Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases

Free radicals and other oxidants have gained importance in the field of biology due to their central role in various physiological conditions as well as their implication in a diverse range of diseases. The free radicals, both the reactive oxygen species (ROS) and reactive nitrogen species (RNS), are derived from both endogenous sources (mitochondria, peroxisomes, endoplasmic reticulum, phagocytic cells etc.) and exogenous sources (pollution, alcohol, tobacco smoke, heavy metals, transition metals, industrial solvents, pesticides, certain drugs like halothane, paracetamol, and radiation). Free radicals can adversely affect various important classes of biological molecules such as nucleic acids, lipids, and proteins, thereby altering the normal redox status leading to increased oxidative stress. The free radicals induced oxidative stress has been reported to be involved in several diseased conditions such as diabetes mellitus, neurodegenerative disorders (Parkinson’s disease-PD, Alzheimer’s disease-AD and Multiple sclerosis-MS), cardiovascular diseases (atherosclerosis and hypertension), respiratory diseases (asthma), cataract development, rheumatoid arthritis and in various cancers (colorectal, prostate, breast, lung, bladder cancers). This review deals with chemistry, formation and sources, and molecular targets of free radicals and it provides a brief overview on the pathogenesis of various diseased conditions caused by ROS/RNS.

[1]  D. Fabian,et al.  The global burden of asthma: executive summary of the GINA Dissemination Committee Report , 2004, Allergy.

[2]  J. Kanofsky Singlet oxygen production by lactoperoxidase. , 1983, The Journal of biological chemistry.

[3]  L. Ghiadoni,et al.  Endothelial function in hypertension. , 1997, JN. Journal of Nephrology (Milano. 1992).

[4]  B. Goldstein,et al.  Free radicals and carcinogenesis. , 1990, Free radical research communications.

[5]  W. O. Fenn,et al.  Oxygen poisoning and x-irradiation: a mechanism in common. , 1954, Science.

[6]  C. Marya,et al.  Rheumatoid arthritis: a review and dental care considerations. , 2011, Nepal Medical College journal : NMCJ.

[7]  A. D. de Grey HO2*: the forgotten radical. , 2002, DNA and cell biology.

[8]  R. Lerner,et al.  Ozone in biology , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[9]  E. Stadtman,et al.  Protein Oxidation in Aging, Disease, and Oxidative Stress* , 1997, The Journal of Biological Chemistry.

[10]  B. Goldstein,et al.  Ozone and lipid peroxidation. , 1969, Archives of environmental health.

[11]  L. Loeb,et al.  Mutagenesis by apurinic/apyrimidinic sites. , 1986, Annual review of genetics.

[12]  C. Winterbourn Comparative reactivities of various biological compounds with myeloperoxidase-hydrogen peroxide-chloride, and similarity of the oxidant to hypochlorite. , 1985, Biochimica et biophysica acta.

[13]  F. Murad,et al.  Activation of guanylate cyclase by superoxide dismutase and hydroxyl radical: a physiological regulator of guanosine 3',5'-monophosphate formation. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[14]  I. Rahman,et al.  Oxidant and antioxidant balance in the airways and airway diseases. , 2006, European journal of pharmacology.

[15]  R. Meacham,et al.  Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype. , 2008, Cancer research.

[16]  Y. Soini,et al.  8-hydroxydeguanosine and nitrotyrosine are prognostic factors in urinary bladder carcinoma. , 2011, International journal of clinical and experimental pathology.

[17]  B. Commoner,et al.  Free Radicals in Biological Materials , 1954, Nature.

[18]  A D Négrel,et al.  Global data on blindness. , 1995, Bulletin of the World Health Organization.

[19]  R. Gonsette Neurodegeneration in multiple sclerosis: The role of oxidative stress and excitotoxicity , 2008, Journal of the Neurological Sciences.

[20]  K. Hirata,et al.  Role of nitric oxide on airway microvascular permeability in patients with asthma. , 2005, Osaka city medical journal.

[21]  D. Harrison,et al.  Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. , 1996, The Journal of clinical investigation.

[22]  A. Khan,et al.  Antioxidants and diabetes , 2012, Indian journal of endocrinology and metabolism.

[23]  S. Rhee,et al.  Isoforms of mammalian peroxiredoxin that reduce peroxides in presence of thioredoxin. , 1999, Methods in enzymology.

[24]  P. Pinton,et al.  Oxidative Stress in Cardiovascular Diseases and Obesity: Role of p66Shc and Protein Kinase C , 2013, Oxidative medicine and cellular longevity.

[25]  L. Marnett Lipid peroxidation-DNA damage by malondialdehyde. , 1999, Mutation research.

[26]  R. Ross Atherosclerosis is an inflammatory disease , 1999 .

[27]  Olivier Hermine,et al.  Phenotypic and Genotypic Characteristics of Mastocytosis According to the Age of Onset , 2008, PloS one.

[28]  B. Bielski,et al.  Superoxide and Hydroxyl Radical Chemistry in Aqueous Solution , 1995 .

[29]  C. Chiueh,et al.  Neuroprotective Properties of Nitric Oxide , 1999, Annals of the New York Academy of Sciences.

[30]  R. Leavitt,et al.  Reaction of ozone with amino acids and proteins. , 1969, Atmospheric environment.

[31]  F. Marshall,et al.  Increased Nox1 and hydrogen peroxide in prostate cancer , 2005, The Prostate.

[32]  R. S. Sohal,et al.  Substrate and site specificity of hydrogen peroxide generation in mouse mitochondria. , 1998, Archives of biochemistry and biophysics.

[33]  Christopher S. Foote,et al.  Active oxygen in chemistry , 1996 .

[34]  D. Butterfield,et al.  Structural and Functional Changes in Proteins Induced by Free Radical‐mediated Oxidative Stress and Protective Action of the Antioxidants N‐tert‐Butyl‐α‐phenylnitrone and Vitamin E a , 1998 .

[35]  P. Bass,et al.  Differences in the reducing power along the rat GI tract: Lower antioxidant capacity of the colon , 1999, Molecular and Cellular Biochemistry.

[36]  T. Mizutani,et al.  In vivo singlet-oxygen generation in blood of chromium(VI)-treated mice , 2000, Biological Trace Element Research.

[37]  J. Ravanat,et al.  Hydrogen peroxide causes greater oxidation in cellular RNA than in DNA , 2005, Biological chemistry.

[38]  A. Young,et al.  Nox1 expression determines cellular reactive oxygen and modulates c-fos-induced growth factor, interleukin-8, and Cav-1. , 2007, The American journal of pathology.

[39]  J. Mudd,et al.  Reaction of ozone with sulfhydryls of human erythrocytes. , 1981, Archives of biochemistry and biophysics.

[40]  C. Boonla,et al.  Elevated urinary total sialic acid and increased oxidative stress in patients with bladder cancer , 2010 .

[41]  A. Tamakoshi,et al.  Serum oxidized low-density lipoprotein levels and risk of colorectal cancer: a case-control study nested in the Japan Collaborative Cohort Study. , 2004, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[42]  J. Mehta,et al.  Oxidant stress in mitochondrial DNA damage, autophagy and inflammation in atherosclerosis , 2013, Scientific Reports.

[43]  Zhihong Yang,et al.  Recent advances in understanding endothelial dysfunction in atherosclerosis. , 2006, Clinical medicine & research.

[44]  S. Minucci,et al.  Electron Transfer between Cytochrome c and p66Shc Generates Reactive Oxygen Species that Trigger Mitochondrial Apoptosis , 2005, Cell.

[45]  L. Terada Specificity in reactive oxidant signaling: think globally, act locally , 2006, The Journal of Cell Biology.

[46]  J S Hothersall,et al.  The effect of diabetes and dietary ascorbate supplementation on the oxidative modification of rat lens beta L crystallin. , 1993, Biochemical medicine and metabolic biology.

[47]  A. Kettle,et al.  Biomarkers of myeloperoxidase-derived hypochlorous acid. , 2000, Free radical biology & medicine.

[48]  L. Paz-Ares,et al.  Identification of proteomic signatures associated with lung cancer and COPD. , 2013, Journal of proteomics.

[49]  R. Ahmed The Physiological and Biochemical Effects of Diabetes on the Balance between Oxidative Stress and Antioxidant Defense System , 2005 .

[50]  D. J. Reed,et al.  Cellular recovery of glyceraldehyde-3-phosphate dehydrogenase activity and thiol status after exposure to hydroperoxides. , 1990, Archives of biochemistry and biophysics.

[51]  A. Starkov The Role of Mitochondria in Reactive Oxygen Species Metabolism and Signaling , 2008, Annals of the New York Academy of Sciences.

[52]  Fritz Haber,et al.  The catalytic decomposition of hydrogen peroxide by iron salts , 1934 .

[53]  L. Marnett,et al.  Oxyradicals and DNA damage. , 2000, Carcinogenesis.

[54]  P. Kovacic Free Radicals in Biology and Medicine , 1986 .

[55]  H. Uzun,et al.  Changes in malondialdehyde levels in bronchoalveolar fluid and serum by the treatment of asthma with inhaled steroid and beta2‐agonist , 2000, Respirology.

[56]  B. Halliwell,et al.  Lipid peroxidation in rheumatoid arthritis: thiobarbituric acid-reactive material and catalytic iron salts in synovial fluid from rheumatoid patients. , 1984, Clinical science.

[57]  L. Flohé,et al.  Respiratory chain linked H2O2 production in pigeon heart mitochondria , 1971, FEBS letters.

[58]  C. Leeuwenburgh,et al.  Part X • Chapter 30 – Molecular mechanisms of oxidative stress in aging: free radicals, aging, antioxidants and disease , 2000 .

[59]  P. Haycock,et al.  Oxidative damage to hyaluronate and glucose in synovial fluid during exercise of the inflamed rheumatoid joint. Detection of abnormal low-molecular-mass metabolites by proton-n.m.r. spectroscopy. , 1991, The Biochemical journal.

[60]  G. Zalba,et al.  Role of NAD(P)H Oxidase , 2001 .

[61]  J. Povlishock,et al.  Appearance of Superoxide Anion Radical in Cerebral Extracellular Space during Increased Prostaglandin Synthesis in Cats , 1985, Circulation research.

[62]  J. Kanofsky,et al.  Singlet oxygen production by biological systems. , 1989, Chemico-biological interactions.

[63]  A. Kettle,et al.  Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing. , 1998, Blood.

[64]  Sujata Joshi,et al.  Lycopene attenuates oxidative stress induced experimental cataract development: an in vitro and in vivo study. , 2003, Nutrition.

[65]  Edward A. Boettner,et al.  Transmission of the Ocular Media , 1962 .

[66]  D. Butterfield,et al.  Structural and functional changes in proteins induced by free radical-mediated oxidative stress and protective action of the antioxidants N-tert-butyl-alpha-phenylnitrone and vitamin E. , 1998, Annals of the New York Academy of Sciences.

[67]  U. Çakatay,et al.  Relation between bladder cancer and protein oxidation , 2004, International Urology and Nephrology.

[68]  P. Barnes,et al.  Reactive oxygen species and airway inflammation. , 1990, Free radical biology & medicine.

[69]  A. Dominiczak,et al.  Endothelial function in hypertension: the role of superoxide anion. , 1999, Hypertension.

[70]  G. Pasinetti,et al.  Peroxisome proliferator activator receptor gamma coactivator-1alpha (PGC-1α) improves motor performance and survival in a mouse model of amyotrophic lateral sclerosis , 2011, Molecular Neurodegeneration.

[71]  M. Gomberg,et al.  AN INSTANCE OF TRIVALENT CARBON: TRIPHENYLMETHYL. , 1900 .

[72]  R L Guyer,et al.  The molecule of the year. , 1989 .

[73]  A. Eiján,et al.  Nitric oxide in patients with transitional bladder cancer , 2002, Journal of surgical oncology.

[74]  M. Dizdaroglu,et al.  Free radical-induced damage to DNA: mechanisms and measurement. , 2002, Free radical biology & medicine.

[75]  O. Riess,et al.  Localization of sequence variations in PGC-1α influence their modifying effect in Huntington disease , 2011, Molecular Neurodegeneration.

[76]  I. Geçit,et al.  Serum prolidase activity, oxidative stress, and nitric oxide levels in patients with bladder cancer , 2012, Journal of Cancer Research and Clinical Oncology.

[77]  T. McAlindon,et al.  Association of periodontal disease and tooth loss with rheumatoid arthritis in the US population. , 2008, The Journal of rheumatology.

[78]  T. Fujisawa Role of oxygen radicals on bronchial asthma. , 2005, Current drug targets. Inflammation and allergy.

[79]  D. Gackowski,et al.  The relationship between 8-oxo-7,8-dihydro-2'-deoxyguanosine level and extent of cytosine methylation in leukocytes DNA of healthy subjects and in patients with colon adenomas and carcinomas. , 2008, Mutation research.

[80]  H. Esterbauer,et al.  4-Hydroxynonenal formation during ischemia and reperfusion of rat small intestine. , 1995, Life sciences.

[81]  A. Junod,et al.  Role of oxygen free radicals in cancer development. , 1996, European journal of cancer.

[82]  E. Eren,et al.  Ischemia modified albumin levels and oxidative stress in patients with bladder cancer. , 2013, Asian Pacific journal of cancer prevention : APJCP.

[83]  Takamichi Ichinose,et al.  The role of iNOS‐mediated DNA damage in infection‐ and asbestos‐induced carcinogenesis , 2010, Annals of the New York Academy of Sciences.

[84]  W. Dröge Free radicals in the physiological control of cell function. , 2002, Physiological reviews.

[85]  Agostino Virdis,et al.  Endothelial function in hypertension: role of gender. , 2002, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[86]  R. Dean,et al.  Biochemistry and pathology of radical-mediated protein oxidation. , 1997, The Biochemical journal.

[87]  A. Klungland,et al.  Urinary excretion of DNA repair products correlates with metabolic rates as well as with maximum life spans of different mammalian species. , 2004, Free radical biology & medicine.

[88]  R Goldsmith,et al.  The epidemiology of bladder cancer. A second look , 1977, Cancer.

[89]  A. Rudich,et al.  Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species. , 2009, Physiological reviews.

[90]  Y. Rojanasakul,et al.  Inflammation and Lung Cancer: Roles of Reactive Oxygen/Nitrogen Species , 2008, Journal of toxicology and environmental health. Part B, Critical reviews.

[91]  P. Di Mascio,et al.  DNA damage by singlet oxygen and cellular protective mechanisms. , 2012, Mutation research. Reviews in mutation research.

[92]  E. Karlson,et al.  Cigarette smoking and autoimmune disease: what can we learn from epidemiology? , 2006, Lupus.

[93]  T. Slater,et al.  An introduction to free radical biochemistry. , 1993, British medical bulletin.

[94]  Pobed'onna Hp [Antioxidant protection, metabolites of nitrogen oxide on the forming of oxidative stress in patients with bronchial asthma]. , 2005 .

[95]  W. Garrison REACTION MECHANISMS IN THE RADIOLYSIS OF PEPTIDES, POLYPEPTIDES AND PROTEINS II REACTIONS AT SIDE-CHAIN LOCI IN MODEL SYSTEMS , 1982 .

[96]  Y. Seo,et al.  Base excision DNA repair defect in thioredoxin-1 (Trx1)-deficient cells. , 2013, Mutation research.

[97]  P. Raskin,et al.  Report of the expert committee on the diagnosis and classification of diabetes mellitus. , 1999, Diabetes care.

[98]  A. Harris,et al.  Thymidine phosphorylase induces carcinoma cell oxidative stress and promotes secretion of angiogenic factors. , 2000, Cancer research.

[99]  M. Mustafa,et al.  Biochemical basis of ozone toxicity. , 1990, Free radical biology & medicine.

[100]  K. Chung Role of inflammation in the hyperreactivity of the airways in asthma. , 1986, Thorax.

[101]  D. Garland,et al.  The oxidative modification of lens proteins. , 1988, Basic life sciences.

[102]  W. Pryor,et al.  One- and two-electron oxidations of methionine by peroxynitrite. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[103]  Roberto Colombo,et al.  Protein carbonyl groups as biomarkers of oxidative stress. , 2003, Clinica chimica acta; international journal of clinical chemistry.

[104]  K. Uchida,et al.  2‐Oxo‐histidine as a novel biological marker for oxidatively modified proteins , 1993, FEBS letters.

[105]  T. Shearer,et al.  Cataract and the acceleration of calpain-induced beta-crystallin insolubilization occurring during normal maturation of rat lens. , 1994, Investigative ophthalmology & visual science.

[106]  T. Murrell Epidemiological and biochemical support for a theory on the cause and prevention of breast cancer. , 1991, Medical hypotheses.

[107]  Kevin F Krenitsky,et al.  NOX5 NAD(P)H oxidase regulates growth and apoptosis in DU 145 prostate cancer cells. , 2003, American journal of physiology. Cell physiology.

[108]  S. Ylä-Herttuala Oxidized LDL and atherogenesis. , 1999, Annals of the New York Academy of Sciences.

[109]  C. Pearce,et al.  Effects of (5Z)-7-oxozeaenol on the oxidative pathway of cancer cells. , 2012, Anticancer research.

[110]  A. Jemal,et al.  Cancer Statistics, 2007 , 2007, CA: a cancer journal for clinicians.

[111]  S. Veeramani,et al.  Mitochondrial redox signaling by p66Shc is involved in regulating androgenic growth stimulation of human prostate cancer cells , 2008, Oncogene.

[112]  R. Kavlock,et al.  Morphometric, biochemical, and physiological assessment of perinatally induced renal dysfunction. , 1983, Journal of toxicology and environmental health.

[113]  Michael Schrader,et al.  Peroxisomes and oxidative stress. , 2006, Biochimica et biophysica acta.

[114]  J. Stamler,et al.  Redox signaling: Nitrosylation and related target interactions of nitric oxide , 1994, Cell.

[115]  Stanton A. Glantz,et al.  Cardiovascular Effects of Secondhand Smoke: Nearly as Large as Smoking , 2005, Circulation.

[116]  R. Touyz Reactive oxygen species and angiotensin II signaling in vascular cells -- implications in cardiovascular disease. , 2004, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[117]  D. Hegner,et al.  Do mitochondria produce oxygen radicals in vivo? , 1978, European journal of biochemistry.

[118]  Elias S. J. Arnér,et al.  Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. , 2001, Free radical biology & medicine.

[119]  C. Sen,et al.  Handbook of oxidants and antioxidants in exercise , 2000 .

[120]  A. Natarajan Reflections on a lifetime in cytogenetics. , 2012, Mutation research. Reviews in mutation research.

[121]  D. Wink,et al.  Chemical biology of nitric oxide: Insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. , 1998, Free radical biology & medicine.

[122]  H. Hansen,et al.  Lung cancer. , 1990, Cancer chemotherapy and biological response modifiers.

[123]  N. Holbrook,et al.  Oxidants, oxidative stress and the biology of ageing , 2000, Nature.

[124]  E. Beyer,et al.  Oxidative stress, lens gap junctions, and cataracts. , 2009, Antioxidants & redox signaling.

[125]  Yasuto Itoyama,et al.  Systemic Increase of Oxidative Nucleic Acid Damage in Parkinson's Disease and Multiple System Atrophy , 2002, Neurobiology of Disease.

[126]  B. Halliwell Oxidants and human disease: some new concepts 1 , 1987, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[127]  M. Aguilar-martínez,et al.  Oxidative stress, progressive damage in the substantia nigra and plasma dopamine oxidation, in rats chronically exposed to ozone. , 2010, Toxicology letters.

[128]  P. Riesz,et al.  A STUDY OF THE PHOTODYNAMIC EFFICIENCIES OF SOME EYE LENS CONSTITUENTS , 1991, Photochemistry and photobiology.

[129]  S. Podos,et al.  Lipid peroxidation in cataract of the human. , 1986, Life sciences.

[130]  J. K. Hurst,et al.  Biological reactivity of hypochlorous acid: implications for microbicidal mechanisms of leukocyte myeloperoxidase. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[131]  C. Menck,et al.  Singlet oxygen induced DNA damage. , 1992, Mutation research.

[132]  C. Sevier,et al.  Generating disulfides enzymatically: reaction products and electron acceptors of the endoplasmic reticulum thiol oxidase Ero1p. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[133]  J. Díez,et al.  Oxidative Stress in Arterial Hypertension: Role of NAD(P)H Oxidase , 2001, Hypertension.

[134]  R. Mason,et al.  The metabolism of 17 beta-estradiol by lactoperoxidase: a possible source of oxidative stress in breast cancer. , 1994, Carcinogenesis.

[135]  R. Dean,et al.  The action of defined oxygen-centred free radicals on human low-density lipoprotein. , 1989, The Biochemical journal.

[136]  B. Halliwell,et al.  DNA and free radicals , 1993 .

[137]  Y. Itoyama,et al.  Oxidative stress and predominant Aβ42(43) deposition in myopathies with rimmed vacuoles , 2003, Acta Neuropathologica.

[138]  David C. Beebe,et al.  Oxidative Damage and the Prevention of Age-Related Cataracts , 2010, Ophthalmic Research.

[139]  R. W. Gracy,et al.  Increased carbonyl content of proteins in synovial fluid from patients with rheumatoid arthritis. , 1989, The Journal of rheumatology.

[140]  Antonio Vidal-Puig,et al.  DNA Damage Links Mitochondrial Dysfunction to Atherosclerosis and the Metabolic Syndrome , 2010, Circulation research.

[141]  O. Hayaishi,et al.  Nature and mechanisms of oxygenases. , 1969, Science.

[142]  E. Stadtman,et al.  Protein Oxidation , 2000, Annals of the New York Academy of Sciences.

[143]  P. Baudhuin,et al.  Peroxisomes (microbodies and related particles). , 1966, Physiological reviews.

[144]  E. Stadtman,et al.  Human studies related to protein oxidation: protein carbonyl content as a marker of damage. , 2000, Free radical research.

[145]  Aubrey D.N.J. de Grey,et al.  HO2*: the forgotten radical. , 2002 .

[146]  S. Masetti,et al.  Evidence for DNA damage in patients with coronary artery disease. , 2001, Mutation research.

[147]  K. Griendling,et al.  Basic mechanisms of oxidative stress and reactive oxygen species in cardiovascular injury. , 2007, Trends in cardiovascular medicine.

[148]  E. Floor,et al.  Increased Protein Oxidation in Human Substantia Nigra Pars Compacta in Comparison with Basal Ganglia and Prefrontal Cortex Measured with an Improved Dinitrophenylhydrazine Assay , 1998, Journal of neurochemistry.

[149]  A. Ross,et al.  Reactivity of HO2/O−2 Radicals in Aqueous Solution , 1985 .

[150]  Abraham Nyska,et al.  Invited Review: Oxidation of Biological Systems: Oxidative Stress Phenomena, Antioxidants, Redox Reactions, and Methods for Their Quantification , 2002, Toxicologic pathology.

[151]  C. Hitchon,et al.  Review Oxidation in rheumatoid arthritis , 2004 .

[152]  L. Ignarro,et al.  Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[153]  Wei Liu,et al.  CORRIGENDUM: Biodegradation-inspired bioproduction of methylacetoin and 2-methyl-2,3-butanediol , 2013, Scientific Reports.

[154]  H. Ohshima,et al.  Formation of 8‐nitroguanine in DNA treated with peroxynitrite in vitro and its rapid removal from DNA by depurination , 1995, FEBS letters.

[155]  R. Fetner Ozone-induced Chromosome Breakage in Human Cell Cultures , 1962, Nature.

[156]  A. Al-Mehdi,et al.  Peroxynitrite‐mediated oxidative protein modifications , 1995, FEBS letters.

[157]  S. Cappa,et al.  Ceruloplasmin Oxidation, a Feature of Parkinson's Disease CSF, Inhibits Ferroxidase Activity and Promotes Cellular Iron Retention , 2011, The Journal of Neuroscience.

[158]  I. Fridovich,et al.  Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). , 1969, The Journal of biological chemistry.

[159]  R. Guevara-Guzmán,et al.  Oxidative stress caused by ozone exposure induces loss of brain repair in the hippocampus of adult rats. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[160]  H. Chan Singlet oxygen analogs in biological systems. Coupled oxygenation of 1,3-dienes by soybean lipoxidase , 1971 .

[161]  L. Oberley Free radicals and diabetes. , 1988, Free radical biology & medicine.

[162]  O. Aruoma Free radicals, oxidative stress, and antioxidants in human health and disease , 1998, Journal of the American Oil Chemists' Society.

[163]  E. Schwedhelm,et al.  Urinary excretion of biomarkers of oxidatively damaged DNA and RNA in hereditary hemochromatosis. , 2009, Free radical biology & medicine.

[164]  J. Cadet,et al.  Peroxynitrite mediated oxidation of purine bases of nucleosides and isolated DNA. , 1996, Free radical research.

[165]  B. Mayer,et al.  Enzymatic function of nitric oxide synthases. , 1999, Cardiovascular research.

[166]  Lien Ai Pham-Huy,et al.  Free Radicals, Antioxidants in Disease and Health , 2008, International journal of biomedical science : IJBS.

[167]  I. Harris,et al.  Cancer cell metabolism. , 2011, Cold Spring Harbor symposia on quantitative biology.

[168]  W. Markesbery,et al.  Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[169]  H. Fenton,et al.  LXXIII.—Oxidation of tartaric acid in presence of iron , 1894 .

[170]  R. Touyz Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: what is the clinical significance? , 2004, Hypertension.

[171]  J S Beckman,et al.  Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. , 1996, The American journal of physiology.

[172]  N. Scolding,et al.  Mechanisms of Oxidative Damage in Multiple Sclerosis and a Cell Therapy Approach to Treatment , 2010, Autoimmune diseases.

[173]  A. Kettle,et al.  Myeloperoxidase and oxidative stress in rheumatoid arthritis. , 2012, Rheumatology.

[174]  J. Pourová,et al.  [Oxidative stress and its role in respiratory diseases]. , 2007, Ceska a Slovenska farmacie : casopis Ceske farmaceuticke spolecnosti a Slovenske farmaceuticke spolecnosti.

[175]  Q. Husain,et al.  Relation of oxidant-antioxidant imbalance with disease progression in patients with asthma , 2012, Annals of thoracic medicine.

[176]  V. Dzau Theodore Cooper Lecture: Tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. , 2001, Hypertension.

[177]  Christopher J. Rhodes,et al.  Role of oxygen radicals in DNA damage and cancer incidence , 2004, Molecular and Cellular Biochemistry.

[178]  S. Goldstein,et al.  The role of the reactions of .NO with superoxide and oxygen in biological systems: a kinetic approach. , 1995, Free radical biology & medicine.

[179]  D E Koshland,et al.  The Molecule of the Year. , 1989, Science.

[180]  Nikolaos Gkantidis,et al.  Clinical Significance , 2022, The SAGE Encyclopedia of Research Design.

[181]  M. Genestra Oxyl radicals, redox-sensitive signalling cascades and antioxidants. , 2007, Cellular signalling.

[182]  G. Nalini,et al.  Status of oxidative stress in rheumatoid arthritis , 2009, International journal of rheumatic diseases.

[183]  G. D. De Meyer,et al.  Reactive oxygen species induce RNA damage in human atherosclerosis , 2004, European journal of clinical investigation.

[184]  S. Zarina,et al.  Osmotic stress induced oxidative damage: possible mechanism of cataract formation in diabetes. , 2012, Journal of diabetes and its complications.

[185]  A. Lavy,et al.  Enhanced Oxidative Stress and Leucocyte Activation in Neoplastic Tissues of the Colon , 2007, Digestive Diseases and Sciences.

[186]  G. Barja The flux of free radical attack through mitochondrial DNA is related to aging rate , 2000, Aging.

[187]  J. Matés,et al.  Antioxidant enzymes and human diseases. , 1999, Clinical biochemistry.

[188]  F. Gage,et al.  Radical directions in Parkinson's disease , 1995, Nature Medicine.

[189]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[190]  P. Cerutti Prooxidant states and tumor promotion. , 1985, Science.

[191]  E. Gottlin,et al.  Haptoglobin and posttranslational glycan‐modified derivatives as serum biomarkers for the diagnosis of nonsmall cell lung cancer , 2007, Cancer.

[192]  M. Santoro,et al.  Manipulating Redox signaling to block tumor angiogenesis , 2013 .

[193]  B. Halliwell,et al.  Hydrogen peroxide in the human body , 2000, FEBS letters.

[194]  M. Yüksel,et al.  Different kinds of reactive oxygen and nitrogen species were detected in colon and breast tumors. , 2001, Cancer letters.

[195]  W. Prütz Hypochlorous acid interactions with thiols, nucleotides, DNA, and other biological substrates. , 1996, Archives of biochemistry and biophysics.

[196]  David B. Leake,et al.  Evidence for oxidised low density lipoprotein in synovial fluid from rheumatoid arthritis patients , 2000, Free radical research.

[197]  C. Hitchon,et al.  Oxidation in rheumatoid arthritis , 2004, Arthritis research & therapy.

[198]  E. Stadtman,et al.  Age-related changes in oxidized proteins. , 1987, The Journal of biological chemistry.

[199]  K. Kikugawa,et al.  Damage of amino acids and proteins induced by nitrogen dioxide, a free radical toxin, in air. , 1994, Free radical biology & medicine.

[200]  J. Zweier,et al.  Characterization of free radical generation by xanthine oxidase. Evidence for hydroxyl radical generation. , 1989, The Journal of biological chemistry.

[201]  D. Borchelt,et al.  Messenger RNA Oxidation Occurs Early in Disease Pathogenesis and Promotes Motor Neuron Degeneration in ALS , 2008, PloS one.

[202]  Hong Wang,et al.  Inflammasomes: sensors of metabolic stresses for vascular inflammation. , 2013, Frontiers in bioscience.

[203]  A. Spector,et al.  Hydrogen peroxide and human cataract. , 1981, Experimental eye research.

[204]  Adam J. Trexler,et al.  Allostery in a disordered protein: oxidative modifications to α-synuclein act distally to regulate membrane binding. , 2011, Journal of the American Chemical Society.

[205]  Marjorie C. Caserio Reaction mechanisms in organic chemistry. Concerted reactions , 1971 .

[206]  Fuqiang Wen,et al.  Hydrogen-rich saline reduces airway remodeling via inactivation of NF-κB in a murine model of asthma. , 2013, European review for medical and pharmacological sciences.

[207]  P. Desai,et al.  Oxidative stress and enzymatic antioxidant status in rheumatoid arthritis: a case control study. , 2010, European review for medical and pharmacological sciences.

[208]  N. Dilsiz,et al.  Determination of calcium, sodium, potassium and magnesium concentrations in human senile cataractous lenses , 2000, Cell biochemistry and function.

[209]  I. Fridovich Superoxide and Superoxide Dismutases , 1977 .

[210]  N. Nagai,et al.  Effect of magnesium deficiency on intracellular ATP levels in human lens epithelial cells. , 2007, Biological & pharmaceutical bulletin.

[211]  D. Leibfritz,et al.  Free radicals and antioxidants in normal physiological functions and human disease. , 2007, The international journal of biochemistry & cell biology.

[212]  Paolo Zamboni,et al.  Oxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options , 2009, Current neuropharmacology.

[213]  D. Butterfield,et al.  Oxidative Stress in Alzheimer's Disease Brain: New Insights from Redox Proteomics , 2006 .

[214]  Barry Halliwell,et al.  Free Radicals and Other Reactive Species in Disease , 2005 .

[215]  H. Tohgi,et al.  Remarkable increase in the concentration of 8‐hydroxyguanosine in cerebrospinal fluid from patients with Alzheimer's disease , 2002, Journal of neuroscience research.

[216]  Z. Stelmasiak,et al.  Free radical peroxidation products in cerebrospinal fluid and serum of patients with multiple sclerosis after glucocorticoid therapy. , 2010, Folia neuropathologica.

[217]  B. Halliwell,et al.  Free radicals in biology and medicine , 1985 .

[218]  Jing Zhang,et al.  Microglial phagocytosis induced by fibrillar β-amyloid is attenuated by oligomeric β-amyloid: implications for Alzheimer's disease , 2011, Molecular Neurodegeneration.

[219]  J. Kehrer,et al.  Oxidation state of tissue thiol groups and content of protein carbonyl groups in chickens with inherited muscular dystrophy. , 1989, The Biochemical journal.