The Flavonoid 7,4'-Dihydroxyflavone Inhibits MUC5AC Gene Expression, Production, and Secretion via Regulation of NF-κB, STAT6, and HDAC2.
The Flavonoid 7,4'-Dihydroxyflavone Inhibits MUC5AC Gene Expression, Production, and Secretion via Regulation of NF-κB, STAT6, and HDAC2.
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DOI：
10.1002/ptr.5334
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发表时间：
2015-06
期刊：
影响因子：
--
通讯作者：
Li XM
中科院分区：
文献类型：
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作者：
Liu C;Weir D;Busse P;Yang N;Zhou Z;Emala C;Li XM
粘液分泌过多是阻塞性肺疾病病理生理学的重要组成部分。目前，只有少数药物可抑制粘液产生。以往的研究表明，甘草素是甘草中的一种三萜类化合物。uralensis）抑制粘蛋白5AC（MUC 5AC）mRNA和蛋白质表达。G.乌拉尔没有得到充分的研究。本研究的目的是确定G.乌拉尔黄酮类化合物7，4 '-二羟基黄酮（7，4'-DHF）抑制MUC 5AC基因表达、粘液产生和分泌，如果是这样，则阐明这种抑制的机制。7，4 '-DHF显著降低佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）刺激的NCI-H292人气道上皮细胞MUC 5AC基因表达和粘液产生，其浓度比曲马多苷低28倍（IC 50值分别为1.4μM和38 μM），7，4'-DHF还抑制MUC 5AC粘液分泌。抑制与NF-κB、STAT 6活化的抑制和HDAC 2表达的增强有关。在哮喘的鼠模型中，与对照小鼠相比，7，4 '-DHF处理的小鼠显示出支气管肺泡灌洗液（BAL）中MUC 5AC分泌的显著减少。这些发现，以及先前将NF-κB、STAT 6和HDAC 2调节与MUC 5AC表达控制联系起来的发现，证明7，4 '-DHF是G. uralensis通过调节NF-κB、STAT 6和HDAC 2来调节MUC 5AC的表达和分泌。
Mucus overproduction is a significant component of the pathophysiology of obstructive lung diseases. Currently, there are only a few medications available that inhibit mucus production. Previous studies showed that glycyrrhizin, a triterpenoid in Glycyrrhiza uralensis (G. uralensis) inhibits mucin 5AC (MUC5AC) mRNA and protein expression. Other potential mucus production inhibitory compounds contained within in G. uralensis have not been fully investigated. The aim of the present study was to determine if the G. uralensis flavonoid 7,4'-dihydroxyflavone (7,4'-DHF), inhibits MUC5AC gene expression, mucus production and secretion and if so, to elucidate the mechanism of this inhibition. 7,4'-DHF significantly decreased phorbol 12-myristate 13-acetate (PMA) stimulated NCI-H292 human airway epithelial cell MUC5AC gene expression and mucus production, at a 28 fold lower concentration than glycyrrhizin (IC50 value of 1.4µM vs 38 µM, respectively), 7,4'-DHF also inhibited MUC5AC mucus secretion. Inhibition was associated with the suppression of NF-κB, STAT6 activation and enhanced HDAC2 expression. In a murine model of asthma, 7,4'-DHF treated mice exhibited a marked reduction in MUC5AC secretion in the bronchoalveolar lavage (BAL) fluid compared with control mice. These findings, together with previous findings linking NF-κB, STAT6 and HDAC2 modulation to the control of MUC5AC expression, demonstrate that 7,4'-DHF is a newly identified component of G. uralensis that regulates MUC5AC expression and secretion via regulation of NF-κB, STAT6 and HDAC2.