Hyperhomocysteinemia and MTHFR C677T polymorphism in SARS-CoV-2 infection severity

Abstract

COVID-19 virus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) has imposed a huge burden of mortality, morbidity, and socio-economic issues worldwide. Dominating transmission efficacy and the surge in instant genetic mutations pose challenges to the overwhelmed healthcare system. In this study, we aim to explore the role of homocysteine (Hcy) as a biomarker in COVID-19 and to develop strategies to mitigate the severity of SARS-CoV-2 infection. We reviewed the biochemical, physiological, and genetic implications of COVID-19. Upon SARS-CoV-2 exposure, Hcy metabolism is disrupted, leading to hyperhomocysteinemia (HHcy) and inducing inflammatory markers, e.g., interleukins (IL-6 and IL-7), tumor necrosis factor, interferon-γ, and C-reactive protein, which are characterized as a cytokine storm. HHcy develops numerous complications, including cardiovascular disorders, neural problems, and musculoskeletal disorders. However, nutritional deficiencies, e.g., folic acid, vitamin B6, and vitamin B12, and elevated serum creatinine are the important determinants of Hcy concentrations in the body. Additionally, the MTHFR C677T polymorphism is also a key factor that modulates Hcy levels and increases the risk of viral incidence. Overall, the identification of biochemical, metabolic, and genetic biomarkers may improve risk stratification, inform COVID-19 management, and help identify potential therapeutic targets.

Keywords

SARS-CoV-2 / Hyperhomocysteinemia / MTHFR C677T polymorphism / Folic acid / Vitamin B

References

[1] Rabaan AA, Alenazy MF, Alshehri AA, et al. An updated review on pathogenic coronaviruses (CoVs) amid the emergence of SARS-CoV-2 variants: A look into the repercussions and possible solutions. J Infect Public Health. 2023; 16(11):1870-1883. doi: 10.1016/j.jiph.2023.09.004

[2] Zheng J. SARS-CoV-2: an Emerging Coronavirus that Causes a Global Threat. Int J Biol Sci. 2020; 16(10):1678-1685. doi: 10.7150/ijbs.45053

[3] Rahbar Saadat Y, Hosseiniyan Khatibi SM, Zununi Vahed S, Ardalan M. Host Serine Proteases: A Potential Targeted Therapy for COVID-19 and Influenza. Front Mol Biosci. 2021; 8. doi: 10.3389/fmolb.2021.725528

[4] Simon V, Floda D, Gleason C, et al. The pandemic gap of respiratory viruses during the COVID-19 pandemic. mBio. 2025; 17(1):e03376-25. doi: 10.1128/mbio.03376-25

[5] Hao Y, Wang Y, Wang M, et al. The origins of COVID‐19 pandemic: A brief overview. Transbound Emerg Dis. 2022; 69: 3181-3197. doi: 10.1111/tbed.14732

[6] Zhang Q, Xiang R, Huo S, et al. Molecular mechanism of interaction between SARS-CoV-2 and host cells and interventional therapy. Sig Transduct Target. 2021; 6(1):1. doi: 10.1038/s41392-021-00653-w

[7] Stojanovic M, Djuric M, Nenadic I, et al. Vascular Complications of Long COVID-From Endothelial Dysfunction to Systemic Thrombosis: A Systematic Review. Int J Mol Sci. 2026; 27(1):433. doi: 10.3390/ijms27010433

[8] Dhochak N, Singhal T, Kabra SK, Lodha R. Pathophysiology of COVID-19: Why Children Fare Better than Adults? Indian J Pediatr. 2020; 87(7):537-546. doi: 10.1007/s12098-020-03322-y

[9] Tsabouri S, Makis A, Kosmeri C, Siomou E. Risk Factors for Severity in Children with Coronavirus Disease 2019. Pediatr Clin North Am. 2021; 68(1):321-338. doi: 10.1016/j.pcl.2020.07.014

[10] Ponti G, Pastorino L, Manfredini M, et al. COVID‐19 spreading across world correlates with C677T allele of the methylenetetrahydrofolate reductase (MTHFR) gene prevalence. J Clin Lab Anal. 2021; 35(7):e23798. doi: 10.1002/jcla.23798

[11] Rehman T, Shabbir MA, Inam-Ur-Raheem M, et al. Cysteine and homocysteine as biomarker of various diseases. Food Sci Nutr. 2020; 8(9):4696-4707. doi: 10.1002/fsn3.1818

[12] Smith AD, Refsum H, Bottiglieri T, et al. Homocysteine and Dementia: An International Consensus Statement1. J Alzheimers Dis. 2018. 62(2):561-570. doi: 10.3233/JAD-171042

[13] Singh HS, Salam K, Saraswathy KN. A Study on MTHFR C677T Gene Polymorphism and Alcohol Dependence among Meiteis of Manipur, India. J Biomark. 2014; 2014:310241. doi: 10.1155/2014/310241

[14] Dell’Edera D, L’Episcopia A, Simone F, Lupo MG, Epifania AA, Allegretti A. Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms and susceptibility to recurrent pregnancy loss. Biomed Rep. 2018; 8(2):172-175. doi: 10.3892/br.2018.1039

[15] Hoss GRW, Poloni S, Blom HJ, Schwartz IVD. Three Main Causes of Homocystinuria: CBS, cblC and MTHFR Deficiency. What do they Have in Common? J Inborn Errors Metab Screen. 2019;7. doi: 10.1590/2326-4594-JIEMS-2019-0007

[16] Hampshire A, Trender W, Chamberlain SR, et al. Cognitive deficits in people who have recovered from COVID-19. EclinicalMedicine. 2021; 39:101044. doi: 10.1016/j.eclinm.2021.101044

[17] Im JH, Je YS, Baek J, Chung MH, Kwon HY, Lee JS. Nutritional status of patients with COVID-19. Int J Infect Dis. 2020; 100:390-393. doi: 10.1016/j.ijid.2020.08.018

[18] Richardson DP, Lovegrove JA. Nutritional status of micronutrients as a possible and modifiable risk factor for COVID-19: a UK perspective. Br J Nutr. 2021; 125(6):678-684. doi: 10.1017/S000711452000330X

[19] Shakoor H, Feehan J, Al Dhaheri AS, et al. Immune-boosting role of vitamins D, C, E, zinc, selenium and omega-3 fatty acids: Could they help against COVID-19? Maturitas. 2021; 143:1-9. doi: 10.1016/j.maturitas.2020.08.003

[20] Herrmann W, Herrmann M. The Controversial Role of HCY and Vitamin B Deficiency in Cardiovascular Diseases. Nutrients. 2022; 14(7):1412. doi: 10.3390/nu14071412

[21] Tan CW, Ho LP, Kalimuddin S, et al. Cohort study to evaluate the effect of vitamin D, magnesium, and vitamin B12 in combination on progression to severe outcomes in older patients with coronavirus (COVID-19). Nutrition. 2020; 79:111017. doi: 10.1016/j.nut.2020.111017

[22] Islam MdA. A review of SARS-CoV-2 variants and vaccines: Viral properties, mutations, vaccine efficacy, and safety. Infect Med. 2023; 2(4):247-261. doi: 10.1016/j.imj.2023.08.005

[23] Harvey WT, Carabelli AM, Jackson B, et al. SARS-CoV-2 variants, spike mutations and immune escape. Nat Rev Microbiol. 2021; 19(7):7. doi: 10.1038/s41579-021-00573-0

[24] Ciaccio M, Agnello L. Biochemical biomarkers alterations in Coronavirus Disease 2019 (COVID-19). Diagnosis. 2020; 7(4):365-372. doi: 10.1515/dx-2020-0057

[25] Akhmerov A, Marbán E. COVID-19 and the Heart. Circ Res. 2020; 126(10):1443-1455. doi: 10.1161/CIRCRESAHA.120.317055

[26] Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID- 19 associated with acute respiratory distress syndrome. Lancet Respir. Med 2020; 8(4):420-422. doi: 10.1016/S2213-2600(20)30076-X

[27] Al Mutairi F. Hyperhomocysteinemia: Clinical Insights. J Cent Nerv Syst Dis. 2020; 12:1179573520962230. doi: 10.1177/1179573520962230

[28] Hasan T, Arora R, Bansal AK, Bhattacharya R, Sharma GS, Singh LR. Disturbed homocysteine metabolism is associated with cancer. Exp Mol Med. 2019; 51(2):21. doi: 10.1038/s12276-019-0216-4

[29] Ibrahimagić OĆ, Smajlović D, Dostović Z, Vidović M, Tupković E, Kunić S. COMMENT ON AN ARTICLE: “Homocysteine as a potential predictor of cardiovascular risk in patients with COVID-19”. Med Hypotheses. 2020; 143:110107. doi: 10.1016/j.mehy.2020.110107

[30] Fouda EM, Wahba NS, Elsharawy AIM, Ishak SR. Serum homocysteine level in pediatric patients with COVID‐19 and its correlation with the disease severity. Pediatr Pulmonol. 2022; 57(7):1701-1708. doi: 10.1002/ppul.25920

[31] Carpenè G, Negrini D, Henry BM, Montagnana M, Lippi G. Homocysteine in coronavirus disease (COVID-19): a systematic literature review. Diagnosis. 2022; 9(3):306-310. doi: 10.1515/dx-2022-0042

[32] Du X, Xiao L, Sun R, et al. A prospective cohort study of MTHFR C677T gene polymorphism and its influence on the therapeutic effect of homocysteine in stroke patients with hyperhomocysteinemia. BMC Neurol. 2020; 20(1):128. doi: 10.1186/s12883-020-01701-8

[33] Peterson CT, Rodionov DA, Osterman AL, Peterson SN. B Vitamins and Their Role in Immune Regulation and Cancer. Nutrients. 2020; 12(11):3380. doi: 10.3390/nu12113380

[34] Karst M, Hollenhorst J, Achenbach J. Life-threatening course in coronavirus disease 2019 (COVID-19): Is there a link to methylenetetrahydrofolic acid reductase (MTHFR) polymorphism and hyperhomocysteinemia? Med Hypotheses. 2020; 144:110234. doi: 10.1016/j.mehy.2020.110234

[35] Ibrahimagic OC, Smajlovic D, Dostovic Z, et al. Hyperhomocysteinemia and its treatment in patients with Parkinson’s disease. Mater Sociomed. 2016; 28(4):303-306. doi: 10.5455/msm.2016.28.303-306

[36] Ssentongo P, Ssentongo AE, Heilbrunn ES, Ba DM, Chinchilli VM. Association of cardiovascular disease and 10 other pre-existing comorbidities with COVID-19 mortality: A systematic review and meta-analysis. PLoS ONE. 2020; 15(8):e0238215. doi: 10.1371/journal.pone.0238215

[37] Miesbach W, Makris M. COVID-19: Coagulopathy, Risk of Thrombosis, and the Rationale for Anticoagulation. Clin Appl Thromb Hemost. 2020; 26:1076029620938149. doi: 10.1177/1076029620938149

[38] Keskin A, U Ustun G, Aci R, Duran U. Homocysteine as a marker for predicting disease severity in patients with COVID-19. Biomark Med. 2022; 16(7):559-568. doi: 10.2217/bmm-2021-0688

[39] Ponti G, Roli L, Oliva G, et al. Homocysteine (Hcy) assessment to predict outcomes of hospitalized Covid-19 patients: a multicenter study on 313 Covid-19 patients. Clin Chem Lab Med. 2021; 59(9):e354-e357. doi: 10.1515/cclm-2021-0168

[40] Yang Z, Shi J, He Z, et al. Predictors for imaging progression on chest CT from coronavirus disease 2019 (COVID-19) patients. Aging. 2020; 12(7):6037-6048. doi: 10.18632/aging.102999

[41] Perła-Kaján J, Jakubowski H. COVID-19 and One-Carbon Metabolism. Int J Mol Sci. 2022; 23(8):4181. doi: 10.3390/ijms23084181

[42] Ponti G, Ruini C, Tomasi A. Homocysteine as a potential predictor of cardiovascular risk in patients with COVID-19. Med Hypotheses. 2020; 143:109859. doi: 10.1016/j.mehy.2020.109859

[43] Caterino M, Costanzo M, Fedele R, et al. The Serum Metabolome of Moderate and Severe COVID-19 Patients Reflects Possible Liver Alterations Involving Carbon and Nitrogen Metabolism. Int J Mol Sci. 2021; 22(17):9548. doi: 10.3390/ijms22179548

[44] Kryukov EV, Ivanov AV, Karpov VO, et al. Plasma S-Adenosylmethionine Is Associated with Lung Injury in COVID-19. Dis Markers. 2021; 2021:7686374. doi: 10.1155/2021/7686374

[45] Wang C, Zhang X, Qiu B. Genetically predicted circulating serum homocysteine levels on osteoporosis: a two-sample mendelian randomization study. Sci Rep. 2023; 13:9063. doi: 10.1038/s41598-023-35472-2

[46] Alsaffar SF, Baqer NN. Association between Methylenetetrahydrofolate Reductase (MTHFR) and 5-Methyltetrahydrofolate-Homocysteine Methyltransferase Reductase (MTRR) Polymorphisms in Iraqi Patients with COVID-19. Iran J Med Sci. 2024; 49(7):430-440. doi: 10.30476/IJMS.2023.99555.3162

[47] Cao J, Chen X, Jiang L, et al. DJ-1 suppresses ferroptosis through preserving the activity of S-adenosyl homocysteine hydrolase. Nat Commun. 2020; 11(1):1251. doi: 10.1038/s41467-020-15109-y

[48] Press Trust of India. 51,775 cases of mucormycosis reported in India:Health Minister Mansukh Mandaviya. India Today. 2021. Available from:https://www.indiatoday.in/india/story/mucormycosis-cases-india-health-minister-mansukh-mandaviya-1883980-2021-12-04 [Last Accessed on 10 December, 2021].

[49] Shrotri M, van Schalkwyk MCI, Post N, et al. T cell response to SARS-CoV-2 infection in humans: A systematic review. PLoS ONE. 2021; 16(1):e0245532. doi: 10.1371/journal.pone.0245532

[50] Bhatt K, Agolli A, Patel MH, et al. High mortality co-infections of COVID-19 patients: mucormycosis and other fungal infections. Discoveries. 9(1):e126. doi: 10.15190/d.2021.5

[51] Soni S, Namdeo Pudake R, Jain U, Chauhan N. A systematic review on SARS-CoV-2-associated fungal coinfections. J Med Virol. 2022; 94(1):99-109. doi: 10.1002/jmv.27358

[52] Silva DL, Lima CM, Magalhães VCR, et al. Fungal and bacterial coinfections increase mortality of severely ill COVID-19 patients. J Hosp Infect. 2021; 113:145-154. doi: 10.1016/j.jhin.2021.04.001

[53] Gómez-Mesa JE, Galindo-Coral S, Montes MC, Muñoz Martin AJ. Thrombosis and Coagulopathy in COVID-19. Curr Probl Cardiol. 2021; 46(3):100742. doi: 10.1016/j.cpcardiol.2020.100742

[54] Pinto BGG, Oliveira AER, Singh Y, et al. ACE2 Expression Is Increased in the Lungs of Patients With Comorbidities Associated With Severe COVID-19. J Infect Dis. 2020; 222(4):556-563. doi: 10.1093/infdis/jiaa332

[55] Djaharuddin I, Munawwarah S, Nurulita A, Ilyas M, Tabri NA, Lihawa N. Comorbidities and mortality in COVID-19 patients. Gac Sanit. 2021; 35:S530-S532. doi: 10.1016/j.gaceta.2021.10.085

[56] Jindal R, Gupta M, Khan FR, Chaudhry G. Prevalence of co-morbidities and its association with mortality in Indian patients with COVID-19: A meta-analysis. Indian J Anaesth. 2022; 66(6):399-418. doi: 10.4103/ija.ija_845_21

[57] Tinelli C, Di Pino A, Ficulle E, Marcelli S, Feligioni M. Hyperhomocysteinemia as a Risk Factor and Potential Nutraceutical Target for Certain Pathologies. Front Nutr. 2019; 6:49. doi: 10.3389/fnut.2019.00049

[58] Škovierová H, Vidomanová E, Mahmood S, et al. The Molecular and Cellular Effect of Homocysteine Metabolism Imbalance on Human Health. Int J Mol Sci. 2016; 17(10):10. doi: 10.3390/ijms17101733

[59] Azzini E, Ruggeri S, Polito A. Homocysteine: Its Possible Emerging Role in At-Risk Population Groups. Int J Mol Sci. 2020; 21(4):4. doi: 10.3390/ijms21041421

[60] Kaye AD, Jeha GM, Pham AD, et al. Folic Acid Supplementation in Patients with Elevated Homocysteine Levels. Adv Ther. 2020; 37(10):4149-4164. doi: 10.1007/s12325-020-01474-z

[61] McCaddon A, Regland B. COVID-19: A methyl-group assault? Med Hypotheses. 2021; 149:110543. doi: 10.1016/j.mehy.2021.110543

[62] van de Poll MC, Soeters PB, Deutz NE, Fearon KC, Dejong CH. Renal metabolism of amino acids: its role in interorgan amino acid exchange. Am J Clin Nutr. 2004; 79(2):185-197. doi: 10.1093/ajcn/79.2.185

[63] Adapa S, Chenna A, Balla M, et al. COVID-19 Pandemic Causing Acute Kidney Injury and Impact on Patients With Chronic Kidney Disease and Renal Transplantation. J Clin Med Res. 2020; 12(6):352-361. doi: 10.14740/jocmr4200

[64] Umansky C, Morellato AE, Rieckher M, et al. Endogenous formaldehyde scavenges cellular glutathione resulting in redox disruption and cytotoxicity. Nat Commun. 2022; 13(1):1. doi: 10.1038/s41467-022-28242-7

[65] Kim J, Hannibal L, Gherasim C, Jacobsen DW, Banerjee R. A Human Vitamin B12 Trafficking Protein Uses Glutathione Transferase Activity for Processing Alkylcobalamins. J Biol Chem. 2009; 284(48):33418-33424. doi: 10.1074/jbc.M109.057877

[66] Khanfar A, Al Qaroot B. Could glutathione depletion be the Trojan horse of COVID-19 mortality? Eur Rev Med Pharmacol Sci. 2020; 24(23):12500-12509. doi: 10.26355/eurrev_202012_24046

[67] Polonikov A. Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients. ACS Infect Dis. 2020; 6(7):1558-1562. doi: 10.1021/acsinfecdis.0c00288

[68] Horowitz RI, Freeman PR, Bruzzese J. Efficacy of glutathione therapy in relieving dyspnea associated with COVID- 19 pneumonia: A report of 2 cases. Respir Med Case Rep. 2020; 30:101063. doi: 10.1016/j.rmcr.2020.101063

[69] Ayako RM, Patel K, Ndede I, Nordgren J, Larrson M, Mining SK. Inflammatory, Hematological, and Biochemical Biomarkers in COVID‐19 Patients. Immun Inflamm Dis. 2024; 12(12):e70078. doi: 10.1002/iid3.70078

[70] Sun Y, Dong Y, Wang L, et al. Characteristics and prognostic factors of disease severity in patients with COVID-19: The Beijing experience. J Autoimmun. 2020; 112:102473. doi: 10.1016/j.jaut.2020.102473

[71] Urban S, Fułek M, Błaziak M, et al. COVID-19 Related Myocarditis in Adults: A Systematic Review of Case Reports. J Clin Med. 2022; 11(19):5519. doi: 10.3390/jcm11195519

[72] Ponti G, Maccaferri M, Ruini C, Tomasi A, Ozben T. Biomarkers associated with COVID-19 disease progression. Crit Rev Clin Lab Sci. 2020:1-11. doi: 10.1080/10408363.2020.1770685

[73] Ali A, Noman M, Guo Y, et al. Myoglobin and C-reactive protein are efficient and reliable early predictors of COVID- 19 associated mortality. Sci Rep. 2021; 11:5975. doi: 10.1038/s41598-021-85426-9

[74] Zlojutro B, Jandric M, Momcicevic D, et al. Dynamic changes in coagulation, hematological and biochemical parameters as predictors of mortality in critically ill COVID-19 patients: A prospective observational study. Clin Hemorheol Microcirc. 2023; 83(2):137-148. doi: 10.3233/CH-221583

[75] Lippi G, South AM, Henry BM. Electrolyte Imbalances in Patients with Severe Coronavirus Disease 2019 (COVID- 19). Ann Clin Biochem. 2020; 57(3):262-265. doi: 10.1177/0004563220922255

[76] Illg Z, Muller G, Mueller M, Nippert J, Allen B. Analysis of absolute lymphocyte count in patients with COVID-19. Am J Emerg Med. 2021; 46:16-19. doi: 10.1016/j.ajem.2021.02.054

[77] Reusch N, De Domenico E, Bonaguro L, et al. Neutrophils in COVID-19. Front Immunol. 2021; 12:652470. doi: 10.3389/fimmu.2021.652470

[78] Fard MB, Fard SB, Ramazi S, Atashi A, Eslamifar Z. Thrombosis in COVID-19 infection: Role of platelet activation-mediated immunity. Thrombosis J. 2021; 19(1). doi: 10.1186/s12959-021-00311-9

[79] Asakura H, Ogawa H. COVID-19-associated coagulopathy and disseminated intravascular coagulation. Int J Hematol. 2021; 113(1):45-57. doi: 10.1007/s12185-020-03029-y

[80] Raychaudhuri S, Pujani M, Menia R, et al. COVID- 19 Associated Coagulopathy in an Indian Scenario: A Correlation with Disease Severity and Survival Status. Indian J Hematol Blood Transfus. 2022; 38(2):341-351. doi: 10.1007/s12288-021-01465-2

[81] Luo H chun, You C yan, Lu S wei, Fu Y qiang. Characteristics of coagulation alteration in patients with COVID-19. Ann Hematol. 2021; 100(1):45-52. doi: 10.1007/s00277-020-04305-x

[82] Samprathi M, Jayashree M. Biomarkers in COVID-19: An Up-To-Date Review. Front Pediatrics. 2021; 8. doi: 10.3389/fped.2020.607647

[83] Meidaninikjeh S, Sabouni N, Marzouni HZ, Bengar S, Khalili A, Jafari R. Monocytes and macrophages in COVID- 19: Friends and foes. Life Sci. 2021; 269:119010. doi: 10.1016/j.lfs.2020.119010

[84] Hwaiz R, Merza M, Hamad B, HamaSalih S, Mohammed M, Hama H. Evaluation of hepatic enzymes activities in COVID-19 patients. Int Immunopharmacol. 2021; 97:107701. doi: 10.1016/j.intimp.2021.107701

[85] Violi F, Cangemi R, Romiti GF, et al. Is albumin predictor of mortality in COVID-19? Antioxid Redox Signal. 2021; 35(2):139-142. doi: 10.1089/ars.2020.8142

[86] Li L, Zhou Q, Xu J. Changes of Laboratory Cardiac Markers and Mechanisms of Cardiac Injury in Coronavirus Disease 2019. BioMed Res Int. 2020; 2020:e7413673. doi: 10.1155/2020/7413673

[87] Lippi G, Sanchis-Gomar F, Henry BM, Lavie CJ. Cardiac Biomarkers in COVID-19: A Narrative Review. EJIFCC. 2021; 32(3):337-346

[88] Husain-Syed F, Villa G, Wilhelm J, et al. Renal markers for monitoring acute kidney injury transition to chronic kidney disease after COVID-19. Nephrol Dial Transplant. 2021; 36(11):2143-2147. doi: 10.1093/ndt/gfab235

[89] De Rosa A, Pinuccia Verrengia E, Merlo I, et al. Muscle manifestations and CK levels in COVID infection: Results of a large cohort of patients inside a pandemic COVID-19 area. J Neurol Sci. 2021; 429:119838. doi: 10.1016/j.jns.2021.119838

[90] Muhammad Y, Kani YA, Iliya S, et al. 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: 10.1177/2050312121991246

[91] Yaghoubi N, Youssefi M, Jabbari Azad F, Farzad F, Yavari Z, Zahedi Avval F. Total antioxidant capacity as a marker of severity of COVID‐19 infection: Possible prognostic and therapeutic clinical application. J Med Virol. 2022; 94(4):1558-1565. doi: 10.1002/jmv.27500

[92] Michele CA, Angel B, Valeria L, et al. Vitamin supplements in the Era of SARS-Cov2 pandemic. GSC Biol Pharm Sci. 2020; 11(2):2. doi: 10.30574/gscbps.2020.11.2.0114

[93] Lin LY, Husnayain A, Chen YT, Kuo CY. The association between interest of nutritional supplements and COVID- 19 pandemic - evidence from Google Trends. BMC Public Health. 2024; 24(1):109. doi: 10.1186/s12889-023-17607-2

[94] Yaghoubi N, Youssefi M, Jabbari Azad F, Farzad F, Yavari Z, Zahedi Avval F. Total antioxidant capacity as a marker of severity of COVID-19 infection: Possible prognostic and therapeutic clinical application. J Med Virol. 2022; 94(4):1558-1565. doi: 10.1002/jmv.27500

[95] Škrbić R, Travar M, Stojiljković MP, Djuric DM, Suručić R. Folic Acid and Leucovorin Have Potential to Prevent SARS-CoV-2-Virus Internalization by Interacting with S-Glycoprotein/Neuropilin-1 Receptor Complex. Molecules. 2023; 28(5):2294. doi: 10.3390/molecules28052294

[96] Shakoor H, Feehan J, Mikkelsen K, et al. Be well: A potential role for vitamin B in COVID-19. Maturitas. 2021; 144:108-111. doi: 10.1016/j.maturitas.2020.08.007

[97] Sobczyńska-Malefora A, Delvin E, McCaddon A, Ahmadi KR, Harrington DJ. Vitamin B12 status in health and disease: a critical review. Diagnosis of deficiency and insufficiency - clinical and laboratory pitfalls. Crit Rev Clin Lab Sci. 2021; 58(6):399-429. doi: 10.1080/10408363.2021.1885339

[98] Mikkelsen K, Stojanovska L, Prakash M, Apostolopoulos V. The effects of vitamin B on the immune/cytokine network and their involvement in depression. Maturitas. 2017; 96:58-71. doi: 10.1016/j.maturitas.2016.11.012

[99] Wolffenbuttel BHR, Wouters HJCM, Heiner-Fokkema MR, van der Klauw MM. The Many Faces of Cobalamin (Vitamin B12) Deficiency. Mayo Clin Proc Innov Qual Outcomes. 2019; 3(2):200-214. doi: 10.1016/j.mayocpiqo.2019.03.002

[100] Kim J, Kim H, Roh H, Kwon Y. Causes of hyperhomocysteinemia and its pathological significance. Arch Pharm Res. 2018; 41(4):372-383. doi: 10.1007/s12272-018-1016-4

[101] Sabry W, Elemary M, Burnouf T, Seghatchian J, Goubran H. Vitamin B12 deficiency and metabolism-mediated thrombotic microangiopathy (MM-TMA). Transfus Apher Sci. 2020; 59(1):102717. doi: 10.1016/j.transci.2019.102717

[102] Grangé S, Bekri S, Artaud-Macari E, et al. Adult-onset renal thrombotic microangiopathy and pulmonary arterial hypertension in cobalamin C deficiency. Lancet. 2015; 386(9997):1011-1012. doi: 10.1016/S0140-6736(15)00076-8

[103] Batista KS, Cintra VM, Lucena PAF, et al. The role of vitamin B12 in viral infections: a comprehensive review of its relationship with the muscle-gut-brain axis and implications for SARS-CoV-2 infection. Nutr Rev. 2022; 80(3):561-578. doi: 10.1093/nutrit/nuab092

[104] Miyara M, Tubach F, Pourcher V, et al. Lower Rate of Daily Smokers With Symptomatic COVID-19: A Monocentric Self-Report of Smoking Habit Study. Front Med. 2022; 8:668995. doi: 10.3389/fmed.2021.668995

[105] Qomara WF, Primanissa DN, Amalia SH, Purwadi FV, Zakiyah N. Effectiveness of Remdesivir, Lopinavir/Ritonavir, and Favipiravir for COVID-19 Treatment: A Systematic Review. Int J Gen Med. 2021; 14:8557-8571. doi: 10.2147/IJGM.S332458

[106] Choy KT, Wong AYL, Kaewpreedee P, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res. 2020; 178:104786. doi: 10.1016/j.antiviral.2020.104786

[107] Choi MJ, Kang M, Shin SY, et al. Comparison of antiviral effect for mild-to-moderate COVID-19 cases between lopinavir/ritonavir versus hydroxychloroquine: A nationwide propensity score-matched cohort study. Int J Infect Dis. 2021; 102:275-281. doi: 10.1016/j.ijid.2020.10.062

[108] Gavriatopoulou M, Ntanasis-Stathopoulos I, Korompoki E, et al. Emerging treatment strategies for COVID-19 infection. Clin Exp Med. 2021; 21(2):167-179. doi: 10.1007/s10238-020-00671-y

[109] Khataniar A, Pathak U, Rajkhowa S, Jha AN. A Comprehensive Review of Drug Repurposing Strategies against Known Drug Targets of COVID-19. COVID. 2022; 2(2):2. doi: 10.3390/covid2020011

[110] Sabitha S, Shobana N, Prakash P, et al. A Review of Different Vaccines and Strategies to Combat COVID-19. Vaccines. 2022; 10(5):737. doi: 10.3390/vaccines10050737

[111] Helmy SA, El-Morsi RM, Helmy SAM, El-Masry SM. Towards novel nano-based vaccine platforms for SARS-CoV-2 and its variants of concern: Advances, challenges and limitations. J Drug Deliv Sci Technol. 2022; 76:103762. doi: 10.1016/j.jddst.2022.103762

[112] Chakraborty C, Lo YH, Bhattacharya M, Das A, Wen ZH. Looking beyond the origin of SARS-CoV-2: Significant strategic aspects during the five-year journey of COVID-19 vaccine development. Mol Ther Nucleic Acids. 2025; 36(2). doi: 10.1016/j.omtn.2025.102527

[113] Asrani P, Eapen MS, Hassan MI, Sohal SS. Implications of the second wave of COVID-19 in India. Lancet Respir Med. 2021; 9(9):e93-e94. doi: 10.1016/S2213-2600(21)00312-X

[114] Zeyaullah Md, AlShahrani AM, Muzammil K, et al. COVID-19 and SARS-CoV-2 Variants: Current Challenges and Health Concern. Front Genet. 2021; 12:693916. doi: 10.3389/fgene.2021.693916

[115] Hill V, Githinji G, Vogels CBF, et al. Toward a global virus genomic surveillance network. Cell Host Microbe. 2023; 31(6):861-873. doi: 10.1016/j.chom.2023.03.003

[116] Joshi RK, Mehendale SM. Prevention and control of COVID-19 in India: Strategies and options. Med J Armed Forces India. 2021; 77(Suppl 2):S237-S241. doi: 10.1016/j.mjafi.2021.05.009

[117] Ghosh N, Saha I, Sarkar JP, Maulik U. Strategies for COVID- 19 Epidemiological Surveillance in India: Overall Policies Till June 2021. Front Public Health. 2021; 9:988. doi: 10.3389/fpubh.2021.708224

[118] Kumar A, Palfrey HA, Pathak R, Kadowitz PJ, Gettys TW, Murthy SN. The metabolism and significance of homocysteine in nutrition and health. Nutr Metab. 2017; 14:78. doi: 10.1186/s12986-017-0233-z

[119] Fu Y, Wang X, Kong W. Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets. Br J Pharmacol. 2018; 175(8):1173-1189. doi: 10.1111/bph.13988

[120] Ganguly P, Alam SF. Role of homocysteine in the development of cardiovascular disease. Nutr J. 2015; 14:6. doi: 10.1186/1475-2891-14-6

[121] Sydow K, Böger RH. Reloaded: ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inaemia: effects of l-arginine and B vitamins: Authors’ retrospective. Cardiovasc Res. 2012; 96(2):167-171. doi: 10.1093/cvr/cvs205

[122] Mustafa M, Hussain S, Qureshi S, Malik SA, Kazmi AR, Naeem M. Study of the effect of antiviral therapy on homocysteinemia in hepatitis C virus- infected patients. BMC Gastroenterol. 2012; 12:117. doi: 10.1186/1471-230X-12-117

[123] Deminice R, Silva TCV, de Oliveira VHF. Elevated homocysteine levels in human immunodeficiency virus-infected patients under antiretroviral therapy: A meta-analysis. World J Virol. 2015; 4(2):147-155. doi: 10.5501/wjv.v4.i2.147

[124] Tian W, Ju J, Guan B, et al. Role of hyperhomocysteinemia in atherosclerosis: from bench to bedside. Ann Med. 2025; 57(1):2457527. doi: 10.1080/07853890.2025.2457527

[125] Nägele MP, Haubner B, Tanner FC, Ruschitzka F, Flammer AJ. Endothelial dysfunction in COVID-19: Current findings and therapeutic implications. Atherosclerosis. 2020; 314:58-62. doi: 10.1016/j.atherosclerosis.2020.10.014

[126] Keskin A, U Ustun G, Aci R, Duran U. Homocysteine As A Marker for Predicting Disease Severity in Patients with Covid-19. Biomark Med. 2022; 16(7):559-568. doi: 10.2217/bmm-2021-0688

[127] Suručić R, Tubić B, Stojiljković MP, et al. Computational study of pomegranate peel extract polyphenols as potential inhibitors of SARS-CoV-2 virus internalization. Mol Cell Biochem. 2021; 476(2):1179-1193. doi: 10.1007/s11010-020-03981-7