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Title: [Therapeutic efficacy and mechanism of action of ginsenoside Rg1 in treating acute hepatic failure in mice].
Author: Luo H, Huang WX, Yang C, Zhao JQ, Liu S, Xu YS, Liu CW.
Journal: Zhonghua Gan Zang Bing Za Zhi; 2017 Mar 20; 25(3):217-222. PubMed ID: 28482410.
Abstract:
Objective: To examine the regulatory effect of ginsenoside Rg1 (G-Rg1) on endoplasmic reticulum stress and its effect on hepatocellular apoptosis in carbon tetrachloride (CCl(4))-induced acute liver failure (ALF). Methods: Forty healthy, adult male C57/BL mice were randomly divided into normal saline control (NS) group, G-Rg1 blank control (G-Rg1) group, CCl(4) model (CCl(4)) group, and G-Rg1 preventive treatment (CCl(4)+G-Rg1) group, and an ALF mouse model was established by CCl(4) induction. Blood and liver specimens were collected from all mice upon sacrifice at 12 hours post-intraperitoneal injection. Serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST) and total bilirubin (TBil) levels were determined using commercial test kits. The mRNA expression of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) was measured using real-time PCR. The protein expression of GRP78, CHOP, caspase12, and caspase3 were measured by Western blot. Histological changes in the liver were assessed by hematoxylin-eosin staining, and the expression of GRP78 and caspase3 was detected by immunohistochemistry. Hepatocyte apoptosis was determined using terminal transferase dUTP nick end labeling. Quantitative data were analyzed using one-way ANOVA, and subsequent pairwise comparisons were performed using the LSD-t method. Results: Serum ALT, AST, and TBil levels in the CCl(4)+G-Rg1 group were significantly reduced compared with those in the CCl(4) group (ALT: 691.30 ± 108.06 U/L vs 980.66 ± 110.29 U/L, F = 365.07, P < 0.05; AST: 195.40 ± 15.41 U/L vs 319.44 ± 89.32 U/L, F = 115.64, P < 0.05; TBil: 1.09 ± 0.11 mg/dl vs 1.56 ± 0.12 mg/dl, F = 211.29, P < 0.05). The relative mRNA expression of GRP78 and CHOP was significantly lower in the CCl(4) + G-Rg1 group than in the CCl(4) group (P < 0.05). The relative protein expression of caspase3, GRP78, caspase12, and CHOP was significantly reduced to different extents in the CCl(4)+G-Rg1 group compared with those in the CCl4 group (P < 0.05). The CCl(4) + G-Rg1 group showed reduced liver tissue degeneration and necrosis compared with the CCl(4) group. Furthermore, the CCl(4)+G-Rg1 group showed significantly fewer brown granules in the liver than the CCl4 group (P < 0.05), indicating that G-Rg1 preventive treatment reduced CCl(4)-induced hepatocyte apoptosis. Conclusion: G-Rg1 prophylaxis can inhibit inflammation and reduce hepatocyte necrosis and apoptosis during CCl(4)-induced ALF. Its mechanism may involve the suppression of endoplasmic reticulum stress-related signaling molecules to alleviate hepatocyte endoplasmic reticulum stress and apoptosis. The results of this study suggest that G-Rg1 may inhibit liver inflammation and hepatocyte apoptosis through multiple targets to protect liver function. 目的： 在四氯化碳（CCl(4)）诱导的急性肝衰竭模型中，人参皂苷Rg1（G-Rg1）对内质网应激的调节作用，以及对肝细胞凋亡的影响。 方法： 将40只健康成年C57/BL雄性小鼠随机分为等渗盐水对照（NS）组，G-Rg1空白对照（G-Rg1）组，CCl(4)模型（CCl(4)）组，G-Rg1预防治疗（CCl(4)+G-Rg1）组，并建立CCl(4)小鼠急性肝衰竭模型。建模12 h后，分别采集各组小鼠血清和肝脏组织，用试剂盒法检测血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、总胆红素（TBil）水平；定量PCR法检测肝脏葡萄糖调节蛋白78（GRP78）、C/EBP家族同源蛋白（CHOP）的表达量；Western blot检测GRP78、CHOP、半胱氨酸蛋白酶12（caspase12）、caspase3的表达情况；HE染色评价肝脏组织病理学改变；免疫组织化学法分析GRP78、caspase3的表达情况；TUNEL法检测肝脏组织细胞凋亡情况。计量数据进行单因素方差分析，进一步两两比较采用LSD-t法。 结果： NS组、G-Rg1组、CCl(4)组、CCl(4)+G-Rg1组ALT值分别为（50.12±9.25）U/L、（40.48± 6.38）U/L、（980.66±110.29）U/L和（691.30±108.06）U/L，F = 365.07，P < 0.05；AST值分别为（9.69±2.78）U/L、（9.40±3.84）U/L、（319.44±89.32）U/L和（195.40±15.41）U/L，F = 115.64, P < 0.05；TBil值分别为（0.46±0.13）mg/dl（1 mg/dl = 17.1 μmol/L）、（0.48±0.08）mg/dl、（1.56±0.12）mg/dl和（1.09±0.11）mg/dl，F = 211.29, P < 0.05，CCl(4)+G-Rg1组血清ALT、AST、TBil水平低于CCl(4)组，差异均有统计学意义。CCl(4)+G-Rg1组GRP78、CHOP的mRNA相对表达量均较CCl(4)组下降，差异均有统计学意义（F值分别为34.4、44.1，P值均< 0.05）。Western bolt结果显示CCl(4)+G-Rg1组与CCl(4)组相比，caspase3、GRP78、caspase12、CHOP蛋白相对表达量均有不同程度降低，差异有统计学意义(P值均< 0.05)。CCl(4)+G-Rg1组HE染色显示肝脏组织变性坏死较CCl(4)组轻。TUNEL结果显示CCl(4)+G-Rg1组棕色颗粒物质较CCl(4)组明显减少（F = 330.9，P < 0.05），提示G-Rg1预防治疗可以减轻CCl(4)引起的肝细胞凋亡程度。 结论： G-Rg1预防用药可抑制CCl(4)诱导的小鼠急性肝衰竭的炎症反应，同时可减轻肝细胞坏死和凋亡。其作用机制可能通过抑制内质网应激相关信号分子，改善肝细胞内质网应激进而减轻肝细胞凋亡。结合课题组之前的研究结果提示G-Rg1可能通过多个作用靶点抑制肝脏炎症反应和肝细胞凋亡，实现保护肝脏功能作用。.

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