Blocking the receptor EP3 to PGE2 as a way to safely prevent atherothrombosis

Aspirin inhibits the platelet production of thromboxane A2 and its beneficial effect on myocardial infarction was demonstrated more than two decades ago. This result validated the strategy aimed at targeting platelet function to prevent myocardial infarction. Since then, numerous drugs targeting various activators of platelets have been developed to further improve prevention. However, the beneficial effect of all these drugs on atherothrombosis is limited by an increased risk of bleeding, because they target thrombosis effectors which are also key players in hemostasis. Since aspirin blocks the generation of numerous prostanoids, including inhibitors of platelet activation, targeting one of them might allow the antithrombotic activity to be maintained without promoting bleeding. In examining the roles of various arachidonic acid metabolites on atherothrombosis, we studied the prostaglandin E2 (PGE2). In vivo, PGE2 facilitates the responses of platelets to all their various activators through its receptor EP3. PGE2 is produced in relatively high amounts in the context of chronic inflammation such as atherosclerosis, and aggravates murine atherothrombosis. Conversely, PGE2 is not involved in hemostasis. As expected, blocking EP3 strikingly reduced atherothrombosis in mice without impacting bleeding tests. In a recent paper published in Prostaglandins & Other Lipid Mediators, we reviewed literature data about the effect of PGE2 and its receptor EP3 on platelet thrombosis and hemostasis in mice and humans. We concluded that cumulated data now justifies validating the role of EP3 blockers with phase III trials to safely improve the prevention of myocardial infarction

Antioxidant Potential is Correlated to ω6 / ω3 Ratio and Brasfield Score in Cystic Fibrosis Children

International audienceOBJECTIVES:Oxidative stress is associated with the condition of cystic fibrosis (CF), but no guidelines exist for its assessment or treatment. Our aim was to evaluate a test that measures the blood antioxidant capability in CF children.METHODS:This antioxidant capability was assessed by the Kit Radicaux Libres (KRL) test in 44 CF children (24 boys). We recorded also anthropometric measures, pulmonary function, CF severity scores, and plasma nutritional and inflammatory parameters (proteins, vitamins, erythrocyte fatty acids, and micronutrients). We performed univariate and multivariate analyses with linear regression models.RESULTS:The mean age at the first KRL assessment was 12.2 ± 3.8 years. Factors that correlated with decreased antioxidant capacity were mostly related to the severity of pulmonary disease [ forced expiratory volume at 1 second (FEV1), acute exacerbation, and congestion. In multivariate analysis, the correlation between Brasfield score and erythrocyte antioxidant potential remained significant (β = - 0.611, p < 0.001). Among nutritional factors, the ω6/ω3 ratio was significantly correlated to erythrocyte antioxidant potential (β = - 1.213, p = 0.01).CONCLUSION:The blood antioxidant capability, measured by the KRL test, appears to be an interesting biomarker to evaluate oxidative stress in CF. This study suggests that the ω6/ω3 ratio should be regarded as a nutritional marker in antioxidant management in CF children

Longitudinal immunomonitoring following Tocilizumab in rheumatoid arthritis

Poster presentationInternational audienc

IIAC – Laboratoire d’anthropologie et d’histoire de l’institution de la culture (LAHIC)

Marie Scarpa, professeur à l’Université de Metz/Paul-VerlaineJean-Marie Privat, professeur à l’Université de Metz/Paul-VerlaineThierry Wendling, chargé de recherche au CNRSDaniel Fabre, directeur d’étudesFranck Beuvier, Odile Vincent, ingénieurs d’études Marie Scarpa, professeur à l’Université de Metz/Paul-Verlaine Jean-Marie Privat, professeur à l’Université de Metz/Paul-Verlaine Ethnocritique de la littérature Marie Scarpa a poursuivi son étude de la situation de ces personnages des seuils ..

Étude du plectre de clavecin : modélisation et résultats expérimentaux

Le clavecin est un instrument à cordes pincées dont la mécanique peut être décrite simplement. Les plectres sont notamment modélisés par des poutres de type encastrée-libre classiques, avec une section constante le long de leur fibre neutre. Pourtant, le processus d'harmonisation réalisé par le facteur, c'est-à-dire l'ensemble des opérations qui donnent au clavecin une réponse uniforme sur toute sa tessiture, semble montrer que la géométrie réelle des plectres, qui a été négligée jusqu'à présent dans leur description, est primordiale pour obtenir un modèle satisfaisant de l'interaction qui a lieu entre ceux-ci et les cordes. Un dispositif expérimental mettant en ?uvre un doigt robotisé permet de valider cette hypothèse avant de poursuivre plus loin dans cette voie

Dexamethasone enhances constitutive androstane receptor expression in human hepatocytes: consequences on cytochrome P450 gene regulation.

ABSTRACT The barbiturate phenobarbital induces the transcription of cytochromes P450 (CYPs) 2B through the constitutive androstane receptor (CAR; NR1I3). CAR is a member of the nuclear receptor family (NR1) mostly expressed in the liver, which heterodimerizes with retinoid X receptor (RXR) and was shown to transactivate both the phenobarbital responsive element module of the human CYP2B6 gene and the CYP3A4 xenobiotic response element. Because previous studies in rodent hepatocyte cultures have shown that the phenobarbital-mediated induction of CYP2B genes is potentiated by glucocorticoids, we examined the role of activated glucocorticoid receptor in this process. We show that submicromolar concentrations of dexamethasone enhance phenobarbital-mediated induction of CYP3A4, CYP2B6, and CYP2C8 mRNA in cultured human hepatocytes. In parallel, we observed that glucocorticoid agonists, such as dexamethasone, prednisolone, or hydrocortisone, specifically increase human car (hCAR) mRNA expression. Accumulation of hCAR mRNA parallels that of tyrosine aminotransferase: both mRNAs reach a maximum at a concentration of 100 nM dexamethasone and are downregulated by concomitant treatment with the glucocorticoid antagonist RU486. Moreover, the effect of dexamethasone on hCAR mRNA accumulation appears to be of transcriptional origin because the addition of protein synthesis inhibitor cycloheximide has no effect, and dexamethasone does not affect the degradation of hCAR mRNA. Furthermore, dexamethasone increases both basal and phenobarbital-mediated nuclear translocation of CAR immunoreactive protein in human hepatocytes. The up-regulation of CAR mRNA and protein in response to dexamethasone explains the synergistic effect of this glucocorticoid on phenobarbital-mediated induction of CYP2B genes and the controversial role of the glucocorticoid receptor on phenobarbital-mediated CYP gene inductions

Etude de filtres millimétriques accordables en technologie microfluidique

National audienceCet article présente les travaux initiés au Lab-STICC et au LAAS sur la conception de dispositifs passifs hyperfréquences accordables sur la basse d'une approche microfluidique. L'idée est d'utiliser des micros canaux dans lesquels circulent des fluides. Ces fluides, diélectriques dans un premier temps, sont utilisés pour modifier la permittivité effective d'un substrat sur lequel est réalisée une structure planaire. La perturbation apportée par le fluide diélectrique va ainsi modifier la fréquence de travail du dispositif. En première approche, des stubs quart d'onde et des filtres passe-bande à stubs sont examinés

IIAC-LAHIC – Laboratoire d’anthropologie et d’histoire de l’institution de la culture

Jean-Marie Privat, Marie Scarpa, professeurs à l’Université de Metz/Paul-Verlaine Ethnocritique de la littérature Les premières séances ont poursuivi l’investigation de la littérature à la croisée de signes culturellement prédictifs ou plus généralement de systèmes de créances et de contraintes sémiotiques liées au(x) processus même de la narrativité et de la fiction. Jean-Marie Privat a repris son travail de cartographie des espaces discursifs (littéraires ou non) qui configurent des partage..

A randomized trial comparing adjuvant chemotherapy with gemcitabine plus cisplatin with docetaxel plus cisplatin in patients with completely resected non-small-cell lung cancer with quality of life as the primary objective

International audienceOBJECTIVES: Adjuvant chemotherapy with vinorelbine plus cisplatin (VC) improves survival in resected non-small-cell lung cancer (NSCLC), but has negative impact on quality of life (QoL). In advanced NSCLC, gemcitabine plus cisplatin (GC) and docetaxel plus cisplatin (DC) exhibit comparable efficacy, with possibly superior QoL compared to VC. This trial investigated these regimens in the adjuvant setting. METHODS: Patients with Stage IB to III NSCLC were eligible following standardized surgery. Overall, 136 patients were included, with 67 and 69 assigned to the GC and DC arms, respectively. Cisplatin (75 mg/m(2), Day [D] 1) plus gemcitabine (1250 mg/m(2), D1 and D8) or docetaxel (75 mg/m(2) D1) were administered for three cycles. Primary end-point was QoL (EORTC QLQ-C30), with the study designed to detect a 10-point difference between arms. Overall survival, safety and cost were secondary end-points. RESULTS: No between-group imbalance was observed in terms of patient characteristics. At inclusion, global health status (GHS) scores (/100) were 63.5 and 62.7 in GC and DC, respectively (P = 0.8), improving to 64.5 and 65.4 after 3 months (P = 0.8). No significant difference in functional or symptoms scores was observed between the arms except for alopecia. Grade 3/4 haematological and non-haematological toxicities were found in 33.8 and 21.7% (P = 0.11), and 33.8 and 26.1% (P = 0.33) of patients, in GC and DC, respectively. At 2 years, 92.9 and 89.8% of patients remained alive in GC and DC, respectively (P = 0.88). CONCLUSIONS: DC and GC adjuvant chemotherapies for completely resected NSCLC were well tolerated and appear free of major QoL effects, and are therefore representing candidates for comparison with the standard VC regimen

Membrane estrogen receptor-α contributes to female protection against high-fat diet-induced metabolic disorders

BackgroundEstrogen Receptor α (ERα) is a significant modulator of energy balance and lipid/glucose metabolisms. Beyond the classical nuclear actions of the receptor, rapid activation of intracellular signaling pathways is mediated by a sub-fraction of ERα localized to the plasma membrane, known as Membrane Initiated Steroid Signaling (MISS). However, whether membrane ERα is involved in the protective metabolic actions of endogenous estrogens in conditions of nutritional challenge, and thus contributes to sex differences in the susceptibility to metabolic diseases, remains to be clarified.MethodsMale and female C451A-ERα mice, harboring a point mutation which results in the abolition of membrane localization and MISS-related effects of the receptor, and their wild-type littermates (WT-ERα) were maintained on a normal chow diet (NCD) or fed a high-fat diet (HFD). Body weight gain, body composition and glucose tolerance were monitored. Insulin sensitivity and energy balance regulation were further investigated in HFD-fed female mice.ResultsC451A-ERα genotype had no influence on body weight gain, adipose tissue accumulation and glucose tolerance in NCD-fed mice of both sexes followed up to 7 months of age, nor male mice fed a HFD for 12 weeks. In contrast, compared to WT-ERα littermates, HFD-fed C451A-ERα female mice exhibited: 1) accelerated fat mass accumulation, liver steatosis and impaired glucose tolerance; 2) whole-body insulin resistance, assessed by hyperinsulinemic-euglycemic clamps, and altered insulin-induced signaling in skeletal muscle and liver; 3) significant decrease in energy expenditure associated with histological and functional abnormalities of brown adipose tissue and a defect in thermogenesis regulation in response to cold exposure.ConclusionBesides the well-characterized role of ERα nuclear actions, membrane-initiated ERα extra-nuclear signaling contributes to female, but not to male, protection against HFD-induced obesity and associated metabolic disorders in mouse