Enhanced expression of glutathione peroxidase protects islet <i>β</i> cells from hypoxia‐reoxygenation

Lepore, Diana A.; Shinkel, Trixie A.; Fisicaro, Nella; Mysore, Tharun; Johnson, Lucinda E A; d’Apice, Anthony J.F.; Cowan, Peter J.

doi:10.1111/j.1399-3089.2004.00082.x

Cited by 39 publications

(30 citation statements)

References 40 publications

(52 reference statements)

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“…1A). The cDNAs for hemagglutinin-tagged Cu/Zn SOD and His-tagged Gpx-1 were as described previously (24) except that the latter lacked its endogenous intron. Construction of a modified extracellular SOD cDNA required several steps.…”

Section: Methodsmentioning

confidence: 99%

“…Gpx-1 has a high affinity for H 2 O 2 and catalyzes the reduction of organic and lipid hydroperoxides, which impair insulin secretion by islets (22). Gpx-1 overexpression protects against Fas-mediated apoptosis (23), increases the resistance of cultured ␤-cells to hypoxia/reoxygenation (24), and neutralizes peroxynitrite (25). Peroxynitrite is thought to be responsible for much of the oxidative damage previously ascribed to other radicals (26,27).…”

mentioning

confidence: 99%

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Overexpression of Glutathione Peroxidase With Two Isoforms of Superoxide Dismutase Protects Mouse Islets From Oxidative Injury and Improves Islet Graft Function

Mysore

Shinkel²,

Collins³

et al. 2005

Diabetes

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Primary nonfunction of transplanted islets results in part from their sensitivity to reactive oxygen species (ROS) generated during the isolation and transplantation process. Our aim was to examine whether coexpression of antioxidant enzymes to detoxify multiple ROS increased the resistance of mouse islets to oxidative stress and improved the initial function of islet grafts. Islets from transgenic mice expressing combinations of human copper/zinc superoxide dismutase (SOD), extracellular SOD, and cellular glutathione peroxidase (Gpx-1) were subjected to oxidative stress in vitro. Relative viability after hypoxanthine/xanthine oxidase treatment was as follows: extracellular SOD ؉ Gpx-1 ؉ Cu/Zn SOD > extracellular SOD ؉ Gpx-1 > extracellular SOD > wild type. Expression of all three enzymes was the only combination protective against hypoxia/ reoxygenation. Islets from transgenic or control wildtype mice were then transplanted into streptozotocininduced diabetic recipients in a syngeneic marginal islet mass model, and blood glucose levels were monitored for 7 days. In contrast to single-and double-transgenic grafts, triple-transgenic grafts significantly improved control of blood glucose compared with wild type. Our results indicate that coexpression of antioxidant enzymes has a complementary beneficial effect and may be a useful approach to reduce primary nonfunction of islet grafts. Diabetes 54:2109 -2116, 2005

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Overexpression of Glutathione Peroxidase With Two Isoforms of Superoxide Dismutase Protects Mouse Islets From Oxidative Injury and Improves Islet Graft Function

Mysore

Shinkel²,

Collins³

et al. 2005

Diabetes

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“…Given the limited supply of donor pancreatic islets and the prevalence of type 1 diabetes, considerable efforts have been made to prevent the loss of islet mass in the posttransplantation period. 7,[20][21][22][23] For example, overexpression of molecules known to enhance revascularization, such as vascular endothelial growth factor, had been attempted in our laboratory. 24 In contrast to the overexpression of therapeutic genes, ex vivo silencing of harmful genes also offers an alternative approach to improve islet viability after transplantation.…”

Section: Discussionmentioning

confidence: 99%

Caspase-3 Gene Silencing for Inhibiting Apoptosis in Insulinoma Cells and Human Islets

2008

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Abstract:Although islet transplantation has great potential to treat type I diabetes, most islet grafts do not function due to the host immune rejection, nonspecific inflammatory response and poor revascularization. Since caspase-3 plays a crucial role in apoptosis of transplanted islet cells, we used chemically synthesized small interfering RNAs (siRNAs) to silence caspase-3 in insulinoma (INS-1E) cells and human islets, and then determined whether caspase-3 gene silencing can prevent these cells from cytokine-induced apoptosis. Transfection of INS-1E cells and islets with siRNAs reduced caspase-3 transcripts by 50-67% and 50%, respectively. Additionally, apoptosis in transfected insulinoma cells was markedly inhibited. Since gene silencing did not last beyond two days, we converted potent siRNA into shRNA and constructed replication deficient adenoviral (Adv) vectors encoding these shRNAs driven by a U6 or H1 promoter. Compared to chemically synthesized siRNA, Adv-caspase-3-shRNA efficiently transduced islets, showed relatively higher and prolonged levels of gene silencing beyond five days, with higher gene silencing with a U6 promoter, and protected islets from cytokine-induced apoptosis. Finally, return to normoglycemia was achieved at 1 day post-transplantation of Advcaspase-3-shRNA transduced islets under the kidney capsules of streptozotocin induced nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice and maintained beyond two weeks. Blood glucose levels returned to g325 mg/dL upon removal of the islet graft-bearing kidney at 32 days after transplantation, confirming that transplanted islets were functional.

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“…CAT has also exhibited a protective effect against H 2 O 2 and streptozotocin-induced oxidative stress in vivo (31). Additionally, combinatorial overexpression of CAT and GSH-px has been shown to have a protective effect against ROS-induced oxidative stress through improving the activity of CuZnSOD or MnSOD (32)(33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

Protective effects of Lagerstroemia speciosa on 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in HIT-T15 pancreatic β cells

Song

Zhao

Wang

et al. 2013

Molecular Medicine Reports

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Abstract. Reactive oxygen species (ROS)-induced pancreatic β cell death affects insulin secretion and is important in the pathogenesis of diabetes. Lagerstroemia speciosa, a traditional folk medicine, has been used for t he prevention and treatment of diabetes. However, whether Lagerstroemia speciosa has a cytoprotective effect on pancreatic β cells remains to be elucidated. The present study aimed to investigate the cytoprotective effects of hot water extracts from Lagerstroemia speciosa leaves (LWE) on 3-morpholinosydnonimine (SIN-1)-induced oxidative damage in Syrian hamster pancreatic insulinoma HIT-T15 cells. The HIT-T15 cells were first treated with SIN-1 (50 µM) for 24 h and then co-incubated with LWE for 48 h. SIN-1 significantly decreased HIT-T15 cell viability (P<0.05); however, LWE did not exert a significant cytotoxic effect and increased the viability of HIT-T15 cells in a dose-dependent manner. To further investigate the protective effects of LWE on SIN-1-induced oxidative stress in HIT-T15 cells, the cellular levels of ROS, lipid peroxidation and endogenous antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-px), were determined. LWE decreased the intracellular levels of ROS and lipid peroxidation, and increased the activities of antioxidant enzymes. These results suggest that LWE has a cytoprotective effect against SIN-1-induced oxidative stress in HIT-T15 cells through the inhibition of lipid peroxidation, a decrease in ROS levels and an increase in antioxidant enzyme activity. In addition, LWE increased insulin secretion in SIN-1-treated HIT-T15 cells. Our results suggested that LWE were effective in the treatment of diabetes. Further studies are required to study the anti-diabetic molecular mechanism in a cell model.

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Enhanced expression of glutathione peroxidase protects islet β cells from hypoxia‐reoxygenation

Cited by 39 publications

References 40 publications

Overexpression of Glutathione Peroxidase With Two Isoforms of Superoxide Dismutase Protects Mouse Islets From Oxidative Injury and Improves Islet Graft Function

Overexpression of Glutathione Peroxidase With Two Isoforms of Superoxide Dismutase Protects Mouse Islets From Oxidative Injury and Improves Islet Graft Function

Caspase-3 Gene Silencing for Inhibiting Apoptosis in Insulinoma Cells and Human Islets

Protective effects of Lagerstroemia speciosa on 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in HIT-T15 pancreatic β cells

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