Abstract
Plant lignans are diphenolic compounds widely present in vegetables, fruits, and grains. These compounds have been demonstrated to have protective effect against cancer, hypertension and diabetes. In the present study, we showed that two lignan compounds, kobusin and eudesmin, isolated from Magnoliae Flos, could modulate intestinal chloride transport mediated by cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride channels (CaCCs). The compounds activated CFTR channel function in both FRT cells and in HT-29 cells. The modulating effects of kobusin and eudesmin on the activity of CaCCgie (CaCC expressed in gastrointestinal epithelial cells) were also investigated, and the result showed that both compounds could stimulate CaCCgie-mediated short-circuit currents and the stimulation was synergistic with ATP. In ex vivo studies, both compounds activated CFTR and CaCCgie chloride channel activities in mouse colonic epithelia. Remarkably, the compounds showed inhibitory effects toward ANO1/CaCC-mediated short-circuit currents in ANO1/CaCC-expressing FRT cells, with IC50 values of 100 μM for kobusin and 200 μM for eudesmin. In charcoal transit study, both compounds mildly reduced gastrointestinal motility in mice. Taken together, these results revealed a new kind of activity displayed by the lignan compounds, one that is concerned with the modulation of chloride channel function.
Highlights
Plant lignans are widely distributed in vegetables, fruits, and grains, especially in rye, flax, and sesame seeds
We found a large number of compounds, including two lignan compounds, kobusin and eudesmin, which had CFTR and calciumactivated chloride channels (CaCCs) Cl− channel modulation activities
Activation of CFTR by eudesmin depended on cAMP level and phosphorylation level of CFTR more than kobusin, which is that eudesmin showed a stronger activation effect under high concentrations of FSK (Figure 2F)
Summary
Plant lignans are widely distributed in vegetables, fruits, and grains, especially in rye, flax, and sesame seeds. Active Cl− secretion mediated by chloride channels provides a driving force for the transepithelial fluid secretion in the apical membrane of the intestines. CFTR is a cAMPdependent chloride channel predominantly expressed in the crypt cells in the intestines, and is permeable to Cl− and HCO3− (Zhang et al, 2012). ANO1/CaCC (TMEM16A) is the Modulation of Chloride Channel by Kobusin and Eudesmin first molecular identity of CaCCs that was found to express abundantly in the intestinal pacemaker Cajal cells, where it generates smooth muscle contraction (Huang et al, 2009; Hwang et al, 2009; Ferrera et al, 2010). CaCCgie (CaCC that located in the gastrointestinal epithelial cells), which is CaCC apart from ANO1, is predominantly localized in the gastrointestinal epithelial cells and is involved in fluid secretion, though its molecular identity remains unclear
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