School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea; College of Pharmacy, Kyungsung University, Busan 48434, Republic of Korea.
School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea.
Bioorg Med Chem Lett. 2021 Jun 1;41:127989. doi: 10.1016/j.bmcl.2021.127989. Epub 2021 Mar 30.
Hepatic fibrosis is a chronic liver disease characterized by the accumulation of extracellular matrix (ECM). Activation of hepatic stellate cells (HSCs) after repetitive liver damage is a key event in hepatic fibrogenesis. As part of ongoing research projects to identify pharmacologically effective natural products, the phytochemical investigation of a MeOH extract of Centipeda minima led to the isolation of a sesquiterpene lactone, brevilin A, which was explored to elucidate potential anti-fibrotic effects by reversing HSC activation. First, we observed that transforming growth factor (TGF)-β1 treatment significantly increased the expression levels of HSC activation marker, α-smooth muscle actin (α-SMA), and ECM protein such as collagen and fibronectin. Then, we demonstrated that brevilin A reversed the TGF-β1-induced increase in protein and mRNA expression levels of α-SMA and collagen. To investigate the underlying molecular mechanism of brevilin A, we evaluated the effects of brevilin A on the STAT3 signaling pathway. STAT3 phosphorylation, increased by TGF-β1 treatment, was strongly inhibited by brevilin A; the expression levels of fibronectin and connective tissue growth factor were also significantly decreased by brevilin A. The present study indicated that brevilin A has a preventive and therapeutic potential against hepatic fibrosis.
肝纤维化是一种慢性肝病，其特征是细胞外基质（ECM）的积累。肝星状细胞（HSCs）在反复肝损伤后的激活是肝纤维化发生的关键事件。作为正在进行的识别具有药理作用的天然产物的研究项目的一部分，对 Centipeda minima 的甲醇提取物进行了植物化学研究，导致分离出一种倍半萜内酯，即 brevilin A，通过逆转 HSC 激活来探索其潜在的抗纤维化作用。首先，我们观察到转化生长因子（TGF）-β1 处理显著增加了 HSC 激活标志物α-平滑肌肌动蛋白（α-SMA）和细胞外基质蛋白如胶原和纤维连接蛋白的表达水平。然后，我们证明了 brevilin A 逆转了 TGF-β1 诱导的 α-SMA 和胶原的蛋白和 mRNA 表达水平的增加。为了研究 brevilin A 的潜在分子机制，我们评估了 brevilin A 对 STAT3 信号通路的影响。STAT3 磷酸化水平因 TGF-β1 处理而增加，被 brevilin A 强烈抑制；纤维连接蛋白和结缔组织生长因子的表达水平也被 brevilin A 显著降低。本研究表明，brevilin A 具有预防和治疗肝纤维化的潜力。
