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Synergic effects of oxygen supply and antioxidants on pancreatic ?-cell spheroids.

ABSTRACT: Diabetes is one of the most common metabolic disorders, and is characterized by the inability to secrete/sense insulin and abnormal blood glucose concentration. Many researchers have concentrated their efforts on improving islet transplantation, in particular by fabricating bioartificial pancreatic islets in vitro. One of the critical points for the success of this research direction is the improvement of culture conditions, such as oxygen supply, in the engineering of bioartificial pancreatic islets to ensure their viability and functionality after transplantation. In this work, we fabricated microwell spheroid culture devices made of oxygen-permeable polydimethylsiloxane (PDMS), with which hypoxia in the core of bioartificial islets was alleviated and glucose-stimulated insulin secretion was increased ~2.5-fold compared to a device with the same configuration but made of non-oxygen-permeable plastic. We also demonstrated that antioxidants, such as ascorbic acid-2-phosphate (AA2P), could neutralize islet damage caused by increased reactive oxygen species (ROS) in the cell culture environment. These results suggest that supply of oxygen together with removal of ROS may lead to a better approach to prepare highly viable and functional bioartificial pancreatic islets.

SUBMITTER: Myasnikova D

PROVIDER: S-EPMC6372787 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Synergic effects of oxygen supply and antioxidants on pancreatic β-cell spheroids.

Myasnikova Dina D Osaki Tatsuya T Onishi Kisaki K Kageyama Tatsuto T Zhang Molino Binbin B Fukuda Junji J

Scientific reports 20190212 1

Diabetes is one of the most common metabolic disorders, and is characterized by the inability to secrete/sense insulin and abnormal blood glucose concentration. Many researchers have concentrated their efforts on improving islet transplantation, in particular by fabricating bioartificial pancreatic islets in vitro. One of the critical points for the success of this research direction is the improvement of culture conditions, such as oxygen supply, in the engineering of bioartificial pancreatic i ...[more]

PMID: 30755634

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Project description:Pancreatic β-cells are vulnerable to oxidative stress due to their low content of redox buffers, such as glutathione, but possess a rich content of thioredoxin, peroxiredoxin, and other proteins capable of redox relay, transferring redox signaling. Consequently, it may be predicted that cytosolic antioxidants could interfere with the cytosolic redox signaling and should not be recommended for any potential therapy. In contrast, mitochondrial matrix-targeted antioxidants could prevent the primary oxidative stress arising from the primary superoxide sources within the mitochondrial matrix, such as at the flavin (IF) and ubiquinone (IQ) sites of superoxide formation within respiratory chain complex I and the outer ubiquinone site (IIIQ) of complex III. Therefore, using time-resolved confocal fluorescence monitoring with MitoSOX Red, we investigated various effects of mitochondria-targeted antioxidants in model pancreatic β-cells (insulinoma INS-1E cells) and pancreatic islets. Both SkQ1 (a mitochondria-targeted plastoquinone) and a suppressor of complex III site Q electron leak (S3QEL) prevented superoxide production released to the mitochondrial matrix in INS-1E cells with stimulatory glucose, where SkQ1 also exhibited an antioxidant role for UCP2-silenced cells. SkQ1 acted similarly at nonstimulatory glucose but not in UCP2-silenced cells. Thus, UCP2 can facilitate the antioxidant mechanism based on SkQ1+ fatty acid anion- pairing. The elevated superoxide formation induced by antimycin A was largely prevented by S3QEL, and that induced by rotenone was decreased by SkQ1 and S3QEL and slightly by S1QEL, acting at complex I site Q. Similar results were obtained with the MitoB probe, for the LC-MS-based assessment of the 4 hr accumulation of reactive oxygen species within the mitochondrial matrix but for isolated pancreatic islets. For 2 hr INS-1E incubations, some samples were influenced by the cell death during the experiment. Due to the frequent dependency of antioxidant effects on metabolic modes, we suggest a potential use of mitochondria-targeted antioxidants for the treatment of prediabetic states after cautious nutrition-controlled tests. Their targeted delivery might eventually attenuate the vicious spiral leading to type 2 diabetes.

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Synergic effects of oxygen supply and antioxidants on pancreatic ?-cell spheroids.

Publications

Synergic effects of oxygen supply and antioxidants on pancreatic β-cell spheroids.

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