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      Role of miR-223 in the pathophysiology of liver diseases

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          Abstract

          MiRNAs are small, noncoding RNAs, which can regulate gene expression posttranscriptionally, and they have emerged as key factors in disease biology by aiding in disease development and progression. MiR-223 is highly conserved during evolution and it was first described as a modulator of hematopoietic lineage differentiation. MiR-223 has an essential part in inflammation by targeting the nuclear factor-κB pathway and the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome. Recent studies have shown that miR-223 expression is deregulated in various types of liver diseases, including hepatitis virus infections, alcohol-induced liver injury, drug-induced liver injury, non-alcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma. As inflammatory and immune factors are involved in the occurrence and progress of liver diseases, deregulated miR-223 may participate in the pathogenesis of these conditions by influencing neutrophil infiltration, macrophage polarization, and inflammasome activation. This review first summarizes the present understanding of the biological functions of miR-223, including its gene location and transcription regulation, as well as its physiological role in hematopoietic differentiation. This review then focuses on the role of miR-223 in liver pathophysiology and its potential applications as a diagnostic biomarker and therapeutic target in liver diseases.

          Liver disease: a tiny trigger for liver damage

          A tiny RNA molecule involved with gene regulation may offer an appealing target for diagnosing and treating various liver diseases. MicroRNA-223 (miR-223) was first identified as controlling gene activity in a wide variety of immune cells. A review from researchers led by Yanning Liu at China’s Zhejiang University in Hangzhou details how abnormal miR-223 also contributes to liver damage in a variety of conditions, although questions still remain about how it functions in different liver disorders. The authors highlight studies linking miR-223 with the development of fibrosis and cirrhosis, and with the inflammatory response to injury from drugs, alcohol, or infection. This could make this microRNA a useful diagnostic biomarker. The authors also identify therapeutic opportunities to modulate this molecule, referring to several studies on the manipulation of miR-223 to treat hepatitis.

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          Most cited references60

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          Origins and Mechanisms of miRNAs and siRNAs.

          Over the last decade, approximately 20-30 nucleotide RNA molecules have emerged as critical regulators in the expression and function of eukaryotic genomes. Two primary categories of these small RNAs--short interfering RNAs (siRNAs) and microRNAs (miRNAs)--act in both somatic and germline lineages in a broad range of eukaryotic species to regulate endogenous genes and to defend the genome from invasive nucleic acids. Recent advances have revealed unexpected diversity in their biogenesis pathways and the regulatory mechanisms that they access. Our understanding of siRNA- and miRNA-based regulation has direct implications for fundamental biology as well as disease etiology and treatment.
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            Regulation of progenitor cell proliferation and granulocyte function by microRNA-223.

            MicroRNAs are abundant in animal genomes and have been predicted to have important roles in a broad range of gene expression programmes. Despite this prominence, there is a dearth of functional knowledge regarding individual mammalian microRNAs. Using a loss-of-function allele in mice, we report here that the myeloid-specific microRNA-223 (miR-223) negatively regulates progenitor proliferation and granulocyte differentiation and activation. miR-223 (also called Mirn223) mutant mice have an expanded granulocytic compartment resulting from a cell-autonomous increase in the number of granulocyte progenitors. We show that Mef2c, a transcription factor that promotes myeloid progenitor proliferation, is a target of miR-223, and that genetic ablation of Mef2c suppresses progenitor expansion and corrects the neutrophilic phenotype in miR-223 null mice. In addition, granulocytes lacking miR-223 are hypermature, hypersensitive to activating stimuli and display increased fungicidal activity. As a consequence of this neutrophil hyperactivity, miR-223 mutant mice spontaneously develop inflammatory lung pathology and exhibit exaggerated tissue destruction after endotoxin challenge. Our data support a model in which miR-223 acts as a fine-tuner of granulocyte production and the inflammatory response.
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              Reaching a genetic and molecular understanding of skeletal development.

              In the last ten years, we have made considerable progress in our genetic and molecular understanding of all aspects of skeletal development, chondrogenesis, joint formation, and osteogenesis. This review addresses the role of the principal growth factors and transcription factors affecting these different processes and presents, in several cases, the genetic cascade leading to cell differentiation.
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                Author and article information

                Contributors
                liuyanning@zju.edu.cn
                Journal
                Exp Mol Med
                Exp. Mol. Med
                Experimental & Molecular Medicine
                Nature Publishing Group UK (London )
                1226-3613
                2092-6413
                26 September 2018
                26 September 2018
                September 2018
                : 50
                : 9
                : 128
                Affiliations
                [1 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Department of Endocrinology and Metabolism, The First Affiliated Hospital of School of Medicine, , Zhejiang University, ; Hangzhou, China
                [2 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of School of Medicine, , Zhejiang University, ; Hangzhou, China
                Article
                153
                10.1038/s12276-018-0153-7
                6158210
                30258086
                d1e90dad-48f9-487f-ac19-71c6e0db9d6f
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 2 February 2018
                : 17 May 2018
                : 12 June 2018
                Funding
                Funded by: the Key R & D projects of Zhejiang province (2018C03019)
                Funded by: the National Natural Science Fund (81500616)and Zhejiang Provincial Natural Science Foundation (LQ16H070002)
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2018

                Molecular medicine
                Molecular medicine

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