Isorhapontigenin, a bioavailable dietary polyphenol, suppresses airway epithelial cell inflammation through a corticosteroid‐independent mechanism

Abstract

*Equal contribution. BACKGROUND AND PURPOSEChronic obstructive pulmonary disease (COPD) is a corticosteroid-resistant airway inflammatory condition. Resveratrol exhibits anti-inflammatory activities in COPD but has weak potency and poor pharmacokinetics. This study aimed to evaluate the potential of isorhapontigenin, another dietary polyphenol, as a novel anti-inflammatory agent for COPD by examining its effects in vitro and pharmacokinetics in vivo. EXPERIMENTAL APPROACHPrimary human airway epithelial cells derived from healthy and COPD subjects, and A549 epithelial cells were incubated with isorhapontigenin or resveratrol and stimulated with IL-1β in the presence or absence of cigarette smoke extract. Effects of isorhapontigenin and resveratrol on the release of IL-6 and chemokine (C-X-C motif) ligand 8 (CXCL8), and the activation of NF-κB, activator protein-1 (AP-1), MAPKs and PI3K/Akt/FoxO3A pathways were determined and compared with those of dexamethasone. The pharmacokinetic profiles of isorhapontigenin, after i.v. or oral administration, were assessed in Sprague-Dawley rats. KEY RESULTSIsorhapontigenin concentration-dependently inhibited IL-6 and CXCL8 release, with IC 50 values at least twofold lower than those of resveratrol. These were associated with reduced activation of NF-κB and AP-1 and, notably, the PI3K/Akt/FoxO3A pathway, that was relatively insensitive to dexamethasone. In vivo, isorhapontigenin was rapidly absorbed with abundant plasma levels after oral dosing. Its oral bioavailability was approximately 50% higher than resveratrol. CONCLUSIONS AND IMPLICATIONSIsorhapontigenin, an orally bioavailable dietary polyphenol, displayed superior anti-inflammatory effects compared with resveratrol. Furthermore, it suppressed the PI3K/Akt pathway that is insensitive to corticosteroids. These favourable efficacy and pharmacokinetic properties support its further development as a novel anti-inflammatory agent for COPD. AbbreviationsA549, human alveolar epithelial cells; AP-1, activator protein-1; AUC 0!last , plasma exposure; Cl, clearance; C max , maximal plasma concentration; COPD, chronic obstructive pulmonary disease; CXCL8, chemokine (C-X-C motif) ligand 8; ECL, Enhanced chemiluminescence; F, absolute oral bioavailability; FoxO3A, forkhead box O3A; H 2 DCF-DA, 2′,7′-dichlorodihydrofluorescein diacetate; MTT 0!last , mean transition time; TBS, Tris balanced salt solution

Pre-clinical Pharmacokinetic and Metabolomic Analyses of Isorhapontigenin, a Dietary Resveratrol Derivative

“…Similar to resveratrol, its anti-cancer, anti-oxidation, and cardio-protective activities have been observed in various pre-clinical studies ( Wang et al, 2001 ; Liu and Liu, 2004 ; Li et al, 2005 ; Fang et al, 2012 , 2013 ; Zeng et al, 2016 ; Jiang et al, 2018 ). In a recent study, the anti-inflammatory effects of ISO were assessed in in vitro models for chronic obstructive pulmonary disease (COPD) using resveratrol as a comparator ( Yeo et al, 2017 ). ISO suppressed the activation of several critical inflammatory pathways that are important in COPD ( Yeo et al, 2017 ).…”

“…In a recent study, the anti-inflammatory effects of ISO were assessed in in vitro models for chronic obstructive pulmonary disease (COPD) using resveratrol as a comparator ( Yeo et al, 2017 ). ISO suppressed the activation of several critical inflammatory pathways that are important in COPD ( Yeo et al, 2017 ). Of note, the potency of ISO was much higher than resveratrol and its anti-inflammatory activities were mediated through a mechanistic pathway that is distinct from corticosteroids, which indicates its potential in tackling the corticosteroid-resistant inflammation in COPD ( Yeo et al, 2017 ).…”

A practical guide for transparent reporting of research on natural products in the British Journal of Pharmacology: Reproducibility of natural product research

“…In general, it may be wise to ask the following question: 'can the An interesting study that investigated the in vivo relevance of a concentration used in vitro was recently published in BJP (Yeo, Fenwick, Barnes, Lin, & Donnelly, 2017). The authors found that the dietary polyphenol isorhapontigenin inhibited IL-6 release from airway epithelial cells.…”

“…The authors found that the dietary polyphenol isorhapontigenin inhibited IL-6 release from airway epithelial cells. On the basis of pharmacokinetic data obtained in rats in vivo, the authors postulated that the concentration used in vitro can be reached following oral dosing of isorhapontigenin and that at least 30% inhibition of IL-6 release can be attained through a single oral dose of isorhapontigenin (Yeo et al, 2017).…”

Oral delivery system enhanced the bioavailability of stilbenes: Resveratrol and pterostilbene

“…On the other hand, trans ‐3,5,2′,4′‐tetrahydroxystilbene showed a faster absorption rate and higher AUC value than resveratrol due to improved solubility given by its one additional hydroxyl group on the structure . As additional hydroxyl group augmented solubility, which elevated the compound's accessibility to the enterocytes, isorhapontigenin with one methoxyl group at 3′ position making it more lipophilic and, thus, improved its oral bioavailability potentially due to the higher transport rate across intestinal lining . In this sense, substantial amount of attention was shifted to the polymethoxylated derivatives that their better compatibility with the cell wall of enterocyte could grant them better oral bioavailability and leads to higher bioefficacy.…”