Regulation of c-Jun NH2-Terminal Kinase for Islet Transplantation

Abstract

Islet transplantation has been demonstrated to provide superior glycemic control with reduced glucose lability and hypoglycemic events compared with standard insulin therapy. However, the insulin independence rate after islet transplantation from one donor pancreas has remained low. The low frequency of islet grafting is dependent on poor islet recovery from donors and early islet loss during the first hours following grafting. The reduction in islet mass during pancreas preservation, islet isolation, and islet transplantation leads to β-cell death by apoptosis and the prerecruitment of intracellular death signaling pathways, such as c-Jun NH2-terminal kinase (JNK), which is one of the stress groups of mitogen-activated protein kinases (MAPKs). In this review, we show some of the most recent contributions to the advancement of knowledge of the JNK pathway and several possibilities for the treatment of diabetes using JNK inhibitors.

Long noncoding RNA MAPKAPK5-AS1 promotes colorectal cancer progression by cis-regulating the nearby gene MK5 and acting as a let-7f-1-3p sponge

“…The p38MAPK pathway responds and adapts to numerous extracellular stimuli through downstream targets, which include protein kinases, phosphatases, transcription factors, and cell-cycle regulators. It has come to light that c-Jun participates in the JNK and stress-activated MAPK signaling pathways [ 50 ]. MK5, which is directly phosphorylated by MAPK4/6 (Erk3/4), could be phosphorylated and catalyzed by p38 MAP kinase instead of JNK [ 51 ].…”

Long noncoding RNA MAPKAPK5-AS1 promotes colorectal carcinogenesis by cis-regulating the nearby gene MK5 and acting as a let-7f-1-3p sponge

“…The p38MAPK pathway responds and adapts to numerous extracellular stimuli through downstream targets, which include protein kinases, phosphatases, transcription factors, and cell-cycle regulators. It has come to light that c-Jun participates in the JNK and stress-activated MAPK signaling pathways [49]. MK5, which is directly phosphorylated by MAPK4/6 (Erk3/4), could be phosphorylated and catalyzed by p38 MAP kinase instead of JNK [50].…”

The Influence of Microenvironment on Survival of Intraportal Transplanted Islets

“…Although most pancreatic islet transplants use organs from heart-beating brain-dead (BD) donors, acute physiological changes after brain death of BD donors may still cause significant damage to islets from inflammatory events. Brain death can stimulate various cells to produce pro-inflammatory cytokines, and produce a so-called “cytokine storm”, including IL-1β in BD donors, which greatly reduces the islet yield, functionality, vitality, and engraftment after transplantation ( 8 ). One study has shown that the administration of exendin-4 to BD donors can reduce the expression of IL-1β, thereby increasing both the islet viability and insulin secretion in the pancreas after glucose stimulation in a BD rat model ( 81 ).…”

“…It was observed that only 10% of recipients remain insulin dependent for more than 5 years and that most recipients re-use insulin because of a decline in the islet function over time ( 7 ). During transplantation, islet grafts are damaged by multiple challenges, including enzyme and mechanical damage caused by the isolation process, hypoxia, inflammation, immune rejection and toxicity of immunosuppressive drugs ( 8 ). The liver is currently the preferred transplantation site because the procedure is minimally invasive, easy to perform, and has low rates of bleeding and thrombosis ( 9 ).…”