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      Non-coding RNAs and Exosomes: Their Role in the Pathogenesis of Sepsis

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          Abstract

          Sepsis is characterized as an uncontrolled host response to infection, and it represents a serious health challenge, causing excess mortality and morbidity worldwide. The discovery of sepsis-related epigenetic and molecular mechanisms could result in improved diagnostic and therapeutic approaches, leading to a reduced overall risk for affected patients. Accumulating data show that microRNAs, non-coding RNAs, and exosomes could all be considered as novel diagnostic markers for sepsis patients. These biomarkers have been demonstrated to be involved in regulation of sepsis pathophysiology. However, epigenetic modifications have not yet been widely reported in actual clinical settings, and further investigation is required to determine their importance in intensive care patients. Further studies should be carried out to explore tissue-specific or organ-specific epigenetic RNA-based biomarkers and their therapeutic potential in sepsis patients.

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          Abstract

          Non-coding RNAs and exosomes present an opportunity for early diagnosis as well as an ability to interact with key points of the biological mechanisms, suggesting that measurement of non-coding RNAs and exosomes are a promising approach for intensive care patients.

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          Most cited references156

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          Nuclear export of microRNA precursors.

          MicroRNAs (miRNAs), which function as regulators of gene expression in eukaryotes, are processed from larger transcripts by sequential action of nuclear and cytoplasmic ribonuclease III-like endonucleases. We show that Exportin-5 (Exp5) mediates efficient nuclear export of short miRNA precursors (pre-miRNAs) and that its depletion by RNA interference results in reduced miRNA levels. Exp5 binds correctly processed pre-miRNAs directly and specifically, in a Ran guanosine triphosphate-dependent manner, but interacts only weakly with extended pre-miRNAs that yield incorrect miRNAs when processed by Dicer in vitro. Thus, Exp5 is key to miRNA biogenesis and may help coordinate nuclear and cytoplasmic processing steps.
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            Physiological and pathological roles for microRNAs in the immune system.

            Mammalian microRNAs (miRNAs) have recently been identified as important regulators of gene expression, and they function by repressing specific target genes at the post-transcriptional level. Now, studies of miRNAs are resolving some unsolved issues in immunology. Recent studies have shown that miRNAs have unique expression profiles in cells of the innate and adaptive immune systems and have pivotal roles in the regulation of both cell development and function. Furthermore, when miRNAs are aberrantly expressed they can contribute to pathological conditions involving the immune system, such as cancer and autoimmunity; they have also been shown to be useful as diagnostic and prognostic indicators of disease type and severity. This Review discusses recent advances in our understanding of both the intended functions of miRNAs in managing immune cell biology and their pathological roles when their expression is dysregulated.
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              Exosomal microRNA: a diagnostic marker for lung cancer.

              To date, there is no screening test for lung cancer shown to affect overall mortality. MicroRNAs (miRNAs) are a class of small noncoding RNA genes found to be abnormally expressed in several types of cancer, suggesting a role in the pathogenesis of human cancer. We evaluated the circulating levels of tumor exosomes, exosomal small RNA, and specific exosomal miRNAs in patients with and without lung adenocarcinoma, correlating the levels with the American Joint Committee on Cancer (AJCC) disease stage to validate it as an acceptable marker for diagnosis and prognosis in patients with adenocarcinoma of the lung. To date, 27 patients with lung adenocarcinoma AJCC stages I-IV and 9 controls, all aged 21-80 years, were enrolled in the study. Small RNA was detected in the circulating exosomes. The mean exosome concentration was 2.85 mg/mL (95% CI, 1.94-3.76) for the lung adenocarcinoma group versus 0.77 mg/mL (95% CI, 0.68-0.86) for the control group (P < .001). The mean miRNA concentration was 158.6 ng/mL (95% CI, 145.7-171.5) for the lung adenocarcinoma group versus 68.1 ng/mL (95% CI, 57.2-78.9) for the control group (P < .001). Comparisons between peripheral circulation miRNA-derived exosomes and miRNA-derived tumors indicated that the miRNA signatures were not significantly different. The significant difference in total exosome and miRNA levels between lung cancer patients and controls, and the similarity between the circulating exosomal miRNA and the tumor-derived miRNA patterns, suggest that circulating exosomal miRNA might be useful as a screening test for lung adenocarcinoma. No correlation between the exosomal miRNA levels and the stage of disease can be made at this point.
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                Author and article information

                Contributors
                Journal
                Mol Ther Nucleic Acids
                Mol Ther Nucleic Acids
                Molecular Therapy. Nucleic Acids
                American Society of Gene & Cell Therapy
                2162-2531
                15 May 2020
                04 September 2020
                15 May 2020
                : 21
                : 51-74
                Affiliations
                [1 ]Chronic Respiratory Diseases Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
                [2 ]Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Disease, Shahid Beheshti University of Medical Sciences, Tehran, Iran
                [3 ]Halal Research Center of IRI, FDA, Tehran, Iran
                [4 ]Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
                [5 ]Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, 40 Blossom Street, Boston, MA 02114, USA
                [6 ]Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
                Author notes
                []Corresponding author: Hamed Mirzaei, Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran. h.mirzaei2002@ 123456gmail.com
                [∗∗ ]Corresponding author: Michael R. Hamblin, Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, 40 Blossom Street, Boston, MA 02114, USA. hamblin@ 123456helix.mgh.harvard.edu
                Article
                S2162-2531(20)30138-4
                10.1016/j.omtn.2020.05.012
                7272511
                32506014
                c6645ff2-5c2d-4149-a6d6-f29d18f43ead
                © 2020 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Categories
                Article

                Molecular medicine
                sepsis,microrna,long non-coding rna,exosomes,biomarker,diagnosis,septic shock,critical care
                Molecular medicine
                sepsis, microrna, long non-coding rna, exosomes, biomarker, diagnosis, septic shock, critical care

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