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1.
Clin Cancer Res ; 24(13): 3204-3216, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29514844

RESUMO

Purpose: Hypoxia-inducible factor-2α (HIF2α) is regarded as a preferential target for individualized hepatocellular carcinoma (HCC) treatment and sorafenib resistance. Our study aimed to identify the regulatory mechanisms of HIF2α activity under hypoxic conditions. We sought to determine whether the COX-2/PGE2 axis is involved in the regulatory mechanisms of HIF2α activity and of sorafenib resistance in hypoxic HCC cells.Experimental Design: The cell viability, migration, and invasion abilities were measured to analyze the effects of HIF2α on hypoxic HCC cells. Both in vitro and in vivo HCC models were used to determine whether the COX-2/PGE2 axis is a driver of HIF2α level and activity, which then reduces the sensitivity of sorafenib treatment in hypoxic HCC cells.Results: Under hypoxic conditions, the COX-2/PGE2 axis effectively stabilized HIF2α and increased its level and activity via decreasing von Hippel-Lindau protein (p-VHL) level, and also enhanced HIF2α activity by promoting HIF2α nuclear translocation via MAPK pathway. The activation of HIF2α then led to the enhanced activation of VEGF, cyclin D1, and TGFα/EGFR pathway to mediate HCC development and reduce the sensitivity of sorafenib. More importantly, COX-2-specific inhibitors synergistically enhanced the antitumor activity of sorafenib treatment.Conclusions: Our data obtained demonstrate that the COX/PGE2 axis acts as a regulator of HIF2α expression and activity to promote HCC development and reduce sorafenib sensitivity by constitutively activating the TGFα/EGFR pathway. This study highlights the potential of COX-2-specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment. Clin Cancer Res; 24(13); 3204-16. ©2018 AACR.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Sorafenibe/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclina D1/metabolismo , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Humanos , Hipóxia/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Neovascularização Patológica/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteólise , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Am J Transl Res ; 10(12): 4367-4375, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30662678

RESUMO

The aim of this study was to facilitate the clinical treatment and prognosis of stroke-associated pneumonia (SAP) by examining changes in T-lymphocyte subsets. Stroke patients admitted in Suzhou Hospital between 2014 and 2016 participated in the study. Patients were divided into a pneumonia group (50 patients) and a non-pneumonia group (254 patients) based on a diagnosis of pneumonia. Information regarding risk factors for ischemic stroke was collected from all patients using a questionnaire. Compared with non-SAP patients, SAP patients were older, dysphagic, smokers, had higher NIH stroke scale (NIHSS) scores and neutrophil: lymphocyte ratio, had higher leukocyte, neutrophil, and CD8 levels, had lower CD3, CD4, and lymphocyte levels, and had a lower CD4:CD8 ratio. Patients with a higher NIHSS score had higher CD8 levels, lower CD3 and CD4 levels, and a lower CD4:CD8 ratio. No significant differences in T-lymphocyte subsets were found between the left and right cerebral hemispheres. After adjusting for other variables, smoking, dysphagia, NIHSS score, and CD4:CD8 ratio were positively associated with SAP. The areas under the receiver operating characteristic curve for dysphagia, NIHSS score, CD4:CD8 ratio, CD4:CD8 ratio + NIHSS score, and Dysphagia+ CD4:CD8 ratio + NIHSS score were 0.583 (95% CI: 0.490-0.675), 0.791 (95% CI: 0.724-0.859), 0.676 (95% CI: 0.593-0.759), 0.846 (95% CI: 0.790-0.902), and 0.867 (95% CI: 0.815-0.918), respectively. A few T-lymphocyte subsets may increase susceptibility to pneumonia after acute ischemic stroke. Thus, the detection of T-lymphocyte subsets may predict the risk of SAP in such patients.

3.
Am J Transl Res ; 9(10): 4553-4563, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29118917

RESUMO

We examined whether the association between total homocysteine (tHCY) and risk of ischemic stroke (IS) varies depending on renal function to gain insight into why tHCY-lowering vitamins do not reduce the incidence of cardiovascular disease in clinical trials. We analyzed data from 542 IS patients with large artery atherosclerosis (LAA) or small artery occlusion (SAO) after stratification by estimated glomerular filtration rate (eGFR) to evaluate renal function. We found that tHCY level was positively associated with the occurrence of IS in both LAA (OR: 1.159, 95% CI: 1.074-1.252, P<0.001) and SAO (OR: 1.143, 95% CI: 1.064-1.228, P<0.001) patients and in LAA (OR: 1.135, 95% CI: 1.047-1.230, P=0.002) and SAO (OR: 1.159, 95% CI: 1.060-1.268, P=0.001) subgroups with normal renal function but not in LAA or SAO subgroups with renal insufficiency. eGFR level was positively associated with IS in LAA (OR: 1.022, 95% CI: 1.010-1.034, P<0.001) and SAO (OR: 1.024, 1.012-1.037, P<0.001) subgroups with normal renal function but was negatively associated with IS in LAA (OR: 0.875, 95% CI: 0.829-0.925, P<0.001) and SAO (OR: 0.890, 95% CI: 0.850-0.932, P<0.001) subgroups with renal insufficiency. Folic acid level was negatively associated with IS in LAA (OR: 0.734, 95% CI: 0.606-0.889, P=0.002) and SAO (OR: 0.861, 95% CI: 0.767-0.967, P=0.012) subgroups with renal insufficiency. Therefore, renal function as evaluated by eGFR exerts a significant influence on the association between tHCY and risk of IS.

4.
Metab Brain Dis ; 32(3): 859-865, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28261756

RESUMO

This study was conducted to investigate the role of different homocysteine metabolism-related vitamin (HMRV) levels in the correlation between hyperhomocysteinemia (HHCY) and ischemic stroke (IS) subtypes. Three hundred and forty-eight IS patients manifesting different vascular subtypes were subclassified on the basis of HMRV deficiencies. Correlation between HHCY and IS subtypes was investigated in all the subgroups. In this study, HHCY was significantly correlated with the IS subtypes in large artery atherosclerosis (OR 1.126, 95%CI: 1.051 ~ 1.206, P = 0.001) and small artery occlusion (OR 1.105, 95%CI: 1.023 ~ 1.193, P = 0.012). Subgroup analysis revealed a correlation between HHCY and IS subgroup (OR 1.201, 1.178, 95%CI: 1.081 ~ 1.334, 1.058 ~ 1.313, P = 0.001, P = 0.003, respectively) in HMRV deficiency, but not significantly with the IS subgroup in normal HMRV levels. Serum vitamin B12 concentrations are inversely correlated with both IS subtypes in HMRV deficiency subgroups (OR 0.992, 0.995, 95%CI: 0.987 ~ 0.996, 0.991 ~ 0.999, P < 0.001, P = 0.007, respectively), which may contribute to HHCY incidence in these populations. The correlation between HHCY and IS subtypes is affected by HMRV levels in this case-control study. Our findings are helpful to understand the inconsistency in prior homocysteine studies. Serum vitamin B12 levels may play a critical role in HHCY incidence in this Chinese population.Cerebrovascular disease has emerged as the leading cause of disability and mortality in both urban and rural areas of China (Neurology branch of Chinese Medical Association 2015). Ischemic stroke (IS) constitutes 60% to 80% of all cerebrovascular disease (Neurology branch of Chinese Medical Association 2014). Among a variety of risk factors, hyperhomocysteinemia (HHCY) has been closely correlated with IS due to intracranial small-vessel disease and extracranial large-artery disease (Selhub et al. 1995; Eikelboom et al. 2000; Alvarez et al. 2012; Jeon et al. 2014). However, the failure to lower homocysteine (HCY) via homocysteine metabolism-related vitamin (HMRV, including folic acid and vitamin B12 but not vitamin B6 in this study) supplementation to reduce stroke morbidity questions the role of HCY as a risk factor for stroke (Lonn et al. 2006; Hankey et al. 2010). Theoretically, HMRV supplementation merely lowers the incidence of stroke induced by HHCY resulting from HMRV deficiency, whereas HHCY-induced stroke concomitant with normal HMRV levels may be refractory to treatment. The correlation between HCY varying with HMRV levels and IS subtypes is still unclear. In this study, we investigated the impact of variation in HMRV levels on the correlation between HHCY and IS subtypes in 348 acute IS patients with large and small vessel diseases. We sought to determine the factors underlying the conflicting results associated with lowering HCY by HMRV supplementation to reduce stroke incidence.


Assuntos
Ácido Fólico/sangue , Homocisteína/sangue , Hiper-Homocisteinemia/sangue , Arteriosclerose Intracraniana/sangue , Rim/fisiologia , Acidente Vascular Cerebral/sangue , Vitamina B 12/sangue , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Transtornos Cerebrovasculares/sangue , Transtornos Cerebrovasculares/diagnóstico por imagem , Transtornos Cerebrovasculares/epidemiologia , China/epidemiologia , Feminino , Humanos , Hiper-Homocisteinemia/diagnóstico por imagem , Hiper-Homocisteinemia/epidemiologia , Arteriosclerose Intracraniana/diagnóstico por imagem , Arteriosclerose Intracraniana/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/epidemiologia
5.
Guang Pu Xue Yu Guang Pu Fen Xi ; 36(9): 2906-10, 2016 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-30084624

RESUMO

Siliva as a kind of biomarker containing a variety of bioactive components can be used to help disease diagnosis. Compared with the urine and blood, the collection of saliva is more simple and convenient while the collection process is completely non-invasive. Therefore, saliva detection attracts more and more attention in non-invasive disease diagnosis. Histatins are a family of small, cationic, histidine-rich peptides, which secreted by salivary bringing innate defense of the oral cavity. It has been reported that histatins are related to many other diseases, such as HIV and AIDs. Thus the detection of histatins in saliva is significantly important for oral healthy monitoring and disease diagnosis. In this paper, a new label free method for rapid detection of histidine-rich peptides was developed based on the fact that histidine-rich peptides can interact with 3-azidocoumarin through hydrogen bonds which decreases the electron-donating ability of the azido group and results in fluorescence enhancement of the system. The results showed that the fluorescence intensities were dramatically increased when histatin 5 were incubation with 3-azidocoumarin. There is a good relationship with the linear co r of 0.994 between the enhanced fluorescence and histatin 5 concentration ranging from 0.23 to 31.05 µmol·L-1, and the limit of detection is 72 nmol·L-1 (3σ/k). Moreover, the detection of histidine-rich peptides in saliva was successfully achieved by the new developed label free method since amino acids and proteins in saliva will not be interfered with the detection with the recoveries between 96.7%~111.6%. Compared with the existing saliva analysis methods, this method has the advantage of simple, fast and low cost. It might be applied in non-invasive disease diagnosis.


Assuntos
Saliva , Sequência de Aminoácidos , Histatinas , Histidina , Proteínas e Peptídeos Salivares
6.
Ying Yong Sheng Tai Xue Bao ; 27(10): 3335-3343, 2016 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-29726161

RESUMO

According to the theory of system science, the paper took 12 central cities in Gansu Province as an example, and respectively built the quality assessment index system of population urbanization and land urbanization on the basis of scientific definition of the quality of population urbanization and land urbanization. Then the coupled coordination model was introduced to calculate the comprehensive development index and coupling coordination degree between quality of population urbanization and land urbanization by the dimension of time and space during 2005-2013. The results showed that population urbanization and land urbanization could only represent the speed of urbanization, it could not measure the quality of urbanization. Single index could only represent the urbanization development level in the narrow sense. Observed in time sequence, the quality and coupling coordination level of land and population urbanization in Gansu Province showed an overall rising trend. In general, the poorly intensive utilization of land resources was still the key factor restricting the quality of urbanization in Gansu Province. From the point of spatial pattern, in 2013, the quality of land urbanization lagged behind the quality of population urbanization to varying degrees in 11 central cities except Lanzhou, which belonged to the population urbanization lagging type. The urbanization quality of 12 central cities in Gansu Province was at an overall low coordinating stage.


Assuntos
Cidades , Urbanização , China , Humanos , Densidade Demográfica , Análise Espaço-Temporal
7.
Acta Neurol Belg ; 116(3): 287-93, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26615535

RESUMO

Vertebral artery dominance (VAD), which is a common congenital variation of vertebral artery, may be associated with an increased risk of cerebral posterior circulation infarction (PCI). The aims of this study were to investigate the correlation of VAD with incidence and laterality of PCI, and oblige the correlation of VAD and basilar artery (BA) curvature. Incidence of separate territory infarction in posterior circulation and incidence of BA curvature were compared between 78 VAD patients and 68 controls. VA dominance, laterality of BA curvature and separate territory infarction, and their directional relationships were observed in VAD group. The incidence of BA curvature in VAD group was significantly higher than that in controls (P = 0.000). 89.7 % (35/39) of patients had an opposite directional relationship between dominant VA and BA curvature. The total incidence of PCI in VAD group was significantly higher than that in controls (P = 0.001). The incidences of posterior inferior cerebellar artery (PICA) and BA territory infarction were both significantly higher than those in controls [11.5 % (9/78) vs. 1.5 % (1/68), P = 0.016; 20.5 % (16/78) vs. 7.4 % (5/68), P = 0.024]. No differences were found in superior cerebellar artery and posterior cerebral artery territory infarction between two groups. 77.8 % (7/9) of PICA infarction were on the opposite side of dominant VA. 75.0 % (12/16) of BA infarction were on the side of dominant VA. The incidence of PCI in BA curvature patients was significantly higher than that in BA straight patients. The incidence of BA curvature is higher in VAD patients, and BA usually bends to the opposite side of dominant VA. The incidence of PCI is higher in VAD patients, especially in PICA infarction and BA infarction patients.


Assuntos
Artéria Basilar/diagnóstico por imagem , Infarto Encefálico/etiologia , Angiografia Cerebral , Circulação Cerebrovascular/fisiologia , Imagem por Ressonância Magnética , Artéria Vertebral/diagnóstico por imagem , Adulto , Idoso , Infarto Encefálico/fisiopatologia , Cerebelo/irrigação sanguínea , Angiografia Cerebral/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
World J Gastroenterol ; 21(27): 8262-70, 2015 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-26217078

RESUMO

Liver cancer, a large proportion of which is hepatocellular carcinoma (HCC), is diagnosed in more than 700000 people each year worldwide. Liver cancer is particularly prevalent in Asia, Sub-Saharan Africa and the South Pacific, where hepatitis B and hepatitis C infection rates are very high. However, due to resistance to chemotherapy, patients with intermediate and advanced-stage disease cannot benefit from this treatment. Clusterin, which is overexpressed in many different cancers, is a stress-induced cytoprotective protein that confers treatment resistance. Custirsen (OGX-011) is a novel 2'-methoxyethyl modified phosphorothioate antisense oligonucleotide that targets secretory clusterin protein expression and is currently in clinical trials for patients with different cancers. In recent years, a number of different clinical trials have been performed, and two phase III clinical trials of custirsen evaluating combinations with chemotherapy in patients with metastatic castration-resistant prostate cancer and metastatic non-small cell lung cancer are currently in progress. The aims of this review are to summarize the current state of research on clusterin, predict future research directions and analyze the potential of the clinical application of custirsen in HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Clusterina/metabolismo , Neoplasias Hepáticas/metabolismo , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Clusterina/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Oligonucleotídeos Antissenso/uso terapêutico , Transdução de Sinais , Tionucleotídeos/uso terapêutico , Resultado do Tratamento
9.
Mol Med Rep ; 11(5): 3499-504, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25572981

RESUMO

The cysteine protease cathepsin B (Cat B) is important in the progression of tumor cells, however, the function and molecular mechanisms of Cat B in hepatocellular carcinoma (HCC) remain to be elucidated. Our previous study demonstrated that integrin αvß3 regulated the biological behavior of HCC. The present study demonstrated that Cat B was also important in cell proliferation and apoptosis in HCC. Notably, Cat B was observed to activate the phosphoinositide 3­kinase (PI3K)/Akt signaling pathway to promote HCC proliferation. Furthermore, inhibition of integrin αvß3 significantly prevented Cat B­induced activation of PI3K/Akt and the progression of HCC. Thus, the results of the present study suggested the presence of a Cat B/integrin αvß3/PI3K/Akt axis in the regulation of the progression of HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Catepsina B/metabolismo , Integrina alfaVbeta3/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Animais , Carcinoma Hepatocelular/genética , Catepsina B/genética , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Expressão Gênica , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Integrina alfaVbeta3/genética , Neoplasias Hepáticas/genética , Camundongos
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