BACKGROUND Hepatic fibrosis is a serious condition,and the development of hepatic fibrosis can lead to a series of complications.However,the pathogenesis of hepatic fibrosis remains unclear,and effective therapy optio...BACKGROUND Hepatic fibrosis is a serious condition,and the development of hepatic fibrosis can lead to a series of complications.However,the pathogenesis of hepatic fibrosis remains unclear,and effective therapy options are still lacking.Our group identified hepatitis C virus nonstructural protein 3-transactivated protein 1(NS3TP1) by suppressive subtractive hybridization and bioinformatics analysis,but its role in diseases including hepatic fibrosis remains undefined.Therefore,additional studies on the function of NS3TP1 in hepatic fibrosis are urgently needed to provide new targets for treatment.AIM To elucidate the mechanism of NS3TP1 in hepatic fibrosis and the regulatory effects of calcitriol on NS3TP1.METHODS Twenty-four male C57BL/6 mice were randomized and separated into three groups,comprising the normal,fibrosis,and calcitriol treatment groups,and liver fibrosis was modeled by carbon tetrachloride(CCl4).To evaluate the level of hepatic fibrosis in every group,serological and pathological examinations of the liver were conducted.TGF-β1 was administered to boost the in vitro cultivation of LX-2 cells.NS3TP1,α-smooth muscle actin(α-SMA),collagen I,and collagen Ⅲ in every group were examined using a Western blot and real-time quantitative polymerase chain reaction.The activity of the transforming growth factor beta 1(TGFβ1)/Smad3 and NF-κB signaling pathways in each group of cells transfected with pcDNA-NS3TP1 or siRNA-NS3TP1 was detected.The statistical analysis of the data was performed using the Student’s t test.RESULTS NS3TP1 promoted the activation,proliferation,and differentiation of hepatic stellate cells(HSCs)and enhanced hepatic fibrosis via the TGFβ1/Smad3 and NF-κB signaling pathways,as evidenced by the presence of α-SMA,collagen I,collagen Ⅲ,p-smad3,and p-p65 in LX-2 cells,which were upregulated after NS3TP1 overexpression and downregulated after NS3TP1 interference.The proliferation of HSCs was lowered after NS3TP1 interference and elevated after NS3TP1 overexpression,as shown by the luciferase assay.NS3TP1 inhibited the apoptosis of HSCs.Moreover,both Smad3 and p65 could bind to NS3TP1,and p65 increased the promoter activity of NS3TP1,while NS3TP1 increased the promoter activity of TGFβ1 receptor I,as indicated by coimmunoprecipitation and luciferase assay results.Both in vivo and in vitro,treatment with calcitriol dramatically reduced the expression of NS3TP1.Calcitriol therapy-controlled HSCs activation,proliferation,and differentiation and substantially suppressed CCl4-induced hepatic fibrosis in mice.Furthermore,calcitriol modulated the activities of the above signaling pathways via downregulation of NS3TP1.CONCLUSION Our results suggest that calcitriol may be employed as an adjuvant therapy for hepatic fibrosis and that NS3TP1 is a unique,prospective therapeutic target in hepatic fibrosis.展开更多
激素性股骨头坏死(steroid-induced osteonecrosis of the femoral head,SIONFH)是由于糖皮质激素使用不当或过度而引起的髋关节疾病,发病机制尚未统一,临床疗效亦不佳。当前,没有效果明确的药物可以延缓疾病进程,而中医药治疗SIONFH在...激素性股骨头坏死(steroid-induced osteonecrosis of the femoral head,SIONFH)是由于糖皮质激素使用不当或过度而引起的髋关节疾病,发病机制尚未统一,临床疗效亦不佳。当前,没有效果明确的药物可以延缓疾病进程,而中医药治疗SIONFH在临床上取得一定疗效。即便如此,仍未能完整的从分子生物及细胞生物学角度阐明中药治疗SIONFH的作用机制。转化生长因子-β(TGF-β)/骨形态发生蛋白(BMP)/Smad信号通路的转导是防治SIONFH的研究热点之一,故该文阐明了该信号通路的转导机制以及与SIONFH的联系,检索了基于该通路治疗SIONFH的全部中药及复方并阐述其影响机制。基于中医对SIONFH的认识,现临床上使用补肝肾强筋骨以及活血祛瘀通络类的方药治疗SIONFH,且具有良好的疗效。中药通过调控该通路,可刺激骨髓间充质干细胞成骨分化,降低破骨细胞含量,减少脂肪生成,改善微循环,抗氧化损伤,促进股骨头内血管新生,从而促进股骨头损伤的修复。现基于TGF-β/BMP/Smad信号通路对中医药治疗SIONFH的研究进展做一综述,期许为中医药治疗SIONFH提供理论依据及参考。展开更多
基金the National Key Research and Development Program of China,No.2017YFC0908104National Science and Technology Projects,No.2017ZX10203201,No.2017ZX10201201,and No.2017ZX10202202.
文摘BACKGROUND Hepatic fibrosis is a serious condition,and the development of hepatic fibrosis can lead to a series of complications.However,the pathogenesis of hepatic fibrosis remains unclear,and effective therapy options are still lacking.Our group identified hepatitis C virus nonstructural protein 3-transactivated protein 1(NS3TP1) by suppressive subtractive hybridization and bioinformatics analysis,but its role in diseases including hepatic fibrosis remains undefined.Therefore,additional studies on the function of NS3TP1 in hepatic fibrosis are urgently needed to provide new targets for treatment.AIM To elucidate the mechanism of NS3TP1 in hepatic fibrosis and the regulatory effects of calcitriol on NS3TP1.METHODS Twenty-four male C57BL/6 mice were randomized and separated into three groups,comprising the normal,fibrosis,and calcitriol treatment groups,and liver fibrosis was modeled by carbon tetrachloride(CCl4).To evaluate the level of hepatic fibrosis in every group,serological and pathological examinations of the liver were conducted.TGF-β1 was administered to boost the in vitro cultivation of LX-2 cells.NS3TP1,α-smooth muscle actin(α-SMA),collagen I,and collagen Ⅲ in every group were examined using a Western blot and real-time quantitative polymerase chain reaction.The activity of the transforming growth factor beta 1(TGFβ1)/Smad3 and NF-κB signaling pathways in each group of cells transfected with pcDNA-NS3TP1 or siRNA-NS3TP1 was detected.The statistical analysis of the data was performed using the Student’s t test.RESULTS NS3TP1 promoted the activation,proliferation,and differentiation of hepatic stellate cells(HSCs)and enhanced hepatic fibrosis via the TGFβ1/Smad3 and NF-κB signaling pathways,as evidenced by the presence of α-SMA,collagen I,collagen Ⅲ,p-smad3,and p-p65 in LX-2 cells,which were upregulated after NS3TP1 overexpression and downregulated after NS3TP1 interference.The proliferation of HSCs was lowered after NS3TP1 interference and elevated after NS3TP1 overexpression,as shown by the luciferase assay.NS3TP1 inhibited the apoptosis of HSCs.Moreover,both Smad3 and p65 could bind to NS3TP1,and p65 increased the promoter activity of NS3TP1,while NS3TP1 increased the promoter activity of TGFβ1 receptor I,as indicated by coimmunoprecipitation and luciferase assay results.Both in vivo and in vitro,treatment with calcitriol dramatically reduced the expression of NS3TP1.Calcitriol therapy-controlled HSCs activation,proliferation,and differentiation and substantially suppressed CCl4-induced hepatic fibrosis in mice.Furthermore,calcitriol modulated the activities of the above signaling pathways via downregulation of NS3TP1.CONCLUSION Our results suggest that calcitriol may be employed as an adjuvant therapy for hepatic fibrosis and that NS3TP1 is a unique,prospective therapeutic target in hepatic fibrosis.
文摘激素性股骨头坏死(steroid-induced osteonecrosis of the femoral head,SIONFH)是由于糖皮质激素使用不当或过度而引起的髋关节疾病,发病机制尚未统一,临床疗效亦不佳。当前,没有效果明确的药物可以延缓疾病进程,而中医药治疗SIONFH在临床上取得一定疗效。即便如此,仍未能完整的从分子生物及细胞生物学角度阐明中药治疗SIONFH的作用机制。转化生长因子-β(TGF-β)/骨形态发生蛋白(BMP)/Smad信号通路的转导是防治SIONFH的研究热点之一,故该文阐明了该信号通路的转导机制以及与SIONFH的联系,检索了基于该通路治疗SIONFH的全部中药及复方并阐述其影响机制。基于中医对SIONFH的认识,现临床上使用补肝肾强筋骨以及活血祛瘀通络类的方药治疗SIONFH,且具有良好的疗效。中药通过调控该通路,可刺激骨髓间充质干细胞成骨分化,降低破骨细胞含量,减少脂肪生成,改善微循环,抗氧化损伤,促进股骨头内血管新生,从而促进股骨头损伤的修复。现基于TGF-β/BMP/Smad信号通路对中医药治疗SIONFH的研究进展做一综述,期许为中医药治疗SIONFH提供理论依据及参考。
