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BACKGROUND AND OBJECTIVES: Cannabinoid-1 receptor signaling increases the rewarding effects of food intake and promotes the growth of adipocytes, whereas cannabinoid-2 receptor (CB2) possibly opposes these pro-obesity effects by silencing the activated immune cells that are key drivers of the metabolic syndrome. Pro- and anti-orexigenic cannabimimetic signaling may become unbalanced with age because of alterations of the immune and endocannabinoid system. METHODS: To specifically address the role of CB2 for age-associated obesity, we analyzed metabolic, cardiovascular, immune and neuronal functions in 1.2-1.8-year-old CB2(-/-) and control mice, fed with a standard diet and assessed effects of the CB2 agonist, HU308, during high-fat diet (HFD) in 12-16-week-old mice. RESULTS: The CB2(-/-) mice were obese with hypertrophy of visceral fat, immune cell polarization toward pro-inflammatory subpopulations in fat and liver and hypertension, as well as increased mortality despite normal blood glucose. They also developed stronger paw inflammation and a premature loss of transient receptor potential responsiveness in primary sensory neurons, a phenomenon typical for small fiber disease. The CB2 agonist HU308 prevented HFD-evoked hypertension, reduced HFD-evoked polarization of adipose tissue macrophages toward the M1-like pro-inflammatory type and reduced HFD-evoked nociceptive hypersensitivity, but had no effect on weight gain. CONCLUSIONS: CB2 agonists may fortify CB2-mediated anti-obesity signaling without the risk of anti-CB1-mediated depression that caused the failure of rimonabant.
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Tejido Adiposo/metabolismo , Cannabinoides/farmacología , Grasa Intraabdominal/patología , Obesidad/metabolismo , Receptor Cannabinoide CB2/metabolismo , Células 3T3-L1 , Adipocitos/metabolismo , Tejido Adiposo/patología , Animales , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Inflamación/metabolismo , Grasa Intraabdominal/metabolismo , Ratones , Ratones Noqueados , Receptor Cannabinoide CB2/deficienciaRESUMEN
Significant lead-induced tricuspid regurgitation after cardiovascular implantable electronic devices is not uncommon. Absolute or relative contraindications to place the lead in the right ventricle after tricuspid valve (TV) surgery still remains a challenge. We report about successful lead extraction followed by transvenous implantable cardioverter defibrillator lead placement in the side branches of coronary sinus after TV reconstruction. Furthermore, we discuss therapeutic options to deliver concomitant anti-bradycardia therapy, technical pitfalls, and surgical approaches.
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A high proportion of tumors arise due to mutation of the p53 tumor suppressor protein. A p53 hotspot mutation at amino acid position 273 from R to H, flanking a peptide epitope that spans residues 264-272, renders cells resistant to killing by human histocompatibility leukocyte antigen (HLA)-A*0201-restricted cytotoxic T lymphocytes (CTLs) specific for this epitope. Acquisition of the R to H mutation at residue 273 of the human p53 protein promotes tumor growth in vivo by selective escape from recognition by p53.264-272 peptide-specific CTLs. Synthetic 27-mer p53 polypeptides covering the antigenic nonamer region 264-272 of p53 were used as proteasome substrates to investigate whether the R to H mutation at the P1' position of the COOH terminus of the epitope affects proteasome-mediated processing of the protein. Analysis of the generated products by tandem mass spectrometry and the kinetics of polypeptide processing in conjunction with CTL assays demonstrate that the R to H mutation alters proteasomal processing of the p53 protein by inhibiting proteolytic cleavage between residues 272 and 273. This prevents the release of the natural CTL epitope that spans flanking residues 264-272 as well as a putative precursor peptide. These results demonstrate that mutation of p53 not only leads to malignant transformation but may also, in some instances, affect immune surveillance and should be considered in the design of cancer vaccines.
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Citotoxicidad Inmunológica/genética , Epítopos de Linfocito T/inmunología , Mutación Puntual/inmunología , Linfocitos T Citotóxicos/inmunología , Proteína p53 Supresora de Tumor/genética , Secuencia de Aminoácidos , Animales , Presentación de Antígeno/genética , Arginina/genética , Sitios de Unión/genética , Sitios de Unión/inmunología , División Celular/genética , División Celular/inmunología , Cisteína Endopeptidasas/metabolismo , Pruebas Inmunológicas de Citotoxicidad , Antígenos HLA-A/inmunología , Antígenos HLA-A/metabolismo , Histidina/genética , Humanos , Hidrólisis , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Complejos Multienzimáticos/metabolismo , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Péptidos/síntesis química , Péptidos/inmunología , Péptidos/metabolismo , Complejo de la Endopetidasa Proteasomal , Especificidad por Sustrato/genética , Especificidad por Sustrato/inmunología , Células Tumorales CultivadasRESUMEN
Bioactive lipids contribute to the pathophysiology of multiple sclerosis. Here, we show that lysophosphatidic acids (LPAs) are dysregulated in multiple sclerosis (MS) and are functionally relevant in this disease. LPAs and autotaxin, the major enzyme producing extracellular LPAs, were analyzed in serum and cerebrospinal fluid in a cross-sectional population of MS patients and were compared with respective data from mice in the experimental autoimmune encephalomyelitis (EAE) model, spontaneous EAE in TCR1640 mice, and EAE in Lpar2 -/- mice. Serum LPAs were reduced in MS and EAE whereas spinal cord LPAs in TCR1640 mice increased during the 'symptom-free' intervals, i.e. on resolution of inflammation during recovery hence possibly pointing to positive effects of brain LPAs during remyelination as suggested in previous studies. Peripheral LPAs mildly re-raised during relapses but further dropped in refractory relapses. The peripheral loss led to a redistribution of immune cells from the spleen to the spinal cord, suggesting defects of lymphocyte homing. In support, LPAR2 positive T-cells were reduced in EAE and the disease was intensified in Lpar2 deficient mice. Further, treatment with an LPAR2 agonist reduced clinical signs of relapsing-remitting EAE suggesting that the LPAR2 agonist partially compensated the endogenous loss of LPAs and implicating LPA signaling as a novel treatment approach. Graphical summary of lysophosphatidic signaling in multiple sclerosis.
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Encefalomielitis Autoinmune Experimental/metabolismo , Lisofosfolípidos/metabolismo , Esclerosis Múltiple/metabolismo , Adolescente , Adulto , Animales , Biomarcadores/metabolismo , Estudios de Cohortes , Estudios Transversales , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/patología , Femenino , Humanos , Factores Inmunológicos/farmacología , Masculino , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/patología , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos , Receptores del Ácido Lisofosfatídico/agonistas , Receptores del Ácido Lisofosfatídico/genética , Receptores del Ácido Lisofosfatídico/metabolismo , Adulto JovenRESUMEN
Experimental autoimmune encephalomyelitis (EAE) is a widely-used rodent model for multiple sclerosis (MS), but a single model can hardly capture all features of MS. We investigated whether behavioral parameters in addition to clinical motor function scores could be used to assess treatment efficacy during score-free intervals in the relapsing-remitting EAE model in SJL/J mice. We studied the effects of the clinical reference compounds FTY720 (fingolimod, 0.5mg/kg/day) and dimethyl fumarate (DMF, 20-30 mg/kg/day) on clinical scores in several rodent EAE models in order to generate efficacy profiles. SJL/J mice with relapsing-remitting EAE were studied using behavioral tests, including rotarod, gait analysis, locomotor activity and grip strength. SJL/J mice were also examined according to Crawley's sociability and preference for social novelty test. Prophylactic treatment with FTY720 prevented clinical scores in three of the four EAE rodent models: Dark Agouti (DA) and Lewis rats and C57BL/6J mice. Neither prophylactic nor late-therapeutic treatment with FTY720 reduced clinical scores or reversed deficits in the rotarod test in SJL/J mice, but we observed effects on motor functions and sociability in the absence of clinical scores. Prophylactic treatment with FTY720 improved the gait of SJL/J mice whereas late-therapeutic treatment improved manifestations of reduced social (re)cognition or preference for social novelty. DMF was tested in three EAE models and did not improve clinical scores at the dose used. These data indicate that improvements in behavioral deficits can occur in absence of clinical scores, which indicate subtle drug effects and may have translational value for human MS.
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Dimetilfumarato/farmacología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Clorhidrato de Fingolimod/farmacología , Inmunosupresores/farmacología , Actividad Motora/efectos de los fármacos , Conducta Social , Animales , Encefalomielitis Autoinmune Experimental/fisiopatología , Encefalomielitis Autoinmune Experimental/psicología , Femenino , Marcha/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratas Endogámicas Lew , Reconocimiento en Psicología/efectos de los fármacos , Índice de Severidad de la Enfermedad , TiempoRESUMEN
The disappointing clinical results of cancer immunotherapy of the past few decades have not diminished the optimism about the potential of the new generation of immunotherapeutic strategies towards treatment of malignant disease. Tremendous progress has been made over recent years in unveiling the molecular basis of antigen presentation and recognition by cytotoxic T lymphocytes (CTL). The molecular concepts that have emerged from these studies have led to the design of novel anticancer vaccines and CTL-based immunotherapeutics. This review is to highlight the current molecular insights of antigen presentation and CTL recognition/activation, and their impact on the rational design of therapeutic interventions that may result in protective, CTL-based antitumor immunity.
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Presentación de Antígeno/inmunología , Inmunoterapia/métodos , Neoplasias/terapia , Linfocitos T Citotóxicos/inmunología , Secuencia de Aminoácidos , Animales , Vacunas contra el Cáncer/inmunología , Humanos , Datos de Secuencia MolecularRESUMEN
Prehensile behavior is a popular task in current research on human motor control. Most studies on reaching used stationary target objects and, therefore, most models do not address the challenges the motor system must respond to when reaching for moving objects. The machines used in earlier studies to produce object motion offered a limited range of trajectories and restricted control over various movement parameters. We have developed a device that allows a great variety of object trajectories along a flat-table surface and gives the experimenter full control over all movement parameters. A linear positioning system is used to move a sled beneath the table surface. Magnetic coupling transfers the sled's movement to the target object on the tabletop. This arrangement allows fast movements of the object (up to 5 m/s) and at the same time protects subjects from any harm due to the moving parts. The system is connected to LC shutter glasses, a 3-D movement registration device, and a switch that detects the onset of hand motion. This allows the selective withdrawal of vision during the reaching task or the introduction of changes in the object motion depending on the subject's reactions.