广西医学

目的基于网络药理学和分子对接技术探讨清热化瘀排石方治疗尿石症的作用机制。方法在中药系统药理学数据库与分析平台筛选清热化瘀排石方的活性成分及作用靶点，在OMIM®数据库、GeneCards®数据库、DrugBank数据库筛选尿石症相关靶点，对两类靶点取交集。基于交集靶点，通过Cytoscape软件构建药物⁃成分⁃靶点网络，利用STRING数据库构建蛋白⁃蛋白相互作用网络，通过DAVID数据库进行功能富集分析和通路富集分析。最后对核心有效成分和核心靶点蛋白进行分子对接验证。结果筛选得到清热化瘀排石方的活性成分共128种，相应作用靶点共200个，尿石症相关靶点共659个，两者的交集靶点共51个。核心有效成分为槲皮素、山柰酚、β⁃谷甾醇、芒柄花黄素、柚皮素、甘草查尔酮A等。核心靶点包括白细胞介素（IL）⁃6、IL⁃1β、肿瘤坏死因子（TNF）、丝氨酸/苏氨酸激酶1（AKT1）等。富集分析结果显示，交集靶点富集于囊泡腔、膜筏等细胞组分，主要涉及受体配体活性、信号受体激活剂活性等分子功能，以及调节细胞⁃细胞黏附、活性氧代谢等生物过程，主要涉及糖尿病并发症晚期糖基化终末化产物（AGE）⁃晚期糖基化终末产物受体（RAGE）信号通路、磷脂酰肌醇3⁃激酶（PI3K）⁃AKT 信号通路等信号通路。分子对接显示，核心有效成分槲皮素、山柰酚与核心靶点IL⁃6、IL⁃1β、TNF、AKT1均具有较好的结合活性。结论清热化瘀排石方治疗尿石症的作用机制可能与槲皮素、山柰酚等黄酮类化合物作用于IL⁃6、IL⁃1β、TNF、AKT1等核心靶点，调控AGE⁃RAGE、PI3K⁃AKT、炎性肠病、胰岛素抵抗等信号通路，从而影响氧化应激和炎症反应、调节物质代谢、抑制肾纤维化、调节细胞凋亡等有关。

Objective To explore the mechanism of Qingre Huayu Paishi Prescription for the treatment of urolithiasis based on network pharmacology and molecular docking technique. Methods Active components and effect targets of Qingre Huayu Paishi Prescription were screened from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. Targets related to urolithiasis were screened from the databases of OMIM®, GeneCards®, and DrugBank, and the intersection of the two targets was acquired. A drug⁃component⁃target network was established using the Cytoscape software, and a protein⁃protein interaction network was established using the STRING database. Functional and pathway enrichment analyses were performed using the DAVID database. Finally, molecular docking validation was performed between core effective components and core target proteins. Results A total of 128 active components and 200 corresponding effect targets of Qingre Huayu Paishi Prescription were screened, along with 659 urolithiasis⁃related targets. The intersection targets of the two as above were 51. Core effective components included quercetin, kaempferol, β⁃sitosterol, formononetin, naringenin, and licochalcone A. The core targets involved interleukin (IL)⁃6, IL⁃1β, tumor necrosis factor (TNF), and serine/threonine kinase 1 (AKT1), etc. The results of enrichment analyses revealed that the intersection targets were primarily enriched in cellular components such as vesicle lumens and membrane rafts, involved in molecular function such as receptor ligand activity and signal receptor activator activity, in biological processes such as regulation of cell⁃cell adhesion and reactive oxygen species metabolism, and in signaling pathways such as advanced glycation end products (AGE)⁃receptor for AGE (RAGE) signaling pathway, phosphatidylinositol 3⁃kinase (PI3K)⁃AKT signaling pathway. Molecular docking demonstrated favorable binding affinity between core effective components (quercetin and kaempferol) and core targets (IL⁃6, IL⁃1β, TNF, and AKT1). Conclusion The mechanism of Qingre Huayu Paishi Prescription for the treatment of urolithiasis may be related to quercetin, kaempferol and other flavonoids acting on the core targets such as IL⁃6, IL⁃1β, TNF, AKT1, and regulating the signaling pathways such as AGE⁃RAGE, PI3K⁃AKT, inflammatory bowel disease, and insulin resistance. Thus, it can affect oxidative stress and inflammatory response, regulate substance metabolism, inhibit renal fibrosis, and regulate cell apoptosis, etc.

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