基于网络药理学的地榆-槐花药对治疗直肠癌作用机制的研究
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摘要
目的基于网络药理学,探究地榆-槐花药对治疗直肠癌可能的作用机制。方法利用TCMSP数据库,获取地榆-槐花药对的活性成分及活性成分所对应的靶标。通过Genecards数据库和OMIM数据库,收集与直肠癌相关的靶标,并与药物成分所对应的靶标相比较,筛选出共同部分,作为药对的预测作用靶标。利用string数据库获取预测作用靶标之间的相互关系,根据相互关系大小筛选出核心靶标。通过Systems Dock WebSite网络服务器进行核心靶标与活性成分的分子对接。在DAVID数据库中进行核心靶标的KEGG通路富集分析和GO分类富集分析。利用Cytoscape 3.6.0软件,绘制"药物-成分-作用靶标"网络图、核心靶标相互作用网络图以及"成分-靶标-通路"网络关系图。利用Omicshare平台绘制直肠癌靶标与药对靶标匹配图、KEGG通路富集分析结果图、GO分类富集分析结果图、分子对接柱状图。结果收集到地榆-槐花药对的12个活性成分,包括β-谷甾醇(beta-sitosterol)、山奈酚(kaempferol)、槲皮素(quercetin)等,主要作用于Akt1、TP53、IL6、VEGFA、TNF 5个靶标,涉及PI3K-Akt、MAPK、TNF、RAS、Toll-like receptor等通路发挥治疗直肠癌的作用。结论本研究基于网络药理学的方法,初步探究了地榆-槐花药对治疗直肠癌可能的靶标和通路,其作用特点与中医药治疗疾病的特点相符合,可为地榆-槐花药对的临床应用提供参考。
Objective This study was designed to explore possible mechanism of"Sanguisorbae radix-Sophorae flos"(DY-HH)on rectal cancer based on network pharmacology. Methods The active components and their targets of"Sanguisorbae radix-Sophorae flos"were obtained through TCMSP strategies. Targets related to rectal cancer were collected in Genecards database and OMIM database. The common ones between the active targets of "Sanguisorbae radix-Sophorae flos"and targets related to rectal cancer were selected to be the candidate targets. String database was utilized to obtain a network of candidate targets, based on which the major targets were selected. Molecular docking between the active components of "Sanguisorbae radix-Sophorae flos" and the major targets was carried out by Systems Dock Web Site. The GO classified enrichment analysis and the KEGG pathway enrichment analysis were performed in DAVID database. In order to visualize the above steps,Cytoscape 3.6.0 software was utilized to construct the medicine-components-targets network,the candidate targets interaction network,and the components-targets-pathways network. Besides,Wayne diagrams of the target matching,histogram of molecular docking,and figures of GO pathway enrichment analysis and KEGG pathway enrichment analysis were made with the help of Omicshare platform. Results Twelve active components of"Sanguisorbae radix-Sophorae flos"were collected,including beta-sitosterol,kaempferol,quercetin,and so on. The active components mainly act on 5 targets:Akt1,TP53,IL6,VEGFA and TNF. "Sanguisorbae radix-Sophorae flos"probably execute their effects on rectal cancer by regulating signal pathways including PI3 K-Akt, MAPK, TNF, RAS, Toll-like receptor signaling pathways.Conclusion This study preliminarily explored the major targets and pathways of"Sanguisorbae radix-Sophorae flos".The functional characteristics of the herbal pair are consistent with the characteristics of traditional Chinese medicine in the treatment of diseases. The results are expected to provide references for the clinical application of"Sanguisorbae radix-Sophorae flos".
Objective This study was designed to explore possible mechanism of"Sanguisorbae radix-Sophorae flos"(DY-HH)on rectal cancer based on network pharmacology. Methods The active components and their targets of"Sanguisorbae radix-Sophorae flos"were obtained through TCMSP strategies. Targets related to rectal cancer were collected in Genecards database and OMIM database. The common ones between the active targets of "Sanguisorbae radix-Sophorae flos"and targets related to rectal cancer were selected to be the candidate targets. String database was utilized to obtain a network of candidate targets, based on which the major targets were selected. Molecular docking between the active components of "Sanguisorbae radix-Sophorae flos" and the major targets was carried out by Systems Dock Web Site. The GO classified enrichment analysis and the KEGG pathway enrichment analysis were performed in DAVID database. In order to visualize the above steps,Cytoscape 3.6.0 software was utilized to construct the medicine-components-targets network,the candidate targets interaction network,and the components-targets-pathways network. Besides,Wayne diagrams of the target matching,histogram of molecular docking,and figures of GO pathway enrichment analysis and KEGG pathway enrichment analysis were made with the help of Omicshare platform. Results Twelve active components of"Sanguisorbae radix-Sophorae flos"were collected,including beta-sitosterol,kaempferol,quercetin,and so on. The active components mainly act on 5 targets:Akt1,TP53,IL6,VEGFA and TNF. "Sanguisorbae radix-Sophorae flos"probably execute their effects on rectal cancer by regulating signal pathways including PI3 K-Akt, MAPK, TNF, RAS, Toll-like receptor signaling pathways.Conclusion This study preliminarily explored the major targets and pathways of"Sanguisorbae radix-Sophorae flos".The functional characteristics of the herbal pair are consistent with the characteristics of traditional Chinese medicine in the treatment of diseases. The results are expected to provide references for the clinical application of"Sanguisorbae radix-Sophorae flos".
引文
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[21]马怡晖,王青杰,高汉青,等.TOPⅡα、TP53和HER2在胃腺癌中的表达及其临床意义[J].肿瘤防治研究,2018,45(9):656-659.
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[23]杨勇,田敏.结直肠癌患者TNF-α、IL-6、IL-8水平与临床分期的关系与研究[J].标记免疫分析与临床,2016,23(7):790-793.
[24]郑旦,高东萍,李岗.姜黄素对SW480细胞凋亡的影响及机制研究[J].中药材,2018,41(11):2430-2433
[25]FEARNLEY G W,SMITH G A,ABDUL Z I,et al.VEGF-Aisoforms program differential VEGFR2 signal transduction,trafficking and proteolysis[J].Biol Open,2016,5:571-583.
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[27]马仕虎,余昌达,陈志冰,等.新辅助化疗前后直肠癌患者血清NSE和TNF-α水平变化及其临床意义探讨[J].临床医药实践,2019,28(01):18-20.
[28]HAO J,YANG Z,WANG L,et al.Downregulation of BRD4 inhibits gallbladder cancer proliferation and metastasis and induces apoptosis via PI3K/Akt pathway[J].Int J Oncol,2017,51(3):823-831.
[29]高瑞林,陈祥荣,李毅宁,等.盐酸小檗碱通过PI3K/Akt信号通路抑制MMP2和MMP9的表达影响膀胱癌T24细胞侵袭性[J].暨南大学学报(自然科学与医学版),2015,36(6):472-476.
[30]闫康鹏,江长安,吴昆.COX-2活化PI3K/Akt信号通路促结直肠癌肝转移的实验研究[J].中国医学创新,2017,14(35):1-5.
[31]徐伟丽,孙文广,马莺.MAPK信号通路与结直肠癌[J].现代肿瘤医学,2010,18(2):389-392.
[32]KATANOV C,LERRER S,LIUBOMIRSKI Y,et al.Regulation of the inflammatory profile of stromal cells in human breast cancer:prominent roles for TNF-αand the NF-κB pathway[J].Stem cell Research&Therapy,2015,6(1):87.
[33]张艳辉,骆亚莉,刘永琦,等.黄芪多糖对骨髓间充质干细胞向肿瘤相关成纤维细胞分化中IL-6/STAT3、TNF-α/NF-κB通路的影响[J].中国中医药信息杂志,2018,25(10):54-59.
[34]耿文文,蒲倩,高海东.Shoc2介导的Ras通路调控与肿瘤[J].中国现代普通外科进展,2018,21(2):113-115.
[35]KAPALN F M,KUGEL C H,DADPEY N,et al.SHOC2 and CRAF mediate ERK1/2 reactivation in mutant NRAS-mediated resistance to RAF inhibitor[J].J Biol Chem,2012,287(50):41797-41807.
[36]LEE C C,AVALOS A M,PLOEGH H L.Accessory molecules for Toll-like receptors and their function[J].Nat Rev Immunol,2012,12(3):168-179.
[37]张济,丁永斌,夏建国,等.结肠癌TLR4信号促进免疫逃逸[J].江苏医药,2013,39(7):776-778.
[38]江现强,曾家耀.Toll样受体与肿瘤相关性及其在靶向治疗中的作用研究进展[J].广西医学,2018,40(19):2328-2331.
[2]FANG W.Chemotherapy in patient with colon cancer after renal transplantation:a case report with literature review[J].Medicine(Baltimore),2018,97(5):e9678.
[3]LEE C,KONG J C,ISMAIL H,et al.Systematic review and metaanalysis of objective assessment of physical fitness in patients undergoing colorectal cancer surgery[J].Dis Colon Rectum,2018,61(3):400-409.
[4]吴泽华,邓艳红.结直肠癌流行病学东西方差异对肿瘤部位的影响[J].中国癌症防治杂志,2017,9(5):356-360.
[5]CHEN W,ZHENG R,BAADE P D,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115-132.
[6]朱紫薇,顾媛媛,韩玉生,等.中医药在癌症治疗中的定位思考与研究[J].辽宁中医杂志,2018,45(2):423-425.
[7]徐浩,刘磊,楼招欢,等.中医“药对”治疗癌症的研究进展[J].中华中医药杂志,2018,33(10):4533-4538.
[8]冉爱华.中医辨证论治结直肠癌术后的临床研究[J].中国实用医药,2019,14(3):120-122.
[9]曾浩涛,赵淼,陈地灵,等.基于化学成分相互作用的槐花-地榆配伍[J].中国实验方剂学杂志,2015,21(15):74-78.
[10]代良敏,熊永爱,范奎,等.地榆化学成分与药理作用研究进展[J].中国实验方剂学杂志,2016,22(20):189-195.
[11]陈宇杰,马丽杰,胡雷,等.槐米对S180荷瘤小鼠的抑瘤作用及机制[J].中药药理与临床,2014,30(5):100-102.
[12]张海英,徐水凌,张力衡,等.槐米中槲皮素提纯、鉴定以及诱导人乳腺癌MCF-7细胞凋亡作用[J].中国临床药理学与治疗学,2012,17(9):995-1000.
[13]李秋红,栾仲秋,王继坤.中药槐米的化学成分、炮制研究及药理作用研究进展[J].中医药学报,2017,45(3):112-116.
[14]刘秋伟,姜亚玲,翟广玉.槲皮素酯的合成及其抗肿瘤活性研究[J].化学试剂,2018,40(9):836-840.
[15]王莉,归绥琪.β-谷甾醇抗肿瘤作用研究[J].国际肿瘤学杂志,2009,36(9):676-679.
[16]武峰,秦志丰,李勇进,等.半夏化学成分抗肿瘤研究进展[J].中华中医药学刊,2013,31(2):270-272.
[17]简文文,鱼庆,王敏,等.山奈酚致敏TRAIL诱导人卵巢癌细胞凋亡的相关机制及前景[J].中国实验诊断学,2018,22(8):1477-1479.
[18]LEE H S,CHO H J,YU R,et al.Mechanisms underlying apoptosisinducing effects of kaempferol in HT-29 human colon cancer cells[J].Int J Mol Sci,2014,15:2722
[19]HANG M,ZHAO F,CHEN S B,et al.Kaempferol modulates the metastasis of human non-small cell lung cancer cells by inhibiting epithelial-mesenchymal transition[J].Bangl J Pharmacol,2015,10:267.
[20]许晓阳,吴淑华,孙晨博,等.结直肠癌中PHLPP2、PTEN与pAkt1表达的相关性及其临床意义[J].临床与实验病理学杂志,2018,34(8):827-833.
[21]马怡晖,王青杰,高汉青,等.TOPⅡα、TP53和HER2在胃腺癌中的表达及其临床意义[J].肿瘤防治研究,2018,45(9):656-659.
[22]GAZDAR A F,BUNN P A,MINNA J D.Small-cell lung cancer:what we know,what we need to know and the path forward[J].Nat Rev Cancer,2017,17(12):725-737.
[23]杨勇,田敏.结直肠癌患者TNF-α、IL-6、IL-8水平与临床分期的关系与研究[J].标记免疫分析与临床,2016,23(7):790-793.
[24]郑旦,高东萍,李岗.姜黄素对SW480细胞凋亡的影响及机制研究[J].中药材,2018,41(11):2430-2433
[25]FEARNLEY G W,SMITH G A,ABDUL Z I,et al.VEGF-Aisoforms program differential VEGFR2 signal transduction,trafficking and proteolysis[J].Biol Open,2016,5:571-583.
[26]张钰涵,陈雪华,张浩.下调极光激酶A活性抑制Hep2细胞的促血管生成作用和迁移、侵袭能力[J].上海交通大学学报(医学版),2018,38(10):1181-1185.
[27]马仕虎,余昌达,陈志冰,等.新辅助化疗前后直肠癌患者血清NSE和TNF-α水平变化及其临床意义探讨[J].临床医药实践,2019,28(01):18-20.
[28]HAO J,YANG Z,WANG L,et al.Downregulation of BRD4 inhibits gallbladder cancer proliferation and metastasis and induces apoptosis via PI3K/Akt pathway[J].Int J Oncol,2017,51(3):823-831.
[29]高瑞林,陈祥荣,李毅宁,等.盐酸小檗碱通过PI3K/Akt信号通路抑制MMP2和MMP9的表达影响膀胱癌T24细胞侵袭性[J].暨南大学学报(自然科学与医学版),2015,36(6):472-476.
[30]闫康鹏,江长安,吴昆.COX-2活化PI3K/Akt信号通路促结直肠癌肝转移的实验研究[J].中国医学创新,2017,14(35):1-5.
[31]徐伟丽,孙文广,马莺.MAPK信号通路与结直肠癌[J].现代肿瘤医学,2010,18(2):389-392.
[32]KATANOV C,LERRER S,LIUBOMIRSKI Y,et al.Regulation of the inflammatory profile of stromal cells in human breast cancer:prominent roles for TNF-αand the NF-κB pathway[J].Stem cell Research&Therapy,2015,6(1):87.
[33]张艳辉,骆亚莉,刘永琦,等.黄芪多糖对骨髓间充质干细胞向肿瘤相关成纤维细胞分化中IL-6/STAT3、TNF-α/NF-κB通路的影响[J].中国中医药信息杂志,2018,25(10):54-59.
[34]耿文文,蒲倩,高海东.Shoc2介导的Ras通路调控与肿瘤[J].中国现代普通外科进展,2018,21(2):113-115.
[35]KAPALN F M,KUGEL C H,DADPEY N,et al.SHOC2 and CRAF mediate ERK1/2 reactivation in mutant NRAS-mediated resistance to RAF inhibitor[J].J Biol Chem,2012,287(50):41797-41807.
[36]LEE C C,AVALOS A M,PLOEGH H L.Accessory molecules for Toll-like receptors and their function[J].Nat Rev Immunol,2012,12(3):168-179.
[37]张济,丁永斌,夏建国,等.结肠癌TLR4信号促进免疫逃逸[J].江苏医药,2013,39(7):776-778.
[38]江现强,曾家耀.Toll样受体与肿瘤相关性及其在靶向治疗中的作用研究进展[J].广西医学,2018,40(19):2328-2331.