基于网络分析细辛毒理学
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摘要
目的:采用网络毒理学的方法,通过建立化合物、蛋白、基因和毒物反应的网络关系,分析细辛中有毒物质的毒理作用机制,预测未知毒性。方法:通过在中药系统药理数据库和分析平台(TCMSP)数据库查询到的细辛候选化合物,以及在比较毒物基因组学数据库(CTD)中查询到的毒物信息的比对,筛选出细辛中13种有毒成分,并用Pharm Mapper Server中查询到13种成分相应的靶点蛋白等详细信息。使用Cytospace软件对这13种化学成分以及对应靶点蛋白,构建了网络结构图,发现了其中联系度最高的几种靶点蛋白。使用Cytospace软件中的Clue GO+Clue Pedia插件,进行gene ontology(GO)基因本体分析以及京都基因和基因组百科全书(KEGG)通路富集分析,得出了细辛中有毒物质可能通过哪些通路对人体有害。结果:细辛中毒性成分可能通过p53,白细胞介素(IL)-17,核转录因子(NF)-kappa B,肿瘤坏死因子(TNF)-α信号通路,细胞凋亡通路诱导肿瘤以及癌的形成;通过对神经元的调节,对中枢神经系统产生抑制作用;还可能通过IL-17,TNF-α和细胞凋亡调节引起其他自身免疫系统疾病。结论:探讨细辛的毒理机制,并预测了细辛可能存在的毒性,并为预测中药成分的毒性以及探究毒性机制提供了一个方法。
Objective: To analyze the known mechanism of toxicology and predict the unknown toxicity in Asari Radix et Rhizoma sinensis by establishing the network relationship of compound,protein,gene and toxicant reaction. Method: After comparing the Asari Radix et Rhizoma candidate compounds obtained from the traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform( TCMSP) database and the toxicological information obtained from the Comparative Toxicogenomics Database( CTD) database,we screened out 13 toxic components from Asari Radix et Rhizoma. And use the Pharm Mapper Server website to find the detailed information of target proteins of the 13 components. The network structure of these 13 chemical components and their corresponding target proteins were drawn by using Cytospace software,and several target proteins with the highest degree of association were found. ClueGO + CluePedia plug-in of Cytospace software was applied in gene ontology( GO) enrichment analysis of genes and kyoto encyclopedia of genes and genomes( KEGG) pathway enrichment analysis,so as to determine the pathways through which toxic substances in Asari Radix et Rhizoma might be harmful to human body. Result: The toxic substances in Asari Radix et Rhizoma may induce tumor and cancer formation through p53 signaling pathway,interleukin( IL)-17 signaling pathway,nuclear factor( NF)-kappa B signaling pathway,tumor necrosis factor( TNF)-signaling pathway. Asari Radix et Rhizoma could inhibit the central nervous system by regulating apoptosis pathways and neurons,and may also cause other autoimmune diseases by IL-17,TNF-α pathway and apoptosis regulation. Conclusion: This study preliminarily explores related mechanisms of toxicity of Asari Radix et Rhizoma,this method can be used to predict toxicity and explain toxicity mechanism of traditional Chinese medicine.
Objective: To analyze the known mechanism of toxicology and predict the unknown toxicity in Asari Radix et Rhizoma sinensis by establishing the network relationship of compound,protein,gene and toxicant reaction. Method: After comparing the Asari Radix et Rhizoma candidate compounds obtained from the traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform( TCMSP) database and the toxicological information obtained from the Comparative Toxicogenomics Database( CTD) database,we screened out 13 toxic components from Asari Radix et Rhizoma. And use the Pharm Mapper Server website to find the detailed information of target proteins of the 13 components. The network structure of these 13 chemical components and their corresponding target proteins were drawn by using Cytospace software,and several target proteins with the highest degree of association were found. ClueGO + CluePedia plug-in of Cytospace software was applied in gene ontology( GO) enrichment analysis of genes and kyoto encyclopedia of genes and genomes( KEGG) pathway enrichment analysis,so as to determine the pathways through which toxic substances in Asari Radix et Rhizoma might be harmful to human body. Result: The toxic substances in Asari Radix et Rhizoma may induce tumor and cancer formation through p53 signaling pathway,interleukin( IL)-17 signaling pathway,nuclear factor( NF)-kappa B signaling pathway,tumor necrosis factor( TNF)-signaling pathway. Asari Radix et Rhizoma could inhibit the central nervous system by regulating apoptosis pathways and neurons,and may also cause other autoimmune diseases by IL-17,TNF-α pathway and apoptosis regulation. Conclusion: This study preliminarily explores related mechanisms of toxicity of Asari Radix et Rhizoma,this method can be used to predict toxicity and explain toxicity mechanism of traditional Chinese medicine.
引文
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[2]李明,周强,杨丽娜,等.基于历代中医文献的细辛证治规律与常用剂量探索[J].中国实验方剂学杂志,2018,24(8):23-28.
[3]徐建兵,文竹,杨国正,等.细辛毒性研究进展[J].西部医学,2011,23(12):2473-2475.
[4]范骁辉,赵筱萍,金烨成,等.论建立网络毒理学及中药网络毒理学研究思路[J].中国中药杂志,2011,36(21):2920-2922.
[5]樊耀华,欧海亚,王汉裕,等.基于网络药理学的茵陈五苓散作用机制分析[J].中国实验方剂学杂志,2018,24(11):193-200.
[6]赖艳妮,严一文,徐培平.基于系统药理学探索莪术有效成分的药理作用机制[J].中国实验方剂学杂志,2017,23(14):177-182.
[7] Chakraborty R,Hampton O A,SHEN X,et al. Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis[J]. Blood,2014,124(19):3007-3015.
[8] DING W,Levy D D,Bishop M E,et al. Methyleugenol genotoxicity in the fischer 344 rat using the comet assay and pathway-focused gene expression profiling[J].Toxicol Sci,2011,123(1):103-112.
[9] Brzóska K,Bart?omiejczyk T,Sochanowicz B,et al.Matrix metalloproteinase 3 polymorphisms as a potential marker of enhanced susceptibility to lung cancer in chronic obstructive pulmonary disease subjects[J]. Ann Agric Environ Med,2014,21(3):546-551.
[10]竺越.晚期阿尔茨海默氏病PNMT蛋白的转运减少[J].国际老年医学杂志,1991(6):41.
[11]朱新贤,夏红,李莉,等.子宫肌瘤组织中性激素结合球蛋白mRNA的表达[J].同济大学学报:医学版,2002,23(1):36-38.
[12]袁野,周歧新.单胺氧化酶B-治疗神经元退行性变的可能靶点[J].临床与病理杂志,2006,26(1):67-70.
[13] Oefner C,Pierau S,Schulz H,et al. Structural studies of a bifunctional inhibitor of neprilysin and DPP-Ⅳ[J].Acta Crystallogr. Sect D:Biol Crystallogr,2007,63(9):975-981.
[14]冯庆兴. FABP6在肾透明细胞癌中的表达研究[D].汕头:汕头大学,2011.
[15]游姣娥,周祯祥,黄芳,等.细辛长期毒性对SD大鼠心电图及心肌酶谱的影响[J].湖北中医药大学学报,2015,17(4):1-3.
[16] Muenke M,Schell U,Hehr A,et al. A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome[J]. Nat Genet,1994,8(3):269-274.
[17]宋俊斋,李家亿,杨念,等.中药细辛的遗传毒性实验研究[J].中国药物警戒,2010,7(5):262-264.
[18]赵海燕.细辛毒性的药理和毒理作用探讨[J].中国保健营养旬刊,2014(5):2860-2860.
[19]刘敏,刘振权,吴莹,等.基于效毒二重性的细辛免疫调节研究及前景展望[C]//第九届全国免疫学学术大会论文集,2014-10,济南,2014:721-722.
[20]地力下·司马义,李锋,张文杰. IL-17结构及其信号通路与肿瘤的关系[J].农垦医学,2012,34(2):166-171.
[21]徐文达,高平,杨文君. p53信号通路与肿瘤关系的研究进展[J].宁夏医科大学学报,2012,34(9):971-976.
[22] ZHANG Q,Lenardo M J,Baltimore D. 30 years of NF-κB:a blossoming of relevance to human pathobiology[J]. Cell,2017,168(1/2):37-57.
[23]姜珊.肿瘤坏死因子调控TNF-信号通路新机制的研究[D].北京:中国科学院大学,2016.
[24]王文珊,傅冷西,叶君健. TNF-α信号传导通路的研究进展[J].福建医科大学学报,2005,39(s1):27-31.
[25]张学军,郭礼和.细胞凋亡失调与疾病关系的研究[J].中华医学杂志,1998,78(8):565-566.
[26]曲淑岩,毋英杰,王一华.细辛对中枢神经系统的抑制作用[J].中医杂志,1982,23(6):72-74.