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The impact of calcitriol and estradiol on the SARS-CoV-2 biological activity: a molecular modeling approach

Mansouri et al., Scientific Reports, doi:10.1038/s41598-022-04778-y
Jan 2022  
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Vitamin D for COVID-19
8th treatment shown to reduce risk in October 2020, now with p < 0.00000000001 from 122 studies, recognized in 9 countries.
No treatment is 100% effective. Protocols combine treatments.
5,000+ studies for 109 treatments. c19early.org
In Silico study predicting that calcitriol and estradiol disrupt the interaction between the SARS-CoV-2 spike protein and ACE2. Authors note that calcitriol may be more effective in the presence of estradiol.
21 preclinical studies support the efficacy of vitamin D for COVID-19:
Vitamin D has been identified by the European Food Safety Authority (EFSA) as having sufficient evidence for a causal relationship between intake and optimal immune system function20-23. Vitamin D inhibits SARS-CoV-2 replication in vitro10,17, mitigates lung inflammation, damage, and lethality in mice with an MHV-3 model for β-CoV respiratory infections10,17, reduces SARS-CoV-2 replication in nasal epithelial cells via increased type I interferon expression13, downregulates proinflammatory cytokines IL-1β and TNF-α in SARS-CoV-2 spike protein-stimulated cells9, attenuates nucleocapsid protein-induced hyperinflammation by inactivating the NLRP3 inflammasome through the VDR-BRCC3 signaling pathway14, may be neuroprotective by protecting the blood-brain barrier, reducing neuroinflammation, and via immunomodulatory effects24, downregulates ACE2 and TMPRSS2 in human trophoblasts and minimizes spike protein-induced inflammation12, minimizes platelet aggregation mediated by SARS-CoV-2 spike protein via inhibiting integrin αIIbβ3 outside-in signaling8, and improves regulatory immune cell levels and control of proinflammatory cytokines in severe COVID-1925. Symptomatic COVID-19 is associated with a lower frequency of natural killer (NK) cells and vitamin D has been shown to improve NK cell activity26,27.
Mansouri et al., 13 Jan 2022, peer-reviewed, 5 authors. Contact: kowsarzar@yahoo.com, akiomiya@obihiro.ac.jp.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
This PaperVitamin DAll
The impact of calcitriol and estradiol on the SARS-CoV-2 biological activity: a molecular modeling approach
Alireza Mansouri, Rasoul Kowsar, Mostafa Zakariazadeh, Hassan Hakimi, Akio Miyamoto
Scientific Reports, doi:10.1038/s41598-022-04778-y
The novel coronavirus disease (COVID-19) is currently a big concern around the world. Recent reports show that the disease severity and mortality of COVID-19 infected patients may vary from gender to gender with a very high risk of death for seniors. In addition, some steroid structures have been reported to affect coronavirus, SARS-CoV-2, function and activity. The entry of SARS-CoV-2 into host cells depends on the binding of coronavirus spike protein to angiotensin converting enzyme-2 (ACE2). Viral main protease is essential for the replication of SARS-CoV-2. It was hypothesized that steroid molecules (e.g., estradiol, progesterone, testosterone, dexamethasone, hydrocortisone, prednisone and calcitriol) could occupy the active site of the protease and could alter the interaction of spike protein with ACE2. Computational data showed that estradiol interacted more strongly with the main protease active site. In the presence of calcitriol, the binding energy of the spike protein to ACE2 was increased, and transferring Apo to Locked S conformer of spike trimer was facilitated. Together, the interaction between spike protein and ACE2 can be disrupted by calcitriol. Potential use of estradiol and calcitriol to reduce virus invasion and replication needs clinical investigation. The novel coronavirus disease (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first recognized in the Hubei Province of China in December 2019 and has been reported as a very widespread disease with people-to-people transmission. Clinical evidence suggests that women are more resilient than men in terms of COVID-19 [1] [2] [3] [4] [5] . In the previous study, the critical factors involved in increasing the mortality and severity of COVID-19 in patients were investigated and higher disease severity and mortality were found in male patients 2 . It has been reported that 12.8% of 86 men died and 75.6% recovered, while 7.3% of 82 females died and 86.6% recovered 6 . In addition, the reports showed a relatively low risk of incidence in children but a very high risk of death in seniors 7 . Elderly patients diagnosed with COVID-19 aged 60 or older 8 had higher clinical signs, higher severity and longer periods of illness 9 . Sex steroid hormones are the primary cause of female and male differences. Testosterone (T) known as the predominant sex steroid hormone in males plays an essential role in sexual and reproductive development. In women, the predominant sex steroid hormones progesterone (P4) and estradiol (E2) are produced by ovaries. With respect to the menstrual cycle, the concentration of E2 reaches the highest level just before ovulation (during the follicular or proliferative phase) and then decreases shortly afterwards (during the luteal or secretory phase). P4 is released at peak level during the luteal phase, and then drops before the next menstrual period. Decreases in menopausal-associated ovarian hormones have been..
Author contributions Conceptualization: R.K., A.M.; Funding acquisition: R.K., A.M.; Investigation: Al.M., R.K., M.Z.; Methodology: Al.M., R.K., M.Z.; Software and Visualization: Al.M., M.Z.; Supervision: A.M., R.K.; Validation: Al.M., R.K., H.H., M.Z.; Writing-original draft: Al.M., R.K., M.Z., H.H.; Writing-review and editing: Al.M., R.K., M.Z., H.H., A.M. Competing interests The authors declare no competing interests. Additional information Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1038/ s41598-022-04778-y. Correspondence and requests for materials should be addressed to R.K. or A.M. Reprints and permissions information is available at www.nature.com/reprints. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Immunol.'}, { 'key': '4778_CR74', 'first-page': '102116', 'volume': '50', 'author': 'AJ Li', 'year': '2020', 'unstructured': 'Li, A. J. & Li, X. Sex-dependent immune response and lethality of ' 'COVID-19. Stem Cell Res. 50, 102116 (2020).', 'journal-title': 'Stem Cell Res.'}, { 'key': '4778_CR75', 'doi-asserted-by': 'crossref', 'unstructured': 'Aguilar-Pineda, J. A. et al. Structural and functional analysis of ' 'female sex hormones against SARS-Cov2 cell entry. bioRxiv (2020).', 'DOI': '10.1101/2020.07.29.227249'}, { 'key': '4778_CR76', 'doi-asserted-by': 'crossref', 'first-page': '473', 'DOI': '10.1016/S0140-6736(20)30317-2', 'volume': '395', 'author': 'CD Russell', 'year': '2020', 'unstructured': 'Russell, C. D., Millar, J. E. & Baillie, J. K. Clinical evidence does ' 'not support corticosteroid treatment for 2019-nCoV lung injury. Lancet ' '395, 473–475 (2020).', 'journal-title': 'Lancet'}, { 'key': '4778_CR77', 'doi-asserted-by': 'crossref', 'first-page': '2866', 'DOI': '10.1002/jmv.26165', 'volume': '92', 'author': 'L Kolilekas', 'year': '2020', 'unstructured': 'Kolilekas, L. et al. Can steroids reverse the severe COVID-19 induced ' '“cytokine storm”?. J. Med. Virol. 92, 2866–2869 (2020).', 'journal-title': 'J. Med. Virol.'}, { 'key': '4778_CR78', 'first-page': 'e00596', 'volume': '8', 'author': 'C So', 'year': '2020', 'unstructured': 'So, C., Ro, S., Murakami, M., Imai, R. & Jinta, T. High-dose, short-term ' 'corticosteroids for ARDS caused by COVID-19: A case series. Respirol. ' 'Case Rep. 8, e00596 (2020).', 'journal-title': 'Respirol. Case Rep.'}, { 'key': '4778_CR79', 'unstructured': 'The epidemiological characteristics of an outbreak of 2019 novel ' 'coronavirus diseases (COVID-19) in China. Zhonghua liu xing bing xue za ' 'zhi = Zhonghua liuxingbingxue zazhi 41, 145–151 (2020).'}, { 'key': '4778_CR80', 'first-page': '1', 'volume': '10', 'author': 'S Zhao', 'year': '2020', 'unstructured': 'Zhao, S. et al. The time-varying serial interval of the coronavirus ' 'disease (COVID-19) and its gender-specific difference: A data-driven ' 'analysis using public surveillance data in Hong Kong and Shenzhen, China ' 'from January 10 to February 15, 2020. Infect. Control Hosp. Epidemiol. ' '10, 1–8 (2020).', 'journal-title': 'Infect. Control Hosp. Epidemiol.'}, { 'key': '4778_CR81', 'doi-asserted-by': 'crossref', 'first-page': '669', 'DOI': '10.1111/liv.13303', 'volume': '37', 'author': 'A Magri', 'year': '2017', 'unstructured': 'Magri, A. et al. 17, β-estradiol inhibits hepatitis C virus mainly by ' 'interference with the release phase of its life cycle. Liver Int. 37, ' '669–677 (2017).', 'journal-title': 'Liver Int.'}], 'container-title': 'Scientific Reports', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://www.nature.com/articles/s41598-022-04778-y.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.nature.com/articles/s41598-022-04778-y', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.nature.com/articles/s41598-022-04778-y.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2022, 11, 24]], 'date-time': '2022-11-24T21:06:37Z', 'timestamp': 1669323997000}, 'score': 1, 'resource': {'primary': {'URL': 'https://www.nature.com/articles/s41598-022-04778-y'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2022, 1, 13]]}, 'references-count': 81, 'journal-issue': {'issue': '1', 'published-online': {'date-parts': [[2022, 12]]}}, 'alternative-id': ['4778'], 'URL': 'http://dx.doi.org/10.1038/s41598-022-04778-y', 'relation': {}, 'ISSN': ['2045-2322'], 'subject': ['Multidisciplinary'], 'container-title-short': 'Sci Rep', 'published': {'date-parts': [[2022, 1, 13]]}, 'assertion': [ { 'value': '6 July 2021', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '30 December 2021', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '13 January 2022', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': 'The authors declare no competing interests.', 'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}], 'article-number': '717'}
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Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
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