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Review
. 2024 Jan 22:15:1298181.
doi: 10.3389/fphar.2024.1298181. eCollection 2024.

Modulation of the vitamin D receptor by traditional Chinese medicines and bioactive compounds: potential therapeutic applications in VDR-dependent diseases

Minghe Yao #  1   2 , Patrick Kwabena Oduro #  3 , Ayomide M Akintibu  4 , Haifeng Yan  5
Affiliations
Review

Modulation of the vitamin D receptor by traditional Chinese medicines and bioactive compounds: potential therapeutic applications in VDR-dependent diseases

Minghe Yao et al. Front Pharmacol. .

Abstract

The Vitamin D receptor (VDR) is a crucial nuclear receptor that plays a vital role in various physiological functions. To a larger extent, the genomic effects of VDR maintain general wellbeing, and its modulation holds implications for multiple diseases. Current evidence regarding using vitamin D or its synthetic analogs to treat non-communicable diseases is insufficient, though observational studies suggest potential benefits. Traditional Chinese medicines (TCMs) and bioactive compounds derived from natural sources have garnered increasing attention. Interestingly, TCM formulae and TCM-derived bioactive compounds have shown promise in modulating VDR activities. This review explores the intriguing potential of TCM and bioactive compounds in modulating VDR activity. We first emphasize the latest information on the genetic expression, function, and structure of VDR, providing a comprehensive understanding of this crucial receptor. Following this, we review several TCM formulae and herbs known to influence VDR alongside the mechanisms underpinning their action. Similarly, we also discuss TCM-based bioactive compounds that target VDR, offering insights into their roles and modes of action.

Keywords: 1α,25-dihydroxyvitamin D3; TCM; VDR; VDR-dependent diseases; bioactive compounds.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
A schematic overview of the human VDR. The promoter region, coding exons region, the three prime untranslated region (UTR), and the well-known polymorphic sites are shown.
FIGURE 2
FIGURE 2
Overview of VDR transcriptional signaling. (A) A schematic representation of 1α,25-dihydroxy vitamin D3 [1α, 25 (OH)2D3]-induced activation of cytosolic VDR. On binding, VDR complexes with the retinoid-X-receptor coupled with 9-cis-retinoic acid (9cRA) and moves into the nucleus. (B) In the nucleus, the 1α, 25 (OH)2D3-VDR-RXR-9cRA complex binds to nuclear vitamin D response elements (nVDRE) and recruits several coactivators [nuclear coactivator—62 kDa-Ski-interacting protein (NCoA62-SKIP), steroid receptor coactivators (SRC1), CREB binding protein-p300 (CBP/p300), and SWI-2-related gene 1 associated factor (PBAF-SNF)] to promote histone acetylation and unwrap chromatin. (C) The mediator complex VDR-interacting proteins (DRIPs) are brought in by binding VDR-interacting protein 205. Transcription initiation is triggered by transcription factor 2B (TF2B) and RNA polymerase II. (D) In certain situations, transcriptional activation is prevented in 1α, 25 (OH)2D3 presence. This happens when 1α, 25 (OH)2D3-VDR-RXR-9cRA complex binds to a VDR-interacting repressor (VDIR) recognized by nVDRE, resulting in the dissociation of histone acetyltransferase (HAT) coactivators and the association of corepressors NCoR1/SMRT with histone deacetylase (HDAC) activity. The subsequent recruitment and interaction with the Williams syndrome transcription factor (WSTF) hinder gene transcription expression via the multifunctional ATP-dependent chromatin-remodeling complex (WINAC). (E) VDR that is not bound to 1α, 25 (OH)2D3 and is linked to RXR-9cRA moves into the nucleus and then binds to nVDRE. With the help of corepressors (NCoR1/SMRT) with histone deacetylase activity, transcription is inhibited.
FIGURE 3
FIGURE 3
Basic structural features of human VDR. (A) Diagram of the functional domains of the human VDR. (B) The full-length 3-dimensional structure of apo-human VDR, showing the functional domains. (C) A close view of the crystal structure of the ligand-unbound ligand-binding domain of VDR. The α-helices are shown as cylindrical and numbered from H1-H12. (D) A cartoon representation of the ligand-binding domain of human VDR bound to 1α,25-dihydroxy vitamin D3 analog. (E) A magnified view of the binding site showing the binding mode of the inset ligand 1α,25-dihydroxy vitamin D3 analog. Full-length apo-human VDR (alpha fold model); Crystal structure of apo-human VDR ligand-binding domain (PDB ID: 3A78); and crystal structure of the nuclear receptor for vitamin D ligand binding domain bound to 1α,25-dihydroxy vitamin D3 analog (PDB ID: 1IE9).
FIGURE 4
FIGURE 4
Disease mutants VDR but not wild-type VDR causes diseases. Wild-type VDR, upon binding to its ligand 1α,25-dihydroxy vitamin D3, plays a vital role in maintaining overall health by facilitating calcium and phosphate absorption and promoting bone mineralization. In addition, it also inhibits angiogenesis, promotes protein synthesis, and induces cell differentiation. In contrast, disease-associated mutants of VDR are resistant to 1α,25-dihydroxy vitamin D3, disrupting VDR signaling and leading to the development of various bone-related diseases and the progression of cancer, diabetes, and CVDs.
FIGURE 5
FIGURE 5
Chemical structure of 1α,25-dihydroxy vitamin D3 and its analogs on the market.
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by HSRP-DFCTCM-2023.

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