Consumption of diets high in fat and calories leads to hyperphagia and obesity, which is associated with chronic "low-grade" systemic inflammation. Ingestion of a high-fat diet alters the gut microbiota, pointing to a possible role in the development of obesity. The present study used Sprague-Dawley rats that, when fed a high-fat diet, exhibit either an obesity-prone (DIO-P) or obesity-resistant (DIO-R) phenotype, to determine whether changes in gut epithelial function and microbiota are diet or obese associated. Food intake and body weight were monitored daily in rats maintained on either low- or high-fat diets. After 8 or 12 wk, tissue was removed to determine adiposity and gut epithelial function and to analyze the gut microbiota using PCR. DIO-P but not DIO-R rats exhibit an increase in toll-like receptor (TLR4) activation associated with ileal inflammation and a decrease in intestinal alkaline phosphatase, a luminal enzyme that detoxifies lipopolysaccharide (LPS). Intestinal permeability and plasma LPS were increased together with phosphorylation of myosin light chain and localization of occludin in the cytoplasm of epithelial cells. Measurement of bacterial 16S rRNA showed a decrease in total bacterial density and an increase in the relative proportion of Bacteroidales and Clostridiales orders in high-fat-fed rats regardless of phenotype; an increase in Enterobacteriales was seen in the microbiota of DIO-P rats only. Consumption of a high-fat diet induces changes in the gut microbiota, but it is the development of inflammation that is associated with the appearance of hyperphagia and an obese phenotype.
BackgroundThe mechanisms governing the correlation between exposure to ultrafine particles and the increased incidence of cardiovascular disease remain unknown. Ultrafine particles appear to cross the pulmonary epithelial barrier into the bloodstream, raising the possibility of direct contact with the vascular endothelium.ObjectivesBecause endothelial inflammation is critical for the development of cardiovascular pathology, we hypothesized that direct exposure of human aortic endothelial cells (HAECs) to ultrafine particles induces an inflammatory response and that this response depends on particle composition.MethodsTo test the hypothesis, we incubated HAECs for 1–8 hr with different concentrations (0.001–50 μg/mL) of iron oxide (Fe2O3), yttrium oxide (Y2O3), and zinc oxide (ZnO) nanoparticles and subsequently measured mRNA and protein levels of the three inflammatory markers intra-cellular cell adhesion molecule-1, interleukin-8, and monocyte chemotactic protein-1. We also determined nanoparticle interactions with HAECs using inductively coupled plasma mass spectrometry and transmission electron microscopy.ResultsOur data indicate that nanoparticle delivery to the HAEC surface and uptake within the cells correlate directly with particle concentration in the cell culture medium. All three types of nanoparticles are internalized into HAECs and are often found within intracellular vesicles. Fe2O3 nanoparticles fail to provoke an inflammatory response in HAECs at any of the concentrations tested; however, Y2O3 and ZnO nanoparticles elicit a pronounced inflammatory response above a threshold concentration of 10 μg/mL. At the highest concentration, ZnO nanoparticles are cytotoxic and lead to considerable cell death.ConclusionsThese results demonstrate that inflammation in HAECs following acute exposure to metal oxide nanoparticles depends on particle composition.
Background-Several epidemiological studies have associated depressive symptoms with cardiovascular disease. We investigated whether depressive symptoms constituted a risk for coronary heart disease (CHD) and total mortality among an apparently healthy elderly cohort. Methods and Results-In a prospective cohort of 5888 elderly Americans (Ն65 years) who were enrolled in the Cardiovascular Health Study, 4493 participants who were free of cardiovascular disease at baseline provided annual information on their depressive status, which was assessed using the Depression Scale of the Center for Epidemiological Studies. These 4493 subjects were followed for 6 years for the development of CHD and mortality. The cumulative mean depression score was assessed for each participant up to the time of event (maximum 6-year follow-up). Using time-dependent, proportional-hazards models, the unadjusted hazard ratio associated with every 5-unit increase in mean depression score for the development of CHD was 1.15 (Pϭ0.006); the ratio for all-cause mortality was 1.29 (PϽ0.0001). In multivariate analyses adjusted for age, race, sex, education, diabetes, hypertension, cigarette smoking, total cholesterol, triglyceride level, congestive heart failure, and physical inactivity, the hazard ratio for CHD was 1.15 (Pϭ0.006) and that for all-cause mortality was 1.16 (Pϭ0.006). Among participants with the highest cumulative mean depression scores, the risk of CHD increased by 40% and risk of death by 60% compared with those who had the lowest mean scores. Conclusions-Among elderly Americans, depressive symptoms constitute an independent risk factor for the development of CHD and total mortality.
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