Redox Signaling and Regulation in Biology and Medicine -- Contents -- Preface -- The Editors -- List of Authors -- 1 Introduction -- 2 Biological Systems Relevant for Redox Signaling and Control -- 2.1 Introduction -- 2.2 Reactive Oxygen Species -- 2.2.1 The Superoxide Radical -- 2.2.1.1 Generation of the Superoxide Radical -- 2.2.1.2 The Superoxide Radical as a Redox Signal -- 2.2.1.3 Decomposition of the Superoxide Radical -- 2.2.2 Hydrogen Peroxide -- 2.2.2.1 Generation of Hydrogen Peroxide -- 2.2.2.2 Mechanisms of Hydrogen Peroxide Signaling -- 2.2.2.3 Decomposition of Hydrogen Peroxide -- 2.3 Reactive Nitrogen Species -- 2.3.1 Nitric Oxide -- 2.3.1.1 Generation of Nitric Oxide -- 2.3.1.2 Mechanisms of Nitric Oxide Signaling -- 2.3.1.3 Decomposition of Nitric Oxide -- 2.3.2 Peroxynitrite and Reactive Nitrogen Species -- 2.3.2.1 Generation of Peroxynitrite and Other Important Reactive Nitrogen Species -- 2.3.2.2 Mechanisms of Peroxynitrite- and Reactive Nitrogen Species-Mediated Redox Signaling -- 2.4 Lipid Peroxidation Products -- 2.4.1 Generation of Lipid Peroxidation Products -- 2.4.2 Mechanisms of Signaling with Lipid Peroxidation Products -- 2.4.3 Decomposition of Lipid Peroxides -- 2.5 Conclusions -- References -- 3 Cellular Generation of Oxidants: Relation to Oxidative Stress -- 3.1 Introduction -- 3.2 Molecular Oxygen and Reactive Oxygen Species: Biochemical Relations and Endogenous Sources -- 3.2.1 Endogenous Sources of Superoxide and Superoxide-Derived Reactive Oxygen Species -- 3.2.2 Singlet Oxygen -- 3.2.3 "Secondary" Reactive Oxygen Species Generated in Radical Chain Reactions -- 3.3 Generation of Oxidative Stress Under the Influence of Xenobiotics and Stressful Stimuli -- 3.3.1 Quinones and Other Redox Cyclers -- 3.3.2 Antioxidant Depletion by Alkylation: Acetaminophen Toxicity -- 3.3.3 Ultraviolet Radiation.

3.3.4 Ultrafine or Nanoparticles -- References -- 4 The Chemical Basis of Biological Redox Control -- 4.1 Introduction -- 4.2 Forms of Elemental Oxygen as Reactive Oxygen Species -- 4.2.1 Reactive Oxygen Species and Related Cellular Oxidants -- 4.2.2 Singlet Oxygen (1O2) -- 4.2.3 Ozone (O3) -- 4.3 Reduced, Yet Oxidizing: the Chemistry of Oxygen in Oxidation States between 0 and -2 -- 4.3.1 Superoxide Radicals (O2 ˙ ̄) -- 4.3.2 The Superoxide to Peroxide Conversion as a Key Event in Redox Signaling -- 4.3.3 Hydrogen Peroxide (H2O2) -- 4.3.4 Hydroxyl Radicals (HO·) -- 4.3.5 Enzymatic Reduction of Hydrogen Peroxide by Peroxiredoxins, Catalase and Glutathione Peroxidase -- 4.4 The Role of Labile Metal Ions in Oxidative Stress -- 4.5 Follow-on Species Generated by Chemical Interactions of Reactive Oxygen Species -- 4.5.1 Hypochlorous Acid (HOCl) -- 4.5.2 Peroxynitrite (ONOO ̄) -- 4.6 Nitrogen Monoxide and Reactive Nitrogen Species -- 4.6.1 Reactive Nitrogen Species -- 4.6.2 S-Nitrosothiols -- 4.7 Sulfur as a Prime Target of Oxidative Stress -- 4.7.1 Thiol Groups in Peptides and Proteins -- 4.7.2 The Concept of Reactive Sulfur Species -- 4.7.3 Sulfur-Centered Radicals -- 4.7.4 Disulfide-S-Oxides (RS(O)xSR') -- 4.7.5 Sulfenic and Sulfinic Acids (RSOH and RS(O)OH) -- 4.7.6 Oxidation of Methionine: Sulfoxides (RS(O)R) and Sulfones (RS(O)2R') -- 4.7.7 S-Thiolation as Chemical Protection -- 4.7.8 Oxidation of Disulfides -- 4.8 A Brief Overview of Hydroxylation and Nitration Reactions -- 4.8.1 Hydroxylation and Nitration of Aromatic Residues -- 4.8.2 Fatty Acid Chemistry -- 4.9 Conclusion -- References -- 5 Protein Glutathiolation -- 5.1 Introduction: Glutathione - From Antioxidant to Redox Signal -- 5.2 Glutathiolation -- 5.3 Mechanisms of Glutathiolation -- 5.3.1 ROS-Dependent Glutathiolation by Thiol/Disulfide Exchange Reactions.

5.3.2 ROS-Dependent Glutathiolation via Sulfenic Acid -- 5.3.3 ROS-Dependent Glutathiolation by Radical Reactions -- 5.3.4 ROS-Independent Glutathiolation -- 5.4 Toxicological Aspects of Glutathiolation -- 5.5 Mechanisms of Deglutathiolation -- 5.6 Enzymes Implicated in Glutathiolation -- 5.7 Specificity of Glutathiolation -- 5.8 Genetic Factors Affecting Glutathiolation -- 5.8.1 Mouse Beta-Globin -- 5.8.2 Glucose-6-Phosphate Dehydrogenase Mutations -- 5.8.3 Glutathione S-Transferase Mutations -- 5.9 Future Perspectives -- References -- 6 Structure and Function of the Human Peroxiredoxin-Based Antioxidant System: the Interplay between Peroxiredoxins, Thioredoxins, Thioredoxin Reductases, Sulfiredoxins and Sestrins -- 6.1 Introduction -- 6.2 Peroxiredoxins -- 6.3 Thioredoxins -- 6.4 Thioredoxin Reductases -- 6.5 Sulfiredoxin and Sestrins -- 6.6 Regulation of the Expression and Activity of the Peroxiredoxin-Based System Enzymes -- 6.7 Cell Signaling and the Peroxiredoxin-Based System: Regulation of Transcription Factors, Cell Cycle and Apoptosis -- 6.8 Peroxiredoxin-Based System in Cells and Organs of the Body -- 6.9 Summary -- References -- 7 Hydrogen Peroxide and Cysteine Protein Signaling Pathways -- 7.1 Introduction -- 7.2 Hydrogen Peroxide Production in Cells and Tissues -- 7.3 Sources and Concentrations of Hydrogen Peroxide -- 7.4 Hydrogen Peroxide and the Formation of Secondary Oxidants such as Peroxynitrite -- 7.5 Exogenous Hydrogen Peroxide as an Experimental Tool -- 7.6 Hydrogen Peroxide Sensing and Cysteine Sensors -- 7.7 Low Molecular Weight Oxidized Thiols and S-Thiolated Protein Adducts -- 7.8 Protein Thiol Modifications -- 7.9 Protein Regulation via Sulfination-Dependent Proteolysis -- References -- 8 Protein Tyrosine Phosphatases as Mediators of Redox Signaling -- 8.1 Introduction -- 8.2 Protein Tyrosine Phosphatases.

8.3 Protein Tyrosine Phosphatases are Sensitive to Oxidation -- 8.4 Allosteric Regulation of Receptor Protein Tyrosine Phosphatases by Oxidation -- 8.5 Activation of Sdp1 by Oxidation -- 8.6 Physiological Relevance of Protein Tyrosine Phosphatase Oxidation -- 8.7 Conclusions -- References -- 9 Hypoxia-Induced Gene Regulation through Hypoxia Inducible Factor-1α -- 9.1 Introduction -- 9.2 The Proteins and Mechanism -- 9.3 Hypoxia Inducible Factor Target Genes -- 9.4 Non-Hypoxia-Induced Activation of Hypoxia Inducible Factor -- 9.5 Diseases Involving Hypoxia Inducible Factor -- 9.6 The Promise of Hypoxia Inducible Factor-Targeted Therapies -- 9.7 Conclusions -- References -- 10 Eicosanoid-Based Signaling -- 10.1 Introduction -- 10.2 Biosynthesis and Structures of Eicosanoids -- 10.2.1 Lipoxygenases -- 10.2.2 Cyclooxygenases -- 10.2.3 Cytochrome P450 -- 10.3 Signaling by Eicosanoids -- 10.4 Metabolism of Eicosanoids -- 10.5 Summary -- References -- 11 Redox-Controlled Transcription Factors and Gene Expression -- 11.1 Introduction -- 11.2 Redox Signaling and Gene Microarry Data: The Global Picture -- 11.3 The Antioxidant Response Element -- 11.4 The Transcription Factor Nrf2: The Master Regulator of Antioxidant Transcription -- 11.5 The Keap1-Nrf2 Complex: A Sensor for Cellular Stress -- 11.5.1 Reactive Oxygen Species, Reactive Nitrogen Species and Electrophile Sensing by Keap1 -- 11.5.2 Structural Basis for the Sensing Function of the Keap1-Nrf2 Complex -- 11.6 Redox Reactions of Transcription Factors -- 11.6.1 Nuclear Factor kB: Redox Control of the Immune Response -- 11.6.2 Activator Protein 1 (AP-1): Redox Control of Proliferation and Apoptosis -- 11.6.3 The Role of the Nuclear Redox State in Gene Expression -- 11.7 Summary -- References -- 12 Nitric Oxide Regulation in Redox Signaling -- 12.1 Introduction -- 12.2 Nitric Oxide Formation.

12.3 Factors Affecting Nitric Oxide Reactivity and Signaling -- 12.3.1 Compartmentalization and Diffusion -- 12.3.2 Interaction with Metal Centers -- 12.3.3 Nitric Oxide Reaction with Free Radicals -- 12.3.3.1 Nitric Oxide and Superoxide -- 12.3.3.2 Peroxynitrite -- 12.3.3.3 Nitrogen Dioxide/Dinitrogen Trioxide -- 12.4 Nitric Oxide Signaling Beyond Soluble Guanylate Cyclase -- 12.4.1 Nitric Oxide and Mitochondria -- 12.4.2 S-Nitrosation -- 12.4.3 Nitrated Lipids -- 12.4.4 3-Nitrotyrosine -- 12.5 Redox Derivatives of Nitric Oxide -- 12.5.1 Nitroxyl Anion -- 12.5.2 Nitrite -- 12.5.3 Nitrite - a Potential Reservoir for Nitric Oxide Bioactivity During Hypoxia -- 12.6 Summary -- References -- 13 Is Hydrogen Sulfide a Regulator of Nitric Oxide Bioavailability in the Vasculature? -- 13.1 Introduction -- 13.2 Reactive Nitrogen Species -- 13.3 Reactive Nitrogen Species in the Heart and Vasculature -- 13.4 Hydrogen Sulfide Biosynthesis -- 13.5 Hydrogen Sulfide Measurement, Catabolism and Removal -- 13.6 Hydrogen Sulfide in the Heart and Vasculature -- 13.7 What is the Evidence for "Crosstalk" between Nitric Oxide and Hydrogen Sulfide -- 13.8 Nitric Oxide/Hydrogen Sulfide and Evidence for the Formation of A Novel Intermediate -- 13.9 Concluding Remarks -- References -- 14 Aspects of Nox/Duox Signaling -- 14.1 Introduction -- 14.2 The Nox/Duox Enzymes (Expression and Domain Structure) -- 14.2.1 NOXO1 and NOXA1 -- 14.3 Mechanism of the Nox/Duox Activation -- 14.3.1 Nox1 -- 14.3.2 Nox3 -- 14.3.3 Nox4 -- 14.3.4 Nox5 -- 14.3.5 Duox -- 14.4 Redox Signaling Activated by NADPH Oxidase -- 14.4.1 Activation of Kinases and Phospholipases -- 14.4.2 Activation of Ion Channels and Calcium Signaling -- 14.4.3 Oxidative Inactivation of Protein Tyrosine Phosphatase -- 14.4.4 Specific Localization of NADPH Oxidase as Mechanism of Activation of Specific Redox Signaling.

14.5 Transcription Factors and Gene Expression Regulated by ROS.