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1.
Brain Nerve ; 73(4): 303-313, 2021 Apr.
Artículo en Japonés | MEDLINE | ID: mdl-33824218

RESUMEN

Migraine is the sixth most common cause of disability worldwide. Historically, three theories regarding the etiology of headache have been suggested: vascular, neuronal, and trigeminovascular. However, the mechanism of migraine is still unknown. The advantages of studying the premonitory phase are several as it is the earliest clinical change during a migraine attack, and hence, is likely to disclose brain areas involved right at the beginning. Studying this phase may also allow to reveal the generator of migraine. In human neurophysiology, human functional neuroimaging, and preclinical biochemical studies, the relationship between the premonitory phase and hypothalamus has been suggested. On the other hand, calcitonin gene-related peptide (CGRP) has now been firmly established as a key player in migraine. Trigeminal CGRP and its roles in vasodilation, neurogenic inflammation, and peripheral sensitization are likely to be the most relevant peripheral actions causing the condition. CGRP could also be acting as a neuromodulator of light aversion, central sensitization, and cortical spreading depression (CSD).


Asunto(s)
Péptido Relacionado con Gen de Calcitonina , Trastornos Migrañosos , Encéfalo/metabolismo , Péptido Relacionado con Gen de Calcitonina/metabolismo , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Humanos , Trastornos Migrañosos/tratamiento farmacológico , Neuronas/metabolismo
2.
Brain Nerve ; 73(4): 359-367, 2021 Apr.
Artículo en Japonés | MEDLINE | ID: mdl-33824223

RESUMEN

Although the involvement of genomic factors in bipolar disorder is clear, its neural basis remains a question. We proposed the mitochondrial dysfunction hypothesis of bipolar disorder in 2000 and have since been testing it. Our results showed that mitochondrial DNA (mtDNA) polymorphisms affected mitochondrial Ca2+ concentration, and mitochondrial Ca2+ uptake and intracellular Ca2+ signaling were altered. Spontaneous repetitive depressive episodes were seen in mice in which mtDNA mutations accumulated in the brain (mutant Polg transgenic mice). We searched for the brain regions with the accumulation of mutant mtDNA in these mice, and found that it was most abundant in the paraventricular nucleus of the thalamus (PVT). Neural circuit manipulation of the PVT caused similar repetitive hypoactive episodes, suggesting that the PVT may be involved in causing bipolar disorder.


Asunto(s)
Trastorno Bipolar , Animales , Trastorno Bipolar/genética , Encéfalo/metabolismo , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Ratones , Ratones Transgénicos , Mitocondrias/genética
3.
Nat Commun ; 12(1): 1647, 2021 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-33712584

RESUMEN

Major depressive disorder (MDD) has been shown to be associated with structural abnormalities in a variety of spatially diverse brain regions. However, the correlation between brain structural changes in MDD and gene expression is unclear. Here, we examine the link between brain-wide gene expression and morphometric changes in individuals with MDD, using neuroimaging data from two independent cohorts and a publicly available transcriptomic dataset. Morphometric similarity network (MSN) analysis shows replicable cortical structural differences in individuals with MDD compared to control subjects. Using human brain gene expression data, we observe that the expression of MDD-associated genes spatially correlates with MSN differences. Analysis of cell type-specific signature genes suggests that microglia and neuronal specific transcriptional changes account for most of the observed correlation with MDD-specific MSN differences. Collectively, our findings link molecular and structural changes relevant for MDD.


Asunto(s)
Encéfalo/metabolismo , Encéfalo/patología , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/metabolismo , Transcriptoma , Adulto , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Persona de Mediana Edad , Neuroimagen/métodos , Neuronas
4.
Int J Nanomedicine ; 16: 2203-2217, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33762821

RESUMEN

Background: It is well known that smoking is harmful to health; however, it can also ameliorate anxiety. To date, it is unclear whether any nanoparticles found in cigarette mainstream smoke (CS) contribute to this effect. Aim: The aim of this study was to assess the particle composition of CS to identify novel anti-anxiety components. Methods: Carbon dots (CDs) from CS (CS-CDs) were characterised using high-resolution transmission electron microscopy, Fourier-transform infrared, ultraviolet, fluorescence, X-ray photoelectron spectroscopy, X-ray diffraction and high-performance liquid chromatography. The anti-anxiety effects of CS-CDs in mouse models were evaluated and confirmed with the elevated plus maze and open-field tests. Results: The quantum yield of CS-CDs was 13.74%, with a composition of C, O, and N. In addition, the surface groups contained O-H, C-H, C=O, C-N, N-H, C-O-C, and COO- bonds. Acute toxicity testing revealed that CS-CDs had low in vitro and in vivo toxicity within a certain concentration range. The results of the elevated plus maze and open-field tests showed that CS-CDs had a significant anti-anxiety effect and a certain sedative effect in mice. The mechanism of these effects may be related to the decrease in glutamate levels and promotion of norepinephrine production in the mouse brain, and the decrease in dopamine in mouse serum due to CS-CDs. Conclusion: CS-CDs may have anti-anxiety and certain sedative effects. This study provides a new perspective for a more comprehensive understanding of the components, properties, and functions of CS. Furthermore, it offers a novel target for the development of smoking cessation treatments, such as nicotine replacement therapy.


Asunto(s)
Conducta Animal , Carbono/química , Fumar Cigarrillos/efectos adversos , Sistema Endocrino/metabolismo , Neurotransmisores/metabolismo , Puntos Cuánticos/química , Agua/química , Hormona Adrenocorticotrópica/sangre , Animales , Ansiedad/sangre , Ansiedad/patología , Encéfalo/metabolismo , Encéfalo/patología , Cromatografía Líquida de Alta Presión , Corticosterona/sangre , Hormona Liberadora de Corticotropina/sangre , Dopamina/sangre , Masculino , Ratones , Ratones Endogámicos ICR , Espectroscopía de Fotoelectrones , Puntos Cuánticos/ultraestructura , Células RAW 264.7 , Espectrometría de Fluorescencia , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría Raman , Pruebas de Toxicidad Aguda , Difracción de Rayos X
5.
Medicine (Baltimore) ; 100(11): e20722, 2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33725920

RESUMEN

ABSTRACT: Bladder cancer-associated transcript 1 (BLACAT1) is one of the most common cancer-associated long non-coding RNAs (lncRNAs), which has been reported as a tumor promotor in several malignancies. Previously, BLACAT1 was found to be overexpressed in glioma tissues and cell lines. Functional assays determined that BLACAT1 promoted glioma cell proliferation, migration, invasion and epithelial-mesenchymal transition, suggesting that BLACAT1 might serve as an oncogene in glioma. In the present study, we aimed to investigate its clinical significance and prognostic value in glioma patients.A total of 137 paired glioma tissue samples and adjacent normal brain tissue samples were collected from 137 glioma patients who underwent surgery from May 2014 to February 2019. The Student t test was applied to determine the statistical significance of the observed differences between 2 groups. Survival curves were constructed and differences among groups were calculated using the Kaplan-Meier method.The relative expression of BLACAT1 in glioma samples was significantly higher than that of matched normal tissues (P < .001). The expression level of tissue BLACAT1 was statistically correlated with tumor size (P = .04), Karnofsky Performance Status (KPS) (P = .006), and WHO grade (P = .017). Kaplan-Meier analysis with the log-rank test revealed that BLACAT1 up-regulation was correlated with shorter overall survival time of patients with glioma (Log Rank test, P = .012). In multivariate Cox analysis, BLACAT1 expression was found to be an independent prognostic factor for overall survival in patients with glioma (HR = 2.739; 95% CI: 1.785-8.229; P = .035). Our study demonstrates that up-regulation of BLACAT1 is able to predict aggressive clinicopathologic characteristics and poor prognosis of glioma patients. These findings may have significant implications for potential treatment options and prognosis for patients with glioma.


Asunto(s)
Regulación Neoplásica de la Expresión Génica/genética , Glioma/genética , ARN Largo no Codificante/metabolismo , Regulación hacia Arriba/genética , Encéfalo/metabolismo , Estudios de Casos y Controles , Movimiento Celular/genética , Proliferación Celular/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Glioma/mortalidad , Humanos , Estimación de Kaplan-Meier , Estado de Ejecución de Karnofsky , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/genética , Pronóstico , Modelos de Riesgos Proporcionales
6.
Sci Total Environ ; 772: 144568, 2021 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-33770895

RESUMEN

BACKGROUND: Temperature stress was reported to impact the gut-brain axis including intestinal microbiome and neuroinflammation, but the molecular markers involved remain unclear. We aimed to examine the effects of different temperature stress on the intestinal microbiome and central nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes. MATERIALS AND METHODS: Mice models were established under low temperature (LT), room temperature (RT), high temperature (HT), and temperature variation (TV) respectively for seven days. We examined temperature-induced changes of intestinal microbiome composition and the levels of its metabolites short-chain fatty acids (SCFAs), as well as the expressions of central NLRP3 inflammasomes and inflammatory cytokines. Redundancy analysis and Spearman correlation analysis were performed to explore the relationships between microbiome and NLRP3 inflammasomes and other indicators. RESULTS: HT and LT significantly increased the Alpha diversity of intestinal microbiome. Compared with RT group, Bacteroidetes were most abundant in LT group while Actinobacteria were most abundant in HT and TV groups. Nineteen discriminative bacteria were identified among four groups. LT increased the expressions of acetate and propionate while decreased that of NLRP3 inflammasomes; HT decreased the expression of butyrate while increased that of NLRP3 inflammasomes, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α; TV decreased the expression of propionate while increased that of NLRP3 inflammasomes and TNF-α. Microbiome distribution could significantly explain the differences in NLRP3 between comparison groups (LT&RT: R2 = 0.82, HT&RT: R2 = 0.86, TV&RT: R2 = 0.94; P < 0.05). The discriminative bacteria were significantly correlated with SCFAs but were correlated with NLRP3 inflammasomes and cytokines in the opposite direction. CONCLUSIONS: LT inhibits while HT and TV promote the activation of NLRP3 inflammasomes in brain, and intestinal microbiome and its metabolites may be the potential mediators. Findings may shed some light on the impact of temperature stress on gut-brain axis.


Asunto(s)
Microbioma Gastrointestinal , Inflamasomas , Animales , Encéfalo/metabolismo , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR , Temperatura
7.
Pestic Biochem Physiol ; 173: 104785, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33771263

RESUMEN

Luteolin (LUT) as a natural compound found in vegetables and fruits has various pharmacological effects. Fipronil (FPN), as a pesticide, has been considered for its effect on the antioxidant system and induction of oxidative stress. This study was designed to investigate the protective effects of LUT against the oxidative stress and mitochondrial toxicity induced by FPN on the rat brain. Several parameters such as mitochondrial reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP) collapse, mitochondrial swelling, cytochrome c release, mitochondrial glutathione (GSH), lipid peroxidation (LPO) and Adenosine triphosphate (ATP) levels were assessed. Results indicated that the administration of LUT (25 µM) significantly improved oxidative stress and mitochondrial damages induced via FPN (6, 12 and 24 µM) in isolated mitochondria from the brain. These results show that LUT exerted protective effects against FPN-induced neurotoxicity in vitro through improving oxidative stress and mitochondrial damages.


Asunto(s)
Luteolina , Estrés Oxidativo , Animales , Encéfalo/metabolismo , Peroxidación de Lípido , Luteolina/farmacología , Potencial de la Membrana Mitocondrial , Mitocondrias/metabolismo , Pirazoles , Ratas , Especies Reactivas de Oxígeno/metabolismo
8.
Nat Commun ; 12(1): 1490, 2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33674568

RESUMEN

The brain of mammals lacks a significant ability to regenerate neurons and is thus particularly vulnerable. To protect the brain from injury and disease, damage control by astrocytes through astrogliosis and scar formation is vital. Here, we show that brain injury in mice triggers an immediate upregulation of the actin-binding protein Drebrin (DBN) in astrocytes, which is essential for scar formation and maintenance of astrocyte reactivity. In turn, DBN loss leads to defective astrocyte scar formation and excessive neurodegeneration following brain injuries. At the cellular level, we show that DBN switches actin homeostasis from ARP2/3-dependent arrays to microtubule-compatible scaffolds, facilitating the formation of RAB8-positive membrane tubules. This injury-specific RAB8 membrane compartment serves as hub for the trafficking of surface proteins involved in astrogliosis and adhesion mediators, such as ß1-integrin. Our work shows that DBN-mediated membrane trafficking in astrocytes is an important neuroprotective mechanism following traumatic brain injury in mice.


Asunto(s)
Astrocitos/metabolismo , Lesiones Traumáticas del Encéfalo/metabolismo , Cicatriz/metabolismo , Neuropéptidos/genética , Neuropéptidos/metabolismo , Complejo 2-3 Proteico Relacionado con la Actina , Actinas/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Lesiones Traumáticas del Encéfalo/patología , Movimiento Celular , Sistema Nervioso Central/metabolismo , Modelos Animales de Enfermedad , Gliosis/metabolismo , Gliosis/patología , Ratones , Ratones Noqueados , Neuroprotección , Transcriptoma , Proteínas de Unión al GTP rab/metabolismo
9.
Aquat Toxicol ; 233: 105788, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33662878

RESUMEN

The gene expression response thought to underlie the negative apical effects resulting from estrogen exposure have been thoroughly described in fish. Although epigenetics are believed to play a critical role translating environmental exposures into the development of adverse apical effects, they remain poorly characterized in fish species. This study investigated alterations of DNA methylation of estrogen receptor alpha (esr1) in brain and liver tissues from 8 to 10 month old male fathead minnows (Pimephales promelas) after a 2d exposure to either 2.5 ng/L or 10 ng/L 17α-ethynylestradiol (EE2). Changes in the patterns of methylation were evaluated using targeted deep sequencing of bisulfite treated DNA in the 5' region of esr1. Methylation and gene expression were assessed at 2d of exposure and after a 7 and 14d depuration period. After 2d EE2 exposure, males exhibited significant demethylation in the 5' upstream region of esr1 in liver tissue, which was inversely correlated to gene expression. This methylation pattern reflected what was seen in females. No gene body methylation (GBM) was observed for liver of exposed males. Differential methylation was observed for a single upstream CpG site in the liver after the 14d depuration. A less pronounced methylation response was observed in the upstream region in brain tissue, however, several CpGs were necessarily excluded from the analysis. In contrast to the liver, a significant GBM response was observed across the entire gene body, which was sustained until at least 7d post-exposure. No differential expression was observed in the brain, limiting functional interpretation of methylation changes. The identification of EE2-dependent changes in methylation levels strongly suggests the importance of epigenetic mechanisms as a mediator of the organismal response to environmental exposures and the need for further characterization of the epigenome. Further, differential methylation following depuration indicates estrogenic effects persist well after the active exposure, which has implications for the risk posed by repeated exposures..


Asunto(s)
Cyprinidae/metabolismo , Metilación de ADN/efectos de los fármacos , Receptor alfa de Estrógeno/genética , Etinilestradiol/toxicidad , Expresión Génica/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cyprinidae/genética , Estrógenos/metabolismo , Femenino , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Vitelogeninas/metabolismo
10.
Am J Alzheimers Dis Other Demen ; 36: 1533317521996147, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33719595

RESUMEN

Alzheimer's Disease (AD) is pathologically characterized by the accumulation of soluble oligomers causing extracellular beta-amyloid deposits in form of neuritic plaques and tau-containing intraneuronal neurofibrillary tangles in brain. One proposed mechanism explaining the formation of these proteins is impaired phagocytosis by microglia/macrophages resulting in defective clearance of soluble oligomers of beta-amyloid stimulating aggregation of amyloid plaques subsequently causing AD. However, research indicates that activating macrophages in M2 state may reduce toxic oligomers. NEU1 mutation is associated with a rare disease, sialidosis. NEU1 deficiency may also cause AD-like amyloidogenic process. Amyloid plaques have successfully been reduced using NEU1.Thus, NEU1 is suggested to have therapeutic potential for AD, with lysosomal exocytosis being suggested as underlying mechanism. Studies however demonstrate that NEU1 may activate macrophages in M2 state, which as noted earlier, is crucial to reducing toxic oligomers. In this review, authors discuss the potential therapeutic role of NEU1 in AD via immune system.


Asunto(s)
Enfermedad de Alzheimer , Neuraminidasa , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Humanos , Sistema Inmunológico/metabolismo , Placa Amiloide
11.
Nat Commun ; 12(1): 1537, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750804

RESUMEN

Quaking RNA binding protein (QKI) is essential for oligodendrocyte development as myelination requires myelin basic protein mRNA regulation and localization by the cytoplasmic isoforms (e.g., QKI-6). QKI-6 is also highly expressed in astrocytes, which were recently demonstrated to have regulated mRNA localization. Here, we define the targets of QKI in the mouse brain via CLIPseq and we show that QKI-6 binds 3'UTRs of a subset of astrocytic mRNAs. Binding is also enriched near stop codons, mediated partially by QKI-binding motifs (QBMs), yet spreads to adjacent sequences. Using a viral approach for mosaic, astrocyte-specific gene mutation with simultaneous translating RNA sequencing (CRISPR-TRAPseq), we profile ribosome associated mRNA from QKI-null astrocytes in the mouse brain. This demonstrates a role for QKI in stabilizing CLIP-defined direct targets in astrocytes in vivo and further shows that QKI mutation disrupts the transcriptional changes for a discrete subset of genes associated with astrocyte maturation.


Asunto(s)
Astrocitos/metabolismo , Encéfalo/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Animales , Secuencia de Bases , Citoplasma/metabolismo , Expresión Génica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína Básica de Mielina/genética , Proteína Básica de Mielina/metabolismo , Isoformas de Proteínas , ARN Mensajero/metabolismo , Análisis de Secuencia de ARN , Transcriptoma
12.
Biomed Khim ; 67(1): 5-16, 2021 Jan.
Artículo en Ruso | MEDLINE | ID: mdl-33645518

RESUMEN

This review discusses our current knowledge on the nociceptin/orphanin (N/OFQ) system regarding its role in regulation of brain functions. Nociceptin receptor (NOPr) was identified in 1994 [Bunzow et al., 1994; Mollereau et al., 1994]. In 1995 a 17 amino acid endogenous peptide was found to be the high-affinity ligand for the NOPr [Reinscheid et al., 1995]. N/OFQ has a broad spectrum of activity and can act as on opioid-like as well as an anti-opioid peptide. Considering high level of N/OFQ and NOPr mRNA expression in the limbic brain regions, the N/OFQ/NOP system is suggested to be involved in regulation of emotions, resward, pain sensitivity, stress responsibility, sexual behavior, aggression, drug abuse and addiction. However it is still not well understood whether an increased vulnerability to drugs of abuse may be associated with dysregulation of N/OFQ/NOP system. Current review further highlights a need for further research on N/OFQ/NOP system as it could have clinical utility for substance abuse, depression, and anxiety pharmacotherapy.


Asunto(s)
Analgésicos Opioides , Péptidos Opioides , Ansiedad , Encéfalo/metabolismo , Péptidos Opioides/metabolismo
13.
Biomed Khim ; 67(1): 51-65, 2021 Jan.
Artículo en Ruso | MEDLINE | ID: mdl-33645522

RESUMEN

Mitochondrial dysfunction and ubiquitin-proteasome system (UPS) failure contribute significantly to the development of Parkinson's disease (PD). The proteasome subunit Rpn13 located on the regulatory (19S) subparticle play an important role in the delivery of proteins, subjected to degradation, to the proteolytic (20S) part of proteasome. We have previously found several brain mitochondrial proteins specifically bound to Rpn13 (Buneeva et al. (2020) Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry, 14, 297-305). In this study we have investigated the effect of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the neuroprotector isatin on the mitochondrial subproteome of Rpn13-binding proteins of the mouse brain. Administration of MPTP (30 mg/kg) to animals caused movement disorders typical of PD, while pretreatment with isatin (100 mg/kg, 30 min before MPTP) reduced their severity. At the same time, the injection of MPTP, isatin, or their combination (isatin + MPTP) had a significant impact on the total number and the composition of Rpn13-binding proteins. The injection of MPTP decreased the total number of Rpn13-binding proteins in comparison with control, and the injection of isatin prior to MPTP or without MPTP caused an essential increase in the number of Rpn13-binding proteins, mainly of the functional group of proteins participating in the protein metabolism regulation, gene expression, and differentiation. Selected biosensor validation confirmed the interaction of Rpn13 subunit of proteasome with some proteins (glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase, histones H2A and H2B) revealed while proteomic profiling. The results obtained testify that under the conditions of experimental MPTP-induced parkinsonism the neuroprotective effect of isatin may be aimed at the interaction of mitochondria with the components of UPS.


Asunto(s)
Isatina , Neurotoxinas , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Encéfalo/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Isatina/metabolismo , Isatina/farmacología , Ratones , Mitocondrias/metabolismo , Neurotoxinas/metabolismo , Neurotoxinas/farmacología , Proteómica
14.
Biomed Khim ; 67(1): 95-99, 2021 Jan.
Artículo en Ruso | MEDLINE | ID: mdl-33645527

RESUMEN

Intracellular signaling mediated by the HMGB1 protein, an agonist of TLRs, is considered as a possible target for the correction of pathologies of the neuroimmune system, however, the expression level of the Hmgb1 gene has not been previously studied in various brain structures of rats exposed to prolonged alcoholization followed by ethanol withdrawal. The study showed that long-term use of ethanol caused to an increase in the level of Hmgb1 mRNA in the striatum of rat brain. Alcohol withdrawal changed the level Hmgb1 mRNA in the striatum and amygdala on the 1st and 14th day. The data obtained may indicate that in different structures of the brain there are multidirectional changes in the molecular mechanisms of the neuroimmune response with prolonged use of ethanol and its withdrawal.


Asunto(s)
Alcoholismo , Proteína HMGB1 , Síndrome de Abstinencia a Sustancias , Alcoholismo/genética , Animales , Encéfalo/metabolismo , Etanol/toxicidad , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Ratas , Síndrome de Abstinencia a Sustancias/genética
15.
Arq Neuropsiquiatr ; 79(1): 56-67, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33656113

RESUMEN

BACKGROUND: Increased concentrations of serum proteins in cerebrospinal fluid (CSF) are interpreted as blood-CSF barrier dysfunction. Frequently used interpretations such as barrier leakage, disruption or breakdown contradict CSF protein data, which suggest a reduced CSF flow rate as the cause. RESULTS: Even the severest barrier dysfunctions do not change the molecular size-dependent selectivity or the interindividual variation of the protein transfer across barriers. Serum protein concentrations in lumbar CSF increase with hyperbolic functions, but the levels of proteins that do not pass the barrier remain constant (brain proteins) or increase linearly (leptomeningal proteins). All CSF protein dynamics above and below a lumbar blockade can also be explained, independent of their barrier passage, by a reduced caudally directed flow. Local accumulation of gadolinium in multiple sclerosis (MS) is now understood as due to reduced bulk flow elimination by interstitial fluid (ISF). Nonlinear change of the steady state in barrier dysfunction and along normal rostro-caudal gradients supports the diffusion/flow model and contradicts obstructions of diffusion pathways. Regardless of the cause of the disease, pathophysiological flow blockages are found in bacterial meningitis, leukemia, meningeal carcinomatosis, Guillain-Barré syndrome, MS and experimental allergic encephalomyelitis. In humans, the fortyfold higher albumin concentrations in early fetal development decrease later with maturation of the arachnoid villi, i.e., with beginning CSF outflow, which contradicts a relevant outflow to the lymphatic system. Respiration- and heartbeat-dependent oscillations do not disturb net direction of CSF flow. CONCLUSION: Blood-CSF and blood-brain barrier dysfunctions are an expression of reduced CSF or ISF flow rate.


Asunto(s)
Barrera Hematoencefálica , Encéfalo , Proteínas Sanguíneas/metabolismo , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Líquido Cefalorraquídeo/metabolismo , Humanos
16.
Nat Commun ; 12(1): 1557, 2021 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-33692361

RESUMEN

Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. CGG-repeat expansion in the FMR1 gene leads to FMR1 silencing, loss-of-expression of the Fragile X Mental Retardation Protein (FMRP), and is a common cause of FXS. Missense mutations in the FMR1 gene were also identified in FXS patients, including the recurrent FMRP-R138Q mutation. To investigate the mechanisms underlying FXS caused by this mutation, we generated a knock-in mouse model (Fmr1R138Q) expressing the FMRP-R138Q protein. We demonstrate that, in the hippocampus of the Fmr1R138Q mice, neurons show an increased spine density associated with synaptic ultrastructural defects and increased AMPA receptor-surface expression. Combining biochemical assays, high-resolution imaging, electrophysiological recordings, and behavioural testing, we also show that the R138Q mutation results in impaired hippocampal long-term potentiation and socio-cognitive deficits in mice. These findings reveal the functional impact of the FMRP-R138Q mutation in a mouse model of FXS.


Asunto(s)
Disfunción Cognitiva/genética , Disfunción Cognitiva/fisiopatología , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/metabolismo , Mutación Missense/fisiología , Receptores de Glutamato/metabolismo , Animales , Biotinilación , Encéfalo/metabolismo , Encéfalo/fisiopatología , Células Cultivadas , Disfunción Cognitiva/metabolismo , Femenino , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Hipocampo/metabolismo , Hipocampo/fisiopatología , Humanos , Immunoblotting , Potenciación a Largo Plazo/genética , Potenciación a Largo Plazo/fisiología , Masculino , Ratones , Mutación Missense/genética , Técnicas de Placa-Clamp , Receptores de Glutamato/genética
17.
Nat Commun ; 12(1): 1745, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741971

RESUMEN

Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). Despite the known importance of persulfidation, tissue-specific persulfidome profiles and their associated functions are not well characterized, specifically under conditions and interventions known to modulate H2S production. We hypothesize that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific persulfidomes. Here, we find protein persulfidation enriched in liver, kidney, muscle, and brain but decreased in heart of young and aged male mice under two forms of DR, with DR promoting persulfidation in numerous metabolic and aging-related pathways. Mice lacking cystathionine γ-lyase (CGL) have overall decreased tissue protein persulfidation numbers and fail to functionally augment persulfidomes in response to DR, predominantly in kidney, muscle, and brain. Here, we define tissue- and CGL-dependent persulfidomes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health.


Asunto(s)
Cistationina gamma-Liasa/química , Cistationina gamma-Liasa/metabolismo , Dieta , Proteínas/química , Proteínas/metabolismo , Envejecimiento/metabolismo , Animales , Encéfalo/metabolismo , Cistationina gamma-Liasa/genética , Sulfuro de Hidrógeno/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Longevidad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculos/metabolismo , Proteínas/genética , Transcriptoma
18.
Molecules ; 26(4)2021 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-33671835

RESUMEN

Sulfasalazine (SAS), an anti-inflammatory drug with potent cysteine/glutamate antiporter system xc-(SXC) inhibition has recently shown beneficial effects in brain-related diseases. Despite many reports related to central nervous system (CNS) effect of SAS, pharmacokinetics (PK) and metabolite identification studies in the brain for SAS were quite limited. The aim of this study was to investigate the pharmacokinetics and metabolite identification of SAS and their distributions in mouse brain. Using in vivo brain exposure studies (neuro PK), the PK parameters of SAS was calculated for plasma as well as brain following intravenous and oral administration at 10 mg/kg and 50 mg/kg in mouse, respectively. In addition, in vivo metabolite identification (MetID) studies of SAS in plasma and brain were also conducted. The concentration of SAS in brain was much lower than that in plasma and only 1.26% of SAS was detected in mouse brain when compared to the SAS concentration in plasma (brain to plasma ratio (%): 1.26). In the MetID study, sulfapyridine (SP), hydroxy-sulfapyridine (SP-OH), and N-acetyl sulfapyridine (Ac-SP) were identified in plasma, whereas only SP and Ac-SP were identified as significant metabolites in brain. As a conclusion, our results suggest that the metabolites of SAS such as SP and Ac-SP might be responsible for the pharmacological effect in brain, not the SAS itself.


Asunto(s)
Encéfalo/metabolismo , Sulfasalazina/análisis , Sulfasalazina/metabolismo , Animales , Masculino , Espectrometría de Masas , Ratones , Ratones Endogámicos ICR , Sulfasalazina/farmacocinética , Factores de Tiempo
19.
Adv Pharmacol ; 90: 145-171, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33706931

RESUMEN

Signal transduction designates the set of molecular events that take place within a cell upon extracellular stimulation to mediate a functional outcome. Decades after the discovery that dopamine triggers opposing signaling pathways in D1- and D2-expressing medium spiny neurons, it is now clear that there are as many different flavors of signaling pathways in the brain as there are neuron types. One of the biggest challenges in molecular neuroscience is to elucidate cell-type specific signaling, in order to understand neurological diseases with regional vulnerability, but also to identify targets for precision drugs devoid of off-target effects. Here, we make a case for the importance of the study of neuron-type specific molecular characteristics. We then review the technologies that exist to study neurons in their full diversity and highlight their disease-relevant idiosyncrasies.


Asunto(s)
Encéfalo/metabolismo , Transducción de Señal , Animales , Desarrollo de Medicamentos , Reposicionamiento de Medicamentos , Humanos , Enfermedades del Sistema Nervioso/metabolismo , Biología de Sistemas
20.
Nat Neurosci ; 24(3): 437-448, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33542524

RESUMEN

Neuronal activity-dependent gene expression is essential for brain development. Although transcriptional and epigenetic effects of neuronal activity have been explored in mice, such an investigation is lacking in humans. Because alterations in GABAergic neuronal circuits are implicated in neurological disorders, we conducted a comprehensive activity-dependent transcriptional and epigenetic profiling of human induced pluripotent stem cell-derived GABAergic neurons similar to those of the early developing striatum. We identified genes whose expression is inducible after membrane depolarization, some of which have specifically evolved in primates and/or are associated with neurological diseases, including schizophrenia and autism spectrum disorder (ASD). We define the genome-wide profile of human neuronal activity-dependent enhancers, promoters and the transcription factors CREB and CRTC1. We found significant heritability enrichment for ASD in the inducible promoters. Our results suggest that sequence variation within activity-inducible promoters of developing human forebrain GABAergic neurons contributes to ASD risk.


Asunto(s)
Encéfalo/metabolismo , Epigénesis Genética , Neuronas GABAérgicas/metabolismo , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Regiones Promotoras Genéticas
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