Postgraduate Training Base in Shanghai Gongli Hospital, Ningxia Medical University, Shanghai, China.
Department of Orthopedics, Gongli Hospital of Pudong New Area, Shanghai, China.
Front Endocrinol (Lausanne). 2022 Oct 19;13:1030278. doi: 10.3389/fendo.2022.1030278. eCollection 2022.
Type 2 diabetes (T2D) is a common chronic disease with many serious complications. Celastrol can prevent and treat type 2 diabetes by reversing insulin resistance in a number of ways. However, the specific mechanisms by which celastrol prevents and treats T2D are not well understood. The aim of this study was to explore the key gene targets and potential signaling pathway mechanisms of celastrol for the treatment of T2D.
GSE184050 was downloaded from the Gene Expression Omnibus online database. Blood samples from patients and healthy individuals with T2D were analyzed to identify differentially expressed genes (DEGs), and a protein-protein interaction network (PPI) was constructed. Key gene analysis of DEGs was performed using the MCODE plugin in Cystoscope as well as the Hubba plugin, and intersections were taken to obtain hub genes, which were displayed using a Venn diagram. Enrichment analysis was then performed the ClueGo plugin in Cytoscape and validated using Gene Set Enrichment Analysis. The therapeutic targets of celastrol were then analyzed by pharmacophore network pharmacology, intersected to identify the therapeutic targets of celastrol, enriched for all targets, and intersected to obtain the signaling pathways for celastrol treatment. The protein structures of the therapeutic targets were predicted using the artificial intelligence AlphaFold2. Finally, molecular docking was used to verify whether celastrol could be successfully docked to the predicted targets.
618 DEGs were obtained, and 9 hub genes for T2D were identified by the MCODE and Hubba plug-ins, including ADAMTS15, ADAMTS7, ADAMTSL1, SEMA5B, ADAMTS8, THBS2, HBB, HBD and HBG2. The DEG-enriched signaling pathways mainly included the ferroptosis and TGF-beta signaling pathways. A total of 228 target genes were annotated by pharmacophore target analysis, and the therapeutic targets were identified, including S100A11, RBP3, HBB, BMP7 and IQUB, and 9 therapeutic signaling pathways were obtained by an intersectional set. The protein structures of the therapeutic targets were successfully predicted by AlphaFold2, and docking was validated using molecular docking.
Celastrol may prevent and treat T2D through key target genes, such as HBB, as well as signaling pathways, such as the TGF-beta signaling pathway and type II diabetes mellitus.
2 型糖尿病（T2D）是一种常见的慢性疾病，有许多严重的并发症。藜芦醇通过多种方式逆转胰岛素抵抗，可预防和治疗 2 型糖尿病。然而，藜芦醇预防和治疗 T2D 的具体机制尚不清楚。本研究旨在探讨藜芦醇治疗 T2D 的关键基因靶点和潜在信号通路机制。
从在线基因表达综合数据库（Gene Expression Omnibus，GEO）中下载 GSE184050 数据集。分析 T2D 患者和健康对照人群的血液样本，以鉴定差异表达基因（differentially expressed genes，DEGs），构建蛋白质-蛋白质相互作用网络（protein-protein interaction network，PPI）。使用 Cystoscope 中的 MCODE 插件和 Hubba 插件对 DEGs 进行关键基因分析，取交集获得枢纽基因，并用韦恩图展示。然后使用 Cytoscape 中的 ClueGo 插件进行富集分析，并通过基因集富集分析进行验证。利用基于配体的网络药理学分析藜芦醇的治疗靶点，取交集鉴定藜芦醇的治疗靶点，对所有靶点进行富集分析，取交集获得藜芦醇治疗的信号通路。使用人工智能 AlphaFold2 预测治疗靶点的蛋白结构。最后，进行分子对接以验证藜芦醇是否能成功与预测的靶点结合。
获得了 618 个 DEGs，通过 MCODE 和 Hubba 插件鉴定了 9 个与 T2D 相关的枢纽基因，包括 ADAMTS15、ADAMTS7、ADAMTSL1、SEMA5B、ADAMTS8、THBS2、HBB、HBD 和 HBG2。DEG 富集的信号通路主要包括铁死亡和 TGF-β信号通路。通过基于配体的网络药理学分析共注释了 228 个靶基因，鉴定了藜芦醇的治疗靶点，包括 S100A11、RBP3、HBB、BMP7 和 IQUB，并通过交集获得了 9 个治疗信号通路。使用人工智能 AlphaFold2 成功预测了治疗靶点的蛋白结构，并用分子对接进行了验证。
藜芦醇可能通过 HBB 等关键靶基因以及 TGF-β信号通路和 2 型糖尿病等信号通路来预防和治疗 T2D。
