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1572_title 11/17/05 4:39 PM Page 1

Dictionary of
Nutraceuticals
and Functional
Foods
N. A. Michael Eskin
Snait Tamir

Boca Raton London New York

A CRC title, part of the Taylor & Francis imprint, a member of the
Taylor & Francis Group, the academic division of T&F Informa plc.
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Version Date: 20130919

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 Dedication

This book is dedicated

to
a wonderful wife
Nella Eskin
and
a wonderful daughter
Orr Tamir
Preface
The current emphasis in preventative medicine encourages healthy lifestyles such as a balanced
diet and exercise. In recent years a balanced diet has focused on ensuring functional foods are part
of our diet. Functional foods are similar in appearance to conventional foods, but in addition to
providing basic nutritional components, have physiological benefits that can reduce the risk of
chronic diseases. The bioactive components responsible for the health benefits of functional foods
are referred to as nutraceuticals. The past decade has witnessed a dramatic expansion in research
activities worldwide to identify new functional foods and nutraceuticals. The latter will hopefully
enhance the health and wellbeing of an aging population.
Research on functional foods and nutraceuticals is scattered throughout the scientific literature
with only a very few journals devoted specifically to nutraceuticals. We have attempted to bring
together, in a concise and informative manner, some of the literature published on 480 functional
foods and nutraceuticals. This dictionary, which is more of a mini-encyclopedia, provides the reader
with useful information on the nature of the bioactives in functional foods and their reported efficacy
in cell cultures, animal studies, and, in some cases, human clinical trials. In addition to providing
the structures of some of the bioactives or nutraceuticals, data showing their efficacy are also
included. The information is presented alphabetically with some areas more extensively researched
in the literature than others. We hope this book will prove a useful resource for researchers, teachers,
as well as those working in the functional food and nutraceutical industry by providing reliable
and accurate information based solely on peer-reviewed literature.
The authors acknowledge the professional help afforded by the staff of Taylor & Francis as
well as the assistance of Marie Speare, reference librarian at the University of Manitoba. The
authors are particularly appreciative of the support given by their respective families and academic
institutions in preparing this unique volume.

N.A. Michael Eskin

S. Tamir
 A A
Bifidobacterium spp., Int. J. Food Microbiol.,
Acacia gum Acacia gums, or gum arabic, are 24:199–210, 1994.
Acacia-tree exudates that are highly branched
Gamal el-adin, A.M., Mostafa, A.M., Al-Shabanah,
galactan polymers with galactose or arabinose O.A., Al-Bekairi, A.M., and Nagi, M.N., Protective
side chains terminated by rhamnose or glucu- effect of arabic gum against acetaminophen-induced
ronic acid. It cannot be digested in the small hepatoxicity in mice, Pharmacol. Res., 48:631–635,
intestine but behaves as a prebiotic by enhanc- 2003.
ing the growth of the probiotic bifidobacteria
(Wyatt et al., 1986; Crociani et al., 1994). Hosobuchi, C., Lapa Rutanassee, B.S., Bassin, S.L.
and Wong, N.D., Efficacy of acacia, pectin, and guar
Michel and coworkers (1998) confirmed the
gum-based fiber supplementation in the control of
similarity between two acacia gums and a pre-
hypercholesterolemia, Nutr. Res. 19:643-649, 1999.
biotic fructooligosaccharide with respect to
their ability to decrease Clostridium sp. levels Michel, C., Kravtchenko, T.P., David, A., Gueneau,
in human intestinal microbiota, as well as S., Kozlowski, F., and Cherbut, C., In vitro prebiotic
increase Lactobacillus sp. counts. However, the effects of acacia gums onto the human intestinal
fructooligosaccharide preparation induced microbiota depends on both botanical and environ-
mental pH, Anaerobe, 4:257–266, 1998.
higher levels of Lactobacillu sp. The overall
effect was attributed to increased production of Rehman, K., Wingertzahn, M.A., Harper, R.G., and
short-chain fatty acids. Wapnir, R.A., Proabsorptive action of gum arabic:
Hosobuchi et al. (1999) demonstrated the Regulation of nitric oxide metabolism in basolateral
efficacy of supplementing diets with acacia potassium channel of the small intestine, Gastroen-
gum, pectin, and guar gum for controlling terol. Nutr., 35:429–533, 2001.
hypercholesterolemia. A significant reduction Wyatt, G.M., Bayliss, C.E., and Holcroft, J.D., A
was observed for both total and LDL choles- change in human faecal flora in response to inclusion
terol in 50 adults after four weeks on the sup- of gum arabic in the diet, Br. J. Nutr., 55:261–266,
plemented diet. 1986.
Arabic gum was shown by Rehman et al.
(2001) to scavenge nitric oxide. The decrease
in the production of nitric oxide by arabic gum
was later shown by Gamal el-adin et al. (2003) Acetyl-L-carnitine see also Carnitine
to protect against acetaminophen-induced Acetyl-L-carnitine, an acetyl ester of carnitine,
hepatoxicity in mice. This reduction in oxida- functions as a carrier of long-chain fatty acids
tive stress (nitric-oxide production) was similar into the mitochondria for β-oxidation. It also
to the protection by arabic gum against genta- contributes to oxidative phosphorylation by the
mycin-induced nephrotoxicity reported previ- acetyl group forming acetyl-CoA, which
ously by Al-Majed et al. (2002). enhances the supply of energy substrates to the
Krebb’s cycle (Dolezal and Tucek, 1981). Dur-
References ing normal oxidative metabolism, the continu-
Al-Majed, A., Mostafa, A.M., Al-Rikabi, A.C., and ous production of reactive-oxygen metabolites
Al-Shabanah, O.A., Protective effects of oral arabic (ROM) is extremely reactive, causing extensive
gum administration in gentamycin-induced nephro- mitochondrial DNA, cellular, and tissue dam-
toxicity, Pharmacol. Res., 47:4456–451, 2002. age over time. Such changes are associated with
Crociani, F., Alessandrini, A., Mucci, M.M., and Bia- many chronic diseases, such as atherosclerosis,
vati, B., Degradation of complex carbohydrates by arthritis, autoimmune diseases, cancers, heart

1
 2 ACETYL-L-CARNITINE

disease, and cerebrovascular accidents, as well potential in the therapeutic treatment of Parkin-
as aging. Seidman and coworkers (2000) exam- son’s disease.
A ined the ability of two mitochondrial metabo- Tomassini et al. (2003) found that acetyl-L-
lites, including acetyl-L-carnitine, to enhance carnitine was well-tolerated as an alternative to
mitochondrial function and reverse age-related the drug amantadine for the treatment of fatigue
processes in experimental rats. Acetyl-L-car- in multiple-sclerosis patients. A recent review
nitine was found to delay the decline in mito- by Ilias et al. (2004) pointed to the potential of
acetyl-L-carnitine for treating complications
H3C associated with HIV infection and antiretroviral
+ O
therapy. However, the data obtained so far were
N
based on small, uncontrolled clinical trials and
H3C
CH3 require further investigation.
OH
H3C O
References
Acetyl-L-carnitine. (From Ilias et al., Mitochon- Biagiotti, G. and Cavallini, G., Acetyl-L-carnitine vs
drion. 4:163–168, 2004. With permission.) tamoxifen in the oral treatment of Peyronie’s disease:
a preliminary report, B.J.U. Int., 88(1):63–67, 2001.
chondrial function by reducing age-associated Dolezal, V. and Tucek, S., Utilization of citrate, ace-
deterioration in auditory sensitivity and improv- tylcarnitine and carnitine palmityltransferase in the
ing cochlear function. Kopke and colleagues transport of fatty acyl groups across mitochondrial
(2002) also found that acetyl-L-carnitine membranes, J. Neurochem., 36:1323–1330, 1981.
reduced noise-induced hearing loss in animals
Ilias, I., Manoli, I., Blackman, M.R., Gold, P.W., and
due to cochlear injury from oxidative stress.
Alesci, S., L-Carnitine and acetyl-L-carnitine in the
Turpeinen et al. (2000) showed acetyl-L-car-
treatment of complications associated with HIV
nitine prevented loss of myocardial sympathetic infection and antiretroviral therapy, Mitochondrion.
nervous function in patients with diabetes. Kaur 4:163–168, 2004.
and coworkers (2001) demonstrated new anti-
aging effects of acetyl-L-carnitine by its ability Kaur, J., Sharma, D., and Singh, R., Acetyl-L-car-
to enhance glutathione S-transferase and multi- nitine enhances Na(+), K(+)-ATP-ase glutathione-S-
transferase and multiple unit activity and reduces
ple-unit activity and reduce lipid peroxidation
lipid peroxidation and lipofuscin concentration in
and lipofuscin levels in the brain regions of aged rat brain regions, Neurosci. Lett., 301:1–4, 2001.
aged rats. Biagiotti and Cavallini (2001)
reported acetyl-L-carnitine was a far more Kopke, R.D., Coleman, J.K., Liu, J., Campbell, K.C.,
effective and safer alternative to tamoxifen in and Riffenburgh, R.H., Candidate’s thesis: Enhanc-
the treatment of Peyronie’s disease. A recent ing intrinsic cochlear stress defenses to reduce noise-
induced hearing loss, Laryngoscope, 112(9):1515–
study by Mazzio et al. (2003) showed acetyl-
1532, 2002.
L-carnitine prevented neurological damage in
mouse brain neuroblastoma cells by 1-methyl- Loots, D.T., Mienie, L.J., Bergh, J.J., and Van der-
4-phenyl-1,2,3,6-tetrahydropyridine (MPTP+), Schyf, C.J., Acetyl-L-carnitine prevents total body
a cogent Parkinson-causing agent. This benefi- hydroxyl free radical and uric acid production
cial effect may be due to its ability to sustain induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropy-
neuronal energy supplies in the absence of oxy- ridine (MPTP) in the rat, Life Sci., 75:1243–1253,
2004.
gen or when there is a malfunction of mitochon-
drial oxygen utilization, typical of Parkinson’s Mazzio, E., Yoon, K.J., and Soliman, K.F.A., Acetyl-
disease. Recent studies by Loots et al. (2004) L-carnitine protection against 1-methyl-4-phenylpy-
suggested acetyl-L-carnitine may prevent ridinium toxicity in neuroblastoma cells, Biochem.
MPTP+ toxicity by denying cation access to the Pharmacol., 66:297–306, 2003.
inner mitochondrial membrane, thereby atten- Seidman, M.D., Khan, M.J., Bai, U., Shirwany, N.,
uating its ability to produce radical-oxygen spe- and Quirk, W.S., Biologic activity of mitochondrial
cies via the electron-transport chain. These metabolites on aging and age-related hearing loss,
results suggest acetyl-L-carnitine may have Am. J. Otol., 21(2):161–167, 2000.
 ACRIDONE ALKALOIDS 3

O OH
O OH O OH

6
1 2 R1
N
R1

O
A
R4
R5 5 N 4 3 R2 N O
R3 R2 R2
R4 CH3 R3 OH CH3 R1

R1 R2 R3 R4 R5 R1 R2 R3 R4 R1 R2
1 H OH H H H 9 H H H H 16 OCH3 H
2 OCH3 OCH3 H OH H 10 H CH3 H H 17 H prenyl
3 H OCH3 H OH OCH3 11 H H OCH3 OH
4 H OCH3 OCH3 OH H 12 prenyl H H H
5 H OCH3 OCH3 OCH3 OH 13 prenyl H OH H
6 H OH prenyl H H 14 prenyl CH3 H H
7 H OCH3 prenyl H H 15 prenyl CH3 OH H
8 geranyl OH H OH H
18 prenyl OH prenyl H H
prenyl = geranyl =

SCHEME A.1 Structures of acridone alkaloids tested for inhibition of TPA-induced EBV-EA activation. (From
Itoigawa et al., Cancer Lett., 193:133–138, 2003. With permission.)

Tomassini, V., Pozzilli, C., Onesti, E., Pasqualetti, P., when tested in a short-term, in vitro assay of
Marinelli, F., Pisani, A., and Fieschi, C., Comparison 12-O-tetradecanoylphorbol-13-acetate (TPA)-
of the effects of acetyl-L-carnitine and amantadine induced Epstein–Barr virus early antigen (EBV-
for the treatment of fatigue in multiple sclerosis: EA) activation in Raji cells. The prenylated
Results of a pilot, randomised, double-blind, cross-
acridone alkaloids included glycocitrin-II (6),
over study, J. Neurol. Sci., 218:103–108, 2004.
O-methylglycocirine-II (7), severifoline (12),
Turpeinen, A.K., Kuikka, J.T., Vanninen, E., Yang, and ataphyllinine (13). The importance of the
J., and Uusitupa, M.I., Long-term effect of acetyl-L- prenyl group was confirmed with the synthetic
carnitine on myocardial 1231-MIBG uptake in diprenylated acridone, 1,3-dihydroxy-10-
patients with diabetes, Clin. Auton. Res., 10(1):13– methyl-2,4-diprenylacridone (18). Using an in
16, 2000. vivo, two-stage mouse skin carcinogenesis
model, it reduced the percentage of tumor-bear-
ing mice to 73 percent after 10 weeks (Figure
A.1), and the number of papillomas by approx-
Acridone alkaloids Acridone alkaloids have
imately 48 percent after 20 weeks (Figure
been isolated from a number of plant sources,
A.1B), compared to the nonprenylated acri-
including citrus plants (family Rutacea). Some
dones, 1,3-dihydroxy-10-methylacridone (1)
of them have been shown to exhibit cytotoxic,
and glycofilinine (5).
antiviral, and antimalarial properties (Kawaii et
al., 1999; Yamamoto et al., 1989; Queener et References
al., 1991). A screening test showed that acri- Itoigawa, M., Ito, C., Wu, T-S., Enjo, F., Tokuda, H.,
done alkaloids from citrus plants exhibited the Nishino, H., and Furukawa, H., Cancer chemopre-
most potent inhibition of 12-O-tetrade- ventive activity of acridone alkaloids on
canoylphorbol-13-acetate (TPA)-induced Epstein–Barr virus activation and two-stage mouse
Epstein–Barr virus early antigen (EBV-EA) skin carcinogenesis, Cancer Lett., 193:133–138,
activation (Takemura et al., 1995). Further stud- 2003.
ies by Itoigawa and coworkers (2003) isolated Kawaii, S., Tomono, Y., Katase, E., Ogawa, K., Yano,
17 acridone alkaloids from Rutaceous plants. M., Takemura, Y., Ju-ichi, M., Ito, C., and Furukawa
Their structures are shown in Scheme A.1. Of H., The antiproliferative effect of acridone alkaloids
these, the prenylated acridones were found to on several cancer cell lines, J. Nat. Prod.,
be the most potent cancer protective agents 62:587–589, 1999.
 4 ADLAY

100 10

A
Papillomas bearers (%)
80 8

Papillomas/Mouse
60 6

40 4

20 2

0 0
5 10 15 20 5 10 15 20
Weeks after promotion Weeks after promotion
(a) (b)

FIGURE A.1 Inhibitory effects of acridone alkaloids on DMBA-TPA mouse skin carcinogenesis. Tumor
formation in all mice was initiated with DMBA (dimethylbenz[α]anthracene) (390 nmol) and promoted with
TPA (1.7 nmol) twice weekly, starting one week after initiation. (a) Percentage of mice with papillomas. (b)
Average number of papillomas per mouse: ●, control TPA alone; o, TPA + 85 nmol of 1,3-dihydroxy-10-
methyl-2.4-diprenylacridone (18); ∆, TPA + 85 nmol of 1,3-dihydroxy-10-methylacridone (1); ▫ , TPA + 85
nmol of glycofolinine (5). After 20 weeks of promotion, a difference in the number of papillomas per mouse
between the groups treated with acridones and the control was evident (p < 0.05). (From Itoigawa et al.,
Cancer Lett., 193:133–138, 2003. With permission.)

Queener, S.F., Fujioka, H., Nishiyama, Y., Furikawa, showed dehulled adlay had a significant effect
H., Bartlett, M.S., and Smith, J.W., In vitro activities on the growth of intestinal bacteria in rats. Ani-
of acridone alkaloids against Pneumocystis carnii, mals fed adlay had normal, healthy walls with
Antimicrob. Agents. Chemother., 33:6–9, 1991. no pathogenic signs. In addition, there were
Takemura, Y., Ju-Ichi, J., Ito, C., Furukawa, H., and higher concentrations of short-chain fatty acids
Tokuda, H., Studies on the inhibitory effects of some in the GI tracts. One of these, butyric acid, was
acridone alkaloids on Epstein–Barr virus activation, shown to inhibit the growth of colonic tumors
Planta Med., 61:366–368, 1995. (Smith and German, 1995). Kuo and coworkers
(2001) found that methanolic extracts of adlay
Yamamoto, N., Furukawa, H., Ito, Y., Yoshida, S.,
hulls exhibited multiple antioxidant properties
Maeno, K., and Nishiyama, Y., Anti-herpesvirus
activity of citrusinine-1, a new acridone alkaloid, and and induced apoptosis in human histolytic lym-
related compounds, Antiviral Res., 12:21–36, 1989. phoma monocytic cells. The antitumor proper-
ties of adlay were further demonstrated by
Chiang et al. (2000b) by its inhibition of sar-
coma-180 tumors in mice. A methanolic extract
Adlay Adlay (Coix lachryma-jobi L.), a grass of adlay was subsequently shown by Chang et
crop grown in China, is used as an herbal med- al. (2003) to be antiproliferative on A549 lung
icine and a food. A number of bioactive sub- cancer cells in mice by inducing cell cycle
stances isolated from different parts of adlay arrest and apoptosis. Shih et al. (2004) recently
were shown to exhibit anti-inflammatory, anti- found that a diet containing 20 percent dehulled
tumor, and hypoglycemic activities. Early stud- adlay suppressed the early events in the devel-
ies by Ukita and Tanimura (1961) and Tanimura opment of cancer and not the formation of
(1961) showed the active component in adlay tumors in azoxymethane-induced colon car-
that inhibited the growth of Ehrlich ascites sar- cinogenesis in rats.
coma was coixenolide. A number of benzox- Kuo and coworkers (2002) identified the
azines isolated from adlay seeds were later antioxidants in a 1-butanol extract of adlay hulls
found to have anti-inflammatory activity exhibiting strong, radical-scavenging activity as
(Nagao et al., 1985). Chiang et al. (2000a) coniferyl alcohol, syringic acid, ferulic acid,
 ADLAY 5

2.5

2.0
Control
10% dehulled adlay
20% dehulled adlay
A
50% dehulled adlay

1.5

Elisa unit *
1.0 *
*
0.5

0.0

FIGURE A.2 Effects of different dosages of dehulled adlay on OVA-specific IgE levels in serum of mice
consuming the test diets for six weeks and then intraperitoneally immunized with OVA plus alum. (From Hsu
et al., J. Agric. Food Chem., 51:3763–3769, 2003. With permission.)

syringaresinol, 4-ketopinoresinol, and a new Hsu, H.-Y., Lin, B.-F., Lin, J.-Y., Kuo, C.C., and
lignan, mayuenolids. Hsu et al. (2003) showed Chiang, W., Suppression of allergic reactions by
that oral administration of several fractions dehulled adlay in association with the balance of
obtained from dehulled adlay modulated Th1/Th2 cell responses, J. Agric. Food Chem.,
51:3763–3769, 2003.
Th1/Th2 cytokine production in cultured sple-
nocytes obtained from ovalbumin (OVA)- Kim, S.O., Yun, S.-J., Jung, B., Lee, E.H., Hahm, D.-
immunized male BALB/c mice. This caused Y., Shim, I., and Lee, H.-J. Hypolipidemic effects of
suppression of IgE biosynthesis (Figure A.2), crude extract of adlay seed (Coix lachrymajobi var:
which suggested it could be used to alleviate mayuen) in obesity rat fed high fat diet: Relation of
allergic symptoms. TNF-α and leptin mRNA expressions and serum
lipid levels, Life Sci., 75:1391–1404, 2004.
A crude adlay-seed extract was shown by
Kim and coworkers (2004) to exert hypolipi- Kuo, C.-C., Shih, M.-C., Kuo, Y.-H., and Chiang, W.,
demic effects in obese rats maintained on a Antagonism of free-radical-induced damage of adlay
high-fat diet. The adlay extract modulated seed and its antiproliferative effect in human his-
expression of both leptin and TNF-α, reducing tolytic lymphoma U937 monocytic cells, J. Agric.
body weight, food intake, fat size, adipose tis- Food Chem., 49:1564–1570, 2001.
sue mass, and serum hyperlipidemia. Adlay Kuo, C.-C., Chiang, W., Liu, G.-P., Chien, Y.-L.,
appears to have therapeutic potential for treat- Chang, J.-Y., Lee, C.K., Lo, J.M., Huang, S.L., Shih,
ing obesity. M.C., and Kuo, Y.H., 2,2′-Diphenyl-1-picrylhydrazyl
radical-scavenging active components from Adlay
References (Coix lachryma-jobi L. var. ma-yuen Stapf) hulls, J.
Agric. Food Chem., 50:5850–5855, 2002.
Chang, H.-C., Huang, Y.-C., and Hung, W.-C., Anti-
proliferative and chemopreventive effects of adlay Nagao, T., Otsuka, H., Kohda, H., Sato, T., and
seed on lung cancer in vitro and in vivo, J. Agric. Yamasaki, K., Benzoxazinone from Coix lachryma-
Food Chem., 51:3656–3660, 2003. jobi var. ma-yuen, Phytochemistry, 24:2959–2962,
1985.
Chiang, W., Cheng, C., Chiang, M., and Chung,
K.-T., Effects of dehulled adlay on the culture count Shih, C.-K., Chiang, W., and Kua, M.-L., Effects of
of some microbiota and their metabolism in the gas- adlay on azoxymethane-induced colon carcinogene-
trointestinal tract of rats, J. Agric. Food Chem., sis in rats, Food Chem. Toxicol., 42:1339–1347,
48:829–832, 2000a. 2004.
Chiang, W., Shyu, M.-L., Su, J.-P., and Pangm V.F., Smith, M.L. and German, J.B., Molecular and
Evaluation of the accessory anti-tumor effect of adlay genetic effects of dietary derived butyric acid, Food
processing food, J. Health Sci., 2:113–122, 2000b. Technol., 49:87–90, 1995.
 6 ADZUKI BEANS

Tanimura, A., Studies on the antitumor components

in the seeds of Coix lachryma-jobi L. var. ma-yuen. Agrimony Agrimony (Agrimonia eupatoria)
A Stapf. II. The structure of coixenolide, Chem. Pharm. is a valuable medicinal herb used mainly as a
Bull., 9:47–53, 1961. gastrointestinal tonic. It is characterized by long
Ukita, T. and Tanimura, A., Studies on the antitumor leaves with small, yellow flowers, one above
components in the seeds of Coix lachryma-jobi L. the other in long spikes on a hairy, brown stalk,
var. ma-yuen (Roman.) Stapf. I. Isolation and antitu- 2 to 3 feet high. A recent study by Gallagher
mor activity of coixenolide, Chem. Pharm. Bull., and coworkers (2003) showed that compared to
9:43–46, 1961. eight other plant sources, agrimony and avo-
cado were the most effective in inhibiting the
movement of glucose across a dialysis mem-
brane. Previous research incorporating an aque-
Adzuki beans Adzuki beans (Vigna angu- ous extract of agrimony into the diet or drinking
laris), an important pulse crop in Asia, are par- water of STZ-treated diabetic mice decreased
ticularly popular in Japan, China, and Korea. weight loss, polydipsia, hyperphagia, and
As a legume, its protein content and quality are hyperglycemia (Swanston-Flatt et al., 1989;
high. A novel, antifungal peptide was recently Gray and Flatt, 1998). This was accompanied
isolated from adzuki beans by affinity chroma- by increased secretion of pancreatic insulin and
tography and ion-exchange chromatography insulin glucose uptake and metabolism in vitro.
(Ye and Ng, 2002). The peptide, referred to as These studies suggest that the addition of agri-
angularin, had a molecular weight of 8 kDa and mony as a dietary supplement could help to
was effective against fungal species, such as improve glycemic control in type 2 diabetic
Mycospharella arachidiocola and Botyris individuals.
cinerea.
Three triterpenoid saponins were isolated References
from the hypocotyls of adzuki beans by Iida et Gallagher, A.M., Flatt, P.R., Duffy, G., and Abdel-
al. (1999). Related compounds are known to Wahab, Y.H.A., The effects of traditional antidiabetic
scavenge superoxide radicals, as well as exhibit plants on in vitro glucose diffusion, Nutr. Res.,
antioxidant and chelating activities (Yoshiki et 23:413–424, 2003.
al., 1995, 1996, 1997).
Gray, A.M. and Flatt, M., Actions of the traditional
References antidiabetic plant, Agrimony eupatoria (agrimony):
Iida, T., Yoshiki, Y., Okubo, K., Ohrui, H., Kinjo, J., effects on hyperglycaemia, cellular glucose metabo-
and Nohara, T., Triterpenoid saponins from Vigna lism and insulin secretion, Br. J. Nutr., 80:109–114,
angularis, Phytochemistry, 51:1055–1058, 1999. 1998.

Ye, X.Y. and Ng, T.B., Purification of angularin, a Swanston-Flatt, S.K., Day, C., Bailey, C.J., and Flatt,
novel antifungal peptide from adzuki beans, J. Pep- P.R., Evaluation of traditional plant treatments for
tide Sci., 8:101–106, 2002. diabetes: Studies in streptozocotin diabetic mice,
Acta Diabetol. Lat., 26:51–55, 1989.
Yoshiki, Y., Kim, J.H., Okubo, K., Nagoya, L., Sak-
abe, T., and Tamura, N., A saponin in conjugated
with 2,3-dihydro-2,5-dihydroxy-6-methyl-4H-
pyran-2-ene from Dolichos lablab, Phytochemistry,
38:229–231, 1995.
Ajoene Ajoene (E,Z)-4,5,9-trithiadodeca-1,6,11-
triene 9 oxide), an organic trisulphur compound
Yoshiki,Y., Kinumi, M., Kahara, T., and Okubo, K., originally isolated from garlic, is formed from
Chemiluminescence of soybean saponins in the pres- the spontaneous degradation of allicin.
ence of active oxygen species, Plant Sci.,
116:125–129, 1996. CH2 CHCH2SSCH CHCH2S(O)CH2CH CH2
Yoshiki, Y., Okuba, K., and Igarashi, K., In Food
Factors for Cancer Prevention, H. Ogihashi, T. Ajoene. (From MacDonald and Langler, Biochem.
Osawa, J. Terao, S. Watanabe, and T. Yoshikawa, Biophys. Res. Comm., 273:421–424, 2000. With per-
Eds., Tokyo, Spinger, Tokyo, 1997, p. 313. mission.)
 AJOENE 7

The possible pharmacological role of garlic effect was activation of caspase-3, a prerequi-
in the prevention and treatment of cancers was site for apoptosis. A recent study by Ledezma
attributed to the presence of ajoene. Rendu and et al. (2004) showed the cytotoxic effect of A
coworkers (1989) reported ajoene was the anti- ajoene on murine melanoma B16F10 cells was
platelet compound in garlic responsible for also associated with activation of caspase-3 and
inhibiting platelet aggregation. Later work by subsequent apoptosis.
Apitz et al. (1992) showed the antiplatelet activ- Using the water-maze test, Yamada et al.
ity of ajoene prevented thrombus formation (2004) recently found that only Z-ajoene, and
induced by vascular damage. Urbina and not alliin or diallyl disulfide, reduced acetylcho-
coworkers (1993) also found ajoene to be a linesterase (AChE) activity in the brain of sco-
potent antiplatelet compound capable of inhib- polamine-induced, memory-impaired mice.
iting both epimastogotes and amastigotes of Excessive production of AChE leads to a defi-
Trypanoso-ma cruiz, the causative agent for ciency of acetyl choline, resulting in a loss of
Chaga’s disease. Dirsch et al. (1998) reported memory and cognitive-impairment characteris-
ajoene-induced apoptosis in human promylelo-
tic of Alzheimer’s disease. Improvements
leukemic cells but not in periphereal mononu-
observed following treatments with Z-ajoene
clear cells of healthy donors. The mechanism
suggest it could be used to treat this disease.
proposed was that ajoene stimulated peroxide
formation in the leukemic cells and activated Gallwitz and coworkers (1999) also showed
NF-κΒ. The antitumor properties of ajoene that the antiparasitic and cytostatic properties
were demonstrated in vivo by Li et al. (2002ab, of ajoene were due to its effect on key enzymes
2003), who showed it inhibited proliferation involved in antioxidant thiol metabolism.
and induced apoptosis in several cancer-cell Ajoene was previously found to inhibit HMG-
lines by activation of NF-κΒ and caspase-8. CoA reductase, a key enzyme in cholesterol
Hassan (2004) suggested that inhibition of pro- biosynthesis, as well as in the later steps of the
liferation and induction of apoptosis by ajoene mevalonate pathway in rat hepatocytes and
was associated with blocking the G2/M phase HepG2 cells (Gebhardt et al., 1994). In addition
of the cell cycle and activation of caspase-3 by to being a precursor of cholesterol, mevalonate
ajoene, making it a new antileukemia agent for is also a precursor of other nonsteroid iso-
acute myeloid leukemia therapy (AML). prenoids (e.g., farnesyl and geranylgeranyl) that
Ajoene could be effective in elderly AML attach themselves to proteins and are crucial for
patients with poor tolerance to conventional cell proliferation (Grunler et al., 1994). Ferri
chemotherapies. For example, Table A.1 shows and coworkers (2003) reported, for the first
the effect of ajoene with traditional drugs, cyt- time, inhibition of protein prenylation and cell
arabine and fludarabine, on bcl-2 expression proliferation by ajoene in the smooth-muscle
and caspase-3 activation in human-resistant cells cultured from the aorta of Sprague–Daw-
myeloid leukemia cells. The most significant ley rats.

TABLE A.1
Bcl-2 Expression and Caspase-3 Activation in CD34 + CD7 + Human Resistant
Myeloid Leukemia Cells Following Treatment with Cytarabine or Fludarabine
in Presence or Absence of Ajoene
Bcl-2 (U/million cells) Activated caspase-3 (pg/million cells)
No ajoene With ajoene P No ajoene With ajoene P

Control 227.7 ± 15.0 212.9 ± 14. NS 51.4 ± 5.0 97.8 ± 9.0 NS

Cytarabine 24.8 ± 3.0 4.1 ± 0.3 < 0.001 210.5 ± 13.0 657.9 ± 11.0 < 0.001
Fludarabine 104.5 ± 12.0 70.3 ± 8.0 NS 183.7 ± 10.0 265.9 ± 16.0 NS

Source: From Hassan, Leukemia Res., 28:667–671, 2004. With permission.

 8 ALCOHOL

References compounds, Biochem. Biophys. Res. Commun., 273:

421–424, 2000.
A Apitz, C.R., Badimon, J.J., and Badimon, L., Effect
of ajoene, the major antiplatelet compound from gar- Rendu, F., Daveloose, D., Debouzy, J.C., Bourdeau,
lic, on platelet thrombus formation, Thromb. Res., N., Levy-Toledano, S., Jain, M.K., and Apitz-Castro,
68:142–145, 1992. R., Ajoene, the antiplatelet compound derived from
Dirsch, V.M., Gerbes, A.L., and Vollmar, A.M., garlic, specifically inhibits platelet release reaction
Ajoene, a compound in garlic, induces apoptosis in by affecting the plasma membrane internal microvis-
human promyeloleukemic cells, accompanied by cosity, Biochem. Pharmacol., 38:1321–1328, 1989.
generation of reactive oxygen species and activation
Urbina, J.A., Marchan, E., Lazardi, K., Visbal, G.,
of nuclear factor κB, Mol. Pharmacol., 53:402– 407,
Apitz, C.R., Gill, F., Aguirre, T., Piras, M.M., and
1998.
Piras, R., Inhibition of phosphatidylcholine biosyn-
Ferri, N., Yokoyama, K., Sadilek, M., Paoletti, R., thesis and cell proliferation in Trypanosoma cruzi by
Apitz-Castro, R., Gelb, M.H., and Corsini, A., ajoene, an antiplatelet compound isolated from gar-
Ajoene, a garlic compound, inhibits protein prenyla- lic, Biochem. Pharmacol., 45:2381–2387, 1993.
tion and arterial smooth muscle cell proliferation, Br.
Yamada, N., Hattori, A., Hayashi, T., Nishikawa, T.,
J. Pharmacol., 138:811–818, 2003.
Fukuda, H., and Fujino, T., Improvement of scopo-
Gallwitz, H., Bonse, S., Martinez-Cruz, A., Schlich- lamine-induced memory impairment by Z-ajoene in
ting, I., Schumacher, K., and Krauth-Sigel, R.L., the water maze in mice, Pharmacol. Biochem.
Ajoene is an inhibitor and subversive substrate of Behav., 78:787–791, 2004.
human glutathione reductase and Trypanosoma cruzi
Trypanothione reductase: Crystallographic, kinetic,
and spectroscopic studies, J. Med. Chem., 42:364–
372, 1999. Alcohol see also Ethanol A considerable
Gebhardt, R., Beck, H., and Wagner, K.G., Inhibition body of evidence associates moderate alcohol
of cholesterol biosynthesis by allicin and ajoene in intake with a lower incidence of, and mortality
rat hepatocytes and HepG2 cells, Biochem. Biophys. from, coronary heart disease. Kannel and Elli-
Acta, 1213:57–62, 1994. son (1996) reviewed evidence of a protective
Grunler, J., Ericsson, J., and Dallner, G., Branch- effect due to alcohol raising HDL subfractions.
point reactions in the biosythesis of cholesterol, A further discussion on the cardioprotective
dolichol, ubiquinone and prenylated proteins, Bio- effects of alcohol by Gorinstein et al. (2002)
chem. Biophys. Acta, 1212:259–277, 1994. suggested that, in addition to polyphenols, the
antioxidant properties of ethanol can also pre-
Hassan, H.T., Ajoene (natural garlic) compound: A
new anti-leukemia agent for AML therapy, Leukemia
vent oxidation of LDL-cholesterol. This
Res., 28:667–671, 2004. research further illustrates the importance of
moderate alcohol consumption, as chronic alco-
Ledezma, E., Apitz-Castro, R., and Cardier, J., Apo- hol consumption was shown to induce hepatic
ptotic and anti-adhesion effect of ajoene, a garlic oxidation, leading to increased malondialde-
derived compound, on the murine melanoma B16F10
hyde levels in Wistar rats. Figure A.3 summa-
cells: possible role of caspase-3 and the α4β1 integrin,
rizes a study of 115 premenopausal, nonsmok-
Cancer Lett., 206:35–41, 2004.
ing women conducted in four different regions
Li, M., Min, J.M., Cui, J.R., Zhang, L.H., Wang, K., in Europe. Bianchini et al. (2001) found an
and Valettle, A., Z-ajoene induces apoptosis in HL- inverse correlation between alcohol consump-
60 cells: Involvement of bcl-2 cleavage, Nutr. Can- tion and 8-hydroxy-2′-deoxyguanosine (8-
cer, 42:241–247, 2002a
oxodGuo) lymphocyte levels (Figure A.3). The
Li, M., Cui, J.R., Ye, Y., Min, J.M., Zhang, L.H., and formation of 8-oxodGuo is a measure of oxida-
Wang, K., Anti-tumor activity of z-ajoene, a natural tive damage to lymphocyte DNA. This unex-
compound purified from garlic: Antimitotic and pected finding pointed to the beneficial effects
microtubule-interaction properties, Carcinogen, 23: of moderate alcohol consumption. In a 12-year
573–579, 2002b. study of 38,077 males, Mukamal and coworkers
McDonald, J.A. and Langler, R.F., Structure-activity (2003) confirmed the inverse relationship
relationships for selected sulfur-rich antithrombotic between alcohol consumption, at least three to
 ALFALFA 9

2.50

2.00
Granada
? A
1.50
? Turin
?
1.00

0.50

0.00
0 2 4 6 8 10 12 14
Alcohol (ml)

FIGURE A.3 Association between geometric mean 8-oxodGuo × 104 levels and mean alcohol consumption
among nonsmoking, premenopausal women between the four centers. (From Bianchi et al., Carcinogenesis,
22:885–890, 2001. With permission.)

four days a week, and the risk of coronary heart

disease. Alfalfa Alfalfa (Medicago satiova L.) has
been grown extensively as a livestock feed,
while alfalfa sprouts are consumed as a garnish.
It contains a large number of compounds,
References including saponins, flavonoids, tannins,
Bianchini, F., Jaeckel, A., Vineis, P., Martinez-Gar-
coumestrol, carotenoids, and tocols. Flavonoids
are known to have important health properties
cia, C., Elmstahl, S., van Kappel, A.-L., Boeing, H.,
and include glycosides of apigenin, luteolin,
Ohshima, H., Riboli, E., and Kaaks, R., Inverse cor-
and tricin (Packer et al., 1999). In addition to
relation between alcohol and lymphocyte levels of
five known apigenin and luteolin glycosides and
8-hydroxyguanosine in humans, Carcinogenesis, 22: adenosine, Stochmal and coworkers (2001a)
885–890, 2001. identified four new apigenin glycosides and a
Gorinstein, S., Caspi, A., Libman, I., and Trakhten- luteolin glycoside in alfalfa not reported previ-
ously. Further work by Stochmal et al. (2001b)
berg, S., Cardioprotective effect of alcohol consump-
characterized 10 flavone glycosides, including
tion: Contemporary concepts, Nutr. Res., 22:659–
six tricin, one 3′-O-methyltricetin, and three
666, 2002.
chrysoeriol glycosides in the areial parts of
Kannel, W.B. and Ellison, R.C., Alcohol and coro- alfalfa. Hwang et al. (2001) showed that pre-
nary heart disease: The evidence for a protective treatment of soy and alfalfa extracts with
effect, Clin. Chim. Acta, 246:59–76, 1996. acerola cherry extracts, a rich source of vitamin
C, enhanced the antioxidant activity of soy and
Mukamal, K.J., Conigrave, K.M., Mittleman, M.A., alfalfa extracts to inhibit LDL-oxidation (LDL-)
Camargo, C.A., Jr., Stampfer, M.J., Willett, W.C., (Figure A.4). The protective effect, only evident
and Rimm, E.B., Roles of drinking pattern and type between alfalfa or soybean extracts and acerola
of alcohol consumed in coronary heart disease in cherry extracts, was attributed to synergistic
men, N. Eng. J. Med., 348:109–118, 2003. interaction between its flavonoids and phy-
toestrogens with ascorbic acid in the cherry
Roig, R., Cascon, E., Arola, L., Blade, C., and Sal- extract. In the case of alfalfa and acerola cherry
vado, M.J., Effects of chronic wine and alcohol extracts, this corresponded to 0.5 µM genistein
intake on glutathione and malondialdehyde levels in and daidzein, 0.1 µM coumestrol and apigenin,
rats, Nutr. Res., 20:1547–1555, 2000. and 102 µM ascorbic acid.
 10 ALLICIN

120

A 100
*
**
**
***

LDL formation (%)

80

60 ***
***
40

20

0
Control

Alfalfa
Soy
Acerola

Alfalfa + Acerola
Soy + Acerola
FIGURE A.4 LDL- formation mediated by cells after addition of 100 µg/mL LDL protein. Cells were
incubated under standard conditions (control) and preincubated with acerola, soy, soy and acerola, alfalfa, and
alfalfa and acerola, extracts for five days, with male rabbit aortic endothelial cells. (From Hwang et al., J.
Agric. Food Chem., 49:308–314, 2001. With permission.)

References (Scheme A.2). Eilat and coworkers (1995)

Hwang, J., Hodis, H.N., and Sevanian, A., Soy and showed allicin altered the serum lipids in hyper-
alfalfa phytoestrogen extracts become potent low- lipidemic rabbits. Elkayam et al. (2001) found
density lipoprotein antioxidants in the presence of a synthetic preparation of allicin reduced blood
acerola cherry extract, J. Agric. Food Chem., 49:308– pressure in fructose-induced hyperinsulenemic,
314, 2001. hyperlipidemic, hypertensive rats from a max-
Packer, L., Hiramatsu, M., and Yoshikawa, T., Anti- imum of 153.4 mm Hg to 139.7 mm after 2
oxidant Food Supplements in Human Health, Aca- weeks. Allicin acted similarly to enalapril with
demic Press, San Diego, 1999. respect to blood pressure, insulin, and triglyc-
erides, suggesting it as a potential alternative
Stochmal, A., Piacente, S., Pizza, C., De Riccardis,
F., Leitz, R., and Oleszek, W., Alfalfa (Medicago
treatment of blood pressure. Kang et al. (2001)
sativa L.) flavonoids. 1. Apigenin and luteolin gly- showed allicin had immunomodulating activity,
cosides from aerial parts, J. Agric. Food Chem., especially on macrophages. Inflammatory
49:753–758, 2001a. murine peritoneal macrophages treated with
increasing levels of allicin induced tumoricidal
Stochmal, A., Simonet, S., Francisco, S., Macias, A.,
and Oleszek, W., Alfalfa (Medicago sativa L.) fla-
activity in a dose-dependent manner (Figure A.5).
vonoids. 2. Tricin and chrysoeriol glycosides from This was accompanied by corresponding
aerial parts, J. Agric. Food Chem., 49:5310–5314, increases in the production of the tumor necro-
2001b. sis factor (TNF-α) and nitric oxide.
Further research was recommended to estab-
lish the mode of this modulation and to what
degree it occurs in vivo.
Allicin Allicin (dially sulfonate) is one of the
bioactive components of garlic (Rabinkov et al., References
1994). It is formed in garlic by the action of the Eilat, S., Oestraqicher, Y., Rabinkov, A., Ohad, D.,
enzyme alliinase (alliin lyase, EC 4.4.1.4) on Mirelman, D., Battler, A., Eldar, M., and Vered, Z.,
alliin [(+)S-2-propenyl L-cysteine S-oxide] Alteration of lipid profile in hyperlipidemic rabbits