Li Taiping, Xiao Yong, Wang Zhen, Xiao Hong, Liu Hongyi
Department of Neuro-Psychiatric Institute, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, China.
Department of Neurosurgery, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, China.
Evid Based Complement Alternat Med. 2022 Jan 31;2022:2198722. doi: 10.1155/2022/2198722. eCollection 2022.
Glioma is the most common primary intracranial tumor in adult patients. Among them, glioblastoma is a highly malignant one with a poor prognosis. Flavonoids are a class of phenolic compounds widely distributed in plants and have many biological functions, such as anti-inflammatory, antioxidant, antiaging, and anticancer. Nowadays, flavonoids have been applied to the therapy of glioma; however, the molecular mechanism underlying the therapeutic effects has not been fully elaborated. This study was carried out to explore the mechanism of selected active flavonoid compounds in treating glioma using network pharmacology and molecular docking approaches.
Active ingredients and associated targets of flavonoids were acquired by using the Traditional Chinese Medicine Database and Analysis Platform (TCMSP) and Swiss TargetPrediction platform. Genes related to glioma were obtained from the GeneCards and DisGeNET databases. The intersection targets between flavonoid targets and glioma-related genes were used to construct protein-protein interaction (PPI) network via the STRING database, and the results were analyzed by Cytoscape software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed and displayed by utilizing the Metascape portal and clusterProfiler R package. Molecular docking was carried out by iGEMDOCK and SwissDock, and the results were visually displayed by UCSF Chimera software.
Eighty-four active flavonoid compounds and 258 targets overlapped between flavonoid targets and glioma-related genes were achieved. PPI network revealed potential therapeutic targets, such as AKT1, EGFR, VEGFA, MAPK3, and CASP3, based on their node degree. GO and KEGG analyses showed that core targets were mainly enriched in the PI3K-Akt signaling pathway. Molecular docking simulation indicated that potential glioma-related targets-MAPK1 and HSP90AA1 were bounded more firmly with epigallocatechin-3-gallate (EGCG) than with quercetin.
The findings of this study indicated that selected active flavonoid compounds might play therapeutic roles in glioma mainly through the PI3K-Akt signaling pathway. Moreover, EGCG had the potential antiglioma activity by targeting MAPK1 and HSP90AA1.
胶质瘤是成年患者中最常见的原发性颅内肿瘤。其中，胶质母细胞瘤是一种高度恶性的肿瘤，预后较差。黄酮类化合物是一类广泛分布于植物中的酚类化合物，具有多种生物学功能，如抗炎、抗氧化、抗衰老和抗癌等。目前，黄酮类化合物已应用于胶质瘤的治疗；然而，其治疗效果的分子机制尚未完全阐明。本研究采用网络药理学和分子对接方法，探讨了选定的活性黄酮类化合物治疗胶质瘤的机制。
通过中药系统药理学数据库与分析平台（TCMSP）和瑞士靶点预测平台获取黄酮类化合物的活性成分及相关靶点。从基因卡片（GeneCards）和疾病基因数据库（DisGeNET）中获取与胶质瘤相关的基因。通过STRING数据库，利用黄酮类化合物靶点与胶质瘤相关基因的交集靶点构建蛋白质-蛋白质相互作用（PPI）网络，并使用Cytoscape软件对结果进行分析。利用Metascape门户和clusterProfiler R包进行基因本体（GO）和京都基因与基因组百科全书（KEGG）通路富集分析并展示。通过iGEMDOCK和瑞士分子对接（SwissDock）进行分子对接，并使用UCSF Chimera软件直观显示结果。
获得了84种活性黄酮类化合物，以及黄酮类化合物靶点与胶质瘤相关基因之间重叠的258个靶点。PPI网络基于节点度揭示了潜在的治疗靶点，如AKT1、表皮生长因子受体（EGFR）、血管内皮生长因子A（VEGFA）、丝裂原活化蛋白激酶3（MAPK3）和半胱天冬酶3（CASP3）。GO和KEGG分析表明，核心靶点主要富集于磷脂酰肌醇-3-激酶-蛋白激酶B（PI3K-Akt）信号通路。分子对接模拟表明，潜在的胶质瘤相关靶点丝裂原活化蛋白激酶1（MAPK1）和热休克蛋白90α家族成员1（HSP90AA1）与表没食子儿茶素-3-没食子酸酯（EGCG）的结合比与槲皮素的结合更紧密。
本研究结果表明，选定的活性黄酮类化合物可能主要通过PI3K-Akt信号通路在胶质瘤中发挥治疗作用。此外，EGCG通过靶向MAPK1和HSP90AA1具有潜在的抗胶质瘤活性。
