Stimulation of Airway and Intestinal Mucosal Secretion by Natural Coumarin CFTR Activators

Abstract

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.

Enantioseparation and Absolute Configuration Determination of Angular-Type Pyranocoumarins from Peucedani Radix Using Enzymatic Hydrolysis and Chiral HPLC-MS/MS Analysis

“…The stereoselectivity in pharmacological actions [ 13 ], metabolism [ 14 ] and absorption [ 28 ] of praeruptorin A have been revealed by previous studies, indicating that it is of great importance to determine the absolute configurations of the angular-type pyranocoumarins when correlate their structures with the resultant biological interactions during pharmacological/toxicological evaluation and/or ADME screening. Furthermore, because most pyranocoumarins from Qian-hu naturally exist as enantiomers and/or diastereoisomers, misidentification of the identity of the compound studied has occurred [ 29 , 30 , 31 ]. Thus, it is crucial to establish a method which enables rapid determination of the absolute configurations of the pyranocoumarin compounds to be worked on.…”

Osthole: A Review on Its Bioactivities, Pharmacological Properties, and Potential as Alternative Medicine

“…Similarly, osthole showed antifibrotic effect in both hepatic and myocardial tissues, which contribute to the protective effect on liver and cardiovascular system. Osthole has also been suggested as a natural activator of defective DeltaF508-cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel gating and thus may be a lead compound for cystic fibrosis therapies [ 116 , 117 ]. In addition, liver plays a critical role in metabolism including catabolism, storage, and anabolism.…”

“…Effect of osthole on these ion channels is closely related to bioactivities of osthole as vasorelaxant, immunomodulatory, antifibrotic effects, and, in particular, its neuronal and neuroendocrine functions including neuroprotective, anticonvulsant, and pain relieving properties. On the other hand, calcium concentration regulates the osteoprogenitors behavior which play important roles in both bone homeostasis and regeneration [ 117 , 118 ], thereby making calcium channel a prospective direction to study the mechanism of osteogenic effect of osthole. cAMP and cGMP have been well documented as important regulators of L-type Ca 2+ channel and some other ion channels [ 119 – 121 ].…”

Gastroprotective Efficacy and Safety Evaluation of Scoparone Derivatives on Experimentally Induced Gastric Lesions in Rodents

“…The first line of defense against acid is the gastric mucus, which together with bicarbonate, covers the entire gastric mucosa and protects against ulcerogenic factors [ 4 , 5 , 51 ]. Scoparone ( 1 ) is known to stimulate airway and intestinal mucosal secretion [ 52 ]. However, scoparone ( 1 ) and its derivatives have never been evaluated for their effect on gastric mucus secretion.…”