Type 2 diabetes mellitus (T2DM) is characterized by disrupted glucose homeostasis and metabolic abnormalities, with oxidative stress and inflammation playing pivotal roles in its pathophysiology. Poly(ADP-ribosyl)ation (PARylation) is a post-translational process involving the addition of ADP-ribose polymers (PAR) to target proteins. While preclinical studies have implicated PARylation in the interplay between oxidative stress and inflammation in T2DM, direct clinical evidence in humans remains limited. This study investigates the relationship between oxidative stress, PARylation, and inflammatory response in T2DM patients. This cross-sectional investigation involved 61 T2DM patients and 48 controls. PAR levels were determined in peripheral blood cells (PBMC) by ELISA-based methodologies. Oxidative stress was assessed in plasma and PBMC. In plasma, we monitored reactive oxygen metabolites (d-ROMs) and ferric-reducing antioxidant power. In PBMC, we measured the expression of antioxidant enzymes , and by qPCR. Further, we evaluated the expression of inflammatory mediators such as , , and by qPCR in PBMC. T2DM patients exhibited elevated PAR levels in PBMC and increased d-ROMs in plasma. Positive associations were found between PAR levels and d-ROMs, suggesting a link between oxidative stress and altered PAR metabolism. Mediation analysis revealed that d-ROMs mediate the association between HbA1c levels and PAR, indicating oxidative stress as a potential driver of increased PARylation in T2DM. Furthermore, elevated PAR levels were found to be associated with increased expression of pro-inflammatory cytokines and in the PBMC of T2DM patients. This study highlights that hyperactivation of PARylation is associated with poor glycemic control and the resultant oxidative stress in T2DM. The increase of PAR levels is correlated with the upregulation of key mediators of the inflammatory response. Further research is warranted to validate these findings and explore their clinical implications.

中文翻译：

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PAR 水平介导 2 型糖尿病患者 ROS 与炎症反应之间的联系


2 型糖尿病 (T2DM) 的特点是葡萄糖稳态破坏和代谢异常，氧化应激和炎症在其病理生理学中发挥着关键作用。聚 (ADP-核糖基) 化 (PARylation) 是一种翻译后过程，涉及将 ADP-核糖聚合物 (PAR) 添加到靶蛋白上。虽然临床前研究表明 PARylation 与 T2DM 氧化应激和炎症之间的相互作用有关，但人类的直接临床证据仍然有限。本研究探讨了 T2DM 患者氧化应激、PARylation 和炎症反应之间的关系。这项横断面调查涉及 61 名 T2DM 患者和 48 名对照者。通过基于 ELISA 的方法测定外周血细胞 (PBMC) 中的 PAR 水平。评估血浆和 PBMC 中的氧化应激。在血浆中，我们监测了活性氧代谢物 (d-ROM) 和铁还原抗氧化能力。在 PBMC 中，我们通过 qPCR 测量了抗氧化酶的表达。此外，我们通过 qPCR 评估了 PBMC 中炎症介质的表达，例如 、 、 和 。 T2DM 患者的 PBMC 中 PAR 水平升高，血浆中 d-ROM 增加。 PAR 水平与 d-ROM 之间存在正相关关系，表明氧化应激与 PAR 代谢改变之间存在联系。中介分析显示，d-ROM 介导 HbA1c 水平与 PAR 之间的关联，表明氧化应激是 T2DM 中 PARy 化增加的潜在驱动因素。此外，发现 PAR 水平升高与 T2DM 患者 PBMC 中促炎细胞因子表达增加有关。 这项研究强调，PARylation 的过度激活与 T2DM 中血糖控制不佳以及由此产生的氧化应激有关。 PAR 水平的增加与炎症反应关键介质的上调相关。需要进一步的研究来验证这些发现并探索其临床意义。