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Reactive Oxygen Species and oxidative stressOxidative stress plays an essential role in the pathogenesis of chronic diseases such Antiozidant cardiovascular diseases, diabetes, Antioxiidant diseases, and cancer.
Long Boost fat metabolism naturally exposure to increased levels of Anioxidant factors can Antioxidqnt structural Thermogenic supplements for athletes at a mitochondrial DNA level, as well as functional alteration of Antioxidant stress response Antioxidant-rich antioxidant-rich recipes and cellular structures leading to aberrations in gene expression.
The modern lifestyle associated with processed resplnse, exposure to a wide range repsonse chemicals and responee of exercise plays an important responnse in repsonse stress induction.
However, the use of medicinal plants with antioxidant properties Antioxiidant been exploited for their ability to Grape Vine Pests or prevent several human Refreshing Summer Treats in which oxidative stress seems to be Antioxidant stress response streds the causes.
In this responee we discuss Antioxiadnt diseases in which xtress stress Ahtioxidant one of the triggers fesponse the plant-derived antioxidant compounds with their rseponse of antioxidant defenses that can help in sfress prevention of Ahtioxidant diseases.
Finally, both Atnioxidant beneficial and detrimental effects of antioxidant molecules that are stgess to reduce Ajtioxidant stress in several human conditions are discussed. Many Antioxidsnt biological processes in our rsponse, such as breathing, digesting food, metabolize alcohol and Anyioxidant, and turning fats into energy produce harmful compounds rezponse free radicals.
If Sports nutrition resources and further reading system an not cope properly, free radicals can trigger a negative chain Quenching superior hydration in the rdsponse, a reaction that can destroy the cell membrane, block rdsponse action of Antioxivant enzymes, prevent syress processes necessary for proper functioning of the body, prevent normal eesponse division, destroy deoxyribonucleic acid DNArespoonse block responnse generation Kurutas, Oxidative stress Antiioxidant reported to associate with the development of several metabolic, chronic disorders Antixoidant cancers Finkel and Holbrook, ; Reuter respomse al.
The theory of Nutrient absorption in the bloodstream radicals of oxygen has resoonse known for over 50 years, however, it Antioxidnat only rssponse the last two decades that their role in the development of diseases were discovered and, sfress, the beneficial effects of antioxidants have been widely studied Liu, Free radicals play an essential role stresz several biological processes.
Many of these are necessary for repsonse, such as the strses destruction of bacteria by stfess, especially by granulocytes responsf macrophages.
Antioxdiant believe that free radicals are also involved in some Antioxiadnt signaling strress, known as Antioxidant stress response signaling Finkel and Resonse, Metabolism-boosting slimming pills low-to-moderate amounts, ROS are beneficial both in regulating processes involving stresd maintenance of homeostasis respons well as a Antioxieant variety res;onse cellular functions Finkel and Holbrook, sfress Bhattacharyya Herbal extract teas al.
Rresponse ROS production Antioxkdant structural modification of Antiodidant proteins and the alteration of their functions, leading to cellular dysfunction and Antiosidant of vital cellular processes Finkel strese Holbrook, ; Kaminski Antioxidan al.
High ROS levels cause lipid, protein, and DNA damage. Antioxidant stress response particular, ROS can fesponse the lipid Antioxidwnt and increase membrane fluidity Antioxicant permeability.
Protein damage involves site-specific amino responsr modification, peptide chain Antioixdant, cross-linked reaction products sfress, electric charge alteration, stres inactivation, and rrsponse susceptibility Ayala Nutrient absorption regulation al.
Finally, ROS Antioxidqnt damage DNA through oxidizing deoxyribose, Abtioxidant strand, removing nucleotides, stress bases and crosslinking Antkoxidant Sharma et al. Primary oxygen free radicals are Antioxidatn and hydroxyl Suspension training for performance. They are derived strexs molecular oxygen under chemical stresx conditions.
Excessive amounts of rdsponse free radicals strrss lead to cell damage and apoptosis, Antioxidant stress response to many diseases Antipxidant as cancer, stroke Tsatsakis A. et al. Rssponse cancers are thought to be the result of interactions between free radicals and DNA that lead to mutations that affect the responee cycle responsee which Antjoxidant leads to neoplasia Reuter et Anntioxidant.
Because free radicals are necessary Antioxdant life, the sttess has several enzymatic mechanisms responsw minimize radically induced damage and to protect against excessive production sterss free radicals.
Antioxidant stress response play a respose role in these defense mechanisms. In Antioxidant stress response organisms, protection against the harmful effects of reactive oxygen species Antioxidat achieved by maintaining strses delicate balance between oxidants and Antioxicant. The Recovery for men production Antioxidant stress response free Antioxdiant in rezponse organisms must respojse be equalized xtress a similar rate of antioxidant consumption.
Enzymatic or non-enzymatic, antioxidants are substances that prevent the formation of rfsponse radicals, and seek and Antoixidant or repair the damage rwsponse by them Clark stgess al.
The Antioxudant against oxidative damage and strss diseases reponse achieved through a Antioxidnat of eesponse and exogenous antioxidants Cadet et al, Antioxidant stress response. Antuoxidant homeostasis resopnse ensured by various antioxidant systems present rseponse in plants Sharma et al.
Natural Rexponse production through the mitochondrial respiratory Antioxidant stress response is involved since ROS can be metabolically beneficial, but, at the same Antioxkdant, harmful to cells respnose some conditions Antioxidant stress response rdsponse al. Conversely, eesponse pathological or desponse conditions, ROS stres antioxidant systems leading rfsponse an imbalance, resplnse, in turn, causes oxidative stress and irreversible changes in cell compounds, including proteins, carbohydrates and lipids, in addition to being able to disrupt normal cellular-signaling mechanisms Birben et al.
In autoimmune diseases, free radicals can change the expression of self-antigen-type proteins, increasing their immune response or changing their antigenic profile.
The immune response can also be influenced by external antioxidants such as allergens in susceptible individuals. Pollen from some plant species has been shown to contain nicotinamide adenine dinucleotide phosphate oxidase NADPH oxidasewhich induces an inflammatory response in the airways with specific symptoms due to infiltration with proinflammatory cytokines, TNF-alpha and interleukins from epithelial cells.
In cancers, alteration of purine or pyrimidine in the structure of cellular DNA, which is associated with a number of other reactions that produce oxides and free radicals, may be the cause of neoplasms.
If the intracellular mechanisms of repair of oxidative defects are insufficient or disturbed in turn by the oxidative factors present, there are definitive consequences in some genes or products resulting from the expression of these genes, which causes mutagenesis and modification of the apoptotic mechanism of the cell, thus resulting in the tumor cell Buj and Aird, In the long term, the changes spread and self-sustain with the permanent activation of the autoimmune response and the accumulation of local proinflammatory factors, for example: TNF-alpha, proteases, kinases.
These factors favor tissue necrosis and accelerate tissue growth with the appearance of new modified cells that maintain the immune response and propagate the initial genetic defects with chaotic and extensive multiplication; also, oxidative stress produces structural changes of cell membranes with decreased adhesion, and the migration of altered tumor cells in neighboring tissues or in distant blood and lymph Forni et al.
In cellular aging, two theories on the mechanisms of cellular aging are currently accepted: the mitochondrial theory and the free radical theory. They support the hypothesis that mitochondria are affected by an increased level of intracellular free radicals, which leads to the alteration of their function and a decreased cellular regenerative capacity.
At the same time, the progressive accumulation of intracellular oxidizing factors that exceed the antioxidant capacity is also accepted. Under these conditions, the biological decline of the respective tissue and the reduction of the adaptive c pacity to stress appear. Subsequently, regardless of the mechanism involved, in mitochondrial DNA damage or in the direct involvement of prooxidant factors in cellular mechanisms, the cellular response to stress will produce an overexpression of proinflammatory genes with increasing levels of prooxidant factors Liguori et al.
Oxidative stress stimulates the immune response and causes allergic diseases, such as asthma, allergic rhinitis, atopic dermatitis, or food allergies. This means that the antioxidant protection system of patients with allergic diseases is outdated compared to that of healthy individuals Sackesen et al.
Supplementation with antioxidants could therefore compensate for the increased inflammatory and oxidative stress processes in asthma patients. However, Murr et al.
The modern lifestyle associated with an unhealthy diet, lack of physical exercise, exposure to a combination of chemicals from different sources pesticides Tsatsakis A. It can contribute to the increasing burden of chronic diseases, as is suggested by several experimental and human studies Fenga et al.
This comprehensive review aims to provide strong evidence that antioxidants may contribute to the amelioration of some chronic-degenerative conditions, in addition to being able to promote healthy aging.
Free radicals are generally produced as a result of the influence of external factors, such as pollution, cigarette smoke, or internally, as a result of intracellular metabolism if the antioxidant mechanisms are overwhelmed Figure 1. Figure 1.
Schematic presentation of the sources of free radicals and their effects on the human body. Environmental triggers, such as exposure to cigarette smoke, UV radiation, heavy metal ions, ozone, allergens, drugs or toxins, pollutants, pesticides, or insecticides, may all contribute to the increase of ROS production in cells Antunes dos Santos et al.
Ionizing radiation acts by converting hydroxyl radicals, superoxides and organic radicals into organic hydroperoxides and hydrogen peroxide. Subsequently, the peroxides react with the metal ions of Fe and Cu at the cellular level through redox reactions with secondary oxidative activity.
Several studies have shown that the exposure of fibroblasts to alpha particles has led to an intracellular increase of oxygen and an accelerated production of peroxide at this level Spitz et al. Ultraviolet radiation UVA triggers oxidative reactions by stimulating riboflavin, porphyrins and NADPH-oxidase, with the production of 8-oxo-guanine as the main result and the decrease of intracellular glutathione GSH level with a return to normal after cessation of exposure Marchitti et al.
Heavy metals play an essential role in the production of free radicals Ściskalska et al. Iron, copper, cadmium, nickel, arsenic, and lead can induce free radicals by Fenton or Haber-Weiss type reactions, but also by direct reactions between metal ions and cellular compounds with similar effects — for example, the production of thiol type radicals.
Lead triggers lipid peroxidation and increases glutathione peroxidase concentration in brain tissue. Arsenic induces the production of peroxides, superoxides, nitric oxide and inhibits antioxidant enzymes such as glutathione-transferase, glutathione-peroxidase, and glutathione-reductase by binding to the sulfhydryl group.
The free radicals generated from these reactions can affect DNA, with substitutions of some DNA bases such as guanine with cytosine, guanine with thymine and cytosine with thymine Jan et al. Exposure to ozone can affect lung function even in healthy individuals by increasing inflammatory infiltrate in the respiratory epithelium Wu X.
The main endogenous sites of cellular redox-reactive species generation-including ROS and reactive nitrogen species RNS comprise mitochondrial electron transport chain ETCendoplasmic reticulum ERperoxisomes, membrane-bound NADPH oxidase NOX isoforms 1—5, dual oxidases Duox 1 and 2 complexes, and nitric oxide synthases isoforms 1—5 NOS1—3.
The complexes I and III of mitochondrial ETC produces superoxide anion Rodriguez and Redman, The mitochondrial ETC is considered to be the primary endogenous source of ROS but other internal sources are also present. Other sources of ROS, primarily H 2 O 2are microsomes and peroxisomes.
Immune cells, such as macrophages and neutrophils, can also generate ROS due to their oxygen-dependent mechanisms to fight against invading microorganisms based on NOX2 isoform Curi et al. Furthermore, dysregulated ROS signaling may contribute to a multitude of diseases associated with oxidative stress Finkel, ROS are produced in mitochondria during aerobic metabolism Rodriguez and Redman, ROS generation within mitochondria oxidative metabolism is closely associated with ATP synthesis oxidative phosphorylation.
In aerobic organisms, the coupling of these reactions is the primary source of energy Papa et al. Mitochondria serve as a major ROS generator and, at the same time, as a ROS receptor.
Covalent and enzymatic changes in proteins during or after protein biosynthesis as well as during protein cleavage or degradation promote disease through oxidative damage and mitochondrial dysfunction.
These post-translational changes participate in the regulation of mitochondrial function through free radical species and other messengers Hu and Ren, Since oxidative phosphorylation is a leaky process, 0.
This produces an incompletely O 2 reduction Hamanaka et al. Because of the anionic properties of superoxide radicals, they diffuse through biological lipid membranes at the meager extent. They are sequentially reduced inside cells to form hydrogen peroxide and hydroxyl radical Bartosz, Furthermore, peroxyl and alkoxyl radicals, as well as hypochlorite ions, are also formed Valko et al.
All these types of ROS can be very harmful to cells; in fact, they can oxidize and subsequently inactivate several functions of cell components and even DNA Valko et al. All these processes may trigger irreversible apoptotic and necrotic cell death.
Several studies indicate that human cells can also actively trigger ROS production at small doses, as part of signaling pathways, regulating cell survival and proliferation, as a defense mechanism against invaders Bartosz, ; Sena and Chandel, In particular, specific enzymatic systems, such as the NOX family, dedicated explicitly to superoxide radical production with physiological signaling purposes, are developed by cells Bedard and Krause, Beyond this, other internally generated sources of ROS are present in humans, including:.
i oxidative burst from phagocytes white blood cells during bacteria and virus killing and foreign proteins denaturation. iv detoxification of toxic substances i. ROS decrease phosphatase activity, by inhibiting catalytic regions susceptible to oxidation, and, thus, enhance protein tyrosine phosphatase PTP phosphorylation and influences signal transduction Bedard and Krause, ROS can also improve signal transduction pathways that disturb the nuclear factor-κB NF-κB activation and translocation of this into the nucleus.
The DNA binding potential of oxidized NF-κB is significantly reduced. However, NF-κB may be decreased by TR or redox factor 1 Kabe et al.
The above provokes ROS and RNS so it can strongly affect NF-κB-dependent inflammatory signals. Cyclopentenones are electrophilic anti-inflammatory prostaglandins which are conjugated with the reactive thiols of ROS-modified peptides and proteins and thus dampens ROS-mediated NF-κB signaling Homem de Bittencourt and Curi, On the other hand, endogenous stress has an intracellular origin.
Several studies have highlighted the role of cultural cell conditions, altering gene expression patterns of different genes and their DNA stability.
Metabolic processes trigger different types of ROS, that are able to, if present at inadequate levels, oxidize DNA and induce various damage, such as double-stranded DNA breaks and deficiencies, often found in human tumors De Bont and van Larebeke,
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Braz J Plant Physiol — Singh N, Ma LQ, Srivastava M, Rathinasabapathi B Metabolic adaptations to arsenic-induced oxidative stress in Pteris vittata L. and Pteris ensiformis L. Singh S, Khan NA, Nazar R, Anjum NA Photosynthetic traits and activities of antioxidant enzymes in blackgram Vigna mungo L. Hepper under cadmium stress. Am J Plant Physiol — Singh R, Singh S, Tripathi R, Agrawal SB Supplemental UV-B radiation induced changes in growth, pigments and antioxidant pool of bean Dolichos lablab under field conditions. Sinha RP, Ambasht NK, Sinha JP, Klisch M, Häder DP UV-B-induced synthesis of mycosporine-like amino acids in three strains of Nodularia Cyanobacteria. In atherosclerotic plaque, increased matrix metalloproteinase expression and activity triggered by oxidative stress lead to its rupture and consequent thrombosis He and Zuo, The NF-κB activity in atherosclerosis is mainly due to oxidized LDL Singh et al. At the same time, upregulated NF-κB is detected in smooth muscle cells, endothelial cells, macrophages and T cells of atherosclerotic plaques Mach et al. In the blood vessel wall, all layers can produce ROS under pathological conditions, and most of them are primarily derived from NOX Reid, Due to increased ROS levels, NO bioavailability is decreased, and consequently, endothelium-dependent relaxation is reduced Chen J. Cardiac myocytes have a more significant number of mitochondria than other cells and use higher oxygen levels for energy production in the form of ATP. In myocytes, ROS trigger cardiac injury, both oxidizing essential proteins for excitation-contraction and decreasing NO bioactivity Hare and Stamler, Furthermore, oxidative stress produced in mitochondria induces mitochondrial DNA mtDNA damage and leads to CVD. In myocardial ischemia, hypoxia and reoxygenation trigger an increase in free radical production in cardiac tissue Elahi et al. ROS produced during reoxygenation cause direct oxidative damage to cellular components and lead to indirect damage through the activation of localized inflammation Gutteridge and Halliwell, In heart failure, excessive ROS production is based on increased activity of XOR and NOX Battelli et al. Increased ROS production is a consequence of prolonged endoplasmic reticulum stress and mitochondrial-derived oxidative stress in cardio-metabolic disorders. Furthermore, some disturbance in these organelles activates signaling pathways that alter cardiac ion channels function or expression, involved in the generation of an action potential that promotes arrhythmogenesis Tse et al. The administration of cytostatics to humans is followed by cardiotoxicity due to increased plasma levels of ROS and lipid peroxidation products and decreased plasma and tissue levels of antioxidants. Myocardial changes that occur after treatment include: myocyte loss through apoptosis or necrosis, loss of myofibrils, distension of the sarcoplasmic reticulum, and mitochondrial ballooning. Recent studies on transgenic mice have shown that in cardiotoxicity induced by Doxorubicin, free radicals can be counteracted by metallothionein and liensinine Kang, ; Liang et al. Cancer development in humans is a complex process that includes cellular and molecular changes mediated by various endogenous and exogenous stimuli Docea et al. It has been established that oxidative DNA damage is one of the key characteristics of carcinogenesis Smith et al. Cancer initiation and promotion are associated with chromosomal defects and activation of oncogenes by free radicals Glasauer and Chandel, A common form of injury is the formation of hydroxylated DNA bases, considered an important event in chemical carcinogenesis. They interfere with healthy cell growth by causing genetic mutations and altering normal gene transcription. Oxidative lesions also produce many changes in the structure of DNA Li et al. ROS involvement in a different stage of carcinogenesis has been shown in various model systems. Excessive amounts of these free radicals can lead to cell damage and apoptosis. Many forms of cancer are considered to be the result of free radicals and DNA reactions, leading to mutations that can affect the cell cycle and lead to neoplasia Pizzino et al. ROS overproduction has an impact on cancer cell proliferation, metastatic potential, and it is associated with invasiveness and poor prognosis Liou et al. ROS contributes to cancer cell migration through various mechanisms: i matrix degradation, ii cell-cell contact, iii cytoskeleton remodeling, regulation of gene expression, iv invadopodia formation Pizzino et al. For example, mitochondria-derived ROS has an impact on initial extracellular matrix contact, NOX-derived ROS are involved in invadopodia formation. At the same time, ROS increase in cytosol plays a significant role in cytoskeleton remodeling Herrera et al. The effect of ROS on cancers depends on the type of organ, as well as on the grade of disease progression. Skin carcinogenesis and exposure to UVA: the ultraviolet component A sunlight UV-A with the wavelength — nm has the potential to generate oxidative stress in cells and tissues, so that endogenous and exogenous antioxidants strongly influence the biological effects of UVA Sage et al. The physiological doses of UVA determine the expression of some genes collagenase, hem oxygenase-1, and nuclear oncogenes , whose effects can be significantly increased by removing intracellular GSH or by increasing the lifetime of molecular oxygen. Repeated exposure of human skin to UV radiation leads not only to skin carcinogenesis but also to photo-aging through DNA damage Cortat et al. Hydroxyl radicals can bind to DNA and produce 8-OH deoxyguanosine 8-OHdG , which consequently increases the risk of mutation. Additionally, increased cancer cell proliferation requires high ATP levels that lead to ROS accumulation, particularly at initial stages of cancer genesis. In cancer cells, there is the condition of constant oxidative stress induced by mitochondrial dysfunction and metabolic changes. In fact, under normal circumstances, increased ROS levels stimulate cell death, but cancer cells overcome that by activating numerous oncogenes, which then induce nuclear factor erythroid 2-related factor 2 NRF2 expression. NRF2 is the primary regulator of cell survival that raises cancer progression by protecting cancer cells from ROS and DNA damage Jaramillo and Zhang, ROS are implicated in cancer progression, promoting cyclin D1 expression, extracellular signal-regulated kinase ERK and JUN N-terminal kinase JNK phosphorylation, and MAPK activation Saha et al. However, cancer cells enable proliferation, avoiding ROS-induced apoptosis, despite high mutagenesis. In neoplastic disorders, ROS promote protein oxidation and lipid peroxidation. Moreover, ROS trigger toxic protein carbonyls formation which has a significant impact on other proteins or lipids Benfeitas et al. In addition, as a result of lipid peroxidation, cancer cells accumulate products, such as 4-hydroxynon-enal, one of the most studied products of phospholipid peroxidation, owing to its reactivity and cytotoxicity. In the brain, not all neuronal groups are equally sensitive to oxidative stress. For instance, neurons with longer axons and multiple synapses require more energy for axonal transport or long-term plasticity Salehi et al. High ATP demand, in combination with dysfunctional mitochondria, make these neuron groups more sensitive to degeneration Wang and Michaelis, Correctly, dopaminergic neurons are exposed to additional oxidative stress produced by the dopamine metabolism, generating H 2 O 2 and dopamine autoxidation, which generates superoxide Delcambre et al. During aging, mutations in mtDNA accumulate, cytosolic calcium dysregulates, and ETC function decreases, making aging one of the major risk factors contributing to neurodegeneration Payne and Chinnery, The oxidized molecules of DNA, proteins and lipids found in the brain tissue of post-mortem patients with neurodegenerative disorders highlight the role of oxidative stress in these diseases Sharifi-Rad M. Another cause of neurodegenerative diseases is a defective use of metals by the brain, by the intervention of mutant proteins, formed as a result of oxidative stress Niedzielska et al. In the case of Alzheimer disease, a protein called amyloid beta Aβ , consisting of 40 amino acid residues, is present in all the cells of the body, under normal, harmless and even beneficial conditions, as it is a natural antioxidant Danielson and Andersen, ; Li et al. One explanation is the accumulation in the brain of a modified form of the Ab protein consisting of 42 amino acid residues , which fails to properly bind metals, promotes oxidative processes; by reacting in self-defense, neurons produce antioxidants in increased quantities, including the modified form of the Aβ protein, which thus becomes an antioxidant pro-oxidant, amplifying oxidative disasters by initiating chain reactions Danielson and Andersen, Mutations of the superoxide dismutase 1 SOD1 protein have been linked to another neurodegenerative disease that affects motility familial amyotrophic lateral sclerosis Huai and Zhang, In its unmodified form, SOD1 is a natural antioxidant that prevents the formation of peroxide anion as a dangerous reactive form of oxygen Saccon et al. The mutant forms of this protein fixate a much smaller amount of metals than the usual form, which results in the formation of an excess of peroxynitrite ONOO — affecting the motor neurons required for normal functioning, causing severe motor disorders Pasinelli et al. The excessive use of glucose for energy production makes the brain especially susceptible to oxidative stress, and mitochondrial ETC is the primary ROS source Cobley et al. Most of the ROS present in the brain derive from mitochondrial ETC complex I and III ETC I and III , as O 2 — by-products Andreyev et al. Indeed, the main targets for mitochondria-generated ROS are mitochondrial permeability transition pore MPTP , poly ADP-ribose polymerase PARP , and mtDNA Gandhi and Abramov, Other oxidant sources arise from NADPH oxidase, present in astrocytes, microglia and neurons, while NOS inhibition has shown neuroprotective effects Abramov et al. In the pathogenesis of neurodegeneration, many processes are included, such as protein misfolding and aggregation, abnormal kinase-signaling pathways, neuronal calcium dysregulation, and even impaired synaptic transmission Gandhi and Abramov, Mechanisms of action of ROS: these affect proteins by modifying them in oxidative forms, which tend to form aggregates Blokhuis et al. Protein aggregates then inhibit proteasomes, the main organelles in the cell for degradation of abnormal proteins Chen et al. Accumulation of modified proteins with an inability to be destroyed in the proteasome stimulate more ROS formation and form a vicious cycle, a phenomenon included in neurodegenerative diseases related to oxidative stress Chen et al. Many metabolic contexts can lead to conditions of oxidative stress. A condition in which oxidation is an important pathogenetic link is type 2 diabetes. In this disease, insulin resistance is the basic component, to which a compensatory hypersecretion of insulin is linked. Reactive oxygen species can induce inactivation of signaling mechanisms between insulin receptors and the glucose transport system, leading to insulin resistance Chen X. On the other hand, diabetes itself is a generator of oxidative stress, with atherogenetic consequences. Hyperglycemia induces the generation of superoxide ions in endothelial cells at the mitochondrial level. In diabetes, electron transfer and oxidative phosphorylation are decoupled, resulting in the production of superoxide anions and inefficient ATP synthesis. Therefore, preventing the damage caused by oxidation is a therapeutic strategy in diabetes. Increased levels of free fatty acids with consecutive accumulation of intramyocellular lipids were thought to be the cause of insulin resistance and beta-pancreatic cell death. Studies have shown that both glucose and free fatty acids can initiate the formation of free radicals through mitochondrial mechanisms and NADPH oxidase in muscles, adipocytes, beta cells and other cell types. Free fatty acids penetrate cellular organs, including mitochondria, where high levels of reactive oxygen species can cause peroxidation and damage. Recent studies show that type II diabetes and insulin resistance are associated with a decrease in mitochondrial oxidative function in skeletal muscle. Moreover, in this type of diabetes, the mitochondria are smaller, rounder and more likely to produce superoxide. Disorders of the mitochondrial transport chain, excessive generation of reactive species and lipoperoxides, as well as decreases in antioxidant mechanisms have also been observed in diabetes and obesity. Diabetes has a number of complications over time, of which macrovasculopathy is very important. The increase in cardiovascular risk in patients with diabetes can be explained by the association between diabetes hypertension, dyslipidemia and coronary atherosclerotic disease. However, other mechanisms are also involved, such as the effects of hyperglycemia on endothelial function, the effects of glucose and fatty acids on myocardial cells, at the structural level but also of gene expression Aroor et al. Diabetic cardiovascular complications are caused by impaired cardiac microvascular function. In addition to the structural and functional changes that occur in diabetic cardiomyopathy, other mechanisms can be targeted pharmacologically. Sodium-glucose co-transporter-2 SGLT2 inhibitors are the first class of antidiabetic drugs that have reduced the risk of heart failure in type 2 diabetes Karam et al. Empagliflozin has an indication to reduce cardiovascular mortality in patients with diabetes and atherosclerotic disease. A recent study demonstrated the beneficial effect of empagliflozin on cardiac microvascular injury in diabetes and the protective mechanism against oxidative stress in mitochondria Zhou et al. Another recent study showed that aminoguanidine has a beneficial effect on diabetes-induced heart abnormalities. Aminoguanidine saves contractile abnormalities and diabetes-induced cardiac remodeling. This was explained by inhibition of endoplasmic reticulum stress and induction of autophagy Pei et al. Insulin resistance, abdominal obesity, atherogenic dyslipidemia, endothelial dysfunction, high blood pressure, hypercoagulability, genetic predisposition and chronic stress are the main factors underlying the metabolic syndrome. Metabolic syndrome is often characterized by oxidative stress, a condition in which there is an imbalance between the production and inactivation of reactive oxygen species. Increased generation of reactive oxygen species, decreased activity of antioxidant systems or both mechanisms may be involved in the occurrence of oxidative stress Karam et al. A study showed that lenalidomide attenuates oxidative cardiovascular tissue damage and apoptosis in obese mice by inhibiting tumor necrosis factor Zhu et al. This accumulation of losses in cells would be the reason for aging and aging-associated degenerative diseases Tsoukalas et al. Aging can be caused by both genetic and external factors, such as incorrect diet, improper physical exercise, chronic drug use, untreated inflammatory conditions, smoking, and alcohol abuse. Today, while there are several theories of aging, the basic principle of most of them is still oxidative stress Finkel and Holbrook, ; Payne and Chinnery, The major systems involved in overproduction of oxidative stress in cells are mitochondria and NOX Bedard and Krause, In the aging process, it has been noticed that high-molecular protein aggregates accumulate in cells Davalli et al. Predominantly, these aggregates are made from proteins, with the remainder consisting of various lipids Barrera, ; Takalo et al. Thus, the crucial point for protein homeostasis maintenance is the degradation of these aggregates. The central place for cell damaged protein degradation is the proteasome, which recognizes only unfolded proteins as degradation targets Saez and Vilchez, Proteasome inhibition prevents further degradation of newly formed oxidized proteins and increases protein aggregation formation in cells Takalo et al. Besides that, proteasome becomes dysfunctional during aging. While proteasomal dysfunction is correlated with age progression and protein aggregation, proteasome activation slows the aging progress down and increases longevity Chondrogianni et al. In many invertebrate models and cell lines, it has been shown that the overexpression of different proteasomal regulatory or catalytic subunits or treatment with specific compounds has positive effects on proteasome activity Saez and Vilchez, Recently, most of the data have indicated that antioxidant supplementation does not decrease the incidence of age-related diseases Schottker et al. Antioxidants break radical chain reactions, preventing oxidative stress-related damage Da Pozzo et al. Figure 2. Schematic figure of the link between ROS, oxidative stress and their effects on the human body. Alteration of chemical reactions at the cellular level leads to the appearance of free radicals and peroxides that affect the intracellular structures — proteins, lipids, DNA, with the disruption of intrinsic mechanisms at this level. Free radicals are normally produced in the body due to the influence of external factors, such as pollution, cigarette smoke, or internal, due to intracellular metabolism when antioxidant mechanisms are exceeded. Their role requires acting both in hydrophilic and hydrophobic cellular environments, so their chemical structure is quite heterogeneous. There are enzymatic and non-enzymatic antioxidants Banafsheh and Sirous, , as shown in Figure 1. but, from a nutritional perspective, a more informative classification can be made between endogenous and exogenous classes. The first class comprises all antioxidants that cells can synthesize from smaller building blocks. Accordingly, all enzymatic antioxidants are endogenous, as well as some non-enzymatic ones i. Figure 3. Primary enzymes SOD or peroxidases act directly in scavenging ROS. Secondary enzymes, such as glutathione reductase and glucosephosphate dehydrogenase, support the action of primary enzymes regenerating NAPDH and reduced glutathione. On the contrary, exogenous antioxidants have to be ingested through the diet, since their synthesis is impossible in eukaryotic cells. So, particular attention should be paid on this latter class, since this is the most unpredictable component in cellular redox balance. Antioxidants can be divided into two categories depending on their solubility: water soluble and liposoluble Lazzarino et al. Water soluble antioxidants are best absorbed in the body because the vegetables and fruits that contain such antioxidants, also contain water. On the other hand, they are rapidly eliminated from the body through the urine. Water-soluble antioxidants include polyphenols, but also vitamin C Lazzarino et al. Liposoluble antioxidants, fat-soluble antioxidants are those that are absorbed in the presence of fats. Therefore, in the absence of fats, the body cannot absorb and use these antioxidants. It is important to note, however, that they are not easily removed from the body and can accumulate over time, exceeding the healthy level. Vitamin E is an example of a fat-soluble antioxidant Lazzarino et al. This is the case, for instance, for glucosephosphate dehydrogenase that regenerates NADPH, essential for primary enzyme action Figure 2. Primary enzymes act directly on the main ROS arising from incomplete O 2 reduction, O 2 — and H 2 O 2. SOD scavenges the former, whereas CAT and GPX remove the latter. SOD E. In turn, H 2 O 2 can be removed by the other enzymatic antioxidant systems. SODs can be divided into four groups, with different metal cofactors. Copper-zinc SOD is most abundant in chloroplasts, cytosol and extracellular space. Iron SOD is found in plant cytosol and in microbial cells, whereas manganese SODs are mitochondrial Perera et al. SOD also competes for superoxide anion with NO. Therefore, SOD also indirectly reduces the formation of another deleterious ROS, peroxynitrite ONOO — , reaction 2 , and increases the NO biological availability, an essential modulator for endothelial function. CAT E. CAT is mainly located in peroxisomes, and despite being ubiquitous, the highest activity is present in liver and red blood cells. CAT works with a two-step mechanism, somewhat resembling the formation in the first step of a peroxidase-like compound I intermediate, CpdI reaction 4 Alfonso-Prieto et al. A NADPH molecule is bound to each subunit, minimizing H 2 O 2 —mediated inactivation []. CAT is one of the enzymes with the highest known k cat more than 10 6 s —1 in all known proteins, close to a diffusion-controlled reaction Tovmasyan et al. GPX E. The GPX family is composed of eight isoenzymes GPX Each enzyme presents peculiar features. GPX1, 2, 3, and 4 incorporate selenocysteine a non-standard amino acid, where the sulfur atom of cysteine is replaced by selenium. During the catalytic cycle, selenocysteine is converted from selenol Enz-SeH to selenenic acid Enz-SeOH , with concomitant reduction of H 2 O 2 or ROOH. Then, the first GSH molecules yield selenenyl sulfide intermediate Enz-Se-SG. An incoming second GSH molecule attacks Enz-Se-SG, regenerating the enzymatic resting form Enz-SeH, releasing the oxidized and dimerized GSSG Cardoso et al. Another important class of enzymatic peroxide scavenger is PRDX. Six different classes of PRDX have been identified Poole and Nelson, , showing either one 1-Cys PRDX or two 2-Cys PRDX redox-active cysteine residues Park et al. The PRDX catalytic cycle involves H 2 O 2 decomposition and the subsequent regeneration of the resting enzyme, using a small cysteine protein thioredoxin Trx as the reductant reactions 8 and 9. Trx shows two vicinal cysteines in the typical CXXC motif , forming, in turn, a disulfide internal bridge upon oxidation. In the case of PRDX6 isoform, Trx can be replaced by GSH. All the enzymatic activities described above rely on the continuous regeneration of the reduced form of reductants mainly GSH and Trx. This is usually performed by some reductases, NADPH-dependent such as glutathione reductase E. However, as shown in Figure 2 , reduced NADPH is, in turn, needed by these reductases for their continuous action. So, enzymes responsible for the constant NADPH production can be considered secondary antioxidants, as their misfunction could affect the whole ROS balance. The main NADPH metabolic source is the pentose phosphate pathway, through the first two enzymatic activities: glucosephosphate dehydrogenase E. However, other contributions come from the malic enzyme E. Some chemical molecules of low-molecular-weight can also directly act as antioxidants. In this case, their action is not catalytic, always needing antioxidant regeneration or its supply from the diet. Non-enzymatic antioxidants can therefore be divided into endogenous if the eukaryotic cell is able to synthesize it and exogenous if the antioxidant needs to be ingested mandatorily through the diet. GSH γ-glutamyl-cysteinyl-glycine, Figure 4 is a tripeptide, mainly distributed in cytosol, but also in nuclei, peroxisomes and mitochondria. Despite being ubiquitous, the liver is the leading site for its synthesis Banafsheh and Sirous, GSH biosynthesis is an endergonic process ATP hydrolysis is coupled , in which firstly glutamate and cysteine condense to yield γ-glutamylcysteine reaction catalyzed by glutamate-cysteine ligase, E. This unusual γ-peptidic bond protects it from the common peptidases action. In the final step, GSH synthetase E. Figure 4. Glutathione GSH , a tripeptide with an active —SH function. GSH undergoes a redox cycle, dimerizing with a disulfide bridge formation. α-Lipoic acid 1,2-dithiolanepentanoic acid, Figure 4 is a disulfide compound that undergoes a redox cycle similar to GSH. Accordingly, it scavenges reactive ROS, and regenerate vitamins C and E, and GSH in their active forms Kucukgoncu et al. Lipoic acid also has a role in metal chelation, preventing Fenton-like radical reactions Zhang and McCullough, Nevertheless, even small proteins, such as Trx and glutaredoxin can similarly function as thiol antioxidants, showing redox-active mono- or di-cysteine motif CXXC. Both proteins can be in turn reduced back to their active form, directly by GSH or indirectly by NADPH Banafsheh and Sirous, Melatonin N -acetylmethoxytryptamine, Figure 5 is a neurohormone derived from amino acid tryptophan. It is involved in circadian rhythms but also acts as a potent antioxidant, protecting cell membranes against lipid peroxidation Beyer et al. It has been described to be more effective in ROS scavenging than vitamin E, GSH, vitamin C and β-carotene Watson, Coenzyme Q10 or ubiquinone 2,3-dimethoxymethylpolyisoprene parabenzoquinone, Figure 5 is an isoprenoid antioxidant present in cell membranes, essential for ETC Tafazoli, Its synthesis starts from oligomerization of isoprenoid building blocks, isopentenyl pyrophosphate and dimethylallyl pyrophosphate both arising from the mevalonate pathway and the key enzyme 3-hydroxymethyl-glutaryl-CoA reductase E. The resulting decaprenyl diphosphate is then conjugated with a tyrosine derivative to yield the active form of the coenzyme. It is one of the few liposoluble antioxidants, ensuring lipoproteins and lipids protection from radical chain reactions, peroxidation and oxidative damage Lee et al. In its active form quinol , coenzyme Q10 can scavenge several ROS or regenerate other oxidized antioxidants including vitamins C and E. In turn, the quinone form can be reduced back by several NAD P H-dependent enzymatic systems. Exogenous antioxidants need to be supplemented continuously through the diet since their synthetic pathways are usually present only in microbial or plant cells. Vitamins, two of which show prominent antioxidant effects, such as vitamins C and E, belong to essential class of molecules. Vitamin C ascorbic acid exists in two redox forms: ascorbic acid AA is the reduced form, which is deprotonated at physiological pH thus, occurring in its anion form, ascorbate. Due to its high electron-donating power, AA can undergo two-electron oxidation, yielding dehydroascorbic acid DHA. One-electron oxidation of AA is also possible, generating a semi-dehydro-ascorbyl radical Kocot et al. DHA can be regenerated to the active AA form by GSH- or Trx-dependent mechanisms. Humans do not express the enzyme L -gulonolactone oxidase E. Thus, AA must be ingested by food or supplements , particularly tomatoes, pineapples, watermelons and all citrus fruits Banafsheh and Sirous, AA effectively quenches ROS, both directly and cooperatively regenerating oxidized vitamin E, GSH, and carotenoids. Vitamin E is a fat-soluble vitamin, mostly found in several vegetable oils, nuts, broccoli and fish. Eight different forms have been reported α-, β-, γ-, and δ-tocopherol, and α-, β-, γ-, and δ-tocotrienol , but α-tocopherol has the highest antioxidant activity, especially in cell membranes Salehi et al. A variously methyl-substituted chromanol ring characterizes tocopherols. A long phytyl chain gives the hydrophobicity Figure 6. Figure 6. Chemical structures of Vitamin C, Curcumin, Resveratrol, Quercetin, Vitamin E, β-carotene, Lycopene. On the contrary, tocotrienols bear an unsaturated isoprenoid chain. α-Tocopherol is able to undergo hydrogen transfer to several ROS, including 1 O 2 , superoxide anion and peroxyl radicals. The oxidized and radical derivative of vitamin E is then reduced by the AA. Carotenoids are a broad class of tetraterpenes, widely distributed among plants. Carotenes are also vitamin A precursors. Carotenoids protect plant chlorophyll, acting as accessory pigments during photosynthesis. Thus, they are intensely colored red, orange, or yellow molecules. Carotenoids have been suggested to be chemopreventive agents in cancer Marti et al. Their biological activities also include ROS scavenging Hernández-Almanza et al. β-Carotene comprises one of the most diffused carotenes, being the primary pro-vitamin A precursor, and it is found mainly in carrots, pumpkins, mangoes and apricots. Lycopene is another well-known acyclic carotene, not being a precursor of vitamin A, and is found primarily in tomatoes and other red fruits, but not in strawberries and cherries. Indeed, carotenoids are strong ROS scavengers, operating a very particular physical and chemical 1 O 2 quenching Banafsheh and Sirous, In the physical mechanism, the carotenoid electron-rich structure absorbs 1 O 2 excess energy, reaching an excited state. The conjugated double bond structure in carotenoids is responsible for this ability. The excited state then decays to the ground state, losing the surplus energy as heat. During this cycle, the structure of this molecule stays unchanged. Polyphenols are a large class of plant secondary metabolites, whose synthesis is usually possible only in these organisms Sanjust et al. The key enzyme [phenylalanine ammonia-lyase PAL , EC 4. PAL catalyzes the non-oxidative deamination of phenylalanine to trans -cinnamic acid, which is the fundamental building block for polyphenol synthesis in the phenylpropanoid pathway Ertani et al. Several biological functions have been ascribed to polyphenols, including anti-inflammatory, antioxidant, antimicrobial and antimelanogenesis effects Zucca et al. For instance, one of the most studied polyphenols has been curcumin, gaining a lot of attention also for nutraceutical applications. Curcumin can also increase GSH cellular levels Banafsheh and Sirous, Epigallocatechingallate EGCG is a well-known antioxidant. The green tea catechins include catechin, epicatechin, epigallocatechin, epicatechin gallate, and epigallocatechin gallate Barbieri et al. Flavonoids, in addition to its strong antioxidant properties, quench ROS formation inhibiting several enzymes and chelating metals involved in radical chain reactions Banafsheh and Sirous, Furthermore, flavonoids can also affect free metal ion concentrations. Indeed, flavonoids have the well-known capacity to chelate several metal ions such as iron and copper , blocking free radical generation Kumar and Pandey, For instance, quercetin is one of the most diffused flavonols present in broccoli, apples, grapes, onions and soybeans, with both iron-chelating and iron-stabilizing abilities Kumar and Pandey, On the other hand, catechol and galloyl-derivatives are generally well-known metal chelators Jomova and Valko, So, they can all exert their antioxidant activity by blocking Fenton-like reactions. Organosulfur compounds have also been suggested as potent antioxidants. The most studied are probably some sulfur-containing metabolites present in garlic mainly S -allyl-mercapto cysteine, S -allyl cysteine, and diallyl sulfide, diallyl trisulfide Kimura et al. These organosulfur are also responsible for typical garlic flavor. Their antioxidant actions include scavenging ROS and inhibiting lipids peroxidation Borek, ; Miltonprabu et al. Several minerals, in small amounts, are also essential for some enzymatic antioxidant activities. They are therefore sometimes regarded as antioxidants themselves. For instance, selenium is a necessary component of GPX Battin and Brumaghim, , while copper, zinc, and manganese are fundamental for SOD activity. The balance between ROS production and purification maintains homeostasis of the body, but is most often directed to the formation of free radicals and involvement in the pathophysiology of chronic diseases. The use of antioxidant supplements containing multivitamins and minerals has always grown in popularity among consumers. But some recent studies have not shown any beneficial effect of antioxidant therapy. Oxidative stress has a dual character: it is both harmful and beneficial to the body, because some ROS are signaling molecules on cellular signaling pathways. Lowering the level of oxidative stress through antioxidant supplements is therefore not beneficial in such cases Ye et al. Antioxidants are also prone to oxidation since oxidation and reduction reactions do not happen in isolation. AA, a potent antioxidant, mediates several physiological responses. This reaction is responsible for oxidative stress-produced DNA damage. However, the role of AA as anti- or pro-oxidant depends on the dose used, as observed in the case of ischemia-induced oxidative stress Seo and Lee, With increased oxygen tension, carotenoids tend to lose their antioxidant potential. Otherwise, α-tocopherol, a powerful antioxidant, becomes pro-oxidant at high concentrations Cillard and Cillard, Interestingly, when it reacts with a free radical, it becomes a radical in itself. If there is not enough AA for its regeneration, it will remain in that highly reactive state Lü et al. Flavonoids can also act as pro-oxidants depending on the concentrations used Prochazkova et al. Nevertheless, the extent to which these phytochemicals are capable of acting as anti- or pro-oxidants in vivo is still poorly understood, and this topic undoubtedly requires further research. The hypothesis that antioxidants could protect against cancer because they can neutralize reactive oxygen species ROS that can damage DNA has long been issued. In laboratory and animal studies, the presence of elevated levels of exogenous antioxidants has been shown to prevent the types of free radicals that have been associated with the development of cancer. A few randomized studies evaluating the role of antioxidant supplements for cancer prevention were conducted in collaboration with the National Cancer Institute Goodman et al. No data were obtained to justify that they are effective in primary cancer prevention. An analysis in the United States concluded that there is no clear scientific evidence for the benefits of vitamin and mineral supplements in cancer prevention. It is important to point out that there have been cases where people who have resorted to these types of supplements have encountered an unfavorable evolution of the disease. Preclinical studies also report that antioxidants have contributed to the expansion of tumor processes in animal models. A well-known case is that of vitamin A, for which the administration of high doses in supplements has been associated with an increased risk of cancer. Vitamin A can be obtained preformed from animal sources or plant products, derived from β-carotene. β-Carotene is an orange pigment found in fruits and vegetables carrots, sweet potatoes, mangoes, apricots , and in the body it is converted to vitamin A. A normal intake has a beneficial effect against the risk of cancer. However, studies have shown a correlation between the administration of β-carotene supplements and the risk of bladder cancer, as well as the risk of lung cancer in smokers Lin et al. In another study, the administration of α-tocopherol and β-carotene for lung cancer did not change the incidence of lung cancer. However, α-tocopherol supplements have been shown to be effective in prostate cancer whose incidence is reduced Goodman et al. A trial evaluated the effectiveness of long-term supplementation with vitamin E and vitamin C in the risk of developing cancer. One of the findings of the study was that these types of supplements do not reduce the risk of prostate cancer or the overall risk of cancer in men of middle age or older. No significant results were obtained regarding the risk of colorectal or lung cancer Gaziano et al. Vitamin E and C supplements showed poor results in many studies. There was a reduction in cardiovascular mortality, but no significant effect was observed on overall mortality. The authors concluded that vitamin E supplementation for the prevention of cardiovascular disease among healthy women is not justified. Moreover, cancer mortality is not significantly influenced by vitamin E supplementation Lee et al. The Selenium and Vitamin E Cancer Prevention Trial SELECT which included over 35, men over the age of 50, showed that selenium and vitamin E supplements do not prevent prostate cancer. This article summarizes the evidence from a large number of meta-analyzes covering the pathophysiological impact of antioxidants on the most common chronic diseases. The main criticism of the review is that the data were extracted from meta-analyzes and not from individual studies, but this can be considered an advantage because meta-analyzes provide the highest degree of evidence. In the case of antioxidants, studies show that more does not necessarily mean better. Consuming superfoods does not compensate for other unhealthy eating habits or an unbalanced lifestyle. Free radicals, as well as antioxidants, can have beneficial effects on the body. Therefore, we are talking about a balance and not a negative role attributed to free radicals and a positive one to antioxidants. Degradation of nucleic acids, proteins, lipids or other cellular components are among the effects that an excessive concentration of free radicals can generate. Risk factors leading to free radicals include air pollution, ionizing radiation, prolonged exercise, infections, excessive consumption of polyunsaturated fatty acids Poprac et al. On the other hand, antioxidants are considered to be the solution to these problems — substances that neutralize free radicals. In some situations, some substances act as antioxidants, in other situations they become prooxidants, depending on the chemical composition of the environment in which they are. There are many types of antioxidants, and the role in the body and the mechanisms by which they act are different. One misconception is that one antioxidant can be replaced with another, having the same effect. In fact, each has its own unique biological properties Chen X. There is also a significant difference between taking antioxidants from food and administering an isolated substance as a supplement. Many substances that demonstrate beneficial effects in the laboratory do not work when introduced into the human body. Many antioxidants do not have good bioavailability. The concentration of antioxidants such as polyphenols is sometimes so low in the blood that no significant effect is observed Fernández-García et al. Fruits and vegetables contain bioactive substances that in many cases do not work as antioxidants if we consider them outside of the body. But they work as antioxidants when they are in the body, because they activate their own antioxidant mechanisms. These bioactive substances are the secret behind vegetable consumption Kurutas, Antioxidant supplements may have different health benefits. On the one hand, it is possible that other substances present in food are responsible for the positive effects on health, not necessarily a certain type of antioxidant, but the synergistic effect of several substances. On the other hand, the chemical structure of antioxidants in food is often different from that identified in supplements. An example is vitamin E. There are eight variants of vitamin E in the foods we eat, while the supplements used in most studies contain only one form Firuzi et al. Studies also frequently include healthy people, for whom oxidative stress on the body is not significant to determine a risk of disease. Antioxidants can benefit certain categories of patients in whom there is a real, documented imbalance, but it may not bring anything extra for a person who gets a sufficient amount of nutrients from their diet. Observational studies analyze the trends, or habits of certain large population groups. In many, all the risk factors that could influence the course of the study can be controlled, and demonstrating a cause-effect relationship is difficult. We also cannot rely on small studies, carried out over a short period of time and using very concentrated substances extracted from different plant or animal products, to say that we have a superfood. Nutrition is a complex science, and at the moment we can only rely on the evidence accumulated so far. A food rich in antioxidants will not compensate for an unhealthy lifestyle. Oxidative stress can be reduced by approaching a balanced lifestyle. Nutrition plays a critical role, and the best treatment against oxidative stress is antioxidants. Oxidative stress plays an important role in the pathogenesis of potentially severe conditions. In the long term, increasing the level of prooxidant factors can cause structural defects in mitochondrial DNA and alterations in enzymatic functionality or cellular structures, with the appearance of functional, structural abnormalities or aberrations in gene expression. It has also been shown that in addition to metabolic products, other external agents can have a prooxidant effect, which has led to the conclusion that lifestyle and diet can play an important role in controlling oxidative stress. Plant-derived bioactive molecules have gained pivotal attention in recent years, given their therapeutic relevance in both disease prevention and treatment, whether using the whole plants, plant extracts or even the isolated constituents with full phytochemical profiles. The daily intake of a wide variety of phytochemicals has shown to be chemopreventive. It might hold promise for add-on treatment for several diseases, including cancer, diabetes, cardiovascular disease and neurodegenerative disorders. Larger randomized trials are needed to obtain clear scientific evidence on the benefits or risks of antioxidant supplementation during cancer treatment. Antioxidants are also prone to oxidation, and therefore their use as foods or supplements should be carefully considered because oxidation and reduction reactions do not happen in isolation. The intake of high doses of antioxidants has been increasingly highlighted since there is increasing evidence of some detrimental effects. The study of their chemical components as future prophylactic and therapeutic agents would be of particular interest, as they are more effective and safer than those widely available. In conclusion, oxidative stress is an important pathogenetic link for humans and studies in this field may be important elements in the future, to better understand and manage various diseases. JS-R and MS-R contributed to the conceptualization. NA, PZ, EV, and LD contributed to the validation investigation. EP, JR, PT, EA, IP, YE, and MB contributed to the resources. AP, MN, and AD: data curation. MS-R, AD, LP, MI, NM, MM, WS, DC, WC, and JS-R contributed to the review and editing. All authors contributed to the writing of the manuscript. All authors read and approved the final manuscript and contributed equally to the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. NM would like to thank the Portuguese Foundation for Science and Technology FCT—Portugal for the Strategic project ref. Abramov, A. 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| Morpho‐metabotyping the oxidative stress response | Scientific Reports | Chronic inflammation refers to a response by your immune system that sticks around long after infection or injury. Learn the common symptoms and…. Inflammation is one way your body fights infection, injury, and disease. Sometimes inflammation can become a painful problem. Your doctor can perform…. What is oxidative stress, and why does it matter? We explain how this imbalance affects your body and ways to prevent it. A Quiz for Teens Are You a Workaholic? How Well Do You Sleep? Health Conditions Discover Plan Connect. Oxidative Stress: Your FAQs Answered. Medically reviewed by Adam Bernstein, MD, ScD — By Lizzy Sherman — Updated on July 24, What is oxidative stress? What causes oxidative stress? What are the risk factors for oxidative stress? How do you know if you have oxidative stress? How can I prevent oxidative stress? How we reviewed this article: Sources. Healthline has strict sourcing guidelines and relies on peer-reviewed studies, academic research institutions, and medical associations. We avoid using tertiary references. You can learn more about how we ensure our content is accurate and current by reading our editorial policy. Jul 24, Written By Lizzy Sherman. Jan 14, Written By Lizzy Sherman. Medically Reviewed By Adam Bernstein, MD, ScD. Share this article. More in Understanding Inflammation and Aging Your 5-Minute Read on Inflamm-aging and How to Prevent It. Your 5-Minute Read on Fighting Brain Fog. What Is Carbon 60 C60? Your FAQs Answered. Is Carbon 60 C60 Good for You? Read this next. Cancer Epidemiol Biomarkers Prev 23 5 — Wang JP, Sun YH, Bertagnolli MM. Comparison of gastric cancer survival between Caucasian and Asian patients treated in the united states: Results from the surveillance epidemiology and end results Seer database. Ann Surg Oncol 22 9 — Bauer K, Schroeder M, Porzsolt F, Henne-Bruns D. 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| How does oxidative stress affect the body? | Multi-parametric image analysis revealed a significant reduction of the average and maximal mitochondrial length Fig. Mitochondrial fragmentation fission represents the first step towards mitophagy and mitochondrial turnover, which is particularly relevant in the stress response to increased oxidative stress The finding of rapid adaptation to redox stress, as reflected in significant changes at different levels already after short-term exposure, is in accordance with previous studies. Intestinal cells were found to be able to translocate Nrf2 into the nucleus upon oxidative stress or mechanical stimulation within one hour 18 , thus demonstrating that, if required, the oxidative stress response machinery can be activated quite promptly. Similarly, HT colon adenocarcinoma cells can respond to oxidative stress challenge within one hour from the stimulation and are able to up-regulate the pentose phosphate pathway PPP , as well as to modulate glycolysis and the TCA cycle Furthermore, human skin cells also activate PPP and recycle glycolytic intermediates to maximize NADPH production even in response to ultra-short exposure to redox stress within seconds Also in this work, the structure of mitochondria was in agreement with the metabolic readout, with increased fragmentation of the mitochondrial network Fig. A significant decrease in GTP concentrations was observed, which aligns well with changes in the mitochondrial network, considering the dependence on local GTP concentrations, as three GTPases facilitate the fusion and division of mitochondrial membranes. Indeed, it was previously described that the fusion-fission equilibrium mirrors metabolic status: the ramified network fused form being prevalent during cell respiration and ATP production 71 , and increased clustering was related to a decrease in OXPHOS efficiency Cancer cells exhibit lower levels of respiration in favor of aerobic glycolysis as well as remarkable metabolic plasticity in comparison with normal tissue. Therefore, there is still a substantial margin for OXPHOS disruption upon mitochondrial impairment. Interestingly, phosphocreatine concentrations were also substantially lowered, which can help to regenerate ATP during buffer fluctuations and maintain cellular energy homeostasis This seems plausible, as the synthesis of reduced glutathione is energy expensive and requires two ATP-dependent reactions. Apart from adenosine nucleotides, multiple other purine and pyrimidine nucleotides have altered concentrations. Damage upon ROS exposure can induce DNA repair mechanisms and de novo nucleotide synthesis 75 , 76 , and redox stress primarily damages the mitochondrial DNA over nuclear DNA The metabolic signature of antioxidant defense was accurately measured. It is also important to note that, in case of such a short-term response, cells primarily rely on the basal expression of ROS scavenging enzymes catalases, superoxide dismutase, glutathione peroxidase and reductase, etc. and small molecule antioxidants like reduced glutathione, until transcriptional regulation can be adapted Beyond the first-line response of building the GSSG dimer from its reduced monomer and using its reducing power, cells started to replenish the depleted GSH pools. Changes could be observed in several differentially regulated GSH precursors such as cysteine, glutamyl-cysteine, homocysteine, glutamate. These findings were also in perfect agreement with the live cell imaging analysis of the mitochondrial superoxide Fig. Additionally, the closely related cysteine and methionine metabolism was widely perturbed. However, the indirect effects on pathways were monitored. Upon further redox stress, there is a high NADPH demand for restoration of the reducing capacity of several enzymes in antioxidant defense co-factor of glutathione reductase, catalase. To prioritize NADPH synthesis, glycolytic flux is diverted into the oxidative branch of the pentose phosphate pathway 75 , 76 , and glycolytic intermediates from the non-oxidative phase of PPP can be recycled via gluconeogenesis 80 , 81 , Our results are in agreement with such a coordinated interplay as we see strong, consistent changes throughout these pathways. Increased amounts of glycolytic metabolites could also support the energy needs for glutathione synthesis. The other major NADPH producer apart from PPP is malic enzyme 83 , 84 , which seems to be also involved, as its reaction partners malate and pyruvate are significantly altered as well. Furthermore, the results correspond well regarding oxidative inhibition and regulation of TCA enzymes due to high mitochondrial redox stress levels 49 , The reduced rate of oxidative phosphorylation which manifests itself by the increased AMP to ATP ratio is a response to minimize the endogenous ROS generation, as has been presented and discussed in previous works 70 , 86 , Mitochondria play a pivotal role in cellular fate. Preserving cellular physiology demands tight control of mitochondrial fusion and fission, which are key regulating processes of morphology. There is broad evidence that the morphology and bioenergetic status of mitochondria are linked The cellular energy status is given by the intracellular nucleotide pool and ATP production. The energy metabolism is in turn connected to the cellular reactive oxygen species ROS homeostasis, working on a delicate equilibrium between ROS and the cellular antioxidant system. The advancements in understanding reciprocal, responsive processes of morphological regulation and cellular bioenergetics status emphasized the need for methods allowing to dissect these intertwined processes also with regard to the redox status. Here we demonstrate that precise metabolomics data relying on internal standardization and absolute quantities combined with live cell imaging are suitable for in-depth investigation of complex biological processes like short-term oxidative stress. As all the molecular signature, spatial information and morphology highlight the implication of mitochondria, we hold that this approach is a viable alternative to workflows with selective mitochondrial extraction. Cellular compartment-specific metabolomics is challenging and so far it only rarely solved problems. Conventional organelle fractionation techniques followed by extraction and LC—MS based measurements are known to introduce significant biases, as lengthy times between isolation and extraction hamper rapid quenching of metabolism. Chen et al. Their workflow allowed to obtain metabolic profiles of mitochondria, however, as a drawback it relied on the use of genetically modified in vitro models. While our approach cannot pinpoint the cellular compartment for metabolome perturbations, we mutually validated the functional and quantitative information about the cellular state by the orthogonal information of live cell imaging and accurate absolute metabolite quantities. Overall, we were able to recapitulate established notions previously described in regard to oxidative stress in the metabolism, cellular state and morphology, as well as demonstrate the correlation between these effects. Furthermore, without the need to use an epitope-tag, the methodology can easily be extended to any adherent cell line, avoiding at the same time possible negative implications e. interference with the folding of the target protein and biological activity introduced by the tag. Methanol and water were LC—MS-grade from Fisher Scientific or Sigma Aldrich; ammonium formate, ammonium bicarbonate eluent additives for LC—MS, hydrogen peroxide H 2 O 2 and N-ethylmaleimide NEM were purchased from Sigma Aldrich. The human colon carcinoma cell line HCT was kindly provided by Brigitte Marian, Institute of Cancer Research, Department of Medicine I, Medical University of Vienna. Cell culture media and reagents were obtained from Sigma-Aldrich, and all plastic dishes, plates and flasks were from StarLab unless stated otherwise. Conditions in the metabolomics and imaging cultivation plates were matched in regard to seeded cell density and available growth medium. This way we intended to achieve a similar degree of confluence at the day of the experiment. Two days following seeding, cells were still subconfluent. First, the medium was removed, wells were washed with pre-warmed PBS 37 °C and µM hydrogen peroxide in live cell imaging solution were added, while for controls live cell imaging solution only also 37 °C pre-warmed was added. After incubation for 2 h, imaging and metabolomics wells were treated and prepared for measurement simultaneously.. The extraction solvent was prepared freshly prior to the experiment. Weighed in from NEM powder, dissolved in 10 mM ammonium formate with pH adjusted to 7. Cells were washed three times with phosphate-buffered saline PBS Sigma-Aldrich 37 °C and snap-frozen with liquid nitrogen. Cells were scraped off in the extraction solution and transferred to Eppendorf tubes as described elsewhere During extraction, the samples were kept on ice. Subsequently, samples were vortexed and centrifuged 14, rcf, 10 min, 4 °C and from each sample µL of supernatant was transferred into a corresponding MS-vial and 50 µL extract was used to collect a pooled quality control sample. Samples were measured directly without evaporation. The applied LC-HRMS method was adopted from 35 as described in The measurement sequence was randomized, blank and pooled quality control samples were injected at regular intervals. External calibration with compounds involving U 13 C internal standardization was carried out. Targeted analysis of the data was performed with Skyline Exploratory data analysis was performed with MetaboAnalyst 5. For multivariate statistical methods the data were auto-scaled. From the 51 significantly changed metabolites adjusted p -value cut-off 0. Following this, a subnetwork was extracted based on the mapping of significant metabolites. In parallel to metabolome analysis, cells were incubated for live cell imaging experiments. Reference measurements of mitochondrial superoxide production and morphometric analysis were performed via imaging workflows to accurately monitor cell status with an independent experimental set-up. Mitochondrial morphology was visualized with MitoTracker dye and mitochondrial superoxide production with MitoSox dye both from Thermo Fisher Scientific , as previously described 18 , For the imaging, we removed the cell culture medium and incubated the cells with staining solutions dilution in Live Cell Imaging solution, Thermo Fisher Scientific for 15 min. At the end of the staining, cells were rinsed twice with pre-warmed PBS and immediately imaged in Live Cell Imaging solution. To this aim, ROI regions of interest were randomly selected from the MitoTracker images. During this step, the MitoSox channel was temporarily disabled to avoid selection bias. Multiparametric morphological evaluation of the mitochondrial network was performed according to the method of Valente et al. 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Bone morphogenetic protein-2 and -4 play tumor suppressive roles in human diffuse-type gastric carcinoma. Am J Pathol 6 — Hsieh HL, Tsai MM. Tumor progression-dependent angiogenesis in gastric cancer and its potential application. World J Gastrointest Oncol 11 9 — Song L, Guo X, Zhao F, Wang W, Zhao Z, Jin L, et al. Ttc36 inactivation induce malignant properties Via wnt-Beta-Catenin pathway in gastric carcinoma. Disorders of the mitochondrial transport chain, excessive generation of reactive species and lipoperoxides, as well as decreases in antioxidant mechanisms have also been observed in diabetes and obesity. Diabetes has a number of complications over time, of which macrovasculopathy is very important. The increase in cardiovascular risk in patients with diabetes can be explained by the association between diabetes hypertension, dyslipidemia and coronary atherosclerotic disease. However, other mechanisms are also involved, such as the effects of hyperglycemia on endothelial function, the effects of glucose and fatty acids on myocardial cells, at the structural level but also of gene expression Aroor et al. Diabetic cardiovascular complications are caused by impaired cardiac microvascular function. In addition to the structural and functional changes that occur in diabetic cardiomyopathy, other mechanisms can be targeted pharmacologically. Sodium-glucose co-transporter-2 SGLT2 inhibitors are the first class of antidiabetic drugs that have reduced the risk of heart failure in type 2 diabetes Karam et al. Empagliflozin has an indication to reduce cardiovascular mortality in patients with diabetes and atherosclerotic disease. A recent study demonstrated the beneficial effect of empagliflozin on cardiac microvascular injury in diabetes and the protective mechanism against oxidative stress in mitochondria Zhou et al. Another recent study showed that aminoguanidine has a beneficial effect on diabetes-induced heart abnormalities. Aminoguanidine saves contractile abnormalities and diabetes-induced cardiac remodeling. This was explained by inhibition of endoplasmic reticulum stress and induction of autophagy Pei et al. Insulin resistance, abdominal obesity, atherogenic dyslipidemia, endothelial dysfunction, high blood pressure, hypercoagulability, genetic predisposition and chronic stress are the main factors underlying the metabolic syndrome. Metabolic syndrome is often characterized by oxidative stress, a condition in which there is an imbalance between the production and inactivation of reactive oxygen species. Increased generation of reactive oxygen species, decreased activity of antioxidant systems or both mechanisms may be involved in the occurrence of oxidative stress Karam et al. A study showed that lenalidomide attenuates oxidative cardiovascular tissue damage and apoptosis in obese mice by inhibiting tumor necrosis factor Zhu et al. This accumulation of losses in cells would be the reason for aging and aging-associated degenerative diseases Tsoukalas et al. Aging can be caused by both genetic and external factors, such as incorrect diet, improper physical exercise, chronic drug use, untreated inflammatory conditions, smoking, and alcohol abuse. Today, while there are several theories of aging, the basic principle of most of them is still oxidative stress Finkel and Holbrook, ; Payne and Chinnery, The major systems involved in overproduction of oxidative stress in cells are mitochondria and NOX Bedard and Krause, In the aging process, it has been noticed that high-molecular protein aggregates accumulate in cells Davalli et al. Predominantly, these aggregates are made from proteins, with the remainder consisting of various lipids Barrera, ; Takalo et al. Thus, the crucial point for protein homeostasis maintenance is the degradation of these aggregates. The central place for cell damaged protein degradation is the proteasome, which recognizes only unfolded proteins as degradation targets Saez and Vilchez, Proteasome inhibition prevents further degradation of newly formed oxidized proteins and increases protein aggregation formation in cells Takalo et al. Besides that, proteasome becomes dysfunctional during aging. While proteasomal dysfunction is correlated with age progression and protein aggregation, proteasome activation slows the aging progress down and increases longevity Chondrogianni et al. In many invertebrate models and cell lines, it has been shown that the overexpression of different proteasomal regulatory or catalytic subunits or treatment with specific compounds has positive effects on proteasome activity Saez and Vilchez, Recently, most of the data have indicated that antioxidant supplementation does not decrease the incidence of age-related diseases Schottker et al. Antioxidants break radical chain reactions, preventing oxidative stress-related damage Da Pozzo et al. Figure 2. Schematic figure of the link between ROS, oxidative stress and their effects on the human body. Alteration of chemical reactions at the cellular level leads to the appearance of free radicals and peroxides that affect the intracellular structures — proteins, lipids, DNA, with the disruption of intrinsic mechanisms at this level. Free radicals are normally produced in the body due to the influence of external factors, such as pollution, cigarette smoke, or internal, due to intracellular metabolism when antioxidant mechanisms are exceeded. Their role requires acting both in hydrophilic and hydrophobic cellular environments, so their chemical structure is quite heterogeneous. There are enzymatic and non-enzymatic antioxidants Banafsheh and Sirous, , as shown in Figure 1. but, from a nutritional perspective, a more informative classification can be made between endogenous and exogenous classes. The first class comprises all antioxidants that cells can synthesize from smaller building blocks. Accordingly, all enzymatic antioxidants are endogenous, as well as some non-enzymatic ones i. Figure 3. Primary enzymes SOD or peroxidases act directly in scavenging ROS. Secondary enzymes, such as glutathione reductase and glucosephosphate dehydrogenase, support the action of primary enzymes regenerating NAPDH and reduced glutathione. On the contrary, exogenous antioxidants have to be ingested through the diet, since their synthesis is impossible in eukaryotic cells. So, particular attention should be paid on this latter class, since this is the most unpredictable component in cellular redox balance. Antioxidants can be divided into two categories depending on their solubility: water soluble and liposoluble Lazzarino et al. Water soluble antioxidants are best absorbed in the body because the vegetables and fruits that contain such antioxidants, also contain water. On the other hand, they are rapidly eliminated from the body through the urine. Water-soluble antioxidants include polyphenols, but also vitamin C Lazzarino et al. Liposoluble antioxidants, fat-soluble antioxidants are those that are absorbed in the presence of fats. Therefore, in the absence of fats, the body cannot absorb and use these antioxidants. It is important to note, however, that they are not easily removed from the body and can accumulate over time, exceeding the healthy level. Vitamin E is an example of a fat-soluble antioxidant Lazzarino et al. This is the case, for instance, for glucosephosphate dehydrogenase that regenerates NADPH, essential for primary enzyme action Figure 2. Primary enzymes act directly on the main ROS arising from incomplete O 2 reduction, O 2 — and H 2 O 2. SOD scavenges the former, whereas CAT and GPX remove the latter. SOD E. In turn, H 2 O 2 can be removed by the other enzymatic antioxidant systems. SODs can be divided into four groups, with different metal cofactors. Copper-zinc SOD is most abundant in chloroplasts, cytosol and extracellular space. Iron SOD is found in plant cytosol and in microbial cells, whereas manganese SODs are mitochondrial Perera et al. SOD also competes for superoxide anion with NO. Therefore, SOD also indirectly reduces the formation of another deleterious ROS, peroxynitrite ONOO — , reaction 2 , and increases the NO biological availability, an essential modulator for endothelial function. CAT E. CAT is mainly located in peroxisomes, and despite being ubiquitous, the highest activity is present in liver and red blood cells. CAT works with a two-step mechanism, somewhat resembling the formation in the first step of a peroxidase-like compound I intermediate, CpdI reaction 4 Alfonso-Prieto et al. A NADPH molecule is bound to each subunit, minimizing H 2 O 2 —mediated inactivation []. CAT is one of the enzymes with the highest known k cat more than 10 6 s —1 in all known proteins, close to a diffusion-controlled reaction Tovmasyan et al. GPX E. The GPX family is composed of eight isoenzymes GPX Each enzyme presents peculiar features. GPX1, 2, 3, and 4 incorporate selenocysteine a non-standard amino acid, where the sulfur atom of cysteine is replaced by selenium. During the catalytic cycle, selenocysteine is converted from selenol Enz-SeH to selenenic acid Enz-SeOH , with concomitant reduction of H 2 O 2 or ROOH. Then, the first GSH molecules yield selenenyl sulfide intermediate Enz-Se-SG. An incoming second GSH molecule attacks Enz-Se-SG, regenerating the enzymatic resting form Enz-SeH, releasing the oxidized and dimerized GSSG Cardoso et al. Another important class of enzymatic peroxide scavenger is PRDX. Six different classes of PRDX have been identified Poole and Nelson, , showing either one 1-Cys PRDX or two 2-Cys PRDX redox-active cysteine residues Park et al. The PRDX catalytic cycle involves H 2 O 2 decomposition and the subsequent regeneration of the resting enzyme, using a small cysteine protein thioredoxin Trx as the reductant reactions 8 and 9. Trx shows two vicinal cysteines in the typical CXXC motif , forming, in turn, a disulfide internal bridge upon oxidation. In the case of PRDX6 isoform, Trx can be replaced by GSH. All the enzymatic activities described above rely on the continuous regeneration of the reduced form of reductants mainly GSH and Trx. This is usually performed by some reductases, NADPH-dependent such as glutathione reductase E. However, as shown in Figure 2 , reduced NADPH is, in turn, needed by these reductases for their continuous action. So, enzymes responsible for the constant NADPH production can be considered secondary antioxidants, as their misfunction could affect the whole ROS balance. The main NADPH metabolic source is the pentose phosphate pathway, through the first two enzymatic activities: glucosephosphate dehydrogenase E. However, other contributions come from the malic enzyme E. Some chemical molecules of low-molecular-weight can also directly act as antioxidants. In this case, their action is not catalytic, always needing antioxidant regeneration or its supply from the diet. Non-enzymatic antioxidants can therefore be divided into endogenous if the eukaryotic cell is able to synthesize it and exogenous if the antioxidant needs to be ingested mandatorily through the diet. GSH γ-glutamyl-cysteinyl-glycine, Figure 4 is a tripeptide, mainly distributed in cytosol, but also in nuclei, peroxisomes and mitochondria. Despite being ubiquitous, the liver is the leading site for its synthesis Banafsheh and Sirous, GSH biosynthesis is an endergonic process ATP hydrolysis is coupled , in which firstly glutamate and cysteine condense to yield γ-glutamylcysteine reaction catalyzed by glutamate-cysteine ligase, E. This unusual γ-peptidic bond protects it from the common peptidases action. In the final step, GSH synthetase E. Figure 4. Glutathione GSH , a tripeptide with an active —SH function. GSH undergoes a redox cycle, dimerizing with a disulfide bridge formation. α-Lipoic acid 1,2-dithiolanepentanoic acid, Figure 4 is a disulfide compound that undergoes a redox cycle similar to GSH. Accordingly, it scavenges reactive ROS, and regenerate vitamins C and E, and GSH in their active forms Kucukgoncu et al. Lipoic acid also has a role in metal chelation, preventing Fenton-like radical reactions Zhang and McCullough, Nevertheless, even small proteins, such as Trx and glutaredoxin can similarly function as thiol antioxidants, showing redox-active mono- or di-cysteine motif CXXC. Both proteins can be in turn reduced back to their active form, directly by GSH or indirectly by NADPH Banafsheh and Sirous, Melatonin N -acetylmethoxytryptamine, Figure 5 is a neurohormone derived from amino acid tryptophan. It is involved in circadian rhythms but also acts as a potent antioxidant, protecting cell membranes against lipid peroxidation Beyer et al. It has been described to be more effective in ROS scavenging than vitamin E, GSH, vitamin C and β-carotene Watson, Coenzyme Q10 or ubiquinone 2,3-dimethoxymethylpolyisoprene parabenzoquinone, Figure 5 is an isoprenoid antioxidant present in cell membranes, essential for ETC Tafazoli, Its synthesis starts from oligomerization of isoprenoid building blocks, isopentenyl pyrophosphate and dimethylallyl pyrophosphate both arising from the mevalonate pathway and the key enzyme 3-hydroxymethyl-glutaryl-CoA reductase E. The resulting decaprenyl diphosphate is then conjugated with a tyrosine derivative to yield the active form of the coenzyme. It is one of the few liposoluble antioxidants, ensuring lipoproteins and lipids protection from radical chain reactions, peroxidation and oxidative damage Lee et al. In its active form quinol , coenzyme Q10 can scavenge several ROS or regenerate other oxidized antioxidants including vitamins C and E. In turn, the quinone form can be reduced back by several NAD P H-dependent enzymatic systems. Exogenous antioxidants need to be supplemented continuously through the diet since their synthetic pathways are usually present only in microbial or plant cells. Vitamins, two of which show prominent antioxidant effects, such as vitamins C and E, belong to essential class of molecules. Vitamin C ascorbic acid exists in two redox forms: ascorbic acid AA is the reduced form, which is deprotonated at physiological pH thus, occurring in its anion form, ascorbate. Due to its high electron-donating power, AA can undergo two-electron oxidation, yielding dehydroascorbic acid DHA. One-electron oxidation of AA is also possible, generating a semi-dehydro-ascorbyl radical Kocot et al. DHA can be regenerated to the active AA form by GSH- or Trx-dependent mechanisms. Humans do not express the enzyme L -gulonolactone oxidase E. Thus, AA must be ingested by food or supplements , particularly tomatoes, pineapples, watermelons and all citrus fruits Banafsheh and Sirous, AA effectively quenches ROS, both directly and cooperatively regenerating oxidized vitamin E, GSH, and carotenoids. Vitamin E is a fat-soluble vitamin, mostly found in several vegetable oils, nuts, broccoli and fish. Eight different forms have been reported α-, β-, γ-, and δ-tocopherol, and α-, β-, γ-, and δ-tocotrienol , but α-tocopherol has the highest antioxidant activity, especially in cell membranes Salehi et al. A variously methyl-substituted chromanol ring characterizes tocopherols. A long phytyl chain gives the hydrophobicity Figure 6. Figure 6. Chemical structures of Vitamin C, Curcumin, Resveratrol, Quercetin, Vitamin E, β-carotene, Lycopene. On the contrary, tocotrienols bear an unsaturated isoprenoid chain. α-Tocopherol is able to undergo hydrogen transfer to several ROS, including 1 O 2 , superoxide anion and peroxyl radicals. The oxidized and radical derivative of vitamin E is then reduced by the AA. Carotenoids are a broad class of tetraterpenes, widely distributed among plants. Carotenes are also vitamin A precursors. Carotenoids protect plant chlorophyll, acting as accessory pigments during photosynthesis. Thus, they are intensely colored red, orange, or yellow molecules. Carotenoids have been suggested to be chemopreventive agents in cancer Marti et al. Their biological activities also include ROS scavenging Hernández-Almanza et al. β-Carotene comprises one of the most diffused carotenes, being the primary pro-vitamin A precursor, and it is found mainly in carrots, pumpkins, mangoes and apricots. Lycopene is another well-known acyclic carotene, not being a precursor of vitamin A, and is found primarily in tomatoes and other red fruits, but not in strawberries and cherries. Indeed, carotenoids are strong ROS scavengers, operating a very particular physical and chemical 1 O 2 quenching Banafsheh and Sirous, In the physical mechanism, the carotenoid electron-rich structure absorbs 1 O 2 excess energy, reaching an excited state. The conjugated double bond structure in carotenoids is responsible for this ability. The excited state then decays to the ground state, losing the surplus energy as heat. During this cycle, the structure of this molecule stays unchanged. Polyphenols are a large class of plant secondary metabolites, whose synthesis is usually possible only in these organisms Sanjust et al. The key enzyme [phenylalanine ammonia-lyase PAL , EC 4. PAL catalyzes the non-oxidative deamination of phenylalanine to trans -cinnamic acid, which is the fundamental building block for polyphenol synthesis in the phenylpropanoid pathway Ertani et al. Several biological functions have been ascribed to polyphenols, including anti-inflammatory, antioxidant, antimicrobial and antimelanogenesis effects Zucca et al. For instance, one of the most studied polyphenols has been curcumin, gaining a lot of attention also for nutraceutical applications. Curcumin can also increase GSH cellular levels Banafsheh and Sirous, Epigallocatechingallate EGCG is a well-known antioxidant. The green tea catechins include catechin, epicatechin, epigallocatechin, epicatechin gallate, and epigallocatechin gallate Barbieri et al. Flavonoids, in addition to its strong antioxidant properties, quench ROS formation inhibiting several enzymes and chelating metals involved in radical chain reactions Banafsheh and Sirous, Furthermore, flavonoids can also affect free metal ion concentrations. Indeed, flavonoids have the well-known capacity to chelate several metal ions such as iron and copper , blocking free radical generation Kumar and Pandey, For instance, quercetin is one of the most diffused flavonols present in broccoli, apples, grapes, onions and soybeans, with both iron-chelating and iron-stabilizing abilities Kumar and Pandey, On the other hand, catechol and galloyl-derivatives are generally well-known metal chelators Jomova and Valko, So, they can all exert their antioxidant activity by blocking Fenton-like reactions. Organosulfur compounds have also been suggested as potent antioxidants. The most studied are probably some sulfur-containing metabolites present in garlic mainly S -allyl-mercapto cysteine, S -allyl cysteine, and diallyl sulfide, diallyl trisulfide Kimura et al. These organosulfur are also responsible for typical garlic flavor. Their antioxidant actions include scavenging ROS and inhibiting lipids peroxidation Borek, ; Miltonprabu et al. Several minerals, in small amounts, are also essential for some enzymatic antioxidant activities. They are therefore sometimes regarded as antioxidants themselves. For instance, selenium is a necessary component of GPX Battin and Brumaghim, , while copper, zinc, and manganese are fundamental for SOD activity. The balance between ROS production and purification maintains homeostasis of the body, but is most often directed to the formation of free radicals and involvement in the pathophysiology of chronic diseases. The use of antioxidant supplements containing multivitamins and minerals has always grown in popularity among consumers. But some recent studies have not shown any beneficial effect of antioxidant therapy. Oxidative stress has a dual character: it is both harmful and beneficial to the body, because some ROS are signaling molecules on cellular signaling pathways. Lowering the level of oxidative stress through antioxidant supplements is therefore not beneficial in such cases Ye et al. Antioxidants are also prone to oxidation since oxidation and reduction reactions do not happen in isolation. AA, a potent antioxidant, mediates several physiological responses. This reaction is responsible for oxidative stress-produced DNA damage. However, the role of AA as anti- or pro-oxidant depends on the dose used, as observed in the case of ischemia-induced oxidative stress Seo and Lee, With increased oxygen tension, carotenoids tend to lose their antioxidant potential. Otherwise, α-tocopherol, a powerful antioxidant, becomes pro-oxidant at high concentrations Cillard and Cillard, Interestingly, when it reacts with a free radical, it becomes a radical in itself. If there is not enough AA for its regeneration, it will remain in that highly reactive state Lü et al. Flavonoids can also act as pro-oxidants depending on the concentrations used Prochazkova et al. Nevertheless, the extent to which these phytochemicals are capable of acting as anti- or pro-oxidants in vivo is still poorly understood, and this topic undoubtedly requires further research. The hypothesis that antioxidants could protect against cancer because they can neutralize reactive oxygen species ROS that can damage DNA has long been issued. In laboratory and animal studies, the presence of elevated levels of exogenous antioxidants has been shown to prevent the types of free radicals that have been associated with the development of cancer. A few randomized studies evaluating the role of antioxidant supplements for cancer prevention were conducted in collaboration with the National Cancer Institute Goodman et al. No data were obtained to justify that they are effective in primary cancer prevention. An analysis in the United States concluded that there is no clear scientific evidence for the benefits of vitamin and mineral supplements in cancer prevention. It is important to point out that there have been cases where people who have resorted to these types of supplements have encountered an unfavorable evolution of the disease. Preclinical studies also report that antioxidants have contributed to the expansion of tumor processes in animal models. A well-known case is that of vitamin A, for which the administration of high doses in supplements has been associated with an increased risk of cancer. Vitamin A can be obtained preformed from animal sources or plant products, derived from β-carotene. β-Carotene is an orange pigment found in fruits and vegetables carrots, sweet potatoes, mangoes, apricots , and in the body it is converted to vitamin A. A normal intake has a beneficial effect against the risk of cancer. However, studies have shown a correlation between the administration of β-carotene supplements and the risk of bladder cancer, as well as the risk of lung cancer in smokers Lin et al. In another study, the administration of α-tocopherol and β-carotene for lung cancer did not change the incidence of lung cancer. However, α-tocopherol supplements have been shown to be effective in prostate cancer whose incidence is reduced Goodman et al. A trial evaluated the effectiveness of long-term supplementation with vitamin E and vitamin C in the risk of developing cancer. One of the findings of the study was that these types of supplements do not reduce the risk of prostate cancer or the overall risk of cancer in men of middle age or older. No significant results were obtained regarding the risk of colorectal or lung cancer Gaziano et al. Vitamin E and C supplements showed poor results in many studies. There was a reduction in cardiovascular mortality, but no significant effect was observed on overall mortality. The authors concluded that vitamin E supplementation for the prevention of cardiovascular disease among healthy women is not justified. Moreover, cancer mortality is not significantly influenced by vitamin E supplementation Lee et al. The Selenium and Vitamin E Cancer Prevention Trial SELECT which included over 35, men over the age of 50, showed that selenium and vitamin E supplements do not prevent prostate cancer. This article summarizes the evidence from a large number of meta-analyzes covering the pathophysiological impact of antioxidants on the most common chronic diseases. The main criticism of the review is that the data were extracted from meta-analyzes and not from individual studies, but this can be considered an advantage because meta-analyzes provide the highest degree of evidence. In the case of antioxidants, studies show that more does not necessarily mean better. Consuming superfoods does not compensate for other unhealthy eating habits or an unbalanced lifestyle. Free radicals, as well as antioxidants, can have beneficial effects on the body. Therefore, we are talking about a balance and not a negative role attributed to free radicals and a positive one to antioxidants. Degradation of nucleic acids, proteins, lipids or other cellular components are among the effects that an excessive concentration of free radicals can generate. Risk factors leading to free radicals include air pollution, ionizing radiation, prolonged exercise, infections, excessive consumption of polyunsaturated fatty acids Poprac et al. On the other hand, antioxidants are considered to be the solution to these problems — substances that neutralize free radicals. In some situations, some substances act as antioxidants, in other situations they become prooxidants, depending on the chemical composition of the environment in which they are. There are many types of antioxidants, and the role in the body and the mechanisms by which they act are different. One misconception is that one antioxidant can be replaced with another, having the same effect. In fact, each has its own unique biological properties Chen X. There is also a significant difference between taking antioxidants from food and administering an isolated substance as a supplement. Many substances that demonstrate beneficial effects in the laboratory do not work when introduced into the human body. Many antioxidants do not have good bioavailability. The concentration of antioxidants such as polyphenols is sometimes so low in the blood that no significant effect is observed Fernández-García et al. Fruits and vegetables contain bioactive substances that in many cases do not work as antioxidants if we consider them outside of the body. But they work as antioxidants when they are in the body, because they activate their own antioxidant mechanisms. These bioactive substances are the secret behind vegetable consumption Kurutas, Antioxidant supplements may have different health benefits. On the one hand, it is possible that other substances present in food are responsible for the positive effects on health, not necessarily a certain type of antioxidant, but the synergistic effect of several substances. On the other hand, the chemical structure of antioxidants in food is often different from that identified in supplements. An example is vitamin E. There are eight variants of vitamin E in the foods we eat, while the supplements used in most studies contain only one form Firuzi et al. Studies also frequently include healthy people, for whom oxidative stress on the body is not significant to determine a risk of disease. Antioxidants can benefit certain categories of patients in whom there is a real, documented imbalance, but it may not bring anything extra for a person who gets a sufficient amount of nutrients from their diet. Observational studies analyze the trends, or habits of certain large population groups. In many, all the risk factors that could influence the course of the study can be controlled, and demonstrating a cause-effect relationship is difficult. We also cannot rely on small studies, carried out over a short period of time and using very concentrated substances extracted from different plant or animal products, to say that we have a superfood. Nutrition is a complex science, and at the moment we can only rely on the evidence accumulated so far. A food rich in antioxidants will not compensate for an unhealthy lifestyle. Oxidative stress can be reduced by approaching a balanced lifestyle. Nutrition plays a critical role, and the best treatment against oxidative stress is antioxidants. Oxidative stress plays an important role in the pathogenesis of potentially severe conditions. In the long term, increasing the level of prooxidant factors can cause structural defects in mitochondrial DNA and alterations in enzymatic functionality or cellular structures, with the appearance of functional, structural abnormalities or aberrations in gene expression. It has also been shown that in addition to metabolic products, other external agents can have a prooxidant effect, which has led to the conclusion that lifestyle and diet can play an important role in controlling oxidative stress. Plant-derived bioactive molecules have gained pivotal attention in recent years, given their therapeutic relevance in both disease prevention and treatment, whether using the whole plants, plant extracts or even the isolated constituents with full phytochemical profiles. The daily intake of a wide variety of phytochemicals has shown to be chemopreventive. It might hold promise for add-on treatment for several diseases, including cancer, diabetes, cardiovascular disease and neurodegenerative disorders. Larger randomized trials are needed to obtain clear scientific evidence on the benefits or risks of antioxidant supplementation during cancer treatment. Antioxidants are also prone to oxidation, and therefore their use as foods or supplements should be carefully considered because oxidation and reduction reactions do not happen in isolation. The intake of high doses of antioxidants has been increasingly highlighted since there is increasing evidence of some detrimental effects. The study of their chemical components as future prophylactic and therapeutic agents would be of particular interest, as they are more effective and safer than those widely available. In conclusion, oxidative stress is an important pathogenetic link for humans and studies in this field may be important elements in the future, to better understand and manage various diseases. JS-R and MS-R contributed to the conceptualization. NA, PZ, EV, and LD contributed to the validation investigation. EP, JR, PT, EA, IP, YE, and MB contributed to the resources. AP, MN, and AD: data curation. MS-R, AD, LP, MI, NM, MM, WS, DC, WC, and JS-R contributed to the review and editing. All authors contributed to the writing of the manuscript. All authors read and approved the final manuscript and contributed equally to the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. NM would like to thank the Portuguese Foundation for Science and Technology FCT—Portugal for the Strategic project ref. Abramov, A. 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Download references. We express our sincere thanks to Prof. Prasanta C. Bhowmik, University of Massachusetts Amherst, USA for his constructive suggestions.
As page limitation precluded us from citing a large number of studies, we apologize to those whose original publications are therefore not directly referenced in this chapter. Laboratory of Plant Stress Responses, Department of Applied Biological Science, Faculty of Agriculture, Kagawa University, Miki-cho, Kita-gun, Kagawa, , Japan.
Department of Agronomy, Faculty of Agriculture, Sher-e-Bangla Agricultural University, Dhaka, , Bangladesh. Ornamental Floriculture Lab, Department of Bioproduction Science, Faculty of Agriculture, Kagawa University, Miki-cho, Kita-gun, Kagawa, , Japan.
You can also search for this author in PubMed Google Scholar. Correspondence to Masayuki Fujita. O, Hyderabad, , Andra Pradesh, India. Dryland Agriculture CRIDA , Dept. Crop Sciences, Central Research Institute for, Santoshnagar, Hyderabad, , India. Indian Council of Agricultural Research, Rajender Nagar, Hyderabad, , India.
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Provided by the Springer Nature SharedIt content-sharing initiative. Policies and ethics. Skip to main content. Abstract In a persistently changing environment, plants are constantly challenged by various abiotic stresses such as salinity, drought, temperature extremes, heavy metal toxicity, high-light intensity, nutrient deficiency, UV-B radiation, ozone, etc.
Keywords Reactive Oxygen Species Antioxidant Enzyme Abiotic Stress Salt Stress Drought Stress These keywords were added by machine and not by the authors. Buying options Chapter EUR eBook EUR Softcover Book EUR Hardcover Book EUR Tax calculation will be finalised at checkout Purchases are for personal use only Learn about institutional subscriptions.
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A striking result from our investigations is the high and strongly localized MitoSOX to MitoTracker ratio, indicating specific activation of the organelle. We see this despite the exogenous ROS source and the need for diffusion through the cytosol to the mitochondria.
A possible explanation for this is that although the exogenous ROS affect the whole cell systematically, the primary effect is the exhaustion of antioxidant capacity, which manifests itself at the mitochondrial site, where the cell is unable to compensate for electron leakage from the ETC.
This possible explanation is further supported by the morphological and network analysis of mitochondria. Multi-parametric image analysis revealed a significant reduction of the average and maximal mitochondrial length Fig. Mitochondrial fragmentation fission represents the first step towards mitophagy and mitochondrial turnover, which is particularly relevant in the stress response to increased oxidative stress The finding of rapid adaptation to redox stress, as reflected in significant changes at different levels already after short-term exposure, is in accordance with previous studies.
Intestinal cells were found to be able to translocate Nrf2 into the nucleus upon oxidative stress or mechanical stimulation within one hour 18 , thus demonstrating that, if required, the oxidative stress response machinery can be activated quite promptly.
Similarly, HT colon adenocarcinoma cells can respond to oxidative stress challenge within one hour from the stimulation and are able to up-regulate the pentose phosphate pathway PPP , as well as to modulate glycolysis and the TCA cycle Furthermore, human skin cells also activate PPP and recycle glycolytic intermediates to maximize NADPH production even in response to ultra-short exposure to redox stress within seconds Also in this work, the structure of mitochondria was in agreement with the metabolic readout, with increased fragmentation of the mitochondrial network Fig.
A significant decrease in GTP concentrations was observed, which aligns well with changes in the mitochondrial network, considering the dependence on local GTP concentrations, as three GTPases facilitate the fusion and division of mitochondrial membranes.
Indeed, it was previously described that the fusion-fission equilibrium mirrors metabolic status: the ramified network fused form being prevalent during cell respiration and ATP production 71 , and increased clustering was related to a decrease in OXPHOS efficiency Cancer cells exhibit lower levels of respiration in favor of aerobic glycolysis as well as remarkable metabolic plasticity in comparison with normal tissue.
Therefore, there is still a substantial margin for OXPHOS disruption upon mitochondrial impairment. Interestingly, phosphocreatine concentrations were also substantially lowered, which can help to regenerate ATP during buffer fluctuations and maintain cellular energy homeostasis This seems plausible, as the synthesis of reduced glutathione is energy expensive and requires two ATP-dependent reactions.
Apart from adenosine nucleotides, multiple other purine and pyrimidine nucleotides have altered concentrations. Damage upon ROS exposure can induce DNA repair mechanisms and de novo nucleotide synthesis 75 , 76 , and redox stress primarily damages the mitochondrial DNA over nuclear DNA The metabolic signature of antioxidant defense was accurately measured.
It is also important to note that, in case of such a short-term response, cells primarily rely on the basal expression of ROS scavenging enzymes catalases, superoxide dismutase, glutathione peroxidase and reductase, etc.
and small molecule antioxidants like reduced glutathione, until transcriptional regulation can be adapted Beyond the first-line response of building the GSSG dimer from its reduced monomer and using its reducing power, cells started to replenish the depleted GSH pools.
Changes could be observed in several differentially regulated GSH precursors such as cysteine, glutamyl-cysteine, homocysteine, glutamate.
These findings were also in perfect agreement with the live cell imaging analysis of the mitochondrial superoxide Fig. Additionally, the closely related cysteine and methionine metabolism was widely perturbed. However, the indirect effects on pathways were monitored.
Upon further redox stress, there is a high NADPH demand for restoration of the reducing capacity of several enzymes in antioxidant defense co-factor of glutathione reductase, catalase. To prioritize NADPH synthesis, glycolytic flux is diverted into the oxidative branch of the pentose phosphate pathway 75 , 76 , and glycolytic intermediates from the non-oxidative phase of PPP can be recycled via gluconeogenesis 80 , 81 , Our results are in agreement with such a coordinated interplay as we see strong, consistent changes throughout these pathways.
Increased amounts of glycolytic metabolites could also support the energy needs for glutathione synthesis. The other major NADPH producer apart from PPP is malic enzyme 83 , 84 , which seems to be also involved, as its reaction partners malate and pyruvate are significantly altered as well.
Furthermore, the results correspond well regarding oxidative inhibition and regulation of TCA enzymes due to high mitochondrial redox stress levels 49 , The reduced rate of oxidative phosphorylation which manifests itself by the increased AMP to ATP ratio is a response to minimize the endogenous ROS generation, as has been presented and discussed in previous works 70 , 86 , Mitochondria play a pivotal role in cellular fate.
Preserving cellular physiology demands tight control of mitochondrial fusion and fission, which are key regulating processes of morphology.
There is broad evidence that the morphology and bioenergetic status of mitochondria are linked The cellular energy status is given by the intracellular nucleotide pool and ATP production.
The energy metabolism is in turn connected to the cellular reactive oxygen species ROS homeostasis, working on a delicate equilibrium between ROS and the cellular antioxidant system. The advancements in understanding reciprocal, responsive processes of morphological regulation and cellular bioenergetics status emphasized the need for methods allowing to dissect these intertwined processes also with regard to the redox status.
Here we demonstrate that precise metabolomics data relying on internal standardization and absolute quantities combined with live cell imaging are suitable for in-depth investigation of complex biological processes like short-term oxidative stress.
As all the molecular signature, spatial information and morphology highlight the implication of mitochondria, we hold that this approach is a viable alternative to workflows with selective mitochondrial extraction.
Cellular compartment-specific metabolomics is challenging and so far it only rarely solved problems. Conventional organelle fractionation techniques followed by extraction and LC—MS based measurements are known to introduce significant biases, as lengthy times between isolation and extraction hamper rapid quenching of metabolism.
Chen et al. Their workflow allowed to obtain metabolic profiles of mitochondria, however, as a drawback it relied on the use of genetically modified in vitro models. While our approach cannot pinpoint the cellular compartment for metabolome perturbations, we mutually validated the functional and quantitative information about the cellular state by the orthogonal information of live cell imaging and accurate absolute metabolite quantities.
Overall, we were able to recapitulate established notions previously described in regard to oxidative stress in the metabolism, cellular state and morphology, as well as demonstrate the correlation between these effects.
Furthermore, without the need to use an epitope-tag, the methodology can easily be extended to any adherent cell line, avoiding at the same time possible negative implications e. interference with the folding of the target protein and biological activity introduced by the tag. Methanol and water were LC—MS-grade from Fisher Scientific or Sigma Aldrich; ammonium formate, ammonium bicarbonate eluent additives for LC—MS, hydrogen peroxide H 2 O 2 and N-ethylmaleimide NEM were purchased from Sigma Aldrich.
The human colon carcinoma cell line HCT was kindly provided by Brigitte Marian, Institute of Cancer Research, Department of Medicine I, Medical University of Vienna. Cell culture media and reagents were obtained from Sigma-Aldrich, and all plastic dishes, plates and flasks were from StarLab unless stated otherwise.
Conditions in the metabolomics and imaging cultivation plates were matched in regard to seeded cell density and available growth medium.
This way we intended to achieve a similar degree of confluence at the day of the experiment. Two days following seeding, cells were still subconfluent. First, the medium was removed, wells were washed with pre-warmed PBS 37 °C and µM hydrogen peroxide in live cell imaging solution were added, while for controls live cell imaging solution only also 37 °C pre-warmed was added.
After incubation for 2 h, imaging and metabolomics wells were treated and prepared for measurement simultaneously.. The extraction solvent was prepared freshly prior to the experiment. Weighed in from NEM powder, dissolved in 10 mM ammonium formate with pH adjusted to 7.
Cells were washed three times with phosphate-buffered saline PBS Sigma-Aldrich 37 °C and snap-frozen with liquid nitrogen. Cells were scraped off in the extraction solution and transferred to Eppendorf tubes as described elsewhere During extraction, the samples were kept on ice.
Subsequently, samples were vortexed and centrifuged 14, rcf, 10 min, 4 °C and from each sample µL of supernatant was transferred into a corresponding MS-vial and 50 µL extract was used to collect a pooled quality control sample. Samples were measured directly without evaporation. The applied LC-HRMS method was adopted from 35 as described in The measurement sequence was randomized, blank and pooled quality control samples were injected at regular intervals.
External calibration with compounds involving U 13 C internal standardization was carried out. Targeted analysis of the data was performed with Skyline Exploratory data analysis was performed with MetaboAnalyst 5.
For multivariate statistical methods the data were auto-scaled. From the 51 significantly changed metabolites adjusted p -value cut-off 0. Following this, a subnetwork was extracted based on the mapping of significant metabolites. In parallel to metabolome analysis, cells were incubated for live cell imaging experiments.
Reference measurements of mitochondrial superoxide production and morphometric analysis were performed via imaging workflows to accurately monitor cell status with an independent experimental set-up. Mitochondrial morphology was visualized with MitoTracker dye and mitochondrial superoxide production with MitoSox dye both from Thermo Fisher Scientific , as previously described 18 , For the imaging, we removed the cell culture medium and incubated the cells with staining solutions dilution in Live Cell Imaging solution, Thermo Fisher Scientific for 15 min.
At the end of the staining, cells were rinsed twice with pre-warmed PBS and immediately imaged in Live Cell Imaging solution. To this aim, ROI regions of interest were randomly selected from the MitoTracker images. During this step, the MitoSox channel was temporarily disabled to avoid selection bias.
Multiparametric morphological evaluation of the mitochondrial network was performed according to the method of Valente et al. Metabolomics data LC high-resolution mass spectrometry-based metabolomics dataset in rawdata have been deposited to the EMBL-EBI MetaboLights database Haug et al.
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Antioxidative stress is an overabundance of bioavailable respinse compounds that Antioxidant stress response with the Coping with anxiety attacks system 's ability to syress Antioxidant stress response threats. The fundamental Antioxidant stress response is oxidative stress Antioxidanh, which can lead to such disease states as coronary Minerals disease or cancer. Antioxidant compounds reduce Anntioxidant oxygen Antioxidannt ROS Antioxidant stress response, stresss reduces emitted free-radicals. When ROS function is impaired, there is more susceptibility to atopic disorders or diseases due to impairment of the attack-kill-present-respond behavior of the Th-1 immune response chain. Over-consumption of antioxidants could thus lead to antioxidative stress, where antioxidants might weaken or block the adaptive stress responses and cause dangerous health conditions and cause harm. The concept of antioxidative stress may best be described by excessive or detrimental nutritional consumption of a diet rich in antioxidants, [3] unbalancing the immune systems' pathogenic response processes. Serious health conditions can result if these processes are chronically unbalanced, ranging from acute to chronic.
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