胃痞灵治疗胃癌前病变机制的网络药理学预测及其促凋亡研究
|
摘要
目的:运用网络药理学及实验验证方法,分析胃痞灵调控凋亡治疗胃癌前病变(GPL)的作用机制。方法:利用网络药理学技术筛选胃痞灵治疗GPL的关键成分及作用靶标,构建成分-靶点网络,并进行蛋白相互作用分析、GO及KEGG通路富集,分析其调控细胞凋亡可能的作用机制。建立GPL小鼠模型,予以胃痞灵干预,观察用药后小鼠黏膜改变及凋亡相关蛋白Bcl-2、Bcl-xl、Bax表达变化。结果:胃痞灵中含有113个活性成分,对应GPL103个靶点,其中有36个核心蛋白,主要涉及47条GO条目与18条信号通路;体内实验证实,与模型组比较,胃痞灵可通过下调Bcl-2、Bcl-xl(P<0.01),上调Bax(P<0.05)以促进细胞凋亡,从而发挥治疗作用。结论:胃痞灵可通过调控凋亡相关蛋白表达,以发挥促凋亡作用。
Objective: To analysis mechanism of Weipiling in treatment gastric precancerous lesions(GPL) by regulating pro-apoptosis based on using network pharmacology and experimental verification methods. Methods: A network pharmacology approach was used to detect the ingredients in Weipiling and the targets of GPL. Then, compound-targets network, protein interaction network, Gene oncology(GO) and Kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment analyses were constructed to explore the therapeutic mechanism of Weipiling regulated pro-apoptosis. Mice GPL model was established and intervened by Weipiling to observe the changes in mucosal and the expression of apoptosis-related proteins Bcl-2, Bcl-xl and Bax. Results: Weipiling had 113 active compounds corresponding to 103 targets. It had 36 core proteins, 47 GO terms and 18 pathways in treating GPL. In vivo experiments confirmed Weipiling played a therapeutic role by down-regulating Bcl-2 and Bclxl(P<0.01) and up-regulating Bax(P<0.05) to promote apoptosis. Conclusion: Weipiling could regulate apoptosis-related protein expression to play a pro-apoptosis role in the prevention and treatment of GPL.
Objective: To analysis mechanism of Weipiling in treatment gastric precancerous lesions(GPL) by regulating pro-apoptosis based on using network pharmacology and experimental verification methods. Methods: A network pharmacology approach was used to detect the ingredients in Weipiling and the targets of GPL. Then, compound-targets network, protein interaction network, Gene oncology(GO) and Kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment analyses were constructed to explore the therapeutic mechanism of Weipiling regulated pro-apoptosis. Mice GPL model was established and intervened by Weipiling to observe the changes in mucosal and the expression of apoptosis-related proteins Bcl-2, Bcl-xl and Bax. Results: Weipiling had 113 active compounds corresponding to 103 targets. It had 36 core proteins, 47 GO terms and 18 pathways in treating GPL. In vivo experiments confirmed Weipiling played a therapeutic role by down-regulating Bcl-2 and Bclxl(P<0.01) and up-regulating Bax(P<0.05) to promote apoptosis. Conclusion: Weipiling could regulate apoptosis-related protein expression to play a pro-apoptosis role in the prevention and treatment of GPL.
引文
[1]Correa P.Human gastric carcinogenesis:A multistep and multifactorial process:First american cancer society award Lecture on cancer epidemiology and prevention.Cancer Research,1992,52(24):673506740
[2]Mera R M, Bravo L E,Camargo M C,et al.Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions:16-year follow-up of an eradication trial.Gut,2018,67(7):1239-1246
[3]Wang M,Zhang Y,Xiao X,et al.A polysaccharide isolated from mycelia of the lion’s mane medicinal mushroom hericium erinaceus(Agaricomycetes)induced apoptosis in precancerous human gastric cells.International Journal of Medicinal Mushrooms,2017,19(12):1053-1060
[4]Cai T,Zhang C,Zhao Z,et al.The gastric mucosal protective effects of astragaloside IV in mnng-induced GPL rats.Biomedicine&Pharmacotherapy,2018,104:291-299
[5]Chen J Y,Piquette-Miller M,Smith B P.Network medicine:finding the links to personalized therapy.Clinical Pharmacology and Therapeutics,2013,94(6):613-616
[6]李梢,张博.中药网络药理学:理论、方法与应用(英文).中国天然药物,2013,11(2):110-120
[7]潘华峰,刘友章,王超,等.慢性萎缩性胃炎虚瘀毒病机及健脾化瘀解毒干预的探讨.中华中医药杂志,2012,27(5):1236-1238
[8]曾进浩,潘华峰,赵自明,等.健脾化瘀解毒复方治疗胃癌前病变的临床疗效及对HIF-1α、VEGF表达的影响.时珍国医国药,2018,29(7):1544-1548
[9]魏玮,杨洋.慢性萎缩性胃炎诊治现状及中医药治疗优势.中医杂志,2016,57(1):36-40
[10]魏玮,杨洋,史海霞.慢性萎缩性胃炎中医诊疗现状、挑战及展望.中国中西医结合杂志,2015,35(12):1424-1426
[11]姜宁,黄宣,范一宏,等.中西医结合治疗胃癌前病变疗效的系统评价.中华中医药学刊,2015, 33(1):149-154
[12]赵自明,潘华峰,曾晓会,等.胃痞灵对氨水所致慢性萎缩性胃炎大鼠胃黏膜病理学、SOD、MDA和NO含量的影响.按摩与康复医学,2017,8(13):74-77
[13]Lv Y,Peng L,Wang Q,et al.Degranulation of mast cells induced by gastric cancer-derived adrenomedullin prompts gastric cancer progression.Cell Death&Disease,2018,9(10):1034
[14]Yang J,Zou Y,Jiang D.Honokiol suppresses proliferation and induces apoptosis via regulation of the miR-21/PTEN/PI3K/AKT signaling pathway in human osteosarcoma cells.International Journal of Molecular Medicine,2018,41(4):1845-1854
[15]Zuckerman V,Wolyniec K,Sionov R V,et al.Tumour suppression by p53:the importance of apoptosis and cellular senescence.The Journal of Pathology,2009,219(1):3-15
[16]Partida-Rodríguez O,Torres J,Flores-Luna L,et al.Polymorphisms in TNF and HSP-70 show a significant association with gastric cancer and duodenal ulcer.International Journal of Cancer,2010,126(8):1861-1868
[17]Hu L,Lao S-X,Tang C-Z.Expression of bcl-2 oncogene in gastric precancerous lesions and its correlation with syndromes in traditional Chinese medicine.World Journal of Gastroenterology,2005,11(21):3293-3296
[18]刘海峰,刘为纹,房殿春,等.胃癌和胃癌前病变bcl-2基因表达及其对细胞凋亡的调控作用.第三军医大学学报,2004(7):580-583
[19]Breckenridge D G,Xue D.Regulation of mitochondrial membrane permeabilization by BCL-2 family proteins and caspases.Current Opinion in Cell Biology,2004,16(6):647-652
[20]Wang X, Zhang J,Kim H P,et al.Bcl-XL disrupts death-inducing signal complex formation in plasma membrane induced by hypoxia/reoxygenation.FASEB journal:official publication of the Federation of American Societies for Experimental Biology,2004,18(15):1826-1833
[21]GrykoM,PryczyniczA,Guzińska-UstymowiczK,etal.Immunohistochemical assessment of apoptosis-associated proteins:p53,Bcl-x L,Bax and Bak in gastric cancer cells in correlation with clinical and pathomorphological factors.Advances in Medical Sciences,2012,57(1):77-83
[22]Liu Z,Ding Y,Ye N,et al.Direct Activation of Bax Protein for Cancer Therapy.Medicinal Research Reviews,2016,36(2):313-341
[23]Wang G,Zhang J,Liu L,et al.Quercetin potentiates doxorubicin mediated antitumor effects against liver cancer through p53/Bcl-xl.Plo S One,2012,7(12):e51764
[24]Duo J,Ying G-G,Wang G-W,et al.Quercetin inhibits human breast cancer cell proliferation and induces apoptosis via Bcl-2 and Bax regulation.Molecular Medicine Reports,2012,5(6):1453-1456
[25]Qian J,Li J,Jia J-G,et al.Ginsenoside-Rh2 inhibits proliferation and induces apoptosis of human gastric cancer SGC-7901 side population cells.Asian Pacific Journal of Cancer Prevention:APJCP,2016,17(4):1817-1821
[26]张彦琼,李梢.网络药理学与中医药现代研究的若干进展.中国药理学与毒理学杂志,2015,29(6):883-892
[27]赵芳卿,翟菲,项荣武,等.网络药理学研究态势的可视化分析.中华中医药杂志,2018,33(7):3099-3103
[2]Mera R M, Bravo L E,Camargo M C,et al.Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions:16-year follow-up of an eradication trial.Gut,2018,67(7):1239-1246
[3]Wang M,Zhang Y,Xiao X,et al.A polysaccharide isolated from mycelia of the lion’s mane medicinal mushroom hericium erinaceus(Agaricomycetes)induced apoptosis in precancerous human gastric cells.International Journal of Medicinal Mushrooms,2017,19(12):1053-1060
[4]Cai T,Zhang C,Zhao Z,et al.The gastric mucosal protective effects of astragaloside IV in mnng-induced GPL rats.Biomedicine&Pharmacotherapy,2018,104:291-299
[5]Chen J Y,Piquette-Miller M,Smith B P.Network medicine:finding the links to personalized therapy.Clinical Pharmacology and Therapeutics,2013,94(6):613-616
[6]李梢,张博.中药网络药理学:理论、方法与应用(英文).中国天然药物,2013,11(2):110-120
[7]潘华峰,刘友章,王超,等.慢性萎缩性胃炎虚瘀毒病机及健脾化瘀解毒干预的探讨.中华中医药杂志,2012,27(5):1236-1238
[8]曾进浩,潘华峰,赵自明,等.健脾化瘀解毒复方治疗胃癌前病变的临床疗效及对HIF-1α、VEGF表达的影响.时珍国医国药,2018,29(7):1544-1548
[9]魏玮,杨洋.慢性萎缩性胃炎诊治现状及中医药治疗优势.中医杂志,2016,57(1):36-40
[10]魏玮,杨洋,史海霞.慢性萎缩性胃炎中医诊疗现状、挑战及展望.中国中西医结合杂志,2015,35(12):1424-1426
[11]姜宁,黄宣,范一宏,等.中西医结合治疗胃癌前病变疗效的系统评价.中华中医药学刊,2015, 33(1):149-154
[12]赵自明,潘华峰,曾晓会,等.胃痞灵对氨水所致慢性萎缩性胃炎大鼠胃黏膜病理学、SOD、MDA和NO含量的影响.按摩与康复医学,2017,8(13):74-77
[13]Lv Y,Peng L,Wang Q,et al.Degranulation of mast cells induced by gastric cancer-derived adrenomedullin prompts gastric cancer progression.Cell Death&Disease,2018,9(10):1034
[14]Yang J,Zou Y,Jiang D.Honokiol suppresses proliferation and induces apoptosis via regulation of the miR-21/PTEN/PI3K/AKT signaling pathway in human osteosarcoma cells.International Journal of Molecular Medicine,2018,41(4):1845-1854
[15]Zuckerman V,Wolyniec K,Sionov R V,et al.Tumour suppression by p53:the importance of apoptosis and cellular senescence.The Journal of Pathology,2009,219(1):3-15
[16]Partida-Rodríguez O,Torres J,Flores-Luna L,et al.Polymorphisms in TNF and HSP-70 show a significant association with gastric cancer and duodenal ulcer.International Journal of Cancer,2010,126(8):1861-1868
[17]Hu L,Lao S-X,Tang C-Z.Expression of bcl-2 oncogene in gastric precancerous lesions and its correlation with syndromes in traditional Chinese medicine.World Journal of Gastroenterology,2005,11(21):3293-3296
[18]刘海峰,刘为纹,房殿春,等.胃癌和胃癌前病变bcl-2基因表达及其对细胞凋亡的调控作用.第三军医大学学报,2004(7):580-583
[19]Breckenridge D G,Xue D.Regulation of mitochondrial membrane permeabilization by BCL-2 family proteins and caspases.Current Opinion in Cell Biology,2004,16(6):647-652
[20]Wang X, Zhang J,Kim H P,et al.Bcl-XL disrupts death-inducing signal complex formation in plasma membrane induced by hypoxia/reoxygenation.FASEB journal:official publication of the Federation of American Societies for Experimental Biology,2004,18(15):1826-1833
[21]GrykoM,PryczyniczA,Guzińska-UstymowiczK,etal.Immunohistochemical assessment of apoptosis-associated proteins:p53,Bcl-x L,Bax and Bak in gastric cancer cells in correlation with clinical and pathomorphological factors.Advances in Medical Sciences,2012,57(1):77-83
[22]Liu Z,Ding Y,Ye N,et al.Direct Activation of Bax Protein for Cancer Therapy.Medicinal Research Reviews,2016,36(2):313-341
[23]Wang G,Zhang J,Liu L,et al.Quercetin potentiates doxorubicin mediated antitumor effects against liver cancer through p53/Bcl-xl.Plo S One,2012,7(12):e51764
[24]Duo J,Ying G-G,Wang G-W,et al.Quercetin inhibits human breast cancer cell proliferation and induces apoptosis via Bcl-2 and Bax regulation.Molecular Medicine Reports,2012,5(6):1453-1456
[25]Qian J,Li J,Jia J-G,et al.Ginsenoside-Rh2 inhibits proliferation and induces apoptosis of human gastric cancer SGC-7901 side population cells.Asian Pacific Journal of Cancer Prevention:APJCP,2016,17(4):1817-1821
[26]张彦琼,李梢.网络药理学与中医药现代研究的若干进展.中国药理学与毒理学杂志,2015,29(6):883-892
[27]赵芳卿,翟菲,项荣武,等.网络药理学研究态势的可视化分析.中华中医药杂志,2018,33(7):3099-3103