Anti-Inflammatory Activity of Wormwood

Summary: Hatziieremia and colleagues studied the effects of Cardamonin, a metabolite isolated for the first time from A. absinthium in 2006. Cardamonin was found to inhibit major pro-inflammatory mediators such as nitric oxide (NO), prostaglandin E-2, and TNF-α by suppressing inducible enzyme expression via inhibition of the mitogen-activated protein kinase (MAPK) pathway and nuclear translocation of critical transcription factors (Hatziieremia, S. et al. 2006)Hatziieremia S, Gray, AI, Ferro V, Paul, A and Plevin, R. The effects of cardamonin on lipopolysaccharide-induced inflammatory protein production and MAP kinase and NFB signalling pathways in monocytes/macrophages British Journal of Pharmacology (2006) 149, 188-198.. The Flavonide p7F isolated from A. absinthium suppresses NFқB and TNF- α (Lee HG, et al. 2004)Lee HG, Kim H, Oh WK, et al (2004).Tetramethoxy hydroxyflavone p7F down-regulates inflammatory mediators via the inhibition of nuclear factor kappaB. Ann NY Acad Sci 1030: 555-68. Artemisinin present in A. annua and to a lesser amount in A. absinthium, and Artesunate a derivative of Artesiminin suppresses TNF-α-induced production of interleukins IL-1beta, IL-6 and IL-8 in human rheumatoid arthritis fibroblast-like synoviocytes (Xu H et al 2007)Xu H, He Y, Yang X et al. (2007) Anti-malarial agent artesunate inhibits TNF-{alpha}-induced production of proinflammatory cytokines via inhibition of NF-{kappa}B and PI3 kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes. Rheumatology (Oxford) Feb. 2007 (ahead of print). Other Artemisia species are also explored for their anti-inflammatory properties (Lee JH., et al. 2006). Some of the major findings are described in more detail as follows:

Cardamonin from A. absinthium has inhibitory effect on iNOS induction

Hatziieremia and colleagues from the University of Strathclyde, Glasgow, UK, studied the effects of Cardamonin, isolated for the first time from A. absinthium in 2006, on LPS-induced nitrite (NO) release, inducible NO-Synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression in two macrophage cell lines. They used Western blotting to investigate its effects on phosphorylation of the mitogen activated protein (MAP) kinases, extracellular signal-regulated kinase (ERK), c-Jun kinase (JNK) and p38 MAP kinase, and activation of the NFkB pathway, at the level of IқBα degradation and phosphorylation of NFқB. Also its effects on NFқB and GAS/GAF-DNA binding were assessed by EMSA (Hatziieremia, S. et al. 2006)Hatziieremia S, Gray, AI, Ferro V, Paul, A and Plevin, R. The effects of cardamonin on lipopolysaccharide-induced inflammatory protein production and MAP kinase and NFB signalling pathways in monocytes/macrophages British Journal of Pharmacology (2006) 149, 188-198..

Cardamonin concentration-dependently inhibited both NO release and iNOS expression but had no effect on COX-2 expression. It did not effect phosphorylation of the MAP kinases, degradation of IқBα or phosphorylation of NFқB. However, it inhibited NFқB DNA-binding in both LPS-stimulated cells and nuclear extracts of the cells (in vitro). It also inhibited IFN?-stimulated iNOS induction and GAS/GAF-DNA binding. The authors suggest that the inhibitory effect of Cardamonin on LPS-induced iNOS induction is not mediated via effects on the initial activation of the NFқB or MAP kinase pathways but is due to a direct effect on transcription factor binding to DNA.

Cardamonin inhibits NO and TNF- α

Ahmad S. and colleagues studied the effects of Cardamonin on two cellular systems that are repeatedly used in the analysis of anti-inflammatory bioactive compounds, namely RAW 264.7 cells and whole blood. Cardamonin inhibited NO and PGE(2) production from lipopolysaccharide- and interferon-gamma-induced RAW cells and whole blood with IC(50) values of 11.4 μM and 26.8 μM respectively. Analysis of thromboxane B(2) (TxB-2) secretion from whole blood stimulated either via the COX-1 or COX-2 pathway, revealed that Cardamonin inhibits the generation of TxB-2 via both pathways with IC(50) values of 2.9 and 1.1 μM, respectively. Analysis of IC(50) ratios determined that Cardamonin was more COX-2 selective in its inhibition of TxB-2 with a ratio of 0.39. Cardamonin also inhibited the generation of intracellular reactive oxygen species and secretion of TNF-α from RAW 264.7 cells in a dose responsive manner with IC(50) values of 12.8 μM and 4.6 μMol, respectively (Ahmad S, et al. 2006)Ahmad S, Israf DA, Lijas NH, Shaari K et al. Cardamonin, inhibits pro-inflammatory mediators in activated RAW 264.7 cells and whole blood. Eur J Pharmacol (2006) 538(1-3):188-94..

Cardamonin inhibits iNOS and NFқB expression in RAW 264.7 macrophage cells

In this report, Israf and colleagues evaluated the ability of Cardamonin to suppress both NO and PGE2 synthesis, iNOS and COX-2 expression and enzymatic activity, and key molecules in the NFқB pathway in order to determine its molecular target. Cardamonin suppressed the production of NO and PGE2 in interferon-gamma (IFN-gamma)- and lipopolysaccharide (LPS)-induced RAW 264.7 cells. This inhibition was demonstrated to be caused by a dose-dependent down-regulation of both inducible enzymes, iNOS and COX-2, without direct effect upon iNOS or COX-2 enzyme activity. Subsequently they determined that the inhibition of inducible enzyme expression was due to a dose-dependent inhibition of phosphorylation and degradation of I-kappaBalpha, which resulted in a reduction of p65NF-kappaB nuclear translocation. The authors concluded that Cardamonin is a potential anti-inflammatory drug lead that targets the NFқB pathway (Israf DA., et al.2007)Israf DA, Khairuzin TA, Syahida A et al. Cardamonin inhibits COX and iNOS expression via inhibition of p65NF-kappaB nuclear translocation and Ikappa-B phosphorylation in RAW 264.7 macrophage cells.Mol Immunol (2007) 44(5):673-9 .

Cardamonim blocks the NFқB signaling pathway

Lee Jh and colleaugues from Anticancer Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, Yuseong, Daejeon, Korea studied the NFқB and the signaling pathways that regulate its activity. In their search for NFқB inhibitors from natural resources, they identified Cardamonim, 2',4'-dihydroxy-6'-methoxychalcone, as an inhibitor of NFқB activation In this study, they demonstrated the effect of Cardamonin on NFқB activation in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and LPS-induced mortality. Cardamonin significantly inhibited the induced expression of NFқB reporter gene by LPS or TNF-α in a dose-dependent manner. LPS-induced production of TNF- α and NO as well as expression of inducible nitric-oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was significantly suppressed by the treatment of Cardamonin. Also, Cardamonin inhibited not only LPS-induced degradation and phosphorylation of inhibitor kappaBalpha (IkappaBalpha) but also the activation of inhibitor kappa B (Ikappa B) kinases and nuclear translocation of NFқB. Further analyses revealed that Cardamonin did not directly inhibit Ikappa B kinases, but it significantly suppressed LPS-induced activation of Akt. Moreover, Cardamonin suppressed transcriptional activity and phosphorylation of Ser536 of RelA/p65 subunit of NFқB. However, this compound did not inhibit LPS-induced activation of extracellular signal-regulated kinase and stress-activated protein kinase/c-Jun NH(2)-terminal kinase, but significantly impaired activation of p38 mitogen-activated protein kinase. They also demonstrated that pretreatment of Cardamonin rescued C57BL/6 mice from LPS-induced mortality in conjunction with decreased serum level of TNF-α. (Lee JH., et al. 2006)Lee JH, Jung HS, Giang PM et al. Blockade of nuclear factor-kappaB signaling pathway and anti-inflammatory activity of cardamomin, a chalcone analog from Alpinia conchigera J Pharmacol Exp Ther (2006) 316: 271-278.

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