基于网络药理学的两面针干预炎症靶点预测及作用机制研究
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摘要
目的构建两面针干预炎症的"活性成分-炎症靶点-抗炎通路"网络关系,预测其干预炎症的靶点及机制。方法通过国内外文献调研和中药系统药理学分析平台(TCMSP)数据库及Pharmmapper服务器,以口服利用度(OB)和类药性(DL)作为限定条件对两面针成分进行筛选并预测和收集相关靶点。利用OMIM等数据库筛选炎症相关的基因和蛋白靶点;STRING数据库构建炎症靶点之间的交互网络;蛋白互作(PPI)网络分析获得"活性成分-预测靶点-炎症靶点"网络文件,并将其导入Cytoscape 3.5.1软件构建"活性成分-炎症靶点"网络,从而获得与两面针抗炎直接相关的靶点;利用DAVID数据库对筛选后的靶点进行KEGG通路富集,使用Cytoscape 3.5.1的插件ClueGO对其涉及的靶点进行生物学功能分析,最终合并以上关系构建"活性成分-炎症靶点-抗炎通路"网络。结果经筛选和分析获得两面针活性成分23个,抗炎靶点9个,包括COX-2、i NOS、PPARG、COX1、MAPK-14、JUN等,两面针抗炎的可能通路包括TNF信号通路、TRLs信号通路。结论初步揭示了两面针的抗炎作用是通过多成分和多靶点的相互作用,调控多条通路共同干预实现的,但关键的靶标和具体的调控机制尚待进一步的实验研究加以探索及验证。
Objective To construct the "active components-inflammatory target-anti-inflammatory pathway" network of Zanthoxylumnitidum intervened in inflammation, and predict the target of Z. nitidum intervened in inflammation and its anti-inflammatory mechanism. Methods Using domestic and foreign literatures, TCMSP database, Pharmmapper server, oral availability(OB), and pharmacodynamics(DL) as the limiting conditions, the components of Z. nitidum were screened and the relative targets were predicted and collected. OMIM database was used to screen inflammation-related genes and protein targets; The STRING database was used to construct the interactive network between inflammatory targets; The network file of "active ingredient-predictive target-inflammatory target" was obtained by PPI analysis and imported into Cytoscape 3.5.1 software to construct the network of "active ingredientinflammatory target", so as to obtain the targets directly related to the anti-inflammatory effects of Z. nitidum. DAVID database was used to enrich the KEGG pathway of the selected targets, and then ClueGO plug-in was used to analyze the biological function of the target involved. Finally, the "active component-inflammatory target-anti-inflammatory pathway" network was constructed by combining the above relationships. Results Twenty-three active ingredients were screened, and nine core anti-inflammatory targets were identified as COX-2, iNOS, PPARG, COX1, MAPK-14, JUN, NR3 C1 and so on; The most critical pathways included TNF TRLs signaling pathways. Conclusion It is preliminarily revealed that the anti-inflammatory effect of Z. nitidum is achieved through the interaction of multiple components and multiple targets, regulating the joint intervention of multiple pathways. However, the key targets and specific regulatory mechanisms need to be explored and verified by further experimental studies.
Objective To construct the "active components-inflammatory target-anti-inflammatory pathway" network of Zanthoxylumnitidum intervened in inflammation, and predict the target of Z. nitidum intervened in inflammation and its anti-inflammatory mechanism. Methods Using domestic and foreign literatures, TCMSP database, Pharmmapper server, oral availability(OB), and pharmacodynamics(DL) as the limiting conditions, the components of Z. nitidum were screened and the relative targets were predicted and collected. OMIM database was used to screen inflammation-related genes and protein targets; The STRING database was used to construct the interactive network between inflammatory targets; The network file of "active ingredient-predictive target-inflammatory target" was obtained by PPI analysis and imported into Cytoscape 3.5.1 software to construct the network of "active ingredientinflammatory target", so as to obtain the targets directly related to the anti-inflammatory effects of Z. nitidum. DAVID database was used to enrich the KEGG pathway of the selected targets, and then ClueGO plug-in was used to analyze the biological function of the target involved. Finally, the "active component-inflammatory target-anti-inflammatory pathway" network was constructed by combining the above relationships. Results Twenty-three active ingredients were screened, and nine core anti-inflammatory targets were identified as COX-2, iNOS, PPARG, COX1, MAPK-14, JUN, NR3 C1 and so on; The most critical pathways included TNF TRLs signaling pathways. Conclusion It is preliminarily revealed that the anti-inflammatory effect of Z. nitidum is achieved through the interaction of multiple components and multiple targets, regulating the joint intervention of multiple pathways. However, the key targets and specific regulatory mechanisms need to be explored and verified by further experimental studies.
引文
[1]中国药典[S].一部.2015.
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[13]周文霞,王同兴,程肖蕊,等.网络药理学研究中的网络分析技术[J].国际药学研究杂志,2016,43(3):399-409.
[14]庄静,刘丽娟,周超,等.网络药理学与分子对接技术指导下土大黄苷对慢性粒细胞白血病作用机制研究[J].中华肿瘤防治杂志,2016,23(22):1477-1482.
[15]陶晓倩,张新庄,李娜,等.网络药理学方法研究赤芍和黄柏干预阿尔茨海默病的作用机制[J].中草药,2015,46(11):1634-1639.
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[21]Liz R,Zanatta L,Dos reis G O,et al.Acute effect ofβ-sitosterol on calcium uptake mediates antiinflammatory effect in murine activated neutrophils[J].JPharm Pharmacol,2013,65(1):115-122.
[22]Imam F,Al-Harbi N O,Al-Harbi M M,et al.Diosmin downregulates the expression of T cell receptors,pro-inflammatory cytokines and NF-κB activation against LPS-induced acute lung injury in mice[J].Pharmacol Res,2015,doi:10.1016/j.phrs.2015.09.001.
[23]崔功廷,袁铭.地奥司明对盆腔淤血所致大鼠慢性非细菌性前列腺炎的影响[J].解放军医学杂志,2014,39(6):444-447.
[24]王畅.地奥司明治疗淤积性皮炎40例临床观察[J].中国皮肤性病学杂志,2013,27(5):480-481.
[25]杨德林.地奥司明结合非甾体抗炎药治疗膝关节滑膜炎疗效观察[J].现代中西医结合杂志,2013,22(4):419-420.
[26]李良昌,朴红梅,延光海,等.芝麻素抗哮喘炎症作用研究[J].中国药理学通报,2015,31(3):411-415.
[27]Guo L Q,Yang J R,Kong X.Protective effect of sesamin on endothelial function of type-2 diabetic rats[J].Chin Pharmacol Bull,2012,28(3):392-396.
[28]Yan G H,Cui Y H,Li G Z,et al.Anti-allergic effects of curcumin[J].Chin Pharmacol Bull,2010,26(3):416-417.
[29]Harikumar K B,Sung B,Tharakan S T,et al.Sesamin manifests chemopreventive effects through the suppression of NF kappa B-regulated cell survival,proliferation,invasion,and angiogenic gene produc[J].Mol Cancer Res,2010,8(5):751-761.
[30]Cui Y,Hou X,Chen J,et al.Sesamin inhibits bacterial formylpeptide-induced inflammatory responses in a murine airpouch model and in THP-1 human monocytes[J].J Nutr,2010,140(2):377-381.
[31]Hsieh C C,Kuo C H,Kuo H F,et al.Sesamin suppresses macrophage-derived chemokine expression in human monocytes via epigenetic regulation[J].Food Funct,2014,5(10):2494-2500.
[32]Li L,Piao H,Zheng M,et al.Sesamin attenuates allergic airway inflammation through the suppression of nuclear factor-kappa B activation[J].Exp Ther Med,2016,12(6):4175-4181.
[33]Qiang L,Yuan J,Shouyin J,et al.Sesamin attenuates lipopolysaccharide-induced acute lung injury by inhibition of TLR4 signaling pathways[J].Inflammation,2016,39(1):467-472.
[34]赵洪伟,崔银锋,姜京植,等.芝麻素通过PKCα/NF-κB信号途径抑制肥大细胞活化[J].中国免疫学杂志,2018,34(2):167-171.
[35]Liu J L,Pei M J,Zheng C L,et al.Asystemspharmacology analysis of herbal medicines used in health improvement yreatment:Predicting potential new drugs and targets[J].Evid-Based Compl Alt Med,2013,doi:10.1155/2013/938764.
[36]Castoreno A B,Eggert U S.Small molecule probes of cellular pathways and networks[J].ACS Chem Biol,2011,6(1):86-94.
[37]Zhang J,He J,Zhang L.The down-regulation of micro RNA-137 contributes to the up-regulation of retinoblastoma cell proliferation and invasion by regulating COX-2/PGE2 signaling[J].Biomed Pharmacother,2018,doi:10.1016/j.biopha.2018.06.099.
[38]Al-Kofahi M,Omura S,Tsunoda I,et al.IL-1βreduces cardiac lymphatic muscle contraction via COX-2 and PGE 2 induction:Potential role in myocarditis[J].Biomed Pharmacother,2018,doi:10.1016/j.biopha.2018.08.004.
[39]Liu Q,Sun N N,Wu Z Z,et al.Chaihu-Shugan-San exerts an antidepressive effect by downregulating miR-124 and releasing inhibition of the MAPK14 and Gria3 signaling pathways[J].Neural Regener Res,2018,13(5):837-845.
[40]Lee C H,Kim H J,Lee Y S,et al.Hypothalamic macrophage inducible nitric oxide synthase mediates obesity-associated hypothalamic inflammation[J].Cell Rep,2018,25(4):934-946.
[41]Chu W M.Tumor necrosis factor[J].Cancer Lett,2013,328(2):222-225.
[42]Shuh M,Bohorquez H,Loss G,et al.Tumor necrosis factor-α:Life and death of hepatocytes during liver ischemia/reperfusion injury[J].Ochsner J,2013,13(1):119-130.
[43]Gupta M,Wani A,Ahsan A U,et al.Soluble Aβ1-42suppresses TNF-αand activates NLRP3 inflammasome in THP-1 macrophages[J].Cytokine,2018,doi:10.1016/j.cyto.2018.07.026.
[44]Chen J,Liu G Z,Sun Q,et al.Protective effects of ginsenoside Rg3 on TNF-α-induced human nucleus pulposus cells through inhibiting NF-κB signaling pathway[J].Life Sci,2018,doi:10.1016/j.lfs.2018.11.022.
[2]韩建军,宁娜.两面针的药理作用研究进展[J].药学研究,2013,32(8):473-474.
[3]韦锦斌,周劲帆,冯洁,等.两面针叶不同提取部位的抗炎镇痛作用研究[J].中药新药与临床药理,2013,24(2):122-125.
[4]韩正洲,李茹柳,仰铁锤,等.两面针对盐酸乙醇致大鼠胃黏膜损伤的影响[J].广州中医药大学学报,2012,29(3):292-294.
[5]韩正洲,仰铁锤,陈炜璇,等.两面针不同药用部位镇痛和保护胃黏膜作用的研究[J].中国现代中药,2013,15(3):178-182.
[6]曾天,张笑寒,刘庆,等.三种中药漱口水控制慢性牙龈炎的对比研究[J].现代口腔医学杂志,2018,32(3):166-168.
[7]韩彦琪,孟凡翠,许浚,等.基于网络药理学方法的元胡止痛滴丸治疗原发性痛经的配伍合理性研究[J].中草药,2017,48(3):526-532.
[8]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.
[9]Xie W,Ji L,Zhao T,et al.Identifcation of transcriptional factors and key genes in primary osteoporosis by DNAmicroarray[J].Med Sci Monit,2015,doi:10.12659/MSM.89411.
[10]张彦琼,李梢.网络药理学与中医药现代研究的若干进展[J].中国药理学与毒理学杂志,2015,29(6):883-892.
[11]Liu A L,Du G H.Network pharmacology:New guidelines for drug discovery[J].Acta Pharm Sin,2010,45(12):1472-147.
[12]Li J,Zhao P,Li Y,et al.Systems pharmacology-based dissection of mechanisms of Chinese medicinal formula Bufei Yishen as an effective treatment for chronic obstructive pulmonary disease[J].Sci Rep,2015,doi:10.1038/srep15290.
[13]周文霞,王同兴,程肖蕊,等.网络药理学研究中的网络分析技术[J].国际药学研究杂志,2016,43(3):399-409.
[14]庄静,刘丽娟,周超,等.网络药理学与分子对接技术指导下土大黄苷对慢性粒细胞白血病作用机制研究[J].中华肿瘤防治杂志,2016,23(22):1477-1482.
[15]陶晓倩,张新庄,李娜,等.网络药理学方法研究赤芍和黄柏干预阿尔茨海默病的作用机制[J].中草药,2015,46(11):1634-1639.
[16]Knox C,Law V,Jewison T,et al.DrugBank3.0:Acomprehensive resource for‘Omics’research on drugs[J].Nucleic Acids Res,2011,doi:10.1093/nar/gkq1126.
[17]Zhu F,Shi Z,Qin C,et al.Therapeutic target database update 2012:A resource for facilitating target-oriented drug discovery[J].Nucleic Acids Res,2012,doi:10.1093/nar/gkr797.
[18]Subudhi A K,Boopathi P A,Pandey I,et al.Disease specific modules and hub genes for intervention strategies:A co-expression network based approach for Plasmodium falciparum clinical isolates[J].Infect Genet Evol,2015,doi:10.1016/j.meegid.2015.08.007.
[19]Valerio M,Awad A B.β-Itosterol down-regulates somepro-inflammatory signal transduction pathways by increasing the activity of tyrosine phosphatase shp-1in J774 A.1 murine macrophages[J].Inter Immunopharmacol,2011,11(8):1012-1017.
[20]Choi J N,Choi Y H,Lee J M,et al.Anti-inflammatory effects ofβ-sitosterol-β-D-glucoside from Trachelospermum jasminoides(Apocynaceae)in lipopolysaccharide-stimulated raw 264.7 murine macrophages[J].Nat Prod res,2012,26(24):2340-2343.
[21]Liz R,Zanatta L,Dos reis G O,et al.Acute effect ofβ-sitosterol on calcium uptake mediates antiinflammatory effect in murine activated neutrophils[J].JPharm Pharmacol,2013,65(1):115-122.
[22]Imam F,Al-Harbi N O,Al-Harbi M M,et al.Diosmin downregulates the expression of T cell receptors,pro-inflammatory cytokines and NF-κB activation against LPS-induced acute lung injury in mice[J].Pharmacol Res,2015,doi:10.1016/j.phrs.2015.09.001.
[23]崔功廷,袁铭.地奥司明对盆腔淤血所致大鼠慢性非细菌性前列腺炎的影响[J].解放军医学杂志,2014,39(6):444-447.
[24]王畅.地奥司明治疗淤积性皮炎40例临床观察[J].中国皮肤性病学杂志,2013,27(5):480-481.
[25]杨德林.地奥司明结合非甾体抗炎药治疗膝关节滑膜炎疗效观察[J].现代中西医结合杂志,2013,22(4):419-420.
[26]李良昌,朴红梅,延光海,等.芝麻素抗哮喘炎症作用研究[J].中国药理学通报,2015,31(3):411-415.
[27]Guo L Q,Yang J R,Kong X.Protective effect of sesamin on endothelial function of type-2 diabetic rats[J].Chin Pharmacol Bull,2012,28(3):392-396.
[28]Yan G H,Cui Y H,Li G Z,et al.Anti-allergic effects of curcumin[J].Chin Pharmacol Bull,2010,26(3):416-417.
[29]Harikumar K B,Sung B,Tharakan S T,et al.Sesamin manifests chemopreventive effects through the suppression of NF kappa B-regulated cell survival,proliferation,invasion,and angiogenic gene produc[J].Mol Cancer Res,2010,8(5):751-761.
[30]Cui Y,Hou X,Chen J,et al.Sesamin inhibits bacterial formylpeptide-induced inflammatory responses in a murine airpouch model and in THP-1 human monocytes[J].J Nutr,2010,140(2):377-381.
[31]Hsieh C C,Kuo C H,Kuo H F,et al.Sesamin suppresses macrophage-derived chemokine expression in human monocytes via epigenetic regulation[J].Food Funct,2014,5(10):2494-2500.
[32]Li L,Piao H,Zheng M,et al.Sesamin attenuates allergic airway inflammation through the suppression of nuclear factor-kappa B activation[J].Exp Ther Med,2016,12(6):4175-4181.
[33]Qiang L,Yuan J,Shouyin J,et al.Sesamin attenuates lipopolysaccharide-induced acute lung injury by inhibition of TLR4 signaling pathways[J].Inflammation,2016,39(1):467-472.
[34]赵洪伟,崔银锋,姜京植,等.芝麻素通过PKCα/NF-κB信号途径抑制肥大细胞活化[J].中国免疫学杂志,2018,34(2):167-171.
[35]Liu J L,Pei M J,Zheng C L,et al.Asystemspharmacology analysis of herbal medicines used in health improvement yreatment:Predicting potential new drugs and targets[J].Evid-Based Compl Alt Med,2013,doi:10.1155/2013/938764.
[36]Castoreno A B,Eggert U S.Small molecule probes of cellular pathways and networks[J].ACS Chem Biol,2011,6(1):86-94.
[37]Zhang J,He J,Zhang L.The down-regulation of micro RNA-137 contributes to the up-regulation of retinoblastoma cell proliferation and invasion by regulating COX-2/PGE2 signaling[J].Biomed Pharmacother,2018,doi:10.1016/j.biopha.2018.06.099.
[38]Al-Kofahi M,Omura S,Tsunoda I,et al.IL-1βreduces cardiac lymphatic muscle contraction via COX-2 and PGE 2 induction:Potential role in myocarditis[J].Biomed Pharmacother,2018,doi:10.1016/j.biopha.2018.08.004.
[39]Liu Q,Sun N N,Wu Z Z,et al.Chaihu-Shugan-San exerts an antidepressive effect by downregulating miR-124 and releasing inhibition of the MAPK14 and Gria3 signaling pathways[J].Neural Regener Res,2018,13(5):837-845.
[40]Lee C H,Kim H J,Lee Y S,et al.Hypothalamic macrophage inducible nitric oxide synthase mediates obesity-associated hypothalamic inflammation[J].Cell Rep,2018,25(4):934-946.
[41]Chu W M.Tumor necrosis factor[J].Cancer Lett,2013,328(2):222-225.
[42]Shuh M,Bohorquez H,Loss G,et al.Tumor necrosis factor-α:Life and death of hepatocytes during liver ischemia/reperfusion injury[J].Ochsner J,2013,13(1):119-130.
[43]Gupta M,Wani A,Ahsan A U,et al.Soluble Aβ1-42suppresses TNF-αand activates NLRP3 inflammasome in THP-1 macrophages[J].Cytokine,2018,doi:10.1016/j.cyto.2018.07.026.
[44]Chen J,Liu G Z,Sun Q,et al.Protective effects of ginsenoside Rg3 on TNF-α-induced human nucleus pulposus cells through inhibiting NF-κB signaling pathway[J].Life Sci,2018,doi:10.1016/j.lfs.2018.11.022.