Resveratrol increases F508del-CFTR dependent salivary secretion in cystic fibrosis mice

Abstract

Cystic fibrosis (CF) is a fatal genetic disease associated with widespread exocrine gland dysfunction. Studies have suggested activating effects of resveratrol, a naturally-occurring polyphenol compound with antioxidant and anti-inflammatory properties, on CF transmembrane conductance regulator (CFTR) protein function. We assayed, in F508del-CFTR homozygous (CF) and in wild-type mice, the effect of resveratrol on salivary secretion in basal conditions, in response to inhibition by atropine (basal β-adrenergic-dependent component) and to stimulation by isoprenaline (CFTR-dependent component). Both components of the salivary secretion were smaller in CF mice than in controls. Two hours after intraperitoneal administration of resveratrol (50 mg/kg) dissolved in DMSO, the compound was detected in salivary glands. As in both CF and in wild-type mice, DMSO alone increased the response to isoprenaline in males but not in females, the effect of resveratrol was only measured in females. In wild-type mice, isoprenaline increased secretion by more than half. In CF mice, resveratrol rescued the response to isoprenaline, eliciting a 2.5-fold increase of β-adrenergic-stimulated secretion. We conclude that the salivary secretion assay is suitable to test DMSO-soluble CFTR modulators in female mice. We show that resveratrol applied in vivo to mice reaches salivary glands and increases β-adrenergic secretion. Immunolabelling of CFTR in human bronchial epithelial cells suggests that the effect is associated with increased CFTR protein expression. Our data support the view that resveratrol is beneficial for treating CF. The salivary secretion assay has a potential application to test efficacy of novel CF therapies.

Role of Sox2 in Learning, Memory, and Postoperative Cognitive Dysfunction in Mice

“…In the fourth experiment, some mice received daily intraperitoneal injection of 50 mg/kg resveratrol (Abcam, Cambridge, UK; dissolved in 25% DMSO to a final concentration of 10 mg/mL) based on a previous study [ 30 ] and some mice received intraperitoneal injection of the DMSO solvent (sham solution). This injection was started 2 h after the surgery and was for 7 days.…”

Evidence against resveratrol as a viable therapy for the rescue of defective ΔF508 CFTR

“…Recently, several publications have reported that resveratrol is efficacious in correcting defective ΔF508-CFTR processing and trafficking in cell models [10,11,12,13], and few mouse models [11,13]. Resveratrol (3,4',5-trihydroxystilbene) is a naturally occurring polyphenolic flavonoid compound found in various fruits and vegetables, and is abundant in grapes, berries and peanuts [14].…”

Mitochondrial Stress Responses and “Mito-Inflammation” in Cystic Fibrosis

“…An example may be found in the natural phenolic antioxidant resveratrol (3,4′,5-trihydroxystilbene), which efficiently reduces oxidative stress and subsequent inflammation, preserving mitochondrial Δψ and mtDNA in vitro and in vivo ( Manna et al., 2000 ; Xu et al., 2012 ). At high concentration, in preclinical studies resveratrol rescues the expression of F508del-CFTR, the chloride secretion and the intracellular transport in human primary airway epithelial cells and CF mouse models ( Hamdaoui et al., 2011 ; Dhooghe et al., 2015 ; Lu et al., 2020 ). Indeed, in presence of the modulator, ivacaftor, resveratrol augmented the G155D-CFTR activation in human primary sinonasal cells ( Cho et al., 2019 ).…”