Vitamin D Endocrine System and COVID-19: Treatment with Calcifediol

Jose Manuel Quesada-Gomez, José Lopez-Miranda, Marta Entrenas-Castillo, Antonio Casado-Díaz, Xavier Nogues Y Solans, José Luis Mansur, Roger Bouillon, Jose Manuel Quesada-Gomez, José Lopez-Miranda, Marta Entrenas-Castillo, Antonio Casado-Díaz, Xavier Nogues Y Solans, José Luis Mansur, Roger Bouillon

Abstract

The COVID-19 pandemic is the greatest challenge facing modern medicine and public health systems. The viral evolution of SARS-CoV-2, with the emergence of new variants with in-creased infectious potential, is a cause for concern. In addition, vaccination coverage remains in-sufficient worldwide. Therefore, there is a need to develop new therapeutic options, and/or to optimize the repositioning of drugs approved for other indications for COVID-19. This may include the use of calcifediol, the prohormone of the vitamin D endocrine system (VDES) as it may have potential useful effects for the treatment of COVID-19. We review the aspects associating COVID-19 with VDES and the potential use of calcifediol in COVID-19. VDES/VDR stimulation may enhance innate antiviral effector mechanisms, facilitating the induction of antimicrobial peptides/autophagy, with a critical modulatory role in the subsequent host reactive hyperinflammatory phase during COVID-19: By decreasing the cytokine/chemokine storm, regulating the renin-angiotensin-bradykinin system (RAAS), modulating neutrophil activity and maintaining the integrity of the pulmonary epithelial barrier, stimulating epithelial repair, and directly and indirectly decreasing the increased coagulability and prothrombotic tendency associated with severe COVID-19 and its complications. Available evidence suggests that VDES/VDR stimulation, while maintaining optimal serum 25OHD status, in patients with SARS-CoV-2 infection may significantly reduce the risk of acute respiratory distress syndrome (ARDS) and severe COVID-19, with possible beneficial effects on the need for mechanical ventilation and/or intensive care unit (ICU) admission, as well as deaths in the course of the disease. The pharmacokinetic and functional characteristics of calcifediol give it superiority in rapidly optimizing 25OHD levels in COVID-19. A pilot study and several observational intervention studies using high doses of calcifediol (0.532 mg on day 1 and 0.266 mg on days 3, 7, 14, 21, and 28) dramatically decreased the need for ICU admission and the mortality rate. We, therefore, propose to use calcifediol at the doses described for the rapid correction of 25OHD deficiency in all patients in the early stages of COVID-19, in association, if necessary, with the new oral antiviral agents.

Keywords: COVID-19; SARS-CoV-2; calcifediol; calcitriol; cholecalciferol; vitamin D endocrine system.

Conflict of interest statement

For the preparation of this review the authors have received funding from the Fundación para la Investigación Biomédica de Córdoba (FIBICO) and FAES Farma, Bilbao. Spain. The views and opinions expressed in this publication are those of the authors and do not necessarily reflect the official policy or position of FAES FARMA or any of its officers.

Figures

Figure 1
Figure 1
COVID-19 is characterized by an unbalanced host response to SARS-CoV-2 following viral replication, which depending on its intensity will characterize the development and severity of COVID-19: (1) reduction in innate antiviral defenses; (2) exuberant production of inflammatory cytokines, with inadequate recruitment of inflammatory populations of monocytes and macrophages. Comparison with other viral infections IL: interleukin; IFN: interferon; ISG: interferon-stimulated genes; TNF: tumor necrosis factor; CXCLS: chemokine (C-X-C motif) ligands; IAV: influenza A virus; HPIV3: human parainfluenza virus type 3; RSV: respiratory syncytial virus. * When calcifediol levels are deficient, the cathelicidin response is impaired. Modified from Blanco Melo et al. [18].
Figure 2
Figure 2
Vitamin D Endocrine system. Metabolism and actions.
Figure 3
Figure 3
Antiviral actions of VDES and the innate immune response: autophagy/apoptosis. Autophagy is an essential mechanism by which cells cope with viruses. Autophagic encapsulation of viral particles packages them for lysosomal degradation and subsequent presentation of antigens and adaptive antiviral immune responses. Therefore, autophagy may be highly sensitive to changes in 25OHD serum levels. The specific mechanisms by which VDES promotes autophagy involve down regulation of the mTOR pathway, which inhibits autophagy, and the promotion of Beclin 1 and PI3KC3, key autophagy-driving enzymes. The upregulation of intracellular Ca and NO by VDES also stimulates the activity of PI3KC3 to promote autophagy. DEFB4A: defensin beta 4A. mTOR: mammalian target of rapamycin. Ca: calcium. NO: nitric oxide. PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3. TLR: toll-like receptor. VDR: vitamin D receptor.
Figure 4
Figure 4
Immunomodulatory activity of the vitamin D endocrine system. Activated DC and lymphocytes have the ability to form calcitriol from circulating calcifediol. The calcitriol formed exerts effects through VDR on antigen-presenting cells (APC)/dendritic cell (DC) and T lymphocytes. The effect is an upward regulation of direct inhibition of DC and a downward regulation of antigen presentation. On T lymphocytes, the direct effect consists of an induction of T helper-2 lymphocytes (Th2) and regulatory T lymphocytes (Tregs) (green arrows) represented in green text, together with a downward regulation of T helper-1 (Th1), T helper-17 (Th17)-lymphocytes and T helper-9 (Th9)-lymphocytes (red arrows).
Figure 5
Figure 5
The vitamin D endocrine system (VDES) contributes to the reduction in acute respiratory distress syndrome (ARDS) and related clinics in COVID-19. Vitamin D receptor (VDR) and vitamin D endocrine system enzymes are expressed in activated monocytes/macrophages/granulocytes and lymphocytes and in bronchoalveolar epithelial cells. The availability of 25OHD3 (calcifediol) is essential for synthesizing 1,25(OH)2D3 (calcitriol), which through its endocrine, auto/paracrine action on VDR A: (1) decreases the intensity of the cytokine and chemokine storm, (2) modulates neutrophil activity, (3) maintains the integrity of the pulmonary epithelial barrier, (4) stimulates epithelial repair, and (5) directly and indirectly decreases the risk of hypercoagulability and pulmonary or systemic thrombosis. B: is a powerful negative regulator of the RAAS, inhibiting renin and the ACE/Ang II/AT1R cascade and inducing ACE2/Ang-(1-7) axis activity, contributing to decrease the intensity of ARDS in all its aspects, following SARS-CoV-1 infection. (A) SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; IFN-α, IFN-γ = interferon gamma α and γ; IL-1β, IL-6, IL-12, IL-18, IL-33 = interleukin-1β, 6, 12, 18, 33; TNF-α = tumour necrosis factor-α; TGFβ = transforming growth factor α and β; CCL2, CCL3, CCL5 Chemokine = C-C motif ligand 2, 3, 5; CXCL8, CXCL9, CXCL10 = C-X-C (chemokine motif ligand 8, 9, 10). (B) ACII = alveolar cuboidal cells type II; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; Ang I = angiotensin I; Ang II = angiotensin II; Ang-(1-7) = angiotensin 1-7; MasR = Mas G-protein-coupled receptor; AT1R and AT2R = angiotensin II receptor 1 and 2.
Figure 6
Figure 6
Serum levels of 25OHD, after intake of 0.532 mg calcifediol in soft capsules (AUCu 72 ng/mL). The pharmacokinetic characteristics of calcifediol allow it to be rapidly absorbed within hours, facilitating the immediate availability of 25OHD3 in target tissues (results provided from the technical dossier of the product by FAES-Farma. Lejona. (Spain).
Figure 7
Figure 7
Effect of calcifediol treatment (0.532 mg on day 1 and 0.266 mg on days 3, 7, 14, 21, and 28). Parallel open label randomized double masked, double blinded, pilot clinical trial. Blue: ICU; yellow: no ICU. Elaborated from data obtained from Entrenas Castillo et al. [101].
Figure 8
Figure 8
Early calcifediol administration and outcome of COVID-19. Patients (n = 838) hospitalized for COVID-19 received best available treatment and standard care for pre-existing comorbidities. Treatment groups were based on having received from admission (1) oral calcifediol (25OH D3) in soft gelatin capsules (0.532 mg), then oral calcifediol (0.266 mg) on days 3 and 7, then weekly until discharge or ICU admission (n = 447) represented in red; (2) no calcifediol treatment (n = 391) represented in blue. Cumulative distribution of patients presenting with ICU admission or in-hospital death according to treatment groups. Patients hospitalized with COVID-19 on calcifediol treatment, compared to those who did not receive calcifediol showed) a lower need for ICU admission (45% vs. 21%), reduced risk (OR 0.13, 95% CI 0.07–0.23) p < 0.0001 (left), and significantly lower in-hospital mortality during the first 30 days (7% vs. 15.9%,) OR 0,21 [95% CI 0.10–0.43 p < 0.0001) (right). Elaborated from data obtained from Nogues X et al. [103].

References

    1. Boban M. Novel coronavirus disease (COVID-19) update on epidemiology, pathogenicity, clinical course and treatments. Int. J. Clin. Pract. 2021;75:e13868. doi: 10.1111/ijcp.13868.
    1. Anonim COVID Live—Coronavirus Statistics—Worldometer. [(accessed on 2 April 2022)]. Available online:
    1. COVID-19 Map—Johns Hopkins Coronavirus Resource Center. [(accessed on 31 July 2021)]. Available online: .
    1. Thorne L.G., Bouhaddou M., Reuschl A.K., Zuliani-Alvarez L., Polacco B., Pelin A., Batra J., Whelan M.V.X., Hosmillo M., Fossati A., et al. Evolution of enhanced innate immune evasion by SARS-CoV-2. Nature. 2022;602:487–495. doi: 10.1038/s41586-021-04352-y.
    1. Cele S., Jackson L., Khoury D.S., Khan K., Moyo-Gwete T., Tegally H., San J.E., Cromer D., Scheepers C., Amoako D.G., et al. Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization. Nature. 2021;602:654–656. doi: 10.1038/s41586-021-04387-1.
    1. Wagner C.E., Saad-Roy C.M., Morris S.E., Baker R.E., Mina M.J., Farrar J., Holmes E.C., Pybus O.G., Graham A.L., Emanuel E.J., et al. Vaccine nationalism and the dynamics and control of SARS-CoV-2. Science. 2021;373:eabj7364. doi: 10.1126/science.abj7364.
    1. Loucera C., Esteban-Medina M., Rian K., Falco M.M., Dopazo J., Peña-Chilet M. Drug repurposing for COVID-19 using machine learning and mechanistic models of signal transduction circuits related to SARS-CoV-2 infection. Signal Transduct. Target. Ther. 2020;5:290. doi: 10.1038/s41392-020-00417-y.
    1. Bouillon R., Quesada-Gomez J.M. Vitamin D Endocrine System and COVID-19. JBMR Plus. 2021;5:e10576. doi: 10.1002/jbm4.10576.
    1. Grant W.B., Lahore H., McDonnell S.L., Baggerly C.A., French C.B., Aliano J.L., Bhattoa H.P. Evidence that vitamin d supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients. 2020;12:988. doi: 10.3390/nu12040988.
    1. Li X., Chang J., Chen S., Wang L., Yau T.O., Zhao Q., Hong Z., Ruan J., Duan G., Gao S. Genomic Feature Analysis of Betacoronavirus Provides Insights Into SARS and COVID-19 Pandemics. Front. Microbiol. 2021;12:614494. doi: 10.3389/fmicb.2021.614494.
    1. Wu A., Peng Y., Huang B., Ding X., Wang X., Niu P., Meng J., Zhu Z., Zhang Z., Wang J., et al. Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China. Cell. Host Microbe. 2020;27:325–328. doi: 10.1016/j.chom.2020.02.001.
    1. Yoshimoto F.K. The Proteins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2 or n-COV19), the Cause of COVID-19. Protein J. 2020;39:198–216. doi: 10.1007/s10930-020-09901-4.
    1. Sariol A., Perlman S. Lessons for COVID-19 Immunity from Other Coronavirus Infections. Immunity. 2020;53:248–263. doi: 10.1016/j.immuni.2020.07.005.
    1. NIH Clinical Spectrum . National Institutes of Health; [(accessed on 21 April 2022)]. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Available online:
    1. Guan W., Ni Z., Hu Y., Liang W., Ou C., He J., Liu L., Shan H., Lei C., Hui D.S.C., et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N. Engl. J. Med. 2020;382:1708–1720. doi: 10.1056/NEJMoa2002032.
    1. Zhou F., Yu T., Du R., Fan G., Liu Y., Liu Z., Xiang J., Wang Y., Song B., Gu X., et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet. 2020;395:1054–1062. doi: 10.1016/S0140-6736(20)30566-3.
    1. Nalbandian A., Sehgal K., Gupta A., Madhavan M.V., McGroder C., Stevens J.S., Cook J.R., Nordvig A.S., Shalev D., Sehrawat T.S., et al. Post-acute COVID-19 syndrome. Nat. Med. 2021;27:601–615. doi: 10.1038/s41591-021-01283-z.
    1. Blanco-Melo D., Nilsson-Payant B.E., Liu W.C., Uhl S., Hoagland D., Møller R., Jordan T.X., Oishi K., Panis M., Sachs D., et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020;181:1036–1045. doi: 10.1016/j.cell.2020.04.026.
    1. Maestro M.A., Molnár F., Carlberg C. Vitamin D and its synthetic analogs. J. Med. Chem. 2019;62:6854–6875. doi: 10.1021/acs.jmedchem.9b00208.
    1. Vieth R. Vitamin D supplementation: Cholecalciferol, calcifediol, and calcitriol. Eur. J. Clin. Nutr. 2020;74:1493–1497. doi: 10.1038/s41430-020-0697-1.
    1. DeLuca H.F. History of the discovery of vitamin D and its active metabolites. Bonekey Rep. 2014;3:479. doi: 10.1038/bonekey.2013.213.
    1. Norman A.W. From vitamin D to hormone D: Fundamentals of the vitamin D endocrine system essential for good health. Am. J. Clin. Nutr. 2008;88:491S–499S. doi: 10.1093/ajcn/88.2.491S.
    1. Holick M.F. Vitamin D deficiency. N. Engl. J. Med. 2007;357:266–281. doi: 10.1056/NEJMra070553.
    1. Bikle D.D. Vitamin D: Production, Metabolism and Mechanisms of Action. [(accessed on 21 April 2022)];2000 Available online:
    1. Jones G., Kaufmann M. Diagnostic Aspects of Vitamin D: Clinical Utility of Vitamin D Metabolite Profiling. JBMR Plus. 2021;5:e10581. doi: 10.1002/jbm4.10581.
    1. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium . In: Dietary Reference Intakes for Calcium and Vitamin D. Ross A.C., Taylor C.L., Yaktine A.L., Del Valle H.B., editors. National Academies Press; Washington, DC, USA: 2011.
    1. Holick M.F., Binkley N.C., Bischoff-Ferrari H.A., Gordon C.M., Hanley D.A., Heaney R.P., Murad M.H., Weaver C.M. Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 2011;96:1911–1930. doi: 10.1210/jc.2011-0385.
    1. Bouillon R., Marcocci C., Carmeliet G., Bikle D., White J.H., Dawson-Hughes B., Lips P., Munns C.F., Lazaretti-Castro M., Giustina A., et al. Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions. Endocr. Rev. 2019;40:1109–1151. doi: 10.1210/er.2018-00126.
    1. Vanherwegen A.S., Gysemans C., Mathieu C. Vitamin D endocrinology on the cross-road between immunity and metabolism. Mol. Cell. Endocrinol. 2017;453:52–67. doi: 10.1016/j.mce.2017.04.018.
    1. Dimitrov V., Barbier C., Ismailova A., Wang Y., Dmowski K., Salehi-Tabar R., Memari B., Groulx-Boivin E., White J.H. Vitamin D-regulated Gene Expression Profiles: Species-specificity and Cell-specific Effects on Metabolism and Immunity. Endocrinology. 2021;162:1–18. doi: 10.1210/endocr/bqaa218.
    1. Bishop E.L., Ismailova A., Dimeloe S., Hewison M., White J.H. Vitamin D and Immune Regulation: Antibacterial, Antiviral, Anti-Inflammatory. JBMR Plus. 2021;5:e10405. doi: 10.1002/jbm4.10405.
    1. Gayan-Ramirez G., Janssens W. Vitamin D Actions: The Lung Is a Major Target for Vitamin D, FGF23, and Klotho. JBMR Plus. 2021;5:e10569. doi: 10.1002/jbm4.10569.
    1. Pilz S., Verheyen N., Grübler M.R., Tomaschitz A., März W. Vitamin D and cardiovascular disease prevention. Nat. Rev. Cardiol. 2016;13:404–417. doi: 10.1038/nrcardio.2016.73.
    1. Bouillon R. Vitamin D and cardiovascular disorders. Osteoporos. Int. 2019;30:2167–2181. doi: 10.1007/s00198-019-05098-0.
    1. Sengupta T., Majumder R., Majumder S. Role of vitamin D in treating COVID-19-associated coagulopathy: Problems and perspectives. Mol. Cell. Biochem. 2021;476:2421–2427. doi: 10.1007/s11010-021-04093-6.
    1. Osuchowski M.F., Winkler M.S., Skirecki T., Cajander S., Shankar-Hari M., Lachmann G., Monneret G., Venet F., Bauer M., Brunkhorst F.M., et al. The COVID-19 puzzle: Deciphering pathophysiology and phenotypes of a new disease entity. Lancet Respir. Med. 2021;9:622–642. doi: 10.1016/S2213-2600(21)00218-6.
    1. Hilger J., Friedel A., Herr R., Rausch T., Roos F., Wahl D.A., Pierroz D.D., Weber P., Hoffmann K. A systematic review of vitamin D status in populations worldwide. Br. J. Nutr. 2014;111:23–45. doi: 10.1017/S0007114513001840.
    1. Lips P. Worldwide status of vitamin D nutrition. J. Steroid Biochem. Mol. Biol. 2010;121:297–300. doi: 10.1016/j.jsbmb.2010.02.021.
    1. Bouillon R., Antonio L., Olarte O.R. Calcifediol (25OH Vitamin D3) Deficiency: A Risk Factor from Early to Old Age. Nutrients. 2022;14:1168. doi: 10.3390/nu14061168.
    1. Giustina A., Adler R.A., Binkley N., Bollerslev J., Bouillon R., Dawson-Hughes B., Ebeling P.R., Feldman D., Formenti A.M., Lazaretti-Castro M., et al. Consensus statement from 2nd International Conference on Controversies in Vitamin D. Rev. Endocr. Metab. Disord. 2020;21:89–116. doi: 10.1007/s11154-019-09532-w.
    1. Khademvatani K., Seyyed-Mohammadzad M.H., Akbari M., Rezaei Y., Eskandari R., Rostamzadeh A. The relationship between vitamin D status and idiopathic lower-extremity deep vein thrombosis. Int. J. Gen. Med. 2014;7:303–309. doi: 10.2147/IJGM.S64812.
    1. George B., Amjesh R., Paul A.M., Santhoshkumar T.R., Pillai M.R., Kumar R. Evidence of a dysregulated vitamin D endocrine system in SARS-CoV-2 infected patient’s lung cells. Sci. Rep. 2021;11:8570. doi: 10.1038/s41598-021-87703-z.
    1. Ahmed F. A Network-Based Analysis Reveals the Mechanism Underlying Vitamin D in Suppressing Cytokine Storm and Virus in SARS-CoV-2 Infection. Front. Immunol. 2020;11:590459. doi: 10.3389/fimmu.2020.590459.
    1. Ginde A.A., Mansbach J.M., Camargo C.A. Association between Serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch. Intern. Med. 2009;169:384–390. doi: 10.1001/archinternmed.2008.560.
    1. Greiller C.L., Martineau A.R. Modulation of the immune response to respiratory viruses by vitamin D. Nutrients. 2015;7:4240–4270. doi: 10.3390/nu7064240.
    1. Roth D.E., Jones A.B., Prosser C., Robinson J.L., Vohra S. Vitamin D receptor polymorphisms and the risk of acute lower respiratory tract infection in early childhood. J. Infect. Dis. 2008;197:676–680. doi: 10.1086/527488.
    1. Martineau A.R., Jolliffe D.A., Hooper R.L., Greenberg L., Aloia J.F., Bergman P., Dubnov-Raz G., Esposito S., Ganmaa D., Ginde A.A., et al. Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. doi: 10.1136/bmj.i6583.
    1. Jolliffe D.A., Camargo C.A., Sluyter J.D., Aglipay M., Aloia J.F., Ganmaa D., Bergman P., Bischoff-Ferrari H.A., Borzutzky A., Damsgaard C.T., et al. Vitamin D supplementation to prevent acute respiratory infections: A systematic review and meta-analysis of aggregate data from randomised controlled trials. Lancet Diabetes Endocrinol. 2021;9:276–292. doi: 10.1016/S2213-8587(21)00051-6.
    1. Charoenngam N., Holick M.F. Immunologic effects of vitamin d on human health and disease. Nutrients. 2020;12:1–28. doi: 10.3390/nu12072097.
    1. Zdrenghea M.T., Makrinioti H., Bagacean C., Bush A., Johnston S.L., Stanciu L.A. Vitamin D modulation of innate immune responses to respiratory viral infections. Rev. Med. Virol. 2017;27:e1909. doi: 10.1002/rmv.1909.
    1. Bilezikian J.P., Bikle D., Hewison M., Lazaretti-Castro M., Formenti A.M., Gupta A., Madhavan M.V., Nair N., Babalyan V., Hutchings N., et al. MECHANISMS in ENDOCRINOLOGY Vitamin D and COVID-19. Eur. J. Endocrinol. 2020;183:R133–R147. doi: 10.1530/EJE-20-0665.
    1. Mansur J.L., Tajer C., Mariani J., Inserra F., Ferder L., Manucha W. Vitamin D high doses supplementation could represent a promising alternative to prevent or treat COVID-19 infection. Clin. E Investig. En Arterioscler. 2020;32:267–277. doi: 10.1016/j.arteri.2020.05.003.
    1. Quesada-Gomez J.M., Entrenas-Castillo M., Bouillon R. Vitamin D receptor stimulation to reduce acute respiratory distress syndrome (ARDS) in patients with coronavirus SARS-CoV-2 infections: Revised Ms SBMB 2020_166. J. Steroid Biochem. Mol. Biol. 2020;202:105719. doi: 10.1016/j.jsbmb.2020.105719.
    1. Solanki S.S., Singh P., Kashyap P., Sansi M.S., Ali S.A. Promising role of defensins peptides as therapeutics to combat against viral infection. Microb. Pathog. 2021;155:104930. doi: 10.1016/j.micpath.2021.104930.
    1. Jain S.K., Micinski D. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem. Biophys. Res. Commun. 2013;437:7–11. doi: 10.1016/j.bbrc.2013.06.004.
    1. Campbell G.R., Spector S.A. Vitamin D inhibits human immunodeficiency virus type 1 and Mycobacterium tuberculosis infection in macrophages through the induction of autophagy. PLoS Pathog. 2012;8:e1002689. doi: 10.1371/journal.ppat.1002689.
    1. Yuk J.M., Shin D.M., Lee H.M., Yang C.S., Jin H.S., Kim K.K., Lee Z.W., Lee S.H., Kim J.M., Jo E.K. Vitamin D3 Induces Autophagy in Human Monocytes/Macrophages via Cathelicidin. Cell. Host Microbe. 2009;6:231–243. doi: 10.1016/j.chom.2009.08.004.
    1. Fernández Á.F., Sebti S., Wei Y., Zou Z., Shi M., McMillan K.L., He C., Ting T., Liu Y., Chiang W.C., et al. Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature. 2018;558:136–140. doi: 10.1038/s41586-018-0162-7.
    1. Kong J., Zhang Z., Musch M.W., Ning G., Sun J., Hart J., Bissonnette M., Yan C.L. Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am. J. Physiol. —Gastrointest. Liver Physiol. 2007;294:G208–G216. doi: 10.1152/ajpgi.00398.2007.
    1. Hartmann B., Riedel R., Jör K., Loddenkemper C., Steinmeyer A., Zügel U., Babina M., Radbruch A., Worm M. Vitamin D receptor activation improves allergen-triggered eczema in mice. J. Invest Dermatol. 2012;132:330–336. doi: 10.1038/jid.2011.296.
    1. Chen H., Lu R., Zhang Y.G., Sun J. Vitamin D Receptor Deletion Leads to the Destruction of Tight and Adherens Junctions in Lungs. Tissue Barriers. 2018;6:1–13. doi: 10.1080/21688370.2018.1540904.
    1. Yang L., Xie X., Tu Z., Fu J., Xu D., Zhou Y. The signal pathways and treatment of cytokine storm in COVID-19. Signal Transduct. Target. Ther. 2021;6:255. doi: 10.1038/s41392-021-00679-0.
    1. Cantorna M.T., Snyder L., Lin Y.D., Yang L. Vitamin D and 1,25(OH)2D regulation of T cells. Nutrients. 2015;7:3011–3021. doi: 10.3390/nu7043011.
    1. Colotta F., Jansson B., Bonelli F. Modulation of inflammatory and immune responses by vitamin D. J. Autoimmun. 2017;85:78–97. doi: 10.1016/j.jaut.2017.07.007.
    1. Zhou C., Lu F., Cao K., Xu D., Goltzman D., Miao D. Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1α-hydroxylase knockout mice. Kidney Int. 2008;74:170–179. doi: 10.1038/ki.2008.101.
    1. Xu J., Yang J., Chen J., Luo Q., Zhang Q., Zhang H. Vitamin D alleviates lipopolysaccharide-induced acute lung injury via regulation of the renin-angiotensin system. Mol. Med. Rep. 2017;16:7432–7438. doi: 10.3892/mmr.2017.7546.
    1. Chen L.N., Yang X.H., Nissen D.H., Chen Y.Y., Wang L.J., Wang J.H., Gao J.L., Zhang L.Y. Dysregulated renin-AngioteNsin system contributes to acute lung injury caused by hind-limb ischemia-reperfusion in mice. Shock. 2013;40:420–429. doi: 10.1097/SHK.0b013e3182a6953e.
    1. Mohammad S., Mishra A., Ashraf M.Z. Emerging role of vitamin d and its associated molecules in pathways related to pathogenesis of thrombosis. Biomolecules. 2019;9:649. doi: 10.3390/biom9110649.
    1. Aihara K.I., Azuma H., Akaike M., Ikeda Y., Yamashita M., Sudo T., Hayashi H., Yamada Y., Endoh F., Fujimura M., et al. Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice. J. Biol. Chem. 2004;279:35798–35802. doi: 10.1074/jbc.M404865200.
    1. Martinez-Moreno J.M., Herencia C., De Oca A.M., Muñoz-Castañeda J.R., Rodríguez-Ortiz M.E., Diáz-Tocados J.M., Peralbo-Santaella E., Camargo A., Canalejo A., Rodriguez M., et al. Vitamin D modulates tissue factor and protease-activated receptor 2 expression in vascular smooth muscle cells. FASEB J. 2016;30:1367–1376. doi: 10.1096/fj.15-272872.
    1. Wu W.X., He D.R. Low Vitamin D Levels Are Associated With the Development of Deep Venous Thromboembolic Events in Patients With Ischemic Stroke. Clin. Appl. Thromb. 2018;24:69S–75S. doi: 10.1177/1076029618786574.
    1. Jiang F., Yang Y., Xue L., Li B., Zhang Z. 1α, 25-dihydroxyvitamin D3 attenuates TGF-β-induced pro-fibrotic effects in human lung epithelial cells through inhibition of epithelial-mesenchymal transition. Nutrients. 2017;9:1–13. doi: 10.3390/nu9090980.
    1. Chang J., Nie H., Ge X., Du J., Liu W., Li X., Sun Y., Wei X., Xun Z., Li Y.C. Vitamin D suppresses bleomycin-induced pulmonary fibrosis by targeting the local renin–angiotensin system in the lung. Sci. Rep. 2021;11:16525. doi: 10.1038/s41598-021-96152-7.
    1. Tzilas V., Bouros E., Barbayianni I., Karampitsakos T., Kourtidou S., Ntassiou M., Ninou I., Aidinis V., Bouros D., Tzouvelekis A. Vitamin D prevents experimental lung fibrosis and predicts survival in patients with idiopathic pulmonary fibrosis. Pulm. Pharmacol. Ther. 2019;55:17–24. doi: 10.1016/j.pupt.2019.01.003.
    1. Pereira M., Dantas Damascena A., Galvão Azevedo L.M., de Almeida Oliveira T., da Mota Santana J. Vitamin D deficiency aggravates COVID-19: Systematic review and meta-analysis. Crit. Rev. Food Sci. Nutr. 2022;62:1308–1316. doi: 10.1080/10408398.2020.1841090.
    1. Damascena A.D., Azevedo L.M.G., de Oliveira T.A., da Mota Santana J., Pereira M. Addendum to vitamin D deficiency aggravates COVID-19: Systematic review and meta-analysis. Crit. Rev. Food Sci. Nutr. 2021:1–6. doi: 10.1080/10408398.2021.1951652.
    1. Oscanoa T.J., Amado J., Vidal X., Laird E., Ghashut R.A., Romero-Ortuno R. The relationship between the severity and mortality of SARS-CoV-2 infection and 25-hydroxyvitamin D concentration—A metaanalysis. Adv. Respir. Med. 2021;89:145–157. doi: 10.5603/ARM.a2021.0037.
    1. Bassatne A., Basbous M., Chakhtoura M., El Zein O., Rahme M., El-Hajj Fuleihan G. The link between COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis. Metabolism. 2021;119:154753. doi: 10.1016/j.metabol.2021.154753.
    1. Kazemi A., Mohammadi V., Aghababaee S.K., Golzarand M., Clark C.C.T., Babajafari S. Association of Vitamin D Status with SARS-CoV-2 Infection or COVID-19 Severity: A Systematic Review and Meta-analysis. Adv. Nutr. 2021;12:1636–1658. doi: 10.1093/advances/nmab012.
    1. Kaya M.O., Pamukcu E., Yakar B. The role of vitamin D deficiency on COVID-19: A systematic review and meta-Analysis of observational studies. Epidemiol. Health. 2021;43:e2021074. doi: 10.4178/epih.e2021074.
    1. Wang Z., Joshi A., Leopold K., Jackson S., Christensen S., Nayfeh T., Mohammed K., Creo A., Tebben P., Kumar S. Association of Vitamin D Deficiency with COVID-19 Infection Severity: Systematic Review and Meta-analysis. Clin. Endocrinol. 2021;96:281–287. doi: 10.1111/cen.14540.
    1. Liu N., Sun J., Wang X., Zhang T., Zhao M., Li H. Low vitamin D status is associated with coronavirus disease 2019 outcomes: A systematic review and meta-analysis. Int. J. Infect. Dis. 2021;104:58–64. doi: 10.1016/j.ijid.2020.12.077.
    1. Chiodini I., Gatti D., Soranna D., Merlotti D., Mingiano C., Fassio A., Adami G., Falchetti A., Eller-Vainicher C., Rossini M., et al. Vitamin D Status and SARS-CoV-2 Infection and COVID-19 Clinical Outcomes. Front. Public Health. 2021;9:736665. doi: 10.3389/fpubh.2021.736665.
    1. Dissanayake H.A., de Silva N.L., Sumanatilleke M., de Silva S.D.N., Gamage K.K.K., Dematapitiya C., Kuruppu D.C., Ranasinghe P., Pathmanathan S., Katulanda P. Prognostic and Therapeutic Role of Vitamin D in COVID-19: Systematic Review and Meta-analysis. J. Clin. Endocrinol. Metab. 2022;107:1484–1502. doi: 10.1210/clinem/dgab892.
    1. Martucci G., McNally D., Parekh D., Zajic P., Tuzzolino F., Arcadipane A., Christopher K.B., Dobnig H., Amrein K. Trying to identify who may benefit most from future vitamin D intervention trials: A post hoc analysis from the VITDAL-ICU study excluding the early deaths. Crit. Care. 2019;23:200. doi: 10.1186/s13054-019-2472-z.
    1. Cesareo R., Falchetti A., Attanasio R., Tabacco G., Naciu A.M., Palermo A. Hypovitaminosis D: Is it time to consider the use of calcifediol? Nutrients. 2019;11:1016. doi: 10.3390/nu11051016.
    1. Pérez-Castrillón J.L., Dueñas-Laita A., Brandi M.L., Jódar E., del Pino-Montes J., Quesada-Gómez J.M., Cereto Castro F., Gómez-Alonso C., Gallego López L., Olmos Martínez J.M., et al. Calcifediol is superior to cholecalciferol in improving vitamin D status in postmenopausal women: A randomized trial. J. Bone Miner. Res. 2021;36:1967–1978. doi: 10.1002/jbmr.4387.
    1. Holick M.F. The CO-VID D-Lemma: A Call for Action. Nutrients. 2022;14:963. doi: 10.3390/nu14050963.
    1. Quesada-Gomez J.M., Bouillon R. Is calcifediol better than cholecalciferol for vitamin D supplementation? Osteoporos. Int. 2018;29:1697–1711. doi: 10.1007/s00198-018-4520-y.
    1. Duchow E.G., Sibilska-Kaminski I.K., Plum L.A., DeLuca H.F. Vitamin D esters are the major form of vitamin D produced by UV irradiation in mice. Photochem. Photobiol. Sci. 2022:1–6. doi: 10.1007/s43630-022-00230-2.
    1. Molin A., Wiedemann A., Demers N., Kaufmann M., Do Cao J., Mainard L., Dousset B., Journeau P., Abeguile G., Coudray N., et al. Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition? J. Bone Miner. Res. 2017;32:1893–1899. doi: 10.1002/jbmr.3181.
    1. Bouillon R., Bikle D. Vitamin D Metabolism Revised: Fall of Dogmas. J. Bone Miner. Res. 2019;34:1985–1992. doi: 10.1002/jbmr.3884.
    1. Charoenngam N., Kalajian T.A., Shirvani A., Yoon G.H., Desai S., McCarthy A., Apovian C.M., Holick M.F. A pilot-randomized, double-blind crossover trial to evaluate the pharmacokinetics of orally administered 25-hydroxyvitamin D3 and vitamin D3 in healthy adults with differing BMI and in adults with intestinal malabsorption. Am. J. Clin. Nutr. 2021;114:1189–1199. doi: 10.1093/ajcn/nqab123.
    1. Jolliffe D.A., Stefanidis C., Wang Z., Kermani N.Z., Dimitrov V., White J.H., McDonough J.E., Janssens W., Pfeffer P., Griffiths C.J., et al. Vitamin d metabolism is dysregulated in asthma and chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2020;202:371–382. doi: 10.1164/rccm.201909-1867OC.
    1. Andújar-Espinosa R., Salinero-González L., Illán-Gómez F., Castilla-Martínez M., Hu-Yang C., Ruiz-López F.J. Effect of vitamin D supplementation on asthma control in patients with vitamin D deficiency: The ACVID randomised clinical trial. Thorax. 2021;76:126–133. doi: 10.1136/thoraxjnl-2019-213936.
    1. Bischoff-Ferrari H.A., Dawson-Hughes B., Stöcklin E., Sidelnikov E., Willett W.C., Edel J.O., Stähelin H.B., Wolfram S., Jetter A., Schwager J., et al. Oral supplementation with 25(OH)D3 versus vitamin D3: Effects on 25(OH)D levels, lower extremity function, blood pressure, and markers of innate immunity. J. Bone Miner. Res. 2012;27:160–169. doi: 10.1002/jbmr.551.
    1. Zhang Z., Ai G., Chen L., Liu S., Gong C., Zhu X., Zhang C., Qin H., Hu J., Huang J. Associations of immunological features with COVID-19 severity: A systematic review and meta-analysis. BMC Infect. Dis. 2021;21:738. doi: 10.1186/s12879-021-06457-1.
    1. Okoye C., Calsolaro V., Niccolai F., Calabrese A.M., Franchi R., Rogani S., Coppini G., Morelli V., Caraccio N., Monzani F. A Randomized, Open-Label Study to Assess Efficacy of Weekly Assumption of Cholecalciferol versus Calcifediol in Older Patients with Hypovitaminosis D. Geriatrics. 2022;7:13. doi: 10.3390/geriatrics7010013.
    1. Oristrell J., Oliva J.C., Subirana I., Casado E., Domínguez D., Toloba A., Aguilera P., Esplugues J., Fafián P., Grau M. Association of calcitriol supplementation with reduced COVID19 mortality in patients with chronic kidney disease: A population-based study. Biomedicines. 2021;9:509. doi: 10.3390/biomedicines9050509.
    1. Loucera C., Peña-Chilet M., Esteban-Medina M., Muñoyerro-Muñiz D., Villegas R., Lopez-Miranda J., Rodriguez-Baño J., Túnez I., Bouillon R., Dopazo J., et al. Real world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients. Sci. Rep. 2021;11:23380. doi: 10.1038/s41598-021-02701-5.
    1. Entrenas Castillo M., Entrenas Costa L.M., Vaquero Barrios J.M., Alcalá Díaz J.F., López Miranda J., Bouillon R., Quesada Gomez J.M. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study. J. Steroid Biochem. Mol. Biol. 2020;203:105751. doi: 10.1016/j.jsbmb.2020.105751.
    1. Alcala-diaz J.F., Limia-perez L., Gomez-huelgas R., Martin-escalante M.D., Cortes-rodriguez B., Zambrana-garcia J.L., Entrenas-castillo M., Perez-caballero A.I., López-carmona M.D., Garcia-alegria J., et al. Calcifediol treatment and hospital mortality due to COVID-19: A cohort study. Nutrients. 2021;13:1760. doi: 10.3390/nu13061760.
    1. Nogues X., Ovejero D., Pineda-Moncusí M., Bouillon R., Arenas D., Pascual J., Ribes A., Guerri-Fernandez R., Villar-Garcia J., Rial A., et al. Calcifediol treatment and COVID-19-related outcomes. J. Clin. Endocrinol. Metab. 2021;106:e4017–e4027. doi: 10.1210/clinem/dgab405.
    1. Maghbooli Z., Sahraian M.A., Jamalimoghadamsiahkali S., Asadi A., Zarei A., Zendehdel A., Varzandi T., Mohammadnabi S., Alijani N., Karimi M., et al. Treatment With 25-Hydroxyvitamin D3 (Calcifediol) Is Associated With a Reduction in the Blood Neutrophil-to-Lymphocyte Ratio Marker of Disease Severity in Hospitalized Patients With COVID-19: A Pilot Multicenter, Randomized, Placebo-Controlled, Double-Bli. Endocr. Pract. 2021;27:1242–1251. doi: 10.1016/j.eprac.2021.09.016.
    1. Visser M.P.J., Dofferhoff A.S.M., van den Ouweland J.M.W., van Daal H., Kramers C., Schurgers L.J., Janssen R., Walk J. Effects of Vitamin D and K on Interleukin-6 in COVID-19. Front. Nutr. 2022;8:761191. doi: 10.3389/fnut.2021.761191.
    1. Wen W., Chen C., Tang J., Wang C., Zhou M., Cheng Y., Zhou X., Wu Q., Zhang X., Feng Z., et al. Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19: A meta-analysis. Ann. Med. 2022;54:516–523. doi: 10.1080/07853890.2022.2034936.
    1. Vitiello A., Ferrara F., Auti A.M., Di Domenico M., Boccellino M. Advances in the Omicron variant development. J. Intern. Med. 2022;292:81–90. doi: 10.1111/joim.13478.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe