Nitroxides as Protectors Against Oxidative Stress

氮氧化物作为氧化应激的保护剂

• 批准号: 10926566
• 负责人: James Mitchell
• 金额: $ 58.43万
• 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/10926566
• 关键词: Adipose tissue; Anti-Inflammatory Agents; Antibiotic Therapy; Antibiotics; Antioxidants; Bacteria; Bile Acids; Body Weight decreased; Cells; Chemicals; Chemoprevention; Clinical Trials; Diet; Disease; Exposure to; Free Radicals; Gene Expression; Gene Expression Regulation; Genes; Goals; High Fat Diet; Human; Immune; Ionizing radiation; Laboratories; Lead; Liver; Mediating; Metabolism; Modeling; Molecular; Mus; Nerve Degeneration; Normal tissue morphology; Obesity; Oxidative Stress; Oxygen; Pathologic; Pathway interactions; Phenotype; Process; Proteins; Publishing; Radiation; Radiation induced damage; Reaction; Reactive Oxygen Species; Role; Signal Pathway; Signal Transduction; Superoxide Dismutase; Thinness; Time; Tissues; Toxic effect; Weight Gain; cancer therapy; carcinogenesis; catalase; cell injury; fatty acid metabolism; gut microbiome; gut microbiota; pathogen; tempol

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.

氮氧自由基（铅化合物，Tempol），这是有效的抗氧化剂，被证明有广泛的用途，在几个疾病的过程和/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。我们已经发表的研究表明，Tempol应用可以为暴露于辐射的正常组织提供保护。特别是，这些研究表明，Tempol值得在临床试验中进行评估，以防止辐射引起的正常组织损伤。我们最近的研究在过去的一年中已经证明，高脂肪饮食（HFD）的小鼠肥胖的结果。添加到HFD中的Tempol显著降低了随时间的体重增加，而没有任何毒性作用。此外，我们发现，当这种饮食的小鼠与抗生素鸡尾酒结合3-6周时，观察到肠道微生物菌群的显著减少沿着肝脏和脂肪组织中基因调控、蛋白质和胆汁酸的变化。Tempol HFD显示嗜粘蛋白阿克曼氏菌的增加，嗜粘蛋白阿克曼氏菌被认为是有益的细菌，并且已知与瘦的抗炎表型相关。抗生素治疗没有改变嗜粘蛋白阿克曼氏菌的增加。该研究表明，Tempol减缓喂食HFD的小鼠体重增加涉及肠道微生物组，胆汁酸组成的变化，并导致参与脂肪酸代谢和储存的基因和蛋白质发生显着变化。

项目成果

Effect of Tempol on the prevention of irradiation-induced mucositis in miniature pigs.

• DOI: 10.1111/odi.12667
• 发表时间: 2017-09
• 期刊: Oral diseases
• 影响因子: 3.8
• 作者: Hu L;Wang Y;Cotrim AP;Zhu Z;Gao R;Zheng C;Goldsmith CM;Jin L;Zhang C;Mitchell JB;Baum BJ;Wang S
• 通讯作者: Wang S

The antioxidant tempol transforms gut microbiome to resist obesity in female C3H mice fed a high fat diet.

• DOI: 10.1016/j.freeradbiomed.2021.12.006
• 发表时间: 2022-01
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Choudhuri R;Sowers AL;Chandramouli GVR;Gamson J;Krishna MC;Mitchell JB;Cook JA
• 通讯作者: Cook JA

DNA (cytosine-5)-methyltransferase 1 as a mediator of mutant p53-determined p16(ink4A) down-regulation.

DNA (胞嘧啶-5)-甲基转移酶 1 作为突变 p53 确定的 p16(ink4A) 下调的介体。

• DOI: 10.1007/s11373-007-9222-y
• 发表时间: 2008
• 期刊: Journal of biomedical science
• 影响因子: 11
• 作者: Guo,Zhanjun;Tsai,Mong-Hsun;Shiao,Yih-Horng;Chen,Li-Han;Wei,Mei-Ling;Lv,Xing;Gius,David;Little,JohnB;Mitchell,JamesB;Chuang,EricY
• 通讯作者: Chuang,EricY

An efficient synthesis of 3-(N-piperidinemethyl)-2, 2, 5, 5-tetramethyl-1-oxy-3-pyrroline, a promising radioprotector for cancer radiotherapy.

3-(N-哌啶甲基)-2,2,5,5-四甲基-1-氧基-3-吡咯啉的有效合成，一种有前途的癌症放射治疗放射保护剂。

• DOI: 10.1016/j.tetlet.2014.08.028
• 发表时间: 2014
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Wu,Haitao;Coble,Vincent;Vasalatiy,Olga;Swenson,RolfE;Krishna,MuraliC;Mitchell,JamesB
• 通讯作者: Mitchell,JamesB

Effects of oxygen challenging to tissue redox and pO2 status.

氧气对组织氧化还原和 pO2 状态的影响。

• DOI: 10.1016/j.freeradbiomed.2018.10.454
• 发表时间: 2019
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Matsumoto,Ken-Ichiro;Mitchell,JamesB;Krishna,MuraliC
• 通讯作者: Krishna,MuraliC