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Volume 38 Issue 6
Nov.  2020
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DING Jie, NI Zhexin, CHEN Wen, YU Chaoqin. A network pharmacology approach to explore mechanisms of activating blood circulation and removing blood stasis herbs in the treatment of endometriosis[J]. Journal of Pharmaceutical Practice and Service, 2020, 38(6): 516-522. doi: 10.12206/j.issn.1006-0111.202006002
Citation: DING Jie, NI Zhexin, CHEN Wen, YU Chaoqin. A network pharmacology approach to explore mechanisms of activating blood circulation and removing blood stasis herbs in the treatment of endometriosis[J]. Journal of Pharmaceutical Practice and Service, 2020, 38(6): 516-522. doi: 10.12206/j.issn.1006-0111.202006002

A network pharmacology approach to explore mechanisms of activating blood circulation and removing blood stasis herbs in the treatment of endometriosis

doi: 10.12206/j.issn.1006-0111.202006002
  • Received Date: 2020-06-01
  • Rev Recd Date: 2020-08-26
  • Publish Date: 2020-11-25
  •   Objective  To explore the possible mechanism of activating blood circulation and removing blood stasis herbs in the treatment of endometriosis (EM) with network pharmacology approach.  Methods  Seven kinds of commonly used activating blood circulation and removing blood stasis herbs, such as: peach kernel, safflower, zeilan, salvia miltiorrhiza, leonuri, radix cyathulae, and wang buliuxing were selected as the research subjects. TCMSP platform, a database of traditional Chinese medicine chemical ingredients, was used to retrieve the effective ingredients of 7 herbs. The targets of the effective ingredients were obtained through the Targets information software. GeneCards database was used to collect EM related target genes. Venn diagram tool was used to obtain the target genes of active ingredients of activating blood circulation and removing blood stasis herbs. Cytoscape 3.6.0 software was used to construct the active ingredient-target-disease network. KEGG database was used to analyze the signal pathways of target gene enrichment.  Results  A total of 94 active ingredients and 119 targets of 7 herbs were screened. Quercetin, luteolin and kaempferol were the key active components. PTGS2, PTGS1, NCOA2 and NCOA1 were the key targets. The 7 herbs have 20 related KGEE pathways, involving sex hormones, inflammation, apoptosis and angiogenesis. PI3K-Akt signaling pathway, IL-17 signaling pathway, TNF signaling pathway were the main pathways.  Conclusion  The treatment of EM with activating blood circulation and removing blood stasis herbs has the characteristics of multiple components, multiple targets and multiple pathways, which can relieve the pain, inflammation and menstrual disorders symptoms of EM.
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A network pharmacology approach to explore mechanisms of activating blood circulation and removing blood stasis herbs in the treatment of endometriosis

doi: 10.12206/j.issn.1006-0111.202006002

Abstract:   Objective  To explore the possible mechanism of activating blood circulation and removing blood stasis herbs in the treatment of endometriosis (EM) with network pharmacology approach.  Methods  Seven kinds of commonly used activating blood circulation and removing blood stasis herbs, such as: peach kernel, safflower, zeilan, salvia miltiorrhiza, leonuri, radix cyathulae, and wang buliuxing were selected as the research subjects. TCMSP platform, a database of traditional Chinese medicine chemical ingredients, was used to retrieve the effective ingredients of 7 herbs. The targets of the effective ingredients were obtained through the Targets information software. GeneCards database was used to collect EM related target genes. Venn diagram tool was used to obtain the target genes of active ingredients of activating blood circulation and removing blood stasis herbs. Cytoscape 3.6.0 software was used to construct the active ingredient-target-disease network. KEGG database was used to analyze the signal pathways of target gene enrichment.  Results  A total of 94 active ingredients and 119 targets of 7 herbs were screened. Quercetin, luteolin and kaempferol were the key active components. PTGS2, PTGS1, NCOA2 and NCOA1 were the key targets. The 7 herbs have 20 related KGEE pathways, involving sex hormones, inflammation, apoptosis and angiogenesis. PI3K-Akt signaling pathway, IL-17 signaling pathway, TNF signaling pathway were the main pathways.  Conclusion  The treatment of EM with activating blood circulation and removing blood stasis herbs has the characteristics of multiple components, multiple targets and multiple pathways, which can relieve the pain, inflammation and menstrual disorders symptoms of EM.

DING Jie, NI Zhexin, CHEN Wen, YU Chaoqin. A network pharmacology approach to explore mechanisms of activating blood circulation and removing blood stasis herbs in the treatment of endometriosis[J]. Journal of Pharmaceutical Practice and Service, 2020, 38(6): 516-522. doi: 10.12206/j.issn.1006-0111.202006002
Citation: DING Jie, NI Zhexin, CHEN Wen, YU Chaoqin. A network pharmacology approach to explore mechanisms of activating blood circulation and removing blood stasis herbs in the treatment of endometriosis[J]. Journal of Pharmaceutical Practice and Service, 2020, 38(6): 516-522. doi: 10.12206/j.issn.1006-0111.202006002
  • 子宫内膜异位症(endometriosis,EM)是临床上最为常见的慢性妇科疾病之一,以慢性盆腔疼痛、月经紊乱和不孕为主要的临床表现。EM本质是血瘀证,临床治疗时以活血化瘀为主,常用的药物有桃仁、红花、泽兰、丹参、益母草、川牛膝、王不留行等,能够有效缓解患者痛经、非经期盆腔痛等症状[1]

    目前活血化瘀类中药对EM治疗的具体机制不是很清晰,其针对的靶点也不是很明了。网络药理学将生物网络作为研究对象,探究药物、靶点、疾病之间的联系,系统完整地研究药物的机制,可展现出药物对于多个靶点、多个通路不同影响。因为和中医整体观念天然契合,网络药理学现已广泛应用于中药研究中[2-3] 。在本研究中,笔者采用网络药理学的方法探究活血化瘀类中药治疗EM的作用机制,构建“化合物-靶标-通路-疾病”网络,并初步探析何种活血化瘀药在EM治疗中更具优势,为临床用药以及进一步实验研究提供理论依据。

  • 根据卫生部“十一五”规划教材《中药学》分类,确认桃仁、红花、泽兰、丹参、益母草、川牛膝、王不留行七味活血化瘀药为本次主要研究对象。

  • 利用中药化学成分数据库TCMSP平台(http:// lsp.nwu.edu.cn/tcmsp.php),检索七味中药所含活性成分。依据数据库指南要求,将口服生物利用度(oral bioavailability,OB)≥30%以及类药性(drug-like,DL)≥0.18作为筛选条件,对活性成分进行筛选[4]。OB值是评价药物能否发挥药效的重要药动学参数,DL值是指化合物与所有已知药物之间的相似程度。上述2个参数是评价中药化学成分吸收、分布、代谢、排泄的关键参数。获得符合OB、DL参数有效活性成分后,利用TCMSP数据库查询各有效活性成分对应相关靶点。利用Venn图工具(https://bioinfogp.cnb.csic.es/tools/venny/)对药物化学成分以及相关靶点进行共同点分析,寻找活血化瘀中药共有成分和作用靶点。

  • 利用美国国立生物技术信息中心Gene数据库(https://www.ncbi.nlm.nih.gov/gene/)将所获靶点信息转换成基因名称。查询GeneCards(https://www.genecards.org/)数据库,获得与EM相关基因靶点。最后将每种中药的作用靶点对应的Gene Symbol与EM基因进行比对,获得每种中药可能影响EM的相关基因,利用Cytoscape 3.6.0软件构建化合物-靶点网络[5]

  • 为进一步研究靶点之间的相互关系,将活血化瘀药共同靶点上传至线上软件 STRING(http://string db.org),构建蛋白互作网络。物种选择为Homosapiens,minimum required interaction score调整为highest confidence,隐藏网络图中游离节点,获取PPI网络。

  • 利用KEGG数据库(https://www.keg g.jp/)查询每种中药针对EM的相关基因,获得相关KEGG通路信息。筛选各中药KEGG通路中相关基因富集情况,并利用Prism 8.0软件绘制通路靶点富集热图。

  • 按照要求从TCMSP数据库中筛选出各中药有效成分,删除重复项,共有94种有效成分(supplementary materials table S1)。其中丹参有效活性成分达到65个,而泽兰有效活性成分只有2个。未能发现七味活血化瘀药共同有效成分,但β-谷固醇为川牛膝、红花、桃仁、泽兰所共有,槲皮素为川牛膝、红花、王不留行、益母草所共有,是涉及活血化瘀类中药最多的2种有效成分(supplementary materials table S2)。与此同时,我们找到了七味中药所共有的19个作用靶点(表1),包括孕酮受体(progesterone receptor)、前列腺素G/H合成酶1(prostaglandin G/H synthase 1)、前列腺素G/H合成酶2(prostaglandin G/H synthase 2)、凋亡调节剂Bcl-2(apoptosis regulator Bcl-2)、核受体共激活剂(nuclear receptor coactivator 2)等。

    序号蛋白名称基因名称靶点标识码
    1钠通道蛋白5型亚基SCN5ATAR00070
    2前列腺素G/H合成酶1PTGS1TAR00006
    3Beta-2型肾上腺素受体ADRB2TAR00261
    4毒蕈碱型乙酰胆碱受体M3CHRM3TAR00016
    5孕酮受体PGRTAR00209
    6半胱天冬酶3CASP3TAR04087
    7热休克蛋白HSP 90HSP90TAR00444
    8钾电压门控通道亚家族H成员2KCNH2TAR00037
    9凋亡调节剂Bcl-2BCL2TAR00086
    10PKA催化亚基C-alphaPRKACATAR00699
    11半胱天冬酶9CASP9TAR04090
    12γ-氨基丁酸受体亚基α-1GABRA1TAR00309
    13毒蕈碱型乙酰胆碱受体M1CHRM1TAR00038
    14前列腺素G/H合酶2PTGS2TAR00094
    15转录因子AP-1JUN,FOSTAR00414
    16磷脂酰肌醇-4,5-双磷酸3-激酶催化亚基,γ亚型PIK3CGTAR00491
    17毒蕈碱型乙酰胆碱受体M2CHRM2TAR00210
    18核受体共激活剂2NCOA2TAR03276
    19维甲酸受体RXR-alphaRARATAR00158
  • 利用人类基因数据库查找EM作用靶点,与七味中药有效成分对应靶点进行比对,发现红花所含相关靶点数量最多,达到103个;而桃仁、泽兰所含相关靶点数量最少,为14个(图1A);王不留行所含相关靶点占有效成分作用靶点比例最高,为54.7%;而桃仁最低,为29.8%(图1B)。经过去重处理后,七味中药所含EM相关靶点共119个(supplementary materials table S3)。利用Cytoscape3.6.0软件进行成分-靶点网络分析,获得图2,其中共计216个节点,其中黄色节点为活血化瘀药有效活性成分,而蓝色节点代表EM相关靶点。利用软件自带分析功能,对于网络各节点度值进行分析,网络中某些节点度值较高,提示该节点为网络中的关键节点(supplementary materials table S4)。在各中药所含有效成分中,槲皮素展现出极高的连接度(度值=87),远超其他有效成分,而其余较高连接度值依次是木犀草素(度值=43)、山柰酚(度值=33)、黄芩素(度值=23)、丹参酮A(度值=20)、花生四烯酸(度值=20)、β-谷固醇(度值=18)。中药是一个多有效成分的复杂系统,一个有效成分可作用于多个靶点,协同作用于某种疾病的治疗。而在靶点的分析中,较高连接度的靶点可能在EM的治疗作用中起着重要的作用。前列腺素G/H合酶2(PTGS2,度值=82)、前列腺素G/H合酶1(PTGS1,度值=39)两者拥有最高的度值,是临床上炎性疾病治疗的主要靶点;核受体辅活化子2(NCOA2,度值=35)、核受体辅活化子1(NCOA1,度值=34)紧跟其后,同样在各炎症通路中作用显著;凝血酶(度值=31)是临床上治疗出血的重要靶点,直接作用于血液凝固过程的最后一环;Mu-type阿片受体(OPRM1,度值=30)则涉及到中枢镇痛功能。上述靶点均和EM症状及病机之间有着密切的关系。

  • 利用STRING软件构建靶点PPI网络,图中包含119个节点,505条边,所有节点平均度值为8.49,具体见图3。根据“度值>均值”筛选出PPI网络中关键节点56个(supplementary materials table S6),前9位关键节点,平均度值为88,见表2,与PPI网络74%节点存在相互作用关系,提示它们在网络调控中起着关键作用,可能是活血化瘀药物治疗EM的关键所在。

    节点名称度值节点名称度值节点名称度值
    ALB97IL692PTGS283
    AKT195TNF86CASP380
    VEGFA94MAPK883MAPK180
  • 利用KEGG数据库查询每种中药针对EM的相关基因,获得相关KEGG通路信息。整理各中药KEGG通路相关基因富集情况,发现七味中药共有信号通路44条(supplementary materials table S5),筛选出与EM密切相关的19条通路(表3)。从表3中,不难发现,19条通路涉及性激素、炎症、细胞调亡以及血管生成等各个方面,其中炎症相关通路达到7条,为所有通路中最多。利用Prism 8.0软件绘制通路靶点富集热图,根据图4可知,在系列通路中,泽兰与桃仁作用均弱于其他五味中药。而在PI3K-Akt、IL-17、TNF三条信号通路中,多味中药靶点存在高度富集,红花在PI3K-Akt信号通路中显著富集,远超该药其他通路,值得注意。

    序号标识码信号通路名称类别
    1hsa04151PI3K-Akt信号通路炎症相关
    2hsa04668TNF信号通路炎症相关
    3hsa04657IL-17信号通路炎症相关
    4hsa04625C型凝集素受体信号通路炎症相关
    5hsa04064NF-κB信号通路炎症相关
    6hsa04115p53信号通路炎症相关
    7hsa00590花生四烯酸代谢炎症相关
    8hsa01522内分泌抵抗激素相关
    9hsa04915雌激素信号通路激素相关
    10hsa04919甲状腺激素信号通路激素相关
    11hsa04921催产素信号通路激素相关
    12hsa04210细胞凋亡细胞凋亡
    13hsa04071鞘脂信号通路细胞凋亡
    14hsa01521EGFR酪氨酸激酶抑制剂拮抗血管相关
    15hsa04370VEGF信号通路血管相关
    16hsa01521血小板活化血管相关
    17hsa04722神经营养蛋白信号通路疼痛相关
    18hsa04725胆碱能突触疼痛相关
    19hsa04726血清素能突触疼痛相关
  • 本研究采用网络药理学的研究方法,从TCMSP数据库中提取出了94个符合标准的成分,通过VENE图去重以及分析网络图的拓扑特性后,发现槲皮素为四味活血化瘀药所共有,与83种EM相关靶点存在关联。现代研究表明,槲皮素具有抑制炎症、血小板聚集和血管平滑肌细胞增殖的作用,通过抗氧化作用诱导细胞凋亡,还可通过雌激素受体,调控受体下游多种底物及信号通路而调节雌激素[6-7]。木犀草素与41种EM靶点相关联,具有抗炎、抗纤维化、抑制血管生成等作用[8]。EM发生发展过程中慢性炎症反应一直贯穿始终,且存在纤维化病变,木犀草素或在EM治疗中有一定作用[9-10]

    通过VENE图,发现七味中药共有作用靶点19个,部分共有靶点与Cytoscape网络图以及PPI网络中关键节点高度对应,进一步强调了该部分共有靶点在EM中的作用。如PTGS2,该靶点所调控环氧合酶(COX-2)的高表达会导致细胞的高增殖性、高侵袭性,诱导血管生成从而加重EM的疼痛和不孕症状[11]。NCOA2、NCOA1的水平异常与EM的进展关联密切。趋化因子参与子宫内膜异位种植过程中趋化、黏附、侵袭、血管形成及细胞生长分化等多个重要环节[12]。Xiu等发现,在分泌期,NCOA1和趋化因子CXCL12在异位子宫内膜中的表达明显高于正常子宫内膜;活化血小板对异位内膜具有促炎、促血管生成的作用,促使异位内膜细胞的侵袭和增殖[13-14],子宫内膜基质细胞可分泌F2,以密集依赖的方式诱导血小板活化和聚集,从而影响EM的进展[15-16] 。VEGFA可促进新生血管形成并使血管通透性增加,陈晓莉等[17]研究表明,内异症组血清和腹腔液VEGF水平明显高于对照组,且重度患者腹腔液中VEGF水平高于轻度患者,VEGF在EMT患者血管生成中起促进性作用,在血清与腹腔液中的高表达与疾病发生发展相关。尉伟东等[18]发现CASP3蛋白在异位内膜和在位内膜中的评分明显低于正常对照组,caspase-3的水平下降提示内膜细胞活性下降,促使子宫内膜细胞自发性凋亡增加以及凋亡信号敏感性增强,诱导或加重EM。

    利用KEGG数据库,找到了七味活血化瘀药共有EM相关通路19条,涉及性激素、炎症、细胞凋亡以及血管生成等方面。所有通路中,炎症通路达到36%。其中PI3K-Akt、IL-17、TNF三条信号通路是靶点富集最多的通路,提示活血化瘀药主要通过抗炎作用来对EM起治疗作用。与正常女性相比,EM患者的子宫内膜在位和异位内膜细胞的PI3K表达增加,AKT磷酸化水平升高,证实PI3K/AKT信号通路可影响EM进展[19]。EM是一种雌激素依赖性疾病,呈现出慢性炎症反应,多种炎性因子参与其病理过程,包括NF-κB、TNF-α、IL-1、IL-17等[20]。许丽华等[21]通过实验发现,EM患者血清及腹腔液中TNF-α水平显著高于对照组。EM患者Ⅲ和Ⅳ期血清和腹腔液中TNF-α水平均高于Ⅰ和Ⅱ期,证实了TNF-α与子宫内膜异位症的发生发展密切相关,有助于子宫内膜异位症的诊断。IL-1家族在EM发生发展中作用显著,与正常女性相比,EM患者静脉血中IL-1β浓度显著增高。不仅仅是IL-1β,研究显示,IL-1β前体蛋白(proIL-1β)也可以加重炎症反应,EM患者腹腔液中IL-1β、proIL-1β水平均高于健康女性。IL-1家族细胞因子的损伤,导致EM患者腹腔免疫机制的紊乱,局部以及全身IL-1β、IL-18调控机制的缺陷,使得内膜组织的侵袭性以及生长性大幅增加,从而导致EM[22-24]。炎症相关通路的高富集也与之前网络图中TNF、IL-6等炎性相关靶点的高度值相对应,进一步强调了活血化瘀药物通过抗炎作用治疗EM的作用机制。细胞凋亡是一种独特的程序性细胞死亡,细胞的有效清除而不会引起炎症反应,EM特征为异位内膜细胞凋亡率下降。与健康女性子宫内膜相比,EM异位内膜抗凋亡因子表达增加,促凋亡因子表达减少,证实了细胞凋亡在EM的发病中确有作用,并和炎症反应存在一定关联[25]。EM发生发展过程中亦伴随着血管生成增多以及局部病灶周期性出血,EM患者异位内膜血管内皮生长因子(VEGF)表达量增高,抗血管生成因子(sFlt-1)表达量下降,证实VEGF信号通路、血小板激活通路均参与此过程,与前面靶点分析也形成呼应[26-27] 。脑源性神经营养因子是各种慢性疾病中慢性疼痛形成和维持的调节因子,EM伴有疼痛的患者血清和腹膜液中神经营养因子浓度明显高于无疼痛EM患者[28]。利用KEGG通路分析,可以发现活血化瘀药对于炎症、凋亡、疼痛、血管生成等相关通路均具备调控作用,进一步强调了临床上活血化瘀药对于EM的治疗价值。

    综上所述,活血化瘀中药可通过多靶点、多通路协同作用方式对EM进行治疗,体现了中医药治疗疾病特色。上述七味中药中,桃仁、泽兰对于EM的作用低于其余活血化瘀药,而红花、益母草在EM治疗体系中,EM相关靶点高于其余中药,可能会起到更好的疗效,在临床上可尝试推广使用。本研究从网络药理学角度出发,根据活血化瘀中药有效成分和作用靶点,在一定程度上对活血化瘀中药治疗EM进行了机制的解析,为指导临床用药提供了一定的依据。但本研究仅仅基于TCMSP数据库,利用计算机软件从理论上对活血化瘀中药治疗EM作用机制做了探析,还需要通过实验和临床实践来进一步证实,而且还需要扩大活血化瘀药物探究范围,结合临床实际,深入剖析活血化瘀药共同点与差异之处。

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