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BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a potential therapeutic target in acute coronary syndromes. Although recent evidence does not support the routine use of manual thrombus aspiration (TA) in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI), the use of TA is associated with a significant improvement in myocardial reperfusion, especially in patients with high thrombus burden (HTB). We hypothesized that TA would reduce the serum Lp-PLA2 levels in STEMI patients undergoing PPCI with HTB. METHODS AND RESULTS: Our study cohort included 320 consecutive STEMI patients undergoing PPCI with HTB who were randomly assigned to receive either TA before PPCI (TA group, n = 160) or PPCI alone (standard PPCI group, n = 160). The baseline characteristics of study participants were well-matched. After 30 ± 2 days, serum Lp-PLA2 levels decreased by 53.9% in the TA group (152.9 ± 58.1 ng/mL) and decreased by 31.2% in the standard PPCI group (84.2 ± 86.6 ng/mL, p < 0.001). The TA group had a significantly lower prevalence of balloon predilatation, number of stents used, total stent length and corrected thrombolysis in myocardial infarction frame count, and a higher percentage of myocardial blush grade ≥ 2 compared with the standard PPCI group (all p < 0.001). No significant difference between the groups was observed in 30 ± 2 days for major adverse cardiovascular and cerebrovascular events (p = 0.702). CONCLUSIONS: After 30 ± 2 days of treatment, TA may significantly reduce serum levels of Lp-PLA2 in STEMI patients undergoing PPCI with HTB.
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BACKGROUND: The implementation of the rotation system in the Chinese medical industry has achieved significant results. OBJECTIVES: The present study aims to 1) explore the strengths, weaknesses, opportunities and challenges of rotational nursing department implementation and 2) provide references for developing nursing staff's competencies in leadership, performance evaluation, quality of care, communication in relationships and human resources. METHODS: A total of 16 rotational nursing department staff members from a tertiary tuberculosis specialist hospital in Beijing were interviewed, and the interview data were analysed using a strengths, weaknesses, opportunities and threats analysis and class analysis. RESULTS: The advantages of the rotational nursing department included: (1) stimulating the nursing staff's enthusiasm and creativity; (2) strengthening the communication and collaboration between departments; (3) improving the detailed management of nursing quality; and (4) enhancing the nursing staff's comprehensive abilities. The disadvantages included: (1) the design of the rotation programme focusing on practice; (2) a lack of personalisation; and (3) imperfect performance assessment of the rotating staff. Opportunities included: (1) deepening the connotation of nursing job management and (2) developing the construction of nursing discipline and the need for personal career development and value realisation. Threats included the lack of a sound rotation management model to draw on. CONCLUSION: A rotational nursing department is conducive to enhancing the competence of nursing staff in management positions and providing new ideas for hospitals to select and train nursing management talents. By taking full advantage of the benefits of vertical nursing management, designing personalised rotation training programmes, building a diversified learning and training platform and developing a positive performance incentive mechanism is recommended to fully engage the role of rotation in nursing management talent training.
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Recursos Humanos de Enfermagem Hospitalar , Humanos , Recursos Humanos de Enfermagem Hospitalar/educação , Liderança , Competência Clínica , China , Feminino , Qualidade da Assistência à Saúde , MasculinoRESUMO
OBJECTIVE: To observe the expression variations and influencing factors of programmed death one (PD-1) and DNA demethylation of PD-1 promoter on peripheral blood mononuclear cells (PBMCs) in chronic hepatitis B (CHB) patients and further investigate the relationship between the demethylation pattern of PD-1 gene in promoter region and the PD-1 expression on PBMC in CHB patients. METHODS: A total of 162 subjects, including 144 CHB patients and 18 healthy blood donors, were enrolled. The expression of PD-1 on PBMCs was detected by flow cytometry. And the serum HBV markers, HBV DNA load and liver function were also measured. DNA of PBMCs was treated with sodium bisulfite; the PD-1 promoter fragments were amplified by polymerase chain reaction (PCR) and then transformed into Escherichia coli. Positive clones were selected for sequencing and the methylation status of fragments of PD-1 promoter was examined. RESULTS: With the PD-1 expression in normal controls (10.8% ± 4.4%) as a baseline level, the expression of PD-1 in CHB patients significantly increased. In CHB patients, the serum expression of PD-1 in PBMCs from patients with positive HBeAg (27.1% ± 18.4%) was much higher than that from those with negative HBeAg (19.6% ± 15.6%). And the expression level of PD-1 was not correlated with serum HBV DNA load and serum level of alanine aminotransferase. The results of bisulfite genomic sequencing showed that demethylation probability of some CG points in PD-1 promoter region (-601, -553, -538, -483, -463, -317 bp) were significantly correlated with PD-1 expression level (P < 0.05). CONCLUSION: The demethylation pattern of PD-1 gene in promoter region is associated with the PD-1 expression on PBMC in CHB patients.
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Hepatite B Crônica/sangue , Leucócitos Mononucleares/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Adulto , Estudos de Casos e Controles , Metilação de DNA , DNA Viral/sangue , Feminino , Humanos , Masculino , Receptor de Morte Celular Programada 1/genética , Regiões Promotoras Genéticas , Adulto JovemRESUMO
OBJECTIVE: To investigate the dynamic changes in expression of programmed death (PD)-1, Toll-like receptor (TLR)3, and TLR4 on the surface of peripheral blood mononuclear cells (PBMCs) in patients with chronic hepatitis C (CHC) that occur in response to pegylated-interferon alpha-2a (peg-IFNalpha-2a) plus ribavirin (RBV) combination therapy, and to analyze the relation to achievement of sustained virological response (SVR). METHODS Twenty-three CHC patients and 10 healthy controls were enrolled in the study. All CHC patients underwent 48 weeks of combination therapy with peg-IFNalpha-2a (180 microg, subcutaneous injection, once weekly) plus RBV (15 microg/kg, oral, once daily). Total PBMCs were isolated from both groups (CHC patients at treatment week 0, 12, 24, and 48 and post-treatment week 24; controls at enrollment) and subjected to flow cytometric analysis of PD-1, TLR3, and TLR4 surface expression. In addition, serum levels of alanine aminotransferase (ALT) and hepatitis C virus (HCV) RNA levels were analyzed by enzymatic assay and the AmpliPrep/COBAS (Roche) nucleic acid amplification test, respectively. SVR was defined as undetectable levels of HCV RNA at post-treatment week 24. Intergroup differences were assessed by one-way ANOVA. RESULTS: The expression ratios of PD-1, TLR4 and PD-1: TLR4 on PBMCs were significantly higher in CHC patients before therapy than in the healthy controls (45.20 +/- 7.12% vs. 16.82 +/- 4.13%, 58.45 +/- 15.13% vs. 21.09 +/- 2.89%, and 35.54 +/- 7.69% vs. 14.12 +/- 2.89%; all P < 0.05). In contrast, the expression ratios of TLR3 and PD-1:TLR3 were slightly, but not significantly, higher in CHC patients before therapy than in the healthy controls (P > 0.05). During the course of peg-IFNalpha-2a plus RBV combination therapy, the expression ratios of PD-1 and TLR4 on PBMCs showed a decreasing trend, while TLR3 expression showed an increasing trend. Furthermore, CHB patients who achieved SVR at post-treatment week 24 had a significantly different expression ratio of PD-1 and TLR3 than those who did not achieve SVR (P < 0.05). CONCLUSION: Surface expression of PD-1, TLR4, and PD-1:TLR4 is up-regulated in the total PBMCs of CHC patients. Peg-IFNalpha-2a plus RBV treatment-induced suppression of HCV replication results in a significant reduction in PD-1 and TLR4 expression on the surface of PBMCs, but a remarkably elevated level of TLR3 expression. The dynamic change in PD-1 and TLR3 expression on PBMCs that occurs during antiviral therapy may be related to achievement of SVR.
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Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/metabolismo , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Estudos de Casos e Controles , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Recombinantes/uso terapêutico , Receptor 3 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Resultado do Tratamento , Adulto JovemAssuntos
Leucemia Promielocítica Aguda/genética , Proteínas Mutantes Quiméricas/genética , Receptores do Ácido Retinoico/genética , Fatores de Transcrição TFII/genética , Translocação Genética , Adulto , Sequência de Aminoácidos , Antineoplásicos/uso terapêutico , Sequência de Bases , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 7/genética , Resistencia a Medicamentos Antineoplásicos/genética , Evolução Fatal , Humanos , Cariótipo , Masculino , Dados de Sequência Molecular , Proteínas de Neoplasias/genética , Receptor alfa de Ácido Retinoico , Tretinoína/uso terapêuticoRESUMO
OBJECTIVE: Based on the 2002 WHO health survey data, to explore the latent relationship among self-reported health level, the actual level of health, the social demographic characteristics and the risk factors, and to analyze the influence of the various surveillance indicators on self-reported health and the degree that the self-reported health explained the actual level of health. METHODS: Field tests for various components of the World health survey were conducted in nine countries during 2002, including India, Brazil, Burkina, Hungary, Nepal, Russia, Spain, Tunisia, and Vietnam (29 971). The survey questionnaire included a self-assessment component and anchoring vignette component. The self-assessment component data was adjusted and eliminated the affect of "cut-point bias" by using the anchoring vignette component data, and then was used to build the structural equation model on the relationship among self-reported health level, actual health level, social demographic characteristics and the risk factors. RESULTS: In the final structural equation model, "the actual level of health" = 0.80 × "the self-reported health level" + (-0.04) × "the social demographic characteristics" + (-0.08) × "the risk factors" (R(2) = 0.66), and "the self-reported health level" = (-0.70) × "the social demographic characteristics" + 0.10 × "the risk factors" (R(2) = 0.55). The standardized total effect of self-reported health to the actual level of health was 0.80, and that of the social demographic characteristics to the self-reported health and the actual level of health were -0.70 and -0.60, respectively. And the 16 items of self-reported health consisted of 8 dimensions; and sorted by the power of impact to the actual health level, they were mobility, pain and discomfort, sleep, cognition, feelings, self-care ability, visual capacity and interpersonal activities. CONCLUSION: There were significant linear correlation relationship between the actual level of health and the self-reported health, as well as between the self-reported health and the social demographic characteristics. And the self-reported 16 items used by the 2002 WHO health survey played an important role in the health evaluation of population.
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Nível de Saúde , Inquéritos Epidemiológicos , Modelos Estatísticos , Demografia , Humanos , Fatores de Risco , Autorrelato , Inquéritos e Questionários , Organização Mundial da SaúdeRESUMO
A series of novel 4-(4-(5-methyl-3-arylisoxazol-4-yl)thiazol-2-yl)piperidyl carboxamides and thiocarboxamides were synthesized as potential lead compounds of inhibitors targeting D1 protease in plants. These compounds were designed on the basis of a D1 protease inhibitor hit structure identified by homology modeling and virtual screening. The syntheses of these compounds were accomplished via a four-step procedure including the isoxazole ring formation, alpha-bromination of acetyl group, thiazole ring formation, and carboxamide/thiocarboxamide attachment. The in vivo herbicidal activity tests show that most compounds possess moderate to good herbicidal activities. The enzyme activity of one compound against the native spinach D1 protease exhibits a competitive inhibition. The results suggest that these compounds are indeed potential inhibitors for targeting D1 protease in plants.
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Herbicidas/síntese química , Piperidinas/síntese química , Proteínas de Plantas/antagonistas & inibidores , Inibidores de Proteases/síntese química , Ligação Competitiva , Simulação por Computador , Herbicidas/farmacologia , Isoxazóis , Modelos Moleculares , Piperidinas/farmacologia , Inibidores de Proteases/farmacologia , Spinacia oleracea/enzimologia , TiazóisRESUMO
5-Aryl-4-cyano-1H-1, 2, 3-triazoles bearing a variety of substituting groups on 5-phenyl were synthesized. Their structures were established by MS, IR and 1H NMR spectra. The crystal structures of compounds 3f and 3m were determined by X-ray diffraction analysis. The active H of the triazole was on 1-N from the crystal structures. The compounds, designed as HER2 tyrosine kinase inhibitors, were screened for bioactivity of growth-inhibition of breast cancer MDA-MB-453 cells. The lowest IC50 value of inhibiting HER2 tyrosine kinase phosphorylation in breast cancer cells is 6.6 micromol x L(-1). The inhibiting-growth of breast cancer cells was enhanced from electron-drawing groups joining 5-phenyl on the triazole.
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Neoplasias da Mama/patologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Triazóis/síntese química , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalização , Cristalografia por Raios X , Feminino , Humanos , Fosforilação , Proteínas Tirosina Quinases/metabolismo , Receptor ErbB-2/metabolismo , Triazóis/química , Triazóis/farmacologiaRESUMO
OBJECTIVE: To investigate the relationship between the polymorphism of TET2 gene SNP rs3733609 and JAK2V617F allele burden in patients with myeloproliferative neoplasms (MPN). METHODS: The exon 9 of TET2 gene was amplified by RT-PCR, and the nucleotide sequence of SNP rs3733609 site was analyzed by gene sequencing. The MGB Taqman probe PCR method was used to detect the JAK2V617F allele burden. The correlation of TET2 gene SNP rs3733609 C/T with the JAK2V617F allele burden and clinical parameters was analyzed. RESULTS: TET2 gene rs3733609 C/T heterozygosity (normal T/T) could be detected in 19 cases of 85 cases of JAK2V617F positive MPN (22.4%) patients, while the TET2 gene rs3733609 C/T heterozygosity could be detected only in 9 of the 106 healthy volunteers, and the incidence was only 8.5% (9/106). Compared with the negative group (TET2 rs3733609 T/T), there was no significant difference in the median age, hemoglobin level and platelet count in the patients with TET2 gene SNP rs3733609 (CT/TC) positive, but the WBC count of peripheral blood and JAK2V617F allele burden significantly increased. In JAK2V617F high allele burden group, TET2 gene SNP rs3733609 was positive in 7 cases (36.8%, 7/19), the ratio was higher than that in the low allele burden group(18.2%, 12/66). CONCLUSION: TET2 SNP rs3733609 C/T may be a new susceptible allelee, which affects the clinical characteristics and clonal evolution of MPN patients.
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Proteínas de Ligação a DNA/genética , Janus Quinase 2/genética , Transtornos Mieloproliferativos , Proteínas Proto-Oncogênicas/genética , Alelos , Dioxigenases , Éxons , Humanos , Mutação , Transtornos Mieloproliferativos/genética , NeoplasiasRESUMO
Epstein-Barr virus (EBV) infection in tumor cells is generally restricted to the latent forms of viral infection. Switching the latent form of viral infection into the lytic form may induce tumor cell death. High levels of nuclear factor (NF)-kappaB can inhibit EBV lytic replication, and aspirin has the ability to inhibit NF-kappaB activity. The aims of the current study were to determine the effects of aspirin on inducing EBV lytic infection, and thus to reveal the possibility of targeting EBV-positive cancer cells by aspirin. Our results showed that aspirin depleted NF-kappaB (p65) in the nucleus and reactivated EBV into lytic replication. Cells exhibited decreased viability in a dose- and time-dependent manner when incubated with aspirin. When ganciclovir was used in combination with aspirin to treat EBV-positive B95.8 cells and Raji cells, the cytotoxic effect of aspirin was amplified. We demonstrated that aspirin reduced the viability of EBV-positive B lymphocytes due to its ability to induce EBV lytic replication.
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Antineoplásicos/farmacologia , Aspirina/farmacologia , Linfócitos B/efeitos dos fármacos , Linfoma de Burkitt/patologia , Herpesvirus Humano 4/efeitos dos fármacos , Latência Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Transporte Ativo do Núcleo Celular , Animais , Apoptose/efeitos dos fármacos , Linfócitos B/patologia , Linfócitos B/virologia , Linfoma de Burkitt/virologia , Callithrix , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Efeito Citopatogênico Viral/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo , Ganciclovir/farmacologia , Herpesvirus Humano 4/crescimento & desenvolvimento , Herpesvirus Humano 4/patogenicidade , Humanos , Fatores de Tempo , Fator de Transcrição RelA/metabolismoAssuntos
Substituição de Aminoácidos , Proteínas de Fusão bcr-abl , Janus Quinase 2/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação de Sentido Incorreto , RNA Mensageiro , RNA Neoplásico , Idoso , Povo Asiático , China , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To explore the mRNA expression of Aurora-A,B,C(AUR-A,B,C) in acute leukemia(AL) and their correlations with the clinical indications. METHODS: The mRNA expression levels of AUR-A,B,C in 73 cases of newly diagnosed AL (untreated group), 20 cases of AL with remission (remission group) and 14 healthy volunteers as control (healthy group) were detected by QRT-PCR, and the difference of expression levels in difference groups, their correlations with clinical indicators and the correlation between the AUR-A,B,C mRNA expression levels themselves were analyzed. RESULTS: The mRNA expression levels of AUR-A,B,C in untreated group were all higher than those in healthy group and remission group(P<0.01), but there was not significant difference between healthy group and remission group(P>0.05); the mRNA expressions of AUR-A,B,C in acute lymphoblastic leukemia(ALL) group were all significantly higher than that in AML group(P<0.01). The mRNA expression of AUR-A,B,C in high risk group was higher than that in low risk group(P<0.05), but there was no difference in mRNA expression of AUR-A,B,C between high risk group and middle risk group as well as between middle risk group and low risk group(P>0.05). The mRNA expression of AUR-A, B, C in CD34, CD71 and CD56 negative group was not statistically different from that in CD34,CD71 and CD56 positive group(P>0.05). In 73 cases of newly diagnosed AL, the mRNA expression levels of AUR-A, B significantly were positively correlated with lactate dehydrogenase(LDH) level and risk stratification (r=0.279, P=0.017; r=0.314, P=0.007 and r=0.277, P=0.018; r=0.349, P=0.002), while the mRNA expression levels of AUR-A, B were not significantly correlated with age, WBC count, blast ratio in bone marrow at initial diagnosis and remission or no-remission after 1 cours of chemotherapy; the mRNA expression level of AUR-C was significantly positively correlated with WBC count (r=0.263, P=0.025), and LDH level (r=0.348, P=0.003) at initial diagnosis and risk stratificantion(r=0.376, P=0.001), and negatively correlated with age (r=-0.241, P=0.040), and was not significantly correlated with blast ratio in bone marrow at initial diagnosis and remission or noremission after 1 course of chemotherapy. There were significant positive correlations in the mRNA expression between AUR-A and B (r=0.444, P=0.000), AUR-B and C (r=0.763, P=0.000) as well as AUR-A and C (r=0.616, P=0.000). CONCLUSION: Aur-A, B, C mRNA were highly expressed in patients with newly diagnosed AL, moreover the mRNA expression levels of Aur-A,B,C were positively correlated with each other, the high expression of Aur-A, B, C are associated with leukemia types, risk stratification, WBC count and LDH level at initial diagnosis, so they all maybe used as the prognostic markers and potential therapeutic targets.
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Aurora Quinase A/genética , Aurora Quinase B/genética , Aurora Quinase C/genética , Leucemia Mieloide Aguda/genética , Doença Aguda , Medula Óssea , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , RNA Mensageiro/metabolismoRESUMO
Common germline single-nucleotide polymorphisms (SNPs) at JAK2 locus have been associated with Myeloproliferative neoplasms (MPN). And, the germline sequence variant rs2736100 C in TERT is related to risk of MPN, suggesting a complex association between SNPs and the pathogenesis of MPN. Our previous study (unpublished data) showed that there was a high frequency distribution in rs3733609 C/T genotype at Ten-Eleven Translocation 2 (TET2) locus in one Chinese familial primary myelofibrosis. In the present study, we evaluate the role and clinical significance of rs3733609 C/T genotype in JAK2V617F-positive sporadic MPN (n = 181). TET2 rs3733609 C/T genotype had a higher incidence (13.81%; 25/181) in JAK2V617F-positive sporadic MPN patients than that in normal controls (n = 236) (6.35%; 15/236), which was predisposing to MPN (odds ratio(OR) = 2.361; P = 0.01). MPN patients with rs3733609 C/T genotype had increased leukocyte and platelets counts, elevated hemoglobin concentration in comparison with T/T genotype. Thrombotic events were more common in MPN patients with rs3733609 C/T than those with T/T genotype (P < 0.01). We confirmed that rs3733609 C/T genotype downregulated TET2 mRNA transcription, and the mechanism may be involved in a disruption of the interaction between CCAAT/enhancer binding protein alpha (C/EBPA) and TET2 rs3733609 C/T locus.TET2 rs3733609 C/T genotype stimulated the erythroid hematopoiesis in MPN patients. Altogether, we found a novel hereditary susceptible factor-TET2 rs3733609 C/T variant for the development of MPN, suggesting the variant may be partially responsible for the pathogenesis and accumulation of MPN.
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Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Janus Quinase 2/genética , Policitemia Vera/genética , Polimorfismo de Nucleotídeo Único/genética , Mielofibrose Primária/genética , Proteínas Proto-Oncogênicas/genética , Trombocitemia Essencial/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Dioxigenases , Frequência do Gene/genética , Genótipo , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
Grifolin is a natural biologically active substance isolated from the fresh fruiting bodies of the mushroom Albatrellus confluens. Here, for the first time, we describe a novel activity of grifolin, namely its ability to inhibit the growth of tumor cells by the induction of apoptosis. Grifolin strongly inhibited the growth of tumor cell lines: CNE1, HeLa, MCF7, SW480, K562, Raji and B95-8. Analysis of acridine orange (AO)/ethidium bromide (EB) staining and flow cytometry showed that grifolin possessed apoptosis induction activity to CNE1, HeLa, MCF7 and SW480. Furthermore, the cytochrome c release from mitochondria was detected by confocal microscopy in CNE1 cells after a 12h treatment with grifolin. The increase of caspase-8, 9, 3 activities revealed that caspase was a key mediator of the apoptotic pathway induced by grifolin, and the underexpression of Bcl-2 and up-regulation of Bax resulted in the increase of Bax: Bcl-2 ratio, suggesting that Bcl-2 family involved in the control of apoptosis. Owing to the combination of the significant antitumor activity by inducing apoptosis and natural abundance of the compound, grifolin holds the promise of being an interesting antitumor agent that deserves further laboratory and in vivo exploration.
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Antineoplásicos/farmacologia , Apoptose , Terpenos/farmacologia , Animais , Basidiomycota/química , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocromos c/metabolismo , Regulação para Baixo , Humanos , Camundongos , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação para Cima , Proteína X Associada a bcl-2RESUMO
Icaritin (ICT), a hydrolytic product of icariin from Epimedium genus, exhibits antitumor activities in several human solid-tumor and myeloid leukemia cells with extensive influence on various cell signal molecules, such as MAPKs being involved in cell proliferation and Bcl-2 participating in cell apoptosis. However, the effect of icaritin on Burkitt Lymphoma has not been elucidated. In the present study, we first screened the potential effect of icaritin on Burkitt lymphoma Raji and P3HR-1 cell lines and found that icaritin showed cytotoxicity in both cell lines. We further found that icaritin could significantly inhibit Raji cells proliferation with S-phase arrest of cell cycle and induced cell apoptosis accompanied by activation of caspase-8 and caspase-9 and cleavage of PARP. We also observed that icaritin was able to decrease Bcl-2 levels, thus shifting the Bcl-2/Bax ratio, and it could obviously reduce c-Myc, a specific molecular target in Burkitt lymphoma. Our findings demonstrated that icaritin showed cytotoxicity, inhibited cell growth, caused S arrest, and induced apoptosis in Burkitt lymphoma cells and provided a rationale for the further evaluation of icaritin for Burkitt lymphoma therapy.
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Apoptose/efeitos dos fármacos , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Flavonoides/administração & dosagem , Linfoma de Burkitt/patologia , Linhagem Celular Tumoral , Citotoxinas/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Resultado do TratamentoAssuntos
Proteínas Reguladoras de Apoptose/genética , Caderinas/genética , Dasatinibe/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Mutação , Sequência de Aminoácidos , Sequência de Bases , Humanos , Hibridização in Situ Fluorescente , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Indução de Remissão , Sequenciamento do ExomaRESUMO
PURPOSE: To identify a novel pathogenic gene mutation present in a Chinese family with hereditary hemorrhagic telangiectasia (HHT) and to determine if an intron mutation may influence the transcriptional activity of the ACVRL1 gene. METHODS: HHT family members were ascertained following the presentation of proband and involved subjects. All family members (nâ=â5) and 113 healthy individuals were genotyped for the variant in intron 6 c.772+27G>C of ACVRL1 gene. The genomic structure of ACVRL1 in affected HHT patients and healthy individuals was determined by long range PCR and sequencing. The expression of ACVRL1 mRNA and protein in patients with HHT was evaluated using real-time polymerase chain reaction and immunoblot analysis. Luciferase activity assay and electrophoretic mobility shift assay (EMSA) were performed to uncover the mechanism of intron-related transcriptional regulation. RESULTS: Only one novel mutation in intron 6 (c.772+27G>C) of ACVRL1 gene, no other mutation, abnormal splice, gross genomic deletion or rearrangement was found in this HHT2 family. Compared with healthy individuals, ACVRL1 mRNA and protein were significantly decreased in affected HHT2 individuals. Luciferase activity assay demonstrated that the transcriptional activity of the mutated ACVRL1 was significantly lower than that of the wild-type of intron 6; EMSA results showed that intron 6 c.772+27G>C mutation was able to inhibit the binding of transcriptional factor Sp1. CONCLUSIONS: A novel intron mutation in ACVRL1 gene is associated with familial HHT2. The mechanisms may be involved in the down-regulation of ACVRL1 gene transcription.
Assuntos
Receptores de Activinas Tipo II/genética , Povo Asiático/genética , Predisposição Genética para Doença , Íntrons/genética , Mutação/genética , Telangiectasia Hemorrágica Hereditária/genética , Transcrição Gênica , Adulto , Antígenos CD/genética , Antígenos CD/metabolismo , Sequência de Bases , Sítios de Ligação/genética , Pré-Escolar , China , Sequência Consenso/genética , Regulação para Baixo/genética , Endoglina , Família , Feminino , Mucosa Gástrica/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Ligação Proteica/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Regulação para Cima/genéticaRESUMO
PURPOSE: To explore the effects of Icaritin on chronic myeloid leukemia (CML) cells and underlying mechanisms. METHOD: CML cells were incubated with various concentration of Icaritin for 48 hours, the cell proliferation was analyzed by MTT and the apoptosis was assessed with Annexin V and Hoechst 33258 staining. Cell hemoglobinization was determined. Western blotting was used to evaluate the expressions of MAPK/ERK/JNK signal pathway and Jak-2/Phorpho-Stat3/Phorsph-Akt network-related protein. NOD-SCID nude mice were applied to demonstrate the anti-leukemia effect of Icaritin in vivo. RESULTS: Icaritin potently inhibited proliferation of K562 cells (IC50 was 8 µM) and primary CML cells (IC50 was 13.4 µM for CML-CP and 18 µM for CML-BC), induced CML cells apoptosis and promoted the erythroid differentiation of K562 cells with time-dependent manner. Furthermore, Icaritin was able to suppress the growth of primary CD34+ leukemia cells (CML) and Imatinib-resistant cells, and to induce apoptosis. In mouse leukemia model, Icaritin could prolong lifespan of NOD-SCID nude mice inoculated with K562 cells as effective as Imatinib without suppression of bone marrow. Icaritin could up-regulate phospho-JNK or phospho-C-Jun and down-regulate phospho-ERK, phospho-P-38, Jak-2, phospho-Stat3 and phospho-Akt expression with dose- or time-dependent manner. Icaritin had no influence both on c-Abl and phospho-c-Abl protein expression and mRNA levels of Bcr/Abl. CONCLUSION: Icaritin from Chinese herb medicine may be a potential anti-CML agent with low adverse effect. The mechanism of anti-leukemia for Icaritin is involved in the regulation of Bcr/Abl downstream signaling. Icaritin may be useful for an alternative therapeutic choice of Imatinib-resistant forms of CML.
Assuntos
Antineoplásicos/farmacologia , Flavonoides/farmacologia , Janus Quinase 2/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Humanos , Janus Quinases/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Células Tumorais CultivadasRESUMO
Epstein-Barr virus (EBV) infection in tumor cells is generally restricted to the latent forms of viral infection. Switching the latent form of viral infection into the lytic form may induce tumor cell death. An important nuclear factor, nuclear factor (NF)-kappaB, is thought to play an essential role in EBV lytic infection; high levels of NF-kappaB can inhibit EBV lytic replication. In this study, we tested the effect of inducing EBV lytic replication using two NF-kappaB inhibitors: Bay11-7082 and Z-LLF-CHO, to reveal the possibility of targeting EBV-positive cancer therapy with these two NF-kappaB inhibitors. Our results showed that Bay11-7082 and Z-LLF-CHO reactivated EBV in a dose-dependent manner, thus resulting in EBV-positive 5-8F cell death. In contrast, there was no significant effect on EBV-negative HNE3 cells. When ganciclovir was used in combination with either Bay11-7082 or Z-LLF-CHO to treat 5-8F cells, the cytotoxic effect of the NF-kappaB inhibitor was amplified. The finding indicates that inhibiting the NF-kappaB activity of EBV-positive cells can induce lytic replication of EBV and cause lytic cytotoxicity against these cells.
Assuntos
Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Neoplasias Nasofaríngeas/patologia , Nitrilas/farmacologia , Oligopeptídeos/farmacologia , Sulfonas/farmacologia , Antivirais/farmacologia , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Infecções por Vírus Epstein-Barr/metabolismo , Ganciclovir/farmacologia , Herpesvirus Humano 4/fisiologia , Humanos , NF-kappa B/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/virologia , Fator de Transcrição RelA/metabolismo , Ativação ViralRESUMO
AIM: To isolate, culture pancreatic progenitor cells derived from islets of newborn rats, and to observe the effect of GLP-1 (7-36) NH2 on islet progenitor differentiation. METHODS: Islets were isolated purified, islet progenitor cells were isolated and proliferated in the modified RPMI-1640 medium supplemented with 20 microg/L bFGF and 20 microg/L EGF, then were differentiated with 20 nmol/L GLP-1 (7-36) NH2. The properties of islet progenitor cells were identified primarily by hybridization in situ, immunocytochemistry, dithizone (DTZ)-staining, and radioimmunoassay before and after differentiation. RESULTS: Islet progenitor cells did not express PDX-1, insulin and somatostatin, but nestin. After differentiation, a portion of cells expressing PDX-1, insulin mRNA, insulin, somatostatin, and nestin, islet-like cell clusters (ICCs) were formed, DTZ-stained cells were in peripheral region of it. Insulin release was markedly greater in media harvested after differentiation of 3 weeks. CONCLUSION: A kind of progenitor cells exists in pancreatic islet of newborn SD rats, could be expanded continuously. GLP-1 (7-36) NH2 could differentiate pancreatic islet-derived progenitor cells to form ICCs capable of insulin secretion.