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1.
Clin Exp Allergy ; 38(6): 947-56, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18498541

ABSTRACT

BACKGROUND: Histamine H1-receptor antagonists are used to relieve the symptoms of an immediate allergic reaction. They have additional anti-inflammatory effects that could result from an inhibition of the transcription factors activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappaB). The implication of the H1-receptor in these effects is controversial. Diphenhydramine is a first-generation H1-receptor antagonist while mizolastine and desloratadine are second-generation compounds. Mizolastine is also an inhibitor of 5-lipoxygenase (5-LO), an enzyme that has been involved in NF-kappaB activation. OBJECTIVE: We measured the ability of antihistamines to reverse histamine-induced smooth muscle contraction, an effect that involves the H1-receptor. We then investigated whether these drugs affect NF-kappaB and AP-1 activities in A549 lung epithelial cells, and whether this potential regulation involves H1-receptor and 5-LO. METHODS: Muscle tone was measured on tracheal segments of guinea-pigs. The H1-receptor was overexpressed by transfection and detected by Western blotting and immunofluorescence microscopy. NF-kappaB and AP-1 activities were assessed by reporter gene assays in cells overexpressing or not overexpressing the H1-receptor. Production of regulated upon activation, normal T cell expressed andsecreted (RANTES), a chemokine whose expression is induced through NF-kappaB, was measured using an immunoassay. RESULTS: H1-receptor antagonists reversed histamine-induced contraction in a dose-dependent manner. Induction of AP-1 and NF-kappaB activities by histamine and the down-regulatory effect of antihistamines required overexpression of the H1-receptor. In contrast, when tumour necrosis factor-alpha and a phorbol ester were used to stimulate NF-kappaB and AP-1 activities, respectively, repression of these activities did not involve the H1-receptor. Indeed, repression was triggered only by a subset of H1-receptor antagonists and was not stronger after overexpression of the H1-receptor. Mizolastine and desloratadine dose-dependently decreased tumour necrosis factor-alpha-induced production of RANTES. Diphenhydramine, H2- and H3-receptor antagonists as well as selective inhibitors of 5-LO were ineffective in this assay. CONCLUSION: Repression of NF-kappaB and AP-1 activities by H1-receptor antagonists involves H1-receptor-dependent and -independent mechanisms but not 5-LO.


Subject(s)
Histamine H1 Antagonists/pharmacology , NF-kappa B/metabolism , Receptors, Histamine H1/metabolism , Transcription Factor AP-1/metabolism , Analysis of Variance , Animals , Arachidonate 5-Lipoxygenase/metabolism , Cell Line , Chemokine CCL5/metabolism , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Genetic Techniques , Guinea Pigs , Histamine/pharmacology , Humans , Lipoxygenase Inhibitors/pharmacology , Lung/cytology , Lung/drug effects , Lung/metabolism , Male , Muscle, Smooth/drug effects , Plasmids/genetics , Receptors, Histamine H1/genetics , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , Tetradecanoylphorbol Acetate/pharmacology , Trachea/drug effects , Tumor Necrosis Factor-alpha/pharmacology
2.
Rev Med Interne ; 25(9): 636-47, 2004 Sep.
Article in French | MEDLINE | ID: mdl-15363619

ABSTRACT

BACKGROUND: Glucocorticoids are used as anti-inflammatory, immuno-modulatory, anti-proliferative and cytotoxic drugs, but they also trigger important side-effects. These hormones bind to glucocorticoid receptor alpha (GRalpha), an intracellular protein, which acts essentially in the nucleus. MAIN POINTS: GRalpha is a ligand-activated transcription factor that positively or negatively regulates gene expression by distinct mechanisms. Stimulation of gene transcription occurs after direct binding of the receptor to specific responsive DNA elements. Gene activation by glucocorticoids is mainly responsible for certain adverse effects. In contrast, the therapeutic effects of glucocorticoids are predominantly mediated through repression of genes encoding inflammatory mediators. Inhibitory protein-protein interaction between the hormone-activated receptor and the transcription factors NF-kappaB and AP-1 was found to be the underlying mechanism. However, inhibition of other transcription factors may account for deleterious effects of glucocorticoids, such as adrenal suppression and osteoporosis. GRalpha also mediates rapid non-genomic effects of glucocorticoids. Side-effects are reduced by using topical glucocorticoids which have a low systemic bioavailability. Moreover, it is important to determine the lowest effective maintenance dose of systemic and topical glucocorticoids to further decrease the risk of adverse effects. This is particularly justified because inhibition of AP-1 and NF-kappaB activities, that is the anti-inflammatory effect, occurs at much lower hormone concentrations than transactivation. PERSPECTIVES: Clinical use of glucocorticoids is limited by occurrence of severe adverse effects. Therefore, the current aim is to design GRalpha ligands that retain only the anti-inflammatory activities of GC.


Subject(s)
Anti-Inflammatory Agents , Glucocorticoids , Receptors, Glucocorticoid , Administration, Topical , Adrenal Glands/drug effects , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/adverse effects , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Circadian Rhythm , Glucocorticoids/administration & dosage , Glucocorticoids/adverse effects , Glucocorticoids/pharmacology , Glucocorticoids/therapeutic use , Humans , Mice , Mice, Transgenic , Mineralocorticoids/administration & dosage , Mineralocorticoids/adverse effects , Mineralocorticoids/pharmacology , Mineralocorticoids/therapeutic use , Osteoporosis/chemically induced , Receptors, Glucocorticoid/drug effects , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/physiology , Transcription Factors , Transcription, Genetic
3.
Phytomedicine ; 11(4): 338-41, 2004.
Article in English | MEDLINE | ID: mdl-15185848

ABSTRACT

Sida acuta Burm. (Malvaceae) originating from Ivory Coast was selected after an ethnobotanical survey: traditional healers of malaria commonly used this plant for the treatment. Extracts were tested on two strains of Plasmodium falciparum: FcM29-Cameroon (chloroquine-resistant strain) and a Nigerian chloroquine-sensitive strain. Extracts were obtained by preparing decoction in water of the powdered plant, the technique used by most of the traditional healers. An ethanol extract was then made and tested. The IC50 values obtained for these extracts ranged from 3.9 to -5.4 microg/ml. Purification of this active fraction led to the identification of cryptolepine as the active antiplasmodial constituent of the plant.


Subject(s)
Antimalarials/pharmacology , Malaria, Falciparum/prevention & control , Malvaceae , Phytotherapy , Plant Extracts/pharmacology , Plasmodium falciparum/drug effects , Animals , Antimalarials/administration & dosage , Antimalarials/therapeutic use , Chloroquine , Cote d'Ivoire , Drug Resistance , Inhibitory Concentration 50 , Plant Extracts/administration & dosage , Plant Extracts/therapeutic use
4.
Clin Exp Allergy ; 33(7): 895-901, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12859444

ABSTRACT

BACKGROUND: Glucocorticoids exert their anti-inflammatory effects mainly through transrepression of the transcription factors activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappaB). Certain adverse effects of glucocorticoids are mediated through gene transactivation. Fluticasone propionate (FP) and mometasone furoate (MF) are the most recently developed topical glucocorticoids for the treatment of airway disorders. Their relative capacities to repress AP-1 and NF-kappaB activities are not known and comparison of their transactivation potencies has given unclear results. OBJECTIVE: To determine the relative transactivation and transrepression potencies of FP and MF. METHODS: Transactivation assays were performed in HeLa cells carrying a glucocorticoid-inducible luciferase gene. To measure transrepressive potencies of FP and MF, A549 lung epithelial cells were transiently transfected with an AP-1- or NF-kappaB-dependent luciferase gene. Using an immunoassay, we also evaluated the ability of MF and FP to inhibit the production of Regulated upon Activation, Normal T-cell Expressed and Secreted (RANTES), a pro-inflammatory cytokine, whose gene is controlled by AP-1 and NF-kappaB. Areas under the dose-response curve were calculated to determine relative potencies. RESULTS: FP and MF are equipotent for transactivation. Both molecules show globally the same potency to inhibit AP-1 and NF-kappaB activities and RANTES production. MF and FP have very significant transcriptional effects at 2x10(-10) M, which is the peak concentration reached in the plasma after inhalation of high dosages. Indeed, they produce a 17-fold induction of luciferase in the transactivation assay, and inhibit AP-1 activity, NF-kappaB activity and RANTES release by approximately 40%. CONCLUSION: FP and MF have the same ability to trigger gene activation and also the same potency to inhibit AP-1 and NF-kappaB activities. Their strong transcriptional effects at 2x10(-10) M suggest that these compounds act not only topically but also systemically, with the risk of provoking concomitant adverse effects at high dosages.


Subject(s)
Androstadienes/pharmacology , Anti-Inflammatory Agents/pharmacology , Chemokine CCL5/metabolism , NF-kappa B/metabolism , Pregnadienediols/pharmacology , Transcription Factor AP-1/metabolism , Anti-Inflammatory Agents/antagonists & inhibitors , Chemokine CCL5/antagonists & inhibitors , Dose-Response Relationship, Drug , Fluticasone , HeLa Cells , Humans , Mometasone Furoate , NF-kappa B/antagonists & inhibitors , Transcription Factor AP-1/antagonists & inhibitors , Transcriptional Activation , Transfection
5.
J Ethnopharmacol ; 81(3): 399-401, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12127243

ABSTRACT

Extracts of leaves of Alchornea cordifolia were studied for their antiplasmodial activities. Chloroformic and ether extracts were found to be inactive while the ethanolic extract exhibited mild in vitro activity against Plasmodium falciparum. Fractionation of this extract led us to isolate ellagic acid as the active constituent of the extract with IC(50) in the range of 0.2-0.5 microM. Cytotoxicity of ethanolic fraction and ellagic acid was also estimated on human fibroblasts cells (IC(50) on Hela cells = 7.3 microM at 24 h for ellagic acid).


Subject(s)
Antimalarials/pharmacology , Ellagic Acid/isolation & purification , Ellagic Acid/pharmacology , Euphorbiaceae/chemistry , Plant Extracts/chemistry , Plant Extracts/pharmacology , Animals , Antimalarials/adverse effects , Antimalarials/chemistry , Antimalarials/isolation & purification , Cell Line , Ellagic Acid/adverse effects , HeLa Cells , Humans , Inhibitory Concentration 50 , Molecular Structure , Phytotherapy , Plant Extracts/adverse effects , Plant Leaves/chemistry , Plasmodium falciparum/drug effects
6.
Steroids ; 66(7): 597-604, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11322967

ABSTRACT

The glucocorticoids (GC) betamethasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone and triamcinolone acetonide are currently used in the treatment of inflammatory diseases. Through a process called trans-activation, GC activate gene expression and produce various physiological and pharmacological effects. In particular, by inducing gluconeogenic enzymes, long-term GC treatment may cause diabetes. Using three different assays, we have extensively compared the capacity of the above GC to activate gene expression. trans-Activation of a GC inducible luciferase gene was assessed in HeLa and A549 cells after stable and transient transfection, respectively. In hepatoma tissue culture cells, we measured trans-activation of the endogenous gene encoding tyrosine aminotransferase, a gluconeogenic enzyme. Half-maximal effective concentrations of GC were determined by dose-response analyses. Results obtained with these assays were highly correlated and GC were ranked in three groups according to their trans-activation potency: betamethasone, dexamethasone, and triamcinolone acetonide > methylprednisolone and prednisolone > hydrocortisone. Potencies were not strictly related to receptor binding affinities and not significantly affected by the amount of endogenous GC receptor.


Subject(s)
Glucocorticoids/genetics , Transcriptional Activation/drug effects , Dose-Response Relationship, Drug , Genes, Reporter , Glucocorticoids/pharmacology , Humans , Inhibitory Concentration 50 , Luciferases/genetics , Reproducibility of Results , Tumor Cells, Cultured , Tyrosine Transaminase/genetics
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