细胞自噬与疾病的研究进展
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摘要
细胞自噬(Autophagy)是细胞将受损的细胞器、废弃细胞质和变性或衰老的蛋白质转运至溶酶体(Lysosome),并进行酶解的一个生物学过程。在真核生物中,细胞自噬是一个高度保守的过程,而自噬是细胞的一种自我保护机制,维持了细胞内稳态。自噬在细胞程序性死亡(Programmed cell death,PCD)、心血管疾病、肝脏疾病、神经性疾病、癌症与肿瘤以及自身免疫性疾病等多种疾病过程扮演了重要的角色。该文综述了细胞自噬与多种疾病的研究进展,提示了细胞自噬在免疫相关性疾病过程中发挥着重要的调控作用,从而阐明细胞自噬可能作为疾病治疗的新靶点和突破口,为治疗免疫相关性疾病做铺垫。
Autophagy is a biological process in which cells transport the damaged organelles, waste cytoplasm and denatured or senescent proteins to lysosome, and then undergo enzymatic hydrolysis. Autophagy is a highly conserved process in eukaryotes, and autophagy is a cell self-protective mechanism which maintains the intracellular homeostasis. Autophagy plays an important role in the programmed cell death(PCD), cancer, cardiovascular disease, liver disease, neurodegenic diseases, cancer and tumor, autoimmune diseases and other disases. It was suggested that the autophagy played an important role in the process of immuno related diseases, thus clarifying that cell autophagy may be a new target and breakthrough in the treatment of immune related disease, and pave the way for the treatment of immune related diseases.
Autophagy is a biological process in which cells transport the damaged organelles, waste cytoplasm and denatured or senescent proteins to lysosome, and then undergo enzymatic hydrolysis. Autophagy is a highly conserved process in eukaryotes, and autophagy is a cell self-protective mechanism which maintains the intracellular homeostasis. Autophagy plays an important role in the programmed cell death(PCD), cancer, cardiovascular disease, liver disease, neurodegenic diseases, cancer and tumor, autoimmune diseases and other disases. It was suggested that the autophagy played an important role in the process of immuno related diseases, thus clarifying that cell autophagy may be a new target and breakthrough in the treatment of immune related disease, and pave the way for the treatment of immune related diseases.
引文
[1] 马泰,孙国平,李家斌.细胞自噬的研究方法[J].生物化学与生物物理进展,2012,39(3):204-209.
[2] MIJALJICA D,PRESCOTT M,DEVENISH R J.Autophagy in disease [J].Methods Mol Biol,2010,648:79-92.
[3] ZHOU W Y,ZHAO M Y.How hippo signaling pathway modulates cardiovascular development and diseases [J].Journal of immunology research,2018,2018:3696914.
[4] LI L J,CHAI Y,GUO X J,et al.Effects of endoplasmic reticulum stress on autophagy and apoptosis of human leukemia cells via inhibition of the PI3K/AKT/mTOR signaling pathway [J].Molecular medicine reports,2018,17(6):7886-7892.
[5] SATRIANO J,SHARMA K.Autophagy and metabolic changes in obesity-related chronic kidney disease [J].Nephrol Dial Transplant,2013,28(4):29-36.
[6] FENG Y C,HE D,YAO Z Y,et al.The machinery of macroautophagy [J].Cell Res,2014,24(1):24-41.
[7] SBARDELLA D,TUNDO G R,CAMPAGNOLO L,et al.Retention of mitochondria in mature human red blood cells as the result of autophagy impairment in rett syndrome [J].Sci Rep,2017,7(1):1-12.
[8] SANDAL S,BANSAL P,CANTAROVICH M.The evidence and rationale for the perioperative use of loop diuretics during kidney transplantation:A comprehensive review [J].Transplantation reviews,2018,32(2):92-101.
[9] TANG F,WANG B,LI N,et al.RNF185,a novel mitochondrial ubiquitin E3 ligase,regulates autophagy through interaction with BNIP1[J].PLoS One,2011,6(9):1-13.
[10] DERETIC V,KLIONSKY D J.Autophagy and inflammation:A special review issue[J].Autophagy,2018,14(2):1-4.
[11] CUERVO A M.Autophagy:In sickness and in health[J].Trends Cell Biol,2004,14(2):70-77.
[12] DE SILVA FONSECA A M,DE AZEVEDO SILVA J,PANCOTTO J A T,et al.Polymorphisms in STK17A gene are associated with systemic lupus erythematosus and its clinical manifestations [J].Gene,2013,527(2):435-439.
[13] ZHOU G Y,SPRENGERS D,BOOR P P C,et al.Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating T cells in hepatocellular carcinomas [J].Gastroenterology,2017,153(4):1107-1119.
[14] LU J,LIU D Z,ZHOU X J,et al.Plant natural product plumbagin presents potent inhibitory effect on human cytochrome P450 2J2 enzyme[J].Phytomedicine,2018,39:137-145.
[15] QIU S Q,LIU J,XING F Y.‘Hints’ in the killer protein gasdermin D:Unveiling the secrets of gasdermins driving cell death[J].Cell death & differentiation,2017,24(4):588-596.
[16] MATUSZKIEWICZ M,SOBCZAK M,CABRERA J,et al.The role of programmed cell death regulator LSD1 in nematode-induced syncytium formation[J].Frontiers in plant science,2018,9:314.
[17] DECUYPERE J P,BULTYNCK G,PARYS J B.A dual role for Ca2+ in autophagy regulation[J].Cell calcium,2011,50(3):242-250.
[18] RAVEH T,DROGUETT G,HORWITZ M S,et al.DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation[J].Nat Cell Biol,2001,3(1):1-7.
[19] INBAL B,BIALIK S,SABANAY I,et al.DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death[J].J Cell Biol,2002,157(3):455-468.
[20] KROEMER G,LEVINE B.Autophagic cell death:The story of a misnomer[J].Nat Rev Mol Cell Biol,2009,9(12):1004-1010.
[21] KIM H J,CHO M H,SHIM W H,et al.Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects [J].Molecular psychiatry,2017,22(11):1576-1584.
[22] IWASAKI N,SUGIYAMA Y,MIYAZAKI S,et al.An ATF4-signal-modulating machine other than GADD34 acts in ATF4-to-CHOP signaling to block CHOP expression in ER-stress-related autophagy[J].Journal of cellular biochemistry,2015,116(7):1300-1909.
[23] RUBIO N,COUPIENNE I,DI VALENTIN E,et al.Spatiotemporal auto-phagic degradation of oxidatively damaged organelles after photody-namic stress is amplified by mitochondrial reactive oxygen species [J].Autophagy,2012,8(9):1312-1324.
[24] WANG Y F,DING W X,LI T G.Cholesterol and bile acid-mediated regulation of autophagy in fatty liver diseases and atherosclerosis[J].Biochimica et biophysica acta,2018,1863(7):726-733.
[25] OCHOA C D,WU R F,TERADA L S.ROS signaling and ER stress in cardiovascular disease[J].Molecular aspects of medicine,2018,63:18-29.
[26] DU P Z,CHANG Y W,DAI F J,et al.Role of heat shock transcription factor 1(HSF1)-upregulated macrophage in ameliorating pressure overload-induced heart failure in mice[J].Gene,2018,667:10-17.
[27] DOONAN L M,FISHER E A,BRODSKY J L.Can modulators of apolipoproteinB biogenesis serve as an alternate target for cholesterol-lowering drugs?[J].Biochimica et biophysica acta(BBA)-Molecular and cell biology of lipids,2018,863(7):762-771.
[28] HASHEMZAEI M,HERAVI R E,REZAEE R,et al.Regulation of autophagy by some natural products as a potential therapeutic strategy for cardiovascular disorders[J].European journal of pharmacology,2017,802:44-51.
[29] ZHAO K,XU X S,MENG X,et al.Autophagy of monocytes attenuates thevulnerability of coronary atherosclerotic plaques[J].Coron Artery Dis,2013,24(8):651-656.
[30] NAKAI A,YAMAGUCHI O,TAKEDA T,et al.The role of autophagy in cardiomyocytes in the basal state and in reponse to hemodynamic stress[J].Nat Med,2007,13(5):619-624.
[31] OKA T,HIKOSO S,YAMAGUCHI O,et al.Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure[J].Nature,2012,485(7397):251-255.
[32] JIA G H,CHENG G,GANGAHAR D M,et al.Insulin-like growth factor-1 and TNF-α regulate autophagy through c-jun N-terminal kinase and Akt pathways in human atherosclerotic vascular smooth cells[J].Immunol Cell Biol,2006,84(5):448-454.
[33] MARTINET W,DE BIE M,SCHRIJVERS D M,et al.7-ketocholesterol induces protein ubiquitination,myelin figure formation,and light chain 3 processing in vascular smooth muscle cells[J].Arterioscter Thromb Vasc Bio1,2004,24(12):2296-2301.
[34] GRAY C B B,SUETOMI T,XIANG S,et al.CaMKIIδ subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-κB and TNF-α[J].Journal of molecular & cellular cardiology,2017,103:48-55.
[35] NARKIEWICZ K,WOLF J,LOPEZ-JIMENEZ F,et al.Obstructive sleep apnea and hypertension[J].Curr Cardiol Rep,2005,7(6):435-440.
[36] KURZ T,TERMAN A,BRUNK U T.Autophagy,ageing and apoptosis:The role of oxidative stress and lysosomal iron[J].Arch Biochem Biophys,2007,462(2):220-230.
[37] WANG G Y,BI Y G,LIU X D,et al.Upregulation of connexin 43 and apoptosis-associated protein expression by high glucose in H9c2 cells was improved by resveratrol via the autophagy signaling pathway[J].Molecular medicine reports,2017,16(3):3262-3268.
[38] SISHI B J,LOOS B,VAN ROOYEN J,et al.Autophagy upregulation promotes survival and attenuates doxorubicin-induced cardiotoxicity[J].Biochem Pharmacol,2013,85(1):124-134.
[39] SCIARRETTA S,FORTE M,FRATI G,et al.New insights into the role of mTOR signaling in the cardiovascular system[J].Circulation research,2018,122(3):489-505.
[40] MATSUI Y,TAKAGI H,QU X P,et al.Distinct roles of autophagy in the heart during ischemia and reperfusion:Roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy[ J].Circ Res,2007,100(6):914-922.
[41] YAN Y,FINKEL T.Autophagy as a regulator of cardiovascular redox homeostasis[J].Free radical biology and medicine,2017,109:108-113.
[42] WU N,ZHU Y F,XU X,et al.The anti-tumor effects of dual PI3K/mTOR inhibitor BEZ235 and histone deacetylase inhibitor Trichostatin A on inducing autophagy in esophageal squamous cell carcinoma[J].Journal of Cancer,2018,9(6):987-997.
[43] SCHULTE K L,FISCHER M,LENZ T,et al.Efficacy and tolerability of candesartan cilexetil monotherapy or in combination with other antihypertensive drugs[J].Clinical drug investigation,1999,18(6):453-460.
[44] LATIFI A,ESCALONA R M,QUINN M,et al.Distinct molecular signature of recurrent ovarian tumor cells isolated from the ascites of advanced-stage serous ovarian cancer patients[J].Journal of canncer stem cell research,2014,2(1):1-20.
[45] DENG Q,WANG Z L,WANG L,et al.Lower mRNA and protein expression levels of LC3 and Beclin1,markers of autophagy,were correlated with progression of renal clear cell carcinoma[J].Jpn J Clin Oncol,2013,43(12):1261-1268
[46] ZHONG J,GONG W Q,CHEN J,et al.Micheliolide alleviates hepatic steatosis in db/db mice by inhibiting inflammation and promoting autophagy via PPAR-γ-mediated NF-кB and AMPK/mTOR signaling[J].International immunopharmacology,2018,59:197-208.
[47] YUE Z Y,JIN S K,YANG C W,et al.Beclin 1,an autophagy gene essential for early embryonic development,is a haploinsufficient tumor suppressor[J].Proc Natl Acad Sci USA,2003,100(25):15077-15082.
[48] XIE J,LI Q,DING X,et al.Targeting mTOR by CZ415 inhibits head and neck squamous cell carcinoma cells[J].Cellular physiology & biochemistry,2018,46(2):676-686.
[49] KOREN I,REEM E,KIMCHI A.DAP1,a novel substrate of mTOR,negatively regulates autophagy[J].Curr Biol,2010,20(12):1093-1098.
[50] ROSNER M,HANNEDER M,SIEGEL N,et al.The mTOR pathway anditsrole in human genetic diseases[J].Mutat Res,2008,659(3):284-292.
[51] TERABE T,UCHIDA F,NAGAI H,et al.Expression of autophagy-related markers at the surgical margin of oral squamous cell carcinoma correlates with poor prognosis and tumor recurrence [J].Human pathology,2017,73:156-163.
[52] VAN EDEN W.Immune tolerance therapies for autoimmune diseases based on heat shock protein T-cell epitopes [J].Philosophical transactions of the royal society of London,2018,373(1738):20160531.
[53] FLORES-VALDEZ M A,SEGURA-CERDA C A,GAONA-BERNAL J.Modulation of autophagy as a strategy for development of new vaccine candidates against tuberculosis[J].Molecular immunology,2018,97:16-19.
[54] BRUN S,SCHALL N,JELTSCH-DAVID H,et al.Assessing autophagy in sciatic nerves of a rat model that develops inflammatory autoimmune peripheral neuropathies[J].Cells,2017,6(3):1-11.
[55] ZHOU Z Y,WU S Y,LI X Y,et al.Rapamycin induces autophagy and exacerbates metabolism associated complications in a mouse model of type 1 diabetes[J].Indian J Exp Biol,2010,48(1):31-38.
[56] WANG F J,LI B H,SCHALL N,et al.Assessing autophagy in mouse models and patients with systemic autoimmune diseases[J].Cells,2017,6(3):1-21.
[57] DURAES F V,NIVEN J,DUBROT J,et al.Macroautophagy in endogenous processing of self-and pathogen-derived antigens for MHC class II presentation[J].Frontiers in immunology,2015,6:1-9.
[58] KOVACS J R,LI C,YANG Q,et al.Autophagy promotes T-cell survival through degradation of proteins of the cell death machinery[J].Cell death & differentiation,2012,19(1):144-152.
[59] LAU C M,BROUGHTON C,TABOR A S,et al.RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement[J].J Exp Med,2005,202(9):1171-1177.
[60] HAN J W,ZHENG H F,CUI Y,et al.Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus[J].Nature genetics,2009,41(11):1234-1237.
[61] TAO J,DONG J,LI Y,et al.Up-regulation of cellular FLICE-inhibitory protein in peripheral blood B lymphocytes in patients with systemic lupus erythematosus is associated with clinical characteristics[J].Journal of the European academy of dermatology & venereology,2009,23(4):433-437.
[2] MIJALJICA D,PRESCOTT M,DEVENISH R J.Autophagy in disease [J].Methods Mol Biol,2010,648:79-92.
[3] ZHOU W Y,ZHAO M Y.How hippo signaling pathway modulates cardiovascular development and diseases [J].Journal of immunology research,2018,2018:3696914.
[4] LI L J,CHAI Y,GUO X J,et al.Effects of endoplasmic reticulum stress on autophagy and apoptosis of human leukemia cells via inhibition of the PI3K/AKT/mTOR signaling pathway [J].Molecular medicine reports,2018,17(6):7886-7892.
[5] SATRIANO J,SHARMA K.Autophagy and metabolic changes in obesity-related chronic kidney disease [J].Nephrol Dial Transplant,2013,28(4):29-36.
[6] FENG Y C,HE D,YAO Z Y,et al.The machinery of macroautophagy [J].Cell Res,2014,24(1):24-41.
[7] SBARDELLA D,TUNDO G R,CAMPAGNOLO L,et al.Retention of mitochondria in mature human red blood cells as the result of autophagy impairment in rett syndrome [J].Sci Rep,2017,7(1):1-12.
[8] SANDAL S,BANSAL P,CANTAROVICH M.The evidence and rationale for the perioperative use of loop diuretics during kidney transplantation:A comprehensive review [J].Transplantation reviews,2018,32(2):92-101.
[9] TANG F,WANG B,LI N,et al.RNF185,a novel mitochondrial ubiquitin E3 ligase,regulates autophagy through interaction with BNIP1[J].PLoS One,2011,6(9):1-13.
[10] DERETIC V,KLIONSKY D J.Autophagy and inflammation:A special review issue[J].Autophagy,2018,14(2):1-4.
[11] CUERVO A M.Autophagy:In sickness and in health[J].Trends Cell Biol,2004,14(2):70-77.
[12] DE SILVA FONSECA A M,DE AZEVEDO SILVA J,PANCOTTO J A T,et al.Polymorphisms in STK17A gene are associated with systemic lupus erythematosus and its clinical manifestations [J].Gene,2013,527(2):435-439.
[13] ZHOU G Y,SPRENGERS D,BOOR P P C,et al.Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating T cells in hepatocellular carcinomas [J].Gastroenterology,2017,153(4):1107-1119.
[14] LU J,LIU D Z,ZHOU X J,et al.Plant natural product plumbagin presents potent inhibitory effect on human cytochrome P450 2J2 enzyme[J].Phytomedicine,2018,39:137-145.
[15] QIU S Q,LIU J,XING F Y.‘Hints’ in the killer protein gasdermin D:Unveiling the secrets of gasdermins driving cell death[J].Cell death & differentiation,2017,24(4):588-596.
[16] MATUSZKIEWICZ M,SOBCZAK M,CABRERA J,et al.The role of programmed cell death regulator LSD1 in nematode-induced syncytium formation[J].Frontiers in plant science,2018,9:314.
[17] DECUYPERE J P,BULTYNCK G,PARYS J B.A dual role for Ca2+ in autophagy regulation[J].Cell calcium,2011,50(3):242-250.
[18] RAVEH T,DROGUETT G,HORWITZ M S,et al.DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation[J].Nat Cell Biol,2001,3(1):1-7.
[19] INBAL B,BIALIK S,SABANAY I,et al.DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death[J].J Cell Biol,2002,157(3):455-468.
[20] KROEMER G,LEVINE B.Autophagic cell death:The story of a misnomer[J].Nat Rev Mol Cell Biol,2009,9(12):1004-1010.
[21] KIM H J,CHO M H,SHIM W H,et al.Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects [J].Molecular psychiatry,2017,22(11):1576-1584.
[22] IWASAKI N,SUGIYAMA Y,MIYAZAKI S,et al.An ATF4-signal-modulating machine other than GADD34 acts in ATF4-to-CHOP signaling to block CHOP expression in ER-stress-related autophagy[J].Journal of cellular biochemistry,2015,116(7):1300-1909.
[23] RUBIO N,COUPIENNE I,DI VALENTIN E,et al.Spatiotemporal auto-phagic degradation of oxidatively damaged organelles after photody-namic stress is amplified by mitochondrial reactive oxygen species [J].Autophagy,2012,8(9):1312-1324.
[24] WANG Y F,DING W X,LI T G.Cholesterol and bile acid-mediated regulation of autophagy in fatty liver diseases and atherosclerosis[J].Biochimica et biophysica acta,2018,1863(7):726-733.
[25] OCHOA C D,WU R F,TERADA L S.ROS signaling and ER stress in cardiovascular disease[J].Molecular aspects of medicine,2018,63:18-29.
[26] DU P Z,CHANG Y W,DAI F J,et al.Role of heat shock transcription factor 1(HSF1)-upregulated macrophage in ameliorating pressure overload-induced heart failure in mice[J].Gene,2018,667:10-17.
[27] DOONAN L M,FISHER E A,BRODSKY J L.Can modulators of apolipoproteinB biogenesis serve as an alternate target for cholesterol-lowering drugs?[J].Biochimica et biophysica acta(BBA)-Molecular and cell biology of lipids,2018,863(7):762-771.
[28] HASHEMZAEI M,HERAVI R E,REZAEE R,et al.Regulation of autophagy by some natural products as a potential therapeutic strategy for cardiovascular disorders[J].European journal of pharmacology,2017,802:44-51.
[29] ZHAO K,XU X S,MENG X,et al.Autophagy of monocytes attenuates thevulnerability of coronary atherosclerotic plaques[J].Coron Artery Dis,2013,24(8):651-656.
[30] NAKAI A,YAMAGUCHI O,TAKEDA T,et al.The role of autophagy in cardiomyocytes in the basal state and in reponse to hemodynamic stress[J].Nat Med,2007,13(5):619-624.
[31] OKA T,HIKOSO S,YAMAGUCHI O,et al.Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure[J].Nature,2012,485(7397):251-255.
[32] JIA G H,CHENG G,GANGAHAR D M,et al.Insulin-like growth factor-1 and TNF-α regulate autophagy through c-jun N-terminal kinase and Akt pathways in human atherosclerotic vascular smooth cells[J].Immunol Cell Biol,2006,84(5):448-454.
[33] MARTINET W,DE BIE M,SCHRIJVERS D M,et al.7-ketocholesterol induces protein ubiquitination,myelin figure formation,and light chain 3 processing in vascular smooth muscle cells[J].Arterioscter Thromb Vasc Bio1,2004,24(12):2296-2301.
[34] GRAY C B B,SUETOMI T,XIANG S,et al.CaMKIIδ subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-κB and TNF-α[J].Journal of molecular & cellular cardiology,2017,103:48-55.
[35] NARKIEWICZ K,WOLF J,LOPEZ-JIMENEZ F,et al.Obstructive sleep apnea and hypertension[J].Curr Cardiol Rep,2005,7(6):435-440.
[36] KURZ T,TERMAN A,BRUNK U T.Autophagy,ageing and apoptosis:The role of oxidative stress and lysosomal iron[J].Arch Biochem Biophys,2007,462(2):220-230.
[37] WANG G Y,BI Y G,LIU X D,et al.Upregulation of connexin 43 and apoptosis-associated protein expression by high glucose in H9c2 cells was improved by resveratrol via the autophagy signaling pathway[J].Molecular medicine reports,2017,16(3):3262-3268.
[38] SISHI B J,LOOS B,VAN ROOYEN J,et al.Autophagy upregulation promotes survival and attenuates doxorubicin-induced cardiotoxicity[J].Biochem Pharmacol,2013,85(1):124-134.
[39] SCIARRETTA S,FORTE M,FRATI G,et al.New insights into the role of mTOR signaling in the cardiovascular system[J].Circulation research,2018,122(3):489-505.
[40] MATSUI Y,TAKAGI H,QU X P,et al.Distinct roles of autophagy in the heart during ischemia and reperfusion:Roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy[ J].Circ Res,2007,100(6):914-922.
[41] YAN Y,FINKEL T.Autophagy as a regulator of cardiovascular redox homeostasis[J].Free radical biology and medicine,2017,109:108-113.
[42] WU N,ZHU Y F,XU X,et al.The anti-tumor effects of dual PI3K/mTOR inhibitor BEZ235 and histone deacetylase inhibitor Trichostatin A on inducing autophagy in esophageal squamous cell carcinoma[J].Journal of Cancer,2018,9(6):987-997.
[43] SCHULTE K L,FISCHER M,LENZ T,et al.Efficacy and tolerability of candesartan cilexetil monotherapy or in combination with other antihypertensive drugs[J].Clinical drug investigation,1999,18(6):453-460.
[44] LATIFI A,ESCALONA R M,QUINN M,et al.Distinct molecular signature of recurrent ovarian tumor cells isolated from the ascites of advanced-stage serous ovarian cancer patients[J].Journal of canncer stem cell research,2014,2(1):1-20.
[45] DENG Q,WANG Z L,WANG L,et al.Lower mRNA and protein expression levels of LC3 and Beclin1,markers of autophagy,were correlated with progression of renal clear cell carcinoma[J].Jpn J Clin Oncol,2013,43(12):1261-1268
[46] ZHONG J,GONG W Q,CHEN J,et al.Micheliolide alleviates hepatic steatosis in db/db mice by inhibiting inflammation and promoting autophagy via PPAR-γ-mediated NF-кB and AMPK/mTOR signaling[J].International immunopharmacology,2018,59:197-208.
[47] YUE Z Y,JIN S K,YANG C W,et al.Beclin 1,an autophagy gene essential for early embryonic development,is a haploinsufficient tumor suppressor[J].Proc Natl Acad Sci USA,2003,100(25):15077-15082.
[48] XIE J,LI Q,DING X,et al.Targeting mTOR by CZ415 inhibits head and neck squamous cell carcinoma cells[J].Cellular physiology & biochemistry,2018,46(2):676-686.
[49] KOREN I,REEM E,KIMCHI A.DAP1,a novel substrate of mTOR,negatively regulates autophagy[J].Curr Biol,2010,20(12):1093-1098.
[50] ROSNER M,HANNEDER M,SIEGEL N,et al.The mTOR pathway anditsrole in human genetic diseases[J].Mutat Res,2008,659(3):284-292.
[51] TERABE T,UCHIDA F,NAGAI H,et al.Expression of autophagy-related markers at the surgical margin of oral squamous cell carcinoma correlates with poor prognosis and tumor recurrence [J].Human pathology,2017,73:156-163.
[52] VAN EDEN W.Immune tolerance therapies for autoimmune diseases based on heat shock protein T-cell epitopes [J].Philosophical transactions of the royal society of London,2018,373(1738):20160531.
[53] FLORES-VALDEZ M A,SEGURA-CERDA C A,GAONA-BERNAL J.Modulation of autophagy as a strategy for development of new vaccine candidates against tuberculosis[J].Molecular immunology,2018,97:16-19.
[54] BRUN S,SCHALL N,JELTSCH-DAVID H,et al.Assessing autophagy in sciatic nerves of a rat model that develops inflammatory autoimmune peripheral neuropathies[J].Cells,2017,6(3):1-11.
[55] ZHOU Z Y,WU S Y,LI X Y,et al.Rapamycin induces autophagy and exacerbates metabolism associated complications in a mouse model of type 1 diabetes[J].Indian J Exp Biol,2010,48(1):31-38.
[56] WANG F J,LI B H,SCHALL N,et al.Assessing autophagy in mouse models and patients with systemic autoimmune diseases[J].Cells,2017,6(3):1-21.
[57] DURAES F V,NIVEN J,DUBROT J,et al.Macroautophagy in endogenous processing of self-and pathogen-derived antigens for MHC class II presentation[J].Frontiers in immunology,2015,6:1-9.
[58] KOVACS J R,LI C,YANG Q,et al.Autophagy promotes T-cell survival through degradation of proteins of the cell death machinery[J].Cell death & differentiation,2012,19(1):144-152.
[59] LAU C M,BROUGHTON C,TABOR A S,et al.RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement[J].J Exp Med,2005,202(9):1171-1177.
[60] HAN J W,ZHENG H F,CUI Y,et al.Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus[J].Nature genetics,2009,41(11):1234-1237.
[61] TAO J,DONG J,LI Y,et al.Up-regulation of cellular FLICE-inhibitory protein in peripheral blood B lymphocytes in patients with systemic lupus erythematosus is associated with clinical characteristics[J].Journal of the European academy of dermatology & venereology,2009,23(4):433-437.