Astragaloside IV Ameliorates Streptozotocin Induced Pancreatic β-Cell Apoptosis and Dysfunction Through SIRT1/P53 and Akt/GSK3β/Nrf2 Signaling Pathways

Visfatin is an adipocytokine that plays an important role in attenuating insulin resistance by binding to insulin receptor. It has been suggested that visfatin plays a role in the regulation of cell apoptosis and inflammation by an as yet unidentified mechanism. This study investigated the protective effects of visfatin on palmitate-induced islet β-cell apoptosis in the clonal mouse pancreatic β-cell line MIN6. The cells were treated with palmitate and/or recombinant visfatin. An 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan assay was used to detect cell proliferation, V-FITC/propidium iodide staining was used to measure cell apoptosis and necrosis, and western blot analysis was used to detect the expression of proapoptotic proteins. The incubation of the cells with visfatin led to a concentration-dependent increase of cell proliferation (1.55-fold at 10−7 M and 24 h compared with control,P<0.05). Visfatin significantly reduced the cell apoptosis induced by palmitate and caused a significant change in the expression of several proapoptotic proteins, including upregulation of Bcl-2 and a marked downregulation of cytochromecand caspase 3. Visfatin also activated the ERK1/2 and the phosphoinositide 3-kinase (PI3K)/AKT signaling pathways in a time- and concentration-dependent manner, and the effect of visfatin on apoptosis was blocked by the specific ERK1/2 and PI3K/AKT inhibitors, PD098059 and LY294002. We conclude that visfatin can increase β-cell proliferation and prevent apoptosis, activate intracellular signaling, and regulate the expression of proapoptotic proteins. The antiapoptotic action of visfatin is mediated by activation of mitogen-activated protein kinase-dependent and PI3K-dependent signaling pathways.

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Arsenic induces pancreatic β-cell apoptosis via the oxidative stress-regulated mitochondria-dependent and endoplasmic reticulum stress-triggered signaling pathways

Toxicology Letters ◽

10.1016/j.toxlet.2010.11.019 ◽

2011 ◽

Vol 201 (1) ◽

pp. 15-26 ◽

Cited By ~ 106

Author(s):

Tien-Hui Lu ◽

Chin-Chuan Su ◽

Ya-Wen Chen ◽

Ching-Yao Yang ◽

Chin-Ching Wu ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Signaling Pathways ◽

Cell Apoptosis ◽

Pancreatic Β Cell ◽

Β Cell

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PanK4 inhibits pancreatic β-cell apoptosis by decreasing the transcriptional level of pro-caspase-9

Cell Research ◽

10.1038/cr.2007.93 ◽

2007 ◽

Vol 17 (11) ◽

pp. 966-968 ◽

Cited By ~ 4

Author(s):

Ruo Lan Xiang ◽

Yan Li Yang ◽

Jin Zuo ◽

Xin Hua Xiao ◽

Yong Sheng Chang ◽

...

Keyword(s):

Cell Apoptosis ◽

Transcriptional Level ◽

Pancreatic Β Cell ◽

Caspase 9 ◽

Β Cell

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Dexamethasone induces pancreatic β-cell apoptosis through upregulation of TRAIL death receptor

Journal of Molecular Endocrinology ◽

10.1530/jme-20-0238 ◽

2021 ◽

Author(s):

Kanchana Suksri ◽

Namoiy Semprasert ◽

Mutita Junking ◽

Suchanoot Kutpruek ◽

Thawornchai Limjindaporn ◽

...

Keyword(s):

Cell Apoptosis ◽

Molecular Mechanisms ◽

Cultured Cells ◽

Death Receptor ◽

Caspase 8 ◽

Pancreatic Β Cell ◽

Β Cell ◽

Apoptotic Protein ◽

Induced Apoptosis ◽

Trail Death Receptor

Long-term medication with dexamethasone (a synthetic glucocorticoid (GC) drug) results in hyperglycemia, or steroid-induced diabetes. Although recent studies revealed dexamethasone directly induces pancreatic β-cell apoptosis, its molecular mechanisms remain unclear. In our initial analysis of mRNA transcripts, we discovered the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway may be involved in dexamethasone-induced pancreatic β-cell apoptosis. In the present study, a mechanism of dexamethasone-induced pancreatic β-cell apoptosis through the TRAIL pathway was investigated in cultured cells and isolated mouse islets. INS-1 cells were cultured with and without dexamethasone in the presence or absence of a glucocorticoid receptor (GR) inhibitor, RU486. We found that dexamethasone induced pancreatic β-cell apoptosis in association with the upregulation of TRAIL mRNA and protein expression. Moreover, dexamethasone upregulated the TRAIL death receptor (DR5) protein but suppressed the decoy receptor (DcR1) protein. Similar findings were observed in mouse isolated islets: dexamethasone increased TRAIL and DR5 compared to that of control mice. Furthermore, dexamethasone stimulated pro-apoptotic signaling including superoxide production, caspase-8, -9, and -3 activities, NF-B, and Bax, but repressed the anti-apoptotic protein, Bcl-2. All these effects were inhibited by the GR-inhibitor, RU486. Furthermore, knock down DR5 decreased dexamethasone-induced caspase 3 activity. Caspase-8 and caspase-9 inhibitors protected pancreatic β-cells from dexamethasone-induced apoptosis. Taken together, dexamethasone induced pancreatic β-cell apoptosis by binding to the GR and inducing DR5 and TRAIL pathway.

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

Cellular Physiology and Biochemistry ◽

10.1159/000496047 ◽

2018 ◽

Vol 51 (6) ◽

pp. 2955-2971 ◽

Cited By ~ 16

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.

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AICAR and Metformin Exert AMPK-dependent Effects on INS-1E Pancreatic β-cell Apoptosis via Differential Downstream Mechanisms

International Journal of Biological Sciences ◽

10.7150/ijbs.12108 ◽

2015 ◽

Vol 11 (11) ◽

pp. 1272-1280 ◽

Cited By ~ 16

Author(s):

Yu-Lu Dai ◽

Su-Ling Huang ◽

Ying Leng

Keyword(s):

Cell Apoptosis ◽

Pancreatic Β Cell ◽

Β Cell

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00478.2007 ◽

2008 ◽

Vol 294 (3) ◽

pp. E540-E550 ◽

Cited By ~ 108

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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