Nitroxides as Protectors Against Oxidative Stress

事实证明，氮氧化物是一种有效的抗氧化剂，在许多疾病过程和/或代表过度氧化应激的情况下具有广泛的用途。事实是，氮氧化物在这样一系列疾病条件下发挥作用，说明了组织中自由基反应的重要性。同样，很明显，自由基在正常的分子信号通路和相关基因表达中也是重要的。此外，在小鼠的饮食中应用氮氧化物(先导化合物是坦波尔)已被发现可以预防肥胖。许多研究正在进行中，以阐明肥胖预防的机制。无论是在饮食中还是通过灌胃的方式给小鼠服用坦波尔，都会导致数百种尿液代谢产物的改变，其中包括许多坦波尔代谢物。特别令人感兴趣的是代谢物，如2，8-二羟基喹啉及其葡萄糖苷，与对照相比，其含量升高，而代谢物，如泛甲酸和异丁基肉碱，显著减弱。2，8-二羟基喹啉的存在与肠道微生物区系有关，这促使了一项研究，以确定坦普尔治疗是否会改变小鼠的肠道微生物区系谱。给药可显著改变肠道微生物区系组成，特别是与瘦肉型一致的非米克特/类杆菌比率。这一比率的变化是由于坦普尔药物降低了乳杆菌和胆盐水解酶的活性，导致牛磺酸-β-鼠李酸(T-β-MCA)的积累。升高的T-β-MCA抑制法尼醇(FXR)信号转导，从而影响脂质和葡萄糖代谢，这可能是Tempoll的抗肥胖特性的基础。坦波尔已被证明可以防止自由基对电离辐射和过氧化氢造成的DNA损伤。其他研究表明，逆转录酶抑制剂NRTI和齐多夫定对DNA损伤具有保护作用。最后，小鼠肿瘤的生长导致全身氧化应激，这一点从各种器官的DNA损伤中得到了证明。在含有坦波尔的饮食中，荷瘤动物对器官的DNA损伤显著减少。

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.