基于网络药理学的独活治疗骨关节炎的作用机制研究
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摘要
背景:独活被广泛地应用于骨关节炎的治疗,但其分子作用机制不明确。目的:采用网络药理学方法筛选中药独活中主要化学成分,构建化学成分-作用靶点网络,对其治疗骨关节炎的分子作用机制进行科学阐明。方法:采用中药系统药理学数据库筛选独活中主要活性成分,利用OMIM,TTD和pharm GKB数据库查找治疗骨关节炎的相关靶点。通过Cytoscape3.6.1软件构建独活主要化学成分-化学成分作用靶点和骨关节炎治疗靶点-骨关节炎网络,并利用基因GO功能和KEGG通路富集对参与两网络的共同作用靶点进行分析。结果与结论:从中药系统药理学数据库共筛选出8种主要化学成分,其相对应的化学作用靶点共52个。从OMIM,TTD,pharm GKB数据库筛选出与骨关节炎疾病密切相关的靶点共有120个。参与独活主要化学成分-化学成分作用靶点和骨关节炎治疗靶点-骨关节炎的共同作用靶点共有20个。网络结果分析显示独活涉及与脂肪分解、钙离子运输、T细胞稳定、胚胎期细胞分化、细胞凋亡等生物过程,同时也能对钙、肿瘤坏死因子、催产素、环磷酸腺苷、丝裂原活化蛋白激酶、凋亡等信号通路进行调控。提示实验从分子水平方向进一步揭示独活治疗骨关节炎的潜在化学成分及作用机制,能为后续从独活中开发治疗骨关节炎的新药提供一定依据。
BACKGROUND: Angelicae pubescentis radix has been extensively applied in the treatment of osteoarthritis, but the underlying molecular mechanism remains unclear. OBJECTIVE: To construct the active ingredient-target network through screening the chemical ingredients of angelicae pubescentis radix based on network pharmacology, and to explore the mechanism underlying the treatment of osteoarthritis. METHODS: The main active ingredients of angelicae pubescentis radix were obtained by Traditional Chinese Medicine Systems Pharmacology Database and the targets of osteoarthritis were retrieved from OMIM, TTD, pharmGKB Database. The "active ingredient-target" and "target-related diseases" network were constructed by the Cytoscape3.6.1 software. The biological functions and related pathways were analyzed by GlueGO and KEGG plugin. RESULTS AND CONCLUSION: A total of 8 active ingredients and 52 targets were screened in angelicae pubescentis radix from Traditional Chinese Medicine Systems Pharmacology Database. A total of 120 target-related to osteoarthritis were got from OMIM, TTD, pharmGKB Database. Twenty common targets were found in "active ingredient-target" and "target-related diseases" network. The analysis of GlueGO and KEGG showed the radix angelicae pubescentis not only involved in the biological functions of lipolysis, calcium transport, T cell stabilization, embryonic cell differentiation, and cell apoptosis, but also modulated the signaling pathways of calcium, tumor necrosis factor, oxytocin, cyclic adenosine monophosphate, mitogen-activated protein kinase, and apoptosis. This study reveals that the potential active ingredients and possible mechanism of angelicae pubescentis radix for osteoarthritis, provides a basis for the development of new drugs in the treatment of osteoarthritis.
BACKGROUND: Angelicae pubescentis radix has been extensively applied in the treatment of osteoarthritis, but the underlying molecular mechanism remains unclear. OBJECTIVE: To construct the active ingredient-target network through screening the chemical ingredients of angelicae pubescentis radix based on network pharmacology, and to explore the mechanism underlying the treatment of osteoarthritis. METHODS: The main active ingredients of angelicae pubescentis radix were obtained by Traditional Chinese Medicine Systems Pharmacology Database and the targets of osteoarthritis were retrieved from OMIM, TTD, pharmGKB Database. The "active ingredient-target" and "target-related diseases" network were constructed by the Cytoscape3.6.1 software. The biological functions and related pathways were analyzed by GlueGO and KEGG plugin. RESULTS AND CONCLUSION: A total of 8 active ingredients and 52 targets were screened in angelicae pubescentis radix from Traditional Chinese Medicine Systems Pharmacology Database. A total of 120 target-related to osteoarthritis were got from OMIM, TTD, pharmGKB Database. Twenty common targets were found in "active ingredient-target" and "target-related diseases" network. The analysis of GlueGO and KEGG showed the radix angelicae pubescentis not only involved in the biological functions of lipolysis, calcium transport, T cell stabilization, embryonic cell differentiation, and cell apoptosis, but also modulated the signaling pathways of calcium, tumor necrosis factor, oxytocin, cyclic adenosine monophosphate, mitogen-activated protein kinase, and apoptosis. This study reveals that the potential active ingredients and possible mechanism of angelicae pubescentis radix for osteoarthritis, provides a basis for the development of new drugs in the treatment of osteoarthritis.
引文
[1]Yan M,Zhang J,Yang H,et al.The role of leptin in osteoarthritis.Medicine(Baltimore).2018;97(14):e0257.
[2]Wei Y,Zheng D,Guo X,et al.Transient Receptor Potential Channel,Vanilloid 5,Induces Chondrocyte Apoptosis in a Rat Osteoarthritis Model Through the Mediation of Ca2+Influx.Cell Physiol Biochem.2018;46(2):687-698.
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[4]Gao J,Ceglia SS,Jones MD,et al.A novel compact mass detection platform for the open access(OA)environment in drug discovery and early development.J Pharm Biomed Anal.2016;122:1-8.
[5]Bay-Jensen AC,Thudium CS,Gualillo O,et al.Biochemical marker discovery,testing and evaluation for facilitating OAdrug discovery and development.Drug Discov Today.2018;23(2):349-358.
[6]周刚,马宝花.中药独活的研究进展[J].中国当代医药,2012,19(16):15-16.
[7]Tian S,Li Y,Wang J,et al.ADME evaluation in drug discovery.9.Prediction of oral bioavailability in humans based on molecular properties and structural fingerprints.Mol Pharm.2011;8(3):841-851.
[8]Tian S,Wang J,Li Y,et al.Drug-likeness analysis of traditional Chinese medicines:prediction of drug-likeness using machine learning approaches.Mol Pharm.2012;9(10):2875-2886.
[9]Ru J,Li P,Wang J,et al.TCMSP:a database of systems pharmacology for drug discovery from herbal medicines.JCheminform.2014;6:13.
[10]章亮,陈泽慧,陈韩英,等.基于网络药理学的白屈菜抗肿瘤分子机制研究[J].中草药,2018,49(3):646-657.
[11]孙雨辉,陆景坤,王健,等.基于网络药理学的三味檀香散治疗冠心病的机制初探[J].中国新药与临床杂志,2018,37(5):272-289.
[12]吴丹,高耀,向欢,等.基于网络药理学的柴胡抗抑郁作用机制研究[J].药学学报,2018,53(2):210-219.
[13]袁芳,何晓瑾,石俊,等.骨痹方治疗膝骨关节炎肾虚络痹证临床观察[J].中国实验方剂学杂志,2018,24(7):207-211.
[14]黄育生,袁贤琳,钟瑜,等.HPLC法测定羌活中紫花前胡苷的含量[J].中国民族民间医药,2013,22(10):14-15.
[15]张素清,李敏,虞立,等.半夏3种不同炮制品中β-谷甾醇含量的比较[J].中华中医药学刊,2018,36(1):42-44.
[16]李昌勤,彭琳娜,姚辰,等.加热处理对白芷中欧前胡素、异欧前胡素稳定性及酪氨酸酶活性的影响[J].中国中药杂志,2016,41(5):845-849.
[17]熊友谊,时维静,俞浩,等.紫花前胡苷抑制哮喘小鼠气道炎性反应和NF-κB信号传导通路[J].基础医学与临床,2014,34(5):690-694.
[18]Visser AW,de Mutsert R,Bloem JL,et al.Do knee osteoarthritis and fat-free mass interact in their impact on health-related quality of life in men?Results from a population-based cohort.Arthritis Care Res(Hoboken).2015;67(7):981-988.
[19]Santangelo KS,Radakovich LB,Fouts J,et al.Pathophysiology of obesity on knee joint homeostasis:contributions of the infrapatellar fat pad.Horm Mol Biol Clin Investig.2016;26(2):97-108.
[20]王飞,薛庆云.代谢综合征与骨关节炎发生、发展相关性的研究进展[J].中华骨科杂志,2016,36(4):248-256.
[21]Xin L,Wu Z,Qu Q,et al.Comparative study of CTX-II,Zn2+,and Ca2+from the urine for knee osteoarthritis patients and healthy individuals.Medicine(Baltimore).2017;96(32):e7593.
[22]Faour WH,Mancini A,He QW,et al.T-cell-derived interleukin-17 regulates the level and stability of cyclooxygenase-2(COX-2)mRNA through restricted activation of the p38 mitogen-activated protein kinase cascade:role of distal sequences in the 3'-untranslated region of COX-2 mRNA.J Biol Chem.2003;278(29):26897-26907
[23]Yang D,Chen S,Gao C,et al.Chemically defined serum-free conditions for cartilage regeneration from human embryonic stem cells.Life Sci.2016;164:9-14.
[24]史继德,冯海军,耿喜林,等.α-倒捻子素调节骨关节炎软骨细胞的增殖和凋亡[J].中成药,2018,40(1):8-13.
[25]Zhao J,Li S,Trilok S,et al.Small molecule-directed specification of sclerotome-like chondroprogenitors and induction of a somitic chondrogenesis program from embryonic stem cells.Development.2014;141(20):3848-3858.
[26]苏宁,赵丹,杨丽,等.应用基因芯片技术检测SDS对人表皮细胞TNF信号通路基因差异表达的影响[J].生物技术通讯,2016,27(3):386-390.
[27]Li X,Wu D,Hu Z,et al.The Protective Effect of Ligustilide in Osteoarthritis:An in Vitro and in Vivo Study.Cell Physiol Biochem.2018;48(6):2583-2595.
[28]Barrachina L,Remacha AR,Romero A,et al.Assessment of effectiveness and safety of repeat administration of proinflammatory primed allogeneic mesenchymal stem cells in an equine model of chemically induced osteoarthritis.BMCVet Res.2018;14(1):241.
[29]Wu Y,Wu T,Xu B,et al.Oxytocin prevents cartilage matrix destruction via regulating matrix metalloproteinases.Biochem Biophys Res Commun.2017;486(3):601-606.
[30]Kong D,Guan Q,Li G,et al.Expression of FSHR in chondrocytes and the effect of FSH on chondrocytes.Biochem Biophys Res Commun.2018;495(1):587-593.
[31]王涛,殷红,廖江龙,等.骨关节炎与MAPK信号通路关系的研究概况[J].中国民族民间医药,2017,26(19):27-29.
[32]窦天旭,李旭.MAPK信号通路与骨关节炎[J].解剖科学进展,2017,23(6):649-652.
[33]Xu K,Ma C,Xu L,et al.Polygalacic acid inhibits MMPs expression and osteoarthritis via Wnt/β-catenin and MAPKsignal pathways suppression.Int Immunopharmacol.2018;63:246-252.
[34]Huang X,Xi Y,Pan Q,et al.Caffeic acid protects against IL-1β-induced inflammatory responses and cartilage degradation in articular chondrocytes.Biomed Pharmacother.2018;107:433-439.
[35]Zhao P,Cheng J,Geng J,et al.Curcumin protects rabbit articular chondrocytes against sodium nitroprusside-induced apoptosis in vitro.Eur J Pharmacol.2018;828:146-153.
[36]Ye D,Jian W,Feng J,et al.Role of long noncoding RNAZFAS1 in proliferation,apoptosis and migration of chondrocytes in osteoarthritis.Biomed Pharmacother.2018;104:825-831.
[37]Qi X,Zhu L,Yang B,et al.Mitigation of cell apoptosis induced by ochratoxin A(OTA)is possibly through organic cation transport 2(OCT2)knockout.Food Chem Toxicol.2018;121:15-23.
[38]Seo SU,Min KJ,Woo SM,et al.Z-FL-COCHO,a cathepsin Sinhibitor,enhances oxaliplatin-mediated apoptosis through the induction of endoplasmic reticulum stress.Exp Mol Med.2018;50(8):107.
[39]Nasser MW,Datta J,Nuovo G,et al.Down-regulation of micro-RNA-1(miR-1)in lung cancer.Suppression of tumorigenic property of lung cancer cells and their sensitization to doxorubicin-induced apoptosis by miR-1.JBiol Chem.2018;293(33):12945.
[40]Huang Z,Zhou M,Wang Q,et al.Mechanical and hypoxia stress can cause chondrocytes apoptosis through over-activation of endoplasmic reticulum stress.Arch Oral Biol.2017;84:125-132.
[41]Gu Y,Chen J,Meng Z,et al.Diazoxide prevents H2O2-induced chondrocyte apoptosis and cartilage degeneration in a rat model of osteoarthritis by reducing endoplasmic reticulum stress.Biomed Pharmacother.2017;95:1886-1894.
[42]Zhang Q,Lai S,Hou X,et al.Protective effects of PI3K/Akt signal pathway induced cell autophagy in rat knee joint cartilage injury.Am J Transl Res.2018;10(3):762-770.
[43]Yang Y,Wang Y,Zhao M,et al.Tormentic acid inhibits IL-1β-induced chondrocyte apoptosis by activating the PI3K/Akt signaling pathway.Mol Med Rep.2018;17(3):4753-4758.
[44]Li L,Lv G,Wang B,et al.The role of lncRNA XIST/miR-211axis in modulating the proliferation and apoptosis of osteoarthritis chondrocytes through CXCR4 and MAPKsignaling.Biochem Biophys Res Commun.2018;503(4):2555-2562.
[2]Wei Y,Zheng D,Guo X,et al.Transient Receptor Potential Channel,Vanilloid 5,Induces Chondrocyte Apoptosis in a Rat Osteoarthritis Model Through the Mediation of Ca2+Influx.Cell Physiol Biochem.2018;46(2):687-698.
[3]Urban H,Little CB.The role of fat and inflammation in the pathogenesis and management of osteoarthritis.Rheumatology(Oxford).2018;57(suppl_4):iv10-iv21.
[4]Gao J,Ceglia SS,Jones MD,et al.A novel compact mass detection platform for the open access(OA)environment in drug discovery and early development.J Pharm Biomed Anal.2016;122:1-8.
[5]Bay-Jensen AC,Thudium CS,Gualillo O,et al.Biochemical marker discovery,testing and evaluation for facilitating OAdrug discovery and development.Drug Discov Today.2018;23(2):349-358.
[6]周刚,马宝花.中药独活的研究进展[J].中国当代医药,2012,19(16):15-16.
[7]Tian S,Li Y,Wang J,et al.ADME evaluation in drug discovery.9.Prediction of oral bioavailability in humans based on molecular properties and structural fingerprints.Mol Pharm.2011;8(3):841-851.
[8]Tian S,Wang J,Li Y,et al.Drug-likeness analysis of traditional Chinese medicines:prediction of drug-likeness using machine learning approaches.Mol Pharm.2012;9(10):2875-2886.
[9]Ru J,Li P,Wang J,et al.TCMSP:a database of systems pharmacology for drug discovery from herbal medicines.JCheminform.2014;6:13.
[10]章亮,陈泽慧,陈韩英,等.基于网络药理学的白屈菜抗肿瘤分子机制研究[J].中草药,2018,49(3):646-657.
[11]孙雨辉,陆景坤,王健,等.基于网络药理学的三味檀香散治疗冠心病的机制初探[J].中国新药与临床杂志,2018,37(5):272-289.
[12]吴丹,高耀,向欢,等.基于网络药理学的柴胡抗抑郁作用机制研究[J].药学学报,2018,53(2):210-219.
[13]袁芳,何晓瑾,石俊,等.骨痹方治疗膝骨关节炎肾虚络痹证临床观察[J].中国实验方剂学杂志,2018,24(7):207-211.
[14]黄育生,袁贤琳,钟瑜,等.HPLC法测定羌活中紫花前胡苷的含量[J].中国民族民间医药,2013,22(10):14-15.
[15]张素清,李敏,虞立,等.半夏3种不同炮制品中β-谷甾醇含量的比较[J].中华中医药学刊,2018,36(1):42-44.
[16]李昌勤,彭琳娜,姚辰,等.加热处理对白芷中欧前胡素、异欧前胡素稳定性及酪氨酸酶活性的影响[J].中国中药杂志,2016,41(5):845-849.
[17]熊友谊,时维静,俞浩,等.紫花前胡苷抑制哮喘小鼠气道炎性反应和NF-κB信号传导通路[J].基础医学与临床,2014,34(5):690-694.
[18]Visser AW,de Mutsert R,Bloem JL,et al.Do knee osteoarthritis and fat-free mass interact in their impact on health-related quality of life in men?Results from a population-based cohort.Arthritis Care Res(Hoboken).2015;67(7):981-988.
[19]Santangelo KS,Radakovich LB,Fouts J,et al.Pathophysiology of obesity on knee joint homeostasis:contributions of the infrapatellar fat pad.Horm Mol Biol Clin Investig.2016;26(2):97-108.
[20]王飞,薛庆云.代谢综合征与骨关节炎发生、发展相关性的研究进展[J].中华骨科杂志,2016,36(4):248-256.
[21]Xin L,Wu Z,Qu Q,et al.Comparative study of CTX-II,Zn2+,and Ca2+from the urine for knee osteoarthritis patients and healthy individuals.Medicine(Baltimore).2017;96(32):e7593.
[22]Faour WH,Mancini A,He QW,et al.T-cell-derived interleukin-17 regulates the level and stability of cyclooxygenase-2(COX-2)mRNA through restricted activation of the p38 mitogen-activated protein kinase cascade:role of distal sequences in the 3'-untranslated region of COX-2 mRNA.J Biol Chem.2003;278(29):26897-26907
[23]Yang D,Chen S,Gao C,et al.Chemically defined serum-free conditions for cartilage regeneration from human embryonic stem cells.Life Sci.2016;164:9-14.
[24]史继德,冯海军,耿喜林,等.α-倒捻子素调节骨关节炎软骨细胞的增殖和凋亡[J].中成药,2018,40(1):8-13.
[25]Zhao J,Li S,Trilok S,et al.Small molecule-directed specification of sclerotome-like chondroprogenitors and induction of a somitic chondrogenesis program from embryonic stem cells.Development.2014;141(20):3848-3858.
[26]苏宁,赵丹,杨丽,等.应用基因芯片技术检测SDS对人表皮细胞TNF信号通路基因差异表达的影响[J].生物技术通讯,2016,27(3):386-390.
[27]Li X,Wu D,Hu Z,et al.The Protective Effect of Ligustilide in Osteoarthritis:An in Vitro and in Vivo Study.Cell Physiol Biochem.2018;48(6):2583-2595.
[28]Barrachina L,Remacha AR,Romero A,et al.Assessment of effectiveness and safety of repeat administration of proinflammatory primed allogeneic mesenchymal stem cells in an equine model of chemically induced osteoarthritis.BMCVet Res.2018;14(1):241.
[29]Wu Y,Wu T,Xu B,et al.Oxytocin prevents cartilage matrix destruction via regulating matrix metalloproteinases.Biochem Biophys Res Commun.2017;486(3):601-606.
[30]Kong D,Guan Q,Li G,et al.Expression of FSHR in chondrocytes and the effect of FSH on chondrocytes.Biochem Biophys Res Commun.2018;495(1):587-593.
[31]王涛,殷红,廖江龙,等.骨关节炎与MAPK信号通路关系的研究概况[J].中国民族民间医药,2017,26(19):27-29.
[32]窦天旭,李旭.MAPK信号通路与骨关节炎[J].解剖科学进展,2017,23(6):649-652.
[33]Xu K,Ma C,Xu L,et al.Polygalacic acid inhibits MMPs expression and osteoarthritis via Wnt/β-catenin and MAPKsignal pathways suppression.Int Immunopharmacol.2018;63:246-252.
[34]Huang X,Xi Y,Pan Q,et al.Caffeic acid protects against IL-1β-induced inflammatory responses and cartilage degradation in articular chondrocytes.Biomed Pharmacother.2018;107:433-439.
[35]Zhao P,Cheng J,Geng J,et al.Curcumin protects rabbit articular chondrocytes against sodium nitroprusside-induced apoptosis in vitro.Eur J Pharmacol.2018;828:146-153.
[36]Ye D,Jian W,Feng J,et al.Role of long noncoding RNAZFAS1 in proliferation,apoptosis and migration of chondrocytes in osteoarthritis.Biomed Pharmacother.2018;104:825-831.
[37]Qi X,Zhu L,Yang B,et al.Mitigation of cell apoptosis induced by ochratoxin A(OTA)is possibly through organic cation transport 2(OCT2)knockout.Food Chem Toxicol.2018;121:15-23.
[38]Seo SU,Min KJ,Woo SM,et al.Z-FL-COCHO,a cathepsin Sinhibitor,enhances oxaliplatin-mediated apoptosis through the induction of endoplasmic reticulum stress.Exp Mol Med.2018;50(8):107.
[39]Nasser MW,Datta J,Nuovo G,et al.Down-regulation of micro-RNA-1(miR-1)in lung cancer.Suppression of tumorigenic property of lung cancer cells and their sensitization to doxorubicin-induced apoptosis by miR-1.JBiol Chem.2018;293(33):12945.
[40]Huang Z,Zhou M,Wang Q,et al.Mechanical and hypoxia stress can cause chondrocytes apoptosis through over-activation of endoplasmic reticulum stress.Arch Oral Biol.2017;84:125-132.
[41]Gu Y,Chen J,Meng Z,et al.Diazoxide prevents H2O2-induced chondrocyte apoptosis and cartilage degeneration in a rat model of osteoarthritis by reducing endoplasmic reticulum stress.Biomed Pharmacother.2017;95:1886-1894.
[42]Zhang Q,Lai S,Hou X,et al.Protective effects of PI3K/Akt signal pathway induced cell autophagy in rat knee joint cartilage injury.Am J Transl Res.2018;10(3):762-770.
[43]Yang Y,Wang Y,Zhao M,et al.Tormentic acid inhibits IL-1β-induced chondrocyte apoptosis by activating the PI3K/Akt signaling pathway.Mol Med Rep.2018;17(3):4753-4758.
[44]Li L,Lv G,Wang B,et al.The role of lncRNA XIST/miR-211axis in modulating the proliferation and apoptosis of osteoarthritis chondrocytes through CXCR4 and MAPKsignaling.Biochem Biophys Res Commun.2018;503(4):2555-2562.