Oxidative stress

Chemically, oxidative stress is associated with increased production of oxidizing species or a significant decrease in the effectiveness of antioxidant defenses, such as glutathione.{{Cite journal |vauthors=Schafer FQ, Buettner GR |date=June 2001 |title=Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple |journal=Free Radical Biology & Medicine |volume=30 |issue=11 |pages=1191–1212 |doi=10.1016/S0891-5849(01)00480-4 |pmid=11368918}} The effects of oxidative stress depend upon the size of these changes, with a cell being able to overcome small perturbations and regain its original state. However, more severe oxidative stress can cause cell death, and even moderate oxidation can trigger apoptosis, while more intense stresses may cause necrosis.{{Cite journal |vauthors=Lennon SV, Martin SJ, Cotter TG |date=March 1991 |title=Dose-dependent induction of apoptosis in human tumour cell lines by widely diverging stimuli |journal=Cell Proliferation |volume=24 |issue=2 |pages=203–214 |doi=10.1111/j.1365-2184.1991.tb01150.x |pmid=2009322 |s2cid=37720004}}

Production of reactive oxygen species is a particularly destructive aspect of oxidative stress. Such species include free radicals and peroxides. Some of the less reactive of these species (such as superoxide) can be converted by oxidoreduction reactions with transition metals or other redox cycling compounds (including quinones) into more aggressive radical species that can cause extensive cellular damage.{{Cite journal |vauthors=Valko M, Morris H, Cronin MT |date=2005 |title=Metals, toxicity and oxidative stress |journal=Current Medicinal Chemistry |volume=12 |issue=10 |pages=1161–1208 |citeseerx=10.1.1.498.2796 |doi=10.2174/0929867053764635 |pmid=15892631}} Most long-term effects are caused by damage to DNA.{{Cite journal |vauthors=Evans MD, Cooke MS |date=May 2004 |title=Factors contributing to the outcome of oxidative damage to nucleic acids |journal=BioEssays |volume=26 |issue=5 |pages=533–542 |doi=10.1002/bies.20027 |pmid=15112233 |s2cid=11714476}} DNA damage induced by ionizing radiation is similar to oxidative stress, and these lesions have been implicated in aging and cancer. Biological effects of single-base damage by radiation or oxidation, such as 8-oxoguanine and thymine glycol, have been extensively studied. Recently the focus has shifted to some of the more complex lesions. Tandem DNA lesions are formed at substantial frequency by ionizing radiation and metal-catalyzed {{chem2|H2O2}} reactions. Under anoxic conditions, the predominant double-base lesion is a species in which C8 of guanine is linked to the 5-methyl group of an adjacent 3'-thymine (G[8,5- Me]T).{{Cite journal |vauthors=Colis LC, Raychaudhury P, Basu AK |date=August 2008 |title=Mutational specificity of gamma-radiation-induced guanine-thymine and thymine-guanine intrastrand cross-links in mammalian cells and translesion synthesis past the guanine-thymine lesion by human DNA polymerase eta |journal=Biochemistry |volume=47 |issue=31 |pages=8070–9 |doi=10.1021/bi800529f |pmc=2646719 |pmid=18616294}} Most of these oxygen-derived species are produced by normal aerobic metabolism. Normal cellular defense mechanisms destroy most of these. Repair of oxidative damages to DNA is frequent and ongoing, largely keeping up with newly induced damages. In rat urine, about 74,000 oxidative DNA adducts per cell are excreted daily.{{Cite journal |vauthors=Helbock HJ, Beckman KB, Shigenaga MK, Walter PB, Woodall AA, Yeo HC, Ames BN |date=January 1998 |title=DNA oxidation matters: the HPLC-electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=95 |issue=1 |pages=288–293 |bibcode=1998PNAS...95..288H |doi=10.1073/pnas.95.1.288 |pmc=18204 |pmid=9419368 |doi-access=free}} There is also a steady state level of oxidative damages in the DNA of a cell. There are about 24,000 oxidative DNA adducts per cell in young rats and 66,000 adducts per cell in old rats. Likewise, any damage to cells is constantly repaired. However, under the severe levels of oxidative stress that cause necrosis, the damage causes ATP depletion, preventing controlled apoptotic death and causing the cell to simply fall apart.{{Cite journal |vauthors=Lelli JL, Becks LL, Dabrowska MI, Hinshaw DB |date=October 1998 |title=ATP converts necrosis to apoptosis in oxidant-injured endothelial cells |journal=Free Radical Biology & Medicine |volume=25 |issue=6 |pages=694–702 |doi=10.1016/S0891-5849(98)00107-5 |pmid=9801070}}{{Cite journal |vauthors=Lee YJ, Shacter E |date=July 1999 |title=Oxidative stress inhibits apoptosis in human lymphoma cells |journal=The Journal of Biological Chemistry |volume=274 |issue=28 |pages=19792–8 |doi=10.1074/jbc.274.28.19792 |pmid=10391922 |doi-access=free}}

Polyunsaturated fatty acids, particularly arachidonic acid and linoleic acid, are primary targets for free radical and singlet oxygen oxidations. For example, in tissues and cells, the free radical oxidation of linoleic acid produces racemic mixtures of 13-hydroxy-9Z,11E-octadecadienoic acid, 13-hydroxy-9E,11E-octadecadienoic acid, 9-hydroxy-10E,12-E-octadecadienoic acid (9-EE-HODE), and 11-hydroxy-9Z,12-Z-octadecadienoic acid as well as 4-Hydroxynonenal while singlet oxygen attacks linoleic acid to produce (presumed but not yet proven to be racemic mixtures of) 13-hydroxy-9Z,11E-octadecadienoic acid, 9-hydroxy-10E,12-Z-octadecadienoic acid, 10-hydroxy-8E,12Z-octadecadienoic acid, and 12-hydroxy-9Z-13-E-octadecadienoic (see 13-Hydroxyoctadecadienoic acid and 9-Hydroxyoctadecadienoic acid).{{Cite journal |vauthors=Akazawa-Ogawa Y, Shichiri M, Nishio K, Yoshida Y, Niki E, Hagihara Y |date=February 2015 |title=Singlet-oxygen-derived products from linoleate activate Nrf2 signaling in skin cells |journal=Free Radical Biology & Medicine |volume=79 |pages=164–175 |doi=10.1016/j.freeradbiomed.2014.12.004 |pmid=25499849}}{{Cite journal |vauthors=Yoshida Y, Umeno A, Akazawa Y, Shichiri M, Murotomi K, Horie M |year=2015 |title=Chemistry of lipid peroxidation products and their use as biomarkers in early detection of diseases |journal=Journal of Oleo Science |volume=64 |issue=4 |pages=347–356 |doi=10.5650/jos.ess14281 |pmid=25766928 |doi-access=free}} Similar attacks on arachidonic acid produce a far larger set of products including various isoprostanes, hydroperoxy- and hydroxy- eicosatetraenoates, and 4-hydroxyalkenals.{{Cite journal |display-authors=6 |vauthors=Vigor C, Bertrand-Michel J, Pinot E, Oger C, Vercauteren J, Le Faouder P, Galano JM, Lee JC, Durand T |date=August 2014 |title=Non-enzymatic lipid oxidation products in biological systems: assessment of the metabolites from polyunsaturated fatty acids |url=https://hal.archives-ouvertes.fr/hal-01058094/file/Vigor%20et%20al%20J%20Chromatograph%20B%202014-964-65_HAL.pdf |journal=Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences |volume=964 |pages=65–78 |doi=10.1016/j.jchromb.2014.04.042 |pmid=24856297}} While many of these products are used as markers of oxidative stress, the products derived from linoleic acid appear far more predominant than arachidonic acid products and therefore easier to identify and quantify in, for example, atheromatous plaques.{{Cite journal |vauthors=Waddington EI, Croft KD, Sienuarine K, Latham B, Puddey IB |date=March 2003 |title=Fatty acid oxidation products in human atherosclerotic plaque: an analysis of clinical and histopathological correlates |journal=Atherosclerosis |volume=167 |issue=1 |pages=111–120 |doi=10.1016/S0021-9150(02)00391-X |pmid=12618275}} Certain linoleic acid products have also been proposed to be markers for specific types of oxidative stress. For example, the presence of racemic 9-HODE and 9-EE-HODE mixtures reflects free radical oxidation of linoleic acid whereas the presence of racemic 10-hydroxy-8E,12Z-octadecadienoic acid and 12-hydroxy-9Z-13-E-octadecadienoic acid reflects singlet oxygen attack on linoleic acid. In addition to serving as markers, the linoleic and arachidonic acid products can contribute to tissue and/or DNA damage but also act as signals to stimulate pathways which function to combat oxidative stress.{{Cite journal |vauthors=Riahi Y, Cohen G, Shamni O, Sasson S |date=December 2010 |title=Signaling and cytotoxic functions of 4-hydroxyalkenals |journal=American Journal of Physiology. Endocrinology and Metabolism |volume=299 |issue=6 |pages=E879–E886 |doi=10.1152/ajpendo.00508.2010 |pmid=20858748 |s2cid=6062445}}{{Cite journal |vauthors=Cho KJ, Seo JM, Kim JH |date=July 2011 |title=Bioactive lipoxygenase metabolites stimulation of NADPH oxidases and reactive oxygen species |journal=Molecules and Cells |volume=32 |issue=1 |pages=1–5 |doi=10.1007/s10059-011-1021-7 |pmc=3887656 |pmid=21424583}}{{Cite journal |display-authors=6 |vauthors=Galano JM, Mas E, Barden A, Mori TA, Signorini C, De Felice C, Barrett A, Opere C, Pinot E, Schwedhelm E, Benndorf R, Roy J, Le Guennec JY, Oger C, Durand T |date=December 2013 |title=Isoprostanes and neuroprostanes: total synthesis, biological activity and biomarkers of oxidative stress in humans |url=https://hal.archives-ouvertes.fr/hal-00913158/file/Galano-POLM-2013-95_HAL.pdf |journal=Prostaglandins & Other Lipid Mediators |volume=107 |pages=95–102 |doi=10.1016/j.prostaglandins.2013.04.003 |pmid=23644158 |s2cid=33638363}}{{Cite journal |display-authors=6 |vauthors=Cohen G, Riahi Y, Sunda V, Deplano S, Chatgilialoglu C, Ferreri C, Kaiser N, Sasson S |date=December 2013 |title=Signaling properties of 4-hydroxyalkenals formed by lipid peroxidation in diabetes |journal=Free Radical Biology & Medicine |volume=65 |pages=978–987 |doi=10.1016/j.freeradbiomed.2013.08.163 |pmid=23973638}}{{Cite journal |vauthors=Speed N, Blair IA |date=December 2011 |title=Cyclooxygenase- and lipoxygenase-mediated DNA damage |journal=Cancer and Metastasis Reviews |volume=30 |issue=3–4 |pages=437–447 |doi=10.1007/s10555-011-9298-8 |pmc=3237763 |pmid=22009064}}

Table adapted from.{{Cite book |last=Sies |first=H. |title=Oxidative Stress |date=2020 |publisher=Academic Press |isbn=978-0-12-818606-0 |editor-last=Sies |editor-first=H. |pages=3–12 |chapter=1. Oxidative eustress and oxidative distress: Introductory remarks |doi=10.1016/B978-0-12-818606-0.00001-8 |oclc=1127856933 |chapter-url=https://www.sciencedirect.com/science/article/abs/pii/B9780128186060000018}}{{Cite book |last=Docampo |first=R. |title=Biochemistry and Molecular Biology of Parasites |date=1995 |publisher=Academic Press |isbn=978-012473345-9 |editor-last=Marr |editor-first=J. |pages=147–160 |chapter=Antioxidant mechanisms |doi=10.1016/B978-012473345-9/50010-6 |editor-last2=Müller |editor-first2=M. |chapter-url=https://www.sciencedirect.com/science/article/abs/pii/B9780124733459500106}}{{Cite journal |vauthors=Rice-Evans CA, Gopinathan V |year=1995 |title=Oxygen toxicity, free radicals and antioxidants in human disease: biochemical implications in atherosclerosis and the problems of premature neonates |journal=Essays in Biochemistry |volume=29 |pages=39–63 |pmid=9189713}}

One source of reactive oxygen under normal conditions in humans is the leakage of activated oxygen from mitochondria during oxidative phosphorylation. E. coli mutants that lack an active electron transport chain produce as much hydrogen peroxide as wild-type cells, indicating that other enzymes contribute the bulk of oxidants in these organisms.{{Cite journal |vauthors=Seaver LC, Imlay JA |date=November 2004 |title=Are respiratory enzymes the primary sources of intracellular hydrogen peroxide? |journal=The Journal of Biological Chemistry |volume=279 |issue=47 |pages=48742–50 |doi=10.1074/jbc.M408754200 |pmid=15361522 |doi-access=free}} One possibility is that multiple redox-active flavoproteins all contribute a small portion to the overall production of oxidants under normal conditions.{{Cite journal |vauthors=Messner KR, Imlay JA |date=November 2002 |title=Mechanism of superoxide and hydrogen peroxide formation by fumarate reductase, succinate dehydrogenase, and aspartate oxidase |journal=The Journal of Biological Chemistry |volume=277 |issue=45 |pages=42563–71 |doi=10.1074/jbc.M204958200 |pmid=12200425 |doi-access=free}}{{Cite journal |vauthors=Imlay JA |year=2003 |title=Pathways of oxidative damage |journal=Annual Review of Microbiology |volume=57 |issue=1 |pages=395–418 |doi=10.1146/annurev.micro.57.030502.090938 |pmid=14527285}}

Other enzymes capable of producing superoxide are xanthine oxidase, NADPH oxidases and cytochromes P450. Hydrogen peroxide is produced by a wide variety of enzymes including several oxidases. Reactive oxygen species play important roles in cell signalling, a process termed redox signaling. Thus, to maintain proper cellular homeostasis, a balance must be struck between reactive oxygen production and consumption.{{cn|date=June 2024}}

The best studied cellular antioxidants are the enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase. Less well studied (but probably just as important) enzymatic antioxidants are the peroxiredoxins and the recently discovered sulfiredoxin. Other enzymes that have antioxidant properties (though this is not their primary role) include paraoxonase, glutathione-S transferases, and aldehyde dehydrogenases.{{cn|date=June 2024}}

The amino acid methionine is prone to oxidation, but oxidized methionine can be reversible. Oxidation of methionine is shown to inhibit the phosphorylation of adjacent Ser/Thr/Tyr sites in proteins.{{Cite journal |vauthors=Hardin SC, Larue CT, Oh MH, Jain V, Huber SC |date=August 2009 |title=Coupling oxidative signals to protein phosphorylation via methionine oxidation in Arabidopsis |journal=The Biochemical Journal |volume=422 |issue=2 |pages=305–312 |doi=10.1042/BJ20090764 |pmc=2782308 |pmid=19527223}} This gives a plausible mechanism for cells to couple oxidative stress signals with cellular mainstream signaling such as phosphorylation.

Oxidative stress is suspected to be important in neurodegenerative diseases including Lou Gehrig's disease (aka MND or ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, depression, multiple sclerosis and multiple system atrophy.{{Cite journal |display-authors=6 |vauthors=Haider L, Fischer MT, Frischer JM, Bauer J, Höftberger R, Botond G, Esterbauer H, Binder CJ, Witztum JL, Lassmann H |date=July 2011 |title=Oxidative damage in multiple sclerosis lesions |journal=Brain |volume=134 |issue=Pt 7 |pages=1914–24 |doi=10.1093/brain/awr128 |pmc=3122372 |pmid=21653539}}{{Cite journal |vauthors=Patel VP, Chu CT |date=March 2011 |title=Nuclear transport, oxidative stress, and neurodegeneration |journal=International Journal of Clinical and Experimental Pathology |volume=4 |issue=3 |pages=215–229 |pmc=3071655 |pmid=21487518}} It is also indicated in Neurodevelopmental conditions such as Autism Spectrum Disorder.{{Cite journal |vauthors=Hollis F, Kanellopoulos AK, Bagni C |date=August 2017 |title=Mitochondrial dysfunction in Autism Spectrum Disorder: clinical features and perspectives |journal=Current Opinion in Neurobiology |volume=45 |pages=178–187 |doi=10.1016/j.conb.2017.05.018 |pmid=28628841 |s2cid=3617876}} Indirect evidence via monitoring biomarkers such as reactive oxygen species, and reactive nitrogen species production indicates oxidative damage may be involved in the pathogenesis of these diseases,{{Cite journal |vauthors=Nunomura A, Castellani RJ, Zhu X, Moreira PI, Perry G, Smith MA |date=July 2006 |title=Involvement of oxidative stress in Alzheimer disease |journal=Journal of Neuropathology and Experimental Neurology |volume=65 |issue=7 |pages=631–641 |doi=10.1097/01.jnen.0000228136.58062.bf |pmid=16825950 |doi-access=free}}{{Cite journal |vauthors=Bošković M, Vovk T, Kores Plesničar B, Grabnar I |date=June 2011 |title=Oxidative stress in schizophrenia |journal=Current Neuropharmacology |volume=9 |issue=2 |pages=301–312 |doi=10.2174/157015911795596595 |pmc=3131721 |pmid=22131939}} while cumulative oxidative stress with disrupted mitochondrial respiration and mitochondrial damage are related to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases.{{Cite journal |vauthors=Ramalingam M, Kim SJ |date=August 2012 |title=Reactive oxygen/nitrogen species and their functional correlations in neurodegenerative diseases |journal=Journal of Neural Transmission |volume=119 |issue=8 |pages=891–910 |doi=10.1007/s00702-011-0758-7 |pmid=22212484 |s2cid=2615132}}

Oxidative stress is thought to be linked to certain cardiovascular disease, since oxidation of LDL in the vascular endothelium is a precursor to plaque formation. Oxidative stress also plays a role in the ischemic cascade due to oxygen reperfusion injury following hypoxia. This cascade includes both strokes and heart attacks. Oxidative stress has also been implicated in chronic fatigue syndrome (ME/CFS).{{Cite journal |vauthors=Nijs J, Meeus M, De Meirleir K |date=August 2006 |title=Chronic musculoskeletal pain in chronic fatigue syndrome: recent developments and therapeutic implications |journal=Manual Therapy |volume=11 |issue=3 |pages=187–191 |doi=10.1016/j.math.2006.03.008 |pmid=16781183}} Oxidative stress also contributes to tissue injury following irradiation and hyperoxia, as well as in diabetes. In hematological cancers, such as leukemia, the impact of oxidative stress can be bilateral. Reactive oxygen species can disrupt the function of immune cells, promoting immune evasion of leukemic cells. On the other hand, high levels of oxidative stress can also be selectively toxic to cancer cells.{{Cite journal |vauthors=Domka K, Goral A, Firczuk M |year=2020 |title=cROSsing the Line: Between Beneficial and Harmful Effects of Reactive Oxygen Species in B-Cell Malignancies |journal=Frontiers in Immunology |volume=11 |pages=1538 |doi=10.3389/fimmu.2020.01538 |pmc=7385186 |pmid=32793211 |doi-access=free}}{{Cite journal |vauthors=Udensi UK, Tchounwou PB |date=December 2014 |title=Dual effect of oxidative stress on leukemia cancer induction and treatment |journal=Journal of Experimental & Clinical Cancer Research |volume=33 |pages=106 |doi=10.1186/s13046-014-0106-5 |pmc=4320640 |pmid=25519934 |doi-access=free}}

Oxidative stress is likely to be involved in age-related development of cancer. The reactive species produced in oxidative stress can cause direct damage to the DNA and are therefore mutagenic, and it may also suppress apoptosis and promote proliferation, invasiveness and metastasis.{{Cite journal |vauthors=Halliwell B |date=January 2007 |title=Oxidative stress and cancer: have we moved forward? |journal=The Biochemical Journal |volume=401 |issue=1 |pages=1–11 |doi=10.1042/BJ20061131 |pmid=17150040}} Infection by Helicobacter pylori which increases the production of reactive oxygen and nitrogen species in human stomach is also thought to be important in the development of gastric cancer.{{Cite journal |vauthors=Handa O, Naito Y, Yoshikawa T |year=2011 |title=Redox biology and gastric carcinogenesis: the role of Helicobacter pylori |journal=Redox Report |volume=16 |issue=1 |pages=1–7 |doi=10.1179/174329211X12968219310756 |pmc=6837368 |pmid=21605492 |doi-access=free}}

Oxidative stress can cause DNA damage in neurons. In neuronal progenitor cells, DNA damage is associated with increased secretion of amyloid beta proteins Aβ40 and Aβ42.{{Cite journal |vauthors=Welty S, Thathiah A, Levine AS |date=2022 |title=DNA Damage Increases Secreted Aβ40 and Aβ42 in Neuronal Progenitor Cells: Relevance to Alzheimer's Disease |journal=J Alzheimers Dis |volume=88 |issue=1 |pages=177–190 |doi=10.3233/JAD-220030 |pmc=9277680 |pmid=35570488}} This association supports the existence of a causal relationship between oxidative DNA damage and Aβ accumulation and suggests that oxidative DNA damage may contribute to Alzheimer's disease (AD) pathology. AD is associated with an accumulation of DNA damage (double-strand breaks) in vulnerable neuronal and glial cell populations from early stages onward,{{Cite journal |vauthors=Shanbhag NM, Evans MD, Mao W, Nana AL, Seeley WW, Adame A, Rissman RA, Masliah E, Mucke L |date=May 2019 |title=Early neuronal accumulation of DNA double strand breaks in Alzheimer's disease |journal=Acta Neuropathol Commun |volume=7 |issue=1 |pages=77 |doi=10.1186/s40478-019-0723-5 |pmc=6524256 |pmid=31101070 |doi-access=free}} and DNA double-strand breaks are increased in the hippocampus of AD brains compared to non-AD control brains.{{Cite journal |vauthors=Thadathil N, Delotterie DF, Xiao J, Hori R, McDonald MP, Khan MM |date=January 2021 |title=DNA Double-Strand Break Accumulation in Alzheimer's Disease: Evidence from Experimental Models and Postmortem Human Brains |journal=Mol Neurobiol |volume=58 |issue=1 |pages=118–131 |doi=10.1007/s12035-020-02109-8 |pmid=32895786}}

{{Further|Antioxidant}}

The use of antioxidants to prevent some diseases is controversial.{{Cite journal |vauthors=Meyers DG, Maloley PA, Weeks D |date=May 1996 |title=Safety of antioxidant vitamins |journal=Archives of Internal Medicine |volume=156 |issue=9 |pages=925–935 |doi=10.1001/archinte.156.9.925 |pmid=8624173}} In a high-risk group like smokers, high doses of beta carotene increased the rate of lung cancer since high doses of beta-carotene in conjunction of high oxygen tension due to smoking results in a pro-oxidant effect and an antioxidant effect when oxygen tension is not high.{{Cite journal |vauthors=Ruano-Ravina A, Figueiras A, Freire-Garabal M, Barros-Dios JM |date=2006 |title=Antioxidant vitamins and risk of lung cancer |journal=Current Pharmaceutical Design |volume=12 |issue=5 |pages=599–613 |doi=10.2174/138161206775474396 |pmid=16472151}}{{Cite journal |vauthors=Zhang P, Omaye ST |date=February 2001 |title=Antioxidant and prooxidant roles for beta-carotene, alpha-tocopherol and ascorbic acid in human lung cells |journal=Toxicology in Vitro |volume=15 |issue=1 |pages=13–24 |bibcode=2001ToxVi..15...13Z |doi=10.1016/S0887-2333(00)00054-0 |pmid=11259865}} In less high-risk groups, the use of vitamin E appears to reduce the risk of heart disease.{{Cite journal |vauthors=Pryor WA |date=January 2000 |title=Vitamin E and heart disease: basic science to clinical intervention trials |journal=Free Radical Biology & Medicine |volume=28 |issue=1 |pages=141–164 |doi=10.1016/S0891-5849(99)00224-5 |pmid=10656300}} However, while consumption of food rich in vitamin E may reduce the risk of coronary heart disease in middle-aged to older men and women, using vitamin E supplements also appear to result in an increase in total mortality, heart failure, and hemorrhagic stroke. The American Heart Association therefore recommends the consumption of food rich in antioxidant vitamins and other nutrients, but does not recommend the use of vitamin E supplements to prevent cardiovascular disease.{{Cite journal |vauthors=Saremi A, Arora R |date=2010 |title=Vitamin E and cardiovascular disease |journal=American Journal of Therapeutics |volume=17 |issue=3 |pages=e56–e65 |doi=10.1097/MJT.0b013e31819cdc9a |pmid=19451807 |s2cid=25631305}} In other diseases, such as Alzheimer's, the evidence on vitamin E supplementation is also mixed.{{Cite journal |vauthors=Boothby LA, Doering PL |date=December 2005 |title=Vitamin C and vitamin E for Alzheimer's disease |journal=The Annals of Pharmacotherapy |volume=39 |issue=12 |pages=2073–80 |doi=10.1345/aph.1E495 |pmid=16227450 |s2cid=46645284}}{{Cite journal |vauthors=Kontush K, Schekatolina S |date=December 2004 |title=Vitamin E in neurodegenerative disorders: Alzheimer's disease |journal=Annals of the New York Academy of Sciences |volume=1031 |issue=1 |pages=249–262 |bibcode=2004NYASA1031..249K |doi=10.1196/annals.1331.025 |pmid=15753151 |s2cid=33556198}} Since dietary sources contain a wider range of carotenoids and vitamin E tocopherols and tocotrienols from whole foods, ex post facto epidemiological studies can have differing conclusions than artificial experiments using isolated compounds. AstraZeneca's radical scavenging nitrone drug NXY-059 shows some efficacy in the treatment of stroke.{{Cite journal |vauthors=Fong JJ, Rhoney DH |date=March 2006 |title=NXY-059: review of neuroprotective potential for acute stroke |journal=The Annals of Pharmacotherapy |volume=40 |issue=3 |pages=461–471 |citeseerx=10.1.1.1001.6501 |doi=10.1345/aph.1E636 |pmid=16507608 |s2cid=38016035}}

Oxidative stress (as formulated in Denham Harman's free-radical theory of aging) is also thought to contribute to the aging process. While there is good evidence to support this idea in model organisms such as Drosophila melanogaster and Caenorhabditis elegans,{{Cite journal |vauthors=Larsen PL |date=October 1993 |title=Aging and resistance to oxidative damage in Caenorhabditis elegans |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=90 |issue=19 |pages=8905–9 |bibcode=1993PNAS...90.8905L |doi=10.1073/pnas.90.19.8905 |pmc=47469 |pmid=8415630 |doi-access=free}}{{Cite journal |vauthors=Helfand SL, Rogina B |year=2003 |title=Genetics of aging in the fruit fly, Drosophila melanogaster |journal=Annual Review of Genetics |volume=37 |issue=1 |pages=329–348 |doi=10.1146/annurev.genet.37.040103.095211 |pmid=14616064}} recent evidence from Michael Ristow's laboratory suggests that oxidative stress may also promote life expectancy of Caenorhabditis elegans by inducing a secondary response to initially increased levels of reactive oxygen species.{{Cite journal |vauthors=Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M |date=October 2007 |title=Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress |journal=Cell Metabolism |volume=6 |issue=4 |pages=280–293 |doi=10.1016/j.cmet.2007.08.011 |pmid=17908557 |doi-access=free}} The situation in mammals is even less clear.{{Cite journal |vauthors=Sohal RS, Mockett RJ, Orr WC |date=September 2002 |title=Mechanisms of aging: an appraisal of the oxidative stress hypothesis |journal=Free Radical Biology & Medicine |volume=33 |issue=5 |pages=575–586 |doi=10.1016/S0891-5849(02)00886-9 |pmid=12208343}}{{Cite journal |vauthors=Sohal RS |date=July 2002 |title=Role of oxidative stress and protein oxidation in the aging process |journal=Free Radical Biology & Medicine |volume=33 |issue=1 |pages=37–44 |doi=10.1016/S0891-5849(02)00856-0 |pmid=12086680}}{{Cite journal |vauthors=Rattan SI |date=December 2006 |title=Theories of biological aging: genes, proteins, and free radicals |journal=Free Radical Research |volume=40 |issue=12 |pages=1230–8 |citeseerx=10.1.1.476.9259 |doi=10.1080/10715760600911303 |pmid=17090411 |s2cid=11125090}} Recent epidemiological findings support the process of mitohormesis, but a 2007 meta-analysis finds that in studies with a low risk of bias (randomization, blinding, follow-up), some popular antioxidant supplements (vitamin A, beta carotene, and vitamin E) may increase mortality risk (although studies more prone to bias reported the reverse).{{Cite journal |vauthors=Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C |date=February 2007 |title=Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis |journal=JAMA |volume=297 |issue=8 |pages=842–857 |doi=10.1001/jama.297.8.842 |pmid=17327526}}. See also the [http://jama.ama-assn.org/cgi/content/extract/298/4/401-a letter] {{webarchive|url=https://web.archive.org/web/20080724000517/http://jama.ama-assn.org/cgi/content/extract/298/4/401-a|date=2008-07-24}} to JAMA by Philip Taylor and Sanford Dawsey and the [http://jama.ama-assn.org/cgi/content/extract/298/4/402 reply] {{webarchive|url=https://web.archive.org/web/20080624223353/http://jama.ama-assn.org/cgi/content/extract/298/4/402|date=2008-06-24}} by the authors of the original paper.

The USDA removed the table showing the Oxygen Radical Absorbance Capacity (ORAC) of Selected Foods Release 2 (2010) table due to the lack of evidence that the antioxidant level present in a food translated into a related antioxidant effect in the body.{{Cite web |last= |title=Oxygen Radical Absorbance Capacity (ORAC) of Selected Foods, Release 2 (2010) |url=https://www.ars.usda.gov/northeast-area/beltsville-md-bhnrc/beltsville-human-nutrition-research-center/nutrient-data-laboratory/docs/oxygen-radical-absorbance-capacity-orac-of-selected-foods-release-2-2010/ |website=USDA}}

Metals such as iron, copper, chromium, vanadium, and cobalt are capable of redox cycling in which a single electron may be accepted or donated by the metal. This action catalyzes production of reactive radicals and reactive oxygen species.{{Cite book |title=Interplay between Metal Ions and Nucleic Acids |vauthors=Pratviel G |publisher=Springer |year=2012 |isbn=978-94-007-2171-5 |veditors=Sigel A, Sigel H, Sigel RK |series=Metal Ions in Life Sciences |volume=10 |pages=201–216 |chapter=Oxidative DNA Damage Mediated by Transition Metal Ions and Their Complexes |doi=10.1007/978-94-007-2172-2_7 |pmid=22210340}} The presence of such metals in biological systems in an uncomplexed form (not in a protein or other protective metal complex) can significantly increase the level of oxidative stress. These metals are thought to induce Fenton reactions and the Haber-Weiss reaction, in which hydroxyl radical is generated from hydrogen peroxide.{{Cite book |title=Studies on Experimental Toxicology and Pharmacology |vauthors=Kodali V, Thrall BD |date=2015 |publisher=Springer |isbn=978-3-319-19096-9 |veditors=Roberts SM, Kehrer JP, Klotz LO |series=Oxidative Stress in Applied Basic Research and Clinical Practice |location=Cham |pages=347–367 |chapter=Oxidative Stress and Nanomaterial-Cellular Interactions |doi=10.1007/978-3-319-19096-9_18}} The hydroxyl radical then can modify amino acids. For example, meta-tyrosine and ortho-tyrosine form by hydroxylation of phenylalanine. Other reactions include lipid peroxidation and oxidation of nucleobases. Metal-catalyzed oxidations also lead to irreversible modification of arginine, lysine, proline, and threonine. Excessive oxidative-damage leads to protein degradation or aggregation.{{Cite journal |vauthors=Dalle-Donne I, Aldini G, Carini M, Colombo R, Rossi R, Milzani A |date=2006 |title=Protein carbonylation, cellular dysfunction, and disease progression |journal=Journal of Cellular and Molecular Medicine |volume=10 |issue=2 |pages=389–406 |doi=10.1111/j.1582-4934.2006.tb00407.x |pmc=3933129 |pmid=16796807}}{{Cite journal |vauthors=Grimsrud PA, Xie H, Griffin TJ, Bernlohr DA |date=August 2008 |title=Oxidative stress and covalent modification of protein with bioactive aldehydes |journal=The Journal of Biological Chemistry |volume=283 |issue=32 |pages=21837–41 |doi=10.1074/jbc.R700019200 |pmc=2494933 |pmid=18445586 |doi-access=free}}

The reaction of transition metals with proteins oxidated by reactive oxygen or nitrogen species can yield reactive products that accumulate and contribute to aging and disease. For example, in Alzheimer's patients, peroxidized lipids and proteins accumulate in lysosomes of the brain cells.{{Cite journal |vauthors=Devasagayam TP, Tilak JC, Boloor KK, Sane KS, Ghaskadbi SS, Lele RD |date=October 2004 |title=Free radicals and antioxidants in human health: current status and future prospects |journal=The Journal of the Association of Physicians of India |volume=52 |pages=794–804 |pmid=15909857}}

Certain organic compounds in addition to metal redox catalysts can also produce reactive oxygen species. One of the most important classes of these is the quinones. Quinones can redox cycle with their conjugate semiquinones and hydroquinones, in some cases catalyzing the production of superoxide from dioxygen or hydrogen peroxide from superoxide.{{cn|date=November 2024}}

The immune system uses the lethal effects of oxidants by making the production of oxidizing species a central part of its mechanism of killing pathogens; with activated phagocytes producing both reactive oxygen and nitrogen species. These include superoxide {{chem|(•O|2|-|)}}, nitric oxide (•NO) and their particularly reactive product, peroxynitrite (ONOO-).{{Cite journal |vauthors=Nathan C, Shiloh MU |date=August 2000 |title=Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=97 |issue=16 |pages=8841–8 |bibcode=2000PNAS...97.8841N |doi=10.1073/pnas.97.16.8841 |pmc=34021 |pmid=10922044 |doi-access=free}} Although the use of these highly reactive compounds in the cytotoxic response of phagocytes causes damage to host tissues, the non-specificity of these oxidants is an advantage since they will damage almost every part of their target cell. This prevents a pathogen from escaping this part of immune response by mutation of a single molecular target.

Sperm DNA fragmentation appears to be an important factor in the cause of male infertility, since men with high DNA fragmentation levels have significantly lower odds of conceiving.{{Cite journal |vauthors=Wright C, Milne S, Leeson H |date=June 2014 |title=Sperm DNA damage caused by oxidative stress: modifiable clinical, lifestyle and nutritional factors in male infertility |journal=Reproductive Biomedicine Online |volume=28 |issue=6 |pages=684–703 |doi=10.1016/j.rbmo.2014.02.004 |pmid=24745838 |doi-access=free}} Oxidative stress is the major cause of DNA fragmentation in spermatozoa. A high level of the oxidative DNA damage 8-oxo-2'-deoxyguanosine is associated with abnormal spermatozoa and male infertility.{{Cite journal |display-authors=6 |vauthors=Guz J, Gackowski D, Foksinski M, Rozalski R, Zarakowska E, Siomek A, Szpila A, Kotzbach M, Kotzbach R, Olinski R |date=2013 |title=Comparison of oxidative stress/DNA damage in semen and blood of fertile and infertile men |journal=PLOS ONE |volume=8 |issue=7 |pages=e68490 |bibcode=2013PLoSO...868490G |doi=10.1371/journal.pone.0068490 |pmc=3709910 |pmid=23874641 |doi-access=free}}

The great oxygenation event began with the biologically induced appearance of oxygen in the Earth's atmosphere about 2.45 billion years ago. The rise of oxygen levels due to cyanobacterial photosynthesis in ancient microenvironments was probably highly toxic to the surrounding biota. Under these conditions, the selective pressure of oxidative stress is thought to have driven the evolutionary transformation of an archaeal lineage into the first eukaryotes.{{Cite journal |vauthors=Gross J, Bhattacharya D |date=August 2010 |title=Uniting sex and eukaryote origins in an emerging oxygenic world |journal=Biology Direct |volume=5 |pages=53 |doi=10.1186/1745-6150-5-53 |pmc=2933680 |pmid=20731852 |doi-access=free}} Oxidative stress might have acted in synergy with other environmental stresses (such as ultraviolet radiation and/or desiccation) to drive this selection. Selective pressure for efficient repair of oxidative DNA damages may have promoted the evolution of eukaryotic sex involving such features as cell-cell fusions, cytoskeleton-mediated chromosome movements and emergence of the nuclear membrane. Thus, the evolution of meiotic sex and eukaryogenesis may have been inseparable processes that evolved in large part to facilitate repair of oxidative DNA damages.{{Cite book |last1=Bernstein |first1=H. |title=Biocommunication of Archaea |last2=Bernstein |first2=C. |date=2017 |publisher=Springer |isbn=978-3-319-65535-2 |editor-last=Witzany |editor-first=Guenther |pages=103–117 |chapter=Sexual communication in archaea, the precursor to meiosis |doi=10.1007/978-3-319-65536-9_7 |chapter-url=https://link.springer.com/chapter/10.1007/978-3-319-65536-9_7}}{{Cite journal |vauthors=Hörandl E, Speijer D |date=February 2018 |title=How oxygen gave rise to eukaryotic sex |journal=Proceedings. Biological Sciences |volume=285 |issue=1872 |pages=20172706 |doi=10.1098/rspb.2017.2706 |pmc=5829205 |pmid=29436502}}

It has been proposed that oxidative stress may play a major role in determining cardiac complications in COVID-19.{{Cite journal |display-authors=6 |vauthors=Majumder N, Deepak V, Hadique S, Aesoph D, Velayutham M, Ye Q, Mazumder MH, Lewis SE, Kodali V, Roohollahi A, Guo NL, Hu G, Khramtsov VV, Johnson RJ, Wen S, Kelley EE, Hussain S |date=October 2022 |title=Redox imbalance in COVID-19 pathophysiology |journal=Redox Biology |volume=56 |pages=102465 |doi=10.1016/j.redox.2022.102465 |pmc=9464257 |pmid=36116160}}{{Cite journal |vauthors=Loffredo L, Violi F |date=August 2020 |title=COVID-19 and cardiovascular injury: A role for oxidative stress and antioxidant treatment? |journal=International Journal of Cardiology |volume=312 |pages=136 |doi=10.1016/j.ijcard.2020.04.066 |pmc=7833193 |pmid=32505331 |doi-access=free}}

{{col div|colwidth=30em}}

• Antioxidative stress
• Acatalasia
• Bruce Ames
• Malondialdehyde, an oxidative stress marker
• Mitochondrial free radical theory of aging
• Mitohormesis
• Nitric oxide
• Pro-oxidant
• Reductive stress

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Category:Cell biology

Category:Chemical pathology

Category:Alzheimer's disease

Category:Senescence