113 results on '"Laschet J"'
Search Results
102. Atheroprotective effect of CD31 receptor globulin through enrichment of circulating regulatory T-cells.
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Groyer E, Nicoletti A, Ait-Oufella H, Khallou-Laschet J, Varthaman A, Gaston AT, Thaunat O, Kaveri SV, Blatny R, Stockinger H, Mallat Z, and Caligiuri G
- Subjects
- Animals, Atherosclerosis pathology, Disease Models, Animal, Gene Transfer Techniques, Lymphocyte Activation, Mice, Mice, Knockout, Platelet Endothelial Cell Adhesion Molecule-1 genetics, Receptors, Immunologic metabolism, Reference Values, Treatment Outcome, Atherosclerosis drug therapy, Atherosclerosis immunology, Globulins therapeutic use, Platelet Endothelial Cell Adhesion Molecule-1 immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Objectives: This study was designed to evaluate whether replacing CD31 (PECAM-1) signaling can restore the regulation of lymphocyte activation and improve experimental atherosclerosis., Background: Atherosclerosis, the principal cause of myocardial infarction and stroke, is due to the development of a pathogenic immune response within the vascular wall and is aggravated by the reduction of regulatory T-cells. CD31, a transmembrane adhesion molecule with inhibitory signaling functions, is physiologically expressed on blood and vascular resting cells but is lost in pathologic conditions associated with atherosclerosis., Methods: Replacement therapy with a CD31 receptor globulin (Rg) was delivered by in vivo gene transfer in 6-week-old apolipoprotein E knockout mice (n = 14 per group) every 5 weeks for 6 months. Control groups were treated with a truncated CD31Rg or with vehicle alone. At the end of the study, plaque size and morphology and blood T-cell compartment were analyzed in all mice., Results: Atherosclerotic lesions of CD31Rg-treated mice were smaller (p < 0.01) and showed less neovascularization and intraplaque hemorrhage (p < 0.05) compared with control subjects. Furthermore, circulating regulatory T-cells were increased in vivo (p < 0.01) and showed normal suppressive function on proliferation of conventional T-cells in vitro. Indeed, CD31Rg treatment led to blunted blood T-cell activation (p < 0.05) and reduced T-cell infiltration within plaques (p < 0.01)., Conclusions: Our data suggest that CD31 plays a key role in the regulation of the immune response linked to atherosclerosis. CD31-targeting therapeutic approaches may therefore be envisaged for preventing and treating atherosclerotic diseases.
- Published
- 2007
- Full Text
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103. Dysfunction of GABAA receptor glycolysis-dependent modulation in human partial epilepsy.
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Laschet JJ, Kurcewicz I, Minier F, Trottier S, Khallou-Laschet J, Louvel J, Gigout S, Turak B, Biraben A, Scarabin JM, Devaux B, Chauvel P, and Pumain R
- Subjects
- Epilepsies, Partial physiopathology, Female, Flunitrazepam, Glycolysis, Humans, Male, Patch-Clamp Techniques, Phosphorylation, Tritium, Cerebral Cortex metabolism, Epilepsies, Partial metabolism, Receptors, GABA-A metabolism, Synaptic Transmission physiology
- Abstract
A reduction in GABAergic neurotransmission has been put forward as a pathophysiological mechanism for human epilepsy. However, in slices of human epileptogenic neocortex, GABAergic inhibition can be clearly demonstrated. In this article we present data showing an increase in the functional lability of GABAergic inhibition in epileptogenic tissue compared with nonepileptogenic human tissue. We have previously shown that the glycolytic enzyme GAPDH is the kinase involved in the glycolysis-dependent endogenous phosphorylation of the alpha1-subunit of GABA(A) receptor, a mechanism necessary for maintaining GABA(A) function. In human epileptogenic cortex obtained during curative surgery of patients with partial seizures, we demonstrate an intrinsic deficiency of GABA(A) receptor endogenous phosphorylation resulting in an increased lability of GABAergic currents in neurons isolated from this tissue when compared with neurons from nonepileptogenic human tissue. This feature was not related to a reduction in the number of GABA(A) receptor alpha1-subunits in the epileptogenic tissue as measured by [(3)H]flunitrazepam photoaffinity labeling. Maintaining the receptor in a phosphorylated state either by favoring the endogenous phosphorylation or by inhibiting a membrane-associated phosphatase is needed to sustain GABA(A) receptor responses in epileptogenic cortex. The increased functional lability induced by the deficiency in phosphorylation can account for transient GABAergic disinhibition favoring seizure initiation and propagation. These findings imply new therapeutic approaches and suggest a functional link to the regional cerebral glucose hypometabolism observed in patients with partial epilepsy, because the dysfunctional GABAergic mechanism depends on the locally produced glycolytic ATP.
- Published
- 2007
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- View/download PDF
104. The proatherogenic role of T cells requires cell division and is dependent on the stage of the disease.
- Author
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Khallou-Laschet J, Caligiuri G, Groyer E, Tupin E, Gaston AT, Poirier B, Kronenberg M, Cohen JL, Klatzmann D, Kaveri SV, and Nicoletti A
- Subjects
- Animals, Antiviral Agents, Aorta immunology, Aorta pathology, Apolipoproteins E genetics, Cell Division drug effects, Cell Division immunology, Disease Progression, Female, Ganciclovir, Gene Expression drug effects, Herpesvirus 1, Human genetics, Killer Cells, Natural pathology, Killer Cells, Natural physiology, Mice, Mice, Inbred Strains, Mice, Transgenic, Thymidine Kinase genetics, Transgenes physiology, Atherosclerosis immunology, Atherosclerosis pathology, T-Lymphocytes pathology, T-Lymphocytes physiology
- Abstract
Objective: The mechanism by which T cells exert a proatherogenic potential is unclear. In order to determine whether this potential requires their replication, we crossed atherosclerosis-prone apolipoprotein E knockout mice (ApoE degrees) with transgenic mice in which exclusive and conditional ablation of dividing T cells relies on their specific expression of the herpes simplex type 1 thymidine kinase (TK) suicide gene., Methods and Results: We first showed that conalbumin-immunized ApoE degrees TK mice mounted a significant immune response to the antigen that was fully and specifically blocked by an in vivo ganciclovir (GCV) treatment. Next, ApoE degrees TK mice and ApoE degrees mice were treated or not with GCV either during the first 4 weeks (GCV 1 to 4w), the last 4 weeks (GCV 5 to 8w), or during 8 weeks (GCV 1 to 8w). Strikingly, ApoE degrees TK mice displayed a dramatic decrease in lesion development in the GCV 1 to 8w and GCV 5 to 8w groups, whereas the GCV had no effect when administered during the first 4 weeks. In protected mice, the inflammatory parameters in lesions, the percentage of CD69+ CD3+ splenocytes, and the circulating natural killer T cells were reduced., Conclusions: The present study, therefore, shows that the proatherogenic potential of T cells is crucial in the progression of fatty streaks to mature plaques and requires cell division.
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- 2006
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105. A key glycolytic enzyme plays a dual role in GABAergic neurotransmission and in human epilepsy.
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Pumain R and Laschet J
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- Brain physiopathology, Epilepsy physiopathology, Humans, Neural Inhibition physiology, Phosphorylation, Receptors, GABA-A metabolism, Brain enzymology, Epilepsy enzymology, Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) metabolism, Glycolysis physiology, Synaptic Transmission physiology, gamma-Aminobutyric Acid metabolism
- Abstract
We have previously described a new endogenous phosphorylation mechanism that maintains ionotropic gamma-aminobutyric acid receptor (GABAAR) function and have shown that the kinase involved is the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). This enzyme is closely associated with the receptor and phosphorylates the alpha1 subunit of the receptor. In a wealth of studies, a reduction in GABAergic neurotransmission has been suggested as a pathophysiological mechanism for human epilepsy. In this paper, we present evidence showing both reduced efficacy of this glycolysis-dependent GABAAR phosphorylation mechanism and of GABAergic inhibition in epileptogenic cortical tissue samples obtained during curative surgery of patients with partial seizures, as compared to non-epileptogenic human cortical tissue. This feature is not due to a reduction in the density of GABAAR alpha1 subunits in the epileptogenic tissue as evidenced by photoaffinity labeling. Maintaining the receptor in a phosphorylated state either by favoring the endogenous phosphorylation or by inhibiting a membrane-bound phosphatase sustains the GABAAR responses in the human epileptogenic cortex. The deficiency in endogenous phosphorylation and the associated decreased GABAAR function can account for transient failures of GABAergic inhibition and may favor seizure initiation and propagation. These findings suggest a functional link between epileptic pathology and the regional cerebral glucose hypometabolism observed in patients with partial epilepsies, since the dysfunction of the GABAergic mechanism is dependent on locally produced glycolytic ATP. They also point to new targets for developing molecules active in drug-resistant epilepsies.
- Published
- 2006
- Full Text
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106. Reduced immunoregulatory CD31+ T cells in the blood of atherosclerotic mice with plaque thrombosis.
- Author
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Caligiuri G, Groyer E, Khallou-Laschet J, Al Haj Zen A, Sainz J, Urbain D, Gaston AT, Lemitre M, Nicoletti A, and Lafont A
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- Animals, Apolipoproteins E genetics, Atherosclerosis pathology, Biomarkers, Female, Immunohistochemistry, Lymphocyte Count, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Platelet Endothelial Cell Adhesion Molecule-1 metabolism, Rupture, T-Lymphocytes cytology, T-Lymphocytes metabolism, Thrombosis pathology, Atherosclerosis immunology, Lymphocyte Activation immunology, T-Lymphocytes immunology, Thrombosis immunology
- Abstract
Objective: Lymphocyte activation is thought to play a major role in the pathogenesis of atherosclerotic complications such as plaque thrombosis. Circulating CD31+ T cells have been shown to regulate human T cell activation. Aim of this study was to evaluate whether the proportion of circulating immunoregulatory CD31+ T cells is correlated to the occurrence of plaque thrombosis in aged apolipoprotein (apo) E knockout (KO) mice., Methods and Results: CD31+ T cell depletion of spleen T cells enhanced proliferation (P<0.05) and interferon-gamma production (P<0.01) while reducing interleukin (IL)-4 (P<0.001) and IL-10 (P=0.001) secretion in response to minimally modified low-density lipoprotein. CD31+ T cells were counted in 65 apoE KO mice (46-week-old) by flow cytometry. Organizing thrombi could be documented in 28 of 195 (14%) lesions and in at least one of the aorta root lesions in 23 of 65 mice (35%). CD31+ T cell count was significantly reduced in mice showing plaque thrombosis (72.3+/-1.5% versus 84.1+/-1.2%; P<0.0001), but such reduction did not follow induced plaque rupture or experimentally controlled thrombosis., Conclusions: Reduced CD31+ T cells in circulating blood is a hallmark of atherosclerotic plaque thrombosis. Our data suggest that CD31+ T cells may play an important regulatory role in the development of plaque thrombosis.
- Published
- 2005
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107. Endogenous phosphorylation of distinct gamma-aminobutyric acid type A receptor polypeptides: a possible mechanism involved in the inhibition of epileptogenicity.
- Author
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Bureau M, Laschet J, Minier F, Evrard B, Dandrifosse G, and Chauvel P
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- Animals, Brain metabolism, Cloning, Molecular, Epilepsies, Partial physiopathology, Epilepsy, Temporal Lobe metabolism, Humans, Phosphorylation, Protein Processing, Post-Translational, Receptors, GABA-A genetics, Receptors, GABA-A physiology, Epilepsy prevention & control, Peptide Fragments metabolism, Receptors, GABA-A metabolism
- Published
- 1999
108. [Intervention of GABAergic neurotransmission in partial epilepsies].
- Author
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Bureau M, Laschet J, Minier F, and Chauvel P
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- Animals, Epilepsies, Partial pathology, Humans, Molecular Biology, Receptors, GABA-A genetics, Epilepsies, Partial physiopathology, Receptors, GABA-A physiology, Synaptic Transmission physiology
- Abstract
The gamma-aminobutyric acid (GABA) is one of the most important inhibitory transmitter in the CNS. When GABA is released in the synaptic cleft, it can act on two types of receptors, type A (GABAA-R) and type B. The GABAA-R is an ionotropic receptor whose subunits form a chloride channel. It contains specific binding sites at least for GABA, benzodiazepines, picrotoxin, barbiturates, anesthetic steroids, divalent cations such as Zn2+ and other compounds. Neurotransmitters and neuropeptides that regulate intracellular second messengers may modulate the responses of GABAA-R in the post-synaptic membrane and thus affect the synaptic plasticity. While consensus sites for several kinases are present on many subunit-subtypes, the functional consequences of these phosphorylations are unclear. However, the maintenance of normal GABA currents required the activity of a unique kinase specific for the GABAA-R. This intracellular regulation site might be involved in synaptic plasticity and considered as a site of vulnerability for epileptogenesis. The generation of epileptic discharge, synchronized burst firing and interictal spikes, can be subsequent to the alteration of GABAA-R function. A consequence of GABAergic disinhibition is the formation of new polysynaptic pathways leading to a network of neurons that were previously not connected. Cell loss and plasticity are currently observed in most patients with temporal lobe epilepsy. CA1 pyramidal cells are missing and mossy fibers of dentate granule cells project back through the granule cell layer to form recurrent terminals on granule cell dendrites. This mossy fiber sprouting leads to the destruction of most dentate hilar somatostatine interneurons. Nevertheless, local circuit neurons containing glutamic acid decarboxylase survive in this layer and in all regions of the sclerotic hippocampus. A decrease of the GABA release has been proposed as a basis for disinhibition temporal-lobe epilepsy is partially characterized by a loss of glutamate-stimulated GABA release that is secondary to a reduction in the number of GABA transporters. A molecular reorganization of GABAA-R subunits has been suggested in the kindling model of temporal lobe epilepsy because the zinc released from abberantly sprouted mossy fiber terminals is responsible for a collapse of augmented inhibition by GABA. These results support the concept of a loss of inhibition in chronic epilepsy models and probably in human epilepsies.
- Published
- 1997
109. Astroglial cells express large amounts of GABAA receptor proteins in mature brain.
- Author
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Bureau M, Laschet J, Bureau-Heeren M, Hennuy B, Minet A, Wins P, and Grisar T
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- Animals, Benzodiazepines metabolism, Binding Sites, Brain cytology, Cattle, Cells, Cultured, Picrotoxin metabolism, Rats, Rats, Wistar, gamma-Aminobutyric Acid metabolism, Aging metabolism, Astrocytes metabolism, Brain growth & development, Brain metabolism, Receptors, GABA-A metabolism
- Abstract
GABAA receptors were characterized in cellular fractions isolated from adult bovine brain. The fraction enriched in cortical astrocytes is very rich in high-affinity binding sites for [3H]flunitrazepam and other "central-type" benzodiazepine ligands. The amount of specific [3H]flunitrazepam binding was more than five times higher in the glial fraction than in synaptosomal and perikaryal fractions. [3H]Flunitrazepam was displaced by low concentrations of clonazepam and other specific ligands for central GABAA receptors. Specific binding sites for GABA, flunitrazepam, barbiturates, and picrotoxin-like convulsants were characterized. Allosteric interactions between the different sites were typical of central-type GABAA receptors. The presence of alpha-subunit(s), as revealed by [3H]flunitrazepam photoaffinity labeling, was demonstrated in all brain fractions at molecular mas 51-53 kDa. Photoaffinity labeling was highest in the glial fraction. However, in primary cultured astrocytes from neonate rat cortex, no photoaffinity labeling was detected. Information obtained from astrocytes in culture should thus be taken with caution when extrapolated to differentiated astroglial cells. Our results actually show that, in mature brain, most of the fully pharmacologically active GABAA receptors are extrasynaptic and expressed in astroglia.
- Published
- 1995
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110. [Comparative biochemistry of the triune brain].
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Bureau M, Laschet J, and Schoffeniels E
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- Humans, Neural Conduction physiology, Receptors, GABA genetics, Brain Chemistry, Phylogeny, Receptors, GABA metabolism
- Abstract
The contribution of the phylogenesis to the study of the functional organisation of brain constitutes an essential component in the integration of the current data regarding the knowledge of the central nervous system. The three evolutive structures evidenced by McLean allowed manifestation of a biological diversity particularly expressed in the neommamalian brain. Studying this biological diversity constitutes one of the field of comparative biochemistry. In this article, the authors attempt to characterize evolution through the study of GABA-receptors.
- Published
- 1994
111. Effect of milacemide on audiogenic seizures and cortical (Na+, K+)-ATPase of DBA/2J mice.
- Author
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Laschet J, Guillaume D, Grisar T, Vergniolle-Burette M, and Minet A
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- Acoustic Stimulation, Animals, Cerebral Cortex drug effects, Mice, Mice, Inbred DBA, Seizures etiology, Acetamides pharmacology, Anticonvulsants pharmacology, Cerebral Cortex enzymology, Seizures prevention & control, Sodium-Potassium-Exchanging ATPase metabolism
- Abstract
Milacemide (MLM, CP 1552 S, 2-N-pentylaminoacetamide), a glycinamide derivative, is currently being evaluated clinically for antiepileptic activity. Anticonvulsant properties have been shown in various animal models, but the mechanism of action of MLM is unclear. We studied its activity in audiogenic seizures of DBA/2J mice. MLM was effective in inhibiting the convulsions induced by sound with a biphasic dose-effect relation. The ED50 was 109 mg/kg orally against tonic extension. Higher doses were necessary to abolish clonic convulsion and running response. Because impaired cerebral (Na+, K+)-ATPase activity is supposed to play a role in epileptogenesis, we tested MLM on in vitro cortical enzymatic activity of DBA/2J mice. Basal (Na+, K+)-ATPase activity was unchanged by several concentrations of MLM in normal C57BL/6J and audiogenic DBA/2J mice. K+ activation (from 3 to 18 mM) of (Na+, K+)-ATPase is abolished in DBA/2J mice as compared with C57BL/6J mice, suggesting impaired glial (Na+, K+)-ATPase. In the presence of MLM (from 30 to 1000 mg/L), cortical (Na+, K+)-ATPase of DBA/2J mice is activated by high concentrations of K+, as in C57BL/6J mice. Results suggest that the antiepileptic activity of MLM in audiogenic mice may be secondary to an activation of a deficient glial (Na+, K+)-ATPase.
- Published
- 1991
- Full Text
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112. Two isoenzymes of Na+,K+-ATPase have different kinetics of K+ dephosphorylation in normal cat and human brain cortex.
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Guillaume D, Grisar T, Delgado-Escueta AV, Laschet J, and Bureau-Heeren M
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- Animals, Cats, Electrophoresis, Disc, Humans, Isoenzymes isolation & purification, Kinetics, Molecular Weight, Phosphorylation, Sodium-Potassium-Exchanging ATPase isolation & purification, Species Specificity, Cerebral Cortex enzymology, Isoenzymes metabolism, Potassium pharmacology, Sodium-Potassium-Exchanging ATPase metabolism
- Abstract
Analysis of purified Na+,K+-ATPase from cat and human cortex by sodium dodecyl sulfate-polyacrylamide gel electrophoresis reveals two large catalytic subunits called alpha (-) (lower molecular weight) and alpha (+) (higher molecular weight). Differences in K+ dephosphorylation of these two molecular forms have been investigated by measuring the phosphorylation level of each protein after their separation on sodium dodecyl sulfate gels. In the presence of Na+, Mg2+, and ATP, both subunits are phosphorylated. Increasing concentrations (from 0 to 3 mM) of K+ induce progressive dephosphorylation of both alpha-subunits, although the phosphoprotein content of alpha (-) is decreased significantly less than that of alpha (+). Ka values of alpha (-) for K+ are 40% and 50% greater in cat and human cortex, respectively, than values of alpha (+). alpha (-) and alpha (+) are thought to be localized in specific cell types of the brain: alpha (-) is the exclusive form of nonneuronal cells (astrocytes), whereas alpha (+) is the only form of axolemma. Our results support the hypothesis that glial and neuronal Na+,K+-ATPases are different molecular entities differing at least by their K+ sensitivity. Results are discussed in relation to the role of glial cells in the regulation of extracellular K+ in brain.
- Published
- 1990
- Full Text
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113. Analysis of dansyl derivatives of di- and polyamines in mouse brain, human serum and duodenal biopsy specimens by high-performance liquid chromatography on a standard reversed-phase column.
- Author
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Bontemps J, Laschet J, Dandrifosse G, Van Cutsem JL, and Forget PP
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- Animals, Child, Preschool, Chromatography, High Pressure Liquid methods, Dansyl Compounds blood, Humans, Mice, Polyamines blood, Putrescine analysis, Spermidine analysis, Spermine analysis, Brain Chemistry, Dansyl Compounds analysis, Duodenum analysis, Polyamines analysis
- Abstract
The concentrations of putrescine, spermine and spermidine were measured in human serum, children's duodenal biopsy specimens and mouse brain homogenates by high-performance liquid chromatography. The chromatographic analysis was performed on dansyl derivatives of the polyamines using a reverse-phase system with an ion-pairing retention mechanism (heptane sulphonate). Capacity factors were determined at different concentrations of acetonitrile. Simple linear gradients were set up for fast (15 min) or routine (25 min) analysis. Three fluorescence detectors were compared for these determinations and their detection limits determined. The minimum detectable amount of polyamines was 25 fmol compared to 500 fmol with standard detectors. While samples prepared from tissues did not require a high sensitivity, a detector of better performance was needed to assay the polyamines in human serum.
- Published
- 1984
- Full Text
- View/download PDF
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