中草药黄酮类化合物治疗肝纤维化分子信号通路的研究进展
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摘要
目的:为中草药黄酮类化合物治疗肝纤维化的进一步研究提供参考。方法:以"中草药""黄酮类化合物""肝纤维化""信号通路""Chinese herbal medicine""Flavonoids""Hepatic fibrosis""Signaling pathway"等为关键词,在中国知网、万方数据、维普网、PubMed、Medline等数据库中组合查询2002年1月-2018年8月发表的相关文献,对中草药黄酮类化合物治疗肝纤维化分子信号通路[如转化生长因子β(TGF-β)/Smad、Wnt/β-联蛋白(β-catenin)、Toll样受体4/核因子κB(TLR4/NF-κB)、Janus激酶/信号转导子和转录激活因子(JAK/STAT)、磷酯酰肌醇-3-激酶/蛋白激酶B(PI3K/Akt)等]的相关研究进行论述。结果与结论:共检索到相关文献169篇,其中有效文献47篇。肝纤维化是肝星状细胞活化导致细胞外基质大量沉积的结果,肝纤维化的发生和发展过程受多个分子信号转导通路的调控。柚皮素、槲皮素、荔枝核总黄酮、白杨素、葛根素等黄酮类化合物能干预与肝纤维化发生密切相关的TGF-β/Smad、Wnt/β-catenin、TLR4/NF-κB、JAK/STAT和PI3K/Akt信号通路。该类化合物治疗肝纤维化具有多靶点、多通路、多环节的特点,同一化合物可影响多个信号通路。今后应对黄酮类化合物对分子信号通路介导肝纤维化的作用机制进行研究。
引文
[1]孟明辉.JAK/STAT信号转导通路在肝纤维化发病机制中作用的实验研究[D].石家庄:河北医科大学,2011.
[2]CHEN RJ,WU HH,WANG YJ.Strategies to prevent and reverse liver fibrosis in humans and laboratory animals[J].Arch Toxicol,2015,89(10):1727-1750.
[3]MURPHY F,ARTHUR M,IREDALE J.Developing strategies for liver fibrosis treatment[J].Expert Opin Investig Drugs,2002,11(11):1575-1585.
[4]杨小瑜.肝纤维化的发病机制研究进展[J].山东医药,2017,57(11):108-110.
[5]YIN C,EVASON KJ,ASAHINA K,et al.Hepatic stellate cells in liver development,regeneration,and cancer[J].JClin Invest,2013,123(5):1902-1910.
[6]VAN ROSSEN E,LIU Z,BLIJWEERT D,et al.Syncoilin is an intermediate filament protein in activated hepatic stellate cells[J].Histochem Cell Biol,2014,141(1):85-99.
[7]WELLS RG.Cellular sources of extracellular matrix in hepatic fibrosis[J].Clin Liver Dis,2008,12(4):759-768.
[8]PUCHE JE,SAIMAN Y,FRIEDMAN SL.Hepatic stellate cells and liver fibrosis[J].Compr Physiol,2013,3(4):1473-1492.
[9]穆娟,赵明峰,李玉明.丹参的药理作用研究现况[J].当代医学,2017,23(27):182-184.
[10]杨莹帆,孙懿,赵欣,等.丹参粉针剂对二甲基亚硝胺所致大鼠肝纤维化进程的影响[J].中国药学(英文版),2015,24(1):54-62.
[11]杨莹帆,郑希元,赵欣,等.丹参粉针剂对酒精致大鼠慢性肝纤维化的保护作用[J].中国新药杂志,2014,23(21):2556-2560.
[12]常虹,郭凯,孟洪宇,等.中药有效成分作用于肝星状细胞抗肝纤维化分子机制研究进展[J].中国现代中药,2017,19(1):148-153.
[13]ZHANG YE.Smad-dependent and Smad-independent pathways in TGF-βfamily signalling[J].Nature,2003,425(6958):577-584.
[14]FU R,WU J,DING J,et al.Targeting transforming growth factorβRⅡexpression inhibits the activation of hepatic stellate cells and reduces collagen synthesis[J].Exp Biol Med,2011,236(3):291-297.
[15]ZHANG L,LIU C,MENG XM,et al.Smad2 protects against TGF-β1/Smad3-mediated collagen synthesis in human hepatic stellate cells during hepatic fibrosis[J].Mol Cell Biochem,2015,400(1/2):17-28.
[16]LIU C,GACA MD,SWENSON ES,et al.Smads 2 and3 are differentially activated by transforming growth factor-beta(TGF-beta)in quiescent and activated hepatic stellate cells.Constitutive nuclear localization of Smads in activated cells is TGF-beta-independent[J].J Biol Chem,2003,278(13):11721-11728.
[17]PENG J,LI X,FENG Q,et al.Anti-fibrotic effect of Cordyceps sinensis polysaccharide:inhibiting HSC activation,TGF-β1/Smad signalling,MMPs and TIMPs[J].Exp Biol Med,2013,238(6):668-677.
[18]王薇.柚皮素抑制肝纤维化作用机制的研究[D].北京:北京林业大学,2006.
[19]郭又嘉.玉郎伞总黄酮对肝损伤的保护作用及机制研究[D].南宁:广西医科大学,2012.
[20]简洁.玉郎伞黄酮成分的单体分离与药效研究[D].南宁:广西医科大学,2009.
[21]王雪,蒋志涛,严国俊,等.UPLC-MS/MS法同时测定垂盆草总黄酮中8种成分的含量[J].中国药房,2018,29(9):1222-1226.
[22]林远灿,骆海莺,陈红淑.垂盆草总黄酮对肝纤维化大鼠肝组织TGF-β1和Smad7表达的影响[J].中国药师,2015,18(12):2021-2024.
[23]姜振国.荔枝核的化学成分及降血糖活性研究[D].长春:长春中医药大学,2011.
[24]喻勤,傅向阳,罗伟生,等.荔枝核总黄酮对大鼠肝纤维化TGF-β/Smad信号通路的影响[J].中国实验方剂学杂志,2013,19(18):223-227.
[25]NEJAK-BOWEN K,MONGA SP.Wnt/β-catenin signaling in hepatic organogenesis[J].Organogenesis,2008,4(2):92-99.
[26]KIKUCHI A,KISHIDA S,YAMAMOTO H.Regulation of Wnt signaling by protein-protein interaction and post-translational modifications[J].Exp Mol Med,2006,38(1):1-10.
[27]黄静.水飞蓟宾通过Wnt/β-catenin信号通路对酒精性肝纤维化模型大鼠的保护作用机制的实验研究[D].合肥:安徽中医药大学,2016.
[28]林翔.HDND-7对四氯化碳诱导的小鼠肝纤维化的治疗作用及部分作用机制研究[D].合肥:安徽医科大学,2015.
[29]冯莉芳.槲皮黄酮逆转肝纤维化的分子机制[J].中国医院药学杂志,2017,37(11):1052-1055.
[30]孙利兵.FAC及EGCG对CCl4致小鼠肝纤维化的干预作用及其机制研究[D].苏州:苏州大学,2009.
[31]ZHU J,MOHAN C.Toll-like receptor signaling pathways:therapeutic opportunities[J].Mediators Inflamm,2010,2010.DOI:10.1155/2010/781235.
[32]SHIBATA T,MOTOI Y,TANIMURA N,et al.Intracellular TLR4/MD-2 in macrophages senses Gram-negative bacteria and induces a unique set of LPS-dependent genes[J].Int Immunol,2011,23(8):503-510.
[33]莫晓晖,梁韬.葛根素对四氯化碳所诱导肝纤维化大鼠的干预作用及对TLR-4、NF-κB、AP-1的影响[J].中国医院药学杂志,2017,37(14):1348-1351.
[34]韦铮武,李彩,林丽馨,等.荔枝核总黄酮对体外活化肝星状细胞-T6增殖、凋亡及TLR4/NF-κB途径的影响[J].中华中医药杂志,2016,31(12):5214-5218.
[35]NOBORI K,MUNEHISA Y.Intracellular signaling pathways for cardiac hypertrophy:ERK,JAK-STAT,S6 kinase[J].Nihon Rinsho,2007,65(Suppl 4):S196-S200.
[36]HUI J,GAO J,WANG Y,et al.Panax notoginseng saponins ameliorates experimental hepatic fibrosis and hepatic stellate cell proliferation by inhibiting the JAK2/STAT3pathways[J].J Tradit Chin Med,2016,36(2):217-224.
[37]周辉蓉.白杨素对人肝星状细胞LX-2及肝纤维化小鼠作用的研究[D].桂林:桂林医学院,2016.
[38]曹后康,高雅,黄思茂,等.杠板归总黄酮抗大鼠肝纤维化作用的机制研究[J].中国药理学通报,2017,33(9):1303-1308.
[39]赵超,陈华国,龚小见,等.杠板归的化学成分研究:Ⅱ[J].中草药,2010,41(3):365-367.
[40]SON G,HINES IN,LINDQUIST J,et al.Inhibition of phosphatidylinositol 3-kinase signaling in hepatic stellate cells blocks the progression of hepatic fibrosis[J].Hepatology,2010,50(5):1512-1523.
[41]ZOU CG,GAO SY,ZHAO YS,et al.Homocysteine enhances cell proliferation in hepatic myofibroblastic stellate cells[J].J Mol Med,2009,87(1):75-84.
[42]CANTLEY LC.The phosphoinositide 3-kinase pathway[J].Science,2002,296(5573):1655-1657.
[43]CORPECHOT C,BARBU V,WENDUM D,et al.Hypoxia-induced VEGF and collagenⅠexpressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis[J].Hepatology,2002,35(5):1010-1021.
[44]潘澎.芪术颗粒对肝纤维化形成过程中PI3K/Akt信号转导通路的影响[D].北京:北京中医药大学,2013.
[45]LIN X,BAI F,NIE J,et al.Didymin alleviates hepatic fibrosis through inhibiting ERK and PI3K/Akt pathways via regulation of raf kinase inhibitor protein[J].Chem Biol Interact,2016,40(6):1422.
[46]李晚霞.橙皮素衍生物对四氯化碳诱导的大鼠肝纤维化的治疗作用及部分机制研究[D].合肥:安徽医科大学,2017.
[47]GUO C,XU L,HE Q,et al.Anti-fibrotic effects of puerarin on CCl4-induced hepatic fibrosis in rats possibly through the regulation of PPAR-γexpression and inhibition of PI3K/Akt pathway[J].Food Chem Toxicol,2013,56(19):436-442.
[2]CHEN RJ,WU HH,WANG YJ.Strategies to prevent and reverse liver fibrosis in humans and laboratory animals[J].Arch Toxicol,2015,89(10):1727-1750.
[3]MURPHY F,ARTHUR M,IREDALE J.Developing strategies for liver fibrosis treatment[J].Expert Opin Investig Drugs,2002,11(11):1575-1585.
[4]杨小瑜.肝纤维化的发病机制研究进展[J].山东医药,2017,57(11):108-110.
[5]YIN C,EVASON KJ,ASAHINA K,et al.Hepatic stellate cells in liver development,regeneration,and cancer[J].JClin Invest,2013,123(5):1902-1910.
[6]VAN ROSSEN E,LIU Z,BLIJWEERT D,et al.Syncoilin is an intermediate filament protein in activated hepatic stellate cells[J].Histochem Cell Biol,2014,141(1):85-99.
[7]WELLS RG.Cellular sources of extracellular matrix in hepatic fibrosis[J].Clin Liver Dis,2008,12(4):759-768.
[8]PUCHE JE,SAIMAN Y,FRIEDMAN SL.Hepatic stellate cells and liver fibrosis[J].Compr Physiol,2013,3(4):1473-1492.
[9]穆娟,赵明峰,李玉明.丹参的药理作用研究现况[J].当代医学,2017,23(27):182-184.
[10]杨莹帆,孙懿,赵欣,等.丹参粉针剂对二甲基亚硝胺所致大鼠肝纤维化进程的影响[J].中国药学(英文版),2015,24(1):54-62.
[11]杨莹帆,郑希元,赵欣,等.丹参粉针剂对酒精致大鼠慢性肝纤维化的保护作用[J].中国新药杂志,2014,23(21):2556-2560.
[12]常虹,郭凯,孟洪宇,等.中药有效成分作用于肝星状细胞抗肝纤维化分子机制研究进展[J].中国现代中药,2017,19(1):148-153.
[13]ZHANG YE.Smad-dependent and Smad-independent pathways in TGF-βfamily signalling[J].Nature,2003,425(6958):577-584.
[14]FU R,WU J,DING J,et al.Targeting transforming growth factorβRⅡexpression inhibits the activation of hepatic stellate cells and reduces collagen synthesis[J].Exp Biol Med,2011,236(3):291-297.
[15]ZHANG L,LIU C,MENG XM,et al.Smad2 protects against TGF-β1/Smad3-mediated collagen synthesis in human hepatic stellate cells during hepatic fibrosis[J].Mol Cell Biochem,2015,400(1/2):17-28.
[16]LIU C,GACA MD,SWENSON ES,et al.Smads 2 and3 are differentially activated by transforming growth factor-beta(TGF-beta)in quiescent and activated hepatic stellate cells.Constitutive nuclear localization of Smads in activated cells is TGF-beta-independent[J].J Biol Chem,2003,278(13):11721-11728.
[17]PENG J,LI X,FENG Q,et al.Anti-fibrotic effect of Cordyceps sinensis polysaccharide:inhibiting HSC activation,TGF-β1/Smad signalling,MMPs and TIMPs[J].Exp Biol Med,2013,238(6):668-677.
[18]王薇.柚皮素抑制肝纤维化作用机制的研究[D].北京:北京林业大学,2006.
[19]郭又嘉.玉郎伞总黄酮对肝损伤的保护作用及机制研究[D].南宁:广西医科大学,2012.
[20]简洁.玉郎伞黄酮成分的单体分离与药效研究[D].南宁:广西医科大学,2009.
[21]王雪,蒋志涛,严国俊,等.UPLC-MS/MS法同时测定垂盆草总黄酮中8种成分的含量[J].中国药房,2018,29(9):1222-1226.
[22]林远灿,骆海莺,陈红淑.垂盆草总黄酮对肝纤维化大鼠肝组织TGF-β1和Smad7表达的影响[J].中国药师,2015,18(12):2021-2024.
[23]姜振国.荔枝核的化学成分及降血糖活性研究[D].长春:长春中医药大学,2011.
[24]喻勤,傅向阳,罗伟生,等.荔枝核总黄酮对大鼠肝纤维化TGF-β/Smad信号通路的影响[J].中国实验方剂学杂志,2013,19(18):223-227.
[25]NEJAK-BOWEN K,MONGA SP.Wnt/β-catenin signaling in hepatic organogenesis[J].Organogenesis,2008,4(2):92-99.
[26]KIKUCHI A,KISHIDA S,YAMAMOTO H.Regulation of Wnt signaling by protein-protein interaction and post-translational modifications[J].Exp Mol Med,2006,38(1):1-10.
[27]黄静.水飞蓟宾通过Wnt/β-catenin信号通路对酒精性肝纤维化模型大鼠的保护作用机制的实验研究[D].合肥:安徽中医药大学,2016.
[28]林翔.HDND-7对四氯化碳诱导的小鼠肝纤维化的治疗作用及部分作用机制研究[D].合肥:安徽医科大学,2015.
[29]冯莉芳.槲皮黄酮逆转肝纤维化的分子机制[J].中国医院药学杂志,2017,37(11):1052-1055.
[30]孙利兵.FAC及EGCG对CCl4致小鼠肝纤维化的干预作用及其机制研究[D].苏州:苏州大学,2009.
[31]ZHU J,MOHAN C.Toll-like receptor signaling pathways:therapeutic opportunities[J].Mediators Inflamm,2010,2010.DOI:10.1155/2010/781235.
[32]SHIBATA T,MOTOI Y,TANIMURA N,et al.Intracellular TLR4/MD-2 in macrophages senses Gram-negative bacteria and induces a unique set of LPS-dependent genes[J].Int Immunol,2011,23(8):503-510.
[33]莫晓晖,梁韬.葛根素对四氯化碳所诱导肝纤维化大鼠的干预作用及对TLR-4、NF-κB、AP-1的影响[J].中国医院药学杂志,2017,37(14):1348-1351.
[34]韦铮武,李彩,林丽馨,等.荔枝核总黄酮对体外活化肝星状细胞-T6增殖、凋亡及TLR4/NF-κB途径的影响[J].中华中医药杂志,2016,31(12):5214-5218.
[35]NOBORI K,MUNEHISA Y.Intracellular signaling pathways for cardiac hypertrophy:ERK,JAK-STAT,S6 kinase[J].Nihon Rinsho,2007,65(Suppl 4):S196-S200.
[36]HUI J,GAO J,WANG Y,et al.Panax notoginseng saponins ameliorates experimental hepatic fibrosis and hepatic stellate cell proliferation by inhibiting the JAK2/STAT3pathways[J].J Tradit Chin Med,2016,36(2):217-224.
[37]周辉蓉.白杨素对人肝星状细胞LX-2及肝纤维化小鼠作用的研究[D].桂林:桂林医学院,2016.
[38]曹后康,高雅,黄思茂,等.杠板归总黄酮抗大鼠肝纤维化作用的机制研究[J].中国药理学通报,2017,33(9):1303-1308.
[39]赵超,陈华国,龚小见,等.杠板归的化学成分研究:Ⅱ[J].中草药,2010,41(3):365-367.
[40]SON G,HINES IN,LINDQUIST J,et al.Inhibition of phosphatidylinositol 3-kinase signaling in hepatic stellate cells blocks the progression of hepatic fibrosis[J].Hepatology,2010,50(5):1512-1523.
[41]ZOU CG,GAO SY,ZHAO YS,et al.Homocysteine enhances cell proliferation in hepatic myofibroblastic stellate cells[J].J Mol Med,2009,87(1):75-84.
[42]CANTLEY LC.The phosphoinositide 3-kinase pathway[J].Science,2002,296(5573):1655-1657.
[43]CORPECHOT C,BARBU V,WENDUM D,et al.Hypoxia-induced VEGF and collagenⅠexpressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis[J].Hepatology,2002,35(5):1010-1021.
[44]潘澎.芪术颗粒对肝纤维化形成过程中PI3K/Akt信号转导通路的影响[D].北京:北京中医药大学,2013.
[45]LIN X,BAI F,NIE J,et al.Didymin alleviates hepatic fibrosis through inhibiting ERK and PI3K/Akt pathways via regulation of raf kinase inhibitor protein[J].Chem Biol Interact,2016,40(6):1422.
[46]李晚霞.橙皮素衍生物对四氯化碳诱导的大鼠肝纤维化的治疗作用及部分机制研究[D].合肥:安徽医科大学,2017.
[47]GUO C,XU L,HE Q,et al.Anti-fibrotic effects of puerarin on CCl4-induced hepatic fibrosis in rats possibly through the regulation of PPAR-γexpression and inhibition of PI3K/Akt pathway[J].Food Chem Toxicol,2013,56(19):436-442.