Nitroxides as Protectors Against Oxidative Stress

氮氧化物作为氧化应激的保护剂

• 批准号: 7594762
• 负责人: JAMES B MITCHELL
• 金额: $ 63.51万
• 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/7594762
• 关键词: Acute; Age; Anemia; Animals; Antioxidants; Attenuated; Autoimmune Diseases; Body Weight decreased; Cells; Chemicals; Chemoprevention; Chemopreventive Agent; Chronic; Clinical; Complex; Condition; Data; Disease; Encephalomyelitis; Exhibits; Experimental Autoimmune Encephalomyelitis; Food; Food Supplementation; Free Radicals; Gene Expression; Gene Expression Alteration; Genes; Goals; Human; Hydrogen Peroxide; Immune; Incidence; Inflammation; Inflammatory Response; Insulin-Like Growth Factor I; Ionizing radiation; Iron Regulatory Protein 2; Knockout Mice; Laboratories; Liver; MCF7 cell; Mediating; Metabolism; Modeling; Molecular; Molecular Profiling; Multiple Sclerosis; Mus; Nerve Degeneration; Nervous System Trauma; Nitric Oxide; Numbers; Obesity; Oxidative Stress; Oxygen; Paralysed; Parkinson Disease; Pathway interactions; Patients; Pattern; Process; Property; Quadripareses; Radiation; Range; Reaction; Reactive Oxygen Species; Role; Signal Pathway; Signal Transduction; Superoxide Dismutase; Superoxides; TP53 gene; Tissues; Transduction Gene; Weight; age related neurodegeneration; analog; brain tissue; cancer therapy; carcinogenesis; catalase; cell injury; drinking water; mouse model; novel strategies; pathogen; response; tempol; tumor

Nitroxides as Protectors against Oxidative Stress Summary Nitroxides 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 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 extensively studied the chemical mechanisms of nitroxides as antioxidants and are presently exploring how nitroxides can influence gene expression. Cells treated with non-toxic concentrations of several different nitroxide analogues; including a nitroxide incapable of cellular entry (and protection) all exhibit similar patterns of gene expression. A comparison was made of gene expression profiles for MCF7 cells exposed to nitroxides and various forms of oxidative stress (hydrogen peroxide, superoxide, nitric oxide, and ionizing radiation). A small subset of genes related to inflammatory responses was up regulated for all forms of oxidative stress; whereas, the same genes for nitroxide treatment were all down regulated, implying that nitroxides may be very effective in reducing inflammation. In collaborative studies, the effects of chronic administration of Tempol (supplemented in food) of two mouse models that exhibit neurodegeneration and/or neurological damage have been evaluated. Iron regulatory protein 2 knockout mice (IRP2-/-) exhibit age-related neurodegeneration (similar to Parkinsons disease patients). Tempol treatment attenuated the progression of neurodegeneration in IRP2-/- mice. Tempol was also shown to be highly protective in an experimental autoimmune encephalomyelitis (EAE) mouse model. The EAE mouse model is an acute or chronic demyelinating autoimmune disease whose clinical manifestations of paralysis and quadriparesis that closely resemble those observed in Multiple Sclerosis patients. These preliminary data are exciting and may represent a new approach toward treating these diseases. Lastly, we continue to search for the mechanism(s) of how long-term administration of Tempol (in the food or drinking water) results in dramatic weight reduction and a decrease in spontaneous tumor incidence in mice. With respect to weight reduction we have conducted an extensive gene expression array study evaluating tissue taken from age-matched control mice and mice on Tempol food supplementation for 1 month or 1 year. A number of genes have been identified in Tempol supplemented mice that are differentially up- or down-regulated in liver and brain tissue. Finally, Tempol administration also significantly delays the onset of tumors in Atm and p53 deficient mice and more recently in Fanconis Anemia knockout mice. We have recently found that systemic levels of IGF-1 are decreased in Tempol treated animals, similar to that observed in caloric restricted animals. Gene expression alterations selected tissues from control versus Tempol-treated mice are currently being evaluated. These studies will hopefully enable us to better understand the complex cellular/molecular mechanisms of nitroxides that trigger responses important in the antioxidant properties of nitroxides as well as those related to weight and the chemopreventive findings.

氮氧自由基作为抗氧化应激的保护剂概述氮氧自由基被证明在许多代表过度氧化应激的疾病过程和/或病症中具有广泛的用途。氮氧自由基在这样一系列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。我们已经广泛地研究了氮氧化物作为抗氧化剂的化学机制，目前正在探索氮氧化物如何影响基因表达。用无毒浓度的几种不同的氮氧化物类似物处理的细胞;包括不能进入细胞（和保护）的氮氧化物，都表现出类似的基因表达模式。比较了MCF 7细胞暴露于氮氧化物和各种形式的氧化应激（过氧化氢，超氧化物，一氧化氮和电离辐射）的基因表达谱。与炎症反应相关的一小部分基因在所有形式的氧化应激中均上调;而氮氧化物处理的相同基因均下调，这意味着氮氧化物可能在减轻炎症方面非常有效。在合作研究中，评价了Tempol（在食物中补充）对两种表现出神经变性和/或神经损伤的小鼠模型的长期给药效果。铁调节蛋白2基因敲除小鼠（IRP 2-/-）表现出与年龄相关的神经变性（类似于帕金森病患者）。Tempol治疗减弱了IRP 2-/-小鼠中神经变性的进展。Tempol在实验性自身免疫性脑脊髓炎（EAE）小鼠模型中也显示出高度保护性。EAE小鼠模型是一种急性或慢性脱髓鞘自身免疫性疾病，其瘫痪和四肢轻瘫的临床表现与多发性硬化患者中观察到的非常相似。这些初步数据令人兴奋，可能代表了治疗这些疾病的新方法。最后，我们继续寻找Tempol长期给药（在食物或饮用水中）如何导致小鼠体重显著减轻和自发肿瘤发病率降低的机制。关于体重减轻，我们进行了广泛的基因表达阵列研究，评估了从年龄匹配的对照小鼠和补充Tempol食物1个月或1年的小鼠中采集的组织。已经在补充Tempol的小鼠中鉴定了许多基因，这些基因在肝脏和脑组织中差异性上调或下调。最后，Tempol给药还显著延迟了Atm和p53缺陷小鼠以及最近Fanconis贫血敲除小鼠中肿瘤的发作。我们最近发现，全身水平的IGF-1降低Tempol治疗的动物，类似于热量限制的动物中观察到的。目前正在评估对照组与Tempol治疗组小鼠的基因表达变化。这些研究将使我们能够更好地了解复杂的细胞/分子机制的氮氧化物，触发反应的重要的抗氧化性能的氮氧化物，以及那些相关的重量和化学预防的结果。