Berberine attenuates severity of chronic pancreatitis and fibrosis via AMPK-mediated inhibition of TGF-β1/Smad signaling and M2 polarization

Berberine (BR) acts as an AMP-activated protein kinase (AMPK) activator which possesses antioxidant and antiinflammatory properties. In this study, we have investigated the effects of BR against cerulein-induced chronic pancreatitis (CP) via inhibition of TGF-beta/Smad signaling and M2 macrophages polarization in AMPK dependent manner. Cerulein-induced CP mice were treated with BR (3 and 10 mg/kg), intraperitoneally every day for 21 days. Our results indicated that, BR treatment (10 mg/kg) significantly reduced oxidative-nitrosative stress, histological alterations, inflammatory cells infiltration and collagen deposition in pancreatic tissue. BR treatment also prevented cerulein-induced pancreatic stellate cells (PSCs) activation and extracellular matrix (ECM) deposition via downregulation of alpha-SMA, collagen1a, collagen3a and fibronectin expression. Mechanistically, treatment with BR significantly activated AMPK signaling as compared to cerulein-challenged mice. Further, administration of BR also inhibited TGF-beta/Smad signaling and macrophages polarization in cerulein-induced CP in-vivo models and TGF-beta 1 stimulated RAW 264.7 macrophages in-vitro. Together, our results strongly suggest that BR treatment protected against cerulein-induced CP and associated fibrosis progression by inhibiting TGF-beta 1/Smad signaling and M2 macrophages polarization in an AMPK dependent manner.