本文關(guān)鍵詞：甲氧基黃酮類(lèi)化合物對(duì)囊性纖維化跨膜電導(dǎo)調(diào)節(jié)因子的激活作用，由筆耕文化傳播整理發(fā)布。

甲氧基黃酮類(lèi)化合物對(duì)囊性纖維化跨膜電導(dǎo)調(diào)節(jié)因子的激活作用

Polymethoxylated flavonoids activate cystic fibrosis transmembrane conductance regulator chloride channel

[1] [2] [3] [4] [5] [6]

CAO Huan-Huan, FANG Fang, YU Bo, LUAN Jian, JIANG Yu, YANG Hong College of Life Sciences, Liaoning Normal University, Dalian 116081, China

遼寧師范大學(xué)生命科學(xué)學(xué)院,大連116081

文章摘要：囊性纖維化跨膜電導(dǎo)調(diào)節(jié)因子（CFTR）是一種c AMP依賴(lài)的Cl-通道蛋白,其在上皮液體分泌過(guò)程中具有重要作用。本研究組在前期工作中觀察到兩種甲氧基黃酮類(lèi)化合物3’,4’,5,5’,6,7-六甲氧基黃酮（HMF）和5-羥基-6,7,3’,4’-四甲氧基黃酮（HTF）能夠有效地激活CFTR Cl-通道,但是作用機(jī)制尚不清楚。本研究旨在利用細(xì)胞熒光淬滅模型和短路電流技術(shù)系統(tǒng)研究HMF和HTF對(duì)CFTR Cl-通道的激活作用。熒光淬滅實(shí)驗(yàn)結(jié)果顯示兩種化合物均能以劑量依賴(lài)的方式激活CFTR Cl-通道,該激活作用具有快速、可逆的特點(diǎn),可被CFTR特異性抑制劑CFTRinh-172完全抑制;引人注目的是,HMF（EC50=2μmol/L）是迄今發(fā)現(xiàn)的親和力最高的黃酮類(lèi)CFTR Cl-通道激活劑。HMF和HTF對(duì)CFTR Cl-通道的激活作用具毛喉素（forskolin,FSK）依賴(lài)特性,與FSK和3-異丁基-1-甲基黃嘌呤（3-Isobutyl-1-methylx,IBMX）的作用存在相加效應(yīng),但是與三羥基異黃酮（genistein,GEN）的作用之間不存在協(xié)同效應(yīng)。離體組織研究結(jié)果顯示,HMF和HTF能夠顯著促進(jìn)大鼠結(jié)腸粘膜Cl-電流及小鼠氣管粘膜下腺液體分泌。以上結(jié)果提示,HMF和HTF能夠通過(guò)提高c AMP水平和直接與CFTR蛋白作用兩條途徑發(fā)揮CFTR Cl-通道激活作用。本研究為深入揭示黃酮類(lèi)CFTR Cl-通道激活劑結(jié)構(gòu)與功能之間的關(guān)系奠定了基礎(chǔ)。

Abstr：Cystic fibrosis transmembrane conductance regulator（CFTR）, a c AMP-dependent chloride channel, plays key roles in fluid secretion in serous epithelial cells. Previously, we identified two polymethoxylated flavonoids, 3＇,4＇,5,5＇,6,7-hexamethoxyflavone（HMF） and 5-hydroxy-6,7,3＇,4＇-tetramethoxyflavone（HTF） which could potentiate CFTR chloride channel activities. The present study was aimed to investigate the potentiation effects of HMF and HTF on CFTR Cl- channel activities by using a cell-based fluorescence assay and the short circuit Ussing chamber assay. The results of cell-based fluorescence assay showed that both HMF and HTF could dose-dependently potentiate CFTR Cl- channel activities in rapid and reversible ways, and the activations could be reversed by the CFTR blocker CFTRinh-172. Notably, HMF showed the highest affinity（EC50 = 2 μmol/L） to CFTR protein among the flavonoid CFTR activators identified so far. The activation of CFTR by HMF or HTF was forskolin（FSK） dependent. Both compounds showed additive effect with FSK and 3-Isobutyl-1-methylx（IBMX） in the activation of CFTR, while had no additive effect with genistein（GEN）. In ex vivo studies, HMF and HTF could stimulate transepithelial Cl- secretion in rat colonic mucosa and enhance fluid secretion in mouse trachea submucosal glands. These results suggest that HMF and HTF may potentiate CFTR Cl- channel activities through both elevation of c AMP level and binding to CFTR protein pathways. The results provide new clues in elucidating structure and activity relationship of flavonoid CFTR activators. HMF might be developed as a new drug in the therapy of CFTR-related diseases such as bronchiectasis and habitual constipation.

文章關(guān)鍵詞：

Keyword：:CFTR Cl- transport 3＇,4＇,5,5＇,6,7-hexamethoxyflavone 5-hydroxy-6,7,3＇,4＇-tetramethoxyflavone activator

課題項(xiàng)目：This work was supported by the National Natural Science Foundation of China （No. 81473265 and 30973577） and Specialized Research Fund for the Doctoral Program of Higher Education, China （No. 20112136110002）.

作者信息：會(huì)員可見(jiàn)

  本文關(guān)鍵詞：甲氧基黃酮類(lèi)化合物對(duì)囊性纖維化跨膜電導(dǎo)調(diào)節(jié)因子的激活作用，，由筆耕文化傳播整理發(fā)布。