基于数据挖掘和生物信息分析探讨非酒精性脂肪肝用药规律及作用机制
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摘要
为挖掘非酒精性脂肪肝的组方用药规律,分析处方可能存在的药物靶标及相互作用,探寻药物潜在作用机制。收集中国知网、万方、维普、中国生物数据库和PubMed等数据库中关于中药治疗非酒精性脂肪肝的随机对照试验;运用SPSS 19. 0软件对药物的性味归经进行系统聚类分析;采用Clementine 12. 0软件对数据进行关联规则分析;运用TCMSP,String,KEGG数据库分析常用药物靶标间相互作用及相关通路。筛选出88首处方,挖掘出常用药物为丹参、柴胡、泽泻、山楂,与非酒精性脂肪肝关系密切的潜在通路是PPAR信号通路和钙离子通路。结果表明,中药治疗非酒精性脂肪肝以活血化瘀、清热祛湿、消食健脾为主,其作用机制可能通过PPAR信号通路和钙离子通路实现。
To explore the medication rules of herbal prescriptions for nonalcoholic fatty liver disease,and analyze the possible drug targets and interactions,in order to explore the mechanisms of the herbs. Randomized controlled trials of herbal prescriptions for treating nonalcoholic fatty liver disease were collected from CNKI,Wan Fang,VIP,Sino Med and PubMed databases. The properties,flavors and meridian tropism of herbs were analyzed by using systematic cluster analysis method with SPSS 19. 0 software. Subsequently,the association rules of herbs were analyzed by using Clementine 12. 0 software. Finally,the interactions between targets and relevant signaling pathways were analyzed by Traditional Chinese Medicine Systems Pharmacology Database(TCMSP),Search Tool for the Retrieval of Interacting Genes/Proteins(STRING) and Kyoto Encyclopedia of Genes and Genomes(KEGG). In the 88 prescriptions screened out,the commonly used herbs were Salvia miltiorrhiza,Bupleurum chinense,Alisma orientale,and Crataegus pinnatifida,and the potential signaling pathways were PPAR signaling pathway and calcium signaling pathway. The results showed that the main effects of herbal prescriptions were to improve blood flow/clear blood stasis,clear heatiness/dampness,promote digestion and strengthen spleen. And its mechanism of action may be achieved through the regulation of PPAR signaling pathway and calcium signaling pathway.
To explore the medication rules of herbal prescriptions for nonalcoholic fatty liver disease,and analyze the possible drug targets and interactions,in order to explore the mechanisms of the herbs. Randomized controlled trials of herbal prescriptions for treating nonalcoholic fatty liver disease were collected from CNKI,Wan Fang,VIP,Sino Med and PubMed databases. The properties,flavors and meridian tropism of herbs were analyzed by using systematic cluster analysis method with SPSS 19. 0 software. Subsequently,the association rules of herbs were analyzed by using Clementine 12. 0 software. Finally,the interactions between targets and relevant signaling pathways were analyzed by Traditional Chinese Medicine Systems Pharmacology Database(TCMSP),Search Tool for the Retrieval of Interacting Genes/Proteins(STRING) and Kyoto Encyclopedia of Genes and Genomes(KEGG). In the 88 prescriptions screened out,the commonly used herbs were Salvia miltiorrhiza,Bupleurum chinense,Alisma orientale,and Crataegus pinnatifida,and the potential signaling pathways were PPAR signaling pathway and calcium signaling pathway. The results showed that the main effects of herbal prescriptions were to improve blood flow/clear blood stasis,clear heatiness/dampness,promote digestion and strengthen spleen. And its mechanism of action may be achieved through the regulation of PPAR signaling pathway and calcium signaling pathway.
引文
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[15]陈利.中药柴胡主要活性成分柴胡皂苷D作用于肝细胞LO2的肝损伤机理研究[D].南京:南京中医药大学,2014.
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[18]杨倩,张娜,李鹏,等.柴胡消脂方治疗气滞血瘀型非酒精性脂肪肝性肝病临床研究[J].四川中医,2016,34(3):92.
[19]吕宝伟,冯春青,孙建光.补肾降浊饮对非酒精性脂肪肝大鼠胰岛素抵抗的影响[J].中国实验方剂学杂志,2018,24(12):107.
[20]陈蓓琪.脂肪肝文献评价和辨证论治规律探讨[D].南京:南京中医药大学,2012.
[21]罗先钦,黄崇刚,伍小波,等.山楂总黄酮对复合因素致大鼠脂肪肝模型脂质代谢与低密度脂蛋白受体表达的影响[J].中草药,2011,42(7):1367.
[22] Araujo S,Soares E S A,Gomes F,et al. Effects of the new thiazolidine derivative LPSF/GQ-02 on hepatic lipid metabolism pathways in non-alcoholic fatty liver disease(NAFLD)[J]. Eur J Pharmacol,2016,788:306.
[23] Takahashi H,Sanada K,Nagai H,et al. Over-expression of PPARalpha in obese mice adipose tissue improves insulin sensitivity[J]. Biochem Biophys Res Commun,2017,493(1):108.
[24] Pettinelli P,Videla L A. Up-regulation of PPAR-gamma mRNA expression in the liver of obese patients:an additional reinforcing lipogenic mechanism to SREBP-1c induction[J]. J Clin Endocrinol Metab,2011,96(5):1424.
[25] Wolf G A,Majumdar N,Yang P,et al. Hepatocyte-specific,PPARgamma-regulated mechanisms to promote steatosis in adult mice[J]. J Endocrinol,2017,232(1):107.
[26] Csordas G,Hajnoczky G. SR/ER-mitochondrial local communication:calcium and ROS[J]. Biochim Biophys Acta,2009,1787(11):1352.
[27] Bartlett P J,Gaspers L D,Pierobon N,et al. Calcium-dependent regulation of glucose homeostasis in the liver[J]. Cell Calcium,2014,55(6):306.
[2] Chalasani N,Younossi Z,Lavine J E,et al. The diagnosis and management of non-alcoholic fatty liver disease:practice guideline by the American Association for the Study of Liver Diseases,American College of Gastroenterology,and the American Gastroenterological Association[J]. Hepatology,2012,55(6):2005.
[3] Masarone M,Federico A,Abenavoli L,et al. Nonalcoholic fatty liver:epidemiology and natural history[J]. Rev Recent Clin Trials,2014,9(3):126.
[4] Dong H,Lu F E,Zhao L. Chinese herbal medicine in the treatment of nonalcoholic fatty liver disease[J]. Chin J Integr Med,2012,18(2):152.
[5]潘雨婷,许方园,于希忠,等.中药活性成分治疗非酒精性脂肪肝作用靶点的研究进展[J].中国中药杂志,2017,42(6):1109.
[6]段锦龙,姚魁武,冯潇潇,等.基于网络药理学方法分析中药临床治疗胸痹的作用机制[J].中国中药杂志,2017,42(17):3424.
[7]中华医学会肝脏病学分会脂肪肝和酒精性肝病学组.非酒精性脂肪性肝病诊断标准[J].中华肝脏病杂志,2003(2):8.
[8]中国药典.一部[S]. 2015.
[9]高学敏.中药学[M].北京:中国中医药出版社,2002.
[10]杨丽丽,李正钧,陈静怡,等.中医古籍芳香类方药外治数据挖掘系统构建及应用[J].中华医学图书情报杂志,2017,26(8):8.
[11]吴丽,张峰,郑仕中,等.中医药治疗非酒精性脂肪肝的研究进展[J].中成药,2015(5):1072.
[12]莫新民,刘锐,李建平,等.丹参对非酒精性脂肪肝大鼠血清瘦素Ghrelin的影响[J].中华中医药学刊,2010,28(11):2252.
[13]陈利平,许贤盛,陈丹丹.丹参酮ⅡA磺酸钠注射液联合降脂方治疗非酒精性脂肪肝疗效观察[J].新中医,2014,46(7):67.
[14]李丹,江涛,范华倩,等.柴胡疏肝散对非酒精性脂肪肝大鼠脂质代谢及肝功能的影响[J].中药药理与临床,2013,29(3):8.
[15]陈利.中药柴胡主要活性成分柴胡皂苷D作用于肝细胞LO2的肝损伤机理研究[D].南京:南京中医药大学,2014.
[16]洪学智.泽泻治疗非酒精性脂肪肝病药效及作用机理研究[D].杭州:浙江大学,2006.
[17]郭雨雅.基于TLR4/NF-κB信号通路对加味泽泻汤治疗非酒精性脂肪肝机制的研究[D].南京:南京中医药大学,2017.
[18]杨倩,张娜,李鹏,等.柴胡消脂方治疗气滞血瘀型非酒精性脂肪肝性肝病临床研究[J].四川中医,2016,34(3):92.
[19]吕宝伟,冯春青,孙建光.补肾降浊饮对非酒精性脂肪肝大鼠胰岛素抵抗的影响[J].中国实验方剂学杂志,2018,24(12):107.
[20]陈蓓琪.脂肪肝文献评价和辨证论治规律探讨[D].南京:南京中医药大学,2012.
[21]罗先钦,黄崇刚,伍小波,等.山楂总黄酮对复合因素致大鼠脂肪肝模型脂质代谢与低密度脂蛋白受体表达的影响[J].中草药,2011,42(7):1367.
[22] Araujo S,Soares E S A,Gomes F,et al. Effects of the new thiazolidine derivative LPSF/GQ-02 on hepatic lipid metabolism pathways in non-alcoholic fatty liver disease(NAFLD)[J]. Eur J Pharmacol,2016,788:306.
[23] Takahashi H,Sanada K,Nagai H,et al. Over-expression of PPARalpha in obese mice adipose tissue improves insulin sensitivity[J]. Biochem Biophys Res Commun,2017,493(1):108.
[24] Pettinelli P,Videla L A. Up-regulation of PPAR-gamma mRNA expression in the liver of obese patients:an additional reinforcing lipogenic mechanism to SREBP-1c induction[J]. J Clin Endocrinol Metab,2011,96(5):1424.
[25] Wolf G A,Majumdar N,Yang P,et al. Hepatocyte-specific,PPARgamma-regulated mechanisms to promote steatosis in adult mice[J]. J Endocrinol,2017,232(1):107.
[26] Csordas G,Hajnoczky G. SR/ER-mitochondrial local communication:calcium and ROS[J]. Biochim Biophys Acta,2009,1787(11):1352.
[27] Bartlett P J,Gaspers L D,Pierobon N,et al. Calcium-dependent regulation of glucose homeostasis in the liver[J]. Cell Calcium,2014,55(6):306.