Wei Shizhang, Ma Xiao, Niu Ming, Wang Ruilin, Yang Tao, Wang Dan, Wen Jianxia, Li Haotian, Zhao Yanling
College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Department of Pharmacy, PLA General Hospital, Beijing, China.
Front Pharmacol. 2020 Oct 20;11:586806. doi: 10.3389/fphar.2020.586806. eCollection 2020.
Paeoniflorin (PF) is the main active component of Pall., which is used in the treatment of severe cholestatic hepatitis. However, its biological mechanism in regulating bile acid metabolism and cholestatic liver injury has not been fully revealed. Our study aimed to reveal the mechanism of PF in the treatment of cholestatic liver injury in an metabolic environment using bioinformatics analysis. The serum of rats with bile duct ligation (BDL)-induced cholestatic liver injury treated with PF was analyzed by UHPLC-Q-TOF, and specific metabolites were screened using a metabolomics method. These specific metabolites were further analyzed by network pharmacology to identify the upstream signaling pathways and key protein targets. Finally, the key target proteins were verified by immunohistochemistry using cholestatic rat liver tissue. The serum ALT, AST, TBA, and TBIL levels, as well as the pathological state of the liver tissues, were significantly improved by PF. Twenty-five specific metabolites and 157 corresponding target proteins were screened for the treatment of cholestatic liver injury by PF. The "PF-target-metabolite" interaction network was constructed, and five protein targets (MAP2K1, MAPK1, ILBP, ABCB1, and LTA4H) that may regulate specific metabolites were obtained. The results of immunohistochemistry showed that PF improved the expression of these proteins. The integrated application of multiple bioinformatics methods revealed that PF plays a key role in the treatment of cholestatic liver injury by intervening in important targets related to bile acid metabolism and inflammation.
芍药苷（PF）是芍药的主要活性成分，用于治疗重度胆汁淤积性肝炎。然而，其在调节胆汁酸代谢和胆汁淤积性肝损伤中的生物学机制尚未完全阐明。我们的研究旨在通过生物信息学分析揭示PF在代谢环境中治疗胆汁淤积性肝损伤的机制。采用超高效液相色谱-四极杆飞行时间质谱（UHPLC-Q-TOF）分析PF治疗胆管结扎（BDL）诱导的胆汁淤积性肝损伤大鼠的血清，并使用代谢组学方法筛选特定代谢物。通过网络药理学对这些特定代谢物进行进一步分析，以确定上游信号通路和关键蛋白靶点。最后，使用胆汁淤积大鼠肝组织通过免疫组织化学验证关键靶蛋白。PF显著改善了血清谷丙转氨酶（ALT）、谷草转氨酶（AST）、总胆汁酸（TBA）和总胆红素（TBIL）水平以及肝组织的病理状态。筛选出25种特定代谢物和157种相应的靶蛋白用于PF治疗胆汁淤积性肝损伤。构建了“PF-靶标-代谢物”相互作用网络，获得了5个可能调节特定代谢物的蛋白靶标（丝裂原活化蛋白激酶激酶1（MAP2K1）、丝裂原活化蛋白激酶1（MAPK1）、肝内胆汁结合蛋白（ILBP）、ATP结合盒转运蛋白B1（ABCB1）和白三烯A4水解酶（LTA4H））。免疫组织化学结果显示PF改善了这些蛋白的表达。多种生物信息学方法的综合应用表明，PF通过干预与胆汁酸代谢和炎症相关的重要靶点在治疗胆汁淤积性肝损伤中起关键作用。
