Chinese Journal of Tissue Engineering Research ›› 2020, Vol. 24 ›› Issue (29): 4613-4619.doi: 10.3969/j.issn.2095-4344.2811
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Nong Jiao1, Zeng Ping2, Li Juan2, Liu Jinfu1, Li Jinyi2
Received:
2019-08-27
Revised:
2019-09-06
Accepted:
2019-10-26
Online:
2020-10-18
Published:
2020-09-11
Contact:
Zeng Ping, MD, Professor, First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
About author:
Nong Jiao, Master candidate, Guangxi University of Chinese Medicine, Nanning 530001, Guangxi Zhuang Autonomous Region, China
Supported by:
CLC Number:
Nong Jiao, Zeng Ping, Li Juan, Liu Jinfu, Li Jinyi. Immunoinflammatory mechanism of Panax notoginseng in the treatment of osteonecrosis of the femoral head based on network pharmacology[J]. Chinese Journal of Tissue Engineering Research, 2020, 24(29): 4613-4619.
2.2 股骨头坏死相关“活性成分-靶点网络”构建和分析 通过GeneCards、OMIM数据库共筛选出1 612个基因与股骨头坏死相关。通过对三七靶点与股骨头坏死疾病发病机制靶点进行统计,并利用R软件绘制三七药物潜在靶点与股骨头坏死发病机制靶点韦恩图,见图1,共筛选出98个作用靶蛋白,其中包括丝氨酸苏氨酸蛋白激酶(AKT1)、白细胞介素6(IL-6)、血管内皮生长因子A(VEGFA)、胱天蛋白酶3(CASP3)、氨基末端激酶(JUN)、表皮细胞生长因子(EGF)、丝裂原活化蛋白激酶(MAPK1)、前列腺素内过氧化物合酶(PTGS2)、表皮生长因子受体(EGFR)、白细胞介素1β(IL-1β)等。运用cytoscape3.7.1将药物、药物成分以及疾病作用靶蛋白绘制成三七对股骨头坏死作用靶点的蛋白互作网络关系,见图2,应用R软件绘制三七对股骨头坏死作用靶点的PPI网络核心靶点柱状图,见图3,运用cytoscape3.7.1进行三七对股骨头坏死作用靶点的蛋白互作网络的拓扑学分析,经插件CytoHubba分析网络拓扑学属性发现,该PPI网络中 ClusteringCoefficient为0.657,Betweenness为66.680,Radiality在2.146-2.792之间,Closeness在45.333-86之间,Degree最大值为76。研究发现,一个蛋白的Degree值和基因的重要性直接相关,也就是说具有高Degree的蛋白更倾向于是关键蛋白,在三七对股骨头坏死作用靶点的拓扑学分析中,如丝氨酸苏氨酸蛋白激酶、白细胞介素6、血管内皮生长因子A、胱天蛋白酶3、氨基末端激酶、表皮细胞生长因子、丝裂原活化蛋白激酶、前列腺素内过氧化物合酶、表皮生长因子受体、白细胞介素1β等蛋白Degree值在43-76之间,说明在三七对股骨头坏死作用靶点的蛋白互作网络的拓扑学分析中起到关键蛋白作用。 "
2.2 股骨头坏死相关“活性成分-靶点网络”构建和分析 通过GeneCards、OMIM数据库共筛选出1 612个基因与股骨头坏死相关。通过对三七靶点与股骨头坏死疾病发病机制靶点进行统计,并利用R软件绘制三七药物潜在靶点与股骨头坏死发病机制靶点韦恩图,见图1,共筛选出98个作用靶蛋白,其中包括丝氨酸苏氨酸蛋白激酶(AKT1)、白细胞介素6(IL-6)、血管内皮生长因子A(VEGFA)、胱天蛋白酶3(CASP3)、氨基末端激酶(JUN)、表皮细胞生长因子(EGF)、丝裂原活化蛋白激酶(MAPK1)、前列腺素内过氧化物合酶(PTGS2)、表皮生长因子受体(EGFR)、白细胞介素1β(IL-1β)等。运用cytoscape3.7.1将药物、药物成分以及疾病作用靶蛋白绘制成三七对股骨头坏死作用靶点的蛋白互作网络关系,见图2,应用R软件绘制三七对股骨头坏死作用靶点的PPI网络核心靶点柱状图,见图3,运用cytoscape3.7.1进行三七对股骨头坏死作用靶点的蛋白互作网络的拓扑学分析,经插件CytoHubba分析网络拓扑学属性发现,该PPI网络中 ClusteringCoefficient为0.657,Betweenness为66.680,Radiality在2.146-2.792之间,Closeness在45.333-86之间,Degree最大值为76。研究发现,一个蛋白的Degree值和基因的重要性直接相关,也就是说具有高Degree的蛋白更倾向于是关键蛋白,在三七对股骨头坏死作用靶点的拓扑学分析中,如丝氨酸苏氨酸蛋白激酶、白细胞介素6、血管内皮生长因子A、胱天蛋白酶3、氨基末端激酶、表皮细胞生长因子、丝裂原活化蛋白激酶、前列腺素内过氧化物合酶、表皮生长因子受体、白细胞介素1β等蛋白Degree值在43-76之间,说明在三七对股骨头坏死作用靶点的蛋白互作网络的拓扑学分析中起到关键蛋白作用。 "
2.2 股骨头坏死相关“活性成分-靶点网络”构建和分析 通过GeneCards、OMIM数据库共筛选出1 612个基因与股骨头坏死相关。通过对三七靶点与股骨头坏死疾病发病机制靶点进行统计,并利用R软件绘制三七药物潜在靶点与股骨头坏死发病机制靶点韦恩图,见图1,共筛选出98个作用靶蛋白,其中包括丝氨酸苏氨酸蛋白激酶(AKT1)、白细胞介素6(IL-6)、血管内皮生长因子A(VEGFA)、胱天蛋白酶3(CASP3)、氨基末端激酶(JUN)、表皮细胞生长因子(EGF)、丝裂原活化蛋白激酶(MAPK1)、前列腺素内过氧化物合酶(PTGS2)、表皮生长因子受体(EGFR)、白细胞介素1β(IL-1β)等。运用cytoscape3.7.1将药物、药物成分以及疾病作用靶蛋白绘制成三七对股骨头坏死作用靶点的蛋白互作网络关系,见图2,应用R软件绘制三七对股骨头坏死作用靶点的PPI网络核心靶点柱状图,见图3,运用cytoscape3.7.1进行三七对股骨头坏死作用靶点的蛋白互作网络的拓扑学分析,经插件CytoHubba分析网络拓扑学属性发现,该PPI网络中 ClusteringCoefficient为0.657,Betweenness为66.680,Radiality在2.146-2.792之间,Closeness在45.333-86之间,Degree最大值为76。研究发现,一个蛋白的Degree值和基因的重要性直接相关,也就是说具有高Degree的蛋白更倾向于是关键蛋白,在三七对股骨头坏死作用靶点的拓扑学分析中,如丝氨酸苏氨酸蛋白激酶、白细胞介素6、血管内皮生长因子A、胱天蛋白酶3、氨基末端激酶、表皮细胞生长因子、丝裂原活化蛋白激酶、前列腺素内过氧化物合酶、表皮生长因子受体、白细胞介素1β等蛋白Degree值在43-76之间,说明在三七对股骨头坏死作用靶点的蛋白互作网络的拓扑学分析中起到关键蛋白作用。 "
2.3 靶点生物学功能分析 将“图1”疾病基因-药物靶点导入Protein name进行注释,注释结果导入David数据库,在DAVID数据库Functional Annotation Tool的Upload中粘贴筛选出关键基因,以人类全基因组为背景和参照,分析结果设置阈值EASE< 0.05,Count≥4,FDR< 0.01,P < 0.05,获得显著性较高的生物过程和通路富集的结果,点击通路名称可以链接到KEGG数据库查看通路图及详情,分析得出12个生物过程(biological process,BP):包括炎症反应、免疫反应、脂多糖介导的信号通路、通过死亡域受体对外源性凋亡信号通路的负调节等;4个细胞组分(cellular component,CC):包括细胞外间隙、细胞外基质、细胞核、高尔基体;8个分子功能(molecular function,MF):包括转录因子活性、序列特异性DNA结合、生长因子活性等,见图4;经R语言运行后共得到105个功能,做前15个功能的GO功能富集的柱状图,P 值代表富集的显著性,相应的P 值也越小,其颜色越偏向红色,反之颜色偏向蓝色;横坐标表示富集数目,见图5。由结果可知GO功能富集后富集数目较多的有DNA结合转录激活活性、受体配体活性(receptor ligand activity)、细胞因子受体结合转录因子活性(cytokine receptor binding、transcription factor activity)、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结合转录激活因子活性(DNA-binding transcription activator activity)、RNA聚合酶II特异性(RNA polymerase II-specific)、细胞因子活性(cytokine activity)等。 "
2.3 靶点生物学功能分析 将“图1”疾病基因-药物靶点导入Protein name进行注释,注释结果导入David数据库,在DAVID数据库Functional Annotation Tool的Upload中粘贴筛选出关键基因,以人类全基因组为背景和参照,分析结果设置阈值EASE< 0.05,Count≥4,FDR< 0.01,P < 0.05,获得显著性较高的生物过程和通路富集的结果,点击通路名称可以链接到KEGG数据库查看通路图及详情,分析得出12个生物过程(biological process,BP):包括炎症反应、免疫反应、脂多糖介导的信号通路、通过死亡域受体对外源性凋亡信号通路的负调节等;4个细胞组分(cellular component,CC):包括细胞外间隙、细胞外基质、细胞核、高尔基体;8个分子功能(molecular function,MF):包括转录因子活性、序列特异性DNA结合、生长因子活性等,见图4;经R语言运行后共得到105个功能,做前15个功能的GO功能富集的柱状图,P 值代表富集的显著性,相应的P 值也越小,其颜色越偏向红色,反之颜色偏向蓝色;横坐标表示富集数目,见图5。由结果可知GO功能富集后富集数目较多的有DNA结合转录激活活性、受体配体活性(receptor ligand activity)、细胞因子受体结合转录因子活性(cytokine receptor binding、transcription factor activity)、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结合转录激活因子活性(DNA-binding transcription activator activity)、RNA聚合酶II特异性(RNA polymerase II-specific)、细胞因子活性(cytokine activity)等。 "
2.4 KEGG靶点通路分析 使用R语言程序将所得的98个共作靶点进行KEGG通路富集分析,运行R程序后得到76条信号转导通路,将靶点富集最多的前20的信号通路经R程序绘制KEGG通路富集分析柱状图,见图6,P 值代表富集的显著性,相应的P值也越小,其颜色越偏向红色,反之颜色偏向蓝色;富集分析结果显示,三七治疗股骨头坏死除涉及到糖尿病并发症中的糖化终末产物及其受体信号通路(AGE-RAGE signaling pathway in diabetic complications)、流体剪切力及动脉硬化(Fluid shear stress and atherosclerosis)、卡波西肉瘤相关疱疹病毒感染(Kaposi sarcoma-associated herpesvirus infection)、甲型流感(Influenza A)、磷脂酰肌醇3激酶/蛋白激酶B信号通路(PI3K-Akt signaling pathway)、丝裂原活化蛋白激酶信号通路(MAPK signaling pathway)等通路比较明显外,另外还得到肿瘤坏死因子信号通路(TNF signaling pathway)、核转录因子κB信号通路(NF-κB signaling pathway)、单磷酸腺苷活化蛋白激酶信号通路(AMPK signaling pathway)、Toll样受体信号通路(Toll-like receptor signaling pathway)等与细胞免疫炎症有关的通路。通过上述提到的有关免疫炎症的信号通路图,筛选出基因靶点富集靠前的5条通路并进行整合绘制最终的通路图,见图7。图中以不同颜色箭头代表不同的通路,其中箭头表示促进作用,┤表示抑制作用。通路靶点标记为紫蓝色,三七治疗股骨头坏死的免疫炎症潜在作用靶点标记为红色。图中显示出了磷脂酰肌醇3激酶/蛋白激酶B信号通路、丝裂原活化蛋白激酶信号通路、肿瘤坏死因子信号通路、核转录因子κB信号通路、Toll样受体信号通路,涉及21个三七抗免疫炎症靶点,占三七治疗股骨头坏死的免疫炎症潜蛋白靶点的40%,提示三七抗免疫炎症靶点分散于这5条信号通路中,通过调节其中的几个环节发挥作用,绝大多数靶点分散在多条通路中发挥作用,如丝氨酸苏氨酸蛋白激酶、核转录因子κB、白细胞介素1β和白细胞介素1受体。 "
2.4 KEGG靶点通路分析 使用R语言程序将所得的98个共作靶点进行KEGG通路富集分析,运行R程序后得到76条信号转导通路,将靶点富集最多的前20的信号通路经R程序绘制KEGG通路富集分析柱状图,见图6,P 值代表富集的显著性,相应的P值也越小,其颜色越偏向红色,反之颜色偏向蓝色;富集分析结果显示,三七治疗股骨头坏死除涉及到糖尿病并发症中的糖化终末产物及其受体信号通路(AGE-RAGE signaling pathway in diabetic complications)、流体剪切力及动脉硬化(Fluid shear stress and atherosclerosis)、卡波西肉瘤相关疱疹病毒感染(Kaposi sarcoma-associated herpesvirus infection)、甲型流感(Influenza A)、磷脂酰肌醇3激酶/蛋白激酶B信号通路(PI3K-Akt signaling pathway)、丝裂原活化蛋白激酶信号通路(MAPK signaling pathway)等通路比较明显外,另外还得到肿瘤坏死因子信号通路(TNF signaling pathway)、核转录因子κB信号通路(NF-κB signaling pathway)、单磷酸腺苷活化蛋白激酶信号通路(AMPK signaling pathway)、Toll样受体信号通路(Toll-like receptor signaling pathway)等与细胞免疫炎症有关的通路。通过上述提到的有关免疫炎症的信号通路图,筛选出基因靶点富集靠前的5条通路并进行整合绘制最终的通路图,见图7。图中以不同颜色箭头代表不同的通路,其中箭头表示促进作用,┤表示抑制作用。通路靶点标记为紫蓝色,三七治疗股骨头坏死的免疫炎症潜在作用靶点标记为红色。图中显示出了磷脂酰肌醇3激酶/蛋白激酶B信号通路、丝裂原活化蛋白激酶信号通路、肿瘤坏死因子信号通路、核转录因子κB信号通路、Toll样受体信号通路,涉及21个三七抗免疫炎症靶点,占三七治疗股骨头坏死的免疫炎症潜蛋白靶点的40%,提示三七抗免疫炎症靶点分散于这5条信号通路中,通过调节其中的几个环节发挥作用,绝大多数靶点分散在多条通路中发挥作用,如丝氨酸苏氨酸蛋白激酶、核转录因子κB、白细胞介素1β和白细胞介素1受体。 "
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