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1.
Mol Cell ; 79(3): 521-534.e15, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32592681

RESUMO

Genome-wide mapping of chromatin interactions at high resolution remains experimentally and computationally challenging. Here we used a low-input "easy Hi-C" protocol to map the 3D genome architecture in human neurogenesis and brain tissues and also demonstrated that a rigorous Hi-C bias-correction pipeline (HiCorr) can significantly improve the sensitivity and robustness of Hi-C loop identification at sub-TAD level, especially the enhancer-promoter (E-P) interactions. We used HiCorr to compare the high-resolution maps of chromatin interactions from 10 tissue or cell types with a focus on neurogenesis and brain tissues. We found that dynamic chromatin loops are better hallmarks for cellular differentiation than compartment switching. HiCorr allowed direct observation of cell-type- and differentiation-specific E-P aggregates spanning large neighborhoods, suggesting a mechanism that stabilizes enhancer contacts during development. Interestingly, we concluded that Hi-C loop outperforms eQTL in explaining neurological GWAS results, revealing a unique value of high-resolution 3D genome maps in elucidating the disease etiology.


Assuntos
Cromatina/metabolismo , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Genoma Humano , Neurogênese/genética , Regiões Promotoras Genéticas , Adulto , Linhagem Celular , Cérebro/citologia , Cérebro/crescimento & desenvolvimento , Cérebro/metabolismo , Cromatina/ultraestrutura , Mapeamento Cromossômico , Feto , Histonas/genética , Histonas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteínas do Tecido Nervoso/classificação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurônios/citologia , Neurônios/metabolismo , Lobo Temporal/citologia , Lobo Temporal/crescimento & desenvolvimento , Lobo Temporal/metabolismo , Fatores de Transcrição/classificação , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
2.
Neurocirugía (Soc. Luso-Esp. Neurocir.) ; 31(1): 24-36, ene.-feb. 2020. graf
Artigo em Espanhol | IBECS | ID: ibc-190369

RESUMO

La monitorización continua de la oxigenación cerebral y su aplicación al manejo del paciente neurológico grave es uno de los grandes retos actuales de la medicina crítica. Aunque han sido descritas diversas técnicas para la monitorización de la oxigenación cerebral, la monitorización tisular cerebral de oxígeno proporciona una relevante información sobre los niveles de oxígeno a nivel del tejido cerebral. Su desarrollo se ha asociado a la necesidad de responder no solamente aspectos técnicos sobre la misma, sino también al significado de la alteración de los valores de la oxigenación cerebral en el paciente neurocrítico. El documento de consenso da respuesta a diversas cuestiones relativas a la monitorización de la oxigenación cerebral mediante sensor de presión tisular cerebral de oxígeno. Para ello se elaboró un panel de preguntas y se realizó una revisión de la literatura médica, y evaluando la calidad de la evidencia y el nivel de recomendación mediante la metodología GRADE


Continuous monitoring of cerebral oxygenation and its application to the management of the severe neurological patient is a challenge for the management of patients with acute critical brain damage. Although several techniques have been described for monitoring brain, brain tissue oxygen monitoring provides relevant information about oxygen levels of brain tissue. However, the development of this technique has been associated with the need to answer not only some technical aspects of it as well as the meaning of the changes of the cerebral oxygenation in the neurocritical patient. The consensus document responds to various questions related to the monitoring of cerebral oxygenation by means of a cerebral oxygen tissue pressure sensor. For this purpose, a list of questions was prepared and a reviewed of the medical literature was made. The quality of the evidence and the degree of recommendation was evaluated using the GRADE methodology


Assuntos
Humanos , Conferências de Consenso como Assunto , Pressão Intracraniana/fisiologia , Lesões Encefálicas/metabolismo , Cuidados Críticos , Oximetria/métodos , Monitorização Fisiológica/normas , Consumo de Oxigênio/fisiologia , Lesões Encefálicas/complicações , Circulação Cerebrovascular , Cérebro/metabolismo
3.
Adv Exp Med Biol ; 1232: 299-306, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893424

RESUMO

Hypoxic ischemic encephalopathy (HIE) is a significant cause of death and neurological disability in newborns. Therapeutic hypothermia at 33.5 °C is one of the most common treatments in HIE and generally improves outcome; however 45-55% of injuries still result in death or severe neurodevelopmental disability. We have developed a systems biology model of cerebral oxygen transport and metabolism to model the impact of hypothermia on the piglet brain (the neonatal preclinical animal model) tissue physiology. This computational model is an extension of the BrainSignals model of the adult brain. The model predicts that during hypothermia there is a 5.1% decrease in cerebral metabolism, 1.1% decrease in blood flow and 2.3% increase in cerebral tissue oxygenation saturation. The model can be used to simulate effects of hypothermia on the brain and to help interpret bedside recordings.


Assuntos
Circulação Cerebrovascular , Cérebro , Hipotermia , Modelos Biológicos , Animais , Animais Recém-Nascidos , Circulação Cerebrovascular/fisiologia , Cérebro/metabolismo , Simulação por Computador , Humanos , Hipotermia Induzida , Hipóxia-Isquemia Encefálica , Suínos
4.
Adv Exp Med Biol ; 1232: 209-214, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893412

RESUMO

Cognitive function is reported to improve by moderate aerobic exercise. However, the effects of intermittent exercise with rest between the moderate-intensity exercise are unclear. Therefore, this study aimed to compare the effects of continuous and intermittent exercise on cerebral oxygenation and cognitive function. This study included 18 healthy adults. For the continuous exercise protocol, 5 min of rest was followed by 30 min of exercise; 5 min of rest was allowed after each exercise. For the intermittent exercise protocol, 3 sets of 10 min of exercise were completed, with 5 min of rest between the sets. Exercise intensity was 50% of maximum oxygen uptake. Oxyhemoglobin (O2Hb) in the prefrontal cortex (PFC) was measured during each protocol, and cognitive tasks (Stroop test) were performed before and after exercise. O2Hb levels for the left and right PFCs were significantly higher post-exercise than pre-exercise for both exercise protocols (p < 0.01). The average reaction time in the Stroop test was significantly shorter post-exercise than pre-exercise for both protocols (p < 0.01). There was no significant difference in the error rate pre- and post-exercise for both protocols (continuous p = 0.22; intermittent p = 0.44). There was no significant difference between both protocols in all measurement results (O2Hb: p = 0.67; average reaction time p = 0.50; error rate p = 0.24). O2Hb was higher and average reaction time was shorter after exercise than before exercise for both exercise protocols. Intermittent and continuous exercise may improve cognitive function to the same degree after exercise.


Assuntos
Cérebro , Cognição , Exercício Físico , Oxigênio , Espectroscopia de Luz Próxima ao Infravermelho , Adulto , Cérebro/metabolismo , Cognição/fisiologia , Humanos , Oxigênio/metabolismo , Consumo de Oxigênio
5.
J Shoulder Elbow Surg ; 29(1): 79-85, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31405715

RESUMO

BACKGROUND: The beach chair position is commonly used when performing shoulder arthroplasty. However, this position has been associated with hypotension, potentially leading to cerebral hypoperfusion, which may cause neurologic injury. In addition, shoulder arthroplasty cases are associated with longer operative times, posing a potentially greater risk of cerebral hypoperfusion. We aim to evaluate the risk of cerebral desaturation events (CDEs) during the course of total shoulder arthroplasty. METHODS: Twenty-six patients undergoing shoulder arthroplasties were monitored for changes in cerebral perfusion. Seven specific time-points during the procedure were labeled for comparison of events: baseline, beach chair, incision, humeral broaching, glenoid reaming, glenoid component implantation, and humeral component implantation. Cerebral oxygen perfusion was measured using near-infrared spectroscopy. A CDE was described as a decrease of oxygen saturation greater than 20%. RESULTS: Nineteeen of 25 subjects experienced a CDE. 42% of these patients experienced CDEs during semi-beach chair positioning. Patients experienced the largest oxygen saturation drop during semi-beach chair positioning. Transition from baseline to semi-beach chair was the only event to have a statistically significant decrease in cerebral perfusion (8%, P < .05). There was a statistically significant percentage change in mean oxygen saturation in the semi-beach chair interval (10%, P < .01) and the semi-beach chair to incision interval (7%, P < .01). CONCLUSIONS: Most patients experienced an intraoperative CDE, with greatest incidence during semi-beach chair positioning. The largest decline in cerebral oxygen saturation occurred during semi-beach chair positioning. Implant implantation was not associated with decrease in cerebral oximetry.


Assuntos
Artroplastia do Ombro , Cérebro/metabolismo , Oxigênio/metabolismo , Posicionamento do Paciente , Idoso , Circulação Cerebrovascular , Feminino , Humanos , Hipotensão/etiologia , Hipotensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Oximetria , Posicionamento do Paciente/efeitos adversos , Estudos Prospectivos , Espectroscopia de Luz Próxima ao Infravermelho
6.
Int J Mol Sci ; 20(23)2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31779068

RESUMO

Data-independent acquisition (DIA)-mass spectrometry (MS)-based proteomic analysis overtop the existing data-dependent acquisition (DDA)-MS-based proteomic analysis to enable deep proteome coverage and precise relative quantitative analysis in single-shot liquid chromatography (LC)-MS/MS. However, DIA-MS-based proteomic analysis has not yet been optimized in terms of system robustness and throughput, particularly for its practical applications. We established a single-shot LC-MS/MS system with an MS measurement time of 90 min for a highly sensitive and deep proteomic analysis by optimizing the conditions of DIA and nanoLC. We identified 7020 and 4068 proteins from 200 ng and 10 ng, respectively, of tryptic floating human embryonic kidney cells 293 (HEK293F) cell digest by performing the constructed LC-MS method with a protein sequence database search. The numbers of identified proteins from 200 ng and 10 ng of tryptic HEK293F increased to 8509 and 5706, respectively, by searching the chromatogram library created by gas-phase fractionated DIA. Moreover, DIA protein quantification was highly reproducible, with median coefficients of variation of 4.3% in eight replicate analyses. We could demonstrate the power of this system by applying the proteomic analysis to detect subtle changes in protein profiles between cerebrums in germ-free and specific pathogen-free mice, which successfully showed that >40 proteins were differentially produced between the cerebrums in the presence or absence of bacteria.


Assuntos
Cérebro/metabolismo , Vida Livre de Germes , Proteômica/métodos , Organismos Livres de Patógenos Específicos , Animais , Cromatografia Líquida , Bases de Dados de Proteínas , Regulação da Expressão Gênica , Células HEK293 , Humanos , Camundongos , Nanotecnologia , Software , Espectrometria de Massas em Tandem
7.
Artigo em Inglês | MEDLINE | ID: mdl-31422159

RESUMO

Previous studies showed that mild iron deficiency anaemia (IDA) induced by feeding an iron deficient (ID) diet to female guinea pigs during gestation and lactation to alters the auditory functions of the offspring when corn oil is the only source of dietary lipids. Conversely, feeding an ID diet with a dietary fatty acid composition similar to that of typical human western diets induced minor impairments. Since tissue fatty acid metabolism is affected by dietary iron, the current study measured the impacts of these ID diets (ID-corn and ID-west) compared to the corresponding iron-sufficient control diets (IS-corn and IS-west) on encephalum fatty acid metabolism in the offspring at post-natal day 24. IDA induced by the ID-corn diet resulted in significant increases in encephalum n-6 PUFA content, but IDA induced by the ID-west diet had little impact on fatty acid profiles compared to the IS-west group. Brain COX II protein expression and FADS2 mRNA expression were statistically unaffected in both experiments, but encephalum PGE2 concentrations were significantly reduced in ID-west pups. These results suggest IDA studies during prenatal development should consider dietary lipid compositions.


Assuntos
Cérebro/metabolismo , Gorduras na Dieta , Eicosanoides/metabolismo , Ferro na Dieta , Ferro/deficiência , Lactação/sangue , Anemia Ferropriva/metabolismo , Animais , Animais Recém-Nascidos , Dieta , Feminino , Cobaias , Ferro/sangue , Masculino , Fenômenos Fisiológicos da Nutrição , Gravidez , Efeitos Tardios da Exposição Pré-Natal
8.
Environ Toxicol Pharmacol ; 71: 103216, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31260942

RESUMO

Methylmercury is an environmental pollutant that shows selective toxicity to the central nervous system. We previously reported that brain-specific expression of chemokine CCL3 increases in mice administered methylmercury. However, the relationship between CCL3 and methylmercury toxicity has not been elucidated. Here, we confirmed that induction of CCL3 expression occurs before pathological change by methylmercury treatment was observed in the mouse brain. This induction was also observed in C17.2 mouse neural stem cells before methylmercury-induced cytotoxicity. In addition, cells in which CCL3 was knocked-down showed higher methylmercury sensitivity than did control cells. Moreover, activation of transcription factor NF-κB was observed following methylmercury treatment, and methylmercury-mediated induction of CCL3 expression was partially suppressed by knockdown of p65, an NF-κB subunit. Our results suggest that NF-κB plays a role in the induction of methylmercury-mediated CCL3 expression and that this action may be a cellular response to methylmercury toxicity.


Assuntos
Quimiocina CCL3/biossíntese , Poluentes Ambientais/toxicidade , Compostos de Metilmercúrio/toxicidade , NF-kappa B/biossíntese , Células-Tronco Neurais/efeitos dos fármacos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cerebelo/patologia , Cérebro/efeitos dos fármacos , Cérebro/metabolismo , Cérebro/patologia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia
9.
Nat Commun ; 10(1): 2780, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31239441

RESUMO

In the developing central nervous system, cell departure from the apical surface is the initial and fundamental step to form the 3D, organized architecture. Both delamination of differentiating cells and repositioning of progenitors to generate outer radial glial cells (oRGs) contribute to mammalian neocortical expansion; however, a comprehensive understanding of their mechanisms is lacking. Here, we demonstrate that Lzts1, a molecule associated with microtubule components, promotes both cell departure events. In neuronally committed cells, Lzts1 functions in apical delamination by altering apical junctional organization. In apical RGs (aRGs), Lzts1 expression is variable, depending on Hes1 expression levels. According to its differential levels, Lzts1 induces diverse RG behaviors: planar division, oblique divisions of aRGs that generate oRGs, and their mitotic somal translocation. Loss-of-function of lzts1 impairs all these cell departure processes. Thus, Lzts1 functions as a master modulator of cellular dynamics, contributing to increasing complexity of the cerebral architecture during evolution.


Assuntos
Cérebro/crescimento & desenvolvimento , Cérebro/metabolismo , Células Ependimogliais/metabolismo , Neurogênese , Neurônios/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Movimento Celular , Cérebro/citologia , Células Ependimogliais/citologia , Camundongos , Camundongos Transgênicos , Neurônios/citologia , Fatores de Transcrição HES-1/genética , Fatores de Transcrição HES-1/metabolismo , Proteínas Supressoras de Tumor/genética
10.
Hum Brain Mapp ; 40(13): 3940-3950, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31179620

RESUMO

Major depressive disorder (MDD) is highly prevalent and associated with considerable morbidity, yet its pathophysiology remains only partially understood. While numerous studies have investigated the neurobiological correlates of MDD, most have used only a single neuroimaging modality. In particular, diffusion tensor imaging (DTI) studies have failed to yield uniform results. In this context, examining key tracts and using information from multiple neuroimaging modalities may better characterize potential abnormalities in the MDD brain. This study analyzed data from 30 participants with MDD and 26 healthy participants who underwent DTI, magnetic resonance spectroscopy (MRS), resting-state functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG). Tracts connecting the subgenual anterior cingulate cortex (sgACC) and the left and right amygdala, as well as connections to the left and right hippocampus and thalamus, were examined as target areas. Reduced fractional anisotropy (FA) was observed in the studied tracts. Significant differences in the correlation between medial prefrontal glutamate concentrations and FA were also observed between MDD and healthy participants along tracts connecting the sgACC and right amygdala; healthy participants exhibited a strong correlation but MDD participants showed no such relationship. In the same tract, a correlation was observed between FA and subsequent antidepressant response to ketamine infusion in MDD participants. Exploratory models also suggested group differences in the relationship between DTI, fMRI, and MEG measures. This study is the first to combine MRS, DTI, fMRI, and MEG data to obtain multimodal indices of MDD and antidepressant response and may lay the foundation for similar future analyses.


Assuntos
Cérebro , Transtorno Depressivo Maior , Imagem Multimodal , Neuroimagem , Adulto , Cérebro/diagnóstico por imagem , Cérebro/metabolismo , Cérebro/patologia , Cérebro/fisiopatologia , Conectoma , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/patologia , Transtorno Depressivo Maior/fisiopatologia , Imagem de Tensor de Difusão , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Magnetoencefalografia , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
Neuroimage ; 199: 336-341, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31176832

RESUMO

The relationship between the topological characteristics of the white matter (WM) network have been shown to be related to neural development, intelligence, and various diseases; however, few studies have been conducted to explore the relationship between topological characteristics of the WM network and cerebral metabolism. In a recent study we investigated the relationship between WM network topological and metabolic metrics of the cerebral parenchyma in healthy volunteers using the newly developed T2-relaxation-under-spin-tagging (TRUST) magnetic resonance imaging technique and graph theory approaches. Ninety-six healthy adults (25.5 ±â€¯1.8 years of age) were recruited as volunteers in the current study. The cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction, and the global topological metrics of the WM network (global efficiency [Eglob], local efficiency, and small-worldliness) were assessed. A stepwise multiple linear regression model was estimated. CMRO2 was entered as the dependent variable. The topological and demographic parameters (age, gender, FIQ, SBP, gray matter volume, and WM volume) were entered as independent variables in the model. The final performing models were comprised of predictors of Eglob, FIQ, and age (adjusted R2 values were 0.489 [L-AAL] and 0.424 [H-1024]). Our study initially revealed a relationship between Eglob and cerebral oxygen metabolism in healthy young adults.


Assuntos
Cérebro , Imagem por Ressonância Magnética/métodos , Rede Nervosa , Substância Branca , Adulto , Cérebro/anatomia & histologia , Cérebro/diagnóstico por imagem , Cérebro/metabolismo , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Masculino , Rede Nervosa/anatomia & histologia , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/metabolismo , Consumo de Oxigênio/fisiologia , Substância Branca/anatomia & histologia , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo , Adulto Jovem
12.
Neonatology ; 116(2): 132-139, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31096224

RESUMO

BACKGROUND: Cerebral regional oxygen saturation (crSO2) during immediate transition and resuscitation immediately after birth is of increasing interest. OBJECTIVES: The aim of the present study was to assess whether the type of maternal anesthesia during cesarean section (CS; general anesthesia vs. spinal anesthesia) has an influence on cerebral oxygenation during immediate neonatal transition after birth. METHODS: Secondary outcome parameters of prospective observational studies were analyzed. Neonates born by CS from November 2009 to September 2016 at the Medical University of Graz (Austria) were eligible. Term and preterm neonates were included, provided that: (1) crSO2 was measured by near-infrared spectroscopy, and (2) peripheral arterial oxygen saturation (SpO2) and heart rate (HR) were measured by pulse oximetry during the first 15 min after birth. Administration of supplemental oxygen was recorded and cerebral fractional tissue oxygen extraction (cFTOE) was calculated out of crSO2 and SpO2. For comparison, term and preterm neonates with maternal general anesthesia were matched to neonates with maternal spinal anesthesia during CS. RESULTS: Out of 760 eligible neonates, 64 term (38.8 ± 0.9 weeks of gestation; 32 neonates in each group) and 54 preterm neonates (32.0 ± 2.9 weeks of gestation; 27 neonates in each group) were included. In term neonates, maternal general anesthesia was associated with lower initial SpO2, HR values, and Apgar scores. The fraction of inspired oxygen (FiO2) was statistically significantly higher in the general anesthesia group. Nevertheless, crSO2 and cFTOE did not differ statistically significantly between the groups. In preterm neonates there were no statistically significant differences in SpO2, HR, crSO2, and cFTOE between the general and spinal anesthesia groups. Apgar scores at 1 min were statistically significantly lower and FiO2 was statistically significantly higher in the general anesthesia group. CONCLUSION: Cerebral tissue oxygenation in neonates during immediate transition after birth was similar after maternal general and spinal anesthesia during CS, despite differences in SpO2, HR, and supplemental oxygen in term neonates and differences in supplemental oxygen in preterm neonates.


Assuntos
Anestesia Obstétrica/métodos , Cérebro/metabolismo , Cesárea , Consumo de Oxigênio , Anestesia Geral , Raquianestesia , Áustria , Feminino , Idade Gestacional , Frequência Cardíaca , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Oximetria , Oxigênio , Oxigenoterapia , Gravidez , Espectroscopia de Luz Próxima ao Infravermelho
13.
Am J Pathol ; 189(7): 1435-1450, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30980800

RESUMO

Pathologic inflammation in response to injury, infection, or oxidative stress is a proposed mechanism relating cognitive decline to dementia. The kynurenine pathway and thioredoxin-interacting protein (TXNIP) activity regulate inflammation and neurotoxicity in Alzheimer disease (AD). We examined cognitive deficits, kynurenine pathway mediators, TXNIP, and oxidative damage in the cerebrum and spleen, including inflammatory cytokine production by stimulated splenocytes, from female triple transgenic (3xTg-AD) mice in early and late stages of disease progression, and characterized tissue-specific epigenetic regulation of Txnip gene expression. We show that cognitive deficits in 7-month-old 3xTg-AD mice are associated with a stable increase in cerebrum and spleen tryptophan metabolites, with a concomitant increase in amyloid ß 40 (Aß40)/Aß42 and tau/hyperphosphorylated tau pathologies and a coordinated reduction in spleen proinflammatory cytokine production in 17-month-old mice. The enhanced cerebrum TXNIP expression is associated with increased histone acetylation, transcription factor [Aß42 or CCCTC-binding factor (CTCF)] binding, and Txnip promoter hypomethylation, whereas the attenuated spleen TXNIP expression is associated with increased histone methylation, reduced CTCF binding, and Txnip promoter hypermethylation. These results suggest a causal relationship among epigenomic state, TXNIP expression, cerebral-spleen tryptophan metabolism, inflammatory cytokine production, and cognitive decline; and they provide a potential mechanism for Txnip gene regulation in normal and pathologic conditions, suggesting TXNIP levels may be a useful predictive or diagnostic biomarker for Aß40/Aß42 targeted AD therapies.


Assuntos
Doença de Alzheimer , Cérebro , Disfunção Cognitiva , Estresse Oxidativo , Baço , Triptofano , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Cérebro/metabolismo , Cérebro/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Baço/metabolismo , Baço/patologia , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Triptofano/genética , Triptofano/metabolismo
14.
Mol Neurobiol ; 56(10): 6770-6776, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30919215

RESUMO

In a previous study (Mol Neurobiol 55:7476-7486, 2017), newly synthesized brain metabolic DNA (BMD) from rat subcellular fractions has been shown to behave as a DNA-RNA hybrid when analyzed in cesium gradients at early [3H] thymidine incorporation times but to assume the double-stranded configuration at later times. Conversely, BMD from purified nuclei displayed the dsDNA configuration even at early incorporation times. The results were interpreted to support the BMD origin by reverse transcription in the cytoplasm and its later acquisition of the double-stranded configuration before the partial transfer to the nuclei. This interpretation has now been confirmed by immunofluorescence analyses of newly synthesized BrdU-labeled BMD from the mouse brain that demonstrates its cytoplasmic localization and colocalization with DNA-RNA hybrids. In addition, BrdU-labeled BMD has been shown to colocalize with astroglial anti-GFAP antibodies and with presynaptic anti-synaptophysin antibodies.


Assuntos
Encéfalo/metabolismo , Citoplasma/metabolismo , DNA/metabolismo , Transcrição Genética , Animais , Anticorpos/metabolismo , Bromodesoxiuridina/metabolismo , Núcleo Celular/metabolismo , Cérebro/metabolismo , Imunofluorescência , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Mitocôndrias/metabolismo , Ratos Wistar , Sinaptofisina/metabolismo
15.
Proc Natl Acad Sci U S A ; 116(14): 7089-7094, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30894491

RESUMO

The primate cerebrum is characterized by a large expansion of cortical surface area, the formation of convolutions, and extraordinarily voluminous subcortical white matter. It was recently proposed that this expansion is primarily driven by increased production of superficial neurons in the dramatically enlarged outer subventricular zone (oSVZ). Here, we examined the development of the parietal cerebrum in macaque monkey and found that, indeed, the oSVZ initially adds neurons to the superficial layers II and III, increasing their thickness. However, as the oSVZ grows in size, its output changes to production of astrocytes and oligodendrocytes, which in primates outnumber cerebral neurons by a factor of three. After the completion of neurogenesis around embryonic day (E) 90, when the cerebrum is still lissencephalic, the oSVZ enlarges and contains Pax6+/Hopx+ outer (basal) radial glial cells producing astrocytes and oligodendrocytes until after E125. Our data indicate that oSVZ gliogenesis, rather than neurogenesis, correlates with rapid enlargement of the cerebrum and development of convolutions, which occur concomitantly with the formation of cortical connections via the underlying white matter, in addition to neuronal growth, elaboration of dendrites, and amplification of neuropil in the cortex, which are primary factors in the formation of cerebral convolutions in primates.


Assuntos
Cérebro/crescimento & desenvolvimento , Cérebro/metabolismo , Ventrículos Laterais/crescimento & desenvolvimento , Ventrículos Laterais/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Animais , Astrócitos/metabolismo , Cérebro/citologia , Cérebro/embriologia , Embrião de Mamíferos , Proteínas de Homeodomínio/metabolismo , Ventrículos Laterais/citologia , Ventrículos Laterais/embriologia , Macaca , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Fator de Transcrição PAX6/metabolismo , Primatas , Proteínas Supressoras de Tumor/metabolismo
16.
Neurochem Int ; 125: 7-15, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30716357

RESUMO

Altered endocannabinoid (eCB) signalling is suggested as an important contributor to the pathophysiology of depression. To further elucidate this, we conducted a study using a genetic rat model of depression, the Flinders Sensitive Line (FSL), and their controls, the Flinders Resistant Line (FRL) rats. Plasma, right and left prefrontal cortex, and hippocampus were isolated from FSL and FRL rats. We analyzed each region for the eCB anandamide (AEA) and 2-arachidonoylglycerol (2-AG) levels by liquid chromatography/multiple reaction monitoring (LC/MRM), mRNA and protein levels of the cannabinoid type 1 receptor (CB1R), fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) by real time qPCR and Western blotting. Content of 2-AG was lower in the left side of the hippocampus and prefrontal cortex in FSL rats compared to FRL rats. Inversely, levels of AEA were higher in right hippocampus than in left hippocampus. In plasma, AEA levels were increased and 2-AG decreased. Cannabinoid receptor 1 (Cnr1), Faah and Magl mRNA levels were prominently decreased in right prefrontal cortex of FSL rats as compared to FRL rats. Protein expression of CB1R and FAAH were decreased in left hippocampus. In summary, our data suggest a decreased eCB signalling in the FSL rats, which could contribute to the depressive-like behaviour. Interestingly, the altered eCB system activity appear to be hemisphere-specific in the limbic regions. Our study support the existing literature and showed altered eCB system activity in this particular animal model of depression.


Assuntos
Depressão/metabolismo , Endocanabinoides/metabolismo , Hipocampo/metabolismo , Córtex Pré-Frontal/metabolismo , Animais , Cérebro/metabolismo , Depressão/genética , Masculino , Ratos , Ratos Transgênicos , Especificidade da Espécie
18.
Crit Care ; 23(1): 45, 2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760295

RESUMO

BACKGROUND: Hyperventilation-induced hypocapnia (HV) reduces elevated intracranial pressure (ICP), a dangerous and potentially fatal complication of traumatic brain injury (TBI). HV decreases the arteriolar diameter of intracranial vessels, raising the risk of cerebral ischemia. The aim of this study was to characterize the effects of moderate short-term HV in patients with severe TBI by using concomitant monitoring of cerebral metabolism, brain tissue oxygen tension (PbrO2), and cerebral hemodynamics with transcranial color-coded duplex sonography (TCCD). METHODS: This prospective trial was conducted between May 2014 and May 2017 in the surgical intensive care unit (ICU) at the University Hospital of Zurich. Patients with nonpenetrating TBI older than 18 years of age with a Glasgow Coma Scale (GCS) score < 9 at presentation and with ICP monitoring, PbrO2, and/or microdialysis (MD) probes during ICU admission within 36 h after injury were included in our study. Data collection and TCCD measurements were performed at baseline (A), at the beginning of moderate HV (C), after 50 min of moderate HV (D), and after return to baseline (E). Moderate HV was defined as arterial partial pressure of carbon dioxide 4-4.7 kPa. Repeated measures analysis of variance was used to compare variables at the different time points, followed by post hoc analysis with Bonferroni adjustment as appropriate. RESULTS: Eleven patients (64% males, mean age 36 ± 14 years) with an initial median GCS score of 7 (IQR 3-8) were enrolled. During HV, ICP and mean flow velocity (CBFV) in the middle cerebral artery decreased significantly. Glucose, lactate, and pyruvate in the brain extracellular fluid did not change significantly, whereas PbrO2 showed a statistically significant reduction but remained within the normal range. CONCLUSION: Moderate short-term hyperventilation has a potent effect on the cerebral blood flow, as shown by TCCD, with a concomitant ICP reduction. Under the specific conditions of this study, this degree of hyperventilation did not induce pathological alterations of brain metabolites and oxygenation. TRIAL REGISTRATION: NCT03822026 . Registered on 30 January 2019.


Assuntos
Lesões Encefálicas Traumáticas/terapia , Cérebro/metabolismo , Hiperventilação/fisiopatologia , Adulto , Análise de Variância , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , Cérebro/fisiopatologia , Feminino , Escala de Coma de Glasgow/estatística & dados numéricos , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Humanos , Hiperventilação/complicações , Hipocapnia/etiologia , Hipocapnia/fisiopatologia , Pressão Intracraniana/efeitos dos fármacos , Pressão Intracraniana/fisiologia , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Oxigênio/uso terapêutico , Estudos Prospectivos , Ultrassonografia Doppler Transcraniana/métodos
19.
Med Sci Monit ; 25: 525-531, 2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30657131

RESUMO

BACKGROUND The incidence of postoperative cognitive dysfunction (POCD) after major joint arthroplasty is high. In the etiology of POCD, many factors have been cited, including thromboembolic complications. The incidence of cerebral embolization after lower extremity arthroplasty may be as high as 40-60%. The potential events of cerebral embolization could lead to a decrease in the regional cerebral oxygenation (rSO2) and increased serum levels of biochemical markers of brain damage. The objective of the study was to test whether there are any changes in the rSO2 values and serum markers of brain damage in patients who underwent total hip arthroplasty. MATERIAL AND METHODS Fifteen patients who underwent primary hip arthroplasty under spinal anesthesia were analyzed. The rSO2 was monitored using infrared spectroscopy. Biochemical analyses of S100 calcium-binding protein B (S100B) protein and fibrillary acidic protein (GFAP) serum concentrations were performed using immunoassay methods. RESULTS The values of rSO2 decreased during the surgery, but this was not related to mean arterial pressure variations or hemoglobin saturation. The concentration of S100B was increased compared to its preoperative values, and there were no changes in GFAP values. The changes in rSO2 readings correlated with the biomarkers' levels just after the surgery. CONCLUSIONS Our results suggest that S100B may be a more specific marker of astroglial damage in patients after primary total hip arthroplasty. The decrease in rSO2 readings may be due to micro-thromboembolic events that occurred during the surgery. However, the results of this study are preliminary, and further studies are needed to establish its clinical efficacy.


Assuntos
Artroplastia de Quadril/efeitos adversos , Cérebro/metabolismo , Oxigênio/metabolismo , Idoso , Idoso de 80 Anos ou mais , Artroplastia/efeitos adversos , Biomarcadores/sangue , Encéfalo/metabolismo , Lesões Encefálicas/sangue , Artérias Cerebrais/metabolismo , Cérebro/irrigação sanguínea , Feminino , Proteína Glial Fibrilar Ácida/análise , Proteína Glial Fibrilar Ácida/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Oximetria/métodos , Oxigênio/análise , Oxigênio/sangue , Período Perioperatório/métodos , Projetos Piloto , Subunidade beta da Proteína Ligante de Cálcio S100/análise , Subunidade beta da Proteína Ligante de Cálcio S100/sangue
20.
Bull Exp Biol Med ; 166(3): 317-320, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30627909

RESUMO

The in vitro and in vivo models of ethanol-induced neurodegeneration were used to evaluate the content and functional activity of various types of regeneration-competent cells in subventricular zone of the cerebral hemispheres in C57Bl/6JY mice. In nervous tissue culture, ethanol (65 mM) produced no effect on formation of neurospheres. When administered per os in a daily dose of 3 g/kg for 8 weeks, ethanol produced no effect on the number of neural CFU in situ. In both cases, ethanol reduced proliferative activity of neural CFU. Long-term administration of ethanol in vivo suppressed differentiation of neural stem cells and decreased the number of committed precursors (neural cluster-forming units) in the subventricular zone of cerebral hemispheres. In vitro application of ethanol stimulated secretion of humoral growth factors by the cluster-forming neural glial cells. In contrast, in vivo administration of ethanol suppressed this secretion.


Assuntos
Alcoolismo/patologia , Cérebro/efeitos dos fármacos , Etanol/farmacologia , Ventrículos Laterais/efeitos dos fármacos , Doenças Neurodegenerativas/patologia , Neurônios/efeitos dos fármacos , Alcoolismo/metabolismo , Animais , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cérebro/metabolismo , Cérebro/patologia , Cérebro/fisiopatologia , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intercelular/agonistas , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Ventrículos Laterais/metabolismo , Ventrículos Laterais/patologia , Ventrículos Laterais/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Doenças Neurodegenerativas/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/patologia , Cultura Primária de Células , Esferoides Celulares/efeitos dos fármacos
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