Liu Changda, Weir David, Busse Paula, Yang Nan, Zhou Zhenwen, Emala Charles, Li Xiu-Min
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Phytother Res. 2015 Jun;29(6):925-32. doi: 10.1002/ptr.5334. Epub 2015 Mar 23.
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 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'-Dihydroxyflavone significantly decreased phorbol 12-myristate 13-acetate-stimulated NCI-H292 human airway epithelial cell MUC5AC gene expression and mucus production, at a 28-fold lower concentration than glycyrrhizin (The half maximal inhibitory concentration IC50 value of 1.4 μM vs 38 μM, respectively); 7,4'-DHF also inhibited MUC5AC mucus secretion. Inhibition was associated with the suppression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), signal transducer and activator of transcription 6 (STAT6) activation, and enhanced histone deacetylase 2 (HDAC2) expression. In a murine model of asthma, 7,4'-DHF-treated mice exhibited a marked reduction in MUC5AC secretion in the bronchoalveolar lavage 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.
黏液过度分泌是阻塞性肺疾病病理生理学的一个重要组成部分。目前，仅有少数几种药物可抑制黏液分泌。先前的研究表明，甘草中的三萜类化合物甘草酸可抑制黏蛋白5AC（MUC5AC）的mRNA和蛋白表达。甘草中含有的其他潜在黏液分泌抑制化合物尚未得到充分研究。本研究的目的是确定甘草黄酮7,4'-二羟基黄酮（7,4'-DHF）是否抑制MUC5AC基因表达、黏液产生和分泌，若如此，则阐明这种抑制作用的机制。7,4'-二羟基黄酮显著降低了佛波醇12-肉豆蔻酸酯13-乙酸酯刺激的NCI-H292人气道上皮细胞MUC5AC基因表达和黏液产生，其浓度比甘草酸低28倍（半数最大抑制浓度IC50值分别为1.4 μM和38 μM）；7,4'-DHF还抑制了MUC5AC黏液分泌。这种抑制作用与活化B细胞核因子κB轻链增强子（NF-κB）、信号转导和转录激活因子6（STAT6）的激活受到抑制以及组蛋白去乙酰化酶2（HDAC2）表达增强有关。在哮喘小鼠模型中，与对照小鼠相比，经7,4'-DHF处理的小鼠支气管肺泡灌洗液中的MUC5AC分泌显著减少。这些发现，连同先前将NF-κB、STAT6和HDAC2调节与MUC5AC表达控制联系起来的发现，表明7,4'-DHF是甘草中一种新发现的成分，它通过调节NF-κB、STAT6和HDAC2来调节MUC5AC的表达和分泌。
