Yeo Samuel Chao Ming, Fenwick Peter S, Barnes Peter J, Lin Hai Shu, Donnelly Louise E
Airway Disease, National Heart and Lung Institute, Imperial College London, London, UK.
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
Br J Pharmacol. 2017 Jul;174(13):2043-2059. doi: 10.1111/bph.13803. Epub 2017 May 16.
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 IC 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.
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.
慢性阻塞性肺疾病（COPD）是一种对皮质类固醇耐药的气道炎症性疾病。白藜芦醇在COPD中具有抗炎活性，但其效力较弱且药代动力学不佳。本研究旨在通过检测异丹叶大黄素（另一种膳食多酚）的体外作用和体内药代动力学，评估其作为COPD新型抗炎药的潜力。
将来自健康和COPD受试者的原代人气道上皮细胞以及A549上皮细胞与异丹叶大黄素或白藜芦醇一起孵育，并在有或无香烟烟雾提取物的情况下用IL-1β刺激。测定异丹叶大黄素和白藜芦醇对IL-6和趋化因子（C-X-C基序）配体8（CXCL8）释放的影响，以及对NF-κB、活化蛋白-1（AP-1）、丝裂原活化蛋白激酶（MAPKs）和磷脂酰肌醇-3激酶/蛋白激酶B/叉头转录因子O3A（PI3K/Akt/FoxO3A）通路的激活作用，并与地塞米松进行比较。在Sprague-Dawley大鼠中评估异丹叶大黄素静脉注射或口服后的药代动力学特征。
异丹叶大黄素浓度依赖性地抑制IL-6和CXCL8的释放，其半数抑制浓度（IC）值至少比白藜芦醇低两倍。这些与NF-κB和AP-1的激活减少有关，值得注意的是，PI3K/Akt/FoxO3A通路对地塞米松相对不敏感。在体内，异丹叶大黄素口服给药后迅速吸收，血浆水平丰富。其口服生物利用度比白藜芦醇高约50%。
异丹叶大黄素是一种口服生物可利用的膳食多酚，与白藜芦醇相比显示出更强的抗炎作用。此外，它抑制了对皮质类固醇不敏感的PI3K/Akt通路。这些良好的疗效和药代动力学特性支持其作为COPD新型抗炎药的进一步开发。
