Experimental research of regulation of σmethoxyphenol-related compounds on the inflammatory cytokine expression.

天然抗氧化剂邻甲氧基酚，如丁香酚(4-烯丙基-2-甲氧基苯酚)和异丁香酚(4-丙烯-2-甲氧基苯酚)，是三叶草油的组成成分，通常用作化妆品和食品的调味剂。这些化合物显示出抗炎作用，但当它们在较高浓度下使用时，会产生以炎症和过敏反应为特征的不良反应，可能是因为它们具有促氧化活性，从而形成反应性的甲基苯醌中间体。它们的有益生物活性可以通过降低这些化合物的强氧化活性来避免这些不利影响来获得。因此，我们最近设计了几个丁香酚、异丁香酚或阿魏酸的合成二聚体来降低这些单体诱导的促氧化活性，并证明了这些二聚体化合物由于减少了自由基的产生而显示出降低细胞毒性的作用。这些发现表明邻甲氧基苯酚二聚体可能起…的作用。S更是一种有效抑制炎症和过敏反应的药物。然而，这些化合物抑制炎症反应的机制仍不是很清楚。在本研究中，我们研究了二聚体化合物如双丁香酚、脱氢二异丁香酚和双阿魏酸对内毒素诱导的小鼠巨噬细胞系RAW264.7炎症介质表达的抑制作用。丁香酚、异丁香酚、阿魏酸和异阿魏酸购自东京嘉成公司，橙皮素和橙皮苷购自西格玛化学公司，o-香草素购自Wako化学公司，大肠杆菌O111B4LPS购自LBLInc.此外，橙皮素、橙皮苷、邻香草素和异阿魏酸等邻甲氧基酚类化合物也可在较高浓度下抑制脂多糖诱导的COX-2表达。在低浓度下表现出COX-2抑制作用的邻甲氧基苯酚化合物具有中等的键离解能(BDE)值，这是预测苯酚作用效果的参数。这些观察表明，邻甲氧基酚的二聚化导致高水平的酚类功能，可能对各种炎症性或肿瘤性疾病表现出强大的抗炎和抗癌作用，也可能是发现有效的非甾体抗炎药类化合物的有用工具。较少

Natural antioxidants, o-methoxyphenols such as eugenol (4-allyl-2-methoxyphenol) and isoeugenol (4-propenyl-2-methoxyphenol), which are components of clover oil, are commonly used as a flavoring agent in cosmetics and food products. These compounds show an anti-inflammatory effect but have adverse effects characterized by inflammatory and allergic reactions when they used at higher concentrations, possibly due to their prooxidant activity and consequent formation of reactive quinone methide intermediates. Their beneficial biological activity may be obtained by avoiding these adverse effects by lessening the potent oxidative activity of these compounds. Thus, we recently designed several synthetic dimers of eugenol, isoeugenol or ferulic acid to lessen the prooxidant activity induced by these monomers, and demonstrated that these dimeric compounds showed the reduced cytotoxicity due to the decrease in the radical production. These findings suggest that o-methoxyphenol dimers might act a … More s a potent inhibitor of inflammatory and allergic responses. However, the inhibitory mechanism of these compounds on inflammatory responses has still not been clarified in detail. In the present study, we examined the inhibitory effect of dimer compounds such as bis-eugenol, dehydrodiisoeugenol, and bis-ferulic acid, on the lipopolysaccharide (LPS)- induced inflammatory mediator expression in mouse macrophage cell line RAW264.7. Eugenol, isoeugenol, ferulic acid and isoferulic acid were purchased from Tokyo Kasei Co. ; hesperetin and hesperidin was from Sigma Chemical Co. ; o-vanilin was from Wako Chemical Co. Escherichia coli O111B4 LPS purchased from LBL Inc. LPS-induced inflammatory cytokine such as IL-1β, TNF-α, and mouse neutrophil chemoattractant KC and cyclooxygenase (COX)-2 expressions were strongly inhibited by these dimer compounds, but not by their parent monomers. In addition, other o-methoxyphenol compounds such as hesperetin, hesperidin, o-vanilin and isoferulic acid also inhibited LPS-induced COX-2 expression at higher concentrations. o-Methoxyphenol compounds which exhibited the COX-2 inhibitory effect at low concentrations possessed the moderate bond dissociation energy (BDE) value ; parameter to predict the effect of a phenol function. These observations suggest that dimerization of o-methoxyphenols, leading to a high level of phenolic function, may exhibit a potent anti-inflammatory and anti-carcinogenic action on the various inflammatory or neoplastic diseases, and also may be a useful tool for the discovery of effective NSAID-like compounds. Less