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1.
Nefrología (Madr.) ; 37(2): 118-125, mar.-abr. 2017. ilus, graf, tab
Artigo em Espanhol | IBECS | ID: ibc-162165

RESUMO

El conocimiento de las vías de señalización implicadas en distintas enfermedades ha permitido avances en el entendimiento del modelo fisiopatológico, diagnóstico y terapéutico de varias enfermedades inflamatorias y autoinmunes. El lupus eritematoso sistémico es una enfermedad autoinmune ampliamente estudiada, la cual puede afectar múltiples órganos, con un importante impacto en la morbimortalidad cuando existe afectación renal. Durante los últimos 10 años ha aumentado el interés sobre el papel de la vía de señalización del TWEAK/Fn14 en la nefritis lúpica al igual que en otros escenarios clínicos. Este artículo realiza una revisión de la literatura del papel de esta vía dentro de la nefritis lúpica, recalca la importancia del TWEAK en orina (uTWEAK) como biomarcador de la enfermedad, indica los resultados favorables obtenidos en la inhibición de la vía del TWEAK/Fn14 como diana terapéutica en modelos experimentales animales publicados en la literatura y muestra su posible utilidad en otros escenarios. Los diferentes ensayos clínicos en curso y otras futuras investigaciones darán un mejor panorama en cuanto al beneficio real del bloqueo de esta vía en el curso clínico de estas enfermedades (AU)


Knowledge of the signalling pathways involved in various diseases has enabled advances in the understanding of pathophysiological, diagnostic and therapeutic models of several inflammatory and autoimmune diseases. Systemic lupus erythematosus is a widely studied autoimmune disease that can affect multiple organs, with a major impact on morbidity and mortality when it involves the kidneys. Over the past 10 years, interest in the role of the TWEAK/Fn14 signalling pathway in lupus nephritis, as well as other clinical settings, has increased. By reviewing the literature, this article assesses the role of this pathway in lupus nephritis, underlines the importance of TWEAK in urine (uTWEAK) as a biomarker of the disease and stresses the favourable results published in the literature from the inhibition of the TWEAK/Fn14 pathway as a therapeutic target in experimental animal models, demonstrating its potential application in other settings. Results of ongoing clinical trials and future research will give us a better understanding of the real benefit of blocking this pathway in the clinical course of several conditions (AU)


Assuntos
Humanos , Transdução de Sinais/genética , Nefrite Lúpica/genética , Biomarcadores/análise , Lúpus Eritematoso Sistêmico/complicações , Fator de Indução de Apoptose/urina , Urinálise
2.
Clín. investig. arterioscler. (Ed. impr.) ; 27(1): 17-25, ene.-feb. 2015. ilus
Artigo em Espanhol | IBECS | ID: ibc-131379

RESUMO

Objetivos: La interacción del factor inductor débil de apoptosis similar al factor de necrosis tumoral (TWEAK) con su receptor Fn14 acelera el desarrollo de la lesión aterosclerótica en ratones deficientes en ApoE (ApoE KO). En este trabajo hemos analizado el efecto de un inhibidor de la HMG-CoA reductasa, la atorvastatina, sobre el desarrollo de la lesión aterosclerótica acelerada por TWEAK en ratones ApoE KO. Materiales y métodos: Se alimentaron ratones ApoE KO de 8 semanas de edad durante 4 semanas con una dieta hiperlipidémica y se aleatorizaron en 3 grupos: ratones tratados i.p. con salino (control), tratados con TWEAK recombinante (10 μg/kg/2 veces a la semana) o tratados con TWEAK recombinante más atorvastatina (1 mg/kg/día) durante 4 semanas más. Se analizó el tamaño, la composición celular, la respuesta inflamatoria y la expresión de Fn14 en las lesiones ateroscleróticas presentes en la raíz aórtica de los ratones. Resultados: La inyección sistémica de TWEAK aumentó el tamaño de la lesión y el cociente colágeno/lípidos así como la respuesta inflamatoria asociada a un aumento en la actividad de NF-κB, expresión de MCP-1 y RANTES y a una mayor presencia de macrófagos en las placas ateroscleróticas de ratones ApoE KO. El tratamiento con atorvastatina fue capaz de prevenir los cambios inducidos por TWEAK en las lesiones ateroscleróticas. Finalmente, el tratamiento con atorvastatina disminuyó la expresión de Fn14 en las lesiones ateroscleróticas de ratones ApoE KO. Conclusiones: La atorvastatina previene los efectos proaterogénicos inducidos por TWEAK en el ratón ApoE KO, efecto relacionado con la inhibición de la expresión de Fn14. Estos resultados aportan nueva información sobre los efectos beneficiosos de las estatinas en el tratamiento de las enfermedades cardiovasculares


Aim: Interaction of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) with its receptor Fn14 accelerates atherosclerotic plaque development in ApoE deficient mice (ApoE KO). In this work, an analysis has been made on the effect of an HMG-CoA reductase inhibitor, atorvastatin, on atherosclerotic plaque development accelerated by TWEAK in ApoE KO mice. Materials and methods: Eight week-old ApoE KO mice were fed with a high cholesterol diet for 4 weeks. The animals were then randomized into 3 groups: mice injected i.p. with saline, recombinant TWEAK (10 μg/kg/twice a week), or recombinant TWEAK plus atorvastat in (1 mg/kg/day) for 4 weeks. The lesion size, cellular composition, lipid and collagen content were analyzed, as well as inflammatory response in atherosclerotic plaques present in aortic root of mice. Results: TWEAK treated mice showed an increase in atherosclerotic plaque size, as well as in collagen/lipid ratio compared with control mice. In addition, macrophage content, MCP-1 and RANTES expression, and NF-κB activation were augmented in atherosclerotic plaques present in aortic root of TWEAK treated mice compared with control mice. Treatment with atorvastatin prevented all these changes induced by TWEAK in atherosclerotic lesions. Atorvastatin treatment also decreased Fn14 expression in the atherosclerotic plaques of ApoE KO mice. Conclusions: Atorvastatin prevents the pro-atherogenic effects induced by TWEAK in ApoE KO mice, which could be related to the inhibition of Fn14 expression. The results of this study provide new information on the beneficial effects of statin treatment in cardiovascular diseases


Assuntos
Animais , Camundongos , Anticolesterolemiantes/farmacocinética , Aterosclerose/tratamento farmacológico , Fator de Indução de Apoptose , Progressão da Doença , Inflamação/fisiopatologia , Modelos Animais de Doenças , Apolipoproteínas E/deficiência
3.
Clin. transl. oncol. (Print) ; 17(1): 41-49, ene. 2015. tab, ilus
Artigo em Inglês | IBECS | ID: ibc-131903

RESUMO

Objectives. The present study is to evaluate the expression level of enhancer of zeste homolog 2 (EZH2) and vascular endothelial growth factor (VEGF), and analyze their correlations with clinicopathological characteristics and survival in patients with clear cell renal cell carcinoma (CCRCC). The effect of EZH2 on apoptosis and cell proliferation in 786-O renal cancer cell line is investigated. Methods. The expression level of EZH2 and VEGF was detected in 185 primary CCRCC patients’ tissues using tissue microarray and immunohistochemistry. Small interfering RNA or enhanced green fluorescent protein transfection was employed to investigate the effect of EZH2 inhibition or overexpression on VEGF expression, apoptosis and cell proliferation in 786-O cells using flow cytometry, immunofluorescence microscopy, quantitative real-time reverse-transcription polymerase chain reaction and Western blot analysis. Results. High expression level of EZH2 and VEGF was observed in advanced CCRCC and correlated with the TNM stage (p = 0.013, p = 0.001) and distant metastasis (p = 0.011, p = 0.038), respectively. EZH2 was positively correlated with VEGF in CCRCC tissues (correlation coefficient = 0.850, p < 0.001). Kaplan–Meier survival analysis revealed that patients with positive EZH2 expression had a shorter overall survival time compared to patients with negative EZH2 expression (34.3 vs. 67.2, p < 0.001). In 786-O cells, EZH2 silencing inhibited VEGF expression and cell proliferation while increasing apoptosis (p < 0.001). EZH2 overexpression promoted VEGF expression and cell proliferation while inhibiting apoptosis (p < 0.001). Conclusions. EZH2 correlates positively with VEGF and associates with adverse clinicopathologic characteristics and shorter survival time in CCRCC patients. EZH2 accelerates antiapoptosis and cell cycle in 786-O cells (AU)


No disponible


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Carcinoma de Células Renais/diagnóstico , Regulação Neoplásica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/imunologia , Receptor 3 de Fatores de Crescimento do Endotélio Vascular , MicroRNAs , Western Blotting/métodos , Western Blotting/tendências , Estimativa de Kaplan-Meier , Apoptose , Fator de Indução de Apoptose , Citometria de Fluxo/tendências
5.
Rev. esp. enferm. dig ; 102(1): 41-50, ene. 2010. ilus
Artigo em Inglês | IBECS | ID: ibc-78232

RESUMO

Infection with H. pylori plays a role in the pathogenesis of gastritis,peptic ulcer, gastric carcinoma, and gastric lymphoma, butmechanisms leading to the various clinical manifestations remainobscure and are the primary focus of research in this field.Proliferation and apoptosis are essential in the maintenance ofgastric tissue homeostasis, and changes seen in their balance maycondition gastric mucosal changes during infection. Thus, excessiveapoptosis or proliferation inhibition will result in cell massloss, which is observed in gastric ulcers. On the other hand, acceleratedepithelial cell turnover is characteristic of carcinogenic mucosas.There is also scientific evidence that demonstrates an associationbetween H. pylori infection and exacerbated synthesis offree radicals, the latter being well known as a primary cause of celldeath.A thorough review of the literature and the results of our experimentalresearch lead to conclude that H. pylori-induced oxidativestress activates the intrinsic pathway of apoptosis. Structuraland functional changes caused by this process on mitochondrialorganelles lie at the origin of gastric mucosal toxicity, and lead tothe development of the various manifestations associated with thisinfection. Based on these data we suggest that therapy with antioxidantsshould prove beneficial for the clinical management ofpatients with H. pylori infection(AU)


Assuntos
Humanos , Masculino , Feminino , Estresse Oxidativo/imunologia , Estresse Oxidativo/fisiologia , Helicobacter pylori/isolamento & purificação , Helicobacter pylori/metabolismo , Apoptose/fisiologia , Fator de Indução de Apoptose/metabolismo , Estresse Oxidativo/genética , Helicobacter pylori/patogenicidade , Infecções por Helicobacter/fisiopatologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Citometria de Fluxo/métodos , Citometria de Fluxo
6.
Actas dermo-sifiliogr. (Ed. impr.) ; 100(5): 420-424, jun.-jul. 2009. ilus
Artigo em Espanhol | IBECS | ID: ibc-60350

RESUMO

Introducción y objetivos. La psoriasis es una enfermedad inflamatoria cutánea de naturaleza inmunológica mediada por citoquinas de tipo Th1. El tratamiento con anticuerpos anti-factor de necrosis tumoral α (TNF-α) (infliximab) ha proporcionado respuestas clínicas significativas; sin embargo, los mecanismos implicadosen la curación no están bien aclarados. El objetivo del presente trabajo es evaluar las variaciones de la histología y en la expresión de marcadores de proliferación y apoptosis, en biopsias cutáneas secuenciales de pacientes con psoriasis tratados con in fliximab. Material y métodos. Se estudiaron biopsias de piel (sana y lesionada) de 3 pacientes afectados de psoriasis generalizada moderada-grave (índice de área y gravedad de la soriasis [PASI]: 35 de media) tratados con infusiones por vía intravenosa de infliximab (5 mg/kg) en las semanas 0, 2 y 6. Las biopsias se realizaron en los días 0, 14 y 28, y fueron procesadas para estudio histológico convencional e inmunohistoquímico con marcadores de apoptosis–TP53, BCL-2 y anticaspasas 3 y 8– y de proliferación celular –Ki67–. Resultados. El tratamiento con infliximab se asoció con una significativa mejoría clínica en los 3 pacientes (PASI medio: 21,6 a los 14 días y 13,9 a las 6 semanas), que se correlacionó con la desaparición progresiva de las lesiones histológicas, con disminución de la proliferación epidérmica. Sin embargo, no observamos imágenes de apoptosis ni obtuvimos positividad con los anticuerpos anticaspasas. La expresión de TP53 disminuyó a las2 semanas del inicio del tratamiento, siendo similar a la piel normal a los 28 días. Conclusiones. La respuesta clínica e histológica de la psoriasis con infliximab no se asoció a un incremento significativo en los marcadores de apoptosis evaluados (AU)


Background and objectives. Psoriasis is an inflammatory skin disease of immunologic nature that is mediated by T-helper-1 cytokines. Clinical response to treatment with antitumor necrosis factor (TNF) –α antibodies (infliximab) has been significant; however, the mechanisms for clearance of lesions have not been elucidated. The aim of the present study was to assess variations in the histology and expression of proliferation and apoptotic markers in sequential skin biopsies of patients with psoriasis treated with infliximab. Material and methods. We studied skin biopsies (of lesioned and healthy skin) from 3 patients with extensive moderate-to-severe psoriasis (mean psoriasis area and severity index [PASI] score, 35) treated with intravenous infliximab infusions (5 mg/kg) at weeks 0, 2, and 6. Biopsies were taken on days 0, 14, and 28, and were processed for conventional histological and immunohistochemical study. The apoptotic markers used were TP53, B-cell lymphoma 2 protein, anticaspase 3, and anticaspase 8. The cell proliferation marker used was Ki67. Results. Treatment with infliximab was associated with a significant clinical improvement in 3 patients (mean PASI score, 21.6 at 14 days and 13.9 at 6 weeks), which correlated with the progressive disappearance of histological lesions with a decrease in epidermal proliferation. However, apoptosis was not observed, and the samples tested negative for anticaspase antibodies. Expression of TP53 decreased 2 weeks after starting treatment, and was similar to that in normal skin at 28 days. Conclusions. Clinical and histological response of psoriasis to infliximab was not associated with a significant increase in the apoptotic markers assessed (AU)


Assuntos
Humanos , Anticorpos Monoclonais/farmacocinética , Psoríase/tratamento farmacológico , Fatores de Necrose Tumoral/antagonistas & inibidores , Biomarcadores/análise , Fator de Indução de Apoptose/análise , Caspases/antagonistas & inibidores , Genes p53
7.
Av. odontoestomatol ; 25(1): 11-18, ene.-feb. 2009. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-85491

RESUMO

El liquen plano oral (LPO) es una enfermedad mucocutánea inflamatoria crónica, con una etiología aún desconocida, de base autoinmune, que suele cursar con manifestaciones orales, con una clínica e histología características y de curso evolutivo benigno, pero susceptible de transformación maligna. En los últimos años se ha investigado la relación entre su patogenia y los mecanismos apoptóticos de destrucción celular. Material y método: Búsqueda bibliográfica en el servidor de la U.S. National Library of Medicine and the National Institutes of Health (Pubmed) con las palabras clave “apoptosis AND oral lichen planus”. Discusión: Existen diferentes estudios que evalúan la relación de los diferentes marcadores apoptóticos (TNF-α, bcl-2, Fas, p53, BMP-4, granzima B, MMP…) con la patogenia, evolución, clínica y malignización del LPO. Para la determinación de estos factores se emplean técnicas de anatomía patológica e inmunohistoquímica(TUNEL, PCR,…).Conclusión: no existe consenso en los resultados y las consiguientes conclusiones obtenidas en los diferentes estudios sobre la influencia de cada uno de los marcadores apoptóticos en el desarrollo de las lesiones de LPO. Es necesaria una mayor y más profunda investigación en búsqueda de un factor siempre asociado a las formas clínicas agresivas con mayor tendencia a la malignización (AU)


Oral lichen planus (OLP) is a mucocutaneous inflammatory chronic disease, with unknown etiology, autoinmune, usually associated with characteristical oral manifestations. Despite it has a benign evolution, is possible to become malign. Lately, relation between the pathogenesis and apoptotic cells destroy has been investigated. Methods: A bibliography survey was carried out with the U.S. National Library of Medicine and the National Institutes of Health (Pubmed) with the keywords “apoptosis AND oral lichen planus”. Discussion: Several trials evaluate the relationship among several apoptotic markers (TNF-α, bcl-2, Fas, p53,BMP-4, granzyme B, MMP…) and OLP pathogenesis, evolution, clinic and malignization. These studies employed histology and immunohistochemistry (TUNEL, PCR)Conclusion: Lack of consensus on results and conclusions about the influence of each apoptotic marker in the OLP development. Further investigation is required to obtain an apoptotic marker strongly associated with aggressive clinic and high-risk of malignancy (AU)


Assuntos
Humanos , Apoptose/fisiologia , Líquen Plano Bucal/fisiopatologia , Fator de Indução de Apoptose/análise , Proteína Supressora de Tumor p53/análise , Queratinócitos , Proteínas Proto-Oncogênicas c-bcl-2/análise , Fatores de Risco
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