| 陈盛业,甘宇.基于网络药理学和分子对接技术探讨糖足1号方治疗糖尿病足的机制[J].浙江中医药大学学报,2021,45(7):765-777. |
| 基于网络药理学和分子对接技术探讨糖足1号方治疗糖尿病足的机制 |
| Discussion on the Mechanism of Tangzu No.1 Prescription in Treating Diabetic Foot Based on Network Pharmacology |
| DOI：10.16466/j.issn1005-5509.2021.07.015 |
| 中文关键词: 糖足1号方 糖尿病足 网络药理学 化学成分 信号通路 IL-6 IL-1β 作用机制 |
| 英文关键词: Tangzu No.1 prescription diabetic foot network pharmacology chemical component signaling pathway IL-6 IL-1β mechanism of action |
| 基金项目:沈阳市重大科技创新研发计划-人口与健康专项(19-104-4087) |
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| 中文摘要: |
| [目的]搜索糖足1号方的有效化学成分及对应人体的靶点基因，应用网络药理学方法分析其治疗糖尿病足(diabetic foot，DF)的机制。[方法]登录中药系统药理学数据库与分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform，TCMSP)数据库，搜索并记录糖足1号方中各味中药的化学活性物质及作用于人体的靶点；应用基因组注释数据库平台(genome annotation database platform，GeneCards)进行DF的靶点预测，将方-病靶点进行映射，连同化学活性物质构建网络图；将共同靶点输入String数据库平台，探索靶点之间的关系，寻找蛋白互作(protein protein interaction，PPI)核心基因；进行基因本体(gene ontology，GO)富集分析和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes，KEGG)富集分析，找出所涉及的信号通路，构建靶点-通路网络图。利用PyMoL和AutoDock软件进行分子对接，预测糖足1号方治疗DF的作用机制。验证性实验采用30只大鼠随机分为正常组、模型组、中药组，每组10只，模型组与中药组大鼠建立DF模型，造模成功后正常组与模型组不进行干预，中药组给予糖足1号方的中药外敷治疗。治疗后4周后观察比较3组大鼠白细胞介素-6(interleukin-6，IL-6)、白细胞介素-1β(interleukin-1β，IL-1β)、过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptor gamma，PPARG)、蛋白激酶B1(protein kinase B1，AKT1)水平。[结果]筛选出糖足1号方治疗DF的关键化学成分为槲皮素、汉黄芩素、黄芩素、脱氢丹参酮ⅡA、吴茱萸次碱等共33个，并得到药物-疾病共同靶点29个；GO富集分析结果包括白细胞与细胞黏附的正调控、膜筏、细胞因子受体结合等，KEGG富集分析结果包括晚期糖基化终产物-晚期糖基化终产物受体(advanced glycation end-the receptor of advanced glycation end products，AGE-RAGE)信号通路、流体剪切应力(fluid shear stress，FSS)、肿瘤坏死因子(tumor necrosis factor，TNF)信号通路等。分子对接结果表明靶蛋白与药物关键化学成分结合较好。与正常组比较，模型组血清IL-6、IL-1β水平明显升高，创面组织中的PPARG水平明显下降，AKT1水平明显上升，差异具有统计学意义(P＜0.05)；与模型组比较，中药组血清IL-6、IL-1β水平显著降低，创面组织PPARG水平明显上升，AKT1水平明显下降，差异具有统计学意义(P＜0.05)。[结论]糖足1号方可通过多成分、多靶点、多通路的复杂作用机制发挥抗炎、抗菌、组织修复的作用，进而发挥治疗DF的作用。 |
| 英文摘要: |
| [Objective] To search the effective chemical components of Tangzu No.1 prescription and the corresponding target genes of human body， and analyze the mechanism of Tangzu No.1 prescription in treating diabetic foot(DF) by network pharmacology. [Methods] Through logging on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) database， the chemical active substances of various flavors of traditional Chinese medicine(TCM) in Tangzu No.1 prescription and the targets acting on the human body were searched and recorded. The target of DF was predicted by using genome annotation database platform(GeneCards)， and the prescription-disease targets were mapped to construct the network map together with the chemical active substances; the common targets were input into the String database platform to explore the relationship between targets and find the protein protein interaction(PPI) core genes. Gene ontology(GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis was performed to find out the signaling pathways involved and construct a target-pathway network graph. PyMoL and AutoDock software was used for molecular docking to predict the mechanism of Tangzu No.1 prescription in the treatment of DF. In the confirmatory experiment， 30 rats were randomly divided into normal group， model group， and Chinese medicine group， 10 in each group. Model group and Chinese medicine group were replicated with DF models. After the model was successfully copied， normal group and model group did not intervene during the treatment period. Chinese medicine group was given Tangzu No.1 prescription external application treatment. After 4 weeks of treatment， the levels of interleukin-6(IL-6)， interleukin-1β(IL-1β)， peroxisome proliferator-activated receptor gamma(PPARG)， protein kinase B1(AKT1) were observed and compared.[Results] A total of 33 key chemical components of Tangzu No.1 prescription in treating DF were screened out， such as quercetin， wogonin， baicalein， dehydrotanshinone ⅡA， evodiamine， etc. and 29 drug-disease common targets were obtained; GO enrichment analysis results included positive regulation of leukocytecell-cell adhesion， membrane raft， cytokine receptor binding， etc; KEGG enrichment analysis results included advanced glycation end-the receptor of advanced glycation end products(AGE-RAGE) signaling pathway， fluid shear stress， tumor necrosis factor(TNF) signaling pathway， etc. The results of molecular docking showed that the targets bind well to chemically active substances. Compared with normal group， the serum levels of IL-6 and IL-1β in model group were significantly increased， the levels of PPARG in wound tissue was significantly decreased， and the levels of AKT1 was significantly increased， and the difference was statistically significant(P＜0.05); compared with model group， the serum levels of IL-6 and IL-1β in Chinese medicine group were significantly reduced， the levels of PPARG in wound tissue was significantly increased， and the levels of AKT1 was significantly decreased， the difference was statistically significant(P＜0.05). [Conclusion] Tangzu No.1 prescription can exert anti-inflammatory， antibacterial and tissue repair functions through the complex action mechanism of multiple components， multiple targets and multiple pathways， and then play a therapeutic role on DF. |
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