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

1. Pathophysiological, toxicological and immunoregulatory roles of reactive oxygen and nitrogen species (RONS)1.1. Oxidative and nitrative stress in toxicology and disease1.2. Oxidative and nitrative stress: role in the response to liver toxicants (Roberts)1.2.1. Carcinogenesis and inflammation1.2.2. Cross-talk 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 Parkinson’s disease (PD) (Tjalkens and Stephen Safe)1.4.1. Neuroinflammation and PD1.4.2. Regulation of neuroinflammatory genes in astrocytes1.4.3. Therapeutic strategies to interdict neuroinflammatio1.5. 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 formation1.7. Immunoregulatory role of ROS1.8. ConclusionsReferences

2. Biological mechanisms of reactive oxygen species (ROS)2.1. Exogenous source of oxidants 2.1.1. Cigarette smoke2.1.2. Ozone exposure2.1.3. Hyperoxia2.1.4. Ionizing radiation2.1.5. Heavy metal Ions2.2. Endogenous sources of ROS and their regulation in inflammation2.3. Mitochondria as main source of ROS in autophagy signaling2.4. ROS and mitophagy2.5. Production of ROS and their mechanisms of biological activities2.6. Increased ROS production in photosynthesis during drought2.7. ROS elimination2.8. Types of reactive oxygen species (ROS)References

3. Cellular signaling pathways with reactive oxygen species (ROS)3.1. Oxidative stress and ROS3.2. Sources of ROS3.2.1. Endogenous sources and localization of ROS3.2.1.1. Mitochondria3.2.1.2. Endoplasmic reticulum3.2.1.3. Soluble enzymes3.2.1.4. Lipid metabolism3.2.1.5. NADPH oxidase3.2.2. Exogenous sources of ROS3.2.3. The homeostasis of ROS3.3. Oxidative stress in RA3.4. Molecular targets of ROS3.4.1. Protein tyrosine phosphatases and kinases3.4.2. Lipid metabolism3.4.3. Ca+2 signaling'3.4.4. Small GTP-ases3.4.5. Serine/threonine kinases and phosphatases3.5. Redox regulation of transcription factors3.5.1. NF-κB3.5.2. AP-13.5.3. Other transcription factors3.6. Rheumatoid arthritis (RA), pathogenesis and therapy3.7. Oxidative stress/ROS associated consequences in RA3.7.1. Lipid peroxidation3.7.2. Effects on immunoglobulins advanced glycation end-products3.7.3. Oxidative stress/ROS mediated alteration of auto-antigens3.7.4. Genotoxic effects of oxidative stress3.7.5. Oxidative stress and tissue injury3.7.6. Cartilage/collagen effects3.8. ROS mediated pathways in cell death3.8.1. Extrinsic pathways3.8.2. Intrinsic pathways3.9. ROS mediated cellular signaling in RA3.9.1. MAPKs signaling pathway3.9.2. PI3K-Akt signaling pathway3.9.3. ROS and NF-kB signaling pathway 3.9.4. Oxidative stress/ROS as signaling in T cell tolerance3.10. The homeostasis of ROS3.11. ROS and NF-κB signaling pathway3.12. ROS and MAPKs signaling pathway3.13. ROS and keap1-Nrf2-ARE signaling pathway3.14. ROS and PI3K-Akt signaling pathway3.15. Cross talk between ROS and Ca2+3.16. ROS and mPTP3.17. ROS and protein kinase3.18. ROS and ubiquitination/proteasome system3.19. Lipid accumulation in oleaginous microorganisms under different types of stress3.19.1. Nutrient limitation3.19.2. Physical environmental stresses3.19.3. Stress-induced for generation and its potential role in lipid accumulation3.19.4. Redox homeostasis and oxidative stress3.19.5. Stress sensing and putative concomitant ROS generation3.19.6. Transduction of intracellular ROS signals3.19.7. Possible links between ROS and lipid accumulationReferences

4. Manganese as the essential element in oxidative stress, and metabolic diseases4.1. Effects of manganese on the role of reactive oxygen species4.2. Physiological roles of manganese4.3. Mn as metalloenzymes and as an enzyme activator4.4. Mn stability and transport4.5. Mn administration, distribution, and excretion4.6. Brain manganese targets4.7. Mn and metabolic syndrome4.8. Mn and type 2 diabetes mellitus/insulin resistance4.9. Mn and obesity4.10. Mn and atherosclerosis4.11. Mn and nonalcoholic fatty liver disease4.12. Mn and autoxidation of catecholamines and other neurotransmitters4.13. Mitochondria, the mitochondrial permeability transition, and apoptosis4.14. Mn, ROS, the mitochondria, and apoptosis4.15. A case for the use of mitochondrially targeted antioxidants4.16. Conclusion References

5. Affected energy metabolism is primal cause of manganese toxicity5.1. Affected energy metabolism5.1.1. Gene expression profile under manganese stress.5.1.2. Manganese-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 manganese stress.5.1.5. Affected energy metabolism determines manganese toxicity.5.2. Mechanism of manganese-induced cellular toxicity5.3. Polynitrogen manganese complexes5.3.1. 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 levels 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. ConclusionReferences

6. Heavy metals and free radicals-induced cell death mechanisms6.1. Heavy metal ions6.2. Occurrence and recovery of heavy metals6.3. Free radicals6.3.1. Definition free radicals6.4. Heavy metals and their risk role on organisms of biological systems6.5. Bio-importance of some heavy metals 6.6. Ecotoxicology and metabolism of heavy metals6.7. Toxicity of xenobiotic metals (mercury, lead, cadmium, tin and arsenic)6.7.1. Mercury6.7.2. Lead6.7.3. Cadmium6.7.4. Tin6.7.5. Arsenic References

7. Cytotoxic mechanisms of xenobiotic heavy metals on oxidative stress7.1. Effects of lead on oxidative stress7.2. Effects of iron on oxidative stress7.3. Effects of mercury on oxidative stress7.4. Effects of copper on oxidative stress7.5. Effects of cadmium and zinc on oxidative stress7.6. Effects of arsenic on oxidative stress7.7. Effects of chromium on oxidative stress7.8. Effects of vanadium on oxidative stress7.9. Cytotoxic and cellular functions of heavy metalsReferences

8. Oxidative stress and oxidative damage-induced cell death8.1. Oxidative stress8.2. ROS regulation of signaling molecules8.2.1. Kinases and phosphatases8.2.2. Transcription factors8.2.3. ROS-induced transcriptional activation8.2.4. Signaling pathways8.2.5. Mitogen signaling8.2.6. Integrin signaling8.2.7. Wnt signaling8.3. Cellular processes regulated by ROS8.3.1. Proliferation8.3.2. Differentiation8.3.3. Cell death8.4. Autophagy and oxidative stress8.4.1. Redox signaling in autophagy8.5. Oxidative damage8.6. ROS and oxidative damage on biomolecules8.6.1. Effects of oxidative stress on lipids8.6.2. Effects of oxidative stress on proteins8.6.3. Effects of oxidative stress on DNA8.7. ROS/RNS and nucleic acid destabilizationReferences

9. Cell death mechanisms–apoptosis pathways and their implications in toxicology9.1. Apoptosis: Historical perspectives9.2. Apoptosis: Mechanisms and different pathways9.2.1. Extrinsic pathway9.2.2. Intrinsic pathway9.2.3. Perforin/granzyme pathway9.2.4. Execution pathway9.2.5. Main mechanisms of parasites induced cell apoptosis9.3. Signaling pathways leading to apoptosis in mammalian cells9.4. The role of calcium in cell death9.4.1. The endoplasmic reticulum ER, Ca2+‏, and apoptosis9.4.2. Apoptosis by mitochondrial permeabilization9.4.3. Ca2+‏-activated effector mechanisms9.4.4. Ca2+ and the phagocytosis of apoptotic cells9.5. Oxidative stress and cell death9.6. Targets of ROS9.7. Inflammation and cell death9.8. Some alternative forms of cell death9.8.1. Autophagy9.8.2. Pyroptosis9.8.3. Entosis9.8.4. Mitotic catastrophe (mitotic failure)9.9. Links between apoptosis and other cell death modalities9.10. Toxicity-related cell death9.11. Role of autophagy in toxicity9.11.1. Role of apoptosis in cancers9.11.2. Over-expression of apoptosis9.11.3. Use of anti-apoptotic therapy anti-apoptotic agent9.11.4. Assays used9.12. Chelerythrine induced cell death through ROS-dependent ER stress in human prostate cancer cells9.12.1. CHE reduced cell viability in human prostate cancer cells9.12.2. CHE induced cell apoptosis in human prostate cancer cells9.12.3. CHE increased ROS accumulation in PC-3 cells9.12.4. Blockage of ROS generation reversed CHE-induced cell apoptosis in PC-3 cells9.12.5. CHE induced cell apoptosis through ROS-mediated ER stress in PC-3 cells9.13. ConclusionReferences

10. Programmed cell death mechanisms and nanoparticles toxicity10.1 Molecular mechanisms underlying nanomaterials toxicity10.2 Major forms of programmed cell death10.3 More than one way to skin a cat10.4 Programmed cell death: Apoptosis10.5 Programmed cell death: Autophagy10.6 Programmed cell death: Necrosi10.7 The importance of being small10.8 Effects of nanoparticles on apoptosis 10.9 Nanomaterials and apoptosis10.10 Nanomaterials and mitotic catastrophe10.11 Effects of nanoparticles on autophagy10.12 Nanomaterials and autophagy or "autophagic cell death"10.13 Effects of nanoparticles on necroptosis10.14 Nanomaterials and necrosis10.15 Nanomaterials and pyroptosis10.16 Mechanisms of graphene-induced programmed cell death10.17 GBMs induce apoptosis in cells10.18 The signaling pathways involved in GBM-induced apoptosis10.19 GBMs induce autophagy in cells10.20 The signaling pathways involved in GBMs-induced autophagy10.21 GBMs induce necroptosis and relative pathways involved10.22 Some differences and relationships of GBMs-induced PCDs10.22.1 Differences in PCD10.22.2 Several cross-linked pathways in PCD10.23 Conclusions and perspectivesReferences

11.Endoplasmic reticulum stress (ERS) and associated ROS in disease pathophysiology applications11.1 Endoplasmic reticulum ER11.2 Reactive oxygen species (ROS)11.3 Sources of reactive oxygen species (ROS) generation11.4 Endoplasmic reticulum stress (ERS)11.5 Unfolded protein response (UPR)11.5.1 Inositol-requiring protein 1 (IRE1)11.5.2 Protein kinase-like endoplasmic reticulum kinase (PERK)11.5.3 Activating transcription factor 6 (ATF6)11.6 Protein folding challenge in intestinal secretory cells11.7 Endoplasmic reticulum stress and autophagy11.8 How is reactive oxygen species (ROS) induced through endoplasmic reticulum (ER) stress?11.8.1. The specific mechanism of ER stress-induced ROS during the ER folding process 11.9 Specific mechanism of ER stress-induced ROS: NADPH oxidase 4 (Nox4)11.10 Coupled glutathione within the ER11.11 NADPH-dependent p450 reductase and p450 connection involvement in ER stress11.12 ER and mitochondria connection and relationship to ROS11.13 Oxidative stress11.14 Vicious sequence of events between endoplasmic reticulum stress and oxidative stress11.15 Endoplasmic reticulum stress and oxidative stress in inflammatory bowel disease11.16 Disease application11.16.1 ER stress and diseases11.16.2 Neurodegenerative diseases11.16.3 Diabetes mellitus11.16.4 Atherosclerosis11.16.5 Kinds of inflammation 11. 16.6 Liver disease11.16.7 Ischemia11.16.8 Kidney disease11. 17 ConclusionsReferences

12.Endoplasmic reticulum (ER) stress-induced cell death mechanism 12.1 ER stress and unfolded protein response12.2 Protein folding: ER chaperones and foldases12.2.1 General chaperones12.2.2 Lectin chaperones12.2.3 Other folding chaperones and enzymes12.3 Role of ER stress inhibitors in the context of metabolic diseases12.4 ER stress sensors12.4.1 Activation of PERK12.4.2 Activation of IRE1α pathway12.5 ER stress leads to disease progression12.6 Metabolic disorders12.6.1 Diabetes12.6.2 Obesity12.6.3 Lipid disorders12.7 ER stress inhibitors12.7.1 KIRA612.7.2 3-hydroxy-2-naphthoic acid12.7.3 MKC-394612.7.4 4-Phenylbutyric acid12.7.5 Taurine-conjugated ursodeoxycholic acid12.7.6 Olmesartan12.7.7 N-acetylcysteine (NAC)12.7.8 Oleanolic acid12.7.9 Ursolic acid12.7.10 Telmisartan12.7.11 Quercetin12.7.12 Other inhibitors12.7.13 Antidiabetic drugs targeting ER stress12.8 ER stress, UPR signaling, and cell death regulation12.9 UPR independent ER stress-signaling and cell death12.9.1 Calcium12.9.2 MEKK1 (MAP3K4)12.9.3 ER membrane re-organization12.10 Suppressors of ER-stress induced apoptosis12.10.1 Bax-inhibitor 1 (BI-1/Tmbim6)12.10.2 Bcl-2/Bcl-XL12.10.3 MicroRNAs12.10.4 Additional suppressors of ER stress-induced apoptosis12.11 ER stress and autophagy12.12 ER stress involvement in diseases12.12.1 Neurodegenerative diseases12.12.2 Ophthalmology disorders12.12.3 Immunity and inflammation12.12.4 Viral infections12.12.5 Metabolic diseases12.12.6 Atherosclerosis12.13 ER stress and cancer12.13.1 ER chaperones and cancer regulation12.13.2 ER sensors and cancer12.14 The cross talk between ER stress and autophagy in cancer12.15 The relationship between FOXO, ER stress and cancer12.15.1 PERK pathway and FOXO3 story12.15.2 IRE-1 and FOXO regulation12.15.3 Chaperones and FOX regulation12.15.4 ER stress and FOX regulation in worms12.15.5 Daf-16 and dFOXO and regulation of Ire-1 arm12.15.6 Regulation of PERK by dFOXO12.16 Target cancer through the UPR signaling and its FOXO link12.16.1 Targeting IRE1α-XBP112.16.2 Targeting PERK-ATF412.16.3 Chaperones inhibitors and FOXO3References

13.Modulation of endoplasmic reticulum (ER) stress of nanotoxicology for nanoparticles (NPs)13.1. Nanotoxicology and nanomedicine13.2. ER stress as a mechanism for nanotoxicology13.2.1. Morphological changes of ER by NP exposure13.2.2. Effects of NP exposure on ER stress pathway13.2.3. Modulation of ER stress and the toxicity of NPs13.3. Modulation of ER stress by NP in nanomedicine13.3.1. Selective activation of ER stress by NPs for cancer therapy13.3.2. Alleviation of ER stress by NPs for metabolic disease therapy13.4. Silver nanoparticles – allies or adversaries?13.5. Role of AgNPs in cell toxicity13.5.1. Silver nanoparticles-induced apoptosis13.5.2. Silver nanoparticles induce endoplasmic reticulum ER stress13.6. Uptake of AgNP and their intracellular localization13.7. Inhibition of proliferation and cell death13.8. ROS key factor in biological oxidation processes13.9. Oxidative stress as an underlying mechanism for NP toxicity13.10. Genotoxicity13.11. Concluding remarksReferences

14. Nanoparticle cellular uptake and intracellular targeting on reactive oxygen species (ROS) in biological activities 14.1. Nanoparticle (NP) classes and biomedical applications14.1.1. Optical imaging14.1.2. Biosensing14.1.3. Diagnostic applications14.1.4. Drug delivery14.1.5. Other applications14.2. Mechanisms associated with NP-induced ROS generation14.2.1. NP-related factors implicated in ROS generation14.2.2. NP- and cellular-component-induced ROS generation14.3. Biological functions modulated by NP-induced ROS production14.3.1. DNA damage and cytotoxicity14.3.2. Antimicrobial function14.3.3. Cellular differentiation14.3.4. Anticancer14.4. NP-induced modulation of ROS generation in stem cell biology14.5. Nanoparticle cellular uptake and intracellular targeting14.6. Endocytic routes and non-ligand targeted nanomedicines14.7 Receptor-mediated cellular internalization of ligand-targeted nanomedicines14.7.1. Prostate-specific membrane antigen (PSMA) targeting14.7.2. Neonatal Fc-receptor (FcRn) targeting—an avenue to oral delivery of nanomedicine14.8. Intracellular trafficking and subcellular targeting14.8.1. From endosomes/lysosomes to cytoplasm14.8.2. Endoplasmic reticulum and Golgi apparatus14.8.3. Mitochondria14.8.4. Nucleus14.9. Outlook14.10. ConclusionsReferences

15. Metal nanoparticles (MNPs) and particulate matter (PM) induce toxicity15.1 Nano-bio interactions15.2 Nanotoxicology of nanoparticles15.3 Overproduction of ROS and cell damage15.4 Nanotoxicity and generation of ROS15.5 Dependence of ROS production on the properties of nanoparticles15.5.1 Size and shape15.5.2 Particle surface, surface positive charges, and surface containing groups15.5.3 Solubility and particle dissolution15.5.4 Metal ions released from metal and metal oxide nanoparticles15.5.5 Light activation15.5.6 Aggregation and mode of interaction with cells15.5.7 Inflammation leading to ROS formation15.5.8 pH of the system15.6 Particulate matter (PMReferences

16. Mechanisms for nanoparticles-mediated oxidative stress16.1. Introduction to transition metals16.1.1. Generation of ROS16.1.2. ROS and biological system16.2. Exposure routes for nanoparticles16.3. Prooxidant effects of metal oxide nanoparticles16.4. Effects of NPs on cell organisms16.4.1. Absorption of NPs and cytotoxicity16.4.2. Absorption of NPs under environmental conditions16.4.3. NPs in outdoor spaces16.4.4. Interactions among organisms, NPs, and contaminants16.5. Nanoparticles-induced oxidative stress16.6. Oxidant generation via particle-cell interactions16.6.1. Lung injury caused by nanoparticle-induced reactive nitrogen species16.6.2. Mechanisms for ROS production and apoptosis within metal nanoparticles16.7. Modelling nanotoxicity16.8. Cellular signaling affected by metal nanoparticles16.8.1. NF-κB.16.8.2. AP-1.16.8.3. MAPK.16.8.4. PTP.16.8.5. Src.16.9. Carbon nanotubes (CNT)16.10. Carbon nanotube-induced oxidative stress16.11. Role of ROS in CNT-induced inflammation16.12. Role of ROS in CNT-induced genotoxicity16.13. Role of ROS in CNT-induced fibrosis16.14. Difficulties in determination of the mechanism of nanotoxicity in cells and in vivo16.15. ConclusionReferences

17.Nanotechnological modifications of nanoparticles on reactive oxygen and nitrogen species (RONS)17.1. Nanotechnology and nanomaterials17.2. Nanotechnological modifications17.2.1. Nanodiffusion in the environment17.2.2. Nanomaterials in soil17.2.3. Nanoparticles mobility in soil17.3. Nanotechnology and agricultural sustainable development17.3.1. Nano fertilizers17.3.2. Nano pesticides17.3.3. Ecotoxicological implications of the nanoparticles17.4. Growth of cultivated plants and its ecotoxicological sustainability17.5. Applications of nanotechnology in the agricultural sector17.5.1. Nanosilver17.5.2. Nanosilica17.5.3. Nanotitanium dioxide17.5.4. Nanocalcium17.5.5. Nano-iron17.6. Nanotechnologies in food industry17.6.1. Food process17.6.2. Food packaging and labeling17.7. Selenium NPs as a food additive17.7.1. Problems with traditional forms of oral supplementation of selenium and potential benefits of SeNPs17.7.2. Mechanism of passage of NPs through intestinal mucosa17.7.3. Application of SeNPs through oral administration17.7.3.1. Nano-Se as an antioxidant17.7.3.2. Effect of SeNPs on reproductive performance17.7.3.3. Use of nano-Se for increasing hair follicle development and fetal growth17.7.3.4. Antiviral and antibacterial effects of SeNPs17.7.4. Anticancer effects of SeNPs17.7.4.1. Nano-Se as an anticancer drug17.7.4.2. Nano-Se as an anticancer drug delivery carrier17.7.4.3. Nano-Se as a promising orthopedic implant material and an agent reducing bone cancer cell functions17.8. Effect of SeNPs on oxidative stress parameters17.9. Protective effects of nano-Se17.9.1. SeNPs in prevention of cisplatin (CIS) induced reproductive toxicity17.9.2. Protective effect of nano-Se against polycyclic aromatic hydrocarbons17.9.3. Use of SeNPs for minimization of risk of iron overabundance17.9.4. SeNPs in treatment of heavy metal intoxication17.9.5. Nano-Se as an immunostimulatory17.9.6. Effect of Nano-Se on microbial fermentation, nutrients digestibility, and probiotics support17.9.7. Nano-Se in treatment of metabolic disorders17.10. Safety and toxicity concerns of orally delivered SeNPs for use as food additives and drug carriersReferences

18.Medical imaging the complexity of nanoparticles and ROS dynamics in vivo for clinical diagnosis application18.1. Redox signaling 18.2. Dynamics of the EPR signal of nitroxide radicals in leukemic and normal lymphocytes18.3. Redox-sensitive two-photon microscopy18.3.1. Two-photon redox-sensitive probes18.3.2. Two-photon sensitive probes for assessment of glutathione redox state18.3.3. Two-photon NADPH redox state sensitive probes18.3.4. Two-photon H2O2-sensitive probes18.3.5. Two-photon NO-sensitive probes18.4. Chemiluminescent imaging of ROS in vivo18.4.1. NIR fluorescence and chemiluminescence18.4.2. Chemiluminescent nanoparticles and ROS imaging18.5. Ultrasound in ROS imaging18.6. PET/SPECT in vivo imaging of oxidative stress using radiotracers18.6.1. Imaging glucose consumption as a surrogate of oxidative stress18.6.2. Radiotracers with redox potential-dependent cellular retention18.6.3. Radiotracers with hypoxia-dependent cellular retention18.6.4. Radiotracers targeting ROS scavengers or mitochondrial complex I-IV18.7. Magnetic resonance modalities18.7.1. Basic principles and technical considerations18.7.2. Examples of EPRI/MRI of ROS/RNS18.7.3. Brain imaging (without tumors)18.7.4. Tumor imaging18.7.5. Other organs18.7.6. Imaging of trapped radicals18.7.7. Dynamic nuclear polarization DNP-MRI (OMRI, PEDRI)18.8. Dynamics of the EPR signal of mito-TEMPO in cells of different origins and proliferative activities: Correlation with the levels of intracellular superoxide and hydrogen peroxide.18.9. Dynamics of the EPR signal of nitroxide radical in cells of the same origin and different proliferative activities: Correlation with the levels of intracellular superoxide, hydrogen peroxide, and antioxidant enzymes