Nitroxides as Protectors Against Oxidative Stress

氮氧化物作为氧化应激的保护剂

• 批准号: 8938387
• 负责人: James Mitchell
• 金额: $ 63.42万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8938387
• 关键词: Acids; Animals; Antioxidants; Attenuated; Cells; Chemicals; Chemoprevention; DNA Damage; Diet; Disease; Exhibits; Free Radicals; Gene Expression; Goals; Human; Hydrogen Peroxide; Hydrolase; Immune; Ionizing radiation; Laboratories; Lactobacillus; Lead; Mediating; Metabolic; Metabolism; Modeling; Molecular; Mus; Nerve Degeneration; Obesity; Organ; Oxidative Stress; Oxygen; Pathway interactions; Phenotype; Process; Property; Radiation; Reaction; Reactive Oxygen Species; Reverse Transcriptase Inhibitors; Role; Signal Pathway; Signal Transduction; Superoxide Dismutase; Tissues; Transduction Gene; Urine; Zidovudine; bile salts; cancer therapy; carcinogenesis; catalase; cell injury; glucose metabolism; gut microflora; interest; lipid metabolism; muricholic acid; obesity prevention; pathogen; prevent; tempol; tumor; tumor growth

Nitroxides, which are potent antioxidants, are proving to have broad utility in a number of disease processes and/or conditions that represent excessive oxidative stress. The fact that nitroxides exert activity over such a range of disease conditions speaks to the importance of free radical reactions in tissue. Likewise, it is becoming apparent that free radicals are important in normal molecular signaling pathways and related gene expression. Further, nitroxide application (lead compound is Tempol) in the diet of mice has been found to prevent obesity. A number of studies are underway to elucidate the mechanism of obesity prevention. Tempol administration to mice either in the diet or by gavage resulted in hundreds of altered urine metabolic products including numerous Tempol metabolites. Of particular interest were metabolites such as 2,8-dihydroxylquinoline and its glucuonide, which were elevated and metabolites such as panthothenic acid and isobutrylcarnitine, which were significantly attenuated compared to control. The presence of 2,8-dihydroxylquinoline is related to the gut microflora, which prompted a study to determine if Tempol treatment would alter the gut microflora profile in mice. Tempol administration was found to significantly change the gut microflora composition, in particular the Firmicute/Bacteroidete ratio consistent with a lean phenotype. The change in this ratio resulted from Tempol-medicated reduction of Lactobacillus and bile salt hydrolase activity leading to an accumulation of tauro-beta- muricholic acid (T-beta-MCA). Elevated T-beta-MCA inhibits farnesoid (FXR) signaling thus impacting lipid and glucose metabolism, which may underlie the anti-obesity properties of Tempol. Tempol has been shown to protect against free radical mediated DNA damage for ionizing radiation and hydrogen peroxide. Additional studies have demonstrated protection of DNA damage from the reverse transcriptase inhibitor NRTI and zidovudine. Lastly, tumor growth in mice results in systemic oxidative stress as evidenced by DNA damage in a variety of organs. Tumor-bearing animals on a Tempol-containing diet exhibited significantly less DNA damage to organs.

氮氧自由基，这是有效的抗氧化剂，被证明有广泛的用途，在许多疾病的过程和/或条件，代表过度氧化应激。氮氧自由基在如此广泛的疾病条件下发挥活性的事实说明了组织中自由基反应的重要性。同样，自由基在正常分子信号通路和相关基因表达中的重要性也变得越来越明显。此外，已发现在小鼠饮食中施用氮氧化合物（先导化合物是Tempol）可预防肥胖。一些研究正在进行中，以阐明预防肥胖的机制。在饮食中或通过灌胃给予小鼠Tempol导致数百种改变的尿液代谢产物，包括许多Tempol代谢物。特别令人感兴趣的是代谢物，如2，8-二羟基喹啉及其葡糖苷酸，与对照组相比，这些代谢物升高，而代谢物如泛酸和异丁肉碱则显著减弱。2，8-二羟基喹啉的存在与肠道菌群有关，这促使一项研究确定Tempol治疗是否会改变小鼠的肠道菌群。发现Tempol施用显著改变肠道微生物群落组成，特别是与瘦表型一致的厚壁菌/拟杆菌比率。这一比例的变化是由于Tempol药物降低了乳酸杆菌和胆盐水解酶活性，导致牛磺-β-鼠胆酸（T-beta-MCA）积累。升高的T-beta-MCA抑制法尼醇（FXR）信号传导，从而影响脂质和葡萄糖代谢，这可能是Tempol抗肥胖特性的基础。Tempol已被证明可以防止电离辐射和过氧化氢引起的自由基介导的DNA损伤。另外的研究已经证明了逆转录酶抑制剂NRTI和齐多夫定对DNA损伤的保护作用。最后，小鼠中的肿瘤生长导致全身性氧化应激，如各种器官中的DNA损伤所证明的。含Tempo饮食的荷瘤动物对器官的DNA损伤显着减少。