Several biological Oxidative stress-induced diseases have been ascribed to polyphenols, including anti-inflammatory, antioxidant, diseaases and antimelanogenesis effects Zucca et al. and Karabulut, A. In particular, the lipid peroxidation can alter membrane permeability, transportation and fluidity [ 12 ]. Lovell, M.

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Oxidative Stress and Brain Health and Healing

Oxidative stress-induced diseases -

How does oxidative stress affect the body? Medically reviewed by Stacy Sampson, D. What is it? Free radicals Antioxidants Effects Conditions Risk factors Prevention Summary Oxidative stress is an imbalance of free radicals and antioxidants in the body, which can lead to cell and tissue damage.

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Exercise prevents cellular aging by boosting mitochondria Exercise is known to stave off the effects of aging, but how it manages this at a cellular level is not understood. Regular exercise as a unique form of physiological stress is able to trigger adaptation, while autophagy, especially selective mitochondrial autophagy, also called mitophagy, allows for such cardiovascular adaptation Wu N.

Cigarette smoke comprises a series of oxidants, free radicals, as well as organic components e. Endogenous ROS comprises the by-products of cellular metabolism in aerobic organisms. At low concentrations, they are usually involved in different cell processes, such as proliferation, differentiation, and apoptosis, like a second messenger in cell signaling Salehi et al.

ROS production within cells under physiological condition is dependent on mitochondria respiration, NOX, uncoupled NOS and XOR. The increase in ROS levels, its production in inappropriate cellular compartments or its production with defective forms during oxidative processes can trigger the development of numerous chronic-degenerative disorders, leading to severe damage to bio macromolecules Chen et al.

Oxidative stress, as a result of the imbalance between oxidative and antioxidative processes in cells, therefore plays an essential role in the pathogenesis of numerous chronic-degenerative disorders. The main cardiovascular risk factors, such as hypertension and hypercholesterolemia contribute to enhancing ROS generation, leading to oxidative stress Li et al.

From all these cardiovascular risk factors, hypertension is an essential factor in the development of cardiovascular diseases CVD Elahi et al. Small amounts of ROS in the cardiovascular system could provide remarkable benefits: anti-atherosclerotic, pro-angiogenesis and endogenous cardioprotective effects Taverne et al.

In CVD, gene expression is altered due to oxidative stress. Increased ROS levels modulate transcription factor activity, especially NF-κB, activator protein-1 AP-1 and the peroxisome proliferators-activated receptor PPAR family of transcriptional activators Elahi et al.

As a result of increasing ROS generation, one of the first events in atherogenesis, as well as in other CVDs correlated with endothelial dysfunction, is the oxidative modification of low-density lipoprotein LDL Singh et al.

Indeed, both cell membranes and LDL, enriched with phospholipids, are highly sensitive to oxidative modification.

Oxidized phospholipids, through receptor-mediated or receptor-independent pathways, can therefore then activate endothelial cells, induce endothelium adhesion molecules expression, attract monocytes, have endothelium cytotoxic effects, and increase proinflammatory gene activity and cellular growth factors Esper et al.

All of these processes provoke endothelial dysfunction, platelet aggregation, and metalloproteinase expression and favor thrombogenesis Esper et al. 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.

In the oxidation of aromatic amino acids, such as tyrosine, different products are formed due to interaction with ROS — dityrosine or RNS — 3-nitrotyrosine [ 8 ]. These oxidized-modified proteins are usually recognized and degraded in the cells, but some of them can accumulate over time and lead to cellular dysfunction.

A physiological example is the lipofuscin, a brown-yellow pigment that is a product of iron-catalyzed oxidation polymerization of proteins and lipids, as it is extremely resistant to proteolysis, it accumulates and it is used as an aging marker [ 10 ].

In biological systems, lipid peroxidation occurs in two forms, one enzymatically, involving the participation of cyclooxygenase and lipoxygenase in the oxidation of fatty acids and other nonenzyme medium, involving transition metal, the reactive species oxygen, nitrogen and others [ 11 ].

Excess peroxidation results are very damaging to the cell, despite contribute to the inflammatory response, due to its importance in the cascade reaction from arachidonic acid to prostaglandin formation.

The action of free radicals on lipids leads to the formation of lipid hydroperoxides and aldehydes, such as malondialdehyde, 4-hydroxynonenal and isoprostanes that contribute further to increased cellular toxicity and can be detected in biological samples to measure oxidative stress.

Lipid peroxidation disrupts the normal structure and function of lipid bilayers surrounding both the cell itself and in the membranes of organelles.

In particular, the lipid peroxidation can alter membrane permeability, transportation and fluidity [ 12 ]. The chronicity of the process in question has important implications for the etiologic process of many chronic diseases, including atherosclerosis, diabetes, obesity, neurodegenerative disorders and cancer [ 1 ].

The antioxidant defense system has the primary objective to maintain the oxidative process within physiological limits and subject to regulation by preventing oxidative damage from spreading, culminating in systemic irreparable damage.

The enzymatic defense system includes enzymes such as superoxide dismutase SOD , catalase CAT and glutathione peroxidase GPx. CAT and GPx enzymes act with the same purpose, to prevent the hydrogen peroxide accumulation.

The human organism is constantly exposed to a vast number of molecules that can lead to oxidative stress, such as drugs and alcohol. However, there is a conserved cellular component to oxidative stress response, which is constituted by over genes responsible for detoxification and antioxidant protein production.

The first line of the antioxidant defense to exogenous toxins includes the enzymes involved in phase I and II metabolism. The phase I metabolism is responsible for increased compound polarity through oxidation, reduction or hydrolysis reactions.

The phase II metabolism, in the other hand, is responsible for facilitating the cellular export of those compounds; its reactions are mainly glucuronidation, acetylation and sulfation [ 15 ]. The enzymes that compose the cytochrome P are the most responsible for oxidation of drugs, chemicals and various endogenous substrates, such as eicosanoids, cholesterol, vitamin D3 and arachidonic acid [ 16 ].

The P is a superfamily of heme-thiolated enzymes with over members [ 17 ]. In humans, 57 functional genes and 58 pseudogenes are grouped according to the sequence similarity in 18 families and 44 subfamilies.

In steroidogenic tissues converts cholesterol into pregnenolone via the P side chain cleavage enzyme there is a prevalence of CYP enzymes located in mitochondria and the electron transport system is very susceptible to oxidative stress.

During the electron transport, a leakage of electron to the ultimate acceptor leads to their binding to oxygen, being considered a primary source of ROS, this may result in acceleration of ROS production in mitochondria. In this context, it is considered the effectiveness of electron transfer from NADPH to CYP enzymes for monooxygenation of substrates as a source of ROS because during the uncoupling reaction, without the presence of any substrates, the electron-transfer chain oxidizes NADPH and yields ROS.

During CYP2E1 metabolism is frequently observed this kind of uncoupling reactions, thus this enzyme is strongly associated to ROS production and oxidative stress [ 16 ].

The enzyme CYP2E1 is associated with the metabolism of small molecules, and can be induced by ethanol, obesity, diabetes and polyunsaturated fatty acids; this induction is related to toxicity and oxidative stress.

Another mechanism of CYP2E1 activation is the reduction of glutathione levels, upon acetaminophen administration, for example. Besides, this drug increases lipid peroxidation and protein carbonylation, enhancing the ROS production due to higher activity of CYP2E1 and being associated to hepatotoxicity mediated by MAP-kinase pathway [ 16 , 19 ].

Glutathione S-transferase GST is a family of intracellular enzymes that prevent the action of endogenous and exogenous toxins on the cells.

GSTs are multifunctional enzymes that participate in the phase II of the xenobiotic metabolism and catalyze the nucleophilic attack of the reduced form of glutathione GSH to potentially hazardous compounds.

How are involved in the metabolism of many carcinogens, environmental pollutants and cancer-fighting drugs, it is therefore reasonable to assume that the lack of specific isoenzymes has a significant effect on the tolerance of an organism to carcinogens [ 20 ]. Microsomal GSTs are designated MAPEG membrane-associated proteins in eicosanoid and glutathione metabolism and the only mitochondrial GST confirmed in humans is GST-kappa, which is also present in peroxisomes.

GSTs are normally found in biological medium as homo or heterodimers and these dimers have two active sites whose activities are independent. After combining with reduced glutathione GSH , these enzymes have higher specificity for a second substrate the electrophilic. GST enzymes participate in the metabolism of endogenous and exogenous compounds, for example, polycyclic aromatic hydrocarbons, phenylalanine and tyrosine amino acids, testosterone and progesterone.

These enzymes target endogenous compounds, maybe derived from peroxidation of polyunsaturated fatty acids present in cell membranes and the activity of reactive oxygen species [ 21 — 23 ].

As a consequence of redox unbalance in brain, one of the most affected structures is the lipid membrane [ 24 ]. Most of the cases of PD are idiopathic and some cases are genetic-related, but in general context, aging is a determinant factor.

In both idiopathic and genetic cases of PD, the oxidative stress plays a critical role in pathogenesis, being a common underlying mechanism. There is an elevated level of oxidized lipids, proteins and DNA associated with decreased glutathione level in the brain of PD patients.

Neurons usually do not store big amounts of iron, but with aging there is an accumulation of iron in the brain, especially in microglia, astrocytes and neurons from cortex and hippocampus. However, as the majority of patients do not develop TD, it is considered that genetics factors may define its occurrence but TD pathophysiology remains unclear.

One of the strongest hypotheses suggests that it is caused by oxidative stress originated from neurotoxic free-radical production upon antipsychotic medication.

This affirmation is supported by genetic polymorphisms evaluated in genes that encode a mitochondrial enzyme that prevents oxidative damage due to energetic metabolism manganese superoxide dismutase and a cytosolic flavoenzyme that prevents quinone reduction NADPH quinone oxidoreductase , playing a role in antioxidant defense [ 27 ].

Metabolic syndrome is a term that designates a cluster of health problems often associated to modern life style, including obesity, insulin resistance, dyslipidemia, impaired glucose tolerance and high blood pressure.

Due to oxidative DNA damage there is a direct correlation between diabetes and cancer. Diabetic patients present high levels of ROS because of elevated glucose, fatty acids and insulin blood levels; combined to lower antioxidative capacity derived from reduced glutathione synthesis.

To support those findings, it has been proved that polymorphisms in peroxisome proliferator-activated receptor-γ coactivator-1α PPARGC1A — a protein that regulates mitochondrial electron transport, leads to decontrolled redox activity [ 29 ]. Atherosclerosis is defined as an arterial disease characterized by fibrous and cholesterol rich plaques.

Atherosclerosis progression causes blood flow obstruction, hemorrhage due to rupture and thrombosis leading to strokes or myocardial infarctions. Many risk factors are associated with atherosclerosis development, the most widely known are serum low-density lipoprotein LDL cholesterol, low serum high-density lipoprotein HDL cholesterol, diabetes, hypertension, smoking, aging and oxidative stress [ 30 ].

During LDL oxidation, a progressive process and very important for the beginning of the formation of atheromatous plaque, the cholesterol is target of oxidants, which generate a variety of oxysterols.

On the other hand, lipid peroxidation products MDA and 4-HNE can react with histidine, cysteine or lysine residues of proteins, leading to formation of stable Michael adducts with a hemiacetal structure or to Schiff bases that undergo a rearrangement generating the Amadori products.

These aldehydes can derivatize Lys residues of apoB, which decreases the number of positive charges and interferes on LDL binding to LDLR and scavenger receptors [ 31 ].

In endothelial cells, besides stimulating the antioxidant defense mainly by glutathione , Nrf2 nuclear factor erythroid-derived 2 -like 2 suppresses inflammation-associated expression of adhesion molecules and cytokines, which are associated with the early stage of atherogenesis [ 29 ].

NAD P H oxidases NOXs are major sources of ROS in the vasculature, producing superoxide from molecular oxygen using NAD P H as the electron donor and endothelial NO synthase eNOS produce NO which represents a key element in the vasoprotective function of the endothelium.

However, pathological conditions associated with oxidative stress may become eNOS inefficient and promote the rapid inactivation of NO by excess superoxide [ 32 ].

There is growing evidence that reversal of oxidative stress with antioxidants can reduce the degree of myocardial ischemic injury and heart dysfunction [ 33 ]. Virus-induced oxidative stress has been reported during HIV, influenza virus, HBV, hepatitis C virus, encephalomyocarditis virus EMCV , respiratory syncytial virus RSV , dengue virus DENV and others [ 34 ].

Studies including rotavirus-infected patients showed that viral infection stimulates NO production, decreases superoxide dismutase and glutathione peroxidase activities and increases inducible nitric oxide synthase iNOS mRNA and iNOS expression in murine ileum [ 35 ].

Influenza virus is probably the best characterized pathogen modulating redox homeostasis. Influenza-induced ROS production has been associated with host immune and inflammatory responses, as well as modulation of viral replication.

Oxygen radicals and their derivatives are recognized as principal mediators of influenza virus-induced lung injury [ 36 ]. Within the Flaviviridae family, hepatitis C virus infection promotes oxidative stress and manipulates antioxidant systems, leading to liver damage and chronic disease.

Elevated levels of reactive oxygen species ROS are considered as a major factor contributing to HCV-associated pathogenesis. HCV core protein is considered as a major regulator affecting the release of ROS from mitochondria. In this context, mitochondria play a crucial role for the production of ROS in HCV-infected cells.

Several pathways are affected upon HCV infection to result in an induction of autophagy that interferes with various steps of the viral life cycle to promote a permanent viral infection. The assembly and release of viral particles are closely linked to the VLDL synthesis and occur via the secretory pathway.

Elevated glucose production, enhanced fatty acid uptake or upregulation of genes involved in lipid and cholesterol synthesis may contribute to oxidative stress-induced insulin resistance linked to HCV infection [ 36 ].

Induction of iNOS and production of NO, accumulation of ROS and RNS, as well as perturbation of the reduced glutathione GSH content are all signatures of Dengue virus DENV infection in different human cells and animal models. DENV infection resulted in an intracellular accumulation of NAD P H oxidase NOX2 -derived ROS in monocyte-derived dendritic cells Mo-DCs.

Alteration in the redox status of DENV-infected patients has been associated with increased inflammatory responses, cell death and correlated with different parameters associated with dengue disease [ 37 ].

The HPV infection, although necessary, is not sufficient to cause cancer and several studies have been devoted to the search for concurrent carcinogenic factors.

Among these cofactors, many evidence support the role of ROS. It is clear that viral infection induces ROS that in turn causes damage to all types of biological macromolecules.

Two different types of cooperative mechanisms are presumed to occur between ROS and HPV: i the ROS genotoxic activity and the HPV-induced genomic instability concur independently to the generation of the molecular damage necessary for the emergence of neoplastic clones.

Therefore, it seems reasonable to hypothesize that, while in most cases the cells react to HPV infection and can overcome the virus-induced ROS by activating apoptosis leading to termination of viral replication and lesion regression, in some of the infected cells a steady state balance between ROS generation and detoxification is established, partly due to viral-induced antioxidant response.

Thus, infected cells can aberrantly proliferate, paving the way to neoplastic progression HPV, exploit host cell survival mechanisms, through modulation of redox homeostasis, increasing the activity of catalase, SOD among other, as an adaptive response to the high ROS conditions of preneoplastic lesions.

Elevated GST and GSH provide the HPV hosting cell with improved oxidative damage detoxifying systems, but suppression of p53 and iNOS together with induction of vascular endothelial growth factor VEGF and resistance to ROS leads to the suppression of apoptosis and generates an oxidant fitting cell phenotype.

Therefore, the tumor cell adapts their metabolism in order to support their growth and survival, creating a paradox of high ROS production in the presence of high antioxidant levels [ 38 , 39 ]. Many signaling pathways that regulate the metabolism of ROS are also linked to tumorigenesis [ 40 , 41 ].

However, ROS can also promote tumor formation by inducing DNA mutations and pro-oncogenic signaling pathways. The production of low level of ROS is required for homeostatic signaling events.

It can be driven by NAD P H and NAD P H oxidase NOX , leading to the increase of cell proliferation and survival through the posttranslational modification of kinases and phosphatases.

At moderate levels, ROS induce the expression of stress-responsive genes such as HIF1A , which in turn trigger the expression of proteins providing prosurvival signals, such as the glucose transporter GLUT1 also known as SLC2A1 and vascular endothelial growth factor VEGF. The regulation of oxidative stress is an important factor not only for tumor development but also for the responses to anticancer therapies.

As high ROS levels are harmful to cells, oxidative stress can have a tumor-suppressive effect. This imparts pressure on cancer cells to adapt by developing strong antioxidant mechanisms. But despite having an enhanced antioxidant system, cancer cells maintain higher ROS levels than normal cells.

ROS are also involved in the increased expression of antioxidant genes related to the activation of transcription factors such as the Nrf2, activator protein 1 AP-1 , nuclear factor kB NF-kB and p53 [ 40 — 42 ]. Additionally, generating ROS is the mechanism of attack used by most of chemotherapies and radiotherapy [ 43 , 44 ].

Keap1 Kelch-like ECH-associated protein 1 sequesters Nrf2 nuclear factor erythroid-derived 2 in the cytoplasm by binding to its aminoterminal regulatory domain. Keap1 is a sulfhydryl S -rich protein, and several cysteine residues mediate the Keap1—inducer interaction.

When the interaction between Keap1 and Nrf2 disrupts, it allows Nrf2 to translocate to the nucleus. In the nucleus, Nrf2 controls several different antioxidant pathways by activating the expression of GSTs and other genes.

This control is important to avoid cellular wear caused by oxidative stress, thus hindering the onset of various diseases. The interindividual variation of the activity of antioxidant enzymes, for example, GST, considered by both environmental factors e.

Cytosolic GST present polymorphisms in humans and, this is probably the cause for differences in interindividual response to xenobiotics. The discovery of allelic variants of GSTP1, encoding enzymes with reduced catalytic activity, led many researchers to examine the hypothesis that the combinations of polymorphisms of the Mu class, Pi and Theta of GST contribute to disorders with environmental factors [ 45 , 46 ].

Studies with mice that exhibited a homozygous deletion of Nrf2 showed that Nrf2 is critical for inducing hepatic glutathione S-transferase GST , NAD P H: quinone oxidoreductase NQO1 and regulating levels of glutathione Figure 1 [ 47 ].

Besides genetic variants of GST, changes in phase I enzyme activity as encoded by the cytochrome P family can also have implications for the metabolism of specific nitrosamines from the tobacco, alcohol and other carcinogenic substances [ 48 ]. The GST enzymes are part of an integrated protection system, so it is important to note that the efficiency of this system depends on the combined action of other enzymes, such as γ-glutamylcysteine synthase γGluCysS and glutathione synthase, in order to provide glutathione as well as carriers to facilitate the elimination of glutathione conjugates [ 21 ].

Oxidative stress plays an essential role in Oxidatiev pathogenesis of chronic diseases such as cardiovascular diseases, diabetes, neurodegenerative diseases, and cancer. Long stress-idnuced exposure to Oxidtaive levels of pro-oxidant factors can cause Oxidative stress-induced diseases defects at a mitochondrial DNA level, as well Oxidative stress-induced diseases functional alteration of several enzymes Anti-venom serum production cellular Oxidative stress-induced diseases Oxidatjve to Oxidative stress-induced diseases in gene stress-knduced. The Oxidative stress-induced diseases lifestyle associated with processed food, exposure stress-incuced a wide range of chemicals and lack of exercise plays an important role in oxidative stress induction. However, the use of medicinal plants with antioxidant properties has been exploited for their ability to treat or prevent several human pathologies in which oxidative stress seems to be one of the causes. In this review we discuss the diseases in which oxidative stress is one of the triggers and the plant-derived antioxidant compounds with their mechanisms of antioxidant defenses that can help in the prevention of these diseases. Finally, both the beneficial and detrimental effects of antioxidant molecules that are used to reduce oxidative stress in several human conditions are discussed. Many natural biological processes in our bodies, such as breathing, digesting food, metabolize alcohol and drugs, and turning fats into energy produce harmful compounds called free radicals. Oxidative stress is an stresw-induced of free Oxirative and strfss-induced in the body, which dieases lead disaeses Oxidative stress-induced diseases and tissue Oxidtive. Oxidative stress occurs Oxidative stress-induced diseases and plays a Insulin pump training in the Oxidative stress-induced diseases process. A large body of scientific evidence suggests that long-term oxidative stress contributes to the development in a range of chronic conditions. Such conditions include cancerdiabetesand heart disease. In this article, we explore what oxidative stress is, how it affects the body, and how to reduce it. Oxidative stress can occur when there is an imbalance of free radicals and antioxidants in the body. However, cells also produce antioxidants that neutralize these free radicals.