浏览全部资源
扫码关注微信
甘肃中医药大学,兰州 730000
Published:05 November 2023,
Published Online:11 September 2023,
Received:28 June 2023,
扫 描 看 全 文
田萌媛,张铭,赵哲等.基于自噬探讨中医药抗肝纤维化的研究进展[J].中国实验方剂学杂志,2023,29(21):255-263.
TIAN Mengyuan,ZHANG Ming,ZHAO Zhe,et al.Traditional Chinese Medicine Against Liver Fibrosis Based on Autophagy: A Review[J].Chinese Journal of Experimental Traditional Medical Formulae,2023,29(21):255-263.
田萌媛,张铭,赵哲等.基于自噬探讨中医药抗肝纤维化的研究进展[J].中国实验方剂学杂志,2023,29(21):255-263. DOI: 10.13422/j.cnki.syfjx.20231241.
TIAN Mengyuan,ZHANG Ming,ZHAO Zhe,et al.Traditional Chinese Medicine Against Liver Fibrosis Based on Autophagy: A Review[J].Chinese Journal of Experimental Traditional Medical Formulae,2023,29(21):255-263. DOI: 10.13422/j.cnki.syfjx.20231241.
肝纤维化(HF)是各种慢性肝损伤导致的普遍性疾病,严重影响人类健康。HF起病隐秘,症状不显,病变后期可发展为肝硬化甚至肝细胞癌。HF病理机制十分复杂,主要表现为细胞外基质(ECM)的过度堆积。自噬是一种溶酶体介导的降解系统,用于循环利用细胞内容物,清除聚集的蛋白质、受损的细胞器和入侵的病原体(如病毒和细菌),以维持正常的细胞功能和动态平衡。自噬可以通过调节多种信号通路和因子,如哺乳动物雷帕霉素靶蛋白(mTOR)、单磷酸腺苷活化蛋白激酶(AMPK)、转化生长因子-
β
(TGF-
β
)等,减少肝星状细胞(HSC)的活化及肝细胞的坏死凋亡,从而减轻ECM的沉积及延缓HF的进程。且大量研究表明中医药能够有效治疗肝纤维化,且作用机制可能与自噬相关。该文通过汇总分析近年来国内外文献,从自噬的作用机制及相关信号因子、通路,以及中医药通过调控自噬防治HF方面进行综述,以期为防治HF中药的开发与临床合理用药研究提供参考。
Hepatic fibrosis (HF) is a widespread disease caused by various forms of chronic liver injury, significantly impacting human health. HF often has an insidious onset with inconspicuous symptoms, but in its advanced stages, it can progress to cirrhosis or even hepatocellular carcinoma. The pathogenic mechanisms of HF are highly complex, primarily characterized by excessive extracellular matrix (ECM) deposition. Autophagy is a lysosome-mediated degradation system employed by cells to recycle cellular contents, eliminate aggregated proteins, damaged organelles, and invading pathogens (such as viruses and bacteria) to maintain normal cellular function and dynamic balance. Autophagy can regulate various signaling pathways and factors, including mammalian target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase (AMPK), and transforming growth factor-
β
(TGF-
β
), to reduce the activation of hepatic stellate cells (HSCs) and hepatocyte necrosis and apoptosis, thereby mitigating ECM deposition and slowing the progression of HF. Numerous studies also suggest that traditional Chinese medicine (TCM) can effectively treat HF, and its mechanism of action may be related to autophagy. This article provides a review by summarizing recent literature in China and abroad on the mechanisms of autophagy, related signaling factors and pathways, as well as the role of TCM in regulating autophagy for the prevention and treatment of HF, aiming to offer insights and references for the development of TCM in the prevention and clinical rational medication in the treatment of HF.
中医药肝纤维化自噬信号通路研究进展
traditional Chinese medicinehepatic fibrosisautophagysignaling pathwayresearch progress
GINèS P,KRAG A,ABRALDES J G,et al.Liver cirrhosis[J].Lancet,2021,398(10308):1359-1376.
ASRANI S K,DEVARBHAVI H,EATON J,et al.Burden of liver diseases in the world[J].J Hepatol,2019,70(1):151-171.
MARCELLIN P,KUTALA B K.Liver diseases: A major, neglected global public health problem requiring urgent actions and large-scale screening[J].Liver Int,2018,38(Suppl 1):2-6.
罗雅琴,于新阳,张月明,等.基于AMPK/mTOR/ULK1信号通路介导的自噬探讨芪黄益气摄血方治疗免疫性血小板减少症模型小鼠的作用机制[J].中国实验方剂学杂志,2022,28(17):43-51.
CHAO X,QIAN H,WANG S,et al.Autophagy and liver cancer[J].Clin Mol Hepatol,2020,26(4):606-617.
FILALI-MOUNCEF Y,HUNTER C,ROCCIO F,et al.The ménage à trois of autophagy, lipid droplets and liver disease[J].Autophagy,2022,18(1):50-72.
ALMACELLAS E,PELLETIER J,DAY C,et al.Lysosomal degradation ensures accurate chromosomal segregation to prevent chromosomal instability[J].Autophagy,2021,17(3):796-813.
高利昆,袁静萍,洪莉.细胞自噬与肿瘤治疗的研究进展[J].中国组织化学与细胞化学杂志,2020,29(2):183-187.
FLEMING A,BOURDENX M,FUJIMAKI M,et al.The different autophagy degradation pathways and neurodegeneration[J].Neuron,2022,110(6):935-966.
MEMISOGLU G,EAPEN V V,YANG Y,et al.PP2C phosphatases promote autophagy by dephosphorylation of the Atg1 complex[J].Proc Natl Acad Sci USA,2019,116(5):1613-1620.
KE P Y. Mitophagy in the pathogenesis of liver diseases [J]. Cells, 2020, 9(4):831.
HOU L S,ZHANG Y W,LI H,et al.The regulatory role and mechanism of autophagy in energy metabolism-related hepatic fibrosis[J].Pharmacol Ther,2022,234:108117.
GAO J,WEI B,DE ASSUNCAO T M,et al.Hepatic stellate cell autophagy inhibits extracellular vesicle release to attenuate liver fibrosis[J].J Hepatol,2020,73(5):1144-1154.
SHEN Y,MALIK S A,AMIR M,et al.Decreased hepatocyte autophagy leads to synergistic IL-1β and TNF mouse liver injury and inflammation[J].Hepatology,2020,72(2):595-608.
TRELFORD C B,NG E,CAMPBELL C I,et al.p62/Sequestosome 1 regulates transforming growth factor beta signaling and epithelial to mesenchymal transition in A549 cells[J].Cell Signal,2021,85:110040.
GUPTA S, KUMAR M, CHAUDHURI S, et al. The non-canonical nuclear functions of key players of the PI3K-Akt-mTOR pathway [J]. J Cell Physiol, 2022, 237(8): 3181-204.
李钰佳,李定祥,彭珣,等.基于AMPK/mTOR/ULK1自噬相关通路探讨左归降糖通脉方对AGEs合并缺糖缺氧星形胶质细胞炎性损伤的影响[J].中国实验方剂学杂志,2022,28(16):90-99.
AL-BARI M,XU P.Molecular regulation of autophagy machinery by mTOR-dependent and -independent pathways[J].Ann N Y Acad Sci,2020,1467(1):3-20.
RONG Z,ZHENG K,CHEN J,et al.Function and regulation of ULK1:From physiology to pathology[J].Gene,2022,840:146772.
SHAN L,DING Y,FU Y,et al.mTOR overactivation in mesenchymal cells aggravates CCl(4)- induced liver fibrosis[J].Sci Rep,2016,6:36037.
HILL S M,WROBEL L,RUBINSZTEIN D C.Post-translational modifications of Beclin 1 provide multiple strategies for autophagy regulation[J].Cell Death Differ,2019,26(4):617-629.
MATHRE S, REDDY K B, RAMYA V, et al. Functional analysis of the biochemical activity of mammalian phosphatidylinositol 5 phosphate 4-kinase enzymes[J].Biosci Rep,2019,doi:10.1042/BSR20182210http://dx.doi.org/10.1042/BSR20182210.
张静,张宇,唐露露,等.基于Pink1/Parkin通路探讨肝豆汤对Wilson病TX模型小鼠的线粒体自噬的影响[J].中国实验方剂学杂志,2022,28(12):111-118.
WANG J H,AHN I S,FISCHER T D,et al.Autophagy suppresses age-dependent ischemia and reperfusion injury in livers of mice[J].Gastroenterology,2011,141(6):2188-2199.
MOROVICZ A P,MAZLOUMI GAVGANI F,JACOBSEN R G,et al.Phosphoinositide 3-kinase signalling in the nucleolus[J].Adv Biol Regul,2022,83:100843.
BAFFI T R,NEWTON A C.mTOR regulation of AGC kinases:New twist to an old tail[J].Mol Pharmacol,2022,101(4):213-218.
刘蔚,曹俊岭,荆志伟,等.柴胡加龙骨牡蛎汤对帕金森病伴发抑郁模型大鼠的神经保护作用及对AMPK/mTOR信号通路的影响[J].中国实验方剂学杂志,2022,28(8):21-29.
LIN C P,TRAETS J,VREDEVOOGD D W,et al.TSC2 regulates tumor susceptibility to TRAIL-mediated T-cell killing by orchestrating mTOR signaling[J].EMBO J,2023,42(5):e111614.
ZHANG F,PENG W,ZHANG J,et al.PARK7 enhances antioxidative-stress processes of BMSCs via the ERK1/2 pathway[J].J Cell Biochem,2021,122(2):222-234.
ZHOU Q,TANG S,ZHANG X,et al.Targeting PRAS40:A novel therapeutic strategy for human diseases[J].J Drug Target,2021,29(7):703-715.
ZHANG X L,CHEN Z N,HUANG Q F,et al.Methyl helicterate inhibits hepatic stellate cell activation through modulation of apoptosis and autophagy[J].Cell Physiol Biochem,2018,51(2):897-908.
LEE K W,THIYAGARAJAN V,SIE H W,et al.Synergistic effect of natural compounds on the fatty acid-induced autophagy of activated hepatic stellate cells[J].J Nutr Biochem,2014,25(9):903-913.
RAO Q,XIE K,VARIER K M,et al.Design, synthesis, and antileukemic evaluation of a novel mikanolide derivative through the Ras/Raf/MEK/ERK pathway[J].Front Pharmacol,2022,13:809551.
YU Y,ZHAO Y,CHOI J,et al.ERK inhibitor ulixertinib inhibits high-risk neuroblastoma growth in vitro and in vivo[J].Cancers (Basel),2022,doi:10.3390/cancers14225534http://dx.doi.org/10.3390/cancers14225534.
LIU C,YE D,YANG H,et al.RAS-targeted cancer therapy:Advances in drugging specific mutations[J].Med Comm,2023,4(3):e285.
KIDGER A M,SIPTHORP J,COOK S J.ERK1/2 inhibitors:New weapons to inhibit the RAS-regulated RAF-MEK1/2-ERK1/2 pathway[J].Pharmacol Ther,2018,187:45-60.
ELEVELD T F,VERNOOIJ L,SCHILD L,et al.MEK inhibition causes BIM stabilization and increased sensitivity to Bcl-2 family member inhibitors in RAS-MAPK-mutated neuroblastoma[J].Front Oncol,2023,13:1130034.
尹丽梅,袁建,陈楷,等.解毒活血方调控PI3K/Akt/mTOR信号通路对ApoE~(-/-)动脉粥样硬化小鼠斑块稳定性的影响[J].中国实验方剂学杂志,2023,29(12):112-120.
WANG Y,TANG S,WU Y,et al.Upregulation of 6-phosphofructo-2-kinase (PFKFB3) by hyperactivated mammalian target of rapamycin complex 1 is critical for tumor growth in tuberous sclerosis complex[J].IUBMB Life,2020,72(5):965-977.
ZHAO T M,WANG Y,DENG Y,et al.Bicyclol attenuates acute liver injury by activating autophagy, anti-oxidative and anti-inflammatory capabilities in mice[J].Front Pharmacol,2020,11:463.
SHI M J,DONG B S,YANG W N,et al.Preventive and therapeutic role of Tanshinone ⅡA in hepatology[J].Biomed Pharmacother,2019,112:108676.
XU G,HE Z,LIU Y.Alisol A 24-acetate ameliorates osteoarthritis progression by inhibiting reactive oxygen species and inflammatory response through the AMPK/mTOR pathway[J].Immun Inflamm Dis,2023,11(5):e848.
列倍锋,程芳,段婷婷,等.黄芪散微丸对糖尿病肾病大鼠肾脏PI3K/Akt/mTOR通路及自噬的影响[J].中国实验方剂学杂志,2022,28(7):11-17.
KIM J,KIM Y C,FANG C,et al.Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy[J].Cell,2013,152(1/2):290-303.
WEERASEKARA V K,PANEK D J,BROADBENT D G,et al.Metabolic-stress-induced rearrangement of the 14-3-3 interactome promotes autophagy via a ULK1- and AMPK-regulated 14-3-3 interaction with phosphorylated Atg9[J].Mol Cell Biol,2014,34(24):4379-4388.
冯雯敏,苏安宇,黄小玲,等.古方黄芪散调控AMPK/mTOR自噬信号通路改善肝脏脂肪变性的机制[J].中国实验方剂学杂志,2023,29(10):21-30.
WU Y L,ZHANG Y J,YAO Y L,et al.Cucurbitacin E ameliorates hepatic fibrosis in vivo and in vitro through activation of AMPK and blocking mTOR-dependent signaling pathway[J].Toxicol Lett,2016,258:147-158.
WANG M,ZHANG Y,LIU M,et al.Inhibition of STAT3 signaling as critical molecular event in HUC-MSCs suppressed glioblastoma cells[J].J Cancer,2023,14(4):611-627.
YOU L,WANG Z,LI H,et al.The role of STAT3 in autophagy[J].Autophagy,2015,11(5):729-739.
MIAO L J,HUANG F X,SUN Z T,et al.Stat3 inhibits Beclin 1 expression through recruitment of HDAC3 in nonsmall cell lung cancer cells[J].Tumour Biol,2014,35(7):7097-7103.
BHATTACHARYA S,YIN J,YANG C,et al.STAT3 suppresses the AMPKα/ULK1-dependent induction of autophagy in glioblastoma cells[J].J Cell Mol Med,2022,26(14):3873-3890.
HU Y J,ZHONG J T,GONG L,et al.Autophagy-related Beclin1 and head and neck cancers[J].Onco Targets Ther,2020,13:6213-6227.
WEI J,ZHU K,YANG Z,et al.Hypoxia-induced autophagy is involved in radioresistance via HIF1A-associated Beclin-1 in glioblastoma multiforme[J].Heliyon,2023,9(1):e12820.
CHOU Y H,PAN S Y,LIN S L.Pleotropic effects of hypoxia-inducible factor-prolyl hydroxylase domain inhibitors:Are they clinically relevant?[J].Kidney Res Clin Pract,2023,42(1):27-38.
谭悦浩,李灿,邓峰美,等.小檗碱通过抑制肝星状细胞自噬改善小鼠肝纤维化[J].成都医学院学报,2023,18(1):33-38.
张福华,楚胜,李传俊,等.石蒜碱通过PI3K/Akt信号通路调节自噬抑制HBV诱发肝纤维化[J].现代预防医学,2022,49(4):720-726.
马子华,张景允,杨柳,等.氧化苦参碱干预砷致肝星状细胞活化中细胞自噬的研究[J].中国病理生理杂志,2019,35(9):1662-1667.
张海娟,徐军全,康杰,等.川芎嗪对实验性肝纤维化大鼠肝组织中细胞自噬的影响[J].中国实用医药,2015(18):286-287.
WU L,ZHANG Q,MO W,et al.Quercetin prevents hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing autophagy via the TGF-β1/Smads and PI3K/Akt pathways[J].Sci Rep,2017,7(1):9289.
LIU N,FENG J,LU X,et al.Isorhamnetin inhibits liver fibrosis by reducing autophagy and inhibiting extracellular matrix formation via the TGF-β1/Smad3 and TGF-β1/p38 MAPK pathways[J].Mediators Inflamm,2019,2019:6175091.
MA J Q,SUN Y Z,MING Q L,et al.Ampelopsin attenuates carbon tetrachloride-induced mouse liver fibrosis and hepatic stellate cell activation associated with the SIRT1/TGF-β1/Smad3 and autophagy pathway[J].Int Immunopharmacol,2019,77:105984.
ZHU L,MOU Q,WANG Y,et al.Resveratrol contributes to the inhibition of liver fibrosis by inducing autophagy via the microRNA‑20a‑mediated activation of the PTEN/PI3K/Akt signaling pathway[J].Int J Mol Med,2020,46(6):2035-2046.
FENG J,CHEN K,XIA Y,et al.Salidroside ameliorates autophagy and activation of hepatic stellate cells in mice via NF-κB and TGF-β1/Smad3 pathways[J].Drug Des Devel Ther,2018,12:1837-1853.
孔德松,张自力,张峰,等.姜黄素通过影响自噬调控肝细胞上皮间质转化及肝纤维化进程的作用与机制研究[J].中国药理学通报,2019,35(10):1388-1393.
郑洋,徐灿丽,卢能源,等.基于肝星状细胞自噬和凋亡探讨莪术醇抗肝纤维化的作用机制[J].中国中药杂志,2022,47(3):730-736.
LIU X,MI X,WANG Z,et al.Ginsenoside Rg3 promotes regression from hepatic fibrosis through reducing inflammation-mediated autophagy signaling pathway[J].Cell Death Dis,2020,11(6):454.
姜辉,张家富,高家荣,等.疏肝健脾方对肝纤维化大鼠自噬蛋白Beclin-1和LC3-Ⅱ的影响[J].中国中西医结合杂志,2017,37(8):955-960.
徐渴阳,苏晓倩,包剑锋.扶正化瘀胶囊对气虚血瘀型肝纤维化模型大鼠细胞自噬基因LC3Ⅱ和p62的干预作用[J].浙江中西医结合杂志,2019,29(4):281-284,前插3.
辛鑫,蔡蓓玉,陈成,等.扶正化瘀胶囊对非酒精性脂肪性肝纤维化小鼠的影响[J].中国实验方剂学杂志,2021,27(6):37-45.
安祯祥,何远利,唐东昕,等.扶脾柔肝颗粒对肝纤维化模型大鼠的改善作用机制研究[J].中国药房,2021,32(21):2587-2592.
李媛,郑亚东,龙富立,等.白花香莲解毒颗粒调控AMPK/mTOR通路抑制肝星状细胞自噬和活化的作用机制研究[J].中药材,2023,46(2):469-73.
牛媛媛,汪龙德,毛兰芳,等.基于“亢害承制”理论探讨化瘀软肝胶囊对肝纤维化大鼠细胞自噬的影响[J].世界科学技术—中医药现代化,2022,24(9):3651-3658.
毛旭,袁星星,杨磊,等.芪参汤通过细胞自噬对肝窦内皮细胞去分化的影响[J].海南医学院学报,2020,26(16):1222-1227.
陶柏楠,王咏兰,田梦杰,等.柔肝降酶方对CCl4诱导大鼠肝纤维化的作用[J].中成药,2023,45(3):741-747.
0
Views
21
下载量
3
CSCD
Publicity Resources
Related Articles
Related Author
Related Institution