THE IMPLICATIONS OF OXIDATIVE STRESS IN LONG-COVID PATHOGENESIS
Keywords:
long-COVID, oxidative stress, inflammation, polymorphisms, antioxidant defense
Abstract
As far as clinical presentation is concerned, following an episode of acute sickness, the SARS-CoV-2 infection may lead to the development of a number of complications known as post-acute sequelae of SARS-CoV-2 infection (PASC). The definition PASC, as well as its estimated prevalence evolved over the course of time and acquired knowledge. Although COVID-19 was initially characterized as an acute respiratory illness, convalescents frequently report diverse clinical manifestations related to several organ systems, referred to as long-COVID. However, the fundamental molecular mechanisms that are responsible for the incapacitating symptoms, occurring in patients with long-COVID, remain largely unexplained at this time. From molecular medicine point of view, one of the proposed postulates favors the impaired redox balance, that may serve as a central hub responsible for mechanisms disturbing the cellular homeostasis, innate immune response and metabolism. This review will try to tackle the current knowledge about the underlying mechanisms comprising the proposed interplay of the disturbed redox balance and inflammation, that may potentially contribute to the occurrence of tissue or organ damage that is linked with COVID-19, as well as the eventual manifestation of symptoms observed in individuals with long-COVID. One might assume that in certain individuals, there are mechanisms that may dominate over others. Genetic variability may offer some answers, especially in the case of polymorphisms occurring in genes that encode for antioxidant proteins and enzymes.
References
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31. Sutton A, Khoury H, Prip-Buus C, Cepanec C, Pessayre D, Degoul F. The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria. Pharmacogenetics. 2003;13:145–57.
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33. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135:2033–40.
34. Fan BE, Umapathi T, Chua K, Chia YW, Wong SW, Tan GWL, et al. Delayed catastrophic thrombotic events in young and asymptomatic post COVID-19 patients. J Thromb Thrombolysis. 2021;51:971–7.
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46. Ercegovac M, Asanin M, Savic-Radojevic A, Ranin J, Matic M, Djukic T, et al. Antioxidant Genetic Profile Modifies Probability of Developing Neurological Sequelae in Long-COVID. Antioxidants. 2022;11:954.
47. Zhang B-Z, Chu H, Han S, Shuai H, Deng J, Hu Y-F, et al. SARS-CoV-2 infects human neural progenitor cells and brain organoids. Cell Res. 2020;30:928–31.
48. Rutkai I, Mayer MG, Hellmers LM, Ning B, Huang Z, Monjure CJ, et al. Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates. Nat Commun. 2022;13:1745.
49. Stein SR, Ramelli SC, Grazioli A, Chung J-Y, Singh M, Yinda CK, et al. SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature. 2022;612:758–63.
2. Li J, Zhou Y, Ma J, Zhang Q, Shao J, Liang S, et al. The long-term health outcomes, pathophysiological mechanisms and multidisciplinary management of long COVID. Signal Transduct Target Ther. 2023;8:416.
3. Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress. Curr Biol CB. 2014;24:R453-462.
4. Noh H, Ha H. Reactive oxygen species and oxidative stress. Contrib Nephrol. 2011;170:102–12.
5. Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev. 2014;2014:360438.
6. Jarczak D, Nierhaus A. Cytokine Storm-Definition, Causes, and Implications. Int J Mol Sci. 2022;23:11740.
7. Delgado-Roche L, Mesta F. Oxidative Stress as Key Player in Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection. Arch Med Res. 2020;51:384–7.
8. Chernyak BV, Popova EN, Prikhodko AS, Grebenchikov OA, Zinovkina LA, Zinovkin RA. COVID-19 and Oxidative Stress. Biochem Biokhimiia. 2020;85:1543–53.
9. Cecchini R, Cecchini AL. SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression. Med Hypotheses. 2020;143:110102.
10. Carr AC, Rosengrave PC, Bayer S, Chambers S, Mehrtens J, Shaw GM. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Crit Care. 2017;21:300.
11. Jensen IJ, McGonagill PW, Berton RR, Wagner BA, Silva EE, Buettner GR, et al. Prolonged Reactive Oxygen Species Production following Septic Insult. ImmunoHorizons. 2021;5:477–88.
12. Kosanovic T, Sagic D, Djukic V, Pljesa-Ercegovac M, Savic-Radojevic A, Bukumiric Z, et al. Time Course of Redox Biomarkers in COVID-19 Pneumonia: Relation with Inflammatory, Multiorgan Impairment Biomarkers and CT Findings. Antioxidants. 2021;10:1126.
13. Mijatović S, Savić-Radojević A, Plješa-Ercegovac M, Simić T, Nicoletti F, Maksimović-Ivanić D. The Double-Faced Role of Nitric Oxide and Reactive Oxygen Species in Solid Tumors. Antioxidants. 2020;9:374.
14. Cappadona C, Rimoldi V, Paraboschi EM, Asselta R. Genetic susceptibility to severe COVID-19. Infect Genet Evol. 2023;110:105426.
15. Muchtaridi M, Amirah SR, Harmonis JA, Ikram EHK. Role of Nuclear Factor Erythroid 2 (Nrf2) in the Recovery of Long COVID-19 Using Natural Antioxidants: A Systematic Review. Antioxidants. 2022;11:1551.
16. Biolcati G, Aurizi C, Barbieri L, Cialfi S, Screpanti I, Talora C. Efficacy of the melanocortin analogue Nle4-D-Phe7-α-melanocyte-stimulating hormone in the treatment of patients with Hailey-Hailey disease. Clin Exp Dermatol. 2014;39:168–75.
17. Haghjooy Javanmard S, Ziaei A, Ziaei S, Ziaei E, Mirmohammad-Sadeghi M. The effect of preoperative melatonin on nuclear erythroid 2-related factor 2 activation in patients undergoing coronary artery bypass grafting surgery. Oxid Med Cell Longev. 2013;2013:676829.
18. Merry TL, Ristow M. Nuclear factor erythroid-derived 2-like 2 (NFE2L2, Nrf2) mediates exercise-induced mitochondrial biogenesis and the anti-oxidant response in mice. J Physiol. 2016;594:5195–207.
19. Duan F-F, Guo Y, Li J-W, Yuan K. Antifatigue Effect of Luteolin-6-C-Neohesperidoside on Oxidative Stress Injury Induced by Forced Swimming of Rats through Modulation of Nrf2/ARE Signaling Pathways. Oxid Med Cell Longev. 2017;2017:3159358.
20. Marzec JM, Christie JD, Reddy SP, Jedlicka AE, Vuong H, Lanken PN, et al. Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury. FASEB J Off Publ Fed Am Soc Exp Biol. 2007;21:2237–46.
21. Yu C, Xiao J-H. The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging. Oxid Med Cell Longev. 2021;2021:6635460.
22. Baird L, Yamamoto M. The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway. Mol Cell Biol. 2020;40:e00099-20.
23. Saito R, Suzuki T, Hiramoto K, Asami S, Naganuma E, Suda H, et al. Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response. Mol Cell Biol. 2016;36:271–84.
24. Liao W, Wang Z, Fu Z, Ma H, Jiang M, Xu A, et al. p62/SQSTM1 protects against cisplatin-induced oxidative stress in kidneys by mediating the cross talk between autophagy and the Keap1-Nrf2 signalling pathway. Free Radic Res. 2019;53:800–14.
25. Kwon J, Han E, Bui C-B, Shin W, Lee J, Lee S, et al. Assurance of mitochondrial integrity and mammalian longevity by the p62-Keap1-Nrf2-Nqo1 cascade. EMBO Rep. 2012;13:150–6.
26. Wei R, Enaka M, Muragaki Y. Activation of KEAP1/NRF2/P62 signaling alleviates high phosphate-induced calcification of vascular smooth muscle cells by suppressing reactive oxygen species production. Sci Rep. 2019;9:10366.
27. Pljesa-Ercegovac M, Savic-Radojevic A, Matic M, Coric V, Djukic T, Radic T, et al. Glutathione Transferases: Potential Targets to Overcome Chemoresistance in Solid Tumors. Int J Mol Sci. 2018;19:3785.
28. Chang C, Worley BL, Phaëton R, Hempel N. Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer. Cancers. 2020;12:2197.
29. Voetsch B, Jin RC, Bierl C, Benke KS, Kenet G, Simioni P, et al. Promoter polymorphisms in the plasma glutathione peroxidase (GPx-3) gene: a novel risk factor for arterial ischemic stroke among young adults and children. Stroke. 2007;38:41–9.
30. Lubos E, Loscalzo J, Handy DE. Glutathione peroxidase-1 in health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2011;15:1957–97.
31. Sutton A, Khoury H, Prip-Buus C, Cepanec C, Pessayre D, Degoul F. The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria. Pharmacogenetics. 2003;13:145–57.
32. Asanin M, Ercegovac M, Krljanac G, Djukic T, Coric V, Jerotic D, et al. Antioxidant Genetic Variants Modify Echocardiography Indices in Long COVID. Int J Mol Sci. 2023;24:10234.
33. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135:2033–40.
34. Fan BE, Umapathi T, Chua K, Chia YW, Wong SW, Tan GWL, et al. Delayed catastrophic thrombotic events in young and asymptomatic post COVID-19 patients. J Thromb Thrombolysis. 2021;51:971–7.
35. Singh K, Mittal S, Gollapudi S, Butzmann A, Kumar J, Ohgami RS. A meta‐analysis of SARS‐CoV‐2 patients identifies the combinatorial significance of D‐dimer, C‐reactive protein, lymphocyte, and neutrophil values as a predictor of disease severity. Int J Lab Hematol. 2021;43:324–8.
36. Fan BE, Wong SW, Sum CLL, Lim GH, Leung BP, Tan CW, et al. Hypercoagulability, endotheliopathy, and inflammation approximating 1 year after recovery: Assessing the long‐term outcomes in COVID ‐19 patients. Am J Hematol. 2022;97:915–23.
37. Jerotic D, Ranin J, Bukumiric Z, Djukic T, Coric V, Savic-Radojevic A, et al. SOD2 rs4880 and GPX1 rs1050450 polymorphisms do not confer risk of COVID-19, but influence inflammation or coagulation parameters in Serbian cohort. Redox Rep. 2022;27:85–91.
38. Chioh FW, Fong S-W, Young BE, Wu K-X, Siau A, Krishnan S, et al. Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation. eLife. 2021;10:e64909.
39. Tsilingiris D, Vallianou NG, Karampela I, Christodoulatos GS, Papavasileiou G, Petropoulou D, et al. Laboratory Findings and Biomarkers in Long COVID: What Do We Know So Far? Insights into Epidemiology, Pathogenesis, Therapeutic Perspectives and Challenges. Int J Mol Sci. 2023;24:10458.
40. Bellanti F, Lo Buglio A, Vendemiale G. Redox Homeostasis and Immune Alterations in Coronavirus Disease-19. Biology. 2022;11:159.
41. Kong K, Chang Y, Qiao H, Zhao C, Chen X, Rong K, et al. Paxlovid accelerates cartilage degeneration and senescence through activating endoplasmic reticulum stress and interfering redox homeostasis. J Transl Med. 2022;20:549.
42. Zha D, Fu M, Qian Y. Vascular Endothelial Glycocalyx Damage and Potential Targeted Therapy in COVID-19. Cells. 2022;11:1972.
43. Vollbracht C, Kraft K. Oxidative Stress and Hyper-Inflammation as Major Drivers of Severe COVID-19 and Long COVID: Implications for the Benefit of High-Dose Intravenous Vitamin C. Front Pharmacol. 2022;13:899198.
44. Stefanou M-I, Palaiodimou L, Bakola E, Smyrnis N, Papadopoulou M, Paraskevas GP, et al. Neurological manifestations of long-COVID syndrome: a narrative review. Ther Adv Chronic Dis. 2022;13:20406223221076890.
45. Lippi G, Wong J, Henry BM. Myalgia may not be associated with severity of coronavirus disease 2019 (COVID-19). World J Emerg Med. 2020;11:193.
46. Ercegovac M, Asanin M, Savic-Radojevic A, Ranin J, Matic M, Djukic T, et al. Antioxidant Genetic Profile Modifies Probability of Developing Neurological Sequelae in Long-COVID. Antioxidants. 2022;11:954.
47. Zhang B-Z, Chu H, Han S, Shuai H, Deng J, Hu Y-F, et al. SARS-CoV-2 infects human neural progenitor cells and brain organoids. Cell Res. 2020;30:928–31.
48. Rutkai I, Mayer MG, Hellmers LM, Ning B, Huang Z, Monjure CJ, et al. Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates. Nat Commun. 2022;13:1745.
49. Stein SR, Ramelli SC, Grazioli A, Chung J-Y, Singh M, Yinda CK, et al. SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature. 2022;612:758–63.