Bai Yongtao, Zhang Yingchun, Li Shuolei, Zhang Wenzhou, Wang Xinhui, He Baoxia, Ju Wenzheng
Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
Phase I Clinical Research Center, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
Front Pharmacol. 2021 Oct 8;12:711303. doi: 10.3389/fphar.2021.711303. eCollection 2021.
Zhi-Zi-Hou-Po Decoction (ZZHPD) is a well-known traditional Chinese medicine (TCM) that has been widely used in depression. However, the antidepressant mechanism of ZZHPD has not yet been fully elucidated. The purpose of this study was to explore the pharmacological mechanisms of ZZHPD acting on depression by combining ultra flow liquid chromatography with quadrupole time-of-flight mass spectrometry (UFLC-Q-TOF/MS) and network pharmacology strategy. The chemical components of ZZHPD were identified using UFLC-Q-TOF/MS, while the potential drug targets and depression-related targets were collected from databases on the basis of the identified compounds of ZZHPD. Protein-protein interaction (PPI) network, gene ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were used to unravel potential antidepressant mechanisms. The predicted antidepressant targets from the pharmacology-based analysis were further verified . As a result, a total of 31 chemical compounds were identified by UFLC-Q-TOF/MS; 514 promising drug targets were mined by using the Swiss Target Prediction; and 527 depression-related target genes were pinpointed by the GeneCards and OMIM databases. STRING database and Cytoscape's topological analysis revealed 80 potential targets related to the antidepressant mechanism of ZZHPD. The KEGG pathway analysis revealed that the antidepressant targets of ZZHPD were mainly involved in dopaminergic synapse, serotonin synapse, cAMP, and mTOR signaling pathways. Furthermore, based on the animal model of depression induced by chronic corticosterone, the regulatory effects of ZZHPD on the expression of MAOA, MAOB, DRD2, CREBBP, AKT1, MAPK1, HTR1A, and GRIN2B mRNA levels as well as the cAMP signaling pathway and monoaminergic metabolism were experimentally verified in rats. Our study revealed that ZZHPD is expounded to target various genes and pathways to perform its antidepressant effect.
栀子厚朴汤（ZZHPD）是一种著名的传统中药，已广泛应用于抑郁症的治疗。然而，ZZHPD的抗抑郁机制尚未完全阐明。本研究旨在通过超高效液相色谱与四极杆飞行时间质谱联用（UFLC-Q-TOF/MS）和网络药理学策略，探索ZZHPD作用于抑郁症的药理机制。采用UFLC-Q-TOF/MS鉴定ZZHPD的化学成分，根据鉴定出的ZZHPD化合物从数据库中收集潜在的药物靶点和抑郁症相关靶点。利用蛋白质-蛋白质相互作用（PPI）网络、基因本体（GO）和京都基因与基因组百科全书（KEGG）通路富集分析来揭示潜在的抗抑郁机制。对基于药理学分析预测的抗抑郁靶点进行进一步验证。结果，通过UFLC-Q-TOF/MS共鉴定出31种化合物；利用瑞士靶点预测挖掘出514个有前景的药物靶点；通过GeneCards和OMIM数据库确定了527个抑郁症相关靶基因。STRING数据库和Cytoscape的拓扑分析揭示了80个与ZZHPD抗抑郁机制相关的潜在靶点。KEGG通路分析表明，ZZHPD的抗抑郁靶点主要参与多巴胺能突触、5-羟色胺突触、cAMP和mTOR信号通路。此外，基于慢性皮质酮诱导的抑郁症动物模型，在大鼠中实验验证了ZZHPD对MAOA、MAOB、DRD2、CREBBP、AKT1、MAPK1、HTR1A和GRIN2B mRNA水平表达以及cAMP信号通路和单胺能代谢的调节作用。我们的研究表明，ZZHPD通过作用于多种基因和通路发挥其抗抑郁作用。
