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2.
Med Sci Monit ; 26: e921288, 2020 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-32146479

RESUMO

BACKGROUND Leukemia is common in aging adults and has very high mortality worldwide. The present study was designed to investigate the therapeutic efficacy of miR-18a inhibitor against WEHI-3 and THP-1 leukemia cells. MATERIAL AND METHODS The changes in miR-18a inhibitor-transfected WEHI-3 and THP-1 cell proliferative potential was measured by use of the Cell Counting Kit-8 assay. Apoptotic changes were analyzed by electron microscopy, and evaluation of PI3K, AKT, mTOR, and PTEN expression was assessed by RT-qPCR assay. RESULTS Transfection of miR-18a inhibitor significantly (P<0.05) suppressed the proliferative potential of WEHI-3 and THP-1 cells. The WEHI-3 cells showed the presence of characteristic apoptotic bodies on transfection with miR-18a inhibitor at 48 h. Flow cytometry showed that miR-18a inhibitor transfection significantly (P<0.05) increased the WEHI-3 cell percentage in G1 phase. The transfection of miR-18a inhibitor significantly (P<0.05) promoted apoptosis in WEHI-3 cells. In WEHI-3 cells, miR-18a inhibitor transfection markedly suppressed the expression of PI3K, AKT, and mTOR mRNA. The expression of PTEN mRNA was significantly (P<0.05) upregulated by miR-18a inhibitor transfection in WEHI-3 cells. CONCLUSIONS The present study investigated the therapeutic efficacy of miR-18a inhibitor against WEHI-3 and THP1 leukemia cells. The study demonstrated that miR-18a inhibitor suppressed the proliferative potential of WEHI-3 and THP1 cells and activated apoptotic process through upregulation of PTEN mRNA expression. Therefore, miR-18a inhibitor can be of therapeutic importance for the treatment of leukemia.


Assuntos
Proliferação de Células/efeitos dos fármacos , Leucemia/patologia , MicroRNAs/antagonistas & inibidores , PTEN Fosfo-Hidrolase/metabolismo , Apoptose , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia/tratamento farmacológico , Células THP-1 , Transfecção , Regulação para Cima
3.
Zhonghua Xue Ye Xue Za Zhi ; 41(1): 59-63, 2020 Jan 14.
Artigo em Chinês | MEDLINE | ID: mdl-32023756

RESUMO

Objective: To explore the relationship between plasma coagulation factor XIII (FXIII) and bleeding events. Methods: A total of 55 cases of acute leukemia (AL) at the myelosuppression phase after chemotherapy hospitalized in our hospital from August 2017 to March 2018 were enrolled, with 35 normal controls. The concentration of plasma coagulation factor XIII (FXIII) was detected by ELISA to determine the relationship between the plasma FXIII levels in AL patients at the myelosuppression phase after chemotherapy with bleeding events. Results: The level of FXIII in AL patients at the myelosuppression phase after chemotherapy was significantly lower than that in controls (P<0.001) . The level of FXIII was inversely related with the bleeding severity (the Spearman correlation coefficient -0.761) . Given the diagnosis cut-off point of FXIII concentration as 103.9 µg/L, the sensitivity of diagnosing bleeding in AL patients at the myelosuppression phase after chemotherapy was 0.939, and the specificity 0.909. Conclusion: AL patients at the myelosuppression phase after chemotherapy had low level of plasma FXIII, and patients with lower plasma FXIII associated with higher incidence and severity of bleeding. FXIII level was an independent influencing factor of bleeding in AL patients at the myelosuppression phase after chemotherapy.


Assuntos
Leucemia , Doença Aguda , Testes de Coagulação Sanguínea , Fator XIII , Deficiência do Fator XIII , Hemorragia , Humanos
5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 82-87, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32027257

RESUMO

OBJECTIVE: To provide clinical basis for the diagnosis and treatment of chronic neutrophilic leukemia (CNL) and to provide possible molecular targets for the treatment. METHODS: By summarizing the clinical data of 14 patients with CNL, the clinical characteristics, gene mutation types and possible prognostic factors were analyzed. RESULTS: Among the 14 patients with CNL, males (9 cases) were more than females (5 cases), with a median age of 57 years old. The detection rate of CSF3R mutation was 92.86% (13/14), including 12 cases (85.71%) with T318I mutation and 1 case of Y799X mutation, and only 1 case was not detected for mutation of CSF3R. The ASXL1 mutation was detected in 42.86% (6/14) of the patients, all of which were nonsense mutations, including 4 cases with R693X and 2 cases with E705X, and 14.29% (2/14) of the patients was detected for SETBP1 mutation, all of which were with D868N mutation. No patients with simultaneous ASXL1 and SETBP1 mutations were found, and JAK2 and CALR mutations were not detected. All of the patients had normal karyotypes. These patients' median survival time was 30 months (95%CI 13.19-46.80), and the influence of age over 60 years old was statistically significant (21.83 months vs 35.35 months) (P<0.05). CONCLUSION: It is difficult to diagnose CNL. CSF3R T618I mutation is its specific mutation, and ASXL1 mutation and SETBP1 mutation have auxiliary diagnostic significance for CNL. The age>60 years old at diagnosis is a factor of unfavourable prognosis.


Assuntos
Leucemia , Neutrófilos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Receptores de Fator Estimulador de Colônias
6.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 104-109, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32027261

RESUMO

OBJECTIVE: To investigate the effect and mechanism of miRNA-145 on leukemic cell apoptosis. METHODS: After transfection of miRNA-145 mimic and negative control mimic in leukemia cells by Lipofectamine 2000 liposome, the MTT assay was used to detect the effect of miRNA-145 on cell proliferation. Flow cytometry was used to detect the effect of miRNA-145 on cell cycle and apoptosis. Western blotting assay was used to detect the expression levels of BCL-2, CDK6, Cyclin D1, BAX, PI3K p-PI3K, p-AKT and AKT. RESULTS: The relative level of microRNA in HuT 78 cells transfected with miRNA-145 was 2.3±02, which was significantly higher than that in blank control group and miRNA-NC group (P<0.05). MTT assay showed that the proliferation level of HuT 78 cells transfected with miRNA-145 mimic was significantly lower than that of blank control and miRNA-NC group (P<0.05). Flow cytometry showed that the cells at G0/G1, S and G2/M phase of HuT 78 cells were significantly decreased after transfection with miRNA-145 mimic (P<0.05). Annexin V/PI double staining assay showed that the apoptosis rate of HuT 78 cells was 17.6%±3.4%,which was significantly higher than that in blank control group and miRNA-NC group (P<0.05). Western blot showed that the expression levels of BCL-2, CDK6 and Cyclin D1 in HuT 78 cells were significantly lower than those in blank control and miRNA-NC group (P<0.05), and BAX expression in HuT 78 cells was significantly higher than that in blank control and miRNA-NC group (P<0.05). Western blot showed that expression of PI3K, p-PI3K, AKT and p-AKT in HuT 78 cells transfected with miRNA-145 mimic were significantly lower than that in blank control and miRNA-NC group (P<0.05). CONCLUSION: Upregulation of miRNA-145 may inhibit the proliferation of leukemia cells and promote the apoptosis, which may be related with the inhibition of PI3K/AKT signaling pathway.


Assuntos
Leucemia , MicroRNAs/genética , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Leucemia/genética , Fosfatidilinositol 3-Quinases
7.
Gene ; 735: 144405, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32014562

RESUMO

INTRODUCTION: Long non-coding RNAs (lncRNAs) are RNA molecules that structurally resemble mRNA but do not encode proteins. Studies have been associated this class of non-coding RNA with the development of several disease, among them the different types of leukemia. However, the results are contradictory. Thus, we performed a systematic review of the literature available in order to better understand the involvement of lncRNAs in the development of leukemia. MATERIALS AND METHODS: Pubmed and Embase databases were used to identify all studies that evaluated the expression of one or more lncRNA between human samples (peripheral blood, bone marrow) with leukemia (cases) and without leukemia (controls). RESULTS: A total of 3675 articles were found in the databases, and after exclusion of articles that did not meet the eligibility criteria, 86 articles were included in this systematic review. In the 86 included studies, 3927 lncRNAs were differentially expressed between cases and controls. Among these, 110 lncRNAs were reported as being altered in samples from at least 2 studies and only 16 of them in ≥3 studies, which were selected for further evaluation. Of these, 12 lncRNAs were consistently dysregulated between cases and controls (CCAT1, CCDC26, CRNDE, HOTAIR, KCNQ5IT1, LINC00265, MALAT1, PVT1, SNHG5, TUG1: increased in cases, MEG3 and NEAT1: decreased in cases) in human samples of patients with some type of leukemia. CONCLUSION: Our data demonstrate that 12 lncRNAs are dysregulated in leukemia.


Assuntos
Leucemia/genética , RNA Longo não Codificante/genética , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , RNA Longo não Codificante/metabolismo
8.
Chem Biol Interact ; 317: 108963, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31978391

RESUMO

Epigenetic variations can play remarkable roles in different normal and abnormal situations. Such variations have been shown to have a direct role in the pathogenesis of various diseases either through inhibition of tumor suppressor genes or increasing the expression of oncogenes. Enzymes involving in epigenetic machinery are the main actors in tuning the epigenetic-based controls on gene expressions. Aberrant expression of these enzymes can trigger big chaos in the cellular gene expression networks and finally lead to cancer progression. This situation has been shown in different types of leukemia, where high or low levels of an epigenetic enzyme are partly or highly responsible for the involvement or progression of a disease. DNA hypermethylation, different histone modifications, and aberrant miRNA expressions are three main epigenetic variations, which have been shown to play a role in leukemia progression. Epigenetic based treatments now are considered as novel and effective therapies in order to decrease the abnormal epigenetic modifications in patient cells. Different epigenetic-based approaches have been developed and tested to inhibit or reverse the unusual expression of epigenetic agents in leukemia. Acute myeloid leukemia (AML), the most prevalent acute leukemia in adults, is anaggressive hematological malignancy arising in hematopoietic stem and progenitor cells. With the exception of a few specific AML subtypes, the mainstays of treatment have not significantly changed over the last 20 years, and are still based on standard cytotoxic chemotherapy. In this review, we will discuss the recent development of therapeutics specifically targeting these key epigenetic programs in AML, describe their mechanism of action and present their current clinical development. Finally, we will discuss the opportunities presented by epigenetically targeted therapy in AML and will highlight future challenges ahead for the AML community, to ensure that this novel therapeutics are optimally translated into clinical practice and result in clinical improvement for AML patients.


Assuntos
Antineoplásicos/uso terapêutico , Epigênese Genética , Leucemia/tratamento farmacológico , Leucemia/genética , Metilação de DNA/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Terapia de Alvo Molecular/métodos
9.
Ann Hematol ; 99(3): 539-547, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31953585

RESUMO

Macrophages within tissues display a strong plastic ability in respond to environmental cues in both physiologic influences and disease. However, the macrophage phenotype and its distribution in the bone marrow biopsies (BMB) samples of human acute leukemia (AL) remain poorly understood. In this study, 97 BMB samples of patients with acute leukemia and 30 iron-deficiency anemias (IDA) as control group were evaluated with immunohistochemistry. In comparison with controls, the counts of CD68+, CD163+, and CD206+macrophages were remarkably increased in BMB samples of acute leukemia (P < 0.01), as well as their infiltration density was roaring up-regulation (P < 0.01). The expression levels of CD68+, CD163+, and CD206+macrophages were decreased in patients with complete remission, but there still existed statistically significant contrast to the control group (P < 0.01). The ratios of the CD163-positive cells or CD206-positive cells to CD68-positive cells were most prevalent in the BMB samples of human acute leukemia compared with the control group (P < 0.01), which support that macrophages were polarized to M2 macrophages.


Assuntos
Antígenos de Diferenciação/metabolismo , Medula Óssea , Leucemia , Macrófagos , Proteínas de Neoplasias/metabolismo , Doença Aguda , Adolescente , Adulto , Idoso , Biópsia , Medula Óssea/metabolismo , Medula Óssea/patologia , Feminino , Humanos , Leucemia/metabolismo , Leucemia/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade
10.
Environ Pollut ; 258: 113476, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31902537

RESUMO

Exposure to chemicals produced by petrochemical industrial complexes (PICs), such as benzene, ionizing radiation, and particulate matters, may contribute to the development of leukemia. However, epidemiological studies showed controversial results. This systematic review and meta-analysis aimed to summarize the association between residential exposure to PICs and the risk of leukemia incidence, focusing on exposure-response effects. We searched PubMed, Embase, Web of Science, and Cochrane Library databases for studies published before September 1st, 2019. Observational studies investigating residential exposure to PICs and the risk of leukemia were included. The outcome of interest was the incidence of leukemia comparing to reference groups. Relative risk (RR) was used as the summary effect measure, synthesized by characteristics of populations, distance to PICs, and calendar time in meta-regression. We identified 7 observational studies, including 2322 leukemia cases and substantial reference groups, in this meta-analysis. Residential exposure to PICs within a maximal 8-km distance had a 36% increased risk of leukemia (pooled RR = 1.36, 95% CI = 1.14-1.62) compared to controls, regardless of sex and age. In terms of leukemia subtypes, residential exposure to PICs was associated with the risks of acute myeloid leukemia (AML, pooled RR = 1.61, 95% CI = 1.12-2.31) and chronic lymphocytic leukemia (CLL, pooled RR = 1.85, 95% CI = 1.11-6.42). In meta-regression, the positive association occurred after 10 years of follow-up with a pooled RRs of 1.21 (95% CI = 1.02-1.44) and then slightly increased to 1.77 (95% CI = 1.35-2.33) at 30 years after follow-up. No effect modification was found by sex, age, and geographic locations.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Benzeno/toxicidade , Exposição Ambiental/efeitos adversos , Leucemia/induzido quimicamente , Petróleo/toxicidade , Benzeno/efeitos adversos , Indústria Química , Humanos , Incidência , Leucemia/epidemiologia , Petróleo/efeitos adversos , Risco
12.
Acta Cytol ; 64(1-2): 71-80, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31063996

RESUMO

In the era of smaller and smaller biopsies submitted to pathology departments for diagnosis and the advent of personalized medicine, it has become imperative to efficiently and effectively use patient material to reach individualized, actionable diagnoses. The use of fine needle aspirates and core biopsies as acceptable methods for obtaining sufficient material for hematopoietic neoplasms under nonemergent conditions is debatable. There are, however, scenarios where only limited material is obtainable due to anatomic site, size of the lesion or condition of the patient. In these types of settings, thoughtful approaches and unconventional means are often necessary to reach a diagnosis. In this article, we describe three such scenarios and the unique tactics taken in each to obtain a personalized actionable diagnosis.


Assuntos
Biópsia por Agulha Fina/métodos , Biópsia com Agulha de Grande Calibre/métodos , Neoplasias Hematológicas/patologia , Leucemia/patologia , Linfoma Difuso de Grandes Células B/patologia , Adolescente , Idoso , Feminino , Neoplasias Hematológicas/diagnóstico , Humanos , Leucemia/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Masculino
13.
Support Care Cancer ; 28(1): 163-176, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31001692

RESUMO

PURPOSE: We designed a novel, manualized intervention called Emotion And Symptom-focused Engagement (EASE) for acute leukemia (AL) and report here on a phase II randomized controlled trial (RCT) to assess its feasibility and preliminary efficacy. METHODS: Patients were recruited within 1 month of hospital admission and randomized to EASE plus usual care (UC) or UC alone. EASE includes (1) EASE-psy, a tailored psychotherapy delivered over 8 weeks, and (2) EASE-phys, weekly physical symptom screening over 8 weeks to trigger early palliative care. The primary outcome was traumatic stress symptoms; secondary outcomes included physical symptom burden and quality of life. Assessments were conducted at baseline and at 4, 8, and 12 weeks. Between-group differences were evaluated using multilevel modeling. RESULTS: Forty-two patients were randomized to EASE (n = 22) or UC (n = 20), with 76% retention at 12 weeks. Predefined feasibility outcomes were met: 86% (19/22) of EASE participants completed ≥ 50% of EASE-psy sessions (goal ≥ 64%); 100% received Edmonton Symptom Assessment System (ESAS, modified for AL) screenings, 64% (14/22) of whom completed ≥ 50% of planned screenings (goal ≥50%); and 100% with scores ≥ 4/10 on any physical ESAS-AL item had ≥ 1 meeting with the EASE-phys team (goal 100%). Significant treatment-group differences favoring EASE were observed in traumatic stress symptoms at 4 and 12 weeks, and pain intensity and interference at 12 weeks (all p < .05). CONCLUSIONS: EASE is feasible in patients newly diagnosed with AL and shows promise of effectiveness. These results warrant a larger RCT to provide evidence for its more routine use as a standard of care.


Assuntos
Leucemia/terapia , Cuidados Paliativos/métodos , Psicoterapia/métodos , Estresse Psicológico/terapia , Avaliação de Sintomas/métodos , Doença Aguda , Adulto , Idoso , Intervenção Médica Precoce/métodos , Emoções , Estudos de Viabilidade , Feminino , Hospitalização , Humanos , Leucemia/complicações , Leucemia/psicologia , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Estresse Psicológico/etiologia , Adulto Jovem
14.
Support Care Cancer ; 28(1): 35-42, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31444641

RESUMO

Impaired cardiovascular and autonomic function during treatment and during recovery from leukemia has been indicated. In this context, heart rate variability (HRV) is a non-invasive measure that describes the oscillations of the intervals between consecutive heart beats (RR intervals), influenced by the autonomic nervous system. We intend to review literature showing HRV changes in leukemia subjects. The articles selected in the current review were attained up to March 2018, and the search was limited to articles in English language, published in peer-reviewed journals, with both adult and child age samples. The articles were investigated in the five electronic databases: PubMed, Physiotherapy Evidence Database (PEDro), Cochrane Clinical Trials, Scientific Electronic Library Online (SciELO), and Excerpta Medica dataBASE (EMBASE). Towards the end of the research, 9 studies were included. Subjects undergoing treatment for leukemia have reduced HRV, signifying decreased vagal control of heart rate. The subjects that undertook leukemia treatment and their survivors experienced a reduction in HRV with subsequent recovery, but the recovery time is ill defined. HRV is reduced in leukemia subjects who progress to neuropathy secondary to chemotherapy, accompanied by cardiac dysfunction. We advocate the use of HRV to evaluate autonomic function and decide the treatment to prevent autonomic impairment in leukemia subjects.


Assuntos
Doenças do Sistema Nervoso Autônomo/diagnóstico , Cardiopatias/diagnóstico , Frequência Cardíaca/fisiologia , Leucemia/tratamento farmacológico , Leucemia/fisiopatologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças do Sistema Nervoso Autônomo/induzido quimicamente , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Criança , Eletrocardiografia , Cardiopatias/induzido quimicamente , Cardiopatias/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Leucemia/diagnóstico , Padrões de Prática Médica/normas , Padrões de Prática Médica/estatística & dados numéricos
15.
J Sci Med Sport ; 23(1): 75-81, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31526663

RESUMO

OBJECTIVES: To examine iron stores, hemoglobin mass, and performance before, during and after intermittent altitude exposure in a professional male rugby player experiencing iron overload following blood transfusions for treatment for acute myeloid leukemia. DESIGN: Longitudinal, repeated measures, single case-study. METHODS: The player was followed prior to (control), and during (study), an in-season block of altitude training. During the control period two venesections were performed for a total of 750mL of blood removal. Internal and external training load, match statistics, blood volume, plasma volume, haemoglobin mass, serum ferritin and reticulocyte count were monitored throughout. RESULTS: During the control period serum ferritin declined following the two venesections (∼51%) as did haemoglobin mass (∼2%), reticulocyte count remained stable. During the study period serum ferritin further declined (∼30%), however haemoglobin mass and reticulocyte count increased (∼4% and ∼14% respectively). Internal training load for the control and study period was similar, however external training load was lower in the study period. Match statistics were not favourable for the player during the control period, however they improved during the study period. CONCLUSIONS: This case supports the theory that individuals with elevated iron availability are well placed to achieve increases in haemoglobin mass. Furthermore, although therapeutic venesections may still be required to manage iron overload, the addition of altitude exposure may be a method to assist in reducing total body iron by means of mobilising available (excessive) iron to incorporate into haemoglobin. Altitude exposure did not hinder the players' performance. Further research is encouraged.


Assuntos
Altitude , Sobrecarga de Ferro/terapia , Leucemia/terapia , Condicionamento Físico Humano , Adulto , Atletas , Transfusão de Sangue , Ferritinas/sangue , Futebol Americano , Hemoglobinas/análise , Humanos , Sobrecarga de Ferro/etiologia , Leucemia/complicações , Estudos Longitudinais , Masculino , Contagem de Reticulócitos
17.
Quintessence Int ; 51(1): 78-85, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31781693

RESUMO

OBJECTIVES: Video sharing sites are a popular and useful way to spread information. The aim of this study was to evaluate information about oral care for leukemia patients and quality of information related to videos available on YouTube. METHOD AND MATERIALS: In this cross-sectional study, YouTube videos were analyzed according to the information content. The search was performed in English and using the search term: leukemia/oral care. The following information was registered: date of upload, source of upload, duration, total views, number of likes, number of dislikes, number of comments, overall quality. The overall quality of videos was assessed using the following quality criteria presented in the Global Quality Scale (GQS): poor, generally poor, moderate, good, and excellent. In addition, videos were classified as useful, misleading, and patient personal experience. Videos were assessed in terms of definition, etiology, pathogenesis, symptoms, treatment, and oral care for leukemia. RESULTS: Sixty-three videos (78.8%) were classified as useful, 6 (7.5%) as misleading and 11 (13.8%) as a patient's personal experience. Thirteen videos (16.3%) discussed the definition of leukemia, 8 (10.0%) discussed etiology, 6 (7.5%) discussed pathogenesis, 7 (8.8%) discussed symptoms of leukemia, 50 (62.5%) discussed treatment choices, and 15 videos (18.8%) discussed oral care of leukemia. Thirteen videos (16.3%) were assessed as poor, 17 (21.3%) as generally poor, 39 (48.8%) as moderate, 10 (12.5%) as good quality, and 1 (1.3%) as excellent. There was a significant difference between the content of videos and the number of views, number of likes, number of dislikes, and number of comments (P < .05). There was a significant difference between the content of videos and number of views, number of likes, number of dislikes, and number of comments (P = .007, P = .006, P = .049, and P = .011 respectively). There was no significant difference between demographic parameters and quality of video. There was no significant difference between demographic parameters (except duration, P = .025) and source of information. CONCLUSIONS: YouTube is a useful source of information on leukemia. Health care professionals should take into consideration that YouTube is an effective information tool for the patient.


Assuntos
Leucemia , Mídias Sociais , Estudos Transversais , Humanos , Pacientes , Gravação em Vídeo
18.
Cell Physiol Biochem ; 53(S1): 1-10, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31804046

RESUMO

BACKGROUND/AIMS: We have previously shown that inhibition of the mitochondrial Kv1.3 channel results in an initial mitochondrial hyperpolarization and a release of oxygen radicals that mediate mitochondrial depolarization, cytochrome c release and death. Here, we investigated whether inhibition of Kv1.3 channels can also induce cellular resistance mechanisms that counteract the induction of cell death under certain conditions. METHODS: We treated leukemic T cells with the mitochondria-targeted Kv1.3 inhibitor PCARBTP and determined the activity of different kinases associated with cell survival including ZAP70, PI-3-K, AKT, JNK and ERK by measuring the activation-associated phosphorylation of these proteins. Furthermore, we inhibited AKT and JNK and determined the effect of PCARBTP-induced tumor cell death. RESULTS: We demonstrate that treatment of Jurkat T leukemia cells with low doses of the mitochondria-targeted inhibitor of Kv1.3 PCARBTP (0.25 µM or 1 µM) for 10 minutes induced a constitutive phosphorylation/activation of the pro-survival signaling molecules ZAP70, PI-3-K, AKT and JNK, while the phosphorylation/activation of ERK was not affected. Stimulation of Jurkat cells via the TCR/CD3 complex induced an additional activation of a similar pattern of signaling events. Higher doses of the Kv1.3 inhibitor, i.e. 10 µM PCARBTP, reduced the basal phosphorylation/activation of these signaling molecules and also impaired their activation upon stimulation via the TCR/CD3 complex. A low dose of PCARBTP, i.e. 0.25 µM PCARBTP, was almost without any effect on cell death. In contrast, concomitant inhibition of PI-3-K or AKT greatly sensitized Jurkat leukemia cells to the Kv1.3 inhibitor PCARBTP and allowed induction of cell death already at 0.25 µM PCARBTP. CONCLUSION: These studies indicate that Jurkat leukemia cells respond to low doses of the mitochondria-targeted Kv1.3 inhibitor PCARBTP with an activation of survival signals counteracting cell death. Inhibition of these T cell survival signals sensitizes leukemia cells to death induced by mitochondria-targeted Kv1.3 inhibitors. High doses of the Kv1.3 inhibitor inactivate these signals directly permitting death.


Assuntos
Apoptose/efeitos dos fármacos , Cumarínicos/farmacologia , Compostos Organofosforados/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Células Jurkat , Leucemia/metabolismo , Leucemia/patologia , Mitocôndrias/metabolismo , Fosfatidilinositol 3-Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Proteína-Tirosina Quinase ZAP-70/antagonistas & inibidores , Proteína-Tirosina Quinase ZAP-70/metabolismo
20.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(6): 1744-1748, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-31839032

RESUMO

OBJECTIVE: To analyze the effect of down-regulating the CD59 gene expression by RNAi lentivirus as vector on Jurkat cell line of acute T-lineage leukemia. METHODS: The expression of CD59 in Jurkat cell line of acute T-line leukemia was induced to decrease by RNAi lentivirus as vector. The transfection of RNA lentivirus and the localization of CD59 molecule were analyzed by laser confocal technique. The relative expression of CD59 gene in blank control, negative control and RNAi lentivirus transfected group was detected by real-time fluorescence quantitative PCR, and the enzyme-linked immunosorbent assay was used to detect the expression of TNF-ß and IL-3 in supernatants of cultured cells in 3 groups. The expression levels of apoptosis-related molecules including Caspase-3, Survivin, BCL-2 and BCL-2-associated X protein (BAX) were measured by Western blot. RESULTS: The transfection efficiency for Jurkat cells was higher than 90%. CD59 was mainly located on the cell membrane. Compared with the blank control group and the negative control group, the expression level of CD59 mRNA and protein in the RNAi lentivirus transfected group significantly decreased (P<0.05). Compared with the blank control group and the negative control group, the expression of TNF-ß and IL-3 in the RNAi lentivirus transfected group were significantly higher and lower (P<0.05) respectively. The expression levels of Survivin and BCL-2 in the RNAi lentivirus transfected group were significantly lower than those in the blank control group and the negative control group, while the expression levels of Caspase-3 and BAX in the RNAi lentivirus transfected group were significantly higher than those in the blank control group and the negative control group (P< 0.05). CONCLUSION: The down-regulation of CD59 gene expression induced by RNAi lenti-virus can decrease the expression of proliferation and differentiation-promoting molecule such as IL-3 and increase the expression of TNF-related factor in Jurkat cell line of acute T-lineage leukemia, which also can increase the expression of apoptosis-related proteins such as Caspase-3 and BAX, and decrease the expression of anti-apoptosis-related proteins such as Survivin and BCL-2.


Assuntos
Leucemia , Apoptose , Antígenos CD59 , Linhagem da Célula , Proliferação de Células , Regulação para Baixo , Humanos , Células Jurkat , Lentivirus , Interferência de RNA , RNA Interferente Pequeno , Transfecção
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