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Title: Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process

In this study, we determined the effects of transforming growth factor-beta (TGF-β) and Wnt/β-catenin signaling on myofibroblast differentiation of NIH/3T3 fibroblasts in vitro and evaluated the therapeutic efficacy of NSC668036 in bleomycin-induced pulmonary fibrosis murine model. In vitro study, NSC668036, a small organic inhibitor of the PDZ domain in Dvl, suppressed β-catenin-driven gene transcription and abolished TGF-β1-induced migration, expression of collagen I and α-smooth muscle actin (α-SMA) in fibroblasts. In vivo study, we found that NSC668036 significantly suppressed accumulation of collagen I, α-SMA, and TGF-β1 but increased the expression of CK19, Occludin and E-cadherin that can inhibit pulmonary fibrogenesis. Because fibrotic lung exhibit aberrant activation of Wnt/β-catenin signaling, these data collectively suggest that inhibition of Wnt/β-catenin signaling at the Dvl level may be an effective approach to the treatment of fibrotic lung diseases. - Highlights: • NSC668036 inhibited the proliferation and migration of NIH/3T3 fibroblasts. • NSC668036 suppressed the Wnt/β-catenin signaling pathway. • TGF-β-induced stimulation of profibrotic responses were inhibited by NSC668036. • NSC668036 can inhibit the development of bleomycin-induced pulmonary fibrosis.
Authors:
 [1] ;  [2] ;  [2] ;  [3] ;  [1] ;  [2] ;  [2] ;  [2] ;  [1] ;  [2] ;  [2] ;  [1] ;  [2] ;  [2] ;
  1. Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China)
  2. (China)
  3. Department of Respiratory Medicine, Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University (China)
Publication Date:
OSTI Identifier:
22462256
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 331; Journal Issue: 1; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACTIN; BLEOMYCIN; BUILDUP; COLLAGEN; DISEASES; FIBROBLASTS; FIBROSIS; GENES; GROWTH FACTORS; IN VITRO; IN VIVO; INHIBITION; LUNGS; MIGRATION; MUSCLES; PROLIFERATION; SIGNALS; STIMULATION; TRANSCRIPTION