Stimulation of Airway and Intestinal Mucosal Secretion by Natural Coumarin CFTR Activators.
Stimulation of Airway and Intestinal Mucosal Secretion by Natural Coumarin CFTR Activators.
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天然香豆素CFTR激活剂刺激气道和肠粘膜分泌。
DOI：
10.3389/fphar.2011.00052
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发表时间：
2011
影响因子：
5.6
通讯作者：
Ma TH
中科院分区：
文献类型：
--
作者：
Yang H;Xu LN;Sui YJ;Liu X;He CY;Fang RY;Liu J;Hao F;Ma TH
囊性纤维化（CF）跨膜传导调节因子（CFTR）的突变导致致命的遗传性疾病CF，其涉及浆液上皮的广泛破坏和功能障碍。可能的药物治疗包括纠正有缺陷的细胞内加工和异常通道门控。在先前的研究中，我们鉴定了ΔF508-CFTR的五种天然香豆素增效剂，包括蛇床子素、欧前胡素、异甘草素、白花前胡素A和滨蒿内酯。本研究旨在确定这些香豆素化合物对动物组织中CFTR活性的活性，作为其治疗潜力的初步评价。在本研究中，我们分析了这些香豆素增效剂在激活野生型CFTR中的亲和力，发现它们都是有效的激活剂。Ussing小室短路电流法测定蛇床子素的Kd值<50 nmol/L。用短路电流法检测蛇床子素对大鼠结肠粘膜分泌的刺激作用。蛇床子素在5 μmol/L时对结肠Cl−分泌的激活作用达到最大。通过光学测量单个腺体分泌物来分析小鼠气管粘膜分泌物的刺激。10 μmol/L蛇床子素刺激气管单个粘膜下腺体分泌液体的速度比阴性对照快3倍。在这两种情况下，刺激的分泌被CFTRinh-172完全消除。总之，蛇床子素对结肠和气管粘膜中Cl-和液体分泌的有效刺激表明天然香豆素化合物用于治疗CF和其他CFTR相关疾病的治疗潜力。
Mutations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) cause lethal hereditary disease CF that involves extensive destruction and dysfunction of serous epithelium. Possible pharmacological therapy includes correction of defective intracellular processing and abnormal channel gating. In a previous study, we identified five natural coumarin potentiators of ΔF508-CFTR including osthole, imperatorin, isopsoralen, praeruptorin A, and scoparone. The present study was designed to determine the activity of these coumarine compounds on CFTR activity in animal tissues as a primary evaluation of their therapeutic potential. In the present study, we analyzed the affinity of these coumarin potentiators in activating wild-type CFTR and found that they are all potent activators. Osthole showed the highest affinity with Kd values <50 nmol/L as determined by Ussing chamber short-circuit current assay. Stimulation of rat colonic mucosal secretion by osthole was tested by the Ussing chamber short-circuit current assay. Osthole reached maximal activation of colonic Cl− secretion at 5 μmol/L. Stimulation of mouse tracheal mucosal secretion was analyzed by optical measurement of single gland secretion. Fluid secretion rate of tracheal single submucosal gland stimulated by osthole at 10 μmol/L was three-fold more rapid than that in negative control. In both cases the stimulated secretions were fully abolished by CFTRinh-172. In conclusion, the effective stimulation of Cl– and fluid secretion in colonic and tracheal mucosa by osthole suggested the therapeutic potential of natural coumarin compounds for the treatment of CF and other CFTR-related diseases.
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影响因子：
4.8
作者：
Ma, TH;Vetrivel, L;Verkman, AS
通讯作者：
Verkman, AS
影响因子：
158.5
作者：
Cohn, JA;Friedman, KJ;Jowell, PS
通讯作者：
Jowell, PS
影响因子：
4.4
作者：
Levin, MH;Verkman, AS
通讯作者：
Verkman, AS
DOI：
10.1111/j.1440-1681.2008.04943.x
发表时间：
2008-08-01
影响因子：
2.9
作者：
Xu, Li-Na;Na, Wan-Li;Ma, Tong-Hui
通讯作者：
Ma, Tong-Hui
影响因子：
56.9
作者：
KEREM, BS;ROMMENS, JM;TSUI, LC
通讯作者：
TSUI, LC