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1.
EMBO J ; 39(6): e102214, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32030804

RESUMO

Spinal cord microglia contribute to nerve injury-induced neuropathic pain. We have previously demonstrated that toll-like receptor 2 (TLR2) signaling is critical for nerve injury-induced activation of spinal cord microglia, but the responsible endogenous TLR2 agonist has not been identified. Here, we show that nerve injury-induced upregulation of sialyltransferase St3gal2 in sensory neurons leads to an increase in expression of the sialylated glycosphingolipid, GT1b. GT1b ganglioside is axonally transported to the spinal cord dorsal horn and contributes to characteristics of neuropathic pain such as mechanical and thermal hypersensitivity. Spinal cord GT1b functions as an TLR2 agonist and induces proinflammatory microglia activation and central sensitization. Pharmacological inhibition of GT1b synthesis attenuates nerve injury-induced spinal cord microglia activation and pain hypersensitivity. Thus, the St3gal2-GT1b-TLR2 axis may offer a novel therapeutic target for the treatment of neuropathic pain.


Assuntos
Gangliosídeos/metabolismo , Neuralgia/terapia , Traumatismos dos Nervos Periféricos/terapia , Transdução de Sinais , Receptor 2 Toll-Like/agonistas , Animais , Gangliosídeos/antagonistas & inibidores , Regulação da Expressão Gênica , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Neuralgia/etiologia , Traumatismos dos Nervos Periféricos/etiologia , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais , Sialiltransferases/genética , Sialiltransferases/metabolismo , Medula Espinal/metabolismo , Receptor 2 Toll-Like/metabolismo
2.
J Nanobiotechnology ; 20(1): 367, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35953847

RESUMO

BACKGROUND: Astrocyte is a key regulator of neuronal activity and excitatory/inhibitory balance via gliotransmission. Recently, gliotransmission has been identified as a novel target for neurological diseases. However, using the properties of nanomaterials to modulate gliotransmission has not been uncovered. RESULTS: We prepared non-invasive CNT platforms for cells with different nanotopography and properties such as hydrophilicity and conductivity. Using CNT platforms, we investigated the effect of CNT on astrocyte functions participating in synaptic transmission by releasing gliotransmitters. Astrocytes on CNT platforms showed improved cell adhesion and proliferation with upregulated integrin and GFAP expression. In addition, intracellular GABA and glutamate in astrocytes were augmented on CNT platforms. We also demonstrated that gliotransmitters in brain slices were increased by ex vivo incubation with CNT. Additionally, intracellular resting Ca2+ level, which is important for gliotransmission, was also increased via TRPV1 on CNT platforms. CONCLUSION: CNT can improve astrocyte function including adhesion, proliferation and gliotransmission by increasing resting Ca2+ level. Therefore, our study suggests that CNT would be utilized as a new therapeutic platform for central nervous system diseases by modulating gliotransmission.


Assuntos
Nanotubos de Carbono , Astrócitos , Encéfalo , Neurônios/metabolismo , Transmissão Sináptica/fisiologia
3.
Proc Natl Acad Sci U S A ; 115(19): 5004-5009, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29691318

RESUMO

Tonic inhibition in the brain is mediated through an activation of extrasynaptic GABAA receptors by the tonically released GABA, resulting in a persistent GABAergic inhibitory action. It is one of the key regulators for neuronal excitability, exerting a powerful action on excitation/inhibition balance. We have previously reported that astrocytic GABA, synthesized by monoamine oxidase B (MAOB), mediates tonic inhibition via GABA-permeable bestrophin 1 (Best1) channel in the cerebellum. However, the role of astrocytic GABA in regulating neuronal excitability, synaptic transmission, and cerebellar brain function has remained elusive. Here, we report that a reduction of tonic GABA release by genetic removal or pharmacological inhibition of Best1 or MAOB caused an enhanced neuronal excitability in cerebellar granule cells (GCs), synaptic transmission at the parallel fiber-Purkinje cell (PF-PC) synapses, and motor performance on the rotarod test, whereas an augmentation of tonic GABA release by astrocyte-specific overexpression of MAOB resulted in a reduced neuronal excitability, synaptic transmission, and motor performance. The bidirectional modulation of astrocytic GABA by genetic alteration of Best1 or MAOB was confirmed by immunostaining and in vivo microdialysis. These findings indicate that astrocytes are the key player in motor coordination through tonic GABA release by modulating neuronal excitability and could be a good therapeutic target for various movement and psychiatric disorders, which show a disturbed excitation/inhibition balance.


Assuntos
Astrócitos/metabolismo , Cerebelo/metabolismo , Desempenho Psicomotor/fisiologia , Células de Purkinje/metabolismo , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Astrócitos/citologia , Bestrofinas/genética , Bestrofinas/metabolismo , Cerebelo/citologia , Camundongos Endogâmicos BALB C , Camundongos Knockout , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Células de Purkinje/citologia , Ácido gama-Aminobutírico/genética
4.
Sci Rep ; 14(1): 14390, 2024 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-38909074

RESUMO

Recent advances in deep learning have led to a surge in computer vision research, including the recognition and classification of human behavior in video data. However, most studies have focused on recognizing individual behaviors, whereas recognizing crowd behavior remains a complex problem because of the large number of interactions and similar behaviors among individuals or crowds in video surveillance systems. To solve this problem, we propose a three-dimensional atrous inception module (3D-AIM) network, which is a crowd behavior classification model that uses atrous convolution to explore interactions between individuals or crowds. The 3D-AIM network is a 3D convolutional neural network that can use receptive fields of various sizes to effectively identify specific features that determine crowd behavior. To further improve the accuracy of the 3D-AIM network, we introduced a new loss function called the separation loss function. This loss function focuses the 3D-AIM network more on the features that distinguish one type of crowd behavior from another, thereby enabling a more precise classification. Finally, we demonstrate that the proposed model outperforms existing human behavior classification models in terms of accurately classifying crowd behaviors. These results suggest that the 3D-AIM network with a separation loss function can be valuable for understanding complex crowd behavior in video surveillance systems.

5.
Cells ; 12(24)2023 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-38132138

RESUMO

The therapeutic potential of directly reprogrammed neural stem cells (iNSCs) for neurodegenerative diseases relies on reducing the innate tumorigenicity of pluripotent stem cells. However, the heterogeneity within iNSCs is a major hurdle in quality control prior to clinical applications. Herein, we generated iNSCs from human fibroblasts, by transfecting transcription factors using Sendai virus particles, and characterized the expression of iNSC markers. Using immunostaining and quantitative real time -polymerase chain reaction (RT -qPCR), no differences were observed between colonies of iNSCs and iNSC-derived neurons. Unexpectedly, patch-clamp analysis of iNSC-derived neurons revealed distinctive action potential firing even within the same batch product. We performed single-cell RNA sequencing in fibroblasts, iNSCs, and iNSC-derived neurons to dissect their functional heterogeneity and identify cell fate regulators during direct reprogramming followed by neuronal differentiation. Pseudotime trajectory analysis revealed distinct cell types depending on their gene expression profiles. Differential gene expression analysis showed distinct NEUROG1, PEG3, and STMN2 expression patterns in iNSCs and iNSC-derived neurons. Taken together, we recommend performing a predictable functional assessment with appropriate surrogate markers to ensure the quality control of iNSCs and their differentiated neurons, particularly before cell banking for regenerative cell therapy.


Assuntos
Células-Tronco Neurais , Células-Tronco Pluripotentes , Humanos , Neurônios , Células-Tronco Neurais/metabolismo , Diferenciação Celular/genética , Análise de Sequência de RNA
6.
Exp Mol Med ; 55(6): 1232-1246, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37258580

RESUMO

SIRT1, a member of the mammalian sirtuin family, is a nicotinamide adenosine dinucleotide (NAD)-dependent deacetylase with key roles in aging-related diseases and cellular senescence. However, the mechanism by which SIRT1 protein homeostasis is controlled under senescent conditions remains elusive. Here, we revealed that SIRT1 protein is significantly downregulated due to ubiquitin-mediated proteasomal degradation during stress-induced premature senescence (SIPS) and that SIRT1 physically associates with anaphase-promoting complex/cyclosome (APC/C), a multisubunit E3 ubiquitin ligase. Ubiquitin-dependent SIRT1 degradation is stimulated by the APC/C coactivator Cdh1 and not by the coactivator Cdc20. We found that Cdh1 depletion impaired the SIPS-promoted downregulation of SIRT1 expression and reduced cellular senescence, likely through SIRT1-driven p53 inactivation. In contrast, AROS, a SIRT1 activator, reversed the SIRT1 degradation induced by diverse stressors and antagonized Cdh1 function through competitive interactions with SIRT1. Furthermore, our data indicate opposite roles for Cdh1 and AROS in the epigenetic regulation of the senescence-associated secretory phenotype genes IL-6 and IL-8. Finally, we demonstrated that pinosylvin restores downregulated AROS (and SIRT1) expression levels in bleomycin-induced mouse pulmonary senescent tissue while repressing bleomycin-promoted Cdh1 expression. Overall, our study provides the first evidence of the reciprocal regulation of SIRT1 stability by APC/C-Cdh1 and AROS during stress-induced premature senescence, and our findings suggest pinosylvin as a potential senolytic agent for pulmonary fibrosis.


Assuntos
Epigênese Genética , Sirtuína 1 , Animais , Camundongos , Ciclossomo-Complexo Promotor de Anáfase/genética , Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Proteínas de Ciclo Celular/metabolismo , Senescência Celular , Sirtuína 1/genética , Sirtuína 1/metabolismo , Ubiquitina/metabolismo , Ubiquitinação
7.
Nat Neurosci ; 26(9): 1541-1554, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37563296

RESUMO

Social hierarchy is established as an outcome of individual social behaviors, such as dominance behavior during long-term interactions with others. Astrocytes are implicated in optimizing the balance between excitatory and inhibitory (E/I) neuronal activity, which may influence social behavior. However, the contribution of astrocytes in the prefrontal cortex to dominance behavior is unclear. Here we show that dorsomedial prefrontal cortical (dmPFC) astrocytes modulate E/I balance and dominance behavior in adult male mice using in vivo fiber photometry and two-photon microscopy. Optogenetic and chemogenetic activation or inhibition of dmPFC astrocytes show that astrocytes bidirectionally control male mouse dominance behavior, affecting social rank. Dominant and subordinate male mice present distinct prefrontal synaptic E/I balance, regulated by astrocyte activity. Mechanistically, we show that dmPFC astrocytes control cortical E/I balance by simultaneously enhancing presynaptic-excitatory and reducing postsynaptic-inhibitory transmission via astrocyte-derived glutamate and ATP release, respectively. Our findings show how dmPFC astrocyte-neuron communication can be involved in the establishment of social hierarchy in adult male mice.


Assuntos
Astrócitos , Sinapses , Camundongos , Animais , Masculino , Sinapses/fisiologia , Astrócitos/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal , Transmissão Sináptica/fisiologia
8.
Front Cell Neurosci ; 16: 954807, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36072563

RESUMO

Lead (Pb) is one of the most prevalent heavy metals we encounter daily. Although there are many reports regarding their toxic effects on humans, the effects of exposure to low lead concentrations throughout the pregnancy period on the offspring are not fully elucidated yet. This study aimed to investigate the cellular mechanisms that occur in response to lead exposure. To this end, we administered lead-containing water to pregnant mice from the day of conception till delivery or till day 28 postnatally. Furthermore, we performed neurodevelopmental disorder-related behavior tests and RNA-sequencing analysis. We used both genders for all experiments because neurodevelopmental disorders usually show several sex-dependent differences. The results revealed increased levels of gliosis in the cerebella of lead-exposed pups compared to those in littermates belonging to the control group. Additionally, we observed altered behaviors of male mice in the autism spectrum disorder-related tests. RNA-sequencing results revealed changes in gamma-aminobutyric acid (GABA) signaling in the lead-exposed mouse model. Specifically, the lead-exposed male mice showed decreased monoamine oxidase B and increased levels of diamine oxidase enzyme, which is related to the synthesis of GABA in astrocytes. These findings demonstrate sex-dependent basal developmental changes in glial cells and an increased prevalence of autistic-like behaviors in the young pups of mothers exposed to lead during pregnancy.

9.
Rheumatol Int ; 31(6): 725-30, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20130880

RESUMO

Acupuncture has been used to treat various clinical diseases in Eastern medicine. To investigate the analgesic effect of electroacupuncture (EA) pretreatment on carrageenan-induced inflammatory pain, we studied on the effect of EA parameters on an animal model of acute arthritic pain. Pretreatment with 1 mA, 10 Hz EA prior to carrageenan injection under halothane anesthesia suppressed carrageenan-induced pain. Interestingly, EA stimulation of the 'Zu-San-Li' (ST36) acupuncture point (1 mA, 10 Hz) contralateral to the site of the carrageenan injection in the rat synovial cavity produced significantly greater improvement of the weight-bearing force compared with EA stimulation of the 'San-Yin-Jiao' acupuncture point. To determine how ST36 EA treatment suppresses carrageenan-induced inflammatory pain, we examined the effect of a mu opioid receptor antagonist on ST36 EA-induced analgesia. The selective antagonist of the mu opioid receptor (OR) significantly suppressed contralateral ST36 EA-induced analgesia against carrageenan-induced inflammation. These results suggested that the analgesic effect mediated by the mu OR during low-frequency contralateral EA pretreatment has an anti-nociceptive action against inflammatory pain and that it may provide a potential strategy to treat inflammatory arthritic pain.


Assuntos
Eletroacupuntura/métodos , Inflamação/terapia , Dor/prevenção & controle , Receptores Opioides mu/metabolismo , Pontos de Acupuntura , Animais , Carragenina , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/metabolismo , Injeções Intra-Articulares , Masculino , Dor/induzido quimicamente , Dor/metabolismo , Medição da Dor , Limiar da Dor , Ratos , Ratos Sprague-Dawley , Suporte de Carga/fisiologia
10.
Artigo em Inglês | MEDLINE | ID: mdl-18955367

RESUMO

Using spontaneously hypertensive rats (SHR), this study investigated whether electroacupuncture (EA) could reduce early stage hypertension by examining nitric oxide (NO) levels in plasma and nitric oxide synthase (NOS) levels in the mesenteric resistance artery. EA was applied to the acupuncture point Governor Vessel 20 (GV20) or to a non-acupuncture point in the tail twice weekly for 3 weeks under anesthesia. In conscious SHR and normotensive Wistar Kyoto (WKY) rats, blood pressure was determined the day after EA treatment by the tail-cuff method. We measured plasma NO concentration, and evaluated endothelial NO syntheses (eNOS) and neuronal NOS (nNOS) protein expression in the mesenteric artery. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were lower after 3 weeks of GV20 treatment than EA at non-acupuncture point and no treatment control in SHR. nNOS expression by EA was significantly different between both WKY and no treatment SHR control, and EA at GV20 in SHR. eNOS expression was significantly high in EA at GV 20 compared with no treatment control. In conclusion, EA could attenuate the blood pressure elevation of SHR, along with enhancing NO/NOS activity in the mesenteric artery in SHR.

11.
Genesis ; 48(11): 673-8, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20848592

RESUMO

Activin receptor-like kinase 1 (ACVRL1; ALK1) is predominantly expressed in arterial endothelial cells and plays an important role in angiogenesis. ACVRL1 mutations cause hereditary hemorrhagic telangiectasia (HHT), a genetic vascular disorder for which the underlying mechanism is poorly understood. We have found that expression of transmembrane protein 100 (Tmem100) is downregulated in the lung of Acvrl1-deficient mice; however, its function is unknown. To elucidate the role of Tmem100 in vivo, we generated a conditional knockout allele for Tmem100 in which exon3, containing the entire coding sequence, was flanked by loxP sequences. The targeted allele also possessed a lacZ reporter cassette in intron2 for visualization of Tmem100 expression. We found that Tmem100 was predominantly expressed in arterial endothelial cells of developing embryos. The conditional and reporter allele will be a useful resource to investigate the in vivo role of Tmem100, especially in angiogenesis.


Assuntos
Técnicas de Transferência de Genes , Genes Reporter/fisiologia , Proteínas de Membrana/genética , Transgenes , Receptores de Ativinas Tipo I/genética , Receptores de Ativinas Tipo I/fisiologia , Receptores de Activinas Tipo II , Alelos , Sequência de Aminoácidos , Animais , Células Cultivadas , Embrião de Mamíferos , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Dados de Sequência Molecular , Especificidade de Órgãos/genética , Homologia de Sequência de Aminoácidos , Transgenes/fisiologia , Estudos de Validação como Assunto
12.
Cells ; 9(10)2020 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-32992620

RESUMO

Recent studies have revealed synaptic dysfunction to be a hallmark of various psychiatric diseases, and that glial cells participate in synapse formation, development, and plasticity. Glial cells contribute to neuroinflammation and synaptic homeostasis, the latter being essential for maintaining the physiological function of the central nervous system (CNS). In particular, glial cells undergo gliotransmission and regulate neuronal activity in tripartite synapses via ion channels (gap junction hemichannel, volume regulated anion channel, and bestrophin-1), receptors (for neurotransmitters and cytokines), or transporters (GLT-1, GLAST, and GATs) that are expressed on glial cell membranes. In this review, we propose that dysfunction in neuron-glia interactions may contribute to the pathogenesis of neurodevelopmental disorders. Understanding the mechanisms of neuron-glia interaction for synapse formation and maturation will contribute to the development of novel therapeutic targets of neurodevelopmental disorders.


Assuntos
Transtornos do Neurodesenvolvimento/genética , Neurogênese/genética , Neuroglia/metabolismo , Neurônios/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Homeostase/genética , Humanos , Transtornos do Neurodesenvolvimento/patologia , Neuroglia/patologia , Neurônios/patologia
13.
Neuron ; 108(4): 691-706.e10, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-32905785

RESUMO

Sensory discrimination is essential for survival. However, how sensory information is finely controlled in the brain is not well defined. Here, we show that astrocytes control tactile acuity via tonic inhibition in the thalamus. Mechanistically, diamine oxidase (DAO) and the subsequent aldehyde dehydrogenase 1a1 (Aldh1a1) convert putrescine into GABA, which is released via Best1. The GABA from astrocytes inhibits synaptically evoked firing at the lemniscal synapses to fine-tune the dynamic range of the stimulation-response relationship, the precision of spike timing, and tactile discrimination. Our findings reveal a novel role of astrocytes in the control of sensory acuity through tonic GABA release.


Assuntos
Astrócitos/fisiologia , Inibição Neural/fisiologia , Tálamo/fisiologia , Percepção do Tato/fisiologia , Ácido gama-Aminobutírico/fisiologia , Família Aldeído Desidrogenase 1/metabolismo , Amina Oxidase (contendo Cobre)/metabolismo , Animais , Astrócitos/metabolismo , Astrócitos/ultraestrutura , Bestrofinas/biossíntese , Bestrofinas/genética , Feminino , Antagonistas GABAérgicos , Imuno-Histoquímica , Potenciais Pós-Sinápticos Inibidores/fisiologia , Macrolídeos/farmacologia , Masculino , Camundongos , Camundongos Knockout , Microscopia Eletrônica , Neurônios/metabolismo , Neurônios/fisiologia , Técnicas de Patch-Clamp , Picrotoxina/farmacologia , Cultura Primária de Células , Piridazinas/farmacologia , RNA Interferente Pequeno/farmacologia , Retinal Desidrogenase/metabolismo , Ácido gama-Aminobutírico/biossíntese , Ácido gama-Aminobutírico/farmacologia
14.
Anim Cells Syst (Seoul) ; 22(4): 213-218, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30460100

RESUMO

The amyloid-ß (Aß) hypothesis has been the leading explanation for the pathogenesis of Alzheimer's disease (AD). The most common traits of AD are cognitive impairments and memory loss, which are associated with the accumulation of Aß. Aß aggregates activate glial cells, which in turn remove Aß. Because microglia act as immune cells in the brain, most glia-related studies of AD have focused primarily on this cell type. However, astrocytes, another type of glial cell, also participate in the brain immune system, synaptic formation, brain homeostasis, and various other brain functions. Accordingly, many studies on the underlying mechanisms of AD have investigated not only neurons but also glial cells. Although these studies suggest that microglia and astrocytes are effective targets for AD therapeutics, other recent studies have raised questions regarding whether microglial cells and/or astrocytes serve a neuroprotective or neurotoxic function in AD. To gain a better understanding of the mechanisms of AD and identify novel targets for AD treatment, in this review, we consider the role of both microglia and astrocytes in AD.

15.
Sci Rep ; 8(1): 11589, 2018 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-30072733

RESUMO

For decades, the glial function has been highlighted not only as the 'structural glue', but also as an 'active participant' in neural circuits. Here, we suggest that tumor necrosis factor α (TNF-α), a key inflammatory cytokine, alters the neural activity of the cerebellar Purkinje cells (PCs) by facilitating gliotransmission in the juvenile male rat cerebellum. A bath application of TNF-α (100 ng/ml) in acute cerebellar slices elevates spiking activity of PCs with no alterations in the regularity of PC firings. Interestingly, the effect of TNF-α on the intrinsic excitability of PCs was abolished under a condition in which the type1 TNF receptor (TNFR1) in Bergmann glia (BG) was genetically suppressed by viral delivery of an adeno-associated virus (AAV) containing TNFR1-shRNA. In addition, we measured the concentration of glutamate derived from dissociated cerebellar cortical astrocyte cultures treated with TNF-α and observed a progressive increase of glutamate in a time-dependent manner. We hypothesised that TNF-α-induced elevation of glutamate from BGs enveloping the synaptic cleft may directly activate metabotropic glutamate receptor1 (mGluR1). Pharmacological inhibition of mGluR1, indeed, prevented the TNF-α-mediated elevation of the intrinsic excitability in PCs. Taken together, our study reveals that TNF-α triggers glutamate release in BG, thereby increasing the intrinsic excitability of cerebellar PCs in a mGluR1-dependent manner.


Assuntos
Astrócitos/metabolismo , Ácido Glutâmico/metabolismo , Células de Purkinje/metabolismo , Transmissão Sináptica , Fator de Necrose Tumoral alfa/metabolismo , Animais , Astrócitos/citologia , Masculino , Camundongos , Células de Purkinje/citologia , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo
17.
Clin Cancer Res ; 12(9): 2788-94, 2006 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-16675572

RESUMO

PURPOSE: Aberrant DNA methylation, now recognized as a contributing factor to neoplasia, often shows definitive gene/sequence preferences unique to specific cancer types. Correspondingly, distinct combinations of methylated loci can function as biomarkers for numerous clinical correlates of ovarian and other cancers. EXPERIMENTAL DESIGN: We used a microarray approach to identify methylated loci prognostic for reduced progression-free survival (PFS) in advanced ovarian cancer patients. Two data set classification algorithms, Significance Analysis of Microarray and Prediction Analysis of Microarray, successfully identified 220 candidate PFS-discriminatory methylated loci. Of those, 112 were found capable of predicting PFS with 95% accuracy, by Prediction Analysis of Microarray, using an independent set of 40 advanced ovarian tumors (from 20 short-PFS and 20 long-PFS patients, respectively). Additionally, we showed the use of these predictive loci using two bioinformatics machine-learning algorithms, Support Vector Machine and Multilayer Perceptron. CONCLUSION: In this report, we show that highly prognostic DNA methylation biomarkers can be successfully identified and characterized, using previously unused, rigorous classifying algorithms. Such ovarian cancer biomarkers represent a promising approach for the assessment and management of this devastating disease.


Assuntos
Metilação de DNA , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Biomarcadores Tumorais/análise , Mapeamento Cromossômico , Feminino , Humanos , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Reprodutibilidade dos Testes
18.
Exp Neurobiol ; 26(3): 122-131, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28680297

RESUMO

In the healthy brain, gamma-aminobutyric acid (GABA) is regulated by neurons and glia. This begs the question: what happens in the malfunctioning brain? There are many reasons why diseases occur, including genetic mutations, systemic problems, and environmental influences. There are also many ways in which GABA can become dysregulated, such as through alterations in its synthesis or release, and changes in systems that respond to it. Notably, dysregulation of GABA can have a large impact on the brain. To date, few reviews have examined brain diseases in which dysregulation of GABA is implicated as an underlying factor. Accordingly, the time is ripe for investigating alterations in GABAergic signaling that may play a role in changes in neuronal activity observed in the major brain disorders that occur during various stages of life. This review is meant to provide a better understanding of the role of GABA in brain health and contributor to social problems from a scientific perspective.

19.
Exp Neurobiol ; 26(4): 206-212, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28912643

RESUMO

About 5~12% of school-aged children suffer from the Attention-Deficit/Hyperactivity Disorder (ADHD). However, the core mechanism of ADHD remains unclear. G protein-coupled receptor kinase-interacting protein-1 (GIT1) has recently been reported to be associated with ADHD in human and the genetic deletion of GIT1 result in ADHD-like behaviors in mice. Mice lacking GIT1 shows a shift in neuronal excitation/inhibition (E/I) balance. However, the pricise mechanism for E/I imbalance and the role of neuron-glia interaction in GIT1 knockout (KO) mice have not been studied. Especially, a possible contribution of glial GABA and tonic inhibition mediated by astrocytic GABA release in the mouse model for ADHD remains unexplored. Therefore, we investigated the changes in the amount of GABA and degree of tonic inhibition in GIT1 KO mice. We observed a decreased glial GABA intensity in GIT1 KO mice compared to wild type (WT) mice and an attenuation of tonic current from cerebellar granule cells in GIT1 KO mice. Our study identifies the previously unknown mechanism of reduced astrocytic GABA and tonic inhibition in GIT1 lacking mice as a potential cause of hyperactivity disorder.

20.
Cardiovasc Res ; 105(3): 353-60, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25538155

RESUMO

AIMS: TMEM100 was previously identified as a downstream target of activin receptor-like kinase 1 (ALK1; ACVRL1) signalling. Mutations on ALK1 cause hereditary haemorrhagic telangiectasia (HHT), a vascular disorder characterized by mucocutaneous telangiectases and visceral arteriovenous malformations (AVMs). The aims of this study are to investigate the in vivo role of TMEM100 at various developmental and adult stages and to determine the extent to which TMEM100 contributed to the development of AVMs as a key downstream effector of ALK1. METHODS AND RESULTS: Blood vasculature in Tmem100-null embryos and inducible Tmem100-null neonatal and adult mice was examined. We found that TMEM100 deficiency resulted in cardiovascular defects at embryonic stage; dilated vessels, hyperbranching, and increased number of filopodia in the retinal vasculature at neonatal stage; and various vascular abnormalities, including internal haemorrhage, arteriovenous shunts, and weakening of vasculature with abnormal elastin layers at adult stage. However, arteriovenous shunts in adult mutant mice appeared to be underdeveloped without typical tortuosity of vessels associated with AVMs. We uncovered that the expression of genes encoding cell adhesion and extracellular matrix proteins was significantly affected in lungs of adult mutant mice. Especially Mfap4, which is associated with elastin fibre formation, was mostly down-regulated. CONCLUSION: These results demonstrate that TMEM100 has essential functions for the maintenance of vascular integrity as well as the formation of blood vessels. Our results also indicate that down-regulation of Tmem100 is not the central mechanism of HHT pathogenesis, but it may contribute to the development of vascular pathology of HHT by weakening vascular integrity.


Assuntos
Malformações Arteriovenosas/metabolismo , Pulmão/irrigação sanguínea , Proteínas de Membrana/metabolismo , Vasos Retinianos/metabolismo , Telangiectasia Hemorrágica Hereditária/metabolismo , Receptores de Ativinas Tipo I/genética , Receptores de Ativinas Tipo I/metabolismo , Receptores de Activinas Tipo II , Fatores Etários , Animais , Malformações Arteriovenosas/embriologia , Malformações Arteriovenosas/genética , Malformações Arteriovenosas/patologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Modelos Animais de Doenças , Elastina/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genótipo , Idade Gestacional , Glicoproteínas/genética , Glicoproteínas/metabolismo , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfogênese , Fenótipo , Vasos Retinianos/anormalidades , Vasos Retinianos/patologia , Transdução de Sinais , Telangiectasia Hemorrágica Hereditária/embriologia , Telangiectasia Hemorrágica Hereditária/genética , Telangiectasia Hemorrágica Hereditária/patologia
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