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Oxidative stress reflects an imbalance between the systemic manifestation of
reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...
and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal
redox Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...
state of cells can cause toxic effects through the production of
peroxide In chemistry, peroxides are a group of compounds with the structure , where R = any element. The group in a peroxide is called the peroxide group or peroxo group. The nomenclature is somewhat variable. The most common peroxide is hydrogen p ...
s and
free radical A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing. Ageing Ailments of unknown cause Biogerontology Biological processes Causes of death Cellular processes Gerontology Life extension Metabo ...
s that damage all components of the cell, including
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s,
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
s, and DNA. Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by the reactive oxygen species generated, e.g., O2 (
superoxide In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of the ...
radical), OH (
hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
radical) and H2O2 (
hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3% ...
). Further, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruptions in normal mechanisms of
cellular signaling In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
. In humans, oxidative stress is thought to be involved in the development of
attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inap ...
,
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
,
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
,
Lafora disease Lafora disease is a rare, adult-onset and autosomal recessive genetic disorder which results in Myoclonus#Epilepsy forms, myoclonus epilepsy and usually results in death several years after the onset of symptoms. The disease is characterized by t ...
,
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
,
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
,
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
,
myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
,
fragile X syndrome Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features may ...
,
sickle-cell disease Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blo ...
,
lichen planus Lichen planus (LP) is a chronic inflammatory and immune-mediated disease that affects the skin, nails, hair, and mucous membranes. It is not an actual lichen, and is only named that because it looks like one. It is characterized by polygonal, fla ...
,
vitiligo Vitiligo is a disorder that causes the skin to lose its color. Specific causes are unknown but studies suggest a link to immune system changes. Signs and symptoms The only sign of vitiligo is the presence of pale patchy areas of depigmen ...
,
autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
,
infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...
,
chronic fatigue syndrome Chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME) or ME/CFS, is a complex, debilitating, long-term medical condition. The causes and mechanisms of the disease are not fully understood. Distinguishing core symptoms are ...
, and depression; however, reactive oxygen species can be beneficial, as they are used by the
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
as a way to attack and kill
pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
s. Short-term oxidative stress may also be important in prevention of
aging Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...
by induction of a process named
mitohormesis Hormesis is a characteristic of many biological processes, namely a biphasic or triphasic response to exposure to increasing amounts of a substance or condition. Within the hormetic zone, the biological response to low exposures to toxins and othe ...
, and is required to initiate stress response processes in plants.


Chemical and biological effects

Chemically, oxidative stress is associated with increased production of oxidizing species or a significant decrease in the effectiveness of
antioxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricant ...
defenses, such as
glutathione Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pero ...
. 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 Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, while more intense stresses may cause
necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...
. Production of reactive oxygen species is a particularly destructive aspect of oxidative stress. Such species include
free radical A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing. Ageing Ailments of unknown cause Biogerontology Biological processes Causes of death Cellular processes Gerontology Life extension Metabo ...
s and
peroxide In chemistry, peroxides are a group of compounds with the structure , where R = any element. The group in a peroxide is called the peroxide group or peroxo group. The nomenclature is somewhat variable. The most common peroxide is hydrogen p ...
s. Some of the less reactive of these species (such as
superoxide In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of the ...
) can be converted by oxidoreduction reactions with
transition metal In chemistry, a transition metal (or transition element) is a chemical element in the d-block of the periodic table (groups 3 to 12), though the elements of group 12 (and less often group 3) are sometimes excluded. They are the elements that can ...
s or other redox cycling compounds (including
quinone The quinones are a class of organic compounds that are formally "derived from aromatic compounds
uch as benzene or naphthalene Uch ( pa, ; ur, ), frequently referred to as Uch Sharīf ( pa, ; ur, ; ''"Noble Uch"''), is a historic city in the southern part of Pakistan's Punjab province. Uch may have been founded as Alexandria on the Indus, a town founded by Alexand ...
by conversion of an even number of –CH= groups into –C(=O)– groups with any necessary rearrangement of double ...
s) into more aggressive radical species that can cause extensive cellular damage. Most long-term effects are caused by damage to DNA. DNA damage induced by
ionizing radiation Ionizing radiation (or ionising radiation), including nuclear radiation, consists of subatomic particles or electromagnetic waves that have sufficient energy to ionize atoms or molecules by detaching electrons from them. Some particles can travel ...
is similar to oxidative stress, and these lesions have been implicated in
aging Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...
and cancer. Biological effects of single-base damage by radiation or oxidation, such as
8-oxoguanine 8-Oxoguanine (8-hydroxyguanine, 8-oxo-Gua, or OH8Gua) is one of the most common DNA lesions resulting from reactive oxygen species modifying guanine, and can result in a mismatched pairing with adenine resulting in G to T and C to A substitutions ...
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 Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
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 ,5- Me). Most of these
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
-derived species are produced by normal
aerobic metabolism Cellular respiration is the process by which biological fuels are oxidised in the presence of an inorganic electron acceptor such as oxygen to produce large amounts of energy, to drive the bulk production of ATP. Cellular respiration may be des ...
. 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. 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.
Polyunsaturated fatty acids Polyunsaturated fatty acids (PUFAs) are fatty acids that contain more than one double bond in their backbone. This class includes many important compounds, such as essential fatty acids and those that give drying oils their characteristic proper ...
, particularly
arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
and
linoleic acid Linoleic acid (LA) is an organic compound with the formula COOH(CH2)7CH=CHCH2CH=CH(CH2)4CH3. Both alkene groups are cis-trans isomerism, ''cis''. It is a fatty acid sometimes denoted 18:2 (n-6) or 18:2 ''cis''-9,12. A linoleate is a salt (chem ...
, 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 In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
mixtures of 13-hydroxy-9''Z'',11''E''-octadecadienoic acid, 13-hydroxy-9''E'',11''E''-octadecadienoic acid, 9-hydroxy-10''E'',12-''E''-octadecadienoic acid (9-EE-HODE), and 11-hydroxy-9''Z'',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-9''Z'',11''E''-octadecadienoic acid, 9-hydroxy-10''E'',12-''Z''-octadecadienoic acid, 10-hydroxy-8''E'',12''Z''-octadecadienoic acid, and 12-hydroxy-9''Z''-13-''E''-octadecadienoic (see 13-Hydroxyoctadecadienoic acid and
9-Hydroxyoctadecadienoic acid 9-Hydroxyoctadecadienoic acid (or 9-HODE) has been used in the literature to designate either or both of two stereoisomer metabolites of the essential fatty acid, linoleic acid: 9(''S'')-hydroxy-10(''E''),12(''Z'')-octadecadienoic acid (9(''S'')- ...
). Similar attacks on arachidonic acid produce a far larger set of products including various isoprostanes, hydroperoxy- and hydroxy- eicosatetraenoates, and 4-hydroxyalkenals. 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. 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-8''E'',12''Z''-octadecadienoic acid and 12-hydroxy-9''Z''-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. Table adapted from.


Production and consumption of oxidants

One source of reactive oxygen under normal conditions in humans is the leakage of activated oxygen from
mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
during
oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...
. ''
E. coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
'' mutants that lack an active electron transport chain produce as much
hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3% ...
as wild-type cells, indicating that other enzymes contribute the bulk of oxidants in these organisms. One possibility is that multiple redox-active
flavoprotein Flavoproteins are proteins that contain a nucleic acid derivative of riboflavin. Flavoproteins are involved in a wide array of biological processes, including removal of radicals contributing to oxidative stress, photosynthesis, and DNA repair ...
s all contribute a small portion to the overall production of oxidants under normal conditions. Other enzymes capable of producing superoxide are
xanthine oxidase Xanthine oxidase (XO, sometimes XAO) is a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species. These enzymes catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthin ...
, 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 ''Antioxidants & Redox Signaling '' is a peer-reviewed scientific journal covering reduction–oxidation (redox) signaling and antioxidant research. It covers topics such as reactive oxygen species/reactive nitrogen species (ROS/RNS) as messenge ...
. Thus, to maintain proper cellular
homeostasis In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
, a balance must be struck between reactive oxygen production and consumption. The best studied cellular antioxidants are the enzymes
superoxide dismutase Superoxide dismutase (SOD, ) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide () radical into ordinary molecular oxygen (O2) and hydrogen peroxide (). Superoxide is produced as a by-product of oxygen me ...
(SOD),
catalase Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting t ...
, and
glutathione peroxidase Glutathione peroxidase (GPx) () is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid h ...
. Less well studied (but probably just as important) enzymatic antioxidants are the peroxiredoxins and the recently discovered
sulfiredoxin In enzymology, a sulfiredoxin () is an enzyme that catalyzes the chemical reaction :peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH \rightleftharpoons peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R The 3 substrates of thi ...
. Other enzymes that have antioxidant properties (though this is not their primary role) include paraoxonase, glutathione-S transferases, and aldehyde dehydrogenases. 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. This gives a plausible mechanism for cells to couple oxidative stress signals with cellular mainstream signaling such as phosphorylation.


Diseases

Oxidative stress is suspected to be important in
neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
s including
Lou Gehrig's disease Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most com ...
(aka MND or ALS),
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
,
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
,
Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...
, depression, and
multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
. It is also indicated in Neurodevelopmental conditions such as
Autism Spectrum Disorder The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental disorder, neurodevelopmental condition (or conditions) ...
. Indirect evidence via monitoring biomarkers such as reactive oxygen species, and
reactive nitrogen species Reactive nitrogen species (RNS) are a family of antimicrobial molecules derived from nitric oxide (•NO) and superoxide (O2•−) produced via the enzymatic activity of inducible nitric oxide synthase 2 ( NOS2) and NADPH oxidase respectivel ...
production indicates oxidative damage may be involved in the pathogenesis of these diseases, while cumulative oxidative stress with disrupted mitochondrial respiration and mitochondrial damage are related to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Oxidative stress is thought to be linked to certain
cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
, since oxidation of
LDL Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...
in the vascular
endothelium The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
is a precursor to
plaque Plaque may refer to: Commemorations or awards * Commemorative plaque, a plate or tablet fixed to a wall to mark an event, person, etc. * Memorial Plaque (medallion), issued to next-of-kin of dead British military personnel after World War I * Pla ...
formation. Oxidative stress also plays a role in the
ischemic cascade The ischemic (ischaemic) cascade is a series of biochemical reactions that are initiated in the brain and other aerobic tissues after seconds to minutes of ischemia (inadequate blood supply). This is typically secondary to stroke, injury, or cardi ...
due to oxygen
reperfusion injury Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when blood supply returns to tissue ('' re-'' + '' perfusion'') after a period of ischemia or lack of oxygen (anoxia or h ...
following hypoxia. This cascade includes both
strokes A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop funct ...
and
heart attacks A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tr ...
. Oxidative stress has also been implicated in
chronic fatigue syndrome Chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME) or ME/CFS, is a complex, debilitating, long-term medical condition. The causes and mechanisms of the disease are not fully understood. Distinguishing core symptoms are ...
(ME/CFS). Oxidative stress also contributes to tissue injury following irradiation and
hyperoxia Hyperoxia occurs when cells, tissues and organs are exposed to an excess supply of oxygen (O2) or higher than normal partial pressure of oxygen. In medicine, it refers to excessive oxygen in the lungs or other body tissues, which can be caused ...
, 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. 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 In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer in ...
, and it may also suppress
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
and promote proliferation, invasiveness and
metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
. Infection by ''
Helicobacter pylori ''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, microaerophilic, spiral (helical) bacterium usually found in the stomach. Its helical shape (from which the genus name, helicobacter, derives) is though ...
'' 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 Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lymph ...
.


Antioxidants as supplements

The use of antioxidants to prevent some diseases is controversial. In a high-risk group like smokers, high doses of
beta carotene Beta (, ; uppercase , lowercase , or cursive ; grc, βῆτα, bē̂ta or ell, βήτα, víta) is the second letter of the Greek alphabet. In the system of Greek numerals, it has a value of 2. In Modern Greek, it represents the voiced labio ...
increased the rate of lung cancer since high doses of beta-carotene in conjunction of high
oxygen tension Blood gas tension refers to the partial pressure of gases in blood. There are several significant purposes for measuring gas tension. The most common gas tensions measured are oxygen tension (PxO2), carbon dioxide tension (PxCO2) and carbon monox ...
due to smoking results in a
pro-oxidant Pro-oxidants are chemicals that induce oxidative stress, either by generating reactive oxygen species or by inhibiting antioxidant systems. The oxidative stress produced by these chemicals can damage cells and tissues, for example an overdose of th ...
effect and an antioxidant effect when oxygen tension is not high. In less high-risk groups, the use of
vitamin E Vitamin E is a group of eight fat soluble compounds that include four tocopherols and four tocotrienols. Vitamin E deficiency, which is rare and usually due to an underlying problem with digesting dietary fat rather than from a diet low in vitami ...
appears to reduce the risk of
heart disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, hea ...
. 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 A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...
. 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. In other diseases, such as
Alzheimer's Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...
, the evidence on vitamin E supplementation is also mixed. 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 AstraZeneca plc () is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, England. It has a portfolio of products for major diseases in areas includin ...
's radical scavenging nitrone drug
NXY-059 Disufenton sodium (Cerovive, OKN-007, NXY-059, HPN-07) is a free radical trapping nitrone-based antioxidant compound that has been under development for several medical conditions. Chemistry Disufenton sodium is the disulfonyl derivative of th ...
shows some efficacy in the treatment of stroke. Oxidative stress (as formulated in
Denham Harman Denham Harman (February 14, 1916 – November 25, 2014) was an American medical academic who latterly served as professor emeritus at the University of Nebraska Medical Center. Harman is known as the "father of the free radical theory of aging". ...
's
free-radical theory of aging The free radical theory of aging (FRTA) states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell.Erbas M, Sekerci H. "Importance ...
) 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 ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly" or "pomace fly". Starting with Ch ...
'' and ''
Caenorhabditis elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (ro ...
'', 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. The situation in mammals is even less clear. Recent
epidemiological Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and determinants of health and disease conditions in a defined population. It is a cornerstone of public health, and shapes policy decisions and evidenc ...
findings support the process of
mitohormesis Hormesis is a characteristic of many biological processes, namely a biphasic or triphasic response to exposure to increasing amounts of a substance or condition. Within the hormetic zone, the biological response to low exposures to toxins and othe ...
, however a 2007 meta-analysis indicating studies with a low risk of bias (randomization, blinding, follow-up) find that some popular antioxidant supplements (Vitamin A, Beta Carotene, and Vitamin E) may increase mortality risk (although studies more prone to bias reported the reverse).. See also th
letter
to
JAMA ''The Journal of the American Medical Association'' (''JAMA'') is a peer-reviewed medical journal published 48 times a year by the American Medical Association. It publishes original research, reviews, and editorials covering all aspects of biom ...
by Philip Taylor and Sanford Dawsey and th
reply
by the authors of the original paper.
The USDA removed the table showing the
Oxygen Radical Absorbance Capacity Oxygen radical absorbance capacity (ORAC) was a method of measuring antioxidant capacities in biological samples ''in vitro''. Because no physiological proof ''in vivo'' existed in support of the free-radical theory or that ORAC provided informat ...
(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.


Metal catalysts

Metals such as
iron Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in f ...
,
copper Copper is a chemical element with the symbol Cu (from la, cuprum) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkis ...
,
chromium Chromium is a chemical element with the symbol Cr and atomic number 24. It is the first element in group 6. It is a steely-grey, lustrous, hard, and brittle transition metal. Chromium metal is valued for its high corrosion resistance and hardne ...
,
vanadium Vanadium is a chemical element with the symbol V and atomic number 23. It is a hard, silvery-grey, malleable transition metal. The elemental metal is rarely found in nature, but once isolated artificially, the formation of an oxide layer ( pas ...
, and
cobalt Cobalt is a chemical element with the symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. The free element, pr ...
are capable of redox cycling in which a single
electron The electron ( or ) is a subatomic particle with a negative one elementary electric charge. Electrons belong to the first generation of the lepton particle family, and are generally thought to be elementary particles because they have no kn ...
may be accepted or donated by the metal. This action catalyzes production of reactive
radical Radical may refer to: Politics and ideology Politics *Radical politics, the political intent of fundamental societal change *Radicalism (historical), the Radical Movement that began in late 18th century Britain and spread to continental Europe and ...
s and reactive oxygen species. 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 The hydroxyl radical is the diatomic molecule . The hydroxyl radical is very stable as a dilute gas, but it decays very rapidly in the condensed phase. It is pervasive in some situations. Most notably the hydroxyl radicals are produced from the ...
is generated from hydrogen peroxide. The hydroxyl radical then can modify amino acids. For example, meta-
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
and ortho-
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
form by hydroxylation of
phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...
. 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. 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 Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...
patients, peroxidized lipids and proteins accumulate in lysosomes of the brain cells.


Non-metal redox catalysts

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
quinone The quinones are a class of organic compounds that are formally "derived from aromatic compounds
uch as benzene or naphthalene Uch ( pa, ; ur, ), frequently referred to as Uch Sharīf ( pa, ; ur, ; ''"Noble Uch"''), is a historic city in the southern part of Pakistan's Punjab province. Uch may have been founded as Alexandria on the Indus, a town founded by Alexand ...
by conversion of an even number of –CH= groups into –C(=O)– groups with any necessary rearrangement of double ...
s. Quinones can redox cycle with their conjugate
semiquinone Semiquinone (or ubisemiquinone) is a free radical resulting from the removal of one hydrogen atom with its electron during the process of dehydrogenation of a hydroquinone, such as hydroquinone itself or catechol, to a quinone or alternatively the ...
s and
hydroquinone Hydroquinone, also known as benzene-1,4-diol or quinol, is an aromatic organic compound that is a type of phenol, a derivative of benzene, having the chemical formula C6H4(OH)2. It has two hydroxyl groups bonded to a benzene ring in a ''para'' ...
s, in some cases catalyzing the production of superoxide from dioxygen or hydrogen peroxide from superoxide.


Immune defense

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
phagocyte Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek ', "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek ...
s producing both reactive oxygen and nitrogen species. These include superoxide , nitric oxide (•NO) and their particularly reactive product, peroxynitrite (ONOO-). 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.


Male infertility

Sperm Sperm is the male reproductive cell, or gamete, in anisogamous forms of sexual reproduction (forms in which there is a larger, female reproductive cell and a smaller, male one). Animals produce motile sperm with a tail known as a flagellum, whi ...
DNA fragmentation DNA fragmentation is the separation or breaking of DNA strands into pieces. It can be done intentionally by laboratory personnel or by cells, or can occur spontaneously. Spontaneous or accidental DNA fragmentation is fragmentation that gradually a ...
appears to be an important factor in the
aetiology Etiology (pronounced ; alternatively: aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek (''aitiología'') "giving a reason for" (, ''aitía'', "cause"); and ('' -logía''). More completely, e ...
of
male infertility Male infertility refers to a sexually mature male's inability to impregnate a fertile female. In humans it accounts for 40–50% of infertility. It affects approximately 7% of all men. Male infertility is commonly due to deficiencies in the semen, ...
, since men with high DNA fragmentation levels have significantly lower odds of conceiving. Oxidative stress is the major cause of DNA fragmentation in
spermatozoa A spermatozoon (; also spelled spermatozoön; ; ) is a motile sperm cell, or moving form of the haploid cell that is the male gamete. A spermatozoon joins an ovum to form a zygote. (A zygote is a single cell, with a complete set of chromosomes, ...
. A high level of the oxidative DNA damage
8-oxo-2'-deoxyguanosine 8-Oxo-2'-deoxyguanosine (8-oxo-dG) is an oxidized derivative of deoxyguanosine. 8-Oxo-dG is one of the major products of DNA oxidation. Concentrations of 8-oxo-dG within a cell are a measurement of oxidative stress. In DNA Steady-state leve ...
is associated with abnormal spermatozoa and male infertility.


Aging

In a rat model of premature aging, oxidative stress induced
DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
in the
neocortex The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sensory perception, cognition, generation of motor commands, sp ...
and
hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...
was substantially higher than in normally aging control rats. Numerous studies have shown that the level of 8-oxo-2'-deoxyguanosine, a product of oxidative stress, increases with age in the brain and muscle DNA of the
mouse A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...
, rat,
gerbil The Mongolian gerbil or Mongolian jird (''Meriones unguiculatus'') is a small rodent belonging to the subfamily Gerbillinae. Their body size is typically , with a tail, and body weight , with adult males larger than females. The animal is use ...
and
human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
. Further information on the association of oxidative DNA damage with aging is presented in the article
DNA damage theory of aging The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear ...
. However, it was recently shown that the fluoroquinolone antibiotic
Enoxacin EnoxacinEnoxacin is sold under the following trade names: Almitil, Bactidan, Bactidron, Comprecin, Enoksetin, Enoxen, Enroxil, Enoxin, Enoxor, Flumark, Penetrex, Gyramid, Vinone. is an oral broad-spectrum fluoroquinolone antibacterial agent used in ...
can diminish aging signals and promote lifespan extension in nematodes ''C. elegans ''by inducing oxidative stress.


Origin of eukaryotes

The
great oxygenation event The Great Oxidation Event (GOE), also called the Great Oxygenation Event, the Oxygen Catastrophe, the Oxygen Revolution, the Oxygen Crisis, or the Oxygen Holocaust, was a time interval during the Paleoproterozoic era when the Earth's atmosphere ...
began with the biologically induced appearance of oxygen in the
Earth's atmosphere The atmosphere of Earth is the layer of gases, known collectively as air, retained by Earth's gravity that surrounds the planet and forms its planetary atmosphere. The atmosphere of Earth protects life on Earth by creating pressure allowing for ...
about 2.45 billion years ago. The rise of oxygen levels due to
cyanobacteria Cyanobacteria (), also known as Cyanophyta, are a phylum of gram-negative bacteria that obtain energy via photosynthesis. The name ''cyanobacteria'' refers to their color (), which similarly forms the basis of cyanobacteria's common name, blu ...
l
photosynthesis Photosynthesis is a process used by plants and other organisms to convert light energy into chemical energy that, through cellular respiration, can later be released to fuel the organism's activities. Some of this chemical energy is stored i ...
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
archaea Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebac ...
l lineage into the first
eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s. Oxidative stress might have acted in synergy with other environmental stresses (such as
ultraviolet Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nanometer, nm (with a corresponding frequency around 30 Hertz, PHz) to 400 nm (750 Hertz, THz), shorter than that of visible light, but longer than ...
radiation and/or
desiccation Desiccation () is the state of extreme dryness, or the process of extreme drying. A desiccant is a hygroscopic (attracts and holds water) substance that induces or sustains such a state in its local vicinity in a moderately sealed container. ...
) 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 fusion Cell fusion is an important cellular process in which several uninucleate cells (cells with a single nucleus) combine to form a multinucleate cell, known as a syncytium. Cell fusion occurs during differentiation of myoblasts, osteoclasts and tropho ...
s,
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
-mediated
chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
movements and emergence of the
nuclear membrane The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer membranes that in eukaryotic cells surround the nucleus, which encloses the genetic material. The nuclear envelope consists of two lipid bilayer membrane ...
. Thus, the evolution of
meiotic Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately res ...
sex and eukaryogenesis may have been inseparable processes that evolved in large part to facilitate repair of oxidative DNA damages.


COVID-19 and cardiovascular injury

It has been proposed that oxidative stress may play a major role to determine cardiac complications in COVID-19.


See also

* Antioxidative stress * Acatalasia *
Bruce Ames Bruce Nathan Ames (born December 16, 1928) is an American biochemist. He is a professor of Biochemistry and Molecular Biology Emeritus at the University of California, Berkeley, and was a senior scientist at Children's Hospital Oakland Research ...
*
Malondialdehyde Malondialdehyde (MDA) is the organic compound with the nominal formula CH2(CHO)2. A colorless liquid, malondialdehyde is a highly reactive compound that occurs as the enol. It occurs naturally and is a marker for oxidative stress. Structure and ...
, an oxidative stress marker * Mitochondrial free radical theory of aging *
Mitohormesis Hormesis is a characteristic of many biological processes, namely a biphasic or triphasic response to exposure to increasing amounts of a substance or condition. Within the hormetic zone, the biological response to low exposures to toxins and othe ...
*
Nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
*
Pro-oxidant Pro-oxidants are chemicals that induce oxidative stress, either by generating reactive oxygen species or by inhibiting antioxidant systems. The oxidative stress produced by these chemicals can damage cells and tissues, for example an overdose of th ...
* Reductive stress


References

{{Authority control Cell biology Chemical pathology Alzheimer's disease Senescence