基于网络药理学及生物信息学探讨冬瓜皮对动静脉内瘘成熟的潜在作用与机制

doi:10.3877/cma.j.issn.2095-3216.2026.03.006

目的

基于网络药理学及生物信息学探讨冬瓜皮对自体动静脉内瘘(arteriovenous fistula, AVF)成熟的潜在作用与机制。

方法

从基因表达数据库(Gene Expression Omnibus, GEO)下载AVF血管组织基因表达数据集GSE220796与GSE119296；从基因集富集分析(Gene Set Enrichment Analysis, GSEA)软件配套的分子特征数据库(Molecular Signatures Database, MSigDB)获取炎症反应相关基因集，筛选差异表达炎症相关基因(differentially expressed inflammation-related gene, DE-IRG)，并利用基因本体(Gene Ontology, GO)与京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes, KEGG)进行通路富集分析。构建蛋白质-蛋白质相互作用(protein-protein interaction, PPI)网络，借助Cytoscape生物信息可视化软件内置插件的7种拓扑算法筛选网络核心基因。通过高通量实验与文献中药数据库(High-throughput Experiment- and Reference-guided database of traditional Chinese medicine, HERB)、症状映射中药数据库(Symptom Mapping database, SymMap)检索冬瓜皮所含化学成分，利用瑞士靶点预测数据库SwissTargetPrediction预测冬瓜皮活性成分对应的潜在靶点基因；选取冬瓜皮活性成分靶点与AVF相关核心基因，采用空腔探测导向盲对接软件2(cavity-detection-guided blind docking version 2, CB-DOCK2)进行分子对接验证。

结果

鉴定出44个AVF成熟相关DE-IRG，主要富集于细菌分子应答、白细胞-细胞黏附、细胞生物刺激应答等生物学过程，以及两面神激酶/信号转导与转录激活因子(Janus kinase / signal transducer and activator of transcription, JAK/STAT)信号通路和肿瘤坏死因子(tumor necrosis factor, TNF)信号通路。PPI网络筛选出核心基因：IL10、SELL、ICAM1、CXCL9、CD69、CCL2、LIF、CXCL8、CCRL2、IL6；并筛选出14种冬瓜皮活性化学成分。借助SwissTargetPrediction工具预测到448个潜在靶点基因，将靶点基因与DE-IRG取交集后得到5个共有基因，分别为PDE4B、ICAM1、CCL2、HIF1A、NFKBIA。分子对接结果显示：乌拉尔醇和甘草黄酮醇与AHIF1A结合能分别为－7.8 kcal/mol和－6.9 kcal/mol；阿魏酸和甘草利酮与PDE4B的结合能分别为－7.4 kcal/mol、－10.1 kcal/mol；乌拉列宁与CCL2结合能为-8.4 kcal/mol。

结论

冬瓜皮可能通过靶向调控AVF成熟相关炎症基因、抑制炎症反应、介导血管重塑等途径，促进AVF成熟。

关键词: 血液透析, 动静脉内瘘, 冬瓜皮, 机制, 网络药理学, 生物信息学

Objective

To explore the potential effects and mechanisms of Benincasae Exocarpium on arteriovenous fistula maturation based on network pharmacology and bioinformatics.

Methods

The AVF vascular tissue gene expression datasets GSE220796 and GSE119296 were downloaded from the Gene Expression Omnibus (GEO). The inflammation response-related gene sets were obtained from the Molecular Signatures Database (MSigDB) matched with the Gene Set Enrichment Analysis (GSEA) software, and differentially expressed inflammation-related genes (DE-IRGs) were screened. Pathway enrichment analysis was conducted via the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). A protein-protein interaction (PPI) network was constructed, and hub genes of the network were screened using seven topological algorithms built into plugins of the bioinformatics visualization software Cytoscape. Chemical constituents contained in Benincasae Exocarpium were retrieved via the High-throughput Experiment- and Reference-guided database of traditional Chinese medicine (HERB) and the Symptom Mapping database (SymMap). The SwissTargetPrediction database was adopted to predict potential target genes corresponding to the active ingredients of Benincasae Exocarpium. The target genes of active ingredients from Benincasae Exocarpium and core genes associated with AVF were screened out, and cavity-detection-guided blind docking software version 2 (CB-DOCK2) was used for molecular docking verification.

Results

A total of 44 DE-IRGs associated with AVF maturation were identified, being mainly enriched in biological processes such as cellular response to bacterial molecules, leukocyte-cell adhesion, and cellular response to biological stimuli, as well as the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway and the tumor necrosis factor (TNF) signaling pathway. PPI network analysis identified hub genes as IL10, SELL, ICAM1, CXCL9, CD69, CCL2, LIF, CXCL8, CCRL2, and IL6, while 14 active chemical constituents of Benincasae Exocarpium were screened out. The SwissTargetPrediction tool was used to predict 448 potential target genes, and the intersection of these target genes and DE-IRGs yielded 5 shared genes as PDE4B, ICAM1, CCL2, HIF1A and NFKBIA. The molecular docking results showed that the binding energies of uralenol and licoflavonol A with HIF1A were -7.8 kcal/mol and -6.9 kcal/mol, respectively. The binding energies of ferulic acid and licoricone with PDE4B were -7.4 kcal/mol and -10.1 kcal/mol, respectively. And the binding energy of uralenin with CCL2 was -8.4 kcal/mol.

Conclusion

Benincasae Exocarpium may promote the maturation of AVF through pathways such as targeted regulation of inflammation genes related to AVF maturation, inhibition of inflammatory responses, and mediation of vascular remodeling.

Key words: Hemodialysis, Arteriovenous fistula, Benincasae Exocarpium, Mechanism, Network pharmacology, Bioinformatics

图1 筛选动静脉内瘘成熟有关的差异表达炎症基因注：A：从GSE220796数据集筛选出差异表达基因，取上调及下调前30个基因进行热图分析，粉色表示AVF成熟组样本、绿色表示AVF失败组样本，红色表示高表达(颜色越红表达越高)、蓝色表示低表达(颜色越蓝表达越低)，左侧连线代表基因表达模式的相似度即近层连线代表基因间功能更相近或受共同调控、远层连线代表相似度较低；B：韦恩图分析差异表达基因与炎性反应相关基因；AVF: arteriovenous fistula，动静脉内瘘

图2 与动静脉内瘘成熟有关的差异表达炎症相关基因GO和KEGG途径富集分析注：A：GO富集分析；B：KEGG富集分析；条柱越长表示富集基因数量越多，颜色深浅代表富集显著性即颜色越深(橙)表示显著性越高、颜色越浅(蓝)表示显著性越低；ERK：extracellular signal-regulated kinase，细胞外信号调节激酶；GO: Gene Ontology,基因本体；KEGG: Kyoto Encyclopedia of Genes and Genomes,京都基因与基因组百科全书；TNF：tumor necrosis factor,肿瘤坏死因子；JAK/STAT：Janus kinase/signal transducer and activator of transcription,两面神激酶/信号转导与转录激活因子；AGE：advanced glycation end products,晚期糖基化终末产物；RAGE：receptor for AGE，AGE受体；NOD：nucleotide-binding oligomerization domain，核苷酸结合寡聚化结构域；PI3K：phosphatidylinositol 3-kinase磷脂酰肌醇3激酶；Akt：protein kinase B，蛋白激酶B；IL-17：interleukin-17,白介素-17；Th17：T helper 17 cell，T辅助细胞17；HIF-1：hypoxia？inducible factor-1，缺氧诱导因子-1

图3 构建蛋白质-蛋白质相互作用网络和筛选核心基因及其功能富集分析注：A：应用Cytoscape软件构建差异表达炎症相关基因之间蛋白的PPI网络，连线表示蛋白-蛋白之间存在相互作用即连线数量越多表明该蛋白在网络中调控作用越强；B：Cytoscape软件确定7个共同的枢纽基因作为核心基因，矩阵中的每一列代表一个交集组合，每一行对应一个算法，●实心圆点表示该指标属于当前交集、○空心圆点表示该指标不属于当前交集；C：应用Metascape软件分析核心基因分子功能，图中条柱长度表示-log10(P)即条柱越长表示富集显著性越高，颜色代表原始P值大小即深色表示P值较小(更显著)而浅色表示P值较大(不显著)；D：利用GeneMANIA分析核心基因及其共表达基因，连线表示基因与该功能术语之间存在显著关联即连线数量(节点度数)反映基因的多功能性或功能术语的富集广度：连线越多，表示该基因参与的生物学过程越广泛，或该功能涉及的基因越多

图4 韦恩图分析冬瓜皮成分预测靶基因及差异表达炎症相关基因之间的交集注：A：在数据集GSE119296中验证；B：HIF1A表达水平；C：NFKBIA表达水平；D：CCL2表达水平；E：PDE4B表达水平；F：ICAM1表达水平；小提琴图的宽度反映该组数据的密度分布即宽度越大表示该数值范围内的样本越多，中间粗线表示中位数，箱体表示四分位距及数据范围，蓝色代表成数组，红色代表失败组；与失败组相比较，^a表示P<0.05；ns表示无意义

图5 分子对接分析炎症相关基因与冬瓜皮药物成分之间亲和力

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Exploration of the potential effects and mechanisms of Benincasae Exocarpium on arteriovenous fistula maturation based on network pharmacology and bioinformatics

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Exploration of the potential effects and mechanisms of Benincasae Exocarpium on arteriovenous fistula maturation based on network pharmacology and bioinformatics