肥胖是许多恶性肿瘤的既定危险因素，尽管目前尚不确定疾病本身或减肥药物是否会导致更容易患癌症。本研究的目的是确定度拉糖肽对肥胖引起的遗传和表观遗传 DNA 损伤的影响，肥胖是癌症发展的关键因素。小鼠接受低脂或高脂饮食 12 周，然后用度拉鲁肽治疗 5 周。随后，使用彗星测定法检查 DNA 碱基的修饰。为了阐明潜在的分子机制，对氧化和甲基化的 DNA 碱基、氧化还原状态的变化、炎症细胞因子的水平以及一些 DNA 修复基因的表达水平进行了评估。喂食高脂肪饮食的动物表现出体重增加、DNA损伤增加、DNA碱基氧化和DNA高甲基化。此外，肥胖小鼠表现出炎症反应、氧化还原失衡和修复基因表达的改变。研究结果表明，度拉鲁肽在研究条件下不表现出遗传毒性。给予度拉鲁肽后，喂食高脂肪饮食的动物表现出较低的 DNA 损伤、较少的 DNA 碱基氧化和甲基化、恢复氧化还原平衡并改善炎症反应。此外，度拉鲁肽治疗恢复了上调的 DNMT1、Ogg1 和 p53 基因表达。总体而言，度拉鲁肽可有效维持肥胖动物的 DNA 完整性。它通过恢复氧化还原平衡、调节炎症反应和恢复改变的基因表达来减少氧化 DNA 损伤和高甲基化。这些发现证明了度拉鲁肽在治疗肥胖及其相关并发症方面的功效。© 2024 Wiley periodicals LLC。

Obesity is an established risk factor for numerous malignancies, although it remains uncertain whether the disease itself or weight-loss drugs are responsible for a greater predisposition to cancer. The objective of the current study was to determine the impact of dulaglutide on genetic and epigenetic DNA damage caused by obesity, which is a crucial factor in the development of cancer. Mice were administered a low-fat or high-fat diet for 12 weeks, followed by a 5-week treatment with dulaglutide. Following that, modifications of the DNA bases were examined using the comet assay. To clarify the underlying molecular mechanisms, oxidized and methylated DNA bases, changes in the redox status, levels of inflammatory cytokines, and the expression levels of some DNA repair genes were evaluated. Animals fed a high-fat diet exhibited increased body weights, elevated DNA damage, oxidation of DNA bases, and DNA hypermethylation. In addition, obese mice showed altered inflammatory responses, redox imbalances, and repair gene expressions. The findings demonstrated that dulaglutide does not exhibit genotoxicity in the investigated conditions. Following dulaglutide administration, animals fed a high-fat diet demonstrated low DNA damage, less oxidation and methylation of DNA bases, restored redox balance, and improved inflammatory responses. In addition, dulaglutide treatment restored the upregulated DNMT1, Ogg1, and p53 gene expression. Overall, dulaglutide effectively maintains DNA integrity in obese animals. It reduces oxidative DNA damage and hypermethylation by restoring redox balance, modulating inflammatory responses, and recovering altered gene expressions. These findings demonstrate dulaglutide's expediency in treating obesity and its associated complications.© 2024 Wiley Periodicals LLC.