title: Molecular mechanism of the anti-inflammatory activity of a natural diarylnonanoid, malabaricone C.
abstract: 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-α, interleukin-1β, 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-κB activation and iNOS promoter activity, which correlated with its inhibitory effect on IκB phosphorylation and degradation, and NF-κB nuclear translocation, in the LPS-stimulated macrophages. It also inhibited LPS-induced phosphorylation of p38 and JNK, which are also upstream activators of NF-κB, without affecting Akt phosphorylation. Mal C also effectively blocked the PKR-mediated activation of NF-κB. These findings indicate that mal C exerts an anti-inflammatory effect through NF-κB-responsive inflammatory gene expressions by inhibiting the p38 and JNK-dependent canonical NF-κB pathway as well as the PKR pathway, and is a potential therapeutic agent against acute inflammation.
authors.affiliation: Department of Biochemistry, Dr. B.C. Roy Post Graduate Institute of Basic Medical Sciences & IPGME&R, 244B, Acharya Jagadish Chandra Bose Road, Kolkata 700 020, India.
authors.forename: Biswanath
authors.initials: B
authors.lastname: Maity
authors.forename: Sudhir Kumar
authors.initials: SK
authors.lastname: Yadav
authors.forename: Birija S
authors.initials: BS
authors.lastname: Patro
authors.forename: Mrityunjay
authors.initials: M
authors.lastname: Tyagi
authors.forename: Sandip Kumar
authors.initials: SK
authors.lastname: Bandyopadhyay
authors.forename: Subrata
authors.initials: S
authors.lastname: Chattopadhyay
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation; D012118:Resorcinols / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D017931:DNA Primers; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012118:Resorcinols; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C071787:malabaricone C