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1.
Therap Adv Gastroenterol ; 12: 1756284819878046, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31598135

RESUMO

Background: Nonalcoholic fatty liver disease (NAFLD) has become prevalent in recent decades, especially in developed countries, and approaches for the prevention and treatment of NAFLD are not clear. The aim of this research was to analyze and summarize randomized controlled trials that investigated the effects of probiotics on NAFLD. Methods: Seven databases (PubMed, Embase, the Web of Science, the Cochrane Library, China National Knowledge Infrastructure, Wan Fang Data, and VIP Database) were searched. Then, eligible studies were identified. Finally, proper data extraction, synthesis and analysis were performed by trained researchers. Results: Anthropometric parameters: with use of probiotics weight was reduced by 2.31 kg, and body mass index (BMI) was reduced by 1.08 kg/m2. Liver function: probiotic treatment reduced the alanine aminotransferase level by 7.22 U/l, the aspartate aminotransferase level by 7.22 U/l, the alkaline phosphatase level by 25.87 U/l, and the glutamyl transpeptidase level by -5.76 U/l. Lipid profiles: total cholesterol, low-density lipoprotein cholesterol, and triglycerides were significantly decreased after probiotic treatment. Their overall effects (shown as standard mean difference) were -0.73, -0.54, and -0.36, respectively. Plasma glucose: probiotics reduced the plasma glucose level by 4.45 mg/dl and the insulin level by 0.63. Cytokines: probiotic treatment decreased tumor necrosis factor alpha by 0.62 and leptin by 1.14. Degree of liver fat infiltration (DFI): the related risk of probiotics for restoring DFI was 2.47 (95% confidence interval, 1.61-3.81, p < 0.001). Conclusion: Probiotic treatment or supplementation is a promising therapeutic method for NAFLD.

2.
Int J Oncol ; 54(3): 1086-1098, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628664

RESUMO

Globally, gastric cancer is the fifth most common malignancy, with high rates of incidence and mortality. The high mortality rate and poor prognosis of gastric cancer are closely associated with its profound invasiveness, high incidence of metastasis, rapid proliferation, and high rate of recurrence. Previous studies have confirmed that stathmin (STMN) has an important role in the occurrence, development and prognosis of gastric cancer. However, the detailed mechanisms by which STMN affects these processes remain unclear. The aim of the present study was to determine how STMN promotes invasion, migration and proliferation in gastric cancer tumor cells. The results of immunohistochemistry indicated that STMN is overexpressed in stomach neoplasm tissues, and that it is associated with migration, invasion, proliferation and anti­apoptotic states of gastric cancer cells. The secretory proteins of gastric cancer cells with or without STMN knockdown were further analyzed using the isobaric tags for relative and absolute quantitation method to identify differentially expressed proteins verified by reverse transcription­quantitative polymerase chain reaction and western blot analysis. Inhibition of STMN decreases the levels of clusterin, cystatin C and matrix metalloproteinases, followed by inhibiting the protein kinase B and signal transducer and activation of transcription activation. These findings suggest that STMN could be a promising therapeutic target for gastric cancer.


Assuntos
Clusterina/metabolismo , Inativação Gênica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genética , Estatmina/genética , Neoplasias Gástricas/patologia , Idoso , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Movimento Celular/genética , Proliferação de Células/genética , Clusterina/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Proteínas Proto-Oncogênicas c-akt/genética , Fator de Transcrição STAT3/genética , Estatmina/metabolismo , Neoplasias Gástricas/metabolismo
3.
Nutr Res ; 60: 1-12, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30527253

RESUMO

Oxidative stress (OS) is associated with aging and multiple diseases, yet the effects of curcumin in humans are not definite. We undertook a meta-analysis of the effects of curcumin on OS biomarkers. In January 2018, we searched PubMed, Books@Ovid, Journals@Ovid, EMBASE, MEDLINE(R), and Web of Science to identify randomized controlled trials conducted ≥4 weeks and investigating the effects of curcumin on OS biomarkers, including glutathione peroxidase (GPX) activity in red blood cells (RBC), serum malondialdehyde (MDA) concentrations, and superoxide dismutase (SOD) activity. The standardized mean difference (SMD) with a 95% confidence interval (CI) was used to present the results. The meta-analysis included eight clinical studies (626 patients). There was a significant reduction in circulating MDA concentrations (SMD = -0.769, 95% CI: -1.059 to -0.478) and a significant increase in SOD activity (SMD = 1.084, 95% CI: 0.487 to 1.680) following curcumin supplementation. There was no change in the GPX activity in RBC. There was no significant association between the MDA-lowering effect of curcumin with underlying diseases or treatment duration. However, curcumin showed the MDA-lowering effect at curcuminoids doses ≥600 mg/d (P < .0001). This effect was greater when combined with piperine than curcuminoids alone (SMD = -1.085, 95% CI: -1.357 to -0.813; SMD = -0.850, 95% CI: -1.158 to -0.542). Curcumin may play an anti-oxidative role by reducing circulating MDA concentrations and increasing SOD activity. Further research of curcumin in different populations with multiple biomarkers of redox status is required.


Assuntos
Antioxidantes/farmacologia , Curcuma/química , Curcumina/farmacologia , Suplementos Nutricionais , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Antioxidantes/metabolismo , Humanos , Malondialdeído/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Superóxido Dismutase/metabolismo
4.
Cell Physiol Biochem ; 48(2): 741-752, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30025407

RESUMO

BACKGROUND/AIMS: C reactive protein (CRP) levels are elevated in many diseases, including malignant tumors and cardiovascular disorders. In this study, the protein interaction network for CRP was evaluated to determine the importance of CRP and its interacting proteins in the molecular pathogenesis of hepatocellular carcinoma (HCC). METHODS: Isobaric tags for relative and absolute quantitation (iTRAQ) and mass spectrometry were used to identify CRP interacting proteins in SMMC7721 cells. Moreover, Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to evaluate enriched genes and pathways for differentially expressed genes using DAVID and WebGestalt. Co-immunoprecipitation and western blot analyses were employed to assess interactions between CRP and KRT8, ANXA2, ENO2, and HSP90B1. RESULTS: In total, 52 proteins that interact with CRP were identified. A GO analysis suggested that most of the interacting proteins were involved in CRP complexes and regulated metabolic processes. A KEGG pathway analysis suggested that most CRP-interacting proteins contribute to the TRAIL signaling pathway, Class I PI3K/Akt signaling pathway, plasma membrane estrogen receptor signaling, Nectin adhesion pathway, and S1P1 pathway. Immunoprecipitation and western blot analyses revealed interactions between CRP and KRT8, ANXA2, ENO2, and HSP90B1. CONCLUSIONS: iTRAQ based proteomic profiling revealed the network of CRP interacting proteins. This network may activate the PI3K/Akt signaling pathway, thereby contributing to the pathogenesis of HCC.


Assuntos
Proteína C-Reativa/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Proteômica , Anexina A2/metabolismo , Proteína C-Reativa/antagonistas & inibidores , Proteína C-Reativa/genética , Carcinoma Hepatocelular/metabolismo , Perfilação da Expressão Gênica , Humanos , Queratina-8/metabolismo , Neoplasias Hepáticas/metabolismo , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Nectinas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
5.
Cell Physiol Biochem ; 45(2): 744-760, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29414802

RESUMO

BACKGROUND/AIMS: Hepatitis B virus (HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma. Therefore, we aimed to obtain further information on HBV pathogenesis, and to search for novel putative molecules for anti-HBV therapy. METHODS: We utilized Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) to identify the secretory proteins that are differentially expressed in the HBV DNA-transfected HepG2.2.15 cell line and its parental HepG2 cell line. Immunohistochemistry (IHC) was employed to assess the clinical relevance of the observations. Small interfering (si)RNA-based silencing transfection methods were carried out to study the function of ENPP2. RESULTS: Totally, 133 unique proteins were identified as differentially expressed in HepG2.2.15 cell line compared with HepG2 cell line. Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 precursor (ENPP2) is one of the most significantly up-regulated secretory proteins associated with HBV replication. This differential expression of ENPP2 was further validated by real-time quantitative RT-PCR, Western Blot and immunohistochemical analysis. To study the function of ENPP2, we knockdown ENPP2 expression in HepG2.2.15 cell line by RNA interference. ENPP2 silencing increased HBV replication approximately 2.3-fold by enhancing, via the type I IFN signaling pathway, HBV cccDNA (covalently closed circular DNA) translation into viral RNA. Moreover, attenuation of ENPP2 expression inhibited both the invasion and migration ability of hepatoma cells in vitro via interacting with the molecules in the tumor microenvironment. CONCLUSION: Our study demonstrates that ENPP2 may be a novel anti-HBV target and indicate that suppression of its expression may inhibit the invasion and migration ability of hepatoma cells.


Assuntos
Carcinoma Hepatocelular/patologia , Vírus da Hepatite B/fisiologia , Neoplasias Hepáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/metabolismo , Linhagem Celular , Movimento Celular , DNA Viral/fisiologia , Regulação da Expressão Gênica , Células Hep G2 , Humanos , Interferon Tipo I/metabolismo , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/metabolismo , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Diester Fosfórico Hidrolases/sangue , Diester Fosfórico Hidrolases/química , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo , Proteoglicanas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Replicação Viral
6.
Nutr J ; 16(1): 68, 2017 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-29020971

RESUMO

BACKGROUND: Dyslipidemia is an important and common cardiovascular risk factor in the general population. The lipid-lowering effects of turmeric and curcumin are unconfirmed. We performed a meta-analysis to assess the efficacy and safety of turmeric and curcumin in lowering blood lipids in patients at risk of cardiovascular disease (CVD). METHODS: A comprehensive literature search was conducted on PubMed, Embase, Ovid, Medline and Cochrane Library databases to identify randomized controlled trials (published as of November 2016) that assessed the effect of turmeric and curcumin on blood lipid levels including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Pooled standardized mean difference (SMD) with 95% confidence interval (CI) was used to assess the effect. RESULTS: The analysis included 7 eligible studies (649 patients). Turmeric and curcumin significantly reduced serum LDL-C (SMD = -0.340, 95% confidence interval [CI]: -0.530 to -0.150, P < 0.0001) and TG (SMD = -0.214, 95% CI: -0.369 to -0.059, P = 0.007) levels as compared to those in the control group. These may be effective in lowering serum TC levels in patients with metabolic syndrome (MetS, SMD = -0.934, 95% CI: -1.289 to -0.579, P < 0.0001), and turmeric extract could possibly have a greater effect on reducing serum TC levels (SMD = -0.584, 95% CI: -0.980 to -0.188, P = 0.004); however, the efficacy is yet to be confirmed. Serum HDL-C levels were not obviously improved. Turmeric and curcumin appeared safe, and no serious adverse events were reported in any of the included studies. CONCLUSIONS: Turmeric and curcumin may protect patients at risk of CVD through improving serum lipid levels. Curcumin may be used as a well-tolerated dietary adjunct to conventional drugs. Further research is required to resolve uncertainties related to dosage form, dose and medication frequency of curcumin.


Assuntos
HDL-Colesterol/sangue , LDL-Colesterol/sangue , Curcuma/química , Curcumina/farmacologia , Fitoterapia , Triglicerídeos/sangue , Doenças Cardiovasculares/sangue , Humanos , Preparações de Plantas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco
7.
Dig Liver Dis ; 49(7): 780-788, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28377286

RESUMO

BACKGROUND: Liver fibrosis can lead to cirrhosis and hepatocellular carcinoma if not treated in the early stages. The molecular mechanisms of the pathogenesis of hepatic fibrosis remain unclear. AIM: To identify the molecules involved in the pathogenesis of liver fibrosis and to investigate the potential effect and mechanism of Annexin A2 up-regulation during liver fibrosis progression. METHODS: Twenty Sprague-Dawley rats were divided into two groups: the carbon tetrachloride (CCl4)-induced liver fibrosis group and the normal control group. Hematoxylin and eosin staining or Masson Trichrome staining and enzyme-linked immunosorbent assay were applied to assess the degree of liver damage and fibrosis in rats with CCl4-induced liver fibrosis. Liver tissue protein profiles were analyzed using iTRAQ and mass spectrometry. RT-PCR and western blotting analyses were employed to validate differentially expressed proteins. Small interfering RNA-based silencing was performed to study the function of Annexin A2. RESULTS: Twelve weeks after CCl4 injection, significant body weight changes and liver injury and liver fibrosis were observed in rats. In addition, 130 proteins were differentially expressed in the liver fibrosis group. Overexpression of Annexin A2 was confirmed by RT-PCR and Western blotting analysis. Silencing of Annexin A2 expression in HepG2 and LX-2 cells significantly reduced the secretion of von Willebrand factor (vWF). CONCLUSION: Annexin A2 promotes liver fibrosis by mediating vWF secretion, which can be used to mitigate the progression of liver fibrosis.


Assuntos
Anexina A2/metabolismo , Cirrose Hepática Experimental/metabolismo , Fator de von Willebrand/metabolismo , Animais , Western Blotting , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Inativação Gênica , Cirrose Hepática Experimental/etiologia , Espectrometria de Massas , Ligação Proteica , RNA Interferente Pequeno , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Regulação para Cima
8.
Int J Oncol ; 2017 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-28350119

RESUMO

Hepatocellular carcinoma (HCC) is one of most common malignant cancers and is the second leading cause of cancer related deaths. The prognosis and survival of patients are closely related to the degree of tumor metastasis. The mechanism of HCC metastasis is still unclear. In the present study, we investigated the molecular mechanism of C-reaction protein in promoting migration and invasion of hepatocellular carcinoma cells in vitro. We estimated that CRP is overexpressed in liver cancer tissues and that it promotes invasion and metastasis of HCC in vitro. In the present study, we employed iTRAQ-based mass spectrometry to analyze the HepG2 secretory proteins of CRP siRNA-treated cells and negative control siRNA-treated cells. We identified 109 differentially expressed proteins after silencing CRP, of which 45 were upregulated and 64 were downregulated. Some of the differentially expressed proteins were confirmed by western blot analysis and real-time quantitative PCR. Furthermore, we found that knockdown of CRP substantially abrogates HIF-1α expression levels, the luciferase activity of HIF-1α and ERK and Akt phosphorylation in HepG2 cells. The present study provides a novel mechanism by which CRP promotes the proliferation, migration, invasion and metastasis of hepatocellular carcinoma cells. Inhibition of CRP suppressed migration, invasion and healing of hepatoma carcinoma cells by decreasing HIF-1α activity and CTSD.

9.
Int J Oncol ; 50(3): 883-892, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28197637

RESUMO

Hepatocellular carcinoma is the second most common cause of cancer-related deaths worldwide. Due to a high propensity to metastasize, active angiogenesis and rapid proliferation, recurrence and poor prognosis are major obstacles for treatment and cure of this disease. However, the detailed mechanisms of how fatty acid synthase (FASN) promotes migration, invasion and healing in tumor cells remain unclear. In the present study, the previous results that FASN was expressed higher in cancer samples than in non-cancerous samples, and influenced migration, invasion of hepatoma carcinoma cells, were verified by immunohistochemistry, tissue microarrays, Transwell assay and wound healing assay. The secretory proteins of hepatocellular carcinoma cells with or without FASN knockdown were analyzed using the isobaric tags for relative and absolute quantitation (iTRAQ) method to identify differentially expressed proteins (DEPs). The DEPs were verified by RT-PCR and western blot analysis, and were consistent with the iTRAQ results. Inhibition of FASN can decrease the levels of IGFBP1, and the expression, activity, and ubiquitination of HIF-1α. Inhibition of FASN can suppress migration, invasion and healing of hepatoma carcinoma cells by decreasing HIF-1α, and IGFBP1.


Assuntos
Carcinoma Hepatocelular/patologia , Movimento Celular/genética , Ácido Graxo Sintase Tipo I/antagonistas & inibidores , Ácido Graxo Sintase Tipo I/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Invasividade Neoplásica/genética , Interferência de RNA , RNA Interferente Pequeno/genética
10.
Oncotarget ; 8(3): 4549-4562, 2017 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-27999186

RESUMO

BACKGROUND AND AIMS: Hepatitis B virus (HBV) infection is a major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). To gain a better understanding of the pathogenesis of HBV infection, this study aimed to investigate the differentially expressed proteins (DEPs) in liver tissues from patients with chronic hepatitis B (CHB) infection. RESULTS: Seventy-one DEPs were identified. Overexpression of multi-drug resistance protein 1 (MDR1) was validated by RT-qPCR and western blot analyses. Moreover, its expression was increased at both the mRNA and protein levels in response to overexpression of HBV large surface protein (LHBs). Furthermore, screening of transcription factors suggested the possible involvement of hypoxia-inducible factor 1α (HIF-1α) in the interaction between LHBs and MDR1. The function of HIF-1α in the MDR1 activation was confirmed by EMSA and reporter gene analyses. MATERIALS AND METHODS: Liver samples from CHB patients and controls without HBV infection were collected and subjected to isobaric tags for relative and absolute quantitation (iTRAQ) and mass spectrometric analysis. CONCLUSIONS: These results imply that LHBs, in association with HIF-1α, induces MDR1 overexpression, which may contribute to the pathogenic changes in CHB infection.


Assuntos
Carcinoma Hepatocelular/virologia , Hepatite B Crônica/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/virologia , Proteínas do Envelope Viral/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Vírus da Hepatite B/metabolismo , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/genética , Humanos , Fígado/metabolismo , Fígado/virologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Proteômica/métodos , Adulto Jovem
11.
PLoS One ; 11(9): e0162241, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27612199

RESUMO

T follicular helper cells (Tfh) provide help to B cells to support their activation, expansion and differentiation. However, the role of Tfh cells in chronic HBV infection is poorly defined. The aim of this research was to examine the function of Tfh cells and whether they are involved in HBV related disease. Blood CXCR5+CD4+T cells and B cells in 85 patients with chronic HBV infection (HBV patients) and health controls (HC) were examined by flow cytometry. The molecule expression in blood CXCR5+CD4+ T cells was detected by real-time PCR. Blood CXCR5+CD4+ T cells and B cells were co-cultured and the production of Ig and cytokines was detected by ELISA. Autoantibodies were detected by indirect immunofluorescence and immunospot assay. We found that blood CXCR5+CD4+ T cells in patients with chronic HBV infection (HBV patients) expressed higher level of activation related molecules and cytokines than that from health controls (HC).In HBV patients, the frequency of blood CXCR5+CD4+ T cells was significantly correlated with serum ALT and AST. We also found that blood CXCR5+CD4+ T cells from HBV patients could induce B cells to secret higher level of immunoglobulin than that from HC. Several autoantibodies, including ANA, ss-A, ss-B, Scl-70, Jo-1, ect, were indeed positive in 65% HBV patients. Among HBV patients, expression of function related molecules was significantly higher in blood CXCR5+CD4+ T cells from patients with autoantibodies than that without autoantibodies. Our research indicated that blood CXCR5+CD4+ T cells from HBV patients were over activated and show augmented capacity to help B cells for antibody secreting, which might correlated with liver inflammation and the production of autoantibodies in extrahepatic manifestations.


Assuntos
Autoanticorpos/sangue , Linfócitos T CD4-Positivos/imunologia , Hepatite B Crônica/imunologia , Adulto , Autoanticorpos/biossíntese , Linfócitos B/imunologia , Contagem de Linfócito CD4 , Feminino , Humanos , Imunofenotipagem , Masculino , Receptores CXCR5/metabolismo
12.
Mol Med Rep ; 14(5): 4422-4428, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27665963

RESUMO

MicroRNA (miR)-138 has previously been demonstrated to have a suppressive role in numerous types of human cancer, including non-small cell lung cancer (NSCLC). LIM domain kinase 1 (LIMK1) is a serine/threonine kinase that regulates actin polymerization via phosphorylation and inactivation of cofilin. Previous studies have reported that LIMK1 is associated with NSCLC; however, the underlying regulatory mechanism of LIMK1, and the association between LIMK1 and miR­138 in NSCLC cells, remains largely unknown. The present study aimed to reveal the regulatory roles of miR­138 and LIMK1 in NSCLC cell migration and invasion. Reverse transcription­quantitative polymerase chain reaction and western blot analysis were used to examine the mRNA and protein expression levels. Transwell and wound healing assays were conducted to determine cell invasion and migration. A luciferase reporter assay was used to determine the target association between miR­138 and LIMK1. The present study demonstrated that miR­138 was markedly downregulated in NSCLC tissues and cell lines, whereas the expression levels of LIMK1 were significantly upregulated. LIMK1 was further identified as a direct target of miR­138 in NSCLC H460 cells. Furthermore, overexpression of miR­138 significantly inhibited the protein expression of LIMK1, whereas knockdown of miR­138 upregulated the protein expression of LIMK1 in H460 cells. In addition, overexpression of miR­138 significantly inhibited the migration and invasion of NSCLC cells; however, overexpression of LIMK1 significantly promoted NSCLC cell migration and invasion. An investigation into the underlying molecular mechanism revealed that overexpression of miR­138 significantly decreased cofilin signaling activity, whereas knockdown of miR­138 notably enhanced cofilin signaling activity. In conclusion, the present study suggests that miR­138 may inhibit the migration and invasion of NSCLC cells by targeting the LIMK1/cofilin signaling pathway. Therefore, miR-138/LIMK1/cofilin may be considered a potential therapeutic target for the treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Cofilina 1/biossíntese , Quinases Lim/biossíntese , MicroRNAs/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Cofilina 1/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Quinases Lim/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , RNA Mensageiro/genética , Transdução de Sinais/genética
13.
PLoS One ; 11(8): e0160171, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27513564

RESUMO

BACKGROUND: Natural killer (NK) cells are the main effective component of the innate immune system that responds to chronic hepatitis B (CHB) infection. Although numerous studies have reported the immune profiles of NK cells in CHB patients, they are limited by inconsistent results. Thus, we performed a meta-analysis to characterize reliably the immune profiles of NK cells after CHB infection, specifically frequency, phenotype, and function. METHODS: A literature search of the computer databases MEDLINE, PUBMED, EMBASE, and Cochrane Center Register of Controlled Trails was performed and 19 studies were selected. The standard mean difference (SMD) and 95% confidence interval (CI) of each continuous variable was estimated with a fixed effects model when I2 < 50% for the test for heterogeneity, or the random effects model otherwise. Publication bias was evaluated using Begg's and Egger's tests. RESULTS: The meta-analysis of publications that reported frequency of peripheral NK cells showed that NK cell levels in CHB patients were significantly lower compared with that of healthy controls. A higher frequency of CD56bright NK subsets was found in CHB patients, but the CD56dim NK subsets of CHB patients and healthy controls were similar. CHB patients before and after antiviral therapy with nucleotide analogues (NUCs) showed no statistical difference in NK frequency. The activating receptors were upregulated, whereas inhibitory receptors were comparable in the peripheral NK cells of CHB individuals and healthy controls. NK cells of CHB patients displayed higher cytotoxic potency as evidenced by CD107a protein levels and conserved potency to produce interferon-gamma (IFNγ), compared with their healthy counterparts. CONCLUSION: Our results revealed that CHB patients had a lower frequency of NK cells compared with healthy individuals not treatable with antiviral NUC therapy. With an activating phenotype, NK cells in CHB patients showed better cytotoxic potency and conserved IFNγ production.


Assuntos
Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Células Matadoras Naturais/imunologia , Animais , Hepatite B Crônica/virologia , Humanos
14.
Oncotarget ; 7(32): 50952-50962, 2016 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-27447555

RESUMO

The role of immunity in the pathogenesis of acute hepatitis B virus (HBV) infection is poorly understood. The purpose of this research was to define the intrahepatic immune factors responsible for viral clearance during acute HBV infection. The model of acute HBV infection was established by hydrodynamically transfecting mice with pCDNA3.1-HBV1.3 plasmids which contained a supergenomic HBV1.3-length transgene. The frequency of CD4+ CXCR5+ T cells, CD19+ B cells and their surface molecules in livers, spleens and peripheral blood were detected using flow cytometry. The lymphomononuclear cells isolated from the livers of transfected mice were further stimulated by HBc-derived peptides and then the frequency and cytokine secretion of HBV-specific CD4+CXCR5+ T cells were detected. We found that the frequency of CXCR5+ in CD4+ T cells was specifically increased; the expression of PD-1 was decreased while the expression of ICOS was increased on intrahepatic CD4+CXCR5+ T cells. Although the frequency of CD19+ B cells was not affected, the expression of PDL-1, ICOSL and IL-21R on B cells was increased in the livers of mice. The frequency of HBV-specific CD4+CXCR5+ T cells and the production of IL-21 by intrahepatic CD4+CXCR5+ T cells of mice with acute HBV infection were increased after stimulation. Furthermore, the expression of function-related molecules of intrahepatic CD4+CXCR5+ T, including Bcl-6, CXCR5, IL-6, IL-6R, IL-21 and IL-4 in the liver was increased during acute HBV infection. In conclusion, the activation of intrahepatic CD4+CXCR5+ T cells and B cells was associated with the clearance of HBV during acute infection.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Hepatite B/imunologia , Subpopulações de Linfócitos/imunologia , Animais , Antígenos CD19/imunologia , Fígado/imunologia , Ativação Linfocitária/imunologia , Camundongos , Receptores CXCR5/imunologia
15.
Sci Rep ; 6: 26296, 2016 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-27192960

RESUMO

Vδ2 γδ (Vδ2) T cells, a major human γδ T cell subset, exhibit broad anti-tumor and anti-infective activity; however, their precise role in chronic hepatitis C virus (HCV) infections remains unclear. In this study, we analyzed the phenotype and function of Vδ2 T cells in 43 HCV-infected patients compared to 39 healthy controls (HCs). Vδ2 T cells from HCV-infected patients were activated and differentiated into effector cells. Vδ2 T cells in patients expressed significantly higher levels of natural killer (NK) cell markers CD56 and CD16 than in HCs, acquiring cytotoxic NK-like phenotype. The Vδ2 T cell phenotype was associated with increased cytolytic effector molecules expression in HCV-infected patients with elevated serum ALT levels. Surprisingly, Vδ2 T cells in patients had a markedly impaired capacity to produce IFN-γ. Further in vitro and in vivo analysis showed that interferon-α, which was induced during HCV infection, caused Vδ2 T cell function bias toward cytotoxicity. These results suggest a functional dichotomy for Vδ2 T cells in chronic HCV infections: a role in cytotoxicity but not for IFN-γ production, which may contribute to both the liver inflammation and HCV persistence.


Assuntos
Hepatite C Crônica/imunologia , Interferon gama/biossíntese , Linfócitos Intraepiteliais/imunologia , Adolescente , Adulto , Alanina Transaminase/sangue , Estudos de Casos e Controles , Citotoxicidade Imunológica , Feminino , Humanos , Interferon-alfa/metabolismo , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade
16.
Gastroenterol Res Pract ; 2016: 7214020, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26880896

RESUMO

Background/Aims. It remains unclear whether tenofovir disoproxil fumarate- (TDF-) based combination therapy produces better outcomes than TDF monotherapy in chronic hepatitis B (CHB) patients. The aim of this study was to compare the efficacy of the two regimens by performing a meta-analysis. Methods. A comprehensive literature search was performed on the comparison of TDF-based combination therapy and monotherapy for CHB patients in the PubMed, Embase, Web of Science, and the Cochrane Libraries. Both dichotomous and continuous variables were extracted and pooled outcomes were expressed as risk ratio (RR) or standard mean difference (SMD). Results. Nine eligible studies (1089 subjects in total) were included in our analysis. The proportion of patients with undetectable HBV DNA at 24, 48, and 96 weeks were similar between the two comparable groups (62.5% versus 70.9%, P = 0.086; 78.1% versus 83.7%, P = 0.118; 86.4% versus 87.9%, P = 0.626, resp.). HBV DNA reduction, rates of ALT normalization, hepatitis B e antigen (HBeAg) loss, and HBeAg seroconversion were also similar between the two groups. Conclusions. On the current data, TDF-based combination therapy seemed to be no better than those achieved by monotherapy. Further studies are needed to verify this comparison.

17.
PLoS One ; 10(11): e0142457, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26556483

RESUMO

BACKGROUND AND AIM: Previous studies have demonstrated that coffee consumption may be inversely correlated with hepatic fibrosis and cirrhosis. However, the reported results have been inconsistent. To summarize previous evidences quantitatively, a meta-analysis was performed. METHODS: The Medline, Web of Science, and Embase databases (from inception to June 2015) were searched to identify relevant trials that evaluated the effects of coffee consumption on hepatic fibrosis or cirrhosis. Odds ratios (ORs) of advanced hepatic fibrosis or cirrhosis for low or moderate, high, and any coffee consumption versus no consumption were pooled. Two cups per day was used as the cut-off level between low or moderate and high consumption. RESULTS: Sixteen studies were included, involving 3034 coffee consumers and 132076 people who do not consume coffee. The pooled results of the meta-analysis indicated that coffee consumers were less likely to develop cirrhosis compared with those who do not consume coffee, with a summary OR of 0.61 (95%CI: 0.45-0.84). For low or moderate coffee consumption versus no consumption, the pooled OR of hepatic cirrhosis was 0.66 (95%CI: 0.47-0.92). High coffee consumption could also significantly reduce the risk for hepatic cirrhosis when compared with no coffee consumption (OR = 0.53, 95%CI: 0.42-0.68). The effect of coffee consumption on hepatic fibrosis was summarized as well. The pooled OR of advanced hepatic fibrosis for coffee consumption versus no consumption was 0.73 (95%CI: 0.58-0.92). The protective effect of coffee on hepatic fibrosis and cirrhosis was also identified in subgroup meta-analyses of patients with alcoholic liver disease and chronic hepatitis C virus (HCV) infection. CONCLUSION: Coffee consumption can significantly reduce the risk for hepatic fibrosis and cirrhosis.


Assuntos
Café , Cirrose Hepática/prevenção & controle , Humanos , Fatores de Proteção
18.
Virol J ; 12: 179, 2015 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26527281

RESUMO

BACKGROUND & AIM: The aim was to extract factors from virologic and biochemical profiles at baseline and 24 weeks of treatment to predict HBeAg seroconversion in patients treated with ETV. METHODS: HBeAg positive chronic hepatitis B patients receiving ETV naïve-treatment were enrolled. HBV DNA, ALT, and serological markers were prospectively monitored every 6 months for 240 weeks. The cumulative rates of virologic response (VR), biochemical response (BR), and HBeAg seroconversion were determined, and potential predictors for HBeAg seroconversion were identified through uni/multivariate analysis. RESULT: Two hundred twenty nine patients were eligible for this study. The cumulative rates of VR, BR, and HBeAg seroconversion at 240 weeks were 88.4 %, 100 %, and 36.7 %, respectively. Multivariate analysis showed that HBV DNA (OR, 2.8, p = 0.003), ALT (OR, 2.6, p = 0.005) at baseline, undetectable HBV DNA within 24 weeks (OR = 3.2, p < 0.001), and body mass index (BMI) ≥24kg/m(2) (OR = 0.038, p = 0.013) were associated with HBeAg seroconversion. A prediction model for probability of HBeAg seroconversion was constructed. Patients can be classified into high (>40 %), intermediate (20-40 %), or low (≤20 %) groups based on the calculated probability of HBeAg seroconversion. The cumulative rates of HBeAg seroconversion were different among the three groups (p < 0.001). About 58 % patients in the high probability group achieved HBeAg seroconversion while almost 90 % patients within the low group remained HBeAg positive. CONCLUSION: A combination of HBV DNA, ALT and BMI values at baseline, and undetectable HBV DNA level within 24 weeks can predict HBeAg seroconversion. Both viral and metabolic factors likely determine HBeAg status with ETV treatment. TRIAL REGISTRATION: CTR20132358.


Assuntos
Alanina Transaminase/sangue , Antivirais/uso terapêutico , Índice de Massa Corporal , DNA Viral/sangue , Guanina/análogos & derivados , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Adulto , Feminino , Guanina/uso terapêutico , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Estudos Longitudinais , Masculino , Modelos Estatísticos , Prognóstico , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
19.
Int J Oncol ; 47(5): 1932-44, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26398045

RESUMO

Gastric cancer (GC) is now one of the most common malignancies with a relatively high incidence and high mortality rate. The prognosis is closely related to the degree of tumor metastasis. The mechanism of metastasis is still unclear. Proteomics analysis is a powerful tool to study and evaluate protein expression in tumor tissues. In the present study, we collected 15 gastric cancer and adjacent normal gastric tissues and used the isobaric tags for relative and absolute quantitation (iTRAQ) method to identify differentially expressed proteins. A total of 134 proteins were differentially expressed between the cancerous and non-cancerous samples. Azurocidin 1 (AZU1), CPVL, olfactomedin 4 (OLFM4) and Villin 1 (VIL1) were upregulated and confirmed by western blot analysis, real-time quantitative PCR and immunohistochemical analyses. These results were in accordance with iTRAQ. Furthermore, silencing the OLFM4 expression suppressed the migration, invasion and proliferation of the GC cells in vitro. The present study represents a successful application of the iTRAQ method in analyzing the expression levels of thousands of proteins. Overexpression of OLFM4 in gastric cancer may induce the development of gastric cancer. Overall, suppression of OLFM4 expression may be a promising strategy in the development of novel cancer therapeutic drugs.


Assuntos
Biomarcadores Tumorais/biossíntese , Fator Estimulador de Colônias de Granulócitos/biossíntese , Proteômica , Neoplasias Gástricas/genética , Idoso , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Gástricas/patologia
20.
Hepatol Int ; 9(4): 543-57, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26162453

RESUMO

PURPOSE: The efficacy of on-treatment hepatitis B surface antigen (HBsAg) levels in guiding pegylated interferon (PEG-IFN) therapy for chronic hepatitis B (CHB) infections is still controversial. The aim of this study is to quantitatively evaluate the efficacy of on-treatment HBsAg levels as a response-guided therapy strategy to guide PEG-IFN-based therapies for CHB. METHODS: We searched PUBMED, EMBASE, and the Cochrane Library (1997-2013) for clinical research involving HBsAg quantification, and the response to PEG-IFN-based therapy. Pooled effect of HBsAg levels on guiding PEG-IFN-based therapies for CHB was evaluated using fixed-effects or random-effects model. RESULTS: From 13 studies (n = 1493 patients), patients with optimal on-treatment HBsAg levels were found to have a greater chance of attaining a response (RR 5.17, 95 % CI 3.75-7.11, p < 0.00001), and the pooled total response rate was 54 % (95 % CI 44-63 %). At week 12, patients without optimal on-treatment HBsAg levels had hardly achieved a response (the early non-response rate: 99 %, 95 % CI 98-100 %). At 24 weeks, the response rate increased to 79 % in HBeAg-negative patients. CONCLUSION: This meta-analysis suggested that on-treatment HBsAg quantification is effective in guiding the therapy of PEG-IFN in CHB infections, especially in HBeAg-negative patients.


Assuntos
Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/imunologia , Hepatite B Crônica , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Antivirais/uso terapêutico , Portadores de Fármacos , Antígenos de Superfície da Hepatite B/imunologia , Hepatite B Crônica/sangue , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Humanos , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento
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