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El pdf del artículo es el manuscrito de autor. ; Coadministration of entacapone with levodopa attenuates motor complications in experimental models of Parkinson's disease. The mechanisms underlying entacapone effects are unknown. We investigated the effect of entacapone, on: long-duration response (LDR) to levodopa, levodopa-induced postsynaptic pharmacodynamic mechanisms and molecular changes in hemiparkinsonian rats. 6-Hydroxydopamine-unilaterally lesioned rats were treated with levodopa (25 mg/kg) + vehicle; levodopa + entacapone (30 mg/kg) or saline, twice daily for 22 days. The LDR and the apomorphine-induced rotations were measured. In situ hybridization was performed measuring the expression of striatal preproenkephalin, preprodynorphin and dopamine D-3 receptor mRNAs, subthalamic cytochrome oxidase mRNA and nigral glutamic acid decarboxylase mRNA. Entacapone potentiated the LDR but did not modify either the apomorphine-induced rotational behavior or the molecular changes. Our results suggest that the effects of entacapone on levodopa-induced motor response are not mediated by postsynaptic mechanisms and that administration of entacapone is not able to normalize the molecular alterations induced by levodopa in the basal ganglia. ; This work was supported by an unrestricted grant from Novartis-Orion Pharma (Barcelona, Spain). JAO serves as external adviser for Novartis Pharmaceutical (Barcelona, Spain). EA is partially financed by the program: Ayudas para Contratos de Apoyo a la Investigación en el Sistema Nacional de Salud from the Ministerio de Sanidad y Consumo of the Spanish Government. ; Peer reviewed

[Abstract] Epithelial-mesenchymal-transition promotes intra-tumoral heterogeneity, by enhancing tumor cell invasiveness and promoting drug resistance. We integrated transcriptomic data for two clonal subpopulations from a prostate cancer cell line (PC-3) into a genome-scale metabolic network model to explore their metabolic differences and potential vulnerabilities. In this dual cell model, PC-3/S cells express Epithelial-mesenchymal transition markers and display high invasiveness and low metastatic potential, while PC-3/M cells present the opposite phenotype and higher proliferative rate. Model-driven analysis and experimental validations unveiled a marked metabolic reprogramming in long-chain fatty acids metabolism. While PC-3/M cells showed an enhanced entry of long-chain fatty acids into the mitochondria, PC-3/S cells used long-chain fatty acids as precursors of eicosanoid metabolism. We suggest that this metabolic reprogramming endows PC-3/M cells with augmented energy metabolism for fast proliferation and PC-3/S cells with increased eicosanoid production impacting angiogenesis, cell adhesion and invasion. PC-3/S metabolism also promotes the accumulation of docosahexaenoic acid, a long-chain fatty acid with antiproliferative effects. The potential therapeutic significance of our model was supported by a differential sensitivity of PC-3/M cells to etomoxir, an inhibitor of long-chain fatty acid transport to the mitochondria ; [Author summary] The coexistence within the same tumor of a variety of subpopulations, featuring different phenotypes (intra-tumoral heterogeneity) represents a challenge for diagnosis, prognosis and targeted therapies. In this work, we have explored the metabolic differences underlying tumor heterogeneity by building cell-type-specific genome-scale metabolic models that integrate transcriptome and metabolome data of two clonal subpopulations derived from the same prostate cancer cell line (PC-3). These subpopulations display either highly proliferative, cancer stem cell (PC-3/M) or highly invasive, epithelial-mesenchymal-transition-like phenotypes (PC-3/S). Our model-driven analysis and experimental validations have unveiled a differential utilization of the long-chain fatty acids pool in both subpopulations. More specifically, our findings show an enhanced entry of long-chain fatty acids into the mitochondria in PC-3/M cells, while in PC-3/S cells, long-chain fatty acids are used as precursors of eicosanoid metabolism. The different utilization of long-chain fatty acids between subpopulations endows PC-3/M cells with a highly proliferative phenotype while enhances PC-3/S invasive phenotype. The present work provides a tool to unveil key metabolic nodes associated with tumor heterogeneity and highlights potential subpopulation-specific targets with important therapeutic implications ; This work was supported by the European Commission Seventh Framework Programme FP7 (METAFLUX-Marie Curie FP7-PEOPLE-2010 ITN-264780); the Spanish Government and the European Union FEDER funds (SAF2014-56059-R, SAF2015-70270-REDT and SAF2015-66984-C2-1-R); Generalitat de Catalunya-AGAUR (2014SGR1017, xarxa de referència en biotecnologia, (TMT) and the support received through the prize "ICREA Academia" for excellence in research (MC), the Lendület Program of the Hungarian Academy of Sciences (BP) and the Welcome Trust (BP) ; Peer reviewed

Altres ajuts: Project Integrative of Excellence (PIE 16/00014); Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER; #CB15/00010); "La Caixa" Foundation (ID 100010434, under the agreement LCF/PR/HR17/52150001); The Safra Foundation (J.D.), and Fundació CELLEX (J.D.); Centres de Recerca de Catalunya (CERCA) program by La Generalitatde Catalunya (J.R.); Pla Estratègic de Recerca i Innovació en Salut (PERIS, SLT002/16/00346, J.P.); Basque Government Doctoral Fellowship Program (PRE_ 2019_1_0255; E.M.) ; To determine whether maternofetal transfer of NMDA receptor (NMDAR) antibodies has pathogenic effects on the fetus and offspring, we developed a model of placental transfer of antibodies. Pregnant C57BL/6J mice were administered via tail vein patients' or controls' immunoglobulin G (IgG) on days 14-16 of gestation, when the placenta is able to transport IgG and the immature fetal blood-brain barrier is less restrictive to IgG crossing. Immunohistochemical and DiOlistic (gene gun delivery of fluorescent dye) staining, confocal microscopy, standardized developmental and behavioral tasks, and hippocampal long-term potentiation were used to determine the antibody effects. In brains of fetuses, patients' IgG, but not controls' IgG, bound to NMDAR, causing a decrease in NMDAR clusters and cortical plate thickness. No increase in neonatal mortality was observed, but offspring exposed in utero to patients' IgG had reduced levels of cell-surface and synaptic NMDAR, increased dendritic arborization, decreased density of mature (mushroom-shaped) spines, microglial activation, and thinning of brain cortical layers II-IV with cellular compaction. These animals also had a delay in innate reflexes and eye opening and during follow-up showed depressive-like behavior, deficits in nest building, poor motor coordination, and impaired social-spatial memory and hippocampal plasticity. Remarkably, all these paradigms progressively improved (becoming similar to those of controls) during follow-up until adulthood. In ...