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Zaitseva II Størling J Mandrup-Poulsen T Berggren PO Zaitsev SV 《Cellular and molecular life sciences : CMLS》2008,65(7-8):1248-1255
An insufficient number of insulin-producing β-cells is a major cause of defective control of blood glucose in both type 1
and type 2 diabetes. The aim of this study was to clarify whether the insulinotropic imidazolines can affect the survival
of highly proliferating insulin-secreting cells, here exemplified by the MIN6 cell line. Our data demonstrate that RX871024,
but not efaroxan, triggered MIN6 cell death and potentiated death induced by a combination of the pro-inflammatory cytokines
interleukin-1β, interferon- γ and tumor necrosis factor-α. These effects did not involve changes in nitric oxide production
but correlated with stimulation of c-jun N-terminal kinase (JNK) activity and activation of caspases-1, -3, -8 and -9. Our
results suggest that the imidazoline RX871024 causes death of highly proliferating insulin-secreting cells, putatively via augmentation of JNK activity, a finding that may impact on the possibility of using compounds of similar activity in the
treatment of diabetes.
Received 13 December 2007; received after revision 5 February 2008; accepted 6 February 2008 相似文献
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Sharoyko VV Zaitseva II Leibiger B Efendić S Berggren PO Zaitsev SV 《Cellular and molecular life sciences : CMLS》2007,64(22):2985-2993
The mechanism by which the novel, pure glucose-dependent insulinotropic, imidazoline derivative BL11282 promotes insulin secretion
in pancreatic islets has been investigated. The roles of KATP channels, α2-adrenoreceptors, the I1-receptor-phosphatidylcholine-specific phospholipase (PC-PLC) pathway and arachidonic acid signaling in BL11282 potentiation
of insulin secretion in pancreatic islets were studied. Using SUR1(-/-) deficient mice, the previous notion that the insulinotropic activity of BL11282 is not related to its interaction with KATP channels was confirmed. Insulinotropic activity of BL11282 was not related to its effect on α2-adrenoreceptors, I1-imidazoline receptors or PC-PLC. BL11282 significantly increased [3H]arachidonic acid production. This effect was abolished in the presence of the iPLA2 inhibitor, bromoenol lactone. The data suggest that potentiation of glucose-induced insulin release by BL11282, which is
independent of concomitant changes in cytoplasmic free Ca2+ concentration, involves release of arachidonic acid by iPLA2 and its metabolism to epoxyeicosatrienoic acids through the cytochrome P-450 pathway.
Received 5 July 2007; received after revision 18 September 2007; accepted 20 September 2007 相似文献
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Irina I. Zaitseva Monica Hultcrantz Vladimir Sharoyko Malin Flodström-Tullberg Sergei V. Zaitsev Per-Olof Berggren 《Cellular and molecular life sciences : CMLS》2009,66(23):3787-3795
Pancreatic beta cell damage caused by pro-inflammatory cytokines interleukin-1β (IL-1β), interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα) is a key event in the pathogenesis of type 1 diabetes. The suppressor of cytokine signaling-1 (SOCS-1) blocks IFNγ-induced signaling and prevents diabetes in the non-obese diabetic mouse. Here, we investigated if SOCS-1 overexpression in primary beta cells provides protection from cytokine-induced islet cell dysfunction and death. We demonstrate that SOCS-1 does not prevent increase in NO production and decrease in glucose-stimulated insulin secretion in the presence of IL-1β, IFNγ, TNFα. However, it decreases the activation of caspase-3, -8 and -9, and thereby, promotes a robust protection from cytokine-induced beta cell death. Our data suggest that SOCS-1 overexpression may not be sufficient in preventing all the biological activities of IFNγ in beta cells. In summary, we show that interference with IFNγ signal transduction pathways by SOCS-1 inhibits cytokine-stimulated pancreatic beta cell death. 相似文献
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