免疫应激介导的赤芍缓解补骨脂肝脏毒性作用评价及其调控代谢网络分析

Paeoniae Rubra Radix decreases the hepatotoxicity of Psoraleae Fructus in an immunologically stressed rat model:a metabolic network analysis

本研究基于免疫应激大鼠模型,研究补骨脂与赤芍配伍前后对其特异质肝损伤作用的影响及其代谢网络调控机制。采用低剂量脂多糖(lipopolysaccharide,LPS)注射致免疫应激SD大鼠模型,分别比较补骨脂单用及补骨脂赤芍配伍给药后,模型动物肝脏谷草转氨酶(aspartate aminotransferase,AST)、谷丙转氨酶(alanine aminotransferase,ALT)的活性及肝脏病理变化;通过UHPLC-QTOF/MS分析不同组别大鼠血清代谢轮廓特征,结合主成分分析法(principal component analysis,PCA)、偏最小二乘判别分析法(orthogonal partial least squares discriminant analysis,OPLS-DA),研究补骨脂与赤芍配伍后对特异质肝损伤大鼠血清中内源性代谢产物的影响,并应用HMDB数据库及MetaboAnalyst在线通路富集工具进行生物标志物的鉴定和代谢通路富集分析。结果显示,对于LPS致免疫应激大鼠模型,补骨脂组AST、ALT均显著升高(P<0.01),肝脏切片可见明显的病理损伤,而其配伍赤芍后肝损伤作用显著降低。代谢组学分析显示赤芍主要通过调节花生四烯酸代谢和甘油磷脂代谢等信号通路改善补骨脂致肝毒性大鼠体内的血清代谢异常。

An immunologically stressed rat model was used in a metabolomics study on the ability of Paeoniae Rubra Radix to reduce the liver toxicity of Psoraleae Fructus.Different groups of rats were given the extracts of Psoraleae Fructus and Psoraleae Fructus together with Paeoniae Rubra Radix or combined with a non-toxic dose of lipopolysaccharide(LPS).The biochemical indices of liver function and pathological changes in liver tissue were used to evaluate histopathological changes.UHPLC-QTOF/MS was used to analyze the metabolic profile of serum samples,combined with principal component analysis(PCA)and orthogonal partial least squares discriminant analysis(OPLS-DA)methods.The HMDB database and Metabo Analyst online tool were used for biomarker identification and metabolic pathway-enrichment analysis.The results show that the co-treatment Psoraleae Fructus and LPS resulted in significant liver injury,indicated by the elevation of aspartate aminotransferase(AST)and alanine aminotransferase(ALT)activities,as well as obvious pathological changes.Liver injury was significantly decreased by treatment with Paeoniae Rubra Radix.Metabolomic analysis showed that the addition of Paeoniae Rubra Radix ameliorated the abnormal serum metabolism in rats mainly through regulation of arachidonic acid metabolism and glycerophospholipid metabolism pathways.