Duan Bailu, Ye Yan, Zhou Zhenxiang, Han Lintao, Huang Fang, Li Jingjing, Wang Qiong, Zeng Xiangfa, Yu Xiaoming
College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, China.
Postdoctoral Research Station, General Hospital of Central Theater Command of PLA, Wuhan, 430065, China.
Chem Biodivers. 2022 Oct;19(10):e202200386. doi: 10.1002/cbdv.202200386. Epub 2022 Sep 26.
Myocardial ischemia is a cardio-physiological condition due to a decrease in blood perfusion to the heart, leading to reduced oxygen supply and abnormal myocardial energy metabolism. Guizhi-Fuling (GZFL) is effective in treating Myocardial ischemia. However, its mechanism of action is unclear and requires further exploration. We attempt to decipher the mechanisms behind GZFL treating Myocardial ischemia by integrating metabolomics and network pharmacology. In this study, myocardial metabolomic analysis was performed using GC/MS to identify the potential mechanism of action of GZFL during myocardial ischemia. Then, network pharmacology was utilized to analyze key pathways and construct a pathway-core target network. Molecular docking was incorporated to validate core targets within network pharmacological signaling pathways. Finally, western blots were utilized to verify core targets of metabolomics, network pharmacology integrated pathways, and key signaling targets. Thus, 22 critical biomarkers of GZFL for treating myocardial ischemia were identified. Most of these metabolites were restored using modulation after GZFL treatment. Based on the network pharmacology, 297 targets of GZFL in treating myocardial ischemia were identified. The further comprehensive analysis focused on three key targets, such as Tyrosine hydroxylase (TH), myeloperoxidase (MPO), and phosphatidylinositol 3-kinases (PIK3CA), and their related metabolites and pathways. Compared with the model group, the protein expression levels of TH, MPO and PIK3CA were reduced in GZFL. Therefore, the mechanism of GZFL for treating myocardial ischemia could inhibit myocardial inflammatory factors, reduce myocardial inflammation, and restore endothelial function while controlling norepinephrine release and uric acid concentration.
心肌缺血是一种心脏生理状况，由于心脏血液灌注减少，导致氧气供应减少和心肌能量代谢异常。桂枝茯苓（GZFL）对治疗心肌缺血有效。然而，其作用机制尚不清楚，需要进一步探索。我们试图通过整合代谢组学和网络药理学来解读GZFL治疗心肌缺血背后的机制。在本研究中，使用气相色谱/质谱联用仪（GC/MS）进行心肌代谢组学分析，以确定GZFL在心肌缺血过程中的潜在作用机制。然后，利用网络药理学分析关键途径并构建途径-核心靶点网络。引入分子对接来验证网络药理学信号通路中的核心靶点。最后，利用蛋白质免疫印迹法验证代谢组学、网络药理学整合途径的核心靶点以及关键信号靶点。因此，确定了22个GZFL治疗心肌缺血的关键生物标志物。这些代谢物中的大多数在GZFL治疗后通过调节得以恢复。基于网络药理学，确定了GZFL治疗心肌缺血的297个靶点。进一步的综合分析聚焦于三个关键靶点，如酪氨酸羟化酶（TH）、髓过氧化物酶（MPO）和磷脂酰肌醇3激酶（PIK3CA），以及它们相关的代谢物和途径。与模型组相比，GZFL组中TH、MPO和PIK3CA的蛋白表达水平降低。因此，GZFL治疗心肌缺血的机制可能是在控制去甲肾上腺素释放和尿酸浓度的同时，抑制心肌炎症因子，减轻心肌炎症，并恢复内皮功能。
