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基于网络药理学探讨白花蛇舌草治疗口腔癌的作用机制

更新时间:2020-10-16 08:25点击:

摘    要:
目的 探讨白花蛇舌草治疗口腔癌的作用机制及其药用价值。方法 采用HIT、中药综合资源数据库(TCMID)、PubMed、中药系统药理数据库和分析平台(TCMSP)数据库检索白花蛇舌草的化合物成分,根据毒药物动力学(ADME)参数和里宾斯基五规则筛选具有成药性的化合物成分,采用TCMSP,TargetNet,Pharmmapper数据库检索并筛选潜在靶点,采用DiseaseGene Network数据库检索口腔癌的相关靶点。采用STRING数据库建立蛋白质-蛋白质相互作用(PPI)关系,通过基因映射、拓扑分析与富集分析的方法,预测白花蛇舌草治疗口腔癌的核心靶点与通路,以及生物过程(BP)、细胞成分(CC)、分子功能(MF)。结果 共收集到93种白花蛇舌草的化合物成分,经ADME标准及里宾斯基五规则进行筛选后共获得32个化学结构不同的化合物成分,353个不同的白花蛇舌草化合物的相关靶点;通过DiseaseGene Network数据库,共收集到281个口腔癌的相关靶点;通过基因映射与拓扑分析,共获得200个白花蛇舌草治疗口腔癌的作用靶点,75个具有拓扑重要性的靶点;通过富集分析获得白花蛇舌草治疗口腔癌的336个BP、38个CC、105个MF、25条相关作用通路(P <0.05时),51个BP、7个CC、31个MF、4条核心作用通路(P <0.01,FDR <0.01时)。结论 白花蛇舌草治疗口腔癌的作用机制涉及多个靶点和信号通路,其与细胞凋亡、增殖、炎性反应、氧化应激等多个生物过程相关。
 
关键词:
白花蛇舌草 口腔癌 网络药理学 靶点 信号通路
口腔癌是临床常见的恶性肿瘤,也是导致患者死亡的重要原因[1],具有高发病率、高致死率的特点[2-3],临床多采用手术切除、放射线治疗、化学治疗、中药治疗等方式治疗。中医学认为,癌症多由热、毒、痰、瘀及体虚等因素诱发[4],中药以其疗效确切、应用广泛、不良反应小等优点,受到临床医师和科研人员的广泛关注[5]。白花蛇舌草Oldenlandia diffusa属茜草科植物,为临床治疗癌症的常用药物之一[6],广泛用于治疗结直肠癌[7]、白血病[8]、肝癌[9]、肺癌[10]、卵巢癌[11]、乳腺癌[12]等。TING等[9]对台湾地区中草药处方频度进行横断面分析发现,白花蛇舌草治疗肝癌具有显著疗效。此外,白花蛇舌草具有抗增殖[13]、促凋亡[11,14-15]抗炎[16-17]、抗氧化[18]、抗血管生成[19]、调节免疫功能[16,20-23]等多种抗癌作用机制;其提取物可通过激活p53诱导细胞凋亡,从而抑制癌细胞的生长[13],还可增强巨噬细胞功能,从而抑制小鼠肾癌细胞生长。鉴于白花蛇舌草在抗肿瘤治疗中的广泛应用及其良好的临床疗效,本研究中采用网络药理学方法整体、系统地阐述药物、靶点和疾病间的关系[24-25],直观地呈现药物靶点网络[26],探讨了白花蛇舌草治疗口腔癌的作用机制及其药用价值,为白花蛇舌草治疗口腔癌药效机制的定位和产生协同作用的潜在蛋白靶点的确定提供新的研究方法。现报道如下。
 
1 资料与方法
1.1 数据集构建
数据集收集:检索HIT(http://lifecenter.biosino.org/hit/)[27]、中药综合资源数据库(TCMID,http://www.megabionet.org/tcmid/)[28]数据库,Pub Med数据库(https://pubchem.ncbi.nlm.nih.gov/)[29]和中药系统药理数据库和分析平合(TCMSP)数据库(http://lsp.nwu.edu.cn/)[30],从生物医学文献中收集白花蛇舌草的化合物成分,构建白花蛇舌草化合物数据集。
 
化合物筛选:根据毒药物动力学(ADME)药物筛选标准,口服生物利用度(OB)≥30%,类药性指数(DL)≥0.18,血脑屏障(BBB)>-0.3,可旋转键数目(RBN)≤10,分子极性表面积(PSA)≤60,对化合物进行初筛,剔除重复出现的化合物成分。进一步运用Pub Chem数据库(https://pubchem.ncbi.nlm.nih.gov/)查询获得化合物的化学结构式[31],基于化学结构式,运用Target Net数据库(http://targetnet.scbdd.com)[32],根据里宾斯基五规则对化合物的成药性进行评分。
 
1.2 靶点预测
通过搜索TCMSP数据库中白花蛇舌草化合物的名称,获得其对应的靶蛋白信息;在基于当前化学基因组学数据构建大量的QSAR模型来预测化合物靶点的Target Net数据库中检索,并筛选Prob≥0.9的靶点[32]。运用Pharmmapper数据库(http://lilab-ecust.edu.cn/Pharmmapper/)[33],通过反向药效团映射方法识别小分子的潜在靶点。
 
1.3 靶点收集及蛋白质-蛋白质相互作用(PPI)网络建立
采用Disease Gene Network数据库(http://www.disgenet.org/)[34]和Drug Bank数据库(https://www.drugbank.ca/)[35],搜索与“Oral Cavity Carcinoma”相关的疾病靶点,采用Gene MANIA数据库(http://genemania.org/)[36]建立与已获取疾病靶点关联性较强的靶点。基于收集的口腔癌相关靶点,采用STRING数据库(https://string-db.org/)[37]建立PPI网络,作为基因映射的背景网络。
 
1.4 预测靶点的基因映射提取及PPI网络建立
采用Cytoscape软件将白花蛇舌草化合物的靶点映射在口腔癌疾病靶点的PPI背景网络上,提取白花蛇舌草治疗口腔癌的预测靶点,并将其在STRING数据库建立PPI网络[37],进一步研究具有高置信度(>0.7)的PPI。
 
1.5 拓扑分析与富集分析
拓扑分析:采用Cytoscape软件,对获取的上述相关靶点,计算“Degree”“Closeness Centrality”“Betweenness Centrality”3个拓扑性质,选取3个指标均大于中位数的靶点[38],筛选出具有拓扑重要性的Hub节点,将其定义为白花蛇舌草治疗口腔癌的核心靶点。
 
富集分析:采用DAVID数据库(https://david.ncifcrf.gov/)[39]对生物过程(BP)、细胞成分(CC),分子功能(MF)及作用通路进行富集分析。P<0.05为白花蛇舌草治疗口腔癌的相关作用通路;P<0.01和FDR<1为白花蛇舌草治疗口腔癌的核心作用通路。
 
基于收集获得的白花蛇舌草治疗口腔癌的预测靶点,采用KEGG数据库(http://www.kegg.jp/)[40]搜索并建立核心通路的路线图,标注通路内的预测作用靶点。
 
1.6“靶点-通路”网络建立
基于收集获得的预测靶点及富集分析核心作用通路,采用Cytoscape软件建立白花蛇舌草治疗口腔癌的“靶点-通路”网络。
 
2 结果
2.1 数据集构建及靶点预测
通过HIT,TCMID,Pub Med,TCMSP数据库,共获得93种白花蛇舌草化学成分,根据ADME药物筛选标准及里宾斯基五规则,共筛选出32种具有良好成药性的化学成分。基于此,采用3种方法预测白花蛇舌草的靶点信息,获得1 468个靶点信息,删除不同化合物间的重复靶点,共获得353个白花蛇舌草的预测靶点。
 
2.2 口腔癌疾病相关靶点及PPI网络的建立
检索Disease Gene Network和Drug Bank数据库,共收集获得281个口腔癌的预测靶点,采用STRING数据库建立口腔癌的PPI网络,获得1个具有281个节点、4 096条边的PPI网络。详见图1。
 
2.3 基因映射结果与拓扑分析结果
基因映射:采用Cytoscape软件,将353个白花蛇舌草预测靶点映射在以口腔癌PPI网络为背景的网络上,共获得200个预测靶点,占口腔癌疾病靶点的71.17%。详见图2。
拓扑分析:白花蛇舌草治疗口腔癌的200个预测靶点中,“Degree”中位数为23,“Closeness Centrality”中位数为0.476 534 985,“Betweenness Centrality”中位数为0.002 067 075,其中,“Degree”“Closeness Centrality”“Betweenness Centrality均大于中位数,且具有重要拓扑意义的节点共75个,即为Hub节点,为白花蛇舌草治疗口腔癌的核心靶点。
 
2.4 预测靶点的PPI网络建立、富集分析结果及“靶点-通路”网络建立
基于已获得的200个白花蛇舌草治疗口腔癌的预测靶点信息,建立PPI网络,得1个具有200个节点、2 604条边的PPI网络,选择高置信度PPI,得1个具有200个节点、1 204条边的PPI网络,详见图3。对预测靶点信息进行富集分析,P<0.05时包括336个BP、38个CC、105个MF、25条相关作用通路,P<0.01及FDR<0.01时包括51个BP、7个CC、31个MF、4条核心作用通路。基于此,构建白花蛇舌草治疗口腔癌的“靶点-通路”网络图,详见图4。基于在KEGG建立的4个核心作用通路的可视化通路网络图,建立白花蛇舌草治疗口腔癌的可视化通路网络图,详见图5。
 
 
3 讨论
本研究中,根据里宾斯基五规则和ADME参数[30,32]筛选出白花蛇舌草中32种具有良好成药性的不同化合物成分,根据这些化合物成分,采用TCMSP,Target Net,Pharmmapper数据库检索,收集到353个白花蛇舌草靶点,结合在Disease Gene Network及Drug Bank数据库收集的281个口腔癌相关靶点,通过基因映射获得了白花蛇舌草治疗口腔癌的200个预测靶点,由此建立了一个具有200个节点、1 204条边的高置信度PPI网络,通过拓扑分析,获得了白花蛇舌草治疗口腔癌的75个核心靶点。
 
富集分析结果显示,白花蛇舌草治疗口腔癌主要作用于胞浆、核质、细胞器膜、质膜、细胞核等7个细胞成分,涉及了包括凋亡、增殖、炎性反应、氧化应激等51个生物过程及31个分子功能,这与已有的体内外实验研究结果一致[13-16],其还参与如类固醇、单萜类、杂环类等多种物质的生物代谢过程,这些代谢过程也一定程度上促进了白花蛇舌草的抗癌作用,LIEW等[41]研究发现,单萜吲哚生物碱具有显著的细胞生长抑制作用,且对癌细胞具有靶向选择性。通路富集分析结果表明,HIF-1 signaling pathway,Prolactin signaling pathway,Estrogen signaling pathway,TNF signaling pathway为核心作用通路。HIF-1 signaling pathway可通过调节细胞凋亡、炎症、氧化应激及细胞周期等发挥抗癌作用。有研究发现,HIF-1通路的激活可诱导癌细胞线粒体解偶联从而发挥抗癌作用,核心靶点HIF-1被认为具有广泛前景的抗肿瘤药物靶点[42]。ALBADARI等[43]研究认为,HIF-1/2抑制剂及HIFs调节的广泛复杂性有利于开发更精确的抗癌治疗方法。Prolactin signaling pathway及Estrogen signaling pathway被认为是参与乳腺癌、前列腺癌等多种恶性肿瘤的经典作用通路[44-45]。YAMAGUCHI等[46]研究发现,阻断Estrogen signaling pathway可显著降低芳香化酶基因表达,从而抑制癌细胞的生长,这2条通路与p53 signaling pathway,PI3K signaling pathway,MAPK signaling pathway等多条通路间存在复杂的交互作用,从而发挥抗肿瘤作用[47-49]。TNF signaling pathway在肿瘤相关研究中一直是被关注的焦点,ROBAYE等[50]及TARTAGLIA等[51]研究发现,TNFR1可触发肿瘤内皮细胞凋亡机制。MONTFORT等[52]研究发现,在肿瘤细胞中输送高浓度的肿瘤坏死因子能显著提高免疫治疗效果,TNF signaling pathway不仅是与炎症、凋亡密切相关的信号通路,与PI3K-Akt signaling pathway间的交叉作用还参与细胞周期调节[53]。WANG等[54]研究发现,通过TNF-α/NF-κB与PI3K/AKT signaling pathway逆转EMT可抑制癌细胞的侵袭与迁移。
综上所述,本研究中通过网络药理学的方法建立了白花蛇舌草治疗口腔癌的可视化“靶点-通路”网络图及作用机制图,并明确了白花蛇舌草治疗口腔癌的多通路、多靶点的作用机制,白花蛇舌草治疗口腔癌药效机制的定位和协同作用的潜在蛋白靶点与通路。
 
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