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基于网络药理学及分子对接技术探讨沙棘治疗阿尔茨海默病的作用机制
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| 篇名： | 基于网络药理学及分子对接技术探讨沙棘治疗阿尔茨海默病的作用机制 |
| TITLE： | Mechanism of Hippophae rhamnoides in the Treatment of Alzheimer ’s Disease Based on Network Pharmacology and Molecular Docking Technology |
| 摘要： | 目的：揭示沙棘治疗阿尔茨海默病（AD）的作用机制，为进一步探究沙棘治疗AD的药效物质基础提供理论参考。方法：通过TCMSP、Uniprot、GeneCards等数据库筛选沙棘活性成分、靶点及AD相关靶点基因；采用Cytoscope3.7.1软件构建化合物-靶点-疾病网络图；通过STRING数据库制作靶点相互作用（PPI）网络，筛选度值较高的沙棘治疗AD的潜在靶点与沙棘活性成分进行分子对接；采用ClueGO插件对沙棘治疗AD的潜在靶点进行GO基因本体（GO）分析、京都基因与基因组百科全书（KEGG）通路富集分析。取50只小鼠随机分为空白组、模型组[D-半乳糖120mg/（kg·d）及AlCl3溶液20mg/（mL·d）]、阳性药物组[奥拉西坦260mg/（kg·d）]、沙棘果油提取物组[1.6g/（kg·d）]、沙棘多酚提取物组[1.6g/（kg·d）]，每组10只。各组小鼠分别灌胃相应药物的同时灌胃造模剂，空白组灌胃等体积蒸馏水，每天1次，连续给药60d。通过Morris水迷宫实验测定各组小鼠学习记忆能力，采用酶联免疫吸附（ELISA）法检测小鼠海马体组织免疫因子水平，采用苏木素-伊红染色（HE）法观察海马体的病理学变化，对沙棘治疗AD的作用机制进行初步验证。结果：沙棘22个活性成分（槲皮素、山柰酚、异鼠李素、β-胡萝卜素、β-谷固醇等）可能通过调控丝氨酸/苏氨酸激酶编码蛋白（AKT1）、氨基端激酶（JUN）、丝裂原活化蛋白激酶（MAPK1）等147个靶点影响核受体活性、脂多糖介导的信号通路等生物过程及白细胞介素17（IL-17）信号传导途径、肿瘤坏死因子（TNF）信号传导途径等114条代谢通路。分子对接结果显示，沙棘主要活性成分与主要靶点蛋白结合分值均在4.25以上，具有较好的结合活性。药理学实验结果显示，沙棘提取物能够使AD模型小鼠的逃避潜伏期缩短、穿越平台次数增加，减轻其脑海马体组织损伤，降低其脑海马体组织中炎性因子TNF-α、IL-1β、IL-6、IL-17含量。结论：沙棘的活性成分可调控AD发病重要通路中的多个靶点；动物实验初步验证其可通过抑制炎症因子的表达，来减轻AD模型小鼠海马体损伤，改善小鼠学习记忆能力。 |
| ABSTRACT： | OBJECTIVE：To explore the mechanism of Hippophae rhamnoides in the treatment of Alzheimer ’s disease （AD）， and to provide theoretic reference for further exploring the material basis. METHODS ：TCMSP，Uniprot，GeneCards database were used to screen the active components of H. rhamnoides ，targets and AD-related target gene. The “ingredients-targets-related diseases”network was constructed by Cytoscape 3.7.1 software. STRING database was adopted to construct protein interaction （PPI）network，molecular docking was conducted between the potential targets with high degree values and active components of H. rhamnoides . The gene ontology （GO）analysis and Kyoto encyclopedia of genes and genomes （KEGG）pathway enrichment analysis were performed by Clue GO for the potential target of H. rhamnoides in the treatment of AD. Totally 50 mice were randomly divided into blank group ，model group [ D-galactose 120 mg/（kg·d），AlCl3 solution 20 mg/（mL·d）]，positive drug group [oxiracetam 260 mg/（kg·d）]，seabuckthorn oil extract group [ 1.6 g/（kg·d）]，seabuckthorn polyphenols group [1.6 g/（kg·d）]，with 10 mice in each group. The mice was given relevant medicine intragastrically and modeling agent ；blank group was given constant volume of distilled water intragastrically ，once a day ，for consecutive 60 d. The learning and memory abilities were detected by Morris water maze test ；the levels of immune factors in hippocampus tissue were measured by ELISA. Pathological morphology of hippocampus tissue was observed by HE staining. The mechanism of H. rhamnoides in the treatment of AD was validated preliminarily. RESULTS ：Totally 22 active components of H. rhamnoides （quercetin，kaempferol，isorhamnetin， β-carotene，β-sitosterol） may affect biological processes such as nuclear receptor activity ，lipopolysaccharide-mediated signal pathway，and may affect 114 methabolism pathways such as IL- 17 signal transduction pathway ，TNF signal transduction pathway by regulating 147 targets such as serine/threonine kinase coding protein （AKT1），amino terminal kinase （JUN）and mitogen activated protein kinase （MAPK1）. The results of molecular docking showed that binding scores of the main active components of H. rhamnoides and the main target proteins were all above 4.25，which showed good binding activity. Results of pharmacology experiment showed that H. rhamnoides extract could shorten the escape latency of AD model mice ，increased the times of crossing platform，relieved hippocampus injury of cerebral tissue ，and decreased the contents of inflammatory factors TNF-α，IL-1β，IL-6 and IL- 17 in hippocampus of cerebral tissue. CONCLUSIONS ：The active components of H. rhamnoides can regulate multiple targets in the important pathway of AD ；animal experiments preliminarily verify that H. rhamnoides can relieve the hippocampus injury and improve the learning and memory ability of AD model mice by inhibiting the expression of inflammatory factors. |
| 期刊： | 2020年第31卷第19期 |
| 作者： | 汤威威，赵宏，孔令洲，高琪，焦莹莹，张宇，吴丽丽，沈宇，王宇亮 |
| AUTHORS： | TANG Weiwei， ZHAO Hong，KONG Lingzhou，GAO Qi，JIAO Yingying，ZHANG Yu，WU Lili，SHEN Yu，WANG Yuliang |
| 关键字： | 沙棘；阿尔茨海默病；网络药理学；分子对接 |
| KEYWORDS： | Hippophae rhamnoides ；Alzheimer’s disease ；Network pharmacology ；Molecular docking |
| 阅读数： | 523 次 |
| 本月下载数： | 8 次 |
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