Wang Dan, Li Ruisheng, Wei Shizhang, Gao Sijia, Xu Zhuo, Liu Honghong, Wang Ruilin, Li Haotian, Cai Huadan, Wang Jian, Zhao Yanling
1Provincial and State Key Laboratory Breeding Base of System Research, Development and Utilization of Chinese Herbal Medicine Resources, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China.
2Department of Pharmacy, The Fifth Medical Center of PLA General Hospital, Beijing, 100039 China.
Chin Med. 2019 Aug 28;14:30. doi: 10.1186/s13020-019-0251-z. eCollection 2019.
(AR) is widely-used for improving liver fibrosis, but, the mechanism of action has not been systematically explained. This study aims to investigate the mechanism of AR intervention in liver fibrosis based on comprehensive metabolomics combined with network pharmacology approach.
UPLC-Q-TOF/MS based metabolomics technique was used to explore the specific metabolites and possible pathways of AR affecting the pathological process of liver fibrosis. Network pharmacology analysis was introduced to explore the key targets of AR regarding the mechanisms on liver fibrosis.
AR significantly reduced the levels of ALT, AST and AKP in serum, and improved pathological characteristics. Metabolomics analysis showed that the therapeutic effect of AR was mainly related to the regulation of nine metabolites, including sphingosine, 6-keto-prostaglandin F1a, LysoPC (O-18:0), 3-dehydrosphinganine, 5,6-epoxy-8,11,14-eicosatrienoic acid, leukotriene C4, taurochenodesoxycholic acid, LysoPC (18:1 (9Z)) and 2-acetyl-1-alkyl-sn-glycero-3-phosphocholine. Pathway analysis indicated that the treatment of AR on liver fibrosis was related to arachidonic acid metabolism, ether lipid metabolism, sphingolipid metabolism, glycerophospholipid metabolism and primary bile acid biosynthesis. Validation of the key targets by network pharmacology analysis of potential metabolic markers showed that AR significantly down-regulated the expression of CYP1B1 and up-regulated the expression of CYP1A2 and PCYT1A.
Metabolomics combined with network pharmacology was used for the first time to clarify that the treatment of AR on liver fibrosis, which is related to the regulation of arachidonic acid metabolism and ether lipid metabolism by modulating the expression of CYP1A2, CYP1B1 and PCYT1A. And the integrated approach can provide new strategies and ideas for the study of molecular mechanisms of traditional Chinese medicines in the treatment of liver fibrosis.
抗类风湿药（AR）被广泛用于改善肝纤维化，但其作用机制尚未得到系统阐释。本研究旨在基于综合代谢组学结合网络药理学方法，探究AR干预肝纤维化的机制。
采用基于超高效液相色谱-四极杆飞行时间质谱（UPLC-Q-TOF/MS）的代谢组学技术，探索AR影响肝纤维化病理过程的特定代谢物及可能途径。引入网络药理学分析，探究AR在肝纤维化机制方面的关键靶点。
AR显著降低血清中谷丙转氨酶（ALT）、谷草转氨酶（AST）和碱性磷酸酶（AKP）水平，并改善病理特征。代谢组学分析表明，AR的治疗作用主要与9种代谢物的调节有关，包括鞘氨醇、6-酮-前列腺素F1a、溶血磷脂酰胆碱（O-18:0）、3-脱氢鞘氨醇、5,6-环氧-8,11,14-二十碳三烯酸、白三烯C4、牛磺鹅去氧胆酸、溶血磷脂酰胆碱（18:1(9Z)）和2-乙酰-1-烷基-sn-甘油-3-磷酸胆碱。通路分析表明，AR对肝纤维化的治疗与花生四烯酸代谢、醚脂代谢、鞘脂代谢、甘油磷脂代谢和初级胆汁酸生物合成有关。通过对潜在代谢标志物的网络药理学分析验证关键靶点，结果显示AR显著下调细胞色素P450 1B1（CYP1B1）的表达，上调细胞色素P450 1A2（CYP1A2）和磷脂酰胆碱转运蛋白1A（PCYT1A）的表达。
首次运用代谢组学结合网络药理学阐明AR对肝纤维化的治疗作用，这与通过调节CYP1A2、CYP1B1和PCYT1A的表达来调控花生四烯酸代谢和醚脂代谢有关。该综合方法可为中药治疗肝纤维化分子机制的研究提供新策略和思路。
