Berberine attenuates severity of chronic pancreatitis and fibrosis via AMPK-mediated inhibition of TGF-β1/Smad signaling and M2 polarization
Berberine attenuates severity of chronic pancreatitis and fibrosis via AMPK-mediated inhibition of TGF-β1/Smad signaling and M2 polarization
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DOI：
10.1016/j.taap.2020.115162
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发表时间：
2020-09-15
影响因子：
3.8
通讯作者：
Godugu, Chandraiah
中科院分区：
文献类型：
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作者：
Bansod, Sapana;Doijad, Nandkumar;Godugu, Chandraiah
黄连素(BR)是一种AMP活化蛋白激酶(AMPK)激活剂，具有抗氧化和抗炎作用。在本研究中，我们通过抑制转化生长因子-β/Smad信号和AMPK依赖的M2巨噬细胞极化来研究BR对雨果素诱导的慢性胰腺炎(CP)的作用。用BR(3 mg/kg和10 mg/kg)灌胃给药，连续21天。结果表明，BR治疗(10 mg/kg)可显著减轻胰腺组织的氧化亚硝化应激、组织学改变、炎性细胞浸润和胶原沉积。BR治疗还通过下调α-SMA、胶原蛋白1a、3a胶原蛋白和纤维粘连蛋白的表达，阻止了雨蛙素诱导的胰星状细胞(PSCs)激活和细胞外基质(ECM)沉积。从机制上讲，与蓝蛋白攻击的小鼠相比，BR处理显著激活了AMPK信号。此外，BR还能抑制在体蓝蛋白诱导的CP模型和转化生长因子-β1刺激的RAW 264.7巨噬细胞的转化生长因子-β/Smad信号转导和巨噬细胞极化。综上所述，我们的结果有力地表明，BR治疗通过抑制转化生长因子-β1/Smad信号通路和AMPK依赖的M2巨噬细胞极化来保护雨蛋白诱导的CP和相关的纤维化进展。
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.