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多叶重楼皂苷 VI 通过 Fas 死亡途径和线粒体依赖性途径诱导 HepaRG 细胞系细胞凋亡的分子机制。

Molecular Mechanisms of Apoptosis in HepaRG Cell Line Induced by Polyphyllin VI via the Fas Death Pathway and Mitochondrial-Dependent Pathway.

机构信息

School of Chinese Materia Medica, Beijing University of Traditional Chinese Medicine, Beijing 100102, China.

School of Pharmacy, Inner Mongolia Medical University, Hohhot 010110, China.

出版信息

Toxins (Basel). 2018 May 15;10(5):201. doi: 10.3390/toxins10050201.

Abstract

Polyphyllin VI, which is an active saponin, is mainly isolated from traditional medicinal plant , which causes liver damage in rats. In the present study, we aimed to explore the potential cytotoxicity of polyphyllin VI on the growth of HepaRG cells and to determine the molecular mechanism. The results revealed that polyphyllin VI changed cell morphology and induced apoptosis in HepaRG cells. Flow cytometric assay displayed that polyphyllin VI promoted the generation of reactive oxygen species (ROS), depolarized the mitochondrial membrane potential (MMP), and induced S phase cell cycle arrest by decreasing the expression of cyclin A2 and CDK2, while significantly increasing the expression of p21 protein. Polyphyllin VI induced the release of cytochrome c from the mitochondria to the cytosol and activated Fas, caspase-3, -8, -9, and PARP proteins. Pretreatment with NAC and Z-VAD-FMK (ROS scavenger and caspase inhibitor, respectively) on HepaRG cells increased the percentage of viable cells, which indicated that polyphyllin VI induced cell apoptosis through mitochondrial pathway by the generation of ROS and Fas death-dependent pathway. All of the effects are in dose- and time-dependent manners. Taken together, these findings emphasize the necessity of risk assessment to polyphyllin VI and offer an insight into polyphyllin VI-induced apoptosis of HepaRG cells.

摘要

重楼皂苷 VI 是一种活性皂甙,主要从传统药用植物中分离得到,会导致大鼠肝损伤。在本研究中,我们旨在探讨重楼皂苷 VI 对 HepaRG 细胞生长的潜在细胞毒性作用,并确定其分子机制。结果表明,重楼皂苷 VI 改变 HepaRG 细胞的形态并诱导其凋亡。流式细胞术检测显示,重楼皂苷 VI 通过增加活性氧(ROS)的产生、使线粒体膜电位(MMP)去极化以及降低 cyclin A2 和 CDK2 的表达、同时显著增加 p21 蛋白的表达,诱导 S 期细胞周期停滞。重楼皂苷 VI 诱导细胞色素 c 从线粒体释放到细胞质,并激活 Fas、caspase-3、-8、-9 和 PARP 蛋白。用 NAC 和 Z-VAD-FMK(ROS 清除剂和 caspase 抑制剂)预处理 HepaRG 细胞,增加了活细胞的百分比,表明重楼皂苷 VI 通过产生 ROS 和 Fas 死亡依赖途径诱导细胞通过线粒体途径发生凋亡。所有这些作用均呈剂量和时间依赖性。总之,这些发现强调了对重楼皂苷 VI 进行风险评估的必要性,并深入了解了重楼皂苷 VI 诱导 HepaRG 细胞凋亡的机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c757/5983257/f59e2eaa8e97/toxins-10-00201-g001.jpg

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