Cai Yawen, Huang Guiqin, Ren Menghui, Chai Yuhui, Huang Xi, Yan Tianhua
Institute of TCM-Related Comorbid Depression, Nanjing University of Chinese Medicine, Nanjing, China.
School of Basic Medical Science and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Apr;398(4):4539-4558. doi: 10.1007/s00210-024-03555-0. Epub 2024 Nov 6.
Alzheimer's disease (AD) is a neurological disorder leading to cognitive deficits. Salidroside (Sal), a primary bioactive ingredient extracted from the roots of Rhodiola rosea L., has potent neuroprotective effects in AD. However, studies on potential targets for Sal-anchored AD are limited. In this study, we combined network pharmacology, bioinformatics, and experimental validation to identify potential targets of Sal treating AD. First, we screened 10 pyroptosis-related genes (PRGs) in Sal and AD using public databases. Then, we used Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes enrichment analysis to explore the biological functions of the shared PRGs (Sal and AD). This finding exhibited that pathways linked to inflammation, like the nucleotide oligomerization domain (NOD)-like receptors signaling pathway, are important for Sal to help fight AD. The GeneMANIA functional results subsequently revealed an association between AD and the processes of inflammasome complex and inflammatory response. Additionally, nine hub genes were identified in the protein-protein interaction network of these shared PRGs. Subsequent analysis of the genes and phenotypes confirmed that these nine hub genes were directly correlated with AD. Subsequently, an in vitro AD model was created using rat adrenal pheochromocytoma cell line (PC12) cells induced by amyloid β-peptide (Aβ) 25-35 (20 µM). Sal significantly reduced the pyroptosis caused by Aβ 25-35 in PC12 cells and decreased the expression levels of IL-1β, CASP1, IL-18, PYCARD, and NLRP3. Furthermore, molecular docking and molecular dynamics simulations confirmed that Sal could stably bind to NLRP3. Druggability analysis revealed that Sal had excellent druggability. These results demonstrated that Sal could alleviate AD by targeting IL-1β, CASP1, IL-18, PYCARD, and NLRP3 to regulate the NLRP3-mediated pyroptosis signaling pathway.
阿尔茨海默病（AD）是一种导致认知缺陷的神经疾病。红景天苷（Sal）是从蔷薇红景天根部提取的主要生物活性成分，在AD中具有强大的神经保护作用。然而，关于Sal治疗AD的潜在靶点的研究有限。在本研究中，我们结合网络药理学、生物信息学和实验验证来确定Sal治疗AD的潜在靶点。首先，我们使用公共数据库在Sal和AD中筛选了10个焦亡相关基因（PRG）。然后，我们使用基因本体论和京都基因与基因组百科全书富集分析来探索共享PRG（Sal和AD）的生物学功能。这一发现表明，与炎症相关的途径，如核苷酸寡聚化结构域（NOD）样受体信号通路，对Sal对抗AD很重要。随后的基因共表达网络分析（GeneMANIA）功能结果揭示了AD与炎性小体复合物和炎症反应过程之间的关联。此外，在这些共享PRG的蛋白质-蛋白质相互作用网络中鉴定出9个枢纽基因。对这些基因和表型的后续分析证实，这9个枢纽基因与AD直接相关。随后，使用由淀粉样β肽（Aβ）25-35（20µM）诱导的大鼠肾上腺嗜铬细胞瘤细胞系（PC12）细胞创建了体外AD模型。Sal显著降低了Aβ 25-35诱导的PC12细胞焦亡，并降低了IL-1β、CASP1、IL-18、PYCARD和NLRP3的表达水平。此外，分子对接和分子动力学模拟证实Sal可以稳定地与NLRP3结合。成药分析表明Sal具有良好的成药潜力。这些结果表明，Sal可以通过靶向IL-1β、CASP1、IL-18、PYCARD和NLRP3来调节NLRP3介导的焦亡信号通路，从而缓解AD。
