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1.
Transplantation ; 104(9): 1869-1878, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32058468

RESUMO

BACKGROUND: Triple progressive thermopreconditioning (3PTP) may induce high Hsp-70 expression to maintain cardiac function. We suggest that 3PTP may reduce myocardial ischemia/reperfusion (I/R) injury during organ transplantation through Bag3/Hsp-70 mediated defense mechanisms. METHODS: Male Wistar rats were divided into sham control group and 72 h after 3PTP in a 42°C water bath (3PTP) group. Rats underwent 60 min of ischemia by occlusion of the left anterior descending coronary artery followed by 240 min reperfusion. Hemodynamic parameters, including the electrocardiogram, microcirculation, heart rate, left ventricular end-diastolic pressure, maximal rate of rise (+dp/dt), and fall (-dp/dt) in the left ventricular pressure for index of contraction and relaxation were determined. Myocardial infarct size was evaluated by the Evans blue-2,3,5-triphenyltetrazolium chloride method. 3PTP-induced protective mechanisms were determined by Western blot and immunohistochemistry. RESULTS: Cardiac I/R depressed cardiac microcirculation, induced S-T segment elevation, and R-R and P-R interval elongation increased infarct size associated with erythrocyte extravasation, leukocytes and macrophage/monocyte infiltration, granulocyte colony-stimulating factor, poly(ADP-ribose) polymerase 1 stain, and transferase-mediated dUTP-biotin nick end labeling positive cells. However, 3PTP evoked significant cardioprotection against I/R injury, characterized by the increased +dp/dt value and the decreased elevated left ventricular end-diastolic pressure, erythrocyte extravasation, leukocyte and macrophage/monocyte infiltration, granulocyte colony-stimulating factor expression, poly(ADP-ribose) polymerase 1 expression, transferase-mediated dUTP-biotin nick end labeling positive cells, and fragmentation and infarct area. In addition, 3PTP increased Hsp-70 and Bag3 expression and decreased Bax/Bcl-2 ratio, but did not affect the Beclin-1 and LC3-II/LC3-I ratio in the heart with I/R injury. CONCLUSIONS: 3PTP therapies may through Bag3 upregulation alleviate I/R injury-induced left ventricular structural deterioration and dysfunction.


Assuntos
Ventrículos do Coração/patologia , Precondicionamento Isquêmico Miocárdico , Contração Miocárdica/fisiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Disfunção Ventricular Esquerda/prevenção & controle , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Animais , Apoptose , Proteínas Reguladoras de Apoptose/fisiologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Masculino , Microcirculação , Traumatismo por Reperfusão Miocárdica/patologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Ratos , Ratos Wistar
2.
Biochem Biophys Res Commun ; 524(2): 502-509, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32008743

RESUMO

Embryonic stem cells (ESCs) provide an ideal model for investigating developmental processes and are great sources for developing regenerative medicine. Harnessing apoptosis facilitates accurate recapitulation of signalling events during embryogenesis and allows efficient expansion of the ESCs during differentiation. Bcl2, a key regulator of intrinsic anti-apoptotic pathway, encodes two splicing isoforms. However, the identification and functional comparison of Bcl2 splicing isoforms in mouse ESCs (mESCs) remains to be elucidated. Here, we provide the evidence that both Bcl2 splicing variants are expressed in mESCs. Despite the structural difference, they have similar subcellular localisation. Both Bcl2α and Bcl2ß enhance differentiation efficiency of the ESCs and effectively improve the survival and growth of ESCs under serum-free conditions. However, the functional effect of Bcl2α was more potent than that of Bcl2ß. Moreover, only Bcl2α could maintain the long-term expansion and pluripotency of ESCs cultured in serum-free medium. Taken together, our results demonstrate previously unknown functional differences in Bcl2 alternative splicing isoforms in ESCs, and lay the foundation for future efforts to engineer ESCs for regenerative medicine.


Assuntos
Células-Tronco Embrionárias Murinas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Processamento Alternativo , Animais , Diferenciação Celular , Linhagem Celular , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Isoformas de Proteínas/análise , Isoformas de Proteínas/genética , Proteínas Proto-Oncogênicas c-bcl-2/análise
3.
Int. microbiol ; 22(3): 317-323, sept. 2019. graf
Artigo em Inglês | IBECS | ID: ibc-184838

RESUMO

In recent years, the beneficial impact of targeted gut microbiota manipulation in various neurological disorders has become more evident. Therefore, probiotics have been considered as a promising approach to modulate brain gene expression and neuronal pathways even in some neurodegenerative diseases. The purpose of this study was to determine the effect of probiotic biotherapy with combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 on the expression levels of proteins critical to neuronal apoptosis in hippocampus of lipopolysaccharide (LPS)-exposed rats. Four groups of animals (Control, LPS, Probiotic + LPS, and Probiotic) were treated with maltodextrin (placebo) or probiotic (109 CFU/ml/rat) for 2 weeks by gavage. On the 15th day, a single intraperitoneal dose of saline or LPS (1 mg/kg) was injected and 4 h later, protein assessment was performed by western blotting in hippocampal tissues. LPS significantly increased the Bax, Bax/Bcl-2 ratio, and cleaved caspase-3 expression along with decreased the Bcl-2 and procaspase-3 protein levels. However, probiotic pretreatment (L. helveticus R0052 + B. longum R0175) significantly downregulated the Bax and Bax/Bcl-2 ratio accompanied with upregulated Bcl-2 expression. Prophylactic treatment with these bacteria also attenuated LPS-induced caspase-3 activation by remarkably increasing the expression of procaspase-3 while reducing the level of cleaved caspase-3 in target tissues. Our data indicate that probiotic formulation (L. helveticus R0052 + B. longum R0175) alleviated hippocampal apoptosis induced by LPS in rats via the gut-brain axis and suggest that this probiotic could play a beneficial role in some neurodegenerative conditions


No disponible


Assuntos
Animais , Ratos , Apoptose , Bifidobacterium longum/crescimento & desenvolvimento , Hipocampo/patologia , Lactobacillus helveticus/crescimento & desenvolvimento , Probióticos/administração & dosagem , Western Blotting , Caspase 3/análise , Hipocampo/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Placebos/administração & dosagem , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteína X Associada a bcl-2/análise
4.
Int J Dermatol ; 58(12): 1444-1450, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31218676

RESUMO

BACKGROUND: Lichen planus (LP) is an inflammatory disease that affects skin, hair follicles, mucous membranes, and nails. Ki-67 is an antigen associated with the proliferation of cells in all stages of cell cycle except G0. Bcl-2 is a protooncogene that protects cells from apoptosis. COX-2 is an antiapoptotic protein that increases in inflammation. The infiltration of T cells in LP seems to be responsible in the apoptosis of the basal keratinocytes. OBJECTIVE: The purpose of this study was to investigate the effects of prednisolone and acitretin treatments on Ki-67, Bcl-2, and COX-2 expression and apoptosis in patients with LP and the role of Ki-67, Bcl-2, and COX-2 proteins in LP. METHODS: Fifty-eight patients with clinically and histopathologically diagnosed LP who had not been treated with systemic treatment before and 15 healthy volunteers were evaluated prospectively. Pretreatment and posttreatment biopsies were immunohistochemically stained with Ki-67, Bcl-2, and COX-2. The percentage of the stained cells were calculated and recorded. RESULTS: Although the percentage of staining with Ki-67 and Bcl-2 after treatment with prednisolone and acitretin decreased significantly (P < 0.05) in both groups, there was no significant difference between groups (P > 0.05). COX-2 decreased but was not statistically significant. CONCLUSIONS: With this study in cutaneous lichen planus, prednisolone and acitretin treatments reduced Bcl-2 and Ki-67 levels and did not effect COX-2 levels. It should be clarified whether these results can be obtained with any treatment effective in cutaneous lichen planus.


Assuntos
Acitretina/administração & dosagem , Ceratolíticos/administração & dosagem , Líquen Plano/tratamento farmacológico , Prednisolona/administração & dosagem , Pele/patologia , Administração Oral , Adolescente , Adulto , Idoso , Apoptose/efeitos dos fármacos , Biópsia , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/análise , Ciclo-Oxigenase 2/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Antígeno Ki-67/metabolismo , Líquen Plano/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pele/efeitos dos fármacos , Adulto Jovem
5.
Medicine (Baltimore) ; 98(15): e15204, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30985716

RESUMO

RATIONALE: Second diffuse large B-cell lymphoma (DLBCL) after treatment of acute lymphoblastic leukemia (ALL) is uncommon. To our knowledge, primary middle ear DLBCL which presents CD20-negative and coexpression of MYC and BCL-2 has not been reported yet. PATIENT CONCERNS: A 20-year-old Chinese man complained fever and weakness for 2 months. Subsequently bone marrow morphology and flow cytometry immunophenotype suggested ALL. Administrated with 9 cycles of multiagent combined chemotherapy, he felt right ear progressive hearing loss, otalgia, aural fullness. Otoendoscopic examination revealed a pitchy mass obstructing the right external auditory canal. Then the mass resection was performed for biopsy and immunohistochemistry examination. DIAGNOSIS: The mass was diagnosed as DLBCL which was negative for CD20 and double expression of MYC and BCL-2. INTERVENTIONS: Chemotherapy. OUTCOMES: The patient eventually gave up and died of severe infection. LESSONS: Although intensive chemotherapy has markedly improved the survival of ALL, more and more secondary cancers have been reported. In addition, primary middle ear lymphoma is much rare; hence, it is easy to be misdiagnosed. Furthermore, DLBCL with negative CD20 and double expression of MYC and BCL-2 is aggressive, which is characterized by chemotherapy resistance and inferior survival rates. We discuss this case aiming at raising awareness of tumors secondary to ALL and exploring the appropriate treatment options for the rare DLBCL.


Assuntos
Neoplasias da Orelha/diagnóstico , Orelha Média , Linfoma Difuso de Grandes Células B/diagnóstico , Segunda Neoplasia Primária/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-myc/análise , Antígenos CD20/análise , Biomarcadores Tumorais/análise , Diagnóstico Diferencial , Neoplasias da Orelha/química , Neoplasias da Orelha/tratamento farmacológico , Neoplasias da Orelha/patologia , Evolução Fatal , Humanos , Linfoma Difuso de Grandes Células B/química , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto Jovem
6.
J Chin Med Assoc ; 82(1): 11-18, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30839397

RESUMO

BACKGROUND: Piroxicam is a non-steroidal anti-inflammatory drug widely used in rheumatic diseases. It has analgesic and antipyretic activity, and is one of the drugs being introduced in clinical practice. Piroxicam-hepatotoxicity has been reported as one of its principal side effects. Several natural antioxidants were found to be effective against drug induced toxicity. Ginger is known by its antioxidant activities and hepatoprotective effects. The present study aimed at studying the protective effect of Ginger on Piroxicam-induced histopathological changes in livers of male mice. METHODS: Forty adult mice were randomly divided into 4 groups: Group I served as the control group. Group II received Ginger orally in a dose of 200 mg/kg per day for four weeks. Group III received Piroxicam intraperitoneally in a dose of 0.3 mg/kg per day for four weeks. Group IV received (Piroxicam + Ginger). At the end of the experiment, liver functions were estimated and then the liver was removed, and sampled for histopathological, immunohistochemistry and biochemical studies. RESULTS: Administration of ginger decreased elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) and immunoexpression of the proapoptotic protein (Bax), induced by piroxicam. It increased immunoexpression of the antiapoptotic protein (Bcl2). It also ameliorated the morphological changes induced by piroxicam. CONCLUSION: Piroxicam has toxic effects on the liver as indicated by biochemical, histological and immunohistochemical results. Ginger has protective effects against piroxicam-hepatotoxicity by reducing serum marker enzymes, liver fibrosis and apoptosis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Gengibre , Fitoterapia , Piroxicam/toxicidade , Animais , Fígado/química , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteína X Associada a bcl-2/análise
7.
J Chin Med Assoc ; 82(2): 92-98, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30839497

RESUMO

BACKGROUND: Halofuginone, which is the main active ingredient of Dichroa fabrifuga, was used to inhibit the synthesis of type I collagen and played increasingly important roles in tumor therapy. This study aims to investigate the protective effects of halofuginone on human umbilical vein endothelial cells (HUVECs) from H2O2-induced apoptosis and oxidative stress. METHODS: Propidium iodide and Annexin-V double staining assay was used to measure the apoptosis. Cell viability assay, the measurements of reactive oxygen species (ROS) parameters malondialdehyde and superoxide dismutase, western-blot assays, and quantitative PCR were used to elucidate the effects and mechanisms of halofuginone in protecting H2O2-induced injury. RESULTS: The results showed that halofuginone counteracted H2O2-induced cell viability decline and PCNA downregulation. Furthermore, halofuginone decreased ROS levels and protected HUVECs from H2O2-induced apoptosis. In detail, it showed that H2O2 induced a transient activation of Mitogen-activated protein kinases members ERK1/2 and p38, whereas induced a sustained activation of c-Jun N-terminal kinase (JNK), which play dominant roles in triggering apoptosis. Inhibition of JNK activation also inhibited H2O2-mediated apoptosis. Finally, it was shown that halofuginone upregulated VEGF expressions, which functioned by inhibiting sustained JNK activation, thus protecting HUVECs. CONCLUSION: Halofuginone has powerful effects in protecting HUVECs from H2O2-induced apoptosis, via upregulating VEGF and inhibiting overactivated JNK phosphorylation. Halofuginone might be a promising preventive drug for cardiovascular diseases.


Assuntos
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Piperidinas/farmacologia , Quinazolinonas/farmacologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/análise
8.
Med Sci Monit ; 25: 1769-1779, 2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30848248

RESUMO

BACKGROUND Cardiac remote ischemic conditioning (RIC) is a noninvasive cardioprotective method in ischemia-reperfusion injury and acute myocardial infarction (AMI). The aims of this study were to investigate the effects of RIC in a rat model of AMI. MATERIAL AND METHODS Adult male Sprague-Dawley rats included the AMI group that underwent ligation of the left anterior descending (LAD) coronary artery (n=24), the RIC group that consisted the AMI rat model treated with RIC once daily in the left hind limb until days 1, 7 and 14 (n=24), and the sham group (n=24). Myocardial infarct size was measured by routine histology with triphenyltetrazolium chloride (TTC) and Masson's trichrome histochemical staining for myocardial necrosis and fibrosis, respectively. Serum levels of Bcl-2, Bax, caspase-3, and inducible nitric oxide synthase (iNOS) were measured by enzyme-linked immunosorbent assay (ELISA). The apoptosis index was detected using the TUNEL assay. Spectrophotometry of the myocardium was used to identify mitochondrial complexes and myocardial ATP. RESULTS The RIC group showed improved cardiac hemodynamics, reduced the size of the myocardial infarction, upregulated expression of Bcl-2, and down-regulation of the levels of Bax, caspase-3, and iNOS, and reduced cardiac myocyte apoptosis and inhibited the opening of the mitochondrial permeability transition pore (MPTP). CONCLUSIONS In a rat model of AMI, RIC improved the hemodynamic index, reduce the levels of apoptosis and myocardial injury, and improved mitochondrial function.


Assuntos
Precondicionamento Isquêmico/métodos , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose , Cardiotônicos , Caspase 3/análise , Caspase 3/sangue , Modelos Animais de Doenças , Traumatismos Cardíacos/prevenção & controle , Hemodinâmica , Masculino , Mitocôndrias/metabolismo , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-2/sangue , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/terapia , Proteína X Associada a bcl-2/análise , Proteína X Associada a bcl-2/sangue
9.
Scand J Urol ; 53(1): 45-50, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30806186

RESUMO

Background: Response to neoadjuvant cisplatin treatment in bladder cancer has been linked to expression of Bcl-2 protein by cancer cells. The objective of this study was to test Bcl-2 as a predictive marker of neoadjuvant cisplatin chemotherapy response in a patient cohort from randomized cystectomy trials. Methods: Tumor samples were taken from 247 patients with T2-T4 bladder cancer enrolled in two randomized trials comparing cystectomy with or without neoadjuvant chemotherapy. Tissue microarrays from pre-intervention transurethral resection specimens were assessed for Bcl-2 protein status by immunohistochemistry. Extension of staining above 10% was regarded as positive. Downstaging and survival ratios in relation to Bcl-2 immunoreactivity and neoadjuvant chemotherapy utilization were calculated using the log rank test and multivariate Cox proportional hazards regression analyses. Results: Bcl-2 expression was positive in 38% and negative in 62% of the 236 evaluable patients. Bcl-2 negative patients receiving neoadjuvant chemotherapy had a significant increase in survival (p = 0.009), while Bcl-2 positive patients showed no difference (p = 0.4). However, the interaction variable between neoadjuvant chemotherapy and biomarker status was not significant (p = 0.38). When the prognostic value was assessed in the no-chemotherapy group, 5-year overall survival times were significantly better among Bcl-2 positive patients than among Bcl-2 negative patients (42 months vs 33 months, p = 0.04), but again Bcl-2 status did not remain independent when other factors were adjusted. Also, in a multivariate analysis with all patients, Bcl-2 was not significant. Conclusions: Bcl-2 status is not an independent predictor of neoadjuvant cisplatin chemotherapy response and is not prognostic in muscle-invasive bladder cancer.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células de Transição/química , Carcinoma de Células de Transição/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/análise , Neoplasias da Bexiga Urinária/química , Neoplasias da Bexiga Urinária/tratamento farmacológico , Carcinoma de Células de Transição/cirurgia , Quimioterapia Adjuvante , Cistectomia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Valor Preditivo dos Testes , Estudos Prospectivos , Resultado do Tratamento , Neoplasias da Bexiga Urinária/cirurgia
10.
Oral Dis ; 25(4): 1158-1168, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30801855

RESUMO

OBJECTIVES: Ameloblastomas are the most common odontogenic epithelial tumors with high recurrence rate. The aim of this study was to identify apoptosis-related genes with recurrence of ameloblastomas and to evaluate its feasibility as a prognostic marker and as a target molecule preventing from recurrence. MATERIALS AND METHODS: Public microarray data were analyzed. To evaluate their expression in ameloblastoma patients, immunohistochemical staining was performed in 89 human ameloblastoma tissues. Quantitative PCR was performed by use of ameloblastoma cell line (AM-1). Fluorescence activated cell sorting analysis and western blotting were conducted following transfection with siRNA. Further, AM-1 cells were implanted in the renal subcapsular layer of immunodeficient mice. RESULTS: Microarray data analysis revealed that osteoprotegerin (OPG) and B-cell lymphoma 2 (Bcl-2) were the two most upregulated genes in ameloblastoma. Only Bcl-2 expression was significantly (p = 0.020) associated with recurrence in conservative treatment group (n = 17) among 89 patients. Silencing of Bcl-2 increased apoptosis in AM-1 cells in vitro and inhibited tumor nodule formation of AM-1 cells in vivo. CONCLUSION: These results suggest that Bcl-2 expression is a useful biomarker to predict recurrence of ameloblastomas, and as a therapeutic target molecule to prevent recurrence of ameloblastoma.


Assuntos
Ameloblastoma/patologia , Neoplasias Maxilomandibulares/patologia , Linfoma de Células B/genética , Osteoprotegerina/genética , Adulto , Ameloblastoma/genética , Animais , Apoptose , Feminino , Humanos , Neoplasias Maxilomandibulares/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-2/sangue , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
11.
Int Microbiol ; 22(3): 317-323, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30810993

RESUMO

In recent years, the beneficial impact of targeted gut microbiota manipulation in various neurological disorders has become more evident. Therefore, probiotics have been considered as a promising approach to modulate brain gene expression and neuronal pathways even in some neurodegenerative diseases. The purpose of this study was to determine the effect of probiotic biotherapy with combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 on the expression levels of proteins critical to neuronal apoptosis in hippocampus of lipopolysaccharide (LPS)-exposed rats. Four groups of animals (Control, LPS, Probiotic + LPS, and Probiotic) were treated with maltodextrin (placebo) or probiotic (109 CFU/ml/rat) for 2 weeks by gavage. On the 15th day, a single intraperitoneal dose of saline or LPS (1 mg/kg) was injected and 4 h later, protein assessment was performed by western blotting in hippocampal tissues. LPS significantly increased the Bax, Bax/Bcl-2 ratio, and cleaved caspase-3 expression along with decreased the Bcl-2 and procaspase-3 protein levels. However, probiotic pretreatment (L. helveticus R0052 + B. longum R0175) significantly downregulated the Bax and Bax/Bcl-2 ratio accompanied with upregulated Bcl-2 expression. Prophylactic treatment with these bacteria also attenuated LPS-induced caspase-3 activation by remarkably increasing the expression of procaspase-3 while reducing the level of cleaved caspase-3 in target tissues. Our data indicate that probiotic formulation (L. helveticus R0052 + B. longum R0175) alleviated hippocampal apoptosis induced by LPS in rats via the gut-brain axis and suggest that this probiotic could play a beneficial role in some neurodegenerative conditions.


Assuntos
Apoptose , Bifidobacterium longum/crescimento & desenvolvimento , Hipocampo/patologia , Lactobacillus helveticus/crescimento & desenvolvimento , Lipopolissacarídeos/toxicidade , Probióticos/administração & dosagem , Animais , Western Blotting , Caspase 3/análise , Hipocampo/efeitos dos fármacos , Placebos/administração & dosagem , Proteínas Proto-Oncogênicas c-bcl-2/análise , Ratos , Proteína X Associada a bcl-2/análise
12.
Clin Res Hepatol Gastroenterol ; 43(2): 161-170, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30713033

RESUMO

AIM: The study is aimed to investigate the protective effects and possible mechanism of tacrolimus (FK506) pre-treatment in hepatic ischemia-reperfusion injury in rats. METHODS: The rats were randomly assigned into four groups, which were S, IR, L and H group, and then all groups were subjected to 60min of 70% partial warm liver ischemia, except S group. Rats in the L and H group were pre-treated with two different doses FK506 at 60min before ischemia. The rats of the IR group received an identical volume of normal saline. All animals were sacrificed after 6h of reperfusion. Transaminases were measured by biochemistry analyzer. Elisa kit was used to detect TNF-α, IL-6 and IL-1ß levels in serum. Liver specimens were stained with hematoxylin and eosin (HE) to assess the pathologic changes. The expressions of heme oxygenase-1 (HO-1), hypoxia-inducible factor-1α (HIF-1α), nuclear factor of activated T cells (NFAT3) were measured by real-time quantitative PCR and western blotting and the Bcl-2 and the Bax protein were tested by western blotting. RESULTS: In rats pre-treated with FK506, the levels of transaminases, TNF-α and IL-1ß were reduced significantly and also liver damage was dramatically mitigated compared to those without FK506 pre-treatment. Moreover, the expression of HO-1 at the level of both transcription and translation increased clearly and the activation of the HIF-1α was found in FK506 pre-treated livers. Moreover, NFAT3 protein transportation to the nucleus was reduced and Bax protein expression was decreased, but the expression of Bcl-2 protein was markedly increased after FK506 pre-treatment. CONCLUSION: FK506 pre-treatment could lessen hepatic ischemia-reperfusion injury through up-regulating the expression of HIF-1α and HO-1, and inhibiting nuclear translocation of NFAT3 in liver tissues.


Assuntos
Imunossupressores/uso terapêutico , Fígado/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Tacrolimo/uso terapêutico , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Heme Oxigenase-1/análise , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Imunossupressores/administração & dosagem , Interleucina-1beta/sangue , Interleucina-6/sangue , Fígado/patologia , Masculino , Fatores de Transcrição NFATC/análise , Cuidados Pré-Operatórios , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/sangue , Tacrolimo/administração & dosagem , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangue , Proteína X Associada a bcl-2/análise
13.
Zhonghua Bing Li Xue Za Zhi ; 48(2): 132-136, 2019 Feb 08.
Artigo em Chinês | MEDLINE | ID: mdl-30695866

RESUMO

Objective: To investigate the clinicopathologic features of follicular lymphoma (FL) in children. Methods: One female and one male patients with FL diagnosed in the First College of Clinical Medical Science, China Three Gorges University and Beijing Friendship Hospital of the Capital University of Medical Science in February 2016 and June 2015 were studied by HE immunohistochemistry, EBER in situ hybridization, IgH and IgK gene rearrangement analysis and IRF4 fusion gene detection. Results: The two patients' age were 6.3 and 12 years, respectively. The lesions involved head and neck lymph nodes with duration of more than 2 months. Histopathologically, the lesions consisted of nodular proliferation of lymphoid follicles with diffuse distribution of large cells. Starry sky phenomenon was seen in one of the two cases. Immunohistochemistry showed that one case was positive for bcl-2 and MUM1, but negative for bcl-6 and CD10. Ki-67 index was>50% and oligoclonal IgK rearrangement was observed. The second case showed positivity for bcl-6, and CD10 but negative for bcl-2. Ki-67 index was>50% and clonal IgH FR1-JH and IgH FR2-JH rearrangements were detected. Both cases showed no evidence of IRF4 gene fusion. Conclusions: Childhood FL is a rare B-cell lymphoma with characteristic features and high-grade histomorphology. However, its immunophenotype and molecular genetic characteristics are divergent.


Assuntos
Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma Folicular/genética , Linfoma Folicular/patologia , Criança , China , Feminino , Rearranjo Gênico , Humanos , Imunoglobulinas/genética , Imuno-Histoquímica , Imunofenotipagem , Hibridização in Situ Fluorescente , Fatores Reguladores de Interferon/análise , Antígeno Ki-67/análise , Linfoma de Células B/química , Linfoma Folicular/química , Masculino , Neprilisina/análise , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-6/análise
14.
J Cutan Pathol ; 46(3): 182-189, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30511443

RESUMO

BACKGROUND: Primary cutaneous follicular center-cell lymphoma (PCFCL) is one of the most common types of cutaneous B-cell lymphoma. Differences in immunohistochemical expression of BCL2 and CD10 antigens along with the presence of t(14:18) translocation in neoplastic cells have been postulated as relevant clues in differentiating PCFCL from cutaneous lesions secondary to a systemic follicular lymphoma (SCFL). The aim of this study is to evaluate the significance and usefulness of these parameters in a large series of patients. METHODS: Patients with PCFCL and SCFL diagnosed at three university hospitals in Barcelona, from 2000 to 2015 were reviewed. Clinical, histopathological, immunophenotypical, genetic, and outcome parameters were analyzed. RESULTS: Eighty-one cases (59 PCFCL and 22 SCFL) were included. There were no significant differences between PCFCL and SCFL cases regarding clinical presentation, site of involvement, or predominant type of skin lesions. Most patients in both groups showed positivity for BCL2 and CD10, but strong expression of BCL2 and CD10 was associated with SCFL cases. Although more frequent in SCFL, a small proportion of PCFCL cases also showed the t(14:18) on FISH analysis. CONCLUSION: The intensity of BCL2 expression was found to be the single most valuable clue in differentiating PCFCL from SCFL cases on histopathological grounds.


Assuntos
Biomarcadores Tumorais/análise , Linfoma Folicular/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 18/genética , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neprilisina/análise , Neprilisina/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Translocação Genética/genética , Adulto Jovem
15.
Pathol Res Pract ; 215(3): 446-452, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30558966

RESUMO

Hydatidiform moles (HM) are characterized by an abnormal proliferating trophoblast with a potential for a malignant transformation. Similar to other human tumors, trophoblastic pathogenesis is likely a multistep process involving several molecular and genetic alterations. The study was performed to investigate the expression patterns of c-erbB-2 and Bcl-2 oncoproteins, p53, p21WAF1/CIP1 and p63 tumor suppressor proteins and Ki-67 cell proliferation marker in HM. We conducted a retrospective study of 220 gestational products, including 39 hydropic abortions (HA), 41 partial HM (PHM) and 140 complete HM (CHM). The expression of c-erbB-2, Bcl-2, p53, p21WAF1/CIP1, p63 and Ki-67 was investigated by immunohistochemistry on archival tissues. c-erbB-2 expression was observed in three PHM and 10 CHM. Bcl-2 immunostaining was significantly higher in PHM (61%) and CHM (70.7%) compared with HA (7.7%, p = 0.001 and p < 0.0001, respectively). p53 expression was stronger in CHM (73.6%) compared with PHM (24.4%, p < 0.0001) and HA (12.8%, p < 0.0001). p21WAF1/CIP1 staining was observed as well in molar and non-molar gestations (p > 0.05). p63 immunoexpression was significantly described in CHM (85.7%) and PHM (78%) compared with HA (10.2%, p < 0.0001 and p = 0.0001, respectively). Ki-67 was significantly expressed in CHM (72.1%) compared with HA (46.2%, p = 0.005). Altered expression of Bcl-2, p53, p63 and Ki-67 reflects the HM pathological development. Immunohistochemical analysis is beneficial to recognize the HM molecular and pathogenic mechanisms. Furthermore, it could serve as a useful adjunct to conventional methods for refining HM diagnosis.


Assuntos
Biomarcadores Tumorais/análise , Mola Hidatiforme/patologia , Neoplasias Uterinas/patologia , Adolescente , Adulto , Inibidor de Quinase Dependente de Ciclina p21/análise , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Feminino , Humanos , Mola Hidatiforme/metabolismo , Imuno-Histoquímica , Antígeno Ki-67/análise , Antígeno Ki-67/biossíntese , Proteínas de Membrana/análise , Proteínas de Membrana/biossíntese , Pessoa de Meia-Idade , Gravidez , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Receptor ErbB-2/análise , Receptor ErbB-2/biossíntese , Estudos Retrospectivos , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/biossíntese , Neoplasias Uterinas/metabolismo , Adulto Jovem
16.
Biochem Biophys Res Commun ; 509(1): 194-200, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30579601

RESUMO

Hepatocellular carcinoma (HCC) is associated with poor prognosis due to many unknowns about its inflammatory microenvironment. As a pivotal proinflammatory cytokine, IL-17A exerts a protective effect on the survival and function of HCC cells. It is widely accepted that IL-17A plays an important role in regulating autophagy. Bcl2, a key molecule promoting the survival of HCC cells, also plays an indispensable role as an autophagy regulator. The aim of this study was to investigate the role of Bcl2 in IL-17A-regulated autophagy of HCC cells. The results showed that IL-17A not only inhibited autophagic activity, but also increased Bcl2 levels in HCC cells under starvation. Besides, IL-17A could prevent the dissociation of autophagy protein Beclin1 from Bcl2-Beclin1 complex upon starvation. Overexpression of Beclin1 rescued the autophagy deficiency of HCC cells in presence of IL-17A. Moreover, RNAi-induced Bcl2 silencing impaired the function of IL-17A in inhibiting the activation of autophagy, subsequently reducing the viability and migration of HCC cells, while the inhibition of Beclin1 by spautin-1 could reduce autophagic activity to a certain degree, thus restoring the viability and migration of HCC cells. In summary, it was suggested that the inhibition of Bcl2 degradation may be an important mechanism by which IL-17A inhibits autophagy response, subsequently maintaining the survival in HCC cells.


Assuntos
Autofagia , Carcinoma Hepatocelular/imunologia , Interleucina-17/imunologia , Neoplasias Hepáticas/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Proteína Beclina-1/análise , Proteína Beclina-1/imunologia , Carcinoma Hepatocelular/patologia , Sobrevivência Celular , Células Hep G2 , Humanos , Interleucina-17/análise , Neoplasias Hepáticas/patologia , Lisossomos/imunologia , Lisossomos/patologia , Proteólise , Proteínas Proto-Oncogênicas c-bcl-2/análise
17.
Methods Mol Biol ; 1877: 163-172, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30536005

RESUMO

Flow cytometry is a powerful technique for the detection and quantification of cell surface and intracellular proteins. It enables the ability to measure the expression levels of specific proteins in a cell population of interest without the need to physically separate out the cells from within a heterogeneous population by using the appropriate cell-specific markers. It also requires fewer cells than other traditional techniques such as Western blotting. Here we describe a robust and reproducible method to measure the expression levels of the BCL-2 family members, BCL-2, BCL-XL, and MCL-1 by quantitative flow cytometry (QFCM) using validated antibodies.


Assuntos
Citometria de Fluxo/métodos , Proteínas Proto-Oncogênicas c-bcl-2/análise , Linhagem Celular , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína bcl-X/análise , Proteína bcl-X/metabolismo
18.
Pak J Pharm Sci ; 32(5(Supplementary)): 2237-2243, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31894049

RESUMO

Hispolon, a bioactive polyphenolic entity extracted from Phellinus linteus, possesses anticancer, antiinflammatory and anti-oxidant properties. Despite the reported therapeutic effects of this natural chemical entity, inhibitory potential of hispolon towards prostate carcinoma DU145 cells and mechanism of its action are yet to be explicated. Deregulated STAT3 pathway performs multifaceted functions in facilitating the development of cancer. Here, we have investigated the mechanism of hispolon by which it exerts its anticancer effects in DU145 cells and whether its anticancer activity is mediated by modulation of STAT3. Our outcomes show that hispolon significantly halted the multiplication of DU145 cells as well as arrested cell cycle at S phase. S phase arrest induced by hispolon was associated with downregulation of cyclin B1, cyclin D1 and CDK4 while up-regulation of p21. Moreover, hispolon treatment leads towards induction of apoptosis in a dose-dependent mode in DU145 cells. Hispolon induced modulation of Bcl-2 family proteins lead towards loss of MMP allowing the discharge of cytochrome c from mitochondrial porin channels which triggered the cascade of caspases ultimately causing cellular death. We further investigated the role of hispolon in mediating deregulated STAT3 pathways in DU145 cells. Hispolon has potential to downregulate the p-STAT3 expression with no effect on total STAT3. Contemporaneously, these results represent that hispolon's anticancer mechanism of action proceeds via downregulating the phosphorylation of STAT3 and induction of apoptosis via mitochondrial pathway.


Assuntos
Apoptose/efeitos dos fármacos , Catecóis/farmacologia , Mitocôndrias/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Fator de Transcrição STAT3/fisiologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citometria de Fluxo , Humanos , Masculino , Fosforilação , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Transdução de Sinais/efeitos dos fármacos
19.
Medicine (Baltimore) ; 97(50): e13297, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30557977

RESUMO

PURPOSE: This study aimed to identify the underlying mechanisms in pancreatic cancer (PC) carcinogenesis and those as potential prognostic biomarkers, which can also be served as new therapeutic targets of PC. METHODS: Differentially expressed genes (DEGs) were identified between PC tumor tissues and adjacent normal tissue samples from a public GSE62452 dataset, followed by functional and pathway enrichment analysis. Then, protein-protein interaction (PPI) network was constructed and prognosis-related genes were screened based on genes in the PPI network, before which prognostic gene-related miRNA regulatory network was constructed. Functions of the prognostic gene in the network were enriched before which Kaplan-Meier plots were calculated for significant genes. Moreover, we predicted related drug molecules based on target genes in the miRNA regulatory network. Furthermore, another independent GSE60979 dataset was downloaded to validate the potentially significant genes. RESULTS: In the GSE62452 dataset, 1017 significant DEGs were identified. Twenty-six important prognostic-related genes were found using multivariate Cox regression analysis. Through pathway enrichment analysis and miRNA regulatory analysis, we found that the 5 genes, such as Interleukin 22 Receptor Subunit Alpha 1 (IL22RA1), BCL2 Like 1 (BCL2L1), STAT1, MYC Proto-Oncogene (MYC), and Signal Transducer And Activator Of Transcription 2 (STAT2), involved in the Jak-STAT signaling pathway were significantly associated with prognosis. Moreover, the expression change of these 5 genes was further validated using another microarray dataset. Additionally, we identified camptothecin as an effective drug for PC. CONCLUSION: IL22RA1, BCL2L1, STAT1, MYC, and STAT2 involved in the Jak-STAT signaling pathway may be significantly associated with prognosis of PC.


Assuntos
Biomarcadores/análise , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Prognóstico , Humanos , Estimativa de Kaplan-Meier , Modelos de Riscos Proporcionais , Análise Serial de Proteínas/métodos , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-myc/análise , Receptores de Interleucina/análise , Fator de Transcrição STAT1/análise , Fator de Transcrição STAT2/análise
20.
Expert Rev Hematol ; 11(12): 915-920, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30428277

RESUMO

Introduction: Treatment of multiple myeloma (MM) in the relapsed setting remains challenging, despite recent impressive advances in the management of these patients. Venetoclax (ABT-199) is a BCL-2 inhibitor recently approved by the US food and drug administration for treatment of chronic lymphocytic leukemia but the drug has shown activity in a number of hematological malignancies. Venetoclax has broadened the treatment options for patients with relapsed or refractory MM. Approximately, 20% of myeloma patients will exhibit t (11;14) associated with high BCL-2 expression making venetoclax an attractive therapeutic option. The efficacy of venetoclax is not uniquely restricted to this population. Areas covered: This review will summarize the mechanism of action, toxicity profile, and published data on venetoclax use in MM, moving the field toward personalized medicine in the treatment of myeloma. Expert commentary: Numerous phase 1/2 clinical trials are evaluating the efficacy and safety of venetoclax monotherapy and in combinations in the relapse setting. These trials show better outcomes in the subgroup of patients harboring t(11;14).


Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Sulfonamidas/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Mieloma Múltiplo/patologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Prevenção Secundária , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia
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