RESUMO
OBJECTIVES: The brains of individuals with Down syndrome (DS) present defects in neurogenesis and synaptogenesis during prenatal and early postnatal stages that are partially responsible for their cognitive disabilities. Because oleic and linolenic fatty acids enhance neurogenesis, synaptogenesis, and cognitive abilities in rodents and humans, in this study we evaluated the ability of these compounds to restore these altered phenotypes in the Ts65Dn (TS) mouse model of DS during early postnatal stages. METHODS: TS and euploid mice were treated with oleic or linolenic acid from PD3 to PD15, and the short- and long- term effects of these acids on neurogenesis and synaptogenesis were evaluated. The effects of these treatments on the cognitive abilities of TS mice during early adulthood were also evaluated. RESULTS: Administration of oleic or linolenic acid did not modify cell proliferation immediately after treatment discontinuation or several weeks later. However, oleic acid increased the total number of DAPI+ cells (+ 26%), the percentage of BrdU+ cells that acquired a neural phenotype (+ 9.1%), the number of pre- (+ 29%) and post-synaptic (+ 32%) terminals and the cognitive abilities of TS mice (+ 18.1%). In contrast, linolenic acid only produced a slight cognitive improvement in TS mice. (+12.1%). DISCUSSION: These results suggest that early postnatal administration of oleic acid could palliate the cognitive deficits of DS individuals.
Assuntos
Síndrome de Down , Animais , Cognição , Modelos Animais de Doenças , Síndrome de Down/genética , Síndrome de Down/terapia , Feminino , Hipocampo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ácido Oleico , Gravidez , Ácido alfa-Linolênico/uso terapêuticoRESUMO
Background: Glioblastoma (GBM) remains a major clinical challenge due to its invasive capacity, resistance to treatment, and recurrence. We have previously shown that ODZ1 contributes to glioblastoma invasion and that ODZ1 mRNA levels can be upregulated by epigenetic mechanisms in response to hypoxia. Herein, we have further studied the transcriptional regulation of ODZ1 in GBM stem cells (GSCs) under hypoxic conditions and analyzed whether HIF2α has any role in this regulation. Methods: We performed the experiments in three primary GSC cell lines established from tumor specimens. GSCs were cultured under hypoxia, treated with HIF regulators (DMOG, chetomin), or transfected with specific siRNAs, and the expression levels of ODZ1 and HIF2α were analyzed. In addition, the response of the ODZ1 promoter cloned into a luciferase reporter plasmid to the activation of HIF was also studied. Results: The upregulation of both mRNA and protein levels of HIF2α under hypoxia conditions correlated with the expression of ODZ1 mRNA. Moreover, the knockdown of HIF2α by siRNAs downregulated the expression of ODZ1. We found, in the ODZ1 promoter, a HIF consensus binding site (GCGTG) 1358 bp from the transcription start site (TSS) and a HIF-like site (CCGTG) 826 bp from the TSS. Luciferase assays revealed that the stabilization of HIF by DMOG resulted in the increased activity of the ODZ1 promoter. Conclusions: Our data indicate that the HIF2α-mediated upregulation of ODZ1 helps strengthen the transcriptional control of this migration factor under hypoxia in glioblastoma stem cells. The discovery of this novel transcriptional pathway identifies new targets to develop strategies that may avoid GBM tumor invasion and recurrence.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioblastoma/etiologia , Glioblastoma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas do Tecido Nervoso/genética , Tenascina/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Hipóxia Celular , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Glioblastoma/patologia , Humanos , Células-Tronco Neoplásicas/patologia , Proteínas do Tecido Nervoso/metabolismo , RNA Mensageiro/genética , Tenascina/metabolismoRESUMO
BACKGROUND: The cognitive impairments that characterize Down syndrome (DS) have been attributed to brain hypocellularity due to neurogenesis impairment during fetal stages. Thus, enhancing prenatal neurogenesis in DS could prevent or reduce some of the neuromorphological and cognitive defects found in postnatal stages. OBJECTIVES: As fatty acids play a fundamental role in morphogenesis and brain development during fetal stages, in this study, we aimed to enhance neurogenesis and the cognitive abilities of the Ts65Dn (TS) mouse model of DS by administering oleic or linolenic acid. METHODS: In total, 85 pregnant TS females were subcutaneously treated from Embryonic Day (ED) 10 until Postnatal Day (PD) 2 with oleic acid (400 mg/kg), linolenic acid (500 mg/kg), or vehicle. All analyses were performed on their TS and Control (CO) male and female progeny. At PD2, we evaluated the short-term effects of the treatments on neurogenesis, cellularity, and brain weight, in 40 TS and CO pups. A total of 69 TS and CO mice were used to test the long-term effects of the prenatal treatments on cognition from PD30 to PD45, and on neurogenesis, cellularity, and synaptic markers, at PD45. Data were compared by ANOVAs. RESULTS: Prenatal administration of oleic or linolenic acid increased the brain weight (+36.7% and +45%, P < 0.01), the density of BrdU (bromodeoxyuridine)- (+80% and +115%; P < 0.01), and DAPI (4',6-diamidino-2-phenylindole)-positive cells (+64% and +22%, P < 0.05) of PD2 TS mice with respect to the vehicle-treated TS mice. Between PD30 and PD45, TS mice prenatally treated with oleic or linolenic acid showed better cognitive abilities (+28% and +25%, P < 0.01) and a higher density of the postsynaptic marker PSD95 (postsynaptic density protein 95) (+65% and +44%, P < 0.05) than the vehicle-treated TS animals. CONCLUSION: The beneficial cognitive and neuromorphological effects induced by oleic or linolenic acid in TS mice suggest that they could be promising pharmacotherapies for DS-associated cognitive deficits.
Assuntos
Síndrome de Down/fisiopatologia , Exposição Materna , Ácido Oleico/administração & dosagem , Ácido alfa-Linolênico/administração & dosagem , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Síndrome de Down/patologia , Feminino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/efeitos dos fármacos , Ácido Oleico/farmacologia , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ácido alfa-Linolênico/farmacologiaRESUMO
BACKGROUND: The cognitive dysfunction in Down syndrome (DS) is partially caused by deficient neurogenesis during fetal stages. Curcumin enhances neurogenesis and learning and memory. OBJECTIVES: We aimed to test the ability of curcumin to rescue the neuromorphological and cognitive alterations of the Ts65Dn (TS) mouse model of DS when administered prenatally or during early postnatal stages, and to evaluate whether these effects were maintained several weeks after the treatment. METHODS: To evaluate the effects of prenatal curcumin administration, 65 pregnant TS females were subcutaneously treated with curcumin (300 mg/kg) or vehicle from ED (Embryonic Day) 10 to PD (Postnatal Day) 2. All the analyses were performed on their TS and Control (CO) male and female progeny. At PD2, the changes in neurogenesis, cellularity, and brain weight were analyzed in 30 TS and CO pups. The long-term effects of prenatal curcumin were evaluated in another cohort of 44 TS and CO mice between PD30 and PD45. The neuromorphological effects of the early postnatal administration of curcumin were assessed on PD15 in 30 male and female TS and CO pups treated with curcumin (300 mg/kg) or vehicle from PD2 to PD15. The long-term neuromorphological and cognitive effects were assessed from PD60 to PD90 in 45 mice. Data was compared by ANOVAs. RESULTS: Prenatal administration of curcumin increased the brain weight (+45%, P < 0.001), the density of BrdU (bromodeoxyuridine)- (+150%, P < 0.001) and DAPI (4',6-diamidino-2-phenylindole)- (+38%, P = 0.005) positive cells, and produced a long-term improvement of cognition in TS (+35%, P = 0.007) mice with respect to vehicle-treated mice. Postnatal administration of curcumin did not rescue any of the short- or long-term altered phenotypes of TS mice. CONCLUSION: The beneficial effects of prenatal curcumin administration to TS mice suggest that it could be a therapeutic strategy to treat DS cognitive disabilities.
Assuntos
Encéfalo/crescimento & desenvolvimento , Cognição/efeitos dos fármacos , Curcumina/farmacologia , Síndrome de Down/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Ração Animal/análise , Animais , Encéfalo/efeitos dos fármacos , Curcumina/administração & dosagem , Dieta/veterinária , Esquema de Medicação , Feminino , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Transgênicos , Gravidez , Efeitos Tardios da Exposição Pré-NatalRESUMO
Down syndrome (DS) is characterized by a marked reduction in the size of the brain and cerebellum. These changes play an important role in the motor alterations and cognitive disabilities observed in this condition. The Ts65Dn (TS) mouse, the most commonly used model of DS, reflects many DS phenotypes, including alterations in cerebellar morphology. One of the genes that is overexpressed in both individuals with DS and TS mice is DYRK1A/Dyrk1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which has been implicated in the altered cerebellar structural and functional phenotypes observed in both populations. The aim of this study was to evaluate the effect of Dyrk1A on different alterations observed in the cerebellum of TS animals. TS mice were crossed with Dyrk1A +/- KO mice to obtain mice with a triplicate segment of Mmu16 that included Dyrk1A (TS +/+/+), mice with triplicate copies of the same genes that carried only two copies of Dyrk1A (TS +/+/-), euploid mice that expressed a normal dose of Dyrk1A (CO +/+) and CO animals with a single copy of Dyrk1A (CO +/-). Male mice were used for all experiments. The normalization of the Dyrk1A gene dosage did not rescue the reduced cerebellar volume. However, it increased the size of the granular and molecular layers, the densities of granular and Purkinje cells, and dendritic arborization. Furthermore, it improved the excitatory/inhibitory balance and walking pattern of TS +/+/- mice. These results support the hypothesis that Dyrk1A is involved in some of the structural and functional cerebellar phenotypes observed in the TS mouse model.
Assuntos
Cerebelo/patologia , Síndrome de Down/genética , Síndrome de Down/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Quinases DyrkRESUMO
Down syndrome (DS) is characterized by structural and functional anomalies that are present prenatally and that lead to intellectual disabilities. Later in life, the cognitive abilities of DS individuals progressively deteriorate due to the development of Alzheimer's disease (AD)-associated neuropathology (i.e., ß-amyloid (Aß) plaques, neurofibrillary tangles (NFTs), neurodegeneration, synaptic pathology, neuroinflammation and increased oxidative stress). Increasing evidence has shown that among these pathological processes, neuroinflammation plays a predominant role in AD etiopathology. In AD mouse models, increased neuroinflammation appears earlier than Aß plaques and NFTs, and in DS and AD models, neuroinflammation exacerbates the levels of soluble and insoluble Aß species, favoring neurodegeneration. The Ts65Dn (TS) mouse, the most commonly used murine model of DS, recapitulates many alterations present in both DS and AD individuals, including enhanced neuroinflammation. In this study, we observed an altered neuroinflammatory milieu in the hippocampus of the TS mouse model. Pro-inflammatory mediators that were elevated in the hippocampus of this model included pro-inflammatory cytokine IL17A, which has a fundamental role in mediating brain damage in neuroinflammatory processes. Here, we analyzed the ability of an anti-IL17A antibody to reduce the neuropathological alterations that are present in TS mice during early neurodevelopmental stages (i.e., hippocampal neurogenesis and hypocellularity) or that are aggravated in later-life stages (i.e., cognitive abilities, cholinergic neuronal loss and increased cellular senescence, APP expression, Aß peptide expression and neuroinflammation). Administration of anti-IL17 for 5â¯months, starting at the age of 7â¯months, partially improved the cognitive abilities of the TS mice, reduced the expression of several pro-inflammatory cytokines and the density of activated microglia and normalized the APP and Aß1-42 levels in the hippocampi of the TS mice. These results suggest that IL17-mediated neuroinflammation is involved in several AD phenotypes in TS mice and provide a new therapeutic target to reduce these pathological characteristics.
Assuntos
Síndrome de Down/imunologia , Interleucina-17/imunologia , Interleucina-17/metabolismo , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Síndrome de Down/terapia , Feminino , Hipocampo/fisiologia , Interleucina-17/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Emaranhados Neurofibrilares/metabolismo , Neurogênese , Neuroimunomodulação/fisiologia , Estresse Oxidativo , Fenótipo , Placa Amiloide/metabolismoRESUMO
The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and Aß, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aß load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS.
Assuntos
Doença de Alzheimer/metabolismo , Síndrome de Down/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/patologia , Modelos Animais de Doenças , Síndrome de Down/genética , Síndrome de Down/patologia , Dosagem de Genes , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Degeneração Neural/genética , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Fragmentos de Peptídeos/metabolismo , Fenótipo , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Proteínas tau/metabolismo , Quinases DyrkRESUMO
Previous studies have demonstrated that melatonin administration improves spatial learning and memory and hippocampal long-term potentiation in the adult Ts65Dn (TS) mouse, a model of Down syndrome (DS). This functional benefit of melatonin was accompanied by protection from cholinergic neurodegeneration and the attenuation of several hippocampal neuromorphological alterations in TS mice. Because oxidative stress contributes to the progression of cognitive deficits and neurodegeneration in DS, this study evaluates the antioxidant effects of melatonin in the brains of TS mice. Melatonin was administered to TS and control mice from 6 to 12 months of age and its effects on the oxidative state and levels of cellular senescence were evaluated. Melatonin treatment induced antioxidant and antiaging effects in the hippocampus of adult TS mice. Although melatonin administration did not regulate the activities of the main antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase) in the cortex or hippocampus, melatonin decreased protein and lipid oxidative damage by reducing the thiobarbituric acid reactive substances (TBARS) and protein carbonyls (PC) levels in the TS hippocampus due to its ability to act as a free radical scavenger. Consistent with this reduction in oxidative stress, melatonin also decreased hippocampal senescence in TS animals by normalizing the density of senescence-associated ß-galactosidase positive cells in the hippocampus. These results showed that this treatment attenuated the oxidative damage and cellular senescence in the brain of TS mice and support the use of melatonin as a potential therapeutic agent for age-related cognitive deficits and neurodegeneration in adults with DS.
Assuntos
Antioxidantes/farmacologia , Síndrome de Down/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Melatonina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Animais , Senescência Celular , Modelos Animais de Doenças , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Glutationa Transferase/metabolismo , Hipocampo/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Melatonina/administração & dosagem , Camundongos , Oxirredução/efeitos dos fármacos , Superóxido Dismutase/metabolismoRESUMO
AIM: To evaluate the possibility of implementing a new scheme of rescue treatment after relapse or progression of high-grade glioma (HGG) treated at the first-line with bevacizumab and irinotecan (BVZ+CPT11), evaluating the response and toxicity of associating BVZ and fractionated stereotactic radiotherapy (BVZ+FSRT). MATERIALS AND METHODS: We retrospectively analysed data from 59 patients with relapse of HGG. Nine patients with HGG relapse after treatment using the Stupp protocol that were treated with BVZ+CPT11 for progression between July 2007 and August 2012, after which the response was assessed according to the Revised Assessment in Neuro-Oncology (RANO) criteria. BVZ was administered at a dose of 10 mg/kg and FSRT up to a prescribed dose of 30 Gy, 500 cGy per fraction, three days a week. The median follow-up was 38 months. RESULTS: The treatment was well-tolerated by all patients. The response after nuclear magnetic resonance imaging (MRI) at 3-6 months was progression in two patients, stable disease in four, and three patients had a partial response. The median overall survival (OS) from diagnosis until death or the last control was 36.8 months. The median progression-free survival (PFS) was 10.8 months. The results from tumour sub-group analysis indicated that the PFS was not statistically significant although it seemed that it was higher in grade-III. The OS was higher in grade-III gliomas. CONCLUSIONS: The combination of BVZ+FSRT as a second-line HGG relapse rescue treatment is well-tolerated and seems to offer promising results. We believe that multi-centre prospective studies are needed to determine the long-term efficacy and toxicity of this therapeutic approach.
RESUMO
Down syndrome (DS) is associated with neurological complications, including cognitive deficits that lead to impairment in intellectual functioning. Increased GABA-mediated inhibition has been proposed as a mechanism underlying deficient cognition in the Ts65Dn (TS) mouse model of DS. We show that chronic treatment of these mice with RO4938581 (3-bromo-10-(difluoromethyl)-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]diazepine), a selective GABA(A) α5 negative allosteric modulator (NAM), rescued their deficits in spatial learning and memory, hippocampal synaptic plasticity, and adult neurogenesis. We also show that RO4938581 normalized the high density of GABAergic synapse markers in the molecular layer of the hippocampus of TS mice. In addition, RO4938581 treatment suppressed the hyperactivity observed in TS mice without inducing anxiety or altering their motor abilities. These data demonstrate that reducing GABAergic inhibition with RO4938581 can reverse functional and neuromorphological deficits of TS mice by facilitating brain plasticity and support the potential therapeutic use of selective GABA(A) α5 NAMs to treat cognitive dysfunction in DS.
Assuntos
Síndrome de Down/complicações , Síndrome de Down/patologia , Hipocampo/patologia , Deficiências da Aprendizagem/tratamento farmacológico , Neurônios/fisiologia , Receptores de GABA-A/metabolismo , Estimulação Acústica , Análise de Variância , Animais , Benzodiazepinas/farmacologia , Benzodiazepinas/uso terapêutico , Biofísica , Proteínas de Transporte/metabolismo , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Sinais (Psicologia) , Modelos Animais de Doenças , Síndrome de Down/tratamento farmacológico , Estimulação Elétrica , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Comportamento Exploratório/efeitos dos fármacos , Moduladores GABAérgicos/farmacologia , Moduladores GABAérgicos/uso terapêutico , Glutamato Descarboxilase/metabolismo , Hipocampo/efeitos dos fármacos , Hipercinese/tratamento farmacológico , Hipercinese/etiologia , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Antígeno Ki-67 , Deficiências da Aprendizagem/etiologia , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/genética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Neurônios/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Desempenho Psicomotor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Reflexo/efeitos dos fármacos , Reflexo/genética , Reflexo de Sobressalto/efeitos dos fármacos , Teste de Desempenho do Rota-Rod , Convulsões/etiologia , Filtro Sensorial/efeitos dos fármacos , Trítio/farmacocinética , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismoRESUMO
The Ts65Dn mouse (TS), the most commonly used model of Down syndrome (DS), exhibits several key phenotypic characteristics of this condition. In particular, these animals present hypocellularity in different areas of their CNS due to impaired neurogenesis and have alterations in synaptic plasticity that compromise their cognitive performance. In addition, increases in oxidative stress during adulthood contribute to the age-related progression of cognitive and neuronal deterioration. We have previously demonstrated that chronic melatonin treatment improves learning and memory and reduces cholinergic neurodegeneration in TS mice. However, the molecular and physiological mechanisms that mediate these beneficial cognitive effects are not yet fully understood. In this study, we analyzed the effects of chronic melatonin treatment on different mechanisms that have been proposed to underlie the cognitive impairments observed in TS mice: reduced neurogenesis, altered synaptic plasticity, enhanced synaptic inhibition and oxidative damage. Chronic melatonin treatment rescued both impaired adult neurogenesis and the decreased density of hippocampal granule cells in trisomic mice. In addition, melatonin administration reduced synaptic inhibition in TS mice by increasing the density and/or activity of glutamatergic synapses in the hippocampus. These effects were accompanied by a full recovery of hippocampal LTP in trisomic animals. Finally, melatonin treatment decreased the levels of lipid peroxidation in the hippocampus of TS mice. These results indicate that the cognitive-enhancing effects of melatonin in adult TS mice could be mediated by the normalization of their electrophysiological and neuromorphological abnormalities and suggest that melatonin represents an effective treatment in retarding the progression of DS neuropathology.
Assuntos
Síndrome de Down/tratamento farmacológico , Síndrome de Down/fisiopatologia , Hipocampo , Melatonina/uso terapêutico , Análise de Variância , Animais , Modelos Animais de Doenças , Feminino , Hipocampo/química , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Indóis/química , Antígeno Ki-67/análise , Antígeno Ki-67/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Melatonina/administração & dosagem , Melatonina/farmacologia , Camundongos , Plasticidade Neuronal/efeitos dos fármacosRESUMO
Inclusive education involves the interaction of diverse actors from different societal sectors, such as education, health, and policy. Inclusion laws and regulations in Chile are relatively new and have been taken as a regional model. However, the efforts to implement them have revealed some structural difficulties that must be discussed. This conceptual analysis article aims to provide insights to enrich cross-sectoral collaboration to foster inclusive cultures in Chilean schools. Considering the OECD Analytical Framework, which describes a systemic approach, we provide definitions for the critical components of the model and discuss the advances and challenges of current Chilean public policies in this field -including the Chile Crece Contigo and the School Integration Programs (SIP)-, the Chilean education system functioning, the social contexts, and students' needs and supports based on the available evidence. Building from inclusive education literature and previous experiences, we delve into the model to address the needs of students with disabilities, social and cultural disadvantages, students belonging to the indigenous population, and students with a low socioeconomic level to propose action guidelines with a particular focus on integrating inclusive practices at the school level.
RESUMO
Ts65Dn mice (TS), the most commonly used model of Down syndrome (DS), exhibit phenotypic characteristics of this condition. Both TS mice and DS individuals present cognitive disturbances, age-related cholinergic degeneration, and increased brain expression of ß-amyloid precursor protein (AßPP). These neurodegenerative processes may contribute to the progressive cognitive decline observed in DS. Melatonin is a pineal indoleamine that has been reported to reduce neurodegenerative processes and improve cognitive deficits in various animal models. In this study, we evaluated the potentially beneficial effects of long-term melatonin treatment on the cognitive deficits, cholinergic degeneration, and enhanced AßPP and ß-amyloid levels of TS mice. Melatonin was administered for 5 months to 5- to 6-month-old TS and control (CO) mice. Melatonin treatment improved spatial learning and memory and increased the number of choline acetyltransferase (ChAT)-positive cells in the medial septum of both TS and CO mice. However, melatonin treatment did not significantly reduce AßPP or ß-amyloid levels in the cortex or the hippocampus of TS mice. Melatonin administration did reduce anxiety in TS mice without inducing sensorimotor alterations, indicating that prolonged treatment with this indoleamine is devoid of noncognitive behavioral side effects (e.g., motor coordination, sensorimotor abilities, or spontaneous activity). Our results suggest that melatonin administration might improve the cognitive abilities of both TS and CO mice, at least partially, by reducing the age-related degeneration of basal forebrain cholinergic neurons. Thus, chronic melatonin supplementation may be an effective treatment for delaying the age-related progression of cognitive deterioration found in DS.
Assuntos
Comportamento Animal/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Melatonina/administração & dosagem , Degeneração Neural/metabolismo , Administração Oral , Precursor de Proteína beta-Amiloide/metabolismo , Análise de Variância , Animais , Córtex Cerebral/química , Modelos Animais de Doenças , Síndrome de Down , Esquema de Medicação , Feminino , Hipocampo/química , Masculino , Melatonina/análogos & derivados , Melatonina/urina , CamundongosRESUMO
PURPOSE: This study aims to illustrate how environmental systems shape the peer interactions of an autistic student within the classroom. METHOD: Drawing on the bioecological model of human development, this situated discourse analysis used thematic coding and microanalysis to examine data from semistructured interviews and 10 sessions of direct classroom observations of a 9-year-old autistic student and his classroom communication partners. RESULTS: Convergent data across participants, time, and data sources revealed the following systemic influences on peer interaction: predominant medicalized view of autism (macrosystem), educational practices (exosystem), misaligned roles across adults and peers in the classroom (mesosystem), and multimodal opportunities for direct interaction that were supported by objects and physical contact and inhibited by rapid pacing (microsystem). CONCLUSIONS: Findings illustrate the environmental complexities associated with the development of peer interactions for autistic students. We offer explicit clinical implications for how environmental factors can be addressed in the school-based eligibility determination process and in the Individualized Education Program.
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Transtorno Autístico , Adulto , Humanos , Criança , Grupo Associado , Instituições Acadêmicas , Estudantes , ComunicaçãoRESUMO
INTRODUCTION: The benefit of complete revascularization (CR) on long-term total event reduction in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease (MVD), still remains unclear. We assessed the efficacy of three different revascularization strategies on long-term total recurrent events. METHODS: We retrospectively analyzed 414 consecutive patients admitted with STEMI and MVD who were categorized according to the revascularization strategy used: culprit-vessel-only percutaneous coronary intervention (PCI) (n=163); in-hospital CR (n=136); and delayed CR (n=115). The combined endpoint assessed was all-cause mortality, the total number of myocardial infarctions, ischemia-driven revascularizations or strokes. Negative binomial regression was used to assess the association between the revascularization strategy and total events; risk estimates were expressed as an incidence rates ratio (IRR). RESULTS: At a median follow-up of four years (1.2-6), rates of the combined endpoint per 10 patient-years were 18, 0.8, and 0.6 in culprit-vessel-only PCI, in-hospital CR, and delayed CR strategies, respectively (p<0.001). After multivariable adjustment and when compared with culprit-vessel-only PCI, both in-hospital and delayed CR strategies were significantly associated with a reduction in the combined endpoint (IRR=0.40: 95% confidence interval (CI), 0.25-0.64; p<0.001; and IRR 0.40: 95% CI, 0.24-0.62; p<0.001, respectively). No differences were observed across in-hospital and delayed CR strategies. CONCLUSIONS: Complete revascularization of non-culprit lesions in patients with STEMI and MVD reduces the risk of total recurrent events during long-term follow-up. No differences between in-hospital and delayed CR strategies were found.
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Doença da Artéria Coronariana , Infarto do Miocárdio , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Infarto do Miocárdio com Supradesnível do Segmento ST/etiologia , Doença da Artéria Coronariana/etiologia , Estudos Retrospectivos , Intervenção Coronária Percutânea/efeitos adversos , Infarto do Miocárdio/etiologia , Resultado do Tratamento , Revascularização MiocárdicaRESUMO
Patients with lysosomal storage diseases may require modifications to standard drug desensitization protocols; personalized medicine as well as development of new treatment options are needed.
Assuntos
Condroitina Sulfatases/administração & dosagem , Condroitina Sulfatases/imunologia , Mucopolissacaridose IV/tratamento farmacológico , Mucopolissacaridose IV/imunologia , Antialérgicos/uso terapêutico , Condroitina Sulfatases/sangue , Feminino , Humanos , Mucopolissacaridose IV/sangue , Omalizumab/uso terapêutico , Rinite Alérgica/sangue , Rinite Alérgica/tratamento farmacológico , Rinite Alérgica/imunologia , Resultado do Tratamento , Adulto JovemRESUMO
Two key features of cancer cells are sustained proliferation and invasion, which is preceded by a modification of the adhesion properties to the extracellular matrix. Currently, fluorescence-based techniques are mainly used to detect these processes, including flow cytometry and fluorescence resonance energy transfer (FRET) microscopy. We have previously described a simple, fast and label-free method based on a gold nanohole array biosensor to detect the spectral response of single cells, which is highly dependent on the actin cortex. Here we used this biosensor to study two cellular processes where configuration of the actin cortex plays an essential role: cell cycle and cell-matrix adhesion. Colorectal cancer cells were maintained in culture under different conditions to obtain cells stopped either in G0/G1 (resting cells/cells at the initial steps of cell growth) or G2 (cells undergoing division) phases of the cell cycle. Data from the nanohole array biosensor showed an ability to discriminate between both cell populations. Additionally, cancer cells were monitored with the biosensor during the first 60 min after cells were deposited onto a biosensor coated with fibronectin, an extracellular matrix protein. Spectral changes were detected in the first 20 min and increased over time as the cell-biosensor contact surface increased. Our data show that the nanohole array biosensor provides a label-free and real-time procedure to detect cells undergoing division or changes in cell-matrix interaction in both clinical and research settings.
Assuntos
Técnicas Biossensoriais , Neoplasias , Actinas , Técnicas Biossensoriais/métodos , Divisão Celular , Fibronectinas , OuroRESUMO
Glioblastoma (GBM) is one of the most aggressive cancers, with dismal prognosis despite continuous efforts to improve treatment. Poor prognosis is mostly due to the invasive nature of GBM. Thus, most research has focused on studying the molecular players involved in GBM cell migration and invasion of the surrounding parenchyma, trying to identify effective therapeutic targets against this lethal cancer. Our laboratory discovered the implication of TENM1, also known as ODZ1, in GBM cell migration in vitro and in tumor invasion using different in vivo models. Moreover, we investigated the microenvironmental stimuli that promote the expression of TENM1 in GBM cells and found that macrophage-secreted IL-6 and the extracellular matrix component fibronectin upregulated TENM1 through activation of Stat3. We also described that hypoxia, a common feature of GBM tumors, was able to induce TENM1 by both an epigenetic mechanism and a HIF2α-mediated transcriptional pathway. The fact that TENM1 is a convergence point for various cancer-related signaling pathways might give us a new therapeutic opportunity for GBM treatment. Here, we briefly review the findings described so far about the mechanisms that control the expression of the GBM invasion factor TENM1.
RESUMO
We have previously shown that the transmembrane protein ODZ1 serves for glioblastoma (GBM) cells to invade the surrounding tissue through activation of RhoA/ROCK pathway. However, the transcriptional machinery used by GBM cells to regulate the expression of ODZ1 is unknown. Here we show that interaction with tumor microenvironment elements, mainly activated monocytes through IL-6 secretion, and the extracellular matrix protein fibronectin, induces the Stat3 transcriptional pathway and upregulates ODZ1 which results in GBM cell migration. This signaling route is abrogated by blocking the IL-6 receptor, inhibiting Jak kinases or knocking down Stat3. Furthermore, we have identified a Stat3 responsive element in the ODZ1 gene promoter, about 1 kb from the transcription start site. Luciferase-reporter assays confirmed that the promoter responds to the presence of monocytic cells and this activation is greatly reduced when the Stat3 site is mutated or following treatment with a neutralizing anti-IL-6 receptor antibody or transfecting GBM cells with a dominant negative variant of Stat3. Overall, we show that monocyte-secreted IL-6 and the extracellular matrix protein fibronectin activate the axis Stat3-ODZ1 and promote migration of GBM cells. This is the first described transcriptional mechanism used by tumor cells to promote the expression of the invasion factor ODZ1.
Assuntos
Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Interleucina-6/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fator de Transcrição STAT3/metabolismo , Tenascina/metabolismo , Ativação Transcricional , Microambiente Tumoral , Movimento Celular , Glioblastoma/genética , Glioblastoma/imunologia , Glioblastoma/metabolismo , Humanos , Proteínas do Tecido Nervoso/genética , Regiões Promotoras Genéticas , Receptores de Interleucina-6/metabolismo , Fator de Transcrição STAT3/genética , Transdução de Sinais , Tenascina/genética , Células Tumorais CultivadasRESUMO
All individuals with Down syndrome (DS) eventually develop Alzheimer's disease (AD) neuropathology, including neurodegeneration, increases in ß-amyloid (Aß) expression, and aggregation and neurofibrillary tangles, between the third and fourth decade of their lives. There is currently no effective treatment to prevent AD neuropathology and the associated cognitive degeneration in DS patients. Due to evidence that the accumulation of Aß aggregates in the brain produces the neurodegenerative cascade characteristic of AD, many strategies which promote the clearance of Aß peptides have been assessed as potential therapeutics for this disease. Bexarotene, a member of a subclass of retinoids that selectively activates retinoid receptors, modulates several pathways essential for cognitive performance and Aß clearance. Consequently, bexarotene might be a good candidate to treat AD-associated neuropathology. However, the effects of bexarotene treatment in AD remain controversial. In the present study, we aimed to elucidate whether chronic bexarotene treatment administered to the most commonly used murine model of DS, the Ts65Dn (TS) mouse could reduce Aß expression in their brains and improve their cognitive abilities. Chronic administration of bexarotene to aged TS mice and their CO littermates for 9 weeks diminished the reference, working, and spatial learning and memory of TS mice, and the spatial memory of CO mice in the Morris water maze. This treatment also produced marked hypoactivity in the plus maze, open field, and hole board tests in TS mice, and in the open field and hole board tests in CO mice. Administration of bexarotene reduced the expression of Aß1-40, but not of Aß1-42, in the hippocampi of TS mice. Finally, bexarotene increased Thyroid-stimulating hormone levels in TS mice and reduced Thyroid-stimulating hormone levels in CO mice, while animals of both karyotypes displayed reduced thyroxine levels after bexarotene administration. The bexarotene-induced hypothyroidism could be responsible for the hypoactivity of TS and CO mice and their diminished performance in the Morris water maze. Together, these results do not provide support for the use of bexarotene as a potential treatment of AD neuropathology in the DS population.