Protective effect of nobiletin on isolated human islets survival and function against hypoxia and oxidative stress-induced apoptosis

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.

Exosomes derived from human mesenchymal stem cells preserve mouse islet survival and insulin secretion function

“…Imaging was performed using a fluorescence microscope (CKX53, Olympus, Japan). The viability rate was expressed by the percentage of green area to the total area within intact islet (Keshtkar et al, 2019[ 19 ]).…”

“…Type 1 diabetes comprises 5-10 % of all diabetic cases and is the consequence of the autoimmune destruction of pancreatic beta cells, giving rise to absolute insulin deficiency (Keshtkar et al, 2019[ 19 ]; You and Henneberg, 2016[ 43 ]). Islet transplantation is considered a promising treatment for type 1 diabetes patients who face severe periods of hypoglycemia (Saravanan et al, 2017[ 33 ]).…”

“…Ahead of transplantation, the islet culture must adequately preserve the islet quality while the graft recipient is prepared and the isolated islets are transported to remote clinical centers for transplantation (Shapiro et al, 2017[ 37 ]). However, the culture period can lead to significant islet death triggered by hypoxia and oxidative stress (Keshtkar et al, 2020[ 18 ], 2019[ 19 ]). These insults induce apoptosis and decrease β-cell function, thereby exerting a negative impact on the outcome, sometimes even impeding transplantation (Arzouni et al, 2017[ 2 ]).…”

The Effects of 5,6,7,8,3′,4′-Hexamethoxyflavone on Apoptosis of Cultured Human Choriocarcinoma Trophoblast Cells

“…It has been reported that NOB inhibited apoptosis induced by thapsigargin in INS-1D β-cells [15] and hypoxia/reoxygenation in H9c2 cardiomyocytes [16]. After islets transplantation in humans, apoptosis of isolated islets cells could also be ameliorated by NOB [17]. rational to hypothesize that NOB might induce apoptosis in BeWo cells.…”

The potential of the incorporated collagen microspheres in alginate hydrogel as an engineered three-dimensional microenvironment to attenuate apoptosis in human pancreatic islets

“…The isolation process of the human pancreatic islets from their niche leads to loss of biological and mechanical support of the cells. In this stressful situation, the apoptosis is activated in the islets; hence, eliminating this process becomes critical in order to reduce the number of tissues needed for pancreatic islet transplantation (1)(2)(3)(4). Tissue engineering is an attractive strategy for remodeling extracellular matrix (ECM) and improving the culture and transplantation methods.…”