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1.
Nat Commun ; 10(1): 4799, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641124

RESUMO

Metabolic diseases harm brain health and cognitive functions, but whether maternal metabolic unbalance may affect brain plasticity of next generations is still unclear. Here, we demonstrate that maternal high fat diet (HFD)-dependent insulin resistance multigenerationally impairs synaptic plasticity, learning and memory. HFD downregulates BDNF and insulin signaling in maternal tissues and epigenetically inhibits BDNF expression in both germline and hippocampus of progeny. Notably, exposure of the HFD offspring to novel enriched environment restores Bdnf epigenetic activation in the male germline and counteracts the transmission of cognitive impairment to the next generations. BDNF administration to HFD-fed mothers or preserved insulin sensitivity in HFD-fed p66Shc KO mice also prevents the intergenerational transmission of brain damage to the progeny. Collectively, our data suggest that maternal diet multigenerationally impacts on descendants' brain health via gametic mechanisms susceptible to lifestyle.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Aprendizagem/fisiologia , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Epigênese Genética , Feminino , Proteína Forkhead Box O3/metabolismo , Regulação da Expressão Gênica , Hipocampo/fisiopatologia , Histona Desacetilase 2/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovário/metabolismo , Sirtuína 2/metabolismo , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/genética
2.
Nat Commun ; 10(1): 4223, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530804

RESUMO

Diseases related to impaired blood flow such as peripheral artery disease (PAD) impact nearly 10 million people in the United States alone, yet patients with clinical manifestations of PAD (e.g., claudication and limb ischemia) have limited treatment options. In ischemic tissues, stress kinases such as c-Jun N-terminal kinases (JNKs), are activated. Here, we show that inhibition of the JNK3 (Mapk10) in the neural compartment strikingly potentiates blood flow recovery from mouse hindlimb ischemia. JNK3 deficiency leads to upregulation of growth factors such as Vegfa, Pdgfb, Pgf, Hbegf and Tgfb3 in ischemic muscle by activation of the transcription factors Egr1/Creb1. JNK3 acts through Forkhead box O3 (Foxo3a) to suppress the activity of Egr1/Creb1 transcription regulators in vitro. In JNK3-deficient cells, Foxo3a is suppressed which leads to Egr1/Creb1 activation and upregulation of downstream growth factors. Collectively, these data suggest that the JNK3-Foxo3a-Egr1/Creb1 axis coordinates the vascular remodeling response in peripheral ischemia.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Membro Posterior/irrigação sanguínea , Isquemia/metabolismo , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Neurônios/metabolismo , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Membro Posterior/inervação , Membro Posterior/metabolismo , Humanos , Isquemia/genética , Isquemia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 10 Ativada por Mitógeno/genética , Músculo Esquelético/metabolismo , Fluxo Sanguíneo Regional , Transdução de Sinais
3.
Nat Commun ; 10(1): 4353, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554795

RESUMO

Stat6 is known to drive macrophage M2 polarization. However, how macrophage polarization is fine-tuned by Stat6 is poorly understood. Here, we find that Lys383 of Stat6 is acetylated by the acetyltransferase CREB-binding protein (CBP) during macrophage activation to suppress macrophage M2 polarization. Mechanistically, Trim24, a CBP-associated E3 ligase, promotes Stat6 acetylation by catalyzing CBP ubiquitination at Lys119 to facilitate the recruitment of CBP to Stat6. Loss of Trim24 inhibits Stat6 acetylation and thus promotes M2 polarization in both mouse and human macrophages, potentially compromising antitumor immune responses. By contrast, Stat6 mediates the suppression of TRIM24 expression in M2 macrophages to contribute to the induction of an immunosuppressive tumor niche. Taken together, our findings establish Stat6 acetylation as an essential negative regulatory mechanism that curtails macrophage M2 polarization.


Assuntos
Ativação de Macrófagos , Macrófagos/metabolismo , Neoplasias Experimentais/metabolismo , Proteínas Nucleares/metabolismo , Fator de Transcrição STAT6/metabolismo , Fatores de Transcrição/metabolismo , Acetilação , Animais , Linhagem Celular Tumoral , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Humanos , Lisina/genética , Lisina/metabolismo , Macrófagos/classificação , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Proteínas Nucleares/genética , Fator de Transcrição STAT6/genética , Fatores de Transcrição/genética
4.
Bioengineered ; 10(1): 345-352, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31411110

RESUMO

This study aimed to detect serum miR-203 expression levels in AML and explore its potential clinical significance. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to measure the serum miR-203 levels in 134 patients with AML and 70 healthy controls. The results demonstrated that serum miR-203 expression was significantly reduced in AML patients compared with healthy controls. Receiver operating characteristic curve (ROC) analysis revealed miR-203 could distinguish AML cases from normal controls. Low serum miR-203 levels were associated with worse clinical features, as well as poorer overall survival and relapse free survival of AML patients. Moreover, multivariate analysis confirmed low serum miR-203 expression to be an independent unfavorable prognostic predictor for AML. The bioinformatics analysis showed that the downstream genes and pathways of miR-203 was closely associated with tumorigenesis. Downregulation of miR-203 in AML cell lines upregulated the expression levels of oncogenic promoters such as CREB1, SRC and HDAC1. Thus, these findings demonstrated that serum miR-203 might be a promising biomarker for the diagnosis and prognosis of AML.


Assuntos
Biomarcadores Tumorais/genética , Carcinogênese/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , MicroRNAs/genética , Proteínas de Neoplasias/genética , Antagomirs/genética , Antagomirs/metabolismo , Biomarcadores Tumorais/sangue , Carcinogênese/metabolismo , Carcinogênese/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Biologia Computacional/métodos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/sangue , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Perfilação da Expressão Gênica , Ontologia Genética , Histona Desacetilase 1/sangue , Histona Desacetilase 1/genética , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , MicroRNAs/antagonistas & inibidores , MicroRNAs/sangue , Anotação de Sequência Molecular , Análise Multivariada , Proteínas de Neoplasias/sangue , Prognóstico , Curva ROC , Recidiva , Transdução de Sinais , Análise de Sobrevida , Quinases da Família src/sangue , Quinases da Família src/genética
5.
Mol Med Rep ; 20(2): 1583-1592, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257496

RESUMO

Propofol is a general anesthetic used in surgical operations. Phosphoprotein enriched in astrocytes 15(PEA15) was initially identified in astrocytes. The present study examined the role of PEA15 in the damage induced by propofol in hippocampal neurons. A model of hippocampal neuron damage was established using 50 µmol/l propofol. Cell viability, proliferation and apoptosis of hippocampal neurons were tested by Cell Counting Kit­8 and flow cytometry. Western blotting and reverse transcription­quantitative polymerase chain reaction analysis were performed to measure the expression levels of PEA15, and additional factors involved in apoptosis or in the signaling pathway downstream of PEA15. The present results suggested that propofol significantly decreased PEA15 expression levels in hippocampal neurons. Furthermore, overexpression of PEA15 significantly increased the cell viability and cell proliferation of cells treated with propofol. Additionally, PEA15 overexpression decreased apoptosis, which was promoted by propofol. Treatment with propofol significantly decreased the protein expression levels of pro­caspase­3, B­cell lymphoma-2, phosphorylated extracellular signal­regulated kinases (ERK)1/2, ribosomal S6 kinase 2 (RSK2) and phosphorylated cAMP responsive element binding protein 1 (CREB1). However, propofol upregulated active caspase­3 and Bax expression levels. Notably, PEA15 overexpression was able to reverse the effects of propofol. Collectively, overexpression of PEA15 was able to attenuate the neurotoxicity of propofol in rat hippocampal neurons by increasing proliferation and repressing apoptosis via upregulation of the ERK­CREB­RSK2 signaling pathway.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Apoptose/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Propofol/toxicidade , Animais , Animais Recém-Nascidos , Apoptose/genética , Proteínas Reguladoras de Apoptose/agonistas , Proteínas Reguladoras de Apoptose/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Feminino , Regulação da Expressão Gênica , Hipocampo/citologia , Hipocampo/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Plasmídeos/química , Plasmídeos/metabolismo , Gravidez , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Transdução de Sinais , Transfecção , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
6.
Mol Med Rep ; 20(2): 1837-1845, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257533

RESUMO

Hypoxic preconditioning (HPC) is neuroprotective against ischaemic brain injury; however, the roles of potential anti­apoptotic signals in this process have not been assessed. To elucidate the molecular mechanisms involved in HPC­induced neuroprotection, the effects of HPC on the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element­binding protein (CREB) signalling pathway and apoptosis in Sprague­Dawley pups (postnatal day 7) treated with propofol were investigated. Western blot and histological analyses demonstrated that HPC exerts multiple effects on the hippocampus, including the upregulation of cAMP and phosphorylation of CREB. These effects were partially blocked by intracerebroventricular injection of the protein kinase antagonist H89 (5 µmol/5 µl). Notably, the level of cleaved caspase­3 was significantly downregulated by treatment with the cAMP agonist Sp­cAMP (20 nmol/5 µl). The results indicate that propofol increased the level of cleaved caspase­3 and Bax by suppressing the activity of cAMP­dependent proteins and Bcl­2; thus, HPC prevents propofol from triggering apoptosis via the cAMP/PKA/CREB signalling pathway.


Assuntos
Lesões Encefálicas/terapia , Precondicionamento Isquêmico/métodos , Neurônios/metabolismo , Neuroproteção/genética , Animais , Animais Recém-Nascidos , Apoptose/genética , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Lesões Encefálicas/prevenção & controle , AMP Cíclico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/genética , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Neurônios/patologia , Fosforilação/genética , Propofol/toxicidade , Ratos , Transdução de Sinais/genética , Lobo Temporal/metabolismo , Lobo Temporal/patologia
7.
Biomed Res Int ; 2019: 9734576, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183379

RESUMO

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and rapidly lethal tumors. However, limited advances have been made to prolong the survival and to reduce the mortality over the last decades. Therefore, identifying the master regulators underlying ATC progression is desperately needed. In our present study, three datasets including GSE33630, GSE29265, and GSE65144 were retrieved from Gene Expression Omnibus with a total of 32 ATC samples and 78 normal thyroid tissues. A total of 1804 consistently changed differentially expressed genes (DEGs) were identified from three datasets. KEGG pathways enrichment suggested that upregulated DEGs were mainly enriched in ECM-receptor interaction, cell cycle, PI3K-Akt signaling pathway, focal adhesion, and p53 signaling pathway. Furthermore, key gene modules in PPI network were identified by Cytoscape plugin MCODE and they were mainly associated with DNA replication, cell cycle process, collagen fibril organization, and regulation of leukocyte migration. Additionally, TOP2A, CDK1, CCNB1, VEGFA, BIRC5, MAPK1, CCNA2, MAD2L1, CDC20, and BUB1 were identified as hub genes of the PPI network. Interestingly, module analysis showed that 8 out of 10 hub genes participated in Module 1 network and more than 70% genes of Module 2 consisted of collagen family members. Notably, transcription factors (TFs) regulatory network analysis indicated that E2F7, FOXM1, and NFYB were master regulators of Module 1, while CREB3L1 was the master regulator of Module 2. Experimental validation showed that CREB3L1, E2F7, and FOXM1 were significantly upregulated in ATC tissue and cell line when compared with normal thyroid group. In conclusion, the TFs regulatory network provided a more detail molecular mechanism underlying ATC occurrence and progression. TFs including E2F7, FOXM1, CREB3L1, and NFYB were likely to be master regulators of ATC progression, suggesting their potential role as molecular therapeutic targets in ATC treatment.


Assuntos
Biomarcadores Tumorais/genética , Biologia Computacional , Carcinoma Anaplásico da Tireoide/genética , Transcriptoma/genética , Fator de Ligação a CCAAT/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Fator de Transcrição E2F7/genética , Proteína Forkhead Box M1/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/genética , Transdução de Sinais/genética , Carcinoma Anaplásico da Tireoide/patologia
8.
J Med Food ; 22(7): 685-695, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31225769

RESUMO

The leaves of Aster glehni Fr. Schm. (Asteraceae) have been used to treat insomnia in Korea. Insomnia is a common adverse effect of therapeutic agents for Alzheimer's disease (AD), and the control of sleep disturbance may prevent dementia. We hypothesized that the leaves of A. glehni can attenuate cognitive dysfunctions observed in AD. We observed the ameliorating effects of the ethanolic extract of leaves of A. glehni (AG-D) on memory dysfunction through the Morris water maze test, the passive avoidance test, and the Y-maze test. We performed acetylcholinesterase (AChE) activity assay and Western blotting to determine the mechanism of action of AG-D. AG-D significantly attenuated memory dysfunction observed in the above behavior studies and inhibited the activity of AChE. AG-D also increased the levels of phosphorylation extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), and glycogen synthase kinase 3ß (GSK-3ß) and the expression levels of brain-derived neurotrophic factor (BDNF) in the hippocampi. These results suggest that AG-D ameliorates memory impairments by AChE inhibition and activation of ERK-CREB-BDNF and PI3K-Akt-GSK-3ß signaling pathways. Taken together, this study suggests that AG-D could be used as a potential treatment for cognitive dysfunction.


Assuntos
Aster/química , Disfunção Cognitiva/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Animais , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Masculino , Aprendizagem em Labirinto , Memória/efeitos dos fármacos , Camundongos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Escopolamina/efeitos adversos , Transdução de Sinais/efeitos dos fármacos
9.
PLoS Genet ; 15(5): e1008176, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31150381

RESUMO

Gene expression changes in neural systems are essential for environment-induced behavioral plasticity in animals; however, neuronal signaling pathways mediating the effect of external stimuli on transcriptional changes are largely unknown. Recently, we have demonstrated that the neuropeptide F (NPF)/nitric oxide (NO) signaling pathway plays a regulatory role in phase-related locomotor plasticity in the migratory locust, Locusta migratoria. Here, we report that a conserved transcription factor, cAMP response element-binding protein B (CREB-B), is a key mediator involved in the signaling pathway from NPF2 to NOS in the migratory locust, triggering locomotor activity shift between solitarious and gregarious phases. We find that CREB-B directly activates brain NOS expression by interacting with NOS promoter region. The phosphorylation at serine 110 site of CREB-B dynamically changes in response to population density variation and is negatively controlled by NPF2. The involvement of CREB-B in NPF2-regulated locomotor plasticity is further validated by RNAi experiment and behavioral assay. Furthermore, we reveal that protein kinase A mediates the regulatory effects of NPF2 on CREB-B phosphorylation and NOS transcription. These findings highlight a precise signal cascade underlying environment-induced behavioral plasticity.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Locomoção/genética , Locusta migratoria/genética , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Regulação da Expressão Gênica/genética , Gafanhotos/genética , Gafanhotos/metabolismo , Locusta migratoria/metabolismo , Plasticidade Neuronal/genética , Neuropeptídeos/metabolismo , Neuropeptídeos/fisiologia , Óxido Nítrico/metabolismo , Óxido Nítrico/fisiologia , Fosforilação , Regiões Promotoras Genéticas/genética , Interferência de RNA , Serina/metabolismo , Transdução de Sinais
10.
Mol Med Rep ; 19(6): 5321-5334, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059045

RESUMO

High pressure is the most important factor inducing retinal ganglion cell (RGC) apoptosis. However, the underlying mechanisms remain obscure. The present study investigated the effects of different levels of hydrostatic pressure (HP) on RGCs and the potential mechanisms involved. Primary cultured rat RGCs were exposed to five levels of HP (0, 20, 40, 60 and 80 mmHg) for 24 h. Morphological changes in RGCs were observed. The viability and apoptosis rate of RGCs were detected using a Cell Counting Kit­8 assay and Annexin V­fluorescein isothiocyanate/propidium iodide flow cytometry, respectively. Western blotting, reverse transcription­quantitative polymerase chain reaction and immunofluorescence were used to detect the expression and mRNA levels of nerve growth factor (NGF), protein kinase B (AKT), apoptosis signal­regulating kinase 1 (ASK1), forkhead box O1 (FoxO1) and cAMP response element binding protein (CREB). In the 0­ and 20­mmHg groups, there were no apoptotic morphological changes. In the 40 mmHg group, parts of the cell were shrunken or disrupted. In the 60 mmHg group, neurite extension was weakened and parts of the cells were disintegrating or dying. In the 80 mmHg group, the internal structures of the cells were not visible at all. The apoptosis rates of RGCs were significantly higher and the viability rates significantly lower under 40, 60 and 80 mmHg compared with under 0 or 20 mmHg (all P<0.01). The expression and mRNA levels of NGF, AKT and CREB decreased in a dose­dependent manner in the 40­, 60­ and 80­mmHg groups (all P<0.05), but those of ASK1 and FoxO1 increased in a dose­dependent manner (all P<0.05). Interestingly, the alterations to the expression and mRNA levels of CREB were significantly larger compared with the changes in ASK1 or FoxO1 in the 40­, 60­ and 80­mmHg groups (all P<0.01). The results of the present study demonstrate that elevated HP of 40, 60 or 80 mmHg reduces viability and induces apoptosis in RGCs, which may occur through effects on the NGF/ASK1/FoxO1 and NGF/AKT/CREB pathways, of which the latter is more strongly affected.


Assuntos
Apoptose , Fator de Crescimento Neural/metabolismo , Transdução de Sinais , Animais , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Pressão Hidrostática , Fator de Crescimento Neural/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Células Ganglionares da Retina/citologia , Células Ganglionares da Retina/metabolismo
11.
Tissue Cell ; 58: 61-69, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31133247

RESUMO

This study aimed to investigate the effect of different methylated regions of cyclic-AMP response element binding protein 1 (CREB1) by comparing the high prolificacy (HP) group and low prolificacy (LP) group, which was detected in our previous study. The expression level of CREB1 mRNA in the ovaries of the HP group was higher than in the LP group (P < 0.05). The differential methylated region (DMR) had 4 methylated CG dinucleotides(CGs): -1546, -1544, -1494 and -1464. The DNA methylation levels of -1546 CGs and -1464 CGs were significantly higher in the HP group than in the LP group (P < 0.05). The activity from -1296 to +26 (without DMR) was significantly higher than the activity from -1598 to +26 (with DMR) (P < 0.05). The result of 5-aza-2'-deoxycytidine treatment indicated that the inhibition DNA methylation of DMR reduced the transcription of CREB1. The bioinformatics predictive analysis were found that the -1546 CG site was located in the CCAAT/enhancer-binding protein alpha (CEBPA) binding site and the -1464 CG site was located in the Sp1 binding site. Finally, this study revealed the relationship between the methylation of non-CpG sites of the promoter and transcription of CREB1. This study will provide a theoretical basis of the Hu sheep ovaries associated with DNA methylation.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Metilação de DNA/fisiologia , Regulação da Expressão Gênica/fisiologia , Ovário/metabolismo , Elementos de Resposta/fisiologia , Animais , Ilhas de CpG , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Feminino , Ovinos
12.
Nat Commun ; 10(1): 2315, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31127098

RESUMO

Encoding and retrieval of contextual memories is initially mediated by sparsely activated neurons, so-called engram cells, in the hippocampus. Subsequent memory persistence is thought to depend on network-wide changes involving progressive contribution of cortical regions, a process referred to as systems consolidation. Using a viral-based TRAP (targeted recombination in activated populations) approach, we studied whether consolidation of contextual fear memory by neurons in the medial prefrontal cortex (mPFC) is modulated by memory strength and CREB function. We demonstrate that activity of a small subset of mPFC neurons is sufficient and necessary for remote memory expression, but their involvement depends on the strength of conditioning. Furthermore, selective disruption of CREB function in mPFC engram cells after mild conditioning impairs remote memory expression. Together, our data demonstrate that memory consolidation by mPFC engram cells requires CREB-mediated transcription, with the functionality of this network hub being gated by memory strength.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Medo/fisiologia , Consolidação da Memória/fisiologia , Memória de Longo Prazo/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Comportamento Animal/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/antagonistas & inibidores , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Dependovirus/genética , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microinjeções , Modelos Animais , Neurônios/metabolismo , Técnicas de Patch-Clamp , Córtex Pré-Frontal/citologia , Técnicas Estereotáxicas
13.
Biomed Pharmacother ; 115: 108891, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31082772

RESUMO

Accumulating evidence has indicated the vital roles of long noncoding RNA (lncRNA) in the epithelial ovarian cancer (EOC). However, the function of lncRNA HAS2-AS1 in EOC is still unclear. This study aims to investigate the expression and role of HAS2-AS1 in EOC. In the cells and tissue of EOC, HAS2-AS1 expression was markedly up-regulated. Besides, the overexpression of HAS2-AS1 indicated the poor clinical outcome of EOC patients. Transcription factor CREB1 could bind with the promoter of HAS2-AS1 and activate its transcriptional expression. Functionally, HAS2-AS1 knockdown suppressed the proliferation, invasion and tumor growth of EOC cells in vitro and in vivo. Mechanical investigation found that HAS2-AS1 could relive the RUNX2 protein expression via sponging the miR-466, acting as miRNA sponge. In conclusion, this finding suggests the CREB1/HAS2-AS1/miR-466/RUNX2 axis in the in the EOC tumorigenesis, providing the novel insight for the molecular mechanism of EOC.


Assuntos
Proliferação de Células/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , MicroRNAs/metabolismo , Invasividade Neoplásica/fisiopatologia , Neoplasias Ovarianas/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Linhagem Celular Tumoral , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Nus , MicroRNAs/genética , Neoplasias Experimentais , RNA Longo não Codificante/genética , Organismos Livres de Patógenos Específicos , Transfecção
14.
Mol Med Rep ; 20(1): 216-224, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115504

RESUMO

Glaucoma is a group of eye diseases characterized by alterations in the contour of the optic nerve head, with corresponding visual field defects and progressive loss of retinal ganglion cells. The present study aimed to identify the key genes and upstream regulators in glaucoma. To screen the pathogenic genes involved in glaucoma, an integrated analysis was performed by using the microarray datasets in glaucoma derived from the Gene Expression Omnibus (GEO) database. The functional annotation and potential pathways of differentially expressed genes (DEGs) were additionally examined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A glaucoma­specific transcriptional regulatory network was constructed to identify crucial transcriptional factors that target the DEGs in glaucoma. From two GEO datasets, 1,935 DEGs (951 upregulated and 984 downregulated genes) between glaucoma and normal controls were identified. GO and KEGG analyses identified that 'eye development' [false discovery rate (FDR)=0.00415533] and 'visual perception' (FDR=0.00713283) were significantly enriched pathways for DEGs. The expression of lipocalin 2 (LCN2), monoamine oxidase A (MAOA), hemoglobin subunit ß (HBB), paired box 6 (PAX6), fibronectin (FN1) and cAMP responsive element binding protein 1 (CREB1) were demonstrated to be involved in the pathogenesis of glaucoma. In conclusion, LCN2, MAOA, HBB, PAX6, FN1 and CREB1 may serve roles in glaucoma, regulated by PAX4, solute carrier family 22 member 1, hepatocyte nuclear factor 4 α and ELK1, ETS transcription factor. These data may contribute to the development of novel potential biomarkers, reveal the underlying pathogenesis and additionally identify novel therapeutic targets for glaucoma.


Assuntos
Biologia Computacional , Glaucoma/genética , Fatores de Transcrição/genética , Transcriptoma/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Bases de Dados Genéticas , Fibronectinas/genética , Regulação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes/genética , Glaucoma/patologia , Humanos , Lipocalina-2/genética , Monoaminoxidase/genética , Fator de Transcrição PAX6/genética , Transdução de Sinais
15.
Artigo em Inglês | MEDLINE | ID: mdl-31028911

RESUMO

Cell death-inducing DNA fragmentation factor 45-like effector family proteins, including CIDEA, CIDEB and CIDEC, play an important role in energy metabolism. In the present study, CIDEA, CIDEB and CIDEC cDNAs were firstly isolated and characterized from grass carp Ctenopharyngodon idella, encoding peptides of 205, 208 and 238 amino acids, respectively. Analysis of the exon-intron structures clarified that grass carp CIDEA, CIDEB and CIDEC consisted of 5 coding exons, 5 coding exons and 6 coding exons, respectively, which is similar with human and mouse. Both CIDE family genes mRNAs were expressed in a wide range of tissues, but the abundance of each CIDE family gene mRNA showed the tissue-dependent expression patterns. Time-course analysis of CIDE family expressions indicated that their expression were enhanced significantly from day 0 to day 8 after differentiation. Forskolin caused an increase in CIDEA and CIDEC expression, and the effects were attenuated by treatment with CREB inhibitor, revealing that CIDEA and CIDEC are regulated by CREB. Further study found that CIDEA and CIDEC mRNA levels did not show significant changes during fasting. These results provide the groundwork to elucidate the gene structure and physiological function of CIDE family in fish.


Assuntos
Adipócitos/metabolismo , Proteínas Reguladoras de Apoptose , Carpas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Jejum/metabolismo , Proteínas de Peixes , Animais , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Carpas/genética , Carpas/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Regulação da Expressão Gênica , RNA Mensageiro/biossíntese , RNA Mensageiro/genética
16.
Mol Cancer ; 18(1): 73, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940151

RESUMO

BACKGROUND: As a subclass of noncoding RNAs, circular RNAs (circRNAs) have been demonstrated to play a critical role in regulating gene expression in eukaryotes. Recent studies have revealed the pivotal functions of circRNAs in cancer progression. However, little is known about the role of circTADA2A, also named hsa_circ_0043278, in osteosarcoma (OS). METHODS: CircTADA2A was selected from a previously reported circRNA microarray comparing OS cell lines and normal bone cells. QRT-PCR was used to detect the expression of circTADA2A in OS tissue and cell lines. Luciferase reporter, RNA immunoprecipitation (RIP), RNA pull-down and fluorescence in situ hybridization (FISH) assays were performed to confirm the binding of circTADA2A with miR-203a-3p. OS cells were stably transfected with lentiviruses, and Transwell migration, Matrigel invasion, colony formation, proliferation, apoptosis, Western blotting, and in vivo tumorigenesis and metastasis assays were employed to evaluate the roles of circTADA2A, miR-203a-3p and CREB3. RESULTS: Our findings demonstrated that circTADA2A was highly expressed in both OS tissue and cell lines, and circTADA2A inhibition attenuated the migration, invasion and proliferation of OS cells in vitro as well as tumorigenesis and metastasis in vivo. A mechanistic study revealed that circTADA2A could readily sponge miR-203a-3p to upregulate the expression of CREB3, which was identified as a driver gene in OS. Furthermore, miR-203a-3p inhibition or CREB3 overexpression could reverse the circTADA2A silencing-induced impairment of malignant tumor behavior. CONCLUSIONS: CircTADA2A functions as a tumor promoter in OS to increase malignant tumor behavior through the miR-203a-3p/CREB3 axis, which could be a novel target for OS therapy.


Assuntos
Neoplasias Ósseas/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , MicroRNAs/genética , Osteossarcoma/patologia , RNA/genética , Animais , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Citoplasma/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Masculino , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Osteossarcoma/genética , Regulação para Cima
17.
Nat Hum Behav ; 3(1): 48-56, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30932047

RESUMO

Millions of people now access personal genetic risk estimates for diseases such as Alzheimer's, cancer and obesity1. While this information can be informative2-4, research on placebo and nocebo effects5-8 suggests that learning of one's genetic risk may evoke physiological changes consistent with the expected risk profile. Here we tested whether merely learning of one's genetic risk for disease alters one's actual risk by making people more likely to exhibit the expected changes in gene-related physiology, behaviour and subjective experience. Individuals were genotyped for actual genetic risk and then randomly assigned to receive either a 'high-risk' or 'protected' genetic test result for obesity via cardiorespiratory exercise capacity (experiment 1, N = 116) or physiological satiety (experiment 2, N = 107) before engaging in a task in which genetic risk was salient. Merely receiving genetic risk information changed individuals' cardiorespiratory physiology, perceived exertion and running endurance during exercise, and changed satiety physiology and perceived fullness after food consumption in a self-fulfilling manner. Effects of perceived genetic risk on outcomes were sometimes greater than the effects associated with actual genetic risk. If simply conveying genetic risk information can alter actual risk, clinicians and ethicists should wrestle with appropriate thresholds for when revealing genetic risk is warranted.


Assuntos
Aptidão Cardiorrespiratória/fisiologia , Tolerância ao Exercício/fisiologia , Predisposição Genética para Doença/psicologia , Testes Genéticos , Obesidade , Esforço Físico/fisiologia , Adulto , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Aptidão Cardiorrespiratória/psicologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Teste de Esforço , Tolerância ao Exercício/genética , Feminino , Humanos , Masculino , Obesidade/genética , Obesidade/fisiopatologia , Obesidade/psicologia , Esforço Físico/genética , Risco , Adulto Jovem
18.
Biomed Environ Sci ; 32(3): 189-198, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30987693

RESUMO

OBJECTIVE: To estimate the detrimental effects of shortwave exposure on rat hippocampal structure and function and explore the underlying mechanisms. METHODS: One hundred Wistar rats were randomly divided into four groups (25 rats per group) and exposed to 27 MHz continuous shortwave at a power density of 5, 10, or 30 mW/cm2 for 6 min once only or underwent sham exposure for the control. The spatial learning and memory, electroencephalogram (EEG), hippocampal structure and Nissl bodies were analysed. Furthermore, the expressions of N-methyl-D-aspartate receptor (NMDAR) subunits (NR1, NR2A, and NR2B), cAMP responsive element-binding protein (CREB) and phosphorylated CREB (p-CREB) in hippocampal tissue were analysed on 1, 7, and 14 days after exposure. RESULTS: The rats in the 10 and 30 mW/cm2 groups had poor learning and memory, disrupted EEG oscillations, and injured hippocampal structures, including hippocampal neurons degeneration, mitochondria cavitation and blood capillaries swelling. The Nissl body content was also reduced in the exposure groups. Moreover, the hippocampal tissue in the 30 mW/cm2 group had increased expressions of NR2A and NR2B and decreased levels of CREB and p-CREB. CONCLUSION: Shortwave exposure (27 MHz, with an average power density of 10 and 30 mW/cm2) impaired rats' spatial learning and memory and caused a series of dose-dependent pathophysiological changes. Moreover, NMDAR-related CREB pathway suppression might be involved in shortwave-induced structural and functional impairments in the rat hippocampus.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Eletroencefalografia/efeitos da radiação , Hipocampo/efeitos da radiação , Memória/efeitos da radiação , Corpos de Nissl/efeitos da radiação , Ondas de Rádio/efeitos adversos , Aprendizagem Espacial/efeitos da radiação , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Relação Dose-Resposta à Radiação , Masculino , Corpos de Nissl/fisiologia , Distribuição Aleatória , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo
19.
Food Funct ; 10(5): 2439-2449, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-30968880

RESUMO

The peptide derived from Anchovy hydrolysates, Pro-Ala-Tyr-Cys-Ser (PAYCS), was reported to display a neuroprotective effect in vitro in our previous study. The in vivo memory improving effects of PAYCS were investigated in this study. Prior to the scopolamine-induced amnesia mice trial, the stability of PAYCS during digestion was detected and the digestive products were identified. The results showed that PAYCS was susceptible to proteolytic degradation after incubation with pepsin and pancreatin and Pro-Ala-Tyr (PAY) was released and survived during the simulated GI digestion. The results of scopolamine-induced amnesia model trials showed that PAYCS and PAY treatment exhibited cognitive improvement effects in the behavioral tests and different pathways were determined. The results indicated that only PAYCS facilitated cholinergic activity by up-regulating the amount of acetylcholine (Ach) and acetylcholine receptor (AChR). Additionally, both PAYCS and PAY enhanced the superoxide dismutase (SOD) activity. Furthermore, PAYCS was found to be beneficial for the expression of the nuclear factor (erythroid-derived2)-like 2 protein (Nrf2), brain-derived neurotrophic factor (BDNF) and cAMP response element binding protein (CREB). This indicated that PAYCS could regulate the oxidative stress by activating the Nrf2/antioxidant response elements (Nrf2/ARE) pathway. In our study, we demonstrated that the memory improving effects conferred by PAYCS on amnesia mice were linked to the attenuation of the cholinergic system and the activation of Nrf2/ARE and BDNF/CREB signaling.


Assuntos
Amnésia/tratamento farmacológico , Amnésia/psicologia , Proteínas de Peixes/química , Trato Gastrointestinal/metabolismo , Peptídeos/administração & dosagem , Peptídeos/química , Acetilcolina/metabolismo , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Amnésia/etiologia , Amnésia/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Feminino , Peixes , Humanos , Masculino , Memória/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/administração & dosagem , Peptídeos/metabolismo , Escopolamina/efeitos adversos
20.
BMC Genomics ; 20(1): 199, 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30866796

RESUMO

BACKGROUND: Peroxisome Proliferator-Activated receptor α (PPARα) and cAMP-Responsive Element Binding Protein 3-Like 3 (CREB3L3) are transcription factors involved in the regulation of lipid metabolism in the liver. The aim of the present study was to characterize the interrelationship between PPARα and CREB3L3 in regulating hepatic gene expression. Male wild-type, PPARα-/-, CREB3L3-/- and combined PPARα/CREB3L3-/- mice were subjected to a 16-h fast or 4 days of ketogenic diet. Whole genome expression analysis was performed on liver samples. RESULTS: Under conditions of overnight fasting, the effects of PPARα ablation and CREB3L3 ablation on plasma triglyceride, plasma ß-hydroxybutyrate, and hepatic gene expression were largely disparate, and showed only limited interdependence. Gene and pathway analysis underscored the importance of CREB3L3 in regulating (apo)lipoprotein metabolism, and of PPARα as master regulator of intracellular lipid metabolism. A small number of genes, including Fgf21 and Mfsd2a, were under dual control of PPARα and CREB3L3. By contrast, a strong interaction between PPARα and CREB3L3 ablation was observed during ketogenic diet feeding. Specifically, the pronounced effects of CREB3L3 ablation on liver damage and hepatic gene expression during ketogenic diet were almost completely abolished by the simultaneous ablation of PPARα. Loss of CREB3L3 influenced PPARα signalling in two major ways. Firstly, it reduced expression of PPARα and its target genes involved in fatty acid oxidation and ketogenesis. In stark contrast, the hepatoproliferative function of PPARα was markedly activated by loss of CREB3L3. CONCLUSIONS: These data indicate that CREB3L3 ablation uncouples the hepatoproliferative and lipid metabolic effects of PPARα. Overall, except for the shared regulation of a very limited number of genes, the roles of PPARα and CREB3L3 in hepatic lipid metabolism are clearly distinct and are highly dependent on dietary status.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Perfilação da Expressão Gênica/métodos , Fígado/crescimento & desenvolvimento , PPAR alfa/genética , Ácido 3-Hidroxibutírico/sangue , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Dieta Cetogênica , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Metabolismo dos Lipídeos , Fígado/química , Masculino , Camundongos , PPAR alfa/metabolismo , Transdução de Sinais , Triglicerídeos/sangue , Proteínas Supressoras de Tumor/genética , Sequenciamento Completo do Genoma
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