Aktan Fugen, Henness Sheridan, Tran Van H, Duke Colin C, Roufogalis Basil D, Ammit Alaina J
Faculty of Pharmacy, University of Sydney, New South Wales, Australia.
Planta Med. 2006 Jun;72(8):727-34. doi: 10.1055/s-2006-931588. Epub 2006 May 29.
Ginger (Zingiber officinale) is widely used in traditional Chinese medicine, with beneficial effects reported in numerous diseases, including inflammation. Inducible nitric oxide synthase (iNOS), a proinflammatory enzyme responsible for the generation of nitric oxide (NO), has been implicated in the pathogenesis of inflammatory diseases. Gingerols, the main pungent principles of ginger, have anti-inflammatory properties in vitro. In this study we examine the inhibitory effect of a stable [6]-gingerol metabolite, RAC-[6]-dihydroparadol ([6]-DHP) and a closely related gingerol analogue, RAC-2-hydroxy-1-(4-hydroxy-3-methoxyphenyl)dodecan-3-one [a capsaicin/gingerol (Capsarol) analogue referred to as ZTX42] on NO production, inducible nitric oxide synthase (iNOS) activity and protein expression levels in a murine macrophage cell line, RAW 264.7. Both ZTX42 and [6]-DHP significantly inhibited lipopolysaccharide-induced NO production in a concentration-dependent manner, with an IC (50) of 1.45 +/- 0.03 microM and 7.24 +/- 0.22 microM, respectively (P < 0.05). Although both compounds partially inhibited the catalytic activity of iNOS, their inhibitory effect was predominantly due to attenuation of iNOS protein production. This occurred at the transcriptional level, since the gingerol compounds decreased LPS-induced IkappaB-alpha degradation, prevented nuclear translocation of NF-kappaB p65 and reduced NF-kappaB activity in a concentration-dependent manner. Taken together, these results show that ZTX42 and [6]-DHP suppress NO production in murine macrophages by partially inhibiting iNOS enzymatic activity and reducing iNOS protein production, via attenuation of NF-kappaB-mediated iNOS gene expression, providing a rationale for the anti-inflammatory activity reported for this class of compounds.
生姜（姜科植物姜）在传统中药中广泛应用，据报道对包括炎症在内的多种疾病具有有益作用。诱导型一氧化氮合酶（iNOS）是一种负责生成一氧化氮（NO）的促炎酶，与炎症性疾病的发病机制有关。姜辣素是生姜的主要辛辣成分，在体外具有抗炎特性。在本研究中，我们检测了一种稳定的[6]-姜辣素代谢物RAC-[6]-二氢辣素（[6]-DHP）以及一种密切相关的姜辣素类似物RAC-2-羟基-1-(4-羟基-3-甲氧基苯基)十二烷-3-酮[一种辣椒素/姜辣素（Capsarol）类似物，称为ZTX42]对小鼠巨噬细胞系RAW 264.7中NO生成、诱导型一氧化氮合酶（iNOS）活性及蛋白表达水平的抑制作用。ZTX42和[6]-DHP均以浓度依赖方式显著抑制脂多糖诱导的NO生成，IC（50）分别为1.45±0.03 microM和7.24±0.22 microM（P<0.05）。虽然两种化合物均部分抑制iNOS的催化活性，但其抑制作用主要归因于iNOS蛋白生成的减弱。这发生在转录水平，因为姜辣素化合物以浓度依赖方式减少脂多糖诱导的IkappaB-α降解，阻止NF-κB p65的核转位并降低NF-κB活性。综上所述，这些结果表明ZTX42和[6]-DHP通过部分抑制iNOS酶活性并减少iNOS蛋白生成，经由减弱NF-κB介导的iNOS基因表达来抑制小鼠巨噬细胞中的NO生成，为这类化合物所报道的抗炎活性提供了理论依据。
