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      Small RNA-sequence analysis of plasma-derived extracellular vesicle miRNAs in smokers and patients with chronic obstructive pulmonary disease as circulating biomarkers

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          ABSTRACT

          Extracellular vesicles (EVs) play a vital role in normal lung physiology to maintain homeostasis in the airways via intercellular communication. EVs include exosomes and microvesicles, and are characterized by their phospholipid bilayers. EVs have been recognized as novel circulating biomarkers of disease, which are released by different cell types. In this study, we used different EV isolation and purification methods to characterize the plasma-derived EV miRNAs from non-smokers, smokers and patients with COPD. A small RNA sequencing (RNA-seq) approach was adapted to identify novel circulating EV miRNAs. We found that plasma-derived EVs from non-smokers, smokers and patients with COPD vary in their size, concentration, distribution and phenotypic characteristics as confirmed by nanoparticle tracking analysis, transmission electron microscopy, and immunoblot analysis of EV surface markers. RNA-seq analysis confirmed the most abundant types of small RNAs, such as miRNAs, tRNAs, piRNAs snRNAs, snoRNAs and other biotypes in plasma-derived EVs. We mainly focused on miRNAs as novel biomarkers in smokers and patients with COPD for further analysis. Differential expression by DESeq2 identified distinct miRNA profiles (up-regulated: miR-22-3p, miR-99a-5p, miR-151a-5p, miR-320b, miR-320d; and down-regulated: miR-335-5p, miR-628-3p, miR-887-5p and miR-937-3p) in COPD versus smokers or non-smokers in a pairwise comparison. Gene set enrichment analysis (GSEA) of differentially expressed miRNAs revealed the top pathways, gene ontology and diseases associated with smokers and patients with COPD. We selectively validated miRNAs in EVs isolated from BEAS-2B cells treated with cigarette smoke extract by quantitative PCR analysis. For the first time, we report that plasma-derived EV miRNAs are novel circulating pulmonary disease biomarkers. Thus, molecular profiling of EV miRNAs has great translational potential for the development of biomarkers that may be used in the diagnosis, prognosis, and therapeutics of COPD.

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          Most cited references 41

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          miRDB: an online resource for microRNA target prediction and functional annotations

          MicroRNAs (miRNAs) are small non-coding RNAs that are extensively involved in many physiological and disease processes. One major challenge in miRNA studies is the identification of genes regulated by miRNAs. To this end, we have developed an online resource, miRDB (http://mirdb.org), for miRNA target prediction and functional annotations. Here, we describe recently updated features of miRDB, including 2.1 million predicted gene targets regulated by 6709 miRNAs. In addition to presenting precompiled prediction data, a new feature is the web server interface that allows submission of user-provided sequences for miRNA target prediction. In this way, users have the flexibility to study any custom miRNAs or target genes of interest. Another major update of miRDB is related to functional miRNA annotations. Although thousands of miRNAs have been identified, many of the reported miRNAs are not likely to play active functional roles or may even have been falsely identified as miRNAs from high-throughput studies. To address this issue, we have performed combined computational analyses and literature mining, and identified 568 and 452 functional miRNAs in humans and mice, respectively. These miRNAs, as well as associated functional annotations, are presented in the FuncMir Collection in miRDB.
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            ExoCarta: A Web-Based Compendium of Exosomal Cargo.

            Exosomes are membranous vesicles that are released by a variety of cells into the extracellular microenvironment and are implicated in intercellular communication. As exosomes contain RNA, proteins and lipids, there is a significant interest in characterizing the molecular cargo of exosomes. Here, we describe ExoCarta (http://www.exocarta.org), a manually curated Web-based compendium of exosomal proteins, RNAs and lipids. Since its inception, the database has been highly accessed (>54,000 visitors from 135 countries). The current version of ExoCarta hosts 41,860 proteins, >7540 RNA and 1116 lipid molecules from more than 286 exosomal studies annotated with International Society for Extracellular Vesicles minimal experimental requirements for definition of extracellular vesicles. Besides, ExoCarta features dynamic protein-protein interaction networks and biological pathways of exosomal proteins. Users can download most often identified exosomal proteins based on the number of studies. The downloaded files can further be imported directly into FunRich (http://www.funrich.org) tool for additional functional enrichment and interaction network analysis.
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              The pathology of chronic obstructive pulmonary disease.

              The pathogenesis of chronic obstructive pulmonary disease (COPD) is based on the innate and adaptive inflammatory immune response to the inhalation of toxic particles and gases. Although tobacco smoking is the primary cause of this inhalation injury, many other environmental and occupational exposures contribute to the pathology of COPD. The immune inflammatory changes associated with COPD are linked to a tissue-repair and -remodeling process that increases mucus production and causes emphysematous destruction of the gas-exchanging surface of the lung. The common form of emphysema observed in smokers begins in the respiratory bronchioles near the thickened and narrowed small bronchioles that become the major site of obstruction in COPD. The mechanism(s) that allow small airways to thicken in such close proximity to lung tissue undergoing emphysematous destruction remains a puzzle that needs to be solved.
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                Author and article information

                Journal
                J Extracell Vesicles
                J Extracell Vesicles
                ZJEV
                zjev20
                Journal of Extracellular Vesicles
                Taylor & Francis
                2001-3078
                2019
                7 November 2019
                : 8
                : 1
                Affiliations
                [a ]Department of Environmental Medicine, University of Rochester Medical Center , Rochester, NY, USA
                [b ]Department of Clinical & Translational Research, University of Rochester Medical Center , Rochester, NY, USA
                Author notes
                CONTACT Isaac Kirubakaran Sundar Isaac_Sundar@ 123456urmc.rochester.edu Department of Environmental Medicine, University of Rochester Medical Center , Box 850, 601 Elmwood Avenue, Rochester, NY 14642, USA
                Article
                1684816
                10.1080/20013078.2019.1684816
                6848892
                © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of The International Society for Extracellular Vesicles.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 6, Tables: 4, References: 62, Pages: 22
                Product
                Funding
                Funded by: National Heart, Lung, and Blood Institute 10.13039/100000050
                Award ID: HL137738
                Funded by: National Heart, Lung, and Blood Institute 10.13039/100000050
                Award ID: HL135613
                Funded by: National Heart, Lung, and Blood Institute 10.13039/100000050
                Award ID: 2R01HL085613
                Funded by: National Institute of Environmental Health Sciences 10.13039/100000066
                Award ID: ES028006
                Funded by: University of Rochester’s Lung Biology Strategic Plan
                Award ID: Pilot Project
                This work was supported by the National Heart, Lung, and Blood Institute [HL135613], [2R01HL085613] and National Institute of Environmental Health Sciences [ES028006].
                Categories
                Research Article

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