2130-P: Imeglimin Modulated ER Stress to Prevent ß-Cell Apoptosis Induced by High Glucose or Thapsigargin

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 2130-P ◽  
Author(s):  
JINGHE LI ◽  
JUN SHIRAKAWA ◽  
YU TOGASHI ◽  
YASUO TERAUCHI
Keyword(s):  
Er Stress ◽  
High Glucose ◽  
Cell Apoptosis

NGF Attenuates High Glucose-Induced ER Stress, Preventing Schwann Cell Apoptosis by Activating the PI3K/Akt/GSK3β and ERK1/2 Pathways

2017 ◽  
Vol 42 (11) ◽  
pp. 3005-3018 ◽  
Author(s):  
Rui Li ◽  
Yanqing Wu ◽  
Shuang Zou ◽  
Xiaofang Wang ◽  
Yiyang Li ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Er Stress ◽  
High Glucose ◽  
Cell Apoptosis

scholarly journals Par-4/NF-κB Mediates the Apoptosis of IsletβCells Induced by Glucolipotoxicity

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Wu QiNan ◽  
Gan XiaGuang ◽  
Lei XiaoTian ◽  
Deng WuQuan ◽  
Zhang Ling ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
High Glucose ◽  
Cell Apoptosis ◽  
Mitochondrial Pathway ◽  
Induced Apoptosis

Apoptosis of isletβcells is a primary pathogenic feature of type 2 diabetes, and ER stress and mitochondrial dysfunction play important roles in this process. Previous research has shown that prostate apoptosis response-4 (Par-4)/NF-κB induces cancer cell apoptosis through endoplasmic reticulum (ER) stress and mitochondrial dysfunction. However, the mechanism by which Par-4/NF-κB induces isletβcell apoptosis remains unknown. We used a high glucose/palmitate intervention to mimic type 2 diabetes in vitro. We demonstrated that the high glucose/palmitate intervention induced the expression and secretion of Par-4. It also causes increased expression and activation of NF-κB, which induced NIT-1 cell apoptosis and dysfunction. Overexpression of Par-4 potentiates these effects, whereas downregulation of Par-4 attenuates them. Inhibition of NF-κB inhibited the Par-4-induced apoptosis. Furthermore, these effects occurred through the ER stress cell membrane and mitochondrial pathway of apoptosis. Our findings reveal a novel role for Par-4/NF-κB in isletβcell apoptosis and type 2 diabetes.

scholarly journals High-glucose environment accelerates annulus fibrosus cell apoptosis by regulating endoplasmic reticulum stress

2020 ◽  
Vol 40 (7) ◽  
Author(s):  
Lianglong Pang ◽  
Keshi Yang ◽  
Zhi Zhang
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Expression ◽  
Er Stress ◽  
Disc Degeneration ◽  
High Glucose ◽  
Cell Apoptosis ◽  
Annulus Fibrosus ◽  
Culture Medium ◽  
Caspase 3 ◽  
Apoptosis Ratio

Abstract Diabetes mellitus (DM) is an important risk factor of intervertebral disc degeneration. However, how DM affects annulus fibrosus (AF) biology remains unclear. The present study was aimed to investigate the effects and mechanism of high glucose on AF cell biology. Rat AF cells were cultured in baseline medium and culture medium with 0.2 M glucose. The inhibitor 4-PBA was added along with the high glucose culture medium to study the role of endoplasmic reticulum (ER) stress in this process. Compared with the control cells, high glucose significantly increased cell apoptosis ratio and caspase-3/9 activity, up-regulated mRNA/protein expression of Bax and caspase-3/cleaved caspase-3, but down-regulated mRNA/protein expression of Bcl-2. Moreover, high glucose increased mRNA and protein expression of CHOP, ATF-6 and GRP78. However, once ER stress was inhibited by the inhibitor 4-PBA in the high glucose group, cell apoptosis ratio and caspase-3/9 activity were decreased, mRNA/protein expression of Bax and caspase-3/cleaved caspase-3 was down-regulated, but mRNA/protein expression of Bcl-2 was up-regulated. In conclusion, high glucose condition can promote AF cell apoptosis through inducing ER stress. The present study helps us understand the mechanism of disc degeneration in DM patients.

GDF15 Is Induced by T1D-Associated Cytokines and ER Stress and Promotes Beta-Cell Apoptosis

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 2109-P ◽  
Author(s):  
GUANLAN XU ◽  
LANCE THIELEN ◽  
JUNQIN CHEN ◽  
SEONGHO JO ◽  
ANATH SHALEV
Keyword(s):  
Beta Cell ◽  
Er Stress ◽  
Cell Apoptosis ◽  
Beta Cell Apoptosis

Ufmylation regulates granulosa cell apoptosis via ER stress but not oxidative stress during goat follicular atresia

2021 ◽  
Vol 169 ◽  
pp. 47-55
Author(s):  
Xinyan Zhang ◽  
Tong Yu ◽  
Xinyan Guo ◽  
Ruixue Zhang ◽  
Yanni Jia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Er Stress ◽  
Granulosa Cell ◽  
Cell Apoptosis ◽  
Follicular Atresia

scholarly journals High Glucose Induces Mesangial Cell Apoptosis through miR-15b-5p and Promotes Diabetic Nephropathy by Extracellular Vesicle Delivery

2020 ◽  
Vol 28 (3) ◽  
pp. 963-974 ◽  
Author(s):  
Yi-Chun Tsai ◽  
Mei-Chuan Kuo ◽  
Wei-Wen Hung ◽  
Ling-Yu Wu ◽  
Ping-Hsun Wu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Cell Apoptosis ◽  
Mesangial Cell ◽  
Extracellular Vesicle

Abstract 276: SR-BI Suppresses Apoptosis by Reducing Endoplasmic Reticulum Stress and Promoting Akt Activity in Macrophages

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Huan Tao ◽  
Patricia G Yancey ◽  
Sean S Davies ◽  
L Jackson Roberts ◽  
John L Blakemore ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Apolipoprotein E ◽  
Er Stress ◽  
Cell Apoptosis ◽  
Free Cholesterol ◽  
Oxidized Ldl ◽  
Tunel Staining ◽  
Type I ◽  
Apoptotic Cells ◽  
Atherosclerotic Lesions

Objective: Macrophage apoptosis contributes to atherosclerotic plaque necrosis, inflammation, development and rupture. Scavenger receptor class B type I (SR-BI) is a key regulator of HDL metabolism and cellular cholesterol homeostasis. Here we examined the hypothesis that macrophage SR-BI modulates lipid-associated cellular stress and apoptosis. Methods and Results: In vitro cell apoptosis assays were performed in primary macrophages, and for in vivo evidence, we examined TUNEL staining of atherosclerotic lesions of LDLR -/- mice that were reconstituted with SR-BI -/- or WT bone marrow after 16 weeks on a Western diet. We found that SR-BI deficiency led to ~64.3% more apoptotic cells induced by oxidized LDL or free cholesterol in primary macrophages, and 6-fold more lesional apoptotic cells in SR-BI -/- →LDLR -/- mice compared to WT recipient mice. In macrophages, SR-BI deficiency caused significant accumulations of cellular free cholesterol and elevated markers of endoplasmic reticulum (ER) stress. These were exacerbated by feeding mice a high-cholesterol diet or inactivating the apolipoprotein E gene. Peroxidation of lipoproteins and cell membranes leads to modification of phosphatidylethanolamine by lipid aldehydes including isolevuglandins (IsoLG-PE). Treatment of macrophages with IsoLG-PE induced 52.6% more apoptotic cells in SR-BI -/- macrophages compared to WT. Transgenic expression of SR-BI by transfection of SR-BI -/- macrophages rescued oxidative stress-induced ER stress and cell apoptosis. SR-BI deficiency inhibited the Akt pathway compromising macrophage survival and increasing lesion necrosis. Moreover, Akt Activator was able to rescue SR-BI deficiency associated apoptosis in macrophages. Apolipoprotein E interacts with SR-BI in macrophages, co-operating for cellular lipid homeostasis and cell survival signaling. Conclusion: SR-BI protects against cell apoptosis induced by lipid stress in macrophages and atherosclerotic lesions. The underlying mechanisms are, at least in part, through reducing lipid-associated ER stress and promoting Akt activity in macrophages. Thus, we identify macrophage SR-BI-mediated apoptosis pathways as molecular targets for the prevention of atherosclerotic cardiovascular events.

scholarly journals Intermittent-Hypoxia-Induced Autophagy Activation Through the ER-Stress-Related PERK/eIF2α/ATF4 Pathway is a Protective Response to Pancreatic β-Cell Apoptosis

2018 ◽  
Vol 51 (6) ◽  
pp. 2955-2971 ◽  
Author(s):  
Shuling Song ◽  
Jin Tan ◽  
Yuyang Miao ◽  
Zuoming Sun ◽  
Qiang  Zhang
Keyword(s):  
Er Stress ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Intermittent Hypoxia ◽  
Autophagic Vacuole ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Protective Response

Background/Aims: Intermittent hypoxia (IH) causes apoptosis in pancreatic β-cells, but the potential mechanisms remain unclear. Endoplasmic reticulum (ER) stress, autophagy, and apoptosis are interlocked in an extensive crosstalk. Thus, this study aimed to investigate the contributions of ER stress and autophagy to IH-induced pancreatic β-cell apoptosis. Methods: We established animal and cell models of IH, and then inhibited autophagy and ER stress by pharmacology and small interfering RNA (siRNA) in INS-1 cells and rats. The levels of biomarkers for autophagy, ER stress, and apoptosis were evaluated by immunoblotting and immunofluorescence. The number of autophagic vacuoles was observed by transmission electron microscopy. Results: IH induced autophagy activation both in vivo and in vitro, as evidenced by increased autophagic vacuole formation and LC3 turnover, and decreased SQSTM1 level. The levels of ER-stress-related proteins, including GRP78, CHOP, caspase 12, phosphorylated (p)-protein kinase RNA-like ER kinase (PERK), p-eIF2α, and activating transcription factor 4 (ATF4) were increased under IH conditions. Inhibition of ER stress with tauroursodeoxycholic acid or 4-phenylbutyrate partially blocked IH-induced autophagy in INS-1 cells. Furthermore, inhibition of PERK with GSK2606414 or siRNA blocked the ERstress-related PERK/eIF2α/ATF4 signaling pathway and inhibited autophagy induced by IH, which indicates that IH-induced autophagy activation is dependent on this signaling pathway. Promoting autophagy with rapamycin alleviated IH-induced apoptosis, whereas inhibition of autophagy with chloroquine or autophagy-related gene (Atg5 and Atg7) siRNA aggravated pancreatic β-cell apoptosis caused by IH. Conclusion: IH induces autophagy activation through the ER-stress-related PERK/eIF2α/ATF4 signaling pathway, which is a protective response to pancreatic β-cell apoptosis caused by IH.

Differential activation of ER stress and apoptosis in response to chronically elevated free fatty acids in pancreatic β-cells

2008 ◽  
Vol 294 (3) ◽  
pp. E540-E550 ◽  
Author(s):  
Elida Lai ◽  
George Bikopoulos ◽  
Michael B. Wheeler ◽  
Maria Rozakis-Adcock ◽  
Allen Volchuk
Keyword(s):  
Er Stress ◽  
Cell Lines ◽  
Cell Apoptosis ◽  
Human Islets ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Min6 Cells ◽  
Relative Contribution ◽  
Induced Apoptosis

Chronic exposure to elevated saturated free fatty acid (FFA) levels has been shown to induce endoplasmic reticulum (ER) stress that may contribute to promoting pancreatic β-cell apoptosis. Here, we compared the effects of FFAs on apoptosis and ER stress in human islets and two pancreatic β-cell lines, rat INS-1 and mouse MIN6 cells. Isolated human islets cultured in vitro underwent apoptosis, and markers of ER stress pathways were elevated by chronic palmitate exposure. Palmitate also induced apoptosis in MIN6 and INS-1 cells, although the former were more resistant to both apoptosis and ER stress. MIN6 cells were found to express significantly higher levels of ER chaperone proteins than INS-1 cells, which likely accounts for the ER stress resistance. We attempted to determine the relative contribution that ER stress plays in palmitate-induced β-cell apoptosis. Although overexpressing GRP78 in INS-1 cells partially reduced susceptibility to thapsigargin, this failed to reduce palmitate-induced ER stress or apoptosis. In INS-1 cells, palmitate induced apoptosis at concentrations that did not result in significant ER stress. Finally, MIN6 cells depleted of GRP78 were more susceptible to tunicamycin-induced apoptosis but not to palmitate-induced apoptosis compared with control cells. These results suggest that ER stress is likely not the main mechanism involved in palmitate-induced apoptosis in β-cell lines. Human islets and MIN6 cells were found to express high levels of stearoyl-CoA desaturase-1 compared with INS-1 cells, which may account for the decreased susceptibility of these cells to the cytotoxic effects of palmitate.

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