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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(2): 339-347, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-30998135

RESUMO

OBJECTIVE: To investigate the correlation of E-cadherin expression level with the clinical characterastics in children with acute leukemia (AL), and to explore the possible regulatory mechanism. METHODS: Real-time quantitative RT-PCR was applied to detect the expression level of E-cadherin in bone marrow samples from 135 child patients diagnosed as AL, and its relevance with clinical indicators was statistically analyzed. The expression levels of E-cadherin, ß-catenin, and Akt/p-Akt were detected by using Western blot. The bone marrow samples from 22 children with non-malignant hematological diseases were used as controls. RESULTS: The expression level of E-cadherin significantly decreased in newly diagnosed patients with all 3 types of AL as compared with bone marrow samples from control group (P<0.01). In B-ALL group, compared with standard risk group, E-cadherin expression level significantly decreased in intermediate risk group (P<0.05). Moreover,the expression level of E-cadherin mRNA was also reduced in splenomegaly group (P<0.01). However, the correlation of E-cadherin level with clinical characteristics was not found in T-ALL and AML (P>0.05). The expression level of E-cadherin in the patients from Common-B-ALL group was higher than B-ALL patients with other immunophenotypes (P<0.01), while no significant difference was found among patients grouped by FAB classification. By the correlation analysis of measured data, lower E-cadherin expression level was found to be related with high WBC count and serum lactic dehydrogenase level (LDH) (r=-0.419, r=-0.269), but with low blood platelet count in B-ALL (r=0.335). In T-ALL, expression of E-cadherin was found to be negatively correlated with LDH and percentage of immature cells in the bone marrow (r=-0.567, r=-0.557). In addition, the lower expression of E-cadherin was also found to be related with WBC count and percentage of immature cells in the bone marrow in newly diagnosed AML patients (r=-0.368, r=-0.391). Compared with control group, the expression of E-cadherin was down-regulated significantly (P<0.01), while ß-catenin, Akt significantly was up-regulated in 3 types of AL patients (P<0.01). The expression of p-Akt and p-Akt/Akt was up-regulated significantly in T-ALL (P<0.01). CONCLUSION: Lower expression of E-cadherin is related factor of unfavourable prognosis in children with acute leukemia. The expression deficiency or down-regulation of E-cadherin may activate Wnt/ß-catenin and PI3K/ Akt signaling pathways to promote the genesis and progress of haematological malignancies, thus resulting in a series of malignant biological behaviors in cells. E-cadherin may be a new prognostic indicator for pediatric acute leukemia, thus to guide individualized hemotherapy.


Assuntos
Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Medula Óssea , Caderinas , Criança , Humanos
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 26(1): 65-69, 2018 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-29397820

RESUMO

OBJECTIVE: To investigate the effect of 4' -hydroxywogonin on proliferation and apoptosis of human acute lymphoblastic leukemia SUP-B15 and Jurkat cells, and to analyze its possible mechanism. METHODS: SUP-B15 and Jurkat cells were cultivated in vitro and treated with different concentrations of 4' -hydroxywogonin, the inhibitory effect of 4' -hydroxywogonin on the proliferation of SUP-B15 and Jurkat cells was detected by CCK-8 method; the cell apoptosis was examined by the flow cytometry with Annexin V-APC/7-AAD donble staining; the expression of C-MYC, BCL-2 and cleaved caspase 3 in SUP-B15 and Jurkat cells were measured with Western blot. RESULTS: 4' -hydroxywogonin inhibited the proliferation of SUP-B15 and Jurkat cells in a dose-dependent manner (r=0.78, r=0.89), with IC50 value of (6.32± 0.53) µg/ml in SUP-B15 cells and (12.04± 0.42) µg/ml in Jurkat cells at 24 h. The early apoptotic rate of cell was also enhanced with the increase of 4' -hydroxywogonin concentrations. The results of Western blot showed that 4' -hydroxywogonin could down-regulate the expression of proliferation-related molecule C-MYC(P<0.01) and apoptosis-related molecule BCL-2(P<0.01), the expression of apoptosis-related molecule cleaved caspase 3 was up-regulate(P<0.01). CONCLUSION: 4' -hydroxywogonin shows the effects of anti-tumor by inducing cell apoptosis and inhibiting cell proliferation, its molecular mechanism maybe relate with down-regulation of C-MYC and BCL-2 expression and up-regulation of the cleaved caspase 3 expression.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Flavanonas , Humanos , Células Jurkat
3.
Zhongguo Dang Dai Er Ke Za Zhi ; 19(6): 620-626, 2017 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-28606226

RESUMO

OBJECTIVE: To study the expression of ß-integrin family members in children with T-cell acute lymphoblastic leukemia (T-ALL) and their significance. METHODS: Quantitative real-time PCR analyses were performed to assess the expression levels of ß-integrin family members in bone marrow samples from 22 children with newly-diagnosed T-ALL and 21 controls (16 children with non-malignant hematologic disease and 5 healthy donors with bone marrow transplantation). Jurkat cells were treated with integrin inhibitor arginine-glycine-aspartate (Arg-Gly-Asp, RGD) peptide. The cell viability and apoptosis rate were determined by CCK8 assay and flow cytometry respectively. RESULTS: The mRNA levels of integrins ß2, ß3, and ß5 were significantly lower in children with T-ALL than in controls (P<0.05). In T-ALL patients, high integrin ß3 expression was associated with lower white blood cell counts (<100×109/L), minimal residual disease (MRD) positivity, and day 33 bone marrow negative remission (P<0.05). In T-ALL patients, higher integrin ß5 expression was associated with relapse of T-ALL (P<0.05). Based on survival curve analysis, higher integrin ß3 expression was related to lower event-free survival and overall survival rates. RGD peptide treatment inhibited the proliferation of Jurkat cells and increased their apoptosis rate (P<0.05). CONCLUSIONS: ß-Integrin may play a role in the occurrence and development of T-ALL by affecting cell proliferation and apoptosis. The expression of integrin ß5 is closely related to the risk of relapse of T-ALL. The expression of integrin ß3 is closely related the treatment response and prognosis of T-ALL.


Assuntos
Cadeias beta de Integrinas/fisiologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Criança , Pré-Escolar , Feminino , Humanos , Cadeias beta de Integrinas/genética , Células Jurkat , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , RNA Mensageiro/análise
4.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 25(2): 311-317, 2017 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-28446267

RESUMO

OBJECTIVE: To investigate the correlation between the expression level of PRPS1 and the clinical characteristics in children with acute leukemia(AL). METHODS: Real-time quantitative RT-PCR and Western blot were used to detect the level of PRPS1 mRNA and protein expression in bone marrow samples from 176 patients diagnosed as AL (126 cases were newly diagnosed and 50 cases in complete remission), and its relevance with clinical indicators was statistically analyzed. The bone marrow samples from 21 children with non-malignant hematological disease were used as controls. RESULTS: (1)In B-ALL group, the level of PRPS1 mRNA in newly diagnosed patients were significantly higher than that in control and than that in complete remission patients (both P<0.0001). In T-ALL and AML group, differences was only observed between newly diagnosed patients and complete remission patients(both P<0.0001); (2)In B-ALL group, the expression level of PRPS1 increase with along risk enhancement (P<0.01), while no significant difference was observed in T-ALL (P>0.05). In AML patients, expression difference was shown between low risk group and high risk group(P<0.05); (3)High PRPS1 mRNA expression level were associated with high WBC counts and MRD positive in B-ALL patients (P=0.020, P=0.026, respectively); (4)Expression of NT5C2, an essential gene for relapse and drug resistance, was found to be positively correlated with PRPS1 expression in AL samples(P<0.05). CONCLUSION: High expression of PRPS1 is relevant factor of unfavourable prognosis in B-ALL children, which suggest PRPS1 may be a new indicator for prognosis of pediatric B-ALL and an index to guide individualized chemotherapy.


Assuntos
Leucemia Mieloide Aguda/metabolismo , Ribose-Fosfato Pirofosfoquinase/metabolismo , Medula Óssea/metabolismo , Criança , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Prognóstico , Indução de Remissão
5.
Eur Heart J ; 38(18): 1389-1398, 2017 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-27099261

RESUMO

Aims: Oxidative stress contributes to the development of cardiac hypertrophy and heart failure. One of the mitochondrial sirtuins, Sirt4, is highly expressed in the heart, but its function remains unknown. The aim of the present study was to investigate the role of Sirt4 in the pathogenesis of pathological cardiac hypertrophy and the molecular mechanism by which Sirt4 regulates mitochondrial oxidative stress. Methods and results: Male C57BL/6 Sirt4 knockout mice, transgenic (Tg) mice exhibiting cardiac-specific overexpression of Sirt4 (Sirt4-Tg) and their respective controls were treated with angiotensin II (Ang II, 1.1 mg/kg/day). At 4 weeks, hypertrophic growth of cardiomyocytes, fibrosis and cardiac function were analysed. Sirt4 deficiency conferred resistance to Ang II infusion by significantly suppressing hypertrophic growth, and the deposition of fibrosis. In Sirt4-Tg mice, aggravated hypertrophy and reduced cardiac function were observed compared with non-Tg mice following Ang II treatment. Mechanistically, Sirt4 inhibited the binding of manganese superoxide dismutase (MnSOD) to Sirt3, another member of the mitochondrial sirtuins, and increased MnSOD acetylation levels to reduce its activity, resulting in elevated reactive oxygen species (ROS) accumulation upon Ang II stimulation. Furthermore, inhibition of ROS with manganese 5, 10, 15, 20-tetrakis-(4-benzoic acid) porphyrin, a mimetic of SOD, blocked the Sirt4-mediated aggravation of the hypertrophic response in Ang II-treated Sirt4-Tg mice. Conclusions: Sirt4 promotes hypertrophic growth, the generation of fibrosis and cardiac dysfunction by increasing ROS levels upon pathological stimulation. These findings reveal a role of Sirt4 in pathological cardiac hypertrophy, providing a new potential therapeutic strategy for this disease.


Assuntos
Cardiomegalia/enzimologia , Proteínas Mitocondriais/fisiologia , Sirtuínas/fisiologia , Superóxido Dismutase/antagonistas & inibidores , Angiotensina II/farmacologia , Animais , Técnicas de Silenciamento de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias Cardíacas/enzimologia , Miócitos Cardíacos/enzimologia , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Remodelação Vascular/fisiologia , Vasoconstritores/farmacologia
6.
Oncotarget ; 7(17): 24719-33, 2016 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-27034160

RESUMO

The axon guidance factor netrin-1 promotes tumorigenesis in multiple types of cancers, particularly at their advanced stages. Here, we investigate whether netrin-1 is involved in the in vivo growth of pancreatic adenocarcinoma. We show that netrin-1 is significantly under-expressed in stage-I/II pancreatic ductal adenocarcinoma (PDAC). Netrin-1 over-expression effectively arrests the growth of xenografted PDAC cells without decreasing cell proliferation or increasing apoptosis in two-dimensional cultures in vitro. Integrin-beta4 (ITGB4) expression is significantly reduced, and ITGB4-knockdown mimics the tumor-suppressive effect of netrin-1, implying that ITGB4 is a main target of netrin-1 in constraining PDAC. We further show that netrin-1 signals to UNC5B/FAK to stimulate nitric oxide production, which promotes PP2A-mediated inhibition of the MEK/ERK pathway and decreases phosphorylated-c-Jun recruitment to the ITGB4 promoter. Our findings suggest that netrin-1 can suppress the growth of PDAC and provide a mechanistic insight into this suppression.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/genética , Integrina beta4/metabolismo , Sistema de Sinalização das MAP Quinases , Netrina-1/metabolismo , Neoplasias Pancreáticas/metabolismo , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Embrião de Galinha , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HEK293 , Xenoenxertos , Humanos , Camundongos , Netrina-1/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia
7.
Antioxid Redox Signal ; 21(12): 1693-707, 2014 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-24555791

RESUMO

AIMS: Mitofilin was originally described as a heart muscle protein because of its abundance in the heart tissue; however, its function in the heart is still to be elucidated. Thus, this study aims at investigating the role of mitofilin in the heart in response to hypertrophic stimuli. RESULTS: In this study, a significant increase in mitofilin expression was observed in the hearts of patients with hypertrophic cardiomyopathy. Transgenic (TG) mice with cardiomyocyte-specific overexpression of mitofilin were generated, and cardiac hypertrophy was introduced by transverse aortic constriction (TAC) or chronic infusion of isoproterenol (ISO). In TG mice overexpressing mitofilin, the level of cardiac hypertrophy was significantly greater than that in wild-type (WT) mice after TAC and ISO stimulation. A detailed analysis showed that compared with WT mice, the level of reactive oxygen species was increased after TAC and ISO induction and mitochondrial oxidative phosphorylation (OXPHOS) activity in the TG hearts was lower. These alterations may contribute to the aggravated cardiac hypertrophy observed in response to TAC and ISO stimulation. CONCLUSION: Over-expression of mitofilin promotes cardiac hypertrophy under pathological conditions both in vivo and in vitro. INNOVATION: Mitofilin, a mitochondria protein, is shown to be related to cardiac hypertrophy for the first time, which enhances our understanding of the role of mitochondria in cardiac hypertrophy.


Assuntos
Cardiomegalia/metabolismo , Constrição Patológica/metabolismo , Coração/efeitos dos fármacos , Coração/fisiopatologia , Isoproterenol/farmacologia , Proteínas Mitocondriais/biossíntese , Proteínas Musculares/biossíntese , Animais , Humanos , Isoproterenol/administração & dosagem , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Mitocondriais/metabolismo , Proteínas Musculares/metabolismo , Ratos , Ratos Sprague-Dawley
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