Many tests have shown cyclooxygenase-2 (COX-2) was closely related to the activation of hepatic stellate cells (HSCs), which further promoting the onset and development of hepatic fibrosis. According to these research findings, a series of glycyrrhetinic acid derivatives were designed and synthesized. Meanwhile, their anti-hepaticfibrotic activities were evaluated in vitro and in vivo. Firstly, in the tests of the cell models, all the compounds displayed anti-proliferative effect on the HSC-T6 activated by (transforming growth factor beta) TGF-β1 (10 ng/mL). Among them, compounds 2 and 16 exhibited a stronger activity than the others, and their IC50 values were 17.6 µM and 30.3 µM, respectively; both of them were low toxicity to normal HSC-T6 cells and WI38 cells, and they inhibited the activated HSC-T6 cells proliferation by promoting apoptosis and resting them at the G0/G1 phase. Secondly, compounds 2 and 16 displayed strong inhibitory effect on activation of HSCs; they not only inhibited the expression of α-SMA and Col1 in the activated HSC-T6 cells, but also decreased the levels of COX-2, TGF-β1 and (reactive oxygen species) ROS in a concentration-dependent manner; they down-regulated the levels of three biomarkers in the process of test, but this decrease did not change linearly with the action time of compound. Thirdly, for the rats which induced with (carbontetrachloride) CCl4, the symptoms of liver fibrosis in rats were significantly alleviated after successive administration the tested compound for 14d; the α-SMA level in liver tissue decreased in a concentration dependent manner; and the liver cell necrosis and the fat collagen fiber decreased significantly compared with the positive control group; furthermore, inflammatory infiltration was significantly lower than that of the control. This suggests the compounds possibly are candidates for hepatic fibrosis with promising application in clinic.

中文翻译：

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抑制COX-2的甘草次酸衍生物的合成及其抗肝纤维化作用。

许多测试表明，环氧合酶2（COX-2）与肝星状细胞（HSC）的激活密切相关，后者进一步促进了肝纤维化的发生和发展。根据这些研究结果，设计并合成了一系列甘草次酸衍生物。同时，在体外和体内评估了它们的抗肝纤维化活性。首先，在细胞模型测试中，所有化合物均对由（转化生长因子β）TGF-β1（10 ng / mL）激活的HSC-T6表现出抗增殖作用。其中，化合物2和16表现出比其他化合物更强的活性，它们的IC50值分别为17.6 µM和30.3 µM。它们对正常的HSC-T6细胞和WI38细胞均具有低毒性，它们通过促进细胞凋亡并使它们停留在G0 / G1期来抑制活化的HSC-T6细胞的增殖。其次，化合物2和16对HSC的活化显示出强大的抑制作用。它们不仅抑制α-SMA和Col1在活化的HSC-T6细胞中的表达，而且以浓度依赖的方式降低COX-2，TGF-β1和（活性氧）ROS的水平。他们在测试过程中下调了三种生物标志物的水平，但这种下降并没有随着化合物的作用时间线性变化。第三，对于用（四氯化碳）CCl 4诱导的大鼠，连续施用受试化合物14天后，大鼠的肝纤维化症状得到明显减轻。肝组织中的α-SMA水平以浓度依赖性方式降低；肝细胞坏死和脂肪胶原纤维较阳性对照组明显减少。此外，炎性浸润明显低于对照。这表明该化合物可能是肝纤维化的候选药物，有望在临床上应用。