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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.
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Humans , Hepatic Stellate Cells/pathology , Receptors, Calcitriol , Liver Cirrhosis/pathology , Macrophages/metabolismABSTRACT
Objective To investigate the effect of lentivirus carrying shRNA-VDR vector on GLi1 in pros-tate cancer PC-3 cells. Methods The cells were cultured according to the culture conditions of PC-3 cells. Expression of VDR and GLi1 in PC-3 cells was detected by fluorescence quantitative PCR and immunocytochemistry SP method.The efficiency of PC-3 cell virus infection was evaluated.The effect of VDR gene interference and GLi1 transcription level on PC-3 cells was detected by RT-PCR.Results Cell culture,cell status was recorded and PC-3 cells were in good condition and the passages was 4 days. Fluorescence quantitative and immunocytochemi-cal SP showed that VDR and GLi1 were expressed in PC-3 cells.The virus infection efficiency showed that the in-fection efficiency was about 95% when adding LV3-NC lentivirus to PC-3 cells at 1:10 ratio. RT-PCR showed that VDR-shRNA lentivirus successfully disturbed VDR expression and decreased by 85%(P < 0.05)compared with the control group after 72 days of VDR-shRNA lentivirus transfection. Transcription level of GLi1 gene in the experimental group increased by 9% compared with the control group(P < 0.05). The transcription level of GLi1 gene in the experimental group increased by 248% compared with the control group(P < 0.05). Conclusion The cultured PC-3 cells were in good condition. VDR and GLi1 genes were expressed in PC-3 cells. Lentivirus showed highest efficiency in infecting PC-3 at 1:10 ratio. When VDR was disturbed,the expression of GLi1 in-creased.In prostate cancer cells,vitamin D can inhibit the Hh signaling pathway and cause GLi1 expression down expression.
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Background: Parkinson’s disease comes second comparing to Alzheimer’s disease being responsible for nerve destructing diseases; it is a complex and multifactorial disease. Gene associated studies help to identify the genetic factors that introduce the Single Nucleotide Polymorphisms in different genes as genetic risk factors for non-Mendelian Parkinson’s disease in diverse populations. We intended to study the association of VDR (Vitamin D Receptor) gene polymorphisms with Parkinson’s disease in south western Iranian population. Results: In the present study 150 patients with Parkinson’s disease and 160 Healthy controls from an Iranian population were genotyped for two polymorphic sites. The prevalence of VDR polymorphisms in two restriction fragment length polymorphism sites including FokI and ApaI were analyzed in patients and controls. Our data demonstrated no significant association between VDR FokI polymorphism and PD, whereas the ApaI polymorphism showed a significant association with PD in Iranian patient. Also no association between the age at onset, the male-female ratio and the VDR polymorphism in the PD group was detected. Conclusions: In conclusion these results determined that VDR ApaI (TG and GG) genotype might affect development of PD in our study population. There was no association between FokI polymorphism and the risk of PD. Our results were analogous only with American/Hungarian Caucasian race.
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Objective To observe the effect of vitamin D on angiotensin converting enzyme 2 (ACE2) and vitamin D receptor (VDR) expression in Wister rat models of acute lung injury (ALI) induced by using lipopolysaccharide (LPS).Methods The rat models of ALI induced by LPS were established by intravenous injection of LPS via tail vein.Thirty Wistar rats were randomly (random number) divided into 6 groups:normal control group,LPS group,calcitriol (25 μg/kg) group,LPS + calcitriol 1 μg/kg group,LPS + calcitriol 5 μg/kg group and LPS + calcitriol 25 μg/kg group.The changes of general condition,lung pathology,lung wet/dry weight ratio and changes of VDR mRNA and ACE2 mRNA expressions and protein levels of VDR and ACE2 in rats were observed.Results The clinical manifestations (rapid shallow breathing;listlessness;the oral and nose hemorrhage) in LPS group were obvious,and the clinical manifestations and pathological changes of lung tissues in the LPS + calcitriol groups were significantly milder than those in LPS group.The expressions of VDR mRNA and ACE2 mRNA in LPS group was significantly lower than those in normal control group and calcitriol group (P ＜ 0.05).The expressions of VDR mRNA and ACE2 mRNA in LPS + calcitriol groups were significantly higher than those in LPS group (P ＜ 0.05),and lower than those in normal control group significantly (P ＜ 0.05).Meanwhile,among LPS + calcitriol groups,there was no significant difference in expression of VDR mRNA (P ＞ 0.05) and there was significant difference in ACE2 mRNA expression (P ＜ 0.05).Conclusions Calcitriol can increase the expressions of VDR mRNA and ACE2 mRNA and protein levels of VDR and ACE2 in rat models of LPS-induced ALI,thus suggesting the increased expressions of ACE2 mRNA and VDR mRNA playing a role in protection against the development of ALI.
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Objective To explore the associations between polymorphisms of Vitamin D receptor gene and type 1 diabetes susceptibility. Methods Literatures were retrieved from PubMed ,Web of Science and WanFang databases ,etc.Pooled odds ratios(ORs) with 95% confidence intervals (CIs) were calculated using a random effect model. Results A total of 28 literatures were included. The result of analysis showed that BsmI and ApaI polymorphism were the susceptibility gene for T 1DM in Asian populations [B vs b;OR(95% CI)=1.53(1.06~2.20) ,P=0.024 ;AA vs aa:OR(95% CI)=1.60(1.06~2.40) ,P= 0.023]. Conclusion The BsmI and ApaI polymorphism may be susceptibility gene in Asians populations with T1DM.
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Objective: To investigate the effects of berberine on lipids metabolism of hyper-lipidemic rabbits and to explore whether its mechanism was involved in the vitamin D receptor (VDR) gene and insulin-induced gene 2 (Insig-2) gene expressions in adipose. Methods: Forty male New Zealand white rabbits were randomly divided into five groups: normal diet (ND), high-fat diet (HFD); high-fat diet + pretreatments of either Fenofibrate (30 mg/kg) or berberine low dose (28 mg/kg, BLD), and berberine high dose (112 mg/kg, BHD) groups. The serum TC, TG, LDL-C, HDL-C, ApoA1, ApoB, and LPa in each different treated rabbit group were determined after 8-week administration. The mRNA expressions of VDR and Insig-2 in adipose tissue were quantified by RT-PCR. Results: Compared with normal diet group, the serum TC, TG, LDL-C, ApoB, and LPa in high fat diet group obviously elevated (P < 0.05), while ApoA1 obviously descend (P < 0.05). Compared with the high fat diet group, the levels of serum TC, TG, LDL-C, ApoB, and LPa in berberine treated group were significantly decreased (P < 0.05), while ApoA1 was elevated obviously (P < 0.05). The result of RT-PCR demonstrated that the mRNA expressions of VDR and Insig-2 in high fat diet group were significantly higher than those of the normal diet group (P < 0.05), and the VDR and Insig-2 mRNA expressions were significantly up-regulated by berberine (P < 0.05), especially in BLD. Conclusion: Berberine could significantly decrease the levels of blood lipids of the hyperlipidemic rabbits, the mechanism may be related to elevating the expressions of VDR and Insig-2 gene.