Redox homeostasis, oxidative stress and antioxidant system in health and disease: the possibility of modulation by antioxidants
Abstract
Redox imbalance occurs when the factors of oxidative stress, known as prooxidants, outweigh the mechanisms of antioxidant protection. In a healthy state, homeostatic mechanisms ensure the balanced production of free radicals and a complete series of antioxidants responsible for their safe removal. The generation of free radicals is a part of physiological processes in a healthy organism, some of which act as specific signaling molecules, and their presence and activity are necessary in these processes. In various diseases such as cancer, cardiovascular disease, diabetes, autoimmune diseases, rheumatic diseases, systemic lupus, and skin diseases, the generation of free radicals overwhelms the protective mechanisms, leading to the development of "oxidative stress" that damages cells and tissues. To prevent the harmful effects of free radicals within cells, there exists a system of enzymatic antioxidant protection composed of superoxide dismutase (SOD), glutathione peroxidase (GSHPx), glutathione reductase (GR), glutaredoxin, reduced/oxidized glutathione (GSH/GSSG), and thioredoxin (TRX). The examples of non-enzymatic antioxidants are: antioxidant vitamins such as A, C and E, dihydrolypoic acid, metallothioneins, ceruloplasmin, coenzyme Q 10, urea, creatinine, etc. Redox balance is influenced by the circadian rhythm and external factors that constitute the "exposome", including dietary habits and lifestyle. Antioxidant supplementation has become increasingly popular for maintaining optimal body function. However, it is important to note that some antioxidants can exhibit prooxidant activity, emphasizing the need for controlled use. The relationship between the redox status of the body and the action of antioxidants enables the development of multidisciplinary research that connects biochemistry, molecular biology, nutritional science, natural product chemistry, and clinical practice.
References
1. Sies H. Oxidative Stress: Concept and Some Practical Aspects. Antioxidants. 2020;9:852.
2. Casas AI, Dao VT, Daiber A, Maghzal GJ, Di Lisa F, Kaludercic N, et al. Reactive Oxygen-Related Diseases: Therapeutic Targets and Emerging Clinical Indications. Antioxid Redox Signal. 2015;23:1171-1185.
3. Frijhoff J WPG, Stocker R, Cheng D, Davies SS, Knight A, Taylor E, et al. Clinical relevance of biomarkers of oxidative stress. Antioxid Redox Signal. 2015;23:1144–1170.
4. Halliwell B. Reactive species and antioxidants. Redox biology is a fundamental theme of aerobic life. Plant Physiol. 2006;141:312-322.
5. Sharifi-Rad M, Anil Kumar NV, Zucca P, Varoni EM, Dini L, Panzarini E, et al. Lifestyle, Oxidative Stress, and Antioxidants: Back and Forth in the Pathophysiology of Chronic Diseases. Front Physiol. 2020;11:694.
6. Trachootham D, Lu W, Ogasawara MA, Nilsa RD, Huang P. Redox regulation of cell survival. Antioxid Redox Signal. 2008;10:1343-1374.
7. Kotur-Stevuljević J, Spasić S, Jelić-Ivanović Z, Spasojević-Kalimanovska V, Stefanović A, Vujović A, et al. PON1 status is influenced by oxidative stress and inflammation in coronary heart disease patients. Clin Biochem. 2008;41:1067-1073.
8. Kotur-Stevuljević J, Memon L, Stefanović A, Spasić S, Spasojević-Kalimanovska V, Bogavac-Stanojević N, et al. Correlation of oxidative stress parameters and inflammatory markers in coronary artery disease patients. Clin Biochem. 2007;40:181-187.
9. Kotur-Stevuljević J, Spasić S, Stefanović A, Zeljković A, Stanojević-Bogavac A, Kalimanovska-Oštrić D, et al. Paraoxonase-1 (PON1) activity, but not PON1 Q192R phenotype, is a predictor of coronary artery disease in a middle-aged Serbian population. Clin Chem Lab Med. 2006;44:1106-1113.
10. Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine. 5th ed. Oxford: Oxford Academic; 2015. Online ed. doi: 10.1093/acprof:oso/9780198717478.001.0001.
11. Dröge W. Free Radicals in the Physiological Control of Cell Function. Physiol Rev. 2002;82:47-95.
12. Berlett B, Stadtman E. Protein Oxidation in Aging, Disease and Oxidative Stress. J Biol Chem. 1997;272:20313-20316.
13. Borza C, Muntean D, Dehelean C, Savoiu G, Serban C, Simu G, et al. Oxidative Stress and Lipid Peroxidation – A Lipid Metabolism Dysfunction. Lipid Metabolism. InTech. doi: 10.5772/51627.
14. Gonzalez-Hunt C, Wadhwa M, Sanders L. DNA damage by oxidative stress: Measurement strategies for two genomes. Curr Opin Toxicol. 2018;7:87-94.
15. Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, et al. Oxidative Stress: Harms and Benefits for Human Health. Oxid Med Cell Longev. 2017;2017:8416763.
16. Halliwell B. The antioxidant paradox: less paradoxical now? Br J Clin Pharmacol. 2013;75:637-644.
17. Mattson MP, Cheng A. Neurohormetic phytochemicals: low‐dose toxins that induce adaptive neuronal stress responses. Trends Neurosci. 2006;29:632–639.
18. Ayoka TO, Ezema BO, Eze CN, Nnadi CO. Antioxidants for the Prevention and Treatment of Non-communicable Diseases. J Explor Res Pharmacol. 2022;7:178-188.
19. Zhang P, Li T, Wu X, Nice EC, Huang C, Zhang Y. Oxidative stress and diabetes: antioxidative strategies. Front Med. 2020;14:583–600.
20. Howden R. Nrf2 and cardiovascular defense. Oxid Med Cell Longev. 2013;2013:104308.
21. Tavakoli R, Tabeshpour J, Asili J, Shakeri A, Sahebkar A. Cardioprotective Effects of Natural Products via the Nrf2 Signaling Pathway. Curr Vasc Pharmacol. 2021;19(5):525-541.
22. Davies JMS, Cillard J, Friguet B, Cadenas E, Cadet J, Cayce R, et al. The Oxygen Paradox, the French Paradox, and age-related diseases. Geroscience. 2017;39:499-550.
23. Goszcz K, Deakin SJ, Duthie GG, Stewart D, Leslie SJ, Megson IL. Antioxidants in cardiovascular therapy: panacea or false hope? Front Cardiovasc Med. 2015;2:29.
24. Manach C, Scalbert A, Morand C, Remesy C, Jimenez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr. 2004;79:727–747.
25. Otręba M, Kośmider L, Stojko J, Rzepecka-Stojko A. Cardioprotective Activity of Selected Polyphenols Based on Epithelial and Aortic Cell Lines. A Review. Molecules. 2020;25:5343.
26. Wang M, Simon JE, Aviles IF, He K, Zheng Q, Tadmor Y. Analysis of Antioxidative Phenolic Compounds in Artichoke (Cynara scolymus L.). J Agric Food Chem. 2003;51:601−608.
27. Crevar-Sakac M, Vujić Z, Kotur-Stevuljević J, Ivanisević J, Jelić-Ivanović Z, Milenković M, et al. Effects of atorvastatin and artichoke leaf tincture on oxidative stress in hypercholesterolemic rats. Vojnosanit Pregl. 2016;73:178-187.
28. Ogier N, Amiot M, Georgé S, Maillot M, Mallmann C, Maraninchi M, et al. LDL-cholesterol-lowering effect of a dietary supplement with plant extracts in subjects with moderate hypercholesterolemia. Eur J Nutr. 2013;52:547−557.
29. Irazabal MV, Torres VE. Reactive Oxygen Species and Redox Signaling in Chronic Kidney Disease. Cells. 2020;9:1342.
30. Kotur-Stevuljevic J, Simic-Ogrizovic S, Dopsaj V, Stefanovic A, Vujovic A, Ivanic-Corlomanovic T, et al. A hazardous link between malnutrition, inflammation and oxidative stress in renal patients. Clin Biochem. 2012;45:1202-1205.
31. Ta MH, Schwensen KG, Liuwantara D, Huso DL, Watnick T, Rangan GK. Constitutive renal Rel/nuclear factor-kappaB expression in Lewis polycystic kidney disease rats. World J Nephrol. 2016;5:339–357.
32. Aranda-Rivera AK, Cruz-Gregorio A, Pedraza-Chaverri J, Scholze A. Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls. Antioxidants. 2022;11:1112.
33. Ghosh S, Massey HD, Krieg R, Fazelbhoy ZA, Ghosh S, Sica DA, et al. Curcumin ameliorates renal failure in 5/6 nephrectomized rats: Role of inflammation. Am J Physiol Ren Physiol. 2009;296:F1146–F1157.
34. Kostić K, Brborić J, Delogu G, Simić MR, Samardžić S, Maksimović Z, et al. Antioxidant Activity of Natural Phenols and Derived Hydroxylated Biphenyls. Molecules. 2023;28:2646.
35. Eugenio-Pérez D, Medina-Fernández LY, Saldivar-Anaya JA, Molina-Jijón E, Pedraza-Chaverri J. Role of Dietary Antioxidant Agents in Chronic Kidney Disease. Free Radicals and Diseases. InTech. doi: 10.5772/63669.
36. Johansen JS, Harris AK, Rychly DJ, Ergul A. Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice. Cardiovasc Diabetol. 2005;4:5.
37. Stefanovic A, Kotur-Stevuljevic J, Spasic S, Vekic J, Zeljkovic A, Spasojevic-Kalimanovska V, Jelic-Ivanovic Z. HDL 2 particles are associated with hyperglycaemia, lower PON1 activity and oxidative stress in type 2 diabetes mellitus patients. Clin Biochem. 2010;43:1230-1235.
38. Ma X, Chen Z, Wang L, Wang G, Wang Z, Dong X, et al. The Pathogenesis of Diabetes Mellitus by Oxidative Stress and Inflammation: Its Inhibition by Berberine. Front Pharmacol. 2018;9:782.
39. Xie X, Chang X, Chen L, Huang K, Huang J, Wang S, et al. Berberine ameliorates experimental diabetes-induced renal inflammation and fibronectin by inhibiting the activation of RhoA/ROCK signaling. Mol Cell Endocrinol. 2013;381:56-65.
40. Zhu X, Guo X, Mao G, Gao Z, Wang H, He Q, Li D. Hepatoprotection of berberine against hydrogen peroxide-induced apoptosis by upregulation of Sirtuin 1. Phytother Res. 2013;27(3):417-21.
41. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Gen Develop. 1999;13:76–86.
42. Zhang X, Liang D, Lian X, Jiang Y, He H, Liang W, et al. Berberine activates Nrf2 nuclear translocation and inhibits apoptosis induced by high glucose in renal tubular epithelial cells through a phosphatidylinositol 3-kinase/Akt-dependent mechanism. Apoptosis. 2016;21:721-736.
43. Zhang P, Li T, Wu X, Nice EC, Huang C, Zhang Y. Oxidative stress and diabetes: antioxidative strategies. Front Med. 2020;14:583–600.
