title: Isorhapontigenin, a bioavailable dietary polyphenol, suppresses airway epithelial cell inflammation through a corticosteroid-independent mechanism.
abstract: Chronic 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.
  
  
  
  Primary 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.
  
  
  
  Isorhapontigenin concentration-dependently inhibited IL-6 and CXCL8 release, with IC50values 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.
  
  
  
  Isorhapontigenin, 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.
authors.affiliation: Airway Disease, National Heart and Lung Institute, Imperial College London, London, UK.|Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
authors.forename: Samuel Chao Ming
authors.initials: SCM
authors.lastname: Yeo
authors.affiliation: Airway Disease, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Fenwick
authors.affiliation: Airway Disease, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
authors.forename: Hai Shu
authors.initials: HS
authors.lastname: Lin
authors.affiliation: Airway Disease, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Donnelly
mesh_terms: D000284:Administration, Oral; D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000368:Aged; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D015394:Molecular Structure; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012137:Respiratory System / Q000187:drug effects* / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D013267:Stilbenes; C432307:isorhapontigenin; D000077185:Resveratrol