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1.
Am J Chin Med ; 48(6): 1409-1433, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907360

RESUMO

Scutellaria baicalensis (SB), a herbal medicine, is commonly used to treat metabolic diseases, while Metformin (MF) is a widely used drug for type 2 diabetes. The purpose of this study was to investigate whether co-treatment of SB with MF could produce a potential therapeutic effect on high-fat and high-fructose diet (HFFD)-induced metabolic dysregulation. First, we optimized the dose of SB (100, 200, 400, and 800[Formula: see text]mg/kg) with MF (200[Formula: see text]mg/kg) in HFFD-induced C57BL6J mice. Next, the optimized dose of SB (400[Formula: see text]mg/kg) was co-administered with MF (50, 100, and 200[Formula: see text]mg/kg) in a similar animal model to find the effective combinations of SB and MF. Metabolic markers were determined in serum and tissues using different assays, histology, gene expression, and gut microbial population. The SB and MF co-treatment significantly decreased the body, liver, and VAT weights. The outcome of OGTT was improved, and the fasting insulin, HbA1c, TG, TC, LDL-c, AST, and ALT were decreased, while HDL-c was significantly increased. Histological analyses revealed maintained the integrity of liver, adipose tissue, and intestine prevented lipid accumulation in the liver and intestine and combated neuronal damage in the brain. Importantly, controlled the expression of PPAR[Formula: see text], and IL-6 genes in the liver, and expression of BDNF, Glut1, Glut3, and Glut4 genes in the brain. Treatment-specific gut microbial segregation was observed in the PCA chart. Our findings indicate that SB and MF co-treatment is an effective therapeutic approach for HFFD-induced metabolic dysregulation which is operated through the gut-liver-brain axis.


Assuntos
Encéfalo/metabolismo , Microbioma Gastrointestinal , Fígado/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Metformina/administração & dosagem , Metformina/farmacologia , Fitoterapia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dieta da Carga de Carboidratos/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Quimioterapia Combinada , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/microbiologia , Camundongos Endogâmicos C57BL , PPAR gama/genética , PPAR gama/metabolismo
2.
Anticancer Res ; 40(9): 5151-5158, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878803

RESUMO

BACKGROUND/AIM: Magnetic stimulation is used in the treatment of a diversity of diseases, but a complete understanding of the underlying mechanisms of action requires further investigation. We examined the effect of static magnetic stimulation (SMS) in different cell lines. MATERIALS AND METHODS: A culture plate holder with attached NeFeB magnets was developed. Different magnetic field intensities and periods were tested in tumoral and non-tumoral cell lines. To verify the cellular responses to SMS, cell viability, cell death, cell cycle and BDNF expression were evaluated. RESULTS: Exposure of SH-SY5Y cells to SMS for 24 hours led to a decrease in cell viability. Analysis 24 h after stimulation revealed a decrease in apoptotic and double-positive cells, associated with an increase in the number of necrotic cells. CONCLUSION: The effects of SMS on cell viability are cell type-specific, inducing a decrease in cell viability in SH-SY5Y cells. This suggests that SMS may be a potential tool in the treatment of neuronal tumors.


Assuntos
Sobrevivência Celular/efeitos da radiação , Fenômenos Magnéticos , Apoptose/efeitos da radiação , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Neuroblastoma/genética , Neuroblastoma/metabolismo , Especificidade de Órgãos/efeitos da radiação
3.
PLoS Biol ; 18(8): e3000826, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776935

RESUMO

Ca2+/calmodulin-dependent kinase II (CaMKII) regulates synaptic plasticity in multiple ways, supposedly including the secretion of neuromodulators like brain-derived neurotrophic factor (BDNF). Here, we show that neuromodulator secretion is indeed reduced in mouse α- and ßCaMKII-deficient (αßCaMKII double-knockout [DKO]) hippocampal neurons. However, this was not due to reduced secretion efficiency or neuromodulator vesicle transport but to 40% reduced neuromodulator levels at synapses and 50% reduced delivery of new neuromodulator vesicles to axons. αßCaMKII depletion drastically reduced neuromodulator expression. Blocking BDNF secretion or BDNF scavenging in wild-type neurons produced a similar reduction. Reduced neuromodulator expression in αßCaMKII DKO neurons was restored by active ßCaMKII but not inactive ßCaMKII or αCaMKII, and by CaMKII downstream effectors that promote cAMP-response element binding protein (CREB) phosphorylation. These data indicate that CaMKII regulates neuromodulation in a feedback loop coupling neuromodulator secretion to ßCaMKII- and CREB-dependent neuromodulator expression and axonal targeting, but CaMKIIs are dispensable for the secretion process itself.


Assuntos
Astrócitos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Cálcio/metabolismo , Neurônios/metabolismo , Subunidades Proteicas/genética , Animais , Astrócitos/citologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/deficiência , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Retroalimentação Fisiológica , Regulação da Expressão Gênica , Hipocampo/citologia , Hipocampo/metabolismo , Camundongos , Camundongos Transgênicos , Neurônios/citologia , Fosforilação , Cultura Primária de Células , Subunidades Proteicas/deficiência , Sinapses/fisiologia , Transmissão Sináptica , Imagem com Lapso de Tempo
4.
Rev Assoc Med Bras (1992) ; 66(5): 615-622, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32638952

RESUMO

OBJECTIVE To explore the association of brain-derived neurotrophic factor gene (BDNF) polymorphism with the latent cognitive endophenotype of posttraumatic stress disorder (PTSD) after major natural disasters in Hainan Province, China. METHODS A total of 300 patients with PTSD and 150 healthy controls (HC) were surveyed by psychoanalysis scale to assess their cognitive functions. Polymerase chain reaction (PCR) and polyacrylamide gel electrophoresis (PAGE) were used to detect the BDNF gene polymorphism. RESULTS In terms of the cognitive function, the scores in the PTSD group were worse than those of the HC group (P < 0.05 or P < 0.01). There was a significant difference in the distribution of BDNF genotype and allele frequency between the two groups (P < 0.05). PTSD endophenotypes were significantly different among the BDNF genotypes in the PTSD group (P ≤ 0.01). CONCLUSION There is a statistically significant difference in the polymorphism of BDNF gene between PTSD and HC groups, and the alleles are associated with the incidence of PTSD. Thus, it may be a risk factor for PTSD.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Transtornos de Estresse Pós-Traumáticos , Alelos , China , Endofenótipos , Genótipo , Humanos , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único
5.
Proc Natl Acad Sci U S A ; 117(32): 19566-19577, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719118

RESUMO

The ventromedial hypothalamus (VMH) plays chief roles regulating energy and glucose homeostasis and is sexually dimorphic. We discovered that expression of metabotropic glutamate receptor subtype 5 (mGluR5) in the VMH is regulated by caloric status in normal mice and reduced in brain-derived neurotrophic factor (BDNF) mutants, which are severely obese and have diminished glucose balance control. These findings led us to investigate whether mGluR5 might act downstream of BDNF to critically regulate VMH neuronal activity and metabolic function. We found that mGluR5 depletion in VMH SF1 neurons did not affect energy balance regulation. However, it significantly impaired insulin sensitivity, glycemic control, lipid metabolism, and sympathetic output in females but not in males. These sex-specific deficits are linked to reductions in intrinsic excitability and firing rate of SF1 neurons. Abnormal excitatory and inhibitory synapse assembly and elevated expression of the GABAergic synthetic enzyme GAD67 also cooperate to decrease and potentiate the synaptic excitatory and inhibitory tone onto mutant SF1 neurons, respectively. Notably, these alterations arise from disrupted functional interactions of mGluR5 with estrogen receptors that switch the normally positive effects of estrogen on SF1 neuronal activity and glucose balance control to paradoxical and detrimental. The collective data inform an essential central mechanism regulating metabolic function in females and underlying the protective effects of estrogen against metabolic disease.


Assuntos
Glicemia/metabolismo , Estrogênios/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Núcleo Hipotalâmico Ventromedial/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Metabolismo Energético , Feminino , Glutamato Descarboxilase/metabolismo , Homeostase , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Mutantes , Rede Nervosa , Inibição Neural , Neurônios/metabolismo , Neurônios/fisiologia , Receptor de Glutamato Metabotrópico 5/genética , Receptores Estrogênicos/metabolismo , Fatores Sexuais , Transdução de Sinais , Fator Esteroidogênico 1/metabolismo , Sistema Nervoso Simpático/metabolismo , Transmissão Sináptica , Núcleo Hipotalâmico Ventromedial/citologia , Núcleo Hipotalâmico Ventromedial/metabolismo
6.
PLoS One ; 15(5): e0232284, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401758

RESUMO

BACKGROUND: Long non-coding RNAs (lncRNAs) are characterized as having 200 nucleotides or more and not coding any protein, and several been identified as differentially expressed in several human malignancies, including breast cancer. METHODS: Here, we evaluated lncRNAs differentially expressed in triple-negative breast cancer (TNBC) from a cDNA microarray data set obtained in a previous study from our group. Using in silico analyses in combination with a review of the current literature, we identify three lncRNAs as potential prognostic factors for TNBC patients. RESULTS: We found that the expression of WDFY3-AS2, BDNF-AS, and AFAP1-AS1 was associated with poor survival in patients with TNBCs. WDFY3-AS2 and BDNF-AS are lncRNAs known to play an important role in tumor suppression of different types of cancer, while AFAP1-AS1 exerts oncogenic activity. CONCLUSION: Our findings provided evidence that WDFY3-AS2, BDNF-AS, and AFAP1-AS1 may be potential prognostic factors in TNBC development.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Relacionadas à Autofagia/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Simulação por Computador , RNA Longo não Codificante/genética , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/genética , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico
7.
Am J Physiol Regul Integr Comp Physiol ; 318(6): R1058-R1067, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32348679

RESUMO

Circadian rhythms are endogenous and entrainable daily patterns of physiology and behavior. Molecular mechanisms underlie circadian rhythms, characterized by an ~24-h pattern of gene expression of core clock genes. Although it has long been known that breathing exhibits circadian rhythms, little is known concerning clock gene expression in any element of the neuromuscular system controlling breathing. Furthermore, we know little concerning gene expression necessary for specific respiratory functions, such as phrenic motor plasticity. Thus, we tested the hypotheses that transcripts for clock genes (Bmal1, Clock, Per1, and Per2) and molecules necessary for phrenic motor plasticity (Htr2a, Htr2b, Bdnf, and Ntrk2) oscillate in regions critical for phrenic/diaphragm motor function via RT-PCR. Tissues were collected from male Sprague-Dawley rats entrained to a 12-h light-dark cycle at 4 zeitgeber times (ZT; n = 8 rats/group): ZT5, ZT11, ZT17, and ZT23; ZT0 = lights on. Here, we demonstrate that 1) circadian clock genes (Bmal1, Clock, Per1, and Per2) oscillate in regions critical for phrenic/diaphragm function, including the caudal medulla, ventral C3-C5 cervical spinal cord, and diaphragm; 2) the clock protein BMAL1 is localized within CtB-labeled phrenic motor neurons; 3) genes necessary for intermittent hypoxia-induced phrenic/diaphragm motor plasticity (Htr2b and Bdnf) oscillate in the caudal medulla and ventral C3-C5 spinal cord; and 4) there is higher intensity of immunofluorescent BDNF protein within phrenic motor neurons at ZT23 compared with ZT11 (n = 11 rats/group). These results suggest local circadian clocks exist in the phrenic motor system and confirm the potential for local circadian regulation of neuroplasticity and other elements of the neural network controlling breathing.


Assuntos
Relógios Circadianos/genética , Ritmo Circadiano/fisiologia , Neurônios Motores/metabolismo , Plasticidade Neuronal/genética , Nervo Frênico/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Expressão Gênica , Masculino , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo
8.
Nat Commun ; 11(1): 1950, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327658

RESUMO

BDNF signaling in hypothalamic circuitries regulates mammalian food intake. However, whether BDNF exerts metabolic effects on peripheral organs is currently unknown. Here, we show that the BDNF receptor TrkB.T1 is expressed by pancreatic ß-cells where it regulates insulin release. Mice lacking TrkB.T1 show impaired glucose tolerance and insulin secretion. ß-cell BDNF-TrkB.T1 signaling triggers calcium release from intracellular stores, increasing glucose-induced insulin secretion. Additionally, BDNF is secreted by skeletal muscle and muscle-specific BDNF knockout phenocopies the ß-cell TrkB.T1 deletion metabolic impairments. The finding that BDNF is also secreted by differentiated human muscle cells and induces insulin secretion in human islets via TrkB.T1 identifies a new regulatory function of BDNF on metabolism that is independent of CNS activity. Our data suggest that muscle-derived BDNF may be a key factor mediating increased glucose metabolism in response to exercise, with implications for the treatment of diabetes and related metabolic diseases.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Cálcio/metabolismo , Células Cultivadas , Glucose/metabolismo , Intolerância à Glucose , Humanos , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Knockout , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptor trkB/química , Receptor trkB/genética , Receptor trkB/metabolismo , Transdução de Sinais
9.
PLoS One ; 15(4): e0231597, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32287325

RESUMO

Resident microglia of the central nervous system are being increasingly recognized as key players in diseases such as neuropathic pain. Biochemical and behavioral studies in neuropathic pain rodent models have documented compelling evidence of the critical role of ATP mediated-P2X4R-brain-derived neurotrophic factor (BDNF) signaling pathway in the initiation and maintenance of pain hypersensitivity, a feature driving neuropathic pain-related behavior. The goal of this study was to develop and characterize an in vitro cell line model of activated microglia that can be subsequently utilized for screening neuropathic pain therapeutics. In the present study, we characterized the SIM-A9 microglia cell line for key molecules in the P2X4R-BDNF signaling axis using a combination of biochemical techniques and developed an ATP-activated SIM-A9 microglia model. We present three novel findings: first, SIM-A9 cells expressed P2X4R and BDNF proteins, second, ATP, but not LPS, was cytocompatible with SIM-A9 cells and third, exposure of cells to optimized ATP concentrations for defined periods increased intracellular expression of Iba1 and BDNF proteins. Increased Iba1 levels confirmed microglia activation and increased BDNF expression confirmed ATP-mediated stimulation of the P2X4R signaling pathway. We propose that this ATP-activated SIM-A9 cell line model system can be utilized for screening both small- as well as macro-molecular neuropathic pain therapeutics targeting BDNF and/or P2X4R knockdown.


Assuntos
Microglia/metabolismo , Neuralgia/metabolismo , Transdução de Sinais , Trifosfato de Adenosina/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Técnicas de Cultura de Células/métodos , Lipopolissacarídeos/farmacologia , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Microglia/citologia , Microglia/efeitos dos fármacos , Neuralgia/patologia , Receptores Purinérgicos P2X4/genética , Receptores Purinérgicos P2X4/metabolismo
10.
Acta Diabetol ; 57(7): 891-898, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32124075

RESUMO

BACKGROUND: Studies by our group demonstrated brain-derived neurotrophic factor (BDNF) levels in blood and BDNF-Val66met-SNP as potential biomarkers in chemotherapy-induced peripheral neuropathy. Here, we evaluate symptoms of peripheral neuropathy (PN) and depression in patients with type II diabetes mellitus in search of an association with serum BDNF levels and the Val66Met-SNP. METHODS: In total, 90 patients enrolled in the study; 23 (25.6%) had known PN, as determined by nerve conduction studies (NCS-PN), and 67 (74.4%) were not diagnosed with PN (U-PN). PN symptoms were assessed and graded in these groups using the total neuropathy score (TNSr) and DN4 scales. Small nerve fiber testing of sensitivity thresholds to cold, warm and hot pain signals was performed using the Q-sense device. Depression was assessed using the PHQ9 questionnaire. BDNF protein levels and Val66Met-SNP were determined with ELISA and Sanger sequencing, respectively. RESULTS: NCS-PN patients showed lower serum BDNF levels alongside significantly higher TNSr, DN4 and PHQ9 scores and lower hot pain sensitivity thresholds as compared to U-PN patients. Patients with Met-BDNF-SNP showed increased TNSr scores and lower hot pain sensitivity thresholds as compared to patients with Val-BDNF-SNP. Depression showed a weaker correlation with sensitivity thresholds to hot pain signals as compared to TNSr and DN4 scores. CONCLUSIONS: Diminished peripheral BDNF resources and Met-BDNF-SNP genotype are associated with augmented symptoms of PN in patients with type II diabetes mellitus. Sensitivity thresholds to hot pain signals may be less influenced by depression and possibly more accurately detect PN symptoms in diabetic patients.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/genética , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Substituição de Aminoácidos , Biomarcadores/sangue , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Metionina/genética , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/complicações , Doenças do Sistema Nervoso Periférico/genética , Valina/genética
11.
Psychopharmacology (Berl) ; 237(6): 1657-1669, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32125485

RESUMO

RATIONALE: Clinically, chronic postsurgical pain (CPSP) is very common. Many CPSP patients may experience depression. Thus far, little is known about the mechanism of the comorbidity of CPSP and depression. Ketamine has been confirmed to possess analgesic and rapid antidepressant effects, but it is unclear whether ketamine can relieve the comorbidity of CPSP and depression. OBJECTIVES: The present study evaluated the effects of ketamine in rats with the comorbidity of CPSP and depression. METHODS: We induced CPSP in rats by thoracotomy and screened for rats with or without depression-like phenotype by hierarchical cluster analysis based on the results of depression-related behavioral experiments. Subsequently, rats were intraperitoneally injected with ketamine (20 mg/kg) and were evaluated by mechanical withdrawal threshold, cold hyperalgesia test, sucrose preference test, forced swimming test, and open field test. The inflammatory-related cytokines (IL-1, IL-6, TNF-α, nuclear factor-kappaB), oxidative stress parameters (superoxide dismutase, malondialdehyde, glutathione, catalase), and brain-derived neurotrophic factor (BDNF) in rat hippocampus were detected. RESULTS: In the hippocampus of rats with the comorbidity of CPSP and depression, IL-1, IL-6, TNF-α, nuclear factor-kappaB, and malondialdehyde were significantly increased, while superoxide dismutase, glutathione, catalase, and BDNF were significantly decreased. Ketamine relieved depression but did not attenuate hyperalgesia in CPSP rats. Additionally, ketamine reduced proinflammatory cytokines, inhibited oxidative stress, and elevated BDNF levels in rat hippocampus. CONCLUSIONS: Ketamine can rapidly relieve CPSP-induced depression in rats, which may be related to the reduction of proinflammatory cytokines, regulating oxidative stress and increasing BDNF in the hippocampus.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antidepressivos/uso terapêutico , Antioxidantes/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Depressão/tratamento farmacológico , Ketamina/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Antidepressivos/farmacologia , Antioxidantes/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Depressão/metabolismo , Depressão/psicologia , Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ketamina/farmacologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Dor Pós-Operatória/metabolismo , Dor Pós-Operatória/psicologia , Ratos , Ratos Sprague-Dawley
12.
Vascul Pharmacol ; 128-129: 106674, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32179157

RESUMO

Most of what is known on vascular brain-derived neurotrophic factor (BDNF) derived from experiments on cultured endothelial cells. Therefore, the present study compared BDNF levels/localization in artery (aorta) vs vein (vena cava) from a same territory in rats either sedentary (SED) or exposed to treadmill exercise (EX) as a mean to stimulate endogenous endothelial nitric oxide (NO) production. In SED rats, for both artery and vein, BDNF was strongly expressed by endothelial cells, while only a faint and scattered expression was observed throughout the media. Endothelial and muscular BDNF staining as vascular BDNF protein levels were however higher in artery than in vein, while BDNF mRNA levels did not differ between vessels. Irrespective of the vessels, EX resulted in an increase (+50%) in BDNF protein levels with no change in BDNF mRNA levels, a selective endothelial BDNF overexpression (x4) and an increase in vascular levels of tropomyosin related kinase B receptors (TrkB) phosphorylated at tyrosine 816 (p-TrkBTyr816). Endothelial expressions of BDNF and p-TrkBTyr816 were positively associated when SED and EX rats were simultaneously examined. The results incite to consider endothelial BDNF as a full and NO-dependent endothelium-derived factor that exerts autocrine effects.


Assuntos
Aorta Abdominal/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Células Endoteliais/metabolismo , Vasodilatação , Veias Cavas/metabolismo , Animais , Comunicação Autócrina , Fator Neurotrófico Derivado do Encéfalo/genética , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação , Esforço Físico , Ratos Wistar , Receptor trkB/metabolismo , Comportamento Sedentário , Transdução de Sinais
13.
Gene ; 744: 144616, 2020 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-32222531

RESUMO

AIM: The purpose of this study was to investigate the possible effects of Myrtus communis subsp. communis (MC) on cognitive impairment in ovariectomized diabetic rats. MATERIAL AND METHOD: Female Sprague-Dawley rats were divided into 5 groups consisting of 15 rats each; Control (C), Diabetes (D), Ovariectomy and diabetes (OVX + D), Ovariectomy, diabetes and donepezil (OVX + D + Don), Ovariectomy, diabetes and Myrtus communis subsp. communis (OVX + D + MC). Blood glucose measurements were made at the beginning and end of the experiments. The animals underwent the novel object recognition test (NORT) and their performance was evaluated. In hippocampal tissues; amyloid beta (Aß) and neprilysin levels, acetylcholinesterase (AChE), and choline acetyltransferase (ChAT) activities, polysialylated neural cell adhesion molecule (PSA-NCAM), α7 subunit of neuronal nicotinic acetylcholine receptor (α7-nAChR) and brain derived neurotrophic factor (BDNF) gene expressions were examined. RESULTS: Animals with ovariectomy and diabetes showed increased levels of blood glucose, AChE activity and Aß levels, and decreased neprilysin levels, ChAT activity, α7-nAChR, PSA-NCAM and BDNF gene expressions in parallel with a decrease in NORT performance score. On the other hand, in the MC-treated OVX + D group, there was a significant decrease observed in blood glucose levels and AChE activities while there was improvement in NORT performances and an increase in hippocampal ChAT activity, neprilysin levels, α7-nAChR, PSA-NCAM and BDNF expressions. CONCLUSION: These results suggest that MC extract could improve cognitive and neuronal functions with its anticholinesterase and antihyperglycemic properties.


Assuntos
Cognição/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Myrtus , Fitoterapia , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Glicemia/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Colina O-Acetiltransferase/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/psicologia , Feminino , Hipocampo/metabolismo , Neprilisina/metabolismo , Molécula L1 de Adesão de Célula Nervosa/genética , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Ovariectomia , Extratos Vegetais/uso terapêutico , Ratos Sprague-Dawley , Ácidos Siálicos/genética , Ácidos Siálicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/genética , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
14.
BMC Med Genet ; 21(1): 53, 2020 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-32171272

RESUMO

BACKGROUND: Adolescence is a distinctive stage of various changes and is noted as peak age for onset of many psychiatric disorders, especially linked to stress and depression. Several genetic variations are being increasingly known to be linked with stress and depression. The polymorphisms in two such genes, the BDNF and SLC1A3, have been reported to be linked with either depression/stress or with suicidal behaviour. These genes have not been validated in Indian population, and therefore there is a need to investigate these genes in Indian population. The present study was undertaken to test whether the known polymorphisms SLC1A3 C3590T, SLC1A3 C869G and BDNF G196A are associated or not with stress or depression in an eastern Indian population. METHODS: A case-control association study was performed with 108 cases having variable levels of stress and depression and 205 matched controls. Detection of stress and depression was done by using standard instruments as PSS and CES-D, respectively and demographic profile was obtained for each individual on the basis of personal data sheet. Genotyping for the selected polymorphisms was performed by PCR followed by restriction digestion. RESULTS: The SNP SLC1A3 C3590T was found to be associated with stress and depression (p = 0.0042, OR = 2.072). Therefore, the T allele increases the risk by more than two folds for stress and depression in the present population. The other allele of SLC1A3, G869C, as well as BDNF G196A were not associated with stress or depression in the population studied. CONCLUSION: SLC1A3 C3590T is a predisposition factor for stress and depression in an eastern Indian population, whereas SLC1A3 G869C and BDNF G196A were not found to be a risk factor. Therefore, presence of T allele of SLC1A3 C3590T, may predict the development of stress and depression in an individual. This may also help in the understanding of pathophysiology of the disease. However, these findings warrant a wider study in Indian populations and would be of significance in understanding the predisposition of stress and depression in this population.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Depressão/genética , Transportador 1 de Aminoácido Excitatório/genética , Polimorfismo de Nucleotídeo Único , Estresse Psicológico/genética , Adolescente , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Estudos de Casos e Controles , Depressão/epidemiologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Índia/epidemiologia , Masculino , Psicologia do Adolescente , Fatores de Risco , Estresse Psicológico/epidemiologia , Adulto Jovem
15.
Mol Biol Rep ; 47(3): 2023-2034, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32030599

RESUMO

The purpose of the current study was to examine the neuroprotective effect of rutin against colistin-induced neurotoxicity in rats. Thirty-five male Sprague Dawley rats were randomly divided into 5 groups. The control group (orally received physiological saline), the rutin group (orally administered 100 mg/kg body weight), the colistin group (i.p. administered 15 mg/kg body weight), the Col + Rut 50 group (i.p. administered 15 mg/kg body weight of colistin, and orally received 50 mg/kg body weight of rutin), the Col + Rut 100 group (i.p. administered 15 mg/kg body weight of colistin, and orally received 100 mg/kg body weight of rutin). Administration of colistin increased levels of glial fibrillary acidic protein and brain-derived neurotrophic factor and acetylcholinesterase and butyrylcholinesterase activities while decreasing level of cyclic AMP response element binding protein and extracellular signal regulated kinases 1 and 2 (ERK1/2) expressions. Colistin increased oxidative impairments as evidenced by a decrease in level of nuclear factor erythroid 2-related factor 2 (Nrf-2), glutathione, superoxide dismutase, glutathione peroxidase and catalase activities, and increased malondialdehyde content. Colistin also increased the levels of the apoptotic and inflammatoric parameters such as cysteine aspartate specific protease-3 (caspase-3), p53, B-cell lymphoma-2 (Bcl-2), nuclear factor kappa B (NF-κB), Bcl-2 associated X protein (Bax), tumor necrosis factor-α (TNF-α) and neuronal nitric oxide synthase (nNOS). Rutin treatment restored the brain function by attenuating colistin-induced oxidative stress, apoptosis, inflammation, histopathological and immunohistochemical alteration suggesting that rutin supplementation mitigated colistin-induced neurotoxicity in male rats.


Assuntos
Apoptose/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Colistina/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Inflamação/etiologia , Inflamação/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Rutina/farmacologia , Animais , Biomarcadores , Encéfalo/metabolismo , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Colistina/efeitos adversos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Imuno-Histoquímica , Inflamação/patologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Ratos
16.
J Abnorm Psychol ; 129(3): 237-247, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32077707

RESUMO

The valine66methionine (Val66Met) polymorphism (rs6265) of the brain-derived neurotrophic factor (BDNF) gene has been shown to influence autonomic arousal pathways, which in turn predict elevated syndromal anxiety in healthy humans. We examined whether the BDNF variant is associated with an increased risk of generalized anxiety disorder (GAD), one of the most prevalent anxiety disorders, through altering parasympathetic stress/relaxation reactivity. A total of 2,250 Han Chinese adults (750 GAD patients and 1,500 healthy controls) were included in the genotyping. High-frequency heart rate variability, an index of vagal (parasympathetic) activity, was measured during the supine-standing-supine test (5 min in each position); vagal withdrawal and vagal activation were calculated as baseline supine minus standing and recovery supine minus standing, respectively. Analysis of healthy participants indicated that Val/Val homozygotes displayed significantly blunted vagal withdrawal and vagal activation compared with Met allele carriers. After analyzing the entire sample, these effects remained significant. Furthermore, both attenuated vagal response patterns were found to be significantly associated with a higher incidence of GAD. Lastly, the path analysis identified a significant indirect effect of BDNF on the risk of GAD via diminishing vagal response to either orthostatic stress or supine relaxation. Even when further testing the subsample comprising only comorbidity- and medication-free GAD patients and healthy controls to minimize the confounding bias, the results still remained. Our findings demonstrate that individuals carrying the BDNF Val/Val genotype, compared to Met-carriers, may be at higher risk of GAD due to blunted vagal reactivity in response to both stress and relaxation. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Assuntos
Transtornos de Ansiedade/genética , Ansiedade/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Genótipo , Sistema Nervoso Parassimpático/fisiopatologia , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Ansiedade/fisiopatologia , Transtornos de Ansiedade/fisiopatologia , Nível de Alerta/fisiologia , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Nervo Vago/fisiopatologia
17.
BMC Res Notes ; 13(1): 61, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32033618

RESUMO

OBJECTIVE: Genetic factors underlying different personality traits are not entirely understood, particularly how genes interact to modulate their effect. We studied 76 patients diagnosed with borderline personality disorder (BPD), characterized by extreme levels of personality traits, especially neuroticism (N), in which we genotyped two polymorphisms, the 5HTTLPR of the Serotonin transporter (SERT) gene, and the Val66Met of the Brain-derived neurotrophic factor (BDNF) gene. RESULTS: We found an association with SERT, where S-allele carriers had significantly higher levels of N than L-homozygous. Furthermore, we found that the protective effect of L-homozygosity is only evident on A-allele carriers of the BDNF Val66Met polymorphism. Genetic constitution in SERT and BDNF seems to be important in neuroticism, the most relevant personality trait on BPD.


Assuntos
Transtorno da Personalidade Borderline/genética , Transtorno da Personalidade Borderline/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/genética , Neuroticismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adulto , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
18.
Biochem Biophys Res Commun ; 524(4): 957-962, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32059848

RESUMO

Low levels of brain-derived neurotrophic factor (BDNF), a key regulator of synaptic plasticity, are associated with neurological diseases, including depression and Alzheimer's disease. Therefore, BDNF is a drug target for these diseases. Here we screened for inducers of neuronal Bdnf expression from a pharmacologically validated compound library using our recently developed screening assay based on luciferase activity in cultured cortical neurons. We identified 18 pharmacologically validated compounds, most of which were inferred to induce Bdnf expression by their validated pharmacological actions, such as Gs-coupled receptor activation or neuronal excitation. Unexpectedly, the screening assay identified the antipyretic drug, dipyrone, to increase Bdnf expression. Dipyrone induced endogenous Bdnf expression by Ca2+ influx evoked via L-type voltage-dependent Ca2+ channels and the N-methyl-d-aspartate receptor, indicating that dipyrone induced activity-regulated Bdnf expression in neurons. However, dipyrone-induced Bdnf expression is independent of validated pharmacological effects. Although our screening assay is difficult to reveal how active compounds induce Bdnf expression, this method is convenient to identify inducers of Bdnf expression in primary neurons. Our screening assay evaluated neuronal BDNF induction and can be used to screen for drug re-positioning, as well as novel candidate drugs, for neurological diseases that have low levels of BDNF in the brain.


Assuntos
Antipiréticos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Dipirona/farmacologia , Neurônios/efeitos dos fármacos , Animais , Células Cultivadas , Camundongos , Neurônios/metabolismo , RNA Mensageiro/genética , Regulação para Cima/efeitos dos fármacos
19.
J Sports Med Phys Fitness ; 60(1): 172-179, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32008312

RESUMO

BACKGROUND: Many studies have proven the beneficial effects of regular exercise on psychiatric conditions. This study was set to explore the therapeutic effects and the mechanisms of treadmill exercise on a time-dependent sensitization (TDS) model which is a classical animal model for mimicking posttraumatic stress disorder (PTSD). METHODS: Forty-seven rats were randomly assigned to one of four groups: CON (control), TDS (model), EX (treadmill), or SER (sertraline). TDS model was developed to evaluate the anti-PTSD-like effects of moderate treadmill exercise with 4-week running program. High-performance liquid chromatography technology was used to determine the levels of monoamine neurotransmitters in TDS rats. The expression of key proteins in BDNF/PI3K/Akt/CREB signaling pathway were assayed by the Western blot method. RESULTS: The TDS procedures induced behavioral deficiencies. These deficiencies were reversed by treadmill exercise. Subsequent monoamine assays revealed that the treadmill exercise significantly increased serotonin levels in the hippocampus and decreased dopamine levels in the prefrontal cortex. Data from Western blot experiment demonstrated that exercise could normalize the decreased BDNF/TrkB/pAkt/pCREB levels in the hippocampus. CONCLUSIONS: This study deduced that treadmill exercise ameliorated contextual fear conditioning and anxiety-like behavior in TDS model. According to the study, the mechanism involved in alleviating PTSD symptoms by treadmill exercise was due to increased 5-HT levels in the hippocampus and decreased DA levels in the prefrontal cortex. It also involved the upregulation of BDNF and the related PI3K/AKT/CREB signaling pathway.


Assuntos
Terapia por Exercício , Transtornos de Estresse Pós-Traumáticos/psicologia , Transtornos de Estresse Pós-Traumáticos/terapia , Animais , Ansiedade , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Medo , Hipocampo/metabolismo , Masculino , Neurotransmissores/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Condicionamento Físico Animal , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Transdução de Sinais , Transtornos de Estresse Pós-Traumáticos/metabolismo
20.
J Pharmacol Exp Ther ; 372(3): 248-255, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31888957

RESUMO

Timely nerve restoration is an important factor for the successful regeneration of tissues and organs. It is known that axon regeneration following nerve injury is a multifactorial process that depends on the local expression of neurotrophins, including brain-derived neurotrophic factor (BDNF). Along with the survival of neurons, the active reorganization of the extracellular matrix is an important step for the growth of axons to their targets. Urokinase serine protease is part of the plasminogen activator system, which provides the vectoriality of the process of fibrinolysis and matrix reorganization, facilitating the growth of nerves to their targets. Based on this and in view of the results of our previous studies, we suggest that a combined bicistronic plasmid encoding the complementary proteins BDNF and urokinase may be beneficial in nerve regeneration. The ability of this bicistronic plasmid to stimulate nerve restoration was confirmed by in vitro stimulation of Neuro2a neurite growth and in vivo nerve conductivity and histology studies. To our knowledge, this is the first article that demonstrates the effectiveness of a bicistronic plasmid containing the human genes BDNF and urokinase plasminogen activator in the regeneration of the injured peripheral nerve. The results obtained demonstrate that plasmid vectors encoding several complementary-active therapeutic proteins may serve as a basis for developing prospective treatments for a wide range of multicomponent neural system disorders, such as nerve trauma. SIGNIFICANCE STATEMENT: This study is the first to show the effectiveness of using a bicistronic plasmid encoding complementary-active human protein brain-derived neurotrophic factor and urokinase plasminogen activator in the regeneration of the crushed peripheral nerve in a murine model.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Regeneração Nervosa/genética , Doenças do Sistema Nervoso Periférico/genética , Ativador de Plasminogênio Tipo Uroquinase/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/administração & dosagem , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células HEK293 , Humanos , Injeções Intramusculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças do Sistema Nervoso Periférico/terapia , Plasmídeos , Transfecção , Ativador de Plasminogênio Tipo Uroquinase/administração & dosagem
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