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Mechanisms of Apoptosis Induction in Pancreatic Beta Cells

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 15911

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Special Issue Editor

Prof. Dr. Jan Kovár

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Guest Editor

Department of Biochemistry, Charles University, Prague Praha, Czech Republic
Interests: signaling pathway; iron transporters; Cell proliferation; apoptosis; fatty acids

Special Issue Information

Dear Colleagues,

Increased concentrations of fatty acids in the blood and other factors are known to be responsible for pancreatic beta cell death in type 2 diabetes. The detrimental potential of fatty acids has been described for human as well as animal beta cells in vivo and in vitro. It seems that the toxicity of fatty acids could particularly depend on the degree of their saturation. It was suggested that saturated fatty acids induce apoptosis in pancreatic beta cells whereas the effect of unsaturated fatty acids is not entirely clear. It seems that unsaturated fatty acids at low concentrations are relatively tolerated and are even capable of inhibiting the proapoptotic effect of saturated fatty acids. However, the precise molecular mechanisms of apoptosis induction by fatty acids and other factors remain more or less unclear. The other factors can be represented by increased glycemia, hypoxia, pollutants, etc. The detrimental effect of discussed factors is usually associated with the activation of caspases. However, pathways leading to caspase activation by these factors are not completely clarified. It seems that endoplasmic reticulum stress could also be involved.

Prof. Jan Kovár
Guest Editor

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Keywords

mechanisms of apoptosis induction
pancreatic beta cells
fatty acids
glycemia
hypoxia
pollutants
endoplasmic reticulum stress

Published Papers (4 papers)

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Research

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23 pages, 8650 KiB

Open AccessArticle

Methylmercury Induces Mitochondria- and Endoplasmic Reticulum Stress-Dependent Pancreatic β-Cell Apoptosis via an Oxidative Stress-Mediated JNK Signaling Pathway

by Ching-Yao Yang, Shing-Hwa Liu, Chin-Chuan Su, Kai-Min Fang, Tsung-Yuan Yang, Jui-Ming Liu, Ya-Wen Chen, Kai-Chih Chang, Haw-Ling Chuang, Cheng-Tien Wu, Kuan-I Lee and Chun-Fa Huang

Int. J. Mol. Sci. 2022, 23(5), 2858; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052858 - 05 Mar 2022

Cited by 12 | Viewed by 2883

Abstract

Methylmercury (MeHg), a long-lasting organic pollutant, is known to induce cytotoxic effects in mammalian cells. Epidemiological studies have suggested that environmental exposure to MeHg is linked to the development of diabetes mellitus (DM). The exact molecular mechanism of MeHg-induced pancreatic β-cell cytotoxicity is still unclear. Here, we found that MeHg (1-4 μM) significantly decreased insulin secretion and cell viability in pancreatic β-cell-derived RIN-m5F cells. A concomitant elevation of mitochondrial-dependent apoptotic events was observed, including decreased mitochondrial membrane potential and increased proapoptotic (Bax, Bak, p53)/antiapoptotic (Bcl-2) mRNA ratio, cytochrome c release, annexin V-Cy3 binding, caspase-3 activity, and caspase-3/-7/-9 activation. Exposure of RIN-m5F cells to MeHg (2 μM) also induced protein expression of endoplasmic reticulum (ER) stress-related signaling molecules, including C/EBP homologous protein (CHOP), X-box binding protein (XBP-1), and caspase-12. Pretreatment with 4-phenylbutyric acid (4-PBA; an ER stress inhibitor) and specific siRNAs for CHOP and XBP-1 significantly inhibited their expression and caspase-3/-12 activation in MeHg-exposed RIN-mF cells. MeHg could also evoke c-Jun N-terminal kinase (JNK) activation and reactive oxygen species (ROS) generation. Antioxidant N-acetylcysteine (NAC; 1mM) or 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox; 100 μM) markedly prevented MeH-induced ROS generation and decreased cell viability in RIN-m5F cells. Furthermore, pretreatment of cells with SP600125 (JNK inhibitor; 10 μM) or NAC (1 mM) or transfection with JNK-specific siRNA obviously attenuated the MeHg-induced JNK phosphorylation, CHOP and XBP-1 protein expression, apoptotic events, and insulin secretion dysfunction. NAC significantly inhibited MeHg-activated JNK signaling, but SP600125 could not effectively reduce MeHg-induced ROS generation. Collectively, these findings demonstrate that the induction of ROS-activated JNK signaling is a crucial mechanism underlying MeHg-induced mitochondria- and ER stress-dependent apoptosis, ultimately leading to β-cell death. Full article

(This article belongs to the Special Issue Mechanisms of Apoptosis Induction in Pancreatic Beta Cells)

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16 pages, 3364 KiB

Open AccessArticle

4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene, a Major Active Metabolite of Bisphenol A, Triggers Pancreatic β-Cell Death via a JNK/AMPKα Activation-Regulated Endoplasmic Reticulum Stress-Mediated Apoptotic Pathway

by Cheng-Chin Huang, Ching-Yao Yang, Chin-Chuan Su, Kai-Min Fang, Cheng-Chieh Yen, Ching-Ting Lin, Jui-Min Liu, Kuan-I Lee, Ya-Wen Chen, Shing-Hwa Liu and Chun-Fa Huang

Int. J. Mol. Sci. 2021, 22(9), 4379; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094379 - 22 Apr 2021

Cited by 8 | Viewed by 2566

Abstract

4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), a major active metabolite of bisphenol A (BPA), is generated in the mammalian liver. Some studies have suggested that MBP exerts greater toxicity than BPA. However, the mechanism underlying MBP-induced pancreatic β-cell cytotoxicity remains largely unclear. This study demonstrated the cytotoxicity of MBP in pancreatic β-cells and elucidated the cellular mechanism involved in MBP-induced β-cell death. Our results showed that MBP exposure significantly reduced cell viability, caused insulin secretion dysfunction, and induced apoptotic events including increased caspase-3 activity and the expression of active forms of caspase-3/-7/-9 and PARP protein. In addition, MBP triggered endoplasmic reticulum (ER) stress, as indicated by the upregulation of GRP 78, CHOP, and cleaved caspase-12 proteins. Pretreatment with 4-phenylbutyric acid (4-PBA; a pharmacological inhibitor of ER stress) markedly reversed MBP-induced ER stress and apoptosis-related signals. Furthermore, exposure to MBP significantly induced the protein phosphorylation of JNK and AMP-activated protein kinase (AMPK)α. Pretreatment of β-cells with pharmacological inhibitors for JNK (SP600125) and AMPK (compound C), respectively, effectively abrogated the MBP-induced apoptosis-related signals. Both JNK and AMPK inhibitors also suppressed the MBP-induced activation of JNK and AMPKα and of each other. In conclusion, these findings suggest that MBP exposure exerts cytotoxicity on β-cells via the interdependent activation of JNK and AMPKα, which regulates the downstream apoptotic signaling pathway. Full article

(This article belongs to the Special Issue Mechanisms of Apoptosis Induction in Pancreatic Beta Cells)

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Review

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23 pages, 1108 KiB

Open AccessReview

Mechanisms of Beta-Cell Apoptosis in Type 2 Diabetes-Prone Situations and Potential Protection by GLP-1-Based Therapies

by Safia Costes, Gyslaine Bertrand and Magalie A. Ravier

Int. J. Mol. Sci. 2021, 22(10), 5303; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105303 - 18 May 2021

Cited by 28 | Viewed by 5616

Abstract

Type 2 diabetes (T2D) is characterized by chronic hyperglycemia secondary to the decline of functional beta-cells and is usually accompanied by a reduced sensitivity to insulin. Whereas altered beta-cell function plays a key role in T2D onset, a decreased beta-cell mass was also reported to contribute to the pathophysiology of this metabolic disease. The decreased beta-cell mass in T2D is, at least in part, attributed to beta-cell apoptosis that is triggered by diabetogenic situations such as amyloid deposits, lipotoxicity and glucotoxicity. In this review, we discussed the molecular mechanisms involved in pancreatic beta-cell apoptosis under such diabetes-prone situations. Finally, we considered the molecular signaling pathways recruited by glucagon-like peptide-1-based therapies to potentially protect beta-cells from death under diabetogenic situations. Full article

(This article belongs to the Special Issue Mechanisms of Apoptosis Induction in Pancreatic Beta Cells)

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31 pages, 1958 KiB

Open AccessReview

Molecular Mechanisms of Apoptosis Induction and Its Regulation by Fatty Acids in Pancreatic β-Cells

by Jan Šrámek, Vlasta Němcová-Fürstová and Jan Kovář

Int. J. Mol. Sci. 2021, 22(8), 4285; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084285 - 20 Apr 2021

Cited by 27 | Viewed by 3881

Abstract

Pancreatic β-cell failure and death contribute significantly to the pathogenesis of type 2 diabetes. One of the main factors responsible for β-cell dysfunction and subsequent cell death is chronic exposure to increased concentrations of FAs (fatty acids). The effect of FAs seems to depend particularly on the degree of their saturation. Saturated FAs induce apoptosis in pancreatic β-cells, whereas unsaturated FAs are well tolerated and are even capable of inhibiting the pro-apoptotic effect of saturated FAs. Molecular mechanisms of apoptosis induction by saturated FAs in β-cells are not completely elucidated. Saturated FAs induce ER stress, which in turn leads to activation of all ER stress pathways. When ER stress is severe or prolonged, apoptosis is induced. The main mediator seems to be the CHOP transcription factor. Via regulation of expression/activity of pro- and anti-apoptotic Bcl-2 family members, and potentially also through the increase in ROS production, CHOP switches on the mitochondrial pathway of apoptosis induction. ER stress signalling also possibly leads to autophagy signalling, which may activate caspase-8. Saturated FAs activate or inhibit various signalling pathways, i.e., p38 MAPK signalling, ERK signalling, ceramide signalling, Akt signalling and PKCδ signalling. This may lead to the activation of the mitochondrial pathway of apoptosis, as well. Particularly, the inhibition of the pro-survival Akt signalling seems to play an important role. This inhibition may be mediated by multiple pathways (e.g., ER stress signalling, PKCδ and ceramide) and could also consequence in autophagy signalling. Experimental evidence indicates the involvement of certain miRNAs in mechanisms of FA-induced β-cell apoptosis, as well. In the rather rare situations when unsaturated FAs are also shown to be pro-apoptotic, the mechanisms mediating this effect in β-cells seem to be the same as for saturated FAs. To conclude, FA-induced apoptosis rather appears to be preceded by complex cross talks of multiple signalling pathways. Some of these pathways may be regulated by decreased membrane fluidity due to saturated FA incorporation. Few data are available concerning molecular mechanisms mediating the protective effect of unsaturated FAs on the effect of saturated FAs. It seems that the main possible mechanism represents a rather inhibitory intervention into saturated FA-induced pro-apoptotic signalling than activation of some pro-survival signalling pathway(s) or metabolic interference in β-cells. This inhibitory intervention may be due to an increase of membrane fluidity. Full article

(This article belongs to the Special Issue Mechanisms of Apoptosis Induction in Pancreatic Beta Cells)

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