Parkinson's disease (PD), a neurodegenerative disorder, is characterized by motor symptoms due to the progressive loss of dopaminergic neurons in the substantia nigra (SN) and striatum (STR), alongside neuroinflammation. Asiaticoside (AS), a primary active component with anti-inflammatory and neuroprotective properties, is derived from However, the precise mechanisms through which AS influences PD associated with inflammation are not yet fully understood. This study aimed to explore the protective mechanism of AS in PD. Targets associated with AS and PD were identified from the Swiss Target Prediction, Similarity Ensemble Approach, PharmMapper, and GeneCards database. A protein-protein interaction (PPI) network was constructed to identify potential therapeutic targets. Concurrently, GO and KEGG analyses were performed to predict potential signaling pathways. To validate these mechanisms, the effects of AS on 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice were investigated. Furthermore, neuroinflammation and the activation of the NLRP3 inflammasome were assessed to confirm the anti-inflammatory properties of AS. experiments in BV2 cells were then performed to investigate the mechanisms of AS in PD. Moreover, CETSA, molecular docking, and molecular dynamics simulations (MDs) were performed for further validation. Network pharmacology analysis identified 17 potential targets affected by AS in PD. GO and KEGG analyses suggested the biological roles of these targets, demonstrating that AS interacts with 149 pathways in PD. Notably, the NOD-like receptor signaling pathway was identified as a key pathway mediating AS's effect on PD. studies demonstrated that AS alleviated motor dysfunction and reduced the loss of dopaminergic neurons in MPTP-induced PD mice. experiments demonstrated that AS substantially decreased IL-1β release in BV2 cells, attributing this to the modulation of the NLRP3 signaling pathway. CETSA and molecular docking studies indicated that AS forms a stable complex with NLRP3. MDs suggested that ARG578 played an important role in the formation of the complex. In this study, we first predicted that the potential target and pathway of AS's effect on PD could be NLRP3 protein and NOD-like receptor signaling pathway by network pharmacology analysis. Further, we demonstrated that AS could alleviate symptoms of PD induced by MPTP through its interaction with the NLRP3 protein for the first time by and experiments. By binding to NLRP3, AS effectively inhibits the assembly and activation of the inflammasome. These findings suggest that AS is a promising inhibitor for PD driven by NLRP3 overactivation.

中文翻译：

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积雪草苷通过靶向 NLRP3 炎症小体激活发挥神经保护作用


帕金森病 (PD) 是一种神经退行性疾病，其特征是由于黑质 (SN) 和纹状体 (STR) 中多巴胺能神经元逐渐丧失而导致的运动症状，以及神经炎症。积雪草苷 (AS) 是一种具有抗炎和神经保护特性的主要活性成分，源自积雪草苷。然而，积雪草苷影响与炎症相关的 PD 的确切机制尚不完全清楚。本研究旨在探讨AS对PD的保护机制。与 AS 和 PD 相关的靶标是从 Swiss Target Prediction、Similarity Ensemble Approach、PharmMapper 和 GeneCards 数据库中确定的。构建蛋白质-蛋白质相互作用（PPI）网络来识别潜在的治疗靶点。同时，进行 GO 和 KEGG 分析来预测潜在的信号通路。为了验证这些机制，研究了 AS 对 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 诱导的小鼠 PD 的影响。此外，还评估了神经炎症和 NLRP3 炎症小体的激活，以证实 AS 的抗炎特性。然后在 BV2 细胞中进行实验以研究 AS 在 PD 中的机制。此外，还进行了 CETSA、分子对接和分子动力学模拟（MD）以进行进一步验证。网络药理学分析确定了 PD 中受 AS 影响的 17 个潜在靶点。 GO 和 KEGG 分析表明了这些靶标的生物学作用，证明 AS 与 PD 中的 149 条通路相互作用。值得注意的是，NOD 样受体信号通路被认为是介导 AS 对 PD 影响的关键通路。 研究表明，AS 可以减轻 MPTP 诱导的 PD 小鼠的运动功能障碍并减少多巴胺能神经元的损失。实验表明，AS 显着降低了 BV2 细胞中 IL-1β 的释放，这归因于 NLRP3 信号通路的调节。 CETSA 和分子对接研究表明 AS 与 NLRP3 形成稳定的复合物。 MD 表明 ARG578 在复合物的形成中发挥了重要作用。本研究首先通过网络药理学分析预测AS影响PD的潜在靶点和通路可能是NLRP3蛋白和NOD样受体信号通路。此外，我们通过实验首次证明AS可以通过与NLRP3蛋白的相互作用来缓解MPTP诱导的PD症状。通过与 NLRP3 结合，AS 有效抑制炎症小体的组装和激活。这些发现表明，AS 是一种很有前景的 NLRP3 过度激活驱动的 PD 抑制剂。