NADPH oxidase is a target of hyperglycemia in type 2 diabetes mellitus (T2DM), which causes dysregulation of enzyme. Alterations in regulation of NADPH oxidase activity mediated receptor and non-receptor signaling in bone marrow granulocytes of mice with obesity-induced T2DM were studied. The animals fed high fat diet (516 kcal/100 g) for 16 weeks. NADPH oxidase-related generation of reactive species (RS) at normo- and hyperthermia was estimated using chemiluminescent analysis. The redox status of the cells was assessed by Redox Sensor Red CC-1. Baseline biochemical indicators in blood (glucose, cholesterol, HDL and LDL levels) were significant higher in T2DM mice versus controls. Using specific inhibitors, signaling mediated by formyl peptide receptors (FPRs) to NADPH oxidase was shown to involve PLC, PKC, cytochrome p450 in both control and T2DM groups and PLA2 in controls. In T2DM regulation of NADPH oxidase activity via mFpr1, a high-affinity receptors, occurred with a significant increase of the role of PKC isoforms and suppression of PLA2 participation. Significant differences between this regulation via mFpr2, low-affinity receptors, were not found. Non-receptor activation of NADPH oxidase with ionomycin (Ca ionophore) or phorbol ester (direct activator of PKC isoforms) did not revealed differences in the kinetic parameters between groups at 37 °C and 40 °C. When these agents were used together (synergistic effect), lower sensitivity of cells to ionophore was observed in T2DM at both temperatures. Redox status in responses to opsonized zymosan was higher in T2DM mice at 37 °C and similar to control levels at 40 °C. ROC-analysis identified Tmax, RS production and effect of opsonized zymosan as the most significant predictors for discriminating between groups. It was concluded that Ca-dependent/PKC-mediated regulation of NADPH oxidase activity was altered in BM granulocytes from diabetic mice.

中文翻译：

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肥胖诱发的 2 型糖尿病小鼠模型中粒细胞 NADPH 氧化酶活性的调节发生变化

NADPH 氧化酶是 2 型糖尿病 (T2DM) 中高血糖的靶标，会导致酶失调。研究了肥胖诱导的 T2DM 小鼠骨髓粒细胞中 NADPH 氧化酶活性介导的受体和非受体信号传导的变化。这些动物喂食高脂肪饮食（516 kcal/100 g）16周。使用化学发光分析估计正常和高温下 NADPH 氧化酶相关的反应性物质 (RS) 的产生。细胞的氧化还原状态由氧化还原传感器Red CC-1 评估。 T2DM 小鼠血液中的基线生化指标（葡萄糖、胆固醇、HDL 和 LDL 水平）显着高于对照组。使用特定抑制剂，甲酰基肽受体 (FPR) 介导的 NADPH 氧化酶信号传导涉及对照组和 T2DM 组中的 PLC、PKC、细胞色素 p450 以及对照组中的 PLA2。在 T2DM 中，通过高亲和力受体 mFpr1 对 NADPH 氧化酶活性的调节伴随着 PKC 异构体​​作用的显着增加和 PLA2 参与的抑制。未发现通过低亲和力受体 mFpr2 进行的这种调节之间存在显着差异。使用离子霉素（Ca 离子载体）或佛波酯（PKC 亚型的直接激活剂）对 NADPH 氧化酶进行非受体激活，未显示 37 °C 和 40 °C 下组间动力学参数存在差异。当这些药物一起使用时（协同效应），在两种温度下 T2DM 细胞对离子载体的敏感性均较低。 T2DM 小鼠在 37 °C 时对调理酵母聚糖的反应氧化还原状态较高，与 40 °C 时的对照水平相似。 ROC 分析确定 Tmax、RS 产生和调理酵母聚糖的效果是区分各组的最重要的预测因子。结论是，糖尿病小鼠的 BM 粒细胞中，Ca 依赖性/PKC 介导的 NADPH 氧化酶活性调节发生了改变。