从网络角度研究腰痹通胶囊整体调控腰椎间盘突出的分子作用机制
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摘要
目的研究腰痹通胶囊(三七、川芎、延胡索,等)治疗腰椎间盘突出的分子作用机制。方法采用文献挖掘、分子对接以及分子-靶蛋白网络特征分析的方法研究腰痹通胶囊中化合物群与靶蛋白的相互作用。结果分子对接发现腰痹通胶囊中有46个活性成分,且大部分具有良好的口服生物利用度和较高的中枢神经暴露量,进一步网络分析发现,其中coptisine、diligustilide、corypalmine、chuanxiongterpene等11个化合物为其主要活性成分,可通过与p38、CGRP、MMPs、TNFα等19个靶蛋白作用,抑制过度性炎症反应和椎间盘内毛细血管浸入,降低神经对刺激的敏感性,调控椎间盘内胶原、蛋白聚糖的代谢平衡,从而缓解疼痛,改善腰椎间盘突出。结论通过网络分析明确了腰痹通胶囊调控腰椎间盘突出的分子作用机制,诠释了其科学内涵,有助于推动后续药效物质基础研究和分子机制实验研究。
AIM To explore analgesic mechanism of Yaobitong Capsules( Notoginseng Radix et Rhizoma,Chuanxiong Rhizoma,Corydalis Rhizoma,etc.) on lumbar intervertebral discs. METHODS An array of data mining,molecular docking and network analysis were employed to investigate the active compounds and key target protein. RESULTS Among the forty-six active hits identified by virtual screening,most compounds displayed good oral bioavailability and might confer an optimal CNS exposure. And eleven molecules( coptisine,diligustilide,corypalmine,chuanxiongterpene,etc.) were further confirmed to alleviate lumbar intervertebral discs through their targeting at nineteen proteins( such as p38,CGRP,MMPs,TNFα) to inhibit the inflammatory response and the infiltration of microvasculature,to reduce the nociceptors sensitivity,and to modulate the balance of Collagen and proteoglycans in catabolic and anabolic responses. CONCLUSION Yaobitong Capsules' clear molecular working mechanism and the key active compounds are revealed by this network-assisted investigation highlight the subsequent experiments on targets and active compounds.
AIM To explore analgesic mechanism of Yaobitong Capsules( Notoginseng Radix et Rhizoma,Chuanxiong Rhizoma,Corydalis Rhizoma,etc.) on lumbar intervertebral discs. METHODS An array of data mining,molecular docking and network analysis were employed to investigate the active compounds and key target protein. RESULTS Among the forty-six active hits identified by virtual screening,most compounds displayed good oral bioavailability and might confer an optimal CNS exposure. And eleven molecules( coptisine,diligustilide,corypalmine,chuanxiongterpene,etc.) were further confirmed to alleviate lumbar intervertebral discs through their targeting at nineteen proteins( such as p38,CGRP,MMPs,TNFα) to inhibit the inflammatory response and the infiltration of microvasculature,to reduce the nociceptors sensitivity,and to modulate the balance of Collagen and proteoglycans in catabolic and anabolic responses. CONCLUSION Yaobitong Capsules' clear molecular working mechanism and the key active compounds are revealed by this network-assisted investigation highlight the subsequent experiments on targets and active compounds.
引文
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[19]Zhou K,Hu L,Liao W,et al.Coptisine Prevented IL-β-induced expression of inflammatory mediators in chondrocytes[J].Inflammation,2016,39(4):1558-1565.
[20]Juarez-Reyes K,Angeles-Lopez G E,Rivero-Cruz I,et al.Antinociceptive activity of Ligusticum porteri preparations and compounds[J].Pharm Biol,2014,52(1):14-20.
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[28]Kushwaha S K,Shakya M.Protein interaction network analysis—Approach for potential drug target identification in Mycobacterium tuberculosis[J].J Theor Biol,2010,262(2):284-294.
[29]Hwang W C,Zhang A,Ramanathan M.Identification of information flow-modulating drug targets:a novel bridging paradigm for drug discovery[J].Clin Pharmacol Ther,2008,84(5):563-572.
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[33]Morlion B.Chronic low back pain:pharmacological,interventional and surgical strategies[J].Nat Rev Neurol,2013,9(8):462-473.
[34]Sato M,Inage K,Sakuma Y,et al.Anti-RANKL antibodies decrease CGRP expression in dorsal root ganglion neurons innervating injured lumbar intervertebral discs in rats[J].Eur Spine J,2015,24(9):2017-2022.
[35]Orita S,Ohtori S,Nagata M,et al.Inhibiting nerve growth factor or its receptors downregulates calcitonin gene-related peptide expression in rat lumbar dorsal root ganglia innervating injured intervertebral discs[J].J Orthop Res,2010,28(12):1614-1620.
[36]Yang C,Cao P,Gao Y,et al.Differential expression of p38MAPK alpha,beta,gamma,delta isoforms in nucleus pulposus modulates macrophage polarization in intervertebral disc degeneration[J].Sci Rep,2016,6:22182.
[37]Wang X,Wang H,Yang H,et al.Tumor necrosis factor-α-and interleukin-1β-dependent matrix metalloproteinase-3 expression in nucleus pulposus cells requires cooperative signaling via syndecan 4 and mitogen-activated protein kinase-NF-κB axis:implications in inflammatory disc disease[J].Am J Pathol,2014,184(9):2560-2572.
[38]Colombini A,Lombardi G,Corsi M M,et al.Pathophysiology of the human intervertebral disc[J].Int J Biochem Cell Biol,2008,40(5):837-842.
[39]Yoon S T.Molecular therapy of the intervertebral disc[J].Eur Spine J,2006,5(Suppl 3):s379-388.
[40]Lu X Y,Ding X H,Zhong L J,et al.Expression and significance of VEGF and p53 in degenerate intervertebral disc tissue[J].Asian Pac J Trop Med,2013,6(1):79-81.
[41]Fujita N,Imai J I,Suzuki T,et al.Vascular endothelial growth factor-A is a survival factor for nucleus pulposus cells in the intervertebral disc[J].Biochem Biophys Res Commun,2008,372(2):367-372.
[42]Xin J,Jia F S,Xu Z W.Effect of Yaobitong capsule on histomorphology of dorsal root ganglion and on expression of p38mark phosphorylation in autologous nucleus pulposus transplantation model of rats[J].Asian Pac J Trop Med,2015,8(10):860-863.
[43]姚啸生,孙树椿,张军,等.腰痹通胶囊对退变腰椎间盘Ⅱ型胶原含量和TNF-α、IL-1βm RNA表达的影响[J].中国中医骨伤科杂志,2014,22(7):4-6.
[44]Castoreno A B,Eggert U S.Small molecule probes of cellular pathways and networks[J].ACS Chem Biol,2011,6(1):86-94.
[45]Li Y,Agarwal P.A pathway-based view of human diseases and disease relationships[J].PLo S One,2009,4(2):e4346.
[46]Merino A,Bronowska A K,Jackson D B,et al.Drug profiling:knowing where it hits[J].Drug Discov Today,2010,15(17-18):749-756.
[47]Medina-Franco J L,Giulianotti M A,Welmaker G S,et al.Shifting from the single to the multitarget paradigm in drug discovery[J].Drug Discov Today,2013,18(9-10):495-501.
[48]Sol A D,Balling R,Hood L,et al.Diseases as network perturbations[J].Curr Opin Biotechnol,2010,21(4):566-571.
[49]Lu J J,Pan W,Hu Y J,et al.Multi-target drugs:The trend of drug research and development[J].PLo S One,2012,7(6):e40262.
[50]Csermely P,Agoston V,Pongor S.The efficiency of multi-target drugs:the network approach might help drug design[J].Trends Pharmacol Sci,2005,26(4):178-182.
[51]Hopkins A L.Network pharmacology:the next paradigm in drug discovery[J].Nat Chem Biol,2008,4(11):682-690.
[52]李梢,张博.中药网络药理学:理论、方法与应用(英文)[J].中国天然药物,2013,11(2):110-120.
[53]Gertsch J.Botanical drugs,synergy,and network pharmacology:forth and back to intelligent mixtures[J].Planta Med,2011,77(11):1086-1098.
[2]Risbud M V,Shapiro I M.Role of cytokines in intervertebral disc degeneration:pain and disc content[J].Nat Rev Rheumatol,2014,10(1):44-56.
[3]Schroeder G D,Guyre C A,Vaccaro A R.The epidemiology and pathophysiology of lumbar disc herniations[J].Semin Spine Surg,2016,28(1):2-7.
[4]Beattie P F.Current understanding of lumbar intervertebral disc degeneration:a review with emphasis upon etiology,pathophysiology,and lumbar magnetic resonance imaging findings[J].J Orthop Sports Phys Ther,2008,38(6):329-340.
[5]Hopkins A L.Network pharmacology[J].Nat Biotech,2007,25(10):1110-1111.
[6]Berger S I,Iyengar R.Network analyses in systems pharmacology[J].Bioinformatics,2009,25(19):2466-2472.
[7]Hasan S,Bonde B K,Buchan N S,et al.Network analysis has diverse roles in drug discovery[J].Drug Discov Today,2012,17(15-16):869-874.
[8]Li J,Lu C,Jiang M,et al.Traditional chinese medicine-based network pharmacology could lead to new multicompound drug discovery[J].Evid Based Complement Alternat Med,2012,2012:149762.
[9]Cassinelli E H,Kang J D.Current understanding of lumbar disc degeneration[J].Oper Tech Orthop,2000,10(4):254-262.
[10]Zhao J G,Wang J,Xin Q,et al.Calcium pentosan polysulfate and sodium pentosan polysulfate may be used to treat intervertebral disc degeneration[J].Med Hypotheses,2011,76(4):610-613.
[11]Binch A L,Cole A A,Breakwell L M,et al.Expression and regulation of neurotrophic and angiogenic factors during human intervertebral disc degeneration[J].Arthritis Res Ther,2014,16(5):416.
[12]Blanquer S B G,Grijpma D W,Poot A A.Delivery systems for the treatment of degenerated intervertebral discs[J].Adv Drug Deliv Rev,2015,84:172-187.
[13]Shankar H,Scarlett J A,Abram S E.Anatomy and pathophysiology of intervertebral disc disease[J].Tech Reg Anesth Pain Manag,2009,13(2):67-75.
[14]Fields A J,Liebenberg E C,Lotz J C.Innervation of pathologies in the lumbar vertebral end plate and intervertebral disc[J].Spine J,2014,14(3):513-521.
[15]Grunhagen T,Shirazi-Adl A,Fairbank J C T,et al.Intervertebral disk nutrition:a review of factors influencing concentrations of nutrients and metabolites[J].Orthop Clin North Am,2011,42(4):465-477.
[16]Jones G,Willett P,Glen R C,et al.Development and validation of a genetic algorithm for flexible docking[J].J Mol Biol,1997,267(3):727-748.
[17]Gu J,Gui Y,Chen L,et al.Use of natural products as chemical library for drug discovery and network pharmacology[J].PLo S One,2013,8(4):e62839.
[18]Wang C,Wang S,Fan G,et al.Screening of antinociceptive components in Corydalis yanhusuo W.T.Wang by comprehensive two-dimensional liquid chromatography/tandem mass spectrometry[J].Anal Bioanal Chem,2010,396(5):1731-1740.
[19]Zhou K,Hu L,Liao W,et al.Coptisine Prevented IL-β-induced expression of inflammatory mediators in chondrocytes[J].Inflammation,2016,39(4):1558-1565.
[20]Juarez-Reyes K,Angeles-Lopez G E,Rivero-Cruz I,et al.Antinociceptive activity of Ligusticum porteri preparations and compounds[J].Pharm Biol,2014,52(1):14-20.
[21]Meanwell N A.Improving drug candidates by design:a focus on physicochemical properties as a means of improving compound disposition and safety[J].Chem Res Toxicol,2011,24(9):1420-1456.
[22]Rankovic Z.CNS drug design:balancing physicochemical properties for optimal brain exposure[J].J Med Chem,2015,58(6):2584-2608.
[23]Xu H,Li K,Chen Y,et al.Study on the absorbed fingerprintefficacy of yuanhu zhitong tablet based on chemical analysis,vasorelaxation evaluation and data mining[J].PLo S One,2013,8(12):e81135.
[24]Tao Y,Xu H,Wang S,et al.Identification of the absorbed constituents after oral administration of Yuanhu Zhitong prescription extract and its pharmacokinetic study by rapid resolution liquid chromatography/quadrupole time-of-flight[J].J Chromatogr B,2013,935(2):1-9.
[25]Brohee S,Faust K,Lima-Mendez G,et al.Network Analysis Tools:from biological networks to clusters and pathways[J].Nat Protoc,2008,3(10):1616-1629.
[26]Bauer-Mehren A,Bundschus M,Rautschka M,et al.Genedisease network analysis reveals functional modules in mendelian,complex and environmental diseases[J].PLo S One,2011,6(6):e20284.
[27]Iorio F,Bosotti R,Scacheri E,et al.Discovery of drug mode of action and drug repositioning from transcriptional responses[J].Proc Natl Acad Sci USA,2010,107(33):14621-14626.
[28]Kushwaha S K,Shakya M.Protein interaction network analysis—Approach for potential drug target identification in Mycobacterium tuberculosis[J].J Theor Biol,2010,262(2):284-294.
[29]Hwang W C,Zhang A,Ramanathan M.Identification of information flow-modulating drug targets:a novel bridging paradigm for drug discovery[J].Clin Pharmacol Ther,2008,84(5):563-572.
[30]Tsuchiya M,Selvarajoo K,Piras V,et al.Local and global responses in complex gene regulation networks[J].Physica A,2009,388(8):1738-1746.
[31]Barabási A L.Scale-free networks:a decade and beyond[J].Science,2009,325(5939):412-413.
[32]Hert J,Keiser M J,Irwin J J,et al.Quantifying the relationships among drug classes[J].J Chem Inf Model,2008,48(4):755-765.
[33]Morlion B.Chronic low back pain:pharmacological,interventional and surgical strategies[J].Nat Rev Neurol,2013,9(8):462-473.
[34]Sato M,Inage K,Sakuma Y,et al.Anti-RANKL antibodies decrease CGRP expression in dorsal root ganglion neurons innervating injured lumbar intervertebral discs in rats[J].Eur Spine J,2015,24(9):2017-2022.
[35]Orita S,Ohtori S,Nagata M,et al.Inhibiting nerve growth factor or its receptors downregulates calcitonin gene-related peptide expression in rat lumbar dorsal root ganglia innervating injured intervertebral discs[J].J Orthop Res,2010,28(12):1614-1620.
[36]Yang C,Cao P,Gao Y,et al.Differential expression of p38MAPK alpha,beta,gamma,delta isoforms in nucleus pulposus modulates macrophage polarization in intervertebral disc degeneration[J].Sci Rep,2016,6:22182.
[37]Wang X,Wang H,Yang H,et al.Tumor necrosis factor-α-and interleukin-1β-dependent matrix metalloproteinase-3 expression in nucleus pulposus cells requires cooperative signaling via syndecan 4 and mitogen-activated protein kinase-NF-κB axis:implications in inflammatory disc disease[J].Am J Pathol,2014,184(9):2560-2572.
[38]Colombini A,Lombardi G,Corsi M M,et al.Pathophysiology of the human intervertebral disc[J].Int J Biochem Cell Biol,2008,40(5):837-842.
[39]Yoon S T.Molecular therapy of the intervertebral disc[J].Eur Spine J,2006,5(Suppl 3):s379-388.
[40]Lu X Y,Ding X H,Zhong L J,et al.Expression and significance of VEGF and p53 in degenerate intervertebral disc tissue[J].Asian Pac J Trop Med,2013,6(1):79-81.
[41]Fujita N,Imai J I,Suzuki T,et al.Vascular endothelial growth factor-A is a survival factor for nucleus pulposus cells in the intervertebral disc[J].Biochem Biophys Res Commun,2008,372(2):367-372.
[42]Xin J,Jia F S,Xu Z W.Effect of Yaobitong capsule on histomorphology of dorsal root ganglion and on expression of p38mark phosphorylation in autologous nucleus pulposus transplantation model of rats[J].Asian Pac J Trop Med,2015,8(10):860-863.
[43]姚啸生,孙树椿,张军,等.腰痹通胶囊对退变腰椎间盘Ⅱ型胶原含量和TNF-α、IL-1βm RNA表达的影响[J].中国中医骨伤科杂志,2014,22(7):4-6.
[44]Castoreno A B,Eggert U S.Small molecule probes of cellular pathways and networks[J].ACS Chem Biol,2011,6(1):86-94.
[45]Li Y,Agarwal P.A pathway-based view of human diseases and disease relationships[J].PLo S One,2009,4(2):e4346.
[46]Merino A,Bronowska A K,Jackson D B,et al.Drug profiling:knowing where it hits[J].Drug Discov Today,2010,15(17-18):749-756.
[47]Medina-Franco J L,Giulianotti M A,Welmaker G S,et al.Shifting from the single to the multitarget paradigm in drug discovery[J].Drug Discov Today,2013,18(9-10):495-501.
[48]Sol A D,Balling R,Hood L,et al.Diseases as network perturbations[J].Curr Opin Biotechnol,2010,21(4):566-571.
[49]Lu J J,Pan W,Hu Y J,et al.Multi-target drugs:The trend of drug research and development[J].PLo S One,2012,7(6):e40262.
[50]Csermely P,Agoston V,Pongor S.The efficiency of multi-target drugs:the network approach might help drug design[J].Trends Pharmacol Sci,2005,26(4):178-182.
[51]Hopkins A L.Network pharmacology:the next paradigm in drug discovery[J].Nat Chem Biol,2008,4(11):682-690.
[52]李梢,张博.中药网络药理学:理论、方法与应用(英文)[J].中国天然药物,2013,11(2):110-120.
[53]Gertsch J.Botanical drugs,synergy,and network pharmacology:forth and back to intelligent mixtures[J].Planta Med,2011,77(11):1086-1098.