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1.
Biol Psychiatry ; 82(8): 608-618, 2017 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-28390647

RESUMO

BACKGROUND: The mesolimbic reward system plays a critical role in modulating nociception; however, its underlying molecular, cellular, and neural circuitry mechanisms remain unknown. METHODS: Chronic constrictive injury (CCI) of the sciatic nerve was used to model neuropathic pain. Projection-specific in vitro recordings in mouse brain slices and in vivo recordings from anesthetized animals were used to measure firing of dopaminergic neurons in the ventral tegmental area (VTA). The role of VTA-nucleus accumbens (NAc) circuitry in nociceptive regulation was assessed using optogenetic and pharmacological manipulations, and the underlying molecular mechanisms were investigated by Western blotting, enzyme-linked immunosorbent assays, and conditional knockdown techniques. RESULTS: c-Fos expression in and firing of contralateral VTA-NAc dopaminergic neurons were elevated in CCI mice, and optogenetic inhibition of these neurons reversed CCI-induced thermal hyperalgesia. CCI increased the expression of brain-derived neurotrophic factor (BDNF) protein but not messenger RNA in the contralateral NAc. This increase was reversed by pharmacological inhibition of VTA dopaminergic neuron activity, which induced an antinociceptive effect that was neutralized by injecting exogenous BDNF into the NAc. Moreover, inhibition of BDNF synthesis in the VTA with anisomycin or selective knockdown of BDNF in the VTA-NAc pathway was antinociceptive in CCI mice. CONCLUSIONS: These results reveal a novel mechanism of nociceptive modulation in the mesolimbic reward circuitry and provide new insight into the neural circuits involved in the processing of nociceptive information.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sistema Límbico/metabolismo , Neuralgia/patologia , Neuralgia/fisiopatologia , Nociceptividade/fisiologia , Recompensa , Animais , Baclofeno/farmacologia , Benzazepinas/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Cardiotônicos/farmacologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Lateralidade Funcional , Agonistas dos Receptores de GABA-B/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibição Neural/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Limiar da Dor/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Pirimidinas/farmacologia
2.
Sci Rep ; 6: 18694, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26728971

RESUMO

T helper 9 (Th9) cells, a recently recognized Th cell subset, are involved in autoimmune diseases. We aimed to investigate the role of Th9/interleukin-9 (IL-9) in the pathogenesis of hepatic fibrosis. Th9 and Th17 cells were quantified in chronic hepatitis B (CHB) patients with hepatic fibrosis, HBV-associated liver cirrhosis (LC) patients and healthy controls (HC). The percentages of Th9 and Th17 cells, concentrations of IL-9 and IL-17, as well as expression of IL-17, TNF-α, IL-6, IL-4, IL-21, TGF-ß1 and IFN-γ were significantly increased in plasma of CHB and LC patients compared with those in HC. Splenic Th9 and Th17 cells, plasma concentrations and liver expression of IL-9 and IL-17A were significantly elevated in mice with hepatic fibrosis compared with controls. Neutralization of IL-9 in mice ameliorated hepatic fibrosis, attenuated the activation of hepatic stellate cells, reduced frequencies of Th9, Th17 and Th1 cells in spleen, and suppressed expression of IL-9, IL-17A, IFN-γ, TGF-ß1, IL-6, IL-4 and TNF-α in plasma and liver respectively. Our data suggest a deleterious role of Th9/IL-9 in increasing hepatic fibrosis and exacerbating disease endpoints, indicating that Th9/IL9 based immunotherapy may be a promising approach for treating hepatic fibrosis.


Assuntos
Interleucina-9/metabolismo , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Subpopulações de Linfócitos T , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Adolescente , Adulto , Idoso , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Estudos de Casos e Controles , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Hepatite B Crônica/complicações , Hepatite B Crônica/metabolismo , Humanos , Imunofenotipagem , Interleucina-17/antagonistas & inibidores , Interleucina-17/sangue , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-9/antagonistas & inibidores , Interleucina-9/sangue , Interleucina-9/genética , Cirrose Hepática/patologia , Contagem de Linfócitos , Masculino , Camundongos , Pessoa de Meia-Idade , RNA Mensageiro/genética , Baço/imunologia , Baço/metabolismo , Baço/patologia , Células Th17/imunologia , Células Th17/metabolismo , Adulto Jovem
3.
World J Gastroenterol ; 21(5): 1531-45, 2015 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-25663772

RESUMO

AIM: To investigate the effect of interleukin (IL)-22 on hepatic fibrosis in mice and the possible mechanism involved. METHODS: Liver fibrosis was induced in male BALB/c mice by CCl4. Recombinant IL-22 (rmIL-22) was administered intraperitoneally in CCl4-treated mice. Fibrosis was assessed by histology and Masson staining. The activation of hepatic stellate cells (HSCs) was investigated by analysis of α-smooth muscle actin expression. The frequencies of T helper (Th) 22 cells, Th17 cells and Th1 cells, the expression of inflammatory cytokines [IL-22, IL-17A, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-6, IL-1ß] and transcription factors [aryl hydrocarbon receptor (AHR), RAR-related orphan receptor (RORγt), T-bet] mRNA in the liver were investigated. In addition, the plasma levels of IL-22, IL-17A, IFN-γ, TNF-α, IL-6 and IL-1ß were evaluated. RESULTS: Significant elevations in circulating Th22 cells, Th17 cells, Th1 cells, IL-22, IL-17A, and IFN-γ were observed in the hepatic fibrosis group compared with the control group (P < 0.01). Treatment with rmIL-22 in mice with hepatic fibrosis ameliorated the severity of hepatic fibrosis, which was confirmed by lower hepatic fibrosis pathological scores (P < 0.01). RmIL-22 decreased the frequencies of Th22 cells (6.71% ± 0.97% vs 8.09% ± 0.74%, P < 0.01), Th17 cells (4.34% ± 0.37% vs 5.71% ± 0.24%, P < 0.01), Th1 cells (3.09% ± 0.49% vs 4.91% ± 0.73%, P < 0.01), and the levels of IL-22 (56.23 ± 3.08 vs 70.29 ± 3.01, P < 0.01), IL-17A (30.74 ± 2.77 vs 45.68 ± 2.71, P < 0.01), and IFN-γ (74.78 ± 2.61 vs 124.89 ± 2.82, P < 0.01). Down-regulation of IL-22, IL-17A, IFN-γ, TNF-α, IL-6, IL-1ß, AHR RORγt, and T-bet gene expression in the liver was observed in the rmIL-22 group (P < 0.01). CONCLUSION: The frequencies of Th22, Th17 and Th1 cells are elevated in hepatic fibrosis. RmIL-22 can attenuate HSC activation and down-regulate the levels of inflammatory cytokines, thereby ameliorating liver fibrogenesis.


Assuntos
Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Interleucinas/farmacologia , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Animais , Tetracloreto de Carbono , Citocinas/genética , Citocinas/imunologia , Células Estreladas do Fígado/imunologia , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Mediadores da Inflamação/imunologia , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/imunologia , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Camundongos Endogâmicos BALB C , RNA Mensageiro/metabolismo , Proteínas Recombinantes/farmacologia , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Fatores de Tempo
5.
Asian Pac J Cancer Prev ; 15(8): 3811-5, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24870799

RESUMO

BACKGROUND: Colorectal cancer (CRC) is the worldwide disease which causes enormous losses every year. Recent studies suggested that environmental and gene factors might be the etiologies in increasing the risk of morbidity. Nitric oxide synthase 3 (NOS3) gene polymorphisms are said to be associated with CRC risk but the conclusion is still controversial. MATERIALS AND METHODS: Pubmed and HuGENet databases up to December 2013 were used in this meta-analysis. Three different certain genotypic models were applied, namely dominant (AA+AC versus CC), recessive (AA versus AC+CC), per-allele analysis (A vs C). In addition, information on tumor sites and pathologic stages was collected. The strength of associations was assessed through combining odds ratio (OR) and 95% confidence interval (CI). RESULTS: Finally, five and three studies about the rs1799983 and rs2070744 were covered in the analysis with 2,745 cases and 2,478 controls. Three models were applied, but no significant association was found for NOS3 G894T/rs1799983 (dominant: OR=0.999, 95%CI=0.797-1.253, I2=63.8%; recessive: OR=0.924, 95%CI=0.589-1.450, I2=59.3%; allele analysis: OR=0.979, 95%CI=0.788-1.216, I2=74.9%) and T-786C/rs2070744 (dominant: OR=1.138, 95%CI=0.846-1.530, I2=67.9%; recessive: OR=0.956, 95%CI=0.708-1.291, I2=0.0%; allele analysis: OR=1.110, 95%CI=0.865-1.425, I2=69.4%). The same results were also obtained for tumor sites and pathologic stage subgroups. After further analyzing the NOS3 gene, rs1799983 as the tag- and functional SNP was presented. CONCLUSIONS: On the basis of this meta-analysis and the characteristics of the NOS3 gene, we suggested rs1799983 might be a key locus associated with CRC risk. Further prospective studies were needed to make more comprehensive explanation of the associations.


Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais/genética , Óxido Nítrico Sintase Tipo III/genética , Alelos , Predisposição Genética para Doença , Genótipo , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único
6.
Diagn Microbiol Infect Dis ; 79(1): 102-7, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24629577

RESUMO

The diagnosis of tuberculosis (TB) ascites using standard diagnostic tools is difficult. The aim of the present meta-analysis was to establish the overall diagnostic accuracy of adenosine deaminase (ADA) levels in ascites for diagnosing TB ascites. A systematic review was performed of English language publications prior to April 2013. Sensitivity, specificity, and other measures of the accuracy of ADA for the diagnosis of TB ascites using ascites fluid were summarized using a random-effects model or a fixed-effects model. Receiver operating characteristic curves were used to summarize overall test performance. Seventeen studies involving 1797 subjects were eligible for the analysis. The summary estimates of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and the area under cure of overall analysis were: 0.93, 0.94, 13.55, 0.11, 169.83, and 0.976, respectively; the results of sensitivity analysis of studies that used Giusti method were 0.94, 0.94, 12.99, 0.08, 183.18, and 0.977, respectively. Our results suggest that ADA in the ascites can be a sensitive and specific target and a critical criterion for the diagnosis of TB ascites.


Assuntos
Adenosina Desaminase/análise , Líquido Ascítico/química , Peritonite Tuberculosa/diagnóstico , Peritonite Tuberculosa/enzimologia , Biomarcadores/análise , Humanos , Sensibilidade e Especificidade
7.
Yonsei Med J ; 54(4): 832-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23709415

RESUMO

PURPOSE: The association between Helicobacter pylori (H. pylori) and blood ammonia levels in cirrhotic patients is controversial. We aimed to clarify this controvercy by performing a meta-analysis of published studies. MATERIALS AND METHODS: We searched PubMed, EMBASE and Cochrane library for studies which explored the association between H. pylori and blood ammonia levels in cirrhotic patients before May 2012. Six cohort studies involved in 632 H. pylori positive and 396 H. pylori negative cirrhotic patients were eligible for our analysis. The summary estimates were presented as standard means differences (SMD) and 95% confidence intervals (CI) from individual studies. RESULTS: Overall, there was significant association between H. pylori infection and the elevated blood ammonia levels in cirrhotic patients (SMD=0.34, 95% CI=0.21-0.47, I²=42.1%). Sensitivity analysis further confirmed this association. Subgroup analysis showed that the association was found only in Asian ethnicity, but not in Caucasian ethnicity. CONCLUSION: H. pylori infection is associated with elevated blood ammonia levels in cirrhotic patients, and more large scale studies and stratify analysis are warranted in order to further evaluate this association.


Assuntos
Infecções por Helicobacter/sangue , Cirrose Hepática/sangue , Cirrose Hepática/microbiologia , Amônia/sangue , Grupo com Ancestrais do Continente Asiático , Grupo com Ancestrais do Continente Europeu , Helicobacter pylori/patogenicidade , Humanos , Viés de Publicação , Análise de Regressão
8.
World J Gastroenterol ; 19(10): 1645-51, 2013 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-23539367

RESUMO

AIM: To investigate the performance and diagnostic accuracy of interferon-gamma (IFN-γ) for tuberculous peritonitis (TBP) by meta-analysis. METHODS: A systematic search of English language studies was performed. We searched the following electronic databases: MEDLINE, EMBASE, Web of Science, BIOSIS, LILACS and the Cochrane Library. The Standards for Reporting Diagnostic Accuracy initiative and Quality Assessment for Studies of Diagnostic Accuracy tool were used to assess the methodological quality of the studies. Sensitivity, specificity, and other measures of the accuracy of IFN-γ concentration in the diagnosis of peritoneal effusion were pooled using random-effects models. Receiver operating characteristic (ROC) curves were applied to summarize overall test performance. Two reviewers independently judged study eligibility while screening the citations. RESULTS: Six studies met the inclusion criteria. The average inter-rater agreement between the two reviewers for items in the quality checklist was 0.92. Analysis of IFN-γ level for TBP diagnosis yielded a summary estimate: sensitivity, 0.93 (95%CI, 0.87-0.97); specificity, 0.99 (95%CI, 0.97-1.00); positive likelihood ratio (PLR), 41.49 (95%CI, 18.80-91.55); negative likelihood ratio (NLR), 0.11 (95%CI, 0.06-0.19); and diagnostic odds ratio (DOR), 678.02 (95%CI, 209.91-2190.09). χ(2) values of the sensitivity, specificity, PLR, NLR and DOR were 5.66 (P = 0.3407), 6.37 (P = 0.2715), 1.38 (P = 0.9265), 5.46 (P = 0.3621) and 1.42 (P = 0.9220), respectively. The summary receiver ROC curve was positioned near the desirable upper left corner and the maximum joint sensitivity and specificity was 0.97. The area under the curve was 0.99. The evaluation of publication bias was not significant (P = 0.922). CONCLUSION: IFN-γ may be a sensitive and specific marker for the accurate diagnosis of TBP. The level of IFN-γ may contribute to the accurate differentiation of tuberculosis (TB) ascites from non-TB ascites.


Assuntos
Líquido Ascítico/imunologia , Interferon gama/análise , Peritonite Tuberculosa/diagnóstico , Área Sob a Curva , Líquido Ascítico/microbiologia , Biomarcadores/análise , Humanos , Mycobacterium tuberculosis/imunologia , Variações Dependentes do Observador , Peritonite Tuberculosa/tratamento farmacológico , Peritonite Tuberculosa/imunologia , Peritonite Tuberculosa/microbiologia , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Reprodutibilidade dos Testes
9.
Hepatogastroenterology ; 59(120): 2576-81, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22591680

RESUMO

BACKGROUND/AIMS: The effect of Helicobacter pylori (H. pylori) eradication on blood ammonia levels in cirrhotic patients is still controversial. We aimed to clarify this effect by performing a quantitative meta-analysis of published studies. METHODOLOGY: We searched PubMed, EMBASE and Cochrane library for studies which explored the effect of H. pylori eradication on blood ammonia levels in cirrhotic patients before March 2012. A random-effects meta-analysis was performed. RESULTS: Nine studies (five non-randomized control studies and four before-after studies) involved in 699 cirrhotic patients who were given H. pylori eradication eligible to our analysis. The before-after studies suggested that H. pylori eradication can significantly reduce the blood ammonia levels in cirrhotic patients (SMD=0.32, 95%CI=0.11-0.53, 12=39.6%). After included five non-randomized control studies,the overall results suggested that H. pylori eradication can not reduce the blood ammonia levels in cirrhotic patients (SMD=-0.36, 95% CI=-0.83-0.11) and with significant heterogeneity (1=89.3%). Subgroup analysis suggested that the no effect was found between Caucasian and Asian ethnicity and between cirrhotic patients with Child-Pugh class B/C <70% and >70%. CONCLUSIONS: The effect of eradication of H. pylori on blood ammonia levels in cirrhotic patients is mainly caused by the non-specific effect of antibiotics regardless of patients' ethnicity and impairment of liver function. However, due to limited studies available and low methodological quality that marked by high risks of bias, our study should be interpreted cautiously.


Assuntos
Amônia/sangue , Antibacterianos/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/efeitos dos fármacos , Cirrose Hepática/sangue , Viés , Biomarcadores/sangue , Regulação para Baixo , Medicina Baseada em Evidências , Infecções por Helicobacter/complicações , Infecções por Helicobacter/etnologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/isolamento & purificação , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/etnologia , Pessoa de Meia-Idade , Resultado do Tratamento
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