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Bile acids (BAs) metabolism has a significant impact on the pathogenesis of Alzheimer's disease (AD). We found that deoxycholic acid (DCA) increased in brains of AD mice at an early stage. The enhanced production of DCA induces the up-regulation of the bile acid receptor Takeda G protein-coupled receptor (TGR5), which is also specifically increased in neurons of AD mouse brains at an early stage. The accumulation of exogenous DCA impairs cognitive function in wild-type mice, but not in TGR5 knockout mice. This suggests that TGR5 is the primary receptor mediating these effects of DCA. Furthermore, excitatory neuron-specific knockout of TGR5 ameliorates Aß pathology and cognition impairments in AD mice. The underlying mechanism linking TGR5 and AD pathology relies on the downstream effectors of TGR5 and the APP production, which is succinctly concluded as a "p-STAT3-APH1-γ-secretase" signaling pathway. Our studies identified the critical role of TGR5 in the pathological development of AD.
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Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Neurônios , Receptores Acoplados a Proteínas G , Animais , Humanos , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Encéfalo/metabolismo , Encéfalo/patologia , Ácido Desoxicólico/farmacologia , Modelos Animais de Doenças , Camundongos Knockout , Neurônios/metabolismo , Neurônios/patologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Transdução de SinaisRESUMO
Depressive symptoms usually precede the cognitive decline in Alzheimer disease (AD) and worsen the clinical outcome. However, the neural circuitry mediating early emotional dysfunction, especially depressive symptoms in AD, remains elusive. Anterior cingulate cortex (ACC) is closely related to depression and vulnerable in AD. By quantitative whole-brain mapping and electrophysiological recording, we found that the decreased axonal calcium activity in neurons of ACC and the glutamatergic projection from ACC to the ventral hippocampal CA1 (vCA1) is significantly impaired in 3-month-old 5×FAD mice, which exhibit depressive-like phenotype before cognition defects in early stage. The activation of ACC-vCA1 circuit by chemogenetic manipulation efficiently ameliorated the early depressive-like behaviors in 5×FAD mice. We further identified the upregulated neuregulin-1 (Nrg1) in ACC impaired the excitatory synaptic transmission from the ACC to vCA1 in AD. Our work reveals the role of ACC-vCA1 circuit in regulating AD associated depression symptom in a mouse model of AD.
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INTRODUCTION: To identify the differentially expressed genes of acute myeloid leukaemia (AML) and construct and verify a survival prognosis model combined with patient survival information. METHODS: The TARGET database was searched to identify differentially expressed peripheral blood genes in children with AML and healthy children. A gene set functional analysis and pathway analysis were performed using gene ontology and the KEGG pathway. A prognostic model for children with AML was constructed using univariate Cox, LASSO Cox regression and multivariate Cox regression analyses. Time-dependent receiver operating characteristic (ROC) curves were adopted to assess the predictive capacity of the prognostic models. RESULTS: In total, 1640 differentially expressed genes were screened (1119 upregulated and 521 downregulated genes). The differentially expressed genes were mainly involved in nutrient metabolism and cytochrome P450 metabolism. Six key genes related to the prognosis of AML, FAM157A, GPR78, IRX5, RP4-800G7.1, RP11-179H18.5 and RP11-61N20.3, were identified. Kaplan-Meier curves indicated that 3-year and 5-year overall survival was significantly higher in the low-risk group than in the high-risk group. The area under the ROC curve was 0.722. At different stages of AML, FAM157A and RP4-800G7.1 exhibited significant differences in expression. The expression levels of FAM157A were significantly decreased in AML, whereas the expression levels of GPR78, IRX5, RP4-800G7.1, RP11-179H18.5 and RP11-61N20.3 were significantly increased in AML. CONCLUSION: A prognosis-related gene model of AML was successfully constructed, and the expression levels of the model genes varied with AML stage.
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Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/diagnóstico , Criança , Prognóstico , Feminino , Masculino , Pré-Escolar , Curva ROC , Perfilação da Expressão Gênica , Estimativa de Kaplan-Meier , Biomarcadores Tumorais/genética , LactenteRESUMO
Groupitizing is a well-established strategy in numerosity perception that enhances speed and sensory precision. Building on the ATOM theory, Anobile proposed the sensorimotor numerosity system, which posits a strong link between number and action. Previous studies using motor adaptation technology have shown that high-frequency motor adaptation leads to underestimation of numerosity perception, while low-frequency adaptation leads to overestimation. However, the impact of motor adaptation on groupitizing, and whether visual motion adaptation produces similar effects, remain unclear. In this study, we investigate the persistence of the advantage of groupitizing after motor adaptation and explore the effects of visual motion adaptation. Surprisingly, our findings reveal that proprioceptive motor adaptation weakens the advantage of groupitizing, indicating a robust effect of motor adaptation even when groupitizing is employed. Moreover, we observe a bidirectional relationship, as groupitizing also weakens the adaptation effect. These results highlight the complex interplay between motor adaptation and groupitizing in numerosity perception. Furthermore, our study provides evidence that visual motion adaptation also has an adaptation effect, but does not fully replicate the effects of proprioceptive motor adaptation on groupitizing. In conclusion, our research underscores the importance of groupitizing as a valuable strategy in numerosity perception, and sheds light on the influence of motion adaptation on this strategy.
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Propriocepção , Tecnologia , Movimento (Física) , PercepçãoRESUMO
AIMS: The lipid reference intervals (RIs) that are currently used for children in China are not based on studies of the local population and normally do not consider age or gender differences. This study aimed to establish age- and sex-specific RIs for the fasting serum lipid levels in the pediatric population aged 0 - 15 years in Nanjing, China. METHODS: 5,866 children aged 3 days to ï¼15 years were recruited to establish serum lipid RIs, and the triglyceride (TG), total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C) levels were analyzed using the Roche cobas702 automatic biochemical analyzer. Low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (nHDL-C) levels were calculated (LDL-C=TC-HDL-C-TG/5, and nHDL-C=TC-HDL-C). Smoothed percentile curves for the boys and girls were generated using the LMS method. Age- and sex-specific RIs were the determined according to the methods recommended by the Clinical and Laboratory Standards Institute EP28-A3c guidelines. RESULTS: This study showed that the serum lipid levels varied considerably throughout childhood and adolescence, with sex differences, especially in infants aged less than 2 years and puberty. Based on the Harris-Boyd method, sex partitions were required for ages ï¼6 months in the TC indicator and for ages ≤ 28 days in LDL-C and nHDL-C. Age partitions were also required for all serum lipid parameters. CONCLUSIONS: We established age- and sex-specific RIs for TG, TC, HDL-C, LDL-C, and nHDL-C parameters in children aged 0 days to ï¼15 years in Nanjing, China. These data are thus considered to be useful for the screening of dyslipidemia in children and adolescents.
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Jejum , Lipídeos , Humanos , Masculino , Feminino , Lactente , Adolescente , Criança , Valores de Referência , Pré-Escolar , China/epidemiologia , Lipídeos/sangue , Recém-Nascido , Jejum/sangue , Fatores Sexuais , Fatores Etários , Triglicerídeos/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangueRESUMO
The aim of the study was to test whether the cytokine profile could be used as a marker to differentiate between Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and Kawasaki disease (KD). A total of 70 hospitalized children with HLH and KD admitted to hospital for the first time from March 2017 to December 2021 were enrolled in this study. Fifty-five healthy children were enrolled as normal controls. All patients and normal controls were tested for the six cytokines including interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and interferon-γ (IFN-γ) by flow cytometry. IL-10 and IFN-γ levels were significantly higher in children with EBV-HLH than in the KD, IL-6 was lower in EBV-HLH patients than in the KD. IL-10/IL-6 ratio, IFN-γ/IL-6 ratio and IL10/IFN-γ ratio in children with EBV-HLH were significantly much higher than children in the KD group. When the diagnostic cutoff values of IL-10, IFN-γ, IL-10/IL-6 ratio and IFN-γ/IL-6 ratio were >13.2 pg/ml, >71.0 pg/ml, >0.37 and >1.34, respectively, the sensitivity and specificity of the diagnosis of EBV-HLH disease were 91.7% and 97.1%, 72.2% and 97.1%, 86.1% and 100.0%, and 75.0% and 97.1%, respectively. Notably high IL-10 and IFN-γ and moderately elevated IL-6 suggest the diagnosis of EBV-HLH, while high IL-6 levels with low IL-10 or IFN-γ concentration would suggest KD. Additionally, IL-10/IL-6 ratio or IFN-γ/IL-6 ratio could be used as an index to differentiate between EBV-HLH and KD.
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Infecções por Vírus Epstein-Barr , Linfo-Histiocitose Hemofagocítica , Síndrome de Linfonodos Mucocutâneos , Criança , Humanos , Citocinas , Interleucina-10 , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Infecções por Vírus Epstein-Barr/complicações , Interleucina-6 , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Herpesvirus Humano 4 , Interferon gamaRESUMO
BACKGROUND: China lacks a standard for reference intervals (RIs) of complete blood cell (CBC) counts in newborns. This study aimed to determine local haematological RIs for newborns. METHODS: This prospective study was conducted from January 2020 to December 2020 in Nanjing Maternity and Child Health Care Hospital. We collected capillary blood specimens from 497 healthy newborns aged 5-28 days. We calculated the RIs as nonparametric 2.5th to 97.5th percentiles and 90% confidence intervals following the EP28-A3c guideline. We validated the RIs in another 20 specimens from healthy newborns. RESULTS: The RIs for the 18 CBC parameters were: white blood cell count 7.17-15.69 × 109/L; monocytes# 0.52-1.66 × 109/L; Mono% 5.7-14.1; eosinophils# 0.16-1.08 × 109/L; Eos% 1.5-8.9; Lymphocytes# 4.04-8.08 × 109/L; Lymph% 40.1-67.8; Neutrophils# 1.59-6.41 × 109/L; Neut% 18.1-46.7; Basophils# 0.00-0.04 × 109/L; Baso% 0.0-0.4; red blood cell count 3.38-5.89 × 1012/L; haemoglobin (Hb) 116-198 g/L; Hematocrit % 35.2-61.2; mean corpuscular Hb (MCH) 30.9-36.3 pg/L; MCH concentration 310-341 g/L; mean corpuscular volume 94.5-112.2 fL; and platelets 210-610 × 109/L. The RIs had a conformity rate of 90%-100% in the validation specimens. CONCLUSION: We established region-specific RIs for CBC parameters in healthy newborns to help diagnose haematological disease in neonates.
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Contagem de Células Sanguíneas , Criança , Humanos , Feminino , Recém-Nascido , Gravidez , Estudos Prospectivos , Valores de Referência , Hematócrito , ChinaRESUMO
Background: Physical literacy (PL) is an important tool to promote physical activity of individuals, and the level of physical literacy of individuals affects their physical activity behaviors. Currently, the physical fitness of college students in China is a prominent issue, and assessing physical literacy among college students may provide tools and directions to further promote physical fitness and precisely intervene in physical activity behaviors of college students in the future. This study aimed to develop a college student physical literacy questionnaire (CSPLQ) to address the lack of currently available physical literacy assessment tools for Chinese college students. We hoped to collect validity evidence of this questionnaire to measure the validity of the physical literacy self-assessment questionnaire among Chinese university students. Methods: An initial pool of items was obtained from existing research instruments, literature, and expert advice. An expert review panel evaluated its content. A subsequent validation process reduced the pool of items. We conducted a validation factor analysis of the CSPLQ using structural equation modeling. The relationship between physical literacy and other variables was also examined using correlation analysis. Results: The item content validity index (ICVI) of CSPLQ was 0.70-0.95. The CSPLQ was composed of a total of 38 items across 3 domains (physical and behavioral domain, affective domain, and cognitive domain) and 7 dimensions (motor skills, motor skills, physical activity, perceptions of healthy living, perceptions of physical activity, motivation to engage in physical activity, and confidence to engage in physical activity). The factor validity of the CSPLQ was determined by significant loading of all items on their expected factors, with good data model fit and good stability between two independent samples were demonstrated. Each subscale had a Cronbach α coefficient >0.9 and was strongly correlated with each other. The correlation coefficients between college students' physical literacy and other variables, including athletic ability, physical condition, physical attractiveness, physical fitness, frequency of physical activity, and length of physical activity, all reached a significance level of P < 0.05. Conclusion: The CSPLQ has sufficient evidence of validity. The development of the instrument showed evidence of validity for the content, response process, internal structure, and relationships with other variables.
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Alfabetização , Estudantes , Exercício Físico , Análise Fatorial , Humanos , Estudantes/psicologia , Inquéritos e QuestionáriosRESUMO
RNAs may act as competing endogenous RNAs (ceRNAs), a critical mechanism in determining gene expression regulations in many cancers. However, the roles of ceRNAs in thyroid carcinoma remains elusive. In this study, we have developed a novel pipeline called Molecular Network-based Identification of ceRNA (MNIceRNA) to identify ceRNAs in thyroid carcinoma. MNIceRNA first constructs micro RNA (miRNA)-messenger RNA (mRNA)long non-coding RNA (lncRNA) networks from miRcode database and weighted correlation network analysis (WGCNA), based on which to identify key drivers of differentially expressed RNAs between normal and tumor samples. It then infers ceRNAs of the identified key drivers using the long non-coding competing endogenous database (lnCeDB). We applied the pipeline into The Cancer Genome Atlas (TCGA) thyroid carcinoma data. As a result, 598 lncRNAs, 1025 mRNAs, and 90 microRNA (miRNAs) were inferred to be differentially expressed between normal and thyroid cancer samples. We then obtained eight key driver miRNAs, among which hsa-mir-221 and hsa-mir-222 were key driver RNAs identified by both miRNA-mRNA-lncRNA and WGCNA network. In addition, hsa-mir-375 was inferred to be significant for patients' survival with 34 associated ceRNAs, among which RUNX2, DUSP6 and SEMA3D are known oncogenes regulating cellular proliferation and differentiation in thyroid cancer. These ceRNAs are critical in revealing the secrets behind thyroid cancer progression and may serve as future therapeutic biomarkers.
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BACKGROUND: Recent evidence has suggested that peripheral inflammatory responses induced by lipopolysaccharides (LPS) play an important role in neuropsychiatric dysfunction in rodents. Interleukin-1ß (IL-1ß), a pro-inflammatory cytokine, has been proposed to be a key mediator in a variety of behavioral dysfunction induced by LPS in mice. Thus, inhibition of IL-1ß may have a therapeutic benefit in the treatment of neuropsychiatric disorders. However, the precise underlying mechanism of knock-down of IL-1ß in repairing behavioral changes by LPS remains unclear. METHODS: The mice were treated with either IL-1ß shRNA lentivirus or non-silencing shRNA control (NS shRNA) lentivirus by microinjection into the dentate gyrus (DG) regions of the hippocampus. After 7 days of recovery, LPS (1 mg/kg, i.p.) or saline was administered. The behavioral task for memory deficits was conducted in mice by the novel object recognition test (NORT), the anxiety-like behaviors were evaluated by the elevated zero maze (EZM), and the depression-like behaviors were examined by the sucrose preference test (SPT) and the forced swimming test (FST). Furthermore, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), nuclear factor erythroid-derived 2-like 2 (Nrf2), heme oxygenase 1 (HO1), IL-1ß, tumor necrosis factor (TNF-α), neuropeptide VGF (non-acronymic), and brain-derived neurotrophic factor (BDNF) were assayed. RESULTS: Our results demonstrated that IL-1ß knock-down in the hippocampus significantly attenuated the memory deficits and anxiety- and depression-like behaviors induced by LPS in mice. In addition, IL-1ß knock-down ameliorated the oxidative and neuroinflammatory responses and abolished the downregulation of VGF and BDNF induced by LPS. CONCLUSIONS: Collectively, our findings suggest that IL-1ß is necessary for the oxidative and neuroinflammatory responses produced by LPS and offers a novel drug target in the IL-1ß/oxidative/neuroinflammatory/neurotrophic pathway for treating neuropsychiatric disorders that are closely associated with neuroinflammation, oxidative stress, and the downregulation of VGF and BDNF.
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Comportamento Animal/fisiologia , Hipocampo/imunologia , Hipocampo/metabolismo , Inflamação/complicações , Interleucina-1beta/metabolismo , Animais , Ansiedade/imunologia , Ansiedade/metabolismo , Comportamento Animal/efeitos dos fármacos , Depressão/imunologia , Depressão/metabolismo , Técnicas de Silenciamento de Genes , Inflamação/induzido quimicamente , Lentivirus , Lipopolissacarídeos/toxicidade , Masculino , Transtornos da Memória/imunologia , Transtornos da Memória/metabolismo , CamundongosRESUMO
Peripheral inflammatory responses affect central nervous system (CNS) function, manifesting in symptoms of memory deficits, depression, and anxiety. Previous studies have revealed that neuropeptide VGF (nonacronymic) C-terminal peptide TLQP-62 rapidly reinforces brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling, regulating memory consolidation and antidepressant-like action. However, whether it is beneficial for lipopolysaccharide (LPS)-induced neuropsychiatric dysfunction in mice is unknown. Herein, we explored the involvement of BDNF/TrkB signaling and biochemical alterations in inflammatory or oxidative stress markers in the alleviating effects of TLQP-62 on LPS-induced neuropsychiatric dysfunction. The mice were treated with TLQP-62 (2 µg/side) via intracerebroventricular (i.c.v.) injection 1 h before LPS (0.5 mg/kg, i.p.) administration. Our results showed that a single treatment with LPS (0.5 mg/kg, i.p) is sufficient to produce recognition memory deficits (in the novel object recognition test), depression-like behavior (in the forced swim test and sucrose preference test), and anxiety-like behavior (in the elevated zero maze). However, pretreatment with TLQP-62 prevented LPS-induced behavioral dysfunction, neuroinflammatory, and oxidative responses. In addition, our results further demonstrated that a reduction in BDNF expression mediated by BDNF-shRNA lentivirus significantly blocked the effects of TLQP-62, suggesting the critical role of BDNF/TrkB signaling in the neuroprotective effects of TLQP-62 in the mice. In conclusion, TLQP-62 could be a therapeutic approach for neuropsychiatric disorders, which are closely associated with neuroinflammation and oxidative stress.
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Ansiolíticos/farmacologia , Anti-Inflamatórios/farmacologia , Antidepressivos/farmacologia , Nootrópicos/farmacologia , Peptídeos/farmacologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/imunologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/imunologia , Modelos Animais de Doenças , Escherichia coli , Lipopolissacarídeos , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/imunologia , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Receptor trkB/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Preclinical and clinical studies suggest that neuronal muscarinic acetylcholine receptor (M-AchR) antagonists have antidepressant-like properties. Despite the recent interest in bicaudal C homolog 1 gene (BICC1) as a target for the treatment of depression, the upstream signaling molecules that regulate BICC1 are unknown, and very few studies have addressed the involvement of BICC1 in the antidepressant-like effects of the selective M1-AchR inhibitor, biperiden. Growing evidence indicates that activation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase receptor B (TrkB) signaling may be involved in antidepressant-like activities. In this study, we investigated the role of BDNF/TrkB signaling in the regulation of BICC1 expression in the chronic unpredictable stress (CUS) mouse model of depression. Furthermore, we also examined whether BDNF/TrkB signaling contributes to the antidepressant-like effects of biperiden via down-regulation of BICC1 in the hippocampus and prefrontal cortex of mice. Our current data show that CUS exposure induced significant depression-like behaviors, down-regulation of BDNF/TrkB signaling and up-regulation of BICC1 in the hippocampus and prefrontal cortex of mice. However, biperiden significantly alleviated the CUS-induced abnormalities. Moreover, we found that the effects of biperiden were antagonized by pretreatment with the TrkB antagonist K252a. Our results indicate that BDNF/TrkB signaling may be the major upstream mediator of BICC1 involvement in the antidepressant-like effects of biperiden.
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Antidepressivos/uso terapêutico , Biperideno/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Córtex Pré-Frontal/metabolismo , Proteínas de Ligação a RNA/biossíntese , Receptor trkB/metabolismo , Animais , Antidepressivos/farmacologia , Biperideno/farmacologia , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Carbazóis/farmacologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Hipocampo/efeitos dos fármacos , Alcaloides Indólicos/farmacologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Córtex Pré-Frontal/efeitos dos fármacos , Receptor trkB/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Resultado do TratamentoRESUMO
A high co-morbidity between Alzheimer's disease (AD) and depression suggests there might be similar mechanisms underlying the course of these diseases. Previous studies have shown that p38MAPK plays a critical role in the pathophysiology of AD and depression. However, little is known about whether SB203580, a selective inhibitor of p38MAPK, may protect against AD-associated cognitive impairments and depression-like behavior, simultaneously. Herein, we have shown, for the first time, that SB203580 may reverse memory impairments and depression-like behavior induced by hippocampal infusion of ß-amyloid 1-42 (Aß1-42), as measured by novel object recognition, Morris water maze, tail-suspension and forced-swimming tests. In addition, phorbol 12-myristate 13-acetate (PMA), a PKC activator which also activates p38MAPK, significantly abolished the effects of SB203580. Moreover, Aß1-42 causes increased phosphorylation of p38MAPK and decreased phosphorylation of Ser9-glycogen synthase kinase 3ß (GSK3ß) and cAMP-response element binding protein (CREB) in the hippocampus of mice, which could be significantly reversed by SB203580. Our results suggest that SB203580 reversed Aß1-42-induced cognitive impairments and depression-like behavior via inhibiting p38MAPK signaling pathway, which not only supports p38MAPK as a therapeutic target for AD-associated cognitive dysfunction and depression-like behavior, but also provides experimental basis for the use of SB203580 in co-morbidity of AD and depression.
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Peptídeos beta-Amiloides/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Hipocampo/efeitos dos fármacos , Imidazóis/farmacologia , Transtornos da Memória/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Piridinas/farmacologia , Animais , Depressão/induzido quimicamente , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , Imidazóis/uso terapêutico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Camundongos , Microinjeções , Fosforilação/efeitos dos fármacos , Piridinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
BACKGROUND: MicroRNA-21 (miR-21) is up-regulated in many cancers, including colorectal cancer (CRC). Nevertheless, the function of miR-21 in CRC and the mechanism underlying that function is still unclear. METHODS: After analyzing the expression of miR-21 and Sec23A in CRC cell lines, we transfected the highest miR-21 expressing cell line, SW-480, with a plasmid containing an miR-21 inhibitor and the lowest miR-21 expressing cell line, DLD-1, with a plasmid containing an miR-21 mimic and measured the effects on the expression of Sec23A and on cell proliferation, migration, and invasion. We also evaluated the effect of knocking down Sec23A on miR-21 expression and its effects on cell proliferation, migration, and invasion. Finally, we assessed the effect of miR-21 in a xenograft tumor model in mice. Tumor tissues from these mice were subjected to immunohistochemical staining to detect the expression of Sec23A. RESULTS: Genetic deletion of miR-21 suppressed the proliferation, migration, and invasion of SW-480 cells, while over-expression of miR-21 promoted proliferation, migration, and invasion of DLD-1 cells. Inhibition of miR-21 increased the expression of Sec23A protein in SW-480 cells while over-expression of miR-21 significantly suppressed the expression of Sec23A protein and Sec23A mRNA in DLD-1 cells. Knockdown of Sec23A increased the expression of miR-21 in SW480 and DLD-1 cells and their proliferation (DLD-1 only), migration, and invasion. Over-expression of miR-21 promoted tumor growth in BALB/c nude mice and suppressed tumor expression of Sec23A. CONCLUSION: These findings provide novel insight into the molecular functions of miR-21 in CRC, which may serve as a potential interesting target.
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Movimento Celular , Proliferação de Células , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , Proteínas de Transporte Vesicular/biossíntese , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/genética , Progressão da Doença , Regulação para Baixo , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Invasividade Neoplásica/genética , Proteínas de Transporte Vesicular/genéticaRESUMO
Methylglyoxal (MG) is a highly reactive dicarbonyl compound exhibiting anti-tumor activity. The anti-tumor effects of MG have been demonstrated in some types of cancer, but its role in colon cancer and the mechanisms underlying this activity remain largely unknown. We investigated its role in human colon cancer and the underlying mechanism using human colon cancer cells and animal model. Viability, proliferation, and apoptosis were quantified in DLD-1 and SW480 colon cancer cells by using the Cell Counting Kit-8, plate colony formation assay, and flow cytometry, respectively. Cell migration and invasion were assessed by wound healing and transwell assays. Glucose consumption, lactate production, and intracellular ATP production also were assayed. The levels of c-Myc protein and mRNA were quantitated by western blot and qRT-PCR. The anti-tumor role of MG in vivo was investigated in a DLD-1 xenograft tumor model in nude mice. We demonstrated that MG inhibited viability, proliferation, migration, and invasion and induced apoptosis of DLD-1 and SW480 colon cancer cells. Treatment with MG reduced glucose consumption, lactate production, and ATP production and decreased c-Myc protein levels in these cells. Moreover, MG significantly suppressed tumor growth and c-Myc expression in vivo. Our findings suggest that MG plays an anti-tumor role in colon cancer. It inhibits cancer cell growth by altering the glycolytic pathway associated with downregulation of c-Myc protein. MG has therapeutic potential in colon cancer by interrupting cancer metabolism.
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Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Proteínas Proto-Oncogênicas c-myc/biossíntese , Aldeído Pirúvico/farmacologia , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , Camundongos , Camundongos NusRESUMO
Metformin has been reported to inhibit the growth of various types of cancers, including prostate cancer. Yet the mode of anti-cancer action of metformin and the underlying mechanisms remain not fully elucidated. We hypothesized that the antitumorigenic effects of metformin are mediated through upregulation of pigment epithelium-derived factor (PEDF) expression in prostate cancer cells. In this report, metformin treatment significantly inhibited the proliferation and colony formation of prostate cancer cells, in a dose- and time-dependent manner. Meanwhile, Metformin markedly suppressed migration and invasion and induced apoptosis of both LNCaP and PC3 cancer cells. Metformin also reduced PC3 tumor growth in BALB/c nude mice in vivo. Furthermore, metformin treatment was associated with higher PEDF expression in both prostate cancer cells and tumor tissue. Taken together, metformin inhibits prostate cancer cell proliferation, migration, invasion and tumor growth, and these activities are mediated by upregulation of PEDF expression. These findings provide a novel insight into the molecular functions of metformin as an anticancer agent.
Assuntos
Proteínas do Olho/metabolismo , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Fatores de Crescimento Neural/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Serpinas/metabolismo , Movimento Celular , Proliferação de Células , Humanos , Hipoglicemiantes/farmacologia , Masculino , Metformina/farmacologia , Neoplasias da Próstata/patologia , Regulação para CimaRESUMO
Amyloid-beta (Aß) interacts with the serine/threonine protein kinase AKT (also known as protein kinase B)/glycogen synthase kinase 3ß (GSK3ß) pathway and deactivates GSK3ß signaling, which result in microtubule protein tau phosphorylation. Atorvastatin, a HMG-CoA reductase inhibitor, has been proven to improve learning and memory performance, reduce Aß and phosphorylated tau levels in mouse model of Alzheimer's disease (AD). However, it still remains unclear whether atorvastatin is responsible for regulation of AKT/GSK3ß signaling and contributes to subsequent down-regulation of Aß1-42 and phosphorylated tau in APP/PS1 transgenic (Tg APP/PS1) mice. Herein, we aimed to investigate the possible impacts of atorvastatin (10 mg/kg, p.o.) on the memory deficit by behavioral tests and changes of AKT/GSK3ß signaling in hippocampus and prefrontal cortex by western blot test in Tg APP/PS1 mice. The results showed that treatment with atorvastatin significantly reversed the memory deficit in the Tg APP/PS1 mice in a novel object recognition and the Morris water maze tests. Moreover, atorvastatin significantly attenuated Aß1-42 accumulation and phosphorylation of tau (Ser396) in the hippocampus and prefrontal cortex of Tg APP/PS1 mice. In addition, atorvastatin treatment also increased phosphorylation of AKT, inhibited GSK3ß activity by increasing phosphorylation of GSK3ß (Ser9) and decreasing the beta-site APP cleaving enzyme 1 (BACE1) expression. These results indicated that the memory ameliorating effect of atorvastatin may be, in part, by regulation the AKT/GSK3ß signaling which may contribute to down-regulation of Aß1-42 and tau hyperphosphorylation.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Atorvastatina/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fragmentos de Peptídeos/metabolismo , Proteínas tau/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Atorvastatina/uso terapêutico , Disfunção Cognitiva/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Camundongos , Camundongos Transgênicos , Fosforilação/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Presenilina-1/genéticaRESUMO
Roles of ionotropic purinergic (P2X) receptors in chronic pain have been intensively investigated. However, the contribution of metabotropic purinergic (P2Y) receptors to pathological pain is controversial. In the present study, using single cell RT-PCR (reverse transcription-polymerase chain reaction) and single cell nested-PCR techniques, we examined the expression of P2X(2), P2X(3), P2Y(1) and P2Y(2) mRNA transcripts in retrogradely labeled cutaneous sensory neurons from mouse lumber dorsal root ganglia (DRGs) following peripheral inflammation. The percentage of cutaneous sensory neurons expressing P2Y(2) mRNA transcripts increased after complete Freund's adjuvant (CFA) treatment. Particularly, the P2Y(2) mRNA transcripts were more frequently detected in small-diameter cutaneous neurons from CFA-treated mice than those from control mice. Coexpression of P2Y(2) and P2X (P2X(2) or P2X(3)) mRNAs was more frequently observed in cutaneous sensory neurons from CFA-treated mice relative to controls. Pain behavioral tests showed that the blockade of P2Y receptors by suramin attenuated mechanical allodynia evoked either by CFA or uridine triphosphate (UTP), an endogenous P2Y(2) and P2Y(4) agonist. These results suggest that chronic inflammatory pain enhances expression of P2Y(2) receptor in peripheral sensory neurons that innervate the injured tissue and the activation of P2Y receptors contributes to mechanical allodynia following inflammation.
Assuntos
Dor Crônica/metabolismo , Inflamação/metabolismo , Receptores Purinérgicos P2Y2/biossíntese , Células Receptoras Sensoriais/metabolismo , Animais , Artrite Experimental/metabolismo , Artrite Experimental/psicologia , Comportamento Animal , Dor Crônica/etiologia , Dor Crônica/psicologia , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Hiperalgesia/psicologia , Inflamação/complicações , Inflamação/psicologia , Camundongos , Camundongos Endogâmicos ICR , Nociceptividade , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores Purinérgicos P2Y/biossíntese , Receptores Purinérgicos P2Y/genética , Receptores Purinérgicos P2Y2/genética , Células Receptoras Sensoriais/patologia , Pele/inervação , Regulação para CimaRESUMO
BACKGROUND: VGF (nonacryonimic) and phosphatidylinositol 3-kinase (PI3K)/AKT (also known as protein kinase B, PKB)/mammalian target of rapamycin (mTOR) signaling play pivotal roles in depression. However, whether phosphatidylinositol 3-kinase/AKT/mTOR signaling-mediated VGF participates in rapid-acting antidepressant-like actions of GLYX-13 is unclear. METHODS: Herein, we evaluated the effects of acute treatment of GLYX-13 (0.5, 5, and 10mg/kg, i.p.) in the forced swim test. In addition, we assessed whether the acute treatment with GLYX-13 reverses the depressive-like behaviors induced by chronic unpredictable mild stress. Furthermore, we determined whether the Vgf knockdown in hippocampus of mice blocks the effects of GLYX-13. Moreover, we also demonstrated the effects of intra-hippocampus infusion of LY294002 (10 nmol/side), a specific phosphatidylinositol 3-kinase inhibitor prior to the treatment of GLYX-13 in the forced swim test. Lastly, whether alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mTOR activation involves in the antidepressant-like effects of GLYX-13 was examined. RESULTS: Our results shown that GLYX-13 dose-dependently reversed the depressive-like behaviors in forced swim test. Additionally, GLYX-13 significantly reversed the downregulation of phosphorylation of AKT, mTOR, and eukaryotic elongation factor 2 as well as VGF induced by chronic unpredictable mild stress in hippocampus. Further, Vgf knockdown in hippocampus of mice significantly blocked the rapid-acting antidepressant-like effects and upregulation on phosphatidylinositol 3-kinase/AKT/mTOR/VGF signaling of GLYX-13. Moreover, intra-hippocampus infusion of LY294002 significantly abolished the antidepressant-like effects and upregulation on phosphatidylinositol 3-kinase/AKT/mTOR/VGF signaling of GLYX-13. Finally, antidepressant-like effects of GLYX-13 required AMPA receptor and mTOR activation, as evidenced by the ability of NBQX and rapamycin to block the effects of GLYX-13, respectively. CONCLUSIONS: Our results suggest that phosphatidylinositol 3-kinase/AKT/mTOR signaling-mediated VGF in hippocampus may be involved in the antidepressant-like effects of GLYX-13.