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Protection of pancreatic β-cell by phosphocreatine through mitochondrial improvement via the regulation of dual AKT/IRS-1/GSK-3β and STAT3/Cyp-D signaling pathways
Cell Biology and Toxicology ( IF 6.1 ) Pub Date : 2021-08-28 , DOI: 10.1007/s10565-021-09644-7
Hongyan Wang 1 , Jie Ai 1 , Abdullah Shopit 1 , Mengyue Niu 1 , Nisar Ahmed 1 , Tsehaye Tesfaldet 1 , Zhongyuan Tang 2 , Xiaodong Li 3 , Yazeed Jamalat 1 , Peng Chu 1 , Jinyong Peng 1 , Xiaodong Ma 1 , Eskandar Qaed 1 , Guozhu Han 1 , Weisheng Zhang 4 , Jun Wang 5 , Zeyao Tang 1
Affiliation  

Diabetes mellitus (DM) is a metabolic syndrome, caused by insufficient insulin secretion or insulin resistance (IR). DM enhances oxidative stress and induces mitochondrial function in different kinds of cell types, including pancreatic β-cells. Our previous study has showed phosphocreatine (PCr) can advance the mitochondrial function through enhancing the oxidative phosphorylation and electron transport ability in mitochondria damaged by methylglyoxal (MG). Our aim was to explore the potential role of PCr as a molecule to protect mitochondria from diabetes-induced pancreatic β-cell injury with insulin secretion deficiency or IR through dual AKT/IRS-1/GSK-3β and STAT3/Cyclophilin D (Cyp-D) signaling pathways. MG-induced INS-1 cell viability, apoptosis, mitochondrial division and fusion, the morphology, and function of mitochondria were suppressed. Flow cytometry was used to detect the production of intracellular reactive oxygen species (ROS) and the changes of intracellular calcium, and the respiratory function was measured by oxygraph-2k. The expressions of AKT, IRS-1, GSK-3β, STAT3, and Cyp-D were detected using Western blot. The result showed that the oxidative stress–related kinases were significantly restored to the normal level after the pretreatment with PCr. Moreover, PCr pretreatment significantly inhibited cell apoptosis, decreased intracellular calcium, and ROS production, and inhibited mitochondrial division and fusion, and increased ATP synthesis damaged by MG in INS-1 cells. In addition, pretreatment with PCr suppressed Cytochrome C, p-STAT3, and Cyp-D expressions, while increased p-AKT, p-IRS-1, p-GSK-3β, caspase-3, and caspase-9 expressions. In conclusion, PCr has protective effect on INS-1 cells in vitro and in vivo, relying on AKT mediated STAT3/ Cyp-D pathway to inhibit oxidative stress and restore mitochondrial function, signifying that PCr might become an emerging candidate for the cure of diabetic pancreatic cancer β-cell damage.

Graphical abstract



中文翻译:

磷酸肌酸通过调节 AKT/IRS-1/GSK-3β 和 STAT3/Cyp-D 双重信号通路改善线粒体保护胰腺 β 细胞

糖尿病(DM)是一种代谢综合征,由胰岛素分泌不足或胰岛素抵抗(IR)引起。DM 增强氧化应激并诱导不同类型细胞(包括胰腺 β 细胞)中的线粒体功能。我们之前的研究表明,磷酸肌酸(PCr)可以通过增强甲基乙二醛(MG)损伤线粒体的氧化磷酸化和电子传递能力来促进线粒体功能。我们的目的是探索 PCr 作为一种分子,通过双重 AKT/IRS-1/GSK-3β 和 STAT3/亲环素 D(Cyp- D) 信号通路。MG诱导的INS-1细胞活力、凋亡、线粒体分裂和融合、线粒体的形态和功能均受到抑制。流式细胞仪检测细胞内活性氧(ROS)的产生和细胞内钙离子的变化,采用oxygraph-2k检测呼吸功能。Western blot检测AKT、IRS-1、GSK-3β、STAT3和Cyp-D的表达。结果表明,经PCr预处理后,氧化应激相关激酶明显恢复至正常水平。此外,PCr 预处理显着抑制细胞凋亡,减少细胞内钙和 ROS 的产生,抑制线粒体分裂和融合,增加 INS-1 细胞中 MG 损伤的 ATP 合成。此外,PCr 预处理抑制了细胞色素 C、p-STAT3 和 Cyp-D 的表达,同时增加了 p-AKT、p-IRS-1、p-GSK-3β、caspase-3 和 caspase-9 的表达。综上所述,

图形概要

更新日期:2021-08-29
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