Scavenging of Reactive Oxygen and Nitrogen Species by Cobalamins
钴胺素清除活性氧和氮
基本信息
- 批准号:8180470
- 负责人:
- 金额:$ 21.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-30 至 2014-08-31
- 项目状态:已结题
- 来源:
- 关键词:AgingAnimalsAntioxidantsAsthmaBeliefBindingBiologicalBiological AssayBiological ProcessBlood flowCell DeathCellsChronicChronic Fatigue SyndromeClinical TrialsCobalaminCoenzymesComplexDNADataDietDiseaseDoseEczemaElderlyEndothelial CellsEnzymesExhibitsExposure toGoalsHumanHydrogen PeroxideHydroxyl RadicalImmune responseIn VitroIndividualInflammationInflammatoryInflammatory ResponseKineticsLifeLipidsLiverMammalsMicronutrientsMitochondriaMolecularNitric OxideNitrogenNitrogen DioxideOrganOutcomeOxidative StressOxygenParaquatPeroxonitritePhysiciansPlatelet aggregationPlayPorphyrinsProteinsReactionResearchRheumatoid ArthritisRoleRotenoneSourceSuperoxide DismutaseSuperoxidesSupplementationTherapeutic StudiesTissuesVascular EndotheliumVitamin B 12Vitaminsage relatedaging populationcell injuryclinical effectcob(II)alamincofactordisorder preventionnervous system disordernitrosative stressnovelpreventprotective effectreaction ratevascular endothelial dysfunction
项目摘要
DESCRIPTION (provided by applicant): Cobalamins (Cbl, vitamin B12 derivatives) are essential cofactors in mammals. However, they also have clinical effects that cannot be fully explained solely by their cofactor role. For example, B12 has been used extensively by physicians over several decades to treat inflammatory disorders including chronic fatigue syndrome, rheumatoid arthritis, asthma, neurological diseases and eczema, with little understanding as to why B12 supplementation is beneficial. These diseases are associated with "oxidative and nitrosative stress" - elevated levels of Reactive Oxygen and Nitrogen Species (ROS/RNS), such as nitric oxide, superoxide, the hydroxyl radical, hydrogen peroxide and peroxynitrite. ROS/RNS react with biomolecules including proteins, DNA and lipids, frequently causing irreversible tissue and organ damage. We hypothesize that pharmacological doses of Cbl protect against ROS/RNS-initiated cell damage. We further hypothesize that an important mechanism for this protection is the direct scavenging of ROS/RNS by a major intracellular Cbl form, cob(II)alamin. The overall goal of this study is to determine whether Cbl is a broad spectrum antioxidant, capable of directly scavenging multiple ROS/RNS. In Specific Aim 1 the reactions between cob(II)alamin, Cbl(II), and four ROS/RNS species - hydrogen peroxide, superoxide, the hydroxyl radical and nitrogen dioxide - will be studied. Kinetic and product studies will allow rates and reaction mechanisms to be elucidated. This will provide invaluable information about the potential biological relevance of these reactions. In Specific Aim 2 CNCbl's ability to scavenge excess ROS and RNS in primary human aortic endothelial cells and prevent ROS/RNS-initiated cell death will be determined. CNCbl is the common Cbl form in vitamin supplements and is reduced to Cbl(II) upon entering cells. The vascular endothelium plays an important role in regulating blood flow, in inhibiting platelet aggregation and in the immune and inflammatory response. Vascular endothelial dysfunction is associated with oxidative/nitrosative stress. The ability of CNCbl to scavenge individual ROS/RNS (hydrogen peroxide, superoxide, the hydroxyl radical, and the nitrogen dioxide source peroxynitrite) will be determined using intracellular fluorescent or chemiluminescent probes and/or downstream assays specific for each ROS/RNS. The protective effects of CNCbl against cell death induced by each ROS/RNS will also be investigated. The current proposal challenges the widely-held belief that the sole biological role of Cbl is its coenzyme role in B12-dependent enzyme reactions. It also challenges the common belief that free (non-protein bound) Cbl has no biological role, despite the fact that ~50% free Cbl is achieved in cells upon supplementation, and that Cbl(II) is a radical species capable of reacting rapidly with ROS/RNS. The long-term goal is to identify the mechanism(s) by which Cbl protects against cellular oxidative/nitrosative stress, in order to assess the benefits of Cbl supplementation in the treatment of chronic inflammatory diseases.
PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE This study explores a novel mechanism by which vitamin B12 can provide protection against inflammatory and age-related diseases. Given a rapidly aging population, the study of the therapeutic potential of vitamin B12 is highly relevant since B12 deficiency is increasingly common, especially amongst the elderly.
描述(由申请人提供):钴胺素(Cbl,维生素B12衍生物)是哺乳动物必需的辅助因子。然而,它们也有临床效果,不能完全由它们的辅助因子作用来解释。例如,几十年来,医生们一直广泛使用B12来治疗炎症性疾病,包括慢性疲劳综合征、类风湿关节炎、哮喘、神经系统疾病和湿疹,但很少有人知道为什么补充B12是有益的。这些疾病与“氧化和亚硝化应激”有关,即活性氧和氮物种(ROS/RNS)水平升高,如一氧化氮、超氧化物、羟基自由基、过氧化氢和过氧亚硝酸盐。ROS/RNS与包括蛋白质、DNA和脂质在内的生物分子发生反应,经常造成不可逆的组织和器官损伤。我们假设药理学剂量的Cbl可以防止ROS/ rns引发的细胞损伤。我们进一步假设,这种保护的一个重要机制是通过主要的细胞内Cbl形式cob(II)alamin直接清除ROS/RNS。本研究的总体目标是确定Cbl是否是一种广谱抗氧化剂,能够直接清除多种ROS/RNS。在Specific Aim 1中,将研究cob(II)alamin, Cbl(II)和四种ROS/RNS(过氧化氢,超氧化物,羟基自由基和二氧化氮)之间的反应。动力学和产物研究将使速率和反应机制得以阐明。这将为这些反应的潜在生物学相关性提供宝贵的信息。在Specific Aim 2中,CNCbl清除人原发性主动脉内皮细胞中过量ROS和RNS的能力以及防止ROS/RNS引发的细胞死亡的能力将被确定。CNCbl是维生素补充剂中常见的Cbl形式,在进入细胞后被还原为Cbl(II)。血管内皮在调节血流、抑制血小板聚集、免疫和炎症反应中发挥重要作用。血管内皮功能障碍与氧化/亚硝化应激有关。CNCbl清除单个ROS/RNS(过氧化氢、超氧化物、羟基自由基和二氧化氮源过氧亚硝酸盐)的能力将通过细胞内荧光或化学发光探针和/或针对每种ROS/RNS的下游检测来确定。CNCbl对每种ROS/RNS诱导的细胞死亡的保护作用也将被研究。目前的建议挑战了广泛持有的信念,即Cbl的唯一生物学作用是其辅酶在b12依赖的酶反应中的作用。这也挑战了人们普遍认为的游离(非蛋白结合)Cbl没有生物学作用的观点,尽管事实上,在细胞中补充了~50%的游离Cbl,并且Cbl(II)是一种能够与ROS/RNS快速反应的自由基。长期目标是确定Cbl防止细胞氧化/亚硝化应激的机制,以评估补充Cbl在治疗慢性炎症性疾病中的益处。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Pulse radiolysis studies of the reactions of nitrogen dioxide with the vitamin B12 complexes cob(II)alamin and nitrocobalamin.
二氧化氮与维生素 B12 复合物 cob(II)alamin 和硝基钴胺素反应的脉冲放射分解研究。
- DOI:10.1016/j.jinorgbio.2014.09.014
- 发表时间:2015
- 期刊:
- 影响因子:3.9
- 作者:Dassanayake,RohanS;Cabelli,DianeE;Brasch,NicolaE
- 通讯作者:Brasch,NicolaE
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