Zhang Juanli, Zhao Jiaxin, Ma Yang, Wang Wenjun, Huang Shaojie, Guo Chao, Wang Kai, Zhang Xiaomei, Zhang Wei, Wen Aidong, Shi Ming, Ding Yi
Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Front Pharmacol. 2021 May 13;12:650770. doi: 10.3389/fphar.2021.650770. eCollection 2021.
Guanxin-Shutong capsule (GXSTC), a combination of Mongolian medicines and traditional herbs, has been clinically proven to be effective in treating cerebrovascular diseases (CBVDs). However, the underlying pharmacological mechanisms of GXSTC in CBVDs remain largely unknown. In this study, a combination of systems pharmacology and experimental assessment approach was used to investigate the bioactive components, core targets, and possible mechanisms of GXSTC in the treatment of CBVDs. A total of 15 main components within GXSTC were identified using high-performance liquid chromatography coupled with diode array detector (HPLC-DAD) and a literature research. Fifty-five common genes were obtained by matching 252 potential genes of GXSTC with 462 CBVD-related genes. Seven core components in GXSTC and 12 core genes of GXSTC on CBVDs were further determined using the protein-protein interaction (PPI) and component-target-pathway (C-T-P) network analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis results predicted that the molecular mechanisms of GXSTC on CBVDs were mainly associated with the regulation of the vascular endothelial function, inflammatory response, and neuronal apoptosis. Molecular docking results suggested that almost all of core component-targets have an excellent binding activity (affinity < -5 kcal/mol). More importantly, in middle cerebral artery occlusion (MCAO) -injured rats, GXSTC significantly improved the neurological function, reduced the infarct volume, and decreased the percentage of impaired neurons in a dose-dependent manner. Western blotting results indicated that GXSTC markedly upregulated the expression of vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS), while downregulating the expression of cyclooxygenase-2 (COX-2) and transcription factor AP-1 (c-Jun) in MCAO-injured rats. These findings confirmed our prediction that GXSTC exerts a multi-target synergetic mechanism in CBVDs by maintaining vascular endothelial function, inhibiting neuronal apoptosis and inflammatory processes. The results of this study may provide a theoretical basis for GXSTC research and the clinical application of GXSTC in CBVDs.
冠心舒通胶囊（GXSTC）是一种蒙药与传统草药的复方制剂，临床已证明其对治疗脑血管疾病（CBVDs）有效。然而，GXSTC治疗CBVDs的潜在药理机制仍 largely未知。在本研究中，采用系统药理学与实验评估相结合的方法，研究GXSTC治疗CBVDs的生物活性成分、核心靶点及可能机制。运用高效液相色谱-二极管阵列检测器联用技术（HPLC-DAD）并结合文献研究，共鉴定出GXSTC中的15种主要成分。通过将GXSTC的252个潜在基因与462个CBVD相关基因进行匹配，获得了55个共同基因。利用蛋白质-蛋白质相互作用（PPI）和成分-靶点-通路（C-T-P）网络分析，进一步确定了GXSTC中的7种核心成分以及GXSTC针对CBVDs的12个核心基因。基因本体（GO）和京都基因与基因组百科全书（KEGG）通路富集分析结果预测，GXSTC治疗CBVDs的分子机制主要与血管内皮功能调节、炎症反应和神经元凋亡有关。分子对接结果表明，几乎所有核心成分-靶点都具有良好的结合活性（亲和力＜-5千卡/摩尔）。更重要的是，在大脑中动脉闭塞（MCAO）损伤的大鼠中，GXSTC能显著改善神经功能，降低梗死体积，并以剂量依赖的方式减少受损神经元的比例。蛋白质印迹结果表明，GXSTC能显著上调MCAO损伤大鼠中血管内皮生长因子A（VEGFA）和内皮型一氧化氮合酶（eNOS）的表达，同时下调环氧合酶-2（COX-2）和转录因子AP-1（c-Jun）的表达。这些发现证实了我们的预测，即GXSTC通过维持血管内皮功能、抑制神经元凋亡和炎症过程，在CBVDs中发挥多靶点协同作用机制。本研究结果可能为GXSTC的研究及其在CBVDs中的临床应用提供理论依据。
