An effective therapeutic regimen for hepatic fibrosis requires a deep understanding of the pathogenesis mechanism. Hepatic fibrosis is characterized by activated hepatic stellate cells (aHSCs) with an excessive production of extracellular matrix. Although promoted activation of HSCs by M2 macrophages has been demonstrated, the molecular mechanism involved remains ambiguous. Herein, we propose that the vitamin D receptor (VDR) involved in macrophage polarization may regulate the communication between macrophages and HSCs by changing the functions of exosomes. We confirm that activating the VDR can inhibit the effect of M2 macrophages on HSC activation. The exosomes derived from M2 macrophages can promote HSC activation, while stimulating VDR alters the protein profiles and reverses their roles in M2 macrophage exosomes. Smooth muscle cell-associated protein 5 (SMAP-5) was found to be the key effector protein in promoting HSC activation by regulating autophagy flux. Building on these results, we show that a combined treatment of a VDR agonist and a macrophage-targeted exosomal secretion inhibitor achieves an excellent anti-hepatic fibrosis effect. In this study, we aim to elucidate the association between VDR and macrophages in HSC activation. The results contribute to our understanding of the pathogenesis mechanism of hepatic fibrosis, and provide potential therapeutic targets for its treatment.
Humans ; Hepatic Stellate Cells/pathology* ; Receptors, Calcitriol ; Liver Cirrhosis/pathology* ; Macrophages/metabolism*

Humans ; Comorbidity ; Diabetes Mellitus/genetics* ; East Asian People ; Hypertension/genetics* ; Hypertriglyceridemia/genetics* ; Obesity/genetics* ; Receptors, Calcitriol/genetics*

Humans ; Rural Population ; Hyperglycemia/genetics* ; Receptors, Calcitriol/genetics*

OBJECTIVE: To investigate the expression, clinical significance and prognosis of vitamin D receptor (VDR) gene and NF-κB pathway in children with acute lymphoblastic leukemia (ALL). METHODS: Thirty children with definitive diagnoses of ALL from December 2018 to December 2021 were selected as ALL group, and 30 healthy children under physical examination were selected as control group. Peripheral blood of all study subjects was collected. The VDR and NF-κB mRNA and protein expressions were detected by real-time quantitative PCR and Western blot, respectively. The relationship between mRNA expression of the above genes and clinical characteristics of children was retrospectively analyzed. RESULTS: The relative expression of VDR mRNA in peripheral blood of children with ALL was significantly lower than that in the control group (P < 0.05), while NF-κB mRNA was higher (P < 0.001). The expression of NF-κB mRNA in ALL children with peripheral blood white blood cell count (WBC) < 50×10⁹/L at initial diagnosis was significantly higher than those with WBC≥50×10⁹/L (P < 0.01). The expression of NF-κB mRNA in ALL children with infection was significantly higher than that those without infection (P < 0.05). There were no significant differences in NF-κB mRNA expression between children with different sex, age, hemoglobin at initial diagnosis, platelet, immunologic typing, risk and induced response (P >0.05). CONCLUSION The expression of NF-κB is of value to diagnosis and prognosis of ALL in children.
Child ; Humans ; NF-kappa B ; Receptors, Calcitriol/genetics* ; Retrospective Studies ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; RNA, Messenger/genetics*

Humans ; Warfarin/therapeutic use* ; Cytochrome P-450 CYP2C9/genetics* ; Anticoagulants/therapeutic use* ; Genotype ; Heart Valves ; China ; Apolipoproteins E/genetics* ; Dose-Response Relationship, Drug ; Receptors, Calcitriol/genetics*

Humans ; Diabetes Mellitus, Type 2/genetics* ; Rural Population ; Case-Control Studies ; Obesity/genetics* ; China/epidemiology* ; Receptors, Calcitriol

Objective: To investigate the relationship between vitamin D receptor (VDR) gene polymorphisms and gestational diabetes mellitus (GDM) and provide evidence for the study of the mechanism of GDM. Methods: A case-control study design was used to study pregnant women who delivered in the obstetrics department of the First Hospital of Shanxi Medical University from March 1, 2012 to July 30, 2014. Of these, 334 cases were diagnosed with GDM and were matched 1∶1 by age, gestation time and residence to corresponding healthy controls. DNA genotyping was performed for the study subjects, and those with genotyping deletions >10% were excluded. Finally 323 cases and 320 controls were included in the study. Under co-dominant, dominant, recessive, and allele genetic models, unconditional logistic regression analysis on the relationship between VDR gene locus polymorphism and GDM was conducted. And software Haploview was used to analyze the relationship between haplotype and GDM. Results: At the genetic level, VDR gene was associated with the risk of developing GDM (P<0.05). After adjusting for pre-pregnancy body mass index, family history of diabetes, it was found that rs7967152 loci was associated with an increased risk of developing GDM (AC vs. AA, OR=1.58, 95%CI: 1.13-2.21; AC+CC vs. AA, OR=1.58, 95%CI: 1.15-2.18; C vs. A, OR=1.41, 95%CI: 1.10-1.82) and rs2238140 loci was associated with an increased risk of developing GDM (AA vs. GG, OR=2.24, 95%CI: 1.19-4.20; GA+AA vs. GG, OR=1.48, 95%CI: 1.07-2.03; A vs. G, OR=1.43, 95%CI: 1.11-1.83). Carrying rs2853564 locus AG genotype and AG+GG genotype (OR=1.46, 95%CI: 1.04-2.05; OR=1.45, 95%CI: 1.05-2.00) compared with carrying AA genotype and carrying rs2853566 locus AG genotype and AG+GG genotype (OR=1.43, 95%CI: 1.03-2.00; OR=1.41, 95%CI: 1.02-1.94) compared with carrying AA genotype were risk factors for GDM. Haplotype block consisting of rs1544410, rs7967152 in the VDR gene with GC haplotype was a risk factor for GDM(OR=1.50, 95%CI: 1.15-1.97). Conclusions: VDR gene rs7967152, rs2238140, rs2853564, rs2853566 locus polymorphisms and block (rs1544410, rs7967152) GC haplotype were associated with an incrased risk of developing GDM.
Case-Control Studies ; Diabetes, Gestational/genetics* ; Female ; Genotype ; Humans ; Polymorphism, Single Nucleotide ; Pregnancy ; Receptors, Calcitriol/genetics*

Vitamin D plays an important role in mineral and bone homeostasis, immune responses, cardiovascular function and keratinocyte proliferation and differentiation. Vitamin D performs most of its functions by binding to vitamin D receptors (VDR), which interact with other intracellular signaling pathways to regulate bone metabolism, inflammation, immunity, cell cycle progression and apoptosis. Autophagy is a basic stress response in yeast, plants and mammals, and plays a critical role in maintaining optimal functional states at the level of cells and organs. Vitamin D/VDR plays an anti-infection role via inducing and regulating autophagy.
Animals ; Autophagy ; Humans ; Inflammation ; Mammals/metabolism* ; Receptors, Calcitriol/metabolism* ; Vitamin D/physiology* ; Vitamins

OBJECTIVE: To explore the association of single nucleotide polymorphisms (SNPs) of the vitamin D receptor gene ( VDR) with circulating lipids considering gender differences. METHODS: Of the Han Chinese adults recruited from a health examination center for inclusion in the study, the circulating lipids, 25-hydroxyvitamin D (25OHD), and other parameters were measured. The VDR SNPs of Cdx2 (rs11568820), Fok1 (rs2228570), Apa1 (rs7975232), and Taq1 (rs731236) were genotyped with a qPCR test using blood DNA samples, and their associations with lipids were analyzed using logistic regression. RESULTS: In the female participants ( n = 236 with dyslipidemia and 888 without dyslipidemia), multiple genotype models of Fok1 indicated a positive correlation of B (not A) alleles with LDLC level ( P < 0.05). In the male participants ( n = 299 with dyslipidemia and 564 without dyslipidemia), the recessive model of Cdx2 and the additive and recessive models of Fok1 differed ( P < 0.05) between the HDLC-classified subgroups, respectively, and Fok1 BB and Cdx2 TT presented interactions with 25OHD in the negative associations with HDLC ( P < 0.05). CONCLUSION In the Chinese Han adults included in the study, the Fok1 B-allele of VDR was associated with higher LDLC in females, and the Fok1 B-allele and the Cdx2 T-allele of VDR were associated with lower HDLC in males. The interaction of VD and Fok1 BB or Cdx2 TT in males synergistically decreased HDLC levels.
Adult ; Alleles ; Asians/genetics* ; China/ethnology* ; Dyslipidemias/genetics* ; Female ; Genetic Predisposition to Disease/genetics* ; Genotype ; Humans ; Lipids/blood* ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Receptors, Calcitriol/genetics* ; Sex Factors ; Vitamin D/blood*

OBJECTIVE: To identify the miRNAs targeting vitamin D receptor (VDR) gene and their effect on parathyroid hormone (PTH) secretion in secondary hyperparathyroidism. METHODS: Primary parathyroid cells with secondary hyperparathyroidism were isolated by collagenase digestion and cultured. The miRNAs targeting VDR were screened by bioinformatics methods and full transcriptome sequencing, and dual-luciferase reporter assay was used to verify the targeting relationship between VDR and the screened miRNA. The effects of overexpression or inhibition of the candidate miRNA on VDR mRNA and protein expressions and PTH secretion were evaluated using qRT-PCR and Western blotting. The expression levels of the candidate miRNAs and VDR mRNA in clinical specimens of parathyroid tissues were verified by qRT-PCR, and the expression of VDR protein was detected by immunohistochemistry. RESULTS: We successfully isolated primary parathyroid cells. Dual-luciferase reporter assay verified the targeting relationship of hsa-miR-149-5p, hsa-miR-221-5p, hsa-miR-222-3p, hsa-miR-29a-5p, hsa-miR-301a-5p, hsa-miR-873-5p, hsa-miR-93-3p with VDR, and among them, the overexpression of hsa-miR-149-5p and hsa-miR-301a-5p significantly increased PTH secretion in the parathyroid cells. In patients with secondary hyperparathyroidism, hsa-miR-149-5p was highly expressed in the parathyroid tissues (P=0.046), where the expressions of VDR mRNA (P=0.0267) and protein were both decreased. CONCLUSION The two miRNAs, hsa-miR-149-5p and hsa-miR-301a-5p, may promote the secretion of PTH in patients with secondary hyperparathyroidism by down-regulating the expression of VDR gene.
Humans ; Hyperparathyroidism, Secondary/genetics* ; MicroRNAs/metabolism* ; Parathyroid Hormone ; RNA, Messenger ; Receptors, Calcitriol/genetics*