sibmedСибирский научный медицинский журналСибирский научный медицинский журнал2410-25122410-2520ИЦиГ СО РАН10.18699/SSMJ20250604sibmed-2584Research ArticleОБЗОРЫREVIEWSРоль окислительного стресса в патогенезе COVID-19The role of oxidative stress in COVID-19 pathogenesishttps://orcid.org/0000-0003-4705-3823БыковЮ. В.BykovYu. V.

Быков Юрий Витальевич - к.м.н.

355017, Ставрополь, ул. Мира, 310

Yuri V. Bykov 0 candidate of medicine sciences.

355017, Stavropol, Mira st., 310

yubykov@gmail.comСтавропольский государственный медицинский университет Минздрава РоссииРоссияStavropol State Medical University of Minzdrav of RussiaRussian Federation2025290120264564051Copyright © Быков Ю.В., 20262026Быков Ю.В.Bykov Y.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://sibmed.elpub.ru/jour/article/view/2584

Статья посвящена анализу роли окислительного стресса в патогенезе инфекции, вызванной SARS-CoV-2. Рассматриваются как традиционные, так и альтернативные механизмы нарушения редокс-гомеостаза, включая инактивацию ACE2, митохондриальную дисфункцию, нейроиммунный дисбаланс и микробиота-ассоциированные пути. Окислительный стресс при COVID-19 способствует активации провоспалительных каскадов, транскрипционного фактора NF-κB и подавлению Nrf2-зависимого сигнального пути, усиливая продукцию цитокинов и формирование «цитокинового шторма». Нарушение антиоксидантной защиты сопровождается иммунной и эндотелиальной дисфункцией, способствуя тромбозам и микрососудистым поражениям. Представлены противоречивые клинические и экспериментальные данные, касающиеся эффективности антиоксидантной терапии. Подчеркивается необходимость стратифицированного подхода и дальнейшего изучения редокс-звеньев патогенеза. Особое внимание уделено нерешенным вопросам, включая исходный редокс-статус пациента и механизмы устойчивой активации NADPH-оксидазы и подавления Nrf2-сигналинга.

This article presents an analysis of the role of oxidative stress in the pathogenesis of COVID-19 caused by SARS-CoV-2. Both classical and alternative mechanisms of redox imbalance are discussed, including ACE2 inactivation, mitochondrial dysfunction, neuroimmune dysregulation, and microbiota-associated pathways. Oxidative stress in CODID-19 promotes activation of pro-inflammatory cascades, the NF-κB transcription factor, and suppression of the Nrf2-driven signaling pathway, enhancing cytokine production and promoting a cytokine storm. Impaired antioxidant defense is associated with immune and endothelial dysfunction, facilitating thrombosis and microvascular injury. Contradictory clinical and experimental data regarding the effectiveness of antioxidant therapy are presented. The article highlights the need for a stratified approach and further investigation of redox-related mechanisms in disease progression. Special attention is given to unresolved issues, including the patient’s baseline redox status and the mechanisms underlying persistent activation of NADPH oxidase and suppression of Nrf2 signaling. These aspects may offer new perspectives for the development of targeted therapies for severe forms of COVID-19.

COVID-19окислительный стресссистемный воспалительный ответэндотелиальная дисфункцияNADPH-оксидазаантиоксидантная защитаCOVID-19oxidative stresssystemic inflammatory responseendothelial dysfunctionNADPH oxidaseantioxidant defenseReferencesGuan W., Ni Z., Hu Y., Liang W., Ou C., He J., Liu L., Shan H., Lei C., Hui D.S., … China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 2020;382(18):1708–1720. doi: 10.1056/NEJMoa2002032Guan W., Ni Z., Hu Y., Liang W., Ou C., He J., Liu L., Shan H., Lei C., Hui D.S., … China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 2020;382(18):1708–1720. doi: 10.1056/NEJMoa2002032Alam M.S., Czajkowsky D.M. SARS-CoV-2 infection and oxidative stress: Pathophysiological insight into thrombosis and therapeutic opportunities. Cytokine Growth Factor Rev. 2021;63:44–57. doi: 10.1016/j.cytogfr.2021.11.001Alam M.S., Czajkowsky D.M. SARS-CoV-2 infection and oxidative stress: Pathophysiological insight into thrombosis and therapeutic opportunities. Cytokine Growth Factor Rev. 2021;63:44–57. doi: 10.1016/j.cytogfr.2021.11.001Щулькин А.В., Филимонова А.А. Роль свободно-радикального окисления, гипоксии и их коррекции в патогенезе COVID-19. Терапия. 2020;6(5):187–194. doi: 10.18565/therapy.2020.5.187-194Shchulkin A.V., Filimonova A.A. The role of free radical oxidation, hypoxia and their correction in COVID-19 pathogenesis. Terapiya = Therapy. 2020;6(5):187–194. [In Russian]. doi: 10.18565/therapy.2020.5.187-194Marczewska A., Wojciechowska C., Marczewski K., Gospodarczyk N., Dolibog P., Czuba Z., Wróbel K., Zalejska-Fiolka J. Elevated levels of IL–1Ra, IL–1β, and oxidative stress in COVID-19: Implications for inflammatory pathogenesis. J. Clin. Med. 2025;14(7):2489. doi: 10.3390/jcm14072489Marczewska A., Wojciechowska C., Marczewski K., Gospodarczyk N., Dolibog P., Czuba Z., Wróbel K., Zalejska-Fiolka J. Elevated levels of IL–1Ra, IL–1β, and oxidative stress in COVID-19: Implications for inflammatory pathogenesis. J. Clin. Med. 2025;14(7):2489. doi: 10.3390/jcm14072489Carvajal J.J., García-Castillo V., Cuellar S.V., Campillay-Véliz C.P., Salazar-Ardiles C., Avellaneda A.M., Muñoz C.A., Retamal-Díaz A., Bueno S.M., González P.A., Kalergis A.M., Lay M.K. New insights into the pathogenesis of SARS-CoV-2 during and after the COVID-19 pandemic. Front. Immunol. 2024;15:1363572. doi: 10.3389/fimmu.2024.1363572Carvajal J.J., García-Castillo V., Cuellar S.V., Campillay-Véliz C.P., Salazar-Ardiles C., Avellaneda A.M., Muñoz C.A., Retamal-Díaz A., Bueno S.M., González P.A., Kalergis A.M., Lay M.K. New insights into the pathogenesis of SARS-CoV-2 during and after the COVID-19 pandemic. Front. Immunol. 2024;15:1363572. doi: 10.3389/fimmu.2024.1363572Camargo R.L., Bombassaro B., Monfort-Pires M., Mansour E., Palma A.C., Ribeiro L.C., Ulaf R.G., Bernardes A.F., Nunes T.A., Agrela M.V., … Sposito A.C. Plasma angiotensin ii is increased in critical coronavirus disease 2019. Front. Cardiovasc. Med. 2022;9:847809. doi: 10.3389/fcvm.2022.847809Camargo R.L., Bombassaro B., MonfortPires M., Mansour E., Palma A.C., Ribeiro L.C., Ulaf R.G., Bernardes A.F., Nunes T.A., Agrela M.V., … Sposito A.C. Plasma angiotensin ii is increased in critical coronavirus disease 2019. Front. Cardiovasc. Med. 2022;9:847809. doi: 10.3389/fcvm.2022.847809Georgieva E., Ananiev J., Yovchev Y., Arabadzhiev G., Abrashev H., Abrasheva D., Atanasov V., Kostandieva R., Mitev M., Petkova-Parlapanska K., Nikolova G. COVID-19 complications: oxidative stress, inflammation, and mitochondrial and endothelial dysfunction. Int. J. Mol. Sci. 2023;24(19):14876. doi: 10.3390/ijms241914876Georgieva E., Ananiev J., Yovchev Y., Arabadzhiev G., Abrashev H., Abrasheva D., Atanasov V., Kostandieva R., Mitev M., Petkova-Parlapanska K., Nikolova G. COVID-19 complications: oxidative stress, inflammation, and mitochondrial and endothelial dysfunction. Int. J. Mol. Sci. 2023;24(19):14876. doi: 10.3390/ijms241914876Orea-Tejada A., Sánchez-Moreno C., Aztatzi-Aguilar O.G., Sierra-Vargas M.P., González-Islas D., Debray-García Y., Ortega-Romero M.S., Keirns-Davis C., Cornejo-Cornejo L., Aguilar-Meza J. Plasma endothelial and oxidative stress biomarkers associated with late mortality in hospitalized COVID-19 Patients. J. Clin. Med. 2022;11(14):3950. doi: 10.3390/jcm11143950Orea-Tejada A., Sánchez-Moreno C., AztatziAguilar O.G., Sierra-Vargas M.P., González-Islas D., Debray-García Y., Ortega-Romero M.S., Keirns-Davis C., Cornejo-Cornejo L., Aguilar-Meza J. Plasma endothelial and oxidative stress biomarkers associated with late mortality in hospitalized COVID-19 Patients. J. Clin. Med. 2022;11(14):3950. doi: 10.3390/jcm11143950Wieczfinska J., Kleniewska P., Pawliczak R. Oxidative stress-related mechanisms in SARS-CoV-2 infections. Oxid. Med. Cell Longev. 2022;2022:5589089. doi: 10.1155/2022/5589089Wieczfinska J., Kleniewska P., Pawliczak R. Oxidative stress-related mechanisms in SARS-CoV-2 infections. Oxid. Med. Cell Longev. 2022;2022:5589089. doi: 10.1155/2022/5589089Ciacci P., Paraninfi A., Orlando F., Rella S., Maggio E., Oliva A., Cangemi R., Carnevale R., Bartimoccia S., Cammisotto V., … Loffredo L. Endothelial dysfunction, oxidative stress and low-grade endotoxemia in COVID-19 patients hospitalised in medical wards. Microvasc. Res. 2023;149:104557. doi: 10.1016/j.mvr.2023.104557Ciacci P., Paraninfi A., Orlando F., Rella S., Maggio E., Oliva A., Cangemi R., Carnevale R., Bartimoccia S., Cammisotto V., … Loffredo L. Endothelial dysfunction, oxidative stress and low-grade endotoxemia in COVID-19 patients hospitalised in medical wards. Microvasc. Res. 2023;149:104557. doi: 10.1016/j.mvr.2023.104557Wu Z., McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239–1242. doi: 10.1001/jama.2020.2648Wu Z., McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239–1242. doi: 10.1001/jama.2020.2648Zhou Y., Zhang Z., Tian J., Xiong S. Risk factors associated with disease progression in a cohort of patients infected with the 2019 novel coronavirus. Ann. Palliat. Med. 2020;9(2):428–436. doi: 10.21037/apm.2020.03.26Zhou Y., Zhang Z., Tian J., Xiong S. Risk factors associated with disease progression in a cohort of patients infected with the 2019 novel coronavirus. Ann. Palliat. Med. 2020;9(2):428–436. doi: 10.21037/apm.2020.03.26Laforge M., Elbim C., Frère C., Hémadi M., Massaad C., Nuss P., Benoliel J.J., Becker C. Tissue damage from neutrophil-induced oxidative stress in COVID-19. Nat. Rev. Immunol. 2020;20(9):515–516. doi: 10.1038/s41577-020-0407-1Laforge M., Elbim C., Frère C., Hémadi M., Massaad C., Nuss P., Benoliel J.J., Becker C. Tissue damage from neutrophil-induced oxidative stress in COVID-19. Nat. Rev. Immunol. 2020;20(9):515–516. doi: 10.1038/s41577-020-0407-1Baqi H.R., Farag H.A.M., El Bilbeisi A.H.H., Askandar R.H., El Afifi A.M. Oxidative stress and its association with covid-19: a narrative review. KJAR. 2020;5(3):97–105. doi: 10.24017/covid.11Baqi H.R., Farag H.A.M., El Bilbeisi A.H.H., Askandar R.H., El Afifi A.M. Oxidative stress and its association with covid-19: a narrative review. KJAR. 2020;5(3):97–105. doi: 10.24017/covid.11Delgado-Roche L., Mesta F. Oxidative stress as key player in severe acute respiratory syndrome coronavirus (SARS-CoV) infection. Arch. Med. Res. 2020;51(5):384–387. doi: 10.1016/j.arcmed.2020.04.019Delgado-Roche L., Mesta F. Oxidative stress as key player in severe acute respiratory syndrome coronavirus (SARS-CoV) infection. Arch. Med. Res. 2020;51(5):384–387. doi: 10.1016/j.arcmed.2020.04.019Samsonov A., Urlache S.S. Oxidative stress in children and adolescents: insights into human biology. Am. J. Hum. Biol. 2025;37(1):e24200. doi: 10.1002/ajhb.2420016 Samsonov A., Urlache S.S. Oxidative stress in children and adolescents: insights into human biology. Am. J. Hum. Biol. 2025;37(1):e24200. doi: 10.1002/ajhb.24200Кукес В.Г., Парфенова О.К., Сидоров Н.Г., Олефир Ю.В., Газданова А.А. Окислительный стресс и воспаление в патогенезе COVID-19. Рос. мед. ж. 2020;26(4):244–247. doi: 10.17816/08692106-2020-26-4-244-24717 Kukes V.G., Parfenova O.K., Sidorov N.G., Olefir Yu.V., Gazdanova A.A. Oxidative stress and inflammation in COVID-19 pathogenesis. Rossiyskiy meditsinskiy zhurnal = Medical Journal of the Russian Federation. 2020;26(4):244–247. [In Russian]. doi: 10.17816/0869-2106-2020-26-4-244-247Jankauskas S.S., Kansakar U., Sardu C., Varzideh F., Avvisato R., Wang X., Matarese A., Marfella R., Ziosi M., Gambardella J., Santulli G. COVID-19 causes ferroptosis and oxidative stress in human endothelial cells. Antioxidants (Basel). 2023;12(2):326. doi: 10.3390/antiox12020326Jankauskas S.S., Kansakar U., Sardu C., Varzideh F., Avvisato R., Wang X., Matarese A., Marfella R., Ziosi M., Gambardella J., Santulli G. COVID-19 causes ferroptosis and oxidative stress in human endothelial cells. Antioxidants (Basel). 2023;12(2):326. doi: 10.3390/antiox12020326Орлов Ю.П., Афанасьев В.В., Хиленко И.А. Перспектива сукцинатов в условиях гипоксии при СOVID-19. Антибиотики и химиотерапия. 2021;66(1–2):65–74. doi: 10.37489/0235-2990-2021-66-1-2-65-74Orlov Yu.P., Afanasyev V.V., Khilenko I.A. The prospects of succinates’ use under hypoxic conditions in COVID-19. Antibiotiki i khimioterapiya= Antibiotics and Chemotherapy. 2021;66(1-2): 65–74. [In Russian]. doi: 10.37489/0235-2990-2021-66-1-2-65-74Черняк Б.В., Попова Е.Н., Приходько А.С., Гребенчиков О.А., Зиновкина Л.А., Зиновкин Р.А. COVID-19 и окислительный стресс. Биохимия. 2020;85(12):1816–1828. doi: 10.31857/s0320972520120064Chernyak B.V., Popova E.N., Prikhodko A.S., Grebenchikov O.A., Zinovkina L.A., Zinovkin R.A. COVID-19 and oxidative stress. Biochemistry (Mosc.). 2020;85(12-13): 1543–1553. doi: 10.1134/s0006297920120068Pizzino G., Irrera N., Cucinotta M., Pallio G., Mannino F., Arcoraci V., Squadrito F., Altavilla D., Bitto A. Oxidative stress: harms and benefits for human health. Oxid. Med. Cell. Longev. 2017:2017:8416763. doi: 10.1155/2017/8416763Pizzino G., Irrera N., Cucinotta M., Pallio G., Mannino F., Arcoraci V., Squadrito F., Altavilla D., Bitto A. Oxidative stress: harms and benefits for human health. Oxid. Med. Cell. Longev. 2017:2017:8416763. doi: 10.1155/2017/8416763Kayesh M.E., Kohara M., Tsukiyama-Kohara K. Effects of oxidative stress on viral infections: an overview. Npj Viruses. 2025;3(1):27. doi: 10.1038/s44298025-00110-3Kayesh M.E., Kohara M., Tsukiyama-Kohara K. Effects of oxidative stress on viral infections: an overview. Npj Viruses. 2025;3(1):27. doi: 10.1038/s44298025-00110-3Checa J., Aran J.M. Reactive oxygen species: drivers of physiological and pathological processes. J. Inflamm. Res. 2020:13:1057–1073. doi: 10.2147/JIR. S275595Checa J., Aran J.M. Reactive oxygen species: drivers of physiological and pathological processes. J. Inflamm. Res. 2020:13:1057–1073. doi: 10.2147/JIR.S275595Быков Ю.В. Роль оксидативного стресса в развитии осложнений при сахарном диабете. Мед. вестн. Сев. Кавказа. 2022;17(3):322–327. doi: 10.14300/mnnc.2022.17080Bykov Yu.V. Role of oxidative stress in the development of complications in patients with diabetes mellitus. Meditsinskiy vestnik Severnogo Kavkaza = Medical News of the North Caucasus. 2022;17(3):322–327. [In Russian]. doi: 10.14300/mnnc.2022.17080Liguori I., Russo G., Curcio F., Bulli G., Aran L., Della-Morte D., Gargiulo G., Testa G., Cacciatore F., Bonaduce D., Abete P. Oxidative stress, aging, and diseases. Clin. Interv. Aging. 2018;13:757–777. doi: 10.2147/CIA.S158513Liguori I., Russo G., Curcio F., Bulli G., Aran L., Della-Morte D., Gargiulo G., Testa G., Cacciatore F., Bonaduce D., Abete P. Oxidative stress, aging, and diseases. Clin. Interv. Aging. 2018;13:757–777. doi: 10.2147/CIA.S158513Juan C.A., Perez de la Lastra J.M., Plou F.J., Perez-Lebena E. The chemistry of reactive oxygen species (ROS) revisited: outlining their role in biological macromolecules (DNA, Lipids and Proteins) and induced pathologies. Int. J. Mol. Sci. 2021;22(9):4642. doi: 10.3390/ijms22094642Juan C.A., Perez de la Lastra J.M., Plou F.J., Perez-Lebena E. The chemistry of reactive oxygen species (ROS) revisited: outlining their role in biological macromolecules (DNA, Lipids and Proteins) and induced pathologies. Int. J. Mol. Sci. 2021;22(9):4642. doi: 10.3390/ijms22094642Даренская М.А., Колесникова Л.И., Колесников С.И. COVID-19: окислительный стресс и актуальность антиоксидантной терапии. Вестн. РАМН. 2020;75:318–325. doi: 10.15690/vramn1360Darenskaya M.A., Kolesnikova L.I., Kolesnikov S.I. COVID-19: Oxidative stress and the relevance of antioxidant therapy. Vestnik Rossiyskoy akademii meditsinskikh nauk = Annals of the Russian Academy of Medical Sciences. 2020;75:318–325. [In Russian]. doi: 10.15690/vramn1360Быков Ю.В. Диабетический кетоацидоз и окислительный стресс: патофизиологические механизмы. Сиб. науч. мед. ж. 2023;43(6):6–13. doi: 10.18699/SSMJ20230601Bykov Yu.V. Diabetic ketoacidosis and oxidative stress: pathophysiological mechanisms. Sibirskij nauchnyj medicinskij zhurnal = Siberian Scientific Medical Journal. 2023;43(6):6–13. [In Russian]. doi: 10.18699/SSMJ20230601Nandi A., Yan L.J., Jana C.K., Das N. Role of catalase in oxidative stress-and age-associated degenerative diseases. Oxid. Med. Cell. Longev. 2019;2019:9613090. doi: 10.1155/2019/9613090Nandi A., Yan L.J., Jana C.K., Das N. Role of catalase in oxidative stress-and age-associated degenerative diseases. Oxid. Med. Cell. Longev. 2019;2019:9613090. doi: 10.1155/2019/9613090Semenova N., Vyrupaeva E., Kolesnikov S., Darenskaya M., Nikitina O., Rychkova L., Kolesnikova L. Persistent post COVID-19 endothelial dysfunction and oxidative stress in women. Pathophysiology. 2024;31(3):436–457. doi: 10.3390/pathophysiology31030033Semenova N., Vyrupaeva E., Kolesnikov S., Darenskaya M., Nikitina O., Rychkova L., Kolesnikova L. Persistent post COVID-19 endothelial dysfunction and oxidative stress in women. Pathophysiology. 2024;31(3):436–457. doi: 10.3390/pathophysiology31030033Fukai T., Ushio-Fukai M. Cross-talk between NADPH oxidase and mitochondria: role in ROS signaling and angiogenesis. Cells. 2020;9(8):1849. doi: 10.3390/cells9081849Fukai T., Ushio-Fukai M. Cross-talk between NADPH oxidase and mitochondria: role in ROS signaling and angiogenesis. Cells. 2020;9(8):1849. doi: 10.3390/cells9081849Tan B.L., Norhaizan M.E., Liew W.P.P., Rahman S.H. Antioxidant and oxidative stress: a mutual interplay in age-related diseases. Front. Pharmacol. 2018;9:1162. doi: 10.3389/fphar.2018.01162Tan B.L., Norhaizan M.E., Liew W.P.P., Rahman S.H. Antioxidant and oxidative stress: a mutual interplay in age-related diseases. Front. Pharmacol. 2018;9:1162. doi: 10.3389/fphar.2018.01162Mehta P., McAuley D.F., Brown M., Sanchez E., Tattersall R.S., Manson J.J.; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033–1034. doi: 10.1016/S0140-6736(20)30628-0Mehta P., McAuley D.F., Brown M., Sanchez E., Tattersall R.S., Manson J.J.; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033–1034. doi: 10.1016/S0140-6736(20)30628-0Mohiuddin M., Kasahara K. The emerging role of oxidative stress in complications of COVID-19 and potential therapeutic approach to diminish oxidative stress. Respir. Med. 2021;187:106605. doi: 10.1016/j.rmed.2021.106605Mohiuddin M., Kasahara K. The emerging role of oxidative stress in complications of COVID-19 and potential therapeutic approach to diminish oxidative stress. Respir. Med. 2021;187:106605. doi: 10.1016/j.rmed.2021.106605Khomich O.A., Kochetkov S.N., Bartosch B., Ivanov A.V. Redox biology of respiratory viral infections. Viruses. 2018;10(8):392. doi: 10.3390/v10080392Khomich O.A., Kochetkov S.N., Bartosch B., Ivanov A.V. Redox biology of respiratory viral infections. Viruses. 2018;10(8):392. doi: 10.3390/v10080392Lingappan K. NF-kappaB in Oxidative Stress. Curr. Opin. Toxicol. 2018:7:81–86. doi: 10.1016/j.cotox.2017.11.002Lingappan K. NF-kappaB in Oxidative Stress. Curr. Opin. Toxicol. 2018:7:81–86. doi: 10.1016/j.cotox.2017.11.002Wang Y., Ma J., Jiang Y. Transcription factor Nrf2 as a potential therapeutic target for COVID-19. Cell Stress Chaperones. 2022;28(1):11–20. doi: 10.1007/s12192-022-01296-8Wang Y., Ma J., Jiang Y. Transcription factor Nrf2 as a potential therapeutic target for COVID-19. Cell Stress Chaperones. 2022;28(1):11–20. doi: 10.1007/s12192-022-01296-8Cuadrado A., Pajares M., Benito C., Jiménez-Villegas J., Escoll M., Fernández-Ginés R., Garcia Yagüe A.J., Lastra D., Manda G., Rojo A.I., Dinkova-Kostova A.T. Can activation of Nrf2 be a strategy against COVID-19? Trends Pharmacol. Sci. 2020;41(9):598– 610. doi: 10.1016/j.tips.2020.07.003Cuadrado A., Pajares M., Benito C., JiménezVillegas J., Escoll M., Fernández-Ginés R., Garcia Yagüe A.J., Lastra D., Manda G., Rojo A.I., DinkovaKostova A.T. Can activation of Nrf2 be a strategy against COVID-19? Trends Pharmacol. Sci. 2020;41(9):598– 610. doi: 10.1016/j.tips.2020.07.003Zhang Z., Zhang X., Bi K., He Y., Yan W., Yang C.S. Potential protective mechanisms of green tea polyphenol EGCG against COVID-19. Trends Food Sci. Technol. 2021;114:11–24. doi: 10.1016/j.tifs.2021.05.023Zhang Z., Zhang X., Bi K., He Y., Yan W., Yang C.S. Potential protective mechanisms of green tea polyphenol EGCG against COVID-19. Trends Food Sci. Technol. 2021;114:11–24. doi: 10.1016/j.tifs.2021.05.023Olagnier D., Brandtoft A.M., Gunderstofte C., Villadsen N.L., Krapp C., Thielke A.L., Laustsen A., Peri S., Hansen A.L., Bonefeld L., Thyrsted J., … Holm C.K. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat. Commun. 2018;9(1):3506. doi: 10.1038/s41467-018-05861-7Olagnier D., Brandtoft A.M., Gunderstofte C., Villadsen N.L., Krapp C., Thielke A.L., Laustsen A., Peri S., Hansen A.L., Bonefeld L., Thyrsted J., … Holm C.K. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat. Commun. 2018;9(1):3506. doi: 10.1038/s41467-018-05861-7Zhang S., Wang J., Wang L., Aliyari S., Cheng G. SARS-CoV-2 virus NSP14 Impairs Nrf2/ HMOX1 activation by targeting Sirtuin 1. Cell. Mol. Immunol. 2022;19(8):872–882. doi: 10.1038/s41423022-00887-wZhang S., Wang J., Wang L., Aliyari S., Cheng G. SARS-CoV-2 virus NSP14 Impairs Nrf2/ HMOX1 activation by targeting Sirtuin 1. Cell. Mol. Immunol. 2022;19(8):872–882. doi: 10.1038/s41423022-00887-wde Angelis M., Anichini G., Palamara A.T., Nencioni L., Gori Savellini G. Dysregulation of intracellular redox homeostasis by the SARS-CoV-2 ORF6 protein. Virol. J. 2023;20(1):239. doi: 10.1186/s12985023-02208-7de Angelis M., Anichini G., Palamara A.T., Nencioni L., Gori Savellini G. Dysregulation of intracellular redox homeostasis by the SARS-CoV-2 ORF6 protein. Virol. J. 2023;20(1):239. doi: 10.1186/s12985023-02208-7Yu H., Yang L, Han Z., Zhou X., Zhang Z., Sun T., Zheng F., Yang J., Guan F., Xie J., Liu C. SARS-CoV-2 nucleocapsid protein enhances the level of mitochondrial reactive oxygen species. J. Med. Virol. 2023;95(12):e29270. doi: 10.1002/jmv.29270Yu H., Yang L, Han Z., Zhou X., Zhang Z., Sun T., Zheng F., Yang J., Guan F., Xie J., Liu C. SARS-CoV-2 nucleocapsid protein enhances the level of mitochondrial reactive oxygen species. J. Med. Virol. 2023;95(12):e29270. doi: 10.1002/jmv.29270Agrawal R., Pal V.K., K S.S., Menon G.J., Singh I.R., Malhotra N., Ganesh K., Rajmani R.S., Narain Seshasayee A.S., Chandra N., Joshi M.B., Singh A. Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection. PLoS Pathog. 2025;21(5):e1013164. doi: 10.1371/journal.ppat.1013164Agrawal R., Pal V.K., K S.S., Menon G.J., Singh I.R., Malhotra N., Ganesh K., Rajmani R.S., Narain Seshasayee A.S., Chandra N., Joshi M.B., Singh A. Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection. PLoS Pathog. 2025;21(5):e1013164. doi: 10.1371/journal.ppat.1013164Vlaming-van Eijk L.E., Bulthuis M.L., van der Gun B.T., Wold K.I., Veloo A.C., Vincenti González M.F., de Borst M.H., den Dunnen W.F., Jan-Luuk Hillebrands, van Goor H., Tami A., Bourgonje A.R. Systemic oxidative stress associates with the development of post-COVID-19 syndrome in non-hospitalized individuals. Redox Biol. 2024:76:103310. doi: 10.1016/j.redox.2024.103310Vlaming-van Eijk L.E., Bulthuis M.L., van der Gun B.T., Wold K.I., Veloo A.C., Vincenti González M.F., de Borst M.H., den Dunnen W.F., JanLuuk Hillebrands, van Goor H., Tami A., Bourgonje A.R. Systemic oxidative stress associates with the development of post-COVID-19 syndrome in non-hospitalized individuals. Redox Biol. 2024:76:103310. doi: 10.1016/j.redox.2024.103310Alam M.S., Czajkowsky D.M. SARS-CoV-2 infection and oxidative stress: Pathophysiological insight into thrombosis and therapeutic opportunities. Cytokine Growth Factor Rev. 2022;63:44–57. doi: 10.1016/j.cytogfr.2021.11.001Alam M.S., Czajkowsky D.M. SARS-CoV-2 infection and oxidative stress: Pathophysiological insight into thrombosis and therapeutic opportunities. Cytokine Growth Factor Rev. 2022;63:44–57. doi: 10.1016/j.cytogfr.2021.11.001Fogleman C., Cohen D., Mercier A., Farrell D., Rutz J., Bresz K., Vernon T. J. A Pilot of a randomized control trial of melatonin and vitamin C for mild-to-moderate COVID-19. Am Board Fam. Med. 2022;35(4):695–707. doi: 10.3122/jabfm.2022.04.210529Fogleman C., Cohen D., Mercier A., Farrell D., Rutz J., Bresz K., Vernon T. J. A Pilot of a randomized control trial of melatonin and vitamin C for mild-to-moderate COVID-19. Am Board Fam. Med. 2022;35(4):695–707. doi: 10.3122/jabfm.2022.04.210529Falahieh F.M., Zarabadipour M., Mirani M., Abdiyan M., Dinparvar M., Alizadeh H., Paktinat S., Hosseinirad H. Effects of moderate COVID-19 infection on semen oxidative status and parameters 14 and 120 days after diagnosis. Reprod. Fertil. Dev. 2021;33(12):683– 690. doi: 10.1071/RD21153Falahieh F.M., Zarabadipour M., Mirani M., Abdiyan M., Dinparvar M., Alizadeh H., Paktinat S., Hosseinirad H. Effects of moderate COVID-19 infection on semen oxidative status and parameters 14 and 120 days after diagnosis. Reprod. Fertil. Dev. 2021;33(12):683– 690. doi: 10.1071/RD21153Tepebaşı M.Y., İlhan İ., Temel E.N., Sancer O., Öztürk Ö. Investigation of inflammation, oxidative stress, and DNA damage in COVID-19 patients. Cell Stress Chaperones. 2023;28(2):191–199. doi: 10.1007/s12192-023-01330-3Tepebaşı M.Y., İlhan İ., Temel E.N., Sancer O., Öztürk Ö. Investigation of inflammation, oxidative stress, and DNA damage in COVID-19 patients. Cell Stress Chaperones. 2023;28(2):191–199. doi: 10.1007/s12192-023-01330-3Iddir M., Brito A., Dingeo G., Fernandez Del Campo S.S., Samouda H., La Frano M.R., Bohn T. Strengthening the immune system and reducing inflammation and oxidative stress through diet and nutrition: Considerations during the COVID-19 Crisis. Nutrients. 2020;12(6):1562. doi: 10.3390/nu12061562Iddir M., Brito A., Dingeo G., Fernandez Del Campo S.S., Samouda H., La Frano M.R., Bohn T. Strengthening the immune system and reducing inflammation and oxidative stress through diet and nutrition: Considerations during the COVID-19 Crisis. Nutrients. 2020;12(6):1562. doi: 10.3390/nu12061562Zhou T., Wu J., Zeng Y., Li J., Yan J., Meng W., Han H., Feng F., He J., Zhao S., Zhou P., Wu Y., Yang Y., Han R., Jin W., Li X., Yang Y., Li X. SARS-CoV-2 triggered oxidative stress and abnormal energy metabolism in gut microbiota. MedComm. (2020). 2022;3(1):e112. doi: 10.1002/mco2.112Zhou T., Wu J., Zeng Y., Li J., Yan J., Meng W., Han H., Feng F., He J., Zhao S., Zhou P., Wu Y., Yang Y., Han R., Jin W., Li X., Yang Y., Li X. SARS-CoV-2 triggered oxidative stress and abnormal energy metabolism in gut microbiota. MedComm. (2020). 2022;3(1):e112. doi: 10.1002/mco2.112Zendelovska D., Atanasovska E., Spasovska K., Kirijas M., Kapsarov K., Jakimovski D., Petrushevska M. Effect of supplemental antioxidant-based therapy on the oxidative stress level in COVID-19 patients. Pril. (Makedon. Akad. Nauk. Umet. Odd. Med. Nauki). 2023;44(1):7–16. doi: 10.2478/prilozi-2023-0002Zendelovska D., Atanasovska E., Spasovska K., Kirijas M., Kapsarov K., Jakimovski D., Petrushevska M. Effect of supplemental antioxidant-based therapy on the oxidative stress level in COVID-19 patients. Pril. (Makedon. Akad. Nauk. Umet. Odd. Med. Nauki). 2023;44(1):7–16. doi: 10.2478/prilozi-2023-0002Simadibrata D.M., Calvin J., Wijaya A.D., Ibrahim N.A.A. Neutrophil-to-lymphocyte ratio on admission to predict the severity and mortality of COVID-19 patients: a meta-analysis. Am. J. Emerg. Med. 2021;42:60–69. doi: 10.1016/j.ajem.2021.01.006Simadibrata D.M., Calvin J., Wijaya A.D., Ibrahim N.A.A. Neutrophil-to-lymphocyte ratio on admission to predict the severity and mortality of COVID-19 patients: a meta-analysis. Am. J. Emerg. Med. 2021;42:60–69. doi: 10.1016/j.ajem.2021.01.006Man M.A., Rajnoveanu R.M., Motoc N.S., Bondor C.I., Chis A.F., Lesan A., Puiu R., Lucaciu S.-R., Dantes E., Gergely-Domokos B., Fira-Mladinescu O. Neutrophil-to-lymphocyte ratio, plateletsto-lymphocyte ratio, and eosinophils correlation with high-resolution computer tomography severity score in COVID-19 patients. PLoS One. 2021;16(6):e0252599. doi: 10.1371/journal.pone.0252599Man M.A., Rajnoveanu R.M., Motoc N.S., Bondor C.I., Chis A.F., Lesan A., Puiu R., Lucaciu S.-R., Dantes E., Gergely-Domokos B., Fira-Mladinescu O. Neutrophil-to-lymphocyte ratio, plateletsto-lymphocyte ratio, and eosinophils correlation with high-resolution computer tomography severity score in COVID-19 patients. PLoS One. 2021;16(6):e0252599. doi: 10.1371/journal.pone.0252599Hule G.P., Bargir U.A., Kulkarni M., Kambli P., Taur P., Desai M., Madkaikar M.R. Does pioglitazone lead to neutrophil extracellular traps formation in chronic granulomatous disease patients? Front. Immunol. 2019;10:1739. doi: 10.3389/fimmu.2019.01739Hule G.P., Bargir U.A., Kulkarni M., Kambli P., Taur P., Desai M., Madkaikar M.R. Does pioglitazone lead to neutrophil extracellular traps formation in chronic granulomatous disease patients? Front. Immunol. 2019;10:1739. doi: 10.3389/fimmu.2019.01739Cecchini R., Cecchini A.L. SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression. Med. Hypotheses. 2020;143:110102. doi: 10.1016/j.mehy.2020.110102Cecchini R., Cecchini A.L. SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression. Med. Hypotheses. 2020;143:110102. doi: 10.1016/j.mehy.2020.110102Moro-García M.A., Mayo J.C., Sainz R.M., Alonso-Arias R. Influence of inflammation in the process of T lymphocyte differentiation: proliferative, metabolic, and oxidative changes. Front. Immunol. 2018;9:339. doi: 10.3389/fimmu.2018.00339Moro-García M.A., Mayo J.C., Sainz R.M., Alonso-Arias R. Influence of inflammation in the process of T lymphocyte differentiation: proliferative, metabolic, and oxidative changes. Front. Immunol. 2018;9:339. doi: 10.3389/fimmu.2018.00339Bakadia B.M., Boni B.O.O., Ahmed A.A.Q., Yang G. The impact of oxidative stress damage induced by the environmental stressors on COVID-19. Life Sci. 2021:264:118653. doi: 10.1016/j.lfs.2020.118653Bakadia B.M., Boni B.O.O., Ahmed A.A.Q., Yang G. The impact of oxidative stress damage induced by the environmental stressors on COVID-19. Life Sci. 2021:264:118653. doi: 10.1016/j.lfs.2020.118653Patel V.B., Zhong J.C., Grant M.B., Oudit G.Y. Role of the ACE2/angiotensin 1–7 axis of the renin–angiotensin system in heart failure. Circ. Res. 2016;118(8):1313–1326. doi: 10.1161/CIRCRESAHA.116.307708Patel V.B., Zhong J.C., Grant M.B., Oudit G.Y. Role of the ACE2/angiotensin 1–7 axis of the renin–angiotensin system in heart failure. Circ. Res. 2016;118(8):1313–1326. doi: 10.1161/CIRCRESAHA.116.307708Verdecchia P., Cavallini C., Spanevello A., Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur. J. Intern. Med. 2020;76:14–20. doi: 10.1016/j.ejim.2020.04.037Verdecchia P., Cavallini C., Spanevello A., Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur. J. Intern. Med. 2020;76:14–20. doi: 10.1016/j.ejim.2020.04.037Fodor A., Tiperciuc B., Login C., Orasan O.H., Lazar A.L., Buchman C., Hanghicel P., Sitar-Taut A., Suharoschi R., Vulturar R., Cozma A. Endothelial dysfunction, inflammation, and oxidative stress in COVID-19-mechanisms and therapeutic targets. Oxid. Med. Cell. Longev. 2021;2021:8671713. doi: 10.1155/2021/8671713Fodor A., Tiperciuc B., Login C., Orasan O.H., Lazar A.L., Buchman C., Hanghicel P., Sitar-Taut A., Suharoschi R., Vulturar R., Cozma A. Endothelial dysfunction, inflammation, and oxidative stress in COVID-19-mechanisms and therapeutic targets. Oxid. Med. Cell. Longev. 2021;2021:8671713. doi: 10.1155/2021/8671713Hati S., Bhattacharyya S. Impact of thioldisulfide balance on the binding of COVID-19 spike protein with angiotensin-converting enzyme 2 receptor. ACS Omega. 2020;5(26):16292–16298. doi: 10.1021/acsomega.0c02125Hati S., Bhattacharyya S. Impact of thioldisulfide balance on the binding of COVID-19 spike protein with angiotensin-converting enzyme 2 receptor. ACS Omega. 2020;5(26):16292–16298. doi: 10.1021/acsomega.0c02125Violi F., Oliva A., Cangemi R., Ceccarelli G., Pignatelli P., Carnevale R., Cammisotto V., Lichtner M., Alessandri F., De Angelis M., … Mastroianni C.M. Nox2 activation in COVID-19. Redox Biol. 2020;36:101655. doi: 10.1016/j.redox.2020.101655Violi F., Oliva A., Cangemi R., Ceccarelli G., Pignatelli P., Carnevale R., Cammisotto V., Lichtner M., Alessandri F., De Angelis M., … Mastroianni C.M. Nox2 activation in COVID-19. Redox Biol. 2020;36:101655. doi: 10.1016/j.redox.2020.101655Lei Y., Zhang J., Schiavon C.R., He M., Chen L., Shen H., Zhang Y., Yin Q., Cho Y., Andrade L., … Shyy J.Y. SARS-CoV-2 spike protein impairs endothelial function via downregulation of ACE 2. Circ. Res. 2021;128(9):1323–1326. doi: 10.1161/CIRCRESAHA.121.318902Lei Y., Zhang J., Schiavon C.R., He M., Chen L., Shen H., Zhang Y., Yin Q., Cho Y., Andrade L., … Shyy J.Y. SARS-CoV-2 spike protein impairs endothelial function via downregulation of ACE 2. Circ. Res. 2021;128(9):1323–1326. doi: 10.1161/CIRCRESAHA.121.318902Suhail S., Zajac J., Fossum C., Lowater H., McCracken C., Severson N., Laatsch B., Narkiewicz-Jodko A., Johnson B., Liebau J., Bhattacharyya S., Hati S. Role of oxidative stress on SARS-CoV (SARS) and SARS-CoV-2 (COVID-19) infection: a review. Protein J. 2020;39(6):644–656. doi: 10.1007/s10930-02009935-8Suhail S., Zajac J., Fossum C., Lowater H., McCracken C., Severson N., Laatsch B., Narkiewicz-Jodko A., Johnson B., Liebau J., Bhattacharyya S., Hati S. Role of oxidative stress on SARS-CoV (SARS) and SARS-CoV-2 (COVID-19) infection: a review. Protein J. 2020;39(6):644–656. doi: 10.1007/s10930-02009935-8Chang R., Mamun A., Dominic A., Le N.T. SARS-CoV-2 mediated endothelial dysfunction: the potential role of chronic oxidative stress. Front. Physiol. 2021;11:605908. doi: 10.3389/fphys.2020.605908Chang R., Mamun A., Dominic A., Le N.T. SARS-CoV-2 mediated endothelial dysfunction: the potential role of chronic oxidative stress. Front. Physiol. 2021;11:605908. doi: 10.3389/fphys.2020.605908Vassiliou A.G., Zacharis A., Keskinidou C., Jahaj E., Pratikaki M., Gallos P., Dimopoulou I., Kotanidou A., Orfanos S.E. Soluble angiotensin converting enzyme 2 (ACE2) Is upregulated and soluble endothelial nitric oxide synthase (eNOS) is downregulated in COVID-19-induced acute respiratory distress syndrome (ARDS). Pharmaceuticals (Basel). 2021;14(7):695. doi: 10.3390/ph14070695Vassiliou A.G., Zacharis A., Keskinidou C., Jahaj E., Pratikaki M., Gallos P., Dimopoulou I., Kotanidou A., Orfanos S.E. Soluble angiotensin converting enzyme 2 (ACE2) Is upregulated and soluble endothelial nitric oxide synthase (eNOS) is downregulated in COVID-19-induced acute respiratory distress syndrome (ARDS). Pharmaceuticals (Basel). 2021;14(7):695. doi: 10.3390/ph14070695Pincemail J., Cavalier E., Charlier C., Cheramy– Bien J., Brevers E., Courtois A., Fadeur M., Meziane S., Le Goff C., Misset B., … Rousseau A.F. Oxidative stress status in COVID-19 patients hospitalized in intensive care unit for severe pneumonia. A pilot study. Antioxidants. 2021;10(2):257. doi: 10.3390/antiox10020257Pincemail J., Cavalier E., Charlier C., Cheramy– Bien J., Brevers E., Courtois A., Fadeur M., Meziane S., Le Goff C., Misset B., … Rousseau A.F. Oxidative stress status in COVID-19 patients hospitalized in intensive care unit for severe pneumonia. A pilot study. Antioxidants. 2021;10(2):257. doi: 10.3390/antiox10020257Zhang J., Rao X., Li Y., Zhu Y., Liu F., Guo G., Luo G., Meng Z., De Backer D., Xiang H., Peng Z.Y. High-dose vitamin C infusion for the treatment of critically ill COVID-19. Res. Sq. 2020;100:e25876. doi: 10.21203/rs.3.rs-52778/v1+Zhang J., Rao X., Li Y., Zhu Y., Liu F., Guo G., Luo G., Meng Z., De Backer D., Xiang H., Peng Z.Y. High-dose vitamin C infusion for the treatment of critically ill COVID-19. Res. Sq. 2020;100:e25876. doi: 10.21203/rs.3.rs-52778/v1+Mehri F., Rahbar A.H., Ghane E.T., Souri B., Esfahani M. Changes in oxidative markers in COVID-19 patients. Arch. Med. Res. 2021;52(8):843–849. doi: 10.1016/j.arcmed.2021.06.004Mehri F., Rahbar A.H., Ghane E.T., Souri B., Esfahani M. Changes in oxidative markers in COVID-19 patients. Arch. Med. Res. 2021;52(8):843–849. doi: 10.1016/j.arcmed.2021.06.004Saleh M.G., Chang L., Liang H., Ryan M.C., Cunningham E., Garner J., Wilson E., Levine A.R., Kottilil S., Ernst T. Ongoing oxidative stress in individuals with post-acute sequelae of COVID-19. NeuroImmune Pharm. Ther. 2022;2(2):89–94. doi: 10.1515/nipt-2022-0006Saleh M.G., Chang L., Liang H., Ryan M.C., Cunningham E., Garner J., Wilson E., Levine A.R., Kottilil S., Ernst T. Ongoing oxidative stress in individuals with post-acute sequelae of COVID-19. NeuroImmune Pharm. Ther. 2022;2(2):89–94. doi: 10.1515/nipt-2022-0006Muhammad Y., Kani Y.A., Iliya S., Muhammad J.B., Binji A., El-Fulaty Ahmad A., Kabir M.B., Umar Bindawa K., Ahmed A. Deficiency of antioxidants and increased oxidative stress in COVID-19 patients: a cross-sectional comparative study in Jigawa, Northwestern Nigeria. SAGE Open Med. 2021;9:2050312121991246. doi: 10.1177/2050312121991246Muhammad Y., Kani Y.A., Iliya S., Muhammad J.B., Binji A., El-Fulaty Ahmad A., Kabir M.B., Umar Bindawa K., Ahmed A. Deficiency of antioxidants and increased oxidative stress in COVID-19 patients: a cross-sectional comparative study in Jigawa, Northwestern Nigeria. SAGE Open Med. 2021;9:2050312121991246. doi: 10.1177/2050312121991246Khan N., Singla M., Samal S., Lodha R., Medigeshi G.R. Respiratory syncytial virus-induced oxidative stress leads to an increase in labile zinc pools in lung epithelial cells. mSphere. 2020;5:e00447–e004420. doi: 10.1128/mSphere.00447-20Khan N., Singla M., Samal S., Lodha R., Medigeshi G.R. Respiratory syncytial virus-induced oxidative stress leads to an increase in labile zinc pools in lung epithelial cells. mSphere. 2020;5:e00447–e004420. doi: 10.1128/mSphere.00447-20Ao G., Li J., Yuan Y., Wang Y., Nasr B., Bao M., Gao M., Qi X. Intravenous vitamin C use and risk of severity and mortality in COVID-19: A systematic review and meta-analysis. Nutr. Clin. Pract. 2022;37(2):274–281. doi: 10.1002/ncp.10832Ao G., Li J., Yuan Y., Wang Y., Nasr B., Bao M., Gao M., Qi X. Intravenous vitamin C use and risk of severity and mortality in COVID-19: A systematic review and meta-analysis. Nutr. Clin. Pract. 2022;37(2):274–281. doi: 10.1002/ncp.10832Kow C.S., Hasan S.S., Ramachandram D.S. The effect of vitamin C on the risk of mortality in patients with COVID-19: a systematic review and metaanalysis of randomized controlled trials. Inflammopharmacology. 2023;31(6):3357–3362. doi: 10.1007/s10787-023-01200-5Kow C.S., Hasan S.S., Ramachandram D.S. The effect of vitamin C on the risk of mortality in patients with COVID-19: a systematic review and metaanalysis of randomized controlled trials. Inflammopharmacology. 2023;31(6):3357–3362. doi: 10.1007/s10787-023-01200-5Atefi N., Goodarzi A., Riahi T., Khodabandehloo N., Talebi Taher M., Najar Nobari N., Seirafianpour F., Mahdi Z., Baghestani A., Valizadeh R. Evaluation of the efficacy and safety of oral N-acetylcysteine in patients with COVID-19 receiving the routine antiviral and hydroxychloroquine protocol: A randomized controlled clinical trial. Immun. Inflamm. Dis. 2023;11(11):e1083. doi: 10.1002/iid3.1083Atefi N., Goodarzi A., Riahi T., Khodabandehloo N., Talebi Taher M., Najar Nobari N., Seirafianpour F., Mahdi Z., Baghestani A., Valizadeh R. Evaluation of the efficacy and safety of oral N-acetylcysteine in patients with COVID-19 receiving the routine antiviral and hydroxychloroquine protocol: A randomized controlled clinical trial. Immun. Inflamm. Dis. 2023;11(11):e1083. doi: 10.1002/iid3.1083Paraskevas T., Kantanis A., Karalis I., Michailides C., Karamouzos V., Koniari I., Pierrakos C., Velissaris D. N-acetylcysteine efficacy in patients hospitalized with COVID-19 pneumonia: a systematic review and meta-analysis. Rom. J. Intern. Med. 2023;61(1):41–52. doi: 10.2478/rjim-2023-0001Paraskevas T., Kantanis A., Karalis I., Michailides C., Karamouzos V., Koniari I., Pierrakos C., Velissaris D. N-acetylcysteine efficacy in patients hospitalized with COVID-19 pneumonia: a systematic review and meta-analysis. Rom. J. Intern. Med. 2023;61(1):41–52. doi: 10.2478/rjim-2023-0001Afaghi S., Moghimi N., Malekpour Alamdari N., Rahimi F.S., Irilouzadian R., Esmaeili Tarki F., Moghimi M., Besharat S., Salehi Omran H., Karimi A. N-acetylcysteine as adjuvant therapy for hospitalized COVID-19 patients: A single-center prospective cohort study. Caspian J. Intern. Med. 2023;14(3):543–552. doi: 10.22088/cjim.14.3.553Afaghi S., Moghimi N., Malekpour Alamdari N., Rahimi F.S., Irilouzadian R., Esmaeili Tarki F., Moghimi M., Besharat S., Salehi Omran H., Karimi A. N-acetylcysteine as adjuvant therapy for hospitalized COVID-19 patients: A single-center prospective cohort study. Caspian J. Intern. Med. 2023;14(3):543–552. doi: 10.22088/cjim.14.3.553Pilia E., Alborino E., Covello R.D. Does melatonin reduce mortality in COVID-19? Ann. Med. Surg. (Lond.). 2022:78:103817. doi: 10.1016/j.amsu.2022.103817Pilia E., Alborino E., Covello R.D. Does melatonin reduce mortality in COVID-19? Ann. Med. Surg. (Lond.). 2022:78:103817. doi: 10.1016/j.amsu.2022.103817Huang P.Y., Wu J.Y., Liu T.H., Tsai Y.W., Chen P.T., Liao C.T., Toh H.S. The clinical efficacy of melatonin in the treatment of patients with COVID19: a systematic review and metaanalysis of randomized controlled trials. Front. Med. (Lausanne). 2023;10:1171294. doi: 10.3389/fmed.2023.1171294Huang P.Y., Wu J.Y., Liu T.H., Tsai Y.W., Chen P.T., Liao C.T., Toh H.S. The clinical efficacy of melatonin in the treatment of patients with COVID-19: a systematic review and meta-analysis of ran-

The authors declare that there are no conflicts of interest present.