调控TGF-β1/Smads信号通路抗肝纤维化的中药有效成分研究进展
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摘要
肝纤维化是多种因素影响的肝损伤愈合反应,其形成与多种细胞因子和多条信号通路有关,转化生长因子β1(trans-forming growth factor beta1,TGF-β1)是目前已知最强的促纤维化细胞因子之一,几乎参与了肝纤维化的所有关键环节。TGF-β1/Smads信号通路是TGF-β1发挥促纤维化作用最经典的途径,也是肝纤维化形成过程中最重要的信号通路之一,近年来就该信号通路的研究取得了一系列的科研成果。中药具有"多成分-多靶点-副作用小"的优势,在肝纤维化临床治疗中广泛应用。中药有效成分是从中药中提取纯化的单体化合物,其分子生物学的研究已成为当今热点,运用现代先进技术方法和手段,能直接阐明其作用的靶点和调控的信号通路,揭示了中药治病的机制,更有助于中药产业现代化和国际化发展。该文总结了TGF-β1/Smads信号通路的结构、功能及其在抗肝纤维化进展中的应用,并归纳分析了近5年来各类中药有效成分调控TGF-β1/Smads信号通路干预治疗肝纤维化的作用方式及其可能的机制,为靶向治疗肝纤维化的中药新药的创新开拓思路。
Hepatic fibrosis is a liver damage healing response affected by a variety of factors; its formation is associated with multiple cytokines and a variety of signaling pathways. Transforming growth factor beta1( TGF-β1) is one of the strongest fibrosis cytokines known,and involves almost all the key links in hepatic fibrosis. TGF-β1/Smads signal pathway is the most classical pathway for TGF-β1 to play its role in promoting fibrosis as well as one of the most important signaling pathways of hepatic fibrosis formation. Studies for the signal pathway have made a series of scientific research achievements in recently years. Traditional Chinese medicine has the advantages of " multiple ingredients,multiple targets and less side effects",and is widely used in the clinical treatment of hepatic fibrosis.Effective components of traditional Chinese medicine are monomer compounds,which are extracted and purified from traditional Chinese medicine. Nowadays,the molecular biology studies of effective traditional Chinese medicine have become a hotspot. Modern advanced technology and methods can be used to directly clarify the targets and the signaling pathways,reveal the mechanism of traditional Chinese medicine in treating diseases,and promote the modernization and international development of traditional Chinese medicine industry. This review summarized the structure,function and application of TGF-β1/Smads signaling pathway in the progress of anti-hepatic fibrosis,and analyzed the action mode and possible mechanism of various effective components of traditional Chinese medicine in regulating TGF-β1/Smads signaling pathway and intervening the treatment of hepatic fibrosis in the past five years,so as to put forward new ideas for innovating new targeted traditional Chinese medicine for hepatic fibrosis.
Hepatic fibrosis is a liver damage healing response affected by a variety of factors; its formation is associated with multiple cytokines and a variety of signaling pathways. Transforming growth factor beta1( TGF-β1) is one of the strongest fibrosis cytokines known,and involves almost all the key links in hepatic fibrosis. TGF-β1/Smads signal pathway is the most classical pathway for TGF-β1 to play its role in promoting fibrosis as well as one of the most important signaling pathways of hepatic fibrosis formation. Studies for the signal pathway have made a series of scientific research achievements in recently years. Traditional Chinese medicine has the advantages of " multiple ingredients,multiple targets and less side effects",and is widely used in the clinical treatment of hepatic fibrosis.Effective components of traditional Chinese medicine are monomer compounds,which are extracted and purified from traditional Chinese medicine. Nowadays,the molecular biology studies of effective traditional Chinese medicine have become a hotspot. Modern advanced technology and methods can be used to directly clarify the targets and the signaling pathways,reveal the mechanism of traditional Chinese medicine in treating diseases,and promote the modernization and international development of traditional Chinese medicine industry. This review summarized the structure,function and application of TGF-β1/Smads signaling pathway in the progress of anti-hepatic fibrosis,and analyzed the action mode and possible mechanism of various effective components of traditional Chinese medicine in regulating TGF-β1/Smads signaling pathway and intervening the treatment of hepatic fibrosis in the past five years,so as to put forward new ideas for innovating new targeted traditional Chinese medicine for hepatic fibrosis.
引文
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[2]秦冬梅,张钰,李莉.具有抗肝纤维化作用的植物药研究进展[J].世界华人消化杂志,2017,25(11):958.
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[4]杨华蕊,徐妍,杨永寿,等.天然产物抗肝纤维化作用及其机制研究进展[J].中国实验方剂学杂志,2018,24(14):214.
[5] Duarte S,Baber J,Fujii T,et al. Matrix metalloproteinases inliver injury,repair and fibrosis[J]. Matrix Biol,2015(44/46):147.
[6]朱庆均.黄芩苷与黄芩素治疗纤维化疾病研究进展[J].中国中药杂志,2017,42(7):1271.
[7]黄苗,刘欣,董蕾,等.太白楤木对CCl4诱导肝纤维化大鼠的干预作用[J].中国中药杂志,2015,40(21):4251.
[8] Chen P J,Cai S P,Yang Y,et al. PTP1B confers liver fibrosisby regulating the activation of hepatic stellate cells[J]. ToxicolAppl Pharmacol,2016,292:8.
[9] Nagaraja T,Chen L,Balasubramanian A,et al. Activation of theconnective tissue growth factor(CTGF)-transforming growth factorbeta1(TGF-beta 1)axis in hepatitis C virus-expressing hepato-cytes[J]. PLoS ONE,2012,7(10):e46526.
[10] Zhang Z,Zhao S,Yao Z,et al. Autophagy regulates turnover oflipid droplets via ROS-dependent Rab25 activation in hepaticstellate cell[J]. Redox Biol,2016,11:322.
[11]胡明政.阿魏酸钠对CCl4诱导肝纤维化大鼠肝脏组织中α-SMA及TGF-β1表达的影响[D].衡阳:南华大学,2017.
[12] Wang C,Zhang F,Cao Y,et al. Etoposide induces apoptosis inactivated human hepatic stellate cells via ER stress[J]. Sci Rep,2016,6:34330.
[13] Mao Y,Zhang S,Yu F,et al. Ghrelin attenuates liver fibrosisthrough regulation of TGF-β1 expression and autophagy[J]. Int JMol Sci,2015,16(9):21911.
[14] Lv P Y,Feng H,Huang W H,et al. Aucubin and its hydrolyticderivative attenuate activation of hepatic stellate cells via modula-tion of TGF-βstimulation[J]. Environ Toxicol Pharmacol,2017,50:234.
[15]赵卫华,王燕红,丛敏. TGF-β1/Smads信号通路在肝脏纤维化中的作用研究进展[J].肝脏,2016,21(10):877.
[16]颜小明,张立婷,李敏,等.TGF-β1/Smad信号通路在肝纤维化中的研究进展[J].现代生物医学进展,2016,16(9):1778.
[17] Zhang S,Gong Y,Xiao J,et al. TGF-beta signaling pathway asa pharmacological target in liver diseases[J]. Pharmacol Res,2014,85:15.
[18] Hu H H,Chen D Q,Wang Y N,et al. New insights into TGF-β/Smad signaling in tissue fibrosis[J]. Chem Biol Interact,2018,292:76.
[19] Perumal N,Perumal M,Halagowder D,et al. Morin attenuatesdiethylnitrosamine-induced rat liver fibrosis and hepatic stellatecell activation by coordinated regulation of Hippo/Yap and TGF-beta1/Smad signaling[J]. Biochi,2017,140:10.
[20]郑勇凤,王佳婧,傅超美,等.黄芩的化学成分与药理作用研究进展[J].中成药,2016,38(1):141.
[21]田华,王小平,陈瑜,等.黄芩素对大鼠肝纤维化保护作用的实验研究[J].时珍国医国药,2016,27(9):2305.
[22]周玲.紫花牡荆素靶向TGF-β/Smad信号通路减轻肝纤维化的实验研究[D].广州:南方医科大学,2016.
[23] Eraky S M,El-Mesery M,El-Karef A,et al. Silymarin and caffe-ine combination ameliorates experimentally-induced hepatic fibro-sis through down-regulation of LPAR1expression[J]. BiomedPhamacother,2018,101:49.
[24]许妍妍.二氢杨梅素对四氯化碳致肝纤维化大鼠防护作用及其机制研究[J].世界临床药物,2017,38(8):522.
[25]张玉,周曦,易龙,等.二氢杨梅素通过TGF-β1/Smad信号通路抑制肝星状细胞活化的作用研究[J].第三军医大学学报,2018,40(4):282.
[26]孟庆媛,苏亚楠,郭梦凡,等.灯盏花素对肝纤维化模型大鼠MMP-13及TIMP-1表达的研究[J].黑龙江医药科学,2013,36(3):96.
[27]钟秀宏,张以忠,孙艳美,等.灯盏花素对肝纤维化大鼠肝组织中TGF-β1,Smad3表达的影响[J].中国兽医杂志,2016,52(12):105.
[28]赵宏伟,柏兆方,张振芳,等.氧化苦参碱抗猪血清诱导的免疫性大鼠肝纤维化作用研究[J].成都大学学报:自然科学版,2015,34(4):319.
[29] Wu J,Pan L,Jin X,et al. The role of oxymatrine in regulatingTGF-beta1 in rats with hepatic fibrosis[J]. Acta Cir Bras,2018,33(3):207.
[30]陈爽,张艳,李孝生.川芎嗪对大鼠肝纤维化转化生长因子β1、Smad 2/3表达的影响[J].胃肠病学与肝病学杂志,2013,22(10):970.
[31]魏国微,李克跃.川芎嗪对血管紧张素Ⅱ诱导的大鼠肝星状细胞转化生长因子-β1/Smads通路的影响[J].中国现代医学杂志,2016,26(15):50.
[32]张笑菲,高卓维,吕志平,等.丹参酮ⅡA抑制肝纤维化作用机制的研究进展[J].山东医药,2018,58(28):86.
[33]魏国微,李克跃.丹参酮ⅡA对血管紧张素Ⅱ诱导的大鼠肝星状细胞TGF-β1/Smads通路的影响[J].贵阳中医学院学报,2016,38(2):36.
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