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All Studies   Meta Analysis    Recent:   

Vitamin D3 attenuates SARS‐CoV‐2 nucleocapsid protein‐caused hyperinflammation by inactivating the NLRP3 inflammasome through the VDR‐BRCC3 signaling pathway in vitro and in vivo

Chen et al., MedComm, doi:10.1002/mco2.318
Jun 2023  
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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. * >10% efficacy, ≥3 studies.
4,800+ studies for 98 treatments. c19early.org
In Vitro and mouse study showing that vitamin D3 attenuates SARS-CoV-2 nucleocapsid protein-induced hyperinflammation by inactivating the NLRP3 inflammasome through the VDR-BRCC3 signaling pathway. In human bronchial epithelial cells overexpressing the N protein, vitamin D3 dose-dependently reduced IL-6 and IL-1β expression and secretion. Authors find that vitamin D3 inhibited N protein-triggered NLRP3 inflammasome activation, an effect enhanced by NLRP3 and caspase-1 inhibitors or siRNAs. Vitamin D3 increased NLRP3 ubiquitination and VDR-NLRP3 binding while decreasing BRCC3-NLRP3 association. In N protein-expressing mice, vitamin D3 improved lung injury and decreased NLRP3 inflammasome activation and hyperinflammation in a VDR-dependent manner.
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, 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.
Chen et al., 21 Jun 2023, peer-reviewed, 11 authors. Contact: hongbinsong@263.net, bianxiuwu@263.net.
This PaperVitamin DAll
Vitamin D3 attenuates SARS‐CoV‐2 nucleocapsid protein‐caused hyperinflammation by inactivating the NLRP3 inflammasome through the VDR‐BRCC3 signaling pathway in vitro and in vivo
Mingliang Chen, Ying He, Xiaofeng Hu, Xunhu Dong, Zexuan Yan, Qingning Zhao, Jingyuan Li, Dongfang Xiang, Yong Lin, Ph.D Hongbin Song, M.D Xiuwu Bian
MedComm, doi:10.1002/mco2.318
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-caused coronavirus disease 2019 (COVID-19) is a global crisis with no satisfactory therapies. Vitamin D3 (VD3) is considered a potential candidate for COVID-19 treatment; however, little information is available regarding the exact effects of VD3 on SARS-CoV-2 infection and the underlying mechanism. Herein, we confirmed that VD3 reduced SARS-CoV-2 nucleocapsid (N) protein-caused hyperinflammation in human bronchial epithelial (HBE) cells. Meanwhile, VD3 inhibited the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation in N protein-overexpressed HBE (HBE-N) cells. Notably, the inhibitors of caspase-1, NLRP3, and NLRP3 or caspase-1 small interference RNA (siRNA) enhanced VD3-induced NLRP3 inflammasome inactivation, with subsequent suppression of interleukin-6 (IL6) and IL1β release in HBE-N cells, which were abolished by the NLRP3 agonist. Moreover, VD3 increased NLRP3 ubiquitination (Ub-NLRP3) expression and the binding of the VDR with NLRP3, with decreased BRCA1/BRCA2-containing complex subunit 3 (BRCC3) expression and NLRP3-BRCC3 association. VD3-induced Ub-NLRP3 expression, NLRP3 inflammasome inactivation, and hyperinflammation inhibition were improved by the BRCC3
AUTHOR CONTRIBUTIONS A C K N O W L E D G M E N T S We are particularly grateful to Figdraw (https://www. figdraw.com/static/index.html) for providing a useful tool to draw the diagram of the mechanism. This work was supported by the National Natural Science Foundation of China (grant numbers: 82073544 and 82202189) and the Beijing Municipal Natural Science Foundation of China (grant number: 7232229). C O N F L I C T O F I N T E R E S T S TAT E M E N T The authors declare no conflict of interest. D ATA AVA I L A B I L I T Y S TAT E M E N T All data and materials are available to the researchers once published. E T H I C S S TAT E M E N T All animal experiments were carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals by the National Institutes of Health and were approved by the Animal Care and Use Committee of the Army Medical University (AMUWEC20212432, Chongqing, China). O R C I D Xiaofeng Hu https://orcid.org/0000-0003-0569-8535 R E F E R E N C E S S U P P O R T I N G I N F O R M AT I O N Additional supporting information can be found online in the Supporting Information section at the end of this article.
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