Anti-inflammatory mechanisms, pharmacokinetics of novel metabolites of vitamin E
维生素E新型代谢物的抗炎机制、药代动力学
基本信息
- 批准号:8196666
- 负责人:
- 金额:$ 30.8万
- 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:2011-09-01 至 2013-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdjuvant ArthritisAnti-Inflammatory AgentsAnti-inflammatoryAntioxidantsArachidonate 5-LipoxygenaseAreaArthritisBiological AssayBiological AvailabilityCalciumCarrageenanCellsClinicalClinical ResearchComplementary and alternative medicineComplexDataDinoprostoneDiseaseDrug KineticsEnvironmentEnzymesExhibitsGenerationsHealth BenefitIbuprofenIn VitroInflammationInflammatoryIonophoresLOX geneLeadLeukotriene B4Lipoxygenase InhibitorsMeasurementMeasuresMediatingMethodsModelingNatureNew TerritoriesNon-Steroidal Anti-Inflammatory AgentsOutcomePTGS2 genePain managementPathway interactionsPharmaceutical PreparationsPlayProductionPropertyProstaglandin-Endoperoxide SynthaseRattusReactionResearchRoleSensitivity and SpecificitySignal TransductionSupplementationTestingTherapeutic EffectTimeTocopherolsTranslatingVitamin EVitaminsWorkZileutonanalogantiarthritic agentbasecelecoxibclinical efficacycomparative efficacycyclooxygenase 1improvedin vivoneutrophilnon-drugnovelpre-clinicalprophylacticsuccess
项目摘要
DESCRIPTION (provided by applicant): Vitamin E supplementation has been commonly used as a CAM (Complementary and Alternative Medicine). Clinical studies on vitamin E have focused exclusively on 1-tocopherol (1T), but they have yielded disappointing results regarding potential health benefits. However, we and others have shown that other vitamin E forms and especially their novel metabolites have unique anti-inflammatory properties that are not possessed by 1T. In particular, we have demonstrated that 13'-carboxychromanol (4-13'-COOH), a long-chain metabolite derived from 4- tocopherol (4T), inhibits cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) with potency similar to ibuprofen (a commonly used non-steroid anti-inflammatory drugs - NSAID) and zileuton (a clinically used 5-LOX inhibitor), respectively. Meanwhile, 3-tocopherol (3T) and 4T, but not 1T, inhibited COX-2-mediated prostaglandin E2 generation in cells and suppressed 5-LOX-mediated leukotriene B4 production in neutrophils by blocking calcium influx. In a preliminary study, we have found that 4T exhibited promising anti-arthritis effects. Since these vitamin E forms and metabolites inhibit both COXs- and 5-LOX-mediated pro-inflammatory pathways, we propose that these compounds may be superior to commonly used NSAIDs as anti-inflammatory and anti-arthritis agents because most NSAIDs only inhibit COX- catalyzed pathway. In addition, due to stronger inhibition of COXs and 5-LOX, we propose that 13'-COOH may be more effective than un-metabolized vitamins. To test these hypotheses, we will 1) investigate the effect and mechanism of long-chain carboxychromanols on COX-1/-2 and 5-LOX-catalyzed reactions in cell- and enzyme-based studies, 2) develop a new LC-MS-MS assay for vitamin E metabolites and characterize the pharmacokinetics of 4-13'-COOH, 3T and 4T, 3) translate the unique anti-inflammatory activity of 4-13'-COOH and vitamin E forms observed in vitro to a rat inflammation model and compare their anti-inflammatory efficacy to established NSAIDs, and 4) translate the anti-inflammatory actions to a disease relevant model by investigating anti-arthritis efficacy of 4-13'-COOH, 3T and 4T in the rat adjuvant-induced arthritis model. Our studies on these vitamin E forms and their novel metabolites may lead to discovery of a new class of anti-inflammatory agents that may be safer than some commonly used anti-inflammatory drugs and yet have similar or superior efficacy. The proposed studies will elucidate mechanisms of anti-inflammatory action and generate important preclinical data that are needed to insure maximally informative clinical efficacy studies on these compounds.
PUBLIC HEALTH RELEVANCE: This application will test the hypothesis that specific vitamin E forms and their novel metabolites, long-chain carboxychromanols, may be effective novel anti-inflammatory and anti-arthritis agents. This study may lead to discovery of superior therapy for treatment of inflammatory diseases over commonly used NSAIDs and therefore may result in NSAID replacement with vitamin E metabolites or their combination with NSAIDs in arthritis and pain management, a clinically important area.
描述(由申请人提供):补充维生素E已被用作CAM(互补和替代医学)。维生素E的临床研究仅专注于1-生育酚(1T),但在潜在的健康益处上产生了令人失望的结果。但是,我们和其他人表明,其他维生素E形式及其新型代谢产物具有1T不具有的独特抗炎特性。特别是,我们已经证明了13'-羧基酚(4-13'-COOH),这是一种衍生自4-育托酚(4T)的长链代谢物,抑制环氧酶(Cox-1和cox-1和cox-1和cox-1和cox-1和cox-1和cox-1和cox-1和cox-1和cox-cox-2)和5-脂肪氧合酶(5-lox),具有类似于Ibububuprofem的效力 - 一种常见的效率(一种常见的效率)(常见的效率)( Zileuton(一种临床使用的5-lox抑制剂)。同时,3-生育酚(3T)和4T,但不是1T,抑制了细胞中的Cox-2介导的前列腺素E2 E2的产生,并通过阻断钙涌入钙的中性粒细胞中抑制了5-Lox介导的白细胞B4产生。在一项初步研究中,我们发现4T表现出有希望的抗关节炎作用。由于这些维生素E形式和代谢产物都抑制了Coxs-和5-Lox介导的促炎途径,因此我们建议这些化合物可能优于常用的NSAID,因为大多数NSAID仅抑制Cox催化的催化途径。此外,由于对Coxs和5-Lox的抑制更强,我们建议13'-COOH可能比未代谢维生素更有效。要检验这些假设,我们将1)研究基于细胞和酶的研究中长链羧基酚对Cox-1/-2和5-lox催化反应的影响和机制,2)开发一种新的LC-MS-MS-MS-MS-MS分析,用于维生素E分类物,并表征4-13'-COOH的PharmacoKokinetics,3),3),3),3) 4-13'-COOH和维生素E形式的抗炎活性在体外观察到大鼠炎症模型,并将其抗炎功效与已建立的NSAID进行比较,4)通过研究4-13'-COOH的抗关节炎模型,将抗炎作用转化为疾病相关的模型,以探测4-13'-COOH,3T和4t cARIS 4T和4t cARIS 4T。我们对这些维生素E形式及其新型代谢产物的研究可能导致发现一种新的抗炎药,这些抗炎药可能比某些常用的抗炎药更安全,但具有相似或较高的功效。拟议的研究将阐明抗炎作用的机制,并生成重要的临床前数据,以确保对这些化合物的最大信息临床疗效研究。
公共卫生相关性:该应用将检验以下假设:特定的维生素E及其新型代谢产物长链羧基杂志可能是有效的新型抗炎和抗关节炎。这项研究可能导致发现了与常用NSAID相比的炎症性疾病的出色治疗,因此可能导致NSAID用维生素E代谢物替代,或者它们与关节炎和疼痛管理中的NSAID结合在一起,这是临床上重要的领域。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Qing Jiang其他文献
Qing Jiang的其他文献
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{{ truncateString('Qing Jiang', 18)}}的其他基金
The Role of a Novel Vitamin E Metabolite in Colon Cancer Prevention and Therapy
新型维生素 E 代谢物在结肠癌预防和治疗中的作用
- 批准号:
8230605 - 财政年份:2011
- 资助金额:
$ 30.8万 - 项目类别:
Anti-inflammatory mechanisms, pharmacokinetics of novel metabolites of vitamin E
维生素E新型代谢物的抗炎机制、药代动力学
- 批准号:
8326747 - 财政年份:2011
- 资助金额:
$ 30.8万 - 项目类别:
The Role of a Novel Vitamin E Metabolite in Colon Cancer Prevention and Therapy
新型维生素 E 代谢物在结肠癌预防和治疗中的作用
- 批准号:
8099210 - 财政年份:2011
- 资助金额:
$ 30.8万 - 项目类别:
Gamma-tocopherol as an effective anticancer agent for colon cancer
γ-生育酚作为结肠癌的有效抗癌剂
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7752828 - 财政年份:2009
- 资助金额:
$ 30.8万 - 项目类别:
Gamma-tocopherol as an effective anticancer agent for colon cancer
γ-生育酚作为结肠癌的有效抗癌剂
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7580180 - 财政年份:2009
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NATURAL VITAMIN E FORMS AS ANTI-INFLAMMATORY DRUGS
天然维生素 E 形式作为抗炎药物
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6801784 - 财政年份:2003
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$ 30.8万 - 项目类别:
NATURAL VITAMIN E FORMS AS ANTI-INFLAMMATORY DRUGS
天然维生素 E 形式作为抗炎药物
- 批准号:
7076096 - 财政年份:2003
- 资助金额:
$ 30.8万 - 项目类别:
NATURAL VITAMIN E FORMS AS ANTI-INFLAMMATORY DRUGS
天然维生素 E 形式作为抗炎药物
- 批准号:
7062439 - 财政年份:2003
- 资助金额:
$ 30.8万 - 项目类别:
NATURAL VITAMIN E FORMS AS ANTI-INFLAMMATORY DRUGS
天然维生素 E 形式作为抗炎药物
- 批准号:
7010222 - 财政年份:2003
- 资助金额:
$ 30.8万 - 项目类别:
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