As a result, it is important to seek out natural sources of antioxidants, in the form of a healthful diet. Consuming fruits and vegetables has been linked to a lower rate of chronic diseases, and antioxidants may play a role. However, it is unlikely that consuming added antioxidants, especially in processed foods, will provide significant benefits.

In addition, anyone considering taking antioxidant supplements should speak to a health provider first. Read the article in Spanish. Free radicals are unstable atoms that can cause damage to cells and lead to illnesses and the aging process.

Exactly what impact do they have on the…. Eating a balanced diet is vital for healthful living. Figs contain protein, fiber, and iron, among many other nutrients. Learn more about the…. What are micronutrients? Read on to learn more about these essential vitamins and minerals, the role they play in supporting health, as well as….

Adding saffron supplements to standard-of-care treatment for ulcerative colitis may help reduce inflammation and positively benefit patients, a new….

My podcast changed me Can 'biological race' explain disparities in health? Why Parkinson's research is zooming in on the gut Tools General Health Drugs A-Z Health Hubs Health Tools Find a Doctor BMI Calculators and Charts Blood Pressure Chart: Ranges and Guide Breast Cancer: Self-Examination Guide Sleep Calculator Quizzes RA Myths vs Facts Type 2 Diabetes: Managing Blood Sugar Ankylosing Spondylitis Pain: Fact or Fiction Connect About Medical News Today Who We Are Our Editorial Process Content Integrity Conscious Language Newsletters Sign Up Follow Us.

Medical News Today. Health Conditions Health Products Discover Tools Connect. How can antioxidants benefit our health? Medically reviewed by Natalie Olsen, R. Benefits Types Food sources Diet Risks Supplements.

How we vet brands and products Medical News Today only shows you brands and products that we stand behind. Our team thoroughly researches and evaluates the recommendations we make on our site. To establish that the product manufacturers addressed safety and efficacy standards, we: Evaluate ingredients and composition: Do they have the potential to cause harm?

Fact-check all health claims: Do they align with the current body of scientific evidence? Assess the brand: Does it operate with integrity and adhere to industry best practices?

We do the research so you can find trusted products for your health and wellness. Read more about our vetting process. Was this helpful? Share on Pinterest Colorful fruits and vegetables can offer a range of antioxidants. Food sources. Share on Pinterest Pomegranate is one source of antioxidants.

Dietary tips. Share on Pinterest Drinking a cup or two of green tea is thought to provide health benefits because of the antioxidants. How we reviewed this article: Sources. Medical News Today has strict sourcing guidelines and draws only from peer-reviewed studies, academic research institutions, and medical journals and associations.

If the endpoint of the trial is disease incidence or mortality, such studies could help to validate or disprove the biomarker concept.

On the contrary, free radical-mediated lipid peroxidation proceeds randomly without specificity. Lipid peroxidation can neither be programmed nor regulated. Furthermore, some negative effects of antioxidants when used in dietary supplements ascorbic acid, flavanoids, carotenoids, α-lipoic acid and synthetic compounds have came out in the last few decades [ ].

For example, Ascorbic acid has both antioxidant and pro-oxidant effects, depending upon the dose [ ]. Low electron potential and resonance stability of ascorbate and the ascorbyl radical have enabled ascorbic acid to enjoy the privilege as an antioxidant [ , ].

In ascorbic acid alone treated rats, ascorbic acid has been found to act as a CYP inhibitor. Similar activity has also been observed for other antioxidants-quercetin and chitosan oligosaccahrides [ ], which may act as potential CYP inhibitors. Specifically, Phase I genes of xenobiotic biotransformation, namely, CYP1A1, CYP2E1, and CYP2C29, have been previously reported to be downregulated in female rats in the presence of a well known antioxidant, resveratrol [ ].

At higher oxygen tension, carotenoids tend to lose their effectiveness as antioxidants. In a turn around to this, the pro-oxidant effect of low levels of tocopherol is evident at low oxygen tension [ ]. Moreover, α-lipoic acid exerts a protective effect on the kidney of diabetic rats but a prooxidant effect in nondiabetic animals [ ].

The pro-oxidant effects have been attributed to dehydroxylipoic acid DHLA , the reduced metabolite of α-lipoic acid owing to its ability to reduce iron, initiate reactive sulfur-containing radicals, and thus damage proteins such as alpha 1-antiproteinase and creatine kinase playing a role in renal homeostasis [ ].

An increase in α-lipoic acid and DHLA-induced mitochondrial and submitochondrial production in rat liver and NADPH-induced and expression of p47phox in the nondiabetic kidney has also been observed [ ]. Depending on the type and level of ROS and RNS, duration of exposure, antioxidant status of tissues, exposure to free radicals and their metabolites leads to different responses—increased proliferation, interrupted cell cycle, apoptosis, or necrosis [ ].

There has been ever increasing knowledge in the role of oxygen derived pro-oxidants and antioxidants that play crucial role in both normal metabolism and several clinical disease states. Antioxidants exhibit pro-oxidant activity depending on the specific set of conditions.

Furthermore, while antioxidants may have reduced free-radical damage to normal tissues leading to diminished toxicity, the non-oxidative cytotoxic mechanisms of the drugs may remain unaffected by antioxidant supplementation. Further, the significant reductions in toxicity may alleviate dose-limiting toxicities to such an extent that more patients successfully complete prescribed regimens.

Advances in the field of biochemistry including enzymology have led to the use of various enzymes as well as endogenous and exogenous antioxidants having low molecular weight that can inhibit the harmful effect of oxidants. Kurutas EB, Ciragil P, Gul M, Kilinc M.

The effects of oxidative stress in urinary tract infection. Mediators Inflamm. Article PubMed CAS Google Scholar. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol.

Article CAS PubMed Google Scholar. Barbacanne MA, Souchard JP, Darblade B, Iliou JP, Nepveu F, Pipy B, Bayard F, Arnal JF.

Detection of superoxide anion released extracellularly by endothelial cells using cytochrome c reduction, ESR, fluorescence and lucigenin-enhanced chemiluminescence techniques.

Free Radic Biol Med. Vidrio E, Jung H, Anastasio C. Generation of Hydroxyl Radicals from Dissolved Transition Metals in Surrogate Lung Fluid Solutions.

Atmos Environ. Article CAS PubMed Central Google Scholar. Murphy E, Steenbergen C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury.

Physiol Rev. Article CAS PubMed PubMed Central Google Scholar. Bortoletto P, Lyman K, Camacho A, Fricchione M, Khanolkar A, Katz BZ. Chronic granulomatous disease. Pediatr Infect Dis J. Article PubMed PubMed Central Google Scholar. Tsao PS, Heidary S, Wang A, Chan JR, Reaven GM, Cooke JP. Protein kinase C-epsilon mediates glucose-induced superoxide production and MCP-1 expression in endothelial cells.

FASEB J. Google Scholar. Masters CJ. Cellular signalling: the role of the peroxisome. Cell Signal. Cederbaum AI. Molecular mechanisms of the microsomal mixed function oxidases and biological and pathological implications.

Redox Biol. Dröge W. Free radicals in the physiological control of cell function. Article PubMed Google Scholar. Valko M, Rhodes CJ, Moncol J, Izakovic MM, Mazura M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. Tatsuzawa H, Maruyama T, Hori K, Sano Y, Nakano M.

Singlet oxygen 1 Delta g O 2 as the principal oxidant in myeloperoxidase-mediated bacterial killing in neutrophil phagosomes. Biochim Biophys Res Commun. Article CAS Google Scholar.

Lloyd RV, Hanna PM, Mason RP. The origin of the hydroxyl radical oxygen in the Fenton reaction. Stohs SJ, Bagchi D. Oxidative mechanisms in the toxicity of metal ions. Pepper JR, Mumby S, Gutteridge JC. Sequential oxidative damage, and changes in iron binding and iron oxidizing plasma antioxidants during cardiopulmonary bypass surgery.

Free Radic Res. Jomova K, Valko M. Importance of iron chelation in free radical-induced oxidative stress and human disease.

Curr Pharm Des. Saito H, Hayashi H. Transformation rate between ferritin and hemosiderin assayed by serum ferritin kinetics in patients with normal iron stores and iron overload.

Nagoya J Med Sci. PubMed PubMed Central Google Scholar. Ghafourifar P, Cadenas E. Mitochondrial nitric oxide synthase. Trends Pharmacol Sci.

Bergendi L, Benes L, Durackova Z, Ferencik M. Chemistry, physiology and pathology of free radicals. Life Sci. Chiueh CC. Neuroprotective properties of nitric oxide.

Ann NY Acad Sci. Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol. CAS PubMed Google Scholar. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease.

Young IS, Woodside JV. Antioxidants in health and disease. J Clin Pathol. Flora SJ. Structural, chemical and biological aspects of antioxidants for strategies against metal and metalloid exposure.

Oxid Med Cell Longev. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Uchida K. Prog Lipid Res. Carini M, Aldini G, Facino RM. Mass spectrometry for detection of 4-hydroxy- trans onenal HNE adducts with peptides and proteins. Mass Spectrom Rev. Cracowski JL, Durand T, Bessard G.

Isoprostanes as a biomarker of lipid peroxidation in humans: physiology, pharmacology and clinical implications. Montuschi P, Barnes PJ, Roberts LJ. Isoprostanes: markers and mediators of oxidative stress.

Histidine and lysine as targets of oxidative modification. Amino Acids. Draper HH, Csallany AS, Hadley M. Urinary aldehydes as indicators of lipid peroxidation in vivo. Wilson R, Lyall K, Smyth L, Fernie CE, Riemersma RA. Basu S.

Isoprostanes: novel bioactive products of lipid peroxidation. Miraloglu M, Kurutas EB, Ozturk P, Arican O. Evaluation of local trace element status and 8-Iso-prostaglandin F2α concentrations in patients with Tinea pedis. Biol Proced Online. Morrow JD. Quantification of isoprostanes as indices of oxidant stress and the risk of atherosclerosis in humans.

Arterioscler Thromb Vasc Biol. Moret-Tatay I, Iborra M, Cerrillo E, Tortosa L, Nos P, Beltrán B. Poli G, Leonarduzzi G, Biasi F, Chiarpotto E.

Oxidative stress and cell signalling. Curr Med Chem. Eizirik DL, Manndrup-Poulsen T. A chice of death - the signaltransduction of immuneimediated beta-cell apoptosis.

Buttke TM, Sandstrom PA. Oxidative stress as mediator of apoptosis. Immunol Today. Article Google Scholar. Niki E. Klaunig JE, Kamendulis LM, Hocevar BA. Oxidative stress and oxidative damage in carcinogenesis.

Toxicol Pathol. Pavlovic D, Kocic R, Kocic G, Jevtovic T, Radenkovic S, Mikic D, Stojanovic M, Djordjevic PB.

Effect of a four week metformin treatment on plasma and erythrocyte antioxidative defense enzymes in newly diagnosed obese NIDDM patientes. Diabetes Obes Metab. Diaz MN, Frei B, Vita JA, Keaney JF.

Antioxidants and atherosclerotic heart disease. N Engl J Med. Marinho HS, Real C, Cyrne L, Soares H, Antunes F. Hydrogen peroxide sensing, signaling and transcription factors regulation. Nabavi SF, Barber AJ, Spagnuolo C, Russo GL, Daglia M, Nabavi SM, Sobarzo-Sánchez E.

Nrf2 as molecular target for polyphenols: A novel therapeutic strategy in diabetic retinopathy. Crit Rev Clin Lab Sci. Pang C, Sheng Y, Jiang P, Wei H, Ji L. Chlorogenic acid prevents acetaminophen-induced liver injury: the involvement of CYP metabolic enzymes and some antioxidant signals.

J Zhejiang Univ Sci B. Prasad KN. Simultaneous Activation of Nrf2 and Elevation of Dietary and Endogenous Antioxidant Chemicals for Cancer Prevention in Humans.

J Am Coll Nutr. Chan K, Han XD, Kan YW. An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen.

Proc Natl Acad Sci U S A. High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes.

Toxicol Sci. Chan K, Kan YW. Nrf2 is essential for protection against acute pulmonary injury in mice. Fahey JW, Haristoy X, Dolan PM, Kensler TW, Scholtus I, Stephenson KK, Talalay P, Lozniewski A.

Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, Talalay P, Kensler TW.

Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice.

Braun S, Hanselmann C, Gassmann MG, Auf Dem Keller U, Born-Berclaz C, Chan K, Kan YW, Werner S. Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound.

Mol Cell Biol. Dhakshinamoorthy S, Long DJ, Jaiswal AK. Antioxidant regulation of genes encoding enzymes that detoxify xenobiotics and carcinogens. Curr Top Cell Regul. Lee JM, Moehlenkamp JD, Hanson JM, Johnson JA. Nrf2-dependent activation of the antioxidant responsive element by tert-butylhydroquinone is independent of oxidative stress in IMR human neuroblastoma cells.

Biochem Biophys Res Commun. Lee JM, Hanson JM, Chu WA, Johnson JA. Phosphatidylinositol 3-kinase, not extracellular signal-regulated kinase, regulates activation of the antioxidant-responsive element in IMR human neuroblastoma cells.

J Biol Chem. Alam J, Wicks C, Stewart D, Gong P, Touchard C, Otterbein S, Choi AM, Burow ME, Tou J. Mechanism of heme oxygenase-1 gene activation by cadmium in MCF-7 mammary epithelial cells.

Role of p38 kinase and Nrf2 transcription factor. Kim YC, Masutani H, Yamaguchi Y, Itoh K, Yamamoto M, Yodoi J. Hemin-induced activation of the thioredoxin gene by Nrf2. A differential regulation of the antioxidant responsive element by a switch of its binding factors.

Orino K, Lehman L, Tsuji Y, Ayaki H, Torti SV, Torti FM. Ferritin and the response to oxidative stress. Biochem J. Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors. Chanas SA, Jiang Q, McMahon M, McWalter GK, McLellan LI, Elcombe CR, Henderson CJ, Wolf CR, Moffat GJ, Itoh K, Yamamoto M, Hayes JD.

Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female mice. Hayes JD, Chanas SA, Henderson CJ, McMahon M, Sun C, Moffat GJ, Wolf CR, Yamamoto M.

The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin.

Biochem Soc Trans. Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S, Yamamoto M. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages.

Nguyen T, Huang HC, Pickett CB. Transcriptional regulation of the antioxidant response element. Activation by Nrf2 and repression by MafK. Wild AC, Moinova HR, Mulcahy RT. Regulation of gamma-glutamylcysteine synthetase subunit gene expression by the transcription factor Nrf2.

Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, Cook JL. Yu R, Lei W, Mandlekar S, Weber MJ, Der CJ, Wu J, Kong AN. Role of a mitogen-activated protein kinase pathway in the induction of phase II detoxifying enzymes by chemicals.

Huang HC, Nguyen T, Pickett CB. Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2. Li J, Lee JM, Johnson JA.

Microarray analysis reveals an antioxidant responsive element-driven gene set involved in conferring protection from an oxidative stress-induced apoptosis in IMR cells. Li J, Johnson JA. Time-dependent changes in ARE-driven gene expression by use of a noise-filtering process for microarray data.

Physiol Genomics. Johnson DA, Andrews GK, Xu W, Johnson JA. Activation of the antioxidant response element in primary cortical neuronal cultures derived from transgenic reporter mice. J Neurochem.

Kang KW, Cho MK, Lee CH, Kim SG. Activation of phosphatidylinositol 3-kinase and Akt by tert-butylhydroquinone is responsible for antioxidant response element-mediated rGSTA2 induction in H4IIE cells.

Mol Pharmacol. Lee JM, Johnson JA. An important role of Nrf2-ARE pathway in the cellular defense mechanism. J Biochem Mol Biol. Suzuki T, Yamamoto M. Molecular basis of the Keap1-Nrf2 system.

Niture SK, Khatri R, Jaiswal AK. Regulation of Nrf2 — an update. Forman HJ, Davies KJA, Ursini F. How do nutritional antioxidants really work: nucleophilic tone and para-hormesis free radical scavenging in vivo.

Vnukov VV, Gutsenko OI, Milutina NP, Ananyan AA, Danilenko AO, Panina SB, Kornienko IV. Influence of SkQ1 on expression of Nrf2 transcription factor gene, ARE-controlled genes of antioxidant enzymes, and their activity in rat blood leukocytes. Biochemistry Mosc. Itoh K, Mimura J, Yamamoto M.

Discovery of the negative regulator of Nrf2, Keap1: a historical overview. Antioxid Redox Signal. Kensler TW, Wakabayashi N. Nrf2: friend or foe for chemoprevention?

Solis LM, Behrens C, Dong W, Suraokar M, Ozburn NC, Moran CA, Corvalan AH, Biswal S, Swisher SG, Bekele BN, Minna JD, Stewart DJ, Wistuba II.

Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features. Clin Cancer Res. Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO, Herman JG, Baylin SB, Sidransky D, Gabrielson E, Brock MV, Biswal S.

Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med. Article PubMed PubMed Central CAS Google Scholar. Shibata T, Kokubu A, Gotoh M, Ojima H, Ohta T, Yamamoto M, Hirohashi S. Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer.

Li K, Zhong C, Wang B, He J, Bi J. Nrf2 expression participates in growth and differentiation of endometrial carcinoma cells in vitro and in vivo. J Mol Histol. Zhang P, Singh A, Yegnasubramanian S, Esopi D, Kombairaju P, Bodas M, Wu H, Bova SG, Biswal S.

Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth. Mol Cancer Ther. Ji XJ, Chen SH, Zhu L, Pan H, Zhou Y, Li W, You WC, Gao CC, Zhu JH, Jiang K, Wang HD. Knockdown of NF-E2-related factor 2 inhibits the proliferation and growth of UMG human glioma cells in a mouse xenograft model.

Oncol Rep. Soini Y, Eskelinen M, Juvonen P, Kärjä V, Haapasaari KM, Saarela A, Karihtala P. Nuclear Nrf2 expression is related to a poor survival in pancreatic adenocarcinoma.

Pathol Res Pract. Kansanen E, Kuosmanen SM, Leinonen H, Levonen AL. The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, Yamamoto M, Motohashi H. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming.

Cancer Cell. Lennicke C, Rahn J, Lichtenfels R, Wessjohann LA, Seliger B. Redox proteomics: Methods for the identification and enrichment of redox-modified proteins and their applications. Cell Commun Signal.

Li L, Fath MA, Scarbrough PM, Watson WH, Spitz DR. Combined inhibition of glycolysis, the pentose cycle, and thioredoxin metabolism selectively increases cytotoxicity and oxidative stress in human breast and prostate cancer.

Ji X, Wang H, Zhu J, Zhu L, Pan H, Li W, Zhou Y, Cong Z, Yan F, Chen S. Knockdown of Nrf2 suppresses glioblastoma angiogenesis by inhibiting hypoxia-induced activation of HIF-1α. Int J Cancer. Karki R, Igwe OJ. PLoS One. Gasparini C, Celeghini C, Monasta L, Zauli G. NF-kB pathways in hematological malignancies.

Cell Mol Life Sci. Yamamoto Y, Gaynor RB. Role of NF-kB pathway in the pathogenesois of human disease states. Curr Mol Med. Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. Oliveira-Marques V, Marinho HS, Cyrne L, Antunes F.

Role of hydrogen peroxide in NF-kappaB activation: from inducer to modulator. Jung Y, Kim H, Min SH, Rhee SG, Jeong W. Dynein light chain LC8 negatively regulates NF-kappaB through the redox-dependent interaction with IkappaBalpha. Lee DF, Kuo HP, Liu M, Chou CK, Xia W, Du Y, Shen J, Chen CT, Huo L, Hsu MC, Li CW, Ding Q, Liao TL, Lai CC, Lin AC, Chang YH, Tsai SF, Li LY, Hung MC.

KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta. Mol Cell. Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, Alvarez K, Jayawardena S, De Smaele E, Cong R, Beaumont C, Torti FM, Torti SV, Franzoso G.

Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M. Reactive oxygen species promote TNF alpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases.

Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha.

Ma Q, Kinneer K, Ye J, Chen BJ. Inhibition of nuclear factor kappaB by phenolic antioxidants: interplay between antioxidant signaling and inflammatory cytokine expression. Feng X, Tan W, Cheng S, Wang H, Ye S, Yu C, He Y, Zeng J, Cen J, Hu J, Zheng R, Zhou Y.

Upregulation of microRNA in hepatic stellate cells may affect pathogenesis of liver fibrosis through the NF- B pathway. DNA Cell Biol. Collins T, Cybulsky MI. NF-kB: pivotal mediator or innocent bystander in atherogenesis?

J Clin Invest. Ghashghaeinia M, Toulany M, Saki M, Rodemann HP, Mrowietz U, Lang F, Wieder T. Potential roles of the NFkB and glutathione pathways in mature human erythrocytes. Cell Mol Biol Lett. Nicola JP, Peyret V, Nazar M, Romero JM, Lucero AM, Montesinos Mdel M, Bocco JL, Pellizas CG.

Shi X, Dong Z, Huang C, Ma W, Liu K, Ye J, Chen F, Leonard SS, Ding M, Castranova V, Vallyathan V. The role of hydroxyl radical as a messenger in the activation of nuclear transcription factor NF-kappaB. Mol Cell Biochem. Rahman I, Marwick J, Kirkham P. Redox modulation of chromatin remodeling: impact on histone acetylation and deacetylation, NF-kappaB and pro-inflammatory gene expression.

Biochem Pharmacol. Therapeutic potential of inhibition of NF-kB pathway in the treatment of inflammation and cancer. Karin M, Takahashi T, Kapahi P, Delhase M, Chen Y, Makris C, Rothwarf D, Baud V, Natoli G, Guido F, Li N.

Oxidative stress and gene expression: The AP-1 and NF-kB connections. Whitmarsh AJ, Davis RJ. Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med Berl.

Pinkus R, Weiner LM, Daniel V. Role of Oxidants and Antioxidants in the Induction of AP-1, NF-kB, and Glutathione S-Transferase Gene Expression. Pavlović D, Đorđević V, Kocić G. Facta Unıv Series: Med Biol. Go YM, Patel RP, Maland MC, Park H, Beckman JS, Darley-Usmar VM, Jo H. Evidence for peroxynitrite as a signaling molecule in flow-dependent activation of c-Jun NH 2 -terminal kinase.

Lander HM, Ogiste JS, Teng KK, Novogrodsky A. p21 ras as a common signaling target of reactive free radicals ans cellular redox stress. Nakamura H, Nakamura K, Yodoi J. Redox regulation of cellular activation. Ann Rev Immunol. Circu ML, Aw TY.

Reactive oxygen species, cellular redox systems and apoptosis. Trachootham D, Lu W, Ogasawara MA, Valle NR, Huang P.

Redox regulation of cell survival. Coskun M, Bjerrum JT, Seidelin JB, Nielsen OH. MicroRNAs in inflammatory bowel disease—pathogenesis, diagnostics and therapeutics.

World J Gastroenterol. Leung AKL, Sharp PA. MicroRNA Functions in Stress Responses. Antioxidant supplements may also interact with some medicines.

To minimize risk, tell your health care providers about any antioxidants you use. The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.

On this page Basics Summary Start Here. Learn More Related Issues Specifics. See, Play and Learn No links available. Research Statistics and Research Clinical Trials Journal Articles. Resources Find an Expert.

For You No links available. Examples of antioxidants include: Beta-carotene Lutein Lycopene Selenium Vitamin A Vitamin C Vitamin E Vegetables and fruits are rich sources of antioxidants.

NIH: National Center for Complementary and Integrative Health. Start Here. Antioxidant Supplements: What You Need To Know National Center for Complementary and Integrative Health Antioxidants Harvard School of Public Health Antioxidants: Protecting Healthy Cells Academy of Nutrition and Dietetics Antioxidants: What You Need to Know American Academy of Family Physicians Also in Spanish.

Please note the date of last review or update on all articles. No content on this site, regardless of date, should ever be used as a substitute for direct medical advice from your doctor or other qualified clinician. Thanks for visiting. Don't miss your FREE gift. The Best Diets for Cognitive Fitness , is yours absolutely FREE when you sign up to receive Health Alerts from Harvard Medical School.

Sign up to get tips for living a healthy lifestyle, with ways to fight inflammation and improve cognitive health , plus the latest advances in preventative medicine, diet and exercise , pain relief, blood pressure and cholesterol management, and more.

Get helpful tips and guidance for everything from fighting inflammation to finding the best diets for weight loss from exercises to build a stronger core to advice on treating cataracts. PLUS, the latest news on medical advances and breakthroughs from Harvard Medical School experts.

Sign up now and get a FREE copy of the Best Diets for Cognitive Fitness. Stay on top of latest health news from Harvard Medical School.

Recent Blog Articles. Flowers, chocolates, organ donation — are you in? What is a tongue-tie? What parents need to know. Which migraine medications are most helpful?

How well do you score on brain health? Shining light on night blindness. Can watching sports be bad for your health? Beyond the usual suspects for healthy resolutions. Lead triggers lipid peroxidation and increases glutathione peroxidase concentration in brain tissue.

Arsenic induces the production of peroxides, superoxides, nitric oxide and inhibits antioxidant enzymes such as glutathione-transferase, glutathione-peroxidase, and glutathione-reductase by binding to the sulfhydryl group.

The free radicals generated from these reactions can affect DNA, with substitutions of some DNA bases such as guanine with cytosine, guanine with thymine and cytosine with thymine Jan et al.

Exposure to ozone can affect lung function even in healthy individuals by increasing inflammatory infiltrate in the respiratory epithelium Wu X. The main endogenous sites of cellular redox-reactive species generation-including ROS and reactive nitrogen species RNS comprise mitochondrial electron transport chain ETC , endoplasmic reticulum ER , peroxisomes, membrane-bound NADPH oxidase NOX isoforms 1—5, dual oxidases Duox 1 and 2 complexes, and nitric oxide synthases isoforms 1—5 NOS1—3.

The complexes I and III of mitochondrial ETC produces superoxide anion Rodriguez and Redman, The mitochondrial ETC is considered to be the primary endogenous source of ROS but other internal sources are also present.

Other sources of ROS, primarily H 2 O 2 , are microsomes and peroxisomes. Immune cells, such as macrophages and neutrophils, can also generate ROS due to their oxygen-dependent mechanisms to fight against invading microorganisms based on NOX2 isoform Curi et al.

Furthermore, dysregulated ROS signaling may contribute to a multitude of diseases associated with oxidative stress Finkel, ROS are produced in mitochondria during aerobic metabolism Rodriguez and Redman, ROS generation within mitochondria oxidative metabolism is closely associated with ATP synthesis oxidative phosphorylation.

In aerobic organisms, the coupling of these reactions is the primary source of energy Papa et al. Mitochondria serve as a major ROS generator and, at the same time, as a ROS receptor. Covalent and enzymatic changes in proteins during or after protein biosynthesis as well as during protein cleavage or degradation promote disease through oxidative damage and mitochondrial dysfunction.

These post-translational changes participate in the regulation of mitochondrial function through free radical species and other messengers Hu and Ren, Since oxidative phosphorylation is a leaky process, 0.

This produces an incompletely O 2 reduction Hamanaka et al. Because of the anionic properties of superoxide radicals, they diffuse through biological lipid membranes at the meager extent.

They are sequentially reduced inside cells to form hydrogen peroxide and hydroxyl radical Bartosz, Furthermore, peroxyl and alkoxyl radicals, as well as hypochlorite ions, are also formed Valko et al. All these types of ROS can be very harmful to cells; in fact, they can oxidize and subsequently inactivate several functions of cell components and even DNA Valko et al.

All these processes may trigger irreversible apoptotic and necrotic cell death. Several studies indicate that human cells can also actively trigger ROS production at small doses, as part of signaling pathways, regulating cell survival and proliferation, as a defense mechanism against invaders Bartosz, ; Sena and Chandel, In particular, specific enzymatic systems, such as the NOX family, dedicated explicitly to superoxide radical production with physiological signaling purposes, are developed by cells Bedard and Krause, Beyond this, other internally generated sources of ROS are present in humans, including:.

i oxidative burst from phagocytes white blood cells during bacteria and virus killing and foreign proteins denaturation;. iv detoxification of toxic substances i. ROS decrease phosphatase activity, by inhibiting catalytic regions susceptible to oxidation, and, thus, enhance protein tyrosine phosphatase PTP phosphorylation and influences signal transduction Bedard and Krause, ROS can also improve signal transduction pathways that disturb the nuclear factor-κB NF-κB activation and translocation of this into the nucleus.

The DNA binding potential of oxidized NF-κB is significantly reduced. However, NF-κB may be decreased by TR or redox factor 1 Kabe et al. The above provokes ROS and RNS so it can strongly affect NF-κB-dependent inflammatory signals. Cyclopentenones are electrophilic anti-inflammatory prostaglandins which are conjugated with the reactive thiols of ROS-modified peptides and proteins and thus dampens ROS-mediated NF-κB signaling Homem de Bittencourt and Curi, On the other hand, endogenous stress has an intracellular origin.

Several studies have highlighted the role of cultural cell conditions, altering gene expression patterns of different genes and their DNA stability. Metabolic processes trigger different types of ROS, that are able to, if present at inadequate levels, oxidize DNA and induce various damage, such as double-stranded DNA breaks and deficiencies, often found in human tumors De Bont and van Larebeke, Moreover, there are non-enzymatic reactions, like the mitochondrial respiratory chain which involves NADPH oxidase, XOR, uncoupled endothelial NOS, cytochrome P enzymes, lipoxygenase and COX Sena and Chandel, ; Battelli et al.

Cellular oxidative metabolism produces free radicals and organic peroxides as by-products during cellular mitochondrial electron transport or through metal-catalyzed oxidation of metabolites and oxidoreductases Forman and Torres, ; Hussain et al. Moreover, nitric oxide is produced in hypoxic conditions in a respiratory chain reaction, and RNS may trigger reactive species production, such as reactive aldehydes, malondialdehyde MDA and 4-hydroxynon-enal Hussain et al.

However, an imbalance in this protective mechanism can lead to damage in cell molecules, such as DNA, proteins and lipids, resulting in cell death by necrotic and apoptotic processes Bhattacharyya et al.

Stimulated ROS production was first described in phagocytic cells, including neutrophils and macrophages, during phagocytosis or stimulation with a wide variety of agents through NADPH oxidase activation. The respiratory burst of neutrophils, as well as their degranulation, constitute a defensive response to host tissue damage, whether induced by mechanical muscle damage during exercise, thermal stress , chemical or infectious stimuli Lamy et al.

Nowadays, ROS production has also been observed in a variety of cells other than phagocytes, and their implication in physiologic signaling is well documented Di Meo et al. Lifestyle: smoking, alcohol consumption, adequate or inappropriate diet, exercise, training or untrained condition, contribute to oxidative stress.

Some research has shown the presence of reactive oxygen species and muscle level and their role in regulating muscle activity. Skeletal muscle fibers continuously generate reactive oxygen species at a low level, which increases during muscle contraction.

They exert multiple direct and indirect effects on muscle activity contractility, excitability, metabolism, and calcium homeostasis and are involved in skeletal muscle fatigue during strenuous exercise Pingitore et al.

Exhausting exercises, long exercises, overtraining syndrome, and overcoming limits as a phase of the initial onset of overtraining syndrome, induce a significant response to oxidative stress.

Instead, moderate exercise, low intensity training, and prolonged training, improve endogenous antioxidant status. Reactive oxygen species play an important role in cell signaling and in regulating the expression of antioxidant genes.

Physical exercise is considered the main treatment of non-pharmacological therapies along with lifestyle changes for various chronic diseases, especially cardiovascular diseases Ren and Taegtmeyer, The results of some experimental studies have highlighted the role of autophagy, a conservative process of catabolism for the degradation and recycling of cellular organs and nutrients, in the cardiovascular benefits offered by training Wu N.

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.

Coffee is incredibly high in antioxidants. Several studies have shown that people get more antioxidants from coffee than any other food group.

Antioxidant supplements are popular, but evidence suggests that they have several drawbacks. This article explains what antioxidant supplements are…. Blueberries are highly nutritious and among the world's most powerful sources of antioxidants. Here are 10 evidence-based health benefits of….

Pyrroloquinoline quinone PQQ supplements are purported to boost your energy levels, mental focus, and longevity. This article explains everything….

Black tea offers a variety of health benefits, including improved cholesterol, better gut health and decreased blood pressure. Here are 10 health…. Yerba mate is a type of tea with powerful benefits for your health and weight.

Here are 7 ways that drinking yerba mate can improve your health. Berries are among the healthiest and most nutritious foods on earth. Here are 11 ways that eating berries can improve your health.

Honey is renowned for its rich, sweet flavor, versatility in the kitchen, and health benefits. Here are 7 honey benefits, all backed by science. Discover which diet is best for managing your diabetes. A Quiz for Teens Are You a Workaholic? How Well Do You Sleep?

Health Conditions Discover Plan Connect. Nutrition Evidence Based Antioxidants Explained in Simple Terms. By Atli Arnarson BSc, PhD on July 12, What they are Free radicals Food sources Antioxidant types Supplements Bottom line Antioxidants are molecules that can help your body fight off harmful free radicals, which have been linked to health conditions like diabetes and cancer.

What are antioxidants? How free radicals function. Antioxidants in foods. Types of dietary antioxidants. Should you take antioxidant supplements?