Molecular Basis of Oxidative Stress E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 1930

Veröffentlichungsjahr: 2025

Beschreibung

In-depth resource on mechanisms of oxidative stress and damage and the role of free radicals in disease, diagnosis, and therapeutics

Molecular Basis of Oxidative Stress is a comprehensive resource on the molecular and chemical bases of oxidative stress, providing insight on various diseases caused by oxidative stress (cancer, cardiovascular, neurodegenerative) and the role of reactive oxygen species (ROS) in disease pathogenesis along with in-depth knowledge about the mechanisms of oxidative stress and damage, free radical chemistry, and the role of free radicals in disease, diagnosis, and therapeutics.

Thoroughly updated and expanded to reflect advances in the years since its original publication, the Second Edition includes new chapters covering topics like oxidative stress mechanisms, biomarkers, and therapeutic strategies in the management and treatment of diseases. The disease section features 10 new emerging diseases, including kidney and eye diseases and COPD.

This Second Edition also covers developments in the field in the last several years, such as an increase in mortality rate from air pollution and obstructive pulmonary diseases in which exogenous oxidants are initiators.

Written by a team of highly qualified academics, Molecular Basis of Oxidative Stress discusses sample topics including:

• Classification, physico-chemical properties, sources, and detection of reactive species and etiology of COPD from cigarette smoke and pollution
• Oxidative, reductive and indirect non-redox modifications of key biomolecular systems such as lipids, proteins, and DNA by reactive species
• Gene expression of antioxidant defense enzymes, mitochondrial dysfunction and aberrant activation of NOX and cell signaling
• Biomarkers of oxidative stress in neurodegenerative diseases and emerging fields inbiomarker discovery such as cysteinylated albumin and nitroalkene fatty acids

Imparting strong foundational knowledge of redox chemistry, chemistry of oxidative damage and mechanisms of oxidative stress, and oxidative stress-mediated disease pathogenesis, Molecular Basis of Oxidative Stress is an essential reference for both novice and advanced toxicologists, biochemists, and pharmacologists, along with clinical and medical scientists in various fields such as oncology, cardiovascular, andneuroscience.

Leseprobe

Table of Contents

COVER

TABLE OF CONTENTS

TITLE PAGE

COPYRIGHT

LIST OF CONTRIBUTORS

PREFACE TO SECOND EDITION

PREFACE FIRST EDITION

1 CHEMISTRY OF REACTIVE SPECIES

1.1 REDOX CHEMISTRY

1.2 CLASSIFICATION OF REACTIVE SPECIES

1.3 REACTIVE OXYGEN SPECIES

1.4 REACTIVE NITROGEN SPECIES

1.5 REACTIVE SULFUR AND CHLORINE SPECIES

1.6 REACTIVITY

1.7 ORIGINS OF REACTIVE SPECIES

1.8 METHODS OF DETECTION

REFERENCES

2 LIPID PEROXIDATION AND NITRATION

OVERVIEW

2.1 PEROXIDATION OF PUFAs

2.2 CYCLIC ENDOPEROXIDES AND THEIR PRODUCTS

2.3 FRAGMENTED PRODUCTS OF LIPID PEROXIDATION

2.4 EPOXY FATTY ACIDS

2.5 LIPID NITROSYLATION

SUMMARY

REFERENCES

3 PROTEIN POSTTRANSLATIONAL MODIFICATION

OVERVIEW

3.1 OXIDATIVE STRESS‐RELATED PTMs: OXIDATION REACTIONS

3.2 AMINO ACID MODIFICATION BY OXIDATION‐PRODUCED ELECTROPHILES

3.3 DETECTION OF OXIDATIVE‐STRESS RELATED PTMs

3.4 ROLE OF PTMs IN CELLULAR REDOX SIGNALING

SUMMARY

REFERENCES

4 DNA OXIDATION

OVERVIEW

4.1 THE CONTEXT OF CELLULAR DNA OXIDATION

4.2 OXIDATION OF OLIGONUCLEOTIDES

4.3 EXAMINATION OF SPECIFIC OXIDATIVE LESIONS

FUTURE OUTLOOK OF DNA OXIDATIVE LESIONS

REFERENCES

5 CELLULAR ANTIOXIDANTS AND PHASE 2 PROTEINS

5.1 DEFINITIONS

5.2 ROLE IN OXIDATIVE STRESS

5.3 MOLECULAR REGULATION

5.4 INDUCTION IN CHEMOPREVENTION

5.5 INACTIVATION

5.6 CONCLUSIONS AND PERSPECTIVES

REFERENCES

6 MITOCHONDRIAL DYSFUNCTION

6.1 MITOCHONDRIA AND SUBMITOCHONDRIAL PARTICLES

6.2 ENERGY TRANSDUCTION

6.3 MITOCHONDRIAL STRESS

6.4 SUPEROXIDE ANION RADICAL GENERATION AS MEDIATED BY ΔpH, Δ

ψ

, ETC, AND DISEASE PATHOGENESIS

6.5 SUMMARY

REFERENCES

7 NADPH OXIDASES: STRUCTURE AND FUNCTION

OVERVIEW

7.1 INTRODUCTION

7.2 PHAGOCYTE NADPH OXIDASE STRUCTURE

7.3 PHAGOCYTE ROS PRODUCTION

7.4 PHAGOCYTE NADPH OXIDASE FUNCTION

7.5 NONPHAGOCYTE NADPH OXIDASE STRUCTURE

7.6 NONPHAGOCYTE ROS PRODUCTION

7.7 FUNCTIONS OF NONPHAGOCYTE NADPH OXIDASES

SUMMARY

ACKNOWLEDGMENTS

REFERENCES

8 CELL SIGNALING AND TRANSCRIPTION

OVERVIEW

8.1 COMMON MECHANISMS OF REDOX SIGNALING

8.2 REDOX AND OXYGEN‐SENSITIVE TRANSCRIPTION FACTORS IN PROKARYOTES

8.3 REDOX SIGNALING IN METAZOANS

8.4 OXYGEN SENSING IN METAZOANS

8.5 MEDICAL SIGNIFICANCE OF REDOX AND OXYGEN‐SENSING PATHWAYS

CONCLUDING REMARKS

REFERENCES

9 OXIDATIVE STRESS AND REDOX SIGNALING IN CARCINOGENESIS

OVERVIEW

9.1 REDOX ENVIRONMENT AND CANCER

9.2 OXIDATIVE MODIFICATIONS TO BIOMOLECULES AND CARCINOGENESIS

9.3 MEASUREMENT OF OXIDATIVE DNA DAMAGE IN HUMAN CANCER

9.4 EPIGENETIC INVOLVEMENT IN OXIDATIVE STRESS‐INDUCED CARCINOGENESIS

9.5 DEREGULATION OF CELL DEATH PATHWAYS BY OXIDATIVE STRESS IN CANCER PROGRESSION

CONCLUSIONS AND PERSPECTIVE

ACKNOWLEDGMENTS

REFERENCES

10 NEURODEGENERATION FROM DRUGS AND AGING‐DERIVED FREE RADICALS

OVERVIEW

10.1 ROS FORMATION

10.2 PROTECTION AGAINST ROS

10.3 NRF2 REGULATION OF PROTECTIVE RESPONSES

SUMMARY AND CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

11 CARDIAC ISCHEMIA AND REPERFUSION

OVERVIEW

11.1 OXYGEN IN THE HEART

11.2 SOURCES OF ROS DURING ISCHEMIA AND REPERFUSION

11.3 MODULATION OF SUBSTRATES, METABOLITES, AND COFACTORS DURING I‐R

11.4 ROS‐MEDIATED CELLULAR COMMUNICATION DURING I‐R

11.5 ROS AND CELL DEATH DURING ISCHEMIA AND REPERFUSION

11.6 POTENTIAL THERAPEUTIC STRATEGIES

SUMMARY AND CONCLUSION

REFERENCES

12 ATHEROSCLEROSIS: OXIDATION HYPOTHESIS

OVERVIEW

12.1 LIPID PEROXIDATION

12.2 OXIDATION HYPOTHESIS OF ATHEROSCLEROSIS

12.3 ANIMAL MODELS OF ATHEROSCLEROSIS

12.4 ALDEHYDE GENERATION FROM PEROXIDIZED LIPIDS

SUMMARY

ACKNOWLEDGMENT

REFERENCES

13 CYSTIC FIBROSIS

OVERVIEW

13.1 LUNG DISEASE CHARACTERISTICS IN CF

13.2 ROLE OF CFTR IN THE LUNG

13.3 OXIDATIVE STRESS IN THE CFTR‐DEFICIENT LUNG

13.4 ANTIOXIDANT THERAPIES FOR CF

SUMMARY

REFERENCES

14 CIGARETTE SMOKING AND AIR POLLUTION

14.1 EXPOSURE TO CIGARETTE SMOKE

14.2 AIR POLLUTION PARTICLES

14.3 OZONE

14.4 NITROGEN AND SULFUR OXIDES

14.5 INTERACTION BETWEEN PM AND OXIDANT GASES

14.6 OXIDATIVE STRESS AND MECHANISTIC PATHWAYS OF DISEASE AFTER EXPOSURE TO AIR POLLUTANTS

REFERENCES

15 OXIDATIVE STRESS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

15.1 INTRODUCTION

15.2 INCREASED OXIDATIVE STRESS IN COPD

15.3 EFFECTS OF OXIDATIVE STRESS IN COPD

15.4 STRATEGIES FOR REDUCING OXIDATIVE STRESS

15.5 CONCLUSIONS

REFERENCES

16 OXIDATIVE STRESS IN THE EYE

16.1 INTRODUCTION

16.2 THE CORNEA

16.3 THE LENS

16.4 THE VITREOUS HUMOR

16.5 THE RETINA AND OPTIC NERVE

16.6 THERAPEUTIC APPROACHES TO ROS ELEVATION IN THE EYE

16.7 CONCLUSION

REFERENCES

17 THE ROLE OF OXIDATIVE STRESS IN CHRONIC KIDNEY DISEASE (CKD)

17.1 INTRODUCTION

17.2 SOURCES OF OXIDATIVE STRESS IN CKD

17.3 MECHANISMS BY WHICH OXIDATIVE STRESS CONTRIBUTES TO CKD

17.4 INTERPLAY BETWEEN OXIDATIVE STRESS AND SENESCENCE IN CKD

17.5 TREATMENT OPTIONS FOR CKD

REFERENCES

18 BIOMARKERS OF OXIDATIVE STRESS IN NEURODEGENERATIVE DISEASES

OVERVIEW

18.1 INTRODUCTION

18.2 BIOMARKERS OF PROTEIN OXIDATION/NITRATION

18.3 BIOMARKERS OF LIPID PEROXIDATION

18.4 BIOMARKERS OF CARBOHYDRATE OXIDATION

18.5 BIOMARKERS OF NUCLEIC ACID OXIDATION

ACKNOWLEDGMENTS

REFERENCES

19 CYSTEINYLATED ALBUMIN AS OXIDATIVE STRESS BIOMARKER AND THERAPEUTIC TARGET

19.1 INTRODUCTION

19.2 CELLULAR AND EXTRACELLULAR THIOLS DISTRIBUTION

19.3 HSA AND CYS34

19.4 CYS34 REACTIVITY AND REACTIONS

19.5 CYS34 OXIDIZED FORMS IN PHYSIO‐PATHOLOGICAL CONDITIONS

19.6 ENDOGENOUS REGULATION OF INTRACELLULAR AND EXTRACELLULAR THIOL‐REDOX HOMEOSTASIS

19.7 MOLECULAR AND THERAPEUTIC STRATEGIES FOR REVERSING MERCAPTALBUMIN FROM THE OXIDIZED FORMS

19.8 CONCLUSION

REFERENCES

20 NITROALKENE FATTY ACIDS: FORMATION, METABOLISM, REACTIVITY, AND SIGNALING

20.1 INTRODUCTION

20.2 DIET AND FATTY ACIDS

20.3 NITROALKENE FATTY ACIDS

IN VIVO

FORMATION

20.4 METABOLISM AND DISTRIBUTION

20.5 REACTIVITY OF NITROALKENE FATTY ACIDS

20.6 NITROALKYLATION AS A PROTEIN POST‐TRANSLATIONAL MODIFICATION

20.7 NITROOLEIC ACID AND DISEASE

20.8 CONCLUDING REMARKS

REFERENCES

21 SYNTHETIC ANTIOXIDANTS

OVERVIEW

21.1 ENDOGENOUS ENZYMATIC SYSTEM OF DEFENSE

21.2 METAL‐BASED SYNTHETIC ANTIOXIDANTS

21.3 NONMETAL‐BASED ANTIOXIDANTS

21.4 NITRONES

REFERENCES

INDEX

END USER LICENSE AGREEMENT

List of Tables

Chapter 1

TABLE 1.1 Gibbs Energies of Formation for Various ROS/RNS.

114

,

165

TABLE 1.2 Reduction Potentials for Various Half‐cell Reactions Showing 1‐Ele...

TABLE 1.3 Various Reactions of Reactive Species and Their Respective rate Co...

Chapter 7

TABLE 7.1 Defects in Phagocyte NADPH Oxidase Components Associated with Chro...

TABLE 7.2 Expression of Phagocyte and Nonphagocyte NADPH Oxidase Proteins

Chapter 9

TABLE 9.1 Cases with Documented Elevated Levels of Oxidative DNA Damage Repa...

Chapter 10

TABLE 10.1 Important Reactive Species

TABLE 10.2 Prostanoid Receptor Subtypes, Expression, and Functions

TABLE 10.3 Transcriptional Activation of PHS‐1

TABLE 10.4 Transcriptional Activation of PHS‐2

TABLE 10.5 Comparison of Domain Regions of PHS‐1 and 2

152

TABLE 10.6 Summary of PHS‐Mediated Effects in Neurodegenerative Diseases...

TABLE 10.7 Amphetamine Analog Binding Affinities to Uptake Transporters

TABLE 10.8 Effects of METH

TABLE 10.9 NADPH‐Dependent Enzymes and Systems

TABLE 10.10 G6PD Deficiency Classification

TABLE 10.11 Nrf Domains and Function

TABLE 10.12 Nrf2 Interactions in the Nucleus

TABLE 10.13 Regulatory Mechanisms Provided by Keap1

TABLE 10.14 Examples of Genes Containing AREs in Their Promoter Region

TABLE 10.15 Selective Examples of Nrf2 Activators

TABLE 10.16 Evidence for Nrf2 Activation or Deregulation in Neurodegenerativ...

Chapter 12

TABLE 12.1 Biologically Relevant, Lipid‐Peroxidation‐Derived Aldehydes...

TABLE 12.2 Potential Enzymes and Oxidants Involved in the Oxidation of Lipid...

TABLE 12.3 Proatherogenic Effects of Aldehydes

TABLE 12.4 Potential Carboxylic Acid Products of Lipid Peroxidation

Chapter 13

TABLE 13.1 Glutathione (GSH) and Thiocyanate (SCN) are Two Major Thiols in t...

TABLE 13.2 CF Therapies That May Target Oxidative Stress

Chapter 14

TABLE 14.1 Endpoints of Oxidative Stress Elevated in Cigarette Smokers

Chapter 15

TABLE 15.1 Antioxidants for COPD

Chapter 17

TABLE 17.1 Causes of Chronic Kidney Disease

TABLE 17.2 Treatment Options for CKD and Their Effects on Oxidative Stress

Chapter 18

TABLE 18.1 Summary of Oxidative and Nitrosative Stress Markers in the Centra...

Chapter 20

TABLE 20.1 Evaluation of NO

2

OA in Preclinical Animal Models

Chapter 21

TABLE 21.1 Rate Constants, Oxidation Potential, and Dissociation Constant of...

TABLE 21.2 Some Biochemical Consequences of PBN Administration In Vitro, In ...

List of Illustrations

Chapter 1

Figure 1.1 Oxidation states of the carbon atom calculated as number of valen...

Figure 1.2 Hydrogen, formyl and vinyl σ‐radicals.

Figure 1.3 Methyl, thiyl, hydroxyl, hydroperoxyl, superoxide and nitric oxid...

Figure 1.4 Dissociation enthalpies (Δ

H

0

in kcal/mol) of various dimers showi...

Figure 1.5 Reaction of nitric oxide with hydroxyl radical to produce nitrous...

Figure 1.6 Reaction of nitric oxide with hydroxyl radical to produce nitrous...

Figure 1.7 Molecular orbital diagram of dioxygen showing its biradical natur...

Figure 1.8 Molecular orbital diagram of O

2

•−

.

Figure 1.9 SOD mimetic property of tris‐malonyl‐derivative of fullerene (C

60

Figure 1.10 SOD mimetic property of metal‐complexes.

Figure 1.11 Activation of O

2

•−

by metal ions.

Figure 1.12 Various pathways for the reaction of O

2

•−

with thiol...

Figure 1.13 Free energies (in kcal/mol) of the reaction of O

2

•−

...

Figure 1.14 Molecular orbital diagram of H

2

O

2

.

Figure 1.15 Metal‐independent generation of HO

•

from H

2

O

2

.

Figure 1.16 Malonaldehdye formation from the reaction of hydroxyl radical to...

Figure 1.17 Transition state H‐bonding interaction of hydroxyl radical to ca...

Figure 1.18 Addition reaction of hydroxyl radical to alkenes and subsequent ...

Figure 1.19 Bonding orbitals of singlet oxygens,

1

Δ

g

and

3

Σ

g

+

, in compar...

Figure 1.20 Bonding orbitals of nitric oxide.

Figure 1.21 Binding modes of nitric oxide to metal ions.

Figure 1.22 Mesomeric structures of nitrogen dioxide.

Figure 1.23 Nitration and hydroxylation of PUFA by

•

NO

2

.

Figure 1.24 Radical‐radical addition of

•

NO

2

to tyrosyl radical.

Figure 1.25 Thiyl radical mediated E and Z isomerization of monosaturated fa...

Figure 1.26 β‐ or α‐elimination reactions of hydroxide anion on protein with...

Figure 1.27 Oxidation of disulfide leading to the formation of mixed disulfi...

Figure 1.28 Reactions of hypochlorous acid with various reactive oxygen spec...

Figure 1.29 Reaction of hypochlorous acid with amino acids.

Figure 1.30 Reactions of hypochlorous acid with tyrosine.

Figure 1.31 Chlorination and hydroxylation of pyrimidine by hypochlorous aci...

Figure 1.32 Classical reaction coordinate for an exothermic reaction showing...

Figure 1.33 The ubiquinone cycle of the mitochondrial electron transport cha...

Figure 1.34 Production of superoxide radical anion from nitric oxide synthas...

Figure 1.35 Production of nitric oxide from

L

‐arginine, NADPH and O

2

.

Figure 1.36 Various photochemical mechanisms for the formation of reactive o...

Figure 1.37 NADPH‐mediated redox cycling of ROS by quinones.

Figure 1.38 Proposed mechanism for the generation of peroxynitrite from SIN‐...

Figure 1.39 Fluorescence probes for ROS and their various products.

Figure 1.40 Formation of superoxide radical anion from lucigenin

•+

Figure 1.41 Immuno‐spin trapping of macromolecular radicals using DMPO and a...

Figure 1.42 Radical detection using EPR spectroscopy and various radical pro...

Figure 1.43 Various

N

‐hydroxy‐pyrrole or piperidine derivatives used as prob...

Figure 1.44 Commonly used spin traps for radical detection and identificatio...

Figure 1.45 Reaction of nitric oxide with nitronyl nitroxides (NN), PTIO and...

Figure 1.46 EPR spectrum of nitronyl nitroxides (NN) and imino nitroxide (IN...

Figure 1.47 Complexation of nitric oxide with iron(II) dithiocarbamates, Fe‐...

Figure 1.48 Mechanism of immune‐spin‐trapping reaction showing the formation...

Chapter 2

Figure 2.1 Abstraction of hydrogen by free radical and addition of oxygen fo...

Figure 2.2 Formation of oxygenated fatty acids from lipid peroxyl radical.

Figure 2.3 Products of cyclic endoperoxides.

Figure 2.4 Generation of H

2

‐isoprostane regio‐ and stereo‐isomers.

Figure 2.5 Major products of H

2

‐isoprostane pathway.

Figure 2.6 Fragmentation of polyunsaturated fatty acids by beta‐scission gen...

Figure 2.7 Proposed mechanisms of 4‐hydroxynonenal (HNE) formation by peroxi...

Figure 2.8 Potential mechanism of iron‐mediated malondialdehyde formation fr...

Figure 2.9 Potential mechanism of acrolein formation by peroxidation of PUFA...

Figure 2.10 Formation of epoxy fatty acid by peroxyacids.

Figure 2.11 Formation of lipid‐nitrating species from nitric oxide.

Figure 2.12 Mechanisms of nitrated lipids formation.

Chapter 3

Figure 3.1 Cysteine oxidation pathways in the presence of reactive oxygen an...

Figure 3.2 Cysteine oxidation leading to cysteine‐oxygen adducts. Oxidation ...

Figure 3.3 Peroxiredoxin‐catalyzed peroxidase activity involves reversible s...

Figure 3.4 Formation of cysteine‐nitrogen adducts under conditions of oxidat...

Figure 3.5 Disulfide formation plays a key role in cellular cysteine redox c...

Figure 3.6 Thioredoxin and glutaredoxin catalyze disulfide reduction. (a) Pr...

Figure 3.7 Methionine oxidation creates a new chiral center. (a) Under biolo...

Figure 3.8 Reduction of methionine

S

‐oxides is catalyzed by methionine sulfo...

Figure 3.9 Tyrosine oxidation leads to multiple products. In the presence of...

Figure 3.10 Aromatic amino acid oxidation. (a) The indole ring of tryptophan...

Figure 3.11 Oxidation of aliphatic amino acids yields reactive carbonyls and...

Figure 3.12 Electrophilic reactions leading to protein carbonylation. (a) Cy...

Figure 3.13 Chemoselective detection of oxidized cysteines within proteins. ...

Figure 3.14 Detection of protein carbonylation through hydrazone formation. ...

Chapter 4

Figure 4.1 Repair of DNA base damage. Reactive oxygen species can modify the...

Figure 4.2 List of modified nucleosides discussed.

Figure 4.3 Repair of 2′‐deoxyribose damage. Reactive oxygen species can abst...

Figure 4.4 Tandem and clustered lesions. Oxidation of DNA at base #1 in the ...

Figure 4.5 Representative cross‐link adducts. Representative oxidatively ind...

Chapter 5

Figure 5.1 Activation of Nrf2. As illustrated, stress conditions (e.g., oxid...

Figure 5.2 Potential mechanisms by which drugs and environmental toxicants d...

Chapter 6

Figure 6.1 Schematic representation of a typical mitochondria and submitocho...

Figure 6.2 Schematic representation illustrating the relationship of oxidati...

Figure 6.3 Schematic of the mechanism explaining oxygen free radical(s) gene...

Figure 6.4 (A) Homology model of the 51 kDa subunit of bovine complex I. The...

Figure 6.5 (A) Hydrophobic residues in the ubiquinone‐binding site of

E. col

...

Figure 6.6 (A) Superoxide generation mediated by the Q cycle mechanism in th...

Figure 6.7 Schematic representation of subunits I and II of complex IV. Copp...

Figure 6.8 Generation of superoxide in mitochondria and interactions among G...

Chapter 7

Figure 7.1 Model of phagocyte flavocytochrome b and proposed electron flow. ...

Figure 7.2 Structural models of the NADPH oxidase cytosolic cofactors. Major...

Figure 7.3 Production of reactive oxygen species by phagocytes and potential...

Figure 7.4 NOX family members and their proposed regulatory subunits. NOX pr...

Figure 7.5 A paradigm illustrating the role of ROS in the resolution of infe...

Figure 7.6 Schematic representation of the various regions of the body where...

Chapter 8

Figure 8.1 Redox modification of protein thiols and disulfide bonds by react...

Figure 8.2 The structure of the regulatory metal site in PerR (left) and 2‐o...

Figure 8.3 Cartoon of HIF‐α regulation by hydroxylase activity of PHD and FI...

Figure 8.4 α‐Ketoglutarate and Fe‐dependent hydroxylation of HIF‐α by prolyl...

Figure 8.5 Hypoxic and nonhypoxic induction of hypoxia‐inducible factor (HIF...

Chapter 9

Figure 9.1 Cancer cells exhibit increased generation of ROS and RNS compared...

Figure 9.2 Accumulation and persistence of oxidatively induced DNA damage ca...

Figure 9.3 Apoptotic deregulation and multidrug resistance in cancer cells. ...

Figure 9.4 Redox imbalance in carcinogenesis: a simplified hypothesis. Resti...

Chapter 10

Figure 10.1 Enzymatic pathways involved in reactive intermediate‐mediated ne...

Figure 10.2 Sources of reactive oxygen species (ROS) in the brain. When pro‐...

Figure 10.3 Biosynthesis of prostaglandins. Arachidonic acid (AA) is release...

Figure 10.4 Cell‐dependent PHS‐2‐activation. The figure illustrates the nume...

Figure 10.5 Cyclooxygenase and peroxidase catalysis by PHSs. A two‐electron ...

Figure 10.6 Examples of PHS inhibitors. Aspirin is a covalent modifier of PH...

Figure 10.7 Mechanisms of PHS bioactivation of substrates. (A) In peroxidase...

Figure 10.8 Postulated bioactivation of endogenous substrates to a free radi...

Figure 10.9 Oxidation of aminochrome by NADPH‐cytochrome P450 reductase and ...

Figure 10.10 Amphetamine, its analogs and neurotransmitters, their precursor...

Figure 10.11 Metabolism of methamphetamine by cytochromes P450. Methamphetam...

Figure 10.12 MDMA metabolism by CYPs and P450 reductase. HHA, 3,4‐dihydroxya...

Figure 10.13 METH actions at the dopaminergic nerve terminal. METH are subst...

Figure 10.14 Pentose phosphate pathway. The oxidative phase of the pentose p...

Figure 10.15 Mechanism of Nrf2 in cytoprotection. Nrf2 is frequently activat...

Chapter 11

Figure 11.1 Complete and partial reduction of molecular oxygen in the mitoch...

Figure 11.2 Generation of superoxide radical anion (O

2

•−

) and hy...

Figure 11.3 Generation of superoxide radical anion (O

2

•−

) and hy...

Figure 11.4 Proposed model of cytochrome

c

mediated removal of H

2

O

2

, oxidati...

Figure 11.5 Generation of superoxide radical anion (O

2

•−

) and ni...

Figure 11.6 Reduction of nitrate to nitrite and subsequently to NO.

Figure 11.7 Molecular mechanisms involved in the generation of reactive oxyg...

Chapter 12

Figure 12.1 Oxidative stress affectors.

Figure 12.2 Atherosclerosis‐causing agents.

Figure 12.3 Aldehydes released from the digested lipoprotein due to lysosoma...

Figure 12.4 Prevention of the generation of antiatherogenic and anti‐inflamm...

Chapter 13

Figure 13.1 Formation of oxidants by major peroxidases in the airways. React...

Figure 13.2 Schematic depicts reactive nitrogen and oxygen species formation...

Chapter 14

Figure 14.1 Pathogenesis of biological effect after cigarette smoke exposure...

Figure 14.2 The association of tissue injury with cigarette smoke particle r...

Figure 14.3 The participation of oxidant generation and oxidative stress in ...

Chapter 15

Figure 15.1 Increased exogenous and endogenous oxidative stress in COPD, whi...

Figure 15.2 Increased markers of oxidative stress in the breath of COPD pati...

Figure 15.3 Increased oxidative stress drives the pathology of COPD through ...

Chapter 16

Figure 16.1 The eye. Light enters through the cornea and is focused by the l...

Figure 16.2 Schematic of the cornea, limbus, trabecular meshwork, and iris i...

Figure 16.3 Structure and organization of the lens. Lens epithelial cells un...

Figure 16.4 The structure and various cell types within the mammalian retina...

Chapter 17

Figure 17.1 Current chronic kidney disease (CKD) classification used by KDIG...

Figure 17.2 Endogenous and exogenous RS‐generating sources leading to oxidat...

Chapter 18

Figure 18.1 Potential use of oxidative and nitrosative markers.

Chapter 19

Figure 19.1 Pathways of thiol as key group of the redox equilibrium antioxid...

Figure 19.2 Cellular and extracellular thiols distribution.

Figure 19.3 Panel (A) shows the image of the entire albumin structure highli...

Figure 19.4 Reduced and oxidized forms of circulating HSA in physiological a...

Figure 19.5 Similarity between the architecture surrounding Cys34 in HSA and...

Figure 19.6 HSA‐SH is the main vascular and extravascular antioxidant. Cys34...

Chapter 20

Figure 20.1 Structures of selected biologically relevant nitroalkene fatty a...

Figure 20.2 Main reaction pathways of NO

2

FA in the cell. A NO

2

FA, represente...

Figure 20.3 Mechanism of Michael addition–elimination reaction between a thi...

Figure 20.4 Reaction between NO2CLA and a low‐molecular‐weight thiolate (RS

−

...

Chapter 21

Figure 21.1 General equation of a dismutation reaction and two exemples of d...

Figure 21.2 Catalytic mechanisms of superoxide dismutation by copper superox...

Figure 21.3 Catalytic mechanisms of superoxide dismutation by manganese supe...

Figure 21.4 Catalytic mechanism of lipidic hydroperoxides reduction by selen...

Figure 21.5 Chemical structures of salens and metalloporphyrin.

Scheme 21.1 Synthetic route of Salem EUK‐8.

Figure 21.6 Redox antioxidant‐coupled peroxynitrite reductase activity of Mn...

Figure 21.7 Chemical structures of the pentacoordinated maganese complex Mn(...

Scheme 21.2 Synthetic routes of Ebselen by (A) Weber and Renson and by (B) E...

Figure 21.8 (A) Peroxynitrite‐dependent oxidation of ebselen and (B) H

2

O

2

re...

Figure 21.9 Chemical structures of the ebselen analogues BXT‐51072 and BXT‐5...

Figure 21.10 Tautomeric equilibrium of 3‐methyl‐1‐phenyl‐2‐pyrazoline‐5‐one ...

Figure 21.11 The potential mechanisms of edaravone on endothelial functions....

Figure 21.12 Chemical structures of methylprednisolone, tirilazad mesylate, ...

Figure 21.13 (A) The spin trapping mechanisms of PBN and (B) the two resonan...

Figure 21.14 Chemical structures of simple nitrones agents.

Scheme 21.3 Examples of methods for the synthesis of nitrones. (A) The “one‐...

Figure 21.15 Chemical structures of the CPI‐1429 nitrone and the amphiphilic...

Guide

Cover

Table of Contents

Title Page

Copyright

List of Contributors

Preface to Second Edition

Preface First Edition

Begin Reading

Index

End User License Agreement

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MOLECULAR BASIS OF OXIDATIVE STRESS

Chemistry, Toxicology, Disease Pathogenesis, Diagnosis, and Therapeutics

Second Edition

Edited by

FREDERICK A. VILLAMENAAssociate ProfessorDepartment of Biological Chemistry and PharmacologyCollege of MedicineThe Ohio State University

HENRY JAY FORMANResearch Professor Emeritus of GerontologyUniversity of Southern California

Distinguished Professor Emeritus of Biochemistry and Founding FacultyUniversity of California, Merced

Editor in Chief, Archives of Biochemistry and BiophysicsReceiving Editor, Free Radical Biology and Medicine

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LIST OF CONTRIBUTORS

Ara Aboolian is a PhD student at the German Diabetes Center, who has received his undergraduate and graduate degrees in biology and molecular biomedicine, respectively, at the Heinrich Heine University (Düsseldorf, Germany). His research focuses on oxidative stress in diabetic kidney disease (DKD). By utilizing cell and mouse models of diabetes, he investigates whether attenuating mitochondrial ROS production is sufficient to prevent or delay the progression of DKD.

Giancarlo Aldini is full professor at the University of Milan. He has held various roles within international organizations such as the European Society of Free Radical Research and the HNE international group. He has served as the director of the PhD school in pharmaceutical sciences at the University of Milan. His primary research interest lies in the development and application of high‐resolution mass spectrometric techniques in drug discovery and development, with a particular focus on oxidative stress as a drug target and molecular approaches for its prevention. He has authored more than 250 papers.

D. Allan Butterfield was born in Maine. He obtained his PhD in physical chemistry from Duke University, followed by a NIH postdoctoral fellowship in Neurosciences at the Duke University School of Medicine. He then joined the Department of Chemistry at the University of Kentucky in 1975, rising to full professor in eight years. He is now the UK Alumni Association endowed professor of Biological Chemistry, director of the Center of Membrane Sciences, director of the Free Radical Biology in Cancer Core of the UK Markey Cancer Center, and faculty of the Sanders‐Brown Center on Aging at the University of Kentucky. He has published more than 550 refereed papers on his principal NIH‐supported research areas of oxidative stress and redox proteomics in all phases of Alzheimer disease and in mechanisms of chemotherapy‐induced cognitive dysfunction (referred to by patients as “chemobrain”). His chapter contribution was co‐authored by Rukhsana Sultana and Giovanna Cenini. Dr. Rukhsana Sultana received her PhD in life sciences from the University of Hyderabad. After spending time as a postdoctoral scholar and research associate in the Butterfield laboratory, Dr. Sultana is now a research assistant professor of biological chemistry at the University of Kentucky. She has co‐authored more than 100 refereed scientific papers most on oxidative stress in Alzheimer disease. Dr. Giovanna Cenini received her PhD in pharmacology from the University of Brescia in Italy. After spending two years in the Butterfield laboratory as a predoctoral fellow and two years as a postdoctoral scholar, Dr. Cenini is now a postdoctoral scholar in biochemistry at the University of Bonn. She has published approximately 15 papers from her time in the Butterfield laboratory mostly on oxidative stress and p53 in Alzheimer disease and Down syndrome.

Megan M. Allyn, MS, is a PhD candidate in chemical and biomolecular engineering at The Ohio State University. They received dual BS in chemistry and chemical engineering from Kettering University in Flint, MI. Current research includes the development of polymeric drug delivery devices and their investigation for treatment of retinal diseases.

Alessandra Altomare received her PhD in pharmaceutical sciences from the University of Milan working in the field of mass spectrometry‐based proteomics, where she is currently an associate professor. She has authored 69 papers; her main research interest is devoted to the development and application of proteomics‐based analytical strategies (HR‐MS) for (1) identification of molecular targets; (2) structural characterization of oxidative stress biomarkers; (3) elucidation of the mechanism of action of small and large bioactive molecules of synthetic and natural origin.

Cristina Banfi is the coordinator of the Target Discovery area and group leader of the Proteomics, Metabolomics, and Network Analysis at Centro Cardiologico Monzino IRCCS in Milan. The research activity of Dr Banfi involves basic research with pharmacological, biochemical and molecular biology, as well as clinical research in patients at high risk for atherosclerosis and cardiovascular events. In recent years, Dr Banfi has developed proteomic strategies by means of “state‐of‐the art” techniques and instrumentations for the analysis of differentially expressed proteins in human specimens (tissue, body fluids, and circulating cells), in in vitro cultured cells (human vein and aortic endothelial cells, cardiomyocytes), and in animal models of heart ischemia and stroke. She has authored more than 150 papers.

Peter J. Barnes, FMedSci, FRS, is a professor of thoracic medicine at the National Heart and Lung Institute and was head of respiratory medicine at Imperial College London 1987–2017. He qualified at Cambridge and Oxford Universities and trained in London. He has published more than 1500 peer‐review papers on asthma, COPD (h‐index 230), and has written/edited more than 50 books. He has been the most highly cited respiratory researcher in the world over the last 20 years. He was president of the ERS in 2013/2014 and was knighted for services to respiratory science in 2023.

Ms. Chwen‐Lin Chen (BS) began her career as a research technician at the Davis Heart and Lung Research Institute of Ohio State University from 2002 to 2010. Since 2010, she has held the esteemed position of senior research technician at NEOMED. Her expertise and dedication to scientific research has led to the publication of 35 peer‐reviewed articles, showcasing her commitment to scientific excellence.

Dr. Yeong‐Renn Chen earned his PhD from Oklahoma State University in 1994. He served as an assistant and associate professor of internal medicine at Ohio State University from 2002 to 2010. Currently, Dr. Chen holds the position of full professor at Northeast Ohio Medical University (NEOMED). Dr. Chen’s research is centered around mitochondrial biology and ischemia and reperfusion injury. He has published more than 70 peer‐reviewed articles, and his research has been funded by NIH and AHA. Dr. Chen also contributes to medical education. He teaches renal physiology and bioenergetics in the MD Program at NEOMED, imparting critical knowledge to future physician.

Sean S. Davies was born in Honolulu, Hawaii. He obtained his PhD in experimental pathology from the University of Utah, followed by a postdoctoral fellowship in clinical pharmacology at Vanderbilt University, where he is now an associate professor of pharmacology. His research centers on the role of lipid mediators in chronic diseases including atherosclerosis and diabetes with an emphasis on mediators derived nonenzymatically by lipid peroxidation. His goal is to develop pharmacological strategies to modulate levels of these mediators and thereby treat disease. His chapter contribution was coauthored with Lilu Guo.

Brian J. Day was born in Montana. He obtained his PhD in Pharmacology and Toxicology from Purdue University, followed by a NIH Postdoctoral Fellowship in Pulmonary and Toxicology at Duke University. He then joined the Department of Medicine at National Jewish Health, Denver, Colorado, in 1997 and is currently a full professor and vice chair of research. He has published more than 120 refereed papers on his principal NIH‐supported research areas of oxidative stress and lung disease. He is also a founder of Aeolus Pharmaceuticals and inventor on its product pipeline. He currently serves as chief scientific officer for Aeolus Pharmaceuticals that is developing metalloporphyrins as therapeutic agents. His chapter contribution was co‐authored by Neal Gould. Dr. Gould received his PhD in Toxicology from the University of Colorado at Denver in 2011 and is currently a postdoctoral fellow at the University of Pennsylvania in Dr. Ischiropoulos’ research group. He has published 7 refereed papers in the area of oxidative stress and lung disease.

Grégory Durand was born in Avignon, France. He obtained his PhD in organic chemistry from the Université d’Avignon in 2002. In 2003, he was appointed “Maître de Conférences” at the Université d’Avignon where he obtained his Habilitation Thesis in 2009. In 2007 and 2009, he spent one semester at the Davis Heart & Lung Research Institute (The Ohio State University) as a visiting scholar. He is currently the director of the chemistry department of the Université d’Avignon. His research focuses on the synthesis of novel nitrone compounds as probes and therapeutics. He is also involved in the development of surfactant‐like molecules for handling membrane proteins.

Rodrigo Franco was born in Mexico City, Mexico, and received his BS in science and his PhD in biomedical sciences from the National Autonomous University of Mexico, Mexico City. His postdoctoral training was done at the National Institute of Environmental Health Sciences‐NIH in NC. Then, he joined the Redox Biology Center and the School of Veterinary and Biomedical Sciences at the University of Nebraska‐Lincoln, where he is currently an assistant full professor. His research is focused on the role of oxidative stress and thiol‐redox signaling in neuronal cell death.

Alexandros G. Georgakilas is an associate professor of biology at East Carolina University (ECU) in Greenville, NC, and recently elected assistant professor at the physics department, National Technical University of Athens (NTUA), Greece. At ECU, he has been responsible for the DNA Damage and Repair laboratory and having trained several graduate (1 PhD and 8 MSc) and undergraduate students. His work has been funded by various sources like East Carolina University, NC Biotechnology Center, European Union and International Cancer Control (UICC), which is the largest cancer fighting organization of its kind, with more than 400 member organizations across 120 countries. He holds several editorial positions in scientific journals. His research work has been published in more than 50 peer‐reviewed high‐profile journals like Cancer Research, Journal of Cell Biology and Proceedings of National Academy of Sciences USA, and more than one thousand (1000) citations. Ultimately, he hopes to translate his work of basic research into clinical applications using DNA damage clusters as cancer or radiation biomarkers for oxidative stress. Professor Georgakila co‐authored the chapter with Thomas Kryston. Thomas Kryston, was born in Saint Petersburg, FL, and received his MS in molecular biology and biotechnology at East Carolina University. His graduate work focused on Oxidative Clustered DNA Lesions as potential biomarkers for cancer. Following his graduate studies, he was employed by The Mayo Clinic where his research interests were with exanucleotide expansions in ALS patients.

Andrew J. Ghio is a medical officer with the US Environmental Protection Agency in Chapel Hill, North Carolina, as well as a clinical associate professor in the Pulmonary and Critical Care Division at the University of North Carolina Medical Center in Chapel Hill and an associate consulting professor of medicine at Duke University Medical Center in Durham, NC.

James L. Hougland was born in Rock Island, IL. Following undergraduate studies at Northwestern University where he double majored in Chemistry and Integrated Science, he obtained his PhD in chemistry from the University of Chicago followed by an NIH Postdoctoral Fellowship in Chemistry and Biological Chemistry at the University of Michigan, Ann Arbor. He joined the Department of Chemistry at Syracuse University in 2010 and is currently a professor of chemistry and biology at Syracuse and director of the biochemistry program. His research program focuses on protein posttranslational modifications, in particular the specificity of enzymes that catalyze protein modification and the impact of those modifications on biological function. His chapter contribution was coauthored by Joseph Darling and Susan Flynn.

Professor Karin Jandeleit‐Dahm is a clinician scientist and deputy head of the diabetes department at Monash University, professor of medicine at Monash University and the University of Hannover, Germany. In addition, as the Leibniz chair for Diabetes Research she is group leader of the Diabetic Nephropathy Group at the German Diabetes Center in Düsseldorf, Germany. She is an internationally recognized leader in the field of oxidative stress and complications in diabetes including kidney disease and cardiovascular complications. She recently received two major awards in the field of diabetes, the Kellion award of the Australian Diabetes Society and the Ruth Østerby award of the European Diabetic Nephropathy Study Group (EDNSG).

Peter A. Jansen, MS, is a PhD candidate in the department of biomedical engineering at The Ohio State University and NSF Graduate Research fellow. He completed his BS in biomedical/biosystems engineering and a BA in German at Michigan State University. His research interests include ocular tissue engineering, biofabrication, biomaterials, and stem cell/gene engineering.

Dr. Jay C. Jha is a biomedical‐translational researcher at the Department of Diabetes, Monash University, Australia. He is an emerging leader in the field of diabetes and kidney disease. He completed his PhD in 2014 from Monash University, and the outcome of his thesis provided the rationale for clinical studies to explore the clinical relevance of NOX4 inhibition in diabetic kidney disease. His main focus of research is identifying novel therapeutic targets and biomarkers for diabetic kidney disease. He has been awarded two highly competitive early career fellowships from NHMRC and JDRF, as well as secured grants from Diabetes Australia, highlighting the significance of his achievements in the field of diabetes, nephrology, and oxidative stress.

Urmila Kodavanti is a research biologist with the U.S. Environmental Protection Agency and an Adjunct Faculty, University of North Carolina Chapel Hill, NC. Her research interests are air pollution health and neuroendocrine mechanisms.

Yunbo Li received his PhD from Johns Hopkins University. He is currently a professor and associate dean for research at Duquesne University College of Medicine. Dr. Li has published over 140 journal articles in the areas of pharmacology/toxicology and free radical biomedicine, and written several books, including the well‐received texts, “Cardiovascular Diseases: From Molecular Pharmacology to Evidence‐Based Therapeutics (Wiley)” and “Free Radical Biomedicine: Principles, Clinical Correlations, and Methodologies (Bentham).” His research has been funded by NIH (NCI, NHLBI, NIDDK, & NIGMS).

Aimin Liu is a biochemist studying redox chemistries mediated by Fe‐containing proteins and free radicals in biology. Originally from mainland China with a BS from the University of Science and Technology of China (USTC), he received a PhD from the Lanzhou Institute of Chemical Physics of the Chinese Academy of Sciences and a doctorate in biophysics from Stockholm University in Sweden. He was also a Royal Society scholar at the University of Newcastle upon Tyne and a postdoctoral fellow at Xiamen University and the University of Minnesota. Dr. Liu began his independent career at the University of Mississippi Medical Center. After being promoted to associate professor with tenure, he moved to Georgia State University in 2008. He received the Outstanding Faculty Award, Georgia Cancer Scholar award, and was promoted to full professor in 2012 and University Distinguished professor in 2015. In 2016, he relocated to San Antonio as a Lutcher Brown distinguished chair in Biochemistry in the Department of Chemistry of the University of Texas at San Antonio (UTSA), where he was elected to the Academy of Distinguished Researchers at UTSA. Dr. Liu is an AAAS fellow (Chemistry) and a fellow of the Royal Society of Chemistry (FRSC).

Dr. Jaroslawna Meister is a scientist with a medical background and over ten years of experience in biomedical research. During her postdoctoral training at the National Institutes of Health (Bethesda, MD), she gained expertise in studying G‐protein‐coupled receptor signaling in models of type 2 diabetes and obesity, and in the use of chemogenetic approaches to dissect metabolic pathways in glucose metabolism. As deputy group leader at the German Diabetes Center (Düsseldorf), she focuses on identifying targets for the prevention and treatment of diabetic complications, with a particular emphasis on metabolic adaptations in renal and cardiovascular complications of diabetes.

Edward J. Merino was born San Diego, CA, and received his PhD in bio‐organic chemistry from the University of North Carolina at Chapel Hill. Following as postdoctoral fellow at the California Institute of Technology, he joined the chemistry department of the University of Cincinnati, where he was an associate professor. He then moved to California Health Sciences University and is currently a professor and a director of research and scholarly activities. His research encompasses DNA damage, specifically evaluation of DNA repair signaling, induced from reactive oxygen species, the design of novel antioxidants, and inhibition of NADPH oxidase enzymes.

Mihalis I. Panayiotidis was born in Athens, Greece, and received his PhD in Toxicology from the School of Pharmacy at the University of Colorado, USA. After completion of an NIEHS‐IRTA post‐doctoral fellowship, he followed with assistant professor positions at the Department of Nutrition and the School of Community Health Sciences at the University of North Carolina‐Chapel Hill, USA, and the University of Nevada‐Reno, USA, respectively. Currently, he has joined the Laboratory of Pathological Anatomy, University of Ioannina, Greece, where he is an assistant professor of molecular pathology. His research encompasses the role of oxidative stress and natural products in cancer formation and prevention, respectively.

Aglaia Pappa was born in Ioannina, Greece, and received her PhD in Biological Chemistry & Pharmacology from the University of Ioannina, Greece. After completion of a post‐doctoral training at the School of Pharmacy, University of Colorado, USA, she has joined the Department of Molecular Biology & Genetics, Democritus University of Thrace, Greece as an Assistant Professor of Molecular Physiology & Pharmacology. Her research encompasses the role of oxidative stress in human disease including carcinogenesis.

Sampath Parthasarathy obtained his PhD degree from the Indian Institute of Science, Bangalore, India in 1974. He spent one year at the Kyoto University, Japan, as a postdoctoral fellow and subsequently joined the Duke University at Durham, NC. He then joined the Hormel Institute, University of Minnesota and became an assistant professor. From 1983 to 1993 Dr. Parthasarathy was a member of the faculty and reached the rank of professor at the University of California at San Diego. He developed the concept of oxidized LDL with his colleagues. In 1993, he was invited to become the director of research division in the Department of Gynecology and Obstetrics at Emory University as the McCord‐Cross professor. After serving 10 years at Emory, he joined Louisiana State University Health Science Center at New Orleans in November 2003 as Frank Lowe professor of graduate studies and as professor of pathology. During 2006–2011 he served as the Klassen chair in cardiothoracic surgery at the Ohio State University and was instrumental in developing a large animal model of heartfailure. Currently, he is the Florida Hospital chair in cardiovascular sciences and serves as associate director of research at the Burnett School of Biomedical Sciences at the University of Central Florida in Orlando. Dr. Parthasarathy has published over 240 articles has also written a book “Modified Lipoproteins in the Pathogenesis of atherosclerosis.”

Mark T. Quinn was born in San Jose, CA, and received a PhD in physiology and pharmacology from the University of California at San Diego. Following post‐doctoral training at The Scripps Research Institute, he joined the Department of Chemistry and Biochemistry at Montana State University. Subsequently, he moved to the Department of Microbiology and then to the Department of Immunology of Infectious Diseases, where he is currently a Professor and Department Head. His research is focused on understanding innate immunity, with specific focus on neutrophil NADPH oxidase structure and function and regulation of phagocytic leukocyte activation during inflammation.

Wade W. Rich, MS, is a PhD candidate in the Department of Biomedical Engineering at The Ohio State University. He received his bachelor’s degree in Biomedical Engineering from Purdue University in 2017. His ongoing research interests include ocular biomechanics, aging, mechanobiology, and growth with a particular focus on the crystalline lens.

Matthew A. Reilly, PhD, is an associate professor in the Department of Biomedical Engineering and the Department of Ophthalmology and Visual Sciences at The Ohio State University. His academic background is in chemical and materials engineering, with BChE and MS degrees in chemical and materials engineering from the University of Dayton, followed by a PhD in energy, environmental, and chemical engineering from Washington University in St. Louis. His research interests are primarily in the area of ocular biomechanics related to aging in the ocular lens, as well as ocular trauma.

Dr Alejandra Romero is a Spanish postdoctoral researcher in Austria. She completed her PhD in pharmacological research and physiology in 2020, focusing on vascular aging associated with metabolic syndromes. Afterward, she continued at the German Diabetes Centre, where she studied the role of senescence in the development of diabetes complications including nonalcoholic fatty liver disease or diabetic nephropathy and their causes. She is now continuing her research career at VASCage in collaboration with Oroboros Instruments to study mitochondrial respiration as a potential biomarker.

Annie K. Ryan, MS, is a PhD candidate at The Ohio State University in the Department of Biomedical Engineering. She received her bachelor’s degree from Duquesne University in Biomedical Engineering in 2020. Her current research examines diagnostic visual electrophysiology, in the form of electroretinograms, and therapeutic approaches for traumatic optic neuropathy (TON).

Dr. Francisco J. Schopfer's academic and professional journey is marked by significant achievements, earning his BS in biology and PhD in biochemistry from the University of Buenos Aires. After postdoctoral training at the University of Alabama at Birmingham, he joined the Department of Pharmacology & Chemical Biology, University of Pittsburgh in 2006, becoming professor in 2023. Dr. Schopfer's research program is a testament to his expertise and innovation, focusing on basic lipid signaling and translating research findings into preclinical and clinical developments, specifically focusing on redox signaling, metabolism, and inflammation.

Martín Sosa was born in Canelones, Uruguay. He received his degree in biochemistry from Universidad de la República, in 2022. Martín is interested in the interaction between nitroalkene fatty acids and glutathione metabolism enzymes. During his undergraduate studies, he worked under Lucía Turell and Martina Steglich at the Enzymology Laboratory. His research is focused on the selenoenzyme thioredoxin glutathione reductase from the helminth parasite Echinococcus granulosus and its interaction with nitro‐oleic acid. Currently, Martín is pursuing an MSc degree, studying the metabolism of nitro‐conjugated linolenic acid by human glutathione transferases.

Martina Steglich is an assistant professor at the Enzymology Laboratory at the Universidad de la República, Uruguay. She earned her degree in biochemistry and her master’s in chemistry from the Universidad de la República, Uruguay, and she is about to finish her PhD studies in chemistry with the supervision of Lucía Turell. In her PhD thesis, she is studying the role of cytosolic glutathione transferases in the reaction between nitrooleic acid and glutathione.

Katelyn E. Swindle‐Reilly, PhD, is tenured faculty with appointments in biomedical engineering, chemical & biomolecular engineering, and ophthalmology & visual sciences at The Ohio State University. She has degrees in chemical engineering, with a BS from Georgia Institute of Technology, and MS and PhD from Washington University in St. Louis. She has managed multiple research projects from initial research phase through manufacturing and regulatory approval, including serving as chief technology officer of an ophthalmic startup company. Dr. Swindle‐Reilly’s research focuses on the design of polymeric biomaterials for soft tissue repair and drug delivery with focused applications in ophthalmology.

Lucía Turell is an associate professor at the Enzymology Laboratory at the Universidad de la República, Uruguay. She earned her degree in biochemistry and her PhD in chemistry from the Universidad de la República, Uruguay. Her research is focused on the interaction between thiols and electrophiles of biological and pharmacological interest. In particular, she interested in unraveling the nitroalkene fatty acids reactions with thiols such as glutathione, and the role of glutathione transferases in these reactions. This is important considering the potential of these compounds as drugs for the treatment of several pathologies, since these reactions can affect their pharmacokinetics.

Murugesan Velayutham was born in Tamil Nadu, India, and received his PhD in physical chemistry (magnetic resonance spectroscopy) from the Indian Institute of Technology Madras, Chennai, India. He did his post‐doctoral training at North Carolina State University and Johns Hopkins University. Currently, he is a research scientist at the Davis Heart Lung Research Institute, The Ohio State University College of Medicine. His research interests have been focused on understanding the roles of free radicals/reactive oxygen species and nitric oxide in biological systems as well as measuring and mapping molecular oxygen levels and redox state in in vitro and in vivo systems using EPR spectroscopy/oximetry/imaging techniques. He is a co‐founding member of the Asia‐Pacific EPR/ESR Society and a member of The International EPR Society.

Frederick A. Villamena was born in Manila, Philippines, and earned his bachelor of science degree in chemistry from the University of Santo Tomas. He then obtained his doctorate of philosophy in physical organic chemistry from Georgetown University. After completing postdoctoral fellowships with ORISE, CNRS, and NIH‐NRSA, he joined the pharmacology department and now the Department of Biological Chemistry and Pharmacology at The Ohio State University, College of Medicine, where he currently holds the position of associate professor. His research focuses on the design and synthesis of nitrone‐based antioxidants, as well as studying their application toward understanding the mechanisms of oxidative stress. Additionally, he has authored a book on the topic of Reactive Species Detection in Biology: From fluorescence to electron paramagnetic resonance spectroscopy.

Giulio Vistoli is currently full professor in medicinal chemistry at the University of Milan. Since 2022, he is coordinator of the PhD course in pharmaceutical sciences at the University of Milan. His expertise involves the computational approaches as applied to pharmaceutical sciences in their broadest sense ranging from homology modeling and virtual screening to ADME predictions or drug delivery optimization. His recent research focuses on the development of new docking approaches to be used in both correlative analyses and virtual screening campaigns, as well as in the employment of artificial intelligence approaches to predict the drug metabolism and toxicity. He is co‐author of about 220 scientific publications.

Peter G. Wells was born in Ontario, Canada. He obtained his PharmD at the University of Minnesota, followed by a postdoctoral fellowship at Vanderbilt University, before becoming a professor in the faculties of medicine and pharmacy at the University of Toronto. His research centers on the role of oxidative and antioxidative pathways in determining risk of neurodegenerative diseases and birth defects. His chapter contribution was coauthored by Annmarie Ramkissoon, Aaron Shapiro, and Margaret Loniewska. Dr. Annmarie Ramkissoon received her PhD from the University of Toronto with a focus on drug bioactivation and antioxidative responses in neurodegeneration. She is currently a postdoctoral fellow at the Cincinnati Children’s Hospital Medical Center. Aaron Shapiro received his BSc from the University of Guelph and an MSc from the University of Northern British Columbia. His doctoral research focuses on the role of xenobiotic‐initiated oxidative stress and DNA repair in the formation of neurodevelopmental deficits. Margaret Loniewska received her BSc from Carleton University. Her doctoral research focuses on glucose‐6‐phosphate dehydrogenase in neurodegeneration.

Dr Jordan Younes is a recently graduated junior doctor at Western Health in Melbourne. He undertook his medical studies at Deakin University where he made the Dean’s list for academic excellence. He has a keen interest in acute care and improving hospital outcomes for those with chronic diseases such as diabetes.

Jay L. Zweier was born in Baltimore, MD, and received his baccalaureate degrees in physics and mathematics from Brandeis University. After PhD training in biophysics at the Albert Einstein College of Medicine, he pursued medical training at the University of Maryland, School of Medicine, and received his MD in 1980. Subsequently he completed his residency in internal medicine followed by his cardiology fellowship at Johns Hopkins. In 1987, he joined the faculty of The Johns Hopkins University School of Medicine. In 1998, he was promoted to the rank of professor and in 2000 appointed as chief of cardiology research, at the Johns Hopkins Bayview Campus. He was elected as a fellow in the American College of Cardiology in 1995 and the American Society of Clinical Investigation in 1994. In July 2002, Dr. Zweier joined The Ohio State University College of Medicine as director of the Davis Heart & Lung Research Institute and the John H. and Mildred C. Lumley chair in medicine. Dr. Zweier is currently professor of internal medicine, physiology, and biochemistry, director of the Center for Environmental and Smoking Induced Disease and the Ischemia and Metabolism Program of the Davis Heart & Lung Research Institute. He has published over 400 peer reviewed manuscripts in the fields of cardiovascular research, free radical biology, and magnetic resonance.

PREFACE TO SECOND EDITION

This book is a result of collective effort by experts in the field of redox biology and medicine, an ever‐growing field of interest due to the fundamental role of oxygen play in life processes. An important part of redox biology is oxidative stress, the deleterious side of the use of oxygen. A search of English language scientific articles under the “oxidative stress” keyword in PubMed between 2015 and 2024 yielded 190K plus citations, demonstrating oxidative stress is a continually emerging and relevant mechanism in biology. In 2019, the discovery of oxygen sensing was recognized by the Nobel Prize Committee in physiology and medicine for their role in cellular gene regulation, thus establishing the basis for their effect on cellular metabolism and physiological function leading the way for the development of therapeutic strategies to combat diseases. Oxygen is central to animal life and its subsequent metabolism to form reactive species, particularly H2O2