Kowluru Anjaneyulu
Biomedical Research Service, John D. Dingell VA Medical Center, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
Metabolites. 2020 Nov 24;10(12):480. doi: 10.3390/metabo10120480.
Compelling evidence from earlier studies suggests that the pancreatic beta cell is inherently weak in its antioxidant defense mechanisms to face the burden of protecting itself against the increased intracellular oxidative stress following exposure to proinflammatory cytokines. Recent evidence implicates novel roles for nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Noxs) as contributors to the excessive intracellular oxidative stress and damage under metabolic stress conditions. This review highlights the existing evidence on the regulatory roles of at least three forms of Noxs, namely Nox1, Nox2, and Nox4, in the cascade of events leading to islet beta cell dysfunction, specifically under the duress of chronic exposure to cytokines. Potential crosstalk between key signaling pathways (e.g., inducible nitric oxide synthase [iNOS] and Noxs) in the generation and propagation of reactive molecules and metabolites leading to mitochondrial damage and cell apoptosis is discussed. Available data accrued in investigations involving small-molecule inhibitors and antioxidant protein expression methods as tools toward the prevention of cytokine-induced oxidative damage are reviewed. Lastly, current knowledge gaps in this field, and possible avenues for future research are highlighted.
早期研究的有力证据表明，胰腺β细胞在抗氧化防御机制方面天生薄弱，难以应对接触促炎细胞因子后细胞内氧化应激增加所带来的自我保护负担。最近的证据表明，烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（Noxs）在代谢应激条件下对细胞内过度氧化应激和损伤有新作用。本综述重点介绍了现有证据，即至少三种形式的Noxs，即Nox1、Nox2和Nox4，在导致胰岛β细胞功能障碍的一系列事件中的调节作用，特别是在长期暴露于细胞因子的胁迫下。讨论了关键信号通路（如诱导型一氧化氮合酶[iNOS]和Noxs）在导致线粒体损伤和细胞凋亡的活性分子和代谢产物的产生和传播中的潜在相互作用。综述了在涉及小分子抑制剂和抗氧化蛋白表达方法作为预防细胞因子诱导的氧化损伤工具的研究中积累的现有数据。最后，强调了该领域目前的知识空白以及未来可能进行研究的途径。
