RESUMO
The contraction of heart cells is controlled by the intermolecular signaling between L-type Ca2+ channels (LCCs) and ryanodine receptors (RyRs), and the nanodistance between them depends on the interaction between junctophilin-2 (JPH2) in the sarcoplasmic reticulum (SR) and caveolin-3 (CAV3) in the transversal tubule (TT). In heart failure, decreased expression of JPH2 compromises LCC-RyR communication leading to deficient blood-pumping power. In the present study, we found that JPH2 and CAV3 transcription was concurrently regulated by serum response factor (SRF) and myocardin. In cardiomyocytes from torpid ground squirrels, compared with those from euthermic counterparts, myocardin expression was up-regulated, which boosted both JPH2 and CAV3 expression. Transmission electron microscopic imaging showed that the physical coupling between TTs and SRs was tightened during hibernation and after myocardin overexpression. Confocal Ca2+ imaging under the whole-cell patch clamp condition revealed that these changes enhanced the efficiency of LCC-RyR intermolecular signaling and fully compensated the adaptive down-regulation of LCCs, maintaining the power of heart contraction while avoiding the risk of calcium overload during hibernation. Our finding not only revealed an essential molecular mechanism underlying the survival of hibernating mammals, but also demonstrated a "reverse model of heart failure" at the molecular level, suggesting a strategy for treating heart diseases.
Assuntos
Sinalização do Cálcio , Hibernação , Miócitos Cardíacos/metabolismo , Animais , Caveolinas/genética , Caveolinas/metabolismo , Células Cultivadas , Acoplamento Excitação-Contração , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Nucleares/sangue , Proteínas Nucleares/metabolismo , Sciuridae , Transativadores/sangue , Transativadores/metabolismoRESUMO
BACKGROUND: The application of RNA-seq technology has become more extensive and the number of analysis procedures available has increased over the past years. Selecting an appropriate workflow has become an important issue for researchers in the field. METHODS: In our study, six popular analytical procedures/pipeline were compared using four RNA-seq datasets from mouse, human, rat, and macaque, respectively. The gene expression value, fold change of gene expression, and statistical significance were evaluated to compare the similarities and differences among the six procedures. qRT-PCR was performed to validate the differentially expressed genes (DEGs) from all six procedures. RESULTS: Cufflinks-Cuffdiff demands the highest computing resources and Kallisto-Sleuth demands the least. Gene expression values, fold change, p and q values of differential expression (DE) analysis are highly correlated among procedures using HTseq for quantification. For genes with medium expression abundance, the expression values determined using the different procedures were similar. Major differences in expression values come from genes with particularly high or low expression levels. HISAT2-StringTie-Ballgown is more sensitive to genes with low expression levels, while Kallisto-Sleuth may only be useful to evaluate genes with medium to high abundance. When the same thresholds for fold change and p value are chosen in DE analysis, StringTie-Ballgown produce the least number of DEGs, while HTseq-DESeq2, -edgeR or -limma generally produces more DEGs. The performance of Cufflinks-Cuffdiff and Kallisto-Sleuth varies in different datasets. For DEGs with medium expression levels, the biological verification rates were similar among all procedures. CONCLUSION: Results are highly correlated among RNA-seq analysis procedures using HTseq for quantification. Difference in gene expression values mainly come from genes with particularly high or low expression levels. Moreover, biological validation rates of DEGs from all six procedures were similar for genes with medium expression levels. Investigators can choose analytical procedures according to their available computer resources, or whether genes of high or low expression levels are of interest. If computer resources are abundant, one can utilize multiple procedures to obtain the intersection of results to get the most reliable DEGs, or to obtain a combination of results to get a more comprehensive DE profile for transcriptomes.
Assuntos
Perfilação da Expressão Gênica , Transcriptoma , Animais , Perfilação da Expressão Gênica/métodos , Camundongos , RNA-Seq , Ratos , Análise de Sequência de RNA/métodos , Sequenciamento do ExomaRESUMO
Bridging integrator-1 (BIN1) is a family of banana-shaped molecules implicated in cell membrane tubulation. To understand the curvature sensitivity and functional roles of BIN1 splicing isoforms, we engineered vertical nanobars on a cell culture substrate to create high and low curvatures. When expressed individually, BIN1 isoforms with phosphoinositide-binding motifs (pBIN1) appeared preferentially at high-curvature nanobar ends, agreeing well with their membrane tubulation in cardiomyocytes. In contrast, the ubiquitous BIN1 isoform without phosphoinositide-binding motif (uBIN1) exhibited no affinity to membranes around nanobars but accumulated along Z-lines in cardiomyocytes. Importantly, in pBIN1-uBIN1 coexpression, pBIN1 recruited uBIN1 to high-curvature membranes at nanobar ends, and uBIN1 attached the otherwise messy pBIN1 tubules to Z-lines. The complementary cooperation of BIN1 isoforms (comboBIN1) represents a novel mechanism of T-tubule formation along Z-lines in cardiomyocytes. Dysregulation of BIN1 splicing, e.g., during myocardial infarction, underlied T-tubule disorganization, and correction of uBIN1/pBIN1 stoichiometry rescued T-tubule morphology in heart disease.
Assuntos
Proteínas Nucleares , Proteínas Supressoras de Tumor , Proteínas Adaptadoras de Transdução de Sinal , Morfogênese , Proteínas Nucleares/genética , Isoformas de Proteínas/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
BACKGROUND: Bladder cancer displays a broad mutational spectrum and intratumor heterogeneity (ITH), which results in difference in molecular phenotypes and resistance to therapies. However, there are currently no clinically available measures to predict patient prognosis using ITH. We aimed to establish a clinically relevant biomarker by using ITH for informing predictive of outcomes. METHODS: We used the Bioconductor R package Maftools to efficiently and comprehensively analyze somatic variants of muscle-invasive bladder cancer (MIBC) from The Cancer Genome Atlas (TCGA). We then used a mutant-allele tumor heterogeneity (MATH) algorithm to measure ITH and explored its correlation with clinical parameters as well as mutational subtypes. RESULTS: We observed a broad range of somatic mutations in MIBC from TCGA. MATH value was higher for the high-grade group than for the low-grade group (p < 0.05). There was a strong correlation between higher MATH value and presence of TP53 mutations (p = 0.008), as well as between lower MATH value and presence of FGFR3 mutations (p = 0.006). Patients with FGFR3 mutation and low MATH value exhibit longer overall survival time than that of all BLCA patients (p = 0.044), which was replicated in another bladder cancer database composed of 109 BLCA patients. CONCLUSION: Measures of tumor heterogeneity may be useful biomarkers for identifying patients with bladder cancer. Low MATH value was an independent risk factor that predicted better prognosis for patients with FGFR3 mutation compared to all BLCA patients.
Assuntos
Receptor Tipo 3 de Fator de Crescimento de Fibroblastos , Neoplasias da Bexiga Urinária , Alelos , Biomarcadores Tumorais/genética , Humanos , Mutação , Prognóstico , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genéticaRESUMO
BACKGROUND AND OBJECTIVES: Bladder cancer is one of the most common and highly recurrent cancers worldwide. Recurrence-associated genes may potentially predict cancer recurrence. We aimed to construct a recurrence-associated gene panel to improve the prognostic prediction of bladder cancer. METHODS: Based on DNA sequencing and clinical data from the TCGA-BLCA project, we identified 10 potential driver genes significantly associated with recurrence of bladder cancer. We performed multivariable logistic regression analysis to construct an optimized recurrence prediction model with nine recurrence-associated genes (EME1, AKAP9, ZNF91, PARD3, STAG2, ZFP36L2, METTL3, POLR3B, and MUC7) and clinical information as the independent variables. RESULTS: The area under the receiver operating characteristic (ROC) curve was 0.80 in this model, much higher than that of the baseline model (AUC = 0.73) and the same trend was also validated in its subset. Decision curve analysis also revealed that there is a significant net benefit gained by adding nine genes mutation to the baseline model. Furthermore, Kaplan-Meier survival analysis showed that eight out of the nine genes (excluding MUC7) had good effects on the overall prognosis of patients. CONCLUSIONS: This nine-gene panel will most likely be a useful tool for prognostic evaluation and will facilitate the personalized management of patients with bladder cancer.
Assuntos
Recidiva Local de Neoplasia/genética , Neoplasias da Bexiga Urinária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Genéticas , Feminino , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Transcriptoma , Neoplasias da Bexiga Urinária/patologiaRESUMO
OBJECTIVE: To study the anti-proliferation effect of Taraxacum mongolicum extract in HepG2 cells and its mechanism. METHODS: The total proteins of HepG2 cells treated with Taraxacum mongolicum extract were. extracted and mitochondria-mediated apoptosis-related proteins (Survivin, Mcl-1, BCL-xL, BCL-2, Smac, BAX, Bad, Cytochrome c and Caspase-3/7/9) were detected by Western blot. RESULTS: Taraxacum mongolicum extract obviously inhibited the proliferation of HepG2 cells and the expression of anti-apoptotic proteins (Survivin, BCL-xL and BCL-2), increased the expression of pro-apoptotic proteins (Smac and Caspase-3/7/9), and promoted the release of Cytochrome c from mitochondria to cytoplasm in HepG2 cells. The effects were in a dose-independent mode. CONCLUSION: Taraxacum mongolicum extract can inhibit the proliferation of HepG2 cells and the anti-proliferation mechanism is related to mitochondria-mediated apoptosis.
Assuntos
Apoptose , Mitocôndrias/metabolismo , Extratos Vegetais/farmacologia , Taraxacum/química , Proteínas Reguladoras de Apoptose/metabolismo , Caspases/metabolismo , Proliferação de Células/efeitos dos fármacos , Citocromos c/metabolismo , Células Hep G2/efeitos dos fármacos , HumanosRESUMO
PURPOSE: Explore the value of ultrasonography for observation of early healing of humeral shaft fractures. METHODS: Sixty-five humeral shaft fracture patients were recruited. They were examined sonographically with color Doppler ultrasonography (CDU) and/or power Doppler ultrasonography (PDU) during the 1st week, 2nd week, 3rd week, 4th week, 9th week, and 15th week after the initial surgical procedure of internal fixation. Formation of callus consolidation and the resistance indexes (RI) of blood flow in different durations were compared between the good healing group and bad healing (delayed fracture healing or nonunion) group. RESULTS: Ultrasound showed that 59 patients had good fracture healing. Within the 2nd and 4th week after surgery, the RI decreased over time (P < 0.05) and color Doppler flow imaging (CDFI/PDU) grading ranged from II to III. Six patients had bad fracture healing (delayed healing or nonunion). Insufficient or absent blood flow signals demonstrated that no callus was found in and/or around the fracture sites. CDFI grading ranged from 0 to I. There was significant difference compared with the good healing group (P < 0.05). CONCLUSION: CDFI/PDU is an easy, painless, and effective method for predicting the prognosis of humeral shaft fractures by estimating early healing.
RESUMO
INTRODUCTION: Contactin-6 (CNTN6), also known as NB-3, is a neural recognition molecule and a member of the contactin subgroup of the immunoglobulin superfamily. Gene encoding CNTN6 is expressed in many regions of the neural system, including the accessory olfactory bulb (AOB) in mice. We aim to determine the effect of CNTN6 deficiency on the function of the accessory olfactory system (AOS). METHODS: We examined the effect of CNTN6 deficiency on the reproductive behavior of male mice through behavioral experiments such as urine sniffing and mate preference tests. Staining and electron microscopy were used to observe the gross structure and the circuitry activity of the AOS. RESULTS: Cntn6 is highly expressed in the vomeronasal organ (VNO) and the AOB, and sparsely expressed in the medial amygdala (MeA) and the medial preoptic area (MPOA), which receive direct and/or indirect projections from the AOB. Behavioral tests to examine reproductive function in mice, which is mostly controlled by the AOS, revealed that Cntn6-/- adult male mice showed less interest and reduced mating attempts toward estrous female mice in comparison with their Cntn6+/+ littermates. Although Cntn6-/- adult male mice displayed no obvious changes in the gross structure of the VNO or AOB, we observed the increased activation of granule cells in the AOB and the lower activation of neurons in the MeA and the MPOA as compared with Cntn6+/+ adult male mice. Moreover, there were an increased number of synapses between mitral cells and granule cells in the AOB of Cntn6-/- adult male mice as compared with wild-type controls. CONCLUSION: These results indicate that CNTN6 deficiency affects the reproductive behavior of male mice, suggesting that CNTN6 participated in normal function of the AOS and its ablation was involved in synapse formation between mitral and granule cells in the AOB, rather than affecting the gross structure of the AOS.
Assuntos
Moléculas de Adesão Celular Neuronais , Bulbo Olfatório , Comportamento Sexual Animal , Animais , Feminino , Masculino , Camundongos , Neurogênese , Neurônios/fisiologia , Órgão Vomeronasal/fisiologia , Moléculas de Adesão Celular Neuronais/metabolismoRESUMO
Neural adhesion molecule NB-3 plays an important role in the apical dendrite development of layer V pyramidal neurons in the visual cortex, and receptor-like protein-tyrosine phosphatase α (PTPα) mediates NB-3 signaling in this process. Here we investigated the role of PTPα in regulating cell surface expression of NB-3. We found that cortical neurons from PTPα knock-out mice exhibited a lower level of NB-3 at the cell surface. When expressed in COS1 cells, NB-3 was enriched in the Golgi apparatus with a low level of cell surface expression. However, co-expression of PTPα increased the cell surface distribution of NB-3. Further analysis showed that PTPα facilitated Golgi exit of NB-3 and stabilized NB-3 protein at the cell surface by preventing its release from the plasma membrane. The extracellular region of PTPα but not its catalytic activity is necessary for its effect on NB-3 expression. Thus, the PTPα-mediated increase of NB-3 level at the cell surface represents a novel function of PTPα in NB-3 signaling in neural development.
Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Regulação da Expressão Gênica , Neurônios/citologia , Neurônios/metabolismo , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/metabolismo , Animais , Células COS , Moléculas de Adesão Celular Neuronais/biossíntese , Membrana Celular/metabolismo , Chlorocebus aethiops , Espaço Extracelular/metabolismo , Fibronectinas/química , Complexo de Golgi/metabolismo , Humanos , Imunoglobulinas/química , Camundongos , Estabilidade Proteica , Transporte Proteico , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/química , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/deficiência , Sequências Repetitivas de Aminoácidos , Transdução de Sinais , TransfecçãoRESUMO
Apical dendrites of pyramidal neurons in the neocortex have a stereotypic orientation that is important for neuronal function. Neural recognition molecule Close Homolog of L1 (CHL1) has been shown to regulate oriented growth of apical dendrites in the mouse caudal cortex. Here we show that CHL1 directly associates with NB-3, a member of the F3/contactin family of neural recognition molecules, and enhances its cell surface expression. Similar to CHL1, NB-3 exhibits high-caudal to low-rostral expression in the deep layer neurons of the neocortex. NB-3-deficient mice show abnormal apical dendrite projections of deep layer pyramidal neurons in the visual cortex. Both CHL1 and NB-3 interact with protein tyrosine phosphatase alpha (PTPalpha) and regulate its activity. Moreover, deep layer pyramidal neurons of PTPalpha-deficient mice develop misoriented, even inverted, apical dendrites. We propose a signaling complex in which PTPalpha mediates CHL1 and NB-3-regulated apical dendrite projection in the developing caudal cortex.
Assuntos
Moléculas de Adesão Celular Neuronais/fisiologia , Moléculas de Adesão Celular/fisiologia , Dendritos/enzimologia , Neocórtex/citologia , Molécula L1 de Adesão de Célula Nervosa/fisiologia , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/fisiologia , Animais , Células COS , Moléculas de Adesão Celular/deficiência , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular Neuronais/deficiência , Moléculas de Adesão Celular Neuronais/genética , Linhagem Celular , Chlorocebus aethiops , Dendritos/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neocórtex/enzimologia , Neocórtex/metabolismo , Molécula L1 de Adesão de Célula Nervosa/deficiência , Molécula L1 de Adesão de Célula Nervosa/genética , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/enzimologia , Córtex Pré-Frontal/metabolismo , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/deficiência , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/genéticaRESUMO
Renal cell carcinoma (RCC) is a common type of kidney cancer that lacks effective therapeutic options. Ginsenoside compound K (CK), an active metabolite of ginsenosides, has been reported to induce apoptosis in various types of cancer cells. However, the effects of CK in RCC remain to be elucidated. Thus, the aim of the present study was to investigate the antitumor effects of CK on RCC cells. The effects of CK on the proliferation, migration, invasion, cell cycle and apoptosis of RCC cell lines (Caki1 and 768O) were investigated using MTT, wound healing, Transwell and flow cytometry assays, respectively. Changes in the expression levels of long noncoding RNAs (lncRNAs) and proteins were measured via reverse transcriptionquantitative PCR and western blotting, respectively. Transfections with testis associated oncogenic (THOR) small interfering RNA and pcDNA were performed to knock down and overexpress lncRNA THOR, respectively. It was found that CK could effectively inhibit the proliferation, migration and invasion of RCC cells. CK also induced cell cycle arrest and caspasedependent apoptosis in RCC cells. Furthermore, the generation of reactive oxygen species and inhibition of the lncRNA THOR played important roles in the antitumour effects of CK in RCC cells. The present data revealed that CK was a potent antitumour agent against RCC.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Ginsenosídeos/farmacologia , Neoplasias Renais/tratamento farmacológico , RNA Longo não Codificante/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ginsenosídeos/uso terapêutico , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , RNA Longo não Codificante/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by abnormalities in social interaction, language development and behavior. Recent genetic studies demonstrate that alterations in synaptic genes including those encoding cell adhesion molecules and their interaction partners play important roles in the pathogenesis of ASD. Systematic analyses of different cell adhesion molecule genes will help elucidate their normal functions and regulatory mechanisms in the establishment and maintenance of normal neural circuits and uncover genetic aberrations contributing to ASD.
Assuntos
Moléculas de Adesão Celular/metabolismo , Transtornos Globais do Desenvolvimento Infantil/metabolismo , Animais , Moléculas de Adesão Celular/genética , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Humanos , Modelos Biológicos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismoRESUMO
Trk tyrosine kinases are receptors for members of the neurotrophin family and are crucial for growth and survival of specific populations of neurons. Yet, the functions of neurotrophin-Trk signaling in postnatal development as well as maintenance and plasticity of the adult nervous system are less clear. We report here the generation of mice harboring Trk knockin alleles that allow for pharmacological control of Trk kinase activity. Nanomolar concentrations of either 1NMPP1 or 1NaPP1, derivatives of the general kinase inhibitor PP1, inhibit NGF and BDNF signaling in TrkA(F592A) and TrkB(F616A) neurons, respectively, while no such Trk inhibition is observed in wild-type neurons. Moreover, oral administration of 1NMPP1 leads to specific inhibition of TrkA(F592A), TrkB(F616A), and TrkC(F167A) signaling in vivo. Thus, Trk knockin mice provide valuable tools for selective, rapid, and reversible inhibition of neurotrophin signaling in vitro and in vivo.
Assuntos
Modelos Animais , Fatores de Crescimento Neural/metabolismo , Neurônios/metabolismo , Receptor trkA/metabolismo , Transdução de Sinais/fisiologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Inibidores Enzimáticos/farmacologia , Camundongos , Camundongos Mutantes , Dados de Sequência Molecular , Fatores de Crescimento Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptor trkA/antagonistas & inibidores , Receptor trkA/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
The mechanism by which target-derived Nerve Growth Factor (NGF) signaling is propagated retrogradely, over extremely long distances, to cell bodies to support survival of neurons is unclear. Here we show that survival of sympathetic neurons supported by NGF on distal axons requires the kinase activity of the NGF receptor, TrkA, in both distal axons and cell bodies. In contrast, disruption of TrkA activity exclusively in proximal axonal segments affects neither retrograde NGF-TrkA signaling in cell bodies nor neuronal survival. Ligand-receptor internalization is necessary for survival of neurons supported by NGF on distal axons. Furthermore, antibody neutralization experiments indicate that retrogradely transported NGF, within cell bodies, is critical for neuronal survival but not for growth of distal axons. Taken together, our results indicate that retrogradely transported NGF-TrkA complexes promote sympathetic neuron survival.
Assuntos
Transporte Axonal/fisiologia , Endossomos/metabolismo , Fator de Crescimento Neural/metabolismo , Neurônios/metabolismo , Receptor trkA/metabolismo , Animais , Compartimento Celular/fisiologia , Sobrevivência Celular , Células Cultivadas , Endossomos/ultraestrutura , Neurônios/ultraestrutura , Ratos , Transdução de Sinais/fisiologia , Sistema Nervoso Simpático/citologia , Sistema Nervoso Simpático/metabolismoRESUMO
Schizophrenia is a severe psychiatric disorder. Genetic and functional studies have strongly implicated the disrupted in schizophrenia 1 gene (DISC1) as a candidate susceptibility gene for schizophrenia. Moreover, recent association studies have indicated that several DISC1 single nucleotide polymorphisms (SNPs) are associated with schizophrenia. However, the association is hardly replicate in different ethnic group. Here, we performed a meta-analysis of the association between DISC1 SNPs and schizophrenia in which the samples were divided into subgroups according to ethnicity. Both rs3738401 and rs821616 showed not significantly association with schizophrenia in the Caucasian, Asian, Japanese or Han Chinese populations.
Assuntos
Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Povo Asiático/genética , Estudos de Associação Genética , Humanos , População Branca/genéticaRESUMO
MK-801, a non-competitive NMDA receptor (NMDAR) antagonist, disturbs NMDAR function in rodents and induces psychological and behavioral changes similar to schizophrenia (SCZ). However, the effects of MK-801 treatment on gene expression are largely unknown. Here we performed RNA-sequencing on the prefrontal cortex of MK-801-exposed male mice in order to analyze gene expression and co-expression patterns related to SCZ and to identify mechanisms that underlie the molecular etiology of this disorder. Transcriptome analysis revealed that the differentially expressed genes were more often associated with biological processes that included postsynaptic transmission, immune system process, response to external stimulus and hemostasis. In order to extract comprehensive biological information, we used an approach for biclustering, called FABIA, to simultaneously cluster transcriptomic data across genes and conditions. When combined with analyses using DAVID and STRING databases, we found that co-expression patterns were altered in synapse-related genes and genes central to the mitochondrial network. Abnormal co-expression of genes mediating synaptic vesicle cycling could disturb release, uptake and reuptake of glutamate, and the perturbation in co-expression patterns for mitochondrial respiratory chain complexes was extensive. Our study supports the hypothesis that research using MK-801-exposed male mice as an animal model of SCZ offers important insights into the pathogenesis of SCZ.
Assuntos
Maleato de Dizocilpina/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética , Transcriptoma , Animais , Comportamento Animal , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/genética , Mitocôndrias/metabolismo , Esquizofrenia/metabolismo , Transdução de Sinais , Sinapses/metabolismoRESUMO
INTRODUCTION: CNTN6 is an immunoglobulin domain-containing cell adhesion molecule that belongs to the contactin family. It is involved in the development of the nervous system. We aim to determine the effect of Cntn6 deficiency on the allocentric navigation in mice. METHODS: We recorded the travel distance and escape time of wild-type and Cntn6 mutant male and female mice in the Morris water maze task according to the protocol. RESULTS: There was hardly any Cntn6 expression in the hippocampus of postnatal day 0 (P0) mice, while obvious Cntn6 expression was present in the hippocampal CA1 region of the P7 mice. During the acquisition period of Morris water maze task (Day 1 to 4), Cntn6-/- male mice failed to shorten the escape time to reach platform on the third day, while the travel distance to platform was not significantly different. There was no significant difference in both escape time and travel distance to the platform among all female subjects. In the probe trial test (Day 5), spatial memory of the female mutant mice was mildly affected, while Cntn6-/- male mice were normal. In the spatial relearning test (Day 7 to 10), Cntn6-/- male mice showed no difference in escape time to the platform compared to the wild-type male mice, while Cntn6 deficient female mice required shorter escape time to travel to the platform on day 7, day 8, and day 10. CONCLUSIONS: Cntn6 is expressed in the developing hippocampus in mice. Cntn6 deficiency affects spatial learning and memory, indicating that Cntn6 plays a role in the development of hippocampus and affects allocentric navigation of the animals.
Assuntos
Hipocampo/metabolismo , Aprendizagem em Labirinto/fisiologia , Memória Espacial/fisiologia , Animais , Comportamento Animal/fisiologia , Moléculas de Adesão Celular Neuronais/deficiência , Feminino , Masculino , Camundongos , Camundongos Knockout , Fatores de TempoRESUMO
Gestational and perinatal disruption of neural development increases the risk of developing schizophrenia (SCZ) later in life. Embryonic day 17 (E17) methylazoxymethanol (MAM) treatment leads to histological, physiological and behavioural abnormalities in post-puberty rats that model the neuropathological and cognitive deficits reported in SCZ patients. However, the validity of E17 MAM-exposed mice to model SCZ has not been explored. Here we treated E17 C57BL/6 mouse dams with various dosages of MAM. We found that this mouse strain was more vulnerable to MAM treatment than rats and there were gender differences in behavioural abnormalities, histological changes and prefrontal cortical gene expression profiles in MAM (7.5â¯mg/kg)-exposed mice. Both male and female MAM-exposed mice had deficits in prepulse inhibition. Female MAM-exposed mice exhibited mildly increased spontaneous locomotion activity and social recognition deficits, while male mice were normal. Consistently, only female MAM-exposed mice exhibited reduced brain weight, decreased size of prefrontal cortex (PFC) and enlarged lateral ventricles. Transcriptome analysis of the PFC revealed that there were more differentially expressed genes in female MAM-exposed mice than those in male mice. Moreover, expression of Pvalb, Arc and genes in their association networks were downregulated in the PFC of female MAM-exposed mice. These results indicate that E17 MAM-exposure in C57BL/6 mice leads to behavioural changes that model certain deficits reported in SCZ patients. MAM-exposed female mice may be used to study gene expression changes, inhibitory neural circuit dysfunction and glutamatergic synaptic plasticity deficits with a possible relation to those in the brains of SCZ patients.
Assuntos
Acetato de Metilazoximetanol/análogos & derivados , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética , Esquizofrenia/patologia , Psicologia do Esquizofrênico , Transcriptoma/efeitos dos fármacos , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Hipertrofia , Ventrículos Laterais/patologia , Masculino , Acetato de Metilazoximetanol/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Inibição Pré-Pulso/efeitos dos fármacos , Caracteres Sexuais , Comportamento SocialRESUMO
Colorectal cancer (CRC) is one of the most common types of malignancy with high morbidity and mortality rates worldwide. This biologically heterogeneous disease results in diverse therapeutic responses, thus, novel prognostic biomarkers are required to improve CRC treatment. Estrogen-related receptor α (ERRα) is a nuclear orphan receptor, which is associated with estrogen receptor α. The present study aimed to investigate the expression of ERRα in patients with CRC, and explore the association between ERRα expression and clinicopathological factors, local recurrence and prognosis. In the present study, ERRα expression was detected in 15 fresh CRC tissues using quantitative real-time polymerase chain reaction (RT-qPCR) and in 128 paraffin-embedded CRC tissues using immunohistochemistry. The associations between ERRα expression and prognosis of CRC patients were evaluated by univariate, and multivariate (Cox proportional hazards model) analysis. RT-qPCR demonstrated that the mRNA expression of ERRα in CRC tissues was significantly higher compared with that in matched normal tissues. Immunohistochemistry revealed that ERRα high expression was detected in the nuclei of cancer cells from 39.1% (50/128) of CRC tissues. ERRα expression based on immunohistochemical staining was significantly associated with tumor differentiation, tumor invasion, lymph node status and Dukes stage (all P<0.05). Furthermore, patients with high ERRα expression were significantly associated with an increased risk of recurrence and poor prognosis, compared with patients with low ERRα expression. ERRα expression was identified as an independent prognostic factor for patients with CRC. In conclusion, ERRα serves important roles in the progression of CRC and is a potential prognostic factor for patients with CRC.
RESUMO
The present study aimed to investigate the prognostic factors for recurrence of hepatocellular carcinoma (HCC) following curative resection, and evaluate the efficacy of postoperative adjuvant transarterial chemoembolization (TACE) in improving prognosis. A total of 166 patients who underwent curative resection followed by adjuvant TACE, and 190 patients who underwent curative resection alone were studied retrospectively. Univariate and multivariate analyses were performed to investigate the risk factors of recurrence. Separated based on risk factors, subgroup studies were conducted and the association between TACE and recurrence rates was examined. Postoperative overall survival rates were determined using the Kaplan-Meier method and differences between the two therapeutic strategies were identified through log-rank analysis. Computerized tomography (CT)/magnetic resonance imaging (MRI) images were used to evaluate the function of postoperative adjuvant TACE for enhancing the efficacy of CT/MRI in detecting recurrence. The results of the univariate and multivariate analyses revealed that tumor capsule invasion, vascular invasion, and multiple nodules were risk factors of early recurrence. For patients with these risk factors, recurrence rates were markedly decreased at 6 and 12 months, but not at 18 and 24 months, if TACE was added to curative resection. The hepatitis B virus (HBV) was a risk factor for late recurrence. Postoperative TACE was not effective in reducing the recurrence rate in patients with HBV. Survival increased following curative resection with TACE compared with curative resection alone. Furthermore, adjuvant TACE enhanced the efficacy of CT/MRI in detecting recurrence. Postoperative adjuvant TACE may improve the prognosis of HCC following curative resection.