HIF-1a in immune pathogenesis of SARS-CoV-2-pneumonia

Volchkova E.V.; Kuzubova N.A.; Aleksandrovich Yu.S.; Lebedeva E.S.

doi:https://doi.org/10.17116/anaesthesiology202205171

Close metadata

Recommended articles:

Clinical, laboratory and morphological comparisons in cellular alteration under conditions of hypoxia. Russian Journal of Archive of Pathology. 2024;(5):42-52

The effect of ethylmethylhydroxypyridine succinate on the parameters of chronic neuroinflammation and plastic processes in the brain of old rats during course of dexamethasone administration. S.S. Korsakov Journal of Neurology and Psychiatry. 2024;(9):115-121

Cytokine profile in middle-aged men with acute and chronic coronary syndrome and its relation with coronary bed lesion severity. Russian Journal of Preventive Medicine. 2024;(10):101-107

Oxidative toxemia, hypoxia and intra-abdominal hypertension in acute pancreatitis. Pirogov Russian Journal of Surgery. 2024;(11):38-45

Laboratory tests for diagnostics of cell immunity against SARS-CoV-2 (review of literature). Laboratory Service. 2024;(3):31-36

The effectiveness of rehabilitation measures using the drug Cortexin in children with neuropsychiatric pathology. S.S. Korsakov Journal of Neurology and Psychiatry. 2024;(12):86-92

Development and testing of the first domestic automatic cartridge-type POCT platform for the qualitative determination of SARS-CoV-2 RNA. Laboratory Service. 2024;(4):21-27

The level of hypoxia-induced factor-1a and associated molecules in preeclampsia. Russian Bulletin of Obstetrician-Gynecologist. 2025;(1):5-10

Central nervous system involvement in systemic lupus erythematosus. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(2):124-129

Post-Covid aortitis with cardiac involvement: progressive aortic aneurysm combined with active myocarditis. Russian Journal of Archive of Pathology. 2025;(2):53-58

Abstract:

The review is devoted to cellular and molecular mechanisms of the course and progression of new coronavirus disease, in particular, the role of hypoxia and hypoxia-induced factor 1α (HIF-1α). Literature searching was performed in the PubMed, Medline and Web of Science databases for the period 2019—2022. Hypoxia is a direct consequence of lung damage due to COVID-19 infection. In the areas of SARS-CoV-2-induced damage, focal inflammation occurs, and tissue microenvironment becomes hypoxic («inflammatory hypoxia»). Possible causes of «silent», «happy» or «apathetic» hypoxia in patients with COVID-19 and no symptoms of respiratory discomfort are discussed. HIF-1α activated by hypoxia is generally considered to be the main regulator of cellular response to oxygen deficiency. There is no consensus regarding the role of its activation in pathogenesis of COVID-19. As a transcriptional factor, HIF-1α can reduce penetration of SARS-CoV-2 via proteins controlling its entry into cells. This protein also reduces angiotensin-converting enzyme 2 receptor (ACE2) and serine protease expression, as well as increases expression of ADAM17 enzyme, which cleaves ACE2 from surface membrane of alveolocyte. The reverse side of HIF-1α activation may be fulminant cytokine storm as a result of expression of immune cells releasing pro-inflammatory cytokines. Possible HIF-dependent approaches to the treatment and prevention of COVID-19 are considered. These approaches are aimed at either suppressing HIF-1α activity using HIF-1α suppressor drugs or activating and stabilizing HIF-1α using HIF prolyl hydroxylase inhibitors.

Keywords:

SARS-CoV-2

pneumonia

HIF-1α

Hypoxia-inducible factor 1-alpha

hypoxia

angiotensin converting enzyme 2

pro-inflammatory cytokines

cytokine storm

Authors:

Volchkova E.V.

Saint Petersburg State Pediatric Medical University

Kuzubova N.A.

Pavlov First Saint Petersburg State Medical University

Aleksandrovich Yu.S.

Children’s Scientific Clinical Center for Infectious Diseases

ORCID: 0000-0002-2131-4813

Lebedeva E.S.

Pavlov First Saint Petersburg State Medical University

Received:

30.06.2022

Accepted:

18.07.2022

Close metadata

References:

Goh KJ, Choong MC, Cheong EH, Kalimuddin S, Duu Wen S, Phua GC, Chan KS, Haja Mohideen S. Rapid Progression to Acute Respiratory Distress Syndrome: Review of Current Understanding of Critical Illness from Coronavirus Disease 2019 (COVID-19) Infection. Annals of the Academy of Medicine, Singapore. 2020;49(3):108-118.
Siddiqi HK, Mehra MR. COVID-19 illness in native and immuno-suppressed states: A clinical-therapeutic staging proposal. The Journal of Heart and Lung Transplantation. 2020;39(5):405-407. https://doi.org/10.1016/j.healun.2020.03.012
Wilkerson RG, Adler JD, Shah NG, Brown R. Silent hypoxia: a harbinger of clinical deterioration in patients with COVID-19. The American Journal of Emergency Medicine. 2020;38(10):2243.e5-2243.e6. https://doi.org/10.1016/j.alem.2020.05.044
AbdelMassih A, Yacoub E, Husseiny RJ, Kamel A, Hozaien R, El Shershaby M, Rajab M, Yacoub S, Eid MA, Elahmady M, Gadalla M, Mokhtar S, Hassan AA, Abou-Zeid AS, Hussein M, Aboushadi N, Emad N, Zahra N, Hassan A, Hussein E, Ibrahim N, El Nahhas N, Elahmady T, Khallaf M, Mustafa H, Anis N, Albehairy M, Hanna F, Moris L, Ye J. Hypoxia-inducible factor (HIF): The link between obesity and COVID-19. Obesity Medicine. 2021;22:100317. https://doi.org/10.1016/j.obmed.2020.100317
Darif D, Hammi I, Kihel A, El Idrissi Saik I, Guessous F, Akarid K. The pro-inflammatory cytokines in COVID-19 pathogenesis: What goes wrong? Microbial Pathogenesis. 2021;153:104799. https://doi.org/10.1016/j.micpath.2021.104799
Yousefi B, Valizadeh S, Ghaffari H, Vahedi A, Karbalaei M, Eslami M. A global treatments for coronaviruses including COVID-19. Journal of Cellular Physiology. 2020;235(12):9133-9142. https://doi.org/10.1002/jcp.29785
Jahani M, Dokaneheifard S, Mansouri K. Hypoxia: A key feature of COVID-19 launching activation of HIF-1 and cytokine storm. Journal of Inflammation. 2020;17:33. https://doi.org/10.1186/s12950-020-00263-3
Serebrovska ZO, Chong EY, Serebrovska TV, Tumanovska LV, Xi L. Hypoxia, HIF-1alpha, and COVID-19: from pathogenic factors to potential therapeutic targets. Acta Pharmacologica Sinica. 2020;41(12):1539-1546. https://doi.org/10.1038/s41401-020-00554-8
Wing PAC, Keeley TP, Zhuang X, Lee JY, Prange-Barczynska M, Tsukuda S, Morgan SB, Harding AC, Argles ILA, Kurlekar S, Noerenberg M, Thompson CP, Huang KA, Balfe P, Watashi K, Castello A, Hinks TSC, James W, Ratcliffe PJ, Davis I, Hodson EJ, Bishop T, McKeating JA. Hypoxic and pharmacological activation of HIF inhibits SARS-CoV-2 infection of lung epithelial cells. Cell Reports. 2021;35(3):109020. https://doi.org/10.1016/j.celrep.2021.109020
Gan ES, Ooi EE. Oxygen: viral friend or foe? Virology Journal. 2020;17(1):115. https://doi.org/10.1186/s12985-020-01374-2
Colgan SP, Campbell EL, Kominsky DJ. Hypoxia and mucosal inflammation. Annual Review of Pathology. 2016;11:77-100. https://doi.org/10.1146/annurev-pathol-012615-044231
Cummins EP, Keogh CE, Crean D, Taylor CT. The role of HIF in immunity and inflammation. Molecular Aspects of Medicine. 2016;47-48:24-34. https://doi.org/10.1016/j.mam.2015.12.004
Watts ER, Walmsley SR. Inflammation and hypoxia: HIF and PHD isoform selectivity. Trends in Molecular Medicine. 2019;25(1):33-46. https://doi.org/10.1016/j.molmed.2018.10.006
Donina ZA. Causes of hypoxemia in COVID-19. Journal of Evolutionary Biochemistry and Physiology. 2022;58(1):73-80. https://doi.org/10.1134/S0022093022010070
Manganelli F, Vargas M, Iovino A, Iacovazzo C, Santoro L, Servillo G. Brainstem involvement and respiratory failure in COVID-19. Neurological Sciences. 2020;41(7):1663-1665. https://doi.org/10.1007/s10072-020-04487-2
Eriksson O, Hultström M, Persson B, Lipcsey M, Ekdahl KN, Nilsson B, Frithiof R. Mannose-binding lectin is associated with thrombosis and coagulopathy in critically ill COVID-19 patients. Thrombosis and Haemostasis. 2020;120(12):1720-1724. https://doi.org/10.1055/s-0040-1715835
Mason RJ. Thoughts on the alveolar phase of COVID-19. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2020;319(1):115-120. https://doi.org/10.1152/ajplung.00126.2020
Cavezzi A, Troiani E, Corrao S. COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review. Clinics and Practice. 2020;10(2):1271. https://doi.org/10.4081/cp.2020.1271
Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148(3):399-408. https://doi.org/10.1016/j.cell.2012.01.021
Titova ON, Kuzubova NA, Lebedeva ES, Surkova EA, Preobrazhenskaya TN, Dvorakovskaya IV. Anti-inflammatory and regenerative effect of hypoxic signaling suppression on a model of chronic obstructive pulmonary disease. Pul’monologiya. 2018;28(2):169-176. (In Russ.). https://doi.org/10.18093/0869-0189-2018-28-2-169-176
Gajnitdinova VV, Avdeev SN. Remodeling of large peripheral arteries in patients with chronic obstructive pulmonary disease and its combination with arterial hypertension. Pul’monologiya. 2015;25(1):50-57. (In Russ.). https://doi.org/10.18093/0869-0189-2015-25-1-50-57
Mineev VN, Lalaeva TM, Kuz’mina AA. Possible role of apelinergic signaling in the development of pathology of the bronchopulmonary system. Pul’monologiya. 2013;(2):101-104. (In Russ.). https://doi.org/10.18093/0869-0189-2013-0-2-101-104
Avdeev SN, Batyn SZ, Merzhoeva ZM, Chuchalin AG. High doses of N-acetylcysteine in acute respiratory distress syndrome. Pul’monologiya. 2010;3:31-38. (In Russ.). https://doi.org/10.18093/0869-0189-2010-3-31-38
Dobrynina LA, Gnedovskaya EV, Shabalina AA, Sergeeva AN, Kravchenko MA, Nikolaeva NS. Biomarkers and mechanisms of early vascular damage. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2018;118(12-2):23-32. (In Russ.). https://doi.org/10.17116/jnevro201811812223
Zonneveld M, Keulers T, Rouschop K. Extracellular vesicles as transmitters of hypoxia tolerance in solid cancers. Cancers. 2019;11(2):154. https://doi.org/10.3390/cancers11020154
Li MY, Li L, Zhang Y, Wang XS. Expression of the SARSCoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infectious Diseases of Poverty. 2020;9(1):45. https://doi.org/10.1186/s40249-020-00662-x
Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, Guo L, Guo R, Chen T, Hu J, Xiang Z, Mu Z, Chen X, Chen J, Hu K, Jin Q, Wang J, Qian Z. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nature Communications. 2020;11(1):1620. https://doi.org/10.1038/s41467-020-15562-9
Yan T, Xiao R, Lin G. Angiotensin-converting enzyme 2 in severe acute respiratory syndrome coronavirus and SARS-CoV-2: A double-edged sword? FASEB Journal. 2020;34(5):6017-6026. https://doi.org/10.1096/fj.202000782
Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Medicine. 2020;46(4):586-590. https://doi.org/10.1007/s00134-020-05985-9
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-280.e8. https://doi.org/10.1016/j.cell.2020.02.052
Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. Journal of Virology. 2020;94(7):e00127-20. https://doi.org/10.1128/JVI.00127-20
Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, Vanstapel A, Werlein C, Stark H, Tzankov A, Li WW, Li VW, Mentzer SJ, Jonigk D. Pulmonary vascular endothelialitis, hrombosis, and angiogenesis in Covid-19. The New England Journal of Medicine. 2020;383(2):120-128. https://doi.org/10.1056/NEJMoa2015432
Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nature Reviews. Immunology. 2020;20(6):363-374. https://doi.org/10.1038/s41577-020-0311-8
Zhang R, Su H, Ma X, Xu X, Liang L, Ma G, Shi L. MiRNA let-7b promotes the development of hypoxic pulmonary hypertension by targeting ACE2. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2019;316(3):547-57. https://doi.org/10.1152/ajplung.00387.2018
Lian G, Li X, Zhang L, Zhang Y, Sun L, Zhang X, Liu H, Pang Y, Kong W, Zhang T, Wang X, Jiang C. Macrophage metabolic reprogramming aggravates aortic dissection through the HIF1α-ADAM17 pathway. EBioMedicine. 2019;49:291-304. https://doi.org/10.1016/j.ebiom.2019.09.041
Lisi S, D’Amore M, Sisto M. ADAM17 at the interface between inflammation and autoimmunity. Immunology Letters. 2014;162(1 Pt A):159-169. https://doi.org/10.1016/j.imlet.2014.08.008
Zunke F, Rose-John S. The shedding protease ADAM17: physiology and pathophysiology. Biochimica et Biophysica Acta. Molecular Cell Research. 2017;1864(11 Pt B):2059-2070. https://doi.org/10.1016/j.bbamcr.2017.07.001
Yang J, Petitjean SJL, Koehler M, Zhang Q, Dumitru AC, Chen W, Derclaye S, Vincent SP, Soumillion P, Alsteens D. Molecular interaction and inhibition of SARS-CoV-2 binding to the ACE2 receptor. Nature Communications. 2020;11(1):4541. https://doi.org/10.1038/s41467-020-18319-6
Arias-Reyes C, Zubieta-DeUrioste N, Poma-Machicao L, Aliaga-Raduan F, Carvajal-Rodriguez F, Dutschmann M, Schneider-Gasser EM, Zubieta-Calleja G, Soliz J. Does the pathogenesis of SARS-CoV-2 virus decrease at high-altitude? Respiratory Physiology and Neurobiology. 2020;277:103443. https://doi.org/10.1016/j.resp.2020.103443
Pun M, Turner R, Strapazzon G, Brugger H, Swenson ER. Lower incidence of COVID-19 at high altitude: facts and confounders. High Altitude Medicine and Biology. 2020;21(3):217-222. https://doi.org/10.1089/ham.2020.0114
Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O’Meara MJ, Rezelj VV, Guo JZ, Swaney DL, Tummino TA, Hüttenhain R, Kaake RM, Richards AL, Tutuncuoglu B, Foussard H, Batra J, Haas K, Modak M, Kim M, Haas P, Polacco BJ, Braberg H, Fabius JM, Eckhardt M, Soucheray M, Bennett MJ, Cakir M, McGregor MJ, Li Q, Meyer B, Roesch F, Vallet T, Mac Kain A, Miorin L, Moreno E, Naing ZZC, Zhou Y, Peng S, Shi Y, Zhang Z, Shen W, Kirby IT, Melnyk JE, Chorba JS, Lou K, Dai SA, Barrio-Hernandez I, Memon D, Hernandez-Armenta C, Lyu J, Mathy CJP, Perica T, Pilla KB, Ganesan SJ, Saltzberg DJ, Rakesh R, Liu X, Rosenthal SB, Calviello L, Venkataramanan S, Liboy-Lugo J, Lin Y, Huang XP, Liu Y, Wankowicz SA, Bohn M, Safari M, Ugur FS, Koh C, Savar NS, Tran QD, Shengjuler D, Fletcher SJ, O’Neal MC, Cai Y, Chang JCJ, Broadhurst DJ, Klippsten S, Sharp PP, Wenzell NA, Kuzuoglu-Ozturk D, Wang HY, Trenker R, Young JM, Cavero DA, Hiatt J, Roth TL, Rathore U, Subramanian A, Noack J, Hubert M, Stroud RM, Frankel AD, Rosenberg OS, Verba KA, Agard DA, Ott M, Emerman M, Jura N, von Zastrow M, Verdin E, Ashworth A, Schwartz O, d’Enfert C, Mukherjee S, Jacobson M, Malik HS, Fujimori DG, Ideker T, Craik CS, Floor SN, Fraser JS, Gross JD, Sali A, Roth BL, Ruggero D, Taunton J, Kortemme T, Beltrao P, Vignuzzi M, García-Sastre A, Shokat KM, Shoichet BK, Krogan NJ. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020;583(7816):459-468. https://doi.org/10.1038/s41586-020-2286-9
Huang R, Huestis M, Gan ES, Ooi EE, Ohh M. Hypoxia and viral infectious diseases. JCI Insight. 2021;6(7):e147190. https://doi.org/10.1172/jci.insight.147190
Budinger GRS, Misharin AV, Ridge KM, Singer BD, Wunderink RG. Distinctive features of severe SARS-CoV-2 pneumonia. The Journal of Clinical Investigation. 2021;131(14):e149412. https://doi.org/10.1172/JCI149412
Codo AC, Davanzo GG, Monteiro LB, de Souza GF, Muraro SP, Virgilio-da-Silva JV, Prodonoff JS, Carregari VC, de Biagi Junior CAO, Crunfli F, Jimenez Restrepo JL, Vendramini PH, Reis-de-Oliveira G, Bispo Dos Santos K, Toledo-Teixeira DA, Parise PL, Martini MC, Marques RE, Carmo HR, Borin A, Coimbra LD, Boldrini VO, Brunetti NS, Vieira AS, Mansour E, Ulaf RG, Bernardes AF, Nunes TA, Ribeiro LC, Palma AC, Agrela MV, Moretti ML, Sposito AC, Pereira FB, Velloso LA, Vinolo MAR, Damasio A, Proença-Módena JL, Carvalho RF, Mori MA, Martins-de-Souza D, Nakaya HI, Farias AS, Moraes-Vieira PM. Elevated glucose levels favor SARS-CoV-2 infection and monocyte response through a HIF-1α/glycolysis-dependent axis. Cell Metabolism. 2020;32(3):498-499. https://doi.org/10.1016/j.cmet.2020.07.015
Tian M, Liu W, Li X, Zhao P, Shereen MA, Zhu C, Huang S, Liu S, Yu X, Yue M, Pan P, Wang W, Li Y, Chen X, Wu K, Luo Z, Zhang Q, Wu J. HIF-1α promotes SARS-CoV-2 infection and aggravates inflammatory responses to COVID-19. Signal Transduction and Targeted Therapy. 2021;6(1):308. https://doi.org/10.1038/s41392-021-00726-w
Taylor CT, Doherty G, Fallon PG, Cummins EP. Hypoxia-dependent regulation of inflammatory pathways in immune cells. The Journal of Clinical Investigation. 2016;126(10):3716-3724. https://doi.org/10.1172/JCI84433
Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J, Cheng L, Li J, Wang X, Wang F, Liu L, Amit I, Zhang S, Zhang Z. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nature Medicine. 2020;26(6):842-844. https://doi.org/10.1038/s41591-020-0901-9
Mathew D, Giles JR, Baxter AE, Oldridge DA, Greenplate AR, Wu JE, Alanio C, Kuri-Cervantes L, Pampena MB, D’Andrea K, Manne S, Chen Z, Huang YJ, Reilly JP, Weisman AR, Ittner CAG, Kuthuru O, Dougherty J, Nzingha K, Han N, Kim J, Pattekar A, Goodwin EC, Anderson EM, Weirick ME, Gouma S, Arevalo CP, Bolton MJ, Chen F, Lacey SF, Ramage H, Cherry S, Hensley SE, Apostolidis SA, Huang AC, Vella LA; UPenn COVID Processing Unit, Betts MR, Meyer NJ, Wherry EJ. Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications. Science. 2020;369(6508):eabc8511. https://doi.org/10.1126/science.abc8511
Hsu TS, Lin YL, Wang YA, Mo ST, Chi PY, Lai AC, Pan HY, Chang YJ, Lai MZ. HIF-2α is indispensable for regulatory T cell function. Nature Communications. 2020;11(1):5005. https://doi.org/10.1038/s41467-020-18731-y
Wu D, Yang XO. TH17 responses in cytokine storm of COVID-19: an emerging target of JAK2 inhibitor Fedratinib. Journal of Microbiology, Immunology, and Infection. 2020;53(3):368-370. https://doi.org/10.1016/j.jmii.2020.03.005
Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. The Journal of Infection. 2020;80(6):607-613. https://doi.org/10.1016/j.jinf.2020.03.037
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10233):497-506. https://doi.org/10.1016/S0140-6736(20)30183-5
Hogwood J, Pitchford S, Mulloy B, Page C, Gray E. Heparin and non-anticoagulant heparin attenuate histone-induced inflammatory responses in whole blood. PLoS One. 2020;15(5):e0233644. https://doi.org/10.1371/journal.pone.0233644
Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, Sobolewski A, Condliffe AM, Cowburn AS, Johnson N, Chilvers ER. Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. The Journal of Experimental Medicine. 2005;201(1):105-115. https://doi.org/10.1084/jem.20040624
Teuwen LA, Geldhof V, Pasut A, Carmeliet P. COVID-19: the vasculature unleashed. Nature Reviews. Immunology. 2020;20(7):389-391. https://doi.org/10.1038/s41577-020-0343-0
Polke M, Seiler F, Lepper PM, Kamyschnikow A, Langer F, Monz D, Herr C, Bals R, Beisswenger C. Hypoxia and the hypoxia-regulated transcription factor HIF-1alpha suppress the host defence of airway epithelial cells. Innate Immunity. 2017;23(4):373-380. https://doi.org/10.1177/1753425917698032
Rajasundaram S. Adenosine A2A receptor signaling in the immunopathogenesis of experimental autoimmune encephalomyelitis. Frontiers in Immunology. 2018;9:402. https://doi.org/10.3389/fimmu.2018.00402
Mishra GP, Mulani J. Corticosteroids for COVID-19: the search for an optimum duration of therapy. The Lancet. Respiratory Medicine. 2021;9(1):e8. https://doi.org/10.1016/S2213-2600(20)30530-0
Finney LJ, Glanville N, Farne H, Aniscenko J, Fenwick P, Kemp SV, Trujillo-Torralbo MB, Loo SL, Calderazzo MA, Wedzicha JA, Mallia P, Bartlett NW, Johnston SL, Singanayagam A. Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon. The Journal of Allergy and Clinical Immunology. 2021;147(2):510-519.e5. https://doi.org/10.1016/j.jaci.2020.09.034
Wagner AE, Huck G, Stiehl DP, Jelkmann W, Hellwig-Bürgel T. Dexamethasone impairs hypoxia-inducible factor-1 function. Biochemical and Biophysical Research Communications. 2008;372(2):336-340. https://doi.org/10.1016/j.bbrc.2008.05.061
WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, Diaz JV, Slutsky AS, Villar J, Angus DC, Annane D, Azevedo LCP, Berwanger O, Cavalcanti AB, Dequin PF, Du B, Emberson J, Fisher D, Giraudeau B, Gordon AC, Granholm A, Green C, Haynes R, Heming N, Higgins JPT, Horby P, Jüni P, Landray MJ, Le Gouge A, Leclerc M, Lim WS, Machado FR, McArthur C, Meziani F, Møller MH, Perner A, Petersen MW, Savovic J, Tomazini B, Veiga VC, Webb S, Marshall JC. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020;324(13):1330-1341. https://doi.org/10.1001/jama.2020.17023
Zhang M, Li W, Yu L, Wu S. The suppressive effect of resveratrol on HIF-1α and VEGF expression after warm ischemia and reperfusion in rat liver. PloS One. 2014;9(10):e109589. https://doi.org/10.1371/journal.pone.0109589
Zalpoor H, Bakhtiyari M, Liaghat M, Nabi-Afjadi M, Ganjalikhani-Hakemi M. Quercetin potential effects against SARS-CoV-2 infection and COVID-19-associated cancer progression by inhibiting mTOR and hypoxia-inducible factor-1α (HIF-1α). Phytotherapy Research: PTR. 2022;36(7):2679-2682. https://doi.org/10.1002/ptr.7440
Di Pierro F, Derosa G, Maffioli P, Bertuccioli A, Togni S, Riva A, Allegrini P, Khan A, Khan S, Khan BA, Altaf N, Zahid M, Ujjan ID, Nigar R, Khushk MI, Phulpoto M, Lail A, Devrajani BR, Ahmed S. Possible therapeutic effects of adjuvant quercetin supplementation against early-stage COVID-19 infection: A prospective, randomized, controlled, and open-label study. International Journal of General Medicine. 2021;14:2359-2366. https://doi.org/10.2147/IJGM.S318720
Mathew T, Sarada SKS. Intonation of Nrf2 and Hif1-α pathway by curcumin prophylaxis: A potential strategy to augment survival signaling under hypoxia. Respiratory Physiology and Neurobiology. 2018;258:12-24. https://doi.org/10.1016/j.resp.2018.09.008
Moasefi N, Fouladi M, Norooznezhad AH, Yarani R, Rahmani A, Mansouri K. How could perfluorocarbon affect cytokine storm and angiogenesis in coronavirus disease 2019 (COVID-19): role of hypoxia-inducible factor 1α. Inflammation Research. 2021;70(7):749-752. https://doi.org/10.1007/s00011-021-01469-8
Bahrampour Juybari K, Pourhanifeh MH, Hosseinzadeh A, Hemati K, Mehrzadi S. Melatonin potentials against viral infections including COVID-19: Current evidence and new findings. Virus Research. 2020;287:198108. https://doi.org/10.1016/j.viruses.2020.198108
Reiter RJ, Sharma R, Simko F, Dominguez-Rodriguez A, Tesarik J, Neel RL, Slominski AT, Kleszczynski K, Martin-Gimenez VM, Manucha W, Cardinali DP. Melatonin: highlighting its use as a potential treatment for SARS-CoV-2 infection. Cellular and Molecular Life Sciences: CMLS. 2022;79(3):143. https://doi.org/10.1007/s00018-021-04102-3
Martorina WJ, Tavares A. Possible role of exogenous melatonin in preventing more serious COVID-19 infection in patients with type 2 diabetes mellitus. Revista da Associacao Medica Brasileira. 2021;67(suppl 1):18-21. https://doi.org/10.1590/1806-9282.67.Suppl1.20200968
Hosseini A, Esmaeili Gouvarchin Ghaleh H, Aghamollaei H, Fasihi Ramandi M, Alishiri G, Shahriary A, Hassanpour K, Tat M, Farnoosh G. Evaluation of Th1 and Th2 mediated cellular and humoral immunity in patients with COVID-19 following the use of melatonin as an adjunctive treatment. European Journal of Pharmacology. 2021;904:174193. https://doi.org/10.1016/j.ejphar.2021.174193
He M, Zhou C, Lu Y, Mao L, Xi Y, Mei X, Wang X, Zhang L, Yu Z, Zhou Z. Melatonin antagonizes nickel-induced aerobic glycolysis by blocking ROS-mediated HIF-1alpha/miR210/ISCU axis activation. Oxidative Medicine and Cellular Longevity. 2020;2020:5406284. https://doi.org/10.1155/2020/5406284
Hosseinzadeh MH, Goodarzi A, Malekan M, Ebrahimzadeh MA. Melatonin increased hypoxia-inducible factor (HIF) by inhibiting prolylhydroxylase: A hypothesis for treating anaemia, ischemia, and COVID-19. Clinical and Experimental Pharmacology and Physiology. 2022;49(6):696-698. https://doi.org/10.1111/1440-1681.13639