Vascular effects of the Mangifera indica L. extract (Vimang)

The effects of the Mangiferia indica L. (Vimang) extract, and mangiferin (a C-glucosylxanthone of Vimang) on the inducible isoforms of cyclooxygenase (cyclooxygenase-2) and nitric oxide synthase (iNOS) expression and on vasoconstrictor responses were investigated in vascular smooth muscle cells and mesenteric resistance arteries, respectively, from Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Vimang (0.5-0.1 mg/ml) and mangiferin (0.025 mg/ml) inhibited the interleukin-1beta (1 ng/ml)-induced iNOS expression more in SHR than in WKY, and cyclooxygenase-2 expression more in WKY than in SHR. Vimang (0.25-1 mg/ml) reduced noradrenaline (0.1-30 microM)- and U46619 (1 nM-30 microM)- but not KCl (15-70 mM)-induced contractions. Mangiferin (0.05 mg/ml) did not affect noradrenaline-induced contraction. In conclusion, the antiinflammatory action of Vimang would be related with the inhibition of iNOS and cyclooxygenase-2 expression, but not with its effect on vasoconstrictor responses. Alterations in the regulation of both enzymes in hypertension would explain the differences observed in the Vimang effect.     

Mechanisms underlying intestinal injury induced by anti-inflammatory COX inhibitors

By far the most attention has been paid to the deleterious actions of nonsteroidal anti-inflammatory drugs (NSAIDs), including isoform selective agents that inhibit cyclooxygenase (COX), on the upper gastrointestinal tract, particularly the gastric and duodenal mucosa. However, recent studies confirm a relatively high incidence of serious clinical events, especially with the more-established drugs of this class, involving the small intestine. Pathogenic factors that have been proposed from early studies in such enteropathy have included the enterohepatic circulation of the nonsteroidal anti-inflammatory drugs, inhibition of cyclooxygenase, surface epithelial changes and focal microvascular events. More recent work has concerned the role of infiltrating inflammatory cells, the relative roles of cyclooxygenase isoforms, COX-1 and COX-2 and the key involvement of inducible nitric oxide (NO) synthase and its product in combination with superoxide, peroxynitrite. In the present review, evidence for the underlying involvement of each these processes, and their sequential integration in the development of the intestinal injury and ulceration promoted by nonsteroidal anti-inflammatory drugs has been considered.     

Suppressive effect of inducible nitric oxide synthase (iNOS) expression by the methanol extract of Actinodaphne lancifolia

Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) has played a crucial role in various pathophysiological processes including inflammation and carcinogenesis. Therefore, the inhibitors of NO synthesis or iNOS gene expression have been considered as potential anti-inflammatory and cancer chemopreventive agents. In our continuous search for iNOS inhibitors from natural products we have evaluated indigenous Korean plant extracts using an assay for inhibition of nitric oxide formation on lipopolysaccharide (LPS)-activated mouse macrophage RAW 264.7 cells. As a result, the methanolic stem extract of Actinodaphne lancifolia showed an inhibitory activity of NO production in a dose-dependent manner (IC50 = 2.5 microg/ml). Additional study demonstrated that the extract of Actinodaphne lancifolia significantly suppressed the iNOS protein and gene expression in a dose-dependent manner. These results suggest that Actinodaphne lancifolia could be a potential candidate for developing an iNOS inhibitor from natural products. Further elucidation of active principles for development of new cancer chemopreventive and/or anti-inflammatory agents could be warranted.     

The inhibitory principle of lipopolysaccharide-induced nitric oxide production from<Emphasis Type="Italic">inula britannica</Emphasis> var.<Emphasis Type="Italic">chinensis</Emphasis>

A sesquiterpene lactone, 1-O-acetyl-4R,6S-britannilactone (1) isolated from the flowers of Inula britannica L. var. chinensis (Rupr.) Reg. (Compositae), was found as an iNOS inhibitory constituent for the first time with an IC50 value of 22.1 microM which is more potent than the positive control, L-N6-(1-iminoethyl)lysine (IC50 = 33.7 microM). Structure of compound 1 was identified by 1D and 2D NMR experiments and by comparison with the reference standard.     

Aminoguanidine downregulates expression of cytokine-induced Fas and inducible nitric oxide synthase but not cytokine-enhanced surface antigens of rat islet cells

Autoimmune beta-cell destruction occurs directly by cell-mediated cytotoxicity or indirectly by cytokines released from infiltrating lymphocytes. Cytokines (IL-1beta/IFN-gamma) modify or induce expression of MHC antigens and ICAM-1 on beta-cells which can lead to an improved binding of T-lymphocytes to beta-cells and finally to an enhanced cell-mediated cytotoxicity. Cytokines also induce Fas-expression and inducible nitric oxide synthase (iNOS) causing generation of nitric oxide (NO) which is toxic for beta-cells. The iNOS inhibitor aminoguanidine (AG) delays diabetes onset, but does not reduce diabetes incidence. We wanted to know whether AG inhibits cytokine-induced expression of Fas, MHC antigens and ICAM-1 on beta-cells of LEW.1W and BB/OK rat islets after culture with IL-1beta/IFN-gamma. NO was completely inhibited by 5.0 mmol/L AG while 0.5 mmol/L had no inhibitory effect. AG downregulated Fas-expression on the surface of beta-cells. Cytokine-induced/enhanced expression of MHC class-II and ICAM-1 was not affected by any AG concentration. AG syngergistically increased cytokine-induced enhancement of MHC class-I antigen density. AG possibly blocks the indirect pathway of beta-cell damage in vivo due to inhibition of Fas and iNOS and improves direct cell-mediated cytotoxicity due to drastic increased MHC class-I expression. Inhibition of only one pathway of beta-cell destruction is not sufficient to prevent diabetes.