基于血浆代谢组学和网络分析研究柴归颗粒的抗抑郁作用机制

Based on plasma metabonomics and network analysis to research the mechanisms of Chaigui granules for treating depression

本研究整合代谢组学和生物网络分析工具从生物代谢网络角度系统分析柴归颗粒的抗抑郁作用机制。建立慢性不可预见性轻度应激(chronic unpredictable mild stress,CUMS)抑郁大鼠模型,采用基于LC-MS的血浆代谢组学发现柴归颗粒抗抑郁作用的关键代谢物和代谢途径。整合生物网络分析工具对柴归颗粒调节的关键代谢物进行网络分析,聚焦关键代谢通路,挖掘柴归颗粒抗抑郁作用的潜在靶点。结果显示与对照组相比,模型组大鼠血浆中20个代谢物含量有显著差异(P<0.05),柴归颗粒能显著回调二十二碳三烯酸、3-羟基丁酸、4-羟基苯甲醛、鹅去氧胆酸、胆酸、L-谷氨酰胺、乙醇酸、亚油基肉碱、L-酪氨酸、N-乙酰缬氨酸、棕榈酰肉碱和花生四烯酸等12种代谢物。对柴归颗粒调控的关键代谢物进一步网络分析表明花生四烯酸代谢可能是柴归颗粒发挥抗抑郁作用的重要通路,花生四烯酸代谢途径上的CYP2B6、CYP2E1、CYP2C9、CYP2C8、PLA2G6、PTGS2、ALOX15B、PTGS1、ALOX12和ALOX5等10个蛋白为柴归颗粒发挥抗抑郁作用的潜在靶点。本文涉及的动物实验操作均遵循山西大学动物伦理委员会的规定并通过动物实验伦理审查(批号:SXULL2020028)。

The purpose of this study was to systematically analyze the antidepressant mechanism of Chaigui granules from the perspective of biological metabolic network by using integrated metabolomics and biological network analysis tools.The model of chronic unpredictable mild stress(CUMS)depression rat was established,and LC-MS-based plasma metabolomics was used to identify the key metabolites and analyze metabolic pathways underlying the antidepressant effects of Chaigui Granules.The key metabolites regulated by Chaigui granules was integrated with biological network analysis tools to further focus on the key metabolic pathways and explore the potential targets of the antidepressant effect of Chaigui granules.The results showed that there were significant differences in the plasma levels of 20 metabolites in the model group compared with the control group(P<0.05),Chaigui granules significantly regulated 12 metabolites including docosatrienoic acid,3-hydroxybutyric acid,4-hydroxybenzaldehyde,chenodeoxycholic acid,cholic acid,L-glutamine,glycocholic acid,linoleyl carnitine,L-tyrosine,N-acetylvaline,palmitoylcarnitine,arachidonic acid.Further network analysis of the key metabolites regulated by Chaigui granules indicated that plasma arachidonic acid metabolism might be the core pathway for the antidepressant effect of Chaigui granules,with 10 proteins were potential targets for the antidepressant effect of Chaigui granules,including CYP2B6,CYP2E1,CYP2C9,CYP2C8,PLA2G6,PTGS2,ALOX15B,PTGS1,ALOX12 and ALOX5.The animal experimental operations involved in this paper was followed the regulations of the Animal Ethics Committee of Shanxi University and passed the animal experimental ethical review(Approval No.SXULL2020028).