Unraveling the roles of vitamin D status and melanin during Covid‑19 (Review)

Sidiropoulou,Polytimi; Docea,Anca Oana; Nikolaou,Vasiliki; Katsarou,Martha-Spyridoula; Spandidos,Demetrios A.; Tsatsakis,Aristidis; Calina,Daniela; Drakoulis,Nikolaos

doi:10.3892/ijmm.2020.4802

Unraveling the roles of vitamin D status and melanin during Covid‑19 (Review)

Authors:
- Polytimi Sidiropoulou
- Anca Oana Docea
- Vasiliki Nikolaou
- Martha-Spyridoula Katsarou
- Demetrios A. Spandidos
- Aristidis Tsatsakis
- Daniela Calina
- Nikolaos Drakoulis
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Affiliations: 1st Department of Dermatology‑Venereology, Faculty of Medicine, National and Kapodistrian University of Athens, ‘A. Sygros’ Hospital for Skin and Venereal Diseases, 16121 Athens, Greece, Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania, Research Group of Clinical Pharmacology and Pharmacogenomics, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 15771 Athens, Greece, Laboratory of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion, Greece, Department of Forensic Sciences and Toxicology, School of Medicine, University of Crete, 71003 Heraklion, Greece, Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
Published online on: November 30, 2020 https://doi.org/10.3892/ijmm.2020.4802
Pages: 92-100
Copyright: © Sidiropoulou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

As the coronavirus disease 2019 (COVID‑19) continues to spread worldwide, it has become evident that the morbidity and mortality rates clearly vary across nations. Although several factors may account for this disparity, striking differences within and between populations indicate that ethnicity might impact COVID‑19 clinical outcomes, reflecting the ‘color of disease’. Therefore, the role of key biological variables that could interplay with viral spreading and severity indices has attracted increasing attention, particularly among non‑Caucasian populations. Although the links between vitamin D status and the incidence and severity of COVID-19 remain elusive, several lines of emerging evidence suggest that vitamin D signaling, targeting several immune‑mediated pathways, may offer potential benefits at different stages of SARS-CoV-2 infection. Given that the vitamin D status is modulated by several intrinsic and extrinsic factors, including skin type (pigmentation), melanin polymers may also play a role in variable COVID‑19 outcomes among diverse population settings. Moreover, apart from the well‑known limiting effects of melanin on the endogenous production of vitamin D, the potential crosstalk between the pigmentary and immune system may also require special attention concerning the current pandemic. The present review article aimed to shed light on a range of mostly overlooked host factors, such as vitamin D status and melanin pigments, that may influence the course and outcome of COVID‑19.

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1	Guo YR, Cao QD, Hong ZS, Tan YY, Chen SD, Jin HJ, Tan KS, Wang DY and Yan Y: The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status. Mil Med Res. 7:112020.PubMed/NCBI
2	Docea AO, Tsatsakis A, Albulescu D, Cristea O, Zlatian O, Vinceti M, Moschos SA, Tsoukalas D, Goumenou M, Drakoulis N, et al: A new threat from an old enemy: Re-emergence of coronavirus (Review). Int J Mol Med. 45:1631–1643. 2020.PubMed/NCBI
3	Lai CC, Wang CY, Wang YH, Hsueh SC, Ko WC and Hsueh PR: Global epidemiology of coronavirus disease 2019 (COVID-19): Disease incidence, daily cumulative index, mortality, and their association with country healthcare resources and economic status. Int J Antimicrob Agents. 55:1059462020. View Article : Google Scholar : PubMed/NCBI
4	Goumenou M, Sarigiannis D, Tsatsakis A, Anesti O, Docea AO, Petrakis D, Tsoukalas D, Kostoff R, Rakitskii V, Spandidos DA, et al: COVID-19 in Northern Italy: An integrative overview of factors possibly influencing the sharp increase of the outbreak (Review). Mol Med Rep. 22:20–32. 2020.PubMed/NCBI
5	Stopsack KH, Mucci LA, Antonarakis ES, Nelson PS and Kantoff PW: TMPRSS2 and COVID-19: Serendipity or Opportunity for Intervention? Cancer Discov. 10:779–782. 2020. View Article : Google Scholar : PubMed/NCBI
6	Tsatsakis A, Petrakis D, Nikolouzakis TK, Docea AO, Calina D, Vinceti M, Goumenou M, Kostoff RN, Mamoulakis C, Aschner M, et al: COVID-19, an opportunity to reevaluate the correlation between long-term effects of anthropogenic pollutants on viral epidemic/pandemic events and prevalence. Food Chem Toxicol. 141:1114182020. View Article : Google Scholar : PubMed/NCBI
7	Pareek M, Bangash MN, Pareek N, Pan D, Sze S, Minhas JS, Hanif W and Khunti K: Ethnicity and COVID-19: An urgent public health research priority. Lancet. 395:1421–1422. 2020. View Article : Google Scholar : PubMed/NCBI
8	Nitulescu GM, Paunescu H, Moschos SA, Petrakis D, Nitulescu G, Ion GND, Spandidos DA, Nikolouzakis TK, Drakoulis N and Tsatsakis A: Comprehensive analysis of drugs to treat SARS-CoV-2 infection: Mechanistic insights into current COVID-19 therapies (Review). Int J Mol Med. 46:467–488. 2020. View Article : Google Scholar : PubMed/NCBI
9	Calina D, Sarkar C, Arsene AL, Salehi B, Docea AO, Mondal M, Islam MT, Zali A and Sharifi-Rad J: Recent advances, approaches and challenges in targeting pathways for potential COVID-19 vaccines development. Immunol Res. 68:315–324. 2020. View Article : Google Scholar : PubMed/NCBI
10	Kostoff RN, Kanduc D, Porter AL, Shoenfeld Y, Calina D, Briggs MB, Spandidos DA and Tsatsakis A: Vaccine- and natural infection-induced mechanisms that could modulate vaccine safety. Toxicol Rep. 7:1448–1458. 2020. View Article : Google Scholar : PubMed/NCBI
11	Calina D, Docea AO, Petrakis D, Egorov A M, Ishmukhametov AA, Gabibov AG, Shtilman MI, Kostoff R, Carvalho F, Vinceti M, et al: Towards effective COVID-19 vaccines: Updates, perspectives and challenges (Review). Int J Mol Med. 46:3–16. 2020. View Article : Google Scholar : PubMed/NCBI
12	Calina D, Hartung T, Docea AO, Spandidos DA, Egorov AM, Shtilman MI, Carvalho F and Tsatsakis A: COVID-19 vaccines: Ethical framework concerning human challenge studies. Daru. Aug 27–2020.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI
13	Arboleda JF, Urcuqui-Inchima S and Vitamin D: Vitamin D Supplementation: A Potential Approach for Coronavirus/COVID-19 Therapeutics? Front Immunol. 11:15232020. View Article : Google Scholar : PubMed/NCBI
14	Martineau AR and Forouhi NG: Vitamin D for COVID-19: A case to answer? Lancet Diabetes Endocrinol. 8:735–736. 2020. View Article : Google Scholar : PubMed/NCBI
15	Benskin LL: A Basic Review of the Preliminary Evidence That COVID-19 Risk and Severity Is Increased in Vitamin D Deficiency. Front Public Health. 8:5132020. View Article : Google Scholar : PubMed/NCBI
16	Ali N: Role of vitamin D in preventing of COVID-19 infection, progression and severity. J Infect Public Health. 13:1373–1380. 2020. View Article : Google Scholar : PubMed/NCBI
17	Laird E, Rhodes J and Kenny RA: Vitamin D and inflammation: potential implications for severity of Covid-19. Ir Med J. 113:812020.PubMed/NCBI
18	Darling AL, Ahmadi KR, Ward KA, Harvey NC, Alves AC, Dunn-Waters DK, Lanham-New SA, Cooper C and Blackbourn DJ: Vitamin D status, body mass index, ethnicity and COVID-19: Initial analysis of the first-reported UK Biobank COVID-19 positive cases 580 compared with negative controls 723. MedRxiv. https://doi.org/10.1101/2020.04.29.20084277urisimplehttps://doi.org/10.1101/2020.04.29.20084277.
19	Patel P, Hiam L, Sowemimo A, Devakumar D and McKee M: Ethnicity and covid-19. BMJ. 369:m22822020. View Article : Google Scholar : PubMed/NCBI
20	Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL and Bhattoa HP: Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients. 12:9882020. View Article : Google Scholar :
21	Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, Esposito S, Ganmaa D, Ginde AA, et al: Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 356:i65832017. View Article : Google Scholar : PubMed/NCBI
22	Pike JW and Christakos S: Biology and mechanisms of action of the vitamin D hormone. Endocrinol Metab Clin North Am. 46:815–843. 2017. View Article : Google Scholar : PubMed/NCBI
23	Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, et al: China Novel Coronavirus Investigating and Research Team: A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 382:727–733. 2020. View Article : Google Scholar : PubMed/NCBI
24	Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, et al: Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 395:497–506. 2020. View Article : Google Scholar : PubMed/NCBI
25	Tsatsakis A, Calina D, Falzone L, Petrakis D, Mitrut R, Siokas V, Pennisi M, Lanza G, Libra M, Doukas SG, et al: SARS-CoV-2 pathophysiology and its clinical implications: An integrative overview of the pharmacotherapeutic management of COVID-19. Food Chem Toxicol. 146:1117692020. View Article : Google Scholar : PubMed/NCBI
26	Lanza K, Perez LG, Costa LB, Cordeiro TM, Palmeira VA and Ribeiro VT: Covid-19: The renin-angiotensin system imbalance hypothesis. Clin Sci (Lond). 134:1259–1264. 2020. View Article : Google Scholar
27	Aldridge RW, Lewer D, Katikireddi SV, Mathur R, Pathak N, Burns R, Fragaszy EB, Johnson AM, Devakumar D, Abubakar I, et al: Black, Asian and Minority Ethnic groups in England are at increased risk of death from COVID-19: Indirect standardisation of NHS mortality data. Wellcome Open Res. 5:882020. View Article : Google Scholar : PubMed/NCBI
28	Khunti K, Singh AK, Pareek M and Hanif W: Is ethnicity linked to incidence or outcomes of covid-19? BMJ. 369:m15482020. View Article : Google Scholar : PubMed/NCBI
29	Pan D, Sze S, Minhas JS, Bangash MN, Pareek N, Divall P, Williams CM, Oggioni MR, Squire IB, Nellums LB, et al: The impact of ethnicity on clinical outcomes in COVID-19: A systematic review. EClinicalMedicine. 23:1004042020. View Article : Google Scholar : PubMed/NCBI
30	Sze S, Pan D, Gray LJ, Nevill CR, Martin CA, Nazareth J, Minhas JS, Divall P, Khunti K, Abrams K, et al: Ethnicity and clinical outcomes in COVID-19: A systematic review and meta-analysis. EClinicalMedicine. Nov 12–2020.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI
31	Vahidy FS, Nicolas JC, Meeks JR, Khan O, Pan A, Jones SL, Masud F, Sostman HD, Phillips R, Andrieni JD, et al: Racial and ethnic disparities in SARS-CoV-2 pandemic: Analysis of a COVID-19 observational registry for a diverse US metropolitan population. BMJ Open. 10:e0398492020. View Article : Google Scholar : PubMed/NCBI
32	Clemens TL, Adams JS, Henderson SL and Holick MF: Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet. 1:74–76. 1982. View Article : Google Scholar : PubMed/NCBI
33	Pavan WJ and Sturm RA: The Genetics of Human Skin and Hair Pigmentation. Annu Rev Genomics Hum Genet. 20:41–72. 2019. View Article : Google Scholar : PubMed/NCBI
34	Abdel-Malek ZA and Swope VB: Epidermal melanocytes: regulation of their survival, proliferation, and function in human skin. Melanoma Development. Springer; Vienna: pp. 7–33. 2011, View Article : Google Scholar
35	Rees JL: Genetics of hair and skin color. Annu Rev Genet. 37:67–90. 2003. View Article : Google Scholar : PubMed/NCBI
36	Del Bino S, Duval C and Bernerd F: Clinical and biological characterization of skin pigmentation diversity and its consequences on UV impact. Int J Mol Sci. 19:26682018. View Article : Google Scholar :
37	Costin GE and Hearing VJ: Human skin pigmentation: Melanocytes modulate skin color in response to stress. FASEB J. 21:976–994. 2007. View Article : Google Scholar : PubMed/NCBI
38	Serre C, Busuttil V and Botto JM: Intrinsic and extrinsic regulation of human skin melanogenesis and pigmentation. Int J Cosmet Sci. 40:328–347. 2018. View Article : Google Scholar : PubMed/NCBI
39	Liu LH, Fan X, Li HT, An XX and Yang RY: Angiotensin II promotes melanogenesis via angiotensin II type 1 receptors in human melanocytes. Mol Med Rep. 12:651–656. 2015. View Article : Google Scholar : PubMed/NCBI
40	Liu LH, Fan X, Xia ZK, An XX and Yang RY: Angiotensin II stimulates melanogenesis via the protein kinase C pathway. Exp Ther Med. 10:1528–1532. 2015. View Article : Google Scholar : PubMed/NCBI
41	Steckelings UM, Wollschläger T, Peters J, Henz BM, Hermes B and Artuc M: Human skin: Source of and target organ for angiotensin II. Exp Dermatol. 13:148–154. 2004. View Article : Google Scholar : PubMed/NCBI
42	Brenner M and Hearing VJ: The protective role of melanin against UV damage in human skin. Photochem Photobiol. 84:539–549. 2008. View Article : Google Scholar : PubMed/NCBI
43	Solano F: Photoprotection and skin pigmentation: melanin-related molecules and some other new agents obtained from natural sources. Molecules. 25:15372020. View Article : Google Scholar :
44	Rocha J: The evolutionary history of human skin pigmentation. J Mol Evol. 88:77–87. 2020. View Article : Google Scholar
45	Slominski A and Postlethwaite AE: Skin under the sun: when melanin pigment meets vitamin D. Endocrinology. 156:1–4. 2015. View Article : Google Scholar :
46	Bikle DD: Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 21:319–329. 2014. View Article : Google Scholar : PubMed/NCBI
47	Pearce SH and Cheetham TD: Diagnosis and management of vitamin D deficiency. BMJ. 340:b56642010. View Article : Google Scholar : PubMed/NCBI
48	Webb AR, Kazantzidis A, Kift RC, Farrar MD, Wilkinson J and Rhodes LE: Meeting vitamin D requirements in White Caucasians at UK latitudes: Providing a choice. Nutrients. 10:4972018. View Article : Google Scholar :
49	Farrar MD, Kift R, Felton SJ, Berry JL, Durkin MT, Allan D, Vail A, Webb AR and Rhodes LE: Recommended summer sunlight exposure amounts fail to produce sufficient vitamin D status in UK adults of South Asian origin. Am J Clin Nutr. 94:1219–1224. 2011. View Article : Google Scholar : PubMed/NCBI
50	Bonilla C, Ness AR, Wills AK, Lawlor DA, Lewis SJ and Davey Smith G: Skin pigmentation, sun exposure and vitamin D levels in children of the Avon Longitudinal Study of Parents and Children. BMC Public Health. 14:5972014. View Article : Google Scholar : PubMed/NCBI
51	Hameed A and Akhtar N: The skin melanin: an inhibitor of vitamin-D3 biosynthesis: with special emphasis with structure of skin. A mini review Dermatol Case Rep. 4:12019.
52	Richard A, Rohrmann S and Quack Lötscher KC: Prevalence of vitamin D deficiency and its associations with skin color in pregnant women in the first trimester in a sample from Switzerland. Nutrients. 9:2602017. View Article : Google Scholar :
53	Alzaman NS, Dawson-Hughes B, Nelson J, D'Alessio D and Pittas AG: Vitamin D status of black and white Americans and changes in vitamin D metabolites after varied doses of vitamin D supplementation. Am J Clin Nutr. 104:205–214. 2016. View Article : Google Scholar : PubMed/NCBI
54	Harris SS: Vitamin D and African Americans. J Nutr. 136:1126–1129. 2006. View Article : Google Scholar : PubMed/NCBI
55	ElObeid AS, Kamal-Eldin A, Abdelhalim MAK and Haseeb AM: Pharmacological properties of melanin and its function in health. Basic Clin Pharmacol Toxicol. 120:515–522. 2017. View Article : Google Scholar
56	Mednick AJ, Nosanchuk JD and Casadevall A: Melanization of Cryptococcus neoformans affects lung inflammatory responses during cryptococcal infection. Infect Immun. 73:2012–2019. 2005. View Article : Google Scholar : PubMed/NCBI
57	Patsakas A, Demetriou N and Angelopoulos A: Melanin pigmentation and inflammation in human gingiva. J Periodontol. 52:701–704. 1981. View Article : Google Scholar : PubMed/NCBI
58	Smith JR, Rosenbaum JT and Williams KA: Experimental melanin-induced uveitis: Experimental model of human acute anterior uveitis. Ophthalmic Res. 40:136–140. 2008. View Article : Google Scholar : PubMed/NCBI
59	Kaya M, Edward DP, Tessler H and Hendricks RL: Augmentation of intraocular inflammation by melanin. Invest Ophthalmol Vis Sci. 33:522–531. 1992.PubMed/NCBI
60	Pugh ND, Balachandran P, Lata H, Dayan FE, Joshi V, Bedir E, Makino T, Moraes R, Khan I and Pasco DS: Melanin: Dietary mucosal immune modulator from Echinacea and other botanical supplements. Int Immunopharmacol. 5:637–647. 2005. View Article : Google Scholar : PubMed/NCBI
61	Wilms H, Rosenstiel P, Sievers J, Deuschl G, Zecca L and Lucius R: Activation of microglia by human neuromelanin is NF-kappaB dependent and involves p38 mitogen-activated protein kinase: Implications for Parkinson's disease. FASEB J. 17:500–502. 2003. View Article : Google Scholar : PubMed/NCBI
62	Feller L, Masilana A, Khammissa RA, Altini M, Jadwat Y and Lemmer J: Melanin: the biophysiology of oral melanocytes and physiological oral pigmentation. Head Face Med. 10:82014. View Article : Google Scholar : PubMed/NCBI
63	Fritz MA, Roehm PC, Bannan MA and Lalwani AK: Extracellular and intracellular melanin in inflammatory middle ear disease. Laryngoscope. 124:E241–E244. 2014. View Article : Google Scholar : PubMed/NCBI
64	Na JY, Kim YH, Choi YD and Lee JS: Melanotic oncocytic metaplasia of the nasopharynx: A report of three cases and review of the literature. Korean J Pathol. 46:201–204. 2012. View Article : Google Scholar : PubMed/NCBI
65	Hossein-nezhad A and Holick MF: Vitamin D for health: A global perspective. Mayo Clin Proc. 88:720–755. 2013. View Article : Google Scholar : PubMed/NCBI
66	Wacker M and Holick MF: Sunlight and vitamin D: A global perspective for health. Dermatoendocrinol. 5:51–108. 2013. View Article : Google Scholar
67	Holick MF: Vitamin D: Extraskeletal health. Endocrinol Metab Clin North Am. 39:381–400. 2010. View Article : Google Scholar : PubMed/NCBI
68	Schwalfenberg GK: A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency. Mol Nutr Food Res. 55:96–108. 2011. View Article : Google Scholar
69	Zdrenghea MT, Makrinioti H, Bagacean C, Bush A, Johnston SL and Stanciu LA: Vitamin D modulation of innate immune responses to respiratory viral infections. Rev Med Virol. 27:e19092017. View Article : Google Scholar
70	Prietl B, Treiber G, Pieber TR and Amrein K: Vitamin D and immune function. Nutrients. 5:2502–2521. 2013. View Article : Google Scholar : PubMed/NCBI
71	Hoeck AD and Pall ML: Will vitamin D supplementation ameliorate diseases characterized by chronic inflammation and fatigue? Med Hypotheses. 76:208–213. 2011. View Article : Google Scholar
72	Jolliffe D, Camargo CA, Sluyter J, Aglipay M, Aloia J, Bergman P, Damsgaard C, Dubnov-Raz G, Esposito S, Ganmaa D, et al: Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials. medRxiv. https://doi.org/10.1101/2020.07.14.20152728urisimplehttps://doi.org/10.1101/2020.07.14.20152728.
73	Azmi H, Najwa H and Ennaji MM: Vitamin D Immunomodulatory Role in Chronic and Acute Viral Diseases. Emerging and Reemerging Viral Pathogens. Academic Press; 489. pp. 5062020
74	Beard JA, Bearden A and Striker R: Vitamin D and the anti-viral state. J Clin Virol. 50:194–200. 2011. View Article : Google Scholar : PubMed/NCBI
75	Greiller CL and Martineau AR: Modulation of the immune response to respiratory viruses by vitamin D. Nutrients. 7:4240–4270. 2015. View Article : Google Scholar : PubMed/NCBI
76	Abhimanyu and Coussens AK: The role of UV radiation and vitamin D in the seasonality and outcomes of infectious disease. Photochem Photobiol Sci. 16:314–338. 2017. View Article : Google Scholar : PubMed/NCBI
77	Lang PO, Aspinall R and Vitamin D: Vitamin D status and the host resistance to infections: What it is currently (not) understood. Clin Ther. 39:930–945. 2017. View Article : Google Scholar : PubMed/NCBI
78	Gruber-Bzura BM: Vitamin D and influenza-prevention or therapy? Int J Mol Sci. 19:24192018. View Article : Google Scholar
79	Rondanelli M, Miccono A, Lamburghini S, Avanzato I, Riva A, Allegrini P, Faliva MA, Peroni G, Nichetti M and Perna S: Self-Care for Common Colds: The pivotal role of Vitamin D, Vitamin C, Zinc, and Echinacea in three main immune inter-active clusters (physical barriers, innate and adaptive immunity) involved during an episode of common colds-practical advice on dosages and on the time to take these nutrients/botanicals in order to prevent or treat common colds. Evid Based Complement Alternat Med. 2018:58130952018. View Article : Google Scholar
80	Gombart AF, Pierre A and Maggini S: A review of micronutrients and the immune system-working in harmony to reduce the risk of infection. Nutrients. 12:2362020. View Article : Google Scholar
81	Teymoori-Rad M, Shokri F, Salimi V and Marashi SM: The interplay between vitamin D and viral infections. Rev Med Virol. 29:e20322019. View Article : Google Scholar : PubMed/NCBI
82	Shi YY, Liu TJ, Fu JH, Xu W, Wu LL, Hou AN and Xue XD: Vitamin D/VDR signaling attenuates lipopolysaccharide-induced acute lung injury by maintaining the integrity of the pulmonary epithelial barrier. Mol Med Rep. 13:1186–1194. 2016. View Article : Google Scholar :
83	White JH: Vitamin D as an inducer of cathelicidin antimicrobial peptide expression: Past, present and future. J Steroid Biochem Mol Biol. 121:234–238. 2010. View Article : Google Scholar : PubMed/NCBI
84	Cantorna MT, Snyder L, Lin YD and Yang L: Vitamin D and 1,25(OH)₂D regulation of T cells. Nutrients. 7:3011–3021. 2015. View Article : Google Scholar : PubMed/NCBI
85	Wu D, Lewis ED, Pae M and Meydani SN: Nutritional modulation of immune function: analysis of evidence, mechanisms, and clinical relevance. Front Immunol. 9:31602019. View Article : Google Scholar : PubMed/NCBI
86	Xu S, Chen YH, Tan ZX, Xie DD, Zhang C, Xia MZ, Wang H, Zhao H, Xu DX and Yu DX: Vitamin D3 pretreatment alleviates renal oxidative stress in lipopolysaccharide-induced acute kidney injury. J Steroid Biochem Mol Biol. 152:133–141. 2015. View Article : Google Scholar : PubMed/NCBI
87	Shi Y, Liu T, Yao L, Xing Y, Zhao X, Fu J and Xue X: Chronic vitamin D deficiency induces lung fibrosis through activation of the renin-angiotensin system. Sci Rep. 7:33122017. View Article : Google Scholar : PubMed/NCBI
88	Kong J, Zhu X, Shi Y, Liu T, Chen Y, Bhan I, Zhao Q, Thadhani R and Li YC: VDR attenuates acute lung injury by blocking Ang-2-Tie-2 pathway and renin-angiotensin system. Mol Endocrinol. 27:2116–2125. 2013. View Article : Google Scholar : PubMed/NCBI
89	Ferder M, Inserra F, Manucha W and Ferder L: The world pandemic of vitamin D deficiency could possibly be explained by cellular inflammatory response activity induced by the renin-angiotensin system. Am J Physiol Cell Physiol. 304:C1027–C1039. 2013. View Article : Google Scholar
90	Ajabshir S, Asif A and Nayer A: The effects of vitamin D on the renin-angiotensin system. J Nephropathol. 3:41–43. 2014.PubMed/NCBI
91	Li YC: Vitamin D regulation of the renin-angiotensin system. J Cell Biochem. 88:327–331. 2003. View Article : Google Scholar : PubMed/NCBI
92	Li YC, Kong J, Wei M, Chen ZF, Liu SQ and Cao LP: 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 110:229–238. 2002. View Article : Google Scholar
93	Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, et al: Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 436:112–116. 2005. View Article : Google Scholar : PubMed/NCBI
94	Treml B, Neu N, Kleinsasser A, Gritsch C, Finsterwalder T, Geiger R, Schuster M, Janzek E, Loibner H, Penninger J, et al: Recombinant angiotensin-converting enzyme 2 improves pulmonary blood flow and oxygenation in lipopolysaccharide-induced lung injury in piglets. Crit Care Med. 38:596–601. 2010. View Article : Google Scholar
95	Nair R, Maseeh A and Vitamin D: Vitamin D: The 'sunshine' vitamin. J Pharmacol Pharmacother. 3:118–126. 2012.
96	Holick MF: The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord. 18:153–165. 2017. View Article : Google Scholar : PubMed/NCBI
97	Melamed ML, Michos ED, Post W and Astor B: 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med. 168:1629–1637. 2008. View Article : Google Scholar
98	Mitchell F: Vitamin-D and COVID-19: Do deficient risk a poorer outcome? Lancet Diabetes Endocrinol. 8:5702020. View Article : Google Scholar : PubMed/NCBI
99	House N, Holborn H and Wc L: ICNARC report on COVID-19 in critical care. ICNARC. 17:1–26. 2020.
100	Ilie PC, Stefanescu S and Smith L: The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res. 32:1195–1198. 2020. View Article : Google Scholar : PubMed/NCBI
101	Mok CK, Ng YL, Ahidjo BA, Lee RC, Loe MW, Liu J, Tan KS, Kaur P, Chng WJ, Wong JE, et al: Calcitriol, the active form of vitamin D, is a promising candidate for COVID-19 prophylaxis. bioRxiv. https://doi.org/10.1101/2020.06.21.162396urisimplehttps://doi.org/10.1101/2020.06.21.162396.
102	Daneshkhah A, Agrawal V, Eshein A, Subramanian H, Roy HK and Backman V: Evidence for possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID-19 patients. Aging Clin Exp Res. 32:2141–2158. 2020. View Article : Google Scholar : PubMed/NCBI