Abstract
Islets transplantation, as a treatment of type 1 diabetes, faces challenges, including the loss of islets in the process of isolation and pre-transplantation due to cellular stresses-induced apoptosis. Accordingly, the optimization of culture plays a decisive role in the transplantation success. In this study, we evaluated the effect of nobiletin on the cultured human islets. Isolated human islets were treated by different concentrations of nobiletin and cultured for 24 and 72 hours. Then, the islets viability, apoptosis, insulin and C-peptide secretion, and apoptosis markers were evaluated. Also, the production of reactive oxygen species (ROS), hypoxia inducible factor 1 alpha (HIF-1α), and its target genes in the islets were examined. Our findings showed that the islets were encountered with hypoxia and oxidative stress after isolation and during culture. These insults induced apoptosis and reduced viability during culture period. Moreover, the secretion of insulin and C-peptide decreased. Nobiletin treatments significantly improved the islets survival through reduction of HIF-1α and ROS production and suppression of apoptosis, along with increased islets function. Islet protective effect of nobiletin might be related to its anti-oxidant, anti-apoptotic and insulinotropic properties. Hence, in order to achieve viable and functional islets for clinical transplantation, the application of nobiletin during pre-transplantation period is useful.
Highlights
Diabetes is a rising global health problem
It has been revealed that following ischemic injury of the pancreas due to disconnection from the whole body and during the isolation process, the islets encounter multiple stresses including oxidative stress and hypoxia, which continues during the pre-transplant culture period
The evaluation of islets showed that the percentage of viable islets was nearly 100% in the treatment and control groups at 24 hours, while the viability rate was reduced to fewer than 50% in the control group during 72 hours
Summary
Diabetes is a rising global health problem. It is estimated that more than 400 million people are afflicted with diabetes worldwide[1]. It has been revealed that following ischemic injury of the pancreas due to disconnection from the whole body and during the isolation process, the islets encounter multiple stresses including oxidative stress and hypoxia, which continues during the pre-transplant culture period. These factors seem to be one of the main mediators in the activation of apoptosis, which can affect the islet transplantation outcome because of the low number of viable and functional islets[11,12,13]. Findings have suggested that nobiletin protects the cells from apoptosis through activation of cyclic AMP-responsive element binding protein (CREB) and PI3/Akt pathways. It has been reported that nobiletin reduces the oxidative stress-induced apoptosis via decreasing ROS and increasing the anti-oxidant enzyme activities[21,25,26]
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