The Effects of Nitrate/Nitrite and Conjugated Linoleic Acid Supplementation on the Obese Asthmatic Pathology
硝酸盐/亚硝酸盐和共轭亚油酸补充剂对肥胖哮喘病理的影响
基本信息
- 批准号:9180182
- 负责人:
- 金额:$ 19.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-15 至 2018-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdipocytesAdultAmerican dietAnimal ModelAnimalsAnti-Inflammatory AgentsAnti-inflammatoryArea Under CurveArginineAsthmaBiological AvailabilityBiological MarkersBody CompositionBody mass indexBreathingBronchodilator AgentsCD4 Positive T LymphocytesCardiovascular DiseasesCardiovascular PhysiologyCell Culture TechniquesChronicClinicalClinical MarkersClinical ResearchComorbidityConjugated Linoleic AcidsDairy ProductsDiastolic blood pressureDietDietary SupplementationDiseaseDoseDrug CompoundingEnvironmentEnzymesEpidemiologic StudiesEpithelialExhalationExtrinsic asthmaFDA approvedFatty AcidsForced expiratory volume functionHelper-Inducer T-LymphocyteHomologous GeneHumanHuman VolunteersImmune responseIndividualInfarctionInflammationInflammatoryInjuryIntegrative MedicineInterventionInvestigational DrugsLabelLeptinLinkLungMeasuresMeatMediatingMediator of activation proteinMetabolicMetabolic DiseasesMetabolic syndromeMetabolismMitochondriaModelingNBL1 geneNOS2A geneNitratesNitric OxideNitric Oxide SynthaseNitritesNitrogen OxidesObesityOleic AcidsOutcomeOverweightOxidative StressPathologyPathway interactionsPhase I Clinical TrialsPhenotypePilot ProjectsPlaguePlasmaPost-Translational Protein ProcessingProductionPropertyProteinsPublishingPulmonary Function Test/Forced Expiratory Volume 1Quality of lifeQuestionnairesReactionReportingRespiratory Signs and SymptomsRespiratory physiologyRiskRuminantsSafetySchemeSeveritiesSignal TransductionSteroidsStructureSuperoxidesSupplementationSymptomsTestingTranscription Regulatory ProteinTransferaseUnsaturated Fatty AcidsUrineVital capacityadipokinesairway hyperresponsivenessairway inflammationasthmaticchemokinecytokinedietary constituentdietary supplementshealth care service utilizationimprovedinflammatory markerinsulin sensitivitymethacholinenitrationnitroalkenenitrogen dioxide radicalnitrosative stressnitrosyl hemoglobinnovel strategiesnovel therapeuticspi bondpre-clinicalresponsesafety study
项目摘要
Obesity is an asthma comorbidity associated with increased exacerbation rates and greater healthcare
utilization by mechanisms that are not explained by increases in Type 2 helper T cell (Th2)-related biomarkers
of airway inflammation associated with atopic asthma. In addition to an altered immune response in the lung
(Th1/Th17) obese asthmatics are also plagued by the low-grade, chronic, systemic inflammation attributed to
adipocyte secretion of pro-inflammatory chemokines and cytokines. Also contributing to systemic inflammation
is the uncoupling of nitric oxide synthase (NOS) by the arginine (Arg) metabolite, asymmetric dimethyl arginine
(ADMA). Low Arg/ADMA ratios are correlated with increasing body mass index and the resulting lower
fractional exhaled nitric oxide (FeNO). NOS uncoupling leads to low nitric oxide bioavailability and an increase
in superoxide anion production, thus contributing to the overall oxidative environment. The objective of this
study is to characterize the effects of the dietary supplements nitrate (NO3-) and nitrite (NO2-) (NOx) and
conjugated linoleic acid (cLA) on airway hyperresponsiveness and inflammation in obese asthmatics.
Epidemiological and clinical studies using NOx or cLA (individually) supplementations have reported on their
benefits in relation to disease pathologies including cardiovascular disease and metabolic disorder. A recent
pilot study we conducted demonstrated the formation of the electrophilic fatty acid, nitro-cLA (NO2-cLA) from
NOx + cLA supplementation in healthy subjects at concentrations ~3X endogenous basal levels. Importantly,
these levels are within a dose range that exerts systemic effects in preclinical animal models. This occurs
because nitroalkene fatty acids mediate anti-inflammatory signaling actions via post translational modification
of key transcriptional regulatory proteins and enzymes. These effects have been demonstrated with NO2-cLA
in animal and cell culture models and safety has been demonstrated using a synthetic homolog nitro-oleic acid
in FDA-approved phase 1 clinical trials. Since the individual dietary constituents NO3-, NO2-, and cLA are all
associated with decreased risk of metabolic syndrome symptoms and NO2-cLA is a modulator of inflammation,
it is hypothesized that obese asthmatics treated with NO3- + NO2- (NOx) + cLA will manifest improved
FeNO and reduced airway hyperresponsiveness and inflammation. This hypothesis will be tested by
pursuing two Specific Aims: Aim 1: Improve airway .NO bioavailability and airway hyperresponsiveness with
NOx + cLA treatment. Aim 2: Determine if NOx + cLA reduce the systemic and airway inflammation that
contributes to the obese asthmatic phenotype. FeNO and nitrosyl hemoglobin, inflammatory cytokines and
chemokines, NO2-cLA, and markers of oxidative stress will be measured as well as clinical markers of asthma
including airway hyperresponsiveness and the asthma control test. Positive clinical outcomes using NOx + cLA
dietary supplementation provides a complementary and integrative health intervention as well as a novel
therapeutic strategy for targeting the obese asthmatic pathology.
肥胖是一种哮喘共病,与病情加重和更好的医疗保健有关。
2型辅助T细胞(Th2)相关生物标志物的增加不能解释的机制的利用
与特应性哮喘相关的呼吸道炎症。除了肺部免疫反应的改变
(Th1/Th17)肥胖哮喘患者也受到低级别、慢性、全身性炎症的困扰
脂肪细胞分泌促炎趋化因子和细胞因子。也会导致全身炎症
是一氧化氮合酶(NOS)被精氨酸(Arg)代谢物不对称二甲基精氨酸解偶联
(ADMA)。Arg/ADMA比值低与体重指数增加和由此导致的较低相关
呼出部分一氧化氮(FeNO)。一氧化氮合酶解偶联导致一氧化氮生物利用度降低
在超氧阴离子的产生中,因此有助于整个氧化环境。这样做的目的是
研究是为了表征膳食补充剂硝酸盐(NO3-)和亚硝酸盐(NO2-)(NOx)和
共轭亚油酸对肥胖哮喘患者气道高反应性和炎症的影响。
使用NOx或CLA(单独)补充剂的流行病学和临床研究报告了他们的
与包括心血管疾病和代谢紊乱在内的疾病病理有关的益处。最近
我们进行的初步研究表明,从
NOx+CLA在健康受试者中的补充浓度约为内源性基础水平的3倍。重要的是
这些水平在临床前动物模型中产生全身影响的剂量范围内。这种情况会发生
因为硝基烯烃脂肪酸通过翻译后修饰介导抗炎信号作用
关键的转录调节蛋白和酶。这些效应已经在NO2-ClA中得到了演示
在动物和细胞培养模型中,已证明使用一种合成同系物硝基油酸是安全的
在FDA批准的第一阶段临床试验中。由于个体膳食成分NO3-、NO2-和CLA都是
与代谢综合征症状的风险降低有关,而NO2-CLA是炎症的调节因子,
推测NO3-+NO2-(NOx)+CLA对肥胖哮喘患者的治疗效果会有所改善。
FeNO和减少呼吸道高反应性和炎症。这一假设将通过以下方式检验
追求两个具体目标:目标1:改善气道.NO的生物利用度和气道高反应性
NOx+CLA处理。目的2:确定NOx+CLA是否能减少全身和呼吸道炎症
导致肥胖的哮喘表型。FeNO和亚硝基血红蛋白、炎性细胞因子和
将测量趋化因子、NO2-CLA和氧化应激标记物以及哮喘的临床标记物
包括呼吸道高反应性和哮喘控制试验。使用NOx+CLA获得积极的临床结果
饮食补充提供了一种补充和综合的健康干预以及一种新的
针对肥胖哮喘病理的治疗策略。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Stacy Lynn Gelhaus其他文献
Stacy Lynn Gelhaus的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Stacy Lynn Gelhaus', 18)}}的其他基金
LIMA: Lipid anti-Inflammatory Mediators in Asthma to reduce airway hyperresponsiveness in obese asthmatics
LIMA:哮喘中的脂质抗炎介质可减少肥胖哮喘患者的气道高反应性
- 批准号:
10369934 - 财政年份:2022
- 资助金额:
$ 19.25万 - 项目类别:
LIMA: Lipid anti-Inflammatory Mediators in Asthma to reduce airway hyperresponsiveness in obese asthmatics
LIMA:哮喘中的脂质抗炎介质可减少肥胖哮喘患者的气道高反应性
- 批准号:
10720482 - 财政年份:2022
- 资助金额:
$ 19.25万 - 项目类别:
The Effects of Nitrate/Nitrite and Conjugated Linoleic Acid Supplementation on the Obese Asthmatic Pathology
硝酸盐/亚硝酸盐和共轭亚油酸补充剂对肥胖哮喘病理的影响
- 批准号:
9297207 - 财政年份:2016
- 资助金额:
$ 19.25万 - 项目类别:
Defining PAH-mediated carcinogenesis in lung: CYP metabolism and B[a]P transport
定义 PAH 介导的肺癌致癌作用:CYP 代谢和 B[a]P 转运
- 批准号:
7502209 - 财政年份:2007
- 资助金额:
$ 19.25万 - 项目类别:
Defining PAH-mediated carcinogenesis in lung: CYP metabolism and B[a]P transport
定义 PAH 介导的肺癌致癌作用:CYP 代谢和 B[a]P 转运
- 批准号:
7679487 - 财政年份:2007
- 资助金额:
$ 19.25万 - 项目类别:
Defining PAH-mediated carcinogenesis in lung: CYP metabolism and B[a]P transport
定义 PAH 介导的肺癌致癌作用:CYP 代谢和 B[a]P 转运
- 批准号:
7406263 - 财政年份:2007
- 资助金额:
$ 19.25万 - 项目类别:
相似国自然基金
支链氨基酸代谢紊乱调控“Adipocytes - Macrophages Crosstalk”诱发2型糖尿病脂肪组织功能和结构障碍的作用及机制
- 批准号:81970721
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
相似海外基金
New development of cellular regeneration therapy in jaw bone using stem cells derived from adipocytes jaw bone
利用颌骨脂肪细胞来源的干细胞进行颌骨细胞再生治疗的新进展
- 批准号:
23K16058 - 财政年份:2023
- 资助金额:
$ 19.25万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
A novel mechanism of insulin resistance mediated by uric acid metabolism in adipocytes
脂肪细胞尿酸代谢介导胰岛素抵抗的新机制
- 批准号:
23K10969 - 财政年份:2023
- 资助金额:
$ 19.25万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Hypertrophic adipocytes as biophysical mediators of breast cancer progression
肥大脂肪细胞作为乳腺癌进展的生物物理介质
- 批准号:
10751284 - 财政年份:2023
- 资助金额:
$ 19.25万 - 项目类别:
Development of adipocytes for gene therapy that avoids cellular stress due to overexpression of therapeutic proteins
开发用于基因治疗的脂肪细胞,避免因治疗蛋白过度表达而造成的细胞应激
- 批准号:
23H03065 - 财政年份:2023
- 资助金额:
$ 19.25万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Functional analysis of bitter taste receptors in adipocytes and hepatocytes
脂肪细胞和肝细胞中苦味受体的功能分析
- 批准号:
23K05107 - 财政年份:2023
- 资助金额:
$ 19.25万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Elucidation of mechanisms for conversion of adipocytes to cancer-associated fibroblasts in osteosarcoma microenvironment
阐明骨肉瘤微环境中脂肪细胞转化为癌症相关成纤维细胞的机制
- 批准号:
23K19518 - 财政年份:2023
- 资助金额:
$ 19.25万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
Study on UCP-1 independent metabolic regulation by brown adipocytes
棕色脂肪细胞对UCP-1独立代谢调节的研究
- 批准号:
23K18303 - 财政年份:2023
- 资助金额:
$ 19.25万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
NKA/CD36 signaling in adipocytes promotes oxidative stress and drives chronic inflammation in atherosclerosis
脂肪细胞中的 NKA/CD36 信号传导促进氧化应激并驱动动脉粥样硬化的慢性炎症
- 批准号:
10655793 - 财政年份:2023
- 资助金额:
$ 19.25万 - 项目类别:
The mechanisms of the signal transduction from brown adipocytes to afferent neurons and its significance.
棕色脂肪细胞向传入神经元的信号转导机制及其意义。
- 批准号:
23K05594 - 财政年份:2023
- 资助金额:
$ 19.25万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Characterizing breast cancer invasion and proliferation when co-aggregated with adipocytes in multicellular spheroids created with a custom bioreactor to augment cell-cell connectivity.
当与多细胞球体中的脂肪细胞共聚集时,表征乳腺癌的侵袭和增殖,该多细胞球体是用定制生物反应器创建的,以增强细胞间的连接。
- 批准号:
10334113 - 财政年份:2022
- 资助金额:
$ 19.25万 - 项目类别: