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      PDGF signaling pathway in hepatic fibrosis pathogenesis and therapeutics

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          Abstract

          The platelet-derived growth factor (PDFG) signaling pathway exerts persistent activation in response to a variety of stimuli and facilitates the progression of hepatic fibrosis. Since this pathway modulates a broad spectrum of cellular processes, including cell growth, differentiation, inflammation and carcinogenesis, it has emerged as a therapeutic target for hepatic fibrosis and liver-associated disorders. The present review exhibits the current knowledge of the role of the PDGF signaling pathway and its pathological profiles in hepatic fibrosis, and assesses the potential of inhibitors which have been investigated in the experimental hepatic fibrosis model, in addition to the clinical challenges associated with these inhibitors.

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          Hepatic fibrosis: Concept to treatment.

          Christian Trautwein, Scott Friedman, Detlef Schuppan … (2015)
          Understanding the molecular mechanisms underlying liver fibrogenesis is fundamentally relevant to developing new treatments that are independent of the underlying etiology. The increasing success of antiviral treatments in blocking or reversing the fibrogenic progression of chronic liver disease has unearthed vital information about the natural history of fibrosis regression, and has established important principles and targets for antifibrotic drugs. Although antifibrotic activity has been demonstrated for many compounds in vitro and in animal models, none has been thoroughly validated in the clinic or commercialized as a therapy for fibrosis. In addition, it is likely that combination therapies that affect two or more key pathogenic targets and/or pathways will be needed. To accelerate the preclinical development of these combination therapies, reliable single target validation is necessary, followed by the rational selection and systematic testing of combination approaches. Improved noninvasive tools for the assessment of fibrosis content, fibrogenesis and fibrolysis must accompany in vivo validation in experimental fibrosis models, and especially in clinical trials. The rapidly changing landscape of clinical trial design for liver disease is recognized by regulatory agencies in the United States (FDA) and Western Europe (EMA), who are working together with the broad range of stakeholders to standardize approaches to testing antifibrotic drugs in cohorts of patients with chronic liver diseases.
          Article 0 comments Cited 236 times – based on 0 reviews     Review now
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            Mechanisms of Jak/STAT signaling in immunity and disease.

            Alejandro Villarino, Yuka Kanno, John R Ferdinand … (2015)
            More than two decades ago, experiments on the antiviral mechanisms of IFNs led to the discovery of JAKs and their downstream effectors, the STAT proteins. This pathway has since become a paradigm for membrane-to-nucleus signaling and explains how a broad range of soluble factors, including cytokines and hormones, mediate their diverse functions. Jak/STAT research has not only impacted basic science, particularly in the context of intercellular communication and cell-extrinsic control of gene expression, it also has become a prototype for transition from bench to bedside, culminating in the development and clinical implementation of pathway-specific therapeutics. This brief review synthesizes our current understanding of Jak/STAT biology while taking stock of the lessons learned and the challenges that lie ahead.
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              MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression

              Jeongeun Hyun, Sihyung Wang, Jieun Kim … (2016)
              Hedgehog (Hh) signalling regulates hepatic fibrogenesis. MicroRNAs (miRNAs) mediate various cellular processes; however, their role in liver fibrosis is unclear. Here we investigate regulation of miRNAs in chronically damaged fibrotic liver. MiRNA profiling shows that expression of miR-378 family members (miR-378a-3p, miR-378b and miR-378d) declines in carbon tetrachloride (CCl4)-treated compared with corn-oil-treated mice. Overexpression of miR-378a-3p, directly targeting Gli3 in activated hepatic stellate cells (HSCs), reduces expression of Gli3 and profibrotic genes but induces gfap, the inactivation marker of HSCs, in CCl4-treated liver. Smo blocks transcriptional expression of miR-378a-3p by activating the p65 subunit of nuclear factor-κB (NF-κB). The hepatic level of miR-378a-3p is inversely correlated with the expression of Gli3 in tumour and non-tumour tissues in human hepatocellular carcinoma. Our results demonstrate that miR-378a-3p suppresses activation of HSCs by targeting Gli3 and its expression is regulated by Smo-dependent NF-κB signalling, suggesting miR-378a-3p has therapeutic potential for liver fibrosis.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Med Rep
                Journal ID (iso-abbrev): Mol Med Rep
                Title: Molecular Medicine Reports
                Publisher: D.A. Spandidos
                ISSN (Print): 1791-2997
                ISSN (Electronic): 1791-3004
                Publication date (Print): December 2017
                Publication date (Electronic): 27 September 2017
                Publication date PMC-release: 27 September 2017
                Volume: 16
                Issue: 6
                Pages: 7879-7889
                Affiliations
                [1 ]Key Laboratory of Experimental Animal and Safety Evaluation, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310013, P.R. China
                [2 ]Department of Clinical Laboratory Medicine, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang 310009, P.R. China
                Author notes
                Correspondence to: Professor Chen-Huan Yu, Key Laboratory of Experimental Animal and Safety Evaluation, Zhejiang Academy of Medical Sciences, 182 Tianmushan Road, Hangzhou, Zhejiang 310013, P.R. China, E-mail: yuchenhuan2002@ 123456163.com
                Article
                Publisher ID: mmr-16-06-7879
                DOI: 10.3892/mmr.2017.7641
                PMC ID: 5779870
                PubMed ID: 28983598
                SO-VID: a00d6eb2-8b4f-4ca7-8011-602bdceed8cb
                Copyright © Copyright: © Ying et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                Date received : 23 September 2016
                Date accepted : 20 July 2017
                Categories
                Subject: Review

                Keywords: platelet-derived growth factor isoforms,hepatic fibrosis,signaling pathway,targeted drug,natural product,synergistic effect
                Data availability:
                Keywords: platelet-derived growth factor isoforms, hepatic fibrosis, signaling pathway, targeted drug, natural product, synergistic effect

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