linked to a higher risk of childhood leukemia
[42]. Epidemiological studies by Wertheimer and Leeper in 1979 established an
increased risk of leukemia among American children living in homes with higher
than normal strength of electromagnetic fields [43]. Later on, further experimental
and epidemiological research in this area led the IARC to classify the low frequency
electromagnetic field as a “possible human carcinogen” [44–46]. A recent report
suggested that continuous exposure of human normal (IMR-90) and cancer (HeLa)
cells to a 60 Hz electromagnetic field promoted cell proliferation by decreasing
intracellular reactive oxygen species levels. The findings of this study revealed that
electromagnetic field uniformity at an extremely low frequency (ELF) is an impor-
tant risk factor for altered cellular responses that lead to cancer [47].

3.1.3 Ultraviolet Radiation

Another most common environmental factor affecting the skin is ultraviolet (UV)
radiation, which is primarily responsible for its damaging nature and is considered
as a potential risk factor causing melanoma and other skin malignancies [48].
Chronic and overexposure to UV rays from the sun can often cause adverse early-­
onset symptoms, especially sunburn and late signs of accelerated skin aging. Most
skin cancers are caused by exposure to UV radiations in the sunlight. Epidemiological
and molecular studies have validated that extreme exposure to UV radiation is asso-
ciated with the increased risk of three most common types of skin cancers such as
malignant melanoma, squamous skin carcinoma, and basal cell carcinoma [49]. UV
radiation induces the formation of thymine-thymine pyrimidine-pyrimidone (6-4)
photoproduct (T (6-4) T) and thymine-thymine cyclobutane dimer (T-T), thereby
causing damage to the DNA of epidermal cells [50, 51]. These DNA adducts are
mutagenic, if left unrepaired, get incorporated into the DNA and eventually inter-
fere with the apoptotic pathways and induce cellular proliferation leading to tumor
development [50–52].
The Global Concern for Cancer Emergence and Its Prevention: A Systematic Unveiling… 1441

3.2 Chemical Factors

3.2.1 Alcohol Consumption

Several studies have established an influential link between alcohol consumption

and the risk of developing a variety of diseases, including cancer, and this may be a
prime factor behind the increased burden of disease worldwide [53, 54]. People who
consume more alcoholic beverages are likely to develop alcohol-related vast range
of cancers such as the liver, female breast, rectum, colon, and cancers of the upper
aerodigestive tract (esophagus, throat, mouth and larynx) [55]. Recent data from the
GLOBOCAN 2020 database revealed that these cancers together contributed to 6.3
million new cases and 3.3 million deaths worldwide in 2020 [56]. The pattern of
alcohol consumption in regions around the world varies over time. Decrease in per
capita use has been observed in several European countries, particularly those in
Eastern Europe. However, consumption of alcohol is increasing in Asian countries
such as India, Vietnam, and China, and in many countries in sub-Saharan Africa
[57]. The findings of a new study show just how risky drinking can be. Worldwide,
an estimated 0.75 million people or 4.1% of all newly diagnosed cancer cases in
2020 were due to alcohol consumption. Men accounted for 76.7% of total alcohol-­
related cancer cases, and cancers of the breast (0.0983 million cases), liver (0.1547
million cases) and esophagus (0.1897 million cases) contributed the most cases
[56]. Population attributable fractions (PAFs) were highest in Central and Eastern
Europe (5.6%) and Eastern Asia (5.7%), whereas lowest in Western Asia (0.7%) and
Northern Africa (0.3%). The greatest burden of cancer caused by alcohol was repre-
sented by moderate drinking (0.103 million cases, 13.9%), risky drinking (0.2918
million cases, 39.4%) and heavy drinking (0.3464 million cases, 46.7%), though
consumption up to 10 g/day contributed 0.0413 million cases [56].

3.2.2 Tobacco Use

Tobacco smoking is a significant risk factor and the principal cause of lung carcino-
genesis, which causes more than seven million deaths every year worldwide.
Tobacco smoking accounts for approximately 80–90% of lung cancer in the United
States. It also causes several other types of cancer such as the colon and rectum,
cervix, pancreas, stomach, liver, kidney, bladder, throat, esophagus, mouth, and lar-
ynx [58]. All tobacco products, partly or completely made of tobacco leaves, are
sources of many carcinogens and other toxic substances that damage DNA. The
recent comprehensive statistical data on global trends in cigarette smoking high-
lights that the number of smokers continues to rise and has increased to 1.1 billion
in 2019, among which approximately 90% are new smokers who became addicted
by the age of 25 years [59]. Globally, tobacco use resulted in approximately 7.7 mil-
lion deaths in 2019 out of which nearly 1.3 million people lost their lives due to
bronchial, tracheal, and lung cancer [60]. The findings of the report also suggest that
1442 M. S. Ghufran et al.

if the smoking pattern does not change across the world, the condition would be
more horrible as more than eight million people will die every year from diseases
associated with tobacco use by 2030 [61]. Smokeless tobacco products are a major
threat and create a global burden of disease. Smokeless tobacco refers to various
products containing tobacco consumed by sniffing, chewing, or keeping it in the
mouth. It is being used across the world and poses a major public health issue in
South and South-East Asia as the highest rate of consumption was noticed in these
regions. In 2017, approximately 0.098 million people worldwide died because of
esophageal, pharyngeal, and oral cancers [62]. According to a new report published
by the National Cancer Registry of India (NCR), which works under the Indian
Council of Medical Research (ICMR), cancer cases attributable to tobacco con-
sumption were responsible for more than a quarter, or about 27% of India’s cancer
burden in 2020 [63].

3.2.3 Exposure to Other Chemicals and Environmental Toxicants

Human beings often come into contact with many chemicals used in domestic life,
the environment, and agriculture. The discharge of toxic wastes or pollutants from
industries and the emissions of automobile exhaust contain many compounds in
either gaseous or particulate form, which results in a higher threat of cancer inci-
dence in children [6, 64]. Individuals who are strongly exposed to smoke, pesti-
cides, hair dye, incense including other substances or an aromatic gum may have a
higher risk of getting cancer. Certain medications and other chemical compounds
can also have carcinogenic effects as classified by IARC, such as diethylstilbestrol
used in the prevention of miscarriage, tamoxifen widely used for chemoprevention
of breast cancer and drug for chemotherapy, oxazepam, phenobarbital, and chemi-
cals like organochlorine compounds, derivatives of phenoxyacetic acids, aromatic
benzene derivatives used in the manufacture of drugs in the pharmaceutical industry
[65, 66]. Heavy metal exposure, such as lead, cadmium, arsenic, mercury, and an
extensively used persistent organochlorine pesticide endosulfan, also called as
endocrine disruptor molecules, are well known to possess oncogenic potential with
an ability to induce epigenetic alterations such as chromatin remodeling, changes in
DNA methylation profiles, modulating the expression of oncogenic enzymes as
well as the expression of microRNAs (miRNAs) and non-coding RNAs (ncRNAs),
eventually contributing to the development of various types of cancer [67–69]. A
recent study conducted in Ethiopia has shown that exposure to environmental toxi-
cants such as organochlorine pesticides might be one of the vital factors leading to
tumorigenesis. The findings highlight that several organochlorine pesticides
(dibutyl-­chlorendate, endosulfan, gamma-chlordane, heptachlor, p,p’- dichlorodi-
phenyltrichloroethane, and p,p’-dichlorodiphenyldichloroethylene) were detected
in the serum of the study participants among which heptachlor, a cyclodiene insec-
ticide, was found at a higher concentration in breast cancer patients, suggesting that
organochlorine pesticides could be one of the prime risk factors for breast cancer
incidences in Ethiopia [70].
The Global Concern for Cancer Emergence and Its Prevention: A Systematic Unveiling… 1443

3.3 Biological Factors

3.3.1 Carcinogenic Substances and Toxicants in Food

Food is a vital necessity for everybody, although carcinogenic or toxic substances

can be generated in many food products depending on environmental factors lead-
ing to development of diseases like cancer [71]. These carcinogenic substances can
be either natural or formed during storage of food and its processing. Most of them
are genotoxic in nature that bind covalently to the DNA molecules and can directly
or indirectly modulate the expression of enzymes responsible for the onset of cancer
[72]. Mycotoxins are carcinogenic substances and highly toxic, produced mainly by
the species of Aspergillus, Fusarium, and Penicillium. Presently, more than 400
types of mycotoxins have been recognized among which exposure to zearalenone,
fumonisins, ochratoxins, and aflatoxins predominantly causes liver cancer and can-
cer of other organs namely lung, breast, skin, prostate, and esophagus [73–76].
Among mycotoxins, one of the major dietary contaminants of food is aflatoxins
mainly secreted by Aspergillus flavus and Aspergillus parasiticus. Aflatoxins are
gaining prime attention among the scientific community since they are potentially
enough to modulate the function of epigenetic regulators, namely DNA methyl-
transferases (DNMTs), histone deacetylases (HDACs), histone acetyltransferases
(HATs), polycomb group (PcG) proteins and oncoprotein protein arginine methyl-
transferase 5 (PRMT5), thereby resulting in altered cellular functions and causing
cancer [77–80].

3.3.2 Diet and Physical Activity

Poor dietary habits and sedentary lifestyles play a deleterious role by adversely
affecting the normal health of individuals and are closely associated with cancer
prevalence. Diet, obesity, and physical inactivity are some of the factors which con-
tribute to tumor progression and are accountable for nearly 30–35% of cancer deaths
[81]. A population-based study performed on more than five million adults of
United Kingdom established that higher body mass index (BMI) was directly linked
to the progression of many types of cancer and responsible for nearly 12,000 cases
every year [82]. Prolonged sitting increases the risk of prostate, ovarian, endome-
trial and colorectal cancer and contributes significantly to cancer mortality, espe-
cially in females. Some specific food influences development of specific cancers,
for example, chewing of areca nut may cause oral cancer; a common dietary con-
taminant aflatoxin B1 causes cancer of liver, whereas diet containing high salt con-
centration is linked to stomach (gastric) cancer [74, 83, 84]. Low intake of fruits,
vegetables, and overeating of red or processed meat and the consumption of barbe-
cued or grilled fish and meat may increase the risk of pancreatic, colon and breast
cancer [9, 85]. Dietary differences between populations may have an impact on
cancer incidence. Among the Japanese population, gastric cancer is more common
1444 M. S. Ghufran et al.

because of a high salt diet, whereas colon cancer is more prevalent in the United
States population due to the consumption of more snacks containing refined
sugar [86].

3.3.3 Infections and Infectious Agents

The scientific community is paying more attention to infectious agents because

some chronic infections are significant risk factors for the development of cancer
[12]. Infectious diseases contribute to nearly 18% of deaths from cancer worldwide.
The major carcinogenic infectious agents contribute to the global cancer burden and
cause many types of cancer, including Helicobacter pylori induces gastric carci-
noma, Epstein-Barr virus (EBV) causes Burkitt lymphoma and nasopharyngeal car-
cinoma, hepatitis B virus (HBV) and hepatitis C virus (HCV) causes hepatocellular
carcinoma and certain types of human papillomavirus (HPV) increase the risk for
cervical cancer. Globally, an estimated 2.2 million or 13% of all cancers diagnosed
(excluding non-melanoma skin cancer) in 2018 were attributed to these infectious
agents and the primary causes were H. pylori (0.81 million cases), HPV (0.69 mil-
lion cases), HBV (0.36 million cases) and HCV (0.16 million cases). Kaposi sar-
coma (KS), a cancer that causes tumors in the soft tissues, was the second major
contributor to the burden of cancer in sub-Saharan Africa [12]. Infection with human
immunodeficiency virus (HIV) substantially increases the risk of cervical cancer.
However, conjunctival squamous cell carcinoma is a unique case associated with
HIV infection in sub-Saharan Africa region. It is estimated that in 2018 around 2000
cases of this type of cancer in Africa were caused by HIV, and no other virus was
yet involved in the carcinogenic process [12]. China accounted for more than a third
of global cancer cases caused by infectious agents, driven by high age-standardized
incidence rates (ASIR) of H. pylori (15.6), followed by HBV (11.7) infection. Other
regions with a particularly high HPV-attributable cancer burden include Central and
Eastern Europe (ASIR 10.9 cases), followed by ASIR of 9.6 cases in south eastern
Asia and South America (ASIR 9.6 cases) and India (ASIR 9.0 cases). The cancer
incidences attributed to HPV indicated the clearest relationship with the income
level of the country (from ASIR of 6.9 cases per 100,000 person-years to 16.1 in
high- and low-income countries, respectively) [12]. Chronic infection of hepatitis B
and C virus is one of the main risk factors for the development of hepatocellular
carcinoma (HCC). However, the major risk factors vary by geographic region. In
high-risk HCC region (sub-Saharan Africa, Republic of Korea, and China) chronic
hepatitis B virus infection is one of the key contributing factors, whereas in other
regions (Egypt, Italy and Japan), hepatitis C virus infection is probably the prime
reason [9]. Parasitic infections and other infectious agents such as human herpesvi-
rus-­8 (HHV-8), human T-cell lymphotropic virus type 1 (HTLV-1) and Epstein-Barr
virus were together responsible for the incidence of 0.21 million cancer cases in
2018. Other infectious pathogens that are contributing to the upsurge in the inci-
dence of global cancer burden and whose evidence on causality is firming up and
could be included in future assessment include Epstein-Barr virus (EBV)
The Global Concern for Cancer Emergence and Its Prevention: A Systematic Unveiling… 1445

contributing to gastric cancer and non-Hodgkin lymphoma, hepatitis C virus (HCV)

causing cholangiocarcinoma, Merkel cell virus (MCV) causing Merkel cell carci-
noma, Plasmodium species as a cause of Burkitt lymphoma, and Salmonella typhi
accountable for gallbladder cancer [12].

4 Prevention Strategies to Reduce the Global Cancer Burden

4.1 Reducing the Growing Burden of Cancer

As the global burden of cancer, along with non-communicable diseases, continues

to rise, the pace of research and progress in the development of cures, therapies, and
preventive strategies against cancer is increasing globally. There are four key com-
ponents to control the burden of cancer as recommended by the World Health
Organization, which includes cancer prevention, detection of cancer at the early
stage, diagnosis and treatment, and palliative care [20, 22]. Developing countries
are facing great challenges in these four areas when trying to define the scale of the
cancer problem because of the limited resources, lack of reliable statistics, and
health-related infrastructure. The lack of population-based cancer registries in many
developing countries has led to estimates about the relative frequencies of the vary-
ing degrees of diverse cancer based on global trends. This type of estimation could
be misleading and ambiguous, therefore efforts to build a sustainable infrastructure
and improvement of cancer registries are necessary. Developing countries lack
funds to invest in comprehensive national cancer registries. As a consequence, the
contemporary figures are based mostly on data from hospital-based registries [20,
22, 27]. The IARC’s GLOBOCAN project is the most comprehensive data assess-
ment tool available today to analyze and predict the global cancer incidence and
mortality for 36 cancer types in 185 countries. According to the GLOBOCAN data-
base, the top five most frequent cancer cases in 2020 in countries with low HDIs
were cancers of the breast (16.8%) followed by cervix uteri (12.6%), prostate
(8.5%), liver, and colorectum each (5.1%), whereas in countries with medium HDIs,
the most common cancers were breast (13.2%), cervix uteri (7.9%), lip oral cavity
(7.6%), lung (7.1%), and colorectum cancer (5.2%) [2, 3]. The current data suggests
that there are certain key differences in the incidence pattern of cancer emergence.
The reasons for relatively high rates of breast, lung, prostate, and colorectal cancer
in developing countries are the inclusion of western food, sedentary lifestyle, earlier
exposure to infectious carcinogens and the previous onset of the tobacco epidemic.
On the contrary, a quarter of cancers in developing countries are linked to chronic
infections. Cancer of the stomach is attributable to H. pylori infection, whereas
certain types of HPV cause cervical cancer and liver cancer is often associated with
HBV infection [12]. The incidence of cancer and mortality in developing countries
could be reduced substantially by taking proactive measures such as increasing the
availability and accessibility of vaccines against hepatitis and human papilloma
1446 M. S. Ghufran et al.

virus or by banning tobacco. However, it is more important and essential to focus on

the full array of cancer control including early stage detection, diagnosis, and appro-
priate treatment and palliative care. We know well from extensive research studies
that genetic and environmental factors play an important role in the development of
cancer, with environmental factors being the major threat behind the emergence of
most cancer cases [5, 6]. Only a small percentage of all cancer incidences are asso-
ciated with genetic defects and the majority of cases are caused by environmental
risk factors, although many of these factors are controlled by lifestyle choices,
hence cancer can be potentially preventable [4]. More than half of all cancer cases
could be prevented by taking drastic measures in human lifestyle and avoiding risk
factors, including poor diet (red meat and fried foods), obesity, physical inactivity,
alcohol consumption, tobacco use, cigarette smoking, exposure to UV radiation
resulting from the sun and artificial tanning devices, exposure to toxicants, pollut-
ants, and environmental contaminants and could also be reduced by ensuring the
safe use of radiation for diagnostic and treatment purposes in the health care
system [4].

4.2 Early-Stage Detection of Cancer

A large population in low- and lower-middle-income countries have limited or no

access to early diagnosis and screening of cancer due to the lack of basic infrastruc-
ture and resources in health care system [22]. The burden of cancer can be reduced
by detecting it at an early stage and providing proper care and treatment without any
delay to patients who develop cancer. If detected early, cancer responds better to
treatment and can result in a higher chance of survival and a lower morbidity rate
[22]. In majority of cancer cases, early diagnosis of symptomatic cancer is impor-
tant hence cancer control programs should be designed to improve health infrastruc-
ture, focus on early detection through surveillance and screening and to avoid delays
and reduce barriers to diagnosis and treatment in health care system. Diagnosis of
cancer may result in psychological and mental distress; therefore, psychosocial
interventions, for example talking therapy, may be helpful for individuals to over-
come this condition [87].

4.3 Biomarkers as a Tool for an Early Detection of Cancer

4.3.1 Circulating Nucleic Acids

Deregulated or elevated levels of circulating nucleic acids in the serum or blood

plasma are associated with tumorigenesis and tumor progression and drug resis-
tance in cancer patients which may serve as a liquid biopsy technique and could be
useful in various prognosis and diagnostic applications of many cancer types [5].
The Global Concern for Cancer Emergence and Its Prevention: A Systematic Unveiling… 1447

4.3.2 Epigenetic Markers

Epigenetic modifications could be utilized as biomarkers of disease condition and

exposure of certain environmental and occupational toxicants which may serve as
biomolecular sensors for preventive measure and surveillance. Occupational expo-
sure to carcinogenic chemicals can also be linked to cancer and the process of
tumorigenesis is associated with epigenetic alterations predominantly by methyla-
tion of DNA and histone modifications in its early stages [5].

4.4 Screening

Unlike diagnostic efforts driven by medical signs and symptoms, the screening pro-
cess involves solid efforts to detect cancer once it has developed but before the
appearance of any clear sign and symptoms. For many cancer types, the screening
process is inefficient, not available and generally are more complicated and requires
dedicated person and special equipment. The widespread use of mammography and
screening for prostate cancer are prime examples showing the potential pitfalls of
detection and subsequent redundancy of indolent lesions following overtreatment
[88]. People at high risk can be identified by selective screening such as the knowl-
edge about family history and background. Various factors must be considered to
ensure that the benefits of screening do not outweigh the risk of screening. A screen-
ing program must be cost-effective for the target population and must be accessible
and acceptable. In order to avoid a false positive outcome of screening programs,
the selection of patients should be based on risk factors and age. Examples of
screening methods for cervical cancer include PAP cytology test, HPV testing and
visual inspection with acetic-acid (VIA), whereas breast cancer can be screened by
mammography in setup with a strong or relatively strong health care system [22, 87,
89]. In the future, the emphasis should be on early detection and cancer prevention
efforts involving precise cancer prevention strategies so that screening and cancer
prevention programs could be matched to individual’s cancer risk attributable to
known genomic and environmental factors [88].

4.5 Treatment and Palliative Care

Cancer is a major public health issue and a costly disease in terms of treatment and
cure in both developed and developing countries. Accurate diagnosis of a particular
cancer type is critical for an appropriate and effective treatment strategy because
each type of cancer requires a precise treatment regimen. There are many treatment
options available for existing cancer types. The classical treatment methods include
surgery, hormonal therapy, radiation therapy and chemotherapy, whereas advanced
ones include image-guided radiation therapy, intensity modulated radiotherapy,
1448 M. S. Ghufran et al.

gene therapy, personalized therapy, targeted therapy, and bone marrow transplanta-
tion. Advanced treatment models are more expensive and are not readily available
in low- and middle-income countries [90, 91]. However, they have fewer side effects
with effective results. The choice of a particular treatment model depends on several
parameters, such as the types and stage of cancer, location, grade, and biology of
tumor as well as the preferences of the patient and his/her health status. The cost of
cancer treatment is very expensive in low- and middle-income countries because of
the unaffordable prices of drugs for therapy and limited access to novel treatments
[92]. The cost-effectiveness of a drug or regimen varies between different settings;
for example, some of the drugs that are economical in developed countries remain
unaffordable in low- and middle-income countries. There has been a sharp increase
in cancer drug spending forecasts, but access remains a problem. Therefore, it is
essential to address this issue by increasing uniform global availability, affordabil-
ity, and accessibility to vital cancer drugs within the reach of patients and protecting
them from financial loss, so that the fight against cancer prevention and treatment is
not left behind [93].
Sometimes, after trying many types of available treatments or even providing the
best care to cancer patients, cancer continues to spread and reaches an advanced
stage where it could be a very tough situation for the patient, family members, and
the medical doctor to talk and decide about discontinuing treatment for the cancer
and focusing on end-of-life or hospice care [94]. Palliative care is a treatment, rather
than a cure, to relieve pain, symptoms and stress caused by cancer and helps in
improving the quality of life for patients and that of their relatives by the detailed
assessment and management of the psychosocial, spiritual and physical distress
experienced by patients. Unlike treatment that aims to kill cancer cells directly, the
prime goal of palliative care is to help and support people to live more comfortably
and is especially needed in advanced stage cancer patients where there is little or no
hope of getting cured [94]. Palliative care is required in a wide range of diseases and
among adults with chronic diseases, 34% of the world’s cancer patients need pallia-
tive care. According to the WHO, 78% of the estimated 40 million people living in
low- and middle-income countries are in need of palliative care each year and, at the
same time, the global requirement will continue to rise due to the ageing of popula-
tions and the growing burden of non-communicable diseases including cancer [95].

4.6 Role of Naturally Occurring Phytochemicals

in Cancer Prevention

Phytochemicals are the bioactive compounds and secondary metabolites produced

by plants having health-improving properties. The use of naturally occurring plant
derived compounds or phytochemicals is receiving major attention among the sci-
entific community as a promising target to combat cancer since both conventional
and modern treatment therapies have faced several challenges, including toxicity,
The Global Concern for Cancer Emergence and Its Prevention: A Systematic Unveiling… 1449

multi-drug resistance and enormous economic expenses of hospitalization and

treatment [96, 97]. On the contrary, complementary alternative medicine (CAM),
which uses phytochemicals, has gained prime attention in recent times due to its
ability to modulate numerous molecular mechanisms with less toxicity and minimal
side effects. Growing evidence of preclinical and clinical studies suggests that phy-
tochemicals may favorably modulate multiple signaling pathways indulged in tumor
development and progression [98]. The use of phytochemicals inhibits proliferation
and invasion of the cells, promotes apoptosis, sensitizes cancer cells and enhances
the immune system, and therefore emerges as an attractive alternative to cancer
therapy. Some typical examples of plant derived compounds include vinca alkaloid
agents (vinblastine, vincristine, vindesine, and vinorelbine), taxol analogs (pacli-
taxel and docetaxel), camptothecin derivatives (belotecan, irinotecan and topotecan)
and podophyllotoxin analogs (clinically effective derivatives—etoposide and teni-
poside) which are currently being prescribed as anticancer agents, and many more
related compounds are in clinical trials [4, 97].
Culinary spices and condiments are regularly used to enhance the flavor of food
as they are rich sources of various phytochemicals and provide a unique aroma.
Since ancient times, they have been used for their health benefits and health-­
promoting effects. Currently, “Nutri-epigenetics” has received attention among
researchers with emphasis on investigating the potential to control or regulate sev-
eral epigenetic modifications [4, 96]. Recent studies have uncovered the alterations
induced by these dietary phytochemicals and provided ample evidence for their role
in controlling a number of chronic diseases in humans, including cancer. The largest
class of phytonutrients such as terpenes and terpenoids found primarily in soy
plants, green foods, and grains have been assessed for their epigenetic modifying
potential, which includes tocotrienols, luciferin, γ-bisabolene, and saffron carot-
enoids [96]. Dietary polyphenolic compounds and alkaloids are a large group of
plant secondary metabolites and are capable of reversing aberrant epigenetic modi-
fications. Phenolic and alkaloid compounds nowadays are used as anticancer agents
and have been shown to modulate various epigenetic modifications that include
luteolin, garcinol, apigenin, zingerone, anethole, α-mangostin, quercetin, epigallo-
catechin gallate (EGCG), curcumin, capsaicin, piperine, gingerol, and resveratrol
[4, 96]. The understanding of the epigenetic modifying potential of phytochemicals
renders the identification of epigenetic biomarkers for its dietary exposure and may
predict their ability to combat cancer.

5 Conclusion

One of the biggest challenges the world is facing today in fighting cancer is the lack
of cost-effective solutions, as the entire treatment range from classical to modern
methods is not affordable. To prevent and control cancer-related morbidity and mor-
tality, we need to strengthen and enhance public health systems, especially in low-
and lower-middle-income countries. Now is the time to invest in affordable cancer
1450 M. S. Ghufran et al.

prevention programs through awareness-raising campaigns, introducing healthy

lifestyle behaviors such as abstaining from tobacco use or drinking alcohol, teach-
ing self-care, and establishing sustainable advanced medical practices combined
with low price cancer drugs and precision medicine. On the other hand, naturally
occurring plant-derived bioactive compounds serve as important resources for novel
medicines and may be a promising approach for the treatment of relapsed cancers.
We believe that everything we can do to prevent cancer should also be done at the
policy level. Nation-based cancer policies should reflect the nation’s weaknesses
and strengths in the fight against cancer. In order to avoid future crises such as the
HIV/AIDS pandemic, the time has come to strengthen health infrastructure, change
control policies, and work together with government and non-governmental organi-
zations to overcome the burden of cancer.

Conflict of Interest All authors declare that there is no conflict of interest.

References

1. GBD 2015 Mortality and Causes of Death Collaborators (2016) Global, regional, and national
life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death,
1980–2015: a systematic analysis for the Global Burden of Disease Study 2015 [published
correction appears in Lancet. 2017;389(10064):e1]. Lancet 388(10053):1459–1544. https://
doi.org/10.1016/S0140-­6736(16)31012-­1
2. Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M et al (2020) Global cancer observa-
tory: cancer today. International Agency for Research on Cancer, Lyon. Available from: https://
gco.iarc.fr/today. Accessed 10 Jan 2022
3. Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M et al (2020) Global cancer obser-
vatory: cancer tomorrow. International Agency for Research on Cancer, Lyon. Available from:
https://gco.iarc.fr/tomorrow. Accessed 10 Jan 2022
4. Anand P, Kunnumakkara AB, Sundaram C, et al (2008) Cancer is a preventable disease that
requires major lifestyle changes [published correction appears in Pharm Res 2008;25(9):2200.
Kunnumakara, Ajaikumar B [corrected to Kunnumakkara, Ajaikumar B]]. Pharm Res
25(9):2097–2116. https://doi.org/10.1007/s11095-­008-­9661-­9
5. Budnik LT, Adam B, Albin M et al (2018) Diagnosis, monitoring and prevention of exposure-­
related non-communicable diseases in the living and working environment: DiMoPEx-project
is designed to determine the impacts of environmental exposure on human health. J Occup
Med Toxicol 13:6. https://doi.org/10.1186/s12995-­018-­0186-­9
6. Lewandowska AM, Rudzki M, Rudzki S, Lewandowski T, Laskowska B (2019) Environmental
risk factors for cancer - review paper. Ann Agric Environ Med 26(1):1–7. https://doi.
org/10.26444/aaem/94299
7. Murray CJL, Lopez AD (eds) (1996) The global burden of disease: a comprehensive assess-
ment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected
to 2020. Harvard University Press, Cambridge, MA
8. Stewart BW, Kleihues P (2003) World cancer report. IARC Press, Lyon
9. Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN esti-
mates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin
71(3):209–249. https://doi.org/10.3322/caac.21660
The Global Concern for Cancer Emergence and Its Prevention: A Systematic Unveiling… 1451

10. Siegel RL, Miller KD, Fuchs HE, Jemal A (2021) Cancer statistics, 2021 [published correc-
tion appears in CA Cancer J Clin 2021;71(4):359]. CA Cancer J Clin 71(1):7–33. https://doi.
org/10.3322/caac.21654
11. Jayasekara H, MacInnis RJ, Room R, English DR (2016) Long-term alcohol consumption and
breast, upper aero-digestive tract and colorectal cancer risk: a systematic review and meta-­
analysis. Alcohol Alcohol 51(3):315–330. https://doi.org/10.1093/alcalc/agv110
12. de Martel C, Georges D, Bray F, Ferlay J, Clifford GM (2020) Global burden of cancer attrib-
utable to infections in 2018: a worldwide incidence analysis. Lancet Glob Health 8(2):e180–
e190. https://doi.org/10.1016/S2214-­109X(19)30488-­7
13. Wild CP, Weiderpass E, Stewart BW (eds) (2020) World cancer report. Cancer research for
cancer prevention. International Agency for Research on Cancer, Lyon. Available from: http://
publications.iarc.fr/586. Accessed Jan 2022
14. Wilson L, Bhatnagar P, Townsend N (2017) Comparing trends in mortality from cardiovascu-
lar disease and cancer in the United Kingdom, 1983-2013: joinpoint regression analysis. Popul
Health Metrics 15(1):23. https://doi.org/10.1186/s12963-­017-­0141-­5
15. Omran AR (1971) The epidemiologic transition. A theory of the epidemiology of population
change. Milbank Mem Fund Q 49(4):509–538
16. Gersten O, Wilmoth JR (2002) The cancer transition in Japan since 1951. Demogr Res
7:271–306
17. Global Health Observatory (2016) World Health Organization, Geneva. Available from: http://
www.who.int/gho/database/en/. Accessed Jan 2022
18. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statis-
tics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185
countries [published correction appears in CA. Cancer J Clin 2020;70(4):313]. CA Cancer J
Clin 68(6):394–424. https://doi.org/10.3322/caac.21492
19. NCD Countdown 2030 collaborators (2018) NCD countdown 2030: worldwide trends in non-­
communicable disease mortality and progress towards sustainable development goal target
3.4. Lancet 392(10152):1072–1088. https://doi.org/10.1016/S0140-­6736(18)31992-­5
20. World Health Organization (2020) WHO report on cancer: setting priorities, investing wisely
and providing care for all. World Health Organization, Geneva. Licence: CC BY-NC-SA 3.0 IGO
21. Budreviciute A, Damiati S, Sabir DK et al (2020) Management and prevention strategies for
non-communicable diseases (NCDs) and their risk factors. Front Public Health 8:574111.
https://doi.org/10.3389/fpubh.2020.574111
22. World Health Organization (2021) Cancer fact shee. Available from: https://www.who.int/
news-­room/fact-­sheets/detail/cancer. Accessed Jan 2022
23. Human Development Index (2020) United Nations Development Programme, New York.
Available from: http://hdr.undp.org/en/content/human-­development-­index-­hdi. Accessed
Jan 2022
24. Bray F, Jemal A, Grey N, Ferlay J, Forman D (2012) Global cancer transitions according
to the Human Development Index (2008-2030): a population-based study. Lancet Oncol
13(8):790–801. https://doi.org/10.1016/S1470-­2045(12)70211-­5
25. Lam CG, Howard SC, Bouffet E, Pritchard-Jones K (2019) Science and health for all children
with cancer. Science 363(6432):1182–1186. https://doi.org/10.1126/science.aaw4892
26. CI5plus (2020) Cancer incidence in five continents time trends. International Agency for
Research on Cancer, Lyon. Available from: http://ci5.iarc.fr/CI5plus/Pages/graph1_sel.aspx.
Accessed Jan 2022
27. Allemani C, Matsuda T, Di Carlo V et al (2018) Global surveillance of trends in cancer sur-
vival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diag-
nosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet
391(10125):1023–1075. https://doi.org/10.1016/S0140-­6736(17)33326-­3
28. Bryere J, Dejardin O, Launay L et al (2018) Socioeconomic status and site-specific cancer
incidence, a Bayesian approach in a French Cancer Registries Network study. Eur J Cancer
Prev 27(4):391–398. https://doi.org/10.1097/CEJ.0000000000000326
1452 M. S. Ghufran et al.

29. Bruni L, Diaz M, Barrionuevo-Rosas L et al (2016) Global estimates of human papillomavi-

rus vaccination coverage by region and income level: a pooled analysis [published correction
appears in Lancet Glob Health. 2017;5(7):e662]. Lancet Glob Health 4(7):e453–e463. https://
doi.org/10.1016/S2214-­109X(16)30099-­7
30. Yarchoan R, Uldrick TS (2018) HIV-associated cancers and related diseases. N Engl J Med
378(11):1029–1041. https://doi.org/10.1056/NEJMra1615896
31. Aarts MJ, Kamphuis CB, Louwman MJ, Coebergh JW, Mackenbach JP, van Lenthe FJ (2013)
Educational inequalities in cancer survival: a role for comorbidities and health behaviours? J
Epidemiol Community Health 67(4):365–373. https://doi.org/10.1136/jech-­2012-­201404
32. Stanbury JF, Baade PD, Yu Y, Yu XQ (2016) Cancer survival in New South Wales, Australia:
socioeconomic disparities remain despite overall improvements. BMC Cancer 16:48. https://
doi.org/10.1186/s12885-­016-­2065-­z
33. Brand NR, Qu LG, Chao A, Ilbawi AM (2019) Delays and barriers to cancer care in low- and
middle-income countries: a systematic review. Oncologist 24(12):e1371–e1380. https://doi.
org/10.1634/theoncologist.2019-­0057
34. Bakens MJAM, Lemmens VEPP, de Hingh IHJT (2017) Socio-economic status influences the
likelihood of undergoing surgical treatment for pancreatic cancer in the Netherlands. HPB
(Oxford) 19(5):443–448. https://doi.org/10.1016/j.hpb.2017.01.010
35. Bergeron-Boucher MP, Oeppen J, Holm NV, Nielsen HM, Lindahl-Jacobsen R, Wensink MJ
(2019) Understanding differences in cancer survival between populations: a new approach and
application to breast cancer survival differentials between Danish regions. Int J Environ Res
Public Health 16(17):3093. https://doi.org/10.3390/ijerph16173093
36. Foerster M, Anderson BO, McKenzie F et al (2019) Inequities in breast cancer treatment in
sub-Saharan Africa: findings from a prospective multi-country observational study. Breast
Cancer Res 21(1):93. https://doi.org/10.1186/s13058-­019-­1174-­4
37. World Health Organization (2010) NMH fact sheet. Available from: http://www.who.int/nmh/
publications/fact_sheet_cancers_en.pdf. Accessed Jan 2022
38. Gilbert ES (2009) Ionising radiation and cancer risks: what have we learned from epidemiol-
ogy? Int J Radiat Biol 85(6):467–482. https://doi.org/10.1080/09553000902883836
39. Ali YF, Cucinotta FA, Ning-Ang L, Zhou G (2020) Cancer risk of low dose ionizing radiation.
Front Phys 8:234. https://doi.org/10.3389/fphy.2020.00234
40. Sifri R, Gangadharappa S, Acheson LS (2004) Identifying and testing for hereditary sus-
ceptibility to common cancers. CA Cancer J Clin 54(6):309–326. https://doi.org/10.3322/
canjclin.54.6.309
41. Oeffinger KC, Hudson MM (2004) Long-term complications following childhood and adoles-
cent cancer: foundations for providing risk-based health care for survivors. CA Cancer J Clin
54(4):208–236. https://doi.org/10.3322/canjclin.54.4.208
42. Hore PJ (2019) Upper bound on the biological effects of 50/60 Hz magnetic fields mediated by
radical pairs. elife 8:e44179. https://doi.org/10.7554/eLife.44179
43. Wertheimer N, Leeper E (1979) Electrical wiring configurations and childhood cancer. Am J
Epidemiol 109(3):273–284. https://doi.org/10.1093/oxfordjournals.aje.a112681
44. IARC (2002) Some traditional herbal medicines, some mycotoxins, naphthalene and styrene.
IARC Press, Lyon
45. Szmigielski S, Sobiczewska E (2009) Risk of neoplastic diseases in conditions of exposure to
power magnetic fields--epidemiologic investigations. Med Pr 60(3):223–233
46. Burger M, Catto JW, Dalbagni G et al (2013) Epidemiology and risk factors of urothelial blad-
der cancer. Eur Urol 63(2):234–241. https://doi.org/10.1016/j.eururo.2012.07.033
47. Song K, Im SH, Yoon YJ, Kim HM, Lee HJ, Park GS (2018) A 60 Hz uniform electromagnetic
field promotes human cell proliferation by decreasing intracellular reactive oxygen species
levels. PLoS One 13(7):e0199753. Published 2018 Jul 16. https://doi.org/10.1371/journal.
pone.0199753
48. Postrzech K, Welz K, Kopyra J, Reich A (2010) Impact of ultraviolet B radiation on stratum
corneum. Dermatol Rev. 97:185–190
The Global Concern for Cancer Emergence and Its Prevention: A Systematic Unveiling… 1453

49. D’Orazio J, Jarrett S, Amaro-Ortiz A, Scott T (2013) UV radiation and the skin. Int J Mol Sci
14(6):12222–12248. Published 2013 Jun 7. https://doi.org/10.3390/ijms140612222
50. Stawczyk M, Łakis A, Ulatowska A, Szczerkowska-Dobosz A (2011) Evaluation and com-
parison of the risk of sunbathing addiction among selected population of women. Dermatol
Rev 98:305–311
51. Yadav VK, Awasthi P, Kumar A (2019) Detection of UV-induced thymine dimers. Methods
Mol Biol 2031:313–322. https://doi.org/10.1007/978-­1-­4939-­9646-­9_17
52. Lesiak A, Słowik-Rylska M, Kozłowski W et al (2009) Epidermal proliferation and intracel-
lular adhesion impairment as one mode of action of ultraviolet-B radiation. Adv Dermatol
Allergol XXVI(4):180–185
53. Rehm J, Gmel GE Sr, Gmel G et al (2017) The relationship between different dimensions
of alcohol use and the burden of disease-an update. Addiction 112(6):968–1001. https://doi.
org/10.1111/add.13757
54. GBD 2019 Risk Factors Collaborators (2020) Global burden of 87 risk factors in 204 coun-
tries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study
2019. Lancet 396(10258):1223–1249. https://doi.org/10.1016/S0140-­6736(20)30752-­2
55. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2012) Personal
habits and indoor combustions. Volume 100 E. A review of human carcinogens. IARC Monogr
Eval Carcinog Risks Hum 100(Pt E):1–538
56. Rumgay H, Shield K, Charvat H et al (2021) Global burden of cancer in 2020 attributable to
alcohol consumption: a population-based study. Lancet Oncol 22(8):1071–1080. https://doi.
org/10.1016/S1470-­2045(21)00279-­5
57. Manthey J, Shield KD, Rylett M, Hasan OSM, Probst C, Rehm J (2019) Global alco-
hol exposure between 1990 and 2017 and forecasts until 2030: a modelling study. Lancet
393(10190):2493–2502. https://doi.org/10.1016/S0140-­6736(18)32744-­2
58. World Health Organization (2017) WHO report on the global tobacco epidemic, 2017: moni-
toring tobacco use and prevention policies. World Health Organization. https://apps.who.int/
iris/handle/10665/255874. License: CC BY-NC-SA 3.0 IGO
59. Reitsma MB, Flor LS, Mullany EC, Gupta V, Hay SI, Gakidou E (2021) Spatial, temporal, and
demographic patterns in prevalence of smoking tobacco use and initiation among young peo-
ple in 204 countries and territories, 1990-2019. Lancet Public Health 6(7):e472–e481. https://
doi.org/10.1016/S2468-­2667(21)00102-­X
60. GBD 2019 Tobacco Collaborators (2021) Spatial, temporal, and demographic patterns in prev-
alence of smoking tobacco use and attributable disease burden in 204 countries and territories,
1990–2019: a systematic analysis from the Global Burden of Disease Study 2019 [published
correction appears in Lancet. 2021;397(10292):2336]. Lancet 397(10292):2337–2360. https://
doi.org/10.1016/S0140-­6736(21)01169-­7
61. World Health Organization (2011) WHO report on the global tobacco epidemic, 2011:
warning about the dangers of tobacco. World Health Organization. https://apps.who.int/iris/
handle/10665/44616
62. Siddiqi K, Husain S, Vidyasagaran A, Readshaw A, Mishu MP, Sheikh A (2020) Global burden
of disease due to smokeless tobacco consumption in adults: an updated analysis of data from
127 countries. BMC Med 18(1):222. https://doi.org/10.1186/s12916-­020-­01677-­9
63. World Health Organization (2021) India loses 1% of its GDP to diseases and early deaths
from tobacco use, finds WHO study. Available from: https://www.who.int/india/news/
detail/09-­02-­2021-­india-­loses-­1-­of-­its-­gdp-­to-­diseases-­and-­early-­deaths-­from-­tobacco-­use-­
finds-­who-­study. Accessed Jan 2022
64. Fung TT, Hu FB, Hankinson SE, Willett WC, Holmes MD (2011) Low-carbohydrate diets,
dietary approaches to stop hypertension-style diets, and the risk of postmenopausal breast
cancer. Am J Epidemiol 174(6):652–660. https://doi.org/10.1093/aje/kwr148
65. O’Mahony M, Hegarty J (2009) Help seeking for cancer symptoms: a review of the literature.
Oncol Nurs Forum 36(4):E178–E184. https://doi.org/10.1188/09.ONF.E178-­E184
1454 M. S. Ghufran et al.

66. IARC Monographs on the Evaluations of Carcinogenic Risks to Humans (2011) A review of
human carcinogens. Part A: pharmaceuticals, vol 100. IARC, Lyon
67. Wallace DR, Taalab YM, Heinze S et al (2020) Toxic-metal-induced alteration in miRNA
expression profile as a proposed mechanism for disease development. Cell 9(4):901. https://
doi.org/10.3390/cells9040901
68. de Araújo ML, Gomes BC, Devóz PP et al (2021) Association between miR-148a and DNA
methylation profile in individuals exposed to lead (Pb). Front Genet 12:620744. https://doi.
org/10.3389/fgene.2021.620744
69. Singh VK, Pal R, Srivastava P, Misra G, Shukla Y, Sharma PK (2021) Exposure of androgen
mimicking environmental chemicals enhances proliferation of prostate cancer (LNCaP) cells
by inducing AR expression and epigenetic modifications. Environ Pollut 272:116397. https://
doi.org/10.1016/j.envpol.2020.116397
70. Mekonen S, Ibrahim M, Astatkie H, Abreha A (2021) Exposure to organochlorine pesticides
as a predictor to breast cancer: a case-control study among Ethiopian women [published cor-
rection appears in PLoS One. 2021;16(11):e0260106]. PLoS One 16(9):e0257704. https://doi.
org/10.1371/journal.pone.0257704
71. Ksouri R (2019) Food components and diet habits: chief factors of cancer development. Food
Qual Saf 3(4):227–231. https://doi.org/10.1093/fqsafe/fyz021
72. Bbosa GS, Kitya D, Odda J et al (2013) Aflatoxins metabolism, effects on epigenetic mech-
anisms and their role in carcinogenesis. Sci Res 5(10A):14–34. https://doi.org/10.4236/
health.2013.510A1003
73. Bräse S, Encinas A, Keck J, Nising CF (2009) Chemistry and biology of mycotoxins and
related fungal metabolites. Chem Rev 109(9):3903–3990. https://doi.org/10.1021/cr050001f
74. Hamid AS, Tesfamariam IG, Zhang Y, Zhang ZG (2013) Aflatoxin B1-induced hepatocellular
carcinoma in developing countries: geographical distribution, mechanism of action and pre-
vention. Oncol Lett 5(4):1087–1092. https://doi.org/10.3892/ol.2013.1169
75. Massey TE, Smith GB, Tam AS (2000) Mechanisms of aflatoxin B1 lung tumorigenesis. Exp
Lung Res 26(8):673–683. https://doi.org/10.1080/01902140150216756
76. Boonen J, Malysheva SV, Taevernier L et al (2012) Human skin penetration of selected model
mycotoxins. Toxicology 301(1–3):21–32. https://doi.org/10.1016/j.tox.2012.06.012
77. Soni P, Ghufran MS, Olakkaran S, Puttaswamygowda GH, Duddukuri GR, Kanade SR (2021)
Epigenetic alterations induced by aflatoxin B1: an in vitro and in vivo approach with empha-
sis on enhancer of zeste homologue-2/p21 axis. Sci Total Environ 762:143175. https://doi.
org/10.1016/j.scitotenv.2020.143175
78. Ghufran MS, Soni P, Kanade SR (2019) Aflatoxin-induced upregulation of protein arginine
methyltransferase 5 is mediated by protein kinase C and extracellular signal-regulated kinase.
Cell Biol Toxicol 35(1):67–80. https://doi.org/10.1007/s10565-­018-­9439-­8
79. Soni P, Ghufran MS, Kanade SR (2018) Aflatoxin B1 induced multiple epigenetic modu-
lators in human epithelial cell lines. Toxicon 151:119–128. https://doi.org/10.1016/j.
toxicon.2018.07.011
80. Ghufran MS, Ghosh K, Kanade SR (2016) Aflatoxin B1 induced upregulation of protein argi-
nine methyltransferase 5 in human cell lines. Toxicon 119:117–121. https://doi.org/10.1016/j.
toxicon.2016.05.015
81. Rock CL, Thomson C, Gansler T et al (2020) American cancer society guideline for diet
and physical activity for cancer prevention. CA Cancer J Clin 70(4):245–271. https://doi.
org/10.3322/caac.21591
82. Bhaskaran K, Douglas I, Forbes H, dos-Santos-Silva I, Leon DA, Smeeth L (2014) Body-mass
index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UK
adults. Lancet 384(9945):755–765. https://doi.org/10.1016/S0140-­6736(14)60892-­8
83. Park JH, Moon JH, Kim HJ, Kong MH, Oh YH (2020) Sedentary lifestyle: overview of updated
evidence of potential health risks. Korean J Fam Med 41(6):365–373. https://doi.org/10.4082/
kjfm.20.0165
The Global Concern for Cancer Emergence and Its Prevention: A Systematic Unveiling… 1455

84. Park S, Bae J, Nam BH, Yoo KY (2008) Aetiology of cancer in Asia. Asian Pac J Cancer Prev
9(3):371–380
85. Zheng W, Lee SA (2009) Well-done meat intake, heterocyclic amine exposure, and cancer risk.
Nutr Cancer 61(4):437–446. https://doi.org/10.1080/01635580802710741
86. Brenner H, Rothenbacher D, Arndt V (2009) Epidemiology of stomach cancer. Methods Mol
Biol 472:467–477. https://doi.org/10.1007/978-­1-­60327-­492-­0_23
87. Shah SC, Kayamba V, Peek RM Jr, Heimburger D (2019) Cancer control in low- and middle-­
income countries: is it time to consider screening? J Glob Oncol 5:1–8. https://doi.org/10.1200/
JGO.18.00200
88. Loomans-Kropp HA, Umar A (2019) Cancer prevention and screening: the next step in the
era of precision medicine. NPJ Precis Oncol 3:3. https://doi.org/10.1038/s41698-­018-­0075-­9
89. Azene GK (2021) Visual inspection with acetic-acid (VIA) service utilization and associated
factors among women in Hawassa city, southern Ethiopia: a community based cross-sectional
study. Womens Midlife Health 7(1):6. https://doi.org/10.1186/s40695-­021-­00065-­4
90. Gerber DE (2008) Targeted therapies: a new generation of cancer treatments. Am Fam
Physician 77(3):311–319
91. Kawakami K, Nakajima O, Morishita R, Nagai R (2006) Targeted anticancer immunotoxins
and cytotoxic agents with direct killing moieties. ScientificWorldJournal 6:781–790. https://
doi.org/10.1100/tsw.2006.162
92. Siddiqui M, Rajkumar SV (2012) The high cost of cancer drugs and what we can do about it.
Mayo Clin Proc 87(10):935–943. https://doi.org/10.1016/j.mayocp.2012.07.007
93. Ocran Mattila P, Ahmad R, Hasan SS, Babar ZU (2021) Availability, affordability, access, and
pricing of anti-cancer medicines in low- and middle-income countries: a systematic review
of literature. Front Public Health 9:628744. Published 2021 Apr 30. https://doi.org/10.3389/
fpubh.2021.628744
94. Rome RB, Luminais HH, Bourgeois DA, Blais CM (2011) The role of palliative care at the end
of life. Ochsner J 11(4):348–352
95. World Health Organization (2020) Palliative care fact sheet. Available from: https://www.who.
int/news-­room/fact-­sheets/detail/palliative-­care. Accessed Jan 2022
96. Gupta J, Sharma S, Sharma NR, Kabra D (2020) Phytochemicals enriched in spices: a source
of natural epigenetic therapy. Arch Pharm Res 43(2):171–186. https://doi.org/10.1007/
s12272-­019-­01203-­3
97. Dehelean CA, Marcovici I, Soica C et al (2021) Plant-derived anticancer compounds as new
perspectives in drug discovery and alternative therapy. Molecules 26(4):1109. https://doi.
org/10.3390/molecules26041109
98. Rizeq B, Gupta I, Ilesanmi J, AlSafran M, Rahman MDM, Ouhtit A (2020) The power of
phytochemicals combination in cancer chemoprevention. J Cancer 11(15):4521–4533. https://
doi.org/10.7150/jca.34374
Commonly Used Poisonous Medicinal
Plants in Unani System of Medicine

Shaikh Ajij Ahmed Makbul and Sayeedur Rahman

1 Introduction

Plants have been used since the dawn of time. It’s been a part of human civilization
for millennia. Plants are used in traditional medicine in Africa to cure a variety of
infectious and non-infectious illnesses. Body washes, massages, ingestions and
other treatments are among them. Plants produce a vast range of bio-chemicals that
are beneficial to humans. Food, colours, scents, agricultural chemicals and medica-
tions are all examples of their use. Traditional medicine is used by around 40–90%
of people in underdeveloped nations, according to the World Health Organization
(WHO) [1]. The usage of various portions of multiple medicinal plants to treat spe-
cific ailments has been popular in India since ancient times. For numerous centuries,
the indigenous medical systems of Ayurvedic, Siddha and Unani have existed. The
use of poisonous plants in the Unani system of medicine aids in the treatment of
certain diseases (Table 1). It is critical to be aware of dangerous plants that, when
administered in the correct, prescribed dose can be effective therapeutic agents [2].
Plant intoxication is a topic that has sparked a lot of discussion in the literature,
both in terms of human and animal poisoning (Table 2). Depending on the precise
components and metabolites that they contain, different herbs can have a variety of
impacts on human organ systems. Gastroenteritis, hepatotoxicity, peripheral neu-
ropathy, psychosis, rhabdomyolysis and blood count abnormalities are all possible
side effects, as are cardio toxicity and multisystem organ failure [3]. Poisoning can
occur through touch, which causes skin irritation; ingestion, which causes internal

S. A. A. Makbul (*)
Department of Ilmul Advia (Pharmacology), State Unani Medical College & Hospital,
Prayagraj, Uttar Pradesh, India
S. Rahman
Department of Ilmul Advia (Pharmacology), Eram Unani Medical College and Hospital,
Lucknow, Uttar Pradesh, India

© The Author(s), under exclusive license to Springer Nature 1457

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_61
1458 S. A. A. Makbul and S. Rahman

Table 1 List of Poisonous drugs used in Unani system of medicine with part used, formulations
and indications
Sr. Unani Botanical Part
no. name name used Formulations Indications References
1 Ain-ud-­ Abrus Seed,Dawa-e-Tikor, Bahaq (Pityriasis), Bars [18, 19,
Deek/ precatorius Root Zimad-e-­ (Leukoderma), Kalaf 55]
Ghonchi L. Mohasa, (Freekles), Sabal
Tila-e-Aroosak, (pannus), Bayaz-e-­
Raughan Ganj, Chashm (Corneal
Majoon-e-­ opacity) (as a Surma)
Malook,
Tila-e-Khas-ul-
Khas, Tila-e-­
Jamal Gota
2 Ajwain Hyoscyamus Seed, Barsha’sha, Sahr (Insomnia), [18, 55,
Khurasani niger L. Leaf, Banadiq-ul-­ Malekhuliya 56, 11, 12]
Extract Buzoor, (Melancholia),
Tiryaq-e-Nazla, Waj-ul-Mafasil
Habb-ul-Misk, (rthritis), Irq-un-Nasa
Habb-e-Jadwar, (Sciatica), Naqras
Habb-e-Mumsik (Gout), Dard-edandan
tilayi, Halwa (Tootache), Dard-e-­
supari pak, Gosh (Earache),
Qurs-e-Tinkar, Surat-e-Inzal (Pre-­
Qurs-e-Jaryan, mature ejaculation),
Qurs-e-­ Jarayan-e-Mani
Musallas, (Spermatorrhoea),
Majoon-e-Jalali, Su’al-e-Yabis (Dry
Majoon cough), Ishal (Loose
Murawwih-ul-­ motion)
Arwaah, Majoon
muqawwi wa
mumsik
3 Azaraqi/ Strychnos Seed Habb-e-Azaraqi, Falij (Hemiplegia), [18, 55,
Kuchla nux-vomica Majoon-e-­ Laqwa (Facial 56, 20, 11]
L. Azaraqi, paralysis), Waj-ul-Qutn
Habb-e-Khas, (Backache), Zeeq-un-­
Habb-e-Fauladi, Nafas (Breathlessness),
Safoof-e-­ Sil (Tuberculosis),
Azaraqi, Suzak Gonorrhoea),
Habb-e-­ Su’aal Muzmin
Marwareedi, (Chronic cough),
Roghan-e-­ Zo’f-e-Ishtiha
Kuchla, (Anorexia), Ghashi
Majoon-e-Lana, (Syncope), Behoshi
Habb-e-­ (Unconsciousness),
Muna’yish Zo’f-e-Qalb (Weakness
of heart), Zo’f-e-Meda
(Weakness of
stomach)), Juzam
(Leprosy)
(continued)
Commonly Used Poisonous Medicinal Plants in Unani System of Medicine 1459

Table 1 (continued)
Sr. Unani Botanical Part
no. name name used Formulations Indications References
4 Afyun/ Papaver LatexHabb-e-Jadwar, Qaulanj (Colitis), [18, 55,
Afeem somniferum Barsha’sha, Dard-e-Sar (Headache), 56, 11]
L. Habb-e-Hamal, Waj-ul-Asab (Nervine
Habb-e-Surfa, pain), Wajul-Asnan
Habb-e-Sumaq, (Toothache), Sahr
Habb-e-Mumsik (Insomnia), Junoon
tilayi, Habb-e-­ (Insanity), Waj-ul-­
Mumsik Ambari, Mafasil (Arthritis),
Habb-e-Nazla, Sarsam (Meningitis),
Roghan-e-­ Shahiqa (Whooping
Kuchla, cough), Su’al (Cough),
Roghan-e-Kalan, Zat-ul-janb (Pleurisy),
Shayyaf-e-­ Waj-ul-Qutn
Abyaz, (Backache), Surat-e-­
Ques-e-­ Inzal (Pre-mature
Musallas, ejaculation), Nazla wa
Majoon Zukam (Cold and
muqawwi wa coryza).
Mumsik,
Habb-e-Pechish
5 Baladur/ Semecarpus Fruit, Anqaroya Zof-e-Asab [18, 20,
Bhalawan anacardium Fruit Kabeer, (Neurasthenia), 55, 56]
L. Extract Anqardia Zof-e-Hafiza (Weakness
Sagheer, of memory power),
Majoon-e-­ Zof-e-Qalb (Weakness
Baladur, of heart), Falij
Roghan-e-­ (Hemiplegia), Laqwa
Bhalawan (Facial paralysis)
6 Bed Ricinus Seed, Zimad-e-­ Waja-ul–Mafasil [18, 20,
anjeer/ communis L. leaf Jalinoos, (Arthritis), Falij 55, 56]
Arandi Zimad-e-Sheer-­ (Hemiplegia), Laqwa
e-Shutr, (Facial paralysis),
Marham-e-­ Deedan-e-Ama
Atishk, (Intestinal worms),
Marham-e-­ Ehtebas-e- Haiz
Dakhaliyoon, (amenorrhoea), Sual
Marham-e-­ (Cough), Ra’sha
Rusul, Tiryaq-e-­ (Tremor), Zeeq-un-­
Pechish, Nafas (Breathlessness),
Roghan-e-­ Qaulanj (Colitis),
Chahar Barg Istesqa (Ascites)
(continued)
1460 S. A. A. Makbul and S. Rahman

Table 1 (continued)
Sr. Unani Botanical Part
no. name name used Formulations Indications References
7 Beesh/ Aconitum Root Habb-e-Miskeen Shaqiqa (Migrain), [18, 20,
Bachhnak napellus L. Nawaz, Qurs Irq-un Nasa (Sciatica), 55, 56]
Zat-ul-Janb (Pleurisy),
ikseer-e-Falij wa
laqwa, Zat-ur-Riya
Habb-e-Nuqra, (Pneumonia), Humma
Ikseer-e-Surkh (Fever), Ehtabas-e-Baul
(Retention of Urine),
Ehtabas-e-Haiz
(Amenorrhoea), Juzam
(Leprosy), Bars
(Lucodrema),
Zeeq-un-Nafas
(Breathlessness),
Qurooh-e-Khabisa
(Non-healing ulcer),
Waj-ul-Mafasil
(Arthritis)
8 Habb-us-­ Croton Seed Habb-e-Miskeen Amraz-e-Balghami wa [18, 20,
Salateen/ tiglium L. Nawaz, Sawdavi (Phlegm and 55, 56]
Jamalgota Roghan-e-­ black bile diseases),
Jamalgota, Daad (Ring worm),
Tila-e-Surkh, Ganj, Bars
Habb-e-Mushil, (Leucoderma),
Dawa-e-Siyah-e- Wajaul- Mafasil
Mushil (Arthritis), Qoolanj
(Colitis), Atishk
(Syphilis), Juzam
(leprosy), Istisqa
(Ascites), Qabz qawi
(Chronic constipation),
Sa’fa (Porrigo),
Da’-us-Salab
(Alopecia)
9 Jauz-e-­ Datura Seed, Habb-e-Shifa, Waja-ul –Mafasil [18, 20,
Masil/ metel L. Leaf Habb-e-Ziq-un- (Arthritis), Niqras 55, 56]
Dhatura Nafs, Habb-e-­ (Gout), Sual (Cough),
Mumsik tilayi, Zeequn Nafas
Roghan-e-­ (Breathlessness), Nazla
Dhatura, (Catarrh), Humma
Majoon-e-Falak (Fever), Dama
ser, Roghan-e-­ (Asthma), Shaheeqa
Haft-e-Barg, (Migrain), Kanphed
Tila-e-Jadeed (Mumps), Sahr
(Insomnia), Suda’
(Headache), Surat-e-­
Inzal (Pre-mature
ejaculation)
(continued)
Commonly Used Poisonous Medicinal Plants in Unani System of Medicine 1461

Table 1 (continued)
Sr. Unani Botanical Part
no. name name used Formulations Indications References
11 Qinnab/ Cannabis Whole Habb-e-Hamal, Ishal (Loose motion), [18, 20,
Bhang sativa L. Plant, Habb-e-Mumsik Kasrat-e-Tams 55, 56]
Leaf (Menorrhagia),
tilayi, Habb-e-­
Mumsik Ambari,Bawaseer (Piles), Sual
Majoon Falak (Cough), Waj-ul-Kabid
(Liver pain), Qulanj
ser, Majoon-e-­
Muqawwi wa (Colitis), Sahr
Mumsik, (Insomnia), Junoon
Safof-e-Kalan,(Insanity), Shaqeeqa
Majoon-e-­ (Migrain), Suda-e-­
Muqawwi alvi Dayimi (Chronic
Khan, Majoon-­Headache), Kuzaz
e-­Mubahhi (Tetanus), Syrat-e-Inzal
antaki (Pre-mature
ejaculation), Shaheeqa
(Whooping cough)
12 Tambak/ Nicotiana Leaf Bakhoor-e-­ Waj-ul-Asnan [55, 56]
Tambaku tobacum L. Damah, (Toothache), Warm-e-­
Sanoon-e-­ Lussa (Gum
Tambakoo, inflammation), Dard sar
Marham-e-­ bawajh-e-zukam
Muhallil (Headache due to cold),
Warm-e-Khusyatain
(Orchitis)
13 Ushr/ Calotropis Root, Habb-e-Seen, Zeequn Nafas [18, 55,
Madar procera Bark, Habb-e-Gul-e- (Breathlessness), 56]
(Ait) R.Br. Leaf, Aakh, Roghan-­ Waj-ul-Mafasil
Seed, e-­Auja’-e-Khas, (Arthritis), Bawaseer
Flower Roghan-e-Surhk, (Piles), Zaheer
Raghan-e-Gul-e- (dysentry) Deedan-e-­
Aakh, Qurs-e-­ Ama (Intestinal
Gul-e-Aakh, worms), Zof-e-Meda
Roghan-e-­ (Weakness of stomach),
Chahar Barg, Dad (Ring worm),
Roghan-e-Auraq Dama (Asthma), Su’al
(Cough), Musqit-e-­
Janeen (abortificient),
Kharash-e-Meda
(Roughness of stomach)

poisoning; or absorption, which causes internal poisoning [2]. A wide range of phy-
tochemicals, such as alkaloids and glycosides, are derived from plant sources and
are useful in the treatment of a variety of illnesses. These phytochemicals have anti-­
allergy, anti-inflammatory, purgative, laxative and anti-migraine properties (Table 3)
[4]. There are various plant species that are poisonous or harmful to humans. Plant
toxins have a variety of beneficial effects and can be utilized to cure a variety of ail-
ments. They can be tweaked to improve affinity and effectiveness. Medicinal plants
1462 S. A. A. Makbul and S. Rahman

Table 2 Signs and symptoms of plant intoxication in humans

Sr.
no. Botanical name Signs and symptoms References
1 Strychnos nux The dose and route of administration have been linked to [6, 7]
vomica toxicity. The nervous system, immune system, urinary
system and digestive system are all affected by brucine.
Brucine poisoning can result in severe convulsions, high
blood pressure and possibly death if taken in a toxic dose.
The paralysis of mouth muscles and Risus sardonicus is a
unique aspect of its toxicity.
2 Hyoscyamus Due to high concentration of scopolamine ingestion of high [13, 57]
niger dose leads to hypertension, respiratory arrest, somnolence
that followed by CNS excitation. Dry mouth, thirst, slurred
speech, difficulty speaking, dysphagia, warm flushed skin,
pyrexia, nausea, vomiting, headache, blurred vision and
photophobia, urinary retention, bladder distension,
drowsiness, hyperreflexia, auditory, visual or tactile
hallucinations, confusion, disorientation, delirium,
aggressiveness and combative behaviour are all symptoms
of Hyoscyamus niger intoxication. Mydriasis, tachycardia,
arrhythmia, agitation, convulsions and coma were among
the symptoms and signs of intoxicated people (such as
atropine overdose).
3 Abrus It was reported that abrin as min as 0.00015% of toxin per [7, 58]
precatorius body can cause fatality in humans. Abrus poisoning
generally causes severe vomiting and abdominal pain,
bloody diarrhoea and convulsions are the characteristic of
abrus poisoning. Sensorium alterations, as well as central
nervous system depression, appear to be common aspects.
Death in this situation is due to multi system organ failure as
cellular protein synthesis is disrupted throughout the body.
A few cases of abrin-induced acute demyelinating
encephalitis have been recorded.
4 Datura Typical symptoms of Datura stramonium poisoning are [24, 51]
stramonium represented by dry skin and mucosa, flushing, mydriasis,
sinus tachycardia, hyperpyrexia, decreased bowel activity,
urinary retention and neurological disorders with ataxia,
short-term memory loss, disorientation, confusion,
hallucinations (visual and aural), psychosis, agitated
delirium, seizures and coma. These symptoms resemble
atropine intoxication. Rhabdomyolysis and fulminant
hepatitis have also been reported in rare circumstances. Due
to delayed stomach emptying, Datura stramonium poisoning
usually develops within 60 min of intake and clinical
symptoms can last up to 48 h. TThe anticholinergic effect
causes a delay in action, which results in a longer duration
of activity. Children have a unique susceptibility to atropine
toxicity, as smaller amounts may cause profound central
nervous system disturbances
(continued)
Commonly Used Poisonous Medicinal Plants in Unani System of Medicine 1463

Table 2 (continued)
Sr.
no. Botanical name Signs and symptoms References
5 Croton tiglium Croton tiglium L. is an irritant poison and a drastic purgative [59]
L. drug; its strong cathartic action begins with irritation in
stomach. The mucosa of the gastrointestinal tract has a
tendency to become hypersensitive to Croton tiglium L.,
resulting in symptoms such as searing pain from the mouth
to the oesophagus, nausea, vomiting, bloody faeces and
dehydration, which can lead to a weak pulse, loss of body
temperature and death..
6 Semecarpus The powerful irritant properties of the juice of pericarp have [31]
anacardium L. frequently been made use of by malingerers in producing
ophthalmic and skin lesions and also in producing abortions.
Dermatitis can develop in persons who prepare the oil, apply
it to garments in their job as a laundryman, or wear the
marked clothing. Skin lesions and anuria developed after
exposure to S. anacardium sap, followed by diffused cortical
necrosis. External application of S. anacardium caused
painful micturition, with urine that was scarlet and bloody
and stools that were very painful to pass.
7 C. procera The latex from the plant has used by the tribal people to [33]
(Ait.) R.Br. make poison arrows used for hunting purpose. The latex is
aand Calotropis highly toxic to human eyes cause ocular toxicity and
gigantean (L.) produces loss of vision with photophobia. Latex of C.
R.Br procera was studied for its inflammatory effects using pedal
oedema and air pouch models of inflammation in rats and
could be used to evaluate anti-inflammatory drugs.
Furthermore, latex also produces toxic iridocyclitis,
keratoconjunctivitis, corneal endothelial cytotoxicity and
keratitis when applied accidentally on the eye.
8 Aconitum Spp. In recent years, there have been a few reports of [38, 53]
cardiotoxicity and neurotoxicity caused by insufficient
aconitine ingestion. Toxic effects mostly impact the central
nervous system and heart, with gastrointestinal symptoms
present as well. The development of ventricular
tachyarrhythmia and cardiac arrest was the cause of death.
9 Cannabis sativa Short-term use of cannabis has led to impaired short-term [60]
L. memory; impaired motor coordination; altered judgment;
and paranoia or psychosis at high doses. Addiction, altered
brain development, cognitive impairment, poor educational
outcomes (e.g. dropping out of school) and lower life
satisfaction have all been linked to long-term or excessive
cannabis use, particularly in teens. In people who are
predisposed to such problems, long-term or excessive
cannabis usage is linked to chronic bronchitis and an
increased risk of chronic psychosis-related health
conditions, such as schizophrenia and depressive variations.
Cannabis use has also been linked to vascular disorders such
as myocardial infarction, stroke and transient ischemic
attack.
(continued)
1464 S. A. A. Makbul and S. Rahman

Table 2 (continued)
Sr.
no. Botanical name Signs and symptoms References
10 Nicotiana Nicotine is one of the most deadly poisons available, with a [46]
tobacum L. quick onset of action. The peripheral and central nervous
systems are the target organs, in addition to local activities.
Nicotine produces irritation and burning in the mouth and
throat in humans, as well as increased salivation, nausea,
abdominal pain, vomiting and diarrhoea. The effects on the
gastrointestinal tract are less severe, but they might still
occur following cutaneous and respiratory exposure.
Increased blood pressure and pulse rate. Nicotine also
causes an increase in plasma free fatty acids, hyperglycemia
and a rise in catecholamine levels in the bloodstream. The
blood supply to the heart is lowered, but the blood flow to
the skeletal muscles is enhanced. Tremors, prostration,
cyanosis, dyspnoea, convulsions and collapse are all
symptoms of severe poisoning.

that are poisonous are used to treat a variety of diseases. The Unani school of medi-
cine employs medications derived from plants, animals and minerals, some of
which have toxic ingredients and are even lethal poisons like Semiecarpus anacar-
dium L., Abrus precatorius, Ricinus communis, Strychnos nuxomica etc., Therefore,
these drugs are rectified to minimize their toxicity [5]. Medicinal plants are fre-
quently used and thought to be harmless, yet they can also be harmful. When medi-
cal plant poisoning has been documented, it is usually due to mistaken identity in
the form in which they have been sold, or faulty preparation by untrained persons.
The medications become physically and chemically pure after the purifying pro-
cess, making them more therapeutically effective and less harmful. The purpose of
this chapter is to highlight the toxicity of medications, chemical ingredients, detoxi-
fication methods and pharmacological features of hazardous medicinal plants
employed in the Unani system of medicine.

Strychnos nux-vomica L.
1.1 

Azaraqi is the ripe, dried seed of Strychnos nuxvomica L. (Family: Loganiaceae)

[6]. Strychnos nux-vomica L. has 190 species worldwide, most of which are found
in tropical and subtropical regions [7]. It grows in Sri Lanka, India and Australia. It
is a tiny tree or shrub with a height of 5–25 metres. Its leaves are opposite decussate
and papery, with a suborbicular, broadly elliptic or ovate leaf blade measuring
5–18 cm in length and 4–13 cm in breadth. Its 5-merous flower is dull-green and
white. Its fruit consists of brownish-yellow berries the size of small oranges, and
contains a gelatinous pulp in which one to five seeds are embedded. The dried ripe
seed is exceedingly hard, with a diameter of 1.5–3 cm and a thickness of 3–6 mm.
The seed has a flattened disk shape, is slightly concave and completely covered with
Table 3 Pharmacological actions, chemical constituents of poisonous plants used in Unani system of medicine
Sr. Botanical
no. Unani name name Chemical constituents Pharmacological activities References
1 Azaraqi Strychnos Strychnine, brucine, vomicine, igasurine, loganin, Antidiabetic, analgesic, anti-­ [8, 47, 48]
nux vomica α-colubrine, β-colubrine, n-oxystrychnine, 3 methoxyicajine, inflammatory, hepatoprotective,
isostrychnine, protostrychnine, pseudostrychnine, novacine, antioxidant, antidiarrheal, antisnake
chlorogenic acid and Icajine, venom, antitumour, gastroprotective,
2 Ajwain Khorasani Hyoscyamus Hyoscyamine, Atropine, Tropane, Scopolamine (Hyoscine), Analgesic, antimicrobial, antioxidant, [13, 49]
niger rutin, spiraeoside, 3′, 5-dihydroxy-3, 4′, 5′, 6, 7- antibacterial, anticancer, Antidiabetic,
pentamethoxyflavcm, pongamoside C & D, atroposide A, C anticonvulsant, antipyretic,
& E, petunioside L, Vanillic acid, Vanillin, pinoresinol, antiparkinsonian, insecticidal,
N-trans- feruloyltyramine, hyoscyamoside, hyoscyamilactol, antihypertensive, antispasmotic,
16α-acetoxy-hyoscyamilactol, daturalactone, 1- O - antidepressant, bronchodilator, cardio
octadecanoyl glycerol protective and anti-inflammatory
3 Ain-ud-Deek/ Abrus Abrine, Abrin A, B, C, I, II, III, Abrus agglutinin, Saponin, Antifertility activity, Antidiabetic, [15]
Ghonchi precatorius Flavonoids, abrectorin, precatorin, Lectin, campestanol. antimicrobial, tumour inhibiting,
alanine, serine, choline, valine, methyl ester. Aglucoside, wound heling activity,
brussic acid, haemagglutinin, calcium, magnesium, sodium, antispermatogenic, Immunestimulatory,
potassium, stigmasterol, β-sitosterol. antioxidant, nephroprotective,
4 Bed anjeer/Arandi Ricinus Steroids, saponins, alkaloids, flavonoids, glycosides, ricinine, Antioxidant, antinociceptive, [21]
communis N-demethylricinine flavones glycosides kaempferol-3-O antifertility, antiulcer
kaempferol-3-O-β-D-glucopyranoside, quercetin
xylopyranoside, quercetin-3-O-β-D-glucopyranoside,
kaempferol O-β-rutinoside and quercetin-3-O-β-
Commonly Used Poisonous Medicinal Plants in Unani System of Medicine

monoterpenoids (1, 8-cineole, camphor and α

sesquiterpenoid (β-caryophyllene), gallic acid, quercetin,
gentisic acid, rutin, epicatechin and ellagic acid, indole-3-­
acetic acid, ricinoleic, isoricinoleic, stearic, dihydroxystearic
acids, α thujone, camphor and beta thujone, ricin,
epicatechin, gentisic acid, catechin, linoleic acid
(continued)
1465
Table 3 (continued)
1466

Sr. Botanical
no. Unani name name Chemical constituents Pharmacological activities References
5 Jauz-e-Masil / Datura Atropine, scopolamine, phenolic compounds, tannins, Antiarthritic, antifungal, antistress, [23, 50,
Dhtura stramoniumflavonoids, cardiac glycosides, alanine, phenylalanine, antiulcer, hypoglycaemic, anticancer, 51]
glutamate, tyrosine, tigloidin, aposcopolamine, apoatropin, antiasthmatic, antimicrobial, anti-­
hyoscyamine N-oxide, scopolamine N-oxide17–20, inflammatory, Anticholinergic,
ditigloyloxytropane, 7-hydroxyhyoscyamine Larvicidal, mosquito repellent,
6 Habb-us-Salateen/ Croton alkaloids, flavonoids, saponins, linoleic acid, oleic acid, Antitumour, antioxidant, [25, 52]
Jamalgota tiglium L. myristic acid, tigliane phorbol esters, 13-O-acetylphorbol-20- antidermatophytic, anticonvulsant
linoleate, 13-O-ttigloylphorbol-20-linoleate,
12-oacetylphorbol-13-tigliate, 12-O-decanoylphorbol-13-(2-
methylbutirate) and 12-O-acetlyphorbol-13-decanoate
7 Baladur/Bhalawan Semecarpus Bhilavanol A (monoenepentadecyl catechol I), bhilavanol B Analgesic, Hypoglycemic, [30, 31]
anacardium (dienepentadecyl catechol II), biflavones A, C, A1, A2; Hepatoprotective, Anthelmintic,
L. tetrahydrorobustaflavone, tetrahydroamentoflavone, Anti-Cancer, Anti-Inflammatory,
jeediflavone, jeediflavanone, semecarpuflavanone, Neuroprotective, Antimicrobial,
galluflavanone, amentoflavanone, nallaflavanone, Anti-Spermatogenic, Memory
semicarpetin, anacarduflavanone, otrimethyl bioflavanone Enhancing, Cardioprotective,
A1, o-trimethyl bioflavanone A2, o-tetramethyl bioflavanone Aphrodisiac, Anti-Tuberculosis,
A1, o-hexamethl bichalcone A, o-dimethyl biflavanone B, Anti-arthritic, Antitumour,
o-heptamethyl bichalcone B1, o-hexamethyl bichalcone B2, Antineoplastic, Cytotoxic, Cytostatic,
o-tetramethyl biflavanone C, anacardic acid, cardol, catechol,
alkenyl catechols, fixed oil, semecarpetin, anacardol,
anacardoside, semecarpol. Monolefin I, diolefin II, oleic acid,
linoleic acid, palmitic acid, stearic acid and arachidic acid.
S. A. A. Makbul and S. Rahman
Sr. Botanical
no. Unani name name Chemical constituents Pharmacological activities References
8 Ushr/Madar C. pprocera Calotropin, calotropagenin, calotoxin, calactin, uscharin, Acaricidal, schizonticidal, [32, 33,
(Ait.) R.Br. amyrin, amyrin esters, uscharidin, coroglaucigenin, antimicrobial, Antifertility, 34]
aand frugoside, corotoxigenin, calotropagenin, voruscharine. The anthelmintic, insecticidal, anti-­
Calotropis latex contains fatty acids terpenels, sterols and hydrocarbons. inflammatory, antidiarrheal,
gigantean Lead, zinc, cadmium, nickel, calotoxin, iron, copper were Antimalarial, Gastroprotective,
(L.) R.Br identified in the latex and leaves of calotropis. Calcium anticancerous, larvicidal, Analgesic,
present highest in leaves and magnes in latex. Root barks antinociceptive, antipyretic,
contain calotropterpenyl, mundarol isovalerate and Antibacterial, antiparasitic
rutinoside. antimicrobial, antioxidant,
antiasthmatic, Anticancer
9 Afyun/Afeem Papaver Morphine, codein, neopine, thebain, meconic acid, Lactic, Antiallodynic, analgesics, antitussive, [35]
somniferum Malic, Tartaric acid, Citric acid, Acetic acid, Succinic acid, anti-diarrheal, anti- smoking,
L. sulphuric acid, Phosphoric acid, calcium, phosphorus, antidepressant, anti-anxiety,
sodium, magnesium, etc., Protopine, cryptopine, Benzyl bronchodilator, antibacterial, narcotic
isoquonoline,
10 Beesh/Bachhnak Aconitum benzoylmesaconine, mesaconitine (MA), AC, hypaconitine Anti-inflammatory, analgesia, [38, 53]
Spp. (HA), heteratisine, heterophyllisine, heterophylline, anti-rheumatism, cardiotonic actions
heterophyllidine, atidine, isotisine, hetidine, hetsinone,
benzoylheteratisine. Quercetin 7-O-(6-transcaffeoyl)-β-­
glucopyranosyl-(1 → 3)-α-rhamnopyranoside-3-O-β-­­
glucopyranoside, kaempferol
7-O-(6-trans-caffeoyl)-β-­
glucopyranosyl-(1 → 3)-α-rhamnopyranoside-3-O-β-­­
gglucopyranoside and kaempferol
7-O-(6-trans-p-coumaroyl)-β-­
Commonly Used Poisonous Medicinal Plants in Unani System of Medicine

glucopyranosyl-(1 → 3)-α-rhamnopyranoside-3-O-β-­­
glucopyranoside, together with β-3,4-dihydroxyphenethyl
β-glucopyranoside. Palmitic acid, oleic acid
(continued)
1467
Table 3 (continued)
1468

Sr. Botanical
no. Unani name name Chemical constituents Pharmacological activities References
11 Qinnab/Bhang Cannabis Tetrahydrocannabinol, Cannabidiol, Cannabidiol, Antidiabetic, anticancer, Parkinson’s [42]
sativa L. Cannabinol, β-caryophyllene, Cannabigerol disease, Chronic pain and arthritis,
Nausea vomiting
12 Tambaku Nicotiana Nicotine, nicoteine, nicotimine, anabaine anatalline, Antibacterial, anti-nociceptive, [54]
tabacum L. nornicotine, glucosides, tahacinin, tahacilin and isoquercitrin, antimicrobial, antifungal, anhelmintic,
1-quinic, chlorogenic, caffeic, oxalic acids, anatabine, Anti Alzheimer’s,
nornicotine, Quercetin-3,3′-dimethyl ether, gibberellins-­
nicotiana α, β and γ,
S. A. A. Makbul and S. Rahman
Commonly Used Poisonous Medicinal Plants in Unani System of Medicine 1469

hairs radiating from the centre to the sides, thus giving the seed a very characteristic
sheen. The seed with dark grey horny endosperm, where the small embryo is housed,
has no odour but tastes very bitter [8]. In several southern Asian countries, nux-­
vomica is commonly used as a medication. Although brucine has a promising phar-
macological profile, its therapeutic application is hampered by substantial central
nervous system toxicity. The therapeutic window for brucine is relatively small;
LD50 of 50.10 mg/kg was recorded [7]. Detoxified Azaraqi (seed) used in Unani
medicine for various ailments of brain and nerves. Due to its nerve tonic and nerve
stimulant properties, it is used for the treatment of paralysis, bell’s palsy, chorea,
arthritis etc. [6].

1.1.1 Detoxification/Rectification Methods

Azaraqi 70 g is buried in Multani mitti (Fuller’s earth) and water is poured over it
daily for 10 days, then it is removed and washed. After removing the embryo por-
tion, the outer covering is peeled off using a knife, and the cotyledons are separated.
Subsequently it is washed with hot water and tied it in a clean cloth bag. The bag is
immersed in a vessel containing two litre of milk. The milk is then boiled till it
evaporates; care is taken that the bag does not touch the bottom of the vessel.
Thereafter, it is removed from the bag and washed with water to obtain Azaraqi
Mudabbar [5, 9, 10, 11].

Hyoscyamus niger L.
1.2 

The drug Ajwain khurasani consists dried seed of Hyoscyamus niger L.(Family:
Solanaceae), a small tree found in Pakistan and other Asia’s countries, mostly in
Khurasan, a city of Iran; in India it is found in Akbrabad and Himalayan (Kashmir
to Gadhwal). The fresh herb smells as of Ajwain (Trachyspermum ammi), for this
reason called Ajwain Khurasani [9, 12]. Henbane means ‘hen killer’ in English, and
its name comes from the Anglo-Saxon words hen (chicken) and bana (murderer),
because fowls that ingest its seeds become paralysed and die. Black henbane is an
annual or biennial plant that can reach a height of three feet. Hundreds of tiny black
seeds, 1.5 mm long, are in egg-shaped fruit. One plant produces about 10,000 seeds
[13]. Its seeds are reniform or discoid, minutely pitted; embryo ringlike or
coiled [14].
1470 S. A. A. Makbul and S. Rahman

Abrus precatorius L.
1.3 

Abrus precatorius L. (Family: leguminoseae) is a native plant of India subcontinent

and the East and West Indies, commonly known as Rosary pea, Indian liquorice,
Jequirity and Crab’s eye. In Hindi, it is known as Ratti or Gumchi [15]. The seeds
have remarkably uniform weight of one-tenth of a gram; therefore, they were used
by goldsmiths as standard weight for weighing gold and silver in earlier days [16].
The seeds of this plant are small, scarlet in colour with black spots around the hilum.
The stout of the plant is rectangular in shape and has brownish pods that usually
ripen after the winter season [15]. It is native to India widespread in tropical and
subtropical areas. A woody climber, all along Himalayas ascending to 900 m,
spreading throughout the plains of India, Sri Lanka and other hot countries, flower-
ing in August–September, and fruits ripen during winter. The fruit is a legume (pea
shaped pod) about 3 cm long containing hard ovoid seeds about 1 cm long [17, 10,
12, 18, 19, 20].
Alopecia, oedema, helminths, skin problems, itching and urinary issues are all
treated using detoxified or purified seeds in Ayurveda. Black seeds are never used
medicinally. Abrins, very similar in action to ricin, are the major poisonous phyto-
toxins of the seeds. One seed is reported to contain enough abrin to kill an adult
human. To kill animals, a paste consisting of powdered seeds is used to poison darts
and arrows. The antifertility effects of seed extracts have been inconsistent in ani-
mals. Poisoning of humans due to seeds results in acute demyelinating encephalitis,
increased intracranial pressure and papilledema, which may result in death [20].

Ricinus communis
1.4 

The drug Bed Anjeer consists of mature and dried seeds of Ricinus communis
L. (Family: Euphorbiaceae). Popularly known as ‘castor plant‘a tall glabrous shrub
or almost small tree, 2–12 m high, found throughout India, mostly growing wild on
waste land and also cultivated for its oil seeds [18–20]. The plant is widespread
throughout tropical regions as ornamental plants. The castor oil plant is a fast-­
growing, suckering perennial shrub or occasionally a soft wooded small tree up to
6 m or more, but it is not hardy in nature. The leaves are green or reddish in colour
and have a diameter of 30–60 cm. The leaves are alternating and palmate, with 5–12
deep lobes with coarsely serrated segments. The monoecious flowers are 30–60 cm
long. The fruit is a three-celled thorny capsule. The capsule of fruit covered with
soft spins like processes and dehiscing in to three 2-valved cocci [21]. The seeds are
considerable differences in size and colour. Seeds rectangular, one face convex, the
other slightly flattened, 1–1.5 cm long, 0.6–0.9 cm wide, 0.4–0.8 cm thick. The testa
hard, glossy, smooth, grey or brown to red-dish-brown or black, and may be mar-
bled or striped, raphe runs from caruncle to chalaza. Its taste weakly acrid [19, 21].
Commonly Used Poisonous Medicinal Plants in Unani System of Medicine 1471

Seeds are the primary source of oil which is in use both as an herbal medicine and
as a conventional therapy for various ailments [22].

Datura stramonium/Datura innoxia/D. metel L.

1.5 

Datura stramonium (Family: Solanaceae) is a widespread annual plant from [23].

Datura stramonium (DS), also known as Jimson Weed, Locoweed, Angel’s Trumpet,
Thorn Apple, Devil’s Trumpet. It is a hallucinogenic plant [24]. Datura innoxia
Mill. is herbaceous annual, bushy by nature, and attain a maximum height of 120 cm
seeds are brown. D. metel is an erect annual herb or under shrub reaches a height of
about 1.5 m; whose alkaloid content varies with altitude and season of the year [6].
Datura stramonium has a wide range of toxicity that is highly variable and unpre-
dictable. When consumed, smoked or absorbed topically, particularly through
mucosal membranes, it causes cancer. Toxicity varies from leaf to leaf, plant to
plant and season to season. The highest levels of toxins are found in the seeds
approximating 0.1 mg of atropine per seed [24].

Croton tiglium L.
1.6 

Among Croton species, only C. tiglium (Family: Euphorbiaceae) is indigenous to

India and cultivated and widely distributed in North-Eastern part of India. Croton-­
oil plant, Croton seed, Jamalgota (Hindi), is some of the other names for it [25].
Traditionally utilized as a purgative to treat gastrointestinal and intestinal disorders,
as an abortifacient and counterirritant [26]. Indigestion, abdominal distension, vis-
ceral pain, constipation and other gastrointestinal diseases have all been treated with
C. tiglium L. However, it also causes severe gastrointestinal syndrome and even
mortality following ingestion. Oral medication of croton oil is able to cause gastro-
intestinal oedema and diarrhoea [27].

1.6.1 Detoxification/Rectification Methods

Kernels of the C. tiglium L. 25 g are tied in a cloth bag and boiled in one litre of
Cow’s milk till the milk becomes dense. The kernels are then removed from the bag
and the embryo part of the seeds is removed to obtain Jamalgota Mudabbar when
they have cooled [28, 29, 10].
1472 S. A. A. Makbul and S. Rahman

Semecarpus anacardium L.
1.7 

Semecarpus anacardium L. (Family: Anacardiaceae) is popularly known as mark-

ing nut tree. It can be found in the sub-Himalayan region, as well as the tropical and
central parts of India. Semecarpus anacardium is a deciduous tree, medium in size.
The height of the tree is normally 12–15 m. The leaves are big and simple, with
length of up to 60 cm and width of up to 30 cm. The bark is a deep brown colour
with a rough texture. The blossoms are drab greenish yellow in colour. The colour
of the fruit is black when ripe; it is quite smooth and shiny in texture; however, it is
toxic in nature. The nut is about 1 inch long [30].
Fruits are 2.5 cm long and obliquely ovoid or oblong drupes. When the fruit is
ripe, the upper portion is cup-shaped, smooth, fleshy orange red in colour and sweet
and tasty. It is made up of a thicker disc and a calyx base that is accrescent. The
lower base, which may be turned like a nut, is made up of a smooth, black, shiny
pericarp that is thick and contains rectangular cells filled of corrosive resinous fluid
between its outer and inner laminae. When the fruit is immature, the juice is white,
but when the fruit is ripe, it turns brownish or black. The nut is around
1 × 0.75 × 0.33 in diameter and weighs about 3.5 g on average. The black corrosive
juice is widely used as an effective medication across India: internally for dyspep-
sia, nervous debility, acute rheumatism, asthma and cough; topically for swellings,
piles and a variety of skin diseases [31].

1.7.1 Detoxification/Rectification Methods

With the use of red hot tongs, the juicy contents (Asal-e-Bhilawan) are squeezed out
fully after the fruit‘s cap (thalamus) is removed. After that, the fruits are boiled three
times in freshwater. Finally, the fruits are cooked in milk, rinsed and dried.
Precaution must be taken not to touch the juice with hands as the juice is toxic
[5, 9, 10].

Calotropis procera (Ait.) R.Br. and Calotropis gigantean

1.8 
(L.) R.Br

Calotropis procera and Calotropis gigantean (Family: Apocynaceae) are two com-
mon species of calotropis. Calotropis is a perennial plant and is a genus of flowering
plant. Both species used as substitute for one another and have similar effects.
Calotropis is a milky latex-producing, inflexible, big, tall, much branched, perennial
shrub or small tree that grows to 5.4 m in height. They are pollinated by insects.
Calotropis gigantean can be propagated by seed or stem cutting. Seeds are dis-
persed by water and wind [32]. There are two common species of Calotropis
reported in the literature, viz., C. procera (Ait.) R.Br. and Calotropis gigantean (L.)
Commonly Used Poisonous Medicinal Plants in Unani System of Medicine 1473

R.Br. mentioned by the ancient writers. Both the species consist of similar types of
phytoconstituents discovered till now and may be used as substitutes for one another
that might have similar effects [33]. Calotropis Procera is drought-resistant plant. It
quickly becomes established as a weed along degraded roadsides, waste land and in
overgrazed native pastures [34].

Papaver somniferum L.
1.9 

Papaver somniferum (Family: Papaveraceae) is one of those traditional plants,

which have a long history of usage as medicine. The word ‘opium’ is of Greek
(Unani) origin which is derived from ‘opos’(juice) and ‘opion’ (poppy juice).
Opium is frequently mentioned in classical Unani literature for its pain-relieving
and sleep-inducing action [35]. Opium is the dried extract of the exudates from the
seedpods of unripe poppies, Papaver somniferum [36].

1.9.1 Detoxification/Rectification Methods

The opium is dissolved in in rose water and filtered. The filtrate is heated till it
becomes thick for making the pills [5, 9, 10, 37]. Opium powder is heated in copper
container/pot till it becomes soft and reddish but not burned. After that hot powder
of opium is dissolved in water [10].

Aconitum Spp.
1.10 

Aconitum L. is a large genus (Family: Ranunculaceae), which consists of over 300

species distributed all over the world. In the northern hemisphere, the majority of
them grow naturally at high altitudes. A total of 76 species of aconite grow in China
and the surrounding far-east and Asian countries, and they are utilized for a variety
of medical uses. Aconitum heterophyllum, a less toxic species is applied in both
Ayurvedic and Tibetan medicine as a bitter tonic for the treatment of abdominal
pain, fever and cough [38]. Aconite is a perennial herbaceous plant that grows in
damp but well-draining soils in mountain meadows. Their dark green leaves lack
stipules. They are palmate with 5–7 segments, each of which is 3-lobed with coarse
sharp teeth. The leaves are spirally organized, with lengthy petioles on the lowest
leaves. Racemes of huge blue, purple, white, yellow or pink zygomorphic flowers
with many stamens cap the tall, erect stem. There are 2–10 petals in the form of
nectarines [39].
1474 S. A. A. Makbul and S. Rahman

1.10.1 Detoxification/Rectification Methods

Beesh 30 g is chopped into little pieces, knotted in a fine fabric bag and dipped in a
milk-filled pot before being heated. After that, pieces of Beesh are removed and
thoroughly cleaned in water to obtain Mudabbar Beesh [5, 9 10].

Cannabis sativa L.
1.11 

Cannabis sativa L. (Family: Cannabaceae) is one of the most widely used plants for
both recreational and medicinal purposes. A total of 567 natural constituents have
been discovered so far [40]. Cannabis is a dicotyledonous, angiosperm, annual
plant, normally dioecious, with male and female flowers on different plants, but can
also be monoecious, with flowers of both sexes on the same plant [41]. Commonly,
cannabis is pondered to be monospecific (Cannabis sativa L.) which is separated
into many subspecies, i.e. C. sativa subsp. sativa, C. sativa subsp. indica, C. sativa
subs. p. ruderalis, C. sativa subsp. spontanea, C. sativa subsp. afiristanca. Cannabis
is a dioecious, annual, flowering herb. Male (Staminate) plants are usually taller but
less strong than female (pistillate) plants. The stems are erect and reach a height of
0.2–2.0 m. However, mostly plants reach heights of 1–3 m [42].

Nicotiana tabacum L.
1.12 

Nicotiana tabacum and Nicotiana rustica are native plants of the Americas having
evolved in the Andes around Peru/Ecuador [43]. Nicotiana tabacum L. is a tall
perennial herbaceous plant native to tropical and subtropical America that is cur-
rently grown as a cash crop all over the world. The officinal usage of N. tabacum has
been extensively reviewed elsewhere. In Ethiopian folkloric medicine, N. tabacum
is widely used for managing both human and veterinary ailments such as cancer,
ulcer, cough, snake bite and respiratory tract infections [44]. Tobacco is made from
the dried and processed leaves of the Nicotiana tabaccum plant, which is widely
planted and commercially grown in many countries. Smoking, chewing, snuffing
and dipping tobacco are the most common methods of consumption. It is most com-
monly used as a drug, and is a valuable cash crop for countries such as Cuba, India,
China and the United States [45]. With an LD50 of approximately 30–60 mg of nico-
tine in adults, death by paralysis of respiratory muscles and/or central respiratory
failure is possible. The LD50 in youngsters is approximately 10 mg [46].
Commonly Used Poisonous Medicinal Plants in Unani System of Medicine 1475

2 Conclusion

Herbal poisoning can occur as a result of improper processing and preparation,

overdosing, contamination, misidentification and even suicidal or homicidal behav-
iour. People are growing increasingly reliant on natural medical sources. Many
experts have already studied the many biological effects of this herbal plant for the
treatment of various disorders, demonstrating its medicinal usefulness. Several
alkaloids, carbohydrates, fats, proteins and tannins have been found in various por-
tions of the plants. The presence of the active chemical components may explain the
plant‘s diverse pharmacological actions. Their pharmacological characteristics have
been widely investigated. Despite the fact that all plant parts are poisonous, they can
be used to treat a variety of human problems. To avoid side effects, the pharmaco-
logical qualities of toxic plants should be used with a complete understanding of
potential toxicological consequences. So far, pharmacological research has been
conducted both in vitro and in vivo. As a result, phytoconstituents and pharmaco-
logical profiles must be investigated and quantified. Overall, medicinal herbs are a
double-edged blade that should be used with caution. Finally, efforts must be made
to bring together traditional healers, scientists, and health officials in order to devise
safe and inexpensive protocols for making medicinal plant use safer. Clinical trials
can also be carried out to assess the safety of medicinal plants, ushering in a new era
of medicine.

References

1. Mounanga MB, Mewono L, Angone SA (2015) Toxicity studies of medicinal plants used in sub-­
Saharan Africa. J Ethnopharmacol 174:618–627. https://doi.org/10.1016/j.jep.2015.06.005
2. Salgar SD, Usman RMD, Vadnere GP, Lodhi S, Patil KD (2018) Contribution of poi-
sonous plants in herbal remedies. J Pharm Bio Sci 6:18–35. https://doi.org/10.31555/
jpbs/2018/6/2/18-­35
3. Soulaidopoulos S, Sinakos E, Dimopoulou D, Vettas C, Cholongitas E, Garyfallos A (2017)
Anticholinergic syndrome induced by toxic plants. World J Emerg Med 8:297–301
4. Njugi W (2018) A constructive approach on lethal plants for medicinal use. J Med Toxicol Clin
Forensic Med 4(1):1–5. https://doi.org/10.21767/2471-­9641.100032
5. Rahmana S, Jahana N, Makbul SAA, Ahmad M, Gania MA (2020) Scientific appraisal of
Unani concept of islah-e-advia (rectification/purification of drugs) and its importance. J
Ethnopharmacol 258:112880. https://doi.org/10.1016/j.jep.2020.112880
6. Kalam MA, Yaqoob A, Majeed B, Ahmad A (2020) Azaraqi (Strychnos Nuxvomica L.): a novel
drug of Unani system of medicine for the management of nerve and phlegmatic diseases.
WJPLS 6:100–106
7. Lu L, Huang R, Wu Y, Jin JM, Chen HZ, Zhang LJ, Luan X (2020) Brucine: a review of phy-
tochemistry, pharmacology, and toxicology. Front Pharmacol 11:377. https://doi.org/10.3389/
fphar.2020.00377
8. Guo R, Wang T, Zhou G, Xu M, Yu X, Zhang X, Sui F, Li C, Tang L, Wang Z (2018) Botany,
phytochemistry, pharmacology and toxicity of Strychnos nux-vomica L.: a review. The. Am J
Chin Med 46:1–23. https://doi.org/10.1142/S0192415X18500015
1476 S. A. A. Makbul and S. Rahman

9. Anonymous (2007) The Unani Pharmacopoea of India. Part-1st –1st CCRUM, Ministry of
Health and Family welfare. Govt of India, New Delhi
10. Ghani N (2011) Khazainul Advia (Urdu). Idara Kitabul Shifa, New Delhi, pp 1–1375
11. Khan MA (2012) Muheete Aazm (Urdu) 1st CCRUM. Ministry of Health and Family Welfare
Govt. of India, New Delhi
12. Kabeeruddin M (2007) Makhzanul Mufradat (Urdu). Idara Kitabus Shifa, New Delhi, pp 1–44
13. Alizadeh A, Moshiri M, Alizadeh J, Balali-Mood M (2014) Black henbane and its toxicity – a
descriptive review. Avicenna J Phytomed 4:297–311
14. Al-Snafi AE (2016) Pharmacology and toxicology of Conium Maculatum- a review. Pharma
Chem J 3:136–142
15. Bhakta S, Das SK (2020) The medicinal values of Abrus precatorius: a review study. J Adv
Biotechnol Exp Ther 3:84–91. https://doi.org/10.5455/jabet.2020.d111
16. Tabasum S, Khare S, Jain K (2018) Establishment of quality standards of Abrus precatorius
Linn. Seed. Indian J Pharm Sci 80:541–546
17. Das A, Jain V, Mishra A (2016) A brief review on a traditional herb: abrus precatorius (L.). Int
J Forensic Med Toxicol Sci 1:1–10
18. Khare CP (2007) Indian medicinal plants. Springer, New Delhi
19. Anonymous (2007) The Unani Pharmacopoea of India. Part-1st –4th CCRUM, Ministry of
Health and Family welfare. Govt of India, New Delhi
20. Akbar S (2020) Introduction. In: Handbook of 200 medicinal plants. Springer, Cham. https://
doi.org/10.1007/978-­3-­030-­16807-­0_1
21. Jena J, Gupta AK (2012) Ricinus communis Linn: a phytopharmacological review. Int J Pharm
Pharm Sci 4:25–29
22. Abdul WM, Hajrah NH, Sabir JSM, Al-Garni SM, Sabir MJ, Kabli SA, Saini KS, Bora
RS (2018) Therapeutic role of Ricinus communis L. and its bioactive compounds
in disease prevention and treatment. Asian Pac J Trop Med 11:177–185. https://doi.
org/10.4103/1995-­7645.228431
23. Soni P, Siddiqui AA, Dwivedi J, Soni V (2012) Pharmacological properties of Datura stramo-
nium L. as a potential medicinal tree: an overview. Asian Pac J Trop Biomed 2:1002–1008.
https://doi.org/10.1016/S2221-­1691(13)60014-­3
24. Trancă SD, Szabo R, Cociş M (2017) Acute poisoning due to ingestion of Datura stramo-
nium– a case report. Roman J Anaesth Intensive Care 24:65–68. https://doi.org/10.21454/
rjaic.7518.241.szb
25. Dey T, Saha S, Adhikari S, Ghosh PD (2015) A comprehensive review on medicinally impor-
tant plant, Croton tiglium L. Int J Curr Res Biosci Plant Biol 2:124–128
26. Haak M, Vinke S, Keller W, Droste J, Rückert C, Kalinowski J, Pucker B (2018) High quality
de novo transcriptome assembly of Croton tiglium. Front Mol Biosci 5. https://doi.org/10.3389/
fmolb.2018.00062
27. Liu L, Yu H, Wu H, Yang X, Pan Y, Chen Y, Wang K, Wang W, Zhang W, Jin Y, Zhang C, Jiang
A, Xia C (2017) Toxic proteins from Croton Tiglium L. exert a proinflammatory effect by
inducing release of proinflammatory cytokine and activating the P38-Mapk signaling pathway.
Mol Med Rep 16:631–638. https://doi.org/10.3892/Mmr.2017.6617
28. Anonymous (2007) The Unani Pharmacopoea of India. Part-1st –5th, CCRUM, Ministry of
Health and family welfare. Govt of India, New Delhi
29. Kabeeruddin HM (1938) Bayaze Kabeer, (Urdu). In: Hikmat book depot, vol II. Deccan,
Hyderabad, pp 1–160
30. Kumar MS, Prashant T, Kumar SP (2017) Pharmacology, phytochemistry and toxicology of
Semecarpus anacardium. Int J Pharm Sci Rev Res 42. Article No. 06:25–31
31. Gouthaman T, Kavitha MS, Ahmed BA, Kumar TS, Rao MV (2008) A Review on Semecarpus
anacardium L.: an anticancer medicinal plant. Recent progress in medicinal plant (RPMP).
Phytopharmacol Thera Values I 19:193–222
32. Merzaia AB, Riaz H, Rehman R, Nisar S, Azeem MW (2017) A review of toxicity, therapeutic
and biological activities of Calotropis. IJCBS 11:58–64
Commonly Used Poisonous Medicinal Plants in Unani System of Medicine 1477

33. Parihar G, Balekar N (2016) Calotropis procera: a phytochemical and pharmacological review.
TJPS 40:115–131
34. Verma S (2016) Calotropis Procera (Asclepiadaceae): a review. IJSRST 2:487–490
35. Masihuddin JMA, Siddiqui A, Chaudhary S (2018) Traditional uses, phytochemistry and phar-
macological activities of Papaver somniferum with special reference of Unani medicine: an
updated review. J Drug Delivery Therapeutics 8(5-s):110–1164. https://doi.org/10.22270/jddt.
v8i5-­s.2069
36. Haber I, Pergolizzi J Jr, LeQuang JA (2019) Poppy seed tea: a short review and case study. Pain
Ther 8:151–155. https://doi.org/10.1007/s40122-­019-­0113-­5
37. Nadkarni KM (2009) Indian Materia Medica 1, 3rd edn. Popular Prakashan Private
Limited, Mumbai
38. Nyirimigaboa E, Xu Y, Li Y, Wang Y, Agyemang K, Zhang Y (2015) A review on phytochem-
istry, pharmacology and toxicology studies of Aconitum. J Pharm Pharmacol 67:1–19. https://
doi.org/10.1111/jphp.12310
39. Singh MK, Vinod M, Iyer SK, Khare G, Sharwan G, Larokar YK (2012) Aconite: a pharmaco-
logical update. Int J Res Pharm Sci 3:242–246
40. Elhendawy MA, Wanas AS, Radwan MM, Azzaz NA, Toson ES, El-Sohly MA (2018)
Chemical and biological studies of Cannabis sativa roots. Med Cannabis Cannabinoids
1:104–111. https://doi.org/10.1159/000495582
41. Borille BT, Gonzáleza M, Steffensa L, Ortizb RS, Limbergera RP (2017) Cannabis sativa: a
systematic review of plant analysis. Drug Anal Res 01:1–23
42. Rajput R, Kumar R (2018) A review on Cannabis sativa: its compounds and their effects. Int
J Pharm Sci Rev Res 53:59–63
43. Musk AW, Klerk DE, NH. (2003) History of tobacco and health. Respirology 8:286–290
44. Ameya G, Manilal A, Merdekios B (2017) In vitro antibacterial activity and phytochemical
analysis of Nicotiana tabacum L. extracted in different organic solvents. Open Microbiol J
11:352–359. https://doi.org/10.2174/1874285801711010352
45. Shekins OO, Dorathy EU, Labaran ML, Joel P (2016) Phytochemical Screening of Tobacco
(Nicotiana tabacum) and Its Effects on Some Haematological Parameters and Histopathology
of Liver and Brain in Male Rats. IJBCRR 14:1–9. Article no.IJBCRR.29645. https://doi.
org/10.9734/IJBCRR/2016/29645
46. Mishra A, Chaturvedi P, Datta S, Sinukumar S, Joshi P, Garg A (2015) Harmful effects of
nicotine. Indian J Med Paediatr Oncol 36:24–31. https://doi.org/10.4103/0971-­5851.151771
47. Sah A, Khatik GL, Vyas M, Yadav P (2016) A short review on anticancer investigations of
Strychnos nux-vomica. Int J Green Pharm 10:S87–S90
48. Sreedevi B, Kuchana V, Shobharani S (2021) Ethanobotanical, phytochemical and pharmaco-
logical review on Strychnos nuxvomica. J Natural Products Plant Res 11(1):1–11
49. Azhar M, Mustehasan. (2020) Phytopharmacology of an important Unani drug Bazr-Ul-Banj
(Hyoscyamus niger Linn.) – review. Asian J Pharm Clin Res 13:28–32
50. Kalam MA, Rifat I (2020) Datura species (Dhatura Safed and Dhatura Seyah): a review with
special emphasis on single-use and compound formulations and pharmacological studies rel-
evant to Unani System of Medicine. Indian J Integr Med 2:1–9
51. Sharma M, Dhaliwal I, Rana K, Delta AK, Kaushik P (2021) Phytochemistry, pharmacology,
and toxicology of datura species—a review. Antioxidants 10:1291. https://doi.org/10.3390/
antiox10081291
52. Sinsinwar S, Paramasivam I, Muthuraman MS (2016) An overview of the biological and
chemical perspectives of Croton tiglium. Pharm Lett 8:324–328
53. Gao X, Hu J, Zhang X, Zuo Y, Wang Y, Zhu S (2020) Research progress of aconitine toxicity
and forensic analysis of aconitine poisoning. Forensic Sci Res 5:25–31. https://doi.org/10.108
0/20961790.2018.1452346
54. Rawat A, Mali RR (2013) Phytochemical properties and pharmcological activities of Nicotiana
Tabacum: a review. Indian J Pharm Biol Res 1(2):74–82
55. Anonymous (1998) Qarabadeen-e-Majeedi. NCPUL Publications, pp 1–415
1478 S. A. A. Makbul and S. Rahman

56. Hkm Najm-ul Ghani (2010) Qarabadeen Najmul Gani. CCRUM, New Delhi
57. Al-Snafi AE (2018) Therapeutic importance of Hyoscyamus species grown in Iraq
(Hyoscyamus albus, Hyoscyamus Niger and Hyoscyamus reticulates)- a review. IOSR J Pharm
(IOSRPHR) 8:18–32
58. Meena PP, Chendraya PP, Praveen KM, Soundarrajan S, Srinivasan M, Sampathkumar R
(2015) Pharmacological activities of Abrus precatorius (L.) seeds. Int J Pharm Med Res
3:195–200
59. Harshavardhan B, Ashwin KSB, Ravishankar CA, Ravi M (2015) An experimental study to
assess toxic potential of jayapala (croton tiglium) beeja in relation to gastrointestinal tract. Int
J Health Sci Res 5:346–351
60. Bridgeman MB, Abazia DT (2017) Medicinal cannabis: history. Pharmacol Impl Acute Care
Setting 42:180–188
Herbal Drugs: Safety, Cost-Effectiveness,
Regulation, Current Trends, and Future
Directions

Sidra Nisar Ahmed, Mushtaq Ahmad, Mohammad Zafar, Ghulam Yaseen,

Nadia Iqbal, Neelum Rashid, Samina Kousar, and Adeela Haroon

1 Introduction to Herbal Medicine: A Growing Field

with a Long History

Herbal medicines have always been at forefront virtually in the development of

human culture [1] by organizing a substantial source of folk medicine from time
immemorial [2]. Indeed, for most of the history, herbal medicine was the sole source
to cure disease and is still being practiced [3, 4]. According to “WHO traditional
medicine strategy: 2014–2023,” over 100 million Europeans have tried traditional
herbal medicine products and healthcare services; one-fifth of the users are reported
to be regular consumers [5]. Herbal medicines include herbs, herbal material, and
finished herbal medicines (World Health Organization, https://www.who.int/health-­
topics/traditional-­complementary-­and-­integrative-­medicine) that are complex ther-
apeutic preparations obtained from any unpurified or processed part of plant (stem,
root, leaves, flowers, seeds) [6].

S. N. Ahmed (*) · S. Kousar · A. Haroon

Department of Botany, The Women University Multan, Multan, Pakistan
M. Ahmad · M. Zafar
Department of Plant Sciences, Quaid-i-Azam University, Islamabad, Pakistan
G. Yaseen
Department of Botany, Division of Science and Technology, University of Education, Lahore,
Pakistan
N. Iqbal
Department of Biochemistry and Biotechnology, The Women University Multan, Multan,
Pakistan
N. Rashid
Department of Botany, Mir Pir University of Science and Technology, Mirpur, Pakistan

© The Author(s), under exclusive license to Springer Nature 1479

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_62
1480 S. N. Ahmed et al.

Traditional herbal medicine is the sum total of “knowledge, skill, and practices
based on the theories, beliefs, and experiences indigenous to different cultures, used
in the maintenance of health as well as in the prevention, diagnosis, improvement or
treatment of physical and mental illness” [7]. Herbal medicine has different systems
throughout the world, and all have distinctive philosophy and practices profoundly
influenced by the prevailing conditions, environment as well as geographic region
in which it first evolved [8]. However, a common philosophy is a holistic approach
(an expression of wholeness) to life, considering their emotional, physical, and
social well-being, and a focus on health rather than illness. In general, emphasis is
on the person’s total health rather than the specific affliction or conditions from
which the patient is suffering, and the use of herbs is an integral aspect of all tradi-
tional medicine systems [9–11]. Traditional Chinese medicine (TCM), date back at
least 3000 years, is a good example of how traditional knowledge can be practiced
in a holistic way in modern healthcare system [12]. Ginkgo, garlic, and ginseng,
three of the most popular botanical items, can be traced back to TCM roots and are
now used to treat various ailments [12, 13].
Herbal medicines are valued for a number of reasons all over the map. Herbal
medicines, traditional therapy, and traditional healers are the main, and often only,
source of essential healthcare for thousands of people. It is treatment that is easily
accessible to greater public, more affordable, and closer to people’s homes com-
pared with pharmaceutical drug. It is also accepted and trusted by a huge number of
individuals on a cultural level. In a time of rising healthcare expenses and practi-
cally universal austerity, the affordability of most traditional medicines makes them
all the more appealing. Traditional herbal medicine also stands up as a viable option
for dealing with the onslaught of chronic non-communicable diseases [14].
Furthermore, it is more closely aligned with the patient’s ethos, allays concerns
about the adverse reactions of pharmaceutical treatments, and meets a demand for
even more customized healthcare. Herbal medicines are primarily used to promote
public health and treatment of chronic, rather than life-threatening conditions [15–
18]. In recent decades, the disease spectrum has evolved, with complicated chronic
disorders taking center stage and results of Western medicine treatment are insuffi-
cient [19]. So, traditional medicines, particularly herbal therapy, become more prev-
alent when Western medicine fails to treat an illness, such as advanced cancer or
novel infectious diseases. Recently, herbs are used to treat a variety of chronic and
acute conditions, as well as a number of diseases and problems, including heart
disease, prostate problems, anxiety, arthritis, and to boost the immune system, to
mention a few [20, 21].
As long before recorded history, plants were used as medicines. Numerous
herbal medicines would not exist today if people had not identified the efficacy of
chemicals found in crude plant extracts when they first surfaced in the 1800s [22].
Plants are thought to be responsible for around 25% of all medications prescribed
worldwide, with 121 active chemicals in use. Exclusively 11% of the total 252 med-
ications on the World Health Organization (WHO’s) essential medicine list are
plants-derived [23]. Farnsworth and companions (1985) listed 119 chemical com-
pounds derived from plants [22], of which 88 (74%) were found as a product of
Herbal Drugs: Safety, Cost-Effectiveness, Regulation, Current Trends, and Future… 1481

extracting the active chemicals responsible for the plant‘s traditional therapeutic
characteristics. Metformin (anti-diabetes), paclitaxel (anti-breast cancer), aspirin
(for headaches), morphine (for severe pain), digoxin (against fatal heart symptoms),
and lovastatin (to control high blood cholesterol) are only a few examples of medi-
cines produced from plants. In truth, lovastatin is derived from red yeast rice and
first documented in China during the Tang dynasty (800 AD), where it is named as
Hong Qu (Burke, 2015) [24]. These herbal medicines serve an essential role in the
treatment of several diseases and will continue to confront new challenges in the
future [25, 26].
Despite the fact that herbs are essentially of historic interest, thousands of medic-
inal herbs are to hand over-the-counter and are often used by patients all over the
world. Practitioners may find it easier to advise patients on the use of herbal medi-
cine if they have a better grasp of their authentication as well as regulation, safety,
and efficacy [6].

2 The Global Market Demand of Herbal Medicine

The phrase “High Value Minor Crops” refers to plants that are relatively small con-
tributors to a country’s agricultural output. Despite being little contributions to out-
put, the significance of these plants in aggregate can be shown in the fact that their
global trade in 2006 generated US$ 60 billion [27, 28]. Annual herbal medicines
expenditures in the Republic of Korea increased from US$4.4 billion in 2004 to
US$7.4 billion in 2009 [29]. The annual “out of pocket” expenses for natural prod-
uct in the United States was $14.8 billion in 2008 [30]. Americans spent $33.9 bil-
lion on herbal medicine in 2009, up 25% from the $27 billion they spent on the same
treatments in 1997 [31]. In certain nations, such as Singapore and the Republic of
Korea, where the traditional healthcare system is well-established, herbal medicine
is still widely used by 76 and 86% of the people, respectively [29]. In 2012, the
output of Chinese materia medica was estimated to be worth US$83.1 billion, up
more than 20% from the previous year [5]. Pakistan’s high-value plant exports
reached over US$10.5 million in 2012, with Swat District accounting for a large
portion of the supply [32]. Now the global market of herbal medicines is about 100
billion (see http://www.nutraceuticalsworld.com/). Because of the variety of legis-
lation and regulatory categories for traditional herbal medicine, estimating the size
of the market for traditional herbal medicines across member states is difficult.
However, available evidence indicates that there is a substantial market.

3 Regulation

Herbs are classified as dietary supplements under the “Dietary Supplement Health
and Education Act (DSHEA) of 1994 [33].” Under this law, supplements are defined
as “anything that supplements the diet.” Vitamins, minerals, herbs, amino acids,
1482 S. N. Ahmed et al.

enzymes, organ tissues, metabolites, extracts, and concentrations are all examples
of supplements. Dietary supplements cannot claim to “diagnose, cure, mitigate,
treat, or prevent illness,” which is a fundamental distinction between drugs and
supplements [33]. It’s worth mentioning that dietary supplement companies are
authorized to make certain “structure/function” claims, which are generally vague
health benefits claims. For example, an Echinacea product can promise to “boost the
body’s natural defences” (it’s widely used to cure or prevent the common cold) [6].
As herbs are defined as dietary supplements under the current law, hence manu-
facturers can sell and market their herbal medicines without demonstrating safety
and efficacy as is mandatory for pharmaceutical drugs. Also, unlike medicines,
where a company must provide the Food and Drug Administration (FDA) with evi-
dence of safety and efficacy before a product can be sold, the FDA faces the regula-
tory burden of establishing that a dietary supplement is harmful before it can be
removed from the market [33]. This regulatory framework, predictably, has resulted
in issues with herbal medicine consistency and safety. Many recent studies have
reported that the quantities of probable active components in herbal preparations
vary substantially. For example, a recent study of 25 ginseng products indicated a
variation of 15- to 36-fold and 43- to 200-fold in the concentration of two biologi-
cally active ingredients: ginsenosides and eleutherosides, respectively [34]. As a
result, it may be problematic for patients to determine the precise composition of
the drugs they are interested in taking.
However, WHO has perceived that herbal medicine makes a significant contribu-
tion to providing vital healthcare [35]. The Office of Alternative Medicine was
established within the National Institutes of Health in 1989 to promote scientific
studies in the field of herbal medicine (http://nccam.nih.gov), and the European
Scientific Cooperative on Phytotherapy (ESCOP) was established in 1989 with the
intention of promoting the scientific status and harmonization of herbal medicines
at the European level (https://escop.com/). As a result, investment in the evaluation
of herbal treatments has increased. While this investment is little in comparison to
the pharmaceutical industry’s total investment in research and development, it nev-
ertheless shows genuine public, enterprise, and government concern in this field [36].
With the great growth in interest in and use of traditional medicines around the
world, two major areas of interest have emerged, each posing significant concerns.
These are a wide range of worldwide and national policies governing the production
and use of herbs (and other complementary medicines), as well as their authenticity,
quality, safety, and scientific evidence regarding health claims [8, 37].

4 Efficacy of Herbal Medicine

A national survey in United States documented that the use of an herb to treat a
medical illness within the past year was 18.9% when meal supplements excluded
[38]. Bent (2008) reviewed the evidence for efficacy of most commonly used herbs
(including Echinacea, Ginseng, Ginkgo, Garlic, St. John’s wort, Peppermint,
Herbal Drugs: Safety, Cost-Effectiveness, Regulation, Current Trends, and Future… 1483

Ginger, Soy, Chamomile and Kava), reported that systemic reviews supported effi-
cacy for five out of ten common herbs (Garlic, Ginkgo, St. John’s wort, Soy, and
Kava) for specific indications Table 1 [6] and discussed below.
Garlic has been extensively researched due to several claims of medicinal prop-
erties. But the most substantial body of research documented the effect on choles-
terol and hypertension [40, 41]. For lowering cholesterol, the most recent systematic
review identified 10 randomized, placebo-controlled trials; six of ten studies found
garlic to be effective. The average drop in total cholesterol was about 9.9–11.4%
[42]. The existing evidence suggests that garlic is superior to placebo in lowering
cholesterol levels [40]. However, the magnitude of the effect is modest in compared
to the 17–32% reduction observed with active FDA-approved drug “statin” medica-
tions [43]. Garlic against hypertension has been studied in seven randomized,
placebo-­controlled trials. This meta-analysis found that garlic had a significant
decreasing effect on both systolic weighted mean difference (WMD: 6.71 mmHg;
95% confidence interval [CI]: 12.44 to 0.99; P = 0.02) and diastolic blood pressure
(BP; WMD: 4.79 mmHg; 95% CI: 6.60 to 2.99; P 0.00001) when compared to the
placebo. There were no major side effects noted [41]. It is, however, associated with
gastrointestinal pain and poor garlic breath [40]. It’s also been linked to a higher risk
of blood thinning after using garlic [44, 45].
Ginkgo extracts are one of the well-studied herbal formulation, with flavonoids
and terpenoids standardized to 24% and 6%, respectively. Despite mixed results in
previous trials, ginkgo is generally effective for mild dementia, with a small ben-
efit of about 3% in the Alzheimer’s Disease Assessment Scale-Cognitive subtest [46].
It is important to mention that ginkgo was not effective for improving cognitive
function in elderly patients without dementia [47]. In addition, ginkgo was reported
to enhance pain-free walking distance in claudication patients in a systematic review
of eight trials, a minor benefit with dubious clinical value [40]. While the side
effects of ginkgo and placebo were similar in clinical trials, [48] the documented
link between ginkgo and spontaneous bleeding is a major issue [49].

Table 1 Selected herbal medicine with evidenced-based efficacy

Medicinal Scientific evidence for
herb Uses efficacy Side effects
Garlic Claudication Effective Mild gastrointestinal side effects
Hypercholesterolemia Effective and garlic odor; blood thinning
Ginkgo Dementia Effective Side effects similar to placebo;
case reports of bleeding
St. John’s Depression Likely effective for Numerous reports of drug
wort mild to moderate interactions
depression
Soy Menopausal Not effective Concerns regarding long-term
symptoms estrogenic effects
Kava kava Anxiety Effective Case reports of severe
hepatotoxicity
Source of Scientific evidence [39]
1484 S. N. Ahmed et al.

Antidepressant drugs based on St John’s wort (Hypericum perforatum) extract

are among the most widely prescribed in Europe and are becoming more popular in
the United States [50]. St John’s wort is the leading antidepressant in Germany,
outselling the world’s most commonly used antidepressant, fluoxetine [51]. Prior
trials with St. John’s wort have had mixed results, although the herb is likely useful
in the treatment of mild to moderate depression [45, 52]. Although the specific
mechanism is unknown, it has been linked to decreased serotonin, dopamine, and
norepinephrine breakdown and non-selective reuptake, regulation of neurotransmit-
ter transport systems, and possible neuro-endocrinological effects [53, 54]. It was
proven to be ineffective for people with severe depression in recent investigations
[55]. The numerous well-documented drug interactions temper decision for the use
of St. John’s wort [56].
Soy, a major source of dietary phytoestrogens with low estrogenic activity, is
often used to treat menopausal symptoms (particularly hot flushes) and cholesterol
levels. A recent systematic review found 9 clinical trials exploring the effects of
increasing dietary soy and 9 more trials studying the efficacy of soy extracts, all of
which indicated that neither was useful for menopausal symptoms [57]. Soy was
found to be effective in decreasing total and low-density lipoprotein (LDL) choles-
terol by 4–5% in a recent assessment of 11 trials [58], a minor result comparable to
that seen in garlic studies [40].
Kava has long been used as a sedative and relaxation in the South Pacific islands.
Clinical trials have reported a small benefit for the management of depression [59].
The reported link to many incidences of severe hepatotoxicity has limited the use of
this herb [60].
Evidence of efficacy varied for the remaining reviewed five herbs—Echinacea
for common colds; ginseng to improve energy level as well as physical and cogni-
tive performance; peppermint for upset stomach, irritable bowel syndrome (IBS),
and seasonal allergies; Chamomile for stress, insomnia, and digestive upset; and
ginger to treat nausea [61–63].

5 Quality, Safety, and Scientific Evidences

Herbal medicine has long been practiced for disease treatment and prevention, as
well as for health promotion and prolonging one’s life span and quality of life.
However, a systematic approach to evaluating their safety and effectiveness is lack-
ing. Many individuals find herbal therapy appealing because of its holistic approach
to health treatment, but scientific evaluation is difficult because so many aspects
must be considered. Herbal medicines are widely used and often perceived as “natu-
ral” and therefore safe. They are commonly used in combination with other medica-
tions and are derived from plants, which vary in species, growth conditions, and
biologically active ingredients. Herbal extracts can be contaminated, adulterated, or
contain harmful substances [64, 65]. There are many case reports of nephropathy
induced by the use of some Chinese herbal medicines. A particularly morbid case
Herbal Drugs: Safety, Cost-Effectiveness, Regulation, Current Trends, and Future… 1485

series involves 105 patients in Belgium who suffered nephropathy after consuming
a Chinese herbal medicine (Aristolochia fangchi) for weight loss. End-stage renal
failure affected 43 people, and 39 had their kidneys removed as a precaution.
Urothelial cancer was detected in 18 of these patients, which was linked to the syn-
thesis of DNA adducts from the aristolochic acid in this medicinal herb [66].
Pyrrolizidine alkaloids, which are complex compounds found in certain plants and
may be intentionally or mistakenly added to herbal remedies, are another major
source of toxicity in herbal medicines (for example; comfrey, which is still available
in the United States). Certain alkaloids cause hepatotoxicity by inducing sinusoidal
obstruction syndrome (SOS) that can rapidly progressive and be lethal [67].
Herbal medicine quality management has a direct impact on their safety and
efficacy [64, 65]. However, due to a lack of suitable policies or regulatory require-
ments, as well as a lack of adequate or approved research technique for evaluating
traditional medicines, there is little data on the composition and quality of most
herbal medicines [68, 69]. Furthermore, because the drug approval process does not
allow for undifferentiated mixes of natural compounds, there is relatively little
research on entire herbal mixtures. Isolating each active chemical from each herb
would be extremely time-consuming and expensive, rendering it uneconomical for
manufacturers [70]. Another concern is that, despite the increasing demand of
botanical dietary and herbal supplements, some herbal items on the market are
likely to be of poor quality and efficacy, even though the herbal product has been
proven to have an effect in controlled research using high-quality sources. Herbs, as
natural products, are believed to be intrinsically harmless with no adverse effects,
and that efficacy can be attained at a wide range of doses. However, there are no
established “doses” for herbs, and different drug interactions and undesirable side
effects are possible.
The presence of numerous active components that collectively give a potentiat-
ing effect, may not be achieved by any single active compound, is a key prospective
advantage of botanicals over mainstream single-component medications. This
advantage poses a challenge for the isolation and identification of bioactive con-
stituents. To validate in vivo efficacy, products that are identified by activity-guided
fractionation must be tested in approved model organisms. Preferably, plants should
be grown under controlled conditions particularly when used as a source of botani-
cal extracts and originate from a characterized and uniform genetic source with a
taxonomic record of the genus, species, and cultivar or other extra signifier, and the
concentration of the whole plant extract should be standardized and free of any pos-
sible hazards. The source of the seed, cultivation conditions, location, and any
chemical treatment such as pesticides should all be recorded. Plant extracts can vary
from year to year and may be considerably affected by temperature, drought, or
flood, and geographic location, because the environment can have a considerable
impact on phytochemical profiles and the efficacy of the plant end product. For that
reason, biochemical profiling must be applied to confirm that the product is made
from consistent material. The process of concentrating the bioactive chemicals can
be difficult and challenging and might have a negative impact on their solubility and
bioavailability.
1486 S. N. Ahmed et al.

As a result, increasing concentration to improve drug efficacy can be ineffective,

and the use of solubilizers and bioenhancers should be studied in the same way as
for pharmaceuticals [65]. However, there are significant obstacles in the way.
Although in theory botanicals must be properly described and herbal medicines
should be manufactured to certain standards of quality as pharmaceuticals, the situ-
ation in practice is markedly different. Herbs contain a number of chemicals, some
of which have yet to be identified, and often lack an identifier component. Chemical
fingerprinting is still in its early stages, and virtually all herbs lack it. This makes it
difficult to standardize botanicals, while some are produced to contain a consistent
amount of a crucial component or group of components, like ginsenosides and
anthocyanins in ginseng and bilberry product, respectively. Even if important chem-
icals have been identified and a standardize content has been decided or recom-
mended, there is no guarantee that particular commercial products will contain it.
Another important aspect to consider is that both wild and cultivated medicinal
plants are used as a source of herbal material for commercial products. Plants may
be overharvested as a result of the growing herbal product market, posing a threat to
biodiversity. Collection and cultivation activities that are poorly managed could
result in the extinction of endangered species of plants and the depletion of natural
resources. It has been estimated that 15,000 of the 50,000–70,000 traditional medic-
inal plants are endangered [71]. Botanic Gardens Conservation International’s ini-
tiatives are important to the preservation of plant communities as well as knowledge
on how to cultivate and use plants for therapeutic purposes [36, 71].

6 Cost-Effectiveness and Economic Evaluation

of Herbal Medicines

Over the previous two decades, there has been an expanding body of scientific
knowledge on the efficacy of herbal medicine, understanding of underlying mecha-
nisms, and progress in methods to ensure quality and standard of materials and
products. Research partnerships are primarily focusing on high burden of disease
areas where conventional medicine has produced mixed results, especially in the
prevention and treatment of chronic disease, and towards improving outcomes by
combining complementary and conventional interventions. Once efficacy and safety
have been demonstrated, analyzing the cost-effectiveness of medical interventions,
whether conventional or alternative, is crucial for patients, practitioners, and
policymakers.
Cost-effectiveness analysis (CEA) is a type of economic analysis that analyzes
the relative expenses (costs) and benefits (effects) of several courses of action. CEA
differs from cost-benefit analysis in that it puts a monetary value to the measures of
effect [72].
In past few years, the range of economic evaluations of herbal medicine has
improved [73], with many herbal therapies being demonstrated to be cost-effective
Herbal Drugs: Safety, Cost-Effectiveness, Regulation, Current Trends, and Future… 1487

when compared to standard care. In order to account for the entire benefit of herbal
therapies, economic evaluation of herbal medicine logically should incorporate
proper process and outcome-based evaluation of the humanistic perspective that
characterize its philosophical doctrinism [74].
The unavailability of administrative claims makes it challenging to collect eco-
nomic outcome data because many herbal therapies are accessible over-the-counter
and/or are frequently paid for out-of-pocket. Furthermore, many over-the-counter
drugs, such as ST JOHN’S WORT, are unstandardized and of variable quality. Both
the therapy’s costs and outcomes will be influenced by standardization and quality.
Even if the clinical outcomes of a herbal therapy are equivalent to or somewhat less
favorable than those of conventional medicine, the reduced cost of healthcare can
make such therapies more appealing to decision makers [75].
In many meta-analyses of randomized controlled trials, Hypericum perforatum
formulations were found to be superior to placebo [76, 77] and equally effective as
standard antidepressants in the acute treatment of mild to moderate depression [78].
This benefit has the potential to influence how prescribed medicines, such as antide-
pressants, are used.
Numerous treatment parameters have the ability to influence the treatment’s
cost-effectiveness. In the case of St John’s wort, a distinct benefit over antidepres-
sants has been documented in terms of decreased treatment withdrawal rates, low
rates of side effects, and strong compliance, all of which are important factors in
determining the cost-effectiveness of a certain form of therapy [79].
Therefore, any evidence of therapeutic benefit and likely superiority of St John’s
wort over standard therapies could interpret into obvious cost-effectiveness.
The most significant risk associated with use is the possibility of drug interac-
tions, which can be reduced by using preparations with modest hyperforin levels
[80]. The relatively low cost of Hypericum perforatum extract makes it worth con-
sidering in the cost-effectiveness analysis of mild to moderate depression treat-
ments, given that the indirect costs of depression are greater than five times direct
treatment costs, and given the rising cost of standard antidepressants [75].
Phytodolor™, a patented herbal medicine, when compared to the main non-­
steroidal anti-inflammatory drug Diclofenac, was found to be less expensive in the
treatment of osteoarthritis. The literature review presented similarity of efficacy and
clinical outcomes, with cost thus being the most important factor of cost-­
effectiveness [81].
Furthermore, numerous meta-analyses have shown that acupuncture could be a
credible prophylactic treatment option for migraineurs who suffer from frequent or
uncontrolled migraines, as well as those who are experiencing drug side effects [82,
83]. In terms of incidence of reduced side effects and potential long-term efficacy
after quitting, acupuncture appears to be superior than mainstream treatment [84–
86]. There has been some research that introducing acupuncture to an existing
mainstream treatment can decrease costs by minimizing use of prescription drug,
rate of sick absence, and medical assessment appointments [87]. Despite the over-
whelming evidence for acupuncture’s potential cost-effectiveness in chronic pain
1488 S. N. Ahmed et al.

management, like headache, osteoarthritis, and lower back pain, more research on
acupuncture’s long-term cost-effectiveness is needed [86–89].
A review of the medical, corporate, and payer literature reveals that, to start,
immediate and significant health benefits and cost savings could be realized through-
out our healthcare system by utilizing three integrative strategies: (1) integrative
lifestyle change programs for those with chronic disease, (2) integrative interven-
tions for people experiencing depression, and (3) integrative preventive strategies to
support wellness in all populations [90].

7 Research Needs and Future Directions

Research demands in the field of herbal medicines are tremendous, but they are bal-
anced by the potential health advantages and enormous size of global herbal medi-
cine market. Expended research on the authenticity, safety, pharmacological effects,
and clinical efficacy of the many herbs in regular use is much needed [21, 91, 92].
Several experts have already proposed a number of significant reforms to the
regulation of herbal products that could boost their quality and adequate use [93,
94]. These include requiring producers to register with the FDA, implementing
safety checks just like to those necessary for over-the-counter medicines, requiring
any health claims to be backed up by FDA-approved research, and ensuring that
product labels include a concise list of all contents. While these measures will
undoubtedly improve herbal product safety, more adjustments are required to
improve and promote high-quality research. To maintain uniformity amongst
research, the most important aspect will be to develop definite standards for herbal
medicines [95]. For definitive authenticity and quality of herbal medicines, genomic
testing and chemical fingerprinting procedures using hyphenated techniques are
now available. They should be regulated to safeguard the consumers, but uncertain-
ties about efficacy will continue until sufficient amounts of scientific evidence from
experimental and controlled clinical studies accumulate [21, 91, 92]. Since no evi-
dent, well-established criterion of the chemical fingerprint exists for the most widely
used herbs, so recent researches (such as the aforementioned study of Echinacea)
[96] that even adopted high-quality methodology have always been open to criti-
cism about the composition of the herbal medicine used [95]. Generally, interna-
tional studies on herbal medicines should be conducted to certain ethical standards
as all other research associated with human subjects, with data shared among coun-
tries. Collaboration, cultural value, scientific validity, fair subject selection, favor-
able risk-benefit ratio, independent review, informed consent, and respect for the
subjects should all be considered [21, 91]. However, conducting large, controlled
human trials on the clinical effectiveness of herb is cost prohibitive, especially if the
goal is to promote human well-being. Therefore, innovative biomarkers that are
more clearly inked to health (and illness) outcomes are urgently needed. It is neces-
sary to develop predictive biomarkers and subtle but detectable signs of early
Herbal Drugs: Safety, Cost-Effectiveness, Regulation, Current Trends, and Future… 1489

cellular and molecular changes that can be linked to the emergence of specific dis-
eases [97].
There should be research-based information on whether whole herbs or extracted
chemicals are better to meet the problems of finding the active compounds in the
plants. The subject of drug interactions is also of a great value that demands pro-
gressive awareness and studies, as polypharmacy and polyherbacy [15–18].
If an adequately funded branch of the FDA supports and coordinates the effort to
set standards for herbal medicines, it is most likely to succeed. Research would also
pursue more promptly if a few type of patent protection is available, so that the
producers that invest in clinical trials and document the safety and efficacy of their
products could be remunerated financially. Finally, techniques to improve clinical
research progress would assist in addressing the “backlog” of 20,000 herbs with
insufficient proof of safety and efficacy [95]. Although this technique is still being
investigated, it has the ability to dramatically shorten the time and cost of clinical
trials of herbal medicines.

8 Conclusion

Regardless of why someone uses herbal medicine, it is indeed a flourishing com-

mercial enterprise that delivers a significant healthcare service to people who do not
have physical or financial accessibility to conventional medical therapy. Plants,
herbs, and ethno-botanicals have been used for quality life and disease treatment
since the early human culture, and are still practiced around the world. Plants and
natural-resources are the foundation of modern medicine, and they play a significant
role in the commercial medicinal compositions currently manufactured. Plants are
used to make about a quarter of the medications prescribed around the world. Herbs,
rather than pharmaceuticals, are still commonly used in healthcare system. Plants
are used to make about a quarter of the medications prescribed worldwide. Herbs,
rather than pharmaceuticals, are still commonly used in healthcare. Herbal medicine
is a preferred treatment option for some people. For others, herbs are taken as a
complement to conventional medications. However, traditional medicine, of which
herbal medicine is a key component, is the only accessible or affordable system of
healthcare in many developing countries. Regardless of the reason, consumers who
use herbal medicines should be certain that the products they are purchasing are
healthy and contain exactly what they claim, whether it is a specific herb or a spe-
cific amount of a particular herbal component. In addition, science-based knowl-
edge on dosage, effectiveness, and contraindications must be provided to consumers.
To accomplish this, global standardization of regulations is required to govern ethi-
cal herbal medicine production and marketing. If significant scientific evidence of
advantages is established for a medicinal herb, such law should allow it to be con-
sumed effectively to encourage its use in order to achieve these benefits for the
promotion of public health and well-being (Table 2).
1490 S. N. Ahmed et al.

Table 2 Scientifically reliable evidence-based database

Natural Medicines Comprehensive Database (www.NaturalDatabase.com)
Natural Standard Database (www.NaturalStandard.com)

References

1. Dar RA, Shahnawaz M, Qazi PH (2017) General overview of medicinal plants: a review. J
Phytopharm 6(6):349–351
2. Joharchi MR, Amiri MS (2012) Taxonomic evaluation of misidentification of crude herbal
drugs marketed in Iran. Avicenna J Phytomed 2(2):105
3. Swerdlow J (2000) Modern science embraces medicinal plants. In: Nature’s medicine: plants
that heal. National Geographic Society, Washington, DC, pp 110–157
4. World Health Organization (2019) WHO global report on traditional and complementary med-
icine 2019. World Health Organization
5. World Health Organization (2013) WHO traditional medicine strategy: 2014–2023. World
Health Organization
6. Bent S (2008) Herbal medicine in the United States: review of efficacy, safety, and regulation.
J Gen Intern Med 23(6):854–859
7. World Health Organization. W.H.O. Traditional Medicine 2010, July 21. Available from:
http://www.who.int/topics/traditional_medicine/en/
8. World Health Organization (2005) National policy on traditional medicine and regulation of
herbal medicines: report of a WHO global survey. World Health Organization
9. Conboy L et al (2007) The relationship between social factors and attitudes toward conven-
tional and CAM practitioners. Complement Ther Clin Pract 13(3):146–157
10. Rishton GM (2008) Natural products as a robust source of new drugs and drug leads: past suc-
cesses and present day issues. Am J Cardiol 101(10):S43–S49
11. Schmidt B et al (2008) A natural history of botanical therapeutics. Metabolism 57:S3–S9
12. Xutian S, Zhang J, Louise W (2009) New exploration and understanding of traditional Chinese
medicine. Am J Chin Med 37(03):411–426
13. Li W-F, Jiang J-G, Chen J (2008) Chinese medicine and its modernization demands. Arch Med
Res 39(2):246–251
14. World Health Organization (2009) World health statistics 2009. World Health Organization
15. Canter PH, Ernst E (2004) Herbal supplement use by persons aged over 50 years in Britain.
Drugs Aging 21(9):597–605
16. Qato DM et al (2008) Use of prescription and over-the-counter medications and dietary sup-
plements among older adults in the United States. JAMA 300(24):2867–2878
17. Loya AM, González-Stuart A, Rivera JO (2009) Prevalence of polypharmacy, polyherbacy,
nutritional supplement use and potential product interactions among older adults living on the
United States-Mexico border. Drugs Aging 26(5):423–436
18. Cohen PA, Ernst E (2010) Safety of herbal supplements: a guide for cardiologists. Cardiovasc
Ther 28(4):246–253
19. Zhang J et al (2015) The safety of herbal medicine: from prejudice to evidence. Hindawi
20. De Smet PA (2005) Herbal medicine in Europe—relaxing regulatory standards. N Engl J Med
352(12):1176–1178
21. Tilburt JC, Kaptchuk TJ (2008) Herbal medicine research and global health: an ethical analy-
sis. Bull World Health Organ 86:594–599
22. Farnsworth NR et al (1985) Medicinal plants in therapy. Bull World Health Organ 63(6):965
23. Rates SMK (2001) Plants as source of drugs. Toxicon 39(5):603–613
24. Burke FM (2015) Red yeast rice for the treatment of dyslipidemia. Curr Atheroscler Rep
17(4):22
Herbal Drugs: Safety, Cost-Effectiveness, Regulation, Current Trends, and Future… 1491

25. Ali I et al (2010) Natural products: human friendly anti-cancer medications. Egypt Pharm J
(NRC) 9(2):133–179
26. Lu D et al (2016) Discover natural chemical drugs in modern medicines. Metabolomics (Los
Angel) 6(181):2153-0769.1000181
27. Adhikari B (2001) Socio-economic heterogeneity and income distribution: evidence from
common property resource management. J Forest Livelihoods 1(1):22–24
28. Hamilton A (2013) Plant conservation: an ecosystem approach. Routledge
29. World Health Organization (2012) The regional strategy for traditional medicine in the Western
Pacific (2011–2020)
30. Barnes PM, Bloom B, Nahin RL (2008) Complementary and alternative medicine use among
adults and children; United States, 2007
31. Greg Arnold D. 2010. Study cites cost savings of omega-3 fats and St John’s Wort. http://www.
nowfoods.com/BasicArticles/080683.htm
32. Sher H et al (2014) Economic benefits of high value medicinal plants to Pakistani communi-
ties: an analysis of current practice and potential. J Ethnobiol Ethnomed 10(1):1–16
33. Shneeman B et al (2005) Review of liver-related risks for chaparral. In: Dietary supplements:
a framework for evaluating safety
34. Harkey MR et al (2001) Variability in commercial ginseng products: an analysis of 25 prepara-
tions. Am J Clin Nutr 73(6):1101–1106
35. World Health Organization. W.H.O. Traditional medicine. Available from: http://www.who.
int/topics/traditional_medicine/en/
36. Li JW-H, Vederas JC (2009) Drug discovery and natural products: end of an era or an endless
frontier? Science 325(5937):161–165
37. Sahoo N, Manchikanti P, Dey S (2010) Herbal drugs: standards and regulation. Fitoterapia
81(6):462–471
38. Barnes PM et al (2004) Complementary and alternative medicine use among adults: United
States, 2002. In: Seminars in integrative medicine. Elsevier
39. Bent S, Ko R (2004) Commonly used herbal medicines in the United States: a review. Am J
Med 116(7):478–485
40. Stevinson C, Pittler MH, Ernst E (2000) Garlic for treating hypercholesterolemia: a meta-­
analysis of randomized clinical trials. Ann Intern Med 133(6):420–429
41. Xiong X et al (2015) Garlic for hypertension: a systematic review and meta-analysis of ran-
domized controlled trials. Phytomedicine 22(3):352–361
42. Alder R et al (2003) A systematic review of the effectiveness of garlic as an anti-­hyperlipidemic
agent. J Am Acad Nurse Pract 15(3):120–129
43. Koren MJ (2005) Statin use in a “real-world” clinical setting: aggressive lipid lowering com-
pared with usual care in the aggressive lipid-lowering initiation abates new cardiac events
(ALLIANCE) trial. Am J Med 118(12):16–21
44. Rose KD et al (1990) Spontaneous spinal epidural hematoma with associated platelet dysfunc-
tion from excessive garlic ingestion: a case report. Neurosurgery 26(5):880–882
45. Linde K et al (1998) St John’s wort for depression. Cochrane Database Syst Rev (4)
46. Oken BS, Storzbach DM, Kaye JA (1998) The efficacy of Ginkgo biloba on cognitive function
in Alzheimer disease. Arch Neurol 55(11):1409–1415
47. Solomon PR et al (2002) Ginkgo for memory enhancement: a randomized controlled trial.
JAMA 288(7):835–840
48. Birks J, Grimley E, Van Dongen M (2002) Ginkgo biloba for cognitive impairment and demen-
tia (Cochrane review). Cochrane Libr 4:1–19
49. Bent S et al (2005) Spontaneous bleeding associated with Ginkgo biloba. J Gen Intern Med
20(7):657–661
50. Brevoort P (1998) The blooming US botanical market: a new overview
51. Carpenter C et al (2008) Hypericum and nurses: a comprehensive literature review on the effi-
cacy of St. John’s wort in the treatment of depression. J Holist Nurs 26(3):200–207
1492 S. N. Ahmed et al.

52. Linde K et al (1996) St John’s wort for depression—an overview and meta-analysis of ran-
domised clinical trials. BMJ 313(7052):253–258
53. Butterweck V (2003) Mechanism of action of St John’s wort in depression. CNS Drugs
17(8):539–562
54. Zanoli P (2004) Role of hyperforin in the pharmacological activities of St John’s wort. CNS
Drug Rev 10(3):203–218
55. Shelton RC et al (2001) Effectiveness of St John’s wort in major depression: a randomized
controlled trial. JAMA 285(15):1978–1986
56. Hammerness P et al (2003) St. John’s wort: a systematic review of adverse effects and drug
interactions for the consultation psychiatrist. Psychosomatics 44(4):271–282
57. Lethaby A et al (2007) Phytoestrogens for vasomotor menopausal symptoms. Cochrane
Database Syst Rev (4)
58. Taku K et al (2007) Soy isoflavones lower serum total and LDL cholesterol in humans: a meta-­
analysis of 11 randomized controlled trials. Am J Clin Nutr 85(4):1148–1156
59. Pittler MH, Ernst E (2003) Kava extract versus placebo for treating anxiety. Cochrane Database
Syst Rev (1)
60. Control, C.f.D. and Prevention (2002) Hepatic toxicity possibly associated with kava-­
containing products--United States, Germany, and Switzerland, 1999–2002. MMWR Morb
Mortal Wkly Rep 51(47):1065–1067
61. Rotblatt M, Ziment I (2002) Evidence-based herbal medicine. Hanley & Belfus
62. Ulbricht CE, Basch EM (2005) Natural standard herb & supplement reference: evidence-based
clinical reviews. Mosby
63. Fugh-Berman A (2003) The 5-minute herb and dietary supplement consult. Lippincott
Williams & Wilkins
64. Ernst E, Schmidt K, Wider B (2005) CAM research in Britain: the last 10 years. Complement
Ther Clin Pract 11(1):17–20
65. Ribnicky DM et al (2008) Evaluation of botanicals for improving human health. Am J Clin
Nutr 87(2):472S–475S
66. Nortier JL et al (2000) Urothelial carcinoma associated with the use of a Chinese herb
(Aristolochia fangchi). N Engl J Med 342(23):1686–1692
67. Stickel F, Patsenker E, Schuppan D (2005) Herbal hepatotoxicity. J Hepatol 43(5):901–910
68. World Health Organization (2000) General guidelines for methodologies on research and eval-
uation of traditional medicine. World Health Organization
69. Kantor M (2009) The role of rigorous scientific evaluation in the use and practice of comple-
mentary and alternative medicine. J Am Coll Radiol 6(4):254–262
70. Applequist W (2003) Herbal medicine. Chaos in the Marketplace. Econ Bot 57(1):150–151
71. Brower V (2008) Back to nature: extinction of medicinal plants threatens drug discovery.
Oxford University Press
72. Bleichrodt H, Quiggin J (1999) Life-cycle preferences over consumption and health: when is
cost-effectiveness analysis equivalent to cost–benefit analysis? J Health Econ 18(6):681–708
73. Herman PM, Craig BM, Caspi O (2005) Is complementary and alternative medicine (CAM)
cost-effective? A systematic review. BMC Complement Altern Med 5(1):1–15
74. Van Schaik DJ et al (2004) Patients’ preferences in the treatment of depressive disorder in
primary care. Gen Hosp Psychiatry 26(3):184–189
75. Solomon D et al (2011) Potential of St John’s wort for the treatment of depression: the eco-
nomic perspective. Australian New Zealand J Psychiatry 45(2):123–130
76. Linde K, Berner MM, Kriston L (2008) St John’s wort for major depression. Cochrane
Database Syst Rev (4)
77. Gastpar M, Singer A, Zeller K (2006) Comparative efficacy and safety of a once-daily dosage
of hypericum extract STW3-VI and citalopram in patients with moderate depression: a double-­
blind, randomised, multicentre, placebo-controlled study. Pharmacopsychiatry 39(02):66–75
78. Linde K, St. (2009) John’s wort–an overview. Compl Med Res 16(3):146–155
Herbal Drugs: Safety, Cost-Effectiveness, Regulation, Current Trends, and Future… 1493

79. Sullivan PW et al (2004) A comparison of the direct costs and cost effectiveness of serotonin
reuptake inhibitors and associated adverse drug reactions. CNS Drugs 18(13):911–932
80. Whitten D et al (2006) The effect of St John’s wort extracts on CYP3A: a systematic review of
prospective clinical trials. Br J Clin Pharmacol 62(5):512–526
81. Bensoussan A (2010) Cost effectiveness of complementary medicines
82. Linde K et al (2016) Acupuncture for the prevention of episodic migraine. Cochrane Database
Syst Rev (6)
83. Coeytaux RR, Befus D (2016) Role of acupuncture in the treatment or prevention of
migraine, tension-type headache, or chronic headache disorders. Headache J Head Face Pain
56(7):1238–1240
84. Kim M-R et al (2016) Safety of acupuncture and pharmacopuncture in 80,523 musculoskeletal
disorder patients: a retrospective review of internal safety inspection and electronic medical
records. Medicine 95(18)
85. Zhang J et al (2010) Acupuncture-related adverse events: a systematic review of the Chinese
literature. Bull World Health Organ 88:915–921
86. MacPherson H et al (2017) The persistence of the effects of acupuncture after a course of treat-
ment: a meta-analysis of patients with chronic pain. Pain 158(5):784
87. Kim S-Y et al (2012) A systematic review of cost-effectiveness analyses alongside randomised
controlled trials of acupuncture. Acupunct Med 30(4):273–285
88. Ambrósio E, Bloor K, MacPherson H (2012) Costs and consequences of acupuncture as a
treatment for chronic pain: a systematic review of economic evaluations conducted alongside
randomised controlled trials. Complementary Therapies in Medicine 20(5):364–374
89. Deng Z-Q et al (2012) Health economic evaluation of acupuncture along meridians for treat-
ing migraine in China: results from a randomized controlled trial. BMC Complement Altern
Med 12(1):1–7
90. Guarneri EM, Horrigan BJ, Pechura CM (2010) The efficacy and cost effectiveness of integra-
tive medicine: a review of the medical and corporate literature. Explore 6(5):308–312
91. Giordano J, Engebretson J, Garcia MK (2005) Challenges to complementary and alternative
medical research: focal issues influencing integration into a cancer care model. Integr Cancer
Ther 4(3):210–218
92. Evans S (2008) Changing the knowledge base in Western herbal medicine. Soc Sci Med
67(12):2098–2106
93. Lewis JD, Strom BL (2002) Balancing safety of dietary supplements with the free market. Ann
Intern Med 136(8):616–618
94. Marcus DM, Grollman AP (2002) Botanical medicines—the need for new regulations. Mass
Medical Soc 347(25):2073–2076
95. Jacobs BP et al (2005) An internet-based randomized, placebo-controlled trial of kava and
valerian for anxiety and insomnia. Medicine 84(4):197–207
96. Turner RB et al (2005) An evaluation of Echinacea angustifolia in experimental rhinovirus
infections. N Engl J Med 353(4):341–348
97. Benzie IF, Wachtel-Galor S (2011) Herbal medicine: biomolecular and clinical aspects
Therapeutic Properties of Herbal
Constituents Subjected for Clinical Trials

Esha Vatsa and Mehak Aggarwal

1 Introduction

Nature is source of variety of medicinal products from the very ancient time, with
numerous varieties of drugs useful for the mankind and directly produced from the
plant sources. One particularly strong application of Penicillin’s discovery, together
with the fact that many medications come from microorganisms, etc. In the late
1980s, combinatorial chemistry diverted the focus of efforts of drug discovery
directly from nature to the bench of laboratories, which was further subjected for
clinical trials.
However, natural compounds also face several kinds of challenges in the discov-
ery of new drugs, viz., barriers of technical screening, isolation of new compounds,
and characterization and optimization of the same, which has directly contributed to
rejection in their quest by the pharmacy industries since the early 1990s till now.
Nowadays, several developments in the field of technology exist, which involves
improvement in use of analytical tools, genome studies, and various engineering-­
oriented strategies, and advances in microbial culturing, etc., are opening up new
opportunities in the field of research.
New drug discovery with the use of natural products is a very demanding task in
the field of research for the designing of new compound leads. It provides descrip-
tion of the bioactive compounds originating from natural resources, analysis on the
basis of presence of phytochemicals, and their categorization and investigation on

E. Vatsa (*)
Faculty of Pharmaceutical Sciences, ICFAI University, Baddi,
Solan, Himachal Pradesh, India
M. Aggarwal
Department of Pharmacy, Himachal Institute of Pharmacy,
Paonta Sahib, Himachal Pradesh, India

© The Author(s), under exclusive license to Springer Nature 1495

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_63
1496 E. Vatsa and M. Aggarwal

the basis of therapeutic evidence, because this is the base with which any drug is
subjected for clinical trials.
This chapter provides a brief description about some common natural products
and also reviews clinical trials performed on these natural products. The possible
mechanisms of action for the practical impact of the following natural compounds
are also described.

1.1 Garlic

Garlic (Allium sativum) is an aromatic yearly herbaceous spice and one of the most
seasoned and authenticated herbs that have been used since ancient times. It belongs
to Amaryllidaceae family [1, 2]. Garlic is utilized as a remedy for numerous com-
mon maladies because of hundreds of phytochemicals present in it [2]. Reportedly
it includes sulfur-containing compounds such as ajoenes (E-ajoene, Z-ajoene), thio-
sulfinates (allicin), vinyldithiins (2-vinyl-(4H)-1,3-dithiin; 3-vinyl-(4H)-1,2-­
dithiin), sulfides (diallyl disulfide [DADS], diallyl trisulfide [DATS]), and others,
which account for 82% of the total garlic sulfur content [3].
Garlic has solid antioxidant properties due to its dietary and phenolic com-
pounds. An orderly survey and meta-analysis of 12 randomized controlled trials
(RCTs) uncovered noteworthy increments in serum antioxidant capacity and super-
oxide dismutase levels and diminished serum malondialdehyde levels as a result of
garlic (Allium sativum) supplementation (80–4000 mg/day for 2–24 weeks) [2].
Garlic extract was found to increase the activities of some antioxidant enzymes
(e.g., superoxide dismutase [SOD]) and decrease glutathione peroxidase (GSH-Px)
in rat liver tissues. Notably, several reports indicated that aged garlic extract (AGE)
rich in flavonoids, phenol, and different sulfur compounds, e.g., S-ally-(L)-cysteine
(SAC), shows high radical scavenging activity [4]. Although experimental studies
have shown a clear hypoglycemic effect of garlic, the effect of garlic on human
blood glucose remains controversial. Garlic significantly lowered total cholesterol
and low-density lipoprotein (LDL) cholesterol and moderately increased high-­
density lipoprotein (HDL) cholesterol compared to placebo in diabetic patients [5].
In a double-blind clinical trial (N = 38), a combination of nettle leaves (20% w/w),
onion and garlic (20%), fenugreek seeds (20%), walnut leaves (20%), cinnamon
bark (10%), and berry leaf (10%) powder effectively controlled type 2 diabetes in
human subjects [6]. Aged garlic extract (2400 mg/day orally) reduced volumes of
low attenuation but not total fibrous or fibro fatty plaque in the coronary arteries of
patients with diabetes mellitus (N = 80) compared with placebo [7]. Crushed raw
garlic (100 mg/kg twice daily for 4 weeks) reduced waist circumference, systolic
and diastolic blood pressure, triglycerides, and fasting blood glucose, and increased
serum HDL cholesterol in patients with metabolic syndrome [8]. In an open-label
phase 1 trial, a combination of A. sativum, Aloe vera, Nigella sativa, Plantago psyl-
lium, Silybum marianum, and Trigonella foenum-graecum reduced fasting blood
Therapeutic Properties of Herbal Constituents Subjected for Clinical Trials 1497

glucose, HbA1, LDL, and triglycerides in patients with hyperlipidemia and hyper-
glycemia with advanced type 2 diabetes [9].
Garlic and its preparations are widely known as agents for the prevention and
treatment of cardiovascular diseases. Extensive scientific literature supports the
suggestion that garlic consumption has significant effects on lowering blood pres-
sure, preventing atherosclerosis, reducing cholesterol and triglycerides, inhibiting
platelet aggregation, and increasing fibrinolytic activity [25]. In a randomized con-
trolled trial (N = 104), taking aged garlic extract (2400 mg daily for 1 year) slowed
the development of coronary artery calcification and progression to coronary ath-
erosclerosis, with a significant decrease in systolic blood pressure, in cardiovascular
disease patients [10]; also, aged garlic extract decreased the cardio-ankle vascular
index, a measure of endothelial function and arterial stiffness, over a three-month
period in subjects with type 2 diabetes mellitus (N = 65) [11]. In a randomized,
placebo-controlled study, black garlic, given for 6 months, improved heart function,
as measured by walking distance, left ventricular ejection fraction (LVEF), and
quality of life, in patients with coronary artery disease [12]. The preventive effect of
garlic on atherosclerosis has been attributed to its ability to reduce the lipid content
in the arterial membrane. Allicin, S-allyl cysteine, present in aged garlic extract and
diallyl disulfide, present in garlic oil, are the active compounds responsible for the
anti-atherosclerotic effect [13].
Many in vitro and in vivo studies are done to know the cancer-preventive effects
of garlic preparations and their respective components. It is apparent that garlic
contains a large number of potent bioactive compounds with anticancer properties,
largely derived from allyl sulfide. Different garlic derivatives have been reported to
modulate an increasing number of molecular mechanisms in carcinogenesis, such
as DNA adduct formation, mutagenesis, free radical scavenging, cell proliferation
and differentiation, as well as angiogenesis [14]. A matched case-control study in a
hospital was conducted to explore the association between dietary Allium consump-
tion and breast cancer risk among Iranian women and it shows that high consump-
tion of certain Allium vegetables, particularly garlic and leek, can reduce the risk of
breast cancer [15]. In rodents, garlic and its components have been reported to
inhibit the development of chemically induced tumors in the liver, thus showing
tumor cell growth inhibition and chemopreventive effects [16, 17]. It diminishes the
tumor cell growth in the prostate, bladder, and stomach [18–20].
Extracts of garlic and its related phytochemicals have anti-inflammatory poten-
tial also. One study reported that garlic extracts markedly affected liver inflamma-
tion and damage caused by Eimeria papillata infections [21], and a meta-analysis
of ten trials and one observational study found that garlic intake of 2–2.4 g/day for
four weeks or longer decreased levels of the inflammatory mediators tumor necrosis
factor-alpha (TNF-α), highly sensitive C-reactive protein (CRP), and interleukin
(IL)-6, supporting the use of garlic as an adjuvant treatment for metabolic diseases
[22]. The anti-inflammatory activity of garlic is caused by the inhibition of the emi-
gration of neutrophilic granulocytes in the epithelia. Aged black garlic (ABG) has
shown potent antioxidant activities and these activities may be responsible for its
anti-inflammatory activity [23, 24].
1498 E. Vatsa and M. Aggarwal

Aloe vera
1.2 

Aloe barbadensis Miller commonly known as Aloe vera is the most popular natural
product in the prevention and ailment of various health problems and maladies. It
belongs to the family Asphodelaceae (Liliaceae). It is native to subtropical regions
and tropical climates. There are more than 400 species of Aloe belonging to family
Liliaceae. The main characteristic of the A. vera plant is its high water content,
which ranges between 99 and 99.5% [26]. The remaining 0.5–1.0% solid material
contains over 75 different potentially active compounds, including water-soluble
and fat-soluble vitamins, minerals, enzymes, simple/complex polysaccharides, phe-
nolic compounds, and organic acids [27]. Distinctive mechanisms have been pro-
posed for the wound-healing effects of Aloe vera. Glucomannan, a polysaccharide
rich in mannose, and gibberellin, a growth hormone, interact with growth factor
receptors on fibroblasts, stimulating their activity and proliferation, which in turn
significantly increases collagen synthesis after topical and oral Aloe vera [28]. A
study revealed that Aloe vera-based and chitosan-based hydrogel gels exhibited
wound-healing effects and high biocompatibility with seeded mesenchymal stem
cells used for healing grade II burns in rats [50]. In a randomized controlled clinical
trial, a polyherbal cathartic capsule of Shou Hui Tong Bian, containing Polygonum
multiflorum and Aloe vera, improved arthroscopy, replacement efficacy, recovery
time, time to postoperative exhaustion of borborygmus, and abdominal distention in
postoperative patients (N = 98) after joint replacement arthroscopy compared to
conventional treatment [29]. In a meta-analysis (23 studies, N = 4023), the authors
conclude that Aloe vera may have beneficial effects in reducing pain scores and the
severity of mucocutaneous conditions, such as psoriasis, burns, and wound healing,
compared to placebo [30]. Abbasi reported that in a double-blind RCT of 28 patients,
use of a topical skin ointment containing Aloe vera, honey, and peppermint as a
dressing for skin graft donor sites was superior to petroleum jelly in reducing wound
erythema and improved treatment satisfaction [31]. In a clinical study, to verify the
effectiveness of A. vera gel compared to silver sulfadiazine 1% cream as a burn
dressing for the treatment of superficial and partial burns, burn wound healing was
significantly earlier in patients treated with A. vera than patients treated with 1%
silver sulfadiazine [32]. Polysaccharides isolated from A. vera induce matrix metal-
lopeptidase (MMP)-3 and metallopeptidase inhibitor-2 gene expression during rat
skin wound repair, which directly helps regulate the wound-healing activity of
A. vera gel in rats [33]. Aloe vera enhanced the efficacy of topical human vascular
endothelial cell transplantation on excised full-thickness skin wounds in diabetic
mice in improving angiogenesis in part by improving glycemic control. Oral admin-
istration also promoted wound healing through inhibition of MMP-2 and MMP-9
expression [45].
Clinical studies have suggested that A. vera gel may act as a safe anti-­
hyperglycemic and anti-hypercholesterolemic agent for patients with type 2 diabe-
tes without any significant effects on other normal blood lipid levels or liver or
kidney function [34]. A polyherbal formulation, including Aloe vera, was tested in
Therapeutic Properties of Herbal Constituents Subjected for Clinical Trials 1499

an open-label phase I trial in 30 patients who had hyperlipidemia and hyperglyce-

mia [35]. The formulation was found to be safe and effective in lowering blood
glucose and serum lipid levels in patients with type 2 diabetes [9]. In a randomized
controlled trial, A. vera gel complex reduced body weight, body fat mass, and insu-
lin resistance in obese prediabetics and untreated early diabetic patients [36]. Jain
et al. found that A. vera gel has significant antidiabetic and cardioprotective activity
because it significantly reduces oxidative stress in streptozocin-induced diabetic
rats and improves antioxidant status [37]. A. vera also showed improvement in the
function of isolated rat pancreatic islets in which it increased islet cell survival, their
mitochondrial activity, and insulin levels while reducing the production of reactive
oxygen species [38].
Aloin, a natural compound anthraquinone and the main component of Aloe vera,
has been documented for its momentous potential therapeutic options in cancer,
showing chemotherapeutic effects against 1,2-dimethylhydrazine induced by pre-­
neoplastic lesions within the colon of Wistar rats [39]. In recent studies, a polysac-
charide moiety has been shown to inhibit the binding of benzopyrene to primary rat
hepatocytes, thereby preventing the formation of potentially carcinogenic
benzopyrene-­DNA adducts. An induction of glutathione S-transferase and an inhi-
bition of the tumor-promoting effects of phorbol myristic acetate were also reported,
suggesting a possible benefit of using Aloe gel in cancer chemoprevention [40, 41].
A. vera leaf extricates have been advanced for digestion and are utilized within
the treatment of peptic ulcer for cytoprotective activity whereby A. vera gel
expresses antibacterial properties against both susceptible and resistant Helicobacter
pylori strains and acts as a novel effective natural agent for combination with anti-
biotics for the treatment of H. pylori gastric infection [42]. One study illustrated that
newly designed Aloe- and myrrh-based gels demonstrated to be effective in the topi-
cal application of minor recurrent aphthous stomatitis and was prevalent in dimin-
ishing ulcer size, erythema, and exudation; myrrh resulted in greater pain reduction
in a randomized, double-blind, vehicle-controlled study [43]. Local application of
Aloe vera/Plantago major gel in addition to routine care was evaluated in patients
with diabetic foot ulcer. Patients in the experimental group demonstrated signifi-
cantly reduced ulcer surface and total ulcer score, but not ulcer depth [44]. Acetyl
polysaccharides from Aloe vera leaf gel showed antioxidant and anti-inflammatory
effects against ulcerative colitis in rat serum and colon tissue by attenuating colon
lesions and increasing short-chain fatty acids likely via upregulation of Zonula
occludens-1 (ZO-1), occludin, NAD(P)H Quinone Dehydrogenase 1 (NQO1), and
nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signal-
ing pathways [47].
Several studies have been conducted to test the antioxidant property of A. vera.
Oral administration of Aloe vera leaf gel showed anti-inflammatory and antimicro-
bial effects against parasitic cryptosporidiosis in immunocompetent and immuno-
suppressed mice with dexamethasone by reducing the levels of interferon-gamma
(IFN-γ), IL-4, IL-6, and IL-17, and a reduction in Cryptosporidium DNA or oocysts
in stool samples compared to nitazoxanide [46]. Oral administration of a proprie-
tary Aloe vera gel formula normalized pro-inflammatory and anti-inflammatory
1500 E. Vatsa and M. Aggarwal

cytokines and increased relative abundance of Bacteroides, Butyricimonas,

Ruminococcus, and Mucispirillum in diabetic mice induced by a high-fat diet [48].
Applying Aloe vera gel to experimentally induced penile fractures in rats without
closing the sutures reduced the degree of inflammation in the area [49]. Compared
with control, a new wound dressing composed of alginate and Aloe vera gel and
cross-linked with zinc ions exhibited anti-inflammatory activity, stimulated angio-
genesis in the proliferative phase, increased type I collagen fibers, and decreased
type III collagen fibers in rats compared to control [51]. Aloe vera gel improved
lipid peroxidation and oxidative stress, reduced creatine phosphokinase MB (CK-­
MB) enzymatic activities and glutathione concentration, increased antioxidant
activities, reduced inflammatory cell infiltration, and prevented left ventricular
fibrosis in rats with isoprenaline-induced myocardial infarction [52].
In rats exposed to cartap and malathion, pretreatment with aqueous extract of
Aloe vera demonstrated marked hepatoprotective effects by reducing the oxidative
stress induced by pesticides [53]. Pretreatment with 30 mg/kg Aloe vera attenuated
liver injury with ischemia and reperfusion in a small rat study as evidenced by
decreased levels of malondialdehyde (MDA) in liver tissue, higher levels of SOD,
catalase (CAT), and GSH-Px, and decreased pathological tissue change and immune
activity score in the inducible nitric oxide synthase (iNOS) system compared to the
control group [54]. Jung et al. found that in a rat model of thioacetamide-induced
hepatic retinopathy, aloin suppressed liver damage and swelling of Müller cells
through normalization of Kir4.1 and aquaporin-4 channels. The results indicate that
aloin may be useful in protecting retinal damage associated with liver failure [55].

1.3 Smilax

Smilax ornata, genus of flowers inside the family Smilacaceae (Liliaceae), com-
monly called as sarsaparilla, includes approximately 300 species of woody or her-
baceous vines, variously called catbriers and greenbriers. It is mainly found in
temperate, tropical, and subtropical zones worldwide. The roots of that flora had
been used for hundreds of years in Asia and the Americas as a tonic, diuretic, and
sudorific. The rhizome, roots, stems, and leaves of sarsaparilla are utilized in tradi-
tional medicine [58]. In recent years, interest in the study of the genus Smilax has
increased. The study of the genus Smilax has drawn more attention recently.
Reviews exist about the antioxidant properties described as a 2,2-diphenyl-1-picryl-
hydrazyl (DPPH•) radical scavenger. The phenolic chemicals stilbenes, flavones,
flavanones, flavonols, smilasides, smiglasides, and helionosides are responsible for
this affiliation [66].
Smilax glabra showed protective effects against lead-induced renal oxidative
stress, inflammation, and apoptosis in weaning rats and human embryonic kidney-
­293 (HEK-293) cells. Hence, it is a natural antioxidant and anti-inflammatory agent
for the treatment of lead-induced nephrotoxicity [56]. Astilbin at 5.3 mg/kg reduced
joint damage in the hind paw of complete Freund’s adjuvant (CFA)-induced arthritic
Therapeutic Properties of Herbal Constituents Subjected for Clinical Trials 1501

rats. Astilbin exhibited remarkable inhibitory effects on TNF-α, IL-1β, and IL-6
mRNA expressions and these effects showed inhibition of cytokine production and
inflammatory response in test mice close to anti-rheumatic drug, leflunomide [61].
The methanol extract of Smilax 400 mg/kg claimed to produce anti-inflammatory
activity in the bradykinin-prompted and prostaglandin-induced edema models [65].
Kwon et al. suggested a novel molecular mechanism for water extract of Gleditsia
sinensis thorns (WESGR)-mediated anti-prostate cancer effects at particular steps
such as with migration and adhesion to collagen, and it could provide the possibility
of therapeutic utilization of WESGR against prostate cancer progression [57]. She
et al. observed that the supernatant of water-soluble extract from Smilax glabra
Roxb. (SGR) should enhance adhesion, inhibit migration and invasion of HepG2,
M.D. Anderson - Metastatic Breast 231 (MDA-MB-231), and T24 cells in vitro, as
well as diminish metastasis of MDA-MB-231 cells in vivo. Outcomes of F-actin
and vinculin dual staining showed the improved focal adhesion in SW-dealt-with
cells. Microarray evaluation indicated a repression of transforming growth factor-
beta (TGF-β1) signaling by means of SW remedy, which became verified by real-
time reverse transcription-polymerase chain reaction (RT-PCR) of TGF-β1-associated
genes and immunoblotting of transforming growth factor beta receptor I (TGFBR1)
protein [60]. Song et al. observed the growth inhibitory action of Smilax by treat-
ment of its water-soluble extract 3.5 μg/μL on multiple cancer cells in vitro and in
vivo, and redox-dependent persistent activation of extracellular signal-regulated
kinase 1 (ERK1/2) [62]. Another study revealed that SGR inhibited growth of
human breast cancer mobile line Michigan Cancer Foundation-7 (MCF7), colon
carcinoma mobile line human colorectal adenocarcinoma cell line (HT-29), and
gastric cancer cellular line human gastric cancer cell line (BGC-823) in a dose-
structured way [63].
Huang et al. obtained total flavonoids (which include four marker compounds) of
S. glabra, and the full content became as much as 55.6%. The consequences recom-
mended that total flavonoids of S. glabra (TFSG) has huge effect on reducing uric
acid in hyperuricemic mice by means of inhibiting the xanthine oxidase (XOD)
sports and upregulating the expression of renal organic anion transporter 1 (OAT1)
and organic cation transporter novel family member 2 (OCTN2) and their mRNA in
kidney tissue of hyperuricemic mice [59].
A study revealed that SGR extract inhibited the HepG2 and Hep3B cell growth
by causing cell-cycle arrest at either S phase or S/G2 transition and induced apop-
tosis, evidenced by a DNA fragmentation assay [64]. In vitro assay demonstrated
the antioxidant potential of Smilax. The Smilax triggered a big reduction of the
formalin-evoked flinches in rats, an effect reversed through opioid antagonist nalox-
one [66]. Rafatullah et al. studied the effect of ethanol extract of sarsaparilla 100 mg/
kg/day for 90 days on carbon tetrachloride (CCl4)-induced hepatocellular damage
in rats [67].
Nithyamala et al. investigated analgesic interest of root powder of Smilax by
means of hot plate technique and acetic acid prompted writhing technique in albino
mice. The oral administration of root substantially expanded the response time in a
dose-based manner in warm plate technique. The basis powder also induced
1502 E. Vatsa and M. Aggarwal

inhibitory impact on writhing triggered by using acetic acid [68]. Methanolic extract
of Smilax roots examined for its immunomodulatory interest by means of nitro blue
tetrazolium chloride (NBT) reduction test and anti-arthritic test by in vitro protein
denaturation and in vivo complete Freund’s adjuvant (CFA) precipitated arthritis.
Extract at 200 mg/kg and 400 mg/kg showed statistically significant inhibition
(p < 0.05) of the edema formation in CFA model [69].
Leaf and fruit extracts of Smilax were shown to exhibit antimicrobial and anti-
oxidant activities, which may be attributed to the presence of secondary metabolites
such as alkaloids, flavonoids, tannins, triterpenoids, and sterols [73]. In vitro anti-
oxidant activities of leaf and stem extracts of Smilax were performed, which revealed
the reducing power of leaf and stem extracts of Smilax [70]. Another study revealed
marked reducing activity of methanolic extract of stem when compared to aqueous
extract of stem [71]. Muthu et al. investigated the evaluation of in vivo antioxidant
activity of ethanolic extract of root on aluminum-chloride-induced apoptosis sup-
pressing antioxidative stress in Wistar rats and found that Smilax can be used as an
antioxidant that is beneficial in preventing the progress of various oxidative
stresses [72].

1.4 Meadow Saffron

Meadow saffron, Colchicum autumnale, belonging to family Liliaceae is a flower-

ing species. It is native to mountains in wet grasslands – Turkey and Balkans [81].
It is also known as autumn crocus [74]. Meadow saffron is claimed to have many
therapeutic uses such as anti-inflammatory, antitumoral, possible inhibition of viral
replication, inhibitory effect on coagulation activation, and antifibrotic. It is useful
in treatment of gout and Behçet’s disease. The therapeutic activity of this plant is
attributed to the presence of alkaloids or, in other words, colchicinoids such as col-
chicine and demecolcine [75–78]. Colchicine’s benefits in the treatment of cirrho-
sis, psoriasis, and amyloidosis have been made evident by researchers [79].
Bioactive phenolic compounds such as lignans, flavonoids, phenolic acids, and tan-
nins are also distributed in meadow saffron [80].
A randomized, multicenter, controlled, open-label parallel group (2:1 ratio),
phase III clinical trial demonstrated that early administration of colchicine has clini-
cal effectiveness in reducing the complications of severe acute respiratory syndrome
coronavirus-2 (SARS-CoV-2) infection in a population highly susceptible, and may
mitigate the health crisis and prevent the collapse of the health system in the succes-
sive waves of the coronavirus pandemic [83, 84].
Colchicine has been known as a treatment for gout for several millennia.
Aggravation in gout is intervened by a combination of neutrophil and macrophage
activation, leukocyte adhesion molecules, inflammasome actuation, and IL-1β pro-
duction. It is reported that all of these pathways are influenced by colchicine [85].
Mikkelsen et al. prepared a crystalline alkaloid, desacetyl-methyl-colchicine, from
bulbs of C. autumnale for the clinical trial in certain hematologic disorders and
Therapeutic Properties of Herbal Constituents Subjected for Clinical Trials 1503

acute gout in a 51-year-old patient with history of recurrent acute episodes of arthri-
tis [82]. In a randomized placebo-controlled trial evaluating the efficacy and toxicity
of colchicine in acute gout, patients were treated with an initial dose of 1 mg fol-
lowed by sequential doses of 0.5 mg every two hours until either significant symp-
tomatic relief or intolerance. Patients treated with colchicine were observed to
experience pain relief within 48 hours as compared to placebo [86]. The AGREE—
Acute Gout Flare Receiving Colchicine Evaluation—trial was the first randomized,
placebo-controlled trial to compare low- and high-dose colchicine and it was
observed that there is a comparable response rate in the low-dose group versus high-­
dose group [76]. Also, high-dose group showed more side effects like diarrhea and
nausea [76]. A placebo-controlled randomized trial evaluating colchicine for flare
prophylaxis in patients with chronic gout initiating allopurinol found that subjects
treated with colchicine had fewer and less severe flares [87].
In a randomized controlled clinical trial, two groups were divided: the patients in
the intervention and control groups were treated with Rhazes tablet + Ibuprofen
pearl (400 mg) PRN (pro re nata) and placebo tablet + Ibuprofen pearl (400 mg)
PRN, respectively. It was concluded that Rhazes tablet can be used as a pharmaco-
logical intervention to reduce pain in patients with lower back pain [83].
Since 1974, colchicine is the treatment of choice for Familial Mediterranean
Fever (FMF). It is evident through a randomized controlled trial in which patients
were treated with colchicine and fewer attacks were observed [88]. A randomized
cohort study showed favorable efficacy of colchicine in treatment of secondary
amyloidosis [89]. Colchicine was found more effective than melphalan and predni-
sone in increasing the survival rate of patients [89].
Colchicine was reported to be used in Behçet’s syndrome; 7–12 patients were
reported to show improvement in symptoms when treated with colchicine 0.5 mg
twice a day [90]. A double-blind controlled trial wherein 116 sufferers with Behçet’s
syndrome were randomized to get hold of either colchicine or placebo for 2 years
showed enormous reductions in the occurrence of genital ulcers, erythema nodo-
sum, and arthritis in woman patients, in addition to a decrease in the incidence of
arthritic signs in men [91, 92].
All parts of the plant, especially the bulbs, are highly toxic. If taken in abundance
it can be highly toxic and can be fatal. Cramping, vomiting, diarrhea, increased
blood pressure, and respiratory failure are the poison symptoms [93]. Formerly,
poisoning occurred when people used homemade preparations. Due to this, many
deaths have been reported [94].

1.5 Asparagus

Asparagus officinalis is a medicinal plant belonging to family Liliaceae. It is native

to temperate Himalayas and includes about 300 species around the world. It is ben-
eficial in treating leprosy, dysuria, epilepsy, night blindness, jaundice, disorders of
the kidney and liver, as well as being anticancer, antidiabetic, anti-inflammatory,
diuretic, increase fertility, lessen menstrual cramps, and laxative [95, 96]. The main
1504 E. Vatsa and M. Aggarwal

bioactive constituents of asparagus are a group of steroidal saponins. This plant also
contains vitamins A, B1, B2, C, and E, as well as Mg, P, Ca, Fe, and folic acid. Other
primary chemical constituents of asparagus are essential oils, asparagine, arginine,
tyrosine, flavonoids (kaempferol, quercetin, and rutin), resin, and tannin [97, 98].
Saponins have a wide range of biological activities, including those of antioxidants,
immunostimulants, antihepatotoxic, antibacterial, beneficial for diabetic retinopa-
thy, anticarcinogenic, antimicrobials, that inhibit molds, antidiarrheal, and antiul-
cerogenic agents [97, 99].
The hypoglycemic effects of asparagus extracts were evaluated by streptozoto-
cin (STZ)-induced diabetic rats, which had the same efficacy at a dose of 500 mg/
kg as the antidiabetic drug glibenclamide (5 mg/kg rat body weight) [100].
Asparagus juice (CAJ) from asparagus old stem was used in type I diabetic rat
model, and results showed that CAJ reduced the blood glucose level along with
lipid level in diabetic rats by decreasing the content of serum glucose, total choles-
terol, and MDA, and improved level of serum insulin [101]. Hypoglycemic activity
of asparagus old stem was also reported by Zhao (2010). He reported the presence
of flavonoids, polyphenols, saponins, and polysaccharides, which showed remark-
able hypoglycemic effects at 1.43, 5.58, 1.82, and 4.24 mg/g dry weight, respec-
tively [102]. The extract of A. officinalis in the diabetic rats showed potent
antioxidant activity and improvement in β-cell function both at 250 mg/kg and
500 mg/kg. The insulin–glucose ratio was reported to increase at both doses [103].
A. officinalis also shows antitumorigenic and antimetastatic effects. In a trans-
genic mouse model of high-grade serous ovarian cancer, asparagus was reported to
decrease the cellular viability and caused cell-cycle G1 phase arrest. It inhibited
tumor growth and increased phosphorylation of adenosine monophosphate-acti-
vated protein kinase (AMPK) in the ovarian tumor tissues [104]. The inedible bot-
tom part of asparagus was utilized as a supplement and the saponins from old stem
of asparagus suppressed the cell viability of breast, colon, and pancreatic cancers.
The extract inhibited the tumor cell motility [105]. The popular vegetable dish of
asparagus, i.e., the shoots of white asparagus, was reported to possess antioxidant,
anti-inflammatory, and antitumor activities. The Wistar rats with induced colon car-
cinogenesis were treated with asparagus for seven weeks and the rats exhibited a
50% reduction in the amount of pre-neoplastic lesions and promoted normal cellu-
lar homeostasis [106]. Xiang et al. also reported the anticancer effects of asparagus.
Deproteinized asparagus polysaccharide exhibited widespread anticancer activity in
opposition to hepatocellular carcinoma cells and sensitized the tumoricidal conse-
quences of mitomycin, indicating that asparagus is a chemosensitizer for liver can-
cer therapy [107]. Mechanistic studies revealed the inhibition of migration, invasion,
and angiogenesis of cancer cells [108].
Asparagus showed antioxidant, anti-inflammatory, and antihepatotoxic proper-
ties in the 40 Wistar rats that were given 400 mg/kg of the extract. Asparagus extract
increased the total antioxidative capability and improved function of liver and kid-
ney tissues. According to the researchers, it has a potential protective action against
oxidative stress, and liver and kidney damage [109]. Also, asparagus seed extract
additionally accelerated general antioxidant reputation at a dose of 500 mg/kg in
Therapeutic Properties of Herbal Constituents Subjected for Clinical Trials 1505

streptozotocin-induced diabetic rats [100]. Ku et al. (2017) reported the high bind-
ing capacity of soluble polyphenols of asparagus to human serum albumin and it
also showed the protective effects against bisphenol-A-induced toxicity [110].
Asparagus has potential against bile acids, which are the important excretory
pathways for cholesterol metabolism. Asparagus effect was studied on cholesterol
as it reduced the simulating gastrointestinal digestion and measured binding capac-
ity of the food and bile acid [98]. Another study indicated the cholesterol-lowering
activity of asparagus in hyperlipidemia mouse model; polysaccharides present on
asparagus lowered the lipoprotein cholesterol [111, 112]. Asparagus also showed
the positive results in lowering the blood pressure from human clinical trials and
therefore can be used as an antihypertensive agent [113].
There are various other therapeutic as well as physiological effects of asparagus.
The instant powder of asparagus increased the sleep time in insomnia patients, and
also shortened the sleep time through the food test that was performed on 60 volun-
teers [114]. Jager et al. (2005) proved the antiepileptic activity of asparagus instant
powder [115] and Miura et al. (2016) discovered the stress-relieving property [116].

1.6 Lily of the Valley

Lily of the valley is a common name of Convallaria majalis. This plant belongs to
Liliaceae family. The plant contains numerous steroidal glycosides, cardiac glyco-
sides, flavonoids, chelidonic acid, choline, and azetidine-2-carbonic acid. In rhi-
zomes and roots of the plant, steroidal saponins are predominant [117–120]. From
ancient times, lily of the valley is used for the treatment of various cardiovascular
ailments including congestive heart failure, cardiomyopathy, irregular heartbeat,
urinary tract infections (UTIs), kidney stones, epilepsy, edema, and various eye
infections. It is also used in the treatment of leprosy [121]. An ointment made from
the roots is used in the treatment of burns and to prevent scar tissue. However, owing
of the plant’s potential toxicity, it should never be used without first consulting a
professional [131].
Cardiac glycosides, also known as cardenolides, are a type of steroid that has
long been known to have a positive ionotropic impact on the heart. All cardiac gly-
cosides increase intracellular sodium by affecting ion transport across cardiac mus-
cle cell membranes via effects on Na(+)/K(+)-ATPase enzymes. As a result,
intracellular calcium levels rise, improving heart contractility. Atrial flutter and
fibrillation are also converted to steady sinus rhythm with cardiac glycosides
[123, 124].
Convallaria majalis has been demonstrated in animal trials to raise K+ in the
atria and atrial stroke volume. Despite the fact that convallatoxin is a vasoconstric-
tor, the sum of all cardiac glycosides and other ingredients may have a greater vaso-
tonic effect, improving circulation and coronary flow [125, 126].
A study was done for the determination of whether convallatoxin present in the
plant as a cardiac glycoside induces the expression of tissue factor and leads to
1506 E. Vatsa and M. Aggarwal

hypercoagulable state. The findings indicate that the convallatoxin induces the tis-
sue factor expression in endothelial cells and also induces hypercoagulable
state [122].
Convallaria majalis is a homoeopathic medicine that has a beneficial effect on
the heart and also acts as a diuretic. Lateef et al. (2010) evaluated the effect of lily
of the valley on kidney function by investigating the effect of plant extract on serum
uric acid and creatinine on rabbits for 14 days. After the completion, animals were
sacrificed to collect blood sample. It was concluded that the alcoholic extract at
10 mg/kg acts as a significant hypouricemic agent [127].
Another study indicated the effect of convallamaroside, i.e., the steroidal saponin
present in Convallaria majalis. Isolated extract was injected to the mice and evalu-
ated by intradermal test. Convallamaroside medication to mice reduced the number
of new vasculatures produced by sarcoma mouse cells (p = 0.001) [128].
For a single ingredient, convallatoxol, the dose that killed 50% of a sample popu-
lation (LD50) in cats was 0.14 mg/kg given intraperitoneally [130]. This herb’s
human dose is 0.6 g powdered herb or 5–10 drops tincture, split daily. A case report
detailed a dog that died abruptly after consuming lily of the valley in its enclosed
yard [129].
The essential oil of lily of the valley is used in aromatherapy to treat headaches,
depression, and melancholy. Memory loss, apoplexy, and epilepsy can all be treated
with it. It is utilized to help brain cells grow stronger and to boost cognitive func-
tions. UTI is treated with a tincture made from lily of the valley flowers, which
clears blockages from the urethra. Because of its purgative and laxative properties,
this herb is commonly used as a substitute for aloes. This, in turn, keeps the diges-
tive system running smoothly.
The lily of the valley also has the following advantages:
• Kidney stones are broken down.
• Prevents the body from retaining water.
• Pain associated with joint tissues such as gout and rheumatism are reduced.
• Conjunctivitis is treated with this medication.
• Paralysis, shock, and speech loss are all treated using essential oils.
• Aids in the treatment of leprosy and edema.
• Poisoning and drunkenness are treated by producing vomiting.

2 Conclusions

Natural products act as very potential products for new drug discovery and have the
ability to generate new drug leads that will be further subjected for clinical trials. In
the present study, several advances in the field of technology of natural products
were discussed and how they are subjected for clinical trials were described in
detail. In this chapter, several conclusive points were also discussed on the basis of
analyzed data and therapeutic-evidence-based studies, which provide a very strong
Therapeutic Properties of Herbal Constituents Subjected for Clinical Trials 1507

basis for the conduction of natural-products-based-drug clinical trials to continue

for making major contributions toward change in human health and maintenance of
longevity without any serious adverse effects. There is also a requirement for further
studies to provide more powerful evidence of the adverse effects concerned with the
drugs discussed above. In addition, the safety of consumption of aforementioned
compounds in definite conditions and diseases should also be noted down.
Furthermore, after considering all the evidence-based facts and conditions, it seems
that natural products can be utilized to provide various health-promoting properties.

References

1. Lindstedt S, Wlosinska M, Nilsson AC, Hlebowicz J, Fakhro M, Sheikh R (2021) Successful

improved peripheral tissue perfusion was seen in patients with atherosclerosis after 12 months
of treatment with aged garlic extract. Int Wound J 18(5):681–691. https://doi.org/10.1111/
iwj.13570
2. Askari M, Mozaffari H, Mofrad MD, Jafari A, Surkan PJ, Amini MR, Azadbakht L (2021)
Effects of garlic supplementation on oxidative stress and antioxidative capacity biomark-
ers: a systematic review and meta-analysis of randomized controlled trials. Nat Library Med
35(6):3032–3045. https://doi.org/10.1002/ptr.7021
3. Al-Snafi A (2013) Pharmacological effects of Allium species grown in Iraq. An overview. Int
J Pharmacol Health Care Res 1:132–147
4. Jang HJ, Lee HJ, Yoon DK, Kim JH, Ji DS, Lee CH (2018) Antioxidant and antimicrobial
activities of fresh garlic and aged garlic by-products extracted with different solvents. Food
Sci Biotechnol 27(1):219–225. https://doi.org/10.1007/s10068-­017-­0246-­4
5. Ashraf R, Amir K, Shaikh AR, Ahmed T (2005) Effects of garlic on dyslipidemia in patients
with type 2 diabetes mellitus. J Ayub Med Coll, Abbottabad 17(3):60–64
6. Parham M, Begherzadeh M, Asghari M, Akbari H, Hosseini Z, Rafiee M, Vafaeimanesh J
(2020) Evaluating the effect of a heb on the control of blood glucose and insulin- resistance
in patients with advanced type 2 diabetes (a double-blind clinical trial). Caspian J Intern Med
11(1):12–20. https://doi.org/10.22088/cjim.11.1.12
7. Shaikh K, Kinniger A, Cherukuri L, Birudaraju D, Nakanishi R, Almeida S, Jayawardena E,
Shekar C, Flores F, Hamal S, Sheikh MS, Johanis A, Cu B, Budoff MJ (2020) Aged garlic
extract reduces low attenuation plaque in coronary arteries of patients with diabetes: a ran-
domized, double-blind, placebo-controlled study. Nat Library Med 19(2):1457–1461. https://
doi.org/10.3892/etm.2019.8371
8. Choudhary PR, Jani RD, Sharma MS (2018) Effect of raw crushed garlic (Allium sativum)
on components of metabolic syndrome. J Diet Suppl 15(4):499–506. https://doi.org/10.108
0/19390211.2017.1358233
9. Zarvandi M, Rakhshandeh H, Abazari M, Nick RS, Ghorbani A (2017) Safety and efficacy
of a polyherbal formulation for the management of dyslipidemia and hyperglycemia in
patients with advanced-stage of type-2 diabetes. Biomed Pharmacother 89:69–75. https://
doi.org/10.1016/j.biopha.2017.02.016
10. Wlosinka M, Nilson AC, Hlebowicz J, Hauggaard A, Kjellin M, Fakhro M, Lindstedt S
(2020) The effect of aged garlic extract on the atherosclerotic process-a randomized double-­
blind placebo-controlled trial. BMC Compl Med Ther 20(1):132. https://doi.org/10.1186/
s12906-­020-­02932-­5
11. Hamal S, Cherukuri L, Birudaraju D, Matsumoto S, Kinninger A, Chaganti BT, Flores F,
Shaikh K, Roy SK, Budoff MJ (2020) Short-term impact of aged garlic extracts on endothe-
1508 E. Vatsa and M. Aggarwal

lial function in diabetes: a randomized, double-blind, placebo-controlled trial. Exp Ther Med
19(2):1485–1489. https://doi.org/10.3892/etm.2019.8377
12. Liu J, Zhang G, Cong X, Wen C (2018) Black garlic improves heart function in patients with
coronary heart disease by improving circulating antioxidant levels. Front Physiol 9:1435.
https://doi.org/10.3389/fphys.2018.01435
13. Gebhardt R, Beck H (1996) Differential inhibitory effects of garlic-derived organosul-
fur compounds on cholesterol biosynthesis in primary rat hepatocyte cultures. Lipids
31(12):1269–1276. https://doi.org/10.1007/bf02587912
14. Capasso A (2013) Antioxidant action and therapeutic efficacy of Allium sativum L. Molecules
18(1):690–700
15. Pourzand A, Tajaddini A, Pirouzpanah S, Jafarabadi MA, Samadi N, Ostadrahimi AR, Sanaat
Z (2016) Associations between dietary Allium vegetables and risk of breast cancer: a hospital-­
based matched case-control study. J Breast Cancer 19(3):292–300. https://doi.org/10.4048/
jbc.2016.19.3.292
16. Kweon S, Park KA, Choi H (2003) Chemopreventive effect of garlic powder diet in diethyl-
nitrosamine induced rat hepatocarcinogenesis. Life Sci 73(19):2515–2526
17. Knowles LM, Milner JA (2003) Diallyl disulfide induces ERK phosphorylation and alsters
gene expression profiles in human colon tumor cells. J Nutr 133(9):2901–2906. https://doi.
org/10.1093/jn/133.9.2901
18. Hsing AW, Chokkalingam AP, Gao YT, Madigan MP, Deng J, Gridley G, Fraumeni JF (2002)
Allium vegetables and risk of prostate cancer: a population-based study. J Natl Cancer Inst
94(21):1648–1651. https://doi.org/10.1093/jnci/94.21.1648
19. Lau BH, Woolley JL, Marsh CL, Barker GR, Koobs DH, Torrey RR (1986) Superiority of
intralesional immunotherapy with Corynebacterium parvum and Allium sativum in control of
murine transitional cell carcinoma. J Urol 136(3):701–705
20. Wattenberg LW, Sparnis VL, Barany G (1989) Inhibition of N-nitrosodiethylamine carcino-
genesis in mice by naturally occurring organosulfur compounds and monoterpenes. Cancer
Res 49(10):2689–2692
21. Ahmad TA, Sayed BA, Sayed LH (2016) Development of immunization trials against Eimeria
spp. Trials Vaccinol 5:38–47. https://doi.org/10.1016/j.trivac.2016.02.001
22. Koushki M, Dashatan NA, Pourfarjam Y, Doustimotlagh AH (2021) Effect of garlic intake on
inflammatory mediaors: a systematic review and meta-analysis of randomized controlled tri-
als. Postgrad Med J 97(1145):156–163. https://doi.org/10.1136/postgradmedj-­2019-­137267
23. Hobauer R, Frass M, Gmeiner B, Kaye AD, Frost EA (2000) Garli extract (allium sati-
vum) reduces migration of neutrophils through endothelial cell monolayers. Middle East J
Anaesthesiol 15(6):649–658
24. Gu X, Wu H, Fu P (2013) Allicin attenuates inflammation and suppresses HLA-B27 pro-
tein expression in ankylosing spondylitis mice. Biomed Res Int:171573. https://doi.
org/10.1155/2013/171573
25. Chan JY, Yuen AC, Chan RY, Chan SW (2013) A review of the cardiovascular benefits and
antioxidant properties of allicin. Phytoher Res 27(5):637–646
26. Hamman JH (2008) Composition and application of Aloe vera leaf gel. Molecules
13:1599–1616. https://doi.org/10.3390/molecules13081599
27. Maharjan HR, Nampoothiri PL (2015) Evaluation of biological properties and clinical effec-
tiveness of Aloe vera: a systematic review. J Tradit Complement Med 5(1):21–26. https://doi.
org/10.1016/j.jtcme.2014.10.006
28. Chithra P, Sjithlal GB, Chandrakasen G (1998) Influence of Aloe vera on collagen character-
istics in healing dermal wounds in rats. Mol Cell Biochem 181(1–2):71–76. https://doi.org/1
0.1023/a:1006813510959
29. Huang S, Xie Y, Huang Z, Zhang G, Chen G, Yuan J, Wang J, Xiangyang L, Zhou Y (2021)
Effect of observation of Shou Hui Tong Bian Capsule (Polygonum Multiflorum and Aloe-­
Based Herbal Capsule for Cathartic Effect) in rapid rehabilitation of joint surgery. Evi Based
Compl Alternat Med:2268464. https://doi.org/10.1155/2021/2268464
Therapeutic Properties of Herbal Constituents Subjected for Clinical Trials 1509

30. Metin ZG, Helvaci A, Eren MG (2021) Effects of Aloe vera in adults with mucocutaneous
problems: a systematic review and meta-analysis. J Adv Nurs 77(3):1105–1126. https://doi.
org/10.1111/jan.14653
31. Abbasi MS, Rahmati J, Ehsani AH, Takzare A, Partoazar A, Takzaree N (2020) Efficacy of
a natural topical skin ointment for managing Split-thickness skin graft donor sites: a pilot
double-blind randomized controlled trial. Adv Skin Wound Care 33(7):1–5. https://doi.
org/10.1097/01.asw.0000666916.00983.64
32. Shahzad MN, Ahmed N (2013) Effectiveness of Aloe vera gel compared with 1% silver
sulphadiazine cream as burn wound dressing in second degree burns. J Pak Med Assoc
63:225–230
33. Tabandeh MR, Oryan A, Mohammadalipour A (2014) Polysaccharides of Aloe vera induve
MMP-3 and TIMP-2 gene expression during the skin wound repair of rat. Int J Biol Macromol
65:424–430
34. Huseini HF, Kianbakht S, Hajiaghaee R, Dabaghian FH (2012) Anti-hyperglycemiac and
anti-hypercholesterolemic effects of Aloe vera leaf gel in hyperlipidemic type 2 diabetic
patients: a randomized double-blind placebo-controlled clinical trial. Planta Med 78:311–316
35. Cholesterol Treatment Trialists’ (CTT) Collaborators, Kearney PM, Blackwell L, Collins R,
Keech A, Simes J, Peto R, Armitage J, Baigent C (2008) Efficacy of cholesterol-lowering
therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis.
Lancet. 371:117–125. https://doi.org/10.1016/S0140-6736(08)60104-X
36. Devaraj S, Jialal R, Jialal I, Rockwood R (2008) A pilot randomized placebo-controlled trial
of 2 Aloe vera supplements in patients with pre-diabetes/metabolic syndrome. Planta Med
p. 74–77
37. Jain N, Vijayaraghavan R, Pant SC, Lomash V, Ali m. (2010) Aloe vera gel alleviates cardio-
toxicity in streptozocin-induced diabetes in rats. J Pharm Pharmacol 62:115–123
38. Rahimifard M, Nigjeh MN, Mahroui N (2013) Improvement in the function of isolated rat
pancreatic islets through reduction of oxidative stress using traditional Iranian medicine. Cell
J:147–163
39. Hamiza OO, Rehman MU, Khan R (2014) Chemopreventive effects of aloin against
1,2-dimethylhydrazine-induced preneoplastic lesions in the colon of Wistar rats. Hum Exp
Toxicol 33:148–163. https://doi.org/10.1177/0960327113493307
40. Kim HS, Lee BM (1997) Inhibiting of benzo[a]pyrene-DNA adduct formation by Aloe bar-
badensis miller. Carcinogenesis 18(4):771–776
41. Kim hs, Kacew S, Lee BM. (1999) In vitro chemopreventive effects of plant polysaccharides
(Aloe barbadensis miller, Lentinus edodes, Ganoderma lucidum and Coriolus versicolor).
Carcinogenesis 20(8):1637–1640
42. Babaee N, Zabihi E, Mohseni S, Moghadamnia AA (2012) Evaluation of the therapeutic
effects of Aloe vera gel on minor recurrent aphthous stomatitis. Dent Res J 9:381–385
43. Mansour G, Ouda S, Shaker A, Abdallah HM (2014) Clinical efficacy of new Aloe vera-­
myrrh-­based oral mucoadhesive gels in the management of minor recurrent aphthous stoma-
titis: a randomized, double-blind, vehicle-controlled study. J Oral Pathol Med 43:405–409
44. Najafian Y, Khorasani ZM, Njafi MN, Hamedi SS, Mhjour M, Feyzabadi Z (2019)
Efficacy of Aloe vera/Plantago major gel in diabetic foot ulcer: a randomized double-­
blind clinical trial. Curr Drug Discov Technol 16(2):223–231. https://doi.org/10.217
4/1570163815666180115093007
45. Kaewsrisung S, Sukpat S, Issarasena N, Patumraj S, Somboonwong J (2021) The effects
of oral Aloe vera on the efficacy of transported human endothelial cells and the expression
of matrix metalloproteinases in diabetic wound healing. Heliyon 7(12):e08533. https://doi.
org/10.1016/j.heliyon.2021.e08533
46. Farid A, Tawfik A, Elsioufy B, Safwat G (2021) In vitro and in vivo anti-cryptosporidium and
anti-inflammatory effects of Aloe vera gel in dexamethasone immunosuppressed mice. Int J
Parasitol Drugs Drug Resis:156–167. https://doi.org/10.1016/j.ijpddr.2021.09.002
1510 E. Vatsa and M. Aggarwal

47. Liu C, Hua H, Zhu H, Cheng Y, Guo Y, Yao W, Qian H (2021) Aloe polysaccharides amelio-
rate acute colitis in mice via Nrf2/HO-1 signaling pathway and short-chain fatty acids metab-
olism. Int J Biol Macromol 185:804–812. https://doi.org/10.1016/j.ijbiomac.2021.07.007
48. An J, Lee H, Lee S, Song Y, Kim J, Park IH, Kong H, Kim K (2021) Modulation of pro-­
inflammatory and anti-inflammatory cytokines in the fat by an aloe gel-based formula,
QDMC, is correlated with altered gut microbiota. Immune Netw 21(2):e15. https://doi.
org/10.4110/in.2021.21.e15
49. Akgul KT, Dogantekin E, Ozer E, Kotanoglu M, Gokkurt Y, Hucumenoglu S (2021)
Histopathological effects of aloe vera on wound healing: an experimental study. Turk J Med
Sci 51(4):2193–2197. https://doi.org/10.3906/sag-­2102-­224
50. Sharifi E, Chehelgerdi M, Kelishadrokhi AF, Nafchi FY, Dehkordi KA (2021) Composition
of therapeutic effects of encapsulated Mesenchymal stem cells in Aloe vera gel and Chitosan-­
based gel in healing of grade-II burn injuries. Regen Ther 18:30–37. https://doi.org/10.1016/j.
reth.2021.02.007
51. Koga AY, Felix JC, Silvestre RGM, Lipinski LC, Carletto B, Kawahara FA, Pereira AV
(2020) Evaluation of wound healing effect of alginate film containing Aloe vera gel and
cross-linked with zinc chloride. Acta Cir Bras 35(5):e202000507. https://doi.org/10.1590/
s0102-­865020200050000007
52. Sumi FA, Sikder B, Rahman MM, Lubna SR, Ula A, Hossain MH, Jahan IA, Alam MA,
Subhan N (2019) Phenolic content analysis of Aloe vera gel and evaluation of the effect of
aloe gel supplementation on oxidative stress and fibrosis in isoprenaline-administered cardiac
damage in rats. Prev Nutr Food Sci 24(3):254–264. https://doi.org/10.3746/pnf.2019.24.3.254
53. Gupta VK, Siddiqi NJ, Ojha AK, Sharma B (2019) Hepatoprotective effect of Aloe
vera against cartap- and malathion-induced toxicity in Wistar rats. J Cell Physiol
234(10):18329–18343. https://doi.org/10.1002/jcp.28466
54. Sehitoglu MH, Karaboga I, Kiraz A, Kiraz HA (2018) The hepatoprotective effect of Aloe
vera on ischemia-reperfusion injury in rats. North Clin Istanb 6(3):203–209. https://doi.
org/10.14744/nci.2018.82957
55. Jung E, Kim J (2018) Aloin inhibits muller cells swelling in a rat model of thioacetamide-­
induced hepatic retinopathy. Molecules 23(11):2806. https://doi.org/10.3390/
molecules23112806
56. Shi Y, Tian C, Yu X, Fang Y, Zhao X, Xia D (2020) Protective effects of Smilax glabra Roxb.
Against Lead-induced renal oxidative stress, inflammation and apoptosis in weaning rats and
HEK-293 cells. Front Pharmacol. https://doi.org/10.3389/fphar.2020.556248
57. Kwon OY, Ryu S, Choi JK, Lee SH (2020) Smilax glabra Roxb. Inhibits collagen induced
adhesion and migration of PC3 and LNCaP prostate cancer cells through the inhibition of Beta
1 integrin expression. Molecules 25(13):3006. https://doi.org/10.3390/molecules25133006
58. Saleem SA, Lakshmi B, Kumar JNS (2021) Review article on traditional out look of Smilax
zeylanica. Res J Pharmacol Pharmacodyn. https://doi.org/10.52711/2321-­5836.2021.00014
59. Huang L, Deng J, Chen G, Zhou M, Liang J, Yan B, Shu J, Liang Y, Huang H (2019) The
anti-hyperuricemic effect of four astilbin stereoisomers in S.glabra on hyperuricemic mice. J
Ethnopharmacol. https://doi.org/10.1016/j.jep.2019.03.004
60. She T, Zhao C, Feng J, Wang L, Qu L, Fang K, Cai S, Shou C (2015) Sarsaparilla (Smilax
glabra Rhizome) extract inhibits migration and invasion of cancer cells by suppressing TGF-­
β1 pathway. PLoS One 10(3):e0118287. https://doi.org/10.1371/journal.pone.0118287
61. Dong L, Zhu J, Du H, Nong H, He X, Chen X (2017) Astilbin from Smilax glabra Roxb.
Attenuates inflammatory responses in complete freund’s adjuvant-induced arthritis rats. Evid
Based Complement Alternat Med:8246420. https://doi.org/10.1155/2017/8246420
62. Song G, She T, Feng J, Lian S, Li R, Zhao C, Luo J, Dawuti R, Cai S, Qu L, Shou C (2017)
Sarsaparilla (Smilax glabra rhizome) extract activates redox-dependent ATM/ATR path-
way to inhibit cancer cell growth by Sphase arrest, apoptosis and autophagy. Nutr Cancer
69(8):1281–1289. https://doi.org/10.1080/01635581.2017.1362447
Therapeutic Properties of Herbal Constituents Subjected for Clinical Trials 1511

63. Gao Y, Su Y, Qu L, Xu S, Meng L, Cai SQ, Shou C (2011) Mitochondrial apoptosis contrib-
utes to the anti-cancer effect of Smilax glabra Roxb. Toxicol Lett 207(2):112–120. https://doi.
org/10.1016/j.toxlet.2011.08.024
64. Sa F, Gao JL, Fung KP, Zheng Y, Lee SMY, Wang YT (2008) Anti-proliferative and pro-­
apoptotic effect of Smilax glabra Roxb. Extract on hepatoma cell lines. Chem Biol Interact
171(1):1–14. https://doi.org/10.1016/j.cbi.2007.08.012
65. Khan A, Singh PD, Reese PB, Howden J, Golding M, Thomas TT (2020) Investigation of
the preliminary mechanism of action for the acute anti-inflammatory activity of the metha-
nol extract of Smilax ornate Lem. J Ethanopharmacol 248:112360. https://doi.org/10.1016/j.
jep.2019.112360
66. Hirota BCK, Paula CDS, Oliveira VBD, Cunha JMD, Schreiber AK, Ocampos FMM, Barison
A, Miguel OG, Miguel MD (2016) Phyochemical and antinociceptive, anti-inflammatory and
anti-oxidant studies of Smilax larvata(Smilacaceae). Evi Based Comp Alt Med. https://doi.
org/10.1155/2016/9894610
67. Rafatullah S, Mossa JS, Ageel AM, Yahya MAA (2008) Hepatoprotective and
safety evaluation studies on sarsaparilla. Pharm Biol 29(4):296–301. https://doi.
org/10.3109/13880209109082901
68. Nithyamala I, Ayyasamy S, Pitchiahkumar M, Kumar A, Velapandian V (2013) Evaluation
of analgesic and antiinflammatory activity of siddha drug Karuvilanchiverchoornam (root
powder of Smilax zeylanica Linn) in rodents. IOSR J Pharm Biol Sci 6(1):6–11
69. Babu PV, Ashwini T, Krishna MV, Raju MG (2017) Immunomodulatory and antiarthritic
activities of smilax zeylanica. Int J Phytomed 9(1). https://doi.org/10.5138/09750185.1963
70. Uddin MN, Ahmed T, Pathan S, Al-Amin MM, Rana MS (2015) Antioxidant and cytotoxic
activity of stems of Smilax zeylanica in vitro. J Basic Clin Physiol Pharmacol 26(5):453–463
71. Thirugnanasampandan R, Mutharaiah VN, Bai NV (2009) In vitro propagation and free radi-
cal studies of Smilax zeylanica vent. Afr J Biotechnol 8(3):395–400
72. Muthu AK, Senthil BS, Kalaichelvan VK (2018) In vivo antioxidant activity of ethanolic
extract from root of smilax on aluminium chloride induced oxidative stress in wistar rats. J
Drug Delivery Therapeutics 8(6). https://doi.org/10.22270/jddt.v8i6-­s.2078
73. Shree VSD, Arbin A, Noorain GKS, Sahana BK, Kekuda TRP (2018) Preliminary phy-
tochemical analysis, antimicrobial and antioxidant activity of Smilax. J Drug Delivery
Therapeutics. 8(4). https://doi.org/10.22270/jddt.v8i4.1779
74. Toplan GG, Gurer C, Mat A (2016) Importance of colchicum species in modern therapy and
its significance in Turkey. J Fac Pharm 46:129–144
75. Alali FQ, Tawaha K, El-Elimat T (2007) Determination of (−)-demecolcine and (−)-colchi-
cine content in selected Jordanian Colchicum species. Pharmazie 62(10):739–742
76. Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW (2010) High versus
low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first
multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison
colchicine study. Arthritis Rheum 62(4):1060–1068. https://doi.org/10.1002/art.27327
77. Sakane T, Takeno M (2000) Novel approaches to Behcet’s disease. Expert Opin Investig
Drugs 9(9):1993–2005
78. Cifuentes M, Schilling B, Ravindra R, Winter J, Janik ME (2006) Synthesis and biologi-
cal evaluation of B-ring modified colchicine isocolchicineanalogs. Bioorg Med Chem Lett
16(10):2761–2764. https://doi.org/10.1016/j.bmcl.2006.02.010
79. Cocco G, Chu DC, Pandolfi S (2010) Colchicine in clinical medicine. A guide for internists.
Eur J Intern Med 21(6):503–508. https://doi.org/10.1016/j.ejim.2010.09.010
80. Ondra P, Valka I, Sutlupinar N, Simanek V (1995) Chromatographic determination of con-
stituents of the genus colchicum (Liliaceae). J Chromatogr A 704:351–356
81. Akram M, Alam O, Khan U, Naveed A, Asif HM (2012) Colchicum autumnale:a review.
Acad J 6:8. https://doi.org/10.5897/JMPR.9000370
82. Mikkelsen WM, Salin RW, Duff IF (1956) Alopecia totalis after desacetylmethylcolchicine
therapy of acute gout-report of a case. N Engl J Med 255:769–770
1512 E. Vatsa and M. Aggarwal

83. Estebanez EB, Alconero LL, Fernandez BJ, Marguello MG, Caro JCL, Vallejo JD, Sampedro
MF, Cacho PM, Espiga CR, Saiz MMG (2021) The effectiveness of early colchicine
administration in patients over 60 years old with high risk of developing severe pulmonary
complications associated with coronavirus pneumonia SARS-CoV-2 (COVID-19): study
protocol for an investigator-driven randomized controlled clinical trial in primary health
care—COLCHICOVID study. Trials 22:590–592
84. Malek VG, Parvari S, Jafari F, Rouhani Y, Rahimi R, Abbassian A (2019) Efficacy of a tra-
ditional herbal formula based on Colchicum autumnale L. (Rhazes tablet) in low back pain:
a randomized controlled clinical trial. Int J Ayurvedic Med 10(1). https://doi.org/10.47552/
ijam.v10i1.1178
85. Slobodnick A, Shah B, Pillinger MH, Krasnokutsky S (2015) Colchicine: old and new. Am J
Med 128(5):461–470. https://doi.org/10.1016/j.amjmed.2014.12.010
86. Ahem MJ, Reid C, Gordon TP, McCredie M, Brooks PM, Jones M (1987) Does colchicine
work? The results of the first controlled study in acute gout. Aust NZ J Med 17(3):301–304.
https://doi.org/10.1111/j.1445-­5994.1987.tb01232.x
87. Borstad GC, Bryant LR, Abel MP, Scroggie DA, Harris MD, Alloway JA (2004) Colchicine
for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J
Rheumatol 31(12):2429–2432
88. Dinarello CA, Wolff SM, Goldfinger SE, Dale DC, Alling DW (1974) Colchicine therapy for
familial Mediterranean fever. A double-blind trial. N Engl J Med 291(18):934–937. https://
doi.org/10.1056/nejm197410312911804
89. Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM (1997) A
trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone
and melphalan, prednisone and colchicine. N Engl J Med 336(17):1202–1207. https://doi.
org/10.1056/nejm199704243361702
90. Matsumura N, Mizushima Y (1975) Leucocyte movement and colchicine treatment in
Behcet’s disease. Lancet 2(7939):813. https://doi.org/10.1016/s0140-­6736(75)80031-­6
91. Komlodi-Pasztor E, Sackett DL, Fojo AT (2012) Inhibitors targeting mitosis: tales of how
great drugs against a promosing target were brought down by a flawed rationale. Clin Cancer
Res 18(1):51–63. https://doi.org/10.1158/1078-­0432.ccr-­11-­0999
92. Yurdakul S, Mat C, Tuzun Y, Ozyazgen Y, Hamuryudan V, Uysal O, Senocak M, Yazici H (2001)
A double-blind trial of colchicine in Behcet’s syndrome. Arthritis Rheum 44(11):2686–2692.
https://doi.org/10.1002/1529-­0131(200111)44:11<2686::aid-­art448>3.0.co;2-­h
93. Poutaraud A, Girardin P (2002) Alkaloids in Meadow Saffron, Colchicum autumnalel. J
Herbs Spices Med Plants 9(2):63–79. https://doi.org/10.1300/J044v09n01_08
94. Dasgeb B, Kornreich D, McGuinn K, Okon L, Brownell I, Sackett DL (2019) Colchicine: an
ancient drug with novel applications. Br J Dermatol 178(2):350–356. https://doi.org/10.1111/
bjd.15896
95. Gaur RD (1999) The flora of the district Garhwal North West Himalaya. TransMedia,
Srinagar, Garhwal, p 170
96. Kirtikar KR, Basu BD (1984) Indian medicinal plants. New Connaught Place, Dehradun
India, p 2499
97. Mader TL, Brumm MC (1987) Effect of feeding Sarsaponin in cattle and swine diets. J Anim
Sci 65(1):9–15. https://doi.org/10.2527/jas1987.6519
98. Kahlon TS, Chapman MH, Smith GE (2007) In vitro binding of bile acids by okra, beets,
asparagus, eggplant, turnips, green beans, carrots, and cauliflower. Food Chem 103:676–680.
https://doi.org/10.1016/j.foodchem.2006.07.056
99. Wang NF, Zhang XJ, Wang SW, Guo QB, Li ZJ, Liu HH (2020) Structural characterisation
and immunomodulatory activity of polysaccharides from white asparagus skin. Carbohydr
Polym 227:115314. https://doi.org/10.1016/j.carbpol.2019.115314
100. Wang S, Zhu F (2016) Antidiabetic dietary materials and animal models. Food Res Int
85:315–331. https://doi.org/10.1016/j.foodres.2016.04.028
Therapeutic Properties of Herbal Constituents Subjected for Clinical Trials 1513

101. Zhao JJ, Zhao HJ, Zhao D, Wang JQ, Qu WJ (2012) Hypoglycemic activity of clarified
asparagus juice in streptozotocin induced diabetic rats. Nat Product Res Develop 24:460–464
102. Zhao HJ (2010) Study on functional components and biological activities of old stem extracts
from Asparagus officinalis L. East China Normal University, China
103. Hafizur RM, Kabir N, Chishti S (2012) Asparagus officinalis extract controls blood glucose
by improving insulin secretionβ-cell function in streptozotocin-induced type 2 diabetic rats.
Br J Nutr 108(9):1586–1595
104. Xu G, Kong W, Fang Z, Fan Y, Yin Y, Sullivan SA, Tran AQ, Clark LH, Sun W, Hao T,
Zhao L, Zhou C, Jump VL (2021) Asparagus officinalis exhibits anti-tumorigenic and anti-­
metastatic effects in ovarian cancer. Front Oncol. https://doi.org/10.3389/fonc.2021.688461
105. Wang J, Zhao J, Liu Y, Pang X (2013) Saponins extracted from by-product of Asparagus offi-
cinalis L. suppress tumour cell migration and invasion through targeting rho GTPase signal-
ling pathway. J Sci Food Agric 93(6):1492–1498. https://doi.org/10.1002/jsfa.5922
106. Bousserouel S, Grandois JL, Gosse F, Werner D, Barth SW, Marchioni E, Marescaux J, Raul
F (2013) Methanolic extract of white asparagus shoots activates TRAIL apoptotic death path-
way in human cancer cells and inhibits colon carcinogenesis in a preclinical model. Int J
Oncol 43(2):394–404. https://doi.org/10.3892/ijo.2013.1976
107. Xiang J, Xiang Y, Lin S, Xin D, Liu X, Weng L, Chen T, Zhang M (2014) Anticamcer effects
of deproteinized asparagus polysaccharide on hepatocellular carcinoma in vitro and in vivo.
Tumour Biol 35(4):3517–3524. https://doi.org/10.1007/s13277-­013-­1464-­x
108. Cheng W, Cheng Z, Xing D, Zhang M (2019) Asparagus polysaccharide suppresses the
migration, invasion, and angiogenesis of hepatocellular carcinoma cells partly by targeting
the HIF-1 alpha/VEGF signalling pathway in vitro. Evid Based Complement Alternat Med.
https://doi.org/10.1155/2019/3769879
109. Poormoosavi SM, Najafzadehvarzi H, Behmanesh MA, Amirgholami R (2018) Protective
effects of Asparagus officinalis extract against Bisphenol A- induced toxicity in Wistar rats.
Toxiol Rep 5:427–433. https://doi.org/10.1016/j.toxrep.2018.02.010
110. Ku YG, Bae JH, Ayala M, Vearasilp S, Namiesnik J, Pasko P (2017) Efficient three-­
dimensional fluorescence measurements for characterization of binding properties in some
plants. Sensors Actuators B Chem 248:777–778. https://doi.org/10.1016/j.snb.2017.04.050
111. Middelbeek RJW, Chambers MA, Tantiwong P, Treebak JT, An D, Hirshman MF, Musi N,
Goodyear LJ (2013) Insulin stimulation regulates AS160 and TBC1D1 phosphorylation sites
in human skeletal muscle. Nutrition Diabetes 3:6–9. https://doi.org/10.1038/nutd.2013.13
112. Li J ( 2011) Study on extraction, purification, and lipid lower in related activity of old stem
polysaccharide from Asparagus officinalis L. East China Normal University, China
113. Chrubasik S, Droste C, Dragano N, Glimm E, Black A (2006) Effectiveness and tolerability
of the herbal mixture asparagus P on blood pressure in treatment-requiring antihypertensives.
Phytomedicine 13:740–742. https://doi.org/10.1016/j.phymed.2006.01.009
114. Huang YX (2017) Effect of instant asparagus powder on sleeping improvement. J Anhui
Agric Sci 45(11):80–82
115. Jager AK, Mohoto SP, Heerden FRV, Viljoen AM (2005) Activity of a traditional south
African epilepsy remedy in the GABA-benzodiazepine receptor assay. J Ethnopharmacol
96:603–606. https://doi.org/10.1016/j.jep.2004.10.005
116. Miura T, Yasueda A, Sakaue M, Maeda K, Hayashi N, Ohno S (2016) SUN-LB271: a double-­
blind randomized controlled trial regarding the safety and efficacy of enzyme-treated aspara-
gus extract intake in healthy human subjects. Clin Nutr 35:S145. https://doi.org/10.1016/
S0261-­5614(16)30627-­6
117. Chwedorzewska KJ, Galera H, Kosiński I (2008) Plantations of Convallaria majalis L. as a
threat to the natural stands of the species: genetic variability of the cultivated plants and natu-
ral populations. Biol Conserv 141:2619–2624. https://doi.org/10.1016/j.biocon.2008.07.025
118. Erdogan OI, Gokbulut A (2017) Adonis sp., Convallaria sp., Strophanthus sp., Thevetia sp.,
and Leonurus sp.—cardiotonic plants with known traditional use and a few preclinical and
clinical studies. Curr Pharm Des 23:1051–1059
1514 E. Vatsa and M. Aggarwal

119. Higano T, Kuroda M, Jitsuno M, Mimaki Y (2007) Polyhydroxylated steroidal saponins from
the rhizomes of Convallaria majalis. Nat Prod Commun 2:531–536. https://doi.org/10.117
7/1934578X0700200504
120. Higano T, Kuroda M, Sakagami H, Mimaki Y (2007) Convallasaponin A, a new
5β-spirostanoltriglycoside from the rhizomes of Convallaria majalis. Chem Pharm Bull
55:337–339. https://doi.org/10.1248/cpb.55.337
121. Stansbury J, Saunders P, Winston D, Zampieron ER (2012) The use of convallaria and
Crataegus in the treatment of cardiac dysfunction. J Restro Med 1(1):107–111. https://doi.
org/10.14200/jrm.2012.1.1012
122. Morimoto M, Tatsumi K, Yuui K, Terazawa I, Kudo R, Kasuda S (2021) Convallotoxin, the
primary cardiac glycoside in lily of the valley induces tissue factor expression in endothelial
cells. Vet Med Sci 7(6):2440–2444. https://doi.org/10.1002/vms3.614
123. Khundmiri SJ (2014) Advances in understanding the role of cardiac glycosides in control of
sodium transport in renal tubules. J Endocrinol 222(1):R11–R24
124. Jelliffe RW (2014) The role of digitalis pharmacokinetics in converting atrial fibrillation and
flutter to regular sinus rhythm. Clin Pharmacokinet 53(5):397–407
125. Choi DH, Kang DG, Cui X (2006) The positive inotropic effect of the aqueous extract of
convallaria keiskeiin beating rabbit artia. Life Sci 79(12):1178–1185
126. Lehmann HD (1984) Effect of plant glycosides on resistance and capacitance vessels.
Arzneimittelforschung 34(4):423–429
127. Lateef T, Rukash H, Bibi F, Azmi M, Qureshi S (2010) Effect of convallaria majalison kid-
ney function. J Dow Univ Health Sci 4(3):94–97
128. Nartowska J, Sommer E, Pastewka K, Sommer S, Rozewska ES (2004) Anti-angiogenic
activity of convallamaroside, the steroidal saponin isolated from the rhizomes and roots of
Convallaria majalis L. Med Chem 61(4):279–282
129. Moxley RA, Schneider NR (1989) Apparent toxicosis associated with lily-of-the-valley
(Convallaria majalis) ingestion in a dog. J Am Vet Med Assoc 195:485–487
130. Fitzgerald KT (2010) Lily toxicity in the cat. Top Companion Anim Med 25(4):213–217.
https://doi.org/10.1053/j.tcam.2010.09.006
131. Launert E (1981) Covers plants in Europe. A drawing of each plant, quite a bit of interesting
information. Edible and Medicinal Plants. Hamlyn
Plant-Derived Immunomodulators
Targeting COVID-19 (SARS-CoV-2):
Preclinical Evaluation and Clinical Trials

Robin, Pardeep Kaur, Jagdeep Kaur, Kamaljit Kaur, and Sunidhi Miglani

1 Introduction

Coronavirus disease-2019 (COVID-19) is a contagious and serious disease that has

originated and proliferated via a new pathogenic viral strain named severe acute
respiratory syndrome coronavirus-2 (SARS-CoV-2). The pathogenic strain has
caused extensive morbidity and mortality globally with very high rise in cases dur-
ing winter [1]. The pathogenic virus has been rapidly evolving since 2019 with high
transmissible rate. COVID-19 symptoms are comparable to the flu, such as a sore
throat, fever, cough, and exhaustion [2]. These symptoms are sometimes accompa-
nied by diarrhea and vomiting. COVID-19 has now been shown to cause cell-­
mediated immune deficiency, coagulative stimulation, cardiovascular impairment,
hepatic damage, kidney dysfunction, and multi-organ trauma [3]. Despite the scien-
tific community’s best efforts to understand the pandemic since its initial appear-
ance in December 2019, clinically proven preventive and therapeutic measures are

Robin
Agilent Technologies India Pvt. Ltd., Amritsar, Punjab, India
Regional Water Testing Laboratory, Department of Water Supply and Sanitation,
Government of Punjab, Amritsar, Punjab, India
P. Kaur (*)
Post Graduate Department of Botany, Khalsa College, Amritsar, Punjab, India
J. Kaur
Department of Botanical and Environmental Sciences, Guru Nanak Dev University,
Amritsar, Punjab, India
K. Kaur
Post Graduate Department of Biotechnology, Khalsa College, Amritsar, Punjab, India
S. Miglani
Department of Botany, Sikh National College, Banga, Punjab, India

© The Author(s), under exclusive license to Springer Nature 1515

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_64
1516 Robin et al.

needed. Several antiviral medications are being explored, including the nucleotide
analog remdesivir, although none has been explicitly allowed for COVID-19.
Treatment regime that addresses the immunopathology of infection has been a main
focus, in addition to the research and techniques in vaccines that directly target the
viral strain or inhibit entrance [4]. It has been shown that virus-specific T-cells are
accountable for the cell-mediated immunity, and B-lymphocytes are responsible for
the humoral immunity. Both play crucial roles in the adaptive immune response of
body in all pathogenic viral infections, including COVID-19. Neutrophils, interleu-
kin (IL)-6, and C-reactive protein are increased, but the overall number of lympho-
cytes decreases. T-lymphocyte activation contributes to the aggravation of
inflammatory reactions, while B-lymphocytes aid in the production of virus-specific
neutralizing antibodies. Immunomodulators act as vital stimulants to body for natu-
ral defense against pathogenic diseases including SARS-CoV-2. Immunopotentiating
herbal medicines are considered complementary to contemporary medicine; as a
result, natural immunomodulatory agents have been shown to be safe, nontoxic, and
effective substitutes. Phytoimmunomodulators boost the body’s natural defenses
against pathogens like viruses, allowing the immune system to maintain homeosta-
sis and feasibly preventing viral infections. Allergies, various cancers, inflammatory
bowel disease (IBD), autoimmune disorders, pathogenic viral infections, and a vari-
ety of other chronic illnesses are linked to immune system malfunctions or imbal-
ances. The use of plant-derived immunomodulators to control the present episode of
coronavirus infection may serve as a precedent, demonstrating that conventional
health care may contribute to the effective treatment of patients. The crucial har-
nessing of all knowledge systems accessible around the globe, on the other hand,
would be the desired course of action. The immunomodulatory properties of plants
have been extensively studied, and some of the most well-known are Ocimum sanc-
tum, Tinospora cordifolia, Withania somnifera, Glycyrrhiza glabra, and Emblica
officinalis, indicating that they have both preclinical and clinical potential against
SARS-CoV-2. The chapter addresses the beneficial effects of these phytoimmuno-
modulators in order to uncover further pieces of evidence in the fight against
COVID-19 via preclinical and clinical experiments.

2 Phytoimmunomodulators

Phytoimmunomodulators stimulate the components of adaptive or innate immunity

of body to maintain homeostasis. This section focuses on plant-based immuno-
modulatory substances that are currently being tested in clinical studies. Numerous
key plant-based lead compounds have also been thoroughly addressed in terms of
their potential utility as immunomodulatory drugs, mechanisms of action, and
plant origin.
Plant-Derived Immunomodulators Targeting COVID-19 (SARS-CoV-2): Preclinical… 1517

Ocimum sanctum
2.1 

Ocimum sanctum L. or Ocimum tenuiflorum L. belongs to the Lamiaceae family.

The leaves of O. sanctum are considered functional foods with anti-inflammatory,
antidiabetic, antipyretic, antiasthmatic, antiemetic, antibacterial, anticoagulant,
anticataract, analgesic, hepatoprotective, hypotensive, radioprotective, and immu-
nomodulatory properties [5]. The leaves contain eugenol, carvacrol, methyl euge-
nol, cirsilineol, cirsimaritin, caryophyllene, orientin, vicenin, isothymusin, apigenin,
ursolic acid, rosmarinic acid, luteolin, luteolin-7-O-glucuronide, apigenin-7-O-­
glucuronide, molludistin, α-elemene, bornyl acetate, neral, camphene, myrtenal,
campesterol, α-pinene, β-pinene, stigmasterol, and β-sitosterol [5]. Molecular simu-
lation study implemented by Varshney et al. [6] reflected the prospective role of
O. sanctum extract against novel coronavirus due to its potential in inhibiting repli-
cation supported by its immunomodulatory and angiotensin-converting enzyme-2
(ACE-2) blocking characteristics. The authors found tulsinol A, B, C, D, E, F, and
G, and dihydroeugenol B as attractive SARS coronavirus main protease (Mpro) and
papain-like protease inhibitors. Kumar [7] tested the adhering efficacy of natural
phytochemicals from O. sanctum against three main targets of SARS-CoV-2: 6VSB
(surface glycoprotein accountable for the binding of viral strain), 6 M71 (RNA-­
dependent RNA polymerase accountable for replication of viral strain), and 6Y84
(key protease accountable for replication of viral strain). The scientist concluded
that methyl eugenol, ursolic acid, and oleanolic acid had prominent binding effi-
ciency higher than that of COVID-19 standard medications lopinavir/ritonavir and
remdesivir against the three tested key SARS-CoV-2 targets. Mohapatra et al. [8]
also undertook in silico assessment of the O. sanctum phytochemicals extracted by
ethanol as SARS-CoV-2 Mpro inhibitors and suggested effectiveness of chlorogenic
acid and luteolin-7-O-glucuronide. These compounds irreversibly inhibited the
pathogenic viral enzyme by binding covalently to the main protease catalytic resi-
due Cys145. Another molecular docking and molecular dynamic simulation com-
putational study was conducted by Shree and co-workers [9] to identify stable
natural inhibitors from O. sanctum against novel coronavirus main protease. The
researchers concluded that three bioactive constituents from this tropical medicinal
plant, viz., vicenin, ursolic acid, and isorientin 4′-O-glucoside-2″-O-p-­
hydroxybenzoate, exhibited substantial binding affinity, steady molecular dynam-
ics (MD) simulations, absorption, distribution, metabolism, excretion and toxicity
(ADMET) predictions, and the drug-like characteristics. All of these compounds
obstructed the viral translation into the functional polyproteins necessary for pro-
moting replication of viral strain following disruption of the physiological functions
of host, thus hindering activity of SARS-CoV-2 Mpro. Main protease accounts for
the viral growth via proteolytic cleavage, and acts as a transit point for the entrance
of virus and its replication. Hence, targeting the main protease by the natural bioac-
tive inhibitors would serve as potential checkpoint for the viral entrance, its replica-
tion, and propagation.
1518 Robin et al.

Balkrishna et al. [10] reported the utilization of the humanized zebrafish model,
which was xeno-transplanted with the A549 lung epithelial human cells for assess-
ing the protective actions of the tri-herbal ayurvedic medicine (coronil) consisting
of O. sanctum (leaf extract) along with T. cordifolia and W. somnifera. The research-
ers presented immunomodulatory properties of this herbal combination in retrieving
the pathological features prompted by SARS-CoV-2 spike protein, proposing its
possible utilization in SARS-CoV-2 infection. The combination inhibited SARS-­
CoV-­2 spike protein, restored normal morphological and cellular characteristics in
the swim bladder, and attenuated the skin hemorrhage, degeneration of renal cells,
and necrosis. Besides this, herbal formulation attenuated IL-1, induced secretions of
IL-6 and tumor necrosis factor (TNF)-cytokine, and reduced the TNF-induced tran-
scriptional activity of nuclear factor-kappa B/activator protein 1 (NF-ĸB/AP-1) in
A549 cells. Bioactive molecules that might be responsible for this effect were iden-
tified by ultra high performance liquid chromatography (UHPLC), which included
ursolic acid, rosmarinic acid, withanone, withanoside IV–V, withaferin A, and other
compounds like cordifolioside A, magnoflorine, palmatine, and betulinic acid. In
further studies, the authors established that formulation containing O. sanctum as
one of the ingredients efficiently repressed ACE-2 interaction with wild-type S pro-
tein (SWT), high infectious variant (SD614G), and mutated variant (SW436R) with consid-
erably greater affinity toward ACE-2. It also prevented the cytokine response in
A549 cells mediated by SARS-CoV-2 S-protein pseudotyped vesicular stomatitis
virus (VSVppSARS-2S) by declining the entrance of the pseudoviruses to the host
cells [11].
Devpura et al. [12] designed their research study to assess the clinical efficacy of
O. sanctum and other potent medicinal plants in restraining the pathological symp-
toms of SARS-CoV-2 infection employing an ayurvedic treatment regime. The
researchers reported reduced fold changes in the serum levels of the high sensitive
C-reactive protein (hs-CRP), tumor necrosis factor alpha (TNF-α), and interleukin-
­6 (IL-6), stimulating virological clearance and recovery and concomitantly reduc-
ing the viral dissemination risk.

Tinospora cordifolia
2.2 

Tinospora cordifolia (Willd.) Miers or Tinospora sinensis (Lour.) Merr. is an

ayurvedic herb from the Menispermaceae family. Hepatoprotective, anti-­
inflammatory, antimalarial, antipyretic, antiallergic, antiarthritic, antidiabetic, anti-
spasmodic, antistress, antineoplastic, antioxidant, antileprotic, and
immunomodulatory actions have been documented in Ayurveda. The plant contains
berberine, tembetarine, tinosporafuranol, palmatine, octacosanol, tinoscorside D,
tinosporon, β-D glucan, G1-4A, clerodane furano diterpene glycosides, and epoxy
clerodane diterpene as major active phytoconstituents [13]. The in silico approach
to identify the natural compounds from T. cordifolia against SARS-CoV-2 was ana-
lyzed by Sagar and Kumar [14]. The main targets appraised for the molecular
Plant-Derived Immunomodulators Targeting COVID-19 (SARS-CoV-2): Preclinical… 1519

docking were the surface glycoprotein (6VSB), receptor-binding domain (RBD:

6M0J), RNA-dependent RNA polymerase (6 M71), and protease (6Y84). It was
concluded that tinocordiside, magnoflorine, isocolumbin, and berberine showed
highest binding efficiency against all the four crucial targets, proposing their merit
in clinical management of viral infection. Further, molecular docking computa-
tional studies on T. cordifolia botanochemicals, to target the 3CLpro (main prote-
ase) active site pocket of SARS-CoV-2, recognized compounds, viz., tinosponone,
cardiofolioside, berberine, xanosporic acid, and tembetarine to dock effectively
with 3CLpro [15]. Additional multiple independent computational studies have also
validated that tinocordiside energetically binds to the interface of ACE-2–RBD
complex weakening the interaction, and berberine regulates the entry and replica-
tion of SARS-CoV-2 [16, 17]. Manne et al. [18] implemented chromatographic and
the in silico approaches for the documentation of bioactive compounds from T. cor-
difolia, which might be used as promising scaffolds for the development of anti-­
COVID-­19 drug and reducing human cytokine squall. The results of this study
emphasized cordifolioside, berberine, and magnoflorine as human immunomodula-
tors (Transforming growth factor-beta (TGF-β), TNF-α) and strong inhibitors
against Mpro of SARS-CoV-2 through multiple docking strategies. It was observed
that cordifolioside formed the six stable hydrogen bonds with Ser144, Cys145,
His41, His163, His164, and Glu166 of the Mpro, which revealed a substantial role in
the replication/transcription of virus during contagion acting en route for the con-
served cleft binding, common among all coronavirus viral strains. Other potent bio-
active molecules such as columbin, amritoside A, tinosporide,
N-trans-feruloyl-tyramine-diacetate, tinocordifolin, amritoside C, palmatoside F,
amritoside B, palmatoside G, and maslinic acids have also been reported as effec-
tive inhibitors for SARS-CoV-2 based upon their molecular docking score ranging
from −5.02 to −5.72 [19].
Balakrishna et al. [20] displayed that aqueous extract of T. cordifolia curtailed
the infiltration of granulocytes and macrophages into the swim bladder endorsed by
spike protein and also reversed the renal tissue damage in the humanized zebrafish
model. The authors found cordifolioside A, magnoflorine, β-ecdysone, and palma-
tine as the phytocompounds presenting this viable pharmacological effect against
SARS-CoV-2 spike-protein-stimulated disease phenotypic expression. The reme-
dial effect of T. cordifolia as a constituent part of ayurvedic treatment protocol on
59 SARS-CoV-2 infected patients who were asymptomatic or mildly symptomatic
was evaluated by Balkrishna et al. [21]. It was revealed that the patients getting
ayurvedic medicines only were symptomatically relieved quicker with no visible
adverse effects as compared to group receiving the allopathic and ayurvedic medi-
cines together. Moreover, observations from a randomized placebo-controlled pilot
clinical research appraising the efficacy of this plant on a slightly large asymptom-
atic to mildly symptomatic patient pool also advocated the outcomes of this research
[12]. For the superior patient acquiescence, T. cordifolia stem extract was combined
with G. glabra and O. sanctum, which was formulated into coronil tablet, and, con-
sequently, its pharmacological properties against SARS-CoV-2 spike protein were
established through in vitro and in vivo studies [10, 11].
1520 Robin et al.

Withania somnifera
2.3 

Withania somnifera (L.) Dunal or Ashwagandha belonging to the Solanaceae family

contains ashwagandhine, withananine, choline, cuscohygrine, sitoindosides, isopel-
letierine, anaferine, anahygrine, withanolides, tropine, withanamides, and glycow-
ithanolides [5]. As proposed by the molecular docking and dynamic simulation
computational studies, W. somnifera compound, withanone, has been elucidated to
bind to the interface of SARS-CoV-2 spike protein receptor-binding domain (RBD)
and the host ACE-2 receptor complex. This binding weakened and disrupted
ACE-2–RBD interaction and thus advocated for the control of entrance of the virus
into the host cell [22]. Other computational studies have also reported that witha-
none and caffeic acid phenethyl ester of W. somnifera can also target SARS-CoV-2
Mpro and the host transmembrane protease serine 2 (TMPRSS2) [23, 24]. The pre-
liminary in silico evaluation of SARS-CoV-2 spike protein and papain-like protease
with the withanolides A and B demonstrated stability profile at 300 K, persistent
root mean square deviations (RMSDs) of side chains of protein and the C-α atoms
during the complete simulation run time, proposing the antiviral efficacy of these
phytocompounds [25]. A number of active phytochemicals from W. somnifera are
used for the management of SARS-CoV-2 infection. Some of the key active botano-
chemicals that particularly bind with the crucial targets of various SARS-CoV-2
include withanoside II, IV, and V, somniferine, and sitoindoside IX [9, 26, 27].
Similarly, the probable binding approaches and favorable molecular interaction pro-
file of botanochemicals like 24,25-dihydrowithanolide D, 27-Deoxy-14-­
hydroxywithaferin A, 12-deoxywithastramonolide, and 27-hydroxywithanolide B,
with the lowermost free binding energies against the nonstructural proteins (NSPs)
from SARS-CoV-2, were identified by Parida et al. [28]. It was postulated that
chemical structures of bioactives from W. somnifera with the steroidal moieties in
them formed stable interactions with nonstructural proteins suggesting their poten-
tial to be tested experimentally.
The researchers investigated the propensity of withanone on transmembrane pro-
tease serine 2 expression in cultured cells and observed significant downregulation
of the TMPRSS2 mRNA in MCF-7 cells. The dual impact of withanone to block the
entrance of SARS-CoV-2 to the host cells was envisaged via inhibition of the
TMPRSS2 catalytic action as anticipated by the molecular modeling data and its
transcriptional downregulation in the cultured cells [24].
Some clinical trial investigations are underway to interpret the effectiveness of
the traditional Indian medicinal plants against SARS-CoV-2 infection. In majority
of these trials, medicinal botanicals are examined as auxiliary therapy in addition to
the standard care medicinal regimes or as a prophylactic/defensive measure in the
high-risk population [29]. One of the observational studies that appraised the con-
sumption of W. somnifera tablets as an anticipatory measure is registered
(CTRI/2020/05/025166) with the Clinical Trial Registry-India (CTRI) [30].
Plant-Derived Immunomodulators Targeting COVID-19 (SARS-CoV-2): Preclinical… 1521

Glycyrrhiza glabra
2.4 

Glycyrrhiza glabra L. belonging to the Fabaceae family contains glabridin, glycyr-

rhizin, glycyrrhetinic acid, isoliquiritigenin, liquiritin, licochalcones, isoliquiritin,
and liquiritigenin. The molecular docking simulation study to investigate the active
molecules from G. glabra along with lopinavir and ribavirin (standard antiviral
drugs) was carried out utilizing two protein targets, viz., the spike glycoprotein and
the nonstructural protein-15 endoribonuclease. It was observed that glycyrrhizic
acid exhibited high affinity toward spike glycoprotein prohibiting the entrance of
the viral strain into the host cell, while glyasperin A was indicated to be well-­
matched for the binding pocket of Nsp15 endoribonuclease with uridine specificity
displaying their usefulness against COVID-19 [31]. Overall, they concluded that
ACE-2 receptor of the viral strain was distressed by the glycyrrhizic acid and the
progression in viral replication was hindered by glyasperin. Hejazi et al. [32]
strongly recommended the usage of dehydroglyasperin C, licochalcone D, and
liquiritin (secondary metabolites of G. glabra) for the clinical trials focusing on the
inhibition of replication machinery with a lower level of cellular toxicity against
SARS-CoV-2. Srivastava and co-workers [33] also proposed in their study that bio-
active compounds of G. glabra such as glabridin, glycyrrhizic acid, and liquiriti-
genin are robust inhibitors of the Mpro active site’s enzymes and amino acids (His41,
Gly143, Gln189, Glu 166, Cys 145, Thr25, Asn142, Met49, Cys44, Thr45, and
pro168). The in silico ADMET prediction of properties also showed their good mis-
cibility, absorption, nontoxicity, permeation, and noncarcinogenic features.
Factor Xa (trypsin-like serine protease) can act on the elementary constituents of
the coagulation cascade via prothrombin to thrombin activation and catalyze the
biochemical reaction of fibrin and clot formation. It has been observed that coagula-
tion and thromboembolic-associated complications allied with SARS-CoV-2 infec-
tion are very distinctive, and recently direct factor Xa inhibitors have evolved as an
essential part of the therapeutic procedures in various clinical trials [34, 35]. In an
in vitro study, it was pointed out that four licorice flavonoids (liquiritin,
3,3′,4,4′-tetrahydroxy-­2-methoxychalcone, naringenin-5-O-glucoside, and
7-hydroxy-4′-methoxyisoflavone) exert direct inhibitory action on the coagulation
factor Xa, suggesting the possible utilization of root extract of licorice in the pro-
phylaxis and management of certain complications related with the viral infection.
However, liquiritin presented the most powerful inhibitory action with half-­maximal
inhibitory concentration (IC50) of 5.15 μM [36]. Another study investigated the neu-
tralizing activity of glycyrrhizic acid (a triterpene saponin) against a clinical isolate
employing cell culture comprising of Vero E6 cells and 100 TCID50 (50% tissue
culture infectious dose) of SARS-CoV-2. The half maximal effective concen­tration
(EC50) was estimated to be 0.44 mg/mL, which signposted glycyrrhizin as a power-
ful bioactive constituent highly effective against SARS-CoV-2. Further, inhibition
of SARS-CoV-2 Mpro by this bioactive compound was assessed by utilizing 3CL
protease, maltose-binding protein (MBP)-tagged (SARS-CoV-2) assay kit and a
complete inhibition of Mpro activity was observed at a concentration of 2000 μM
1522 Robin et al.

[37]. In one of the studies, Gowda et al. [38] evaluated the efficacy of glycyrrhizin
as high-mobility group box 1 (HMGB1) inhibitor of SARS-CoV-2 viral protein
expression on the cellular perturbations in the lung cells. As severity of COVID-19
infection is associated with amplified inflammatory responses, HMGB1 (damage-­
associated molecular pattern protein) is an imperative extracellular mediator in the
inflammatory process. It was observed that this natural triterpene of licorice inhib-
ited the viral protein-induced cell pyroptosis, and attenuated proinflammatory cyto-
kines IL-1β, IL-6, and IL-8 release as well as ferritin from the macrophages
cultivated in the lung cells expressing SARS-CoV-2 S-RBD. The researchers con-
cluded the dual capability of this compound to concurrently terminate viral replica-
tion and decline proinflammatory mediators, which could establish it as an appealing
therapeutic alternative in patients with SARS-CoV-2 infection.
Yu et al. [39] also found glycyrrhizin to be the most efficacious among various
active ingredients of traditional Chinese medicine and a nontoxic, broad-spectrum,
anti-coronavirus molecule, predominantly against SARS-CoV-2. Additionally, in
vitro experimental investigations conducted by Tolah et al. [40] also revealed robust
antiviral action of crude licorice extract and glycyrrhizin under various treatment
procedures (simulations of the treatment with the viral infection, post-infection
treatment, and the pre-treatment), signifying multifold mechanisms for its action.
The authors noted that half-maximal inhibitory concentration (IC50) of glycyrrhizin
was significantly lesser than licorice. Li et al. [41] provided experimental and simu-
lation data demonstrating high-affinity interaction of glycyrrhizin with the S-protein,
potentially targeting recombinant S-protein-mediated binding to the host cells
exhibiting its antiviral activity. It has also been observed that G. glabra extract
reduces the expression of ACE-2 at the protein level in the small bowel, which may
serve as an entrance point of SARS-CoV-2. The present findings supported the con-
cept that dietary supplementation of G. glabra extract might mitigate the accumula-
tion of viral strain in the gastrointestinal tract and therefore help in the avoidance of
possible fecal–oral SARS-CoV-2 spread [42]. Such studies highlight the primary
natural bioactives of G. glabra as prospective antiviral candidates that might be
further explored for the preventive treatment of COVID-19.
Derived from G. glabra roots, glycyrrhetinic acid is a hydrolytic product of glyc-
yrrhizic acid that functions as a glucocorticoid-like drug helping in reducing inflam-
mation and in immune regulation against cytokine storm. A case report of
nonhospitalized COVID-19 patients who failed to get relief with the regular treat-
ment of COVID-19 showed significant positive response toward glycyrrhizin as a
potential antiviral drug for the treatment of the disease. Although the patient recov-
ered from this viral illness, further controlled experiments are considered obligatory
to corroborate its therapeutic actions [43]. Later on, a research group in their single-­
center observational study observed that the treatment accommodated immunologic
functions with lesser prevalence of new-onset impediments, which include the acute
respiratory distress syndrome, acute liver, and acute myocardial infarction [44]. An
open-label randomized controlled multicenter trial was implemented in Iran on hos-
pitalized adult patients employing herbal decoction and capsule containing G. gla-
bra as one of the components. Glycyrrhizin (29.505 μg/mL) was found to be the
Plant-Derived Immunomodulators Targeting COVID-19 (SARS-CoV-2): Preclinical… 1523

main marker of this plant via high performance liquid chromatography (HPLC)
analysis. The results of this study presented significant accelerated clinical improve-
ment of symptoms with decrease in muscle pain, chills, headache, dry cough,
fatigue, anorexia, sputum, runny nose, and vertigo in COVID-19 treatment group
[45]. One pilot, nonrandomized study (NCT04487964) is on-going considering the
extract of this plant as a complementary ayurvedic medicine in patients with SARS-­
CoV-­2 disease [46].

Emblica officinalis
2.5 

Emblica officinalis Gaertn. or Phyllanthus emblica L., also known as Amla in

Ayurveda, is a vitamin-C-rich plant with a wide range of pharmacological effects
[5]. Chikhale et al. [47] investigated the potency of 66 phytoconstituents of E. offi-
cinalis against 3 protein targets of SARS-CoV-2, viz., receptor-binding domain of
prefusion spike protein, NSP15 endoribonuclease, and main protease, by means of
molecular docking and dynamic computational studies. The pharmacoinformatic
approach presented the highest binding energies of chlorogenic acid, quercitrin, and
myricetin against the selected protein targets of SARS-CoV-2. In addition to this
network, pharmacological analysis established the role of these bioactive com-
pounds in managing cytokine storm, immunomodulation, and inflammatory cas-
cades through regulation of multiple biological signaling pathways. The research
study conducted by Murugesan et al. [48] indicated that bioactives of E. officinalis
like pectolinarin, astragalin, 7-ketositosterol, and quercetin proficiently occupied
the substrate-binding cleft and interacted noncovalently with the catalytic residues
H41 and C145, signifying their potential as possible inhibitors of COVID-19 Mpro.
In addition to this, natural products such as phyllaemblicin G7 from E. officinalis
displayed potentially high binding affinity to ACE-2 protein, which acts as a host
target for the management of the coronavirus contagion to hinder SARS-CoV-2
from entering the host cells [49].
Rangnekar et al. [50] completed a single-center, parallel-group, randomized, 1:1
ratio, two-arm, double-blind, controlled exploratory trial with investigational dura-
tion of 30 days. The study involved two capsules (one each of investigational prod-
uct 1: 400 mg; and investigational product 2: 450 mg) to be taken twice a day for
15 days and one capsule of product 2 from day 16 to be consumed twice a day up to
day 30 orally with plain water. The investigational products 1 and 2 consisted of
herbal extracts comprising E. officinalis, Zingiber officinale, Embelia ribes, G. gla-
bra, T. cordifolia, Asparagus racemosus, Piper longum, and calcined zinc, shankha
bhasma. The outcome revealed effectiveness of the herbal extracts in declining viral
load with early recovery and as an immunomodulator (Th1 [T helper 1], Th2 [T
helper 2], Th17 [T helper 17], IL6, natural killer [NK] cells, and immunoglobulin
IgG and IgM [Cluster of differentiation (CD) markers]). Further, safety investiga-
tions (liver function and renal function tests) along with the serious allergic reac-
tions like rash, severe dizziness, itching/swelling, and trouble breathing revealed
that this drug treatment is considerably safer.
Table 1 In vivo clinical significance of plant-based products and bioactive ingredients against SARS-CoV-2 infection
1524

S. Case report/Clinical Sample Treatment and drug

no. Plant trial size Subject selection administration Outcome of the study Reference
1. Ocimum sanctum, Randomized, 100 Asymptomatic to Oral administration in the Reduction in serum levels of Devpura
Tinospora placebo-controlled mildly symptomatic form of tablets and each hs-CRP, TNF-α, and IL-6 et al. [12]
cordifolia, and double-blind clinical patients positive on tablet weighed 500 mg;
Withania somnifera trial RT-PCR; T. cordifolia (1 g), swasari
15–80 years from ras (traditional herbo-­
either gender mineral formulation 2 g),
W. somnifera (0.5 g), O.
sanctum (0.5 g) twice per
day for 7 days
T. cordifolia Retrospective 59 Asymptomatic and Total daily dose of 2 g Research appraised the Balkrishna
open-label study mildly symptomatic administered orally with efficacy of this plant on a et al. [21]
COVID-19 patients; lukewarm water 30 min slightly large asymptomatic to
10–80 years from after meals for 21 days mildly symptomatic patient
either gender pool
Robin et al.
2. Glycyrrhetinic acid Case report 1 Nonhospital Diammonium Discontinuation of severe Ding et al.
of Glycyrrhiza COVID-19 glycyrrhizinate (orally COVID-19 symptoms (high [43]
glabra confirmed with 150 mg 3× daily) + body temperature, nausea,
antibody test post Vitamin C (orally 200 mg shortness of breath, dry cough,
recovery; 62 years; 3× daily) for 8 days back pain, fatigue)
female
Glycyrrhetinic acid Retrospective, 207 Hospitalized Diammonium Regulation of proinflammatory Tan et al.
of G. glabra single-center, COVID-19 patients glycyrrhizinate (150 mg factors (IL-1b, IL-6, IL-8, [43]
observational study 3× daily p.o) + Vitamin C TNF-α), anti-inflammatory
(500 mg 3× daily) cytokine (IL-10), sIL-2R, and
continuously for at least number of immune cells (T-,
7 days B-, and NK-cells).
Herbal decoction Multicenter 358 Positive on RT-PCR Polyherbal decoction Decreased duration of hospital Karimi
and capsule open-label, with pneumonia; every 8 h and herbal stay and symptoms such as dry et al. [45]
containing G. randomized, 18–75 years; both capsule every 12 h for cough, dyspnea, muscle pain,
glabra as one of the controlled clinical genders 7 days headache, fatigue, anorexia,
components trial chills, runny nose, sputum
cough, and vertigo
Glycyrrhizin of G. Nonrandomized, 70 Symptomatic and 250 mg standardized On-going Gomaa
glabra pilot study laboratory-confirmed extract (25% Glycyrrhizin, [46]
diagnosis of 62.5 mg) for 10 days
COVID-19;
12–65 years
COVID-19 Coronavirus Disease-2019, hs-CRP high sensitivity C-reactive protein, IL interleukin, NK natural killer, RT-PCR reverse transcription-polymerase
chain reaction, SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus-2, TNF-α tumor necrosis factor-alpha
Plant-Derived Immunomodulators Targeting COVID-19 (SARS-CoV-2): Preclinical…
1525
Table 2 In vitro clinical significance of plant-based products and bioactive ingredients against SARS-CoV-2 infection
1526

Extract/
formulation
(concentration/ Isolated compounds/primary In vitro assay/cell culture Bioactivity/possible mechanism of
Plant dose) bioactive ingredients used/animal model action Reference
Ocimum Zebrafish model: Ursolic acid, betulinic acid, Humanized zebrafish model Inhibition of SARS-CoV-2 Balkrishna
sanctum, 12 and 58 μg/kg rosmarinic acid, cordifolioside A, (N = 24) spike-protein-induced renal cell et al. [10]
Tinospora A549:1–1000 μg/ magnoflorine, palmatine, A549 cells necrosis
cordifolia, and mL withanone, withaferin A, and Attenuation of the interleukin
Withania withanoside IV–V (IL)-1β induced IL-6 and TNF-α
somnifera cytokine secretions
Decrease in TNF-α induced NF-ĸB/
AP-1 transcriptional activity
O. sanctum, T. 0.001–30 μg/mL Rosmarinic acid, betulinic acid, A549 cells Inhibition of the interaction of Balkrishna
cordifolia, and ursolic acid, magnoflorine, ACE-2 with S proteins (SWT, SD614G, et al. [22]
W. somnifera palmatine, cordifolioside A, SW436R)
withaferin A, withanoside IV and Prevention of SARS-CoV-2
V, and withanone S-protein pseudotyped vesicular
stomatitis virus (VSVppSARS-2S)-
mediated cytokine response
T. cordifolia 6, 28, and 142 μg/ Cordifolioside A, magnoflorine, Humanized zebrafish model Reduction in number of granulocytes Balkrishna
kg/day β-ecdysone, and palmatine and macrophages et al. [20]
Restoration of behavioral fever, skin
hemorrhage, and mortality induced
by SARS-CoV-2 spike protein.
Robin et al.
Glycyrrhiza Ethyl acetate Liquiritin, 3,3′,4,4′-tetrahydroxy-­ Chromogenic assay Factor Xa inhibition Ibrahim
glabra fraction (1 mg/ 2-­methoxychalcone, naringenin et al. [36]
mL) 5-O-glucoside, and
7-hydroxy-4′-methoxyisoflavone
Aqueous root Glycyrrhizic acid Vero E6 cells SARS-CoV-2 main protease (Mpro) van de
extract inhibition Sand et al.
(0.004–4 mg/mL) [37]
1 mM Glycyrrhizic acid SARS-CoV-2-S-RBD and Prevention of S-RBD- and Orf3a-­ Gowda
Orf3 transfected BEAS-2B mediated cell death and caspase-1 et al. [38]
cells; Vero E6 cells activation; dampening of
macrophage activation; attenuation
of proinflammatory cytokines IL-6
and CXCL18; diminution of ferritin
release; inhibition of SAR-CoV-2
replication
Glycyrrhizic acid Mouse aorta smooth muscle Inhibition against spike protein of Yu et al.
cells (MASMCs) and human SARS-CoV-2 [39]
bronchial epithelial (16HBE)
cells
Crude licorice Glycyrrhizin between 26.5 African green monkey kidney Antiviral activity against SARS-­ Tolah et al.
312.5 and 100 ng/ and 850 ng/mL cells Vero E6; human CoV-­2 via the targeting of Mpro [40]
mL SARS-CoV-2 clinical patient
isolate (SARS CoV2/human/
SAU/85791C/2020)
Aqueous root Glycyrrhizinic acid Sprague-Dawley rats (N = 48, Reduction in ACE-2 mRNA levels Jezova
extract (150 mg/ male) and ACE-2 protein content in the et al. [42]
kg/day for small intestine
5 weeks)
Plant-Derived Immunomodulators Targeting COVID-19 (SARS-CoV-2): Preclinical…

ACE-2 angiotensin converting enzyme-2, BEAS-2B human bronchial epithelial cell line, CXCL18 C-X-C motif chemokine ligand 18, mRNA messenger ribo-
nucleic acid, NF-ĸB/AP-1 nuclear factor-kappa B/activator protein 1, SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus-2, S-RBD spike protein
receptor-binding domain, TNF-α tumor necrosis factor-alpha
1527
1528 Robin et al.

Overall, Tables 1 and 2 summarize the potential in vivo and in vitro beneficial
effects of Ocimum sanctum, Tinospora cordifolia, Withania somnifera, Glycyrrhiza
glabra, and Emblica officinalis against COVID-19. Due to their bioaction in numer-
ous steps of the viral infection, such as inhibiting transmembrane protease serine 2
(TMPRSS2) and disrupting viral entry via binding to viral fusion proteins and
blocking angiotensin-converting enzyme-2 (ACE-2) receptor, these immunopoten-
tiators as well as their constituents may well be considered as potential adjuvant
therapies to COVID-19 in clinics. By revitalizing the human immune system, plant-­
derived bioactive immunomodulators offer sustenance to immunity and aid in the
fight against SARS-CoV-2.

3 Conclusion

A variety of plant extracts, herbal medicines, and pure plant ingredients have been
demonstrated to have immunomodulatory properties and have been utilized as pre-
ventative or therapeutic treatments for infectious disorders. Through the activation
and modulation of the lymphocytes, macrophages, and cytokine production, these
phytocomponents and their bioactive chemicals influence immunological responses.
Many plant extracts include a variety of bioactive components, such as polysaccha-
rides, alkaloids, glycosides, terpenoids, flavonoids, and essential oils, all of which
have a powerful capacity to sustain and/or activate the immune system via modula-
tion of nonspecific immunological responses. The current analysis emphasizes the
relevance of medicinal plants that contain immunomodulating components of vari-
ous chemistries that might be used to combat viral infections. Therefore, research-
ers’ attempts to create alternative plant-based medicines for infectious illnesses
should be encouraged.

References

1. Nakamura T, Isoda N, Sakoda Y, Harashima H (2022) Strategies for fighting pandemic virus
infections: integration of virology and drug delivery. J Control Release 343:361–378
2. Yuki K, Fujiogi M, Koutsogiannaki S (2020) COVID-19 pathophysiology: a review. Clin
Immunol 215:108427. https://doi.org/10.1016/j.clim.2020.108427
3. Nalbandian A, Sehgal K, Gupta A et al (2021) Post-acute COVID-19 syndrome. Nat Med
27:601–615. https://doi.org/10.1038/s41591-­021-­01283-­z
4. Cao X (2020) COVID-19: immunopathology and its implications for therapy. Nat Rev
Immunol 20:269–270. https://doi.org/10.1038/s41577-­020-­0308-­3
5. Kaur P, Robin MVO, Arora R, Singh B, Arora S (2017) Immunopotentiating significance of
conventionally used plant adaptogens as modulators in biochemical and molecular signal-
ling pathways in cell mediated processes. Biomed Pharmacother 95:1815–1829. https://doi.
org/10.1016/j.biopha.2017.09.081
6. Varshney KK, Varshney M, Nath B (2020) Molecular modeling of isolated phytochemicals
from Ocimum sanctum towards exploring potential inhibitors of SARS coronavirus main
Plant-Derived Immunomodulators Targeting COVID-19 (SARS-CoV-2): Preclinical… 1529

protease and papain-like protease to treat COVID-19. Available at SSRN. https://ssrn.com/

abstract=3554371
7. Kumar AHS (2020) Molecular docking of natural compounds from tulsi (Ocimum sanctum)
and neem (Azadirachta indica) against SARS-CoV-2 protein targets. BEMS Rep 6(1):11–13
8. Mohapatra PK, Chopdar KS, Dash GC et al (2021) In silico screening and covalent binding
of phytochemicals of Ocimum sanctum against SARS-CoV-2 (COVID 19) main protease. J
Biomol Struct Dyn. https://doi.org/10.1080/07391102.2021.2007170
9. Shree P, Mishra P, Selvaraj C et al (2022) Targeting COVID-19 (SARS-CoV-2) main pro-
tease through active phytochemicals of ayurvedic medicinal plants – Withania somnifera
(Ashwagandha), Tinospora cordifolia (Giloy) and Ocimum sanctum (Tulsi) – a molecu-
lar docking study. J Biomol Struct Dyn 40(1):190–203. https://doi.org/10.1080/0739110
2.2020.1810778
10. Balkrishna A, Solleti SK, Verma S et al (2020) Application of humanized zebrafish model in
the suppression of SARS-CoV-2 spike protein induced pathology by tri-herbal medicine coro-
nil via cytokine modulation. Molecules 25:5091. https://doi.org/10.3390/molecules25215091
11. Balkrishna A, Haldar S, Singh H et al (2021) Coronil, a tri-herbal formulation, attenuates
spike- protein mediated SARS-CoV-2 viral entry into human alveolar epithelial cells and pro-­
inflammatory cytokines production by inhibiting spike protein-ACE-2 interaction. J Inflamm
Res 14:869–884
12. Devpura G, Tomar BS, Nathiya D et al (2021) Randomized placebo-controlled pilot clini-
cal trial on the efficacy of ayurvedic treatment regime on COVID-19 positive patients.
Phytomedicine 84:153494. https://doi.org/10.1016/j.phymed.2021.153494
13. Arunachalam K, Yang X, San TT (2022) Tinospora cordifolia (Willd.) Miers: protection mech-
anisms and strategies against oxidative stress-related diseases. J Ethnopharmacol 283:114540.
https://doi.org/10.1016/j.jep.2021.114540
14. Sagar V, Kumar AHS (2020) Efficacy of natural compounds from Tinospora cordifolia against
SARS-CoV-2 protease, surface glycoprotein and RNA polymerase. BEMS Rep 6(1):6–8
15. Krupanidhi S, Peele KA, Venkateswarulu T et al (2020) Screening of phytochemical com-
pounds of Tinospora cordifolia for their inhibitory activity on SARS-CoV-2: an in silico study.
J Biomol Struct Dyn 2020:1–5. https://doi.org/10.1080/07391102.2020.1787226
16. Balkrishna A, Subarna P, Varshney A (2021) Tinocordiside from Tinospora cordifolia (Giloy)
may curb SARS-CoV-2 contagion by disrupting the electrostatic interactions between host
ACE2 and viral S-protein receptor binding domain. Comb Chem High Throughput Screen
24(10):1795–1802. https://doi.org/10.2174/1386207323666201110152615
17. Chowdhury P (2020) In silico investigation of phytoconstituents from Indian medicinal
herb ‘Tinospora cordifolia (giloy)’ against SARS-CoV-2 (COVID-19) by molecular dynam-
ics approach. J Biomol Struct Dyn 39(17):6792–6809. https://doi.org/10.1080/0739110
2.2020.1803968
18. Manne M, Goudar G, Varikasuvu SR et al (2021) Cordifolioside: potent inhibitor against M
pro of SARS-CoV-2 and immunomodulatory through human TGF-β and TNF-α. Biotech
11(3):1–25
19. Thakkar SS, Shelat F, Thakor P (2021) Magical bullets from an indigenous Indian medicinal
plant Tinospora cordifolia: an in silico approach for the antidote of SARS-CoV-2. Egypt J Pet
30(1):53–66
20. Balkrishna A, Khandrika L, Varshney A (2021) Giloy Ghanvati (Tinospora cordifolia (Willd.)
Hook. f. and Thomson) reversed SARS-CoV-2 viral spike-protein induced disease phenotype
in the xenotransplant model of humanized zebrafish. Front Pharmacol 12:534. https://doi.
org/10.3389/fphar.2021.635510
21. Balkrishna A, Bhatt AB, Singh P et al (2021) Comparative retrospective open-label study of
ayurvedic medicines and their combination with allopathic drugs on asymptomatic and mildly-­
symptomatic COVID-19 patients. J Herb Med 29:100472. https://doi.org/10.1016/j.hermed
22. Balkrishna A, Pokhrel S, Singh H et al (2021) Withanone from Withania somnifera attenuates
SARS-CoV-2 RBD and host ACE2 interactions to rescue spike protein induced pathologies
1530 Robin et al.

in humanized zebrafish model. Drug Des Devel Ther 15:1111–1133. https://doi.org/10.2147/

DDDT.S292805
23. Kumar V, Dhanjal JK, Kaul SC et al (2021) Withanone and caffeic acid phenethyl ester are pre-
dicted to interact with main protease (Mpro) of SARS CoV- 2 and inhibit its activity. J Biomol
Struct Dyn 39(11):3842–3854. https://doi.org/10.1080/07391102.2020.1772108
24. Kumar V, Dhanjal JK, Bhargava P et al (2022) Withanone and Withaferin-A are predicted to
interact with transmembrane protease serine 2 (TMPRSS2) and block entry of SARS-CoV-2
into cells. J Biomol Struct Dyn 40(1):1–13. https://doi.org/10.1080/07391102.2020.1775704
25. Srivastava A, Siddiqui S, Ahmad R et al (2022) Exploring nature’s bounty: identification of
Withania somnifera as a promising source of therapeutic agents against COVID-19 by virtual
screening and in silico evaluation. J Biomol Struct Dyn 40(4):1858–1908. https://doi.org/1
0.1080/07391102.2020.1835725
26. Tripathi MK, Singh P, Sharma S et al (2021) Identification of bioactive molecule from
Withania somnifera (Ashwagandha) as SARS-CoV-2 main protease inhibitor. J Biomol Struct
Dyn 39(15):5668–5681. https://doi.org/10.1080/07391102.2020.1790425
27. Jani V, Koulgi S, Uppuladinne VM et al (2021) An insight into the inhibitory mechanism of
phytochemicals and FDA-approved drugs on the ACE2–spike complex of SARS-CoV-2 using
computational methods. Chem Zvesti 1–24. https://doi.org/10.1007/s11696-­021-­01680-­1
28. Parida PK, Chakravorty PD (2021) Nature's therapy for COVID-19: targeting the vital non-­
structural proteins (NSP) from SARS-CoV-2 with phytochemicals from Indian medicinal
plants. Phytomedicine Plus 1(1):100002
29. Singh RS, Singh A, Kaur H et al (2021) Promising traditional Indian medicinal plants for the
management of novel coronavirus disease: a systematic review. Phytother Res 35:4456–4484
30. Muralikrishna DC (2020) Observational study of Ashwagandha tablet intake as a preventive
measure in pandemic of – COVID-19 – an open label, randomized, controlled, prospective,
interventional, community-based clinical study on healthy subjects (Clinical Trials Registry-­
India Identifier: CTRI/2020/05/025166). Retrieved from http://ctri.nic.in/Clinicaltrials/show-
allp.php?mid1=43553 & EncHid= & userName=025166
31. Sinha SK, Prasad SK, Islam MA et al (2020) Identification of bioactive compounds from
Glycyrrhiza glabra as possible inhibitor of SARS-CoV-2 spike glycoprotein and non-­structural
protein-15: a pharmacoinformatics study. J Biomol Struct Dyn 2020:1–15. https://doi.org/1
0.1080/07391102.2020.1779132
32. Hejazi II, Beg MA, Imam MA et al (2021) Glossary of phytoconstituents: can these be repur-
posed against SARS CoV-2? A quick in silico screening of various phytoconstituents from
plant Glycyrrhiza glabra with SARS CoV-2 main protease. Food Chem Toxicol 150:112057
33. Srivastava V, Yadav A, Sarkar P (2022) Molecular docking and ADMET study of bioactive
compounds of Glycyrrhiza glabra against main protease of SARS-CoV2. Mater Today Proc
49:2999–3007. https://doi.org/10.1016/j.matpr.2020.10.055
34. Al-Horani RA (2020) Potential therapeutic roles for direct factor Xa inhibitors in coro-
navirus infections. Am J Cardiovasc Drugs 20(6):525–533. https://doi.org/10.1007/
s40256-­020-­00438-­6
35. Al-Samkari H, Karp Leaf RS, Dzik WH et al (2020) COVID-19 and coagulation: bleeding and
thrombotic manifestations of SARS-CoV-2 infection. Blood 136(4):489–500
36. Ibrahim RS, Mahrous RS, EL-Khair RMA et al (2021) Biologically guided isolation and
ADMET profile of new factor Xa inhibitors from Glycyrrhiza glabra roots using in vitro and
in silico approaches. RSC Adv 11(17):9995–10001. https://doi.org/10.1039%2Fd1ra00359c
37. van de Sand L, Bormann M, Alt M et al (2021) Glycyrrhizin effectively inhibits SARS-CoV-2
replication by inhibiting the viral main protease. Viruses 13(4):609. https://doi.org/10.3390/
v13040609
38. Gowda P, Patrick S, Joshi SD et al (2021) Glycyrrhizin prevents SARS-CoV-2 S1 and Orf3a
induced high mobility group box 1 (HMGB1) release and inhibits viral replication. Cytokine
142:155496. https://doi.org/10.1016/j.cyto.2021.155496
Plant-Derived Immunomodulators Targeting COVID-19 (SARS-CoV-2): Preclinical… 1531

39. Yu S, Zhu Y, Xu J et al (2021) Glycyrrhizic acid exerts inhibitory activity against the spike protein
of SARS-CoV-2. Phytomedicine 85:153364. https://doi.org/10.1016/j.phymed.2020.153364
40. Tolah AM, Altayeb LM, Alandijany TA et al (2021) Computational and in vitro experimental
investigations reveal anti-viral activity of licorice and glycyrrhizin against severe acute respira-
tory syndrome coronavirus 2. Pharmaceuticals (Basel) 14(12):1216. https://doi.org/10.3390/
ph14121216
41. Li J, Xu D, Wang L et al (2021) Glycyrrhizic acid inhibits SARS-CoV-2 infection by blocking
spike protein-mediated cell attachment. Molecules 26(20):6090
42. Jezova D, Karailiev P, Karailievova L et al (2021) Food Enrichment with Glycyrrhiza Glabra
Extract Suppresses ACE2 mRNA and Protein Expression in Rats–Possible Implications for
COVID-19. Nutrients 13(7):2321. https://doi.org/10.3390/nu13072321
43. Ding H, Deng W, Ding L et al (2020) Glycyrrhetinic acid and its derivatives as potential alter-
native medicine to relieve symptoms in nonhospitalized COVID-19 patients. J Med Virol
92(10):2200–2204
44. Tan R, Xiang X, Chen W et al (2021) Efficacy of diammonium glycyrrhizinate combined with
vitamin C for treating hospitalized COVID-19 patients: a retrospective, observational study.
QJM Int J Med hcab184. https://doi.org/10.1093/qjmed/hcab184
45. Karimi M, Zarei A, Soleymani S et al (2021) Efficacy of Persian medicine herbal formulations
(capsules and decoction) compared to standard care in patients with COVID-19, a multicenter
open-labeled, randomized, controlled clinical trial. Phytother Res 35(11):6295–6309
46. Gomaa AA (2020) Complementary intervention for COVID-19 (Clinicaltrials.gov Identifier:
NCT04487964). Retrieved from https://clinicaltrials.gov/ct2/show/NCT04487964
47. Chikhale RV, Sinha SK, Khanal P et al (2021) Computational and network pharmacology stud-
ies of Phyllanthus emblica to tackle SARS-CoV-2. Phytomedicine Plus 1(3):100095
48. Murugesan S, Kottekad S, Crasta I et al (2021) Targeting COVID-19 (SARS-CoV-2) main
protease through active phytocompounds of ayurvedic medicinal plants–Emblica officinalis
(Amla), Phyllanthus niruri Linn.(Bhumi Amla) and Tinospora cordifolia (Giloy)–a molecular
docking and simulation study. Comput Biol Med 136:104683
49. Wu C, Liu Y, Yang Y et al (2020) Analysis of therapeutic targets for SARS-CoV-2 and discov-
ery of potential drugs by computational methods. Acta Pharm Sin B 10(5):766–788
50. Rangnekar H, Patankar S, Suryawanshi K et al (2020) Safety and efficacy of herbal extracts
to restore respiratory health and improve innate immunity in COVID-19 positive patients with
mild to moderate severity: a structured summary of a study protocol for a randomised con-
trolled trial. Trials 21:943. https://doi.org/10.1186/s13063-­020-­04906-­x
Correction to: Bioprospecting
of Tropical Medicinal Plants

Karuppusamy Arunachalam, Xuefei Yang,

and Sreeja Puthanpura Sasidharan

Correction to:
Chapters 4 and 5 in: K. Arunachalam et al. (eds.),
Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-­3-­031-­28780-­0

The original version of Chapter 4 was published with an incorrect statement:

The authors C. V. Jayalekshmi, R. K. Ramesh and M. Vijai died before publication
of this work was completed.
The original version of Chapter 5 was published with an incorrect statement:
The authors “C. V. Jayalekshmi and S. Reshma died before publication of this work
was completed.”
These statements have now been deleted from Chapters 4 and 5.

The updated original version of these chapters can be found at

https://doi.org/10.1007/978-­3-­031-­28780-­0_4
https://doi.org/10.1007/978-­3-­031-­28780-­0_5

© The Author(s), under exclusive license to Springer Nature C1

Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0_65
Index

A 1396, 1399, 1405, 1407, 1412, 1414,

Activities, 3, 22, 25, 40, 120, 154, 159, 172, 1416–1418, 1420–1423, 1430, 1439,
178, 187, 195, 200, 208, 216, 222, 244, 1462, 1464, 1465, 1484, 1486,
253, 258, 269–271, 274, 279, 288, 313, 1496–1502, 1504, 1505, 1517, 1518,
316, 317, 321, 323, 357, 360, 361, 363, 1521, 1522, 1526, 1527
364, 366–368, 371–373, 382, 395, Acute coronary syndrome (ACS), 867
398–403, 409–415, 417–420, 427–450, Aflatoxin B1, 1274, 1443
465–469, 471, 481, 483, 484, 486, 487, Agrobacterium strains, 912
489, 494–502, 513, 518–522, 529–540, Ailments, 1, 3, 4, 8, 9, 14, 17, 20, 21, 45,
545, 547, 548, 550–557, 567–580, 589, 51–59, 92, 93, 97–101, 103, 109, 118,
594, 595, 599, 600, 602–606, 612, 615, 125, 138, 154, 155, 197, 212, 227, 245,
620, 625, 629, 632–634, 636, 637, 639, 247, 253, 260, 269, 279, 295, 314, 329,
650, 662, 677–686, 700, 704, 719, 735, 349–352, 386, 403, 410, 411, 429, 445,
736, 744, 746, 747, 749, 753–757, 770, 450, 546, 566, 591, 707, 724, 727, 741,
771, 774, 778, 789, 791–799, 809–811, 780, 781, 784, 790, 827, 864, 932, 938,
813–817, 822, 825, 830, 831, 848, 851, 1049, 1118, 1200, 1205, 1233, 1248,
852, 856, 857, 864, 866, 869, 870, 876, 1249, 1339, 1357, 1457, 1461, 1469,
877, 879, 880, 894, 908, 929, 932–939, 1471, 1474, 1480, 1498, 1505
941, 943, 944, 951, 955, 965–967, Allium sativum, 58, 95, 231, 265, 278, 484,
976–978, 980, 982, 1006, 1040, 1140, 1218, 1252, 1273, 1496
1047–1049, 1051, 1052, 1065–1067, Aloe vera, 58, 60, 99, 111, 128, 270, 279, 716,
1070, 1072, 1099–1103, 1105, 1106, 724, 725, 1220, 1305, 1420, 1496,
1117–1121, 1125–1130, 1138–1140, 1498–1500
1142, 1146–1149, 1152, 1154, Alopecia, 565, 613, 616–618, 620, 747, 1300,
1156–1158, 1160, 1163, 1187, 1190, 1460, 1470
1191, 1194, 1205, 1206, 1208–1210, Alzheimer’s disease (AD), 262, 315, 412, 469,
1212, 1216, 1217, 1219, 1220, 1234, 519, 896, 937, 1327–1341, 1481
1236, 1237, 1240, 1241, 1252–1256, Amchi medicinal practice, 310, 312, 313, 324
1258, 1265–1282, 1300, 1303, 1305, Angiotensin-converting enzyme-2 (ACE-2),
1306, 1308, 1309, 1311, 1312, 1517, 1518, 1520–1523, 1526–1528
1314–1319, 1327, 1328, 1330, 1331, Anisochillus carnosus, 97, 591–607
1334–1338, 1341, 1347–1353, Annonaceae, 111, 128, 131, 147, 565–574,
1357–1360, 1372, 1375, 1376, 1395, 1140, 1145

© The Editor(s) (if applicable) and The Author(s), under exclusive license to 1533
Springer Nature Switzerland AG 2023
K. Arunachalam et al. (eds.), Bioprospecting of Tropical Medicinal Plants,
https://doi.org/10.1007/978-3-031-28780-0
1534 Index

Antibacterial, 9, 13, 14, 112, 120, 180, 189, 1256–1258, 1329, 1331, 1335, 1336,
195, 196, 200, 216, 217, 257, 271, 278, 1339, 1351, 1353, 1368, 1394, 1413,
316, 395, 411–413, 415, 419, 484, 487, 1420, 1421, 1461, 1463, 1465–1467,
489, 514, 518, 548, 555, 590, 591, 1487, 1497, 1499–1502, 1504, 1517,
594–596, 601, 605, 606, 650, 678, 679, 1518, 1525
686, 707, 714, 722, 735, 809, 810, Antimicrobial, 5, 6, 11, 12, 19, 116, 120, 172,
815–816, 961, 974, 980, 1050, 1065, 178, 200, 208, 216, 271, 272, 278, 374,
1067, 1068, 1100, 1105, 1118, 1212, 395, 410, 412–415, 419, 421, 429, 447,
1267, 1268, 1270, 1271, 1273, 1277, 465, 469, 484, 485, 490, 511, 518, 529,
1280, 1349, 1353, 1358, 1465, 1467, 532, 535, 546, 553–555, 589, 590, 595,
1468, 1517 604–606, 612, 650, 656, 662–680, 686,
Antibacterial activity, 361, 395–398, 469, 553, 700, 727, 735, 736, 749, 753, 790, 793,
554, 592, 595, 596, 600, 601, 604–607, 798–799, 809–810, 813–817, 864, 894,
677, 678, 680, 722, 813–814, 900, 933, 935, 937, 962, 978, 979, 1040,
1127, 1270, 1273–1276, 1278–1281, 1048, 1049, 1051, 1064, 1065, 1067,
1358, 1359 1106, 1125–1127, 1130, 1251, 1252,
Antibiotics, 116, 267, 274, 278, 415, 421, 482, 1265–1282, 1336, 1347–1353, 1357,
604, 605, 815, 912, 915, 916, 1007, 1358, 1360, 1465–1468, 1499, 1502
1008, 1050, 1067, 1266–1271, 1281, Antimicrobial agents, 413, 415, 469–470, 606,
1348, 1351, 1352, 1357, 1360, 1067, 1282, 1347–1360
1435, 1499 Antimicrobial synergism, 1270
Anticancer, 8, 12–14, 16, 18, 20, 175, 178, Antioxidant, 5, 6, 10, 120, 172, 195, 200, 216,
200, 257, 267, 271, 274, 278, 279, 296, 261, 263, 266, 267, 269–274, 278, 296,
395, 399–400, 411–413, 418, 419, 421, 364, 366, 368, 372, 374, 395, 401,
427–450, 466, 470, 489, 490, 495, 502, 410–413, 418, 419, 421, 427, 429, 443,
513, 514, 518, 538, 546, 547, 554, 555, 465, 467, 469, 473, 484–487, 490, 494,
565–581, 591, 636–638, 650, 683–685, 496–497, 500–502, 511, 513, 518, 529,
700, 727–736, 778, 779, 790, 797–799, 533–535, 548, 550–555, 589–592, 594,
894, 961, 979, 980, 1040, 1041, 1050, 595, 599–607, 619, 634, 636, 640, 642,
1065, 1066, 1097, 1105, 1118, 650, 680–683, 686, 704, 705, 707, 727,
1127–1130, 1136, 1137, 1140–1159, 735, 736, 745, 747, 749, 753, 774, 778,
1161–1163, 1178, 1191, 1336, 1339, 779, 790, 792, 797, 799, 807, 816, 817,
1353, 1368, 1369, 1374, 1379, 1408, 864, 871, 879, 880, 894, 900, 928, 929,
1413, 1417, 1418, 1422, 1465–1468, 937, 938, 943, 944, 951, 955, 961, 962,
1497, 1504 965–967, 973–980, 983, 987, 1040,
Anticancer agents, 279, 403, 470, 512, 567, 1050, 1052, 1067, 1070, 1097, 1098,
569, 572, 779, 1161, 1193, 1369, 1449 1100–1102, 1104–1107, 1118, 1119,
Antiepileptic drugs (AEDs), 821–858 1121, 1122, 1125–1130, 1163, 1212,
Anti-inflammatory, 5, 7, 9, 13, 14, 111–118, 1214, 1216, 1217, 1240, 1250–1252,
120, 126, 127, 130, 134, 139, 150, 151, 1256, 1279, 1329, 1331, 1332,
172, 175, 178, 180, 184, 187, 189, 194, 1336–1340, 1348, 1353, 1360, 1368,
216, 263, 265–267, 269–274, 278, 279, 1393, 1407, 1420, 1422, 1423,
294, 297, 300, 367–372, 374, 382, 395, 1465–1467, 1496, 1497, 1499, 1500,
400–401, 410–412, 419–421, 429, 1502, 1504, 1518
447–449, 483, 484, 487, 490, 497, Antiparasitic, 413, 567, 1052, 1064,
499–502, 518, 532, 533, 546, 551, 555, 1118, 1467
567, 590, 591, 603, 639, 650, 683–686, Antiproliferation, 554
735, 736, 744, 745, 747, 749, 753–757, Apocynaceae, 20, 60, 75, 88, 90, 110, 112,
778, 790, 791, 798, 799, 869, 894, 961, 117, 118, 125, 131, 132, 136, 139, 140,
962, 974, 975, 979, 980, 983, 1041, 145, 147, 148, 151, 153, 231, 233, 248,
1050, 1052, 1065–1068, 1097, 1099, 341, 343, 349, 368–369, 428, 484, 511,
1101, 1104–1107, 1118, 1125, 778, 835, 846, 1017, 1018, 1021, 1062,
1129–1130, 1199, 1200, 1203–1221, 1063, 1140, 1141, 1144, 1150, 1193,
1236, 1239, 1240, 1251–1254, 1194, 1314, 1472
Index 1535

Apoptosis, 412, 432–449, 502, 534–538, 554, 1265, 1266, 1271, 1281, 1330, 1418,
555, 569–573, 575–579, 613–615, 619, 1448, 1450, 1495, 1497, 1519,
636, 639, 797, 799, 814, 870, 879, 962, 1521, 1523
975, 1066, 1098, 1118, 1128, 1129, Bioactives, 58, 91, 255, 257, 269, 270, 272,
1144, 1146–1148, 1150, 1152–1154, 294–300, 348, 352, 372, 373, 390, 395,
1157, 1158, 1160, 1161, 1187, 403, 411, 413–415, 418–420, 430,
1191–1193, 1254, 1331, 1339, 1366, 432–442, 450, 466–469, 511, 517–518,
1369, 1370, 1372, 1375, 1376, 1395, 522, 530, 547, 565, 568–570, 574, 603,
1405–1407, 1412, 1413, 1418, 1419, 606, 634, 636, 650, 679, 686, 709, 725,
1422, 1449, 1500–1502 727, 728, 731, 734–736, 739–757, 773,
Asparagus, 5, 20, 21, 58, 62, 111, 126, 129, 209, 774, 776–778, 791, 799, 817, 858, 872,
262, 267, 274, 279, 382, 603, 869, 981, 929, 938, 939, 971–989, 1047–1049,
1141, 1160, 1305, 1503–1505, 1523 1051, 1052, 1056–1058, 1066, 1101,
Assam, 2, 227–229, 231–233, 239, 300, 1118, 1119, 1186, 1199, 1200, 1206,
659–661, 664, 672–676 1208, 1216, 1236–1238, 1248, 1250,
Astaxanthin, 1051 1254, 1256, 1265, 1266, 1269, 1271,
Asthma, 4, 8, 9, 12–14, 16, 18, 21, 55, 60, 68, 1272, 1278, 1281, 1330, 1332, 1413,
72, 74, 77, 81, 83, 86, 88, 89, 101, 111, 1418–1420, 1448, 1450, 1485, 1495,
114, 116, 117, 146, 149, 173, 175–177, 1497, 1502, 1504, 1517–1528
179, 185, 192, 193, 196, 198, 200, 206, Bioactivity, 269, 313, 403, 449, 469, 545,
208, 209, 211, 214, 217, 228, 229, 550–557, 570, 736, 744, 749, 791, 855,
231–233, 239, 263, 266, 268, 274, 297, 938, 943, 1066, 1118, 1119, 1238,
336, 339, 340, 342, 352, 471, 483, 489, 1405, 1407, 1526
498, 501, 790, 798, 979, 983, 1038, Biochanin A, 493, 789–800
1121, 1199, 1200, 1203, 1209, 1353, Biocompatibility, 1370, 1372, 1375, 1389,
1357, 1460, 1461, 1472 1391, 1393, 1399, 1410, 1414, 1418,
Atherosclerotic plaques, 867, 876 1422, 1498
Attappady, 107–120 Biodiversity, 2, 159, 160, 163, 292, 310, 312,
Ayurveda, 1, 123, 227, 254–260, 264, 316–321, 323, 330, 357, 373, 701, 767,
269–273, 279, 281, 287–289, 292, 307, 781–783, 785, 789, 1005, 1053,
429, 489, 545, 612, 649, 768, 927, 928, 1088, 1486
932, 933, 935, 1042, 1103, 1119, 1121, Bioprospecting, 25, 312, 317–318, 322–324
1299–1319, 1329, 1332, 1470, Brain functions, 822, 852
1518, 1523 Brassinosteroids, 1048
Ayurvedic medicines, 255, 258, 281, 295, 487,
488, 500, 707, 932, 1127, 1518,
1519, 1523 C
Azadirachta indica, 58, 62, 94, 96, 99, 110, Cancer, 7, 13, 14, 18, 55, 112, 128, 186, 196,
111, 126, 129, 231, 238, 262, 265, 200, 205, 209, 210, 228, 244, 245, 247,
1251–1252, 1314 266–269, 296, 318, 342, 387, 400–403,
418, 419, 427–450, 470, 483, 495, 501,
502, 511, 512, 519, 520, 522, 529–540,
B 550, 555, 556, 565–567, 569–580, 590,
β-amyloid plaques, 273, 1329 604, 611, 612, 616–620, 636, 638, 640,
Bioactive components, 482, 530, 531, 642, 643, 686, 744, 747, 768, 778–782,
537–539, 555, 571, 606, 744, 776, 790, 791, 794, 797, 798, 809, 812, 815,
984–985, 1047, 1104, 1106, 1528 816, 863, 868, 870, 876, 938, 974–977,
Bioactive compounds, 58, 269, 270, 272, 294, 1042, 1050, 1051, 1065, 1097, 1099,
295, 297, 300, 373, 403, 411, 414, 415, 1118, 1125, 1127–1129, 1136–1164,
530, 547, 565, 574, 650, 679, 686, 727, 1177–1194, 1199, 1216, 1248, 1251,
735, 736, 739–757, 773, 774, 777, 1302, 1335, 1357, 1359, 1365–1378,
971–989, 1047–1049, 1052, 1387–1401, 1405–1423, 1429–1450,
1056–1057, 1118, 1199, 1200, 1206, 1471, 1474, 1480, 1481, 1485, 1497,
1208, 1236–1238, 1248, 1256, 1499, 1501, 1504, 1516
1536 Index

Cancer cell lines, 361, 370, 373, 399, 400, 1495, 1496, 1498, 1502, 1503,
430–436, 438–450, 470, 495, 501, 535, 1505–1507, 1520, 1521, 1524, 1525
554, 555, 568, 570–580, 685, 1066, Clustered often interspaced short palindromic
1067, 1119, 1127–1129, 1160, 1189, repeats (CRISPR), 1054, 1055
1192, 1194, 1372–1374, 1376, 1412, Cognitive decline, 1237, 1327
1413, 1417, 1420, 1422 Computer-aided drug design (CADD),
Cancer therapeutics, 501, 1137, 1138 855, 857
Cancer treatment, 428, 448, 565, 568, 574, Conservation, 21, 22, 47, 50, 102, 160, 163,
611, 745, 778, 1161, 1164, 1189, 1190, 167, 222, 223, 287, 291, 314–324, 330,
1194, 1365, 1367, 1368, 1388–1396, 333, 353, 382, 385, 404, 410, 421, 783,
1399, 1423, 1448 1006, 1012–1021, 1029, 1035–1037,
Carbon nanotubes (CNTs), 1179, 1368–1371, 1039, 1040, 1042, 1043, 1062, 1067,
1379, 1421 1082, 1088–1089, 1486
Cardiovascular disease (CVD), 52, 97, 98, Conservation and utilization, 1088
269, 427, 518, 522, 863, 864, 866–872, Conservation measures, 1036
876–880, 975, 977, 987, 989, 1097, Cosmo-ceuticals, 464, 472–473
1216, 1217, 1429, 1497 Cost effectiveness, 1448, 1487, 1488
Catharanthus, 6, 20, 21, 112, 132, 248, 318, COVID-19, 799, 1266, 1319, 1360,
428, 482, 511–523, 769, 778, 779, 1515–1528
1063, 1065, 1141, 1194, 1368, 1407 CRISPR-associated9 (Cas9)
Cell signalling, 811, 880, 1119 endonuclease, 1054
Characterization, 403, 516, 639, 641, 642, Cryotherapy, 501, 1057
712–713, 771–778, 858, 1055, 1177, Culture, 1, 21, 25, 44, 102, 107, 108, 167, 227,
1184–1186, 1237, 1397, 1495 244, 249–251, 254, 288, 289, 316, 320,
Chemical carcinogens, 1439 347, 360, 374, 385, 466, 482, 486, 516,
Chemotherapeutics, 2, 427, 428, 430, 445, 555, 596, 600, 601, 662, 707–709,
450, 512, 568, 572, 573, 611, 614, 615, 714–716, 723, 725, 880, 910, 912, 920,
618, 620, 826, 1129, 1177, 1189, 1365, 921, 982, 1006, 1010, 1011, 1022,
1366, 1413, 1422, 1499 1024, 1026, 1027, 1029, 1035,
Chemotherapy, 427, 470, 514, 518–520, 565, 1039–1042, 1049, 1055–1058, 1061,
574, 611–620, 798, 870, 983, 1057, 1081–1090, 1100, 1107, 1395, 1422,
1099, 1118, 1160–1162, 1193, 1194, 1480, 1489, 1521, 1526
1367, 1387–1401, 1408, 1442, 1447 Curcumin, 278, 428, 436, 445, 447, 448, 484,
Chittur, 123–156 590, 637, 779, 810, 814, 928, 961,
Chromatographic analysis, 967 1058, 1097–1100, 1138, 1152, 1206,
Cinnamomum, 113, 132, 203, 231, 236, 263, 1208, 1218, 1235, 1238–1240, 1254,
268, 313, 649–686, 1142, 1259, 1279, 1312, 1369, 1371, 1372,
1273, 1314 1374–1378, 1423, 1449
Cinnamomum cassia, 650, 657, 658, 661, 662, Current scenario, 1328
680–684, 686, 1253, 1271, 1339 Cuttings propagation, 1086
Cinnamon, 662, 678, 679, 681, 682, 684, 686, Cyclea peltata, 114, 703, 707–725
1103–1105, 1237, 1269, 1273, 1339, Cyclooxygenase-1 (COX-1), 869, 879, 1068,
1352, 1353, 1358, 1496 1130, 1203, 1204, 1209, 1211
Climber, 27, 58, 90, 119, 125, 172–174, Cytotoxic effect, 362, 418, 432, 434, 437, 444,
178–180, 182, 185–187, 192, 194, 196, 446, 447, 449, 556, 567, 570, 573, 577,
202, 204, 209, 210, 215, 233, 339, 363, 685, 1129, 1160, 1338, 1374, 1375
364, 703, 1036, 1251, 1470
Clinical status, 1377, 1378
Clinical trials, 254, 270, 279, 281, 403, 411, D
482, 501, 520, 611, 617, 638, 778, 791, Data analysis, 44, 51–57, 334
800, 857, 865, 1097–1107, 1177, 1187, Dendrimers, 1368, 1373, 1374, 1379, 1421
1190, 1194, 1328, 1377, 1378, 1401, Desert, 270, 297, 330–345, 347–349,
1405, 1406, 1410, 1412, 1416, 1420, 351–353, 1005, 1062
1438, 1449, 1475, 1483, 1484, 1489, Dhemaji, 228, 229, 231–233
Index 1537

Diabetes, 6, 8, 10, 11, 13, 15, 18, 53, 71, 1373–1376, 1388, 1391–1392, 1396,
73–75, 79–81, 84, 85, 88, 98, 100, 115, 1398–1401, 1410, 1415, 1421
116, 118, 126, 137, 143, 152, 179, 180, Drug discovery, 102, 280, 281, 351, 372–374,
186, 188, 190, 195, 199, 209, 217, 382, 409, 411, 416, 421, 481, 488, 553,
245–247, 262, 265, 266, 268, 269, 274, 557, 649, 767–785, 789, 858, 929,
279, 299, 343, 411, 412, 466, 470, 471, 1212, 1495, 1506
485–487, 489, 494, 497, 501, 502, 511,
552, 553, 638, 640, 650, 743, 745, 757,
794, 863, 866–868, 944, 965, 974, 975, E
977–979, 983, 989, 1038, 1040, 1097, Emblica officinalis, 261, 263, 265, 1376, 1516,
1098, 1101, 1104–1107, 1125, 1199, 1523–1528
1247, 1249–1252, 1260, 1303, 1406, Endangered plants, 1029, 1039–1041,
1496–1499 1081–1083, 1087–1089
Dietary supplement, 638, 640, 753, 1056, Endothelial NOS (eNOS), 799, 879
1414, 1481, 1482 Enhancing cancer therapy, 1413
Diseases, 1, 3, 4, 12, 17, 20, 21, 27, 40, 45, 51, Environmental factors, 222, 1057, 1136, 1201,
52, 54, 55, 67, 72, 80, 89, 92, 93, 1328, 1438–1440, 1443, 1446, 1447
96–98, 100–102, 109, 118–120, 123, Enzymes, 269, 273, 274, 401, 402, 447, 448,
124, 126, 130, 132, 150, 152, 154, 155, 468, 497, 512, 516, 533, 547, 551–555,
174–177, 179, 182, 184–186, 189, 190, 604, 624, 626–629, 631–634, 641, 715,
193, 195–197, 200, 202, 203, 206, 207, 747, 753, 756, 791, 794, 797, 809, 813,
215, 216, 227, 228, 230–233, 239, 244, 816, 817, 826, 854, 856, 865, 869, 871,
245, 253, 255–262, 269, 271–273, 275, 906, 908, 918–923, 943, 945, 962, 973,
278, 281, 289, 290, 292, 298, 309, 314, 976, 978, 980, 982, 1022, 1048, 1051,
349–352, 360–372, 374, 386, 387, 400, 1055, 1058, 1064, 1068, 1098–1101,
401, 403, 410, 411, 414, 415, 420, 448, 1105–1107, 1137, 1139, 1144, 1190,
464, 466, 469, 482–485, 487, 489, 490, 1191, 1193, 1203, 1213, 1217, 1238,
494, 496, 502, 511, 519, 522, 529, 533, 1240, 1258, 1332, 1334, 1336–1338,
534, 545, 546, 550, 551, 554, 557, 565, 1349, 1351, 1352, 1413, 1417, 1418,
604, 624, 629, 631, 638–640, 643, 707, 1442, 1443, 1482, 1496, 1498, 1505,
728, 735, 739, 745, 747, 769, 780, 783, 1517, 1521
790, 791, 796, 798, 799, 814, 822, 823, Epigenetics, 448, 1136–1164, 1442, 1443,
825–827, 857, 863–880, 905, 906, 916, 1447, 1449
917, 927–929, 932, 933, 935, 938, 939, Epilepsy, 7, 17, 115, 117, 120, 173, 188, 199,
941, 944, 961, 965, 971–989, 1035, 217, 273, 298, 412, 414, 418, 701, 704,
1036, 1038, 1039, 1042, 1043, 1050, 821–827, 829–831, 847, 850, 851, 853,
1051, 1057, 1061, 1062, 1064, 1065, 854, 858, 933–935, 1038, 1300,
1067, 1097–1099, 1106, 1107, 1505, 1506
1117–1119, 1121, 1125, 1127, 1129, Essential oils (EOs), 18, 176, 179, 186, 198,
1136, 1139, 1160–1162, 1164, 1194, 208, 212, 272, 296, 297, 363, 364, 366,
1199–1203, 1205–1207, 1209, 1212, 413–418, 421, 428, 430, 434, 436–438,
1217, 1233–1242, 1247–1252, 442, 444, 446, 447, 450, 546, 554, 556,
1254–1260, 1268, 1270, 1275, 567, 569, 572, 612, 649–651, 654,
1300–1304, 1314, 1318, 1327, 656–665, 672, 675, 677–680, 682–686,
1330–1332, 1334–1338, 1340, 1341, 753, 837, 840, 841, 843, 893–900,
1348, 1353, 1357, 1359, 1360, 1365, 933–938, 943, 944, 952, 961, 965,
1371, 1406, 1412, 1419, 1429, 1430, 1049, 1050, 1062–1064, 1067,
1433–1435, 1438, 1441–1445, 1266–1269, 1273–1276, 1278, 1279,
1447–1449, 1457, 1460, 1464, 1468, 1304, 1316–1318, 1336, 1347, 1348,
1471, 1479–1481, 1483, 1484, 1486, 1351–1353, 1357–1359, 1504,
1488, 1489, 1497, 1502, 1507, 1515, 1506, 1528
1516, 1519, 1522, 1523 Ethnobotanical, 1–22, 25, 43–103, 108–110,
Drug delivery, 619, 748, 1163, 1164, 124, 126, 239, 289, 333–334, 358, 410,
1177–1194, 1255, 1366, 1370, 411, 416, 466, 486, 488–490, 1118
1538 Index

Ethno medicinal plant, 171–222 512, 532, 547, 589–607, 617, 623–629,
Ethnomedicine, 1, 40, 227, 228, 290, 296, 333, 631–635, 637–640, 649, 662, 679, 701,
352, 360–372, 382, 383, 428, 429, 768 704, 727, 740–744, 747, 753, 756, 757,
Ethnopharmacology, 50, 318 782, 790, 807–817, 863–865, 880, 893,
Exosomes, 1087, 1375, 1379 894, 905, 917, 928, 935, 944, 965, 966,
Explants sterilization, 716, 1007 971–973, 977–989, 1047, 1055–1057,
Extract, 5–15, 17, 19–21, 40, 57, 126–153, 1061, 1063, 1071, 1097, 1117, 1125,
172, 174–177, 181, 183, 186–192, 1189, 1234–1237, 1241, 1265–1267,
194–197, 200, 202, 206–209, 216, 217, 1269, 1271, 1272, 1274–1277, 1279,
234–239, 258, 261–263, 269, 271–274, 1281, 1304, 1335, 1348, 1357, 1358,
280, 299, 313, 322, 343, 345, 350, 361, 1388, 1414, 1417, 1423, 1439, 1443,
363, 366–369, 371, 373, 388, 390, 395, 1445, 1446, 1449, 1457, 1482,
397, 399–403, 411, 414–416, 418, 420, 1505, 1517
428, 430–446, 448–450, 467–471, 473, Food microbiota, 807, 808, 817
482, 484, 487, 489, 494–501, 511, 516, Food toxicants, 1429, 1443
518, 520–523, 530–536, 538, 546–548, Fourier transformed infrared spectroscopy
551–557, 567–575, 591–606, 615, 617, (FTIR), 592, 594, 599, 602, 713,
629, 634, 651, 655, 657, 659, 663–665, 719–722, 775, 1416
668, 670, 674, 677–686, 700, 703, Fruits, 7, 12–16, 19, 20, 45, 58, 90, 125–134,
707–715, 717–722, 725, 728–736, 745, 136–138, 142, 144–146, 148, 150, 151,
746, 770, 771, 773–780, 782, 797, 809, 153, 173, 174, 177, 178, 181, 182, 184,
839, 841, 842, 844, 845, 847, 865, 187, 192, 193, 196, 203–205, 230,
869–871, 877, 930, 933, 936, 938–945, 234–239, 243, 246–249, 263, 265–268,
947–949, 951, 960–962, 1000, 1002, 271, 278, 296, 336, 338, 339, 343–345,
1015, 1025, 1040, 1067, 1103, 350, 358, 362, 365, 367, 369–371, 384,
1105–1107, 1118–1122, 1125–1130, 429, 431–434, 443, 444, 465, 466, 470,
1136, 1138–1151, 1158–1162, 1164, 472, 484, 487–489, 494–498, 501, 502,
1184, 1206, 1209–1212, 1237, 1241, 566, 567, 569, 570, 572, 574, 576–579,
1255, 1266–1269, 1271, 1272, 1274, 603, 605, 637, 640, 650, 654–656, 660,
1276–1278, 1280, 1281, 1305–1317, 665, 700, 701, 703, 704, 791, 808, 815,
1319, 1329–1337, 1339, 1340, 1357, 843, 863, 864, 871, 877, 894, 906, 917,
1369, 1393–1398, 1412, 1413, 1416, 918, 932, 939, 982, 986–989, 1036,
1458, 1459, 1470, 1473, 1480, 1047, 1067, 1081–1085, 1089, 1103,
1482–1485, 1487, 1496, 1497, 1117–1122, 1125, 1126, 1128–1130,
1500–1502, 1504, 1506, 1517–1519, 1142, 1145, 1146, 1148, 1150, 1151,
1521–1523, 1525–1528 1161, 1200, 1211, 1251, 1255, 1258,
Extraction methods, 591, 994, 995, 998–1002, 1267, 1274–1277, 1305, 1306,
1267, 1354 1310–1313, 1315–1317, 1329, 1330,
1334, 1348, 1349, 1351, 1354, 1369,
1393, 1395, 1397, 1405, 1407, 1414,
F 1417, 1423, 1430, 1443, 1459, 1464,
Ficus, 58, 72, 97, 99, 100, 110, 114, 137, 204, 1469, 1470, 1472, 1502
232, 236, 487–502, 839, 1040, 1238, FTIR analysis, 592, 593, 599, 709, 713,
1396, 1412 725, 943
Floral diversity, 330
Folk medicine, 107, 123–156, 216, 253, 548,
556, 1118, 1336, 1479 G
Food, 2, 10, 11, 21, 40, 44, 45, 107, 110, 123, Garlic, 12, 144, 153, 245–248, 265, 484, 1058,
127, 131, 132, 144, 149, 152, 159, 175, 1140, 1149, 1252, 1309, 1352, 1357,
183, 200, 210, 227, 234, 235, 237, 1358, 1480, 1482–1484, 1496–1497
243–251, 259, 271, 274, 280, 294, 296, Gas chromatography-mass spectrometry
322, 323, 330, 357, 359, 360, 370, 373, (GC-MS), 389, 390, 416–418, 446,
374, 401, 411, 413, 414, 418, 429, 450, 465, 650, 651, 654–656, 659, 733–735,
464, 466, 472, 473, 486, 488, 498, 502, 900, 943
Index 1539

Gastronomy, 243, 244, 251 Hybrid combinations, 1266, 1268

Ginger, 12, 18, 128, 131, 137, 144, 152, Hydrodistillation (HD), 417, 897, 898, 900,
245–248, 313, 429, 430, 444, 445, 448, 1354–1356
449, 484, 1058, 1100–1101, 1151,
1253, 1359, 1483, 1484
Glycyrrhiza glabra, 263, 268, 279, 529–540, I
1065, 1144, 1221, 1238, 1256, 1516, Icacinaceae, 700, 701, 704, 705, 1012
1519, 1521–1523, 1525, 1527, 1528 Immunomodulators, 1301, 1302, 1304, 1317,
Glyoxalase I, 870 1318, 1368, 1516, 1519, 1523, 1528
Grafting propagation, 1082, 1085 Immunomodulatory, 126, 263, 266, 272, 273,
Green nanoparticles, 1419 412, 445, 449, 500, 529, 533–534, 556,
Green synthesis, 472, 1368, 1369, 1389, 779, 799, 962, 975, 1041, 1106, 1250,
1392–1397, 1412, 1419, 1421 1252, 1253, 1299–1319, 1422, 1502,
Grizzled Squirrel Wildlife Sanctuary 1516–1518, 1528
(GSWS), 43–103 Indian Traditional Medicine (ITM), 254,
Group culture fast propagation, 1087 257–260, 264–269, 272, 274, 275,
Growth hormones, 1087, 1498 279–281, 288
Gymnema sylvestre, 99, 262, 263, 267, 463, 1009, Indigenous, 1, 2, 21, 44, 57–58, 98, 102, 107,
1021, 1022, 1025, 1029, 1144, 1307 222, 227, 244, 249, 314, 317–321, 323,
324, 330, 334, 346, 352, 353, 358, 359,
374, 385, 410, 411, 416, 707, 768, 770,
H 935, 1035, 1036, 1040, 1043, 1051,
Hair fall, 29, 32 1056, 1299, 1457, 1471, 1480
Hair follicles (HFs), 611–619, 866, 867 Informant consensus factor (Fic), 51, 98, 103,
Hardening, 709, 1012, 1025–1028, 1206 109, 124, 154, 346, 349, 352
Herbal, 1, 22, 46, 47, 58, 91, 99, 222, 254, Intracellular antigens, 1249
272, 273, 279–281, 287, 292, 316, 333, In vitro, 271, 385–386, 395, 399–401, 403,
334, 353, 381, 386, 388, 403, 410, 429, 404, 414, 419, 428, 430, 434, 435, 437,
450, 463, 468, 482, 484–487, 522, 529, 439, 443–446, 467, 469, 470, 495, 518,
538, 546, 551, 649, 707, 727, 767–785, 534–536, 547, 552, 553, 555, 569–573,
830, 832–847, 855–857, 935, 937, 941, 600, 619, 628, 638, 639, 677, 678, 681,
942, 983, 1035–1037, 1039, 1054, 683, 686, 736, 794, 796, 797, 814, 826,
1057, 1058, 1061, 1097, 1177–1194, 857, 869, 871, 877, 879, 880, 945, 981,
1200, 1206, 1248, 1250, 1254, 1256, 1006, 1008, 1010–1023, 1025–1029,
1257, 1272, 1299, 1311, 1318, 1319, 1055–1057, 1065, 1067, 1072, 1097,
1338, 1340, 1341, 1475, 1479–1489, 1101, 1102, 1105, 1106, 1129, 1130,
1518, 1522, 1523, 1525 1164, 1184, 1209, 1217, 1274, 1275,
Herbal medicines, 58, 92, 94–96, 256, 1279, 1282, 1306, 1309, 1318, 1334,
279–281, 309, 314, 316, 330, 333, 334, 1335, 1348, 1373–1375, 1399–1401,
348, 350–351, 409, 429, 502, 511, 529, 1406, 1422, 1475, 1497, 1501, 1502,
557, 740, 830, 858, 929, 932, 979, 1521, 1522, 1526–1528
1036, 1061, 1070, 1072, 1089, 1100, In vitro propagation, 288, 1006, 1035–1043, 1057
1118, 1200, 1240, 1241, 1247, 1328, In vivo, 270, 271, 279, 385, 400, 401, 403,
1471, 1479–1489, 1516, 1528 414, 428, 430, 433–440, 443–448, 469,
Herbal remedies, 2, 51, 227, 253, 257, 275, 496, 500, 518, 534, 553, 555, 556, 569,
289, 315, 347, 350, 486, 529, 565, 823, 570, 638, 681, 686, 736, 794, 796, 814,
830–831, 932, 933, 1216, 1260, 1485 857, 871, 880, 909, 1065, 1072, 1097,
Herbal sources, 823, 857, 1002 1101, 1106, 1164, 1179, 1184, 1187,
Herbal vendors, 25–40 1194, 1217, 1251, 1282, 1306, 1309,
High-altitude plants, 291, 314 1318, 1334, 1335, 1348, 1374, 1389,
Himalaya, 1–22, 159, 160, 163–165, 167, 227, 1399–1401, 1406, 1410, 1414, 1421,
261, 263, 270, 280, 291, 294, 296–300, 1475, 1485, 1497, 1501, 1502,
308–312, 315, 316, 318, 321, 323, 1524–1525, 1528
381–404, 659, 929–931, 935, 1038, Iron deficiency, 971–973, 982, 983, 986, 989
1470, 1503 Irulas, 98, 107–120
1540 Index

L 410, 415, 430, 519, 529, 603, 870, 871,

Lakhimpur, 228, 229, 231–233 934, 989, 1035, 1036, 1041–1043,
Lamiaceae, 3, 6, 7, 9, 11–13, 15, 58, 61, 78, 1051, 1058, 1071, 1081, 1241, 1475,
79, 81, 83, 110, 115–117, 139, 142, 1481, 1485, 1489
143, 145, 147, 199, 230–233, 248, 249, Medicinal plants, 1–3, 21, 22, 43–103,
361, 366, 409–421, 840, 841, 1016, 107–109, 123–125, 155, 156, 160, 227,
1018, 1062, 1064, 1102, 1145, 1147, 228, 230, 254, 256–258, 264–270, 275,
1149, 1150, 1210, 1315, 1335, 1348, 278, 280, 287–289, 291, 292, 294–300,
1422, 1517 308, 310–317, 320, 323, 324, 330, 333,
Lathyrus sativus, 913, 914, 917, 923 334, 347–350, 352, 353, 357–374, 381,
Leguminosae, 3, 4, 7, 9, 12, 15, 16, 110–114, 382, 403, 409–411, 413, 414, 416, 420,
116–118, 125, 127, 128, 130–134, 138, 421, 446, 463, 464, 466, 481, 483–488,
140, 141, 143, 146–149, 151, 152, 248, 495, 502, 529, 538, 545, 565–574, 602,
249, 367–368, 790, 842, 1308, 1310, 605, 606, 612, 649, 699, 707, 724,
1311, 1314, 1316 778–782, 785, 858, 927–929, 931, 932,
Leguminous seeds, 972–973, 981, 988 938, 941, 944, 966, 967, 1005–1029,
Lemon balm, 1102–1103 1035–1043, 1054, 1055, 1061–1072,
Lethal dose (LD), 628–631, 642 1081–1090, 1097, 1117, 1118, 1127,
Lianas, 699, 700 1158, 1200, 1206–1211, 1213–1221,
Lily of the valley, 1505–1506 1238, 1266, 1318, 1319, 1329–1341,
Liposomes, 448, 616, 792, 810, 1178, 1349, 1350, 1354–1356, 1365, 1405,
1187–1189, 1194, 1275, 1368–1370, 1457, 1461, 1464, 1475, 1486, 1503,
1372, 1374, 1377–1379, 1388, 1517, 1518, 1520, 1528
1414–1415, 1421 Meganucleases (MNs), 1054
Low-density lipoproteins (LDLs), 501, 537, Metal nanoparticle, 1388
864, 867, 868, 871, 877, 879, 975, 980, Methanolic extract, 269, 386, 390, 399, 401,
987, 1099, 1104, 1484, 1496, 1497 402, 442, 467, 499, 500, 531–533, 535,
548, 551, 553–556, 567–569, 572, 573,
591–596, 599, 601, 602, 604, 605, 607,
M 678, 679, 681, 683, 685, 704, 728, 729,
Maceration, 591, 597, 949, 995, 1049 734, 736, 871, 938, 940, 943, 946, 950,
Magnetic nanoparticles (MNPs), 1368, 1369, 961, 962, 1084, 1125, 1127, 1129,
1371–1372, 1379 1211, 1272, 1276, 1305–1307, 1309,
Marine macroalgae, 739–757 1310, 1312, 1359, 1502
Meadow saffron, 1502–1503 Micelle, 448, 1373, 1378, 1379,
Mechanism, 310, 311, 485, 523, 529–540, 1415–1416, 1421
550, 565, 574, 590, 602, 603, 617, 620, Microbiota, 807, 808, 812, 817, 872, 1357
627–632, 636, 642, 705, 727, 753, 798, Micropropagation, 715, 1006, 1026, 1027,
823, 828, 877, 880, 899, 910, 911, 944, 1037, 1039, 1041, 1042, 1055
965, 971, 1100, 1101, 1199, Microwave-assisted hydrodistillation
1203–1205, 1207, 1216, 1251, 1270, (MHD), 900
1271, 1281, 1301, 1303, 1308, 1328, Momordica charantia, 98, 100, 102, 116, 144,
1331, 1336, 1338, 1340, 1347–1360, 262, 267, 1251, 1257, 1315, 1369
1417, 1484, 1501 Momo ricin, 1251
Mechanism of action, 255, 567, 606, 779, 794, Moringa, 80, 102, 116, 144, 263, 266,
827, 828, 880, 1190, 1204, 1210, 270–271, 463–473, 1040, 1146,
1258–1260, 1302, 1303, 1333, 1310, 1395
1351–1353, 1369, 1526 MS media, 386, 710, 714–717, 723, 724,
Medicinal and aromatic plants, 2, 287, 1010, 1011, 1022–1025, 1028,
291–292, 413, 941, 1064 1041, 1087
Medicinal herbs, 1–22, 261, 264, 269, 275, Mucilage, 295, 298, 530, 548, 655,
292, 295, 311–313, 329, 352, 381–404, 668, 707–725
Index 1541

N OD values, 600
Nagaland, 2, 3, 243, 250, 251 Ophiorrhiza brunonis, 727–736
Nano medicinal compounds, 1408, 1413, 1414 Orthosiphon, 81, 409–421
Nanoparticles, 448, 470, 554, 571, 573, 792,
810, 816, 1147, 1178–1189,
1271–1277, 1279–1281, 1366–1369, P
1371–1373, 1375, 1377, 1388–1401, Paliyar tribes, 44–47
1405–1423 Panax ginseng, 278, 777, 1084, 1252
Nanocarrier, 810, 813, 1180, 1278, 1368, Percolation, 995
1374, 1377–1379, 1409, 1410, 1415 Pharmacological, 102, 103, 240, 254, 256,
Nanofibre, 1369, 1376, 1377, 1379 259, 270, 272, 275, 278, 333, 351, 353,
Nanotechnology, 470, 472, 815, 816, 1177, 360–365, 367, 369–372, 381, 382, 395,
1187, 1190, 1194, 1242, 1277, 400, 403, 411, 414, 416, 421, 481–502,
1366–1368, 1371, 1387, 1408 513–514, 518, 522, 532–535, 557, 567,
Nardostachys jatamansi, 188, 311, 611–620, 590, 617, 624, 637, 649–686, 707, 708,
842, 937, 1038, 1238 727, 745, 746, 749, 754–756, 768, 778,
Natural antimicrobials, 605, 815, 1271, 1276 779, 784, 790, 794, 799, 823, 848, 857,
Natural compounds, 257, 318, 410, 420, 483, 880, 945, 961, 1037–1043, 1049, 1051,
605, 606, 757, 767, 783, 794, 798, 989, 1056, 1061–1072, 1097–1107, 1118,
1052, 1097, 1098, 1107, 1138, 1139, 1120, 1162, 1207, 1240, 1251, 1268,
1162, 1191, 1212, 1254, 1255, 1260, 1329, 1331, 1333, 1339, 1405, 1420,
1269, 1272, 1328, 1408, 1485, 1495, 1422, 1423, 1465–1469, 1475, 1488,
1496, 1499, 1518 1503, 1519, 1523
Natural drugs, 258, 309, 740, 743, 830, Pharmacological activities, 269, 272, 363, 365,
1061–1062 372, 374, 403, 411, 413, 414, 418, 419,
Natural products, 253, 254, 261, 308, 329, 429, 494, 501, 502, 511, 512, 518–522,
372, 409, 420, 481–484, 494, 679, 743, 529, 530, 538, 566, 573, 603, 612, 634,
745, 757, 767, 771, 777, 783, 784, 735, 745, 794–799, 942, 966, 1065,
789–790, 798, 808, 811, 815, 961, 994, 1068, 1125–1130, 1212, 1255, 1266,
1051, 1061, 1070, 1097, 1118, 1136, 1319, 1357, 1379, 1465
1162, 1207, 1250, 1254–1260, Pharmacological features, 1464
1265–1282, 1340, 1351, 1360, 1481, Pharmacology, 360–372, 381–383, 395–403,
1485, 1495, 1496, 1498, 1506, 466, 511–523, 768, 770, 853, 880, 929,
1507, 1523 989, 1067–1068
Necrosis, 400, 554, 570–573, 576, 615, 684, Phenolics, 269, 271, 273, 368, 369, 390, 391,
797, 978, 995, 1011, 1098, 1193, 1206, 395, 413, 414, 416, 465, 471, 484, 490,
1209, 1220, 1255, 1256, 1258, 1259, 501, 502, 533, 547, 550, 567, 569, 571,
1301, 1305, 1338, 1372, 1463, 1497, 589–591, 598, 601–604, 606, 623, 624,
1518, 1525–1527 634–643, 651, 655, 657, 662, 668, 670,
Nerve regeneration, 1331 712, 718, 719, 722, 731–732, 749, 753,
Neurodegenerative diseases, 412, 419, 483, 771, 774, 777, 778, 790, 793, 808–812,
631, 684, 798, 1202, 1236, 1237, 1327, 814–817, 864, 865, 869–872, 878, 910,
1328, 1335, 1337, 1340 929, 938–942, 948, 956, 960, 961, 966,
Nigella sativa, 1147, 1251, 1313, 1496 973, 974, 978, 980, 983, 987, 1049,
North Maharashtra, 25–40 1050, 1052, 1055, 1056, 1065–1068,
NO-synthase, 877, 1209 1070, 1072, 1101, 1102, 1105, 1107,
Nutraceuticals, 463–473, 546, 553, 704, 1120–1122, 1126, 1200, 1206, 1207,
739–757, 880, 973, 974, 979, 980, 989, 1209, 1210, 1218, 1219, 1255, 1258,
1055, 1118, 1251 1267, 1270, 1279, 1306, 1310, 1311,
1314, 1317, 1336, 1339, 1347,
1349–1352, 1449, 1466, 1496,
O 1498, 1502
Ocimum sanctum, 21, 110, 263, 266, 1147, Phytochemical analysis, 240, 366, 429, 708,
1280, 1304, 1319, 1516–1519, 1524, 709, 718, 719, 729–731, 733, 735, 929,
1526, 1528 938, 939, 967, 1121, 1418
1542 Index

Phytochemical constituents, 369, 382, 390, 624–629, 634, 636–638, 643, 649–651,
409, 410, 413–421, 547–548, 554, 557, 658, 663, 699–701, 703–705, 707–710,
703, 719, 966, 1049, 1051 712–716, 719, 722–725, 727–729,
Phytochemicals, 102, 103, 253, 272, 280, 292, 733–736, 740, 745, 767–785, 790, 791,
296, 348, 350–353, 360–365, 367, 369, 796, 807–812, 815–817, 830, 832, 833,
370, 372–374, 381–383, 385, 386, 836, 837, 840, 841, 843, 846, 847, 858,
389–391, 402, 403, 409, 411, 413, 414, 863–865, 869, 893–900, 905–924, 927,
416–419, 429–431, 448, 464, 465, 929–941, 943, 945–947, 951, 954, 961,
481–502, 545, 547, 549, 554, 565, 567, 962, 965–967, 971–989, 1002,
569, 571, 572, 574, 592, 602, 606, 640, 1005–1007, 1010–1012, 1022,
649–662, 703–704, 712–713, 718–723, 1026–1029, 1035–1043, 1047–1058,
725, 727, 728, 736, 774, 784, 815, 817, 1061–1068, 1070–1072, 1081–1088,
864, 871, 929, 930, 938, 939, 943, 947, 1102, 1103, 1105–1107, 1117–1123,
959, 961, 963, 966, 967, 978, 1125–1127, 1129, 1130, 1136,
1047–1049, 1056, 1057, 1061, 1072, 1138–1151, 1159–1163, 1191–1194,
1097, 1102, 1105, 1118–1125, 1129, 1199, 1200, 1206–1207, 1212, 1213,
1130, 1136, 1137, 1152–1158, 1216–1218, 1235, 1238–1241, 1248,
1160–1162, 1164, 1199, 1206, 1208, 1250, 1251, 1257, 1260, 1265–1271,
1212–1217, 1236, 1237, 1239, 1240, 1276, 1277, 1280, 1281, 1299–1319,
1242, 1281, 1318, 1328, 1329, 1335, 1328, 1329, 1335–1337, 1340, 1341,
1336, 1341, 1349, 1351, 1352, 1359, 1347–1360, 1366, 1368, 1369, 1374,
1360, 1365–1379, 1405, 1407–1410, 1376, 1379, 1387–1401, 1405–1423,
1414, 1415, 1421, 1422, 1448, 1449, 1448, 1449, 1457, 1461–1475,
1461, 1485, 1495–1497, 1517, 1520 1479–1481, 1484–1486, 1489, 1498,
Phytochemicals nanoencapsulated, 1272 1502–1506, 1516, 1518, 1519, 1523,
Phytochemistry, 360–372, 381–383, 386–395, 1524, 1526, 1528
429–430, 464–466, 483, 490–494, Pneumonia, 4, 132, 175, 194, 196, 228–233,
511–523, 530–532, 649–686, 929, 239, 240, 557, 606, 662, 678, 679,
938–939, 1120 1118, 1203, 1460, 1525
Phyto-constituents, 270, 272, 275, 278, 279, Poisonous medicinal plants, 1457–1475
421, 447, 547, 548, 572, 597, 602, 603, Polymeric nanoparticle (PNP), 1179–1180,
703, 712, 727, 729, 731–735, 821–858, 1184, 1374–1376, 1378, 1379,
938, 961, 1047, 1123–1125, 1130, 1398–1400
1200, 1206, 1251, 1253, 1257, 1473, Polyphenolics, 428, 496, 502, 591, 598,
1475, 1518, 1523 601–603, 605, 607, 650, 749–753, 811,
Phytomedicine, 463–473, 545–557, 932, 812, 815–816, 865, 871, 974, 1047,
1200, 1238 1056, 1101, 1122, 1130, 1209, 1217,
Phyto nanotechnology, 1408, 1410 1237, 1268, 1272, 1314, 1371,
Plant-based anticancer drug, 565, 1374 1423, 1449
Plants, 1–18, 20–22, 25, 27, 40, 43, 44, 50, 51, Polyphenols, 253, 269–271, 463–465, 467,
57, 58, 90–94, 96, 97, 99, 102, 103, 470, 487, 496, 547, 553, 603, 636, 640,
107–120, 123–153, 155, 159, 161, 744, 745, 749, 757, 780, 790, 807–817,
163–165, 172–217, 222, 223, 227, 228, 863–880, 938, 942, 943, 977, 978, 983,
230–235, 237–240, 244, 246–249, 253, 984, 987, 988, 1067, 1101, 1105, 1119,
254, 257–259, 265, 268–275, 278–280, 1138, 1139, 1206, 1216–1221, 1236,
287–289, 292, 298, 300, 308–318, 323, 1270, 1276, 1279, 1313, 1349,
329, 330, 333–335, 337, 339–346, 1422–1423, 1504, 1505
348–353, 357, 359–374, 381–383, Potential cyanide, 628, 630, 632, 633,
385–387, 395, 401–404, 409–414, 635, 642
416–421, 427–450, 463, 464, 466, 467, Preservation, 50, 259, 313, 315, 324, 330, 333,
469, 472, 473, 481–489, 495–497, 358, 411, 591, 604, 605, 753, 781,
500–502, 511, 513, 515, 516, 518, 519, 815–816, 988, 1102, 1348, 1486
529, 532, 545–549, 551–557, 566–575, Psidium guajava, 117, 235, 239, 1216,
589–591, 601, 602, 604–606, 612, 1251, 1420
Index 1543

Q 371, 384, 385, 432–434, 440, 443, 463,

Qualitative analysis, 403, 530, 591, 597, 598, 465–469, 471–473, 488, 489, 502,
929, 939 566–576, 578–580, 603, 625, 650, 682,
Quality control, 280, 281, 771 700, 701, 704, 775, 791, 839, 841, 871,
Quantitative indices, 353 894, 900, 932, 939, 972–983, 985, 989,
996, 998–1001, 1006–1011, 1013,
1016–1019, 1021–1025, 1036, 1037,
R 1039–1042, 1047, 1057, 1067,
Rare and endangered medicinal plants, 1037, 1082–1085, 1087, 1089, 1103, 1117,
1081–1084, 1088–1089 1119, 1140, 1141, 1144–1147, 1211,
Rauvolfia, 117, 148, 318, 511–523, 768, 769, 1237, 1251, 1252, 1257, 1274, 1306,
781, 1007, 1010, 1014, 1023, 1026, 1308, 1312, 1313, 1315–1317, 1348,
1040, 1084 1354, 1357, 1358, 1458–1461, 1464,
Reactive nitrogen species (RNS), 400, 401, 1469–1472, 1479, 1485, 1496, 1504
879, 1052, 1098 Sesame oil, 129, 996–1002
Reactive oxygen species (ROS), 400, 401, Sida cordiflia, 1251
467, 469, 470, 485, 537, 538, 550, 551, Siddha, 1, 52, 254–260, 264, 272, 274,
571, 574, 579, 605, 615, 619, 735, 796, 287–289, 1200, 1457
799, 870, 879, 928, 944, 962, 965, 966, Sjogren’s syndrome, 1249
977, 1052, 1067, 1098, 1101, 1142, Skin diseases, 6, 7, 15, 18, 52, 59, 60, 62,
1215, 1217, 1255, 1306, 1307, 1330, 67–69, 71, 74, 84, 90, 113–118, 120,
1331, 1334, 1337, 1338, 1369, 1395, 125, 126, 128, 130, 132, 140, 149, 153,
1396, 1407, 1417, 1440, 1499 155, 175, 178, 180, 188, 189, 192, 193,
Research investigation, 924, 984 196, 211, 217, 264, 265, 272, 297–299,
Restoration, 485, 1012, 1028–1029, 1037, 344, 489, 498, 545, 546, 612, 699, 701,
1138, 1303, 1526 704, 933, 935, 1472
Resveratrol, 296, 448, 636, 812, 870, Small intestine, 187, 626, 632, 1253, 1357
878–880, 1139, 1155, 1218, 1255, Smilax, 16, 210, 1500–1502
1258, 1373, 1449 Solidifying property, 708, 709, 725
Rheum ribes, 1105–1106 Solid lipid nanoparticles (SLNs), 448,
Ricinus communis, 20, 117, 120, 126, 148, 1374–1375, 1379, 1421
233, 238, 1148, 1459, 1464, 1465, Sowa Rigpa, 307–313
1470–1471 Staple food, 45, 472, 625, 984, 985, 988, 1357
rol gene, 917 Steam distillation (SD), 413, 704, 893–900,
1348, 1354, 1356
Strobilanthes, 169, 198, 545–557, 1148
S Sumac, 246, 248, 1101–1102
Sarcostigma kleinii, 699–705 Sunderdhunga valley, 160, 163, 171
SARS-CoV-2, 1502, 1515–1528 Sustainability, 250, 314, 330
Secondary metabolites, 269, 410, 413, 414, Sustainable utilization, 404, 421, 1037
416, 420, 421, 428–430, 463, 464, 466,
484, 502, 513–514, 529, 530, 547, 550,
555, 571, 602, 727–736, 744, 749, T
754–756, 776, 778, 863, 893, 939, 943, Targeting, 419, 448, 450, 547, 578, 798, 851,
961, 962, 966, 1006, 1035, 1037, 1039, 854, 858, 1052, 1137, 1139, 1162,
1047, 1049, 1051–1053, 1056–1058, 1184, 1186, 1187, 1190, 1205, 1241,
1064–1067, 1070, 1117, 1119, 1206, 1254, 1365–1367, 1370–1373, 1388,
1212, 1250, 1265, 1319, 1353, 1412, 1389, 1400, 1401, 1421, 1517,
1420, 1448, 1449, 1502, 1521 1522, 1527
Seed propagation, 1082–1085 T-DNA, 906, 908–912, 914–917
Seeds, 4, 9, 10, 13, 16, 20, 25–40, 46, 58, 90, Technology, 2, 21, 280, 281, 317, 319, 409,
125–134, 137–141, 143–145, 147–149, 413, 482, 545, 686, 733, 767, 896, 899,
151–153, 163, 174, 179, 182, 189, 905, 985, 989, 1006, 1049, 1055, 1057,
199–203, 206, 207, 234, 235, 237–239, 1086, 1089, 1161, 1177, 1187, 1189,
246–249, 265, 268, 270, 271, 322, 1194, 1387, 1388, 1395, 1410, 1421,
335–339, 341, 342, 345, 350, 361, 366, 1422, 1495, 1506
1544 Index

Terminalia, 88, 94–97, 103, 151, 261, 263, 266, Traditional healers, 3, 43–103, 108, 109, 120,
271–272, 278, 313, 775, 779, 1008, 229, 290, 318, 320, 334, 1475, 1480
1011, 1015, 1023, 1026, 1117–1130, Traditional medicinal knowledge, 292
1211, 1277, 1280, 1306, 1317 Traditional medicinal plants, 229, 287, 352,
Therapeutic agent, 409, 419, 420, 448, 483, 353, 1486
496, 799, 1237, 1248, 1457 Traditional medicine, 1, 43, 44, 102, 156, 227,
Therapeutic efficacy, 280, 411, 781, 244, 253, 254, 256–258, 260, 264, 269,
1340, 1399 271, 272, 274, 275, 280, 281, 287, 288,
Therapeutic properties, 20, 253, 254, 264, 270, 307, 308, 310, 329, 330, 333, 386, 390,
272, 273, 386, 411, 482, 485, 782, 896, 409, 411, 414–416, 444, 481–484, 486,
937, 1049, 1238 502, 511, 522, 529, 538, 545–547, 557,
Therapeutics, 1–4, 8, 11, 16, 18, 20, 21, 253, 569, 573, 649, 735, 736, 739, 740, 767,
255–258, 261, 264, 270–272, 279, 309, 830, 858, 932, 935, 1035, 1036, 1041,
314, 318, 333, 382, 410, 413, 418–421, 1042, 1102, 1117, 1118, 1299, 1335,
430, 447, 448, 468, 471, 481, 483, 486, 1360, 1420, 1457, 1479, 1480, 1482,
487, 498, 501, 502, 519, 522, 523, 540, 1485, 1489, 1500
545, 553, 604, 616, 649, 684, 705, 727, Transcription factors (TFs), 390, 442, 447, 472,
735, 739, 744–745, 748, 768, 770–771, 614, 732, 734, 747, 795, 798, 1048,
779–782, 784, 789–800, 853, 858, 877, 1107, 1137, 1139, 1160, 1216, 1258
932, 933, 938, 939, 942, 975, 976, 980, Transgenesis, 1053
1029, 1040, 1043, 1047, 1049, 1051, Trans-Himalaya, 308, 310, 311, 314, 315,
1068, 1103, 1106, 1118, 1120–1122, 324, 1037
1125, 1127, 1130, 1137, 1161–1163, Transmembrane protease serine 2
1177, 1178, 1186, 1187, 1189, 1190, (TMPRSS2), 1520, 1528
1205, 1211, 1212, 1216, 1236, 1238, Tribes, 25, 44, 45, 98, 107–110, 119, 120, 227,
1239, 1248, 1250, 1251, 1256, 1258, 229, 243, 250, 386, 488, 701, 703, 710
1260, 1266, 1300, 1304, 1329, 1337, Trigonella foenum-graecum L., 38, 262, 268,
1341, 1358, 1375, 1389, 1391, 1401, 1252, 1358, 1496
1407, 1408, 1413, 1418, 1439, 1469, Trillium govanianum, 210, 381–404
1479, 1481, 1486, 1487, 1495–1507, Triphala, 263, 264, 1118, 1127, 1276
1515, 1521, 1522, 1528 Tumour cells, 536, 572, 574, 975, 1177, 1187,
Thymol, 363, 415, 660, 813, 814, 894, 1190, 1194, 1376, 1390–1392, 1400,
996–1002, 1050, 1066, 1267, 1269, 1407, 1438
1277, 1279, 1316, 1357, 1359
Tinosopra cordifolia, 272, 1518, 1519, 1523,
1524, 1526 U
Toxic plants, 939, 1475 Unani medicine, 255, 259, 272, 274, 294,
Traditional, 1–3, 21, 25, 26, 40, 44, 96, 97, 295, 1469
107, 108, 120, 123, 155, 163, Urtica dioica, 205, 1106–1107, 1149, 1273
227–230, 234–239, 243, 244,
249–251, 253–257, 259–261, 264,
269, 280, 281, 287–290, 296, 307, W
308, 310–313, 315–322, 324, 329, Wet tropics, 357–374
330, 333, 350, 352, 358–360, 374, Withania somnifera, 262, 263, 266, 272–273,
381, 382, 386–388, 410–414, 416, 345, 779, 847, 1150, 1200, 1238, 1255,
418, 421, 427, 429, 444, 446, 450, 1329–1331, 1516, 1518, 1520, 1524,
468, 485, 486, 488, 489, 496, 502, 1526, 1528
516, 522, 546, 552, 556, 633, 699,
707, 727, 739, 741, 743, 768, 770,
790, 830, 896, 929, 932, 933, 935, Z
936, 944, 945, 965, 979, 981, 1035, Zingiber officinale, 95, 96, 118, 153, 233, 238,
1036, 1043, 1049, 1054, 1057, 1061, 239, 263, 278, 428, 439, 448, 779,
1067, 1081, 1090, 1100, 1103, 1107, 1100, 1101, 1219, 1313, 1523
1118, 1128, 1162, 1180, 1212, 1259, Zingiberaceae, 4, 8, 11, 20, 69, 73, 111, 113,
1276, 1299, 1300, 1338, 1339, 1365, 118, 134, 135, 138, 141, 153, 208,
1367, 1388, 1395, 1473, 1479–1481, 230–233, 248, 427–450, 1140, 1145,
1520, 1522, 1524 1151, 1208, 1312, 1313, 1317