Supression of the expression of cyclooxygenase-2 by ozonides of oleate ester

油酸酯臭氧化物对环氧合酶-2表达的抑制

• 批准号: 16590080
• 负责人: MIURA Toshiaki
• 金额: $ 2.24万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590080/
• 关键词: Ozonide; Cyclooxygenase-2; anti-inflammatory action; Signaling pathway; NFкB; MAP kinase; TNF-α; IкBα; 抗炎症薬

Ozonized olive oil has been reported to exert anti-inflammatory effect. However, the details of chemical structure of ozonized olive oil and its action mechanism have long been unclear. We have recently demonstrated that the major component of the ozonized olive oil is triozonide of triolein. In this study, we identified several minor components of ozonized olive oil, including "cross ozonides" of low and high molecular weight. In addition, to elucidate the anti-inflammatory action mechanism of ozonized olive oil, we investigated the effects of ozonized olive oil and methyl oleate ozonides on the generation of PGE_2 and the expression of Cyclooxygenase-2 (COX-2) in Lipopolysaccharide (LPS)-stimulated macrophage-like THP-1 cells. Olive oil, methyl oleate and their ozonides did not affect cell viability and morphology within a concentration used. LPS-induced COX-2 expression and PGE_2 generation in macrophage-like THP-1 cells were not affected by olive oil itself. However, ozonized olive oil inhibited both reactions in a concentration-dependent manner. Methyl oleate ozonides also inhibited COX-2 expression and PGE_2 generation whereas oleic acid and methyl oleate did not show such inhibitory effects. Such actions of ozonized olive oil and methyl oleate ozonide were shown to be due to their inhibitory effect on lкB phosphorylation which is required for Nuclear factor-kappa B (NFкB) activation and subsequent COX-2 gene transcription in LPS-stimulated macrophages. The inhibitory effect was also observed with ozonide having no functional group except for ozonide ring. In addition, ozonized olive oil and methyl oleate ozonide showed no effect on the phosphorylations of p38 and JNK, which are involved in the activation of AP-1. These results demonstrate that ozonized olive oil and methyl oleate ozonides suppress LPS-induced PGE_2 generation in macrophage-like THP-1 cells through inhibition of COX-2 gene transcription by suppressing the lкBαNFкB pathway.

据报道，臭氧化橄榄油具有抗炎作用。然而，臭氧化橄榄油的化学结构细节及其作用机制一直不清楚。我们最近证明了臭氧化橄榄油的主要成分是三油酸的三臭氧化物。在这项研究中，我们确定了臭氧化橄榄油的几种次要成分，包括低分子量和高分子量的“交叉臭氧”。此外，为了阐明臭氧化橄榄油的抗炎作用机制，我们研究了臭氧化橄榄油和油酸甲酯臭氧对脂多糖（LPS）刺激的巨噬细胞样THP-1细胞中PGE_2生成和环氧合酶-2 （COX-2）表达的影响。橄榄油、油酸甲酯及其臭氧化物在一定浓度内对细胞活力和形态没有影响。橄榄油本身对lps诱导的巨噬细胞样THP-1细胞中COX-2的表达和PGE_2的生成没有影响。然而，臭氧化的橄榄油以浓度依赖性的方式抑制了这两种反应。油酸甲酯臭氧也能抑制COX-2的表达和PGE_2的生成，而油酸和油酸甲酯则没有这种抑制作用。臭氧化橄榄油和油酸甲酯臭氧的这种作用被证明是由于它们对lкB磷酸化的抑制作用，这是在lps刺激的巨噬细胞中核因子κ B （NFкB）激活和随后的COX-2基因转录所必需的。除臭氧环外不含官能团的臭氧也有抑制作用。此外，臭氧化橄榄油和油酸甲酯臭氧对参与AP-1活化的p38和JNK的磷酸化没有影响。这些结果表明，臭氧化橄榄油和油酸甲酯臭氧化合物通过抑制lкBαNFкB通路抑制COX-2基因转录，从而抑制lps诱导的巨噬细胞样THP-1细胞PGE_2的生成。