ArticleBMC complementary medicine and therapies2025
Identification and pharmacological characterization of a natural folipastatin as a CFTR inhibitor and potential anti-secretory agent in a human colonoid model.
Article in BMC complementary medicine and therapies, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundOverstimulation of cAMP-induced intestinal chloride secretion is a major cause of secretory diarrheas affecting both children and adults. This study aimed to investigate an anti-secretory effect of folipastatin, a natural depsidone derived from Aspergillus unguis, on cAMP-induced transepithelial chloride secretion using both human intestinal epithelial cell lines (T84 cells) and human colonoids.
methodsShort-circuit and apical chloride current measurements were performed to investigate the inhibitory effect of folipastatin on cAMP-induced chloride secretion. Mechanisms of action of folipastatin were studied using apical chloride current analyses, intracellular cAMP measurements and molecular docking analyses. Anti-secretory efficacy of folipastatin was investigated in human colonoids.
resultsIn T84 cells, we found that folipastatin reversibly inhibited the cAMP-induced chloride secretion measured by short-circuit current analyses with an IC50 value of ~ 0.3 µM and with no overt cytotoxicity being observed at 10 µM by MTT assays and transepithelial electrical resistance measurements. Apical chloride current analyses and biochemical assays revealed that folipastatin inhibited the chloride transport function of CFTR, a cAMP-dependent chloride channel, by mechanisms not involving alteration of intracellular cAMP and its negative regulators including protein phosphatases and AMP-activated protein kinases. In addition, the computational molecular docking suggested that folipastatin could bind to CFTR at the canonical ATP-binding site of CFTR at both nucleotide-binding domain (NBD)-1 and NBD-2. Evaluation of anti-secretory efficacy of folipastatin in a three-dimensional (3D) model of human colonoids demonstrated that folipastatin effectively suppressed the cAMP-induced fluid secretion without affecting basal fluid secretion.
conclusionsTaken together, folipastatin represents a novel class of fungus-derived CFTR inhibitors that holds therapeutic promise in the treatment of secretory diarrheas in humans.
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