Project description:Asthma is a complex syndrome associated with episodic decompensations provoked by aeroaller-gen exposures. The underlying pathophysiological states driving exacerbations are latent in the resting state and do not adequately inform biomarker-driven therapy. A better understanding of the pathophysiological pathways driving allergic exacerbations is needed. We hypothesized that disease-associated pathways could be identified in humans by unbiased metabolomics of bron-choalveolar fluid (BALF) during the peak inflammatory response provoked by a bronchial aller-gen challenge. We analyzed BALF metabolites in samples from 12 volunteers who underwent segmental bronchial antigen provocation (SBP-Ag). Metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC–MS/MS) followed by pathway analysis and cor-relation with airway inflammation. SBP-Ag induced statistically significant changes in 549 fea-tures that mapped to 72 uniquely identified metabolites. From these features, two distinct induci-ble metabolic phenotypes were identified by the principal component analysis, partitioning around medoids (PAM) and k-means clustering. Ten index metabolites were identified that in-formed the presence of asthma-relevant pathways, including unsaturated fatty acid produc-tion/metabolism, mitochondrial beta oxidation of unsaturated fatty acid, and bile acid metabolism. Pathways were validated using proteomics in eosinophils. A segmental bronchial allergen chal-lenge induces distinct metabolic responses in humans, providing insight into pathogenic and pro-tective endotypes in allergic asthma.
Project description:Environmental and host predictors of asthma control in older asthmatic patients (>65 years old) are poorly understood.To examine the effects of residential exposure to traffic exhaust and other environmental and host predictors on asthma control in older adults.One hundred four asthmatic patients 65 years of age or older from allergy and pulmonary clinics in greater Cincinnati, Ohio, completed the validated Asthma Control Questionnaire (ACQ), pulmonary function testing, and skin prick testing to 10 common aeroallergens. Patients had a physician's diagnosis of asthma, had significant reversibility in forced expiratory volume in 1 second or a positive methacholine challenge test result, and did not have chronic obstructive pulmonary disease. The mean daily residential exposure to elemental carbon attributable to traffic (ECAT) was estimated using a land-use regression model. Regression models were used to evaluate associations among independent variables, ACQ scores, and the number of asthma exacerbations, defined as acute worsening of asthma symptoms requiring prednisone use, in the past year.In the adjusted model, mean daily residential exposure to ECAT greater than 0.39 ?g/m(3) was significantly associated with poorer asthma control based on ACQ scores (adjusted ? = 2.85; 95% confidence interval [CI], 0.58-5.12; P = .02). High ECAT levels were also significantly associated with increased risk of asthma exacerbations (adjusted odds ratio, 3.24; 95% CI, 1.01-10.37; P = .05). A significant association was found between higher body mass index and worse ACQ scores (adjusted ? = 1.15; 95% CI, 0.53-1.76; P < .001). Atopic patients (skin prick test positive) had significantly better ACQ scores than nonatopic patients (adjusted ? = -0.39; 95% CI, -0.67 to -0.11; P < .01).Higher mean daily residential exposure to traffic exhaust, obesity, and nonatopic status are associated with poorer asthma control among older asthmatic patients.
Project description:The objectives of this study were to understand the effect of phenolic compounds from fermented berry beverages on hyperglycemia and obesity in vivo using mice fed a high fat diet. Our hypothesis was that consumption of a fermented blueberry-blackberry beverage and its phenolic compounds would reduce the development of obesity and hyperglycemia in diet-induced obese mice. Body composition, histomorphological analysis of pancreatic islets and liver, and expression of genes involved in obesity and hyperglycemia were evaluated in order to explain the modulation of diet-induced obesity and hyperglycemia due to treatments. Total RNA was extracted from frozen pancreatic tissue of mice after 12 weeks of high-fat diet, 5 groups treated with sitagliptin, alcohol-free berry beverage (AFFB), 0.1X phenolic extract, 1X phenolic extract and 3X phenolic extract respectively, were compared to the control (water). Four replicates were included for each one of the treatments.
Project description:The severe harm of depression to human life has attracted great attention to neurologists, but its pathogenesis is extremely complicated and has not yet been fully elaborated. Here, we provided a new strategy for revealing the specific pathways of abnormal brain glucose catabolism in depression, which from the supply of energy substrates and the evaluation of mitochondrial structure and function. By using stable isotope-resolved metabolomics technique, we discovered the tricarboxylic acid cycle (TCA cycle) is blocked and the gluconeogenesis is abnormally activated in chronic unpredictable mild stress (CUMS) rats. In addition, our results showed an interesting phenomenon that the brain attempted to activate all possible metabolic enzymes in energy-producing pathways, but CUMS rats still exhibited a low TCA cycle activity due to impaired mitochondria. Depression caused mitochondrial structure and function impaired, and then led to abnormal brain glucose catabolism. The combination of the stable isotope-resolved metabolomics and mitochondrial structure and function analysis can accurately clarify the mechanism of depression. The mitochondrial pyruvate carrier and acetyl-CoA maybe the key targets for depression treatment. The strategy provides a unique insight for exploring the mechanism of depression, the discovery of new targets, and the development of ideal novel antidepressants.
Project description:To identify biosignatures that describe these lifestyle susceptibility factors, we performed parallel exposures of regular weight (RW) C57BL/6 and diet-induced obese (DIO) C57BL/6 mice to cigarette smoke, either mainstream (MS) or sidestream (SS), mimicking both the smoker and environmental exposure through second-hand smoke, respectively. Transcriptional responses were measured by global microarray analysis of lung tissue.
Project description:To identify biosignatures that describe these lifestyle susceptibility factors, we performed parallel exposures of regular weight (RW) C57BL/6 and diet-induced obese (DIO) C57BL/6 mice to cigarette smoke, either mainstream (MS) or sidestream (SS), mimicking both the smoker and environmental exposure through second-hand smoke, respectively. Transcriptional responses were measured by global microarray analysis of lung tissue. Groups (N=8 biological replicates) of RW and DIO C57BL/6 mice (15-weeks old at start of exposures) were exposed to either filtered air (sham controls, SC), mainstream (MS) or sidestream (SS) cigarette smoke by nose-only inhalation exposure for 5 hr/day for a total of eight exposures over two weeks as follows: 5 consecutive days of exposure, followed by 2 days with no exposure, then three days of exposure, with necropsies occurring the day following the last exposure.
Project description:Background: Epigenetic marks, like asthma, are heritable. They are influenced by the environment, direct the maturation of T cellslymphocytes, and have been shown to enhance the development of allergic airways disease in mice. Thus, we hypothesized that epigenetic marks are associated with allergic asthma in inner-city children. Methods: We compared methylation patterns and gene expression in inner-city children with persistent atopic asthma versus healthy controls, using DNA and RNA from peripheral blood mononuclear cells (PBMCs) from inner city children aged 6-12 years with persistent atopic asthma children and healthy controls. Results were externally validated with the GABRIELA study population. Results: Comparing asthmatics (N=97) to controls (N=97), we identified 81 regions that were differentially methylated. Several immune genes were hypomethylated in asthmatics, including IL-13, RUNX3, and a number of specific genes relevant to natural killer cells (KIR2DL4, KIR2DL3, KIR3DL1, and KLRD1) and T cells lymphocytes (TIGIT). 14 differentially methylated regions (DMRs) were associated with the serum IgE concentration of IgE, including RUNX3. These results were internally and externally validated with a global methylation assessment using a different methodology in our inner-city cohort and an independent European cohort (GABRIELA). Hypo- and hypermethylated genes tended to be associated with increased and decreased gene expression, respectively (P<0.6x10-11 for asthma and ; P<0.01 for IgE). To further explore the relationship between methylation and gene expression, we created a matrix of genomic changes in methylation versus transcriptional changes (methyl eQTL) for asthma, and identified cis- and trans-regulated genes whose expression was related to asthma asthma-associated methylation marks. peripheral blood mononuclear cells (PBMCs) from 97 atopic asthmatic and 97 nonatopic nonasthmatic children
Project description:ObjectivesThe aim of this cross-sectional study was to investigate the association between sleep dimensions (duration, patterns, and disturbances) with body mass index (BMI), diet quality, and eating behaviors in school-aged children. Additionally, we aimed to investigate whether obesogenic eating behaviors (higher food responsiveness, lower satiety responsiveness, and less slowness in eating) and poor diet quality could mediate the potential association between sleep and obesity in school-aged children.Materials and methodsFor all participants (n = 588 children, age 5-12 years; 51% girls) we evaluated: sleep dimensions, BMI, diet quality, eating behaviors (food responsiveness, satiety responsiveness and slowness in eating). Linear regression models were used to test associations between exposure and outcome variables. Additionally, path analysis was conducted to test whether eating behaviors mediated the relationship between sleep and obesity.ResultsShorter sleep duration (β = -0.722, p = 0.009) and greater sleep disturbances (β = 0.031, p = 0.012) were significantly associated with BMI. Additionally, we observed that diet quality was significantly associated with sleep duration (β = 0.430, p = 0.004), the midpoint of sleep (β = -0.927, p < 0.001), and sleep disturbances (β = -0.029, p < 0.001). Among other findings, greater sleep disturbances were associated with food responsiveness (β = 0.017, p < 0.001), satiety responsiveness (β = 0.015, p < 0.001), and slowness in eating (β = 0.012, p < 0.001). Importantly, food responsiveness was found as significant mediator of the relationship between sleep and BMI (R = 0.427, R 2 = 0.182, p < 0.001).ConclusionsLate sleep patterns, short sleep duration, and greater sleep disturbances are significantly related with what and how school-aged children eat. Importantly, poor diet quality was significantly related to all three sleep dimensions, while eating behaviors had a significant relationship with greater sleep disturbances. These findings may be relevant to the development of behavioral targets to prevent childhood obesity, including sleep hygiene guidelines as a strategy to improve children's eating habits, as well as their BMI.