Formation of Omega 3-Derived Electrophiles During Inflammation

炎症过程中 Omega 3 衍生的亲电子试剂的形成

基本信息

批准号：
8891371
负责人：
Francisco Jose Schopfer
金额：
$ 36.37万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2011-09-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8891371
关键词：
Accounting Acute Address Anabolism Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Arachidonate 15-Lipoxygenase Arterial Fatty Streak Aspirin Asses Atherosclerosis Biochemical Biological Blood Vessels Cardiovascular Diseases Cardiovascular system Cause of Death Cell model Cells Cessation of life Clinical Research Cytochrome P450 Cytoprotection Data Development Diet Disease Endothelial Cells Enzymes Event Family member Fatty Acids Fatty acid glycerol esters Fish Oils Foundations Gene Expression Generations Glutathione Health Homeostasis Human In Vitro Inflammation Inflammatory Inflammatory Response Isoenzymes Knockout Mice Label Lead Lipids Lipoxygenase Low Density Lipoprotein Receptor Macrophage Activation Maps Measures Mediating Mediator of activation protein Modeling Molecular Target Mus Nature Omega-3 Fatty Acids Oxidoreductase PPAR gamma Pathway interactions Peritonitis Phase Physiological Plasma Polyunsaturated Fatty Acids Property Proteins Pump Reaction Reagent Regulation Research Resolution Signal Pathway Signal Transduction Smooth Muscle Myocytes Solid Structure Testing Tissues United States Zymosan adduct analytical tool animal tissue cell type cyclooxygenase 2 cytokine design enzyme substrate feeding human NOS2A protein improved in vivo in vivo Model macrophage neutrophil novel oxidation reaction rate stem vascular bed

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis accounts for three fourth of all deaths from cardiovascular disease and atherothrombotic diseases are projected to be the leading cause of death worldwide in 2020, representing a major health burden. Omega-3 (ω-3) polyunsaturated fatty acids exert potent anti-inflammatory actions and beneficial cardiovascular effects. Although these properties are widely recognized, the underlying mechanisms remain largely unknown. An electrophilic mapping of lipids formed during macrophage activation showed that keto-derived ω-3 fatty acids omega 3 derived-fatty acids were present at intracellular concentrations up to 200 nM. The formation of these species was dependent on COX-2, and administered aspirin increased the levels of these ω-3 electrophilic fatty acid oxo-derivatives (EFOX). Recently, EFOX have been shown to be formed in human macrophages, neutrophils and animal tissues subjected to inflammation. Additionally, EFOX have been found to form glutathione and protein adducts and to modulate the inflammatory pathways through activation of Nrf2 pathway, inhibition of cytokine expression and reduction of inducible nitric oxide synthase levels. The hypothesis of this proposal is that EFOX are biologically relevant molecules with anti-atherogenic properties formed during inflammation and atherosclerosis that transduce the beneficial effects of ω-3 fatty acids and aspirin through the electrophilic regulation of signaling pathways. To address this hypothesis we propose to chemically generate analytical tools (i.e. deuterated and labeled standards) to aid in the rigorous biological identification and quantitation of EFOX. These standards will be used for the analysis of biosynthetic pathways in macrophages and to assess the in vivo formation in a relevant murine model of atherosclerosis. The biochemical and signaling properties of these species and its targets will be analyzed using cellular models. Finally, the pharmacological effects of EFOX will be tested on a murine atherosclerosis model. At completion, we expect to have determined the different EFOX isomeric species and their in vivo relevance and formation. In addition, we expect to have gained a clear understanding of their electrophilic reactivities, modulation of phase 2 gene expression, in particular the Nrf2/KEAP1 pathway and their PPARγ activation. It is expected that this proposal will lead to a better understanding of ω-3 fatty acid effects and to improved pharmacological approaches to decrease atherosclerosis and its detrimental effects.

描述（由申请人证明）：四分之三的Alll Death Death Death Cular Ases的动脉粥样硬化预计是2020年在全球范围内的主要原因，抑制了主要的健康负担。未知。这些ω-3亲电脂肪酸氧衍生物（EFOX）在人类巨噬细胞，中性粒细胞和动物组织中形成，并通过NRF2途径激活炎症途径。一氧化氮合酶水平是Efox与生物学相关的分子，而动脉粥样硬化会导致ω-3脂肪和阿司匹林的效果。 EFOX将在巨噬细胞中分析生物合成途径，并评估动脉粥样硬化的一个INE模型中的体内形成。我们期望确定差异的Efomeric规范及其体内相关性和形成。了解ω-3脂肪酸效应并改善药物切割，以减少动脉粥样硬化ATS ATS有害的FFECT。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evaluation of 10-Nitro Oleic Acid Bio-Elimination in Rats and Humans.

10-硝基油酸在大鼠和人类中的生物消除评估。

DOI：
10.1038/srep39900
发表时间：
2017
期刊：
Scientific reports
影响因子：
4.6
作者：
Salvatore,SoniaR;Vitturi,DarioA;Fazzari,Marco;Jorkasky,DianeK;Schopfer,FranciscoJ
通讯作者：
Schopfer,FranciscoJ