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

Front Cover Reactive Oxygen Species (ROS), Nanoparticles, and Endoplasmic Reticulum (ER) Stress-Induced Cell Death Mechanisms Copyright Contents About the author Preface Summary Chapter 1: Pathophysiological, toxicological, and immunoregulatory roles of reactive oxygen and nitrogen species (RONS) 1.1. Oxidative and nitrative stress in toxicology and disease 1.2. Oxidative and nitrative stress: Role in the response to liver toxicants (Roberts) 1.2.1. Carcinogenesis and inflammation 1.2.2. Crosstalk with PPARα? 1.3. Characterization of oxidative stress using neuronal cell culture models (Smith) 1.4. Nitrative stress and glial-neuronal interactions in the pathogenesis of Parkinsons disease (Tjalkens and Stephen Safe) 1.4.1. Neuroinflammation and PD 1.4.2. Regulation of neuroinflammatory genes in astrocytes 1.4.3. Therapeutic strategies to interdict neuroinflammation 1.5. Oxidative and nitrative stress in multistage carcinogenesis (Robertson) 1.6. Role of peroxynitrite in the pathogenesis of doxorubicin-induced cardiotoxicity (Szabo) 1.6.1. Molecular mechanisms of peroxynitrite formation 1.7. Immunoregulatory role of ROS 1.8. Conclusions References Chapter 2: Biological mechanisms of reactive oxygen species (ROS) 2.1. Exogenous source of oxidants 2.1.1. Cigarette smoke 2.1.2. Ozone exposure 2.1.3. Hyperoxia 2.1.4. Ionizing radiation 2.1.5. Heavy metal ions 2.2. Endogenous sources of ROS and their regulation in inflammation 2.3. Mitochondria as main source of ROS in autophagy signaling 2.4. ROS and mitophagy 2.5. Production of ROS and their mechanisms of biological activities 2.6. Increased ROS production in photosynthesis during drought 2.7. ROS elimination 2.8. Types of reactive oxygen species References Chapter 3: Cellular signaling pathways with reactive oxygen species (ROS) 3.1. Oxidative stress and ROS 3.2. Sources of ROS 3.2.1. Endogenous sources and localization of ROS 3.2.1.1. Mitochondria 3.2.1.2. Endoplasmic reticulum 3.2.1.3. Soluble enzymes 3.2.1.4. Lipid metabolism 3.2.1.5. NADPH oxidase 3.2.2. Exogenous sources of ROS 3.2.3. The homeostasis of ROS 3.3. Oxidative stress in RA 3.4. Molecular targets of ROS 3.4.1. Protein tyrosine phosphatases and kinases 3.4.2. Lipid metabolism 3.4.3. Ca2+ signaling 3.4.4. Small GTPases 3.4.5. Serine/threonine kinases and phosphatases 3.5. Redox regulation of transcription factors 3.5.1. Nuclear factor κ-light-chain-enhancer of activated B cells 3.5.2. Activator protein-1 3.5.3. Other transcription factors 3.6. RA, pathogenesis, and therapy 3.7. Oxidative stress/ROS-associated consequences in RA 3.7.1. Lipid peroxidation 3.7.2. Effects on immunoglobulin advanced glycation end-products 3.7.3. Oxidative stress/ROS-mediated alteration of autoantigens 3.7.4. Genotoxic effects of oxidative stress 3.7.5. Oxidative stress and tissue injury 3.7.6. Cartilage/collagen effects 3.8. ROS-mediated pathways in cell death 3.8.1. Extrinsic pathways 3.8.2. Intrinsic pathways 3.9. ROS-mediated cellular signaling in RA 3.9.1. MAPK signaling pathway 3.9.2. PI3K-Akt signaling pathway 3.9.3. ROS and NF-κB signaling pathway 3.9.4. Oxidative stress/ROS as signaling in T-cell tolerance 3.10. The homeostasis of ROS 3.11. ROS and the NF-κB signaling pathway 3.12. ROS and MAPK signaling pathway 3.13. ROS and the keap1-Nrf2-ARE signaling pathway 3.14. ROS and the PI3K-Akt signaling pathway 3.15. Crosstalk between ROS and Ca2+ 3.16. Reactive oxygen species and mitochondrial permeability transition pore 3.17. ROS and protein kinase 3.18. ROS and the ubiquitination/proteasome system 3.19. Lipid accumulation in oleaginous microorganisms under different types of stress 3.19.1. Nutrient limitation 3.19.2. Physical environmental stresses 3.19.3. Stress-induced strategies for generation and its potential role in lipid accumulation 3.19.4. Redox homeostasis and oxidative stress 3.19.5. Stress sensing and putative concomitant ROS generation 3.19.6. Transduction of intracellular ROS signals 3.19.7. Possible links between ROS and lipid accumulation References Chapter 4: Manganese as the essential element in oxidative stress and metabolic diseases 4.1. Effects of Mn on the role of reactive oxygen species 4.2. Physiological roles of Mn 4.3. Mn as metalloenzymes and as an enzyme activator 4.4. Mn stability and transport 4.5. Mn administration, distribution, and excretion 4.6. Brain Mn targets 4.7. Mn and metabolic syndrome 4.8. Mn and T2DM/insulin resistance 4.9. Mn and obesity 4.10. Mn and atherosclerosis 4.11. Mn and nonalcoholic fatty liver disease 4.12. Mn and autoxidation of catecholamines and other neurotransmitters 4.13. Mitochondria, the MPT, and apoptosis 4.14. Mn, ROS, the mitochondria, and apoptosis 4.15. A case for the use of mitochondrially targeted antioxidants 4.16. Conclusion References Further reading Chapter 5: Affected energy metabolism is the primal cause of manganese toxicity 5.1. Affected energy metabolism 5.1.1. Gene expression profile under Mn stress 5.1.2. Mn-induced iron depletion blocks ISC and heme protein biogenesis 5.1.3. Mature ISC and heme protein deficiency affects energy metabolism 5.1.4. Reduced ETC function evokes ROS under Mn stress 5.1.5. Affected energy metabolism determines Mn toxicity 5.2. Mechanism of Mn-induced cellular toxicity 5.3. Polynitrogen Mn complexes 5.3.1. Cytotoxicity of Mn complexes 1 and 2 5.3.2. Effects of different concentrations of H2O2 on apoptosis of PC12 cells 5.3.3. Protection of preconditioning with Mn complexes against H2O2-induced death of neuronal cells 5.3.4. Time course analysis of intracellular ROS level changes 5.3.5. Effects of Mn complexes on the mRNA levels of HIF-1α and HIF target genes in cultured cells 5.3.6. Effects of Mn complexes on the protein levels of HIF-1α and HIF target genes in cultured cells 5.3.7. HIF-1α knockdown-induced apoptotic cell death under preconditioning with Mn complexes of neuronal cells 5.4. Neuroprotection-related signaling pathways of Mn complexes 1 and 2 5.5. Conclusion References Chapter 6: Heavy metals and free radical-induced cell death mechanisms 6.1. Heavy metal ions 6.2. Occurrence and recovery of heavy metals 6.3. Free radicals 6.3.1. Definition of free radicals 6.4. Heavy metals and their risky role on organisms of biological systems 6.5. Bioimportance of some heavy metals 6.6. Ecotoxicology and metabolism of heavy metals 6.7. Toxicity of xenobiotic metals (mercury, lead, cadmium, tin, and arsenic) 6.7.1. Mercury 6.7.2. Lead 6.7.3. Cadmium 6.7.4. Tin 6.7.5. Arsenic References Chapter 7: Cytotoxic mechanisms of xenobiotic heavy metals on oxidative stress 7.1. Effects of lead on oxidative stress 7.2. Effects of iron on oxidative stress 7.3. Effects of mercury on oxidative stress 7.4. Effects of copper on oxidative stress 7.5. Effects of cadmium and zinc on oxidative stress 7.6. Effects of arsenic on oxidative stress 7.7. Effects of chromium on oxidative stress 7.8. Effects of vanadium on oxidative stress 7.9. Cytotoxic and cellular functions of heavy metals References Chapter 8: Oxidative stress and oxidative damage-induced cell death 8.1. Oxidative stress 8.2. ROS regulation of signaling molecules 8.2.1. Kinases and phosphatases 8.2.2. Transcription factors 8.2.3. ROS-induced transcriptional activation 8.2.4. Signaling pathways 8.2.5. Mitogen signaling 8.2.6. Integrin signaling 8.2.7. Wnt signaling 8.3. Cellular processes regulated by ROS 8.3.1. Proliferation 8.3.2. Differentiation 8.3.3. Cell death 8.4. Autophagy and oxidative stress 8.4.1. Redox signaling in autophagy 8.5. Oxidative damage 8.6. ROS and oxidative damage on biomolecules 8.6.1. Effects of oxidative stress on lipids 8.6.2. Effects of oxidative stress on proteins 8.6.3. Effects of oxidative stress on DNA 8.7. ROS/RNS and nucleic acid destabilization References Chapter 9: Cell death mechanisms-Apoptosis pathways and their implications in toxicology 9.1. Apoptosis: Historical perspectives 9.2. Apoptosis: Mechanisms and different pathways 9.2.1. Extrinsic pathway 9.2.2. Intrinsic pathway 9.2.3. Perforin/granzyme pathway 9.2.4. Execution pathway 9.2.5. Main mechanisms of parasite-induced cell apoptosis 9.3. Signaling pathways leading to apoptosis in mammalian cells 9.4. The role of calcium in cell death 9.4.1. The endoplasmic reticulum, Ca2+, and apoptosis 9.4.2. Apoptosis by mitochondrial permeabilization 9.4.3. Ca2+-activated effector mechanisms 9.4.4. Ca2+ and the phagocytosis of apoptotic cells 9.5. Oxidative stress and cell death 9.6. Targets of ROS 9.7. Inflammation and cell death 9.8. Some alternative forms of cell death 9.8.1. Necrosis (type 3 cell death) 9.8.2. Autophagy 9.8.3. Pyroptosis 9.8.4. Entosis 9.8.5. Mitotic catastrophe (mitotic failure) 9.9. Links between apoptosis and other cell death modalities 9.10. Toxicity-related cell death 9.11. Role of autophagy in toxicity 9.11.1. Role of apoptosis in cancers 9.11.2. Overexpression of apoptosis 9.11.3. Use of antiapoptotic therapy agents 9.11.4. Assays used 9.12. Chelerythrine-induced cell death through ROS-dependent ER stress in human prostate cancer cells 9.12.1. CHE reduced cell viability in human prostate cancer cells 9.12.2. CHE induced cell apoptosis in human prostate cancer cells 9.12.3. CHE increased ROS accumulation in PC-3 cells 9.12.4. Blockage of ROS generation reversed CHE-induced cell apoptosis in PC-3 cells 9.12.5. CHE induced cell apoptosis through ROS-mediated ER stress in PC-3 cells 9.13. Conclusion References Chapter 10: Programmed cell death mechanisms and nanoparticle toxicity 10.1. Molecular mechanisms underlying nanomaterial toxicity 10.2. Major forms of programmed cell death 10.3. More than one way to skin a cat 10.4. Programmed cell death: Apoptosis 10.5. Programmed cell death: Autophagy 10.6. Programmed cell death: Necrosis 10.7. The importance of being small 10.8. Effects of nanoparticles on apoptosis 10.9. Nanomaterials and apoptosis 10.10. Nanomaterials and mitotic catastrophe 10.11. Effects of nanoparticles on autophagy 10.12. Nanomaterials and autophagy or ``autophagic cell death´´ 10.13. Effects of nanoparticles on necroptosis 10.14. Nanomaterials and necrosis 10.15. Nanomaterials and pyroptosis 10.16. Mechanisms of graphene-induced programmed cell death 10.17. GBMs induce apoptosis in cells 10.18. The signaling pathways involved in GBM-induced apoptosis 10.19. GBMs induce autophagy in cells 10.20. The signaling pathways involved in GBM-induced autophagy 10.21. GBMs induce necroptosis and relative pathways involved 10.22. Some differences and relationships of GBM-induced programmed cell death 10.22.1. Differences in programmed cell death 10.22.2. Several cross-linked pathways in programmed cell death 10.23. Conclusions and perspectives References Chapter 11: Endoplasmic reticulum stress and associated ROS in disease pathophysiology applications 11.1. Endoplasmic reticulum 11.2. Reactive oxygen species 11.3. Sources of reactive oxygen species generation 11.4. Endoplasmic reticulum stress 11.5. Unfolded protein response 11.5.1. Inositol-requiring protein 1 11.5.2. Protein kinase-like endoplasmic reticulum kinase 11.5.3. Activating transcription factor 6 11.6. Protein folding challenge in intestinal secretory cells 11.7. Endoplasmic reticulum stress and autophagy 11.8. How are reactive oxygen species induced through endoplasmic reticulum stress? 11.8.1. The specific mechanism of ERS-induced ROS during the ER folding process 11.9. Specific mechanism of ERS-induced ROS: NADPH oxidase 4 11.10. Coupled glutathione within the ER 11.11. NADPH-dependent P450 reductase and P450 connection involvement in ERS 11.12. ER and mitochondria connection and relationship to ROS 11.13. Oxidative stress 11.14. Vicious sequence of events between endoplasmic reticulum stress and oxidative stress 11.15. Endoplasmic reticulum stress and oxidative stress in inflammatory bowel disease 11.16. Disease application 11.16.1. ERS and diseases 11.16.2. Neurodegenerative diseases 11.16.3. Diabetes mellitus 11.16.4. Atherosclerosis 11.16.5. Kinds of inflammation 11.16.6. Liver disease 11.16.7. Ischemia 11.16.8. Kidney disease 11.17. Conclusions References Chapter 12: Endoplasmic reticulum stress-induced cell death mechanism 12.1. ER stress and unfolded protein response 12.2. Protein folding: ER chaperones and foldases 12.2.1. General chaperones 12.2.2. Lectin chaperones 12.2.3. Other folding chaperones and enzymes 12.3. Role of ER stress inhibitors in the context of metabolic diseases 12.4. ER stress sensors 12.4.1. Activation of PERK 12.4.2. Activation of the IRE1α pathway 12.4.3. Activation of the ATF6 pathway 12.5. ER stress leads to disease progression 12.6. Metabolic disorders 12.6.1. Diabetes 12.6.2. Obesity 12.6.3. Lipid disorders 12.7. ER stress inhibitors 12.7.1. KIRA6 12.7.2. 3-Hydroxy-2-naphthoic acid 12.7.3. MKC-3946 12.7.4. 4-Phenylbutyric acid 12.7.5. Taurine-conjugated ursodeoxycholic acid 12.7.6. Olmesartan 12.7.7. N-Acetylcysteine 12.7.8. Oleanolic acid 12.7.9. Ursolic acid 12.7.10. Telmisartan 12.7.11. Quercetin 12.7.12. Other inhibitors 12.7.13. Antidiabetic drugs targeting ER stress 12.8. ER stress, UPR signaling, and cell death regulation 12.9. UPR-independent ER stress signaling and cell death 12.9.1. Calcium 12.9.2. MEKK1 (MAP3K4) 12.9.3. ER membrane reorganization 12.10. Suppressors of ER stress-induced apoptosis 12.10.1. Bax-inhibitor 1 12.10.2. Bcl-2/Bcl-XL 12.10.3. MicroRNAs 12.10.4. Additional suppressors of ER stress-induced apoptosis 12.11. ER stress and autophagy 12.12. ER stress involvement in diseases 12.12.1. Neurodegenerative diseases 12.12.2. Ophthalmology disorders 12.12.3. Immunity and inflammation 12.12.4. Viral infections 12.12.5. Metabolic diseases 12.12.6. Atherosclerosis 12.13. ER stress and cancer 12.13.1. ER chaperones and cancer regulation 12.13.2. ER sensors and cancer 12.14. The crosstalk between ER stress and autophagy in cancer 12.15. The relationship between FOXO, ER stress, and cancer 12.15.1. PERK pathway and the FOXO3 story 12.15.2. IRE-1 and FOXO regulation 12.15.3. Chaperones and FOX regulation 12.15.4. ER stress and FOX regulation in worms 12.15.5. Daf-16 and dFOXO and regulation of the Ire-1 arm 12.15.6. Regulation of PERK by dFOXO 12.16. Targeting cancer through the UPR signaling and its FOXO link 12.16.1. Targeting IRE1α/XBP1 12.16.2. Targeting PERK/ATF4 12.16.3. Chaperone inhibitors and FOXO3 References Chapter 13: Modulation of endoplasmic reticulum (ER) stress of nanotoxicology for nanoparticles (NPs) 13.1. Nanotoxicology and nanomedicine 13.2. ER stress as a mechanism for nanotoxicology 13.2.1. Morphological changes of the ER by NP exposure 13.2.2. Effects of NP exposure on the ER stress pathway 13.2.3. Modulation of ER stress and the toxicity of NPs 13.3. Modulation of ER stress by NPs in nanomedicine 13.3.1. Selective activation of ER stress by NPs for cancer therapy 13.3.2. Alleviation of ER stress by NPs for metabolic disease therapy 13.4. Silver nanoparticles-Allies or adversaries? 13.5. Role of AgNPs in cell toxicity 13.5.1. Silver nanoparticle-induced apoptosis 13.5.1.1. Results 13.5.1.2. Conclusion 13.5.1.3. Significance 13.5.2. Silver nanoparticles induce ER stress 13.6. Uptake of AgNPs and their intracellular localization 13.7. Inhibition of proliferation and cell death 13.8. ROS key factor in biological oxidation processes 13.9. Oxidative stress as an underlying mechanism for NP toxicity 13.10. Genotoxicity 13.11. Concluding remarks References Chapter 14: Nanoparticle cellular uptake and intracellular targeting on reactive oxygen species (ROS) in biological activ ... 14.1. Nanoparticle classes and biomedical applications 14.1.1. Optical imaging 14.1.2. Biosensing 14.1.3. Diagnostic applications 14.1.4. Drug delivery 14.1.5. Other applications 14.2. Mechanisms associated with NP-induced ROS generation 14.2.1. NP-related factors implicated in ROS generation 14.2.2. NP- and cellular-component-induced ROS generation 14.3. Biological functions modulated by NP-induced ROS production 14.3.1. DNA damage and cytotoxicity 14.3.2. Antimicrobial function 14.3.3. Cellular differentiation 14.3.4. Anticancer 14.4. NP-induced modulation of ROS generation in stem cell biology 14.5. Nanoparticle cellular uptake and intracellular targeting 14.6. Endocytic routes and nonligand targeted nanomedicines 14.7. Receptor-mediated cellular internalization of ligand-targeted nanomedicines 14.7.1. Prostate-specific membrane antigen targeting 14.7.2. Neonatal Fc-receptor targeting-An avenue to oral delivery of nanomedicine 14.8. Intracellular trafficking and subcellular targeting 14.8.1. From endosomes/lysosomes to cytoplasm 14.8.2. Endoplasmic reticulum and Golgi apparatus 14.8.3. Mitochondria 14.8.4. Nucleus 14.9. Outlook 14.10. Conclusions References Chapter 15: Metal nanoparticles (MNPs) and particulate matter (PM) induce toxicity 15.1. Nano-bio interactions 15.2. Economical relevance [42a] 15.3. Nanotoxicology of nanoparticles 15.4. Overproduction of ROS and cell damage 15.5. Nanotoxicity and generation of ROS 15.6. Dependence of ROS production on the properties of nanoparticles 15.6.1. Size and shape 15.6.2. Particle surface, surface positive charges, and surface containing groups 15.6.3. Solubility and particle dissolution 15.6.4. Metal ions released from metal and metal oxide nanoparticles 15.6.5. Light activation 15.6.6. Aggregation and mode of interaction with cells 15.6.7. Inflammation leading to ROS formation 15.6.8. pH of the system 15.7. Particulate matter References Chapter 16: Mechanisms for nanoparticle-mediated oxidative stress 16.1. Introduction to transition metals 16.1.1. Generation of reactive oxygen species 16.1.2. Reactive oxygen species and biological systems 16.2. Exposure routes for nanoparticles 16.3. Prooxidant effects of metal oxide nanoparticles 16.4. Effects of nanoparticles on cell organisms 16.4.1. Absorption of nanoparticles and cytotoxicity 16.4.2. Absorption of nanoparticles under environmental conditions 16.4.3. Nanoparticles in outdoor spaces 16.4.4. Interactions among organisms, nanoparticles, and contaminants 16.5. Nanoparticle-induced oxidative stress 16.6. Oxidant generation via particle-cell interactions 16.6.1. Lung injury caused by nanoparticle-induced reactive nitrogen species 16.6.2. Mechanisms for reactive oxygen species production and apoptosis within metal nanoparticles 16.7. Modeling nanotoxicity 16.8. Cellular signaling affected by metal nanoparticles 16.8.1. NF-κB 16.8.2. AP-1 16.8.3. MAPK 16.8.4. PTP 16.8.5. Src 16.9. Carbon nanotubes 16.10. Carbon nanotube-induced oxidative stress 16.11. Role of reactive oxygen species in carbon nanotube-induced inflammation 16.12. Role of reactive oxygen species in carbon nanotube-induced genotoxicity 16.13. Role of reactive oxygen species in carbon nanotube-induced fibrosis 16.14. Difficulties in determination of the mechanism of nanotoxicity in cells and in vivo 16.15. Conclusion References Chapter 17: Nanotechnological modifications of nanoparticles on reactive oxygen and nitrogen species 17.1. Nanotechnology and nanomaterials 17.2. Nanotechnological modifications 17.2.1. Nanodiffusion in the environment 17.2.2. Nanomaterials in soil 17.2.3. Nanoparticle mobility in soil 17.3. Nanotechnology and agriculturally sustainable development 17.3.1. Nanofertilizers 17.3.2. Nanopesticides 17.3.3. Ecotoxicological implications of nanoparticles 17.4. Growth of cultivated plants and their ecotoxicological sustainability 17.5. Applications of nanotechnology in the agricultural sector 17.5.1. Nanosilver 17.5.2. Nanosilica 17.5.3. Nanotitanium dioxide 17.5.4. Nanocalcium 17.5.5. Nano-iron 17.6. Nanotechnologies in the food industry 17.6.1. Food process 17.6.2. Food packaging and labeling 17.7. Selenium nanoparticles as a food additive 17.7.1. Problems with traditional forms of oral supplementation of selenium and potential benefits of SeNPs 17.7.2. Mechanism of passage of nanoparticles through intestinal mucosa 17.7.3. Application of SeNPs through oral administration 17.7.3.1. Nano-Se as an antioxidant 17.7.3.2. Effect of SeNPs on reproductive performance 17.7.3.3. Use of nano-Se for increasing hair follicle development and fetal growth 17.7.3.4. Antiviral and antibacterial effects of SeNPs 17.7.4. Anticancer effects of SeNPs 17.7.4.1. Nano-Se as an anticancer drug 17.7.4.2. Nano-Se as an anticancer drug delivery carrier 17.7.4.3. Nano-Se as a promising orthopedic implant material and an agent reducing bone cancer cell functions 17.8. Effect of SeNPs on oxidative stress parameters 17.9. Protective effects of nano-Se 17.9.1. SeNPs in prevention of cisplatin-induced reproductive toxicity 17.9.2. Protective effect of nano-Se against polycyclic aromatic hydrocarbons 17.9.3. Use of SeNPs for minimization of risk of iron overabundance 17.9.4. SeNPs in the treatment of heavy metal intoxication 17.9.5. Nano-Se as an immunostimulatory 17.9.6. Effect of nano-Se on microbial fermentation, nutrient digestibility, and probiotic support 17.9.7. Nano-Se in the treatment of metabolic disorders 17.10. Safety and toxicity concerns of orally delivered SeNPs for use as food additives and drug carriers References Chapter 18: Medical imaging of the complexity of nanoparticles and ROS dynamics in vivo for clinical diagnosis application 18.1. Redox signaling 18.2. Dynamics of the EPR signal of nitroxide radicals in leukemic and normal lymphocytes 18.3. Redox-sensitive two-photon microscopy 18.3.1. Two-photon redox-sensitive probes 18.3.2. Two-photon-sensitive probes for assessment of glutathione redox state 18.3.3. Two-photon NADPH redox state-sensitive probes 18.3.4. Two-photon H2O2-sensitive probes 18.3.5. Two-photon NO-sensitive probes 18.4. Chemiluminescent imaging of ROS in vivo 18.4.1. NIR fluorescence and chemiluminescence 18.4.2. Chemiluminescent nanoparticles and ROS imaging 18.5. Ultrasound in ROS imaging 18.6. PET/SPECT in vivo imaging of oxidative stress using radiotracers 18.6.1. Imaging glucose consumption as a surrogate of oxidative stress 18.6.2. Radiotracers with redox potential-dependent cellular retention 18.6.3. Radiotracers with hypoxia-dependent cellular retention 18.6.4. Radiotracers targeting ROS scavengers or mitochondrial complex I-IV 18.7. Magnetic resonance modalities 18.7.1. Basic principles and technical considerations 18.7.2. Examples of EPRI/MRI of ROS/RNS 18.7.3. Brain imaging (without tumors) 18.7.4. Tumor imaging 18.7.5. Other organs 18.7.6. Imaging of trapped radicals 18.7.7. Dynamic nuclear polarization MRI (OMRI, PEDRI) 18.8. Dynamics of the EPR signal of Mito-TEMPO in cells of different origins and proliferative activities: Correlation wi ... 18.9. Dynamics of the EPR signal of nitroxide radical in cells of the same origin and different proliferative activities: ... 18.10. Imaging and drug delivery using theranostic nanoparticles 18.11. Imaging modality 18.11.1. Optical imaging 18.11.2. Magnetic resonance imaging 18.11.3. Radionuclide-based imaging 18.11.4. Computed tomography 18.11.5. Ultrasound 18.12. Nanoparticles 18.13. Localization of intracellular nanoparticles 18.14. Delivery of nanoparticles to the cytosol 18.15. Disturbances of intracellular transport and other cellular processes induced by nanoparticles 18.16. Cellular excretion and degradation of nanoparticles 18.17. Conclusions 18.18. Outlook References Chapter 19: Titanium dioxide nanoparticle-induced cytotoxicity and genotoxicity-Generation of reactive oxygen species and ... 19.1. TiO2NP-induced cytotoxicity and DNA damage 19.2. Nano-TiO2 in biological systems 19.3. TiO2NP-induced toxic effects on human health 19.4. Characterization of nano-TiO2 19.5. Nano-TiO2-induced phototoxicity in human HaCaT keratinocytes 19.6. ESR measurement of ROS generation 19.7. ESR oximetry measurement of lipid peroxidation 19.8. Immuno-spin trapping measurement of protein radicals 19.9. Phototoxic mechanism of TiO2NP-induced free radicals 19.10. Effect of dose and time of TiO2NPs on biochemical disturbance, oxidative stress, and genotoxicity 19.11. Nanosized titanium dioxide toxicity in rat prostate 19.12. Conclusion References Chapter 20: Toxicity of ZnO nanoparticle-induced reactive oxygen species and cancer cells 20.1. ZnO as safe NPs 20.2. Toxicological effects of ZnO NPs 20.3. Nanomedicine market overview 20.4. DDCT 20.5. CM 20.6. Effectiveness of the cervical mucus method 20.6.1. Characterization of ZnO NPs 20.6.2. Cytotoxic effect of ZnO NPs on RGC-5 cells 20.6.3. The alteration of ψm 20.6.4. DAPI staining 20.6.5. Measurement of hydrogen peroxide and hydroxyl radical levels 20.6.6. Annexin V/PI staining analysis 20.6.7. Expression of caspase-12 mRNA 20.6.8. Expression of caspase-12 protein 20.7. ZnO NP-induced ROS and ER stress causing cell damage 20.8. ZnO NPs induce apoptosis via p53 and p38 pathways 20.8.1. Apoptosis induction by ZnO NPs 20.8.2. ZnO NPs induced p53 upregulation and phosphorylation of p53 at Ser33 and Ser46 20.8.3. ZnO NPs induced p38 mitogen-activated protein kinase upregulation 20.9. Immunomodulatory effects of ZnO NPs 20.9.1. Cellular uptake of ZnO NPs 20.9.2. Cytotoxicity assessment 20.9.3. Evaluation of oxidative stress 20.9.4. Cytokine quantitation 20.9.5. Western blot analysis 20.9.6. Genotoxic potential of ZnO NPs 20.10. Selective toxicity of ZnO NPs and cancer cells 20.11. Conclusion References Chapter 21: Silver nanoparticles induce cellular cytotoxicity, genotoxicity, DNA damage, and cell death 21.1. Toxicology of AgNPs 21.1.1. Cytotoxicity of AgNP suspensions strongly depends on the silver ion concentration 21.2. AgNPs induce cytotoxicity 21.2.1. Stability of AgNPs in culture media 21.2.2. Cytotoxicity in cultured RAW264.7 cells 21.2.3. Cell-cycle changes 21.2.4. Decreased intracellular glutathione level 21.2.5. Increased nitric oxide level 21.2.6. Increased protein level and gene expression of tumor necrosis factor-α 21.2.7. Increased gene expression of matrix metalloproteinases 21.2.8. Transfer of AgNPs into RAW264.7 cells 21.3. Oxidative DNA damage of human cells treated with AgNPs 21.3.1. Silver ion release from 20nm AgNP in culture media 21.3.2. Nanoparticle uptake and formation of reactive oxygen species in AgNP-treated cells 21.3.3. DNA breakage and base damage 21.3.4. Clonogenic survival 21.4. Cytotoxicity and genotoxicity of AgNPs 21.4.1. Cellular uptake and intracellular localization of AgNPs 21.4.2. Mitochondrial activity and production of reactive oxygen species 21.5. Cyto- and genotoxic potential of AgNPs in hMSCs 21.5.1. Particle characterization 21.5.2. Cell viability 21.5.3. Genotoxicity 21.5.4. Cytokine secretion 21.5.5. Migration assay 21.6. Cellular toxicity and morphological alterations caused by AgNPs 21.7. Conclusions References Chapter 22: Correlations between oxidative stress and aligning nanoparticle safety assessments 22.1. Aligning nanomaterial safety assessments with the 3Rs principles 22.2. Nanomaterial mechanism of toxicity 22.3. Nanomaterials and inflammation 22.3.1. Neutrophils 22.3.2. Macrophages 22.4. Nanomaterials and oxidative stress 22.5. Alternative models to investigate nanomaterial-mediated inflammogenicity and oxidative stress 22.5.1. Zebrafish 22.5.1.1. Zebrafish and the innate immune response to nanomaterials 22.5.1.2. Zebrafish embryos and oxidative stress 22.5.1.3. Zebrafish: Recommendations for a testing strategy 22.5.1.3.1. Life stage 22.5.1.3.2. Route of administration 22.5.2. In vitro models 22.5.3. In vitro to in vivo extrapolation 22.6. Conclusions References Chapter 23: Effects of interactions between antioxidant defense therapy and ROS 23.1. Enzymatic antioxidants 23.1.1. A toxin and its action via ROS 23.1.2. Antioxidant systems as redox signal transmitters 23.2. Nonenzymatic antioxidants 23.2.1. Vitamin C (ascorbic acid) 23.2.2. Vitamin E (α-tocopherol) 23.2.3. Glutathione 23.2.4. Melatonin 23.2.5. Carotenoids (β-carotene) 23.3. Antioxidants and their mode of action 23.4. ROS can promote pathogen elimination by direct oxidative damage or by a variety of innate and adaptive mechanisms 23.4.1. Direct oxidative damage to microbes 23.4.2. O2- promotes proteolytic elimination of microorganisms indirectly 23.4.3. ROS promote autophagy 23.4.4. ROS inhibit mTOR kinase, triggering an antiviral response 23.4.5. ROS promote NETosis 23.4.6. ROS promote cell death of infected reservoirs 23.4.7. PRRs use ROS as signaling intermediaries in inflammation 23.4.8. ROS are chemoattractors to phagocytes 23.4.9. ROS can activate NRF2 target genes, a part of the antioxidant defense response that interferes with innate immunity 23.4.10. ROS interfere with iron storage and tissue mobilization, influencing iron availability to pathogens 23.4.11. ROS interfere with lipid metabolism and foam cell formation 23.4.12. ROS influence phagosomal proteolysis through cathepsin inactivation 23.4.13. ROS interfere with protein immunogenicity, antigenic presentation, polarization, and costimulation by dendritic ... 23.5. Antioxidant defense toward ROS 23.6. Counteractive antioxidant defense 23.7. Cellular defense against ROS 23.8. Metal chelators as an algal response to heavy metals 23.8.1. l-Cys and N-acetyl cysteine 23.8.2. Taurine 23.8.3. Dietary antioxidants 23.8.4. α-Lipoic acid 23.9. Essential mineral ions 23.9.1. Selenium 23.9.2. Iron 23.9.3. Copper 23.9.4. Zinc 23.10. Redox biology and oxidative stress 23.11. The role of HDL, ABCA1, and ABCG1 transporters in cholesterol efflux and immune responses 23.11.1. ABC transporters and active cholesterol efflux 23.11.1.1. ABCA1 and cholesterol efflux to apoA-I 23.11.1.2. ABCG1 and cholesterol efflux to mature HDL 23.11.2. ABC transporters and the molecular regulation of the immune system 23.11.2.1. Transporters and macrophage inflammation 23.11.2.2. ABC transporters and lymphocyte proliferation 23.11.3. ABC transporters and in vivo relevance of the regulation of the immune system: A role in atherosclerosis and oth ... 23.11.3.1. ABC transporters and atherosclerosis 23.11.3.2. ABC transporters and inflammatory dis