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Nikolova M.,French Institute of Health and Medical Research | Carriere M.,French Institute of Health and Medical Research | Jenabian M.-A.,French Institute of Health and Medical Research | Limou S.,French Institute of Health and Medical Research | And 17 more authors.
PLoS Pathogens | Year: 2011

HIV-1 infection is characterized by a chronic activation of the immune system and suppressed function of T lymphocytes. Regulatory CD4+ CD25 high FoxP3+CD127 low T cells (Treg) play a key role in both conditions. Here, we show that HIV-1 positive patients have a significant increase of Treg-associated expression of CD39/ENTPD1, an ectoenzyme which in concert with CD73 generates adenosine. We show in vitro that the CD39/adenosine axis is involved in Treg suppression in HIV infection. Treg inhibitory effects are relieved by CD39 down modulation and are reproduced by an adenosine-agonist in accordance with a higher expression of the adenosine A2A receptor on patients' T cells. Notably, the expansion of the Treg CD39+ correlates with the level of immune activation and lower CD4+ counts in HIV-1 infected patients. Finally, in a genetic association study performed in three different cohorts, we identified a CD39 gene polymorphism that was associated with down-modulated CD39 expression and a slower progression to AIDS. © 2011 Nikolova et al.


Biermann D.,University of Hamburg | Heilmann A.,University of Hamburg | Didie M.,University of Gottingen | Schlossarek S.,University of Hamburg | And 17 more authors.
PLoS ONE | Year: 2012

Background: The angiotensin II receptor subtype 2 (AT2 receptor) is ubiquitously and highly expressed in early postnatal life. However, its role in postnatal cardiac development remained unclear. Methodology/Principal Findings: Hearts from 1, 7, 14 and 56 days old wild-type (WT) and AT2 receptor-deficient (KO) mice were extracted for histomorphometrical analysis as well as analysis of cardiac signaling and gene expression. Furthermore, heart and body weights of examined animals were recorded and echocardiographic analysis of cardiac function as well as telemetric blood pressure measurements were performed. Moreover, gene expression, sarcomere shortening and calcium transients were examined in ventricular cardiomyocytes isolated from both genotypes. KO mice exhibited an accelerated body weight gain and a reduced heart to body weight ratio as compared to WT mice in the postnatal period. However, in adult KO mice the heart to body weight ratio was significantly increased most likely due to elevated systemic blood pressure. At postnatal day 7 ventricular capillarization index and the density of α-smooth muscle cell actin-positive blood vessels were higher in KO mice as compared to WT mice but normalized during adolescence. Echocardiographic assessment of cardiac systolic function at postnatal day 7 revealed decreased contractility of KO hearts in response to beta-adrenergic stimulation. Moreover, cardiomyocytes from KO mice showed a decreased sarcomere shortening and an increased peak Ca2+ transient in response to isoprenaline when stimulated concomitantly with angiotensin II. Conclusion: The AT2 receptor affects postnatal cardiac growth possibly via reducing body weight gain and systemic blood pressure. Moreover, it moderately attenuates postnatal vascularization of the heart and modulates the beta adrenergic response of the neonatal heart. These AT2 receptor-mediated effects may be implicated in the physiological maturation process of the heart. © 2012 Biermann et al.


Seddik H.,Mohammed v Teaching Military Hospital | Ahid S.,Mohammed V University | Ahid S.,Laboratory of Pharmacology and Toxicology | El Adioui T.,Mohammed v Teaching Military Hospital | And 5 more authors.
European Journal of Clinical Pharmacology | Year: 2013

Purpose: Eradication rates following standard triple therapy for Helicobacter pylori infection are declining. Recent studies, conducted in a number of countries, have shown that sequential therapy for H. pylori infection yields high cure rates. Aim: To compare the efficacy and tolerability of a sequential regimen as a first-line treatment of H. pylori infection with a standard triple treatment regime in Morocco. Methods: A total of 281 naive H. pylori-infected patients, confirmed by histological examination, were assigned randomly to one of two treatment groups: standard triple therapy [omeprazole (20 mg bid) + amoxicillin (1 g bid) + clarithromycin (500 mg bid) for 7 days] or sequential therapy [omeprazole (20 mg bid) + amoxicillin (1 g bid) for 5 days, followed by omeprazole (20 mg bid) + tinidazole (500 mg bid) + clarithromycin (500 mg bid) for an additional 5 days]. H. pylori eradication was checked 4-6 weeks after treatment initiation by using a 13C-urea breath test. Compliance and adverse events were assessed. Results: The two groups did not differ significantly in gender, age, previous disease history, endoscopic and histological features and smoking. The intention-to-treat and per-protocol eradication rates were 65.9 and 71 % in the standard triple therapy group, and 82.8 and 89.9 % in the sequential therapy group, respectively. The eradication rate was significantly higher in the sequential therapy group than in the standard triple therapy group (p < 0.001), There was no statistically significant difference in compliance (97.5 vs. 96.3 %) and incidence of side-effects (27.5 vs. 27.9 %) between the two groups. Conclusions: Based on our results, we conclude that for eradication of H. pylori infection, the 10-day sequential therapy is more effective than the standard triple therapy and is equally tolerated. These results confirm those of other studies in other countries. © 2013 Springer-Verlag Berlin Heidelberg.


Jenabian M.-A.,French Institute of Health and Medical Research | Jenabian M.-A.,University Paris Est Creteil | Seddiki N.,French Institute of Health and Medical Research | Seddiki N.,University Paris Est Creteil | And 20 more authors.
PLoS Pathogens | Year: 2013

The mechanisms by which Regulatory T cells suppress IL-2 production of effector CD4+ T cells in pathological conditions are unclear. A subpopulation of human Treg expresses the ectoenzyme CD39, which in association with CD73 converts ATP/ADP/AMP to adenosine. We show here that Treg/CD39+ suppress IL-2 expression of activated CD4+ T-cells more efficiently than Treg/CD39-. This inhibition is due to the demethylation of an essential CpG site of the il-2 gene promoter, which was reversed by an anti-CD39 mAb. By recapitulating the events downstream CD39/adenosine receptor (A2AR) axis, we show that A2AR agonist and soluble cAMP inhibit CpG site demethylation of the il-2 gene promoter. A high frequency of Treg/CD39+ is associated with a low clinical outcome in HIV infection. We show here that CD4+ T-cells from HIV-1 infected individuals express high levels of A2AR and intracellular cAMP. Following in vitro stimulation, these cells exhibit a lower degree of demethylation of il-2 gene promoter associated with a lower expression of IL-2, compared to healthy individuals. These results extend previous data on the role of Treg in HIV infection by filling the gap between expansion of Treg/CD39+ in HIV infection and the suppression of CD4+ T-cell function through inhibition of IL-2 production. © 2013 Jenabian et al.


Colli-Dula R.C.,University of Florida | Colli-Dula R.C.,National Polytechnic Institute of Mexico | Friedman M.A.,Kennesaw State University | Hansen B.,Laboratory of Pharmacology and Toxicology | Denslow N.D.,University of Florida
Toxicology Reports | Year: 2016

Acrylamide is known to produce follicular cell tumors of the thyroid in rats. RccHan Wistar rats were exposed in utero to a carcinogenic dose of acrylamide (3 mg/Kg bw/day) from gestation day 6 to delivery and then through their drinking water to postnatal day 35. In order to identify potential mechanisms of carcinogenesis in the thyroid glands, we used a transcriptomics approach. Thyroid glands were collected from male pups at 10 PM and female pups at 10 AM or 10 PM in order to establish whether active exposure to acrylamide influenced gene expression patterns or pathways that could be related to carcinogenesis. While all animals exposed to acrylamide showed changes in expected target pathways related to carcinogenesis such as DNA repair, DNA replication, chromosome segregation, among others; animals that were sacrificed while actively drinking acrylamide-laced water during their active period at night showed increased changes in pathways related to oxidative stress, detoxification pathways, metabolism, and activation of checkpoint pathways, among others. In addition, thyroid hormones, triiodothyronine (T3) and thyroxine (T4), were increased in acrylamide-treated rats sampled at night, but not in quiescent animals when compared to controls. The data clearly indicate that time of day for sample collection is critical to identifying molecular pathways that are altered by the exposures. These results suggest that carcinogenesis in the thyroids of acrylamide treated rats may ensue from several different mechanisms such as hormonal changes and oxidative stress and not only from direct genotoxicity, as has been assumed to date. © 2016 The Authors.


Trandaburu I.,Institute of Biology | Oswald I.P.,Laboratory of Pharmacology and Toxicology | Trandaburu T.,University of Pitesti
Acta Histochemica | Year: 2011

The duodenum, jejunum, ileum, cecum and colon of three male hybrid piglets, 4 weeks old just after weaning, were investigated for the immunohistochemical localization of the asialoganglioside, GM1 (asialo-GM1). The study revealed various degrees of labelling for this acid glycosphingolipid in neural, epithelial and blood elements in all the gut segments. The immunolabelled neural structures, represented by ganglionic perikarya and nerve fibers, were distributed throughout the intestinal wall and showed quantitative variations in the various regions. In contrast the numerical evaluation of labelled epithelial cells was encountered only in the terminal jejunum and along the entire ileum, cecum and large intestine. In addition, a heterogenous population of immunolabelled leukocytes was spread randomly in the lamina propria and submucosa of the entire intestine and did not show any apparent quantitative fluctuations between the different parts. The observations regarding the typical distribution patterns of the asialoganglioside GM1 in ganglionic perikarya and epithelial cells of weaned piglets are discussed in relation to their possible functional significance in the intestine and other mammalian organs. © 2009 Elsevier GmbH.


Oukkache N.,Pasteur Institute of Morocco | ElJaoudi R.,Laboratory of Pharmacology and Toxicology | Chgoury F.,Pasteur Institute of Morocco | Rocha M.T.,Butantan Institute | Sabatier J.-M.,Aix - Marseille University
Sheng li xue bao : [Acta physiologica Sinica] | Year: 2015

In the present study, a 'novel' toxin, called Am IT from the venom of scorpion Androctonus mauretanicus is isolated and characterized. A detailed analysis of the action of Am IT on insect axonal sodium currents is reported. Am IT was purified through gel filtration followed by C18 reversed-phase HPLC. Toxicity of Am IT in vivo was assessed on male German cockroach (Blattella germanica) larvae and C57/BL6 mice. Cross-reactivity of Am IT with two β-toxins was evidenced using (125)I-iodinated toxin-based radioimmunoassays with synaptosomal preparations from rat brain. The complete amino acid sequence of Am IT was finally determined by Edman sequencing. Am IT was observed to compete with AaH IT4 purified from the venom of scorpion Androctonus australis in binding assays. It was recognized by an antibody raised against a β-type toxin, which indicated some structural similarity with β-toxins (or related toxin family). The 'novel' toxin exhibited dual activity since it competed with anti-mammal toxins in binding assays as well as showed contracting activity to insect. The toxin competed with radio-labeled β-toxin Css IV by binding to Na(+) channels of rat brain synaptosomes. Analysis of toxin amino acid sequences showed that Am IT shares high structural identity (92%) with AaH IT4. In conclusion, Am IT not only reveals an anti-insect compound properties secreted by 'Old World' scorpions, paralyzing insect larvae by binding to Na(+) channels on larvae's nerve-cell membranes, but also exerts toxic activity in mice, which is similar to anti-mammal toxins from 'New World' scorpions (North and South Americas). Therefore, Am IT appears to be structurally and functionally similar to AaH IT4.


El Jaoudi R.,Laboratory of Pharmacology and Toxicology | Mamouch F.,Laboratory of Pharmacology and Toxicology | El Cadi M.A.,Laboratory of Pharmacology and Toxicology | Bousliman Y.,Laboratory of Pharmacology and Toxicology | And 2 more authors.
Bulletin of Environmental Contamination and Toxicology | Year: 2012

This study aimed to analyze the fluoride concentration in tap drinking water in different cities of Morocco using an electrochemical ion-selective method. Three samples were collected from each thirteen selected cities in the period between March and May 2011. The median value of fluoride was 0.94 mg/L (0.21-2.97). High fluoride concentrations (>0.8 mg/L) were found in sixteen cities. Very high values were found in phosphate regions such as Khouribga which is known to be an endemic dental fluorosis area. This study has shown that the concentration of fluoride in drinking water exceeds the limit especially in phosphate regions. © Springer Science+Business Media, LLC 2012.


Chaouki W.,National Institute for Oncology | Meddah B.,Laboratory of Pharmacology and Toxicology | Hmamouchi M.,Mohammed V University
Pharmazie | Year: 2015

Daphne gnidium L. (Thymeleacees) is a famous Moroccan plant with cancer-related ethnobotanical use. Previously, we demonstrated that ethyl acetate extract of D. gnidium had antiproliferative and pro-apoptotic potential on human breast tumor MCF-7 cells. The purpose of this study was to investigate if the antiproliferative effect of this extract was similar for different human cancer cell lines such as A549 lung cancer and SMMC-7721 hepatoma cells. Moreover, this work essentially focused on the intrinsic apoptotic signaling pathway. Antiproliferative activity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide on A549 and SMMC-7721 cells. The characterization of the mechanisms involved in this effect was determined by lactate dehydrogenase test, apoptosis assays and western blot analyses. Our present study has shown that this extract strongly inhibited proliferation of A549 (IC50: 213±15μg/ml) and SMMC-7721 (IC50: 170±13μg/ml) cells. The characterization of antiproliferative effect demonstrated that this extract was an apoptosis inducer in both cell lines tested. The results of western blot analyses have shown in SMMC-7721 cells that this extract activated caspase signaling triggered by the modulation of Bcl-2 family proteins. These findings suggest that this natural extract-induced effects may have novel therapeutic applications for the treatment of different cancer types.


PubMed | Aix - Marseille University, Butantan Institute, Pasteur Institute of Morocco and Laboratory of Pharmacology and Toxicology
Type: Journal Article | Journal: Sheng li xue bao : [Acta physiologica Sinica] | Year: 2015

In the present study, a novel toxin, called Am IT from the venom of scorpion Androctonus mauretanicus is isolated and characterized. A detailed analysis of the action of Am IT on insect axonal sodium currents is reported. Am IT was purified through gel filtration followed by C18 reversed-phase HPLC. Toxicity of Am IT in vivo was assessed on male German cockroach (Blattella germanica) larvae and C57/BL6 mice. Cross-reactivity of Am IT with two -toxins was evidenced using (125)I-iodinated toxin-based radioimmunoassays with synaptosomal preparations from rat brain. The complete amino acid sequence of Am IT was finally determined by Edman sequencing. Am IT was observed to compete with AaH IT4 purified from the venom of scorpion Androctonus australis in binding assays. It was recognized by an antibody raised against a -type toxin, which indicated some structural similarity with -toxins (or related toxin family). The novel toxin exhibited dual activity since it competed with anti-mammal toxins in binding assays as well as showed contracting activity to insect. The toxin competed with radio-labeled -toxin Css IV by binding to Na(+) channels of rat brain synaptosomes. Analysis of toxin amino acid sequences showed that Am IT shares high structural identity (92%) with AaH IT4. In conclusion, Am IT not only reveals an anti-insect compound properties secreted by Old World scorpions, paralyzing insect larvae by binding to Na(+) channels on larvaes nerve-cell membranes, but also exerts toxic activity in mice, which is similar to anti-mammal toxins from New World scorpions (North and South Americas). Therefore, Am IT appears to be structurally and functionally similar to AaH IT4.

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