Suppression of FoxO1/cell death-inducing DNA fragmentation factor α-like effector A (Cidea) axis protects mouse β-cells against palmitic acid-induced apoptosis

2012 ◽  
Vol 348 (1) ◽  
pp. 297-304 ◽  
Author(s):  
Naoki Omae ◽  
Minoru Ito ◽  
Syoko Hase ◽  
Michiaki Nagasawa ◽  
Junichi Ishiyama ◽  
...  
Keyword(s):  
Cell Death ◽  
Palmitic Acid ◽  
Dna Fragmentation ◽  
Β Cells ◽  
Induced Apoptosis ◽  
Factor Α

scholarly journals Progesterone induces apoptosis of insulin-secreting cells: insights into the molecular mechanism

2014 ◽  
Vol 221 (2) ◽  
pp. 273-284 ◽  
Author(s):  
V A Nunes ◽  
E P Portioli-Sanches ◽  
M P Rosim ◽  
M S Araujo ◽  
P Praxedes-Garcia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Dna Fragmentation ◽  
Islet Cells ◽  
Membrane Integrity ◽  
Reactive Species ◽  
Β Cells ◽  
Β Cell ◽  
Induced Apoptosis ◽  
Stress Dependent

Progesterone has been associated with the development of gestational diabetes (GD) due to the enhancement of insulin resistance. As β-cell apoptosis participates in type 1 and type 2 diabetes pathophysiology, we proposed the hypothesis that progesterone might contribute to the development of GD through a mechanism that also involves β-cell death. To address this question, RINm5F insulin-producing cells were incubated with progesterone (25–100 μM), in the presence or absence of α-tocopherol (40 μM). After 24 or 48 h, membrane integrity and DNA fragmentation were analyzed by flow cytometry. Caspase activity was used to identify the mode of cell death. The involvement of endoplasmic reticulum stress in the action of progesterone was investigated by western blotting. Oxidative stress was measured by 2',7'-dichlorofluorescein diacetate (DCFDA) oxidation. Isolated rat islets were used in similar experiments in order to confirm the effect of progesterone in primary β-cells. Incubation of RINm5F cells with progesterone increased the number of cells with loss of membrane integrity and DNA fragmentation. Progesterone induced generation of reactive species. Pre-incubation with α-tocopherol attenuated progesterone-induced apoptosis. Western blot analyses revealed increased expression of CREB2 and CHOP in progesterone-treated cells. Progesterone caused apoptotic death of rat islet cells and enhanced generation of reactive species. Our results show that progesterone can be toxic to pancreatic β-cells through an oxidative-stress-dependent mechanism that induces apoptosis. This effect may contribute to the development of GD during pregnancy, particularly under conditions that require administration of pharmacological doses of this hormone.

Redistribution of phosphatidylethanolamine and phosphatidylserine precedes reperfusion-induced apoptosis

1998 ◽  
Vol 274 (1) ◽  
pp. H242-H248 ◽  
Author(s):  
Nilanjana Maulik ◽  
Valerian E. Kagan ◽  
Vladimir A. Tyurin ◽  
Dipak K. Das
Keyword(s):  
Cell Death ◽  
Dna Fragmentation ◽  
Genomic Dna ◽  
High Performance ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Apoptotic Cell Death ◽  
Dna Laddering ◽  
Outer Leaflet ◽  
Induced Apoptosis

Although cardiomyocyte death and infarction associated with ischemia-reperfusion are traditionally believed to be induced via necrosis, recent studies implicated apoptotic cell death in ischemic reperfused tissue. To examine whether myocardial ischemic reperfusion injury is mediated by apoptotic cell death, isolated perfused rat hearts were subjected to 15 and 30 min of ischemia as well as 15 min of ischemia followed by 30, 90, or 120 min of reperfusion. At the end of each experiment, hearts were processed for the evaluation of apoptosis and DNA laddering. Apoptosis was studied by visualizing the apoptotic cardiomyocytes by direct fluorescence detection of digoxigenin-labeled genomic DNA using APOPTAG in situ apoptosis detection kit. DNA laddering was evaluated by subjecting the DNA obtained from cardiomyocytes to 1.8% agarose gel electrophoresis and photographed under ultraviolet illumination. In addition, high-performance thin-layer chromatography (HPTLC) of aminophospholipids labeled with 2,4,6-trinitrobenzenesulfonate was performed to evaluate phospholipid topography in cardiomyocytes. The results of our study revealed apoptotic cells only in the 90- and 120-min reperfused hearts as demonstrated by the intense fluorescence of the immunostained digoxigenin-labeled genomic DNA when observed under fluorescence microscope. None of the ischemic hearts showed any evidence of apoptosis. These results corroborated with the findings of DNA fragmentation that showed increased ladders of DNA bands in the 120-min reperfused hearts, representing integer multiples of the internucleosomal DNA length (∼180 bp). Two-dimensional HPTLC of the phospholipids obtained from the cardiomyocytes and transbilayer organization of the phosphatidylethanolamine (PE) and phosphatidylserine (PS) in the myocytes indicated translocation of both PE and PS from the inner leaflet to the outer leaflet of the membrane as early as after 20 min of ischemia. These results demonstrate that the redistribution of PS and PE precedes the apototic cell death and DNA fragmentation associated with the reperfusion of ischemic myocardium, suggesting that ischemia may trigger the signal for apoptosis although it becomes evident during reperfusion.

Tumor necrosis factor-α and ceramide induce cell death through different mechanisms in rat mesangial cells

1999 ◽  
Vol 276 (3) ◽  
pp. F390-F397 ◽  
Author(s):  
Yan-Lin Guo ◽  
Baobin Kang ◽  
Li-Jun Yang ◽  
John R. Williamson
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Mesangial Cells ◽  
Tnf Α ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Necrosis Factor

It has been proposed that ceramide acts as a cellular messenger to mediate tumor necrosis factor-α (TNF-α)-induced apoptosis. Based on this hypothesis, it was postulated that resistance of some cells to TNF-α cytotoxicity was due to an insufficient production of ceramide on stimulation by TNF-α. The present study was initiated to investigate whether this was the case in mesangial cells, which normally are insensitive to TNF-α-induced apoptosis. Our results indicate that although C2ceramide was toxic to mesangial cells, the cell death it induced differed both morphologically and biochemically from that induced by TNF-α in the presence of cycloheximide (CHX). The most apparent effect of C2ceramide was to cause cells to swell, followed by disruption of the cell membrane. It is evident that C2ceramide caused cell death by necrosis, whereas TNF-α in the presence of CHX killed the cells by apoptosis. C2ceramide did not mimic the effects of TNF-α on the activation of c-Jun NH2-terminal protein kinase and nuclear factor-κB transcription factor. Although mitogen-activated protein kinase [extracellular signal-related kinase (ERK)] was activated by both C2ceramide and TNF-α, such activation appeared to be mediated by different mechanisms as judged from the kinetics of ERK activation. Furthermore, the cleavage of cytosolic phospholipase A2during cell death induced by C2ceramide and by TNF-α in the presence of CHX showed distinctive patterns. The present study provides evidence that apoptosis and necrosis use distinctive signaling machinery to cause cell death.

Role of NF-κB in β-cell death

2008 ◽  
Vol 36 (3) ◽  
pp. 334-339 ◽  
Author(s):  
Danielle Melloul
Keyword(s):  
Cell Death ◽  
Lymphocytic Infiltration ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Cell Protection ◽  
Β Cells ◽  
Β Cell ◽  
Ifn Γ ◽  
Induced Apoptosis

Apoptotic β-cell death appears to be central to the pathogenesis of Type 1 diabetes mellitus and in islet graft rejection. The β-cell destruction is partially mediated by cytokines, such as IL-1β (interleukin 1β), TNFα (tumour necrosis factor α) and IFN-γ (interferon γ). IL-1β and TNFα mediate activation of the transcription factor NF-κB (nuclear factor κB) pathway. Use of a degradation-resistant NF-κB protein inhibitor (ΔNIκBα), specifically expressed in β-cells, significantly reduced IL-1β+IFN-γ-induced apoptosis. Moreover, in vivo, it protected against multiple low-dose streptozocin-induced diabetes, with reduced intra-islet lymphocytic infiltration. Thus β-cell-specific activation of NF-κB is a key event in the progressive loss of β-cells in diabetes. Inhibition of this process could be a potential effective strategy for β-cell protection.

scholarly journals Fas Induces Cytoplasmic Apoptotic Responses and Activation of the MKK7-JNK/SAPK and MKK6-p38 Pathways Independent of CPP32-like Proteases

1997 ◽  
Vol 139 (4) ◽  
pp. 1005-1015 ◽  
Author(s):  
Fumiko Toyoshima ◽  
Tetsuo Moriguchi ◽  
Eisuke Nishida
Keyword(s):  
Cell Death ◽  
Dna Fragmentation ◽  
Morphological Changes ◽  
Chromatin Condensation ◽  
Cysteine Proteases ◽  
Cellular Responses ◽  
Jurkat Cells ◽  
Mitogen Activated Protein Kinase ◽  
Fas Signaling ◽  
Induced Apoptosis

IL-1β converting enzyme (ICE) family cysteine proteases are subdivided into three groups; ICE-, CPP32-, and Ich-1–like proteases. In Fas-induced apoptosis, activation of ICE-like proteases is followed by activation of CPP32-like proteases which is thought to be essential for execution of the cell death. It was recently reported that two subfamily members of the mitogen-activated protein kinase superfamily, JNK/SAPK and p38, are activated during Fas-induced apoptosis. Here, we have shown that MKK7, but not SEK1/ MKK4, is activated by Fas as an activator for JNK/ SAPK and that MKK6 is a major activator for p38 in Fas signaling. Then, to dissect various cellular responses induced by Fas, we used several peptide inhibitors for ICE family proteases in Fas-treated Jurkat cells and KB cells. While Z-VAD-FK which inhibited almost all the Fas-induced cellular responses blocked the activation of JNK/SAPK and p38, Ac-DEVD-CHO and Z-DEVD-FK, specific inhibitors for CPP32-like proteases, which inhibited the Fas-induced chromatin condensation and DNA fragmentation did not block the activation of JNK/SAPK and p38. Interestingly, these DEVD-type inhibitors did not block the Fas-induced morphological changes (cell shrinkage and surface blebbing), induction of Apo2.7 antigen, or the cell death (as assessed by the dye exclusion ability). These results suggest that the Fas-induced activation of the JNK/SAPK and p38 signaling pathways does not require CPP32-like proteases and that CPP32-like proteases, although essential for apoptotic nuclear events (such as chromatin condensation and DNA fragmentation), are not required for other apoptotic events in the cytoplasm or the cell death itself. Thus, the Fas signaling pathway diverges into multiple, separate processes, each of which may be responsible for part of the apoptotic cellular responses.

scholarly journals JNK1/2 regulates ER–mitochondrial Ca2+ cross-talk during IL-1β–mediated cell death in RINm5F and human primary β-cells

2013 ◽  
Vol 24 (12) ◽  
pp. 2058-2071 ◽  
Author(s):  
Gaurav Verma ◽  
Himanshi Bhatia ◽  
Malabika Datta
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Mitochondrial Permeability Transition ◽  
Apoptotic Cell ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Β Cells ◽  
Mediating Role ◽  
Induced Apoptosis

Elevated interleukin-1β (IL-1β) induces apoptosis in pancreatic β-cells through endoplasmic reticulum (ER) stress induction and subsequent c-jun-N-terminal kinase 1/2 (JNK1/2) activation. In earlier work we showed that JNK1/2 activation is initiated before ER stress and apoptotic induction in response to IL-1β. However, the detailed regulatory mechanisms are not completely understood. Because the ER is the organelle responsible for Ca2+ handling and storage, here we examine the effects of IL-1β on cellular Ca2+ movement and mitochondrial dysfunction and evaluate the role of JNK1/2. Our results show that in RINm5F cells and human primary β-cells, IL-1β alters mitochondrial membrane potential, mitochondrial permeability transition pore opening, ATP content, and reactive oxygen species production and these alterations are preceded by ER Ca2+ release via IP3R channels and mitochondrial Ca2+ uptake. All these events are prevented by JNK1/2 small interfering RNA (siRNA), indicating the mediating role of JNK1/2 in IL-1β–induced cellular alteration. This is accompanied by IL-1β–induced apoptosis, which is prevented by JNK1/2 siRNA and the IP3R inhibitor xestospongin C. This suggests a regulatory role of JNK1/2 in modulating the ER-mitochondrial-Ca2+ axis by IL-1β in apoptotic cell death.

scholarly journals Heat shock-induced apoptosis in germ line cells of Triatoma infestans Klug

2000 ◽  
Vol 23 (2) ◽  
pp. 301-304 ◽  
Author(s):  
Maria Luiza S. Mello ◽  
Sílvya S. Maria ◽  
Maria Cristina H. Tavares
Keyword(s):  
Cell Death ◽  
Heat Shock ◽  
Dna Fragmentation ◽  
Cellular Differentiation ◽  
Germ Line ◽  
Triatoma Infestans ◽  
Sperm Cells ◽  
Immunocytochemical Assay ◽  
Induced Apoptosis ◽  
Shock Exposure

The survival of Triatoma infestans and of somatic cells from this species is affected by heat shock. In this study, we examined the cell death responses of male germ line cells from 5th instar nymphs 7 and 30 days after heat shock exposure (40ºC, 1 h). The preparations were stained by the Feulgen reaction and the TUNEL immunocytochemical assay. Apoptosis was elicited by heat shock, with positive TUNEL responses in spermatogonial chromatin and chromosomes, spermatids and sperm cells. Spermatogonia were most affected seven days after the shock whereas some spermatids and sperm cells exhibited DNA fragmentation only thirty days after heat shock. The rate of cell death varied among the cells. In some cases, cellular differentiation was unaffected by heat shock, with DNA fragmentation occurring towards the end of spermatogenesis.

Hypersensitivity of mtDNA-depleted cells to staurosporine-induced apoptosis: roles of Bcl-2 downregulation and cathepsin B

2011 ◽  
Vol 300 (5) ◽  
pp. C1090-C1106 ◽  
Author(s):  
Guillaume Rommelaere ◽  
Sébastien Michel ◽  
Ludovic Mercy ◽  
Antoine Fattaccioli ◽  
Catherine Demazy ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
B Cell ◽  
Dna Fragmentation ◽  
Cathepsin B ◽  
Caspase 3 ◽  
B Cell Lymphoma ◽  
Parental Cell Line ◽  
Induced Apoptosis ◽  
Parp 1

We show that mitochondrial DNA (mtDNA)-depleted 143B cells are hypersensitive to staurosporine-induced cell death as evidenced by a more pronounced DNA fragmentation, a stronger activation of caspase-3, an enhanced poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, and a more dramatic cytosolic release of cytochrome c. We also show that B-cell CLL/lymphoma-2 (Bcl-2), B-cell lymphoma extra large (Bcl-XL), and myeloid cell leukemia-1 (Mcl-1) are constitutively less abundant in mtDNA-depleted cells, that the inhibition of Bcl-2 and Bcl-XL can sensitize the parental cell line to staurosporine-induced apoptosis, and that overexpression of Bcl-2 or Bcl-XL can prevent the activation of caspase-3 in ρ0143B cells treated with staurosporine. Moreover, the inactivation of cathepsin B with CA074-Me significantly reduced cytochrome c release, caspase-3 activation, PARP-1 cleavage, and DNA fragmentation in mtDNA-depleted cells, whereas the pan-caspase inhibitor failed to completely prevent PARP-1 cleavage and DNA fragmentation in these cells, suggesting that caspase-independent mechanisms are responsible for cell death even if caspases are activated. Finally, we show that cathepsin B is released in the cytosol of ρ0 cells in response to staurosporine, suggesting that the absence of mitochondrial activity leads to a facilitated permeabilization of lysosomal membranes in response to staurosporine.

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