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1.
Nat Commun ; 11(1): 4727, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948752

RESUMO

The apolipoprotein E (APOE) gene contains both the major common risk variant for late onset Alzheimer's disease (AD), e4, and the major neuroprotective variant, e2. Here we examine the association of APOE e2 with multiple neurodegenerative pathologies, leveraging the NACC v. 10 database of 1557 brains that included 130 e2 carriers and 679 e4 carriers in order to examine potential neuroprotective effects. For AD-related pathologies of amyloid plaques and Braak stage, e2 had large and highly significant protective effects contrasted with e3/e3 and e4 carriers with odds ratios of about 0.50 for e3 contrasts and 0.10 for e4 contrasts. When we separately examined e2/e4 carriers, risk for AD pathologies was similar to that of e4 carriers, not e2 carriers. For multiple fronto-temporal lobar pathologies and tauopathies, e2 was not significantly associated with pathology. In sum, we found that e2 was associated with large but circumscribed protective effects.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteína E2/genética , Apolipoproteína E2/metabolismo , Genótipo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Encéfalo/metabolismo , Feminino , Degeneração Lobar Frontotemporal/metabolismo , Humanos , Modelos Logísticos , Masculino , Placa Amiloide/patologia , Tauopatias/metabolismo , alfa-Sinucleína/metabolismo
2.
Nat Commun ; 11(1): 4411, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879313

RESUMO

The glymphatic system is a network of perivascular spaces that promotes movement of cerebrospinal fluid (CSF) into the brain and clearance of metabolic waste. This fluid transport system is supported by the water channel aquaporin-4 (AQP4) localized to vascular endfeet of astrocytes. The glymphatic system is more effective during sleep, but whether sleep timing promotes glymphatic function remains unknown. We here show glymphatic influx and clearance exhibit endogenous, circadian rhythms peaking during the mid-rest phase of mice. Drainage of CSF from the cisterna magna to the lymph nodes exhibits daily variation opposite to glymphatic influx, suggesting distribution of CSF throughout the animal depends on time-of-day. The perivascular polarization of AQP4 is highest during the rest phase and loss of AQP4 eliminates the day-night difference in both glymphatic influx and drainage to the lymph nodes. We conclude that CSF distribution is under circadian control and that AQP4 supports this rhythm.


Assuntos
Aquaporina 4/metabolismo , Líquido Cefalorraquidiano/metabolismo , Ritmo Circadiano/fisiologia , Sistema Glinfático/metabolismo , Animais , Astrócitos/metabolismo , Encéfalo/metabolismo , Cisterna Magna/metabolismo , Linfonodos/metabolismo , Camundongos
3.
Pharm Res ; 37(10): 194, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32918191

RESUMO

PURPOSE: We characterized three canine P-gp (cP-gp) deficient MDCKII cell lines. Their relevance for identifying efflux transporter substrates and predicting limitation of brain penetration were evaluated. In addition, we discuss how compound selection can be done in drug discovery by using these cell systems. METHOD: hMDR1, hBCRP-transfected, and non-transfected MDCKII ZFN cells (all with knock-down of endogenous cP-gp) were used for measuring permeability and efflux ratios for substrates. The compounds were also tested in MDR1_Caco-2 and BCRP_Caco-2, each with a double knock-out of BCRP/MRP2 or MDR1/MRP2 transporters respectively. Efflux results were compared between the MDCK and Caco-2 models. Furthermore, in vitro MDR1_ZFN efflux data were correlated with in vivo unbound drug brain-to-plasma partition coefficient (Kp,uu). RESULTS: MDR1 and BCRP substrates are correctly classified and robust transporter affinities with control substrates are shown. Cell passage mildly influenced mRNA levels of transfected transporters, but the transporter activity was proven stable for several years. The MDCK and Caco-2 models were in high consensus classifying same efflux substrates. Approx. 80% of enlisted substances were correctly predicted with the MDR1_ZFN model for brain penetration. CONCLUSION: cP-gp deficient MDCKII ZFN models are reliable tools to identify MDR1 and BCRP substrates and useful for predicting efflux liability for brain penetration.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/deficiência , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Proteínas de Neoplasias/metabolismo , Farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Células CACO-2 , Permeabilidade da Membrana Celular , Dibenzocicloeptenos/farmacologia , Dicetopiperazinas/farmacologia , Cães , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Células Madin Darby de Rim Canino , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Prazosina/farmacocinética , Quinidina/farmacocinética , Quinolinas/farmacologia , Especificidade por Substrato , Transfecção
4.
J Environ Pathol Toxicol Oncol ; 39(3): 261-279, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865917

RESUMO

Among the neurodegenerative diseases, Alzheimer's disease (AD) is a predominant public health issue, affecting 16 million people around the world. It is clinically manifested by the presence of amyloid plaques (Aß) and neurofibrillary tangles (NFT) within the brain. Due to intraneuronal processing, Aß interacts with cellular targets such as mitochondria, ER, and Golgi apparatus and hampers their normal functions. Alteration in the mitochondrial function, closely related to the production of reactive oxygen species (ROS), Ca+2 overload, and apoptosis in the brain, is one of the key pathological events studied in AD pathogenesis. It is also an important pivot for the intracellular interaction with ER and Golgi through signal transduction and membrane contact to regulate cell survival and death mechanism. Alteration in mitochondrial function is intimately connected with abnormal ER or Golgi function. Stimuli that enhance perturbation in the normal ER or Golgi organelles function can involve mitochondria mediated apoptotic cell death. In this review, we address the importance of the mitochondria and their cross talk with ER and Golgi in AD pathogenesis and animal models with a therapeutic strategy to improve the mitochondrial functions.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Mitocôndrias/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Apoptose , Encéfalo/patologia , Retículo Endoplasmático/patologia , Complexo de Golgi/patologia , Humanos , Mitocôndrias/patologia , Transdução de Sinais
5.
Korean J Parasitol ; 58(4): 461-466, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32871641

RESUMO

Toxoplasma gondii is an obligate intracellular protozoan parasite that can invade various organs in the host body, including the central nervous system. Chronic intracranial T. gondii is known to be associated with neuroprotection against neurodegenerative diseases through interaction with host brain cells in various ways. The present study investigated the neuroprotective effects of chronic T. gondii infection in mice with cerebral ischemia experimentally produced by middle cerebral artery occlusion (MCAO) surgery. The neurobehavioral effects of cerebral ischemia were assessed by measurement of Garcia score and Rotarod behavior tests. The volume of brain ischemia was measured by triphenyltetrazolium chloride staining. The expression levels of related genes and proteins were determined. After cerebral ischemia, corrected infarction volume was significantly reduced in T. gondii infected mice, and their neurobehavioral function was significantly better than that of the uninfection control group. Chronic T. gondii infection induced the expression of hypoxia-inducible factor 1-alpha (HIF-1α) in the brain before MCAO. T. gondii infection also increased the expression of vascular endothelial growth factor after the cerebral ischemia. It is suggested that chronic intracerebral infection of T. gondii may be a potential preconditioning strategy to reduce neural deficits associated with cerebral ischemia and induce brain ischemic tolerance through the regulation of HIF-1α expression.


Assuntos
Isquemia Encefálica/prevenção & controle , Encéfalo/parasitologia , Interações Hospedeiro-Parasita , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neuroproteção , Toxoplasma/fisiologia , Toxoplasmose/fisiopatologia , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/parasitologia , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos Endogâmicos ICR , Tamanho do Órgão , Toxoplasmose/metabolismo , Toxoplasmose/patologia
6.
Proc Natl Acad Sci U S A ; 117(32): 19544-19555, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32747566

RESUMO

Corresponding attributes of neural development and function suggest arthropod and vertebrate brains may have an evolutionarily conserved organization. However, the underlying mechanisms have remained elusive. Here, we identify a gene regulatory and character identity network defining the deutocerebral-tritocerebral boundary (DTB) in Drosophila This network comprises genes homologous to those directing midbrain-hindbrain boundary (MHB) formation in vertebrates and their closest chordate relatives. Genetic tracing reveals that the embryonic DTB gives rise to adult midbrain circuits that in flies control auditory and vestibular information processing and motor coordination, as do MHB-derived circuits in vertebrates. DTB-specific gene expression and function are directed by cis-regulatory elements of developmental control genes that include homologs of mammalian Zinc finger of the cerebellum and Purkinje cell protein 4 Drosophila DTB-specific cis-regulatory elements correspond to regulatory sequences of human ENGRAILED-2, PAX-2, and DACHSHUND-1 that direct MHB-specific expression in the embryonic mouse brain. We show that cis-regulatory elements and the gene networks they regulate direct the formation and function of midbrain circuits for balance and motor coordination in insects and mammals. Regulatory mechanisms mediating the genetic specification of cephalic neural circuits in arthropods correspond to those in chordates, thereby implying their origin before the divergence of deuterostomes and ecdysozoans.


Assuntos
Evolução Molecular , Redes Reguladoras de Genes , Mesencéfalo/fisiologia , Animais , Comportamento Animal , Encéfalo/embriologia , Encéfalo/metabolismo , Encéfalo/fisiologia , Drosophila , Fator 8 de Crescimento de Fibroblasto/genética , Fator 8 de Crescimento de Fibroblasto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Mesencéfalo/embriologia , Mesencéfalo/metabolismo , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Vias Neurais , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Sequências Reguladoras de Ácido Nucleico , Rombencéfalo/embriologia , Rombencéfalo/metabolismo , Rombencéfalo/fisiologia , Transdução de Sinais
7.
Pediatrics ; 146(3)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32848028

RESUMO

BACKGROUND AND OBJECTIVES: Preterm infants with necrotizing enterocolitis (NEC) are known to have worse neurodevelopmental outcomes, but there is no substantial evidence to support an underlying pathophysiology. We aimed to examine whether cerebral oxygenation differs in those infants who develop NEC compared to cerebral oxygenation in those who do not. METHODS: We examined 48 infants <30 weeks' gestation admitted to a tertiary level NICU from October 2016 to May 2018. Infants with birth weight less than or equal to the second percentile, abnormal antenatal dopplers or twin-to-twin-transfusion-syndrome were excluded. Cerebral oximetry measurements were performed by using a near-infrared spectroscopy (NIRS) monitor weekly for 60 minutes, allowing measurement of cerebral tissue oxygenation index from the first week of life to 36 weeks postconceptional age. Weekly clinical status was also recorded. NEC was defined as greater than or equal to Bell stage 2. RESULTS: The median birth weight was 884 g (range of 460-1600 g), the median weeks' gestational age was 26 + 3/7 (23 + 0/7 to 29 + 6/7), and 52% were girls. In total, 276 NIRS measurements were completed, and 7 infants developed NEC. NIRS measurements from 1 infant with NEC and 4 infants without NEC who developed hemorrhagic parenchymal infarcts were excluded from analysis. Infants who developed NEC had significantly lower cerebral tissue oxygenation index than those who did not (P = .011), even when adjusted for confounders, including gestational age, birth weight, patent ductus arteriosus, enteral feeds, sex, ethnicity, and hemoglobin. CONCLUSIONS: Infants with NEC have significantly lower cerebral tissue oxygenation throughout their neonatal intensive care stay in comparison with those who did not develop NEC. This is a novel finding and could explain their worse neurodevelopmental outcome.


Assuntos
Encéfalo/metabolismo , Enterocolite Necrosante/metabolismo , Consumo de Oxigênio/fisiologia , Antibioticoprofilaxia , Permeabilidade do Canal Arterial/diagnóstico por imagem , Enterocolite Necrosante/etiologia , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Oximetria/instrumentação , Oximetria/métodos , Estudos Prospectivos , Espectroscopia de Luz Próxima ao Infravermelho , Fatores de Tempo
8.
PLoS One ; 15(8): e0236720, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32776946

RESUMO

Hemoglobin (Hb) is associated with cerebral oxygenation status owing to its important role of carrying oxygen to systemic tissues. However, data concerning the associations between Hb levels and cerebral regional oxygen saturation (rSO2) of hemodialysis (HD) patients is limited. We aimed to identify these associations to consider a target Hb level for renal anemia management. This study included 375 HD patients. Cerebral rSO2 before HD was monitored using the INVOS 5100c oxygen saturation monitor. Multivariable linear regression analysis showed that cerebral rSO2 was independently associated with natural logarithm (Ln)-HD duration (standardized coefficient: -0.36), mean blood pressure (standardized coefficient: 0.13), pH (standardized coefficient: -0.10), serum albumin (standardized coefficient: 0.14), presence of diabetes mellitus (standardized coefficient: -0.20), and Hb level (standardized coefficient: 0.29). Furthermore, a generalized linear model with restricted cubic spline function was used to investigate the non-linear association between cerebral rSO2 and Hb levels. In the multivariable analysis for the adjustment with Ln-HD duration, mean blood pressure, pH, serum albumin, and presence of diabetes mellitus, a linear relationship was demonstrated between the two variables (p for linearity = 0.79). Hb levels revealed the positive and significant association with cerebral rSO2 in this study. Moreover, the relationship between cerebral rSO2 and Hb level was proven to be linear. Therefore, the target Hb level in renal anemia management would be considered to be the upper limits for the appropriate management of renal anemia by previous guidelines and position statement from the viewpoint of maintaining cerebral oxygenation in HD patients.


Assuntos
Encéfalo/metabolismo , Hemoglobinas/metabolismo , Oxigênio/metabolismo , Diálise Renal , Espectroscopia de Luz Próxima ao Infravermelho , Idoso , Feminino , Humanos , Falência Renal Crônica/metabolismo , Falência Renal Crônica/terapia , Masculino
9.
Chemosphere ; 260: 127611, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32758780

RESUMO

Mercury (Hg) is known as a highly toxic heavy metal, and its toxicity varies depending on its form due to different toxicokinetics between inorganic and organic Hg. Limited information on comparison of Hg toxicity concerning its chemical form by oral exposure is currently available in cultured fishes. Therefore, we conducted a comparative study to have a better understanding of distinct toxic effects between mercuric chloride (HgCl2) and methylmercury chloride (CH3HgCl) in Korean rockfish. The 12-weeks dietary exposure of HgCl2 and CH3HgCl with its graded levels (0.4-6.4 ppm) (2 × 5 factorial design) in the young-of-the-year rockfish (initial weight: 82 ± 0.3 g) resulted in neither interactive nor main effects on whole-organism responses, including growth, feed utilization, and survival. However, the distinct pattern of Hg accumulation between the two forms in dorsal muscle, brain, liver and kidney tissues was observed, showing that the rockfish fed the CH3HgCl-contained diets exhibited the dose-dependent accumulation throughout the sampling points (1, 2, 4, 8, and 12 weeks post feeding), whereas those fed the HgCl2-contained diets did not show such response. The CH3HgCl exposure induced higher oxidative stress and immunotoxicity, reflected by the elevated plasma superoxide dismutase and lysozyme activities, respectively. In addition, the CH3HgCl-induced alteration in plasma measurements, including the plasma aspartate transaminase activity and total protein level was found. Taken together, the dietary exposure of methylmercury chloride had more pronounced toxic effects than mercuric chloride in the young-of-year rockfish, needed to be taken into consideration for regulation of maximum allowed levels for Hg by its chemical form.


Assuntos
Cloreto de Mercúrio/toxicidade , Compostos de Metilmercúrio/toxicidade , Perciformes/fisiologia , Poluentes Químicos da Água/toxicidade , Animais , Encéfalo/metabolismo , Dieta , Mercúrio/metabolismo , Estresse Oxidativo , Perciformes/metabolismo , República da Coreia , Superóxido Dismutase/metabolismo
10.
PLoS One ; 15(8): e0235691, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32857763

RESUMO

Exercise exerts a beneficial effect on the major pathological and clinical symptoms associated with Alzheimer's disease in humans and mouse models of the disease. While numerous mechanisms for such benefits from exercise have been proposed, a clear understanding of the causal links remains elusive. Recent studies also suggest that cerebral blood flow in the brain of both Alzheimer's patients and mouse models of the disease is decreased and that the cognitive symptoms can be improved when blood flow is restored. We therefore hypothesized that the mitigating effect of exercise on the development and progression of Alzheimer's disease may be mediated through an increase in the otherwise reduced brain blood flow. To test this idea, we performed a pilot study to examine the impact of three months of voluntary wheel running in a small cohort of ~1-year-old APP/PS1 mice on short-term memory function, brain inflammation, amyloid deposition, and baseline cerebral blood flow. Our findings that exercise led to a trend toward improved spatial short-term memory, reduced brain inflammation, markedly increased neurogenesis in the dentate gyrus, and a reduction in hippocampal amyloid-beta deposits are consistent with other reports on the impact of exercise on the progression of Alzheimer's related symptoms in mouse models. Notably, we did not observe any impact of wheel running on overall baseline blood flow nor on the incidence of non-flowing capillaries, a mechanism we recently identified as one contributing factor to cerebral blood flow deficits in mouse models of Alzheimer's disease. Overall, our findings add to the emerging picture of differential effects of exercise on cognition and blood flow in Alzheimer's disease pathology by showing that capillary stalling is not decreased following exercise.


Assuntos
Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/irrigação sanguínea , Terapia por Exercício , Presenilina-1/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Circulação Cerebrovascular , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Neurogênese , Condicionamento Físico Animal , Projetos Piloto , Presenilina-1/genética , Transgenes
11.
Yakugaku Zasshi ; 140(8): 979-983, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741871

RESUMO

Monoamine neurotransmitters are released by specialized neurons that regulate behavioral and cognitive functions. Although localization of monoaminergic neurons in the brain is well known, the distribution, concentration, and kinetics of monoamines remain unclear. We used mass spectrometry imaging (MSI) for simultaneous and quantitative imaging of endogenous monoamines to generate a murine brain atlas of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels. We observed several nuclei rich in both 5-HT and a catecholamine (DA or NE). Additionally, we analyzed de novo monoamine synthesis or fluctuations in those nuclei. We propose that MSI is a useful tool to gain deeper understanding of associations among the localization, levels, and turnover of monoamines in different brain areas and their role in inducing behavioral changes.


Assuntos
Monoaminas Biogênicas/análise , Monoaminas Biogênicas/metabolismo , Mapeamento Encefálico/métodos , Encéfalo/metabolismo , Espectrometria de Massas/métodos , Imagem Molecular/métodos , Neurotransmissores/metabolismo , Animais , Dopamina/análise , Dopamina/metabolismo , Camundongos , Neurônios/metabolismo , Neurotransmissores/fisiologia , Norepinefrina/análise , Norepinefrina/metabolismo , Serotonina/análise , Serotonina/metabolismo
12.
PLoS Biol ; 18(8): e3000548, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32745077

RESUMO

Sleep is vital for survival. Yet under environmentally challenging conditions, such as starvation, animals suppress their need for sleep. Interestingly, starvation-induced sleep loss does not evoke a subsequent sleep rebound. Little is known about how starvation-induced sleep deprivation differs from other types of sleep loss, or why some sleep functions become dispensable during starvation. Here, we demonstrate that down-regulation of the secreted cytokine unpaired 2 (upd2) in Drosophila flies may mimic a starved-like state. We used a genetic knockdown strategy to investigate the consequences of upd2 on visual attention and sleep in otherwise well-fed flies, thereby sidestepping the negative side effects of undernourishment. We find that knockdown of upd2 in the fat body (FB) is sufficient to suppress sleep and promote feeding-related behaviors while also improving selective visual attention. Furthermore, we show that this peripheral signal is integrated in the fly brain via insulin-expressing cells. Together, these findings identify a role for peripheral tissue-to-brain interactions in the simultaneous regulation of sleep quality and attention, to potentially promote adaptive behaviors necessary for survival in hungry animals.


Assuntos
Atenção/fisiologia , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Comportamento Alimentar/fisiologia , Inanição/genética , Percepção Visual/fisiologia , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Corpo Adiposo/metabolismo , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Insulina/genética , Insulina/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Transdução de Sinais , Sono/fisiologia , Privação do Sono/genética , Privação do Sono/metabolismo , Inanição/metabolismo
13.
ACS Chem Neurosci ; 11(15): 2159-2162, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32786343

RESUMO

Immune system and renin-angiotensin-aldosterone system dysregulation with associated cytokine release syndrome may be a key feature of early stage of SARS-CoV-2 organotropism and infection. Following viral mediated brain injury, dysregulated neurochemical activity may cause neurogenic stress cardiomyopathy, which is characterized by transient myocardial dysfunction and arrhythmias. Cardiomyopathy along with acute acute inflammatory thromboembolism and endotheliitis (fragile endothelium) might at least partially explain the underlying mechanisms of rapidly evolving life-threatening COVID-19. Further studies are clearly required to explore these complex pathologies.


Assuntos
Betacoronavirus/metabolismo , Química Encefálica/fisiologia , Encéfalo/metabolismo , Infecções por Coronavirus/metabolismo , Endotélio Vascular/metabolismo , Pneumonia Viral/metabolismo , Animais , Encéfalo/imunologia , Encéfalo/patologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Humanos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Sistema Renina-Angiotensina/fisiologia
14.
Nat Commun ; 11(1): 4060, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792512

RESUMO

Chromatin modifiers affect spatiotemporal gene expression programs that underlie organismal development. The Polycomb repressive complex 2 (PRC2) is a crucial chromatin modifier in executing neurodevelopmental programs. Here, we find that PRC2 interacts with the nucleic acid-binding protein Ybx1. In the mouse embryo in vivo, Ybx1 is required for forebrain specification and restricting mid-hindbrain growth. In neural progenitor cells (NPCs), Ybx1 controls self-renewal and neuronal differentiation. Mechanistically, Ybx1 highly overlaps PRC2 binding genome-wide, controls PRC2 distribution, and inhibits H3K27me3 levels. These functions are consistent with Ybx1-mediated promotion of genes involved in forebrain specification, cell proliferation, or neuronal differentiation. In Ybx1-knockout NPCs, H3K27me3 reduction by PRC2 enzymatic inhibitor or genetic depletion partially rescues gene expression and NPC functions. Our findings suggest that Ybx1 fine-tunes PRC2 activities to regulate spatiotemporal gene expression in embryonic neural development and uncover a crucial epigenetic mechanism balancing forebrain-hindbrain lineages and self-renewal-differentiation choices in NPCs.


Assuntos
Encéfalo/embriologia , Encéfalo/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Fatores de Transcrição/metabolismo , Animais , Western Blotting , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Células Cultivadas , Imunoprecipitação da Cromatina , Drosophila , Epigênese Genética/genética , Citometria de Fluxo , Imunofluorescência , Histona-Lisina N-Metiltransferase/genética , Imunoprecipitação , Camundongos , Camundongos Knockout , Processamento de Proteína Pós-Traducional/genética , Processamento de Proteína Pós-Traducional/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética
15.
Aquat Toxicol ; 226: 105567, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32745893

RESUMO

The increasing contamination of water bodies with mercury (Hg) raises concerns about the possible effects of this metal on native fish species. Our current understanding of its dynamics in fish organs remains limited. In this study, adult individuals of the native species Astyanax eigenmanniorum were exposed to three environmentally relevant HgCl2 concentrations (5, 100, and 170 µg L-1) for 96 h. To evaluate total Hg (THg) elimination, new individuals were exposed to 100 µg L-1 of HgCl2 (96 h), and at the end of the exposure period, half of the fish were placed in tanks with clean water for 168 h. In both assays, the organs were removed, and THg levels were measured using ICP-MS. The uptake of IHg in A. eigenmanniorum showed a differential accumulation in the organs. Gills, intestine, and brain were the tissues with the highest THg levels. Finally, no elimination of THg in the water was observed, but intestine and gills significantly removed the THg accumulated. Probably a Hg redistribution through the tissues could take place.


Assuntos
Characidae/metabolismo , Mercúrio/metabolismo , Poluentes Químicos da Água/metabolismo , Adulto , Animais , Bioacumulação , Encéfalo/metabolismo , Characidae/sangue , Monitoramento Ambiental , Brânquias/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Mercúrio/análise , Mercúrio/toxicidade , Taxa de Depuração Metabólica , Distribuição Tecidual , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
16.
Nat Commun ; 11(1): 4078, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843630

RESUMO

Acute stroke causes complex, pathological, and systemic responses that have not been treatable by any single medication. In this study, using a murine transient middle cerebral artery occlusion stroke model, a novel therapeutic strategy is proposed, where blood replacement (BR) robustly reduces infarctions and improves neurological deficits in mice. Our analyses of immune cell subsets suggest that BR therapy substantially decreases neutrophils in blood following a stroke. Electrochemiluminescence detection demonstrates that BR therapy reduces cytokine storm in plasma and ELISA demonstrates reduced levels of matrix metalloproteinase-9 (MMP-9) in the plasma and brains at different time points post-stroke. Further, we have demonstrated that the addition of MMP-9 to the blood diminishes the protective effect of the BR therapy. Our study is the first to show that BR therapy leads to profoundly improved stroke outcomes in mice and that the improved outcomes are mediated via MMP-9. These results offer new insights into the mechanisms of stroke damage.


Assuntos
Substitutos Sanguíneos/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Encéfalo/metabolismo , Animais , Encéfalo/patologia , Infarto Encefálico/tratamento farmacológico , Isquemia Encefálica/patologia , Morte Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/complicações , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia
17.
Adv Exp Med Biol ; 1265: 167-185, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32761576

RESUMO

Amino acids (AAs) and their metabolites play an important role in neurological health and function. They are not only the building blocks of protein but are also neurotransmitters. In the brain, glutamate and aspartate are the major excitatory neurotransmitters, whereas γ-aminobutyrate (GABA, a metabolite of glutamate) and glycine are the major inhibitory neurotransmitters. Nitric oxide (NO, a metabolite of arginine), H2S (a metabolite of cysteine), serotonin (a metabolite of tryptophan) and histamine (a metabolite of histidine), as well as dopamine and norepinephrine (metabolites of tyrosine) are neurotransmitters to modulate synaptic plasticity, neuronal activity, learning, motor control, motivational behavior, emotion, and executive function. Concentrations of glutamine (a precursor of glutamate and aspartate), branched-chain AAs (precursors of glutamate, glutamine and aspartate), L-serine (a precursor of glycine and D-serine), methionine and phenylalanine in plasma are capable of affecting neurotransmission through the syntheses of glutamate, aspartate, and glycine, as well as the competitive transport of tryptophan and tyrosine across from the blood-brain barrier. Adequate consumption of AAs is crucial to maintain their concentrations and the production of neurotransmitters in the central nervous system. Thus, the content and balance of AAs in diets have a profound impact on food intake by animals. Knowledge of AA transport and metabolism in the brain is beneficial for improving the health and well-being of humans and animals.


Assuntos
Aminoácidos/metabolismo , Encéfalo/metabolismo , Comportamento Alimentar/fisiologia , Animais , Humanos , Neurotransmissores/metabolismo
18.
Ecotoxicol Environ Saf ; 202: 110962, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800233

RESUMO

Chronic exposure to fluoride (F) beyond the permissible limit (1.5 ppm) is known to cause detrimental health effects by induction of oxidative stress-mediated DNA damage overpowering the DNA repair machinery. In the present study, we assessed F induced oxidative stress through monitoring biochemical parameters and looked into the effect of chronic F exposure on two crucial DNA repair genes Ogg1 and Rad51 having important role against ROS induced DNA damages. To address this issue, we exposed Swiss albino mice to an environmentally relevant concentration of fluoride (15 ppm NaF) for 8 months. Results revealed histoarchitectural damages in liver, brain, kidney and spleen. Depletion of GSH, increase in lipid peroxidation and catalase activity in liver and brain confirmed the generation of oxidative stress. qRT-PCR result showed that expressions of Ogg1 and Rad51 were altered after F exposure in the affected organs. Promoter hypermethylation was associated with the downregulation of Rad51. F-induced DNA damage and the compromised DNA repair machinery triggered intrinsic pathway of apoptosis in liver and brain. The present study indicates the possible association of epigenetic regulation with F induced neurotoxicity.


Assuntos
Dano ao DNA , DNA Glicosilases/genética , Reparo do DNA , Epigênese Genética/efeitos dos fármacos , Fluoretos/toxicidade , Rad51 Recombinase/genética , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Relação Dose-Resposta a Droga , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos
19.
Science ; 369(6503): 561-565, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32732423

RESUMO

Most neuropsychiatric disease risk variants are in noncoding sequences and lack functional interpretation. Because regulatory sequences often reside in open chromatin, we reasoned that neuropsychiatric disease risk variants may affect chromatin accessibility during neurodevelopment. Using human induced pluripotent stem cell (iPSC)-derived neurons that model developing brains, we identified thousands of genetic variants exhibiting allele-specific open chromatin (ASoC). These neuronal ASoCs were partially driven by altered transcription factor binding, overrepresented in brain gene enhancers and expression quantitative trait loci, and frequently associated with distal genes through chromatin contacts. ASoCs were enriched for genetic variants associated with brain disorders, enabling identification of functional schizophrenia risk variants and their cis-target genes. This study highlights ASoC as a functional mechanism of noncoding neuropsychiatric risk variants, providing a powerful framework for identifying disease causal variants and genes.


Assuntos
Alelos , Encéfalo/metabolismo , Cromatina/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Esquizofrenia/genética , Elementos Facilitadores Genéticos , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Risco
20.
Nat Commun ; 11(1): 3848, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737286

RESUMO

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper and lower motor neurons (MNs). We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice. Being the retromer involved in trafficking of hydrolases, a pathological hallmark in ALS, we design, synthesize and characterize an array of retromer stabilizers based on bis-guanylhydrazones connected by a 1,3-phenyl ring linker. We select compound 2a as a potent and bioavailable interactor of VPS35-VPS29. Indeed, while increasing retromer stability in ALS mice, compound 2a attenuates locomotion impairment and increases MNs survival. Moreover, compound 2a increases VPS35 in iPSCs-derived MNs and shows brain bioavailability. Our results clearly suggest the retromer as a valuable druggable target in ALS.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Hidrazonas/farmacologia , Neurônios Motores/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas de Transporte Vesicular/genética , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Diferenciação Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Hidrazonas/síntese química , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica , Relação Estrutura-Atividade , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Proteínas de Transporte Vesicular/metabolismo
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