■胃肠上皮化生(IM)是与胃癌相关的癌前阶段。尽管观察到二甲双胍对IM的有益作用,其分子机制仍未完全阐明。本研究旨在基于生物信息学和体内研究揭示二甲双胍治疗IM的作用和潜在机制。
■七个公共数据库(GeneCards,DisGeNet,OMIM,SuperPred,PharmMapper,瑞士目标预测,TargetNet)在这项工作中用于鉴定与肠上皮化生(IM)和二甲双胍相关的靶向基因。通过网络药理学进一步分析二甲双胍和IM之间共享的靶向基因,而两者之间的相互作用是通过分子对接研究的。并行,在IM小鼠模型中评估二甲双胍的治疗效果,而二甲双胍影响的核心靶标和途径在体内得到了验证。
■我们筛选出1,751个IM相关基因和318个二甲双胍靶向基因,通过构建蛋白质-蛋白质相互作用(PPI)网络,可视化了介于两者之间的99个常见基因。前十大核心靶向基因是EGFR,MMP9,HIF1A,HSP90AA1,SIRT1,IL2,MAPK8,STAT1,PIK3CA,和ICAM1。功能富集分析证实,癌变和HIF-1信号通路主要参与二甲双胍治疗IM。基于分子对接和动力学,我们发现二甲双胍通过抑制受体结合影响其靶点的功能。此外,二甲双胍给药显著降低了Atp4a-/-小鼠模型IM病变的进展。值得注意的是,二甲双胍增强MUC5AC的表达水平,同时抑制CDX2的表达水平。我们的结果还表明,二甲双胍通过降低NF-κB和PI3K/AKT/mTOR/HIF-1α信号通路的活性来调节体内核心靶标的表达。
■这项研究证实,二甲双胍通过调节复杂的分子网络来提高IM治疗的功效。二甲双胍在抑制进一步IM进展的炎症/凋亡相关途径中起功能作用。我们的工作为了解二甲双胍和其他胍类药物在IM治疗中的应用提供了分子基础。
UNASSIGNED: Gastric intestinal metaplasia (IM) is a precancerous stage associated with gastric cancer. Despite the observed beneficial effects of metformin on IM, its molecular mechanism remains not fully elucidated. This study aims to reveal the effects and potential mechanisms of metformin in treating IM based on both bioinformatics and in vivo investigations.
UNASSIGNED: The seven public databases (GeneCards, DisGeNET, OMIM, SuperPred, Pharm Mapper, Swiss Target Prediction, TargetNet) were used in this work to identify targeted genes related to intestinal metaplasia (IM) and metformin. The shared targeted genes between metformin and IM were further analyzed by network pharmacology, while the interactions in-between were investigated by molecular docking. In parallel, the therapeutic effect of metformin was evaluated in IM mice model, while the core targets and pathways effected by metformin were verified in vivo.
UNASSIGNED: We screened out 1,751 IM-related genes and 318 metformin-targeted genes, 99 common genes identified in between were visualized by constructing the protein-protein interaction (PPI) network. The top ten core targeted genes were EGFR, MMP9, HIF1A, HSP90AA1, SIRT1, IL2, MAPK8, STAT1, PIK3CA, and ICAM1. The functional enrichment analysis confirmed that carcinogenesis and HIF-1 signaling pathways were primarily involved in the metformin treatment of IM. Based on molecular docking and dynamics, we found metformin affected the function of its targets by inhibiting receptor binding. Furthermore, metformin administration reduced the progression of IM lesions in Atp4a-/- mice model significantly. Notably, metformin enhanced the expression level of MUC5AC, while inhibited the expression level of CDX2. Our results also showed that metformin modulated the expression of core targets in vivo by reducing the activity of NF-κB and the PI3K/AKT/mTOR/HIF-1α signaling pathway.
UNASSIGNED: This study confirms that metformin improves the efficacy of IM treatment by regulating a complex molecular network. Metformin plays a functional role in inhibiting inflammation/apoptosis-related pathways of further IM progression. Our work provides a molecular foundation for understanding metformin and other guanidine medicines in IM treatment.