Recherche de biomarqueurs précoces par SRM 1 H haute résolution dans l'hypoxie ischémie cérébrale néonatale et dans l'inflammation materno-foetale

Le but de cette étude était d'explorer, par une approche métabonomique par spectroscopie de résonance magnétique du proton, les fluides biologiques du nouveau-né (modèle porcelet d'hypoxie ischémie cérébrale) et de la mère (modèle rat d'inflammation materno-foetale) afin de rechercher des biomarqueurs précoces de ces deux pathologies. L'étude des fluides biologiques (urine et liquide céphalorachidien) du porcelet nouveau-né n'a pas permis de mettre en évidence un marqueur diagnostic précoce spécifique de la pathologie. L'inflammation, provoquée chez les animaux à dix-huit et dix-neuf jours de gestation, a provoqué des désordres significatifs sur le devenir de la grossesse, sur le nombre moyen de nouveau-nés, ainsi que sur la croissance des petirs suivis pendant les quatorze premiers jours de vie. L'étude métabonomique du plasma sanguin et du liquide amniotique maternels, couplée aux analyses multi-variées a permis de mettre en évidence des biomarqueurs précoces de l'inflammationA metabonomic approach using high resolution resonance magnetic spectroscopy was investigated on newborn (piglet model of cerebral hypoxia ischemia) and maternal (rat model of maternofetal inflammation induced by E Coli lipopolysaccharid injections) biological fluids. The aim of this study was to evidence an early biomarker of these two pathologies. Neither in the urine and nor in the cerebrospinal fluid of hypoxic ischemic animals, specifi biomarkers of the pathology were evidenced. Metabonomic studies combined with multivaried analysis on the maternal blood plasma and on the amniotic fluid of inflammation-induced animals at day eighteen and nineteen of gestation had evidenced some specific biomarkers. In addition, inflammation impact was demonstrated on pregnancy outcome, on the mean number of newborn per litter and on the newborn growth during the fourteen's days of lifeTOURS-BU Médecine (372612103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Post-insemination level of feeding does not influence embryonic survival and growth in highly prolific gilts

This study was designed to investigate the influence of a high level of feeding during early gestation on embryonic survival and variability of embryonic development in hyperprolific LW gilts. During the 7 days after the first insemination, gilts were fed either 4 or 2 kg daily of a gestation diet (groups High, n = 15, and Control, n = 13, respectively). Gilts were slaughtered at 27.0 +/- 0.1 days of pregnancy. Embryonic survival was 85.4 +/- 1.0% and the number of surviving embryos averaged 17.5 +/- 0.6. Embryos weighed 0.88 +/- 0.17 g and measured 20.6 +/- 1.1 mm, and within-litter variability in embryo weight averaged 11%. None of these criteria was significantly influenced by the level of feeding during the first week of pregnancy. Irrespective of nutritional treatment, embryonic survival was not related to ovulation rate or length of the uterine horns. Number of living embryos was not correlated with embryo weight and length. Within-litter variation in embryo weight or length was not correlated with the number of embryos or embryonic survival. In conclusion, a high level of feeding during early pregnancy of prolific gilts did not reduce embryo survival and had no beneficial nor detrimental effects on embryo size and variability at 27 days of gestation. (C) 2010 Elsevier B.V. All rights reserved

Irinotecan Delivery by Microbubble-Assisted Ultrasound: In Vitro Validation and a Pilot Preclinical Study

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Longitudinal PET Imaging of α7 Nicotinic Acetylcholine Receptors with [18F]ASEM in a Rat Model of Parkinson’s Disease

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Delivery of dopamine transporter tracer (PE2I) through blood brain barrier with ultrasound and microbubbles

International audienceThe blood-brain barrier plays a major role in controlling the delivery of therapeutic and imaging agents to the brain. The aim of this study was to investigate the use of ultrasound and microbubbles to increase its delivery through the BBB and by determining the optimal experimental conditions that achieve a transient and safe BBB disruption. First, we established the ultrasound conditions that achieved a transient BBB disruption in rats using a non-permeant marker, Evans blue. Hence SonoVue (R) (450 mu L/kg) and Evans blue (100 mg/kg) were intravenously administered. BBB leakage was obtained using ultrasound insonation through the rat skull at 1.6 MPa, PRF 1 Hz, duty cycle 1%, burst 10 ms during 120 sec. BBB disruption was observed in all treated animals (N=4) by histological analysis. The same experimental conditions were applied to enhance brain uptake of PE2I. Biological samples were analyzed using a scintillation counter apparatus. The results showed 50% and 20% increase of I-125-PE2I uptake in the striatum and cerebral cortex, respectively, in the treated rats (N=5) versus control (N=4). Similar enhancements were observed using SonoVue (R) at half concentration. This innovative method provides a great potential for intracerebral delivery of molecular ligands that could be used for the therapy of brain diseases

Les antagonistes du récepteur CB1 des cannabinoïdes :une nouvelle approche pour le traitement de la fibrose hépatique.

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CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis.

Hepatic fibrosis, the common response associated with chronic liver diseases, ultimately leads to cirrhosis, a major public health problem worldwide. We recently showed that activation of hepatic cannabinoid CB2 receptors limits progression of experimental liver fibrosis. We also found that during the course of chronic hepatitis C, daily cannabis use is an independent predictor of fibrosis progression. Overall, these results suggest that endocannabinoids may drive both CB2-mediated antifibrogenic effects and CB2-independent profibrogenic effects. Here we investigated whether activation of cannabinoid CB1 receptors (encoded by Cnr1) promotes progression of fibrosis. CB1 receptors were highly induced in human cirrhotic samples and in liver fibrogenic cells. Treatment with the CB1 receptor antagonist SR141716A decreased the wound-healing response to acute liver injury and inhibited progression of fibrosis in three models of chronic liver injury. We saw similar changes in Cnr1-/- mice as compared to wild-type mice. Genetic or pharmacological inactivation of CB1 receptors decreased fibrogenesis by lowering hepatic transforming growth factor (TGF)-beta1 and reducing accumulation of fibrogenic cells in the liver after apoptosis and growth inhibition of hepatic myofibroblasts. In conclusion, our study shows that CB1 receptor antagonists hold promise for the treatment of liver fibrosis.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Extensive exploration of a novel rat model of Parkinson's disease using partial 6-hydroxydopamine lesion of dopaminergic neurons suggests new therapeutic approaches

International audienceParkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons constituting the nigrostriatal pathway. Neuroinflammation, related to microglial activation, plays an important role in this process. Exploration of animal models of PD using neuroimaging modalities allows to better understand the pathophysiology of the disease. Here, we fully explored a moderate lesion model in the rat in which 6-Synaps

Performance evaluation of the IRIS XL-220 PET/CT system, a new camera dedicated to non-human primates

International audienceAbstract Background Non-human primates (NHP) are critical in biomedical research to better understand the pathophysiology of diseases and develop new therapies. Based on its translational and longitudinal abilities along with its non-invasiveness, PET/CT systems dedicated to non-human primates can play an important role for future discoveries in medical research. The aim of this study was to evaluate the performance of a new PET/CT system dedicated to NHP imaging, the IRIS XL-220 developed by Inviscan SAS. This was performed based on the National Electrical Manufacturers Association (NEMA) NU 4-2008 standard recommendations (NEMA) to characterize the spatial resolution, the scatter fraction, the sensitivity, the count rate, and the image quality of the system. Besides, the system was evaluated in real conditions with two NHP with 18 F-FDG and (-)-[ 18 F]FEOBV which targets the vesicular acetylcholine transporter, and one rat using 18 F-FDG. Results The full width at half maximum obtained with the 3D OSEM algorithm ranged between 0.89 and 2.11 mm in the field of view. Maximum sensitivity in the 400–620 keV and 250–750 keV energy windows were 2.37% (22 cps/kBq) and 2.81% (25 cps/kBq), respectively. The maximum noise equivalent count rate (NEC) for a rat phantom was 82 kcps at 75 MBq and 88 kcps at 75 MBq for energy window of 250–750 and 400–620 keV, respectively. For the monkey phantom, the maximum NEC was 18 kcps at 126 MBq and 19 kcps at 126 MBq for energy window of 250–750 and 400–620 keV, respectively. The IRIS XL provided an excellent quality of images in non-human primates and rats using 18 F-FDG. The images acquired using (-)-[ 18 F]FEOBV were consistent with those previously reported in non-human primates. Conclusions Taken together, these results showed that the IRIS XL-220 is a high-resolution system well suited for PET/CT imaging in non-human primates

The sphingosine 1-phosphate receptor S1P2 triggers hepatic wound healing.

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid produced by sphingosine kinase (SphK1 and 2). We previously showed that S1P receptors (S1P1, S1P2, and S1P3) are expressed in hepatic myofibroblasts (hMF), a population of cells that triggers matrix remodeling during liver injury. Here we investigated the function of these receptors in the wound healing response to acute liver injury elicited by carbon tetrachloride, a process that associates hepatocyte proliferation and matrix remodeling. Acute liver injury was associated with the induction of S1P2, S1P3, SphK1, and SphK2 mRNAs and increased SphK activity, with no change in S1P1 expression. Necrosis, inflammation, and hepatocyte regeneration were similar in S1P2(-/-) and wild-type (WT) mice. However, compared with WT mice, S1P2(-/-) mice displayed reduced accumulation of hMF, as shown by lower induction of smooth muscle alpha-actin mRNA and lower induction of TIMP-1, TGF-beta1, and PDGF-BB mRNAs, overall reflecting reduced activation of remodeling in response to liver injury. The wound healing response was similar in S1P3(-/-) and WT mice. In vitro, S1P enhanced proliferation of cultured WT hMF, and PDGF-BB further enhanced the mitogenic effect of S1P. In keeping with these findings, PDGF-BB up-regulated S1P2 and SphK1 mRNAs, increased SphK activity, and S1P2 induced PDGF-BB mRNA. These effects were blunted in S1P2(-/-) cells, and S1P2(-/-) hMF exhibited reduced mitogenic and comitogenic responses to S1P. These results unravel a novel major role of S1P2 in the wound healing response to acute liver injury by a mechanism involving enhanced proliferation of hMF.--Serriere-Lanneau, V., Teixeira-Clerc, F., Li, L., Schippers, M., de Wries, W., Julien, B., Tran-Van-Nhieu, J., Manin, S., Poelstra, K., Chun, J., Carpentier, S., Levade, T., Mallat, A., Lotersztajn, S. The sphingosine 1-phosphate receptor S1P2 triggers hepatic wound healing