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1.
Nature ; 574(7779): 543-548, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645720

RESUMO

Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota1. In mammals, changes in the composition of the microbiota can influence many physiologic processes (including development, metabolism and immune cell function) and are associated with susceptibility to multiple diseases2. Alterations in the microbiota can also modulate host behaviours-such as social activity, stress, and anxiety-related responses-that are linked to diverse neuropsychiatric disorders3. However, the mechanisms by which the microbiota influence neuronal activity and host behaviour remain poorly defined. Here we show that manipulation of the microbiota in antibiotic-treated or germ-free adult mice results in significant deficits in fear extinction learning. Single-nucleus RNA sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in excitatory neurons, glia and other cell types. Transcranial two-photon imaging showed that deficits in extinction learning after manipulation of the microbiota in adult mice were associated with defective learning-related remodelling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Finally, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and have been reported to be related to neuropsychiatric disorders in humans and mouse models, suggesting that microbiota-derived compounds may directly affect brain function and behaviour. Together, these data indicate that fear extinction learning requires microbiota-derived signals both during early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders.


Assuntos
Extinção Psicológica/fisiologia , Medo/fisiologia , Metabolômica , Microbiota/fisiologia , Neurônios/fisiologia , Animais , Antibacterianos/farmacologia , Transtorno Autístico/metabolismo , Sangue/metabolismo , Cálcio/metabolismo , Líquido Cefalorraquidiano/química , Líquido Cefalorraquidiano/metabolismo , Sinais (Psicologia) , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Espinhas Dendríticas/fisiologia , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Fezes/química , Vida Livre de Germes , Indicã/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microbiota/efeitos dos fármacos , Microbiota/imunologia , Inibição Neural , Neuroglia/patologia , Neuroglia/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/patologia , Fenilpropionatos/metabolismo , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/imunologia , Córtex Pré-Frontal/fisiologia , Esquizofrenia/metabolismo , Transcriptoma , Nervo Vago/fisiologia
3.
Psychiatr Danub ; 31(Suppl 3): 517-519, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31488783

RESUMO

BACKGROUND: In the literature we can find evidence that sex hormones are involved the alterations of cognition in schizophrenic patients. Another factor, which may have an impact on cognitive domains in this clinical group inflammatory processes. The objective of this review was to explore studies, in which the role of both immunological factors and sex hormones on cognitive functions in schizophrenia are analyzed. METHODS: The search of papers covering this topic in PubMed and Google Scholar was performed. RESULTS: Endocrine factors like: testosteron, estrogen, as well as immunomodulatory are observed to play a role in cognitive functioning in schizophrenia. CONCLUSIONS: More studies are necessary to confirm these possible co-relations.


Assuntos
Transtornos Cognitivos , Cognição , Hormônios Esteroides Gonadais , Inflamação , Esquizofrenia , Psicologia do Esquizofrênico , Transtornos Cognitivos/complicações , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Hormônios Esteroides Gonadais/metabolismo , Humanos , Inflamação/metabolismo , Esquizofrenia/complicações , Esquizofrenia/metabolismo , Esquizofrenia/patologia
4.
Nat Commun ; 10(1): 3933, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477693

RESUMO

It has remained unclear why schizophrenia typically manifests after adolescence and which neurobiological mechanisms are underlying the cascade leading to the actual onset of the illness. Here we show that the use of induced pluripotent stem cell-derived neurons of monozygotic twins from pairs discordant for schizophrenia enhances disease-specific signal by minimizing genetic heterogeneity. In proteomic and pathway analyses, clinical illness is associated especially with altered glycosaminoglycan, GABAergic synapse, sialylation, and purine metabolism pathways. Although only 12% of all 19,462 genes are expressed differentially between healthy males and females, up to 61% of the illness-related genes are sex specific. These results on sex-specific genes are replicated in another dataset. This implies that the pathophysiology differs between males and females, and may explain why symptoms appear after adolescence when the expression of many sex-specific genes change, and suggests the need for sex-specific treatments.


Assuntos
Perfilação da Expressão Gênica/métodos , Proteoma/genética , Proteômica/métodos , Esquizofrenia/genética , Adolescente , Antipsicóticos/uso terapêutico , Clozapina/uso terapêutico , Doenças em Gêmeos/genética , Doenças em Gêmeos/metabolismo , Feminino , Humanos , Masculino , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Proteoma/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Fatores Sexuais , Gêmeos Monozigóticos/genética
5.
Nat Commun ; 10(1): 3454, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371726

RESUMO

Copy-number variants of the CYFIP1 gene in humans have been linked to autism spectrum disorders (ASD) and schizophrenia (SCZ), two neuropsychiatric disorders characterized by defects in brain connectivity. Here, we show that CYFIP1 plays an important role in brain functional connectivity and callosal functions. We find that Cyfip1-heterozygous mice have reduced functional connectivity and defects in white matter architecture, similar to phenotypes found in patients with ASD, SCZ and other neuropsychiatric disorders. Cyfip1-deficient mice also present decreased myelination in the callosal axons, altered presynaptic function, and impaired bilateral connectivity. Finally, Cyfip1 deficiency leads to abnormalities in motor coordination, sensorimotor gating and sensory perception, which are also known neuropsychiatric disorder-related symptoms. These results show that Cyfip1 haploinsufficiency compromises brain connectivity and function, which might explain its genetic association to neuropsychiatric disorders.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Encéfalo/metabolismo , Predisposição Genética para Doença/genética , Proteínas do Tecido Nervoso/metabolismo , Esquizofrenia/metabolismo , Animais , Transtorno do Espectro Autista/diagnóstico por imagem , Axônios , Comportamento Animal , Encéfalo/diagnóstico por imagem , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Estudos de Associação Genética , Haploinsuficiência , Heterozigoto , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Sistema Nervoso/metabolismo , Fenômenos Fisiológicos do Sistema Nervoso/genética , Fenótipo , Desempenho Psicomotor , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/genética , Filtro Sensorial , Substância Branca
6.
DNA Cell Biol ; 38(10): 1030-1039, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31368785

RESUMO

Both endogenous and exogenous factors can cause DNA damage that compromises genomic integrity and cell viability. A proper DNA damage response (DDR) plays a role in maintaining genome stability and preventing tumorigenesis. DNA double-strand breaks (DSBs) are the most toxic DNA lesion, whose response is dominated by the ataxia-telangiectasia mutated (ATM) protein kinase. After being activated by the sensor Mre11-Rad50-Nbs1 (MRN) complex or acetyltransferase Tip60, ATM rapidly phosphorylates downstream targets to launch DDR signaling when DNA is damaged. However, the exact mechanism of DDR is complex and ambiguous. Ufmylation, one type of ubiquitin-like modification, proceeds mainly through a three-step enzymatic reaction to help ubiquitin-fold modifier 1 (Ufm1), attach to substrates with ubiquitin-like modifier-activating enzyme 5 (Uba5), Ufm1-conjugating enzyme 1 (Ufc1) and Ufm1-specific ligase 1 (Ufl1). Although ubiquitination is essential to the DSBs response, the potential function of ufmylation in DDR is largely unknown. Herein, we review the relationship between ufmylation and DDR to elucidate the function and mechanism of ufmylation in DDR, which would reveal the pathogenesis of some diseases and provide new guidance to create a therapeutic method.


Assuntos
Doenças Cardiovasculares/metabolismo , Quebras de DNA de Cadeia Dupla , Neoplasias/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas/metabolismo , Esquizofrenia/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Reparo do DNA , Genoma Humano , Instabilidade Genômica , Humanos , Neoplasias/genética , Neoplasias/patologia , Ligação Proteica , Proteínas/genética , Esquizofrenia/genética , Esquizofrenia/patologia , Transdução de Sinais , Enzimas Ativadoras de Ubiquitina/genética , Enzimas Ativadoras de Ubiquitina/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
8.
Psychopharmacology (Berl) ; 236(8): 2295-2305, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31273400

RESUMO

RATIONALE: Psychopharmacology needs novel quantitative measures and theoretical approaches based on computational modelling that can be used to help translate behavioural findings from experimental animals to humans, including patients with neuropsychiatric disorders. OBJECTIVES: This brief review exemplifies this approach when applied to recent published studies of the effects of manipulating central dopaminergic and serotoninergic systems in rodents and marmoset monkeys, and possible comparisons with healthy human volunteers receiving systemic agents or patients with depression and schizophrenia. METHODS: Behavioural effects of central depletions of dopamine or serotonin in monkeys in probabilistic learning paradigms are characterised further by computational modelling methods and related to rodent and human data. RESULTS: Several examples are provided of the power of computational modelling to derive new measures and reappraise conventional explanations of regional neurotransmitter depletion and other drug effects, whilst enhancing construct validation in patient groups. Specifically, effects are shown on such parameters as 'stimulus stickiness' and 'side stickiness', which occur over and above effects on standard parameters of reinforcement learning, reminiscent of some early innovations in data analysis in psychopharmacology. CONCLUSIONS: Computational modelling provides a useful methodology for further detailed analysis of behavioural mechanisms that are affected by pharmacological manipulations across species and will aid the translation of experimental findings to understand the therapeutic effects of medications in neuropsychiatric disorders, as well as facilitating future drug discovery.


Assuntos
Biologia Computacional/métodos , Psicofarmacologia/métodos , Pesquisa Médica Translacional/métodos , Animais , Biologia Computacional/tendências , Transtorno Depressivo/diagnóstico por imagem , Transtorno Depressivo/metabolismo , Dopamina/metabolismo , Humanos , Aprendizagem/fisiologia , Psicofarmacologia/tendências , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/metabolismo , Serotonina/metabolismo , Pesquisa Médica Translacional/tendências
9.
Genome Biol ; 20(1): 135, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288836

RESUMO

BACKGROUND: The importance of cell type-specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. We generate cell type-specific whole-genome methylomes (N = 95) and transcriptomes (N = 89) from neurons and oligodendrocytes obtained from brain tissue of patients with schizophrenia and matched controls. RESULTS: The methylomes of the two cell types are highly distinct, with the majority of differential DNA methylation occurring in non-coding regions. DNA methylation differences between cases and controls are subtle compared to cell type differences, yet robust against permuted data and validated in targeted deep-sequencing analyses. Differential DNA methylation between control and schizophrenia tends to occur in cell type differentially methylated sites, highlighting the significance of cell type-specific epigenetic dysregulation in a complex neuropsychiatric disorder. CONCLUSIONS: Our results provide novel and comprehensive methylome and transcriptome data from distinct cell populations within patient-derived brain tissues. This data clearly demonstrate that cell type epigenetic-differentiated sites are preferentially targeted by disease-associated epigenetic dysregulation. We further show reduced cell type epigenetic distinction in schizophrenia.


Assuntos
Encéfalo/metabolismo , Metilação de DNA , Epigênese Genética , Esquizofrenia/genética , Encéfalo/citologia , Estudos de Casos e Controles , Humanos , Esquizofrenia/metabolismo
10.
BMC Genomics ; 20(Suppl 7): 535, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31291891

RESUMO

BACKGROUND: Purpose of study is revealing significant differences in serum proteomes in schizophrenia and bipolar disorder (BD). RESULTS: Quantitative mass-spectrometry based proteomic analysis was used to quantify proteins in the blood serum samples after the depletion of six major blood proteins. Comparison of proteome profiles of different groups revealed 27 proteins being specific for schizophrenia, and 18 - for BD. Protein set in schizophrenia was mostly associated with immune response, cell communication, cell growth and maintenance, protein metabolism and regulation of nucleic acid metabolism. Protein set in BD was mostly associated with immune response, regulating transport processes across cell membrane and cell communication, development of neurons and oligodendrocytes and cell growth. Concentrations of ankyrin repeat domain-containing protein 12 (ANKRD12) and cadherin 5 in serum samples were determined by ELISA. Significant difference between three groups was revealed in ANKRD12 concentration (p = 0.02), with maximum elevation of ANKRD12 concentration (median level) in schizophrenia followed by BD. Cadherin 5 concentration differed significantly (p = 0.035) between schizophrenic patients with prevailing positive symptoms (4.78 [2.71, 7.12] ng/ml) and those with prevailing negative symptoms (1.86 [0.001, 4.11] ng/ml). CONCLUSIONS: Our results are presumably useful for discovering the new pathways involved in endogenous psychotic disorders.


Assuntos
Transtorno Bipolar/metabolismo , Proteoma/metabolismo , Esquizofrenia/metabolismo , Adulto , Antígenos CD/metabolismo , Caderinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Adulto Jovem
11.
Artigo em Russo | MEDLINE | ID: mdl-31156222

RESUMO

AIM: To assess the activity of glutathione reductase (GR) and glutathione-S-transferase (GST) in blood cells of patients at clinical high-risk (HR) state for psychosis, in first-episode patients with schizophrenia and schizoaffective disorder (SD), and control group, and to seek correlations of these biochemical parameters with clinical assessments in patients. MATERIAL AND METHODS: The study included male patients at HR (n=21, 16-25 years old), first-episode patients with schizophrenia (F20, n=14, 18-25 years old) and SD (F25, n=20, 16-25 years old), and 12 people of the control group (19-25 years old). Psychometric scales (SOPS, HDRS, and PANSS) and psychopathological methods were employed. GR and GST enzymatic activities were determined spectrophotometrically. RESULTS: The activities of platelet GR and GST in all groups of patients both before and after treatment were lower than in controls (p<0.01). The platelet GST activity was lower in patients at HR compared to patients with schizophrenia before treatment and lower than in patients with SD after treatment (p<0.05), it was higher in patients with schizophrenia than in patients with SD before treatment (p<0.05). Erythrocyte GST activity in patients with HR was lower than in patients with SD after treatment, and in the latter it exceeded that in patients with schizophrenia and controls (p<0.05). Complex and different patterns of changes in the activities of erythrocyte and platelet GR and GST in patients with schizophrenia spectrum disorders, occurring both before the first psychotic episode in the initial stage of disease, and in the first-episode patients, were detected. CONCLUSION: The activity of glutathione-converting enzymes in endogenous psychoses of the schizophrenic spectrum, including its early stages, can be used as a biomarker for predicting the development of psychosis, the course of disease, and as criteria for evaluation of therapeutic response to antipsychotic treatment.


Assuntos
Glutationa , Transtornos Psicóticos , Esquizofrenia , Adolescente , Adulto , Antipsicóticos/uso terapêutico , Feminino , Glutationa/metabolismo , Glutationa Redutase/metabolismo , Humanos , Masculino , Transtornos Psicóticos/metabolismo , Esquizofrenia/metabolismo , Adulto Jovem
12.
Psychopharmacology (Berl) ; 236(5): 1471-1489, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31197432

RESUMO

Schizophrenia and autism spectrum disorder have long been associated with elevated levels of various small phenolic molecules (SPMs). In turn, the gut microbiota (GMB) has been implicated in the kinetics of many of these analytes. Unfortunately, research into the possible relevance of GMB-mediated SPMs to neuropsychiatry continues to be limited by heterogeneous study design, numerous sources of variance and technical challenges. Some SPMs have multiple structural isomers and most have conjugates. Without specialized approaches, SPMs can be incorrectly assigned or inaccurately quantified. In addition, SPM levels can be affected by dietary polyphenol or protein consumption and by various medications and diseases. Nonetheless, heterotypical excretion of various SPMs in association with schizophrenia or autism continues to be reported in independent samples. Recent studies in human cerebrospinal fluid demonstrate the presence of many SPMs A large number of these are bioactive in experimental models. Whether such mechanisms are relevant to the human brain in health or disease is not known. Systematic metabolomic and microbiome studies of well-characterized populations, an appreciation of multiple confounds, and implementation of standardized approaches across platforms and sites are needed to delineate the potential utility of the phenolic interactome in neuropsychiatry.


Assuntos
Transtorno do Espectro Autista/metabolismo , Encéfalo/metabolismo , Microbioma Gastrointestinal/fisiologia , Fenóis/metabolismo , Esquizofrenia/metabolismo , Transtorno do Espectro Autista/psicologia , Encéfalo/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Polifenóis/administração & dosagem , Polifenóis/metabolismo , Psicologia do Esquizofrênico
13.
Med Sci Monit ; 25: 4322-4332, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31180069

RESUMO

BACKGROUND We previously discovered that 3 long non-coding RNAs (lncRNAs) NONHSAT089447, NONHSAT021545, and NONHSAT041499 were differentially expressed in the peripheral blood of patients with schizophrenia, in comparison to those in normal healthy controls. In this study, we conducted bioinformatic analysis of these 3 lncRNAs and the regulatory role of lncRNA NONHSAT089447 in the dopamine signaling pathway in patients with schizophrenia. MATERIAL AND METHODS There lncRNAs in peripheral blood mononuclear cells (PBMCs) were screened using microarray analysis. Pearson's correlation analysis was performed to assess the levels of co-expressed mRNAs of respective lncRNAs. The Database for Annotation, Visualization and Integrated Discovery (DAVID) software was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes or Genomes (KEGG) enrichment analysis for these lncRNAs. Human neuroblastoma cell lines (SK-N-SH) were cultured and treated with dopamine or olanzapine (OLP), or transfected with siRNA targeting NONHSAT089447 or plasmid expressing NONHSAT089447. Levels of lncRNAs were detected by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). Then, mRNA and protein expression of the dopamine receptors DRD1, DRD2, DRD3, DRD4, and DRD5 were measured by RT-PCR and western blot analysis, respectively. RESULTS OLP treatment significantly inhibited the expression of NONHSAT089447. Knockdown of NONHSAT089447 by siRNA decreased DRD3 and DRD5 expression, while overexpression of NONHSAT089447 significantly upregulated expression of DRD3 and DRD5. Western blot analysis confirmed that levels of NONHSAT089447 regulated downstream DRD signaling. CONCLUSIONS Our results revealed that the lncRNA NONHSAT089447 participated in the dopamine signaling pathway via upregulation of DRDs.


Assuntos
Dopamina/metabolismo , RNA Longo não Codificante/metabolismo , Esquizofrenia/metabolismo , Adulto , Transtornos de Ansiedade/metabolismo , Linhagem Celular Tumoral , Biologia Computacional/métodos , Transtorno Depressivo Maior/metabolismo , Dopamina/genética , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Esquizofrenia/genética , Transdução de Sinais/genética
14.
Biomed Res Int ; 2019: 8941046, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31240228

RESUMO

Chloride (Cl-) homeostasis is an essential process involved in neuronal signalling and cell survival. Inadequate regulation of intracellular Cl- interferes with synaptic signalling and is implicated in several neurological diseases. The main inhibitory neurotransmitter of the central nervous system is γ-aminobutyric acid (GABA). GABA hyperpolarises the membrane potential by activating Cl- permeable GABAA receptor channels (GABAAR). This process is reliant on Cl- extruder K+-Cl- cotransporter 2 (KCC2), which generates the neuron's inward, hyperpolarising Cl- gradient. KCC2 is encoded by the fifth member of the solute carrier 12 family (SLC12A5) and has remained a poorly understood component in the development and severity of many neurological diseases for many years. Recent advancements in next-generation sequencing and specific gene targeting, however, have indicated that loss of KCC2 activity is involved in a number of diseases including epilepsy and schizophrenia. It has also been implicated in neuropathic pain following spinal cord injury. Any variant of SLC12A5 that negatively regulates the transporter's expression may, therefore, be implicated in neurological disease. A recent whole exome study has discovered several causative mutations in patients with epilepsy. Here, we discuss the implications of KCC2 in neurological disease and consider the evolving evidence for KCC2's potential as a therapeutic target.


Assuntos
Canais de Cloreto/metabolismo , Neurônios/metabolismo , Simportadores/antagonistas & inibidores , Simportadores/metabolismo , Ácido gama-Aminobutírico/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Cloretos/metabolismo , Epilepsia/metabolismo , Marcação de Genes , Homeostase , Humanos , Potenciais da Membrana , Neuralgia/metabolismo , Neurotransmissores/farmacologia , Fosforilação , Esquizofrenia/metabolismo , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Traumatismos da Medula Espinal , Simportadores/genética
15.
Cell Mol Neurobiol ; 39(6): 721-727, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31037515

RESUMO

Mental disorders, such as major depressive disorder and schizophrenia, are complex multigenetic conditions, but focused studies of single genes might reveal genes involved in the pathogenesis of mental disorders, including major depressive disorder and schizophrenia. Several candidate genes have been identified using transgenic mice. VGF nerve growth factor inducible (VGF) is a neuropeptide expression of which is induced by nerve growth factor (NGF). VGF is robustly and exclusively synthesized in neuronal and neuroendocrine cells. In central nervous system (CNS), VGF is extensively expressed especially in the cerebral cortex, hippocampus, and hypothalamus. VGF has many roles in the CNS, such as promotion of synaptic plasticity, neurogenesis, and neurite outgrowth. In clinical studies, altered expression and genetic mutations of VGF have been reported in patients with major depressive disorder and schizophrenia. On this basis, studies using transgenic mice to overexpress or knockout VGF have been performed to investigate the roles of upregulation or downregulation of VGF. In this review, we will discuss studies of the roles of VGF using transgenic mice and its relevance to pathologies in major depressive disorder and schizophrenia.


Assuntos
Transtorno Depressivo Maior/metabolismo , Neuropeptídeos/metabolismo , Esquizofrenia/metabolismo , Animais , Transtorno Depressivo Maior/genética , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Neuropeptídeos/genética , Esquizofrenia/genética , Regulação para Cima/genética
16.
Neurotox Res ; 36(2): 306-322, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31077000

RESUMO

Deficit schizophrenia is characterized by leaky intestinal tight and adherens junctions and bacterial translocation. Here we examine whether (deficit) schizophrenia is accompanied by leaky paracellular, transcellular, and vascular barriers in the gut and blood-brain barriers. We measured IgA responses to occludin, claudin-5, E-cadherin, and ß-catenin (paracellular pathway, PARA); talin, actin, vinculin, and epithelial intermediate filament (transcellular pathway, TRANS); and plasmalemma vesicle-associated protein (PLVAP, vascular pathway) in 78 schizophrenia patients and 40 controls. IgA responses to claudin-5, E-cadherin, and ß-catenin, the sum of the four PARA proteins, and the ratio PARA/TRANS were significantly higher in deficit schizophrenia patients than in nondeficit schizophrenia patients and controls. A large part of the variance in PHEMN (psychosis, hostility, excitation, mannerism, and negative) symptoms, psychomotor retardation, formal thought disorders, verbal fluency, word list memory, word list recall, and executive functions was explained by the PARA/TRANS ratio coupled with plasma IgA responses to Gram-negative bacteria, IgM to malondialdehyde, CCL-11 (eotaxin), IgA levels of the ratio of noxious to more protective tryptophan catabolites (NOX/PRO TRYCATs), and a plasma immune activation index. Moreover, IgA levels to Gram-negative bacteria were significantly associated with IgA to E-cadherin, ß-catenin, and PLVAP, while IgA levels to claudin-5 were significantly predicted by IgA to E-cadherin, NOX/PRO TRYCAT ratio, Gram-negative bacteria, and CCL11. The phenomenology of the deficit syndrome is to a large extent explained by the cumulative effects of lowered natural IgM, breakdown of the paracellular and vascular pathways, increased bacterial translocation, peripheral immune-inflammatory responses, and indices of BBB breakdown.


Assuntos
Junções Aderentes/metabolismo , Barreira Hematoencefálica/metabolismo , Endotélio Vascular/metabolismo , Esquizofrenia/metabolismo , Psicologia do Esquizofrênico , Junções Íntimas/metabolismo , Junções Aderentes/imunologia , Adulto , Barreira Hematoencefálica/imunologia , Estudos de Casos e Controles , Endotélio Vascular/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/diagnóstico , Esquizofrenia/imunologia , Junções Íntimas/imunologia
17.
Transl Psychiatry ; 9(1): 126, 2019 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-31011151

RESUMO

Although a number of studies have identified several convincing candidate genes or molecules, the pathophysiology of schizophrenia (SCZ) has not been completely elucidated. Therapeutic optimization based on pathophysiology should be performed as early as possible to improve functional outcomes and prognosis; to detect useful biomarkers for SCZ, which reflect pathophysiology and can be utilized for timely diagnosis and effective therapy. To explore biomarkers for SCZ, we employed fluorescence two-dimensional differential gel electrophoresis (2D-DIGE) of lymphoblastoid cell lines (LCLs) (1st sample set: 30 SCZ and 30 CON). Differentially expressed proteins were sequenced by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and identified proteins were confirmed by western blotting (WB) (1st and 2nd sample set: 60 SCZ and 60 CON). Multivariate logistic regression analysis was performed to identify an optimal combination of biomarkers to create a prediction model for SCZ. Twenty protein spots were differentially expressed between SCZ and CON in 2D-DIGE analysis and 22 unique proteins were identified by LC-MS/MS. Differential expression of eight of 22 proteins was confirmed by WB. Among the eight candidate proteins (HSPA4L, MX1, GLRX3, UROD, MAPRE1, TBCB, IGHM, and GART), we successfully constructed logistic regression models comprised of 4- and 6-markers with good discriminative ability between SCZ and CON. In both WB and gene expression analysis of LCL, MX1 showed reproducibly significant associations. Moreover, Mx1 and its related proinflamatory genes (Mx2, Il1b, and Tnf) were also up-regulated in poly I:C-treated mice. Differentially expressed proteins might be associated with molecular pathophysiology of SCZ, including dysregulation of immunological reactions and potentially provide diagnostic and prognostic biomarkers.


Assuntos
Biomarcadores/análise , Proteômica , Esquizofrenia/metabolismo , Animais , Western Blotting , Linhagem Celular , Cromatografia Líquida , Eletroforese em Gel Bidimensional , Feminino , Humanos , Modelos Logísticos , Masculino , Camundongos , Análise Multivariada , Prognóstico , Esquizofrenia/diagnóstico , Espectrometria de Massas em Tandem
18.
Riv Psichiatr ; 54(2): 43-58, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30985829

RESUMO

Paliperidone is a second-generation antipsychotic drug belonging to the class of benzisoxasole derivatives. Paliperidone is the major active metabolite of risperidone (9-OH-risperidone) and, as such, is comparable to the latter in terms of pharmacodynamic properties. However, due to its peculiar characteristics, paliperidone may be particularly useful in the treatment of schizophrenic patients. In this critical review of the literature the efficacy and tolerability in the short- and in the long-term have been evaluated in patients with schizophrenia. Taking into account the tolerability and efficacy data, together with the use of innovative sustained-release formulation, with a peculiar pharmacokinetic profile that allows single daily administration, paliperidone can be considered a valid option both for the short and the long-term treatment of schizophrenia.


Assuntos
Antipsicóticos/uso terapêutico , Palmitato de Paliperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Antipsicóticos/farmacocinética , Preparações de Ação Retardada , Esquema de Medicação , Humanos , Palmitato de Paliperidona/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Esquizofrenia/metabolismo
20.
J Hum Genet ; 64(7): 653-663, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30976040

RESUMO

Disrupted-in-schizophrenia 1 (DISC1) was reported to be associated with schizophrenia. In a previous study, we found significant association with schizophrenia patients with deficient sustained attention assessed by continuous performance test (CPT). This study aimed to identify risk polymorphisms in this specific neurocognitive subgroup and investigate the expression of different isoforms of DISC1. A total of 83 genetic variants were identified through direct sequencing in 50 controls and 100 schizophrenia patients. Fourteen variants were genotyped in 600 controls and 912 patients. Patients were subgrouped by familial loading (multiplex or simplex) and performance on CPT. The frequency of AA genotype of rs11122324 at the 3'-UTR of Es and Esv1 isoforms and of rs2793091 at intron 4 were significantly higher in multiplex schizophrenia patients than those in controls (corrected p < 0.05). In further subgrouping, the frequency of AA genotype of the two SNPs were significantly higher in multiplex schizophrenia patients with deficient sustained attention than those in controls (corrected p < 0.005). The mRNA expression levels of two extra-short isoforms (Es and Esv1) in the EBV-transformed lymphocytes of schizophrenia were significantly higher than those of controls. Luciferase reporter assays demonstrated that the A-allele of rs11122324 significantly upregulated DISC1 extra-short isoforms transcription compared with the G-allele. We found two SNPs (rs11122324 and rs2793091) of DISC1 may be specifically associated with multiplex schizophrenia patients with deficient sustained attention. The SNP rs11122324 may be a risk polymorphism, which may have functional influence on the transcription of Es and Esv1 through increasing their expression.


Assuntos
Proteínas do Tecido Nervoso/genética , Transtornos Neurocognitivos/genética , Esquizofrenia/genética , Alelos , Éxons , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Proteínas do Tecido Nervoso/metabolismo , Transtornos Neurocognitivos/metabolismo , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Isoformas de RNA/genética , Isoformas de RNA/metabolismo , Esquizofrenia/metabolismo , Taiwan
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