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  • Khan et al investigatedAnomalin a pyranocoumarin constituent


    Khan et al. investigatedAnomalin 44, a pyranocoumarin constituent of S. divaricata, which exhibits potent anti-inflammatory activity. The anomalin 44 dose-dependently inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA and protein expression in LPS-stimulated RAW 264.7 macrophage. Molecular analysis using quantitative real time polymerase chain reaction (qRT-PCR) revealed that several pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were reduced by anomalin, and this reduction correlated with the down-regulation of the NF-κB signaling pathway [78]. Sarrias et al. reported study of urolithins (Uro)-A 45 and B 46, which are metabolized from ellagitannins (ET) and ellagic EDC.HCl kinase (EA) buy gut microbiota. Uro-A 45 and Uro-B 46 (10 microm) inhibited PGE2 production (85 and 40%, respectively) after IL-1beta stimulation, whereas EA did not show any effect. Uro-A 45, but not Uro-B 46, down-regulated cyclo-oxygenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1) mRNA expression and protein levels. The results suggested that Uro, mainly Uro-A 45, was the main compounds that are responsible for the pomegranate anti-inflammatory properties. The mechanism of action implicated seems to be via the inhibition of activation of NF-kappaB and MAPK, down-regulation of COX-2 and mPGES-1 expressions, and consequently, via the reduction of PGE2 production [79]. Nakamura et al. investigated the inhibitory effect of the known oxycoumarins osthol 35, and xanthoxyletin 47, poncitrin 48, newly isolated from Clausena guillauminii (Rutaceae), on inducible-nitric oxide synthase (iNOS) expression induced by lipopolysaccharide (LPS) and the NO generation in RAW 264.7 mouse macrophages. Isolation of active oxycoumarins was guided by Western blot analysis of iNOS protein expression. These oxycoumarins showed an inhibitory effect on iNOS protein expression at 10 microM, Further examination revealed that the synthesis of nitric oxide (NO) and the protein expression of tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2) were inhibited by xanthoxyletin 47 [80]. The authors further investigated the structure-activity relationship between 63 natural oxycoumarin derivatives and their effects on the expression of inducible-nitric oxide synthase (iNOS) induced by lipopolysaccharide and observed that these compounds will show anti-inflammatory activities via inhibition of the expressions of iNOS and COX-2 [81]. Scoparone 49 is a major component of the shoot of Artemisia capillaris (Compositae), which have been used for the treatment of hepatitis and biliary tract infection . Jang et al. reported that, scorparone exhibited no cytotoxic effect in unstimulated macrophages, but reduced the release of nitric oxide (NO) and prostaglandin E2 (PGE2) upon stimulation by IFN-gamma/LPS or LPS. The inhibitory effects were conclusively found to be in conjunction with the suppression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in IFN-gamma/LPS stimulated RAW 264.7 cells. Moreover, scoparone also attenuated the production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 in LPS-stimulated RAW264.7 cells, suggesting that scoparone decreases the production of the inflammatory mediators such as NO and PGE2 in macrophages by inhibiting iNOS and COX-2 expression [82]. Lin et al. have studied inhibitory mechanism of byakangelicol 50, isolated from Angelica dahurica, on interleukin-1beta (IL-1beta)-induced cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) release in human pulmonary epithelial cell line (A549). Byakangelicol 50 (10–50 microM) concentration-dependently attenuated IL-1beta-induced COX-2 expression and PGE2 release. The selective COX- 2 inhibitor, NS-398 (0.01–1 microM), and byakangelicol 50 (10–50 microM) both concentration-dependently inhibited the activity of the COX-2 enzyme. Meanwhile Byakangelicol 50, at a concentration up to 200 microM, did not affect the activity and expression of COX-1 enzyme. IL-1beta-induced p44/42 mitogen-activated protein kinase (MAPK) activation was inhibited by the MAPK/extracellular signal-regulated protein kinase (MEK) inhibitor, PD 98059 (30 microM), while byakangelicol 50 (50 microM) had no effect. Treatment of cells with byakangelicol (50 microM) or pyrrolidine dithiocarbamate (PDTC; 50 microM) partially inhibited IL-1beta-induced degradation of IkappaB-alpha in the cytosol, translocation of p65 NF-kappaB from the cytosol to the nucleus and the NF-kappaB-specific DNA-protein complex formation. The authors have demonstrated that byakangelicol 50 effectively inhibits IL-1beta-induced PGE2 release in A549 cells; this inhibition may be mediated by suppression of COX-2 expression and the activity of COX-2 enzyme. The inhibitory mechanism of byakangelicol on IL-1beta-induced COX-2 expression at least in part, may be through suppression of NF-kappaB activity [83].