The Activation Effect Of Lignans On Cystic Fibrosis Transmenbrance Conductance Regulator Chloride Channel

It becomes a very potential field that using natural compounds which come from Chinese medicinal herbs for the discovery of new medicines because the high safety and low toxic effect. Lignans is a small molecular compounds exists widely in nature, with many kinds of biological activities, such as antitumor, antiviral, protecting liver, antioxidant, platelet activating factor antagonist activity and so on. Although lignan compounds have various targets, but CFTR chloride channel as the molecular target of lignans is not clear.CFTR(cystic fibrosis transmembrane conductance regulator) is a c AMP dependent chloride channel. It is extensively expressed by epithelial cells, and plays key roles in transport of electrolyte and fluid. CFTR channel dysfunction will cause a variety of diseases. such as cystic fibrosis, chronic pancreatitis, habitual constipation, polycystic kidney disease and dry eye syndrome. Therefore, from the traditional Chinese medicine monomer compounds in the search for small molecule activators or inhibitors has important value for study on the mechanism and treatment of cystic fibrosis and other CFTR related diseases.In this study, we investigated activation effect of four lignan compounds:kobusin、eudesmin、epimagnolin A and magnolin on cystic fibrosis transmembrane conductance regulator(CFTR)chloride channel. Four lignan compounds activated wild-type CFTR chloride channel activity in a dose-dependent manner though high halide sensitive YFP(YFP-H148Q) cell based assay. There EC50 value are 10μM、20μM、100μM、50μM.The activation effect of kobusin、eudesmin and epimagnolin A could abolished by CFTR blockers CFTRinh-172 and GlyH101. Primary study indicated that lignans may activate CFTR chloride channel through a direct binding way. Four lignan compounds can be different degrees of activation of mutantΔF508-CFTR chloride channel activity. All four lignan compounds stimulate the trans mucosal chloride current of rat colon by short-circuit current assays and increased fluid secretion in mouse trachea by optical measurement of single gland secretion. It further proved they are effective activators of CFTR chloride channel. Our results provide a basis for the development of lignans as the drug for the treatment of CFTR related diseases.