Nanjing University of Chinese Medicine.
Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University.
Biol Pharm Bull. 2020 Jan 1;43(1):145-152. doi: 10.1248/bpb.b19-00725. Epub 2019 Oct 30.
Schisandra chinensis is widely used and effective in protecting liver. There are many mechanisms of drug-induced hepatocyte injury, among which endoplasmic reticulum (ER) stress-induced cell injury plays an important role. However, little is known about whether schisandra chinensis can inhibit rifampicin (RFP)-induced hepatocyte injury by affecting ER stress. In our study, firstly, L02 cells were treated with different concentrations of RFP for different time intervals, and the apoptosis, survival rate and endoplasmic reticulum stress gene and protein expressions of glucose-regulated protein 78 (GRP 78), PKR-like ER kinase (PERK), activating transcription factor (ATF)4, C/EBP-homologus protein (CHOP), ATF6, arginine-rich, mutated in early stage tumors (ARMET), p-inositol-requiring enzyme 1 (IRE1) and X-box binding protein 1 (XBP-1) were measured. We found that RFP increased apoptosis of L02 cells, decreased cell survival, and increased the gene and protein expression levels of GRP78, PERK, ATF4, CHOP, ATF6, ARMET, p-IRE1 and XBP-1, suggesting that RFP could induce hepatocyte injury, and the degree of injury was positively correlated with the dose and time of RFP. Next, we treated RFP-damaged hepatocytes with schizandrin B. We found that schizandrin B increased cell survival rate in dose-dependent and time-dependent manner, decreased cell apoptosis rate, and reduced protein and gene expression levels of GRP78, PERK, ATF4, CHOP, ATF6, ARMET and XBP-1. These results indicate that schizandrin B alleviates RFP-induced injury in L02 cells by inhibiting ER stress.
五味子在护肝方面应用广泛且效果显著。药物诱导的肝细胞损伤有多种机制，其中内质网（ER）应激诱导的细胞损伤起着重要作用。然而，五味子是否可以通过影响 ER 应激来抑制利福平（RFP）诱导的肝细胞损伤还知之甚少。在我们的研究中，首先，用不同浓度的 RFP 处理 L02 细胞不同时间间隔，测量葡萄糖调节蛋白 78（GRP 78）、PKR 样内质网激酶（PERK）、激活转录因子 4（ATF4）、C/EBP 同源蛋白（CHOP）、内质网跨膜蛋白 6（ATF6）、富含精氨酸、早期肿瘤中突变的（ARMET）、p-肌醇需要酶 1（IRE1）和 X 盒结合蛋白 1（XBP-1）的基因和蛋白表达。结果发现 RFP 增加了 L02 细胞的凋亡，降低了细胞存活率，并增加了 GRP78、PERK、ATF4、CHOP、ATF6、ARMET、p-IRE1 和 XBP-1 的基因和蛋白表达水平，表明 RFP 可以诱导肝细胞损伤，损伤程度与 RFP 的剂量和时间呈正相关。接下来，我们用五味子乙素处理 RFP 损伤的肝细胞。结果发现，五味子乙素呈剂量和时间依赖性地增加细胞存活率，降低细胞凋亡率，并降低 GRP78、PERK、ATF4、CHOP、ATF6、ARMET 和 XBP-1 的蛋白和基因表达水平。这些结果表明，五味子乙素通过抑制 ER 应激缓解 RFP 诱导的 L02 细胞损伤。
