Reactive Oxygen Species (ROS), Nanoparticles, and

Endoplasmic Reticulum (ER) Stress Induced Cell Death

Mechanisms

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Reactive Oxygen Species
(ROS), Nanoparticles, and
Endoplasmic Reticulum (ER)
Stress-Induced Cell Death
Mechanisms

Loutfy H. Madkour
Chemistry Department, Faculty of Science
Al Baha University
Saudi Arabia
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Contents
About the author xix 2.1.2 Ozone exposure 20
Preface xxi 2.1.3 Hyperoxia 21
Summary xxiii 2.1.4 Ionizing radiation 21
2.1.5 Heavy metal ions 21
1. Pathophysiological, toxicological, 2.2 Endogenous sources of ROS and their
and immunoregulatory roles of regulation in inflammation 21
reactive oxygen and nitrogen 2.3 Mitochondria as main source of ROS
species (RONS) in autophagy signaling 23
2.4 ROS and mitophagy 23
1.1 Oxidative and nitrative stress in 2.5 Production of ROS and their
toxicology and disease 1 mechanisms of biological activities 24
1.2 Oxidative and nitrative stress: Role in 2.6 Increased ROS production in
the response to liver toxicants photosynthesis during drought 25
(Roberts) 2 2.7 ROS elimination 28
1.2.1 Carcinogenesis and 2.8 Types of reactive oxygen species 28
inflammation 3 References 31
1.2.2 Crosstalk with PPARa? 4
1.3 Characterization of oxidative stress
using neuronal cell culture models 3. Cellular signaling pathways with
(Smith) 4 reactive oxygen species (ROS)
1.4 Nitrative stress and glial-neuronal
interactions in the pathogenesis of 3.1 Oxidative stress and ROS 37
Parkinson’s disease (Tjalkens and 3.2 Sources of ROS 37
Stephen Safe) 5 3.2.1 Endogenous sources and
1.4.1 Neuroinflammation and PD 6 localization of ROS 37
1.4.2 Regulation of neuroinflammatory 3.2.2 Exogenous sources of ROS 39
genes in astrocytes 6 3.2.3 The homeostasis of ROS 40
1.4.3 Therapeutic strategies to interdict 3.3 Oxidative stress in RA 40
neuroinflammation 7 3.4 Molecular targets of ROS 41
1.5 Oxidative and nitrative stress in 3.4.1 Protein tyrosine phosphatases
multistage carcinogenesis and kinases 41
(Robertson) 7 3.4.2 Lipid metabolism 41
1.6 Role of peroxynitrite in the 3.4.3 Ca2+ signaling 41
pathogenesis of doxorubicin-induced 3.4.4 Small GTPases 41
cardiotoxicity (Szabo) 9 3.4.5 Serine/threonine kinases and
1.6.1 Molecular mechanisms of phosphatases 42
peroxynitrite formation 9 3.5 Redox regulation of transcription
1.7 Immunoregulatory role of ROS 10 factors 42
1.8 Conclusions 13 3.5.1 Nuclear factor k-light-chain-
References 14 enhancer of activated B cells 42
3.5.2 Activator protein-1 42
3.5.3 Other transcription factors 42
2. Biological mechanisms of reactive
3.6 RA, pathogenesis, and therapy 43
oxygen species (ROS) 3.7 Oxidative stress/ROS-associated
2.1 Exogenous source of oxidants 20 consequences in RA 43
2.1.1 Cigarette smoke 20 3.7.1 Lipid peroxidation 43

v
vi Contents

3.7.2 Effects on immunoglobulin 3.19.7 Possible links between ROS and

advanced glycation lipid accumulation 66
end-products 43 References 67
3.7.3 Oxidative stress/ROS-mediated
alteration of autoantigens 44 4. Manganese as the essential
3.7.4 Genotoxic effects of oxidative element in oxidative stress and
stress 45 metabolic diseases
3.7.5 Oxidative stress and tissue
injury 45 4.1 Effects of Mn on the role of reactive
3.7.6 Cartilage/collagen effects 45 oxygen species 81
3.8 ROS-mediated pathways in cell 4.2 Physiological roles of Mn 83
death 46 4.3 Mn as metalloenzymes and as an
3.8.1 Extrinsic pathways 46 enzyme activator 84
3.8.2 Intrinsic pathways 47 4.4 Mn stability and transport 85
3.9 ROS-mediated cellular signaling 4.5 Mn administration, distribution,
in RA 48 and excretion 85
3.9.1 MAPK signaling pathway 48 4.6 Brain Mn targets 86
3.9.2 PI3K-Akt signaling pathway 49 4.7 Mn and metabolic syndrome 87
3.9.3 ROS and NF-kB signaling 4.8 Mn and T2DM/insulin resistance 88
pathway 49 4.9 Mn and obesity 88
3.9.4 Oxidative stress/ROS as signaling 4.10 Mn and atherosclerosis 89
in T-cell tolerance 51 4.11 Mn and nonalcoholic fatty liver
3.10 The homeostasis of ROS 52 disease 89
3.11 ROS and the NF-kB signaling 4.12 Mn and autoxidation of
pathway 53 catecholamines and other
3.12 ROS and MAPK signaling neurotransmitters 90
pathway 53 4.13 Mitochondria, the MPT,
3.13 ROS and the keap1-Nrf2-ARE signaling and apoptosis 90
pathway 56 4.14 Mn, ROS, the mitochondria,
3.14 ROS and the PI3K-Akt signaling and apoptosis 92
pathway 56 4.15 A case for the use of mitochondrially
3.15 Crosstalk between ROS and Ca2+ 56 targeted antioxidants 93
3.16 Reactive oxygen species and 4.16 Conclusion 93
mitochondrial permeability References 94
transition pore 60 Further reading 104
3.17 ROS and protein kinase 60
3.18 ROS and the ubiquitination/ 5. Affected energy metabolism is the
proteasome system 62 primal cause of manganese toxicity
3.19 Lipid accumulation in oleaginous
5.1 Affected energy metabolism 107
microorganisms under different types
5.1.1 Gene expression profile under
of stress 64
Mn stress 108
3.19.1 Nutrient limitation 64
5.1.2 Mn-induced iron depletion blocks
3.19.2 Physical environmental
ISC and heme protein
stresses 64
biogenesis 109
3.19.3 Stress-induced strategies for
5.1.3 Mature ISC and heme protein
generation and its potential
deficiency affects energy
role in lipid accumulation 65
metabolism 111
3.19.4 Redox homeostasis and
5.1.4 Reduced ETC function evokes ROS
oxidative stress 65
under Mn stress 111
3.19.5 Stress sensing and putative
5.1.5 Affected energy metabolism
concomitant ROS
determines Mn toxicity 113
generation 65
5.2 Mechanism of Mn-induced cellular
3.19.6 Transduction of intracellular
toxicity 114
ROS signals 65
5.3 Polynitrogen Mn complexes 118
 Contents vii

5.3.1 Cytotoxicity of Mn complexes 7.3 Effects of mercury on oxidative

1 and 2 119 stress 162
5.3.2 Effects of different concentrations 7.4 Effects of copper on oxidative stress 164
of H2O2 on apoptosis of PC12 7.5 Effects of cadmium and zinc on
cells 119 oxidative stress 165
5.3.3 Protection of preconditioning 7.6 Effects of arsenic on oxidative stress 166
with Mn complexes against 7.7 Effects of chromium on oxidative
H2O2-induced death of stress 168
neuronal cells 120 7.8 Effects of vanadium on oxidative
5.3.4 Time course analysis of intracellular stress 168
ROS level changes 120 7.9 Cytotoxic and cellular functions
5.3.5 Effects of Mn complexes on the of heavy metals 169
mRNA levels of HIF-1a and HIF References 171
target genes in cultured cells 122
5.3.6 Effects of Mn complexes on the 8. Oxidative stress and oxidative
protein levels of HIF-1a and HIF damage-induced cell death
target genes in cultured cells 122
5.3.7 HIF-1a knockdown-induced 8.1 Oxidative stress 175
apoptotic cell death under 8.2 ROS regulation of signaling
preconditioning with Mn molecules 176
complexes of neuronal cells 125 8.2.1 Kinases and phosphatases 176
5.4 Neuroprotection-related signaling 8.2.2 Transcription factors 178
pathways of Mn complexes 1 and 2 125 8.2.3 ROS-induced transcriptional
5.5 Conclusion 127 activation 179
References 127 8.2.4 Signaling pathways 179
8.2.5 Mitogen signaling 180
8.2.6 Integrin signaling 180
6. Heavy metals and free
8.2.7 Wnt signaling 180
radical-induced cell death 8.3 Cellular processes regulated by ROS 180
mechanisms 8.3.1 Proliferation 181
6.1 Heavy metal ions 131 8.3.2 Differentiation 181
6.2 Occurrence and recovery of heavy 8.3.3 Cell death 182
metals 134 8.4 Autophagy and oxidative stress 182
6.3 Free radicals 135 8.4.1 Redox signaling in autophagy 183
6.3.1 Definition of free radicals 135 8.5 Oxidative damage 184
6.4 Heavy metals and their risky role on 8.6 ROS and oxidative damage
organisms of biological systems 136 on biomolecules 185
6.5 Bioimportance of some heavy 8.6.1 Effects of oxidative stress
metals 139 on lipids 185
6.6 Ecotoxicology and metabolism of heavy 8.6.2 Effects of oxidative stress
metals 141 on proteins 186
6.7 Toxicity of xenobiotic metals (mercury, 8.6.3 Effects of oxidative stress
lead, cadmium, tin, and arsenic) 142 on DNA 189
6.7.1 Mercury 143 8.7 ROS/RNS and nucleic acid
6.7.2 Lead 147 destabilization 191
6.7.3 Cadmium 149 References 192
6.7.4 Tin 151
6.7.5 Arsenic 152 9. Cell death mechanisms—
References 153 Apoptosis pathways and their
implications in toxicology
7. Cytotoxic mechanisms of
9.1 Apoptosis: Historical perspectives 200
xenobiotic heavy metals on 9.2 Apoptosis: Mechanisms and different
oxidative stress pathways 201
7.1 Effects of lead on oxidative stress 159 9.2.1 Extrinsic pathway 202
7.2 Effects of iron on oxidative stress 160 9.2.2 Intrinsic pathway 203
viii Contents

9.2.3 Perforin/granzyme pathway 203 10. Programmed cell death

9.2.4 Execution pathway 204 mechanisms and nanoparticle
9.2.5 Main mechanisms toxicity
of parasite-induced
cell apoptosis 204 10.1 Molecular mechanisms underlying
9.3 Signaling pathways leading to nanomaterial toxicity 229
apoptosis in mammalian cells 204 10.2 Major forms of programmed
9.4 The role of calcium in cell death 206 cell death 231
9.4.1 The endoplasmic reticulum, 10.3 More than one way to skin a cat 232
Ca2+, and apoptosis 206 10.4 Programmed cell death:
9.4.2 Apoptosis by mitochondrial Apoptosis 232
permeabilization 206 10.5 Programmed cell death:
9.4.3 Ca2+-activated effector Autophagy 234
mechanisms 206 10.6 Programmed cell death: Necrosis 234
9.4.4 Ca2+ and the phagocytosis 10.7 The importance of being small 236
of apoptotic cells 207 10.8 Effects of nanoparticles
9.5 Oxidative stress and cell death 208 on apoptosis 237
9.6 Targets of ROS 208 10.9 Nanomaterials and apoptosis 238
9.7 Inflammation and cell death 209 10.10 Nanomaterials and mitotic
9.8 Some alternative forms catastrophe 239
of cell death 209 10.11 Effects of nanoparticles
9.8.1 Necrosis (type 3 cell death) 209 on autophagy 241
9.8.2 Autophagy 210 10.12 Nanomaterials and autophagy
9.8.3 Pyroptosis 210 or “autophagic cell death” 241
9.8.4 Entosis 210 10.13 Effects of nanoparticles
9.8.5 Mitotic catastrophe on necroptosis 242
(mitotic failure) 210 10.14 Nanomaterials and necrosis 243
9.9 Links between apoptosis and other 10.15 Nanomaterials and pyroptosis 244
cell death modalities 210 10.16 Mechanisms of graphene-induced
9.10 Toxicity-related cell death 211 programmed cell death 245
9.11 Role of autophagy in toxicity 213 10.17 GBMs induce apoptosis in cells 245
9.11.1 Role of apoptosis in cancers 214 10.18 The signaling pathways involved
9.11.2 Overexpression in GBM-induced apoptosis 246
of apoptosis 214 10.19 GBMs induce autophagy in cells 247
9.11.3 Use of antiapoptotic therapy 10.20 The signaling pathways involved
agents 214 in GBM-induced autophagy 248
9.11.4 Assays used 214 10.21 GBMs induce necroptosis and
9.12 Chelerythrine-induced cell death relative pathways involved 249
through ROS-dependent ER stress 10.22 Some differences and relationships
in human prostate cancer cells 214 of GBM-induced programmed
9.12.1 CHE reduced cell viability cell death 250
in human prostate cancer 10.22.1 Differences in programmed
cells 215 cell death 250
9.12.2 CHE induced cell apoptosis in 10.22.2 Several cross-linked
human prostate cancer cells 215 pathways in programmed
9.12.3 CHE increased ROS cell death 251
accumulation in PC-3 cells 215 10.23 Conclusions and perspectives 251
9.12.4 Blockage of ROS generation References 254
reversed CHE-induced cell
apoptosis in PC-3 cells 217 11. Endoplasmic reticulum stress and
9.12.5 CHE induced cell apoptosis associated ROS in disease
through ROS-mediated ER stress pathophysiology applications
in PC-3 cells 217
9.13 Conclusion 219 11.1 Endoplasmic reticulum 265
References 220 11.2 Reactive oxygen species 267
 Contents ix

11.3 Sources of reactive oxygen species 12.2 Protein folding: ER chaperones and
generation 270 foldases 300
11.4 Endoplasmic reticulum stress 271 12.2.1 General chaperones 300
11.5 Unfolded protein response 271 12.2.2 Lectin chaperones 300
11.5.1 Inositol-requiring 12.2.3 Other folding chaperones
protein 1 272 and enzymes 301
11.5.2 Protein kinase-like endoplasmic 12.3 Role of ER stress inhibitors
reticulum kinase 273 in the context of metabolic
11.5.3 Activating transcription diseases 301
factor 6 273 12.4 ER stress sensors 302
11.6 Protein folding challenge in intestinal 12.4.1 Activation of PERK 302
secretory cells 274 12.4.2 Activation of the IRE1a
11.7 Endoplasmic reticulum stress and pathway 304
autophagy 275 12.4.3 Activation of the ATF6
11.8 How are reactive oxygen species pathway 304
induced through endoplasmic 12.5 ER stress leads to disease
reticulum stress? 275 progression 305
11.8.1 The specific mechanism 12.6 Metabolic disorders 306
of ERS-induced ROS during 12.6.1 Diabetes 306
the ER folding process 275 12.6.2 Obesity 306
11.9 Specific mechanism of ERS-induced 12.6.3 Lipid disorders 306
ROS: NADPH oxidase 4 275 12.7 ER stress inhibitors 307
11.10 Coupled glutathione within 12.7.1 KIRA6 308
the ER 277 12.7.2 3-Hydroxy-2-naphthoic
11.11 NADPH-dependent P450 reductase acid 308
and P450 connection involvement 12.7.3 MKC-3946 309
in ERS 277 12.7.4 4-Phenylbutyric acid 309
11.12 ER and mitochondria connection and 12.7.5 Taurine-conjugated
relationship to ROS 278 ursodeoxycholic acid 309
11.13 Oxidative stress 278 12.7.6 Olmesartan 310
11.14 Vicious sequence of events between 12.7.7 N-Acetylcysteine 310
endoplasmic reticulum stress and 12.7.8 Oleanolic acid 310
oxidative stress 279 12.7.9 Ursolic acid 311
11.15 Endoplasmic reticulum stress and 12.7.10 Telmisartan 311
oxidative stress in inflammatory 12.7.11 Quercetin 311
bowel disease 280 12.7.12 Other inhibitors 312
11.16 Disease application 282 12.7.13 Antidiabetic drugs targeting
11.16.1 ERS and diseases 282 ER stress 312
11.16.2 Neurodegenerative 12.8 ER stress, UPR signaling, and cell
diseases 283 death regulation 312
11.16.3 Diabetes mellitus 284 12.9 UPR-independent ER stress signaling
11.16.4 Atherosclerosis 284 and cell death 313
11.16.5 Kinds of inflammation 284 12.9.1 Calcium 313
11.16.6 Liver disease 285 12.9.2 MEKK1 (MAP3K4) 315
11.16.7 Ischemia 285 12.9.3 ER membrane
11.16.8 Kidney disease 285 reorganization 316
11.17 Conclusions 285 12.10 Suppressors of ER stress-induced
References 286 apoptosis 316
12.10.1 Bax-inhibitor 1 316
12. Endoplasmic reticulum 12.10.2 Bcl-2/Bcl-XL 316
stress-induced cell death 12.10.3 MicroRNAs 317
mechanism 12.10.4 Additional suppressors of ER
stress-induced apoptosis 317
12.1 ER stress and unfolded protein 12.11 ER stress and autophagy 318
response 299 12.12 ER stress involvement in diseases 319
x Contents

12.12.1 Neurodegenerative 13.3.2 Alleviation of ER stress by NPs

diseases 320 for metabolic disease
12.12.2 Ophthalmology disorders 320 therapy 348
12.12.3 Immunity and 13.4 Silver nanoparticles—Allies or
inflammation 320 adversaries? 349
12.12.4 Viral infections 321 13.5 Role of AgNPs in cell toxicity 351
12.12.5 Metabolic diseases 321 13.5.1 Silver nanoparticle-induced
12.12.6 Atherosclerosis 322 apoptosis 351
12.13 ER stress and cancer 322 13.5.2 Silver nanoparticles induce
12.13.1 ER chaperones and cancer ER stress 354
regulation 323 13.6 Uptake of AgNPs and their
12.13.2 ER sensors and cancer 323 intracellular localization 357
12.14 The crosstalk between ER stress and 13.7 Inhibition of proliferation and
autophagy in cancer 324 cell death 358
12.15 The relationship between FOXO, 13.8 ROS key factor in biological
ER stress, and cancer 325 oxidation processes 360
12.15.1 PERK pathway and 13.9 Oxidative stress as an underlying
the FOXO3 story 325 mechanism for NP toxicity 361
12.15.2 IRE-1 and FOXO 13.10 Genotoxicity 362
regulation 326 13.11 Concluding remarks 364
12.15.3 Chaperones and FOX References 364
regulation 327
12.15.4 ER stress and FOX regulation 14. Nanoparticle cellular uptake and
in worms 327 intracellular targeting on reactive
12.15.5 Daf-16 and dFOXO and oxygen species (ROS) in biological
regulation of the Ire-1 arm 327 activities
12.15.6 Regulation of PERK
by dFOXO 328 14.1 Nanoparticle classes and biomedical
12.16 Targeting cancer through the UPR applications 373
signaling and its FOXO link 328 14.1.1 Optical imaging 373
12.16.1 Targeting IRE1a/XBP1 328 14.1.2 Biosensing 373
12.16.2 Targeting PERK/ATF4 328 14.1.3 Diagnostic applications 374
12.16.3 Chaperone inhibitors and 14.1.4 Drug delivery 374
FOXO3 328 14.1.5 Other applications 375
References 329 14.2 Mechanisms associated with
NP-induced ROS generation 375
14.2.1 NP-related factors implicated
13. Modulation of endoplasmic in ROS generation 375
reticulum (ER) stress 14.2.2 NP- and cellular-component-
of nanotoxicology for induced ROS generation 376
nanoparticles (NPs) 14.3 Biological functions modulated
by NP-induced ROS production 377
13.1 Nanotoxicology and 14.3.1 DNA damage and
nanomedicine 343 cytotoxicity 377
13.2 ER stress as a mechanism 14.3.2 Antimicrobial function 378
for nanotoxicology 344 14.3.3 Cellular differentiation 378
13.2.1 Morphological changes 14.3.4 Anticancer 378
of the ER by NP exposure 345 14.4 NP-induced modulation of ROS
13.2.2 Effects of NP exposure generation in stem cell biology 380
on the ER stress pathway 345 14.5 Nanoparticle cellular uptake and
13.2.3 Modulation of ER stress and intracellular targeting 381
the toxicity of NPs 347 14.6 Endocytic routes and nonligand
13.3 Modulation of ER stress by NPs targeted nanomedicines 382
in nanomedicine 348 14.7 Receptor-mediated cellular
13.3.1 Selective activation of ER stress internalization of ligand-targeted
by NPs for cancer therapy 348 nanomedicines 384
 Contents xi

14.7.1 Prostate-specific membrane 16.1.2 Reactive oxygen species and

antigen targeting 384 biological systems 422
14.7.2 Neonatal Fc-receptor 16.2 Exposure routes for
targeting—An avenue to oral nanoparticles 422
delivery of nanomedicine 384 16.3 Prooxidant effects of metal
14.8 Intracellular trafficking and oxide nanoparticles 427
subcellular targeting 385 16.4 Effects of nanoparticles on cell
14.8.1 From endosomes/lysosomes organisms 428
to cytoplasm 385 16.4.1 Absorption of nanoparticles
14.8.2 Endoplasmic reticulum and and cytotoxicity 428
Golgi apparatus 386 16.4.2 Absorption of nanoparticles
14.8.3 Mitochondria 387 under environmental
14.8.4 Nucleus 387 conditions 428
14.9 Outlook 389 16.4.3 Nanoparticles in outdoor
14.10 Conclusions 390 spaces 430
References 390 16.4.4 Interactions among organisms,
nanoparticles, and
15. Metal nanoparticles (MNPs) and contaminants 430
particulate matter (PM) induce 16.5 Nanoparticle-induced oxidative
toxicity stress 432
16.6 Oxidant generation via particle-cell
15.1 Nano-bio interactions 397 interactions 434
15.2 Economical relevance 399 16.6.1 Lung injury caused by
15.3 Nanotoxicology of nanoparticle-induced reactive
nanoparticles 402 nitrogen species 435
15.4 Overproduction of ROS and 16.6.2 Mechanisms for reactive
cell damage 403 oxygen species production and
15.5 Nanotoxicity and generation apoptosis within metal
of ROS 404 nanoparticles 435
15.6 Dependence of ROS production 16.7 Modeling nanotoxicity 435
on the properties of nanoparticles 404 16.8 Cellular signaling affected
15.6.1 Size and shape 405 by metal nanoparticles 436
15.6.2 Particle surface, surface positive 16.8.1 NF-kB 436
charges, and surface containing 16.8.2 AP-1 436
groups 405 16.8.3 MAPK 437
15.6.3 Solubility and particle 16.8.4 PTP 437
dissolution 406 16.8.5 Src 437
15.6.4 Metal ions released from metal 16.9 Carbon nanotubes 437
and metal oxide 16.10 Carbon nanotube-induced
nanoparticles 407 oxidative stress 437
15.6.5 Light activation 407 16.11 Role of reactive oxygen species
15.6.6 Aggregation and mode in carbon nanotube-induced
of interaction with cells 408 inflammation 438
15.6.7 Inflammation leading 16.12 Role of reactive oxygen species
to ROS formation 408 in carbon nanotube-induced
15.6.8 pH of the system 408 genotoxicity 438
15.7 Particulate matter 409 16.13 Role of reactive oxygen species
References 412 in carbon nanotube-induced
fibrosis 439
16. Mechanisms for nanoparticle- 16.14 Difficulties in determination
mediated oxidative stress of the mechanism of nanotoxicity
in cells and in vivo 439
16.1 Introduction to transition metals 421
16.15 Conclusion 440
16.1.1 Generation of reactive oxygen
References 440
species 422
xii Contents

17. Nanotechnological modifications 17.9.3 Use of SeNPs for minimization

of nanoparticles on reactive of risk of iron
oxygen and nitrogen species overabundance 473
17.9.4 SeNPs in the treatment of
17.1 Nanotechnology and heavy metal intoxication 474
nanomaterials 449 17.9.5 Nano-Se as an
17.2 Nanotechnological modifications 450 immunostimulatory 474
17.2.1 Nanodiffusion in the 17.9.6 Effect of nano-Se on microbial
environment 451 fermentation, nutrient
17.2.2 Nanomaterials in soil 451 digestibility, and probiotic
17.2.3 Nanoparticle mobility support 474
in soil 453 17.9.7 Nano-Se in the treatment
17.3 Nanotechnology and agriculturally of metabolic disorders 475
sustainable development 454 17.10 Safety and toxicity concerns of orally
17.3.1 Nanofertilizers 454 delivered SeNPs for use as food
17.3.2 Nanopesticides 456 additives and drug carriers 475
17.3.3 Ecotoxicological implications References 477
of nanoparticles 457
17.4 Growth of cultivated plants and their 18. Medical imaging of the complexity
ecotoxicological sustainability 459
of nanoparticles and ROS
17.5 Applications of nanotechnology
in the agricultural sector 460
dynamics in vivo for clinical
17.5.1 Nanosilver 462
diagnosis application
17.5.2 Nanosilica 462 18.1 Redox signaling 489
17.5.3 Nanotitanium dioxide 462 18.2 Dynamics of the EPR signal
17.5.4 Nanocalcium 463 of nitroxide radicals in leukemic
17.5.5 Nano-iron 463 and normal lymphocytes 492
17.6 Nanotechnologies in the food 18.3 Redox-sensitive two-photon
industry 463 microscopy 494
17.6.1 Food process 463 18.3.1 Two-photon redox-sensitive
17.6.2 Food packaging and probes 495
labeling 463 18.3.2 Two-photon-sensitive probes
17.7 Selenium nanoparticles as a food for assessment of glutathione
additive 464 redox state 495
17.7.1 Problems with traditional 18.3.3 Two-photon NADPH redox
forms of oral supplementation state-sensitive probes 496
of selenium and potential 18.3.4 Two-photon H2O2-sensitive
benefits of SeNPs 465 probes 497
17.7.2 Mechanism of passage 18.3.5 Two-photon NO-sensitive
of nanoparticles through probes 497
intestinal mucosa 467 18.4 Chemiluminescent imaging of ROS
17.7.3 Application of SeNPs through in vivo 497
oral administration 468 18.4.1 NIR fluorescence and
17.7.4 Anticancer effects chemiluminescence 497
of SeNPs 470 18.4.2 Chemiluminescent
17.8 Effect of SeNPs on oxidative stress nanoparticles and ROS
parameters 472 imaging 498
17.9 Protective effects of nano-Se 473 18.5 Ultrasound in ROS imaging 499
17.9.1 SeNPs in prevention of 18.6 PET/SPECT in vivo imaging
cisplatin-induced reproductive of oxidative stress using
toxicity 473 radiotracers 499
17.9.2 Protective effect of nano-Se 18.6.1 Imaging glucose consumption
against polycyclic aromatic as a surrogate of oxidative
hydrocarbons 473 stress 500
 Contents xiii

18.6.2 Radiotracers with redox 18.16 Cellular excretion and degradation

potential-dependent cellular of nanoparticles 522
retention 500 18.17 Conclusions 523
18.6.3 Radiotracers with 18.18 Outlook 524
hypoxia-dependent cellular References 524
retention 500
18.6.4 Radiotracers targeting ROS 19. Titanium dioxide nanoparticle-
scavengers or mitochondrial induced cytotoxicity and
complex I–IV 501 genotoxicity—Generation
18.7 Magnetic resonance modalities 501 of reactive oxygen species and
18.7.1 Basic principles and technical cell damage
considerations 501
18.7.2 Examples of EPRI/MRI of 19.1 TiO2NP-induced cytotoxicity and
ROS/RNS 503 DNA damage 535
18.7.3 Brain imaging (without 19.2 Nano-TiO2 in biological systems 538
tumors) 504 19.3 TiO2NP-induced toxic effects
18.7.4 Tumor imaging 504 on human health 539
18.7.5 Other organs 505 19.4 Characterization of nano-TiO2 541
18.7.6 Imaging of trapped 19.5 Nano-TiO2-induced phototoxicity
radicals 506 in human HaCaT keratinocytes 542
18.7.7 Dynamic nuclear polarization 19.6 ESR measurement of ROS
MRI (OMRI, PEDRI) 507 generation 542
18.8 Dynamics of the EPR signal of 19.7 ESR oximetry measurement of lipid
Mito-TEMPO in cells of different peroxidation 545
origins and proliferative activities: 19.8 Immuno-spin trapping measurement
Correlation with the levels of of protein radicals 546
intracellular superoxide and 19.9 Phototoxic mechanism
hydrogen peroxide 508 of TiO2NP-induced free radicals 546
18.9 Dynamics of the EPR signal of 19.10 Effect of dose and time of TiO2NPs
nitroxide radical in cells of the same on biochemical disturbance,
origin and different proliferative oxidative stress, and genotoxicity 548
activities: Correlation with the levels 19.11 Nanosized titanium dioxide toxicity
of intracellular superoxide, hydrogen in rat prostate 552
peroxide, and antioxidant 19.12 Conclusion 554
enzymes 511 References 554
18.10 Imaging and drug delivery using
theranostic nanoparticles 515 20. Toxicity of ZnO nanoparticle-
18.11 Imaging modality 516 induced reactive oxygen species
18.11.1 Optical imaging 517
and cancer cells
18.11.2 Magnetic resonance
imaging 517 20.1 ZnO as safe NPs 561
18.11.3 Radionuclide-based 20.2 Toxicological effects of ZnO NPs 562
imaging 517 20.3 Nanomedicine market
18.11.4 Computed tomography 517 overview 562
18.11.5 Ultrasound 517 20.4 DDCT 564
18.12 Nanoparticles 517 20.5 CM 564
18.13 Localization of intracellular 20.6 Effectiveness of the cervical
nanoparticles 520 mucus method 564
18.14 Delivery of nanoparticles to 20.6.1 Characterization of
the cytosol 521 ZnO NPs 564
18.15 Disturbances of intracellular 20.6.2 Cytotoxic effect of ZnO NPs
transport and other cellular on RGC-5 cells 564
processes induced by 20.6.3 The alteration of D cm 564
nanoparticles 522 20.6.4 DAPI staining 566
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20.6.5 Measurement of hydrogen 21.2.6 Increased protein level and gene

peroxide and hydroxyl radical expression of tumor necrosis
levels 566 factor-a 596
20.6.6 Annexin V/PI staining 21.2.7 Increased gene expression of
analysis 567 matrix metalloproteinases 596
20.6.7 Expression of caspase-12 21.2.8 Transfer of AgNPs into
mRNA 569 RAW264.7 cells 598
20.6.8 Expression of caspase-12 21.3 Oxidative DNA damage of human cells
protein 570 treated with AgNPs 600
20.7 ZnO NP-induced ROS and ER stress 21.3.1 Silver ion release from 20 nm
causing cell damage 570 AgNP in culture media 600
20.8 ZnO NPs induce apoptosis via p53 21.3.2 Nanoparticle uptake and
and p38 pathways 572 formation of reactive oxygen
20.8.1 Apoptosis induction by ZnO species in AgNP-treated
NPs 572 cells 600
20.8.2 ZnO NPs induced p53 21.3.3 DNA breakage and base
upregulation and damage 602
phosphorylation of p53 at Ser33 21.3.4 Clonogenic survival 603
and Ser46 572 21.4 Cytotoxicity and genotoxicity
20.8.3 ZnO NPs induced p38 of AgNPs 605
mitogen-activated protein 21.4.1 Cellular uptake and intracellular
kinase upregulation 574 localization of AgNPs 606
20.9 Immunomodulatory effects of 21.4.2 Mitochondrial activity and
ZnO NPs 574 production of reactive oxygen
20.9.1 Cellular uptake of species 607
ZnO NPs 575 21.5 Cyto- and genotoxic potential
20.9.2 Cytotoxicity assessment 577 of AgNPs in hMSCs 610
20.9.3 Evaluation of oxidative 21.5.1 Particle characterization 610
stress 578 21.5.2 Cell viability 611
20.9.4 Cytokine quantitation 578 21.5.3 Genotoxicity 611
20.9.5 Western blot analysis 579 21.5.4 Cytokine secretion 613
20.9.6 Genotoxic potential of 21.5.5 Migration assay 614
ZnO NPs 579 21.6 Cellular toxicity and morphological
20.10 Selective toxicity of ZnO NPs and alterations caused by AgNPs 615
cancer cells 580 21.7 Conclusions 617
20.11 Conclusion 583 References 617
References 583
22. Correlations between oxidative
21. Silver nanoparticles induce cellular stress and aligning nanoparticle
cytotoxicity, genotoxicity, DNA safety assessments
damage, and cell death
22.1 Aligning nanomaterial safety
21.1 Toxicology of AgNPs 589 assessments with the 3Rs
21.1.1 Cytotoxicity of AgNP principles 624
suspensions strongly depends 22.2 Nanomaterial mechanism of
on the silver ion toxicity 625
concentration 590 22.3 Nanomaterials and inflammation 625
21.2 AgNPs induce cytotoxicity 592 22.3.1 Neutrophils 626
21.2.1 Stability of AgNPs in culture 22.3.2 Macrophages 626
media 593 22.4 Nanomaterials and oxidative
21.2.2 Cytotoxicity in cultured stress 627
RAW264.7 cells 593 22.5 Alternative models to investigate
21.2.3 Cell-cycle changes 594 nanomaterial-mediated
21.2.4 Decreased intracellular inflammogenicity and oxidative
glutathione level 595 stress 629
21.2.5 Increased nitric oxide level 596 22.5.1 Zebrafish 629
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22.5.2 In vitro models 633 23.4.12 ROS influence phagosomal

22.5.3 In vitro to in vivo proteolysis through cathepsin
extrapolation 634 inactivation 664
22.6 Conclusions 635 23.4.13 ROS interfere with protein
References 636 immunogenicity, antigenic
presentation, polarization,
23. Effects of interactions between and costimulation by
antioxidant defense therapy and dendritic cells 664
ROS 23.5 Antioxidant defense toward
ROS 665
23.1 Enzymatic antioxidants 645 23.6 Counteractive antioxidant
23.1.1 A toxin and its action defense 666
via ROS 648 23.7 Cellular defense against ROS 667
23.1.2 Antioxidant systems as redox 23.8 Metal chelators as an algal response
signal transmitters 650 to heavy metals 667
23.2 Nonenzymatic antioxidants 651 23.8.1 L-Cys and N-acetyl
23.2.1 Vitamin C (ascorbic acid) 651 cysteine 668
23.2.2 Vitamin E (a-tocopherol) 652 23.8.2 Taurine 669
23.2.3 Glutathione 652 23.8.3 Dietary antioxidants 669
23.2.4 Melatonin 653 23.8.4 a-Lipoic acid 669
23.2.5 Carotenoids (b-carotene) 653 23.9 Essential mineral ions 669
23.3 Antioxidants and their mode 23.9.1 Selenium 669
of action 654 23.9.2 Iron 670
23.4 ROS can promote pathogen 23.9.3 Copper 670
elimination by direct oxidative 23.9.4 Zinc 671
damage or by a variety of innate and 23.10 Redox biology and oxidative
adaptive mechanisms 655 stress 671
23.4.1 Direct oxidative damage 23.11 The role of HDL, ABCA1, and ABCG1
to microbes 659 transporters in cholesterol efflux and
23.4.2 O2  promotes proteolytic immune responses 673
elimination of microorganisms 23.11.1 ABC transporters and active
indirectly 660 cholesterol efflux 674
23.4.3 ROS promote autophagy 660 23.11.2 ABC transporters and the
23.4.4 ROS inhibit mTOR kinase, molecular regulation of the
triggering an antiviral immune system 675
response 660 23.11.3 ABC transporters and in vivo
23.4.5 ROS promote NETosis 661 relevance of the regulation of
23.4.6 ROS promote cell death the immune system: A role in
of infected reservoirs 661 atherosclerosis and other
23.4.7 PRRs use ROS as signaling inflammatory diseases 676
intermediaries in 23.12 Response of the antioxidant enzymes
inflammation 661 of nanoparticles 677
23.4.8 ROS are chemoattractors 23.12.1 Response of erythrocytes
to phagocytes 661 to NPs 679
23.4.9 ROS can activate NRF2 target 23.12.2 Response of serum
genes, a part of the biomarkers to NPs 680
antioxidant defense response References 681
that interferes with innate
immunity 662 24. FDA breakthrough—Drug
23.4.10 ROS interfere with iron
therapy designations for clinical
storage and tissue
evidence
mobilization, influencing iron
availability to pathogens 662 24.1 Breakthrough therapy 693
23.4.11 ROS interfere with lipid 24.1.1 Requirements 694
metabolism and foam cell 24.1.2 Incentives 694
formation 663 24.1.3 Issues 694
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24.2 Frequently asked questions: 24.2.11 Where can I find the webcast
Breakthrough therapies 694 and presentations from the
24.2.1 How many requests for FDA public meeting:
breakthrough therapy Breakthrough therapy
designation has the FDA’s designation: Exploring the
Center for Drug Evaluation and qualifying criteria held on April
Research and Center for 24, 2015 in Washington,
Biologics Evaluation and DC? 697
Research received since the 24.2.12 Can a sponsor submit a request
Food and Drug Administration for breakthrough therapy
Safety and Innovation Act was designation for multiple
signed into law on July 9, indications of the same
2012? 694 drug? 697
24.2.2 What are the benefits of a 24.2.13 Can a request for a
breakthrough therapy breakthrough therapy
designation? 695 designation be submitted for a
24.2.3 What other programs does combination product? 697
FDA have to expedite for drug 24.2.14 Can a product be granted a
development for serious breakthrough therapy
conditions? 695 designation if another product
24.2.4 What are the differences has already been granted
between the criteria for breakthrough therapy
breakthrough therapy designation for the same
designation and fast track indication? 697
designation? 696 24.2.15 Whom should sponsors
24.2.5 Is there a deadline for a sponsor contact if they wish to discuss
to submit a request for the potential for their product
breakthrough therapy meeting the breakthrough
designation? 696 therapy criteria? 697
24.2.6 Does a sponsor have to request 24.2.16 Would a clinical trial for a
breakthrough therapy drug that has been designated
designation to be considered as a breakthrough therapy
for the designation? 696 generally have to enroll
24.2.7 Where can I find the fewer patients prior to
“Guidance for Industry” on approval? 697
breakthrough therapies? 696 24.2.17 May a sponsor submit a request
24.2.8 Where can I find the CDER for Special Protocol
Manual of Policies and Assessment (SPA) for a drug
Procedures (MAPP) on the that has breakthrough therapy
management of breakthrough designation? 698
therapy-designated drugs? 696 24.2.18 Will FDA announce when a
24.2.9 Where can I find the CDER drug has been granted
Manual of Policies and breakthrough therapy
Procedures (MAPP) on the designation? 698
review of a marketing 24.2.19 If a drug is denied
application for a breakthrough breakthrough therapy
therapy-designated drug that is designation, is it automatically
receiving an expedited reviewed for fast track
review? 697 designation? 698
24.2.10 Where can I find the CBER 24.2.20 To what section of the
Standard Operating Policy and electronic Common Technical
Procedure (SOPP) on the Document should a sponsor
management of breakthrough submit a request for
therapy-designated breakthrough therapy
products? 697 designation? 698
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24.2.21 Can a sponsor submit a request request evaluations and

for breakthrough therapy processes, application reviews
designation to a pre-IND? 698 for products receiving both
24.2.22 What are the timelines for FDA breakthrough therapy
to respond to a breakthrough designations and eligibility to
therapy designation PRIME (dually designated), and
request? 698 advice to sponsors for dually
24.2.23 Can a sponsor get preliminary designated product
breakthrough therapy development programs? 699
designation (BTD) advice from 24.3 List of drugs granted breakthrough
the review division prior to the therapy designation 699
submission of a formal BTD 24.3.1 Why screening with an FDA-
request? 698 approved drug library? 699
24.2.24 The European Medicines 24.4 Energy metabolism and cellular
Agency (EMA) PRIME program, toxicity 699
similar to the FDA 24.5 Navigating metabolic pathways to
breakthrough therapy enhance antitumor immunity 699
designation program, was 24.6 Conclusion and future directions 719
launched in March 2016 to 24.6.1 Future perspectives 721
enhance support for the 24.6.2 Hackathon homes in on
development of medicines that RNA 724
target an unmet medical need. References 724
To what extent do the two
agencies work together to
harmonize breakthrough List of abbreviations 729
therapy designation/PRIME Index 743