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. 2017 Jul;174(13):2043-2059.
doi: 10.1111/bph.13803. Epub 2017 May 16.

"VSports" Isorhapontigenin, a bioavailable dietary polyphenol, suppresses airway epithelial cell inflammation through a corticosteroid-independent mechanism

Samuel Chao Ming Yeo  1   2 , Peter S Fenwick  1 , Peter J Barnes  1 , Hai Shu Lin  2 , Louise E Donnelly  1
Affiliations

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

Samuel Chao Ming Yeo et al. Br J Pharmacol. 2017 Jul.

Abstract

Background and purpose: 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 VSports手机版. 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 approach: 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 V体育安卓版. .

Key results: Isorhapontigenin concentration-dependently inhibited IL-6 and CXCL8 release, with IC50 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 V体育ios版. Its oral bioavailability was approximately 50% higher than resveratrol. .

Conclusions and implications: Isorhapontigenin, an orally bioavailable dietary polyphenol, displayed superior anti-inflammatory effects compared with resveratrol VSports最新版本. 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. .

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Figures

Figure 1
Figure 1
Structure of stilbene analogues (A) resveratrol and (B) isorhapontigenin. Effects of stilbene analogues on the release of cytokines stimulated by 1 ng·mL−1 IL‐1β + 50% CSE in primary human airway epithelial cells. Primary cells from both (C, E) healthy and (D, F) COPD patients were treated with various concentrations of either resveratrol or isorhapontigenin for 1 h before stimulation with 1 ng·mL−1 IL‐1β + 50% CSE for 24 h. Cell media were harvested and (C, D) IL‐6 and (E, F) CXCL8 measured by elisa (n = 5). Differences in response between cells from healthy subjects and COPD patients were analysed using Mann–Whitney U‐tests but were not significant.
Figure 2
Figure 2
Effects of stilbene analogues and dexamethasone on the NF‐κB pathway. (A) Representative blots and quantification of total pIκBα and IκBα protein expression in A549 cells treated with various concentrations of either isorhapontigenin (ISO) or resveratrol (RES) (1–100 μM) or 1 μM dexamethasone for 1 h before stimulation with 1 ng·mL−1 IL‐1β for 10 min. IL‐1β induced an increase in levels of pIκBα (B), which was not altered by the compounds (n = 4) where * represents P < 0.05 for differences from non‐stimulated cells (NS) by ANOVA followed by Bonferroni correction. However, there was a suppression of expression of IκBα by all treatments where * indicates P < 0.05 for differences between NS cells and treatments (C). Nuclear protein expression of p50 (D, F) and p65 (E, G) were increased by stimulation with 1 ng·mL−1 IL‐1β for 1 h and were not altered by the compounds (n = 3) where TBP is TATA box binding protein and used as a loading control and * represents P < 0.05 for differences from NS by ANOVA followed by Bonferroni correction. A549 cells stably transfected with NF‐κB reporter gene were treated with increasing concentrations of either ISO (●) or RES (formula image) (H) or dexamethasone (I) for 1 h before stimulation with 1 ng·mL−1 IL‐1β for 6 h. ISO reduced luciferase activity to nearly basal levels while RES showed minimal inhibitory effects and the maximum repression by dexamethasone was 60% (n = 5). Data are mean ± SEM.
Figure 3
Figure 3
Effects of stilbene analogues and dexamethasone (DEX) on the AP‐1 pathway. (A) Representative blot and (B) quantification of total c‐Jun protein expression in A549 cells treated with various concentrations of isorhapontigenin (ISO) or resveratrol (RES) (1–100 μM) or 1 μM DEX for 1 h before stimulation with 1 ng·mL−1 IL‐1β for 60 min. IL‐1β increased the expression of c‐Jun where * represents P < 0.05 for differences from non‐stimulated cells (NS). This stimulation was reduced by stilbene analogues and DEX (n = 5), where *indicates P < 0.05 for differences from IL‐1β stimulated cells by ANOVA followed by Bonferroni correction. (C) c‐Jun mRNA levels were significantly increased after IL‐1β stimulation (P < 0.05) for 30 min, and this was significantly attenuated by ISO (P < 0.05) and to a lesser extent by RES and DEX (n = 5) where * represents P < 0.05 as measured by ANOVA with Bonferroni correction for differences from IL‐1β stimulation. (D) Representative blot and quantification (E) of total c‐Fos protein expression in A549 cells treated with 100 μM stilbene analogue or 1 μM DEX for 1 h before stimulation with 1 ng·mL−1 IL‐1β for 60 min. IL‐1β increased the levels of c‐Fos, which was enhanced by stilbene analogues but dexamethasone had no effect (n = 4). Data are mean ± SEM, and * represents P < 0.05 as measured by ANOVA with Bonferroni correction.
Figure 4
Figure 4
Effects of stilbene analogues and dexamethasone (DEX) on the major intracellular inflammatory signalling pathways. (A) Representative blots and quantification of phosphorylated and total p38 (B), JNK (C) and ERK (D) protein expression in A549 cells treated with various concentrations of either isorhapontigenin (ISO) or resveratrol (RES) (1–100 μM) or 1 μM DEX for 1 h before stimulation with 1 ng·mL−1 IL‐1β for 40 min. IL‐1β induced increase in levels of phosphorylated p38, JNK and ERK protein expression, which were suppressed by DEX but not stilbene analogues (n = 4). (E) Representative blots and quantification of phosphorylated Ser473 (F) or Thr308 (G) and total Akt protein expression in A549 cells treated with various concentrations of either ISO or RES (1–100 μM) or 1 μM DEX for 1 h before stimulation for 40 min. IL‐1β induced increase in levels of phosphorylated Akt (at Ser473 and Thr308) protein expression, which were suppressed by stilbene analogues and not by DEX (n = 5). (H) Representative blot of nuclear protein expression of FoxO3A and densitometry (I) showing reduction with IL‐1β at 60 min, and this reduction was prevented by ISO, RES and LY294002 but not DEX (n = 3). Data are mean ± SEM where * represents P < 0.05, for differences from non‐stimulated cells (NS) using ANOVA with Bonferroni correction.
Figure 5
Figure 5
Effects of stilbene analogues and dexamethasone (DEX) on the PI3K/Akt pathway in primary airway epithelial cells. Representative blots of phosphorylated and total Akt protein expressions in primary airway epithelial cells from (A) healthy and (B) COPD patients treated with either isorhapontigenin (ISO) or resveratrol (RES) (30 and 100 μM) or 1 μM DEX for 1 h before stimulation with 1 ng·mL−1 IL‐1β + CSE for 60 min, or either IL‐1β or CSE alone. IL‐1β increased the levels of phosphorylated Akt (at Ser473 and Thr308) protein expression, which was suppressed by stilbene analogues and to a lesser extent by DEX (n = 3). Quantification of (C) phosphorylated Akt (Ser473) and (D) phosphorylated Akt (Thr308) protein expression is presented as mean ± SEM (n = 3) where the black bars represent cells from healthy controls and the red bars represents cells from COPD patients.
Figure 6
Figure 6
Effects of stilbene analogues on intracellular ROS levels. A549 cells were treated with the various concentrations of isorhapontigenin (ISO) or resveratrol (RES) (1–100 μM) for 1 h followed by stimulation with 1 ng·mL−1 IL‐1β. After 30 min, 10 μM H2DCF‐DA, an intracellular oxidant indicator, was loaded and cells incubated for a further 30 min. ROS levels were significantly reduced by ISO and RES (n = 5). Data are mean ± SEM where *P < 0.05 compared with IL‐1β‐stimulated cells.
Figure 7
Figure 7
Pharmacokinetic profiles of isorhapontigenin in Sprague–Dawley rats. Rats were administered (A) 30 μmol·kg−1 isorhapontigenin i.v. or (B) 600 μmol·kg−1 isorhapontigenin p.o. Blood was collected at specific time points and plasma analysed using LC‐MS/MS. Data are presented as mean ± SEM (n = 5).
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