基于UPLC-Q-TOF-MS/MS和网络药理学探讨戊己丸药效物质基础及疾病治疗潜能分析

Pharmacodynamic substances and therapeutic potential of Wuji Pills:based on UPLC-Q-TOF-MS/MS and network pharmacology

戊己丸作为经典名方,药味组成简单且为临床常用有效中药,但相对其他中药名方,其实际应用却很有限,戊己丸中成药制剂国内只有一家制药公司生产。该文采用UPLC-Q-TOF-MS/MS技术,从戊己丸制剂及大鼠含药血浆中分析鉴定出26个相同化合物,并基于这些成分,通过网络药理学方法得到46个潜在靶点,再进行成分-靶点网络构建、GO功能富集、KEGG通路富集分析及疾病预测,推断戊己丸可通过木兰花碱、羟基吴茱萸碱、胡萝卜苷、小檗碱等作用于PTGS2、PTSG1、NCOA2、HSP9OAD1、RXRA等核心靶点,通过钙离子信号通路、PI3K-Akt、VEGF信号通路等多种途径发挥药效作用,提示戊己丸除常规治疗疾病(如肠易激综合征)外,还对阿尔茨海默病、糖尿病、心肌缺血等疾病有治疗潜能,以上研究结果可为全面阐释戊己丸药效物质基础及扩大临床应用提供参考。同时,该实验观察到,戊己丸入血成分及其在体内转化、代谢降解的成分中有非常多的结构和化学相对分子质量相似成分,这些成分理论上对潜在药效单靶点会构成多成分叠加与竞争/拮抗并存的复杂作用,中药“多成分单靶点叠加作用”假说认为,在中药多成分多靶点协同作用网络中局部靶点可存在相似多成分的药效叠加作用,该实验可部分佐证该假说的科学性及提供实验室证据。

As a classic prescription, Wuji Pills is composed of Coptidis Rhizoma, Euodiae Fructus Preparata, and stir-fried Paeo-niae Radix Alba at the ratio of 6∶1∶6. The practical application of it is limited compared with other famous Chinese medicine prescriptions. Only one company produces Wuji Pills in China. In this study, ultra-performance liquid chromatography quadrupole time of flight mass spectrometry(UPLC-Q-TOF-MS/MS) was used to analyze and identify 26 identical compounds from Wuji Pills and drug-containing plasma of rats. Based on these components, 46 potential targets were screened out with network pharmacology methods, followed by the component-target network construction, Gene Ontology(GO) term enrichment, Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment, and disease prediction. It was concluded that Wuji Pills acted on core targets such as PTGS2, PTSG1, NCOA2, HSP9 OAD1, and RXRA through magnoflorine, hydroxyevodiamine, daucosterol, and berberine and exerted pharmacodynamic effects through various pathways such as calcium ion signaling pathway, phosphatidylinositol-3-kinase-protein kinase B(PI3 K-Akt) signaling pathway, and vascular endothelial growth factor(VEGF) signaling pathway. Thus, Wuji Pills has therapeutic potential for Alzheimer′s disease, diabetes mellitus, myocardial ischemia, and other diseases in addition to the conventional disease(irritable bowel syndrome, IBS). The above research results can provide a reference for the comprehensive interpretation of the pharmacodynamic basis of Wuji Pills and the expansion of clinical application. At the same time, a lot of components in serum and the in vivo transformed and metabolized components of Wuji Pills have similar structure and relative molecular weight. In theory, these components may show additive effects and the competitive/antagonistic effects on the same target. According to the hypothesis of "additive effect of multiple components for a single target" in traditional Chinese medicine, multiple similar components may exert the additive effects on local targets. This study can partly prove the scientificity of this hypothesis and provide laboratory evidence.