基于网络药理学的厚朴“发汗”科学内涵探究
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摘要
目的利用网络药理学方法建立厚朴"发汗"前后的差异成分-靶点网络,并探究厚朴"发汗"前后药理作用差异的分子机制,进而揭示其发汗的科学内涵。方法通过查阅文献并筛选厚朴"发汗"前后的差异成分。利用SwissTarget Prediction预测差异成分的潜在靶点。利用STRING数据库筛选出最高置信度(得分0.900)的靶点并通过Cytoscape 3.6.0软件构建蛋白-蛋白互作网络。最后利用RProject中的clusterProfiler包对蛋白-蛋白互作网络进行GO注释和KEGG通路富集分析。结果通过查阅文献共筛选出9种差异成分(阿西米诺宾、β-桉叶醇、和厚朴酚、厚朴三酚B、木兰花碱、厚朴酚、紫丁香苷、瑞枯灵和magnoloside A)并预测得到137个靶点(除重后共86个)。通过对蛋白-蛋白互作网络GO注释及通路富集分析,共得到550个GO注释和30条KEGG通路。结论数据分析结果表明,"发汗"后厚朴药理作用的改变是化学成分相互作用的最终结果。其中,厚朴主要是通过5-羟色胺能突触、花生四烯酸代谢和钙信号通路发挥镇痛和抗胃溃疡作用。厚朴酚、和厚朴酚及β-桉叶醇等化学成分含量的改变是厚朴"发汗"前后疗效差异的主要原因。
Objective Sweating is one of the important processing methods of traditional Chinese medicine. Some ingredient content of Magnoliae Officinalis Cortex(MOC) is changed after sweating which may cause the difference of efficacy. However, the molecular mechanism of how the changes of ingredient content of MOC affect the efficacy is not clear exactly. Based on the network pharmacology, the relationship between the changes of the ingredient content of MOC and the efficacy after sweating was studied. Methods The major difference of chemical ingredients before and after sweating were screened out based on the literatures. Swiss Target Prediction was used to predict the potential targets of these components. The high confidence(score 0.900) genes/targets selected out by STRING database were used to construct protein-protein interactions network by using cytoscape 3.6.0. The clusterProfiler package in R was used to analyze gene ontology(GO) function and Kyoto encyclopedia of genes and genomes(KEGG) pathway. Results Nine different components(asimilobine, β-eudesmol, honokiol, magnatriol B, magnoflorine, magnolol, magnoloside A, reticuline, and syringin) were screened out. A total of 137 genes/targets were obtained(86 after deduplication). After GO annotation and KEGG enrichment analysis of the network, 550 GO-terms and 30 KEGG pathways were obtained. ConclusionThrough analysis, the change in the pharmacological effects of MOC after sweating is the result of the interaction between the components. The analgesic and anti-gastric ulcer effects of MOC may be mainly produced through the serotonergic synapse, arachidonic acid metabolism and calcium signaling pathway. And the changes in the content of chemical components such as magnolol, honokiol and β-eudesmol are the main reasons for the difference in the efficacy of MOC before and after sweating.
Objective Sweating is one of the important processing methods of traditional Chinese medicine. Some ingredient content of Magnoliae Officinalis Cortex(MOC) is changed after sweating which may cause the difference of efficacy. However, the molecular mechanism of how the changes of ingredient content of MOC affect the efficacy is not clear exactly. Based on the network pharmacology, the relationship between the changes of the ingredient content of MOC and the efficacy after sweating was studied. Methods The major difference of chemical ingredients before and after sweating were screened out based on the literatures. Swiss Target Prediction was used to predict the potential targets of these components. The high confidence(score 0.900) genes/targets selected out by STRING database were used to construct protein-protein interactions network by using cytoscape 3.6.0. The clusterProfiler package in R was used to analyze gene ontology(GO) function and Kyoto encyclopedia of genes and genomes(KEGG) pathway. Results Nine different components(asimilobine, β-eudesmol, honokiol, magnatriol B, magnoflorine, magnolol, magnoloside A, reticuline, and syringin) were screened out. A total of 137 genes/targets were obtained(86 after deduplication). After GO annotation and KEGG enrichment analysis of the network, 550 GO-terms and 30 KEGG pathways were obtained. ConclusionThrough analysis, the change in the pharmacological effects of MOC after sweating is the result of the interaction between the components. The analgesic and anti-gastric ulcer effects of MOC may be mainly produced through the serotonergic synapse, arachidonic acid metabolism and calcium signaling pathway. And the changes in the content of chemical components such as magnolol, honokiol and β-eudesmol are the main reasons for the difference in the efficacy of MOC before and after sweating.
引文
[1]张淑洁,钟凌云.厚朴化学成分及其现代药理研究进展[J].中药材,2013,36(5):838-843.
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[3]刘红亮,晏仁义,邵爱娟,等.中药材“发汗”对药材质量的影响[J].中国实验方剂学杂志,2013,19(24):349-352.
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[12]胡慧玲,卫莹芳,傅超美,等.“发汗”对厚朴化学成分及药代动力学影响的研究[A]//世界中医药学会联合会中药药剂专业委员会、中华中医药学会中药制剂分会学术年会暨“江中杯”中药制剂创新与发展论坛[C].南昌:世界中医药学会联合会中药药剂专业委员会、中华中医药学会中药制剂分会,2012.
[13]吕江明,陈景,梁剑雄,等.厚朴干皮“发汗”(加工)前后抗菌镇痛作用的比较研究[J].内蒙古中医药,2004,23(1):25-26.
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[15]尹爱武,田润,黄国文,等.厚朴“发汗”对大鼠胃动力和抗溃疡作用研究[J].中国实验方剂学杂志,2012,18(16):212-215.
[16]Cheng T,Pan Y,Hao M,et al.Pub Chem applications in drug discovery:A bibliometric analysis[J].Drug Discov Today,2014,19(11):1751-1756.
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[19]Yu G,Wang L G,Han Y,et al.clusterProfiler:An Rpackage for comparing biological themes among gene clusters[J].Omics:J Integr Biol,2012,16(5):284-287.
[20]Zhang X,Huang H,Chang H,et al.Magnolol reduces bleomycin-induced rodent lung fibrosis[J].Int J Clin Exp Med,2015,8(9):15450-15457.
[21]Yang B,Xu Y,Yu S,et al.Anti-angiogenic and anti-inflammatory effect of magnolol in the oxygeninduced retinopathy model[J].Inflam Res,2016,65(1):81-93.
[22]Zhang P,Liu X,Zhu Y,et al.Honokiol inhibits the inflammatory reaction during cerebral ischemia reperfusion by suppressing NF-κB activation and cytokine production of glial cells[J].Neurosci Lett,2013,534(1):123-127.
[23]单卿卿,龚玉萍,郭勇,等.六种中药提取物对白血病细胞株的体外抑制作用研究[J].四川大学学报:医学版,2012,43(3):362-366.
[24]Cheng Y C,Hueng D Y,Huang H Y,et al.Magnolol and honokiol exert a synergistic anti-tumor effect through autophagy and apoptosis in human glioblastomas[J].Oncotarget,2016,7(20):29116.
[25]张璐,王飞虎,陈赛贞,等.天然抗抑郁药物与细胞色素P450的相关研究进展[J].中国中药杂志,2015,40(5):828-832.
[26]Kim S B,Kang H E,Cho H J,et al.Metabolic interactions of magnolol with cytochrome P450 enzymes:Uncompetitive inhibition of CYP1A and competitive inhibition of CYP2C[J].Drug Devel Ind Pharm,2016,42(2):263-269.
[27]Cho Y Y,Jeong H U,Kim J H,et al.Effect of honokiol on the induction of drug-metabolizing enzymes in human hepatocytes[J].Drug Design,Devel Therapy,2014,8:2137-2145.
[28]Barann M,Stamer U M,Lyutenska M,et al.Effects of opioids on human serotonin transporters[J].NaunynSchmiedeberg’s Arch Pharmacol,2015,388(1):43-49.
[29]Zhang M F,Shen Y Q.Reseach advances in neuropharmacological effect of Atractylodis Rhizoma and its active constiteuntβ-eudesmol[J].Anti Infect Pharm,2017,14(1):6-11.
[30]Brzozowski T,Konturek P C,Konturek S J,et al.Role of prostaglandins in gastroprotection and gastric adaptation[J].J Physiol Pharmacol,2005,56(5):33-55.
[2]中国药典[S].一部.2015.
[3]刘红亮,晏仁义,邵爱娟,等.中药材“发汗”对药材质量的影响[J].中国实验方剂学杂志,2013,19(24):349-352.
[4]Hsin K Y,Ghosh S,Kitano H.Combining machine learning systems and multiple docking simulation packages to improve docking prediction reliability for network pharmacology[J].PLoS One,2013,8:e83922.
[5]高耀,吴丹,田俊生,等.逍遥散和开心散“同病异治”抑郁症的网络药理学作用机制研究[J].中草药,2018,49(15):3483-3492.
[6]谢盈彧,刘璐,李渊芳,等.基于网络药理学的四妙勇安汤在血管新生中的作用机制研究[J].中草药,2018,49(18):4319-4330.
[7]刘志华,孙晓波.网络药理学:中医药现代化的新机遇[J].药学学报,2012,47(6):696-703.
[8]Zhang G B,Li Q Y,Chen Q L,et al.Network pharmacology:A new approach for Chinese herbal medicine research[J].Evid Based Compl Altern Med,2013,doi:10.1155/2013/621423.
[9]刘红亮.从药材性状及化学成分的角度诠释产地初加工“发汗”对厚朴质量的影响[D].北京:中国中医科学院,2013.
[10]杨红兵,詹亚华,陈科力,等.发汗与去皮对厚朴中酚类成分含量的影响[J].中药材,2007,30(1):22-23.
[11]余盛贤,张春霞,陈承瑜,等.“发汗”对厚朴质量的影响[J].中国中药杂志,2010,35(14):1831-1835.
[12]胡慧玲,卫莹芳,傅超美,等.“发汗”对厚朴化学成分及药代动力学影响的研究[A]//世界中医药学会联合会中药药剂专业委员会、中华中医药学会中药制剂分会学术年会暨“江中杯”中药制剂创新与发展论坛[C].南昌:世界中医药学会联合会中药药剂专业委员会、中华中医药学会中药制剂分会,2012.
[13]吕江明,陈景,梁剑雄,等.厚朴干皮“发汗”(加工)前后抗菌镇痛作用的比较研究[J].内蒙古中医药,2004,23(1):25-26.
[14]吕江明,陈景,梁剑雄,等.厚朴干皮“发汗”(加工)前后的毒性实验研究[J].内蒙古中医药,2003,22(2):25.
[15]尹爱武,田润,黄国文,等.厚朴“发汗”对大鼠胃动力和抗溃疡作用研究[J].中国实验方剂学杂志,2012,18(16):212-215.
[16]Cheng T,Pan Y,Hao M,et al.Pub Chem applications in drug discovery:A bibliometric analysis[J].Drug Discov Today,2014,19(11):1751-1756.
[17]Gfeller D,Grosdidier A,Wirth M,et al.Swiss target prediction:A web server for target prediction of bioactive small molecules[J].Nucleic Acids Res,2014,42(W1):W32-W38.
[18]Szklarczyk D,Franceschini A,Wyder S,et al.STRINGv10:Protein-protein interaction networks,integrated over the tree of life[J].Nucleic Acids Res,2014,43(D1):D447-D452.
[19]Yu G,Wang L G,Han Y,et al.clusterProfiler:An Rpackage for comparing biological themes among gene clusters[J].Omics:J Integr Biol,2012,16(5):284-287.
[20]Zhang X,Huang H,Chang H,et al.Magnolol reduces bleomycin-induced rodent lung fibrosis[J].Int J Clin Exp Med,2015,8(9):15450-15457.
[21]Yang B,Xu Y,Yu S,et al.Anti-angiogenic and anti-inflammatory effect of magnolol in the oxygeninduced retinopathy model[J].Inflam Res,2016,65(1):81-93.
[22]Zhang P,Liu X,Zhu Y,et al.Honokiol inhibits the inflammatory reaction during cerebral ischemia reperfusion by suppressing NF-κB activation and cytokine production of glial cells[J].Neurosci Lett,2013,534(1):123-127.
[23]单卿卿,龚玉萍,郭勇,等.六种中药提取物对白血病细胞株的体外抑制作用研究[J].四川大学学报:医学版,2012,43(3):362-366.
[24]Cheng Y C,Hueng D Y,Huang H Y,et al.Magnolol and honokiol exert a synergistic anti-tumor effect through autophagy and apoptosis in human glioblastomas[J].Oncotarget,2016,7(20):29116.
[25]张璐,王飞虎,陈赛贞,等.天然抗抑郁药物与细胞色素P450的相关研究进展[J].中国中药杂志,2015,40(5):828-832.
[26]Kim S B,Kang H E,Cho H J,et al.Metabolic interactions of magnolol with cytochrome P450 enzymes:Uncompetitive inhibition of CYP1A and competitive inhibition of CYP2C[J].Drug Devel Ind Pharm,2016,42(2):263-269.
[27]Cho Y Y,Jeong H U,Kim J H,et al.Effect of honokiol on the induction of drug-metabolizing enzymes in human hepatocytes[J].Drug Design,Devel Therapy,2014,8:2137-2145.
[28]Barann M,Stamer U M,Lyutenska M,et al.Effects of opioids on human serotonin transporters[J].NaunynSchmiedeberg’s Arch Pharmacol,2015,388(1):43-49.
[29]Zhang M F,Shen Y Q.Reseach advances in neuropharmacological effect of Atractylodis Rhizoma and its active constiteuntβ-eudesmol[J].Anti Infect Pharm,2017,14(1):6-11.
[30]Brzozowski T,Konturek P C,Konturek S J,et al.Role of prostaglandins in gastroprotection and gastric adaptation[J].J Physiol Pharmacol,2005,56(5):33-55.