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Objective: Exosomes from obese adipose contain dysregulated microRNAs linked to insulin signaling, as compared with lean controls, providing a direct connection between adiposity and insulin resistance. This study tested the hypotheses that gastric bypass surgery and its subsequent weight loss would normalize adipocyte-derived exosomal microRNAs associated with insulin signaling and the associated metabolome related to glucose homeostasis.Methods: African American female subjects with obesity (N = 6; age: 38.5 ± 6.8 years; BMI: 51.2 ± 8.8 kg/m2 ) were tested before and 1 year after surgery. Insulin resistance (HOMA), serum metabolomics, and global microRNA profiles of circulating adipocyte-derived exosomes were evaluated via ANCOVA and correlational analyses.Results: One year postsurgery, patients showed decreased BMI (-18.6 ± 5.1 kg/m2 ; P < 0.001), ameliorated insulin resistance (HOMA: 1.94 ± 0.6 presurgery, 0.49 ± 0.1 postsurgery; P < 0.001), and altered metabolites including branched chain amino acids (BCAA). Biological pathway analysis of predicted mRNA targets of 168 surgery-responsive microRNAs (P < 0.05) identified the insulin signaling pathway (P = 1.27E-10; 52/138 elements), among others, in the data set. The insulin signaling pathway was also a target of 10 microRNAs correlated to changes in HOMA (P < 0.05; r > 0.4), and 48 microRNAs correlated to changes in BCAA levels.Conclusions: These data indicate that circulating adipocyte-derived exosomes are modified following gastric bypass surgery and correlate to improved postsurgery insulin resistance. [ABSTRACT FROM AUTHOR]

Background: Innate immune responses are fine-tuned by small noncoding RNA molecules termed microRNAs (miRs) that modify gene expression in response to the environment. During acute infections, miRs can be secreted in extracellular vesicles (EV) to facilitate cell-to-cell genetic communication. The purpose of this study was to characterize the baseline population of miRs secreted in EVs in the airways of young children (airway secretory microRNAome) and examine the changes during rhinovirus (RV) infection, the most common cause of asthma exacerbations and the most important early risk factor for the development of asthma beyond childhood. Methods: Nasal airway secretions were obtained from children (≤3 yrs. old) during PCR-confirmed RV infections (n = 10) and age-matched controls (n = 10). Nasal EVs were isolated with polymer-based precipitation and global miR profiles generated using NanoString microarrays. We validated our in vivo airway secretory miR data in an in vitro airway epithelium model using apical secretions from primary human bronchial epithelial cells (HBEC) differentiated at air-liquid interface (ALI). Bioinformatics tools were used to determine the unified (nasal and bronchial) signature airway secretory miRNAome and changes during RV infection in children. Results: Multiscale analysis identified four signature miRs comprising the baseline airway secretory miRNAome: hsa-miR-630, hsa-miR-302d-3p, hsa- miR-320e, hsa-miR-612. We identified hsa-miR-155 as the main change in the baseline miRNAome during RV infection in young children. We investigated the potential biological relevance of the airway secretion of hsa-mir-155 using in silico models derived from gene datasets of experimental in vivo human RV infection. These analyses confirmed that hsa-miR-155 targetome is an overrepresented pathway in the upper airways of individuals infected with RV. Conclusions: Comparative analysis of the airway secretory microRNAome in children indicates that RV infection is associated with airway secretion of EVs containing miR-155, which is predicted in silico to regulate antiviral immunity. Further characterization of the airway secretory microRNAome during health and disease may lead to completely new strategies to treat and monitor respiratory conditions in all ages. [ABSTRACT FROM AUTHOR]

Hippocampal function varies along its septotemporal axis, with the septal (dorsal) pole more frequently involved in spatial learning and memory and the temporal (ventral) pole playing a greater role in emotional behaviors. One feature that varies across these subregions is adult neurogenesis. New neurons are more numerous in the septal hippocampus but are more active in the temporal hippocampus during water maze training. However, many other aspects of adult neurogenesis remain unexplored in the context of septal versus temporal subregions. In addition, the dentate gyrus contains another functionally important anatomical division along the transverse axis, with the suprapyramidal blade showing greater experience-related activity than the infrapyramidal blade. Here we ask whether new neurons differ in their rates of survival and maturation along the septotemporal and transverse axes. We found that neurogenesis is initially higher in the infrapyramidal than suprapyramidal blade, but these cells are less likely to survive, resulting in similar densities of neurons in the two blades by four weeks. Across the septotemporal axis, neurogenesis was higher in septal than temporal pole, while the survival rate of new neurons did not differ. Maturation was assessed by immunostaining for the neuronal marker, NeuN, which increases in expression level with maturation, and for the immediate-early gene, Arc, which suggests a neuron is capable of undergoing activity-dependent synaptic plasticity. Maturation occurred approximately 1-2 weeks earlier in the septal pole than in the temporal pole. This suggests that septal neurons may contribute to function sooner; however, the prolonged maturation of new temporal neurons may endow them with a longer window of plasticity during which their functions could be distinct from those of the mature granule cell population. These data point to subregional differences in new neuron maturation and suggest that changes in neurogenesis could alter different hippocampus-dependent behaviors with different time courses. [ABSTRACT FROM AUTHOR]

Background The pathogenesis of nonalcoholic fatty liver disease (NAFLD) has been attributed to increased systemic inflammation and insulin resistance mediated by visceral adipose tissue (VAT), although the exact mechanisms are undefined. Exosomes are membrane-derived vesicles containing messenger RNA, microRNA, and proteins, which have been implicated in cancer, neurodegenerative, and autoimmune diseases, which we postulated may be involved in obesity-related diseases. We isolated exosomes from VAT, characterized their content, and identified their potential targets. Targets included the transforming growth factor beta (TGF-β) pathway, which has been linked to NAFLD. We hypothesized that adipocyte exosomes would integrate into HepG2 and hepatic stellate cell lines and cause dysregulation of the TGF-β pathway. Methods Exosomes from VAT from obese and lean patients were isolated and fluorescently labeled, then applied to cultured hepatic cell lines. After incubation, culture slides were imaged to detect exosome uptake. In separate experiments, exosomes were applied to cultured cells and incubated 48-h. Gene expression of TGF-β pathway mediators was analyzed by polymerase chain reaction, and compared with cells, which were not exposed to exosomes. Results Fluorescent-labeled exosomes integrated into both cell types and deposited in a perinuclear distribution. Exosome exposure caused increased tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and integrin αvβ-5 expression and decreased matrix metalloproteinase-7 and plasminogen activator inhibitor-1 expression in to HepG2 cells and increased expression of TIMP-1, TIMP-4, Smad-3, integrins αvβ-5 and αvβ-8, and matrix metalloproteinase-9 in hepatic stellate cells. Conclusions Exosomes from VAT integrate into liver cells and induce dysregulation of TGF-β pathway members in vitro and offers an intriguing possibility for the pathogenesis of NAFLD. [ABSTRACT FROM AUTHOR]