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OBJECTIVE: Kamishoyosan (KSS), a traditional Japanese Kampo medicine, is widely used to treat neuropsychiatric symptoms in perimenopausal and postmenopausal women. We aimed to elucidate the functional mechanisms underlying KSS-mediated reduction of stress response behaviors and neuropsychological symptoms in perimenopausal and postmenopausal women. METHODS: Female mice were bilaterally ovariectomized (OVX) at the age of 12 weeks and exposed to chronic water immersion and restraint stress for three weeks. Among them, mice in the OVX+stress+KSS group were fed chow containing KSS from one week before exposure to chronic stress until the end of the experiment. Firstly, we performed a marble burying test and measured serum corticosterone levels to assess irritability and stress conditions. Next, we examined whether KSS affects microRNA-18 (miR-18) and glucocorticoid receptor (GR) protein expression, as well as the basal dendritic spine morphology of pyramidal neurons in the medial prefrontal cortex (mPFC) of postmenopausal chronic stress-exposed mice. Analyzed data were expressed as mean ± standard deviation. Tukey's post hoc test, followed by analysis of variance (ANOVA), was used for among-group comparisons. RESULTS: KSS administration normalized chronic stress-induced unstable emotion-like behavior and upregulated plasma corticosterone levels. Furthermore, KSS ameliorated GR protein expression by downregulating miR-18 expression in the mPFC and recovered the immature morphological changes in spine formation of pyramidal neurons in the mPFC of OVX mice following chronic stress exposure. CONCLUSIONS: KSS administration in postmenopausal chronic stress-exposed mice exerted anti-stress effects and improved the basal dendritic spine morphology of pyramidal neurons by regulating miR-18 and glucocorticoid receptor expression in the mPFC.
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Major depressive disorder (MDD) is a multifactorial disease affected by several environmental factors. Although several potential onset hypotheses have been identified, the molecular mechanisms underlying the pathogenesis of this disorder remain unclear. Several recent studies have suggested that among many environmental factors, inflammation and immune abnormalities in the brain or the peripheral tissues are associated with the onset of MDDs. Furthermore, several stress-related hypotheses have been proposed to explain the onset of MDDs. Thus, inflammation or immune abnormalities can be considered stress responses that occur within the brain or other tissues and are regarded as one of the mechanisms underlying the stress hypothesis of MDDs. Therefore, we introduce several current advances in inflammation studies in the brain that might be related to the pathophysiology of MDD due to stress exposure in this review.
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Protein arginine methylation has been recognized as one of key posttranslational modifications for refined protein functions, mediated by protein arginine methyltransferases (Prmts). Coactivator-associated arginine methyltransferase (Carm1, also known as Prmt4) participates in various cellular events, such as cell survival, proliferation, and differentiation through its protein arginine methylation activities. Carm1 regulates cell proliferation of a neuronal cell line and is reportedly expressed in the mammalian brain. However, its detailed function in the central nervous system, particularly in glial cells, remains largely unexplored. In this study, Carm1 exhibited relatively high expression in oligodendrocyte (OL) lineage cells present in the corpus callosum of the developing brain, followed by a remarkable downregulation after active myelination. The suppression of Carm1 activity by inhibitors in isolated oligodendrocyte precursor cells (OPCs) reduced the number of Ki67-expressing and BrdU-incorporated proliferating cells. Furthermore, Carm1 inactivation attenuated OL differentiation, as determined by the expression of Plp, a reliable myelin-related marker. It also impaired the extension of OL processes, accompanied by a significant reduction in gene expression related to OL differentiation and myelination, such as Sox10, Cnp, Myrf, and Mbp. In addition, OLs co-cultured with embryonic dorsal root ganglia neurons demonstrated that Carm1 activity is required for the appropriate formation of myelin processes and myelin sheaths around neuronal axons, and the induction of the clustering of Caspr, a node of Ranvier structural molecule. Thus, we propose that Carm1 is an essential molecule for the development of OPCs and OLs during brain development.
Assuntos
Corpo Caloso , Oligodendroglia , Animais , Arginina/metabolismo , Diferenciação Celular , Corpo Caloso/metabolismo , Mamíferos/metabolismo , Metilação , Oligodendroglia/metabolismo , Proteína-Arginina N-MetiltransferasesRESUMO
The diagnosis of coronary artery disease (CAD) with nonstress echocardiography remains challenging. Although the assessment of either early systolic lengthening (ESL) or postsystolic shortening (PSS) allows the sensitive detection of CAD, it is unclear whether the integrated analysis of ESL and PSS in addition to the peak systolic strain can improve the diagnostic accuracy. We investigated the incremental value of ESL and PSS in detecting left anterior descending artery (LAD) stenosis using nonstress speckle-tracking echocardiography. Fifty-nine patients with significant LAD stenosis but without visual wall motion abnormalities on echocardiography at rest (30 single-vessel stenosis, 29 multivessel stenosis) and 43 patients without significant stenosis of any vessel were enrolled. The peak systolic strain, the time to ESL (TESL), and the time to PSS (TPSS) were analyzed in all LAD segments, and the incremental values of the TESL and TPSS in detecting LAD stenosis and the diagnostic accuracy were evaluated. In the apical anterior segment, the peak systolic strain was significantly lower and TESL and TPSS were significantly longer in the single-vessel group than in the no stenosis group. In the single-vessel group, the addition of TESL and TPSS to the peak systolic strain significantly increased the model power in detecting stenosis, and the integrated analysis improved diagnostic accuracy compared with the peak systolic strain alone. In contrast, this incremental value was not demonstrated in the multivessel group. The integrated analysis of the peak systolic strain, ESL, and PSS may allow better screening of single-vessel LAD stenosis using nonstress speckle-tracking echocardiography.
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Doença da Artéria Coronariana/diagnóstico por imagem , Estenose Coronária/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Ecocardiografia/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Females are well known to suffer disproportionately more than males from stress-related neuropsychiatric disorders, especially during perimenopausal and postmenopausal periods. In addition to a decline in serum estradiol levels, environmental stress and social stress likely contribute to the development of neuropsychiatric symptoms in perimenopausal and postmenopausal women. Kamishoyosan (KSS) is a traditional Japanese Kampo medicine, composed of a specified mixture of 10 crude compounds derived from plant sources, widely used for various neuropsychiatric symptoms in perimenopausal and postmenopausal women. However, the molecular mechanisms underlying KSS-mediated attenuation of neuropsychological symptoms and stress-response behaviors in perimenopausal and postmenopausal women remain unknown. In the present study, we first established a mouse model for postmenopausal depression-like signs using chronic water-immersion and restraint-stressed ovariectomized (OVX) mice to investigate the underlying molecular mechanism of KSS. We found that continuous administration of KSS to these mice normalized the activation of the hypothalamic-pituitary-adrenal (HPA) axis, ameliorated stress-induced depressive behavior, and prevented a decrease of neurogenesis in the hippocampus. As previous studies have implicated dysfunction of the hippocampal 5-HT1A receptor (5-HT1AR) in depressive disorders, we also evaluated the effect of KSS on 5-HT1AR expression and the protein kinase A- (PKA-) cAMP response element-binding- (CREB-) brain-derived neurotrophic factor (BDNF) signaling pathway in the hippocampus in this model. The level of 5-HT1AR in the hippocampus decreased in chronic stress-exposed OVX mice, while KSS treatment normalized the stress-induced decrease in 5-HT1AR expression in the hippocampus of chronic stress-exposed OVX mice. Furthermore, we found that KSS treatment upregulated the expression levels of phosphorylated PKA (p-PKA), phosphorylated CREB (p-CREB), and BDNF in the hippocampus in chronic stress-exposed OVX mice. These results suggest that KSS improves neuropsychiatric symptoms through 5-HT1AR and PKA-CREB-BDNF signaling in the hippocampus in postmenopausal women.
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Oligodendrocytes, the myelin-forming cells in the central nervous system (CNS), undergo morphological differentiation characterized by elaborated branched processes to enwrap neuronal axons. However, the basic molecular mechanisms underlying oligodendrocyte morphogenesis remain unknown. Herein, we describe the essential roles of Nuclear Distribution E Homolog 1 (NDE1), a dynein cofactor, in oligodendrocyte morphological differentiation. In the mouse corpus callosum, Nde1 mRNA expression was detected in oligodendrocyte lineage cells at the postnatal stage. In vitro analysis revealed that downregulation of NDE1 by siRNA impaired the outgrowth and extensive branching of oligodendrocyte processes and led to a decrease in the expression of myelin-related markers, namely, CNPase and MBP. In myelinating co-cultures with dorsal root ganglion (DRG) neurons, NDE1-knockdown oligodendrocyte precursor cells (OPCs) failed to develop into MBP-positive oligodendrocytes with multiple processes contacting DRG axons. Immunoprecipitation studies showed that NDE1 interacts with the dynein intermediate chain (DIC) in oligodendrocytes, and an overexpressed DIC-binding region of NDE1 exerted effects on oligodendrocyte morphogenesis that were similar to those following NDE1 knockdown. Furthermore, NDE1-knockdown-impaired oligodendrocyte process formation was rescued by siRNA-resistant wild-type NDE1 but not by DIC-binding region-deficient NDE1 overexpression. These results suggest that NDE1 plays a crucial role in oligodendrocyte morphological differentiation via interaction with dynein.
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Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular , Gânglios Espinais/citologia , Neurogênese , Células Precursoras de Oligodendrócitos/citologia , Oligodendroglia/citologia , Animais , Proteínas de Ciclo Celular/genética , Linhagem da Célula , Células Cultivadas , Técnicas de Cocultura , Gânglios Espinais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos , Bainha de Mielina/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismoRESUMO
Abnormalities in limbic neural circuits have been implicated in the onset of anxiety disorders. However, the molecular pathogenesis underlying anxiety disorders remains poorly elucidated. Here, we demonstrate that myristoylated alanine-rich C-kinase substrate like 1 (MARCKSL1) regulates amygdala circuitry to control the activity of the hypothalamic-pituitary-adrenal (HPA) axis, as well as induces anxiety-like behaviors in mice. MARCKSL1 expression was predominantly localized in the prefrontal cortex (PFC), hypothalamus, hippocampus, and amygdala of the adult mouse brain. MARCKSL1 transgenic (Tg) mice exhibited anxiety-like behaviors dependent on corticotropin-releasing hormone. MARCKSL1 increased spine formation in the central amygdala, and downregulation of MARCKSL1 in the amygdala normalized both increased HPA axis activity and elevated anxiety-like behaviors in Tg mice. Furthermore, MARCKSL1 expression was increased in the PFC and amygdala in a brain injury model associated with anxiety-like behaviors. Our findings suggest that MARCKSL1 expression in the amygdala plays an important role in anxiety-like behaviors.
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Tonsila do Cerebelo/metabolismo , Ansiedade/metabolismo , Ansiedade/patologia , Espinhas Dendríticas/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Envelhecimento/metabolismo , Tonsila do Cerebelo/patologia , Animais , Comportamento Animal , Proteínas de Ligação a Calmodulina , Hormônio Liberador da Corticotropina/biossíntese , Regulação para Baixo , Emoções , Técnicas de Silenciamento de Genes , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos , Núcleo Hipotalâmico Paraventricular/metabolismo , Regulação para CimaRESUMO
Ovarian insufficiency is a serious complication for young women who undergo hematopoietic stem cell transplantation (HSCT). Reduced-intensity conditioning (RIC) has been utilized more widely due to its reduced toxicity; however, there is a lack of data concerning ovarian function after HSCT with RIC. We investigated the ovarian function in patients who received HSCT with RIC, compared to those who received myeloablative conditioning (MAC). The records of 69 female patients who received allogeneic HSCT at the institution under 40 years of age at transplantation from 1991 to 2012 were retrospectively analyzed. Prevalence of ovarian insufficiency was significantly lower in patients conditioned with RIC than in those conditioned with MAC (4/27 = 14.8% for RIC and 36/42 = 85.7% for MAC, p < 0.0001). A younger age at HSCT was associated with a lower risk of ovarian insufficiency. Among the 40 patients with ovarian insufficiency, four patients recovered ovarian function, and two conceived following hormone-replacement therapy (HRT). A higher serum E2 level prior to HRT was a significant predictor for the restoration of ovarian function (p = 0.0028). In conclusion, RIC was significantly less toxic to ovarian function compared with MAC. HSCT-associated ovarian insufficiency is not irreversible, and a higher E2 level may predict the restoration of ovarian function.
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Estradiol/sangue , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Avaliação de Resultados em Cuidados de Saúde , Insuficiência Ovariana Primária/etiologia , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Adulto , Fatores Etários , Feminino , Humanos , Insuficiência Ovariana Primária/sangue , Insuficiência Ovariana Primária/diagnóstico , Prognóstico , Adulto JovemRESUMO
Pregnane X receptor (PXR) is involved in the transactivation of ABCB1 gene by rifampicin (RIF). However, we found that increase in ABCB1 mRNA by RIF was observed in LS180 cells but not in HepG2 cells. Since both cell lines expressed PXR equally, we hypothesized that a factor(s) other than PXR is responsible for PXR-mediated transactivation of the ABCB1 gene. Reporter activities of a distal enhancer module containing direct repeat 4 (DR4) motifs were increased by RIF in LS180 cells but not in HepG2 cells. Mutation of the DR4 motifs diminished the increase in reporter activities in LS180 cells. Gene subtraction showed that epithelial-specific ETS factor 3 (ESE-3) is a transcription factor enriched in LS180 cells compared to HepG2 cells. When ESE-3 and PXR were co-expressed in HepG2 cells, reporter activities were increased by RIF, which were completely abolished by mutation of DR4 motifs. Chromatin immunoprecipitation assays showed specific binding of ESE-3 to the region containing the DR4 motifs of the ABCB1 gene. Finally, knock-down of ESE-3 in LS180 cells resulted in a decrease in the induction of ABCB1 mRNA. These results suggest that ESE-3 is a factor responsible for PXR-mediated transactivation of the ABCB1 gene by RIF in LS180 cells.
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Fígado/metabolismo , Receptores de Esteroides/genética , Fatores de Transcrição/genética , Ativação Transcricional/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Linhagem Celular Tumoral , Genes Reporter/genética , Células Hep G2 , Fator 4 Nuclear de Hepatócito/genética , Humanos , Fígado/efeitos dos fármacos , Mutação/efeitos dos fármacos , Mutação/genética , Receptor de Pregnano X , RNA Mensageiro/genética , Rifampina/farmacologia , Ativação Transcricional/efeitos dos fármacosRESUMO
Repeated stressful events are associated with the onset of major depressive disorder (MDD). We previously showed oligodendrocyte (OL)-specific activation of the serum/glucocorticoid-regulated kinase (SGK)1 cascade, increased expression of axon-myelin adhesion molecules, and elaboration of the oligodendrocytic arbor in the corpus callosum of chronically stressed mice. In the current study, we demonstrate that the nodes and paranodes of Ranvier in the corpus callosum were narrower in these mice. Chronic stress also led to diffuse redistribution of Caspr and Kv 1.1 and decreased the activity in white matter, suggesting a link between morphological changes in OLs and inhibition of axonal activity. OL primary cultures subjected to chronic stress resulted in SGK1 activation and translocation to the nucleus, where it inhibited the transcription of metabotropic glutamate receptors (mGluRs). Furthermore, the cAMP level and membrane potential of OLs were reduced by chronic stress exposure. We showed by diffusion tensor imaging that the corpus callosum of patients with MDD exhibited reduced fractional anisotropy, reflecting compromised white matter integrity possibly caused by axonal damage. Our findings suggest that chronic stress disrupts the organization of the nodes of Ranvier by suppressing mGluR activation in OLs, and that specific white matter abnormalities are closely associated with MDD onset.
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Transtorno Depressivo Maior/fisiopatologia , Oligodendroglia/patologia , Nós Neurofibrosos/patologia , Estresse Psicológico/fisiopatologia , Adulto , Animais , Anisotropia , Moléculas de Adesão Celular Neuronais/metabolismo , Células Cultivadas , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , Canal de Potássio Kv1.1/metabolismo , Imageamento por Ressonância Magnética , Masculino , Camundongos Endogâmicos C57BL , Microscopia Confocal , Pessoa de Meia-Idade , Oligodendroglia/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , Nós Neurofibrosos/metabolismo , Ratos Wistar , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Major depression, one of the most prevalent mental illnesses, is thought to be a multifactorial disease related to both genetic and environmental factors. However, the genes responsible for and the pathogenesis of major depression at the molecular level remain unclear. Recently, we reported that stressed mice with elevated plasma corticosterone levels show upregulation and activation of serum glucocorticoid-regulated kinase (Sgk1) in oligodendrocytes. Active Sgk1 causes phosphorylation of N-myc downstream-regulated gene 1 (Ndrg1), and phospho-Ndrg1 increases the expression of N-cadherin, α-catenin, and ß-catenin in oligodendrocytes. This activation of the Sgk1 cascade results in morphological changes in the oligodendrocytes of nerve fiber bundles, such as those present in the corpus callosum. However, little is known about the molecular functions of the traditional and/or desmosomal cadherin superfamily in oligodendrocytes. Therefore, in this study, we aimed to elucidate the functions of the desmosomal cadherin superfamily in oligodendrocytes. Desmoglein (Dsg) 1, Dsg2, and desmocollin 1 (Dsc1) were found to be expressed in the corpus callosum of mouse brain, and the expression of a subtype of Dsg1, Dsg1c, was upregulated in oligodendrocytes after chronic stress exposure. Furthermore, Dsg1 proteins were localized around the plasma membrane regions of oligodendrocytes. A study in primary oligodendrocyte cultures also revealed that chronic upregulation of Sgk1 by dexamethasone administration is involved in upregulation of Dsg1c mRNA. These results may indicate that chronic stress induced Sgk1 activation in oligodendrocytes, which increases Dsg1 expression near the plasma membrane. Thus, Dsg1 upregulation may be implicated in the molecular mechanisms underlying the morphological changes in oligodendrocytes in response to chronic stress exposure.
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Corpo Caloso/metabolismo , Desmogleína 1/metabolismo , Proteínas Imediatamente Precoces/metabolismo , Oligodendroglia/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Estresse Psicológico/metabolismo , Animais , Caderinas/genética , Caderinas/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Corpo Caloso/patologia , Corticosterona/sangue , Desmogleína 1/genética , Desmogleína 2/genética , Desmogleína 2/metabolismo , Dexametasona/farmacologia , Regulação da Expressão Gênica , Proteínas Imediatamente Precoces/antagonistas & inibidores , Proteínas Imediatamente Precoces/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia , Fosforilação , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Estresse Psicológico/genética , Estresse Psicológico/patologia , alfa Catenina/genética , alfa Catenina/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMO
It is well known that glucocorticoid receptor (GR) signaling regulates the hypothalamic-pituitary-adrenal (HPA) axis, and GR expression level is associated with HPA axis activity. Recent studies revealed that microRNA- (miR-) 18 and/or 124a are candidate negative regulators of GR in the brain. The Kampo medicine Yokukansan (YKS) can affect psychological symptoms such as depression and anxiety that are associated with stress responses. In this study, we evaluated the effect of YKS on miR-18 and 124a and GR levels in mice exposed to stress. We found that YKS pretreatment normalized elevated plasma corticosterone levels in stress-exposed mice. In addition, GR mRNA levels were downregulated in the brain following stress exposure. While miR-124a expression levels were not altered in the hypothalamus of stress-exposed mice, miR-18 levels decreased in the hypothalamus of YKS-pretreated mice after stress exposure. Finally, GR protein levels in the paraventricular nucleus (PVN) of the hypothalamus after stress exposure recovered in YKS-pretreated mice. Collectively, these data suggest that YKS normalizes GR protein levels by regulating miR-18 expression in the hypothalamus, thus normalizing HPA axis activity following stress exposure.
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Medicamentos de Ervas Chinesas/administração & dosagem , Medicina Kampo/efeitos adversos , MicroRNAs/biossíntese , Estresse Psicológico/tratamento farmacológico , Animais , Corticosterona/sangue , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Camundongos , MicroRNAs/genética , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Estresse Psicológico/fisiopatologiaRESUMO
Stressful events are known to down-regulate expression levels of glucocorticoid receptors (GRs) in the brain. Recently, we reported that stressed mice with elevated plasma levels of corticosterone exhibit morphological changes in the oligodendrocytes of nerve fiber bundles, such as those in the corpus callosum. However, little is known about the molecular mechanism of GR expression regulation in oligodendrocytes after stress exposure. A previous report has suggested that GR protein levels might be regulated by microRNA (miR)-18 and/or -124a in the brain. In this study, we aimed to elucidate the GR regulation mechanism in oligodendrocytes and evaluate the effects of yokukansan (YKS), a Kampo medicine, on GR protein regulation. Acute exposure to stress increased plasma corticosterone levels, decreased GR protein expression, and increased miR-124a expression in the corpus callosum of adult male mice, though the GR mRNA and miR-18 expression levels were not significant changes. YKS normalized the stress-induced changes in the plasma corticosterone, GR protein, and miR124a expression levels. An oligodendrocyte primary culture study also showed that YKS down-regulated miR-124a, but not miR-18, expression levels in dexamethasone-treated cells. These results suggest that the down-regulation of miR124a expression might be involved in the normalization of stress-induced decreases in GR protein in oligodendrocytes by YKS. This effect may imply the molecular mechanisms underlying the ameliorative effects of YKS on psychological symptoms and stress-related behaviors.
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Fármacos do Sistema Nervoso Central/farmacologia , Corpo Caloso/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Oligodendroglia/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Estresse Psicológico/tratamento farmacológico , Doença Aguda , Animais , Células Cultivadas , Corpo Caloso/metabolismo , Corticosterona/sangue , Dexametasona/farmacologia , Regulação para Baixo/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Oligodendroglia/metabolismo , RNA Mensageiro/metabolismo , Ratos , Estresse Psicológico/metabolismoRESUMO
Cell positioning and neuronal network formation are crucial for proper brain function. Disrupted-in-Schizophrenia 1 (DISC1) is anterogradely transported to the neurite tips, together with Lis1, and functions in neurite extension via suppression of GSK3ß activity. Then, transported Lis1 is retrogradely transported and functions in cell migration. Here, we show that DISC1-binding zinc finger protein (DBZ), together with DISC1, regulates mouse cortical cell positioning and neurite development in vivo. DBZ hindered Ndel1 phosphorylation at threonine 219 and serine 251. DBZ depletion or expression of a double-phosphorylated mimetic form of Ndel1 impaired the transport of Lis1 and DISC1 to the neurite tips and hampered microtubule elongation. Moreover, application of DISC1 or a GSK3ß inhibitor rescued the impairments caused by DBZ insufficiency or double-phosphorylated Ndel1 expression. We concluded that DBZ controls cell positioning and neurite development by interfering with Ndel1 from disproportionate phosphorylation, which is critical for appropriate anterograde transport of the DISC1-complex.
Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Proteínas de Transporte/metabolismo , Movimento Celular/fisiologia , Córtex Cerebral/citologia , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/fisiologia , Animais , Transporte Biológico , Células Cultivadas , Córtex Cerebral/embriologia , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese , Fosforilação , Gravidez , TransfecçãoRESUMO
The major psychiatric disorders such as schizophrenia (SZ) and major depressive disorder (MDD) are thought to be multifactorial diseases related to both genetic and environmental factors. However, the genes responsible and the molecular mechanisms underlying the pathogenesis of SZ and MDD remain unclear. We previously reported that abnormalities of disrupted-in-Schizophrenia-1 (DISC1) and DISC1 binding zinc finger (DBZ) might cause major psychiatric disorders such as SZ. Interestingly, both DISC and DBZ have been further detected in oligodendrocytes and implicated in regulating oligodendrocyte differentiation. DISC1 negatively regulates the differentiation of oligodendrocytes, whereas DBZ plays a positive regulatory role in oligodendrocyte differentiation. We have reported that repeated stressful events, one of the major risk factors of MDD, can induce sustained upregulation of plasma corticosterone levels and serum/glucocorticoid regulated kinase 1 (Sgk1) mRNA expression in oligodendrocytes. Repeated stressful events can also activate the SGK1 cascade and cause excess arborization of oligodendrocyte processes, which is thought to be related to depressive-like symptoms. In this review, we discuss the expression of DISC1, DBZ, and SGK1 in oligodendrocytes, their roles in the regulation of oligodendrocyte function, possible interactions of DISC1 and DBZ in relation to SZ, and the activation of the SGK1 signaling cascade in relation to MDD.
Assuntos
Proteínas de Ligação a DNA/genética , Transtorno Depressivo Maior/genética , Proteínas Imediatamente Precoces/biossíntese , Proteínas do Tecido Nervoso/metabolismo , Oligodendroglia/metabolismo , Proteínas Serina-Treonina Quinases/biossíntese , Esquizofrenia/genética , Fatores de Transcrição/genética , Diferenciação Celular/genética , Corticosterona/sangue , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/metabolismo , Transtorno Depressivo Maior/etiologia , Transtorno Depressivo Maior/patologia , Regulação da Expressão Gênica , Humanos , Proteínas Imediatamente Precoces/genética , Acontecimentos que Mudam a Vida , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Oligodendroglia/patologia , Proteínas Serina-Treonina Quinases/genética , Esquizofrenia/etiologia , Esquizofrenia/patologia , Fatores de Transcrição/biossíntese , Fatores de Transcrição/metabolismoRESUMO
Recently several potential susceptibility genes for major psychiatric disorders (schizophrenia and major depression) such as disrupted-in-schizophrenia 1(DISC1), dysbindin and pituitary adenylate cyclase-activating polypeptide (PACAP) have been reported. DISC1 is involved in neural development directly via adhesion molecules or via its binding partners of DISC1 such as elongation protein ζ-1 (FEZ1), DISC1-binding zinc-finger protein (DBZ) and kendrin. PACAP also regulates neural development via stathmin 1 or via regulation of the DISC1-DBZ binding. Dysbindin is also involved in neural development by regulating centrosomal microtubule network formation. All such molecules examined to date are involved in neural development. Thus, these findings provide new molecular insights into the mechanisms of neural development and neuropsychiatric disorders. On the other hand, in addition to neurons, both DISC and DBZ have been detected in oligodendrocytes and implicated in regulating oligodendrocyte differentiation. DISC1 inhibits the differentiation of oligodendrocyte precursor cells into oligodendrocytes, while DBZ has a positive regulatory role in oligodendrocyte differentiation. Evidence suggesting that disturbance of oligodendrocyte development causes major depression is also described.
Assuntos
Depressão/genética , Proteínas Associadas à Distrofina/genética , Predisposição Genética para Doença/genética , Proteínas do Tecido Nervoso/genética , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Esquizofrenia/genética , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas de Ligação a Calmodulina/fisiologia , Diferenciação Celular/genética , Proteínas de Ligação a DNA/fisiologia , Disbindina , Proteínas Associadas à Distrofina/fisiologia , Humanos , Proteínas do Tecido Nervoso/fisiologia , Neurogênese/genética , Oligodendroglia/citologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/fisiologia , Ligação Proteica , Estatmina/fisiologia , Fatores de Transcrição/fisiologiaRESUMO
BACKGROUND: There have been no reports that show significant direct relationship between echocardiographic parameters and B-type natriuretic peptide (BNP) level. This could be due to the heterogeneous pathophysiology of heart failure and a lack of appropriate echocardiographic parameters. We sought to determine the best echocardiographic parameter that described elevated BNP level in patients with heart failure with and without systolic dysfunction. METHODS AND RESULTS: We studied 111 consecutive heart failure patients. They were divided into patients with heart failure and preserved ejection fraction (HFPEF, n = 61) and that with heart failure and reduced ejection fraction (HFREF, n = 50). Conventional and new echocardiographic parameters including myocardial strains were measured. BNP did not reflect any single echocardiographic parameter in patients with heart failure in total. The ratio of early diastolic transmitral flow velocity and mitral annular velocity had strong positive correlation with BNP level in the HFPEF group but not in the HFREF group. In the group of HFREF, global longitudinal and circumferential strains were positively correlated. Multivariate analysis revealed that predicted factors for BNP value in HFPEF and in HFREF were different. CONCLUSION: High BNP level may indicate high filling pressure when ejection fraction is preserved and may indicate myocardial dysfunction when it is reduced.
Assuntos
Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico por imagem , Peptídeo Natriurético Encefálico/sangue , Volume Sistólico , Disfunção Ventricular Esquerda/sangue , Disfunção Ventricular Esquerda/diagnóstico por imagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Ecocardiografia/métodos , Feminino , Insuficiência Cardíaca/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Regulação para Cima , Disfunção Ventricular Esquerda/etiologia , Adulto JovemRESUMO
Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a translocation, t(1;11) (q42.1;q14.3), that segregates with major psychiatric disorders, including schizophrenia, recurrent major depression and bipolar affective disorder, in a Scottish family. Here we report that mammalian DISC1 endogenously expressed in oligodendroglial lineage cells negatively regulates differentiation of oligodendrocyte precursor cells into oligodendrocytes. DISC1 expression was detected in oligodendrocytes of the mouse corpus callosum at P14 and P70. DISC1 mRNA was expressed in primary cultured rat cortical oligodendrocyte precursor cells and decreased when oligodendrocyte precursor cells were induced to differentiate by PDGF deprivation. Immunocytochemical analysis showed that overexpressed DISC1 was localized in the cell bodies and processes of oligodendrocyte precursor cells and oligodendrocytes. We show that expression of the myelin related markers, CNPase and MBP, as well as the number of cells with a matured oligodendrocyte morphology, were decreased following full length DISC1 overexpression. Conversely, both expression of CNPase and the number of oligodendrocytes with a mature morphology were increased following knockdown of endogenous DISC1 by RNA interference. Overexpression of a truncated form of DISC1 also resulted in an increase in expression of myelin related proteins and the number of mature oligodendrocytes, potentially acting via a dominant negative mechanism. We also identified involvement of Sox10 and Nkx2.2 in the DISC1 regulatory pathway of oligodendrocyte differentiation, both well-known transcription factors involved in the regulation of myelin genes.
Assuntos
Diferenciação Celular/fisiologia , Corpo Caloso/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Oligodendroglia/metabolismo , Animais , Células Cultivadas , Corpo Caloso/citologia , Proteína Homeobox Nkx-2.2 , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Camundongos , Proteínas do Tecido Nervoso/genética , Oligodendroglia/citologia , Interferência de RNA , Ratos , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Peixe-ZebraRESUMO
Recent studies have shown changes in myelin genes and alterations in white matter structure in a wide range of psychiatric disorders. Here we report that DBZ, a central nervous system (CNS)-specific member of the DISC1 interactome, positively regulates the oligodendrocyte (OL) differentiation in vivo and in vitro. In mouse corpus callosum (CC), DBZ mRNA is expressed in OL lineage cells and expression of DBZ protein peaked before MBP expression. In the CC of DBZ-KO mice, we observed delayed myelination during the early postnatal period. Although the myelination delay was mostly recovered by adulthood, OLs with immature structural features were more abundant in adult DBZ-KO mice than in control mice. DBZ was also transiently upregulated during rat OL differentiation in vitro before myelin marker expression. DBZ knockdown by RNA interference resulted in a decreased expression of myelin-related markers and a low number of cells with mature characteristics, but with no effect on the proliferation of oligodendrocyte precursor cells. We also show that the expression levels of transcription factors having a negative-regulatory role in OL differentiation were upregulated when endogenous DBZ was knocked down. These results strongly indicate that OL differentiation in rodents is regulated by DBZ.
Assuntos
Diferenciação Celular/fisiologia , Sistema Nervoso Central/citologia , Sistema Nervoso Central/metabolismo , Proteínas de Ligação a DNA/fisiologia , Oligodendroglia/fisiologia , Fatores de Transcrição/fisiologia , Sequência de Aminoácidos , Animais , Proteínas de Transporte/fisiologia , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/metabolismo , Ratos , Ratos Endogâmicos WKYRESUMO
Disrupted-in-schizophrenia 1 (DISC1)-binding zinc finger protein (DBZ) is a DISC1-interacting molecule and the interaction between DBZ and DISC1 is involved in neurite outgrowth in vitro. DBZ is highly expressed in brain, especially in the cortex. However, the physiological roles of DBZ in vivo have not been clarified. Here, we show that development of basket cells, a morphologically defined class of parvalbumin (PV)-containing interneurons, is disturbed in DBZ knockout (KO) mice. DBZ mRNA was highly expressed in the ventral area of the subventricular zone of the medial ganglionic eminence, where PV-containing cortical interneurons were generated, at embryonic 14.5 days (E14.5). Although the expression level for PV and the number of PV-containing interneurons were not altered in the cortices of DBZ KO mice, basket cells were less branched and had shorter processes in the somatosensory cortices of DBZ KO mice compared with those in the cortices of WT mice. Furthermore, in the somatosensory cortices of DBZ KO mice, the level of mRNAs for the gamma-aminobutyric acid-synthesizing enzymes GAD67 was decreased. These findings show that DBZ is involved in the morphogenesis of basket cells.