基于网络药理学及分子对接探讨恒古骨伤愈合剂抑制2型糖尿病成骨细胞铁死亡的潜在机制

Based on network pharmacology and molecular docking,to explore the potential mechanism of osteoking in inhibiting ferroptosis of type 2 diabetes osteoporosis

目的从网络药理学及分子对接角度探讨恒古骨伤愈合剂抑制成骨细胞铁死亡治疗2型糖尿病骨质疏松症的潜在作用机制。方法通过TCMSP数据库和BATMAN-TCM数据库检索获得中药成分及作用靶点,通过GeneCards与OMIM数据库查询获得2型糖尿病骨质疏松症的疾病靶点。借助STRING11.0数据库构建蛋白质相互作用网络(PPI)图,进行拓扑分析,筛选网络中重要靶点。将潜在治疗靶点导入DAVID在线数据库,进行基因本体(GO)富集分析、京都基因与基因组百科全书(KEGG)通路富集分析,最后进行分子对接模拟以验证网络药理学结果。结果通过网络药理学筛选共获得223个潜在治疗靶点。恒古骨伤愈合剂治疗2型糖尿病骨质疏松的关键活性物质为木犀草素、20(R)-人参皂苷Rh2、山柰酚、黄芩素、β-谷甾醇等,关键靶点为白细胞介素-6(IL-6)、蛋白激酶B1(Akt1)、肿瘤坏死因子(TNF)、丝裂原活化蛋白激酶3(MAPK3)、缺氧诱导因子-1A(HIF-1A)等。GO和KEGG富集分析结果表明,恒古骨伤愈合剂治疗2型糖尿病骨质疏松主要包括脂多糖的反应、对缺氧的反应、炎症反应等生物学过程,调控HIF-1A、TNF、IL-17、磷脂酰肌醇-3-激酶/蛋白激酶B(PI3K/Akt)等信号通路。分子对接结果表明7-O-甲基异微凸剑叶莎醇、黄芩素、山柰酚、槲皮素与HIF-1A均有较好的结合活性。结论通过网络药理学和分子对接技术发现恒古骨伤愈合剂可能通过多靶点治疗2型糖尿病骨质疏松,可能通过HIF-1A信号通路减少氧化应激,抑制成骨细胞铁死亡,达到治疗2型糖尿病骨质疏松症的目的。

Objective To investigate the potential mechanism of osteoking in the treatment of type 2 diabetic osteoporosis by inhibiting osteoblast ferroptosis from the perspective of network pharmacology and molecular docking.Methods TCMSP database and BATMAN-TCM database were used to retrieve the components and targets of traditional Chinese medicine,and GeneCards and OMIM database were used to obtain the disease targets of osteoporosis in type 2 diabetes.The PPI protein interaction network was constructed with STRING11.0 database,and topological analysis was performed to screen important targets in the network.The potential therapeutic targets were imported into the DAVID online database for gene ontology(GO)enrichment analysis and gene and genome encyclopedia(KEGG)pathway enrichment analysis.Finally,molecular docking simulation was performed to verify the results of network pharmacology.Results A total of 223 potential therapeutic targets were obtained through network pharmacology screening.The key active substances of osteoking in the treatment of type 2 diabetic osteoporosis are luteolin,20(R)-ginsenoside Rh2,kaempferol,baicalein,beta-sitosterol,etc.The key targets are IL-6,Akt,TNF,MAPK3,HIF-1A,etc.The results of GO and KEGG analysis showed that the treatment of osteoporosis in type 2 diabetes by osteoking mainly included biological processes such as lipopolysaccharide response,hypoxia response,and inflammatory response,and regulated HIF-1A,TNF,IL-17,PI3K/Akt and other signaling pathways.The results of molecular docking showed that 7-O-methylisoprostol,baicalein,kaempferol,and quercetin had good binding activity with HIF-1A.Conclusion Through network pharmacology and molecular docking technology,it is found that osteoking may treat type 2 diabetic osteoporosis through multiple targets,and may reduce oxidative stress and inhibit osteoblast ferroptosis through HIF-1A signaling pathway to treat type 2 diabetic osteoporosis.