title: Berberine inhibits Smad and non-Smad signaling cascades and enhances autophagy against pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative lung disorder of unknown aetiology. Transforming growth factor-β1 (TGF-β1)-mediated Smad and non-Smad signaling cascades are considered as central players in accelerating pulmonary fibrosis. We earlier reported berberine's amelioration against TGF-β1-mediated pro-fibrotic effects in bleomycin-induced pulmonary fibrosis. The present study aimed to determine the regulatory role of berberine on abrogated Smad 2/3 and FAK-dependent PI3K/Akt-mTOR signaling cascades in bleomycin-induced pulmonary fibrosis. Male Wistar rats were subjected to single intratracheal instillation of bleomycin (2.5 U/kg) on day 0, and berberine treatments were provided in either preventive or therapeutic modes, respectively. Berberine mitigated the elevated expression of fibrotic markers, α-smooth muscle actin (α-SMA), fibronectin, collagens I and III and reversed bleomycin-induced ultrastructural alterations in the lungs. Berberine inhibited the bleomycin-induced raise in p-Smad 2/3 and enhanced Smad 7 expression. Berberine blocked the activation of FAK and PI3K/Akt against bleomycin-induced dysregulation, with subsequent raise in PTEN expression. In addition, by inhibiting p-mTOR, berberine stimulated autophagy as evidenced by increase in Beclin-1, LC3-II levels with enhanced autophagosome formation. Cumulatively, through targeted inhibition of dysregulated Smad and FAK-dependent PI3K/Akt-mTOR signaling axis, berberine attenuated the fibrotic insults of bleomycin.
  
  
  CONCLUSIONS
  Berberine inhibits Smad 2/3 activation and enhances Smad 7 in bleomycin-induced rat lungs. Bleomycin-induced activation of FAK is inhibited by berberine. Berberine inhibits bleomycin-induced activation of PI3K/Akt cascade. Berberine inhibits mTOR activation to enhance autophagy and suppresses fibrotic markers.
authors: Department of Biochemistry, Cell Biology Laboratory, University of Madras, Guindy Campus, Chennai, Tamil Nadu, 600025, India.
authors: Palanivel
authors: P
authors: Chitra
authors: Department of Biochemistry, Cell Biology Laboratory, University of Madras, Guindy Campus, Chennai, Tamil Nadu, 600025, India.
authors: Gowrikumar
authors: G
authors: Saiprasad
authors: Department of Zoology, University of Madras, Guindy Campus, Chennai, Tamil Nadu, 600025, India.
authors: Ramar
authors: R
authors: Manikandan
authors: Department of Biochemistry, Cell Biology Laboratory, University of Madras, Guindy Campus, Chennai, Tamil Nadu, 600025, India. sudhandiran@yahoo.com.
authors: Ganapasam
authors: G
authors: Sudhandiran
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001599:Berberine / Q000627:therapeutic use*; D001761:Bleomycin / Q000633:toxicity; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D018613:Microscopy, Confocal; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism*
chemical_list: D051785:Smad Proteins; D001599:Berberine; D001761:Bleomycin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Autophagy; FAK; PI3K; Pulmonary fibrosis; Smad; mTOR