Weng Zhiyong, Liu Xuefeng, Hu Jiehua, Mu Jingzhou, Xie Jing, Yao Chenjuan, Li Lihua
Department of Cell Biology, Jinzhou Medical University, Jinzhou, PR China.
Naval University of Engineering, Logistics College, Information Center, Tianjin, PR China.
Oncotarget. 2017 Sep 23;8(50):87903-87913. doi: 10.18632/oncotarget.21233. eCollection 2017 Oct 20.
Dehydroandrographolide (DA) is the main contributor to the therapeutic properties of the medicinal plant Andrographis paniculata (AP). However, it is unknown whether DA has a hepatoprotective effect on obstructive cholestasis in mice and humans.
We administered DA to mice for 5 days prior to bile duct ligation (BDL) and for the 7 days. Liver function markers, liver histology and necrosis, compensatory responses of hepatocytes, liver fibrosis and the expression of hepatic fibrogenesis markers were evaluated in BDL mice and/or human LX-2 cells.
Mice treated with DA demonstrated lower levels of serum alanine transarninase (ALT), milder liver damage, liver necrosis and fibrosis formation than in vehicle control with carboxymethylcellulose (CMC) mice after BDL. DA treatment also enhanced the Mrp3 expression of hepatocytes but not Mrp4 following BDL. Further, DA treatment in BDL mice significantly reduced liver mRNA and/or protein expression of Tgf-β, Col1a1, α-Sma and Mmp2. This result was also supported by hydroxyproline analysis. The molecular mechanisms of DA treatment were also assessed in human hepatic stellate cell line (LX-2 cell). DA treatment significantly inhibited Tgf-β-induced Col1a1, Mmp2 and α-Sma expression in human LX-2 cells. These data suggested that DA treatment reduced liver damage through development of a hepatic adaptive response and inhibition of the activation of HSCs, which led to a reduction in liver fibrosis formation in BDL mice.
DA treatment protected against liver damage and fibrosis following BDL and might be an effective therapy for extrahepatic cholestasis due to bile duct obstruction.
脱水穿心莲内酯（DA）是药用植物穿心莲（AP）治疗特性的主要贡献成分。然而，DA对小鼠和人类梗阻性胆汁淤积是否具有肝保护作用尚不清楚。
我们在胆管结扎（BDL）前5天及结扎后7天给小鼠施用DA。对BDL小鼠和/或人LX-2细胞评估肝功能标志物、肝脏组织学和坏死情况、肝细胞的代偿反应、肝纤维化及肝纤维化标志物的表达。
与BDL后接受羧甲基纤维素（CMC）的溶剂对照组小鼠相比，接受DA治疗的小鼠血清丙氨酸转氨酶（ALT）水平较低，肝损伤、肝坏死和纤维化形成较轻。BDL后，DA治疗还增强了肝细胞的Mrp3表达，但未增强Mrp4表达。此外，BDL小鼠接受DA治疗后，肝脏中Tgf-β、Col1a1、α-Sma和Mmp2的mRNA和/或蛋白表达显著降低。羟脯氨酸分析也支持了这一结果。还在人肝星状细胞系（LX-2细胞）中评估了DA治疗的分子机制。DA治疗显著抑制了人LX-2细胞中Tgf-β诱导的Col1a1、Mmp2和α-Sma表达。这些数据表明，DA治疗通过发展肝脏适应性反应和抑制肝星状细胞激活来减少肝损伤，从而导致BDL小鼠肝纤维化形成减少。
DA治疗可预防BDL后的肝损伤和纤维化，可能是治疗胆管梗阻所致肝外胆汁淤积症的有效疗法。
