中医药通过mTOR途径调节细胞凋亡与自噬的研究进展
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摘要
哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)是一种进化保守的丝氨酸/苏氨酸蛋白激酶,其生物学功能主要是参与细胞的增殖、生长及分化,从而调节机体的代谢过程。诸多国内外研究表明,mTOR是细胞凋亡及自噬信号转导通路的交汇点,营养、药物及氧化应激等多种刺激均可通过mTOR介导的信号通路对细胞的凋亡和自噬起到关键性的调控作用。目前,诸多研究已经证明,mTOR信号通路的改变与多种人类疾病的发病机制密切相关,如癌症、代谢紊乱(肥胖和2型糖尿病)、心血管和神经退行性疾病、与年龄有关的疾病和卵泡发育障碍等。近年来,越来越多的医家以该通路为切入点,以细胞凋亡和自噬为研究载体,研究了中医药对细胞凋亡和自噬的调节。其中包括中药单体、中成药、中药复方以及针灸等药物及物理疗法调控凋亡及自噬的实验研究。本文从mTOR信号通路入手,探讨了mTOR与细胞凋亡及自噬的关系,综述了中医药经mTOR途径调节细胞凋亡与自噬的最新进展,为中医药在该领域的深入研究提供了思路与参考。今后,中医药领域仍可以mTOR信号通路为依托,在中医基础理论的指导下对细胞凋亡和自噬的时效关系进行探索,为中医药在机体的作用机制提供新的现代医学的理论支持和作用靶点。
Mammalian target of rapamycin(mTOR) is an evolutionary conservative serine/threonine protein kinase.Its biological function is mainly to participate in cell proliferation,growth and differentiation,so as to regulate the body's metabolic process.Many domestic and foreign studies have shown that mTOR is the junction of apoptosis and autophagy signal transduction pathways.Various stimuli,such as nutrition,drugs and oxidative stress,may play a key regulatory role in cell apoptosis and autophagy through mTOR-mediated signaling pathways.At present,many studies have shown that the change in mTOR signaling pathways is closely related to the pathogenesis of many human diseases,such as cancer,metabolic disorders(obesity and type 2 diabetes),cardiovascular and neurodegenerative disease,age-related diseases and disorders of follicular.In recent years,more and more doctors have studied the regulatory effect of traditional Chinese medicine on apoptosis and autophagy,with the pathways as the starting point and cell apoptosis and autophagy as the research carriers.These studies include experimental studies on the regulation of apoptosis and autophagy by monomers of traditional Chinese medicine(TCM),Chinese patent medicine,compound prescription of TCM,acupuncture and other drugs and physiotherapy.Starting from the mTOR signaling pathways,this paper discusses the relationship between mTOR,apoptosis and autophagy,and reviews the recent progress of TCM in regulating apoptosis and autophagy through mTOR pathways,so as to provide ideas and references for further studies in this field.In the future,TCM doctors can still explore the time-effect relationship between apoptosis and autophagy based on mTOR signaling pathways under the guidance of the basic theory of Chinese medicine,in order to provide theoretical support and targets for the action mechanism of TCM on bodies.
Mammalian target of rapamycin(mTOR) is an evolutionary conservative serine/threonine protein kinase.Its biological function is mainly to participate in cell proliferation,growth and differentiation,so as to regulate the body's metabolic process.Many domestic and foreign studies have shown that mTOR is the junction of apoptosis and autophagy signal transduction pathways.Various stimuli,such as nutrition,drugs and oxidative stress,may play a key regulatory role in cell apoptosis and autophagy through mTOR-mediated signaling pathways.At present,many studies have shown that the change in mTOR signaling pathways is closely related to the pathogenesis of many human diseases,such as cancer,metabolic disorders(obesity and type 2 diabetes),cardiovascular and neurodegenerative disease,age-related diseases and disorders of follicular.In recent years,more and more doctors have studied the regulatory effect of traditional Chinese medicine on apoptosis and autophagy,with the pathways as the starting point and cell apoptosis and autophagy as the research carriers.These studies include experimental studies on the regulation of apoptosis and autophagy by monomers of traditional Chinese medicine(TCM),Chinese patent medicine,compound prescription of TCM,acupuncture and other drugs and physiotherapy.Starting from the mTOR signaling pathways,this paper discusses the relationship between mTOR,apoptosis and autophagy,and reviews the recent progress of TCM in regulating apoptosis and autophagy through mTOR pathways,so as to provide ideas and references for further studies in this field.In the future,TCM doctors can still explore the time-effect relationship between apoptosis and autophagy based on mTOR signaling pathways under the guidance of the basic theory of Chinese medicine,in order to provide theoretical support and targets for the action mechanism of TCM on bodies.
引文
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[3]蔡竞.基于PI3K/Akt信号通路研究新加归肾丸促卵泡发育的分子机制[D].成都:成都中医药大学,2013.
[4]李雅文.新加归肾丸对雷公藤多苷致卵泡发育障碍模型大鼠卵巢组织FOXO3a、HIF-1a、IGF-1R调控机制的研究[D].成都:成都中医药大学,2016.
[5]廖风娇.新加归肾丸对雷公藤多苷致卵泡发育障碍大鼠模型Cyclin D2、PCNA、Bax、Bcl-2影响的研究[D].成都:成都中医药大学,2015.
[6]龙旭.基于PI3K/Akt信号通路研究新加归肾丸调节大鼠卵巢颗粒细胞增殖、凋亡的分子机制[D].成都:成都中医药大学,2015.
[7]陆柳如.基于PI3K/Akt/m TOR信号通路研究补肾活血法修复雷公藤多苷致卵泡发育障碍的分子机制[D].成都:成都中医药大学,2016.
[8]王蓉.新加归肾丸对雷公藤多苷致卵泡发育障碍模型大鼠p-Akt、XIAP、Apaf-1影响的研究[D].成都:成都中医药大学,2016.
[9]Laplante M,Sabatini D M.m TOR signaling in growth control and disease[J].Cell,2012,149(2):274-293.
[10]Jung C H,Ro S H,CAO J,et al.m TOR regulation of autophagy[J].FEBS Lett,2010,584(7):1287.
[11]Dada S,Demanines N,Dormond O.m TORC2 regulates PGE2-mediated endothelial cell survival and migration[J].Biochem Biophys Res Commun,2008,372(4):875-879.
[12]Vartanian R,Masri J,Martin J,et al.AP-1 regulates cyclin D1 and c-MYC transcription in an Akt-dependent manner in response to m TOR inhibition:Role of AIP4/Itch-mediated JUNB degradation[J].Mol Cancer Res,2011,9(1):115-130.
[13]王凡,肖开转,林超奇,等.PI3K信号通路对哺乳动物HPG轴的调控作用[J].中国细胞生物学学报,2013,35(7):1068-1072.
[14]WANG X,QI W,LI Y,et al.Huaier extract induces autophagic cell death by inhibiting the m TOR/S6Kpathway in breast cancer cells[J].PLo S One,2015,10(7):e0131771.
[15]SONG,OUYANG G,BAO S.The activation of Akt/PKBsignaling pathway and cell survival[J].J Cell Mol Med,2005,9(1):59-71.
[16]Ellis L,Ku S Y,Ramakrishnan S,et al.Combinatorial antitumor effect of HDAC and the PI3K-Akt-mTORpathway inhibition in a Pten defecient model of prostate cancer[J].Oncotarget,2013,4(12):2225-2236.
[17]Hales E C,Taub J W,Matherly L H.New insights into Notch1 regulation of the PI3K-Akt-mTOR1 signaling axis:targeted therapy ofγ-secretase inhibitor resistant T-cell acute lymphoblastic leukemia[J].Cellular Signalling,2014,26(1):149-161.
[18]NI B B,LI B,YANG Y H,et al.The effect of transforming growth factorβ21 on the crosstalk between autophagy and apoptosis in the annulus fibrosus cells under serum deprivation[J].Cytokine,2014,70(2):87-96.
[19]汪丽萍.Rictor/m TORC2通路在卵子发生与早发性卵巢功能不全中的作用及其机制研究[D].广州:南方医科大学,2017.
[20]Bruckova L,Soukup T,Visek B,et al.Proliferative potential and phenotypic analysis of long-term cultivated human granulosa cells initiated by addition of follicular fluid[J].J Assist Reprod Gennt,2011,28(10):939-950.
[21]Levine B,YUAN J.Autophagy in cell death:an innocent convict?[J].J Clin Invest,2005,115(10):2679-2688.
[22]PENG D J,WANG J,ZHOU J Y,et al.Role of the Akt/m TOR survival pathway in cisplatin resistance in ovarian cancer cells[J].Biochem Biophys Res Commun,2010,394(3):600-605.
[23]Russell R C,YUAN H X,GUAN K L.Autophagy regulation by nutrient signaling[J].Cell Res,2014,24(1):42-57.
[24]SUN S Y.Enhancing perifosine's anticancer efficacy by preventing autophagy[J].Autophagy,2010,6(1):184-185.
[25]Kim J,Kundu M,Viollet B,et al.AMPK and m TORregulate autophagy through direct phosphorylation of Ulk1[J].Nat Cell Biol,2011,13(2):132-141.
[26]Corradetti M N,Inoki K,Bardeesy N,et al.Regulation of the TSC pathway by LKB1:evidence of a molecular link between tuberous sclerosis complex and PeutzJeghers syndrome[J].Genes Dev,2004,18(13):1533-1538.
[27]ZHAO R,CHEN M,JIANG Z,et al.Platycodin-Dinduced autophagy in non-small cell lung cancer cells via PI3K/Akt/m TOR and MAPK signaling pathways[J].J Cancer,2015,6(7):623-631.
[28]梁楚燕.基于衰老雌鼠模型探讨铁皮石斛“补肾”功效的科学内涵[D].广州:广州中医药大学,2016.
[29]HUANG C,HU G.Shikonin suppresses proliferation and induces apoptosis in endometrioid endometrial cancer cells via modulating miR-106b/PTEN/Akt/m TORsignaling pathway[J].Bioscience Rep,2018,38(2):BSR20171546.
[30]徐昌君,王鹏飞,刘杨,等.黄芪甲苷对特发性肺纤维化自噬活性作用及PI3K/Akt/m TOR信号调控的影响[J].中国实验方剂学杂志,2017,23(18):75-82.
[31]宋囡,杨芳,曹慧敏,等.绞股蓝总甙调控m TOR/ULK1通路对Apo E(-/-)小鼠动脉粥样硬化的影响[J].中国动脉硬化杂志,2018,26(2):127-132.
[32]郑庆委,高淑娴,吕杰,等.虫草素对人舌癌细胞凋亡、自噬的影响及其分子机制[J].南方医科大学学报,2018,38(4):390-394.
[33]王越,刘春禹,王增艳,等.土槿皮乙酸通过DNA损伤反应诱导细胞自噬来抑制凋亡[J].吉林中医药,2017,37(4):381-384.
[34]陈明,王举涛,吴珍妮,等.半枝莲总黄酮通过PI3K/Akt/m TOR通路诱导肿瘤细胞自噬的体内实验研究[J].中国中药杂志,2017,42(7):1358-1364.
[35]刘建勋,任建勋,林成仁.中药复方功效的研究与发展[J].中国中药杂志,2016,41(6):971-975.
[36]刘荣福.琼玉膏对衰老大鼠脾脏PI3K/Akt信号通路影响的相关研究[D].广州:广州中医药大学,2016.
[37]柴小姝.消积饮维持治疗晚期肺癌及其对PI3K/Akt/m TOR信号通路影响的研究[D].广州:广州中医药大学,2011.
[38]房良华.透脓散抗肿瘤作用及其机制的研究[D].南京:南京中医药大学,2013.
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