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首页> 外文期刊>Antioxidants and redox signalling >Glutathione peroxidase mimic ebselen improves glucose-stimulated insulin secretion in murine islets
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Glutathione peroxidase mimic ebselen improves glucose-stimulated insulin secretion in murine islets

机译：谷胱甘肽过氧化物酶模拟依布硒仑改善小鼠胰岛中葡萄糖刺激的胰岛素分泌

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摘要

Aims: Glutathione peroxidase (GPX) mimic ebselen and superoxide dismutase (SOD) mimic copper diisopropylsalicylate (CuDIPs) were used to rescue impaired glucose-stimulated insulin secretion (GSIS) in islets of GPX1 and(or) SOD1-knockout mice. Results: Ebselen improved GSIS in islets of all four tested genotypes. The rescue in the GPX1 knockout resulted from a coordinated transcriptional regulation of four key GSIS regulators and was mediated by the peroxisome proliferator-Activated receptor gamma coactivator 1 alpha (PGC-1α)-mediated signaling pathways. In contrast, CuDIPs improved GSIS only in the SOD1 knockout and suppressed gene expression of the PGC-1α pathway. Innovation: Islets from the GPX1 and(or) SOD1 knockout mice provided metabolically controlled intracellular hydrogen peroxide (H2O 2) and superoxide conditions for the present study to avoid confounding effects. Bioinformatics analyses of gene promoters and expression profiles guided the search for upstream signaling pathways to link the ebselen-initiated H2O2 scavenging to downstream key events of GSIS. The RNA interference was applied to prove PGC-1α as the main mediator for that link. Conclusion: Our study revealed a novel metabolic use and clinical potential of ebselen in rescuing GSIS in the GPX1-deficient islets and mice, along with distinct differences between the GPX and SOD mimics in this regard. These findings highlight the necessities and opportunities of discretional applications of various antioxidant enzyme mimics in treating insulin secretion disorders. Rebound Track: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16: 293-296, 2012) with the following serving as open reviewers: Regina Brigelius-Flohe, Vadim Gladyshev, Dexing Hou, and Holger Steinbrenner. Antioxid. Redox Signal. 20, 191-203.
机译：目的：谷胱甘肽过氧化物酶（GPX）模拟依布硒啉和超氧化物歧化酶（SOD）模拟二异丙基水杨酸铜（CuDIP）用于挽救GPX1和/或SOD1基因敲除小鼠的胰岛中受损的葡萄糖刺激的胰岛素分泌（GSIS）。结果：Ebselen改善了所有四种测试基因型的胰岛中的GSIS。 GPX1基因敲除的抢救是由四个关键GSIS调节剂的协调转录调控引起的，并由过氧化物酶体增殖物激活受体γ辅激活因子1α（PGC-1α）介导的信号传导途径介导。相反，CuDIP仅在SOD1基因敲除中改善了GSIS，并抑制了PGC-1α途径的基因表达。创新：GPX1和（或）SOD1基因敲除小鼠的胰岛为本研究提供了代谢控制的细胞内过氧化氢（H2O 2）和超氧化物条件，以避免产生混杂效应。基因启动子和表达谱的生物信息学分析指导了上游信号通路的探索，以将依伯硒烯引发的H2O2清除与GSIS的下游关键事件相关联。应用RNA干扰来证明PGC-1α是该链的主要介体。结论：我们的研究揭示了依布硒仑在GPX1缺乏的胰岛和小鼠中拯救GSIS的新的代谢用途和临床潜力，以及GPX和SOD模拟物在这方面的明显差异。这些发现强调了各种抗氧化剂酶模拟物在治疗胰岛素分泌疾病中酌情应用的必要性和机会。反弹轨迹：此项工作在标准同行评审中被拒绝，并被反弹同行评审（Antioxid Redox Signal 16：293-296，2012）挽救，以下人员作为公开审阅者：Regina Brigelius-Flohe，Vadim Gladyshev，侯德兴和Holger Steinbrenner。抗氧化。氧化还原信号。 20，191-203。

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