Chinese Journal of Tissue Engineering Research ›› 2022, Vol. 26 ›› Issue (5): 742-748.doi: 10.12307/2022.121
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Zhao Yuwei1, Gao Yuting2, Li Zhen1, 2, Hao Huiqin1, 2
Received:
2020-11-10
Revised:
2020-11-13
Accepted:
2020-12-14
Online:
2022-02-18
Published:
2021-12-01
Contact:
Hao Huiqin, MD, Professor, Basic Medical College, Basic Laboratory of Integrated Traditional Chinese and Western Medicine, Shanxi University of Chinese Medicine, Jinzhong 030600, Shanxi Province, China
About author:
Zhao Yuwei, MD, Lecturer, Basic Medical College, Shanxi University of Chinese Medicine, Jinzhong 030600, Shanxi Province, China
Supported by:
CLC Number:
Zhao Yuwei, Gao Yuting, Li Zhen, Hao Huiqin . Mechanism of Ermiao San in the treatment of rheumatoid arthritis[J]. Chinese Journal of Tissue Engineering Research, 2022, 26(5): 742-748.
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2.2 类风湿关节炎相关靶点的获取 从 Genecards数据库获得类风湿关节炎靶点4 329个。根据经验设定Score值大于中位数的目标靶点为类风湿关节炎的潜在靶点。GeneCards 数据库中,类风湿关节炎靶点Score值最大值为114.78,最小值为0.23,中位数为1.82,因此Score > 1.82的靶点为类风湿关节炎的潜在靶点。然后,结合其他数据库进行补充,最终预测了2 247个类风湿关节炎相关靶点。 2.3 二妙散成分-类风湿关节炎靶点-通路网络的构建 将预测的二妙散药物靶点与类风湿关节炎疾病靶点取交集,并通过Venny绘制韦恩图,得到二妙散成分-类风湿关节炎共同靶点132 个,见图1。将这132个靶点录入STRING,获得了PPI网络,并导入Cytoscape软件绘制蛋白关系PPI网络图,见图2。该网络包括132个节点,共524条边。节点的大小、颜色与此节点的Degree值成正比,即节点越大、颜色越深对应蛋白的Degree值越大。使用插件CytoHubba计算出得分较高的关键作用靶点,见图3,包括肿瘤坏死因子、JUN、白细胞介素1B、RELA、白细胞介素4、白细胞介素6、CXCL8、CCL2、白细胞介素2和IFNG,这些靶点在蛋白网络中具有枢纽的重要地位,在二妙散治疗类风湿关节炎中具有重要意义,可作为其有效成分作用的靶点。"
2.4 靶点功能与通路的富集分析 文章采用 Metascape平台对二妙散治疗类风湿关节炎相关靶点进行信号通路分析,并使用 Origin Lab 9.1软件绘图。二妙散主要参与的生物学过程包括生物对有毒物质的应答过程(response to toxic substance)、对无机物的应答过程(response to inorganic substance)、对脂多糖的应答过程(response to lipopolysaccharide)、对细菌源分子的应答过程(response to molecule of bacterial origin),细胞因子介导的信号通路(cytokine-mediated signaling pathway),细胞凋亡信号通路(apoptotic signaling pathway),见图5A,参与的通路主要有AGE-RAGE信号通路、MAPK信号通路、白细胞介素17信号通路以及肿瘤坏死因子信号通路等,见图5D。 相关靶点调节类风湿关节炎的功能主要富集于转录因子结合(transcription factor binding),蛋白域特异结合(protein domain specific binding),近端启动子序列特异性DNA结合(proximal promoter sequence-specific DNA binding),RNA聚合酶Ⅱ特异性(DNA-binding transcription activator activity,RNA polymerase Ⅱ-specific),RNA聚合酶Ⅱ近端启动子序列特异性DNA结合(RNA polymerase Ⅱ proximal promoter sequence-specific DNA binding),DNA结合转录激活物活性,染色质结合(chromatin binding)等,见图5C。"
2.6 成分-靶点分子对接验证分析结果 文章选取二妙散活性成分中Degree值排名前3的关键药效物质与核心靶点进行分子对接验证发现,关键药效物质与核心靶点结合活性均较好,见表6。将上述对接结果利用Pymol软件绘图,由图可知,槲皮素与 PTGS2在ASN-382,ALA-202,ALA-199处形成氢键,与JUN在LEU-932,MET-929,GLY-856处形成氢键,与RELA在ARG-327,ARG-241,LYS-243处形成氢键;汉黄芩素与PTGS2在ASN-382,ALA-199和HIS-388处形成氢键,与JUN在LEU-932,MET-929,ASP-994处形成氢键,与RELA在GLN-325,ALA-335和HIS-176处形成氢键;β-谷甾醇与PTGS2在THR-212和TRP-387处形成氢键,与JUN在ASP-939,LYS-857和GLU-1015处形成氢键,与RELA在ASN-306,ALA-335和ARG-295处形成氢键,见图7。"
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