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HCV and oxidative stress: implications for HCV life cycle and HCV-associated pathogenesis. Olagnier D, Amatore D, Castiello L, Ferrari M, Palermo E, Diamond MS, et al. This was noted in squamous cell carcinoma as well as in the well-differentiated adenocarcinoma. Using proteomic and genomic approaches, authors have identified the protein targets Most of the nitrated proteins fall into 4 categories: oxidant defense such as manganese superoxide dismutase and carbonic anhydrase , energy production many glycolytic enzymes , structure such as α-actin, α- and β-tubulin, and vimentin , and those involved in apoptosis annexins.

Tyrosine nitration is one of the earliest markers found in brains from persons affected by AD, in the plaques of brains from persons with multiple sclerosis, and in degenerating upper and lower motor neurons in ALS patients 5 Nitrated α-synuclein selectively accumulates in Lewy bodies and protein inclusions in a wide range of pathologies AD, PD, synucleinopathies, and tauopathies 5.

Nitrated proteins have been evidenced in diverse inflammatory diseases, including ARDS, severe asthma, inflammatory bowel disease, chronic renal failure, rheumatoid arthritis, type 1 and type 2 diabetes, and cystic fibrosis 5.

On the other hand, basal protein nitration has been detected under physiologic conditions in most tissues, including plasma and the human pituitary, and some of these nitrated proteins have been identified. These data are consistent with the emerging perspective that low-level Tyr nitration may be a physiologic regulator of a signaling pathway Its concentration in urine might therefore serve as a noninvasive marker of protein oxidation.

Increased concentrations of di-Tyr have been reported in atherosclerosis, in which its accumulation positively correlates with disease severity, and in AD, cystic fibrosis, endstage renal disease, and acute inflammation with or without sepsis 5 Urinary concentrations of di-Tyr are also markedly increased 3- to 7-fold in children with kwashiorkor a severe form of protein-energy malnutrition , with or without infection Di-Tyr has also been proposed as a marker of whole-body oxidative stress status such as in atherosclerosis, acute inflammation, and systemic bacterial infections.

In this regard, measured di-Tyr concentrations were fold higher in LDL isolated from atherosclerotic lesions than in healthy individuals, and persons suffering from systemic bacterial infections had twice the concentration of di-Tyr in urine than did healthy individuals Several analytical methods have been developed to quantify di-Tyr in vivo and in vitro.

Unfortunately, HPLC with ultraviolet or fluorescence detection does not have sufficient specificity for the analysis of urine or tissue extracts because several other protein modifications e. Furthermore, derivatization-based methods may introduce artifactual oxidation product s because they require extreme pH values and high temperatures during derivatization.

LC-MS—based methods without derivatization may offer a solution to these problems. Furthermore, it offers a great advantage over other described methods, as it does not require any pretreatment other than centrifugation of the urine sample and addition of the labeled internal standard before injection Protein carbonyls may be generated by the oxidation of several amino acid side chains e.

The formation of carbonyl compounds is the most general and widely used marker of severe protein oxidation both in vitro and in vivo, with several assays developed for the quantification of these species 15 16 Specific carbonylated proteins have been detected in both the brain tissue and plasma of AD patients The observation of carbonylated proteins in plasma—a body fluid easily obtainable without invasive procedures and, more importantly and unlike brain samples, before the death of the patient—suggests that these oxidized species may be useful as diagnostic biomarkers for possibly early AD.

The carbonyl content in plasma proteins mainly albumin and γ-globulins from children with different forms of juvenile chronic arthritis was significantly higher than in healthy children, and more importantly, the carbonyls increased in parallel with the activity of the disease.

Correlation between the carbonyl concentration and the activity or the type of chronic juvenile arthritis indicates that plasma protein carbonyl groups are a good marker of inflammatory process activity and may allow the use of carbonyls as a clinical marker of antioxidant barrier impairment in this group of patients as well as for monitoring possible pharmacologic treatments Winterbourn et al.

Moreover, patients with acute pancreatitis had significantly increased plasma concentrations of protein carbonyls, which were related to disease severity, thus confirming that this protein modification could be a useful plasma marker of oxidative injury Cellular DNA damage can be caused by ROS generated under different conditions, and several techniques have been developed to measure the oxidatively modified nucleobases in DNA 7 Oxidative DNA damage seems to relate to an increased risk of cancer development later in life DNA subjected to attack by hydroxyl radical generates a wide range of base and sugar modification products Such products can be measured by HPLC, GC-MS, LC-MS, and antibody-based techniques 7 18 Usually 8-hydroxydeoxyguanosine 8OHdG is measured as an index of oxidative DNA damage 7 18 The advantages of and artifacts produced during measurement of 8OHdG in cellular DNA have been reviewed recently Antibody-based methods have also been developed for 8OHdG and are useful for visualization of damage, but they seem likely to be only semiquantitative 7.

DNA can also be damaged by RNS, undergoing mainly nitration and deamination of purines. Methods for the measurement of DNA base nitration and deamination products have been developed but may need more refinement and validation before they can be routinely applied to human materials 7.

None of the analytical methods mentioned above identifies where the oxidative DNA damage is located. Most studies are performed on DNA isolated from lymphocytes or total leukocytes from human blood, and it is assumed possibly erroneously? This can be achieved by HPLC and MS techniques 7.

However, 8OHdG can arise from degradation of oxidized dGTP in the DNA precursor pool, not just from removal of oxidized guanine residues from DNA by repair processes.

Furthermore, there are many other products of oxidative DNA damage. Hence, urinary 8OHdG is a partial measure of damage to guanine residues in DNA and its nucleotide precursor pool, and 8OHdG concentrations may not truly reflect rates of oxidative damage to DNA Nevertheless, the recently completed Biomarkers of Oxidative Stress Study BOSS , using acute CCl 4 poisoning in rodents as a model for oxidative stress, has demonstrated that 8OHdG in urine is a potential candidate general biomarker of oxidative stress, whereas neither leukocyte DNA-MDA adducts nor DNA-strand breaks resulted from CCl 4 treatment An important question regarding the use of any oxidation product to monitor oxidative stress in vivo is its fate in the body.

We therefore examined currently known aspects related to the in vivo metabolism of selected oxidized biomolecules. However, the metabolic pattern of HNE produced within cell membranes or lipoproteins during lipoperoxidation is inevitably very different from that produced by parenteral administration.

HNE is removed mainly by its intracellular metabolism. Mammalian cells possess highly active pathways of HNE metabolism, the HNE degradation rate depending strongly on the cellular concentration and on the initial HNE concentration.

The metabolic fate of HNE has been investigated in various mammalian cells and organs, such as hepatocytes, intestinal enterocytes, renal tubular cells, aortic and brain endothelial cells, synovial fibroblasts, neutrophils, thymocytes, the heart, and tumor cells Current knowledge indicates that the main primary metabolites of HNE are the HNE—GSH adduct, the corresponding carboxylic acid 4-hydroxynonenoic acid HNA , and the corresponding alcohol 1,4-dihydroxynonene DHN.

In most cell types, including hepatocytes, formation of HNE—GSH and HNA is much higher than that of DHN. Additionally, various other enzymes and nonenzymatic reactions should be taken into account for HNE metabolism.

Glutathione S -transferase activity is more than times faster than the rate of the nonenzymatic Michael addition reaction. Accelerated HNE formation or the addition of HNE to cells leads to a rapid decrease in intracellular GSH concentration The total rate of HNE degradation and the pattern of HNE metabolites vary depending on the pathophysiologically relevant conditions Despite the active and rapid metabolism of HNE, protein modification by HNE does occur.

As to the fate of protein—HNE adducts, there are two general possibilities: one is the degradation of HNE-modified proteins by the 20S proteasome; the other is the cross-linking of proteins and their subsequent accumulation, if they are not or almost not degradable, finally leading to cytotoxicity.

The main urinary metabolites are represented by 2 groups of compounds. One group comes from the formation of mercapturic acid from a DHN-GSH, which originates from the conjugation of HNE with GSH by glutathione S -transferases and the subsequent reduction of the aldehyde by a member of the aldo-keto reductase superfamily; b the lactone of HNA-GSH HNA-lactone—GSH , which originates from the conjugation of HNE followed by the oxidation of the aldehyde by aldehyde dehydrogenase; and c HNA-GSH, which originates from the hydrolysis of the corresponding lactone.

The other group consists of metabolites issuing from the ω-hydroxylation of HNA or HNA-lactone by cytochromes P 4A, followed eventually, in the case of ω-oxidized HNA-lactone, by conjugation with GSH and subsequent mercapturic acid formation The metabolism of HNE—protein adducts, involving probably the proteasome pathway, might take too long for the metabolites to be excreted in urine within 24 or 48 h, particularly because HNE has been shown to reduce some of the proteolytic activities of the proteasome The electrophilic nature of HNE and the high concentrations of endogenous available compounds thiols and His and Lys residues can lead to several competitive reactions among nucleophiles; thus, the accessibility of the nucleophile at a given site of HNE generation is the more relevant factor in which metabolic pathway is followed.

HNE is an endogenous electrophile permanently formed from lipoperoxidation of lipoproteins and cell membranes; it therefore can be expected that HNE is generated everywhere in the organism, but to a different extent. This and the above factors considered together imply that the metabolism of endogenous HNE likely shows quantitative differences dependent on the site of generation and, especially, on the ratio of free GSH to reactive proteins MDA is excreted mainly in the form of adducts with lysine and its N-acetylated derivative, both in humans and rats, indicating that its predominant reaction in vivo is with the ε-amino groups of the Lys residues of proteins.

Smaller amounts of adducts with serine and ethanolamine and the nucleic acid bases guanine and deoxyguanosine reflect reactions with these compounds Alterations in isoprostane biosynthesis, secretion, and excretion in physiologic and pathophysiologic states are attributable to several endogenous and exogenous regulatory mechanisms that control the availability of precursors required for isoprostane synthesis, such as dietary and tissue arachidonic acid content, oxygen concentration, and the generation of various free radical species After formation from esterified arachidonate, isoprostanes are quickly hydrolyzed via various phospholipases and further metabolized by β-oxidation.

A substantial portion of isoprostanes appear to undergo β-oxidation in tissues before their release into the plasma. Intact isoprostanes, together with their β-oxidized metabolites, are efficiently excreted into the urine.

Although urinary isoprostanes can come from lipid peroxidation in the kidney, evidence suggests that they originate mostly from free isoprostanes filtered from the circulation It is generally assumed that excessive isoprostane production, rather than inefficient excretion or metabolism, accounts for increased concentrations of these compounds in pathophysiologic settings in vivo, although this has not been studied carefully 65 There are several factors, at least theoretically, that might regulate endogenous free isoprostane concentrations in tissues and biological fluids, including the initial oxidation step of arachidonate by free radicals, the deesterification process that leads to the formation of free isoprostanes, and the subsequent metabolism and excretion of both the parent compounds and degraded metabolites into the urine.

After formation in tissues, esterified isoprostanes are enzymatically hydrolyzed in situ to form bioactive isoprostanes in their free acid form. This enzymatic cleavage step is also, at least theoretically, an important rate-limiting step for the formation of free isoprostanes in the circulation.

Weight loss has been reported to lead to a decrease in F 2 -IsoP concentrations. It has also been suggested that the lipolysis process during fasting might release 8-iso-PGF 2α from the adipose tissue, accounting for increased circulating concentrations of the compound seen during a h fast One of the major disadvantages of measuring NO 2 -Tyr in tissues or biological fluids is that nitrated proteins are broken down at variable rates, and NO 2 -Tyr is metabolized and excreted NO 2 -Tyr is metabolized to 3-nitrohydroxyphenylacetic acid NHPA , which is excreted in the urine as the major urinary metabolite.

This has led to the notion that measurement of urinary NHPA could be used as a marker of systemic NO 2 -Tyr formation in vivo. However, NHPA is not derived exclusively from metabolism of NO 2 -Tyr; it can also be formed via nitration of circulating para -hydroxyphenylacetic acid PHPA , a metabolite of Tyr that is present at high concentrations in plasma After intravenous injection of NO 2 -Tyr in rats, 0.

Furthermore, it has been observed that both the plasma protein-bound and free NO 2 -Tyr concentrations are not significantly affected by nitrate supplementation Differently, di-Tyr released from proteins is relatively resistant to metabolism into other compounds, is rapidly cleared from the blood, and is excreted by the kidney into urine in near-quantitative yield rather than being recycled into proteins The halogenated Tyr residues are ideal biomarkers for hypohalous acids because they retain chlorine and bromine and are stable under the acidic conditions required to hydrolyze proteins Nothing is currently known about the metabolism of halogenated Tyr residues, but they are potential substrates for dehalogenases or glutathione S -transferases.

Biomarkers may yield information on three progressive levels of disease outcome: a as measurable endpoints of damage to biomolecules such as lipids and proteins; b as functional markers of, for example, cognitive function; and c as endpoints related to specific disease.

Although the clinical symptoms of a disease are endpoints in themselves, they are not suitable, in many cases, for early detection and, therefore, prevention of diseases associated with oxidative stress. A series of biomarkers would be preferred, each validated in sequence.

To this end, the association between a biomarker and a disease should be defined. The most intuitive goals for a biomarker are to help diagnose symptomatic and presymptomatic disease and to provide surrogate endpoints to demonstrate clinical efficacy of new treatments. Validation of biomarkers requires multiple different steps Fig.

One step is analytical validation, which includes development of procedures, analysis of reference materials, and quality control. Another is validation of the fact that changes in biomarker concentration do reflect the later development of disease.

No currently used biomarker has yet fulfilled this key requirement of the ideal biomarker: that it is predictive of the later development of disease. Case—control studies on stored samples should be used to test the efficiency of biomarkers. Care must be taken to define and establish reference values or baseline profiles in healthy tissues, cells, or body fluids.

The use of a panel of biomarkers would enhance the positive predictive value of a test and minimize the proportion of false-positive and false-negative results. In particular, the last step in the validation process of a biomarker, i.

The availability of biomarkers that can provide an accurate assessment of the degree of oxidative damage will become important in clinical trials aimed at investigating the effectiveness of antioxidant therapy for preventing or reducing the risks of complications Fig. Although establishing the occurrence of oxidative stress in a human disease is an important first step, this alone does not determine whether oxidative stress plays a fundamental role in the pathogenesis of that disease.

This can be determined only by demonstrating that amelioration of the oxidative stress via treatment with antioxidants mitigates manifestations of the disease. To accomplish that requires in-depth understanding of the clinical pharmacology of antioxidant agents, which currently is lacking.

Although evidence from in vitro models e. This is particularly relevant and extremely important in the setting of disease research, in that the key reactive species are rarely known mainly because the possible sources for overproduction of reactive species are widespread , although there are a few limited situations in which the etiology is known e.

This is to some extent logical because it is the damage caused by reactive species that is important rather than the total amount of such species generated.

For example, increased concentrations of Cl-Tyr in the bronchoalveolar fluid from children with cystic fibrosis led to the conclusion that HOCl is produced early in cystic fibrosis and that it is a candidate for precipitating the fatal decrease in lung function associated with this disease That is, oxidation of samples can occur during typical sample handling, processing, and analysis such that measured concentrations are not at all reflective of the concentrations encountered in vivo.

This issue has plagued investigations of many different biomarkers of oxidation; for example, artifactual formation of NO 2 -Tyr see below.

The most widely used technique to evaluate lipid peroxidation is the TBARS assay, which includes MDA. TBA reacts with MDA to produce a stable chromogen that can be quantified by either spectrophotometry or HPLC. Although this technique is easy to use mainly the spectrophotometric assay , the use of the TBARS test to assess oxidative stress status in human fluids is problematic for several reasons: a aldehydes other than MDA may react with TBA to produce a compound that absorbs in the same range as MDA; b decomposition of lipid peroxides during the test itself may mask the actual MDA content in the fluid before testing; c the presence or absence of metal ions or other undefined radicals affects the rate of this decomposition, making reliability a problem; and d most TBA-reactive material, including MDA, in human body fluids is not a specific product of lipid peroxidation and may produce false-positive results 1 7.

The lack of specificity has rendered the simple spectrophotometric method rather obsolete. Instead, most researchers today use an HPLC modification of the TBARS method. This approach uses HPLC to separate the MDA—TBA adduct from interfering chromogens, thus improving the sensitivity, specificity, and reproducibility 1 7.

TBARS can be measured in tissues but are generally measured in plasma in the setting of epidemiologic research. Therefore, although the TBARS assay is accepted as an index of oxidative stress, this method quantifies MDA-like material and does not specifically measure MDA or lipid peroxidation.

However, the results of some of the studies we reviewed suggest that, because large differences in GSH and, particularly, in GSSG have been found in different investigations also for control values in healthy people , accurate revision of the methods used is needed The fact that GSSG values in human blood can span up to 2 orders of magnitude, even in controls, based on the method used justifies new efforts to identify and eliminate all possible pitfalls.

Furthermore, it is essential to revise the methods before attempting to interpret the role of an altered GSH or GSSG concentration in blood. Recent reports have documented that NO 2 -Tyr can be generated ex vivo during sample processing, in particular under acidic conditions , illustrating the limitations of some quantitative methods that do not use isotopically labeled internal standards e.

These findings highlight the importance of developing robust analytical methods and validating them in vivo. Numerous markers of oxidative stress and antioxidant status have been evaluated, but there has been little systematic effort to validate sensitive and specific biomarkers for oxidative damage in animal models.

The recently completed BOSS study, which was organized and sponsored by the National Institute of Environmental Health Sciences NIEHS , is the first comprehensive comparative study, to our knowledge, that has examined several proposed markers of oxidative stress in the same model system to determine which of the biomarkers used for noninvasive measurement of oxidative stress are most specific, sensitive, and selective 72 To this end, this multilaboratory validation study, performed by leading investigators in the field, used a well-documented animal model of oxidative stress, CCl 4 , administered to rats.

CCl 4 is a well-known hepatotoxin that induces free radical injury in the liver and other tissues when administered to rats.

In this comprehensive study, the time- and dose-dependent effects of acute CCl 4 poisoning on the oxidation products of lipids, proteins, and DNA were measured in blood, plasma, and urine. The criterion used to identify a good marker for the measurement of oxidative stress was a significant effect seen at both tested doses at more than one time point.

Differently, many other putative markers of oxidative stress, including oxidation products of plasma proteins and leukocyte DNA, are not reliable biomarkers for free radical damage induced by CCl 4 72 CCl 4 -mediated oxidative damage is just one example of the more general phenomenon of oxidative stress.

Other models also need to be studied. It still needs to be determined whether the identified biomarkers of oxidative damage in the present rodent model of CCl 4 poisoning would be applicable to other oxidative insults.

Therefore, other models of oxidative stress must be developed and studied for comparison. There is growing interest in identifying biomarkers for diseases in which oxidative stress is involved. Various invasive and semi-invasive means of assessing oxidative biomarkers are available; these include measurements in cerebrospinal fluid, synovial fluid, BAL fluid, urine, and tissue biopsies.

These other body fluids share some of the protein characteristics of plasma, with specific local additions that reveal interesting clinical information. Unfortunately, these samples are more difficult to obtain or preserve in a useful state than is plasma.

For example, the procedures for collecting cerebrospinal fluid and synovial fluid are invasive, involving pain and some risk, whereas urine is more difficult to process to a useful sample quickly in a clinical setting processing requires centrifugation to remove cells that can undergo lysis if left in suspension, prevention of microbial growth, and concentration.

Recent studies have therefore focused on noninvasive techniques to evaluate oxidative stress, e. The assessment of biomarkers of oxidative stress in exhaled breath condensate is one such approach and is emerging as a promising area of future research in inflammatory lung diseases The collection of exhaled breath condensate has several advantages over the more traditional methods of sampling the pulmonary airspaces, such as BAL fluid.

It is a simple, noninvasive approach, less expensive in terms of both equipment and personnel costs, may be repeated frequently, and can be applied to children, including neonates, and patients with severe disease in whom more invasive procedures are not possible It is currently used as a research and diagnostic tool in the free radical field, yielding information on redox disturbance and the degree and type of inflammation in the lung.

However, the standardization of measured concentrations of potential oxidative stress biomarkers e. With further technical developments, such an approach might ultimately have a role in the clinic, in helping to diagnose specific lung diseases.

The application of any new technical procedure in investigative studies or to the clinic requires its validation in terms of sensitivity, specificity, reproducibility, and correlation of the measurements with disease status.

The validity of exhaled breath condensate as a tool for the assessment of airway oxidative stress is still questionable because of limitations in the reproducibility of analyzed oxidative biomarkers, with respect to both intra- and interindividual variability Quantification of chemical markers of protein oxidation in human urine, plasma, and other biological fluids also may identify pathways that promote oxidative stress in vivo and might indicate the extent of protein damage if these markers are liberated by proteolysis and excreted into such fluids Di-Tyr and NO 2 -Tyr are promising markers for these purposes because they are excreted in the urine in near quantitative yields and are not generated ex vivo during analysis by isotope-dilution GC-MS These observations raise the possibility that assaying oxidized amino acids in urine and plasma might be a useful approach to monitoring oxidative stress for human clinical and epidemiologic studies.

Development of new biomarkers based on disease-induced protein modifications is limited by the lack of easy access to tissues from patient populations; therefore, the majority of discovery work will need to be carried out in animal models. The advantage provided by animal models is the ability to control and define disease stages; correlating these model diseases to actual patient populations has been difficult, however.

As the technology develops to allow higher throughput screening, these candidate markers can be more easily tested against large groups. The successful development of effective antioxidant therapies remains a key goal, the attainment of which is required to elucidate the role played by accumulation of toxic oxidized molecules in the clinical picture of diseases associated with oxidative stress.

The use of biomarkers provides a logical scientific basis for major intervention trials of antioxidants; such trials could, in turn, eventually validate or disprove the biomarker concept.

Any intervention trial that does take place should be accompanied by measurements of one or more relevant biomarkers at intervals during the study. If the endpoint of the trial is disease incidence or mortality, such studies could help to validate or disprove the biomarker concept. However, with regard to this matter, we must highlight the disappointing clinical evidence showing the failure of antioxidant therapy for oxidative stress-associated pathologies such as cardiovascular disease, coronary artery disease, AD, and COPD At best, use of antioxidants is controversial and the ideal antioxidant strategy is still unknown.

Human diseases that were found to be associated with increased oxidative stress on the basis of potential biomarkers of oxidative damage.

Chemical structures of NO 2 -Tyr, halogenated tyrosines, and di-Tyr. Chemical structures of protein carbonyls arising from direct oxidation of amino acid side chains.

Shown are 2-pyrrolidone resulting from direct oxidation of Pro residues , glutamic semialdehyde resulting from direct oxidation of Arg and Pro residues , α-aminoadipic semialdehyde resulting from direct oxidation of Lys residues , and 2-aminoketobutyric acid resulting from direct oxidation of Thr residues.

For simplicity, stereochemistries are not indicated. A biomarker is defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.

The most intuitive use for a biomarker is to help diagnose disease. Ideally, biomarkers of oxidative stress for human studies would be measurable in specimens that can be collected relatively easily, such as blood or urine.

To serve these purposes, however, an ideal biomarker of oxidative damage should fulfill several conditions see text and Fig. We are profoundly grateful to the unknown reviewers whose insightful and constructive suggestions inspired us to produce a better effort.

Preparation of this review was supported in part by FIRST Fondo Interno Ricerca Scientifica e Tecnologica , University of Milan, and by Fondazione Monte dei Paschi di Siena. Halliwell B, Gutteridge JMC.

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Possible methodological, mechanistic and clinical implications. Free radicals are oxygen-containing molecules with an uneven number of electrons. This uneven number of electrons allows free radicals to react easily with other molecules. Free radicals can cause large chain chemical reactions in your body because they react so easily with other molecules.

These reactions are called oxidation. They can be beneficial or harmful. Antioxidants are molecules that can donate an electron to a free radical without making themselves unstable. This causes the free radical to stabilize and become less reactive. Read on to learn how oxidative stress affects the body and how to manage and prevent this imbalance.

Oxidation is a normal and necessary process that takes place in your body. When functioning properly, free radicals can help fight off pathogens.

Pathogens lead to infections. When there are more free radicals present than can be kept in balance by antioxidants, the free radicals can start doing damage to fatty tissue, DNA, and proteins in your body. Proteins, lipids, and DNA make up a large part of your body, so that damage can lead to a vast number of diseases over time.

These include:. Everyone produces some free radicals naturally in their body through processes like exercise or inflammation. However, there are things you can do to minimize the effects of oxidative stress on your body. The main thing you can do is to increase your levels of antioxidants and decrease your formation of free radicals.

Eating five servings per day of a variety of fruits and vegetables is the best way to provide your body what it needs to produce antioxidants. Examples of fruits and vegetables include:. Other healthy lifestyle choices can also prevent or reduce oxidative stress. Here are some lifestyle choices that will help:.

Oxidative stress occurs naturally and plays a role in the aging 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 cancer , diabetes , and 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. In general, the body is able to maintain a balance between antioxidants and free radicals. Several factors contribute to oxidative stress and excess free radical production.

These factors can include:. This type of oxidative stress causes mild inflammation that goes away after the immune system fights off an infection or repairs an injury.

Uncontrolled oxidative stress can accelerate the aging process and may contribute to the development of a number of conditions.

To discover more evidence-based information and resources for healthy aging, visit our dedicated hub. Free radicals, including reactive oxygen species, are molecules with one or more unpaired electron. Examples of free radicals include:. Cells contain small structures called mitochondria, which work to generate energy in the form of adenosine triphosphate ATP.

Mitochondria combine oxygen and glucose to produce carbon dioxide, water, and ATP. Free radicals arise as byproducts of this metabolic process. External substances, such as cigarette smoke, pesticides, and ozone, can also cause the formation of free radicals in the body. Antioxidants are substances that neutralize or remove free radicals by donating an electron.

The neutralizing effect of antioxidants helps protect the body from oxidative stress. Examples of antioxidants include vitamins A, C, and E. Like free radicals, antioxidants come from several different sources.

Cells naturally produce antioxidants such as glutathione. Foods such as fruits and vegetables provide many essential antioxidants in the form of vitamins and minerals that the body cannot create on its own.

The effects of oxidative stress vary and are not always harmful. For example, oxidative stress that results from physical activity may have beneficial, regulatory effects on the body. Exercise increases free radical formation, which can cause temporary oxidative stress in the muscles.

However, the free radicals formed during physical activity regulate tissue growth and stimulate the production of antioxidants. Mild oxidative stress may also protect the body from infection and diseases.

In a study , scientists found that oxidative stress limited the spread of melanoma cancer cells in mice. This can contribute to aging and may play an important role in the development of a range of conditions.

Immune cells called macrophages produce free radicals while fighting off invading germs. These free radicals can damage healthy cells, leading to inflammation. Under normal circumstances, inflammation goes away after the immune system eliminates the infection or repairs the damaged tissue.

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.

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