基于整合用药网络探究中药治疗DR的药物机制

On the Base of Integrated Network Administration to Explore the TCM Mechanism of Medicines for the Ttreatment of Diabetic Retinopathy

目的 基于整合用药网络探究中药治疗糖尿病视网膜病变(DR)的药物机制。方法 纳入建库至2022年10月中国知网、万方、维普、中国生物医学文献服务系统数据库、Pubmed、MEDLINE、Embase、Web of Science中关于中药治疗DR的相关文献。运用古今医案云平台、IBM SPSS Modeler 18.0进行统计分析,得出治疗DR的核心处方;运用中药系统药理学数据库与分析平台、Genecards、OMIM、TTD数据库筛选处方的药物成分、靶点以及DR的疾病靶点,筛选出核心成分和核心靶点;基于Autodock和Pymol软件进行分子对接,得到配体与受体结合能热图并可视化。结果 (1)数据分析与用药网络构建:共纳入文献216篇,整理得到中药处方265首,涉及中药295味,累计频次2,937次。使用频次≥25次的中药(高频中药)有29味。对高频中药进行聚类分析,共得到3类组合。第Ⅰ类功效为清热凉血,补气活血;第Ⅱ类功效为补益肝肾;第Ⅲ类功效为活血化瘀,益气滋阴。对高频中药进行关联规则分析,关联度较高的组合分别为茯苓-泽泻、牡丹皮,茯苓-泽泻、牡丹皮、山萸肉,茯苓-泽泻、牡丹皮、熟地黄,茯苓-泽泻、牡丹皮、山药,茯苓-泽泻、山萸肉、山药。将六味地黄丸加减方作为核心处方,即熟地黄、山萸肉、山药、泽泻、茯苓、牡丹皮、黄芪、丹参、当归、三七、川芎。(2)药靶、蛋白模型的构建与分析:共得到核心处方的药物活性成分114个、作用靶点1,879个;DR疾病的相关靶点1,385个;药物作用靶点与DR交集靶点214个。构建了“药物-活性成分-作用靶点”图,DR的核心成分分别是槲皮素、山柰酚、23-乙酰泽泻醇B、β-谷甾醇。可视化蛋白互作网络(PPI)得到核心靶点为SRC、STAT3、MAPK1、AKT1、TP53。5个核心靶点的蛋白结构与4个核心成分的小分子结构完成了对接。结论 数据分析得到的核心处方六味地黄丸加减治疗DR具有益气养阴、化瘀止血的功效,该处方具有多成分、多靶点、多通路的特点,对促进全身血糖稳态、改善视网膜血管病变以及其他DR相关症状具有一定研究价值。

OBJECTIVE Traditional Chinese Medicine(TCM)in the treatment of diabetic retinopathy(DR).METHODS Relevant literature on TCM treatment for DR from CNKI,Wanfang,VIP,CBM,PubMed,MEDLINE,Embase,and Web of Science databases up to October 2022 was included.Statistical analysis was performed using the Ancient and Modern Medical Case Cloud Platform and IBM SPSS Modeler 18.0 to identify core prescriptions for treating DR.The TCMSP,GeneCards,OMIM,and TTD databases were utilized to screen the prescription's components,targets,and DR-related targets to identify core components and targets.Molecular docking was conducted using Autodock and Pymol software to obtain and visualize the binding energy heatmap of ligands and receptors.RESULTS(1)Data analysis and medication network construction:A total of 216 articles were included,yielding 265 TCM prescriptions involving 295 different Chinese medicines with a cumulative frequency of 2,937 occurrences.29 high-frequency Chinese medicines(used≥25 times)were identified.Cluster analysis of these high-frequency Chinese medicines resulted in three combinations.Class I,Clearing heat and cooling the blood,replenishing Qi,and invigorating blood.Class II,Tonifying the liver and kidney.Class III:Activating blood,removing stasis,replenishing Qi,and nourishing Yin.Association rule analysis identified the following high correlation combinations,Poria-Alisma,Moutan Cortex;Poria-Alisma,Moutan Cortex,Cornu;Poria-Alisma,Moutan Cortex,Rehmannia;Poria-Alisma,Moutan Cortex,Dioscorea and Poria-Alisma,Cornus,Dioscorea.The modified Liuwei Dihuang Pill was identified as the core prescription,consisting of Rehmannia,Cornus,Dioscorea,Alisma,Poria,Moutan Cortex,Astragalus,Salvia,Angelic,Panax Notoginseng,and Rhizoma Chuanxiong.(2)Medicine target and protein model construction and analysis:The core prescription was found to contain 114 active components and 1,879 targets.There were 1,385 DR-related targets,with 214 intersecting targets.The"medicine-active component-target"network identified key components acting on DR,including quercetin,kaempferol,23-acetyl-alismol B,andβ-sitosterol.The visualized protein-protein interaction(PPI)networks revealed core targets as SRC,STAT3,MAPK1,AKT1,and TP53.Molecular docking was completed for the protein structures of five core targets and the small molecule structures of four core components.CONCLUSIONS The data analysis identified that the modified Liuwei Dihuang Pill has the efficacy of replenishing Qi and nourishing Yin,removing stasis,and stopping bleeding for the treatment of DR.The prescription features multiple components,targets,and pathways,offering research value in promoting systemic glucose homeostasis and improving retinal vascular lesions and other DR-related symptoms.