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      MicroRNA expression profiling and bioinformatics analysis of dysregulated microRNAs in obstructive sleep apnea patients

      research-article
      , MD, , MD, , MD, PhD, , MD, PhD
      Medicine
      Wolters Kluwer Health
      bioinformatics analysis, microRNA, obstructive sleep apnea

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          Abstract

          Obstructive sleep apnea (OSA) is a common chronic obstructive sleep disease in clinic. The purpose of our study was to use bioinformatics analysis to identify microRNAs (miRNAs) that are differentially expressed between OSA patients and healthy controls.

          Serum samples were collected from OSA patients and healthy controls. To better reveal the sample specificity of differentially expressed microRNAs, supervised hierarchical clustering was conducted. We used the microT-CDS and TargetScan databases to predict target genes of the differentially expressed microRNAs and selected the common genes. The Search Tool for the Retrieval of Interacting Genes (STRING) was used to evaluate many coexpression relationships. Moreover, we used these potential microRNA-target pairs and coexpression relationships to construct a regulatory coexpression network using Cytoscape software. Functional analysis of microRNA target genes was conducted with FunRich.

          A total of 104 microRNAs that were differentially expressed between OSA patients and healthy controls were identified. Supervised hierarchical clustering was conducted based on the expression of the 104 microRNAs in the OSA patients and healthy controls. Overall, 6621 potential target genes were predicted, and 119 target genes were screened based on coexpression coefficients in the STRING database. A regulatory coexpression network was constructed that included 23 differentially expressed microRNAs and 18 of the most related potential target genes. Metabolic signaling pathways were the most highly enriched category. Differentially expressed microRNAs, such as hsa-miR-485-5p, hsa-miR-107, hsa-miR-574-5p, and hsa-miR-199-3p, might participate in OSA. The target gene CAD might also be closely related to OSA.

          Our results may provide a basis for the pathogenesis of OSA and the study of disease diagnosis, prevention, and treatment. However, more experiments are needed to verify these predictions.

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          Most cited references22

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          Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study.

          The effect of obstructive sleep apnoea-hypopnoea as a cardiovascular risk factor and the potential protective effect of its treatment with continuous positive airway pressure (CPAP) is unclear. We did an observational study to compare incidence of fatal and non-fatal cardiovascular events in simple snorers, patients with untreated obstructive sleep apnoea-hypopnoea, patients treated with CPAP, and healthy men recruited from the general population. We recruited men with obstructive sleep apnoea-hypopnoea or simple snorers from a sleep clinic, and a population-based sample of healthy men, matched for age and body-mass index with the patients with untreated severe obstructive sleep apnoea-hypopnoea. The presence and severity of the disorder was determined with full polysomnography, and the apnoea-hypopnoea index (AHI) was calculated as the average number of apnoeas and hypopnoeas per hour of sleep. Participants were followed-up at least once per year for a mean of 10.1 years (SD 1.6) and CPAP compliance was checked with the built-in meter. Endpoints were fatal cardiovascular events (death from myocardial infarction or stroke) and non-fatal cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, coronary artery bypass surgery, and percutaneous transluminal coronary angiography). 264 healthy men, 377 simple snorers, 403 with untreated mild-moderate obstructive sleep apnoea-hypopnoea, 235 with untreated severe disease, and 372 with the disease and treated with CPAP were included in the analysis. Patients with untreated severe disease had a higher incidence of fatal cardiovascular events (1.06 per 100 person-years) and non-fatal cardiovascular events (2.13 per 100 person-years) than did untreated patients with mild-moderate disease (0.55, p=0.02 and 0.89, p<0.0001), simple snorers (0.34, p=0.0006 and 0.58, p<0.0001), patients treated with CPAP (0.35, p=0.0008 and 0.64, p<0.0001), and healthy participants (0.3, p=0.0012 and 0.45, p<0.0001). Multivariate analysis, adjusted for potential confounders, showed that untreated severe obstructive sleep apnoea-hypopnoea significantly increased the risk of fatal (odds ratio 2.87, 95%CI 1.17-7.51) and non-fatal (3.17, 1.12-7.51) cardiovascular events compared with healthy participants. In men, severe obstructive sleep apnoea-hypopnoea significantly increases the risk of fatal and non-fatal cardiovascular events. CPAP treatment reduces this risk.
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            Control of translation and mRNA degradation by miRNAs and siRNAs.

            The control of translation and mRNA degradation is an important part of the regulation of gene expression. It is now clear that small RNA molecules are common and effective modulators of gene expression in many eukaryotic cells. These small RNAs that control gene expression can be either endogenous or exogenous micro RNAs (miRNAs) and short interfering RNAs (siRNAs) and can affect mRNA degradation and translation, as well as chromatin structure, thereby having impacts on transcription rates. In this review, we discuss possible mechanisms by which miRNAs control translation and mRNA degradation. An emerging theme is that miRNAs, and siRNAs to some extent, target mRNAs to the general eukaryotic machinery for mRNA degradation and translation control.
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              The mTOR Signalling Pathway in Human Cancer

              The conserved serine/threonine kinase mTOR (the mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation. It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival. mTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of multiple elements of the mTOR pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression) has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumour progression. Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogues deforolimus, everolimus and temsirolimus, are submitted to clinical trials for treating multiple cancers, alone or in combination with inhibitors of other pathways. Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma. Small molecules that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed. In this review, we aim to survey relevant research, the molecular mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma.
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                Author and article information

                Journal
                Medicine (Baltimore)
                Medicine (Baltimore)
                MEDI
                Medicine
                Wolters Kluwer Health
                0025-7974
                1536-5964
                August 2017
                25 August 2017
                : 96
                : 34
                : e7917
                Affiliations
                Department of Otolaryngology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
                Author notes
                []Correspondence: Yongxiang Wei, Department of Otolaryngology, Beijing Anzhen Hospital, No. 2 Anzhen Road, Beijing 100029, China (e-mail: anzhenent@ 123456163.com ).
                Article
                MD-D-17-02616 07917
                10.1097/MD.0000000000007917
                5572039
                28834917
                97f5ef77-fe60-40ae-9c80-ab4db942a879
                Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. http://creativecommons.org/licenses/by-nd/4.0

                History
                : 26 April 2017
                : 2 August 2017
                : 4 August 2017
                Categories
                6000
                Research Article
                Observational Study
                Custom metadata
                TRUE

                bioinformatics analysis,microrna,obstructive sleep apnea

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