
Oxidative stress reflects an imbalance between the systemic manifestation of
reactive oxygen species
In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
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 or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is t ...
state of cells can cause toxic effects through the production of
peroxide
In chemistry, peroxides are a group of Chemical compound, compounds with the structure , where the R's represent a radical (a portion of a complete molecule; not necessarily a free radical) and O's are single oxygen atoms. Oxygen atoms are joined ...
s and
free radical
A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing.
Ageing
Biogerontology
Biological processes
Causes of death
Cellular processes
Gerontology
Life extension
Metabolic disorders
Metabolism
...
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 residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s,
lipid
Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...
s, and
DNA
Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
. 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., (
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 t ...
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 (
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 viscosity, viscous than Properties of water, water. It is used as an oxidizer, bleaching agent, and antiseptic, usua ...
). 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 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 symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...
,
cancer
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
,
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
,
Lafora disease
Lafora disease is a rare, autosomal recessive genetic disorder which results in myoclonus epilepsy and usually results in death several years after the onset of symptoms. The disease is characterized by the accumulation of inclusion bodies, kno ...
,
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
,
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
,
heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood.
Although symptoms vary based on which side of the heart is affected, HF ...
,
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
,
fragile X syndrome
Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder. The average IQ in males with FXS is under 55, while affected females tend to be in the borderline to normal range, typically around 70–85. Physical features may include a lo ...
,
sickle-cell disease
Sickle cell disease (SCD), also simply called sickle cell, is a group of inherited haemoglobin-related blood disorders. The most common type is known as sickle cell anemia. Sickle cell anemia results in an abnormality in the oxygen-carrying ...
,
lichen planus
Lichen planus (LP) is a chronic inflammatory and autoimmune disease that affects the skin, nails, hair, and mucous membranes. It is not an actual lichen, but is named for its appearance. It is characterized by polygonal, flat-topped, violaceous p ...
,
vitiligo
Vitiligo (, ) is a chronic autoimmune disorder that causes patches of skin to lose pigment or color. The cause of vitiligo is unknown, but it may be related to immune system changes, genetic factors, stress, or sun exposure, and susceptibili ...
,
autism
Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing d ...
,
infection
An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...
,
chronic fatigue syndrome
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling Chronic condition, chronic illness. People with ME/CFS experience profound fatigue that does not go away with rest, as well as sleep issues and problems with memory ...
,
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 systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...
as a way to attack and kill
pathogen
In biology, a pathogen (, "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 theory of d ...
s.
Oxidative stress due to noise was estimated at cell level using model of growing lymphocytes. Exposure of sound with frequency 1 KHz and intensity 110 dBA for 4 hours and eight hours per day may induce oxidative stress in growing lymphocytes causing the difference in viable cell count. However the catalase activity depends on duration of exposure. In case of noise exposure of 8 hours per day, it declines significantly as compared to noise exposure of 4 hours per day.
Short-term oxidative stress may also be important in prevention of
aging
Ageing (or aging in American English) is the process of becoming Old age, older until death. The term refers mainly to humans, many other animals, and fungi; whereas for example, bacteria, perennial plants and some simple animals are potentiall ...
by induction of a process named
mitohormesis,
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 Chemical compound, compounds that inhibit Redox, oxidation, a chemical reaction that can produce Radical (chemistry), free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants ...
defenses, such as
glutathione
Glutathione (GSH, ) is an organic compound with the chemical formula . It 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 ...
.
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 ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
, 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. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow, who i ...
.
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
Biogerontology
Biological processes
Causes of death
Cellular processes
Gerontology
Life extension
Metabolic disorders
Metabolism
...
s and
peroxide
In chemistry, peroxides are a group of Chemical compound, compounds with the structure , where the R's represent a radical (a portion of a complete molecule; not necessarily a free radical) and O's are single oxygen atoms. Oxygen atoms are joined ...
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 t ...
) 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. The lanthanide and actinid ...
s or other redox cycling compounds (including
quinone
The quinones are a class of organic compounds that are formally "derived from aromatic compounds benzene.html" ;"title="uch as benzene">uch as benzene or naphthalene] by conversion of an even number of –CH= groups into –C(=O)– groups with ...
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 (ionising) radiation, including Radioactive decay, nuclear radiation, consists of subatomic particles or electromagnetic waves that have enough energy per individual photon or particle to ionization, ionize atoms or molecules by detaching ...
is similar to oxidative stress, and these lesions have been implicated in
aging
Ageing (or aging in American English) is the process of becoming Old age, older until death. The term refers mainly to humans, many other animals, and fungi; whereas for example, bacteria, perennial plants and some simple animals are potentiall ...
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 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 a chemical element; it has chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen group (periodic table), group in the periodic table, a highly reactivity (chemistry), reactive nonmetal (chemistry), non ...
-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.
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
In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid (abbreviated PUFA), which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds.
Some polyunsa ...
, 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 a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes.
Together with omega−3 fatty acids an ...
and
linoleic acid
Linoleic acid (LA) is an organic compound with the formula . Both alkene groups () are ''cis''. It is a fatty acid sometimes denoted 18:2 (n−6) or 18:2 ''cis''-9,12. A linoleate is a salt or ester of this acid.
Linoleic acid is a polyunsat ...
, 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 a mixture that has equal amounts (50:50) 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 r ...
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
13-Hydroxyoctadecadienoic acid (13-HODE) is the commonly used term for 13(''S'')-hydroxy-9''Z'',11''E''-octadecadienoic acid (13(''S'')-HODE). The production of 13(''S'')-HODE is often accompanied by the production of its stereoisomer, 13(''R'') ...
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 cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
during
oxidative phosphorylation
Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...
. ''
E. coli'' 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 viscosity, viscous than Properties of water, water. It is used as an oxidizer, bleaching agent, and antiseptic, usua ...
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. These proteins 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 or 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 xanthine to ...
, 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 messenger ...
. Thus, to maintain proper cellular
homeostasis
In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
, 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 () anion radical into normal molecular oxygen (O2) and hydrogen peroxide (). Superoxide is produced as a by-product of oxy ...
(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 ...
, 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 ...
. 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.
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 neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...
s including
Lou Gehrig's disease
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or—in the United States—Lou Gehrig's disease (LGD), is a rare, terminal neurodegenerative disorder that results in the progressive loss of both upper and lo ...
(aka MND or ALS),
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
,
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
,
Huntington's disease
Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...
,
depression,
multiple sclerosis
Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
and
multiple system atrophy
Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by tremors, slow movement, muscle rigidity, postural instability (collectively known as parkinsonism), autonomic dysfunction and ataxia. This is caused by progr ...
.
It is also indicated in Neurodevelopmental conditions such as
Autism Spectrum Disorder
Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing di ...
.
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 (Nitric oxide synthase 2A, NOS2) and NADPH ...
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 any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...
, since oxidation of
LDL in the vascular
endothelium
The endothelium (: endothelia) 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 r ...
is a precursor to
plaque formation. Oxidative stress also plays a role in the
ischemic cascade 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 hy ...
following
hypoxia. This cascade includes both
strokes and
heart attacks
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom is retr ...
. Oxidative stress has also been implicated in
chronic fatigue syndrome
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling Chronic condition, chronic illness. People with ME/CFS experience profound fatigue that does not go away with rest, as well as sleep issues and problems with memory ...
(ME/CFS). Oxidative stress also contributes to tissue injury following irradiation and
hyperoxia
Hyperoxia is the state of being exposed to high levels of oxygen; it may refer to organisms, cells and tissues that are experiencing excessive oxygenation, or to an abnormally high oxygen concentration in an environment (e.g. a body of water).
...
, 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 ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
and promote proliferation, invasiveness and
metastasis
Metastasis is a pathogenic agent's spreading 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, ...
.
Infection by ''
Helicobacter pylori
''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, Flagellum#bacterial, flagellated, Bacterial cellular morphologies#Helical, helical bacterium. Mutants can have a rod or curved rod shape that exhibits l ...
'' 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 malignant tumor of the stomach. It is a cancer that develops in the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes ...
.
Oxidative stress can cause DNA damage in neurons.
[ In neuronal ]progenitor cell
A progenitor cell is a biological cell that can differentiate into a specific cell type. Stem cells and progenitor cells have this ability in common. However, stem cells are less specified than progenitor cells. Progenitor cells can only diffe ...
s, 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. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is constantly modified ...
is associated with increased secretion of amyloid beta proteins Aβ40 and Aβ42. 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
Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
(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, and DNA double-strand breaks are increased in the ]hippocampus
The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
of AD brains compared to non-AD control brains.
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 ; or ) is the second letter of the Greek alphabet. In the system of Greek numerals, it has a value of 2. In Ancient Greek, beta represented the voiced bilabial plosive . In Modern Greek, it represe ...
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. In less high-risk groups, the use of vitamin E
Vitamin E is a group of eight compounds related in molecular structure that includes four tocopherols and four tocotrienols. The tocopherols function as fat-soluble antioxidants which may help protect cell membranes from reactive oxygen speci ...
appears to reduce the risk of heart disease
Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina pectoris, angina, myocardial infarction, heart attack), heart failure, ...
. 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
Stroke is a medical condition in which poor blood flow to a part of 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 ...
. 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 and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
, the evidence on vitamin E supplementation is also mixed. Since dietary sources contain a wider range of carotenoids and vitamin E tocopherol
Tocopherols (; TCP) are a class of organic compounds comprising various methylated phenols, many of which have vitamin E activity. Because the vitamin activity was first identified in 1936 from a dietary fertility factor in rats, it was named ''t ...
s and tocotrienols from whole foods, ''ex post facto'' epidemiological studies can have differing conclusions than artificial experiments using isolated compounds. AstraZeneca
AstraZeneca plc () (AZ) is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, UK. It has a portfolio of products for major diseases in areas includi ...
'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's free-radical theory of aging
The free radical theory of aging 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 of Free ...
) 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 (an insect of the Order (biology), 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", "pomace fly" ...
'' 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 Hybrid word, blend of the Greek ''caeno-'' (recent), ''r ...
'', 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 Risk factor (epidemiology), determinants of health and disease conditions in a defined population, and application of this knowledge to prevent dise ...
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).[. See also th]
letter
to JAMA
''JAMA'' (''The Journal of the American Medical Association'') 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 b ...
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 (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; it has symbol Fe () 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, forming much of Earth's o ...
, copper
Copper is a chemical element; it has symbol Cu (from Latin ) 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 pinkish-orang ...
, chromium
Chromium is a chemical element; it has Symbol (chemistry), symbol Cr and atomic number 24. It is the first element in Group 6 element, group 6. It is a steely-grey, Luster (mineralogy), lustrous, hard, and brittle transition metal.
Chromium ...
, vanadium
Vanadium is a chemical element; it has Symbol (chemistry), 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 ...
, and cobalt
Cobalt is a chemical element; it has Symbol (chemistry), 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. ...
are capable of redox cycling in which a single electron
The electron (, or in nuclear reactions) is a subatomic particle with a negative one elementary charge, elementary electric charge. It is a fundamental particle that comprises the ordinary matter that makes up the universe, along with up qua ...
may be accepted or donated by the metal. This action catalyzes production of reactive radicals 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, •HO, is the neutral form of the hydroxide ion (HO–). Hydroxyl radicals are highly reactive and consequently short-lived; however, they form an important part of radical chemistry. Most notably hydroxyl radicals are pr ...
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 conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
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 conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
form by hydroxylation of phenylalanine
Phenylalanine (symbol Phe or F) is an essential α-amino acid with the chemical formula, formula . It can be viewed as a benzyl group substituent, substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of ...
. 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 and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
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 benzene.html" ;"title="uch as benzene">uch as benzene or naphthalene] by conversion of an even number of –CH= groups into –C(=O)– groups with ...
s. Quinones can redox cycle with their conjugate semiquinones 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 (: sperm or sperms) is the male reproductive Cell (biology), 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 ...
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 cause
Causality is an influence by which one event, process, state, or object (''a'' ''cause'') contributes to the production of another event, process, state, or object (an ''effect'') where the cause is at least partly responsible for the effect, ...
of male infertility
Male infertility refers to a sexually mature male's inability to impregnate a fertile female. Male infertility can wholly or partially account for 40% of infertility among couples who are trying to have children. "A problem with the male is the s ...
, 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; : spermatozoa; ) is a motile sperm cell (biology), cell produced by male animals relying on internal fertilization. A spermatozoon is a moving form of the ploidy, haploid cell (biology), cell that is ...
. 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 levels ...
is associated with abnormal spermatozoa and male infertility.
Origin of eukaryotes
The great oxygenation event
The Great Oxidation Event (GOE) or Great Oxygenation Event, also called the Oxygen Catastrophe, Oxygen Revolution, Oxygen Crisis or Oxygen Holocaust, was a time interval during the Earth's Paleoproterozoic era when the Earth's atmosphere and ...
began with the biologically induced appearance of oxygen in the Earth's atmosphere
The atmosphere of Earth is composed of a layer of gas mixture that surrounds the Earth's planetary surface (both lands and oceans), known collectively as air, with variable quantities of suspended aerosols and particulates (which create weathe ...
about 2.45 billion years ago. The rise of oxygen levels due to cyanobacteria
Cyanobacteria ( ) are a group of autotrophic gram-negative bacteria that can obtain biological energy via oxygenic photosynthesis. The name "cyanobacteria" () refers to their bluish green (cyan) color, which forms the basis of cyanobacteri ...
l photosynthesis
Photosynthesis ( ) is a system of biological processes by which photosynthetic organisms, such as most plants, algae, and cyanobacteria, convert light energy, typically from sunlight, into the chemical energy necessary to fuel their metabo ...
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 ( ) is a Domain (biology), domain of organisms. Traditionally, Archaea only included its Prokaryote, prokaryotic members, but this has since been found to be paraphyletic, as eukaryotes are known to have evolved from archaea. Even thou ...
l lineage into the first eukaryote
The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...
s. Oxidative stress might have acted in synergy with other environmental stresses (such as ultraviolet
Ultraviolet radiation, also known as simply UV, is electromagnetic radiation of wavelengths of 10–400 nanometers, shorter than that of visible light, but longer than X-rays. UV radiation is present in sunlight and constitutes about 10% of ...
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. The ...
) 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 ...
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 package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...
movements and emergence of the nuclear membrane
The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer polar membrane, membranes that in eukaryotic cells surround the Cell nucleus, nucleus, which encloses the genome, genetic material.
The nuclear envelope con ...
. Thus, the evolution of meiotic
Meiosis () is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, the sperm or egg cells. It involves two rounds of division that ultimately result in four cells, each with only one copy ...
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 in determining cardiac complications in COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by the coronavirus SARS-CoV-2. In January 2020, the disease spread worldwide, resulting in the COVID-19 pandemic.
The symptoms of COVID‑19 can vary but often include fever ...
.
See also
* Antioxidative stress
* Acatalasia
* Bruce Ames
* Malondialdehyde, an oxidative stress marker
* Mitochondrial free radical theory of aging
* Mitohormesis
* Nitric oxide
Nitric oxide (nitrogen oxide, nitrogen monooxide, 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 den ...
* Pro-oxidant
* Reductive stress
References
{{Authority control
Cell biology
Chemical pathology
Alzheimer's disease
Senescence