Dihydroartemisinin Prevents Liver Fibrosis in Bile Duct Ligated Rats by Inducing Hepatic Stellate Cell Apoptosis through Modulating the PI3K/Akt Pathway
Dihydroartemisinin Prevents Liver Fibrosis in Bile Duct Ligated Rats by Inducing Hepatic Stellate Cell Apoptosis through Modulating the PI3K/Akt Pathway
复制标题
双氢青蒿素通过调节 PI3K/Akt 通路诱导肝星状细胞凋亡预防胆管结扎大鼠肝纤维化
DOI：
10.1002/iub.1478
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发表时间：
2016-03-01
期刊：
影响因子：
4.6
通讯作者：
Zheng, Shizhong
中科院分区：
文献类型：
--
作者：
Chen, Qin;Chen, Lianyun;Zheng, Shizhong
作为慢性损伤后的一种常见事件，肝纤维化会触发伤口愈合反应，细胞外基质成分在肝脏中积累。在肝纤维化形成过程中，肝星状细胞(HSCs)的激活是关键事件。肝纤维化消退可通过药物诱导HSC凋亡来治疗。在此，我们发现双氢青蒿素(DHA)改善了肝组织结构，降低了肝酶水平，并抑制了肝纤维化大鼠肝脏中HSCs的激活。α-SMA阳性细胞分布减少，体内存在大量裂解的Caspase3阳性细胞，Bcl2表达下调，bax表达上调。此外，体外实验表明，DHA显著抑制HSC的增殖，并导致HSC的形态发生显著变化。我们发现DHA破坏了HSCs的线粒体功能，并导致caspase级联激活。机制研究表明，DHA通过破坏PI3K/Akt通路诱导HSC凋亡，PI3K特异性抑制剂LY294002可模拟DHA的促凋亡作用。DHA是防治肝纤维化的一种有前景的候选药物。©2016 IUBMB Life，68(3)：220-231,2016
As a frequent event following chronic insult, liver fibrosis triggers wound healing reactions, with extracellular matrix components accumulated in the liver. During liver fibrogenesis, activation of hepatic stellate cells (HSCs) is the pivotal event. Fibrosis regression can feasibly be treated through pharmacological induction of HSC apoptosis. Herein we showed that dihydroartemisinin (DHA) improved liver histological architecture, decreased hepatic enzyme levels, and inhibited HSCs activation in the fibrotic rat liver. DHA also induced apoptosis of HSCs in such liver, as demonstrated by reduced distribution of α‐SMA‐positive cells and the presence of high number of cleaved‐caspase‐3‐positive cells in vivo, as well as by down‐regulation of Bcl‐2 and up‐regulation of Bax. In addition, in vitro experiments showed that DHA significantly inhibited HSC proliferation and led to dramatic morphological alterations in HSCs. we found that DHA disrupted mitochondrial functions and led to activation of caspase cascades in HSCs. Mechanistic investigations revealed that DHA induced HSC apoptosis through disrupting the phosphoinositide 3‐kinase (PI3K)/Akt pathway and that PI3K specific inhibitor LY294002 mimicked the pro‐apoptotic effect of DHA. DHA is a promising candidate for the prevention and treatment of liver fibrosis. © 2016 IUBMB Life, 68(3):220–231, 2016