Antioxidants: Positive or Negative Actors?

The term “antioxidant” is one of the most confusing definitions in biological/medical sciences. In chemistry, “antioxidant” is simply conceived “a compound that removes reactive species, mainly those oxygen-derived”, while in a cell context, the conceptual definition of an antioxidant is poorly understood. Indeed, non-clinically recommended antioxidants are often consumed in large amounts by the global population, based on the belief that cancer, inflammation and degenerative diseases are triggered by high oxygen levels (or reactive oxygen species) and that through blocking reactive species production, organic unbalances/disorders can be prevented and/or even treated. The popularity of these chemicals arises in part from the widespread public mistrust of allopathic medicine. In fact, reactive oxygen species play a dual role in dealing with different disorders, since they may contribute to disease onset and/or progression but may also play a key role in disease prevention. Further, the ability of the most commonly used supplements, such as vitamins C, E, selenium, and herbal supplements to decrease pathologic reactive oxygen species is not clearly established. Hence, the present review aims to provide a nuanced understanding of where current knowledge is and where it should go.

[1]  S. Antonyuk,et al.  The cysteine-reactive small molecule ebselen facilitates effective SOD1 maturation , 2018, Nature Communications.

[2]  Maja A. Marinović,et al.  De novo expression of transfected sirtuin 3 enhances susceptibility of human MCF-7 breast cancer cells to hyperoxia treatment , 2018, Free radical research.

[3]  M. Maes,et al.  Major Differences in Neurooxidative and Neuronitrosative Stress Pathways Between Major Depressive Disorder and Types I and II Bipolar Disorder , 2018, Molecular Neurobiology.

[4]  Marcel Deponte The Incomplete Glutathione Puzzle: Just Guessing at Numbers and Figures? , 2017, Antioxidants & redox signaling.

[5]  Ash A. Alizadeh,et al.  Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance. , 2017, Cancer discovery.

[6]  R. Gulati,et al.  Vitamin A toxicity presenting as bone pain , 2017, Archives of Disease in Childhood.

[7]  A. Dinkova-Kostova,et al.  The multifaceted role of Nrf2 in mitochondrial function , 2016, Current opinion in toxicology.

[8]  J. Arbiser,et al.  SIRT3 is attenuated in systemic sclerosis skin and lungs, and its pharmacologic activation mitigates organ fibrosis , 2016, Oncotarget.

[9]  Lei Wang,et al.  NRF2 promotes breast cancer cell proliferation and metastasis by increasing RhoA/ROCK pathway signal transduction , 2016, Oncotarget.

[10]  S. Powers,et al.  Exercise‐induced oxidative stress: past, present and future , 2016, The Journal of physiology.

[11]  A. Sidoroff,et al.  Influence of Vitamins on Secondary Reactive Oxygen Species Production in Sera of Patients with Resectable NSCLC , 2016, Diseases.

[12]  Pawar Rk,et al.  Antioxidants and their role in nurture human life and industry: A review , 2016 .

[13]  Toshinori Ito,et al.  Efficacy and Interaction of Antioxidant Supplements as Adjuvant Therapy in Cancer Treatment , 2016, Integrative cancer therapies.

[14]  P. Maurya,et al.  Quercetin-modulated erythrocyte membrane sodium-hydrogen exchanger during human aging: correlation with ATPase’s , 2016, Archives of physiology and biochemistry.

[15]  P. Álvarez,et al.  Antioxidant Intake and Antitumor Therapy: Toward Nutritional Recommendations for Optimal Results , 2015, Oxidative medicine and cellular longevity.

[16]  Chih-Yi Chen,et al.  Mutant p53 confers chemoresistance in non-small cell lung cancer by upregulating Nrf2 , 2015, Oncotarget.

[17]  J. Viña,et al.  Redox modulation of mitochondriogenesis in exercise. Does antioxidant supplementation blunt the benefits of exercise training? , 2015, Free radical biology & medicine.

[18]  Dean P. Jones,et al.  Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial SIRT3 , 2015, Nature Communications.

[19]  J. Arbiser,et al.  The antioxidant paradox: what are antioxidants and how should they be used in a therapeutic context for cancer. , 2014, Future medicinal chemistry.

[20]  Emily N. J. Ord,et al.  Oxidative Stress and the Use of Antioxidants in Stroke , 2014, Antioxidants.

[21]  Matthew E. Welsch,et al.  Regulation of Ferroptotic Cancer Cell Death by GPX4 , 2014, Cell.

[22]  Liang-Jun Yan Positive oxidative stress in aging and aging-related disease tolerance☆ , 2014, Redox biology.

[23]  Danny L Wang,et al.  SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage. , 2013, Free radical biology & medicine.

[24]  B. Halliwell The antioxidant paradox: less paradoxical now? , 2013, British journal of clinical pharmacology.

[25]  J. Chin,et al.  Vitamin E and the risk of prostate cancer: Updated results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT). , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  J. Crowley,et al.  Vitamin E and the Risk of Prostate Cancer The Selenium and Vitamin E Cancer Prevention Trial ( SELECT ) , 2011 .

[27]  Siegfried Hekimi,et al.  Taking a "good" look at free radicals in the aging process. , 2011, Trends in cell biology.

[28]  Scott E. Kern,et al.  Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis , 2011, Nature.

[29]  A. Dinkova-Kostova,et al.  The cytoprotective role of the Keap1–Nrf2 pathway , 2011, Archives of Toxicology.

[30]  Christophe Tzourio,et al.  Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials , 2010, BMJ : British Medical Journal.

[31]  W. Willett,et al.  Intakes of vitamins A, C, and E and use of multiple vitamin supplements and risk of colon cancer: a pooled analysis of prospective cohort studies , 2010, Cancer Causes & Control.

[32]  N. Chen,et al.  High levels of Nrf2 determine chemoresistance in type II endometrial cancer. , 2010, Cancer research.

[33]  M. Garcia-Conesa,et al.  Occurrence of urolithins, gut microbiota ellagic acid metabolites and proliferation markers expression response in the human prostate gland upon consumption of walnuts and pomegranate juice. , 2010, Molecular nutrition & food research.

[34]  I. Papassotiriou,et al.  FORT and FORD: two simple and rapid assays in the evaluation of oxidative stress in patients with type 2 diabetes mellitus. , 2009, Metabolism: clinical and experimental.

[35]  P. Galan,et al.  Effects of long-term antioxidant supplementation and association of serum antioxidant concentrations with risk of metabolic syndrome in adults. , 2009, The American journal of clinical nutrition.

[36]  S. Ishikawa,et al.  Activation of DNA methyltransferase 1 by EBV latent membrane protein 2A leads to promoter hypermethylation of PTEN gene in gastric carcinoma. , 2009, Cancer research.

[37]  R. Newman,et al.  Impact of antioxidant supplementation on chemotherapeutic toxicity: A systematic review of the evidence from randomized controlled trials , 2008, International journal of cancer.

[38]  A. Vickers,et al.  Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? , 2008, Journal of the National Cancer Institute.

[39]  P. Nguyen,et al.  DNMT1 as a Molecular Target in a Multimodality-Resistant Phenotype in Tumor Cells , 2008, Molecular Cancer Research.

[40]  P. Canter Herb, Nutrient, and Drug Interactions: Clinical Implications and Therapeutic Strategies , 2007 .

[41]  N. Pattabiraman,et al.  Human p53 is inhibited by glutathionylation of cysteines present in the proximal DNA-binding domain during oxidative stress. , 2007, Biochemistry.

[42]  Dean P. Jones Redefining oxidative stress. , 2006, Antioxidants & redox signaling.

[43]  Mar Larrosa,et al.  Urolithins, ellagic acid-derived metabolites produced by human colonic microflora, exhibit estrogenic and antiestrogenic activities. , 2006, Journal of agricultural and food chemistry.

[44]  Timothy H Murphy,et al.  Induction of the Nrf2-driven Antioxidant Response Confers Neuroprotection during Mitochondrial Stress in Vivo* , 2005, Journal of Biological Chemistry.

[45]  G. Koren,et al.  Pregnancy outcome following high doses of Vitamin E supplementation. , 2005, Reproductive toxicology.

[46]  R. Clayman Effect of Vitamin C Supplements on Urinary Oxalate and pH in Calcium Stone-Forming Patients , 2005 .

[47]  J. Arbiser,et al.  Reactive oxygen signaling and MAPK activation distinguish Epstein-Barr Virus (EBV)-positive versus EBV-negative Burkitt's lymphoma. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Alain Favier,et al.  The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. , 2004, Archives of internal medicine.

[49]  A. Folsom,et al.  Does supplemental vitamin C increase cardiovascular disease risk in women with diabetes? , 2004, The American journal of clinical nutrition.

[50]  P. Galan,et al.  A Randomized, Placebo-Controlled Trial of the Health Effects of Antioxidant Vitamins and Minerals , 2004 .

[51]  B. Cassileth,et al.  Herb-Drug Interactions in Oncology , 2003 .

[52]  I. Heilberg,et al.  Effect of vitamin C supplements on urinary oxalate and pH in calcium stone-forming patients. , 2003, Kidney international.

[53]  A. Choi,et al.  Identification of Activating Transcription Factor 4 (ATF4) as an Nrf2-interacting Protein , 2001, The Journal of Biological Chemistry.

[54]  N. Binkley,et al.  Hypervitaminosis A and bone. , 2009, Nutrition reviews.

[55]  G. Pascal,et al.  Vitamin A in pregnancy: requirements and safety limits. , 2000, The American journal of clinical nutrition.

[56]  J. Fahey,et al.  Antioxidant functions of sulforaphane: a potent inducer of Phase II detoxication enzymes. , 1999, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[57]  B. Cartmel,et al.  Effects of long-term intake of retinol on selected clinical and laboratory indexes. , 1999, The American journal of clinical nutrition.

[58]  H Gerster,et al.  High-dose vitamin C: a risk for persons with high iron stores? , 1999, International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition.

[59]  J. Palmgren,et al.  Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. , 1996, Journal of the National Cancer Institute.

[60]  G. Omenn,et al.  Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. , 1996, The New England journal of medicine.

[61]  K. Rothman,et al.  Teratogenicity of high vitamin A intake. , 1995, The New England journal of medicine.

[62]  D. Albanes,et al.  The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. , 1994, The New England journal of medicine.

[63]  N. Davidson,et al.  Chemoprotection by inducers of electrophile detoxication enzymes. , 1993, Basic life sciences.

[64]  B. Halliwell,et al.  The antioxidants of human extracellular fluids. , 1990, Archives of biochemistry and biophysics.

[65]  H. Biesalski Comparative assessment of the toxicology of vitamin A and retinoids in man. , 1989, Toxicology.