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1.
Biochemistry (Mosc) ; 84(11): 1306-1328, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31760920

RESUMO

Focal brain injuries (in particular, stroke and traumatic brain injury) induce with high probability the development of delayed (months, years) cognitive and depressive disturbances which are frequently comorbid. The association of these complications with hippocampal alterations (in spite of the lack of a primary injury of this structure), as well as the lack of a clear dependence between the probability of depression and dementia development and primary damage severity and localization served as the basis for a new hypothesis on the distant hippocampal damage as a key link in the pathogenesis of cognitive and psychiatric disturbances. According to this hypothesis, the excess of corticosteroids secreted after a focal brain damage, in particular in patients with abnormal stress-response due to hypothalamic-pituitary-adrenal axis (HPAA) dysfunction, interacts with corticosteroid receptors in the hippocampus inducing signaling pathways which stimulate neuroinflammation and subsequent events including disturbances in neurogenesis and hippocampal neurodegeneration. In this article, the molecular and cellular mechanisms associated with the regulatory role of the HPAA and multiple functions of brain corticosteroid receptors in the hippocampus are analyzed. Functional and structural damage to the hippocampus, a brain region selectively vulnerable to external factors and responding to them by increased cytokine secretion, forms the basis for cognitive function disturbances and psychopathology development. This concept is confirmed by our own experimental data, results of other groups and by prospective clinical studies of post-stroke complications. Clinically relevant biochemical approaches to predict the risks and probability of post-stroke/post-trauma cognitive and depressive disturbances are suggested using the evaluation of biochemical markers of patients' individual stress-response. Pathogenetically justified ways for preventing these consequences of focal brain damage are proposed by targeting key molecular mechanisms underlying hippocampal dysfunction.


Assuntos
Lesões Encefálicas/patologia , Hipocampo/metabolismo , Animais , Lesões Encefálicas/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/metabolismo , Humanos , Estresse Oxidativo , Sistema Hipófise-Suprarrenal , Receptores de Esteroides/metabolismo
2.
Wei Sheng Yan Jiu ; 48(4): 577-582, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31601338

RESUMO

OBJECTIVE: To investigate the correlation between the polymorphisms of(brain derived neurotrophic factor, BDNF)BDNF gene rs11030104 and rs2030324 and executive function in children with attention deficit hyperactivity disorder(ADHD). METHODS: A total of 206 ADHD children and 212 control children were enrolled in the study. Five mL peripheral venous blood was extracted from each subject and genomic DNA was extracted. The genotypes of rs11030104 and rs2030324 loci were genotyped by PCR/sequencing. The selection was tested by Wisconsin Classification Card Test, Stroop Color-Word Task, Reaction/Nonresponse Task and Stop Signal Task. RESULTS: The distribution of rs2030324 locus gene frequency was different between ADHD group and control group. G allele was the risk factor of ADHD(χ~2=4. 481, P=0. 034; OR=1. 520, 95%CI 1. 031-2. 243); rs11030101 locus gene frequency distribution and genotype distribution had statistical significance between the two groups, and A allele was related to ADHD susceptibility(OR=1. 601, 95%CI 1. 052-2. 436). The error interference score of Stroop test in ADHD group was higher than that in control group(P<0. 05), but there was no significant difference in response time interference score between the two groups(P>0. 05). The SCWT scores of different genotypes of BDNF rs2030324 in ADHD group were different. Compared with AA type and AG type, the SCWT error interference scores of GG type ADHD patients were higher. There was no significant difference among rs11030101 genotypes. The WCST scores of ADHD group were lower than those of control group. The variation of Go/no-go scores in ADHD group was higher than that of control group in missed count, mistaken count and correct reaction time. The variation of SST and correct reaction time in ADHD group were higher than that of control group, but the genotype distribution of rs11030104 and rs2030324 loci had no significant correlation with WCST, Go/no-go and SST scores. CONCLUSION: Children with ADHD have executive dysfunction. ADHD children with BDNF rs2030324 GG genotype showed poor Stroop executive function.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Criança , Função Executiva , Frequência do Gene , Humanos , Polimorfismo de Nucleotídeo Único
3.
Braz J Med Biol Res ; 52(8): e8443, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31365694

RESUMO

Brain-derived neurotrophic factor (BDNF) is widely expressed in the central nervous system and prolongs the survival of dopaminergic neurons in the substantia nigra. Several studies have recently investigated the association between BDNF G196A (Val66Met), a single nucleotide polymorphism influencing cognitive processes, and cognitive impairment in Parkinson's disease (PD), but with contradictory findings. Thus, this meta-analysis was performed to clarify the possible association. Relevant studies were identified by a systematic search of PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases. The strength of the association was evaluated using crude odds ratios and 95% confidence interval. Finally, six studies involving 532 cases and 802 controls were included. Our analyses suggested the G196A (Val66Met) polymorphism was significantly associated with cognitive impairment in PD, especially in Caucasian populations. In conclusion, BDNF G196A (Val66Met) is confirmed to be a risk factor for cognitive impairment in PD.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Disfunção Cognitiva/genética , Doença de Parkinson/genética , Doença de Alzheimer/complicações , Estudos de Casos e Controles , Disfunção Cognitiva/complicações , Grupo com Ancestrais do Continente Europeu , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Razão de Chances , Doença de Parkinson/complicações , Polimorfismo de Nucleotídeo Único , Fatores de Risco
4.
Psychiatr Danub ; 31(2): 141-147, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291217

RESUMO

BACKGROUND: Brain-derived neurotrophic factor (BDNF) polymorphism plays an important role in neural survival and was proposed to be related to obsessive-compulsive disorder (OCD). Genetic association studies of the BDNF Val66Met polymorphism (rs6265) in OCD have produced inconsistent results. A meta-analysis of studies was conducted to compare the frequency of the BDNF Val66Met variant between cases with OCD and age-matched controls. SUBJECTS AND METHODS: Electronic databases were searched for eligible articles in English and ten studies on the association of the BDNF Val66Met polymorphism with OCD were analysed. RESULTS: A total of ten studies involving 2306 cases with OCD and 4968 healthy controls were included. Findings indicated that the BDNF Val66Met polymorphism was not associated with OCD. But there was a marginally significant effect of the BDNF Val66Met variant on OCD in different ethnicity. CONCLUSION: Findings from this meta-analytic investigation of published literature provide little support for the Val66Met variant of BDNF as a predictor of OCD. Future well-powered agnostic genome-wide association studies with more refined phenotype are needed to clarify genetic influences on OCD.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Predisposição Genética para Doença , Transtorno Obsessivo-Compulsivo/genética , Polimorfismo Genético , Humanos
5.
Psychiatr Danub ; 31(2): 227-234, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291230

RESUMO

BACKGROUND: Individuals who are exposed to traumatic events are at an increased risk of developing posttraumatic stress disorder (PTSD), a condition during which an individual's ability to function is impaired by emotional responses to memories of those events. The gene coding for neuropeptide Y (NPY) and the gene coding for brain-derived neurotrophic factor (BDNF) are among the number of candidate gene variants that have been identified as potential contributors to PTSD. The aim of this study was to investigate the association between NPY and BDNF and PTSD in individuals who experienced war-related trauma in the South Eastern Europe (SEE) conflicts (1991-1999). SUBJECTS AND METHODS: This study included participants with current and remitted PTSD and healthy volunteers (N=719, 232 females, 487 males), who were recruited between 2013 and 2015 within the framework of the South Eastern Europe (SEE) - PTSD Study. Psychometric methods comprised the Mini International Neuropsychiatric Interview (M.I.N.I.), the Clinician Administered PTSD Scale (CAPS), and the Brief Symptom Inventory (BSI). DNA was isolated from whole blood and genotyped for NPY rs5574 via PCR - RFLP and NPY rs16147 and BDNF rs6265 using the KASP assay. RESULTS: Tests for deviation from Hardy-Weinberg equilibrium showed no significant results. Analyses at the categorical level yielded no associations between the affected individuals and all three SNPs when compared to controls. Within lifetime PTSD patients, the major alleles of both NPY variants showed a nominally significant association with higher CAPS scores (p=0.007 and p=0.02, respectively). Also, the major allele of rs5574C>T was associated with higher BSI scores with a nominal significance among current PTSD patients (p=0.047). The results did not withstand a Bonferroni adjustment (α=0.002). CONCLUSION: Nominally significant associations between NPY polymorphisms and PTSD susceptibility were found that did not withstand Bonferroni correction.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Neuropeptídeo Y/genética , Polimorfismo de Nucleotídeo Único , Transtornos de Estresse Pós-Traumáticos/genética , Conflitos Armados/psicologia , Europa Oriental , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
6.
Chin J Nat Med ; 17(6): 424-434, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31262455

RESUMO

To examine the effects of Populus tomentiglandulosa (PT) extract on the expressions of antioxidant enzymes and neurotrophic factors in the cornu ammonis 1 (CA1) region of the hippocampus at 5 min after inducing transient global cerebral ischemia (TGCI) in gerbils, TGCI was induced by occlusion of common carotid arteries for 5 min. Before ischemic surgery, 200 mg·kg-1 PT extract was orally administrated once daily for 7 d. We performed neuronal nuclear antigen immunohistochemistry and Fluoro-Jade B staining. Furthermore, we determined in situ production of superoxide anion radical, expression levels of SOD1 and SOD2 as antioxidant enzymes and brain-derived neurotrophic factor (BDNF) and insulin-like growth factor I (IGF-I) as neurotrophic factors. Pretreatment with 200 mg·kg-1 PT extract prevented neuronal death (loss). Furthermore, pretreatment with 200 mg·kg-1 PT extract significantly inhibited the production of superoxide anion radical, increased expressions of SODs and maintained expressions of BDNF and IGF-I. Such increased expressions of SODs were maintained in the neurons after IRI. In summary, pretreated PT extract can significantly increase levels of SODs and protect the neurons against TGCI, suggesting that PT can be a useful natural agent to protect against TGCI.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Região CA1 Hipocampal/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/metabolismo , Extratos Vegetais/administração & dosagem , Populus/química , Células Piramidais/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Superóxido Dismutase/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Região CA1 Hipocampal/metabolismo , Gerbillinae , Humanos , Fator de Crescimento Insulin-Like I/genética , Masculino , Fármacos Neuroprotetores/administração & dosagem , Células Piramidais/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Superóxido Dismutase/genética , Regulação para Cima/efeitos dos fármacos
7.
Life Sci ; 229: 187-199, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31108095

RESUMO

Spinal cord injury (SCI) is a serious neurological disease without efficacious drugs. Anti-apoptosis and suppressing dendritic/synaptic degeneration in the anterior horn are essential targets after SCI. Previous studies found that hyperbaric oxygen therapy (HBOT) significantly protected rats after SCI. However, its potential effects and mechanisms remain unknown. The BDNF/TrkB signaling pathways evidently contribute to the SCI recovery. Currently, we mainly investigate the potential effects and mechanism of HBOT on anti-apoptosis and ameliorating impaired dendrites, dendritic spines and synapses after SCI. Establish SCI model and randomly divide rats into 5 groups. After SCI, rats were subjected to HBOT. ANA-12 is the specific inhibitor of BDNF/TrkB signal pathway. Changes in neurological deficit, neuronal morphology, apoptosis, protein expression and dendrite/synapse were examined by Basso-Beattie-Bresnahan (BBB) locomotor rating scale, Hematoxylin-eosin (HE) and Nissl staining, TUNEL staining, RT-PCR, Western blot, immunofluorescence and Golgi-Cox staining. We found HBOT suppressed dendritic/synaptic degeneration and alleviated apoptosis, consistent with the increase of BDNF and TrkB expression and improved neurological recovery. In contrast to the positive effects of HBOT, inhibitor increased degeneration and apoptosis. Moreover, we observed that these HBOT-mediated protective effects were significantly inhibited by inhibitor, consistent with the lower expression of BDNF/TrkB and worse neurobehavioral state. These findings suggest that hyperbaric oxygen therapy ameliorates spinal cord injury-induced neurological impairment by anti-apoptosis and suppressing dendritic/synaptic degeneration via upregulating the BDNF/TrkB signaling pathways.


Assuntos
Apoptose , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dendritos/metabolismo , Oxigenação Hiperbárica/métodos , Degeneração Neural/prevenção & controle , Receptor trkB/metabolismo , Traumatismos da Medula Espinal/terapia , Sinapses/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Dendritos/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptor trkB/genética , Recuperação de Função Fisiológica , Transdução de Sinais , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Sinapses/patologia
8.
Oncology ; 97(1): 26-37, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31071716

RESUMO

OBJECTIVE: Normally, activation of tropomyosin-related kinase (TRK) receptors by neurotrophins (NTs) stimulates intracellular pathways involved in cell survival and proliferation. Dysregulation of NT/TRK signaling may affect neoplasm prognosis. Data on NT and TRK expression in melanomas are limited, and it is unclear whether NT/TRK signaling pathways are involved in the origin and progression of this neoplasm. METHODS: We examined whether NT/TRK expression differs across different cutaneous melanoma grades and subtypes, and whether it is associated with melanoma prognosis and survival. A cross-sectional study was performed in which the expression of TrkA, TrkB, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) was analyzed by immunohistochemistry of 154 melanoma samples. We investigated NT/TRK expression associations with prognostic factors for melanoma, relapse-free survival (RFS), and overall survival (OS). RESULTS: Of the 154 melanoma samples, 77 (55.4%) were TrkA immunopositive, 81 (58.3%) were TrkB immunopositive, 113 (81.3%) were BDNF immunopositive, and 104 (75.4%) were NGF immunopositive. We found NT/TRK expression associated strongly with several clinical prognostic factors, including the tumor-node-metastasis stage (p < 0.001), histological subtype (p < 0.001), and Clark level (p < 0.05), as well as with a worse OS (p < 0.05 for all, except TrkB) and RFS (p < 0.05 for all). CONCLUSIONS: Our results show strong associations of NT/TRK expression with melanoma stage progression and a poor prognosis.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Melanoma/genética , Glicoproteínas de Membrana/genética , Fatores de Crescimento Neural/genética , Receptor trkA/genética , Receptor trkB/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/imunologia , Melanoma/patologia , Glicoproteínas de Membrana/imunologia , Pessoa de Meia-Idade , Fator de Crescimento Neural/genética , Fatores de Crescimento Neural/imunologia , Prognóstico , Receptor trkA/imunologia , Receptor trkB/imunologia , Transdução de Sinais , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Adulto Jovem
9.
Cell Biochem Funct ; 37(5): 340-347, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31062382

RESUMO

This study was designed to investigate the molecular mechanism and biological roles of long non-coding RNA (lncRNA) brain-derived neurotrophic factor antisense (BDNF-AS) in colorectal cancer (CRC). The quantitative real-time PCR (qRT-PCR) and western blotting were performed to detect the expressions of lncRNA BDNF-AS and glycogen synthase kinase-3ß (GSK-3ß) in human CRC tissues and cell lines. The cell proliferation, transwell migration, and invasion assays were carried out to evaluate the effect of lncRNA BDNF-AS on the growth of CRC cells. RNA pull-down and RNA immunoprecipitation (RIP) assays were conducted to confirm the interaction between lncRNA BDNF-AS and enhancer of Zeste Homologue 2 (EZH2). Chromatin immunoprecipitation (ChIP) assay was used to verify the enrichment of EZH2 and histone H3 lysine 27 trimethylation (H3K27me3) in the promoter region of GSK-3ß in CRC cells. LncRNA BDNF-AS expression was significantly decreased, while GSK-3ß was highly expressed in human CRC tissues and cell lines. Moreover, lncRNA BDNF-AS induced inhibition of proliferation, migration, and invasion of CRC cells via inhibiting GSK-3ß expression. Mechanistically, BDNF-AS led to GSK-3ß promoter silencing in CRC cells through recruitment of EZH2. In conclusion, lncRNA BDNF-AS functioned as an oncogene in CRC and shed new light on lncRNA-directed therapeutics in CRC. SIGNIFICANCE OF THE STUDY: LncRNA BDNF-AS is recently reported to be remarkably downregulated in a variety of tumours and served as a tumour suppressor. However, the functions and underlying mechanism of lncRNA BDNF-AS in CRC pathogenesis have not been reported yet. Our study is the first to demonstrate the effect of lncRNA BDNF-AS in CRC and revealed that lncRNA BDNF-AS expression is negatively correlated with the aggressive biological behaviour of CRC. Further investigation demonstrated that lncRNA BDNF-AS functioned as a tumour suppressor in CRC progression by suppressing GSK-3ß expression through binding to EZH2 and H3K27me3 with the GSK-3ß promoter, shedding light on the diagnosis and therapy for CRC.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Movimento Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Epigênese Genética/genética , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , RNA Longo não Codificante/genética , Proliferação de Células/genética , Glicogênio Sintase Quinase 3 beta/biossíntese , Glicogênio Sintase Quinase 3 beta/deficiência , Células HCT116 , Humanos , RNA Longo não Codificante/metabolismo
10.
Neuron ; 103(2): 250-265.e8, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31122677

RESUMO

Activity-dependent myelination is thought to contribute to adaptive neurological function. However, the mechanisms by which activity regulates myelination and the extent to which myelin plasticity contributes to non-motor cognitive functions remain incompletely understood. Using a mouse model of chemotherapy-related cognitive impairment (CRCI), we recently demonstrated that methotrexate (MTX) chemotherapy induces complex glial dysfunction for which microglial activation is central. Here, we demonstrate that remote MTX exposure blocks activity-regulated myelination. MTX decreases cortical Bdnf expression, which is restored by microglial depletion. Bdnf-TrkB signaling is a required component of activity-dependent myelination. Oligodendrocyte precursor cell (OPC)-specific TrkB deletion in chemotherapy-naive mice results in impaired cognitive behavioral performance. A small-molecule TrkB agonist rescues both myelination and cognitive impairment after MTX chemotherapy. This rescue after MTX depends on intact TrkB expression in OPCs. Taken together, these findings demonstrate a molecular mechanism required for adaptive myelination that is aberrant in CRCI due to microglial activation.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/patologia , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Bainha de Mielina/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Transtornos Cognitivos/genética , Modelos Animais de Doenças , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Bainha de Mielina/patologia , Bainha de Mielina/ultraestrutura , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Compostos Orgânicos/uso terapêutico , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Recognição (Psicologia)/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Ureia/análogos & derivados , Ureia/metabolismo
11.
EBioMedicine ; 43: 424-434, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31085101

RESUMO

BACKGROUND: The delivery of therapeutic proteins to selected sites within the central nervous system (CNS) parenchyma is a major challenge in the treatment of various neurodegenerative disorders. As brain-derived neurotrophic factor (BDNF) is reduced in the brain of people with Alzheimer's disease (AD) and its administration has shown promising therapeutic effects in mouse model of the disease, we generated a novel platform for T cell-based BDNF delivery into the brain parenchyma. METHODS: We generated amyloid beta-protein (Aß)-specific CD4 T cells (Aß-T cells), genetically engineered to express BDNF, and injected them intracerebroventricularly into the 5XFAD mouse model of AD. FINDINGS: The BDNF-secreting Aß-T cells migrated efficiently to amyloid plaques, where they significantly increased the levels of BDNF, its receptor TrkB, and various synaptic proteins known to be reduced in AD. Furthermore, the injected mice demonstrated reduced levels of beta-secretase 1 (BACE1)-a protease essential in the cleavage process of the amyloid precursor protein-and ameliorated amyloid pathology and inflammation within the brain parenchyma. INTERPRETATION: A T cell-based delivery of proteins into the brain can serve as a platform to modulate neurotoxic inflammation and to promote neuronal repair in neurodegenerative diseases.


Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/imunologia , Peptídeos beta-Amiloides/metabolismo , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Biomarcadores , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/genética , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Epitopos de Linfócito T/imunologia , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Células Piramidais/imunologia , Células Piramidais/metabolismo , Células Piramidais/patologia , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
12.
Gene ; 707: 212-215, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31102717

RESUMO

BACKGROUND: Alzheimer's disease is a progressive, irreversible neurodegenerative disorder characterized by loss of memory and cognitive skills. More than 90% of cases are sporadic and have later age of onset. Many studies have shown a genetic predisposition for late onset Alzheimer's disease (LOAD). The most studied genetic predisposition factor is apolipoprotein E gene besides other susceptibility genes involved in vascular pathologies, homocysteine metabolism, and neuronal growth and differentiation such as methylenetetrahydrofolate reductase (MTHFR), angiotensin-converting enzyme (ACE), APOB and brain derived neurotrophic factor (BDNF). METHODS: In this study Factor V Leiden (G1691A) and H1299R, prothrombin G20210A, Factor XIII V34L, B-fibrinogen -455G>A, PAI-1 5G/4G, HPA1 b/a, MTHFR C677T, MTHFR A1298C, APOE, ACE I/D, BDNF C270T and G196A polymorphisms were evaluated in 100 LOAD patients and 100 age matched healthy controls. RESULTS: APOE4 allele, MTHFR CCA1298C and BDNF TTC270T genotypes were significantly higher in LOAD patients compared to the control group (p < 0.001, p = 0.04, p = 0.03, respectively). There were no significant associations between other genotypes and allele frequencies. Mini-Mental State Examination (MMSE) scores and age at onset of the patients were also evaluated for each and combined genotypes. Age at onset was significantly lowered by about approximately 4 and 5 years in patients carrying BDNF TTC270T and MTHFR TTC677T genotypes, respectively. CONCLUSION: APOE, MTHFR A1298C and BDNF C270T polymorphisms may be associated with LOAD and BDNF and MTHFR alleles may play a role in the age at onset of the LOAD.


Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mutação , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
13.
Artigo em Russo | MEDLINE | ID: mdl-31089096

RESUMO

AIM: To search for genetic variants associated with premorbid personality in patients with schizophrenia. MATERIAL AND METHODS: The sample included 272 men diagnosed with schizophrenia or schizoaffective disorder. Patients were divided into 3 groups based on premorbid personality difficulties: mild (group 1, n=110), moderate (group 2, n=113), marked (group 3, n=49). The following polymorphisms were genotyped: 5-HTR2A (T102C), 5-HTTLPR, BDNF (Val66Met), CRP (-717A>G). RESULTS: A significant increase in the frequency of the CC (5-HTR2A T102C), LL (5-HTTLPR) and Met/Met (BDNF Val66Met) genotypes was identified in group 3 compared to group 1. Frequencies of CC and LL genotypes were significantly higher in group 2 compared to group 1 as well. The differences between group 2 and group 3 were found only for the Met/Met genotype. There were no between-group differences in the frequencies of CRP (-717A>G) genotypes. CONCLUSION: 5-HTR2A (T102C), 5-HTTLPR, BDNF (Val66Met) polymorphisms previously reported to modify schizophrenia course are also associated with premorbid personality in schizophrenic patients.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Serina Peptidase 2 de Requerimento de Alta Temperatura A , Personalidade , Transtornos Psicóticos , Esquizofrenia , Proteínas da Membrana Plasmática de Transporte de Serotonina , Fator Neurotrófico Derivado do Encéfalo/genética , Genótipo , Serina Peptidase 2 de Requerimento de Alta Temperatura A/genética , Humanos , Masculino , Personalidade/genética , Polimorfismo Genético , Receptor 5-HT2A de Serotonina , Esquizofrenia/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
14.
J Med Food ; 22(6): 587-593, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31013457

RESUMO

Alzheimer's disease accounts for the majority of dementia and shows hallmarks such as sequential cognitive dysfunction and abnormal behavior. Dendropanax morbifera (DM) has traditionally been used to treat a variety of diseases in East Asia. The aim of this study was to assess the therapeutic effects of DM on brain neuron damage and on cognitive deficit in neuronal cell induced by Aß1-42 in mice. Treatment with DM reduced the levels of intracellular reactive oxygen species and protected against the death of neuronal cells induced by Aß1-42 peptide. In addition, it was also found that pretreatment with DM decreased cognitive damage induced by Aß peptide via enhancing the cholinergic system and antioxidant defense system in mice. Furthermore, the study verified that the change in the expression of both cyclic-adenosine monophosphate response element binding protein and of brain-derived neurotrophic factor in the hippocampus in Aß peptide-treated mice was significantly ameliorated after treatment with DM. Accordingly, these results suggest that pretreatment with DM defends against oxidative stress and cognitive impairment caused by Aß peptide.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/toxicidade , Araliaceae/química , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Colinérgicos/administração & dosagem , Extratos Vegetais/administração & dosagem , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos
15.
Food Funct ; 10(5): 2439-2449, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-30968880

RESUMO

The peptide derived from Anchovy hydrolysates, Pro-Ala-Tyr-Cys-Ser (PAYCS), was reported to display a neuroprotective effect in vitro in our previous study. The in vivo memory improving effects of PAYCS were investigated in this study. Prior to the scopolamine-induced amnesia mice trial, the stability of PAYCS during digestion was detected and the digestive products were identified. The results showed that PAYCS was susceptible to proteolytic degradation after incubation with pepsin and pancreatin and Pro-Ala-Tyr (PAY) was released and survived during the simulated GI digestion. The results of scopolamine-induced amnesia model trials showed that PAYCS and PAY treatment exhibited cognitive improvement effects in the behavioral tests and different pathways were determined. The results indicated that only PAYCS facilitated cholinergic activity by up-regulating the amount of acetylcholine (Ach) and acetylcholine receptor (AChR). Additionally, both PAYCS and PAY enhanced the superoxide dismutase (SOD) activity. Furthermore, PAYCS was found to be beneficial for the expression of the nuclear factor (erythroid-derived2)-like 2 protein (Nrf2), brain-derived neurotrophic factor (BDNF) and cAMP response element binding protein (CREB). This indicated that PAYCS could regulate the oxidative stress by activating the Nrf2/antioxidant response elements (Nrf2/ARE) pathway. In our study, we demonstrated that the memory improving effects conferred by PAYCS on amnesia mice were linked to the attenuation of the cholinergic system and the activation of Nrf2/ARE and BDNF/CREB signaling.


Assuntos
Amnésia/tratamento farmacológico , Amnésia/psicologia , Proteínas de Peixes/química , Trato Gastrointestinal/metabolismo , Peptídeos/administração & dosagem , Peptídeos/química , Acetilcolina/metabolismo , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Amnésia/etiologia , Amnésia/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Feminino , Peixes , Humanos , Masculino , Memória/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/administração & dosagem , Peptídeos/metabolismo , Escopolamina/efeitos adversos
16.
PLoS Comput Biol ; 15(4): e1006975, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31017891

RESUMO

Across the mammalian nervous system, neurotrophins control synaptic plasticity, neuromodulation, and neuronal growth. The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) is known to promote structural and functional synaptic plasticity in the hippocampus, the cerebral cortex, and many other brain areas. In recent years, a wealth of data has been accumulated revealing the paramount importance of BDNF for neuronal function. BDNF signaling gives rise to multiple complex signaling pathways that mediate neuronal survival and differentiation during development, and formation of new memories. These different roles of BDNF for neuronal function have essential consequences if BDNF signaling in the brain is reduced. Thus, BDNF knock-out mice or mice that are deficient in BDNF receptor signaling via TrkB and p75 receptors show deficits in neuronal development, synaptic plasticity, and memory formation. Accordingly, BDNF signaling dysfunctions are associated with many neurological and neurodegenerative conditions including Alzheimer's and Huntington's disease. However, despite the widespread implications of BDNF-dependent signaling in synaptic plasticity in healthy and pathological conditions, the interplay of the involved different biochemical pathways at the synaptic level remained mostly unknown. In this paper, we investigated the role of BDNF/TrkB signaling in spike-timing dependent plasticity (STDP) in rodent hippocampus CA1 pyramidal cells, by implementing the first subcellular model of BDNF regulated, spike timing-dependent long-term potentiation (t-LTP). The model is based on previously published experimental findings on STDP and accounts for the observed magnitude, time course, stimulation pattern and BDNF-dependence of t-LTP. It allows interpreting the main experimental findings concerning specific biomolecular processes, and it can be expanded to take into account more detailed biochemical reactions. The results point out a few predictions on how to enhance LTP induction in such a way to rescue or improve cognitive functions under pathological conditions.


Assuntos
Potenciais de Ação/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Potenciação de Longa Duração/fisiologia , Modelos Neurológicos , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Biologia Computacional , Hipocampo/citologia , Masculino , Memória/fisiologia , Camundongos , Camundongos Knockout , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Ratos Wistar , Transdução de Sinais/fisiologia
17.
Gene ; 705: 51-54, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31004714

RESUMO

Obesity is a major public health concern worldwide. Genetic, behavioral, and environmental factors contribute to the multifactorial etiology of obesity. Evidence suggests an association between human Brain-Derived Neurotrophic Factor (BDNF) Val66Met single nucleotide polymorphism (SNP) and obesity. Reduced plasma BDNF levels have also been reported in patients with eating disorders and obesity. We aimed to evaluate the BDNF Val66Met (rs6265) SNP and also plasma BDNF levels in morbidly obese patients compared with healthy normal controls in southern Iran. One hundred morbidly obese patients and one hundred eight healthy normal controls were enrolled. Blood-derived DNA samples were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and confirmed by DNA sequencing. Plasma BDNF levels were evaluated using a commercially available sandwich enzyme-linked immunosorbent assay (ELISA) kit for human BDNF. Data analysis was performed by SPSS software, version 18.0. Genotype distribution was not significantly different between obese patients and controls. However, plasma BDNF levels were significantly lower in obese patients compared with controls. Interestingly, a significant association was found between BDNF Val66Met SNP and plasma BDNF levels. No relationship was observed between BDNF Val66Met SNP and all assessed demographic and clinical characteristics of obese patients. It seems that plasma BDNF levels were associated with both obesity and BDNF Val66Met SNP. However, this association was not found between BDNF Val66Met SNP and obesity. Further studies with larger sample sizes are needed for more detailed assessment of this genetic variation as a potential biomarker for obesity.


Assuntos
Substituição de Aminoácidos , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/genética , Metionina/genética , Obesidade Mórbida/genética , Valina/genética , Adulto , Estudos de Casos e Controles , Regulação para Baixo , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/sangue , Polimorfismo de Fragmento de Restrição , Análise de Sequência de DNA
18.
Medicine (Baltimore) ; 98(11): e14838, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30882674

RESUMO

The aim of the present case-control study was to explore the association between BDNF Val66Met (rs6265) polymorphism and generalized anxiety disorder in Mexican individuals, and whether this polymorphism plays a role in the symptomatology of anxiety.A total of 212 subjects were included in the study. Around 75 patients with generalized anxiety disorder were diagnosed by psychiatrists based on the DSM-IV instrument and 137 unrelated subjects psychiatrically healthy were used as comparison group. The subclinical symptomatology in patients was assessed with the State-Trait Anxiety Inventory. BDNF rs6265 genotypes were analyzed using the polymerase chain reaction end-point method.The association between BDNF Val66Met with the risk for generalized anxiety disorder was evaluated using 4 inheritance models. The present study showed that carrying the Met allele confers increased risk for the presence of generalized anxiety disorder (χ = 4.7, P = .03; OR (95%) 1.96 (1.05-3.56)) when patients with generalized anxiety disorder were compared with the comparison group.Our results provide evidence of an association between the Val66Met polymorphism of the BDNF gene and generalized anxiety disorder in a Mexican population. However, no association was observed between this polymorphism and the symptomatology of anxiety.


Assuntos
Transtornos de Ansiedade , Fator Neurotrófico Derivado do Encéfalo/genética , Adulto , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/psicologia , Sintomas Comportamentais/diagnóstico , Correlação de Dados , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Predisposição Genética para Doença , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Escalas de Graduação Psiquiátrica
19.
Gene ; 698: 107-112, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-30831210

RESUMO

Brain-derived neurotrophic factor (BDNF) gene is associated with increased risk of posttraumatic stress disorder (PTSD) and plays a role in neuroplasticity, cognition and memory. BDNF has strong potential as a therapeutic target as studies have shown that antidepressants, electroconvulsive treatment and exercise modulate BDNF expression and methylation. In this study we examined the role of BDNF methylation and expression in PTSD and the implications of exercise in mediating these effects. BDNF DNA methylation and gene expression analysis was performed in a sample of 96 male Vietnam veterans. Cases were combat-exposed veterans with current PTSD (n = 48) and controls were combat exposed veterans with no past or current PTSD diagnosis (n = 48). No association between BDNF mRNA and PTSD was identified. PTSD was associated with decreased methylation at three BDNF CpG sites (cg01546433 P = 0.004835; cg24650785 P = 0.000259 and cg002298481 P = 0.000672). Differential BDNF methylation was associated with exercise, with active exercise associated with lower methylation levels at three CpG sites (cg04481212 P = 0.005; cg01546433 P = 0.025 and cg00298481 P = 0.035). Given that exercise mediates BDNF action on cognitive plasticity, exercise may be a non-invasive, drug free option in the treatment of PTSD.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Transtornos de Estresse Pós-Traumáticos/genética , Idoso , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ilhas de CpG/genética , Metilação de DNA/genética , Epigênese Genética/genética , Exercício/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Veteranos/psicologia , Guerra do Vietnã
20.
eNeuro ; 6(1)2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863790

RESUMO

CRISPR-based technology has provided new avenues to interrogate gene function, but difficulties in transgene expression in post-mitotic neurons has delayed incorporation of these tools in the central nervous system (CNS). Here, we demonstrate a highly efficient, neuron-optimized dual lentiviral CRISPR-based transcriptional activation (CRISPRa) system capable of robust, modular, and tunable gene induction and multiplexed gene regulation across several primary rodent neuron culture systems. CRISPRa targeting unique promoters in the complex multi-transcript gene brain-derived neurotrophic factor (Bdnf) revealed both transcript- and genome-level selectivity of this approach, in addition to highlighting downstream transcriptional and physiological consequences of Bdnf regulation. Finally, we illustrate that CRISPRa is highly efficient in vivo, resulting in increased protein levels of a target gene in diverse brain structures. Taken together, these results demonstrate that CRISPRa is an efficient and selective method to study gene expression programs in brain health and disease.


Assuntos
Sistemas CRISPR-Cas , Regulação da Expressão Gênica , Técnicas Genéticas , Neurônios/metabolismo , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Linhagem Celular Tumoral , Proteínas da Matriz Extracelular/metabolismo , Masculino , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Cultura Primária de Células , Distribuição Aleatória , Ratos Sprague-Dawley , Serina Endopeptidases/metabolismo , Transcrição Genética , Transcriptoma
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