Nitroxides as Protectors Against Oxidative Stress

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Nitroxides (lead compound, Tempol), which are potent antioxidants, are proving to have broad utility in several 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. We have published studies that shows Tempol application can provide protection of normal tissues exposed to radiation. In particular, these studies suggest that Tempol is worthy of being evaluated in clinical trials to protect against radiation-induced damage to normal tissues. Our recent studies over the past year have demonstrated that a high fat diet (HFD) in mice results obesity. Tempol added to the HFD significantly reduced the weight gain over time without any toxic effects. Further, we showed that when mice on this diet combined with an antibiotic cocktail for 3-6 weeks, significant reduction of gut microflora was observed along with changes in gene regulation, proteins, and bile acids in liver and adipose tissue. Tempol HFD showed an increase in Akkermansia muciniphila, considered a beneficial bacteria and known to be associated with a lean, anti-inflammatory phenotype. Antibiotic treatment did not change the increase in Akkermansia muciniphila. The study showed that Tempol moderating weight gain in mice fed a HFD involved changes to gut microbiome, bile acid composition, and led to significant changes in genes and proteins involved in fatty acid metabolism and storage.