Obesity, a condition associated with the development of widespread cardiovascular disease, metabolic disorders, and other health complications, has emerged as a significant global health issue. Oleanolic acid (OA), a pentacyclic triterpenoid compound that is widely distributed in various natural plants, has demonstrated potential anti-inflammatory and anti-atherosclerotic properties. However, the mechanism by which OA fights obesity has not been well studied. Network pharmacology was utilized to search for potential targets and pathways of OA against obesity. Molecular docking and molecular dynamics simulations were utilized to validate the interaction of OA with core targets, and an animal model of obesity induced by high-fat eating was then employed to confirm the most central of these targets. The network pharmacology study thoroughly examined 42 important OA targets for the treatment of obesity. The key biological processes (BP), cellular components (CC), and molecular functions (MF) of OA for anti-obesity were identified using GO enrichment analysis, including intracellular receptor signaling, intracellular steroid hormone receptor signaling, chromatin, nucleoplasm, receptor complex, endoplasmic reticulum membrane, and RNA polymerase II transcription Factor Activity. The KEGG/DAVID database enrichment study found that metabolic pathways, PPAR signaling pathways, cancer pathways/PPAR signaling pathways, insulin resistance, and ovarian steroidogenesis all play essential roles in the treatment of obesity and OA. The protein-protein interaction (PPI) network was used to screen nine main targets: PPARG, PPARA, MAPK3, NR3C1, PTGS2, CYP19A1, CNR1, HSD11B1, and AGTR1. Using molecular docking technology, the possible binding mechanism and degree of binding between OA and each important target were validated, demonstrating that OA has a good binding potential with each target. The molecular dynamics simulation’s Root Mean Square Deviation (RMSD), and Radius of Gyration (Rg) further demonstrated that OA has strong binding stability with each target. Additional animal studies confirmed the significance of the core target PPARG and the core pathway PPAR signaling pathway in OA anti-obesity. Overall, our study utilized a multifaceted approach to investigate the value and mechanisms of OA in treating obesity, thereby providing a novel foundation for the identification and development of natural drug treatments.

中文翻译：

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结合网络药理学和动物实验验证探讨齐墩果酸治疗肥胖的作用机制

肥胖是一种与广泛的心血管疾病、代谢紊乱和其他健康并发症的发展相关的疾病，已成为一个重大的全球健康问题。齐墩果酸（OA）是一种五环三萜类化合物，广泛分布于各种天然植物中，已显示出潜在的抗炎和抗动脉粥样硬化特性。然而，OA对抗肥胖的机制尚未得到充分研究。利用网络药理学寻找OA对抗肥胖的潜在靶点和途径。利用分子对接和分子动力学模拟来验证 OA 与核心靶点的相互作用，然后采用高脂饮食诱发肥胖的动物模型来确认这些靶点中最核心的靶点。网络药理学研究彻底检查了 42 个治疗肥胖症的重要 OA 靶点。利用GO富集分析鉴定了OA抗肥胖的关键生物学过程（BP）、细胞成分（CC）和分子功能（MF），包括细胞内受体信号传导、细胞内类固醇激素受体信号传导、染色质、核质、受体复合物、内质网膜和 RNA 聚合酶 II 转录因子活性。KEGG/DAVID数据库富集研究发现，代谢途径、PPAR信号途径、癌症途径/PPAR信号途径、胰岛素抵抗和卵巢类固醇生成在肥胖和OA的治疗中都发挥着重要作用。蛋白质-蛋白质相互作用（PPI）网络用于筛选九个主要靶标：PPARG、PPARA、MAPK3、NR3C1、PTGS2、CYP19A1、CNR1、HSD11B1和AGTR1。利用分子对接技术，验证了OA与各重要靶点可能的结合机制和结合程度，证明OA与各重要靶点具有良好的结合潜力。分子动力学模拟的均方根偏差（RMSD）和回转半径（Rg）进一步证明OA与各个靶点具有很强的结合稳定性。其他动物研究证实了核心靶点 PPARG 和核心通路 PPAR 信号通路在 OA 抗肥胖中的重要性。总的来说，我们的研究采用多方面的方法来研究 OA 在治疗肥胖方面的价值和机制，从而为天然药物治疗的识别和开发提供了新的基础。