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Differential Inhibitory Effects (differential + inhibitory_effects)
Selected AbstractsDifferential Inhibitory Effects of the Polyphenol Ellagic Acid on Inflammatory Mediators NF-,B, iNOS, COX-2, TNF-,, and IL-6 in 1,2-Dimethylhydrazine-Induced Rat Colon CarcinogenesisBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2 2010Syed Umesalma We investigated the effect of ellagic acid on colon cancer induced by 1,2-dimethylhydrazine in rats. Male Wistar albino rats were divided into four groups. Group 1 served as control, group 2 rats received ellagic acid 60 mg/kg bodyweight/every day p.o. throughout the experiment. Rats from groups 3 and 4 were given subcutaneous (s.c.) injections of 1,2-dimethylhydrazine (20 mg/kg body weight) once a week for the first 15 weeks; rats in group 4 received ellagic acid as in group 2 after the last injection of 1,2-dimethylhydrazine and continued till the end of the experimental period of 30 weeks. 1,2-dimethylhydrazine-induced rats exhibited alterations in cancer tumour markers [5,-nucleotidase (5,-ND), gamma glutamyl transpeptidase (,-GT), carcinoembryonic antigen (CEA), alphafetoprotein (AFP) and cathepsin-D (CD)]; pathophysiological markers [alkaline phosphatase (ALP) and lactate dehydrogenase (LDH)] and oral administration of ellagic acid restored the levels of these marker enzymes. Nuclear factor-kappa B (NF-,B) actively involved in the regulation of both pro-inflammatory proteins [inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)] and pro-inflammatory cytokines [tumour necrosis factor (TNF)-, and interleukin (IL)-6] and in our study 1,2-dimethylhydrazine-induced group exhibited elevated expressions of all these inflammatory proteins. Ellagic acid administration reduced the expressions of NF-,B, COX-2, iNOS, TNF-, and IL-6 as confirmed by immunohistochemical, immunoblot and immunofluorescence analysis during 1,2-dimethylhydrazine-induced colon carcinogenesis. In conclusion, ellagic acid demonstrates anti-inflammatory property by iNOS, COX-2, TNF-, and IL-6 down-regulation due to inhibition of NF-,B and exerts its chemopreventive effect on colon carcinogenesis. [source] Differential inhibitory effects of drugs acting at the noradrenaline and 5-hydroxytryptamine transporters in rat and human neocortical synaptosomes,BRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2009M Mantovani Background and purpose:, Although the amino acid sequences of rat and human 5-hydroxytryptamine (5-HT) and noradrenaline (NA) transporters (i.e. SERT and NET) are highly homologous, species differences exist in the inhibitory effects of drugs acting at these transporters. Therefore, comparison of the potencies of drugs acting at SERT and NET in native human and rat neocortex may serve to more accurately predict their clinical profile. Experimental approach:, Synaptosomes prepared from fresh human and rat neocortical tissues were used for [3H]-5-HT and [3H]-NA saturation and competition uptake experiments. The drugs tested included NA reuptake inhibitors (desipramine, atomoxetine and (S,S)-reboxetine), 5-HT reuptake blockers (citalopram, fluoxetine and fluvoxamine) and dual 5-HT/NA reuptake inhibitors (duloxetine and milnacipran). Key results:, In saturation experiments on synaptosomal [3H]-5-HT and [3H]-NA uptake, the dissociation constants did not indicate species differences although a smaller density of both SERT and NET was observed in human tissues. In competition experiments with the various drugs, marked species differences in their potencies were observed, especially at SERT. The rank order of selectivity ratios (SERT/NET) in human neocortex was as follows: citalopram , duloxetine = fluvoxamine , fluoxetine > milnacipran > desipramine = atomoxetine > (S,S)-reboxetine. Significant species differences in these ratios were observed for duloxetine, atomoxetine and desipramine. Conclusions and implications:, This study provides the first compilation of drug potency at native human neocortical SERT and NET. The significant species differences (viz., human vs. rat) in drug potency suggest that the general use of rodent data should be limited to predict clinical efficacy or profile. [source] Effects of glycyrrhetinic acid derivatives on hepatic and renal 11,-hydroxysteroid dehydrogenase activities in ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2003Yoshihito Shimoyama The purpose of this study was to examine the structure and activity relationships of glycyrrhetinic acid derivatives on the inhibition of hepatic and renal 11,-hydroxysteroid dehydrogenases (HSDs) in rats. Furthermore, we explored whether inflammatory effect of the derivatives is involved in the inhibition of 11,-HSD activity. 18,-Glycyrrhetinic acid (Ia) potently inhibited 11,-HSD activity of hepatic (IC50 (concentration giving 50% inhibition of cortisone production) = 0.09 ,m) and renal (IC50 = 0.36 ,m) homogenate. The inhibitory effect of 18,-glycyrrhetol (Id) modified at the 30-position of glycyrrhetinic acid was weaker than that of glycyrrhetinic acid itself. 18,-24-Hydroxyglycyrrhetinic acid (Ie), oxidized at the 24-position, remarkably reduced the inhibitory activity for both enzymes. 18,-11-Deoxoglycyrrhetinic acid (IIc) showed the same inhibitory effect as glycyrrhetinic acid on hepatic 11,-HSD activity, but less effect on renal 11,-HSD activity. Furthermore, the inhibitory activity of 18,-deoxoglycyrrhetol (IIa), modified at the 11- and 30-position, was markedly decreased. Dihemiphthalate derivatives (IIb, IIIb and IVb) of deoxoglycyrrhetol (IIa), 18,-olean-9(11), 12-diene-3,, 30-diol (IIIa) and olean-11, 13(18)-diene-3,, 30-diol (IVa), which are anti-inflammatory agents, also showed weak inhibition against both hepatic and renal 11,-HSDs. While glycyrrhetinic acid (200 mg kg,1, p.o.) significantly inhibited 11,-HSD activity in rat liver and kidney at 3 h after administration, compound IVb (100 mg kg,1, p.o.) had no effect on either enzyme activity. In addition, the circulating corticosterone level was slightly increased by glycyrrhetinic acid but not by compound IVb. These results suggest that the anti-inflammatory effects of compound IVb, derived from glycyrrhetinic acid, are not due to accumulation of steroids induced by the inhibition of 11,-HSD activity. Our data also showed that the 11-, 24- and 30-positions of glycyrrhetinic acid may play important roles in the differential inhibitory effects on 11,-HSD isozyme activity. [source] Purification of citrus limonoids and their differential inhibitory effects on human cytochrome P450 enzymesJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 9 2007Shibu M Poulose Abstract Recent studies demonstrated that citrus limonoids and flavonoids possess numerous health promoting properties. In the present study, glucosides of limonoids and flavonoids were purified from citrus molasses and limonoid aglycones from citrus seeds. Glucosides were separated on styrene (divinylbenzene), Q-sepharose resins with increasing concentration of sodium chloride. A pH-dependent cold precipitation was carried out for the isolation of naringin in large quantity. Major aglycones such as limonin and nomilin were isolated from seeds by direct crystallization and minor limonoids were purified by vacuum liquid chromatography. The structures of the isolated compounds were confirmed by NMR spectra. Individual limonoids were tested for O -dealkylase and hydroxylase activities of human cytochrome P450 (CYP) isoenzymes such as CYP1A2, CYP1B1, CYP3A4 and CYP19, using ethoxyresorufin, methoxyresorufin and dibenzylfluorescein as substrates. Partial to high inhibition of CYPs was observed in dose-dependent assays. Significant (P < 0.001) reductions in enzyme activities were observed with purified compounds above 2 µmol. Kinetic analyses indicated that limonin glucoside inhibited CYP19 competitively (IC50, 7.1 µ mol L,1), whereas Nomilinic acid glucoside inhibited it noncompetitively (IC50, 9.4 µ mol,1). Nomilinic acid glucoside was the most potent limonoid, with an overall IC50 of < 10 µ mol, for all the enzymes tested. The differential inhibition of CYPs can be ascribed to structural variations of the limonoid nucleus. Limonoid inhibition of key CYPs involved in carcinogenesis supports growing evidence that citrus limonoids act as anticancer agents. 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