基于系统药理学的茵陈作用机制研究
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摘要
目的:探讨茵陈可能的药理作用机制,为其进一步开发利用提供参考。方法:利用中药系统药理学分析平台数据库(TCMSP)筛选茵陈的有效成分和相关靶标蛋白;运用Cytoscape 3.5.1软件构建茵陈有效化合物-靶标蛋白可视化网络,并进行拓扑学分析;借助STRING数据库进行蛋白质与蛋白质相互作用(PPI)网络的构建与分析;通过DAVID生物信息学资源数据库对靶标蛋白编码基因进行KEGG通路富集分析。结果:共筛选出茵陈有效化合物13个,靶标蛋白189个,KEGG富集通路34条。槲皮素、β-谷甾醇、异鼠李素、Artepillin C等是主要有效化合物,前列腺素G/H合成酶2(PTGS2)、热休克蛋白90(HSP90)、二肽基肽酶Ⅳ、蛋白激酶A催化亚基Cα等是主要靶标蛋白;转录因子AP-1(JUN)、细胞肿瘤抗原p53在PPI网络中发挥了关键作用;靶标蛋白编码基因主要富集在肿瘤坏死因子α(TNF-α)信号通路、缺氧诱导因子1(HIF-1)信号通路、Toll样受体信号通路、磷脂酰肌醇-3-激酶/丝苏氨酸蛋白激酶(P13K/Akt)信号通路、T细胞受体信号通路、甲状腺激素信号通路、凋亡信号通路等通路上。结论:茵陈中的槲皮素、β-谷甾醇、异鼠李素等化合物可能通过TNF-α信号通路、HIF-1信号通路、PI3K/Akt信号通路等作用于PTGS2、HSP90、JUN等靶标蛋白,进而发挥其抗炎、抗肿瘤等药理作用。
OBJECTIVE:To investigate the possible mechanism of Artemisia capillaries,and to provide reference for further development and utilization of it. METHODS:The effective components and related target protein of A. capillaries were screened by Traditional Chinese Medicine Systems Pharmacology(TCMSP) analysis platform database. The effective compound-target protein visual network of A. capillaries was established by using Cytoscape 3.5.1 software,topology analysis was also performed.The protein-protein interaction(PPI) network was constructed and analyzed by STRING database. KEGG pathway enrichment of target protein coding gene was analyzed by DAVID bioinformatics resource database. RESULTS:A total of 13 kinds of effective compounds,189 target proteins and 34 enrichment pathways were selected. Quercetin,β-glutamol,isorhamnetin and artepillin C were main effective compounds. Prostaglandin G/H sythase 2(PTGS 2),heat shock protein 90(HSP 90),dipeptidyl peptidase Ⅳ,protein kinase A catalytic subunit Cα were main target proteins. Transcription factor AP-1 and cell tumor antigen p53 played a key role in PPI network. The target protein coding gene was rich in TNF-α signaling pathway,HIF-1 signaling pathway,Toll-like receptor signaling pathway,PI3K/Akt signaling pathway,T cell receptor signaling pathway,thyroid hormone signaling pathway,apoptotic signaling pathway,etc. CONCLUSIONS:Quercetin,β-glutamol and isorhamnetin of A. capillaries play an effect on PTGS2,HSP90,transcription factor AP-1 and other target proteins through TNF-α signaling pathway,HIF-1 signaling pathway and PI3K/Akt signaling pathway,so as to play anti-inflammatory and antitumor effect.
OBJECTIVE:To investigate the possible mechanism of Artemisia capillaries,and to provide reference for further development and utilization of it. METHODS:The effective components and related target protein of A. capillaries were screened by Traditional Chinese Medicine Systems Pharmacology(TCMSP) analysis platform database. The effective compound-target protein visual network of A. capillaries was established by using Cytoscape 3.5.1 software,topology analysis was also performed.The protein-protein interaction(PPI) network was constructed and analyzed by STRING database. KEGG pathway enrichment of target protein coding gene was analyzed by DAVID bioinformatics resource database. RESULTS:A total of 13 kinds of effective compounds,189 target proteins and 34 enrichment pathways were selected. Quercetin,β-glutamol,isorhamnetin and artepillin C were main effective compounds. Prostaglandin G/H sythase 2(PTGS 2),heat shock protein 90(HSP 90),dipeptidyl peptidase Ⅳ,protein kinase A catalytic subunit Cα were main target proteins. Transcription factor AP-1 and cell tumor antigen p53 played a key role in PPI network. The target protein coding gene was rich in TNF-α signaling pathway,HIF-1 signaling pathway,Toll-like receptor signaling pathway,PI3K/Akt signaling pathway,T cell receptor signaling pathway,thyroid hormone signaling pathway,apoptotic signaling pathway,etc. CONCLUSIONS:Quercetin,β-glutamol and isorhamnetin of A. capillaries play an effect on PTGS2,HSP90,transcription factor AP-1 and other target proteins through TNF-α signaling pathway,HIF-1 signaling pathway and PI3K/Akt signaling pathway,so as to play anti-inflammatory and antitumor effect.
引文
[1]章林平,孙倩,王威,等.茵陈有效成分的药理作用及其临床应用的研究进展[J].抗感染药学,2014,11(1):28-31.
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[3]李保义,吕晓峰,安春棉,等.茵陈蒿汤加味治疗药物性肝损伤65例[J].中国实验方剂学杂志,2013,19(20):285-288.
[4]刘亚杰,邵文革,王瑞强,等.茵陈蒿汤加味治疗原发性胆汁肝硬化[J].中医学报,2013,28(28):19-20.
[5]吴钉红.网络药理学及其在中药领域的研究概述[J].广州化工,2017,45(11):216-218.
[6]李泮霖,苏薇薇.网络药理学在中药研究中的最新应用进展[J].中草药,2016,47(16):2938-2942.
[7]袁长胜,陈文.基于TCMSP对玫瑰花黄酮和挥发油防治心血管疾病的协同作用及其机制研究[J].石河子大学学报(自然科学版),2016,34(6):731-734.
[8]石海英,王唯红,王金虎,等.新药研发中类药性概念应用现状的研究分析[J].医药卫生,2017,9(1):289.
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[14]王惠丽,胡子有,苑召虎,等.槲皮素抗肿瘤机制的研究进展[J].热带医学杂志,2013,13(1):126-130.
[15]刘鹃,康刚劲.槲皮素对晶状体保护作用的研究进展[J].国际眼科杂志,2015,15(1):49-51.
[16]BIN SAYEED MS,AMEEN SS.Beta-sitosterol:a promising but orphan nutraceutical to fight against cancer[J].Nutr Cancer,2015,67(8):1214-1220.
[17]DIGHE SB,KUCHEKAR BS,WANKHEDE SB.Analgesic and anti-inflammatory activity ofβ-sitosterol isolated from leaves of Oxalis corniculata[J].Int J Pharmacol Res,2016,6(3):109-113.
[18]肖志彬,刘小雷,成日青,等.β-谷甾醇对阿司匹林副作用抵抗及抗炎作用影响的实验研究[J].内蒙古医科大学学报,2015,37(4):350-354.
[19]崔明超,陈少军,崔文,等.基于反向分子对接技术的异鼠李素靶标的预测[J].中国药房,2016,27(28):3921-3924.
[20]李小芳.异鼠李素诱导人结肠癌细胞凋亡及其分子机制的初步研究[J].中国细胞生物学学报,2017,39(6):695-700.
[21]刘芳,于廷和,王智彪.环氧合酶及其抑制剂在卵巢癌中的研究进展[J].重庆医科大学学报,2007,32(增刊):36-38.
[22]FUJITA H,KOSHIDA K,KELLER ET,et al.Cyclooxygenase-2 promotes prostate cancer progression[J].Prostate,2002,53(3):232-240.
[23]邓琳,冯定庆,凌斌.COX2促进卵巢癌细胞迁移及相关机制的研究[J].现代妇产科进展,2016,25(8):561-565.
[24]宋敬锋,刘昊,张岩,等.祛风通络利湿中药治疗湿热痹阻证痛风性关节炎疗效及对MMP-3、COX-2的影响[J].现代中西医结合杂志,2017,26(16):1741-1744.
[25]WANG Y,KOAY YC,MCALPINE SR.How selective are HSP90 inhibitors for cancer cells over normal cells?[J].Chem Med Chem,2017,12(5):353-357.
[26]TAS F,BILGIN E,ERTURK K,et al.Clinical significance of circulating serum cellular heat shock protein 90(HSP90)level in patients with cutaneous malignant melanoma[J].Asian Pac J Cancer Prev,2017,18(3):599-601.
[27]张杰,张宁,芮静安,等.人肝细胞癌及其配对非癌肝组织、正常肝组织中热休克蛋白HSP90基因m RNA水平的分析[J].中国生物化学与分子生物学报,2001,17(3):386-390.
[28]董洁,汤道权,肖冰心,等.二肽基肽酶4抑制剂药物相互作用的研究进展[J].中国药房,2017,28(32):4601-4604.
[29]GORRELL MD.Dipeptidyl peptidaseⅣand related enzymes in cell biology and liver disorders[J].Clin Sci:Lond,2005,108(4):277-292.
[30]陆迪菲,马晓伟,郭晓蕙.二肽基肽酶-4心血管系统作用的研究进展[J].中国糖尿病杂志,2016,24(11):1049-1051.
[31]ISHII S,ABE T,SAITO T,et al.Effects of preconditioning on ischemia/reperfusion injury of hepatocytes determined by immediate early gene transcription[J].J Hepatobiliary Pancreat Surg,2001,8(5):461-468.
[32]WANG S,XU X,XU F,et al.Combined expression of cjun,c-fos,and p53 improves estimation of prognosis in oral squamous cell carcinoma[J].Cancer Invest,2016,34(8):393-400.
[33]CHEOK CF,VERMA CS,BASELGA J,et al.Translating p53 into the clinic[J].Nat Rev Clin Oncol,2011,8(1):25-37.
[34]ATTALLAH AM,SHIHA GE,ISMAIL H,et al.Expression of p53 protein in liver and sera of patients with liver fibrosis,liver cirrhosis or hepatocellular carcinoma associated with chronic HCV infection[J].Clin Biochem,2009,42(6):455-461.
[35]QIN LX,TANG ZY.The prognosic molecular markers in hepatocellular carcinoma[J].World J Gastroenterol,2002,8(3):385-392.
[36]CHENG HW,CHEN YF,WONG JM,et al.Cancer cells increase endothelial cell tube formation and survival by activating the PI3K/Akt signaling pathway[J].J Exp Clin Cancer Res,2017.DOI:10.1186/s13046-017-0495-3.
[37]CHEN H,HUANG Y,HUANG J,et al.Gigantol attenuates the proliferation of human liver cancer Hep G2 cells through the PI3K/Akt/NF-κB signaling pathway[J].Oncol Rep,2017,37(2):865-870.
[38]VARFOLOMEEV E,GONCHAROV T,MAECKER H,et al.Cellular inhibitors of apoptosis are global regulators of NF-kappa B and MAPK activation by members of the TNF family of receptors[J].Sci Signal,2012.DOI:10.1126/scisignal.2001878.
[39]蔡秀红,黄贻涛,张子平,等.缺氧诱导因子-1(HIF-1)及其在水生动物中的研究进展[J].农业生物技术学报,2014,22(1):119-132.
[40]胡韶君,余勤,刘丽珍,等.HIF-1信号通路在介导DMOG动员MSCs中的作用[J].中国比较医学杂志,2015,25(1):9-14.
[41]刘丽愉,杨力芳,曹亚.低氧诱导因子信号通路的研究新进展[J].国际病理科学与临床杂志,2011,31(3):218-222.
[42]MARTINEZ-OUTSCHOORN UE,TRIMMER C,LIN Z,et al.Autophagy in cancer associated fibroblasts promotes tumor cell survival:role of hypoxia,HIF1 induction and NF-κB activation in the tumor stromal microenvironment[J].Cell Cycle,2010,9(17):3515-3533.
[43]LEGENDRE C,HORI T,LOYER P,et al.Drug-metabolising enzymes are down-regulated by hypoxia in differentiated human hepatoma Hepa RG cells:HIF-1αinvolvement in CYP3A4 repression[J].Eur J Cancer,2009,45(16):2882-2892.
[44]XU H,ZHAO L,FANG Q,et al.Mi R-338-3p inhibits hepatocarcinoma cells and sensitizes these cells to sorafenib by targeting hypoxia-induced factor 1alpha[J].PLo S One,2014,9(12):e115565.
[2]覃晓雾,卢杰夫,田惠芳.茵陈蒿汤治疗急性黄疸型肝炎的Meta分析[J].湖南中医杂志,2016,32(7):162-164.
[3]李保义,吕晓峰,安春棉,等.茵陈蒿汤加味治疗药物性肝损伤65例[J].中国实验方剂学杂志,2013,19(20):285-288.
[4]刘亚杰,邵文革,王瑞强,等.茵陈蒿汤加味治疗原发性胆汁肝硬化[J].中医学报,2013,28(28):19-20.
[5]吴钉红.网络药理学及其在中药领域的研究概述[J].广州化工,2017,45(11):216-218.
[6]李泮霖,苏薇薇.网络药理学在中药研究中的最新应用进展[J].中草药,2016,47(16):2938-2942.
[7]袁长胜,陈文.基于TCMSP对玫瑰花黄酮和挥发油防治心血管疾病的协同作用及其机制研究[J].石河子大学学报(自然科学版),2016,34(6):731-734.
[8]石海英,王唯红,王金虎,等.新药研发中类药性概念应用现状的研究分析[J].医药卫生,2017,9(1):289.
[9]RU J,LI P,WANG J,et al.TCMSP:a database of systems pharmacology for drug discovery from herbal medicines[J].J Cheminform,2014.DOI:10.1186/1758-2946-6-13.
[10]LE DH,PHAM VH.HGPEC:a Cytoscape app for prediction of novel disease-gene and disease-disease associations and evidence collection based on a random walk on heterogeneous network[J].BMC Syst Biol,2017.DOI:10.1186/s12918-017-0437-x.
[11]蒋永麟,姜正羽,尤启冬.蛋白-蛋白相互作用:抗肿瘤药物研发的新方向[J].中国新药杂志,2017,26(10):1119-1129.
[12]FRANCESCHINI A,SZKLARCZYK D,FRANKILD S,et al.STRING v 9.1:protein-protein interaction networks:with increased coverage and integration[J].Nucleic Acids Res,2013,41(Database issue):D808-D815.
[13]张志琴,朱双雪.槲皮素的药理活性与临床应用研究进展[J].药学研究,2013,32(7):400-403.
[14]王惠丽,胡子有,苑召虎,等.槲皮素抗肿瘤机制的研究进展[J].热带医学杂志,2013,13(1):126-130.
[15]刘鹃,康刚劲.槲皮素对晶状体保护作用的研究进展[J].国际眼科杂志,2015,15(1):49-51.
[16]BIN SAYEED MS,AMEEN SS.Beta-sitosterol:a promising but orphan nutraceutical to fight against cancer[J].Nutr Cancer,2015,67(8):1214-1220.
[17]DIGHE SB,KUCHEKAR BS,WANKHEDE SB.Analgesic and anti-inflammatory activity ofβ-sitosterol isolated from leaves of Oxalis corniculata[J].Int J Pharmacol Res,2016,6(3):109-113.
[18]肖志彬,刘小雷,成日青,等.β-谷甾醇对阿司匹林副作用抵抗及抗炎作用影响的实验研究[J].内蒙古医科大学学报,2015,37(4):350-354.
[19]崔明超,陈少军,崔文,等.基于反向分子对接技术的异鼠李素靶标的预测[J].中国药房,2016,27(28):3921-3924.
[20]李小芳.异鼠李素诱导人结肠癌细胞凋亡及其分子机制的初步研究[J].中国细胞生物学学报,2017,39(6):695-700.
[21]刘芳,于廷和,王智彪.环氧合酶及其抑制剂在卵巢癌中的研究进展[J].重庆医科大学学报,2007,32(增刊):36-38.
[22]FUJITA H,KOSHIDA K,KELLER ET,et al.Cyclooxygenase-2 promotes prostate cancer progression[J].Prostate,2002,53(3):232-240.
[23]邓琳,冯定庆,凌斌.COX2促进卵巢癌细胞迁移及相关机制的研究[J].现代妇产科进展,2016,25(8):561-565.
[24]宋敬锋,刘昊,张岩,等.祛风通络利湿中药治疗湿热痹阻证痛风性关节炎疗效及对MMP-3、COX-2的影响[J].现代中西医结合杂志,2017,26(16):1741-1744.
[25]WANG Y,KOAY YC,MCALPINE SR.How selective are HSP90 inhibitors for cancer cells over normal cells?[J].Chem Med Chem,2017,12(5):353-357.
[26]TAS F,BILGIN E,ERTURK K,et al.Clinical significance of circulating serum cellular heat shock protein 90(HSP90)level in patients with cutaneous malignant melanoma[J].Asian Pac J Cancer Prev,2017,18(3):599-601.
[27]张杰,张宁,芮静安,等.人肝细胞癌及其配对非癌肝组织、正常肝组织中热休克蛋白HSP90基因m RNA水平的分析[J].中国生物化学与分子生物学报,2001,17(3):386-390.
[28]董洁,汤道权,肖冰心,等.二肽基肽酶4抑制剂药物相互作用的研究进展[J].中国药房,2017,28(32):4601-4604.
[29]GORRELL MD.Dipeptidyl peptidaseⅣand related enzymes in cell biology and liver disorders[J].Clin Sci:Lond,2005,108(4):277-292.
[30]陆迪菲,马晓伟,郭晓蕙.二肽基肽酶-4心血管系统作用的研究进展[J].中国糖尿病杂志,2016,24(11):1049-1051.
[31]ISHII S,ABE T,SAITO T,et al.Effects of preconditioning on ischemia/reperfusion injury of hepatocytes determined by immediate early gene transcription[J].J Hepatobiliary Pancreat Surg,2001,8(5):461-468.
[32]WANG S,XU X,XU F,et al.Combined expression of cjun,c-fos,and p53 improves estimation of prognosis in oral squamous cell carcinoma[J].Cancer Invest,2016,34(8):393-400.
[33]CHEOK CF,VERMA CS,BASELGA J,et al.Translating p53 into the clinic[J].Nat Rev Clin Oncol,2011,8(1):25-37.
[34]ATTALLAH AM,SHIHA GE,ISMAIL H,et al.Expression of p53 protein in liver and sera of patients with liver fibrosis,liver cirrhosis or hepatocellular carcinoma associated with chronic HCV infection[J].Clin Biochem,2009,42(6):455-461.
[35]QIN LX,TANG ZY.The prognosic molecular markers in hepatocellular carcinoma[J].World J Gastroenterol,2002,8(3):385-392.
[36]CHENG HW,CHEN YF,WONG JM,et al.Cancer cells increase endothelial cell tube formation and survival by activating the PI3K/Akt signaling pathway[J].J Exp Clin Cancer Res,2017.DOI:10.1186/s13046-017-0495-3.
[37]CHEN H,HUANG Y,HUANG J,et al.Gigantol attenuates the proliferation of human liver cancer Hep G2 cells through the PI3K/Akt/NF-κB signaling pathway[J].Oncol Rep,2017,37(2):865-870.
[38]VARFOLOMEEV E,GONCHAROV T,MAECKER H,et al.Cellular inhibitors of apoptosis are global regulators of NF-kappa B and MAPK activation by members of the TNF family of receptors[J].Sci Signal,2012.DOI:10.1126/scisignal.2001878.
[39]蔡秀红,黄贻涛,张子平,等.缺氧诱导因子-1(HIF-1)及其在水生动物中的研究进展[J].农业生物技术学报,2014,22(1):119-132.
[40]胡韶君,余勤,刘丽珍,等.HIF-1信号通路在介导DMOG动员MSCs中的作用[J].中国比较医学杂志,2015,25(1):9-14.
[41]刘丽愉,杨力芳,曹亚.低氧诱导因子信号通路的研究新进展[J].国际病理科学与临床杂志,2011,31(3):218-222.
[42]MARTINEZ-OUTSCHOORN UE,TRIMMER C,LIN Z,et al.Autophagy in cancer associated fibroblasts promotes tumor cell survival:role of hypoxia,HIF1 induction and NF-κB activation in the tumor stromal microenvironment[J].Cell Cycle,2010,9(17):3515-3533.
[43]LEGENDRE C,HORI T,LOYER P,et al.Drug-metabolising enzymes are down-regulated by hypoxia in differentiated human hepatoma Hepa RG cells:HIF-1αinvolvement in CYP3A4 repression[J].Eur J Cancer,2009,45(16):2882-2892.
[44]XU H,ZHAO L,FANG Q,et al.Mi R-338-3p inhibits hepatocarcinoma cells and sensitizes these cells to sorafenib by targeting hypoxia-induced factor 1alpha[J].PLo S One,2014,9(12):e115565.