Yuan Naijun, Gong Lian, Tang Kairui, He Liangliang, Hao Wenzhi, Li Xiaojuan, Ma Qingyu, Chen Jiaxu
Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China.
College of Pharmacy, Jinan University, Guangzhou, China.
Front Pharmacol. 2020 Mar 18;11:284. doi: 10.3389/fphar.2020.00284. eCollection 2020.
Clinical studies and basic science experiments have widely demonstrated the antidepressant and anxiolytic effects of the herbal formula Xiao-Yao-San (XYS). However, the system mechanism of these effects has not been fully characterized. The present study conducted a comprehensive network pharmacological analysis of XYS and sorted all pharmacologically active components (149) through the TCMSP webserver. Then, all potential molecular targets (449) were predicted, of which there were 99 genes clearly related to depression. To further investigate the mechanism of antidepressant effects of XYS, a compound-depression targets (C-DTs) network was constructed, and Gene Ontology (GO) functional and KEGG pathway enrichment analyses were performed for the 99 targets. Enrichment results revealed that XYS could regulate multiple aspects of depression through these targets, related to metabolism, neuroendocrine function, and neuroimmunity. Prediction and analysis of protein-protein interactions resulted in selection of three hub genes (AKT1, TP53, and VEGFA). In addition, a total of seven ingredients from XYS could act on these hub genes and they were identified through ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS), including paeoniflorin, quercetin, luteolin, acacetin, aloe-emodin, Glyasperin C, kaempferol. Hereafter, we investigated the effects of paeoniflorin and its predicted target, the results suggest that it can reverse the neurotoxicity produced by CORT and could be a neuroprotective effect by promoting the phosphorylation of Akt. Overall, our research revealed the complicated antidepressant mechanism of XYS, and also provided a rational strategy for revealing the complex composition and function of Chinese herbal formula.
临床研究和基础科学实验已广泛证明中药方剂逍遥散（XYS）具有抗抑郁和抗焦虑作用。然而，这些作用的系统机制尚未完全明确。本研究对逍遥散进行了全面的网络药理学分析，并通过中药系统药理学数据库与分析平台（TCMSP）网站筛选出所有药理活性成分（149种）。然后，预测了所有潜在的分子靶点（449个），其中有99个基因与抑郁症明显相关。为进一步探究逍遥散抗抑郁作用的机制，构建了化合物 - 抑郁症靶点（C-DTs）网络，并对这99个靶点进行了基因本体（GO）功能和京都基因与基因组百科全书（KEGG）通路富集分析。富集结果显示，逍遥散可通过这些靶点调节抑郁症的多个方面，涉及代谢、神经内分泌功能和神经免疫。蛋白质 - 蛋白质相互作用的预测和分析筛选出三个核心基因（AKT1、TP53和VEGFA）。此外，通过超高效液相色谱 - 四极杆飞行时间质谱（UPLC-Q/TOF-MS）鉴定出逍遥散中共有七种成分可作用于这些核心基因，包括芍药苷、槲皮素、木犀草素、刺槐素、芦荟大黄素、甘草asperin C、山柰酚。随后，我们研究了芍药苷及其预测靶点的作用，结果表明它可以逆转皮质酮（CORT）产生的神经毒性，并且可能通过促进Akt的磷酸化发挥神经保护作用。总体而言，我们的研究揭示了逍遥散复杂的抗抑郁机制，也为揭示中药方剂的复杂组成和功能提供了合理策略。
