Chitra Palanivel, Saiprasad Gowrikumar, Manikandan Ramar, Sudhandiran Ganapasam
Department of Biochemistry, Cell Biology Laboratory, University of Madras, Guindy Campus, Chennai, Tamil Nadu, 600025, India.
Department of Zoology, University of Madras, Guindy Campus, Chennai, Tamil Nadu, 600025, India.
J Mol Med (Berl). 2015 Sep;93(9):1015-31. doi: 10.1007/s00109-015-1283-1. Epub 2015 Apr 17.
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.
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.
特发性肺纤维化（IPF）是一种病因不明的纤维增生性肺部疾病。转化生长因子-β1（TGF-β1）介导的Smad和非Smad信号级联被认为是加速肺纤维化的核心因素。我们之前报道了黄连素对博来霉素诱导的肺纤维化中TGF-β1介导的促纤维化作用的改善。本研究旨在确定黄连素对博来霉素诱导的肺纤维化中被破坏的Smad 2/3和FAK依赖性PI3K/Akt-mTOR信号级联的调节作用。雄性Wistar大鼠在第0天经气管内单次注入博来霉素（2.5 U/kg），并分别以预防或治疗模式给予黄连素治疗。黄连素减轻了纤维化标志物α-平滑肌肌动蛋白（α-SMA）、纤连蛋白、I型和III型胶原蛋白的表达升高，并逆转了博来霉素诱导的肺部超微结构改变。黄连素抑制了博来霉素诱导的p-Smad 2/3升高并增强了Smad 7表达。黄连素阻止了FAK和PI3K/Akt的激活，对抗博来霉素诱导的失调，随后PTEN表达升高。此外，通过抑制p-mTOR，黄连素刺激了自噬，这表现为Beclin-1、LC3-II水平增加以及自噬体形成增强。总的来说，通过对失调的Smad和FAK依赖性PI3K/Akt-mTOR信号轴的靶向抑制，黄连素减轻了博来霉素的纤维化损伤。
黄连素抑制博来霉素诱导的大鼠肺中Smad 2/3的激活并增强Smad 7。黄连素抑制博来霉素诱导的FAK激活。黄连素抑制博来霉素诱导的PI3K/Akt级联激活。黄连素抑制mTOR激活以增强自噬并抑制纤维化标志物。
