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Microarray profiling identifies extracellular circulating miRNAs dysregulated in cystic fibrosis.

ABSTRACT: Extracellular circulating miRNAs (ECmiRNAs) play a crucial role in cell-to-cell communication and serve as non-invasive biomarkers in a wide range of diseases, but their abundance and functional relevance in cystic fibrosis (CF) remain poorly understood. In this study, we employed microarray technology to identify aberrantly expressed plasma ECmiRNAs in CF and elucidate the functional relevance of their targets. Overall, we captured several ECmiRNAs abundantly expressed in CF. Expression levels of 11 ECmiRNAs differed significantly between CF and healthy control (HC) samples (FDR?

SUBMITTER: Ideozu JE

PROVIDER: S-EPMC6820733 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Microarray profiling identifies extracellular circulating miRNAs dysregulated in cystic fibrosis.

Ideozu Justin E JE Zhang Xi X Rangaraj Vittobai V McColley Susanna S Levy Hara H

Scientific reports 20191029 1

Extracellular circulating miRNAs (ECmiRNAs) play a crucial role in cell-to-cell communication and serve as non-invasive biomarkers in a wide range of diseases, but their abundance and functional relevance in cystic fibrosis (CF) remain poorly understood. In this study, we employed microarray technology to identify aberrantly expressed plasma ECmiRNAs in CF and elucidate the functional relevance of their targets. Overall, we captured several ECmiRNAs abundantly expressed in CF. Expression levels ...[more]

PMID: 31664087

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Project description:BackgroundPost-prandial and oral glucose tolerance test-related hypoglycemia is common in cystic fibrosis (CF); however, the underlying mechanisms are unclear.MethodsTo understand the relationship of hypoglycemia with meal-related glucose excursion and insulin secretion, we analyzed plasma glucose, insulin, C-peptide, glucagon and incretins obtained during standardized mixed-meal tolerance tests (MMTT) in non-diabetic adolescents and young adults with pancreatic insufficient CF (PI-CF).ResultsHypoglycemia, defined as glucose <70?mg/dL, occurred in 9/34 subjects at 150 (range:120-210) minutes following initial meal ingestion. Hypoglycemia[+] and hypoglycemia[-] groups did not differ in gender, age, lung function, HbA1c, or BMI. While 11/14 hypoglycemia[-] individuals displayed normal glucose tolerance (NGT), only 2/9 hypoglycemia[+] had NGT. Peak glucose was higher in hypoglycemia[+] vs hypoglycemia[-]. Compared to hypoglycemia[-] NGT, hypoglycemia[+] exhibited lower early-phase insulin secretion (ISR-AUC0-30min). ISR-AUC120-180min was not different in hypoglycemia[+] vs hypoglycemia[-] with abnormal glucose tolerance (AGT); however, glucose-AUC120-180min was lower in hypoglycemia[+] vs hypoglycemia[-] AGT. After adjusting for glucose-AUC, hypoglycemia[+] subjects tended to have higher ISR-AUC120-180min than hypoglycemia[-] AGT. Glucagon concentration did not differ between groups. Lower GLP-1-AUC30min and AUC180min and higher GIP-AUC30min were present in hypoglycemia[+] individuals.ConclusionHypoglycemia is common in PI-CF following MMTT and is associated with early glucose dysregulation (higher peak glucose), more impaired early-phase insulin secretion (lower ISR-AUC30min), and possibly late compensatory hyperinsulinemia. Further study is required to understand whether absence of glucagon difference in the hypoglycemia[+] individuals signals counterregulatory impairment, to delineate the role of incretins in hypoglycemia, and to determine the relationship of hypoglycemia to emergence of CFRD.

Project description:BACKGROUND:Extracellular vesicles (EVs) are nano-sized particles secreted by most cells. EVs carry nucleic acids that hold promise as potential biomarkers in various diseases. Human immunodeficiency virus type 1 (HIV) infects CD4+ T cells and induces immune dysfunction, inflammation, and EV secretion, but little is known about EV small RNA cargo in relation to immune dysregulation in HIV-infected individuals. Here, we characterize small RNA carried by circulating EVs in HIV-positive subjects on antiretroviral therapy (ART) relative to uninfected controls by next-generation RNA sequencing. RESULTS:Plasma EVs isolated from HIV-positive and HIV-negative subjects in test (n?=?24) and validation (n?=?16) cohorts were characterized by electron microscopy, nanoparticle tracking analysis, and immunoblotting for exosome markers. EVs were more abundant in plasma from HIV-positive compared to HIV-negative subjects. Small RNA sequencing of plasma EVs in the test cohort identified diverse small RNA species including miRNA, piRNA, snRNA, snoRNA, tRNA, and rRNA, with miRNA being the most abundant. A total of 351 different miRNAs were detected in plasma EVs, with the top 50 miRNAs accounting for 90% of all miRNA reads. miR-26a-5p was the most abundant miRNA, followed by miR-21-5p and miR-148-3p. qRT-PCR analysis showed that six miRNAs (miR-10a-5p, -?21-5p, -27b-3p, -?122-5p, -146a-5p, -?423-5p) were significantly increased in plasma EVs from HIV-positive compared to HIV-negative subjects in the validation cohort. Furthermore, miR-21-5p, -27b-3p, -146a-5p, and?-?423-5p correlated positively with metabolite markers of oxidative stress and negatively with anti-inflammatory polyunsaturated fatty acids. Over-representation and pathway enrichment analyses of miRNAs and their target genes predicted functional association with oxidative stress responses, interferon gamma signaling, Toll-like receptor signaling, TGF beta signaling, and Notch signaling. CONCLUSIONS:HIV-positive individuals on ART have increased abundance of circulating EVs carrying diverse small RNAs, with miRNAs being the most abundant. Several miRNAs associated with inflammation and oxidative stress are increased in circulating EVs of HIV-positive individuals, representing potential biomarkers of targetable pathways that contribute to disease pathogenesis.

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Microarray profiling identifies extracellular circulating miRNAs dysregulated in cystic fibrosis.

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Microarray profiling identifies extracellular circulating miRNAs dysregulated in cystic fibrosis.

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