Rôle de la nociceptine dans le système nerveux périphérique et central et perspectives dans le traitement de la douleur

PARIS-BIUP (751062107) / SudocSudocFranceF

Les lésions hépatiques induites par une ischémie-reperfusion ou une hypoxie-réoxygénation (implication du monoxyde d'azote)

PARIS-BIUP (751062107) / SudocSudocFranceF

Effets protecteurs du resvératrol sur les lésions consécutives à une ischémie-reperfusion hépatique et évaluation de la perfusion du foie grâce à l'utilisation de nanoparticules à luminescence persistante

Le resvératrol, qui est un composé polyphénolique que l on retrouve notamment dans le vin, possède des propriétés antioxydantes et anti-inflammatoires intéressantes. L objectif de notre travail a été d étudier dans un modèle d ischémie (1h)/reperfusion (3h) (IR) hépatique chez le rat, les effets du resvératrol injecté juste avant la reperfusion à deux doses (0,02 et 0,2 mg/kg). L IR provoque des lésions hépatiques qui se traduisent par une augmentation des concentrations des transaminases et l infiltration des polynucléaires dans le foie. Le traitement par le resvératrol diminue significativement les concentrations plasmatiques des transaminases et s accompagne d une diminution des concentrations de l interleukine IL-1b et d IL-6. D autre part, le resvératrol diminue l expression des ARNm de TNF-a, d IL-1b et de la chémokine KC. On observe également une diminution de l infiltration des polynucléaires neutrophiles dans les lobes ischémiés des rats traités. Ces résultats montrent donc que le traitement par le resvératrol est capable de diminuer la réaction inflammatoire en réduisant la production de cytokines et le recrutement des neutrophiles au cours de la phase précoce de la reperfusion. D autre part, dans notre modèle, l expression hépatique de la Thiorédoxine-1 (Trx-1), qui participe au système de défense antioxydant, et celle de la protéine Txnip (Thiorédoxine interacting protein), qui est capable d inhiber l action de Trx-1 sont augmentées de manière significative chez les rats qui subissent une IR. L ischémie-reperfusion se traduit également par une diminution de l activité réductrice de la Trx. Ce défaut d activité de Trx ne semble pas provenir d un défaut de régénération de Trx-1 oxydée en sa forme réduite car l activité de la Trx Réductase (TxR) n est pas modifiée par l IR. L injection de resvératrol avant le début de la reperfusion provoque une diminution significative de l expression de Txnip à la dose de 0,2 mg/kg. D autre part, le resvératrol entraîne une diminution significative de Trx-1 et restaure l activité réductrice de la Trx sans modifier l activité de la TrxR. Il est donc probable que l augmentation de l activité redox de Trx résulte d une diminution de la fixation de Txnip. Cette diminution de l expression de Txnip/Trx-1 ne passe vraisemblablement pas par le voie du NO (nitric oxide) car nous n avons pas observé de modification des concentrations plasmatiques de NOx, métabolites du NO, ni de modification de l expression de la NOSIII (nitric oxide synthase III). Nous n avons pas non plus retrouvé de modification par le resvératrol de l activité de la DDAH (diméthylarginine diméthylaminohydrolase), protéine qui métabolise un inhibiteur endogène de la NOS (nitric oxide synthase) : la diméthyl-L-arginine (ou ADMA). Ces résultats suggèrent donc que le resvératrol aurait un effet antioxydant indirect en diminuant l expression de Txnip au cours de l IR, ce qui permettrait de préserver l activité redox de la Trx. Dans un deuxième temps, pour rechercher si le resvératrol avait un effet sur la qualité de reperfusion, nous avons développé un modèle d IR sur la souris. Nous avons mis en évidence que l utilisation de nanoparticules à luminescence persistante et spécifiquement captées par le foie lorsqu elles sont injectées en iv, permettait de contrôler la qualité de l ischémie et d évaluer ponctuellement la perfusion hépatique. Cette nouvelle technique devrait nous permettre de rechercher si le resvératrol est capable de modifier la vitesse et la qualité de la reperfusion hépatique. En conclusion, nos résultats montrent que le resvératrol permet de lutter contre les lésions hépatiques post-ischémiques grâce à ses propriétés antiinflammatoires et antioxydantes. Le resvératrol constitue donc un bon candidat comme adjuvant aux liquides de préservation des greffons hépatiques en vue d améliorer la qualité et la durée de leur conservation.Oxidative and inflammatory processes are elicited during hepatic post-ischemic reperfusion and generate liver damage. This work investigated the early anti-inflammatory and antioxydatives effects of the natural polyphenolique trans-resveratrol (Res) in liver ischemia-reperfusion (IR). Partial hepatic ischemia was initiated in rats for 1h and Res (0.02 and 0.2 mg/kg) was administered 5 min (iv) before starting reperfusion for 3h. Res treatment (0.02 and 0.2 mg/kg) resulted in a significant decrease in aminotransferases, IL-1b and IL-6 plasma levels and hepatic neutrophil recruitment caused by IR. TNF-a, IL-1b, KC and HO-1 hepatic mRNA expression was reduced by Res without any change in HSP-70 mRNA. Res mediated decrease in early release of cytokines and neutrophil recruitment led to a reduction in the late inflammatory process. We also studied the effects of Res on the liver thioredoxin (Trx)/Txnip system. Txnip (thioredoxin-interacting protein) is involved in intracellular redox regulation. In our model, Res protect Trx redox activity by diminishing the Txnip protein expression independently of NO production. Our work affirms then the importance of the antioxidant and anti-inflammatory effects of Res on the liver post ischemic damage. We also have used negative charged persistent luminescent nanoparticles (PLNP) to assess liver perfusion after ischemia. These PLNP emit visible light (690 nm) for one hour after a short UV excitation before they are injected into the animal, so preventing autofluorescence. The PLNP are rapidly cleared from the blood by the liver and can be used to assess the perfusion state of normal mouse livers, during and after partial hepatic ischemiaPARIS-BIUP (751062107) / SudocSudocFranceF

Le resvératrol, complément alimentaire, à l'officine et sur internet (quels bienfaits, quels dangers ?)

PARIS-BIUP (751062107) / SudocSudocFranceF

NSE S100B protein blood level assessment during a long-distance trail race

The acute and chronic consequences of long-distance running on brain function have received little attention. The impact of such a hard-physical burden associated with sleep privation during such events such has never been explored in terms of neuropsychological function and brain damage

Onset of Exercise and Diet Program in Obese Women: Metabolic and Anorexigenic Responses Related to Weight Loss and Physical Capacities

International audiencePerturbations of energy balance induce compensatory processes that may alter expected weight loss. In obese patients, our aim was to investigate the relationships that occurred between fasting plasma concentrations of anorexigenic peptides and metabolic parameters, appetite, physical capacity, and weight loss in the 5 first days of a program associating exercise and caloric reduction. Thirteen obese women were monitored from day 1 to day 5 with 2 exercise sessions in day 2 and day 4. We measured, in a fasted state, changes in body weight, hunger ratings, and plasma concentrations of fatty acids, triglycerides, leptin, insulin, amylin, peptide YY, and insulin-resistance index. Physical performance was assessed by a 6-min walking test. The program resulted in significantly reduced body weight (0.75±0.4 kg; p=0.001), of plasma concentrations of triglycerides, insulin, amylin, peptide YY, and the insulin-resistance index, and also increased fatty acids (p<0.05). Hunger ratings were increased (p<0.05). Program-induced changes in fatty acids, leptin, and insulin concentrations were related to physical performance (r2=0.45, 0.59, and 0.52; p<0.05, respectively) and to weight loss (r2=0.65, 0.57, 0.55; p<0.05, respectively). Five days of diet and exercise induced weight loss, improved lipid profile, and decreased insulin resistance while hunger ratings increased. Subjects with higher physical capacity lost more weight, presented higher increases in fatty acids and lower changes of leptin and insulin concentrations suggesting a better metabolic flexibility. To reduce the compensatory responses that can occur with energy imbalances, our study supports to account for individual activity level before prescribing weight-loss program associating diet and exercise

Relationship between catalase haplotype and arterial aging

International audienceBackgroundAlthough many conventional factors have been associated with the development of arterial aging, cardiovascular diseases remain the first cause of death in old age. Therefore, identification of new risk factors may prove promising for monitoring this serious health problem. Oxidative stress and particularly catalase (CAT), an antioxidant enzyme, play an important role in endothelial cell pathophysiology, in shear stress response and ultimately in arterial aging.ObjectiveExamine the relationships between CAT haplotypes and phenotypes of arterial aging (mean internal diameter, mean intima–media thickness of the common carotid arteries (CCA), presence of atheromatous plaques) in two French cohorts.Methods and results564 middle-aged French individuals (mean age 53 ± 12 years) from two cohorts (ERA and STANISLAS cohorts) were included in the study. Blood pressure, CCA intima–media thickness, CCA internal diameter and number of atheromatous plaques were measured. Catalase rs769214 SNP genotyping was performed. We identified a CAT haplotype that influences arterial aging. Individuals carrying the CAT2 haplotype had a higher mean internal diameter of CCA with aging and/or with an SBP ≥140 mmHg and were associated with a greater number of atheromatous plaques than CAT1 haplotypes carriers. This CAT2 haplotype appeared as an independent risk factor of arterial aging, similarly to previously identified factors such as age, systolic blood pressure, male, sex, tobacco use, hs-CRP, BMI and diabetes.ConclusionThe present study highlights the roles of CAT haplotypes in arterial aging and underlines the beneficial impact of the CAT1 haplotype on mean internal diameter of the CCA and atheromatous plaque number as well as on potential associated diseases

Resveratrol metabolism in a non-human primate, the grey mouse lemur (Microcebus murinus), using ultra-high-performance liquid chromatography-quadrupole time of flight.

The grey mouse lemur (Microcebus murinus) is a non-human primate used to study the ageing process. Resveratrol is a polyphenol that may increase lifespan by delaying age-associated pathologies. However, no information about resveratrol absorption and metabolism is available for this primate. Resveratrol and its metabolites were qualitatively and quantitatively analyzed in male mouse-lemur plasma (after 200 mg.kg-1 of oral resveratrol) by ultra-high performance liquid chromatography (UHPLC), coupled to a quadrupole-time-of-flight (Q-TOF) mass spectrometer used in full-scan mode. Data analyses showed, in MSE mode, an ion common to resveratrol and all its metabolites: m/z 227.072, and an ion common to dihydro-resveratrol metabolites: m/z 229.08. A semi-targeted study enabled us to identify six hydrophilic resveratrol metabolites (one diglucurono-conjugated, two monoglucurono-conjugated, one monosulfo-conjugated and two both sulfo- and glucurono-conjugated derivatives) and three hydrophilic metabolites of dihydro-resveratrol (one monoglucurono-conjugated, one monosulfo-conjugated, and one both sulfo- and glucurono-conjugated derivatives). The presence of such metabolites has been already detected in the mouse, rat, pig, and humans. Free resveratrol was measurable for several hours in mouse-lemur plasma, and its two main metabolites were trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate. Free dihydro-resveratrol was not measurable whatever the time of plasma collection, while its hydrophilic metabolites were present at 24 h after intake. These data will help us interpret the effect of resveratrol in mouse lemurs and provide further information on the inter-species characteristics of resveratrol metabolism

Defects in Gallbladder Emptying and Bile Acid Homeostasis in Mice With Cystic Fibrosis Transmembrane Conductance Regulator Deficiencies.

International audienceBACKGROUND & AIMS: Patients with cystic fibrosis (CF) have poorly defined defects in biliary function. We evaluated the effects of cystic fibrosis transmembrane conductance regulator (CFTR) deficiency on the enterohepatic disposition of bile acids (BAs). METHODS: Bile secretion and BA homeostasis were investigated in Cftr(tm1Unc) (Cftr(-/-)) and CftrΔF508 (ΔF508) mice. RESULTS: Cftr(-/-) and ΔF508 mice did not grow to normal size, but did not have liver abnormalities. The gallbladders of Cftr(-/-) mice were enlarged and had defects in emptying, based on (99m)technetium-mebrofenin scintigraphy or post-prandial variations in gallbladder volume; gallbladder contraction in response to cholecystokinin-8 was normal. Cftr(-/-) mice had abnormal gallbladder bile and duodenal acidity, and overexpressed the vasoactive intestinal peptide-a myorelaxant factor for the gallbladder. The BA pool was larger in Cftr(-/-) than wild-type mice, although there were no differences in fecal loss of BAs. Amounts of secondary BAs in portal blood, liver, and bile of Cftr(-/-) mice were much lower than normal. Expression of genes that are induced by BAs, including fibroblast growth factor-15 and BA transporters, was lower in the ileum but higher in the gallbladders of Cftr(-/-) mice, compared with wild-type mice, whereas enzymes that synthesize BA were down-regulated in livers of Cftr(-/-) mice. This indicates that BAs underwent a cholecystohepatic shunt, which was confirmed using cholyl-(Ne-NBD)-lysine as a tracer. In Cftr(-/-) mice, cholecystectomy reversed most changes in gene expression and partially restored circulating levels of secondary BAs. The ΔF508 mice overexpressed vasoactive intestinal peptide and had defects in gallbladder emptying and in levels of secondary BAs, but these features were less severe than in Cftr(-/-) mice. CONCLUSIONS: Cftr(-/-) and CftrΔF508 mice have defects in gallbladder emptying that disrupt enterohepatic circulation of BAs. These defects create a shunt pathway that restricts the amount of toxic secondary BAs that enter the liver