Cytoprotective effects of olesoxime on isolated human pancreatic islets in order to attenuate apoptotic pathway

Kaviani, Maryam; Keshtkar, Somayeh; Azarpira, Negar; Aghdaei, Mahdokht Hossein; Geramizadeh, Bita; Karimi, Mohammad Hossein; Shamsaeefar, Alireza; Motazedian, Nasrin; Nikeghbalian, Saman; Al-Abdullah, Ismail H.; Ghahremani, Mohammad Hossein

doi:10.1016/j.biopha.2019.108674

Cited by 17 publications

(15 citation statements)

References 28 publications

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“…Human islets were isolated based on the semi-automated protocol of Ricordi et al . 42 ,with a few modifications 43 . After obtaining the written informed consent for research from dead brain donors’ relatives, four human pancreases (Table 1) were taken in accordance with the institutional ethics committee (IR.TUMS.REC.1394.1306).…”

Section: Methodsmentioning

confidence: 99%

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

Keshtkar

Kaviani

Jabbarpour

et al. 2019

Sci Rep

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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.

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Section: Methodsmentioning

confidence: 99%

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

Keshtkar

Kaviani

Jabbarpour

et al. 2019

Sci Rep

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“…When transplanted islets are healthier, they are normally intact and have a spherical structure [ 34 – 36 ]. However, when islets start to die, they lose their shape due to a loss in plasma membrane integrity and cell death [ 37 ]. In our previous study, we examined the use of AD-MSCs to help facilitate islet engraftment [ 38 ].…”

Section: Resultsmentioning

confidence: 99%

Facilitating islet transplantation using a three-step approach with mesenchymal stem cells, encapsulation, and pulsed focused ultrasound

et al. 2020

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Background The aim of this study was to examine the effect of a three-step approach that utilizes the application of adipose tissue-derived mesenchymal stem cells (AD-MSCs), encapsulation, and pulsed focused ultrasound (pFUS) to help the engraftment and function of transplanted islets. Methods In step 1, islets were co-cultured with AD-MSCs to form a coating of AD-MSCs on islets: here, AD-MSCs had a cytoprotective effect on islets; in step 2, islets coated with AD-MSCs were conformally encapsulated in a thin layer of alginate using a co-axial air-flow method: here, the capsule enabled AD-MSCs to be in close proximity to islets; in step 3, encapsulated islets coated with AD-MSCs were treated with pFUS: here, pFUS enhanced the secretion of insulin from islets as well as stimulated the cytoprotective effect of AD-MSCs. Results Our approach was shown to prevent islet death and preserve islet functionality in vitro. When 175 syngeneic encapsulated islets coated with AD-MSCs were transplanted beneath the kidney capsule of diabetic mice, and then followed every 3 days with pFUS treatment until day 12 post-transplantation, we saw a significant improvement in islet function with diabetic animals re-establishing glycemic control over the course of our study (i.e., 30 days). In addition, our approach was able to enhance islet engraftment by facilitating their revascularization and reducing inflammation. Conclusions This study demonstrates that our clinically translatable three-step approach is able to improve the function and viability of transplanted islets.

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“…We observed decreased expression of BAD and BAX, which are involved in the promotion of the intrinsic apoptosis pathway, and increased expression of BCL-2, which is regarded as an anti-apoptotic marker. The BAX/BCL-2 ratio, as a key regulator of the intrinsic apoptosis pathway, was also reduced in the presence of MSC-Exo (Kaviani et al, 2019[ 14 ][ 16 ][ 15 ]). Besides, the upregulation of PI3K was observed in islets co-cultured with exosomes, which may partially account for the effect of MSC-Exo on islet survival since PI3K can accelerate cell survival via the activation of Akt and the inhibition of BAD and BAX (Downward, 2004[ 9 ]).…”

Section: Discussionmentioning

confidence: 99%

“…The mitochondrial apoptosis pathway is recognized as a major cause of islet death. The members of the B-cell lymphoma-2 (BCL-2) family regulate the apoptosis pathway through interactions between pro-apoptotic and anti-apoptotic factors, including the BCL-2-associated agonist of cell death (BAD), BCL-2-associated X (BAX), and BCL-2 genes (Kaviani et al, 2019[ 14 ][ 16 ][ 15 ]). The balance between BAX and BCL-2 (i.e., the BAX/BCL-2 ratio) represents an index that determines the cellular fate in terms of survival or apoptosis (Greijer and Van der Wall, 2004[ 12 ]; Velmurugan et al, 2012[ 41 ]).…”

Section: Introductionmentioning

confidence: 99%

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

Keshtkar

Kaviani

Sarvestani

et al. 2020

EXCLI Journal; 19:Doc1064; ISSN 1611-2156

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Cytoprotective effects of olesoxime on isolated human pancreatic islets in order to attenuate apoptotic pathway

Cited by 17 publications

References 28 publications

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

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

Facilitating islet transplantation using a three-step approach with mesenchymal stem cells, encapsulation, and pulsed focused ultrasound

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

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