Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Phytomedicine. 2024 Dec;135:156044. doi: 10.1016/j.phymed.2024.156044. Epub 2024 Sep 12.
Myricetin has various biological activities and health benefits; however, its effects on airway remodeling in asthma have not been reported.
We aimed to investigate the possibility that myricetin improves airway remodeling by activating Sirt1 and has potential as a new treatment for asthma.
RAW 264.7 cells were stimulated with lipopolysaccharide and co-cultured with 3T6 cells in vitro to simulate the in vivo effects of inflammation on airway remodeling. Using an ovalbumin-induced chronic asthma mouse model, we compared changes in inflammatory factors and airway remodeling-related factors under treatment with myricetin and/or the Sirt1 inhibitor EX-527 using western blotting and quantitative PCR. Expression plasmids carrying Smad3 site mutations were transfected into 3T6 cells to identify the Sirt1 deacetylation site on Smad3 protein.
Myricetin significantly reduced the infiltration of airway inflammatory cells and the production of interleukin (IL)-6 and IL-5, and inhibited mucus secretion by goblet cells, collagen fiber proliferation, and the increase in inflammatory cells in bronchoalveolar lavage fluid from asthmatic mice. Results of in vitro experiments were consistent with those conducted in vivo. Exploring the mechanism of action of myricetin, we found that myricetin downregulated the levels of phosphorylated (p)-JNK, p-Smad3, and acetylated Smad3 proteins by activating Sirt1 both in vivo and in vitro. K341 was identified as the main deacetylation site of Smad3 by myricetin-activated Sirt1.
Myricetin ameliorates airway inflammation and remodeling in asthma by activating Sirt1 to regulate the JNK/Smad3 pathway.
杨梅素具有多种生物活性和健康益处，但尚未有报道其对哮喘气道重塑的影响。
我们旨在研究杨梅素通过激活 Sirt1 改善气道重塑的可能性，并探讨其作为哮喘新疗法的潜力。
采用脂多糖刺激 RAW 264.7 细胞并与 3T6 细胞共培养的方法在体外模拟炎症对气道重塑的体内影响。通过卵清蛋白诱导的慢性哮喘小鼠模型，我们使用 Western blot 和定量 PCR 比较了杨梅素和/或 Sirt1 抑制剂 EX-527 治疗后炎症因子和气道重塑相关因子的变化。将携带 Smad3 位点突变的表达质粒转染至 3T6 细胞，以鉴定 Smad3 蛋白上 Sirt1 的去乙酰化位点。
杨梅素显著减少气道炎症细胞浸润和白细胞介素（IL）-6 和 IL-5 的产生，并抑制杯状细胞黏液分泌、胶原纤维增殖以及哮喘小鼠支气管肺泡灌洗液中炎症细胞的增加。体内和体外实验结果一致。探索杨梅素的作用机制，我们发现杨梅素通过激活 Sirt1 下调了 p-JNK、p-Smad3 和乙酰化 Smad3 蛋白的水平，无论是在体内还是在体外。通过杨梅素激活的 Sirt1，鉴定出 K341 是 Smad3 的主要去乙酰化位点。
杨梅素通过激活 Sirt1 调节 JNK/Smad3 通路改善哮喘中的气道炎症和重塑。
