Molecular mechanism of the anti-inflammatory activity of a natural diarylnonanoid, malabaricone C
Maity, B; Yadav, SK; Patro, BS; Tyagi, M; Bandyopadhyay, SK; Chattopadhyay, S
Chattopadhyay, S (reprint author), Bhabha Atom Res Ctr, Div Bioorgan, Bombay 400085, Maharashtra, India.
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-alpha, interleukin-1 beta, 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-kappa B activation and iNOS promoter activity, which correlated with its inhibitory effect on I kappa B phosphorylation and degradation, and NF-kappa 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-kappa B, without affecting Akt phosphorylation. Mal C also effectively blocked the PKR-mediated activation of NF-kappa B. These findings indicate that mal C exerts an anti-inflammatory effect through NF-kappa B-responsive inflammatory gene expressions by inhibiting the p38 and JNK-dependent canonical NF-kappa B pathway as well as the PKR pathway, and is a potential therapeutic agent against acute inflammation. (c) 2012 Elsevier Inc. All rights reserved.
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