P38α-Selective Mitogen-Activated Protein Kinase Inhibitor for Improvement of Cultured Human Islet Recovery

Omori, Keiko; Todorov, Ivan; Shintaku, Jonathan; Rawson, Jeffrey; Al-Abdullah, Ismail H.; Higgins, Linda S.; Medicherla, Satyanarayana; Kandeel, Fouad; Mullen, Yoko

doi:10.1097/mpa.0b013e3181c0dd8f

Cited by 12 publications

(22 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The decrease in BBC3 mRNA was, in part, supported by the decrease in TNF mRNA expression as shown in Fig. 1d, as well as by previous findings presented by ourselves [37] and others [33]. Upregulation of BBC3 is associated with translocation of mitochondria to the perinuclear area and partial colocalisation of BBC3 with mitochondria (Fig.…”

Section: Discussionsupporting

confidence: 69%

“…Human islets were incubated for 1 h with several compounds (listed below), stimulated by TNF-α (5 ng/ml) for an additional 4 h, and expression of BBC3, IL8 and TNF was measured. Compounds were selected on the basis of their specific traits: (1) etanercept, a TNF-α receptor blocker reported to improve glycaemic control in clinical trials in patients with type 1 diabetes [34]; (2) FK506, ciclosporin A and rapamycin, clinically used immunosuppressants that modulate inflammatory/immune reactions; (3) imatinib mesylate, a tyrosine kinase inhibitor that suppresses NF-κB activation and has been shown to protect islets from combined cytokines in vitro and to prevent spontaneous onset of diabetes in NOD mice [35]; and (4) SB203580, a p38 mitogen-activated protein kinase inhibitor that has been shown to prevent beta cell death, in part, by regulating TNF-α abundance [32,36,37]. Pre-incubation of islets with etanercept prevented TNF-α-induced upregulation of BBC3 (Fig.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

mRNA of the pro-apoptotic gene BBC3 serves as a molecular marker for TNF-α-induced islet damage in humans

et al. 2011

View full text Add to dashboard Cite

Aims/hypothesis TNF-α plays important roles in the pathogenesis of type 1 and type 2 diabetes mellitus. In light of this, we examined the involvement of a pro-apoptotic gene, BBC3 (also known as PUMA), in TNF-α-mediated beta cell dysfunction and destruction in human islets. Methods Human islets were exposed in vitro to TNF-α alone or in combination with IFN-γ. Gene expression was assessed by RT-PCR using a set of single islets. Protein abundance and cellular localisation of BBC3 were assessed by immunoblot and immunohistochemistry. A marginal number of islets were transplanted into diabetic NODscid mice to correlate in vivo islet function with BBC3 expression. Results BBC3 and IL8 mRNA were upregulated in TNF-α-stimulated islets in a dose-dependent manner and enhanced through addition of IFN-γ, but not upregulated by IFN-γ alone. Immunohistochemistry revealed that TNF-α in combination with IFN-γ upregulated basal BBC3 abundance in the cytoplasm of beta cells along with the perinuclear clustering of mitochondria partially colocalised with BBC3. TNF-α alone did not induce beta cell death, but did abrogate preproinsulin precursor mRNA synthesis in response to high glucose stimulation, which was inversely associated with upregulation of BBC3 mRNA expression by TNF-α. Higher BBC3 mRNA expression in islets correlated with decreased graft function in vivo. Conclusions/interpretation These results suggest that BBC3 mRNA can serve as a molecular marker to detect early TNF-α-induced beta cell stress and may help identify isletprotective compounds for the treatment of diabetes.

show abstract

Section: Discussionsupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

mRNA of the pro-apoptotic gene BBC3 serves as a molecular marker for TNF-α-induced islet damage in humans

et al. 2011

View full text Add to dashboard Cite

show abstract

“…No significant difference in TNF-α expression in overnight-cultured experimental and control islets may be due to the decay of p38IH effect, decreased acinar and monocytes numbers, or both. However, it is likely due to the decay of p38IH effect, since we have shown significant improvement of cultured human islets by adding p38IH in the culture medium (41). …”

Section: Discussionmentioning

confidence: 98%

Improvement of Canine Islet Yield by Donor Pancreas Infusion With a p38MAPK Inhibitor

et al. 2008

Self Cite

View full text Add to dashboard Cite

Background The activation of p38 mitogen-activated protein kinases (MAPK) is implicated in cold ischemia-reperfusion injury of donor organs. The islet isolation process, from pancreas procurement through islet collection, may activate p38MAPK leading to cytokine release and islet damage. This damage may be prevented by treating pancreata with a p38MAPK inhibitor (p38IH) prior to cold preservation. Methods Pancreata removed from Beagle dogs were infused with UW solution containing either the p38IH, SB203580 and Pefabloc (n=6) or vehicle (DMSO and Pefabloc) alone (n=7), through the pancreatic duct and preserved using the two-layer method. After 20–22 hours, islets were isolated and 3000 IEQ/kg were autotransplanted into the corresponding dog to monitor glucose metabolism. Results P38IH-treated pancreata yielded significantly more islets than control pancreata (IEQ/g: 2,134±297 vs. 1,477±145 IEQ/g or 65,012±9,385 vs. 45,700±5,103 IEQ/Pancreas; p<0.05). Apoptotic β-cell percentages assessed by LSC were lower in p38IH-treated than the controls (44±9.4% vs. 61.6±4.8%, p<0.05). TNF-α expression assessed by RT-PCR was significantly lower in the p38IH-treated group than controls. All dogs (3000 IEQ/kg) transplanted with p38IH-treated islets (n=5) became euglycemic vs. 4 of 5 dogs that received untreated islets. Plasma C-peptide levels following glucagon challenge were higher in animals receiving p38IH-treated islets (n=5) vs. untreated islets (n=4) (0.40±0.78 vs. 0.21±0.05 ng/mL, p<0.05). Conclusions Infusion of pancreata with UW solution containing p38IH through the duct prior to peservation suppresses cytokine release, prevents β cell apoptosis, and improves islet yield significantly with no adverse effect on islet function following transplantation. P38IH treatment of human pancreata may improve islet yield for use in clinical transplantation.

show abstract

“…Stress, which is generated throughout the procedure for isolating islets, activates proinflammatory signaling pathways and the destruction of β cells . JNK and p38 are preferentially activated in response to the processing of islets for transplantation and by the inflammation associated with islet transplantation . We reported that treatment with peptide inhibitors of JNK during preservation of the pancreas before islet isolation, islet culture, or islet transplantation prevents islet apoptosis and enhances engraftment of islets in vivo .…”

Section: Introductionmentioning

confidence: 99%

Novel cell-permeable p38-MAPK inhibitor efficiently prevents porcine islet apoptosis and improves islet graft function

Noguchi

Miyagi-Shiohira

Nakashima

et al. 2020

American Journal of Transplantation

View full text Add to dashboard Cite

| INTRODUC TI ONMitogen-activated protein kinases (MAPKs) are activated in response to extracellular stimuli such as growth factors, cytokines, and environmental stressors. The major subgroups of the MAPK family include the extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38 MAPK (p38). ERKs, which are mainly activated by growth factors and phorbol esters, are associated with cellular proliferation. JNKs and p38 are activated by inflammatory cytokines and extracellular stressors such as ultraviolet irradiation, osmotic stress, and mechanical stress. Activation of these MAPKs contributes to cell-type-specific gene expression, cell proliferation, differentiation, cell cycle arrest, apoptosis, and early development. 1,2Stress, which is generated throughout the procedure for isolating islets, activates proinflammatory signaling pathways and the destruction of β cells. 3-6 JNK and p38 are preferentially activated in response to the processing of islets for transplantation and by the inflammation associated with islet transplantation. [7][8][9][10][11][12][13][14] We reported that treatment with peptide inhibitors of JNK during preservation of the pancreas before islet isolation, islet culture, or islet transplantation prevents islet apoptosis and enhances engraftment of islets During islet transplantation, mitogen-activated protein kinase (MAPK) p38 is preferentially activated in response to the isolation of islets and the associated inflammation.Although therapeutic effects of p38 inhibitors are expected, the clinical application of small-molecule inhibitors of p38 is not recommended because of their serious adverse effects on the liver and central nervous system. Here we designed peptides to inhibit p38, which were derived from the sites on p38 that mediate binding to proteins such as MAPK kinases. Peptide 11R-p38I 110 significantly inhibited the activation of p38. To evaluate the effects of 11R-p38I 110 , porcine islets were incubated with 10 µmol/L 11R-p38I 110 or a mutant form designated 11R-mp38I 110 . After islet transplantation, blood glucose levels reached the normoglycemic range in 58.3% and 0% of diabetic mice treated with 11R-p38I 110 or 11R-mp38I 110 , respectively. These data suggest that 11R-p38I 110 inhibited islet apoptosis and improved islet function.Peptide p38I 110 is a noncompetitive inhibitor of ATP and targets a unique docking site. Therefore, 11R-p38I 110 specifically inhibits p38 activation, which may avoid the adverse effects that have discouraged the clinical use of small-molecule inhibitors of p38. Moreover, our methodology to design "peptide inhibitors" could be used to design other inhibitors derived from the binding sites of proteins. K E Y W O R D Sbasic (laboratory) research/science, cell death: apoptosis, islet isolation, islet transplantation

show abstract

P38α-Selective Mitogen-Activated Protein Kinase Inhibitor for Improvement of Cultured Human Islet Recovery

Cited by 12 publications

References 42 publications

mRNA of the pro-apoptotic gene BBC3 serves as a molecular marker for TNF-α-induced islet damage in humans

mRNA of the pro-apoptotic gene BBC3 serves as a molecular marker for TNF-α-induced islet damage in humans

Improvement of Canine Islet Yield by Donor Pancreas Infusion With a p38MAPK Inhibitor

Novel cell-permeable p38-MAPK inhibitor efficiently prevents porcine islet apoptosis and improves islet graft function

Contact Info

Product

Resources

About