Fermented soybeans, Chungkookjang, prevent hippocampal cell death and β-cell apoptosis by decreasing pro-inflammatory cytokines in gerbils with transient artery occlusion

Unfolded protein response (UPR)-mediated pancreatic β-cell death has been described as a common mechanism by which palmitate (PA) and pro-inflammatory cytokines contribute to the development of diabetes. There are evidences that interleukin 6 (IL6) has a protective action against β-cell death induced by pro-inflammatory cytokines; the effects of IL6 on PA-induced apoptosis have not been investigated yet. In the present study, we have demonstrated that PA selectively disrupts IL6-induced RAC-alpha serine/threonine-protein kinase (AKT) activation without interfering with signal transducer and activator of transcription 3 phosphorylation in RINm5F cells. The inability of IL6 to activate AKT in the presence of PA correlated with an inefficient protection against PA-induced apoptosis. In contrast to PA, IL6 efficiently reduced apoptosis induced by pro-inflammatory cytokines. In addition, we have demonstrated that IL6 is unable to overcome PA-stimulated UPR, as assessed by activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) expression, X-box binding protein-1 gene mRNA splicing, and pancreatic eukaryotic initiation factor-2α kinase phosphorylation, whereas no significant induction of UPR by pro-inflammatory cytokines was detected. This unconditional stimulation of UPR and apoptosis by PA was accompanied by the stimulation of CHOP and tribble3 (TRIB3) expression, irrespective of the presence of IL6. These findings suggest that IL6 is unable to protect pancreatic β-cells from PA-induced apoptosis because it does not repress UPR activation. In this way, CHOP and ATF4 might mediate PA-induced TRIB3 expression and, by extension, the suppression of IL6 activation of pro-survival kinase AKT.

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Dysfunctional autophagy following exposure to pro-inflammatory cytokines contributes to pancreatic β-cell apoptosis

Cell Death and Disease ◽

10.1038/s41419-017-0121-5 ◽

2018 ◽

Vol 9 (2) ◽

Cited By ~ 17

Author(s):

Martine Lambelet ◽

Leticia F. Terra ◽

Makiko Fukaya ◽

Kira Meyerovich ◽

Leticia Labriola ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Cell Apoptosis ◽

Pancreatic Β Cell ◽

Β Cell ◽

Pro Inflammatory Cytokines

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Long-chain Saturated Fatty Acid Species Are Not Toxic to Human Pancreatic Β-cells and May Offer Protection Against Pro-inflammatory Cytokine Induced β-cell Death

10.21203/rs.3.rs-96004/v1 ◽

2020 ◽

Author(s):

Patricia Thomas ◽

Kaiyven A Leslie ◽

Hannah J Welters ◽

Noel G Morgan

Keyword(s):

Fatty Acids ◽

Cell Death ◽

Chain Length ◽

Inflammatory Cytokines ◽

Chronic Exposure ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Long Chain ◽

Pro Inflammatory Cytokines

Abstract Obesity is a major risk factor for type 2 diabetes (T2D) although the causal links remain unclear. A feature shared by both conditions however is systemic inflammation and raised levels of circulating fatty acids (FFA). It is widely believed that in obese individuals genetically prone to T2D, elevated levels of plasma FFA may contribute towards the death and dysfunction of insulin-producing pancreatic β-cells in a process of (gluco)lipotoxicity. In support of this, in vitro studies have shown consistently that long-chain saturated fatty acids (LC-SFA) are toxic to rodent β-cells during chronic exposure (>24h). Conversely, shorter chain SFA and unsaturated species are well tolerated, suggesting that toxicity is dependent on carbon chain length and/or double bond configuration. Despite the wealth of evidence implicating lipotoxicity as a means of β-cell death in rodents, the evidence that a similar process occurs in humans is much less substantial. Therefore, the present study has evaluated the effects of chronic exposure to fatty acids of varying chain length and degree of saturation, on the viability of human β-cells in culture. We have also studied the effects of a combination of fatty acids and pro-inflammatory cytokines. Strikingly, we find that LC-FFA do not readily promote the demise of human β-cells and that they may even offer a measure of protection against the toxic effects of pro-inflammatory cytokines. Therefore, these findings imply that a model in which elevated circulating LC-FFA play a direct role in mediating β-cell dysfunction and death in humans, may be overly simplistic.

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Mcl-1 downregulation by pro-inflammatory cytokines and palmitate is an early event contributing to β-cell apoptosis

Cell Death and Differentiation ◽

10.1038/cdd.2010.105 ◽

2010 ◽

Vol 18 (2) ◽

pp. 328-337 ◽

Cited By ~ 83

Author(s):

F Allagnat ◽

D Cunha ◽

F Moore ◽

J M Vanderwinden ◽

D L Eizirik ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Cell Apoptosis ◽

Early Event ◽

Β Cell ◽

Pro Inflammatory Cytokines

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Long-chain saturated fatty acid species are not toxic to human pancreatic β-cells and may offer protection against pro-inflammatory cytokine induced β-cell death

Nutrition & Metabolism ◽

10.1186/s12986-021-00541-8 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Patricia Thomas ◽

Kaiyven A. Leslie ◽

Hannah J. Welters ◽

Noel G. Morgan

Keyword(s):

Fatty Acids ◽

Cell Death ◽

Chain Length ◽

Inflammatory Cytokines ◽

Chronic Exposure ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Long Chain ◽

Pro Inflammatory Cytokines

AbstractObesity is a major risk factor for type 2 diabetes (T2D) although the causal links remain unclear. A feature shared by both conditions however is systemic inflammation and raised levels of circulating fatty acids (FFA). It is widely believed that in obese individuals genetically prone to T2D, elevated levels of plasma FFA may contribute towards the death and dysfunction of insulin-producing pancreatic β-cells in a process of (gluco)lipotoxicity. In support of this, in vitro studies have shown consistently that long-chain saturated fatty acids (LC-SFA) are toxic to rodent β-cells during chronic exposure (> 24 h). Conversely, shorter chain SFA and unsaturated species are well tolerated, suggesting that toxicity is dependent on carbon chain length and/or double bond configuration. Despite the wealth of evidence implicating lipotoxicity as a means of β-cell death in rodents, the evidence that a similar process occurs in humans is much less substantial. Therefore, the present study has evaluated the effects of chronic exposure to fatty acids of varying chain length and degree of saturation, on the viability of human β-cells in culture. We have also studied the effects of a combination of fatty acids and pro-inflammatory cytokines. Strikingly, we find that LC-FFA do not readily promote the demise of human β-cells and that they may even offer a measure of protection against the toxic effects of pro-inflammatory cytokines. Therefore, these findings imply that a model in which elevated circulating LC-FFA play a direct role in mediating β-cell dysfunction and death in humans, may be overly simplistic.

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Deficiency of VCP-Interacting Membrane Selenoprotein (VIMP) Leads to G1 Cell Cycle Arrest and Cell Death in MIN6 Insulinoma Cells

Cellular Physiology and Biochemistry ◽

10.1159/000495865 ◽

2018 ◽

Vol 51 (5) ◽

pp. 2185-2197 ◽

Cited By ~ 1

Author(s):

Lili Men ◽

Juan Sun ◽

Decheng Ren

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Insulin Secretion ◽

Cell Apoptosis ◽

Β Cells ◽

Β Cell ◽

Cycle Arrest ◽

G1 Cell Cycle Arrest ◽

Insulinoma Cells

Background/Aims: VCP-interacting membrane selenoprotein (VIMP), an ER resident selenoprotein, is highly expressed in β-cells, however, the role of VIMP in β-cells has not been characterized. In this study, we studied the relationship between VIMP deficiency and β-cell survival in MIN6 insulinoma cells. Methods: To determine the role of VIMP in β-cells, lentiviral VIMP shRNAs were used to knock down (KD) expression of VIMP in MIN6 cells. Cell death was quantified by propidium iodide (PI) staining followed by flow cytometric analyses using a FACS Caliber and FlowJo software. Cell apoptosis and proliferation were determined by TUNEL assay and Ki67 staining, respectively. Cell cycle was analyzed after PI staining. Results: The results show that 1) VIMP suppression induces β-cell apoptosis, which is associated with a decrease in Bcl-xL, and the β-cell apoptosis induced by VIMP suppression can be inhibited by overexpression of Bcl-xL; 2) VIMP knockdown (KD) decreases cell proliferation and G1 cell cycle arrest by accumulating p27 and decreasing E2F1; 3) VIMP KD suppresses unfolded protein response (UPR) activation by regulating the IRE1α and PERK pathways; 4) VIMP KD increases insulin secretion. Conclusion: These results suggest that VIMP may function as a novel regulator to modulate β-cell survival, proliferation, cell cycle, UPR and insulin secretion in MIN6 cells.

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Treatment with ferulic acid to rats with streptozotocin-induced diabetes: effects on oxidative stress, pro-inflammatory cytokines, and apoptosis in the pancreatic β cell

Endocrine ◽

10.1007/s12020-012-9868-8 ◽

2013 ◽

Vol 44 (2) ◽

pp. 369-379 ◽

Cited By ~ 63

Author(s):

Souvik Roy ◽

Satyajit Kumar Metya ◽

Santanu Sannigrahi ◽

Noorjaman Rahaman ◽

Faiqa Ahmed

Keyword(s):

Oxidative Stress ◽

Ferulic Acid ◽

Inflammatory Cytokines ◽

Pancreatic Β Cell ◽

Β Cell ◽

Streptozotocin Induced Diabetes ◽

Pro Inflammatory Cytokines

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Retinal ganglion cell death is induced by microglia derived pro-inflammatory cytokines in the hypoxic neonatal retina

The Journal of Pathology ◽

10.1002/path.2858 ◽

2011 ◽

Vol 224 (2) ◽

pp. 245-260 ◽

Cited By ~ 73

Author(s):

Viswanathan Sivakumar ◽

Wallace S Foulds ◽

Chi D Luu ◽

Eng-Ang Ling ◽

Charanjit Kaur

Keyword(s):

Cell Death ◽

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Inflammatory Cytokines ◽

Retinal Ganglion ◽

Retinal Ganglion Cell Death ◽

Ganglion Cell Death ◽

Pro Inflammatory Cytokines

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Pro-inflammatory cytokines increase glucose, alanine and triacylglycerol utilization but inhibit insulin secretion in a clonal pancreatic β-cell line

Journal of Endocrinology ◽

10.1677/joe-07-0306 ◽

2007 ◽

Vol 195 (1) ◽

pp. 113-123 ◽

Cited By ~ 40

Author(s):

Aoife Kiely ◽

Neville H McClenaghan ◽

Peter R Flatt ◽

Philip Newsholme

Keyword(s):

Insulin Secretion ◽

Inflammatory Cytokines ◽

Prolonged Exposure ◽

Cell Metabolism ◽

Glutamate Release ◽

Β Cell ◽

Catabolic State ◽

Stimulus Secretion Coupling ◽

Factor Α ◽

Pro Inflammatory Cytokines

We have investigated the effects of prolonged exposure (24 h) to pro-inflammatory cytokines on β-cell metabolism and insulin secretion using clonal BRIN-BD11 β cells. Addition of IL-1β, tumour necrosis factor-α and IFN-γ (at concentrations that did not induce apoptosis) inhibited chronic (24 h) and acute stimulated levels of insulin release (by 59 and 93% respectively), increased cellular glucose and alanine consumption, and also elevated lactate and glutamate release. However, ATP levels and cellular triacylglycerol were decreased while glutathione was increased. We conclude that sub-lethal concentrations of pro-inflammatory cytokines appear to shift β-cell metabolism away from a key role in energy generation and stimulus–secretion coupling and towards a catabolic state which may be related to cell defence.

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