摘要
目的:基于网络药理学、毒理学探讨痔瘘洗剂对混合痔术后创面促愈的作用及安全性机制。方法:在TCMSP数据库中检索并整合痔瘘洗剂组成药物玄明粉、黄柏、花椒、苦参、冰片和樟脑的有效成分,在STRING数据库中获取靶点,导入Cytoscape 3.10.2中筛选关键有效成分,以连接度最高的有效成分为核心成分进行网络毒理预测。在PubChem数据库中检索芒柄花黄素的SMILES序列,并通过中药综合药理研究平台(TCMIP)和SWISS数据库进行毒理学分析;在GeneCards数据库中获取“术后创面”和“皮肤致敏”的相关靶点,分别与痔瘘洗剂和芒柄花黄素整合获取共同靶点,建立蛋白质-蛋白质相互作用网络(PPI),进行基因本体论(GO)与京都基因与基因组百科全书(KEGG)富集分析。结果:TCMSP数据库中未检索到玄明粉有效成分,获得其他药物有效成分:黄柏37个,苦参45个,花椒5个,冰片3个,樟脑1个。STRING数据库中,未检索到冰片有效成分相关靶点基因,获得其他药物靶点共计218个。关键有效成分为芒柄花黄素、槲皮素、(S)-四氢小檗碱、异紫堇定碱、β-谷甾醇,其中芒柄花黄素为核心成分。获得芒柄花黄素靶点68个。毒理学目标显示,皮肤致敏为芒柄花黄素的最高危致病,其次是眼睛刺激和药物性肝损伤。PPI网络显示,痔瘘洗剂与术后创面的共同核心靶点为TP53、JUN、AKT1、TNF、ESR1和HSP90AA1,芒柄花黄素与皮肤致敏的共同核心靶点为AKT1、EGFR和ESR1。GO和KEGG富集分析显示,痔瘘洗剂与术后创面的信号通路主要涉及AGE-RAGE信号通路在糖尿病并发症中的作用等,生物过程主要在于对脂多糖的反应等方面,主要作用场所在膜区等,通过分泌颗粒腔等方式改善术后创面;芒柄花黄素与皮肤致敏信号通路主要涉及乳腺癌等,生物过程涉及成纤维细胞增殖等,主要作用场所在顶端质膜等,通过激活外排跨膜转运蛋白活性等导致皮肤致敏。结论:痔瘘洗剂对混合痔术后创面存在多成分、多靶点、多通路的作用机制,以芒柄花黄素为核心有效成分,各有效成分主要通过靶向TP53等靶点,调控AGE-RAGE信号通路在糖尿病并发症中的作用等信号通路发挥治疗作用,同时可能会引起皮肤过敏,这可能与AKT1等靶点,以及乳腺癌等信号通路密切相关,需进一步研究证实。
Objective To explore the effect and safety mechanism of Zhilou Lotion on promoting wound healing after mixed hemorrhoids surgery based on network pharmacology and toxicology.Methods The effective components of Zhilou Lotion,including Xuanmingfen(Natrii Sulfas Exsiccatus),Huangbo(Phello⁃dendri Chinensis Cortex),Huajiao(Zanthoxyli Pericarpium),Kushen(Sophorae Flavescentis Radix),Bing⁃pian(Borneolum),Zhangnao(Camphor)were retrieved and integrated in the TCMSP database.The targets were obtained in the STRING database and imported into Cytoscape 3.10.2 to screen the key active ingredi⁃ents.The effective component with the highest connectivity was used as the core component for network toxico⁃logical prediction.The SMILES sequence of formononetin was retrieved in the PubChem database,and toxico⁃logical analysis was carried out through the Traditional Chinese Medicine Integrated Pharmacology Research Platform( TCMIP) and the SWISS database. The relevant targets of "postoperative wound" and "skin sensitiza⁃tion" were obtained in the GeneCards database, and the common targets were integrated with the Zhilou Lotion and formononetin, respectively, to establish a protein-protein interaction network( PPI) for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes( KEGG) enrichment analysis. Results There were no retrieved results for the effective components of Xuanmingfen in the TCMSP database. The effective compo⁃nents of other drugs obtained were: 37 for Huangbo, 45 for Kushen, 5 for Huajiao, 3 for Bingpian, and 1 for Zhangnao. In the STRING database, no target genes related to the effective components of Bingpian were retrieved, and a total of 218 other drug targets were obtained. The key effective components were formonone⁃tin, quercetin,( S) -tetrahydroberberine, isocorydine and β-sitosterol, among which formononetin was the core component. Total 68 targets of formononetin were obtained. Toxicological targets showed that skin sensitiza⁃tion was the most high-risk disease of formononetin, followed by eye irritation and drug-induced liver injury. The PPI network showed that the common core targets of Zhilou Lotion and postoperative wounds were TP53, JUN, AKT1, TNF, ESR1 and HSP90AA1, and the common core targets of formononetin and skin sensitiza⁃tion were AKT1, EGFR and ESR1. GO and KEGG enrichment analyses showed that the signaling pathways between Zhilou Lotion and postoperative wounds mainly involved the role of the AGE-RAGE signaling path⁃way in diabetic complications, etc. The biological processes mainly lay in the reaction to lipopolysaccharides, etc. The main sites of action were in the membrane area, etc. , and the postoperative wounds were improved through methods such as secreting the granules cavity. The signaling pathways of formononetin and skin sensiti⁃zation mainly involved breast cancer, etc. The biological processes involved fibroblast proliferation, etc. The main sites of action were at the apical plasma membrane, etc. Skin sensitization was caused by activating the activity of exocytic transmembrane transporters, etc. Conclusion Zhilou Lotion has a multi-component, multi-target and multi-pathway mechanism on the postoperative wound of mixed hemorrhoids. With for⁃mononetin as the core effective component, each effective component mainly exerts therapeutic effects by target⁃ing TP53 and other targets and regulating the role of the AGE-RAGE signaling pathway in diabetic complica⁃tions and other signaling pathways. At the same time, it may cause skin allergies. This may be closely related to targets such as AKT1 and signaling pathways such as breast cancer, and further research is needed for confirmation.
作者
陈力
李明
施阳
唐昆
CHEN Li;LI Ming;SHI Yang;TANG Kun(Dept.of Coloproctology,First Affiliated Hospital of Anhui University of Chinese Medicine,Hefei,Anhui 230031)
出处
《中国肛肠病杂志》
2025年第8期9-14,共6页
Chinese Journal of Coloproctology
基金
安徽中医药大学科研基金项目(2021yfylc37)
2024年安徽省自然科学基金项目(2408085MH227)
“十四五”安徽省级中医优势特色专科项目(皖中医药服务秘[2021]71号)。
关键词
痔瘘洗剂
网络药理学
网络毒理学
混合痔
机制
Zhilou Lotion
Network pharmacology
Network toxicology
Mixed hemorrhoids
Mechanism
