甘露糖抑制内质网应激促进胰岛β细胞存活
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摘要
目的 1型糖尿病(type 1 diabetes,T1D)是由于胰岛β细胞受自身免疫系统的破坏,而导致胰岛素缺乏和血糖升高的一种自身免疫性疾病,胰岛β细胞内质网应激(endoplasmic reticulum stress,ERS)是其发病的重要因素。甘露糖是一种葡萄糖的差向异构体,新近发现其具有减缓甚至阻断T1D进展的作用,但具体机制仍待进一步阐明。方法通过ERS诱导剂(TG/TM)处理NIT-1细胞,荧光定量PCR检测内质网应激标志物mRNA表达水平,CCK-8法检测细胞生存活力,台盼蓝法鉴定细胞生死状态。结果给予适宜浓度的甘露糖预处理,可改善ERS诱导剂引起的胰岛β细胞系(NIT-1)细胞活力下降并逆转ERS诱导剂引发的BiP、ATF4及CHOP mRNA水平升高。结论甘露糖可抑制NIT-1细胞的过度ERS,进而减少凋亡,促进存活,为甘露糖用于治疗T1D提供了新的理论依据。
Type 1 diabetes(T1D) results from the autoimmune destruction of pancreatic β cells, leading to insulin deficiency and hyperglycemia. Endoplasmic reticulum stress(ERS) in β cells plays an important role in the initiation and progression of T1D. It has been found that mannose, an epimer of glucose, could improve the outcome of T1D. However, the mechanism is still unknown. Here, we used an in vitro culture system and found that the treatment of mannose with appropriate concentration improved the decreased viability of β cell line(NIT-1) induced by ERS inducer, and reversed the upregulation of the expression levels of ERS markers such as BiP, ATF4 and cells, thereby reducing apoptosis and promoting survival of β-cells, providing a new theoretical basis for the treatment of T1D.
Type 1 diabetes(T1D) results from the autoimmune destruction of pancreatic β cells, leading to insulin deficiency and hyperglycemia. Endoplasmic reticulum stress(ERS) in β cells plays an important role in the initiation and progression of T1D. It has been found that mannose, an epimer of glucose, could improve the outcome of T1D. However, the mechanism is still unknown. Here, we used an in vitro culture system and found that the treatment of mannose with appropriate concentration improved the decreased viability of β cell line(NIT-1) induced by ERS inducer, and reversed the upregulation of the expression levels of ERS markers such as BiP, ATF4 and cells, thereby reducing apoptosis and promoting survival of β-cells, providing a new theoretical basis for the treatment of T1D.
引文
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[14]Gotoh T,Terada K,Oyadomari S,et al.hsp70-DnaJchaperone pair prevents nitric oxide-and CHOP-induced apoptosis by inhibiting translocation of Bax to mitochondria[J].Cell Death Differ,2004,11(4):390-402.
[15]Julien D,Yannick S,Laetitia F,et al.Crosstalk between neutrophils,B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes[J].Nat Med,2013,19(1):65-73.
[16]Tersey SA,Yurika N,Templin AT,et al.Isletβ-cell endoplasmic reticulum stress precedes the onset of type 1diabetes in the nonobese diabetic mouse model[J].Diabetes,2012,61(4):818-827.
[2]Cao SS,Luo KL,Shi L.Endoplasmic reticulum stress interacts with inflammation in human diseases[J].J Cell Physiol,2015,231(2):288-294.
[3]Brinkworth JF,Barreiro LB.Current opinion in immunology[J].Curr Opin Immunol,2009,31(31):66-78.
[4]张梦军,韩清娟,陈晓玲,等.NOD小鼠人源化后CD4+Tregs和CD8+Tregs频率和功能变化及意义[J].免疫学杂志,2018,34(1):19-26.
[5]Wu J,Kaufman RJ.From acute ER stress to physiological roles of the Unfolded Protein Response[J].Cell Death Differ,2006,13(3):374-384.
[6]Eizirik DL,Cardozo AK,Cnop M.The role for endoplasmic reticulum stress in diabetes mellitus[J].Endocr Rev,2008,29(1):42-61.
[7]Engin F,Yermalovich A,Nguyen T,et al.Restoration of the unfolded protein response in pancreaticβcells protects mice against type 1 diabetes[J].Sci Transl Med,2013,5(211):211ra156.
[8]Zhang D,Chia C,Xue J,et al.D-mannose induces regulatory T cells and suppresses immunopathology[J].Nat Med,2017,23(9):1036-1045.
[9]Schneider A,Thiel C,Rindermann J,et al.Successful prenatal mannose treatment for congenital disorder of glycosylation-Ia in mice[J].Nat Med,2011,18(1):71-73.
[10]Schweizer A,Stahl PD,Rohrer J.A di-aromatic motif in the cytosolic tail of the mannose receptor mediates endosomal sorting[J].J Biological Chem,2000,275(38):29694-29700.
[11]Bertolotti A,Zhang Y,Hendershot LM,et al.Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response[J].Nat Cell Biol,2000,2(6):326-332.
[12]Shen J,Chen X,Hendershot L,et al.ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of golgi localization signals[J].Dev Cell,2002,3(1):99-111.
[13]Harding HP,Novoa I,Zhang Y,et al.Regulated translation initiation controls stress-induced gene expression in mammalian cells[J].Mol Cell,2000,6(5):1099-1108.
[14]Gotoh T,Terada K,Oyadomari S,et al.hsp70-DnaJchaperone pair prevents nitric oxide-and CHOP-induced apoptosis by inhibiting translocation of Bax to mitochondria[J].Cell Death Differ,2004,11(4):390-402.
[15]Julien D,Yannick S,Laetitia F,et al.Crosstalk between neutrophils,B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes[J].Nat Med,2013,19(1):65-73.
[16]Tersey SA,Yurika N,Templin AT,et al.Isletβ-cell endoplasmic reticulum stress precedes the onset of type 1diabetes in the nonobese diabetic mouse model[J].Diabetes,2012,61(4):818-827.