泽泻提取物通过激活法尼醇 X 受体发挥逆转胆汁淤积作用。
Alisma orientale extract exerts the reversing cholestasis effect by activation of farnesoid X receptor.
机构信息
College of Pharmacy, College (Institute) of Integrative Medicine, Dalian Medical University, No. 9, South Road of Lvshun, Dalian 116044, China.
College of Pharmacy, College (Institute) of Integrative Medicine, Dalian Medical University, No. 9, South Road of Lvshun, Dalian 116044, China.
出版信息
Phytomedicine. 2018 Mar 15;42:34-42. doi: 10.1016/j.phymed.2018.03.017. Epub 2018 Mar 8.
BACKGROUND
Cholestasis is a clinical syndrome of liver damage that is caused by accumulation of bile acids in the liver and systemic circulation. Farnesoid X receptor (FXR) can regulate synthesis, metabolism, and excretion of bile acids. The rhizomes of Alisma orientale is a well-known traditional Chinese medicine to treat edema, obesity, gonorrhea, leukorrhea, diarrhea, hyperlipidemia, and diabetes in China.
HYPOTHESIS/PURPOSE: We hypothesized Alisma orientale extract (AOE) to exert hepatoprotective effect against α-naphthylisothiocyanate (ANIT) induced cholestasis in rat. We aimed to investigate the mechanism of AOE.
STUDY DESIGN
Male Sprague Dawley rats with intrahepatic cholestasis induced by ANIT were treated with AOE (150, 300, or 600 mg/kg). Rats receiving vehicle (0.5% CMC-Na) served as control.
METHODS
48 h after ANIT administration, rats were sacrificed. Blood was collected to obtain serum and livers were removed for histopathology and protein preparation. Biochemical indicators in serum were determined using commercial kits and triterpenoids were determined by liquid chromatography tandem Qtrap mass spectrometry. Proteomics was analyzed by liquid chromatography tandem ion-trap mass spectrometry. The differently expressed proteins were analyzed via the network database and verified by western blotting. The interaction between triterpenoids and FXR were evaluated by luciferase assay and molecular docking.
RESULTS
AOE treatment significantly decreased the serum AST, ALT, TBIL, and intrahepatic TBA and improved the liver pathologic change induced by ANIT. Proteomics analysis indicated that AOE regulated proteins related to bile acid homeostasis via activating farnesoid X receptor (FXR) signaling pathway. Luciferase assay and molecular docking results indicated that triterpenoids could activate FXR, which resulting in ameliorative accumulation of bile acids in the liver by increase of metabolism and transportation for bile acids, and decrease of synthesis for bile acids.
CONCLUSION
AOE protected against rat liver injury and cholestasis induced by ANIT by activation of farnesoid X receptor, suggesting that A. orientale could be regarded as a potential hepatoprotective drug.
背景
胆汁淤积是一种临床肝损伤综合征，其特征是胆汁酸在肝脏和全身循环中积累。法尼醇 X 受体（FXR）可以调节胆汁酸的合成、代谢和排泄。泽泻是中国传统医学中治疗水肿、肥胖、淋病、白带、腹泻、高脂血症和糖尿病的一种著名中药。
假说/目的：我们假设泽泻提取物（AOE）对α-萘基异硫氰酸酯（ANIT）诱导的大鼠胆汁淤积具有肝保护作用。我们旨在研究 AOE 的作用机制。
研究设计
用 ANIT 诱导肝内胆汁淤积的雄性 Sprague Dawley 大鼠用 AOE（150、300 或 600mg/kg）治疗。接受载体（0.5% CMC-Na）的大鼠作为对照。
方法
ANIT 给药后 48 小时，处死大鼠。采集血液以获得血清，并取出肝脏进行组织病理学和蛋白质制备。使用商业试剂盒测定血清中的生化指标，并通过液相色谱串联 Qtrap 质谱法测定三萜类化合物。通过液相色谱串联离子阱质谱法进行蛋白质组学分析。通过网络数据库分析差异表达的蛋白质，并通过 Western blot 进行验证。通过荧光素酶测定和分子对接评估三萜类化合物与 FXR 的相互作用。
结果
AOE 治疗可显著降低血清 AST、ALT、TBIL 和肝内 TBA，并改善 ANIT 引起的肝病理变化。蛋白质组学分析表明，AOE 通过激活法尼醇 X 受体（FXR）信号通路调节与胆汁酸稳态相关的蛋白质。荧光素酶测定和分子对接结果表明，三萜类化合物可以激活 FXR，从而通过增加胆汁酸的代谢和转运以及减少胆汁酸的合成来改善肝脏中胆汁酸的积累。
结论
AOE 通过激活法尼醇 X 受体，防止 ANIT 诱导的大鼠肝损伤和胆汁淤积，表明泽泻可作为一种有潜力的肝保护药物。
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