Molecular mechanism of the anti-inflammatory activity of a natural diarylnonanoid, malabaricone C

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• 作者：Biswanath Maity^a ; ¹ ; Sudhir Kumar Yadav^a ; ¹ ; Birija S. Patro^b ; Mrityunjay Tyagi^b ; Sandip Kumar Bandyopadhyay^a ; Subrata Chattopadhyay^b ; ^{schatt@barc.gov.in}
• 关键词：AP-1 ; activator protein-1 ; COX-2 ; cyclooxygenase-2 ; IKK ; I魏B kinase ; IRAK-4 ; IL-1 receptor-associated kinase-4 ; iNOS ; inducible nitric oxide synthase ; IL ; interleukin ; LPS ; lipopolysaccharide ; mal C ; malabaricone C ; MAP ; mitogen-activated protein ; MAPK
• 刊名：Free Radical Biology and Medicine
• 出版年：2012
• 期刊代码：105_08915849
• 类别：med
• 出版时间：1 May, 2012
• 卷：52
• 期：9
• 页码：1680-1691
• 文件大小：1102 K

摘要

The spice-derived phenolic, malabaricone C (mal C), has recently been shown to accelerate healing of the indomethacin-induced gastric ulceration in mice. In this study, we explored its anti-inflammatory activity and investigated the underlying mechanism of the action. Mal C suppressed the microvascular permeability and the levels of tumor necrosis factor-伪, interleukin-1尾, and nitric oxide in the lipopolysaccharide (LPS)-administered mice. At a dose of 10 mg/kg, it showed anti-inflammatory activity comparable to that of omeprazole (5 mg/kg) and dexamethasone (50 mg/kg). It also reduced the expression and activities of inducible nitric oxide synthase, cyclooxygenase-2, as well as the pro- vs anti-inflammatory cytokine ratio in the LPS-treated RAW macrophages. Mal C was found to inhibit LPS-induced NF-kB activation in RAW 264.7 cells by blocking the MyD88-dependent pathway. Mal C suppressed NF-魏B activation and iNOS promoter activity, which correlated with its inhibitory effect on I魏B phosphorylation and degradation, and NF-魏B nuclear translocation, in the LPS-stimulated macrophages. It also inhibited LPS-induced phosphorylation of p38 and JNK, which are also upstream activators of NF-魏B, without affecting Akt phosphorylation. Mal C also effectively blocked the PKR-mediated activation of NF-魏B. These findings indicate that mal C exerts an anti-inflammatory effect through NF-魏B-responsive inflammatory gene expressions by inhibiting the p38 and JNK-dependent canonical NF-魏B pathway as well as the PKR pathway, and is a potential therapeutic agent against acute inflammation.