基于网络药理学和动物实验探讨大黄-柴胡药对治疗酒精性肝病的作用及机制

Effect and mechanism of Rhei radix et Rhizoma-Bupleuri radix drug pair for alcoholic liver disease basedupon network pharmacology and animal experiments

目的:探讨大黄-柴胡药对治疗酒精性肝病(alcoholic liver disease,ALD)的作用及机制。方法:通过网络药理学方法预测大黄-柴胡药对治疗ALD的靶点和通路。灌胃56°白酒复制大鼠ALD模型,各药物组灌胃给予中药煎煮液干预7 d后,检测各组药物对大鼠血清中乙醇浓度,及乙醇脱氢酶(alcohol dehydrogenase,ADH)、乙醛脱氢酶(acetaldehyde dehydrogenase,ALDH)活性的影响,采用HE和油红O染色方法考察各组药物对大鼠肝脏病理形态的影响,检测大鼠血清或肝匀浆中ALT、AST、TG、TC、VLDL、SOD、MDA水平。结果:网络药理学分析共得到大黄-柴胡药对活性成分36个,治疗ALD的靶点218个,核心靶点涉及TP53、MAPK1、AKT1、TNF、CYP2E1、PPARα、ADH、ALDH等。其作用可能与lipid and atherosclerosis、PI3K-Akt signaling pathway、MAPK signaling pathway、TNF signaling pathway、ALD等信号通路相关。与模型组比较,大黄-柴胡药对能明显改善大鼠肝脏病理变化,显著降低大鼠血乙醇浓度(P<0.05),增强血清ADH和ALDH活性(P<0.05),减弱血清AST和ALT活性(P<0.05,P<0.01),降低血清TG和VLDL含量(P<0.05),降低肝脏中TC、TG、VLDL含量(P<0.05,P<0.01),降低MDA含量(P<0.05),升高SOD含量(P<0.01)。结论:大黄-柴胡药对具有治疗大鼠ALD的作用,其机制可能是通过调控PI3K-Akt、MAPK、ALD等信号通路,作用于ADH、ALDH等靶点,进而加速乙醇、乙醛代谢,减少脂肪堆积、减轻氧化损伤等。

OBJECTIVE To explore the effect and mechanism of Dahuang(Rhei radix et Rhizoma,RRR)-Chaihu(Bupleuri radix,BR)drug pair for alcoholic liver disease(ALD).METHODS The targets and pathways of RRR-BR herb pair for ALD were predicted by network pharmacology.ALD model of rats was established by an intragastric injection of 56°liquor.After 7-day intervention with traditional Chinese medicine decoction,the effects of each group on ethanol concentration and serum activities of alcohol dehydrogenase(ADH)and acetaldehyde dehydrogenase(ALDH)were detected.The effects of each dosing group on hepatic pathological morphology were examined by hematoxylin-eosin(HE)and oil red O stain.The levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),triglyceride(TG),total cholesterol(TC),very low-density lipo⁃protein(VLDL),reactive oxygen species(SOD)and malondialdehyde(MDA)in sera or liver homogenate of rats were detected.RESULTS A total of 36 active components and 218 targets for treating ALD were obtained by network pharmacology analysis.The core targets involved TP53, MAPK1, AKT1, TNF, CYP2E1, PPARα, ADH and ALDH. Its effect might be correlatedwith lipid and atherosclerosis, signaling pathways of PI3K-Akt, MAPK & TNF, ALD and other signaling pathways. As com⁃pared with model group, RRR-BR herb pair could significantly improve the pathological changes of rat liver, significantly reduceblood ethanol concentration (P<0. 05), enhance the serum activity of ADH/ALDH (P<0. 05), blunt the serum activity ofAST/ALT( P<0. 05, P<0. 01), decrease the serum contents of TG/VLDL( P<0. 05), reduce the hepatic contents of TC,TG and VLDL (P<0. 05, P<0. 01), lower the content of MDA (P<0. 05) and boost the content of SOD (P<0. 01).CONCLUSION RRR-BR drug pair has the effect of treating ALD in rats. Its mechanism may be correlated with the regulationof PI3K-Akt, MAPK, ALD and other signaling pathways, acting on ADH, ALDH and other targets, thereby accelerating etha⁃nol and acetaldehyde metabolism, blunting fat accumulation and minimizing oxidative damage.