Identification of a highly potent vitamin D receptor antagonist: (25S)-26-Adamantyl-25-hydroxy-2-methylene-22,23-didehydro-19,27-dinor-20-epi-vitamin D3 (ADMI3)

Previously, we have reported that the active vitamin D metabolite, calcitriol and vitamin D3 (cholecalciferol), both remarkably inhibit hepatitis C virus production. The mechanism by which vitamin D3 exerts its effect is puzzling due to the low levels of calcitriol produced in vitamin D3-treated Huh7.5 cells. In this study, we aimed to explore the mechanism of vitamin D3 anti-hepatitis C virus effect. We show that vitamin D3 activity is not mediated by its metabolic conversion to calcitriol, but may be due to its primary metabolic product 25(OH)D3. This is inferred from the findings that 25(OH)D3 could inhibit hepatitis C virus production in our system, and that adequate concentrations needed to exert this effect are produced in Huh7.5 cells treated with vitamin D3. Using the CRISPR-Cas9 editing technology to knockout the vitamin D receptor, we found that the antiviral activity of vitamin D3 and 25(OH)D3 was not impaired in the vitamin D receptor knockout cells. This result indicates that 25(OH)D3 anti-hepatitis C virus effect is exerted by a vitamin D receptor-independent mode of action. The possibility that vitamin D3 and 25(OH)D3, being 3β-hydroxysteroids, affect hepatitis C virus production by direct inhibition of the Hedgehog pathway in a vitamin D receptor-independent manner was ruled out. Taken together, this study proposes a novel mode of action for the anti-hepatitis C virus activity of vitamin D3 that is mediated by 25(OH)D3 in a vitamin D receptor-independent mechanism.

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Vitamin D3/vitamin D receptor signaling mitigates symptoms of post-stroke depression in mice by upregulating hippocampal BDNF expression

Neuroscience Research ◽

10.1016/j.neures.2020.08.002 ◽

2020 ◽

Author(s):

Yunxuan Xu ◽

Lingyun Liang

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Vitamin D3 ◽

Receptor Signaling ◽

Bdnf Expression ◽

Post Stroke ◽

Post Stroke Depression

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Vitamin D Receptor Genetic Variation and Cancer Biomarkers among Breast Cancer Patients Supplemented with Vitamin D3: A Single-Arm Non-Randomized Before and After Trial

Nutrients ◽

10.3390/nu11061264 ◽

2019 ◽

Vol 11 (6) ◽

pp. 1264 ◽

Cited By ~ 1

Author(s):

Elham Kazemian ◽

Mohammad Esmaeil Akbari ◽

Nariman Moradi ◽

Safoora Gharibzadeh ◽

Alison M. Mondul ◽

...

Keyword(s):

Breast Cancer ◽

Vitamin D ◽

Cancer Survivors ◽

Vitamin D Receptor ◽

Adhesion Molecule ◽

Vitamin D3 ◽

Breast Cancer Survivors ◽

Cancer Biomarkers ◽

Vitamin D3 Supplementation ◽

Vdr Polymorphisms

We investigated whether vitamin D receptor (VDR) polymorphisms were associated with cancer biomarkers, i.e., E-cadherin, matrix metallopeptidase 9 (MMP9), interferon β (IFNβ), soluble intercellular adhesion molecule-1 (s-ICAM-1), soluble vascular cell adhesion molecule-1 (s-VCAM-1), tumor necrosis factorα (TNFα), interleukin 6 (IL6), plasminogen activator inhibitor-1(PAI-1), and human high sensitivity C-reactive protein (hs-CRP), among breast cancer survivors who received vitamin D3 supplementation. In a single-arm non-randomized pre- and post trial, 176 breast cancer survivors who had completed treatment protocol including surgery, radio and chemotherapy were enrolled in the study and received 4000 IU of vitamin D3 daily for 12 weeks. The association between the VDR SNPs (ApaI, TaqI, FokI, BsmI and Cdx2) and response variable changes was assessed using linear regression, utilizing the “association” function in the R package “SNPassoc”. We observed that women with AA and GA [codominant model (AA compared to GG) and (GA compared to GG); dominant model (AA & GA compared to GG)] genotypes of Cdx2 showed higher increase in plasma MMP9 levels compared to the GG category. In addition, carriers of BsmI bb showed greater decrease in circulating TNFα levels after vitamin D3 supplementation [recessive model (bb compared to BB & Bb]. Likewise, significant associations were identified between haplotypes of VDR polymorphisms and on-study plasma MMP9 changes. However, our results indicate that VDR genetic polymorphisms were not associated with longitudinal changes in the remaining cancer biomarkers. Overall, our findings suggest that changes in certain inflammatory biomarkers in breast cancer survivors with low plasma 25(OH)D levels, supplemented with vitamin D3, may depend on VDR SNPs and haplotypes.

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