Sun Yuemei, Qin Ningning, Ji Qian, Wang Yanling, Qiu Fangfang, Sun Jielong, Wang Rong
（ 730050） Department of Pharmacy, No 940 Hospital of the PLA Joint Logistics Support Force, Lanzhou 730050, China.
（ 730000） School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
Sichuan Da Xue Xue Bao Yi Xue Ban. 2025 Jan 20;56(1):112-119. doi: 10.12182/20250160603.
To explore the targets and molecular mechanisms of salidroside in improving cognitive function at high altitudes using network pharmacology, molecular docking, and experimental validation.
The SwissTargetPrediction platform was used to screen for salidroside-related targets, and the GeneCards database was used to search for targets associated with high-altitude cognitive function. The VENNY 2.1 platform was used to create a Venn diagram showing the intersection of salidroside and the targets of high-altitude cognitive function. The STRING11.5 database was used to construct a protein-protein interaction network diagram to screen for the key targets. The DAVID database was used to perform the Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and a component-target-pathway network was constructed using the Cytoscape 3.7.2 software platform. Furthermore, molecular docking and experimental studies were conducted for preliminary validation. Male C57BL/6J mice were randomly assigned to three groups, a low-altitude control group (Con group) receiving sterile water via intragastric gavage, a high-altitude hypoxia group (Hyp group) receiving sterile water via intragastric gavage, and a salidroside group administered with 10 mg/kg salidroside via intragastric gavage. The Hyp group and the salidroside group were pre-treated for 3 days (once daily) before rapid ascension to an altitude of 4010 m. Then, the 2 groups were exposed to a hypoxic environment for 1 day and received an additional treatment. Hippocampal tissues were collected from all three groups, and the relevant proteins were measured by Western blot.
A total of 100 salidroside targets, 2212 high-altitude cognition-related gene targets, and 52 common targets were identified. The improvement in high-altitude cognitive function by salidroside could be closely associated with core targets such as VEGFA, GAPDH, MMP-9, HRAS, FGF-2, HSP90AA1, and MAPK1, involving mainly the PI3K-Akt, MAPK, and VEGF signaling pathways. According to the molecular docking results, GAPDH, MMP-9, and VEGFA showed the best binding ability with salidroside. Experimental findings showed that salidroside improved high-altitude cognitive function by regulating the levels of Bcl-2/Bax, SRC-1, NF-κB, Beclin-1, and LC3BⅡ/Ⅰ.
Salidroside exerts its therapeutic effects in improving high-altitude cognitive function by regulating the expression levels of proteins associated with cell apoptosis, cell proliferation, and cell autophagy, inhibiting inflammation and stress response, and reducing apoptosis and excessive autophagy in hippocampal neurons.
运用网络药理学、分子对接和实验验证，探索红景天苷改善高原认知功能的靶点及分子机制。
利用瑞士靶点预测平台筛选红景天苷相关靶点，借助基因卡片数据库搜索与高原认知功能相关的靶点。运用VENNY 2.1平台绘制维恩图，展示红景天苷与高原认知功能靶点的交集。利用STRING11.5数据库构建蛋白质-蛋白质相互作用网络图，筛选关键靶点。使用DAVID数据库进行基因本体（GO）分析和京都基因与基因组百科全书（KEGG）通路富集分析，并使用Cytoscape 3.7.2软件平台构建成分-靶点-通路网络。此外，进行分子对接和实验研究以进行初步验证。将雄性C57BL/6J小鼠随机分为三组，低海拔对照组（Con组）经胃内灌胃给予无菌水，高海拔缺氧组（Hyp组）经胃内灌胃给予无菌水，红景天苷组经胃内灌胃给予10 mg/kg红景天苷。Hyp组和红景天苷组在快速升至海拔4010 m前预处理3天（每日一次）。然后，两组暴露于低氧环境1天并接受额外处理。收集三组小鼠的海马组织，通过蛋白质印迹法检测相关蛋白。
共鉴定出100个红景天苷靶点、2212个高原认知相关基因靶点和52个共同靶点。红景天苷对高原认知功能的改善可能与VEGFA、GAPDH、MMP-9、HRAS、FGF-2、HSP90AA1和MAPK1等核心靶点密切相关，主要涉及PI3K-Akt、MAPK和VEGF信号通路。根据分子对接结果，GAPDH、MMP-9和VEGFA与红景天苷表现出最佳结合能力。实验结果表明，红景天苷通过调节Bcl-2/Bax、SRC-1、NF-κB、Beclin-1和LC3BⅡ/Ⅰ的水平改善高原认知功能。
红景天苷通过调节与细胞凋亡、细胞增殖和细胞自噬相关的蛋白质表达水平，抑制炎症和应激反应，减少海马神经元凋亡和过度自噬，从而发挥改善高原认知功能的治疗作用。
