Sodium salicylate inhibits expression of COX-2 through suppression of ERK and subsequent NF-κB activation in Rat ventricular cardiomyocytes

The expression of cyclooxygenase-2 (COX-2) is a characteristic response to inflammation, which can be inhibited with sodium salicylate. IL-1beta and TNF-alpha can induce extracellular signal-regulated kinase (ERK), IKK, IkappaB degradation and NF-kappaB activation. Salicylate inhibited the IL-1beta and TNF-alpha-induced COX-2 expressions, regulated the activation of ERK, IKK and IkappaB degradation, and the subsequent activation of NF-kappaB, in neonatal rat ventricular cardiomyocytes. The inhibition of the ERK pathway, with a selective inhibitor, PD098059, blocked the expressions of IL-1beta and TNF-alpha-induced COX-2 and PGE2 release. The antioxidant, N-acetyl-cysteine, also reduced the glutathione or catalase- attenuated COX-2 expressions in IL-1beta and TNF-alpha-treated cells. This antioxidant also inhibited the activation of ERK and NF-kappaB in neonatal rat cardiomyocytes. In addition, IL-1beta and TNF-alpha stimulated the release of reactive oxygen species (ROS) in the cardiomyocytes. However, salicylate had no inhibitory effect on the release of ROS in the DCFDA assay. The results showed that salicylate inhibited the activation of ERK and IKK, IkappaB degradation and NF-kappaB activation, independently of the release of ROS, which suggested that salicylate exerts its anti-inflammatory action through the inhibition of ERK, IKK, IkappaB and NF-kappaB, and the resultant COX-2 expression pathway in neonatal rat ventricular cardiomyocytes.     

Anti-inflammatory effect of corymbocoumarin from Seseli gummiferum subsp. corymbosum through suppression of NF-κB signaling pathway and induction of HO-1 expression in LPS-stimulated RAW 264.7 cells

This study investigated the anti-inflammatory activity of corymbocoumarin, an angular-type pyranocoumarin isolated from Seseli gummiferum subsp. corymbosum in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Corymbocoumarin not only inhibited the production of nitric oxide (NO) and prostaglandin E₂ (PGE₂), but also inhibited the protein and mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Corymbocoumarin also attenuated pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Investigation of the effect on nuclear factor κB (NF-κB) signaling pathway showed that corymbocoumarin inhibited the phosphorylation of Akt and inhibitory κB (IκB)-α and decreased the subsequent translocation of the p65 and p50 NF-κB subunits to the nucleus. A further study revealed that corymbocoumarin exerted anti-inflammatory activity through induction of heme oxygenase (HO)-1 expression. The in vivo study showed that corymbocoumarin (20 mg/kg, i.p.) reduced paw swelling in carrageenan-induced acute inflammation model. Taken together, these results suggest that corymbocoumarin exerts its anti-inflammatory effect in LPS-stimulated RAW 264.7 cells by suppressing NF-κB activation and inducing HO-1 expression. Corymbocoumarin may provide a useful therapeutic approach for inflammation-associated diseases.