Song Yunfei, Yang Jianbo, Jing Wenguang, Wang Qi, Liu Yue, Cheng Xianlong, Ye Fei, Tian Jinying, Wei Feng, Ma Shuangcheng
School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
Institute for Control of Chinese Traditional Medicine and Ethnic Medicine, National Institutes for Food and Drug Control, Beijing, 100050, China.
Chin Med. 2020 Nov 18;15(1):121. doi: 10.1186/s13020-020-00401-2.
Diabetes is a complex metabolic disease characterized by hyperglycemia, plaguing the whole world. However, the action mode of multi-component and multi-target for traditional Chinese medicine (TCM) could be a promising treatment of diabetes mellitus. According to the previous research, the TCM of Polygonum multiflorum (PM) showed noteworthy hypoglycemic effect. Up to now, its hypoglycemic active ingredients and mechanism of action are not yet clear. In this study, network pharmacology was employed to elucidate the potential bioactive compounds and hypoglycemic mechanism of PM.
First, the compounds with good pharmacokinetic properties were screened from the self-established library of PM, and the targets of these compounds were predicted and collected through database. Relevant targets of diabetes were summarized by searching database. The intersection targets of compound-targets and disease-targets were obtained soon. Secondly, the interaction net between the compounds and the filtered targets was established. These key targets were enriched and analyzed by protein-protein interactions (PPI) analysis, molecular docking verification. Thirdly, the key genes were used to find the biologic pathway and explain the therapeutic mechanism by genome ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis. Lastly, the part of potential bioactive compounds were under enzyme activity inhibition tests.
In this study, 29 hypoglycemic components and 63 hypoglycemic targets of PM were filtrated based on online network database. Then the component-target interaction network was constructed and five key components resveratrol, apigenin, kaempferol, quercetin and luteolin were further obtained. Sequential studies turned out, AKT1, EGFR, ESR1, PTGS2, MMP9, MAPK14, and KDR were the common key targets. Docking studies indicated that the bioactive compounds could stably bind the pockets of target proteins. There were 38 metabolic pathways, including regulation of lipolysis in adipocytes, prolactin signaling pathway, TNF signaling pathway, VEGF signaling pathway, FoxO signaling pathway, estrogen signaling pathway, linoleic acid metabolism, Rap1 signaling pathway, arachidonic acid metabolism, and osteoclast differentiation closely connected with the hypoglycemic mechanism of PM. And the enzyme activity inhibition tests showed the bioactive ingredients have great hypoglycemic activity.
In summary, the study used systems pharmacology to elucidate the main hypoglycemic components and mechanism of PM. The work provided a scientific basis for the further hypoglycemic effect research of PM and its monomer components, but also provided a reference for the secondary development of PM.
糖尿病是一种以高血糖为特征的复杂代谢性疾病，困扰着全世界。然而，中药多成分、多靶点的作用模式可能是治疗糖尿病的一种有前景的方法。根据以往研究，何首乌显示出显著的降血糖作用。目前，其降血糖活性成分及作用机制尚不清楚。本研究采用网络药理学方法阐明何首乌潜在的生物活性化合物及降血糖机制。
首先，从自行建立的何首乌库中筛选出具有良好药代动力学性质的化合物，并通过数据库预测和收集这些化合物的靶点。通过检索数据库总结糖尿病的相关靶点。很快获得化合物靶点与疾病靶点的交集靶点。其次，建立化合物与筛选出的靶点之间的相互作用网络。通过蛋白质-蛋白质相互作用（PPI）分析、分子对接验证对这些关键靶点进行富集和分析。第三，利用关键基因通过基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析寻找生物学途径并解释治疗机制。最后，对部分潜在生物活性化合物进行酶活性抑制试验。
本研究基于在线网络数据库筛选出何首乌的29种降血糖成分和63个降血糖靶点。然后构建了成分-靶点相互作用网络，并进一步获得了白藜芦醇、芹菜素、山奈酚、槲皮素和木犀草素5种关键成分。后续研究表明，AKT1、EGFR、ESR1、PTGS2、MMP9、MAPK14和KDR是共同的关键靶点。对接研究表明，生物活性化合物能够稳定地结合靶蛋白的口袋。有38条代谢途径，包括脂肪细胞中脂解的调节、催乳素信号通路、TNF信号通路、VEGF信号通路、FoxO信号通路、雌激素信号通路、亚油酸代谢、Rap1信号通路、花生四烯酸代谢和破骨细胞分化，与何首乌的降血糖机制密切相关。酶活性抑制试验表明生物活性成分具有很强的降血糖活性。
综上所述，本研究运用系统药理学阐明了何首乌的主要降血糖成分及机制。该工作为进一步研究何首乌及其单体成分的降血糖作用提供了科学依据，也为何首乌的二次开发提供了参考。
