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Berberine inhibits Smad and non-Smad signaling cascades and enhances autophagy against pulmonary fibrosis

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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.

Key message

  • 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.

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Acknowledgments

This work is in part supported by University Grant Commission (UGC-BSR/meritorious fellowship) New Delhi, India. The authors thank All India Institute of Medical Sciences (AIIMS) and Jawaharlal Nehru University (JNU), New Delhi, India, for their assistance and guidance in ultrastructural studies. The authors also thank Dr. Ramamurthy, director, Ultrafast Process Laboratory, University of Madras, for his assistance in confocal imaging.

Conflict of interest

The authors declared no conflict of interest.

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Authors and Affiliations

  1. Department of Biochemistry, Cell Biology Laboratory, University of Madras, Guindy Campus, Chennai, Tamil Nadu, 600025, India

    Palanivel Chitra, Gowrikumar Saiprasad & Ganapasam Sudhandiran

  2. Department of Zoology, University of Madras, Guindy Campus, Chennai, Tamil Nadu, 600025, India

    Ramar Manikandan

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  1. Palanivel Chitra
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  2. Gowrikumar Saiprasad
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  3. Ramar Manikandan
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  4. Ganapasam Sudhandiran
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Correspondence to Ganapasam Sudhandiran.

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Chitra, P., Saiprasad, G., Manikandan, R. et al. Berberine inhibits Smad and non-Smad signaling cascades and enhances autophagy against pulmonary fibrosis. J Mol Med 93, 1015–1031 (2015). https://doi.org/10.1007/s00109-015-1283-1

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  • DOI: https://doi.org/10.1007/s00109-015-1283-1

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