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1.
Cardiovasc Res ; 119(3): 759-771, 2023 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-36001550

RESUMEN

AIMS: Degenerative mitral valve dystrophy (MVD) leading to mitral valve prolapse is the most frequent form of MV disease, and there is currently no pharmacological treatment available. The limited understanding of the pathophysiological mechanisms leading to MVD limits our ability to identify therapeutic targets. This study aimed to reveal the main pathophysiological pathways involved in MVD via the multimodality imaging and transcriptomic analysis of the new and unique knock-in (KI) rat model for the FilaminA-P637Q (FlnA-P637Q) mutation associated-MVD. METHODS AND RESULTS: Wild-type (WT) and KI rats were evaluated morphologically, functionally, and histologically between 3-week-old and 3-to-6-month-old based on Doppler echocardiography, 3D micro-computed tomography (microCT), and standard histology. RNA-sequencing and Assay for Transposase-Accessible Chromatin (ATAC-seq) were performed on 3-week-old WT and KI mitral valves and valvular cells, respectively, to highlight the main signalling pathways associated with MVD. Echocardiographic exploration confirmed MV elongation (2.0 ± 0.1 mm vs. 1.8 ± 0.1, P = 0.001), as well as MV thickening and prolapse in KI animals compared to WT at 3 weeks. 3D MV volume quantified by microCT was significantly increased in KI animals (+58% vs. WT, P = 0.02). Histological analyses revealed a myxomatous remodelling in KI MV characterized by proteoglycans accumulation. A persistent phenotype was observed in adult KI rats. Signalling pathways related to extracellular matrix homeostasis, response to molecular stress, epithelial cell migration, endothelial to mesenchymal transition, chemotaxis and immune cell migration, were identified based on RNA-seq analysis. ATAC-seq analysis points to the critical role of transforming growth factor-ß and inflammation in the disease. CONCLUSION: The KI FlnA-P637Q rat model mimics human myxomatous MVD, offering a unique opportunity to decipher pathophysiological mechanisms related to this disease. Extracellular matrix organization, epithelial cell migration, response to mechanical stress, and a central contribution of immune cells are highlighted as the main signalling pathways leading to myxomatous MVD. Our findings pave the road to decipher underlying molecular mechanisms and the specific role of distinct cell populations in this context.


Asunto(s)
Prolapso de la Válvula Mitral , Válvula Mitral , Adulto , Humanos , Ratas , Animales , Lactante , Válvula Mitral/metabolismo , Filaminas/genética , Filaminas/metabolismo , Transcriptoma , Microtomografía por Rayos X , Prolapso de la Válvula Mitral/patología , Fenotipo
2.
Cell Immunol ; 344: 103961, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31472938

RESUMEN

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous cancer, which is immunogenic, regardless of the presence of MCPyV (80% of cases). The identification of MCC-specific epitopes recognized by CD8 T cells is crucial to expand the arsenal of immunotherapeutic treatments. Until now, most efforts focused on the identification of virus-specific epitopes, whereas immune responses directed against shared cellular tumor-specific antigens have not been evidenced. In this study, we measured T-cell responses against viral (n = 3) and tumor antigens (n = 47) from TILs derived from 21 MCC tumors. Virus-specific CD8 T-cell responses dominated MCC-specific immune responses, and we identified two new HLA-peptide complexes derived from the LT antigen, located in a region encompassing 3 previously identified epitopes. Finally, we show that MAGE-A3 antigen, frequently expressed by MCC tumors, was recognized by CD8 TILs from a virus-negative MCC tumor and thus could be a target for immunotherapy in this setting.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Carcinoma de Células de Merkel/inmunología , Neoplasias Cutáneas/inmunología , Animales , Antígenos de Neoplasias/inmunología , Antígenos Virales/inmunología , Células COS , Línea Celular Tumoral , Chlorocebus aethiops , Epítopos de Linfocito T/inmunología , Femenino , Antígenos HLA/inmunología , Humanos , Masculino , Proteínas de Neoplasias/inmunología
3.
Neurochem Int ; 52(8): 1416-21, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18442871

RESUMEN

In the present study, the purpose is to determine activities of monoamine oxidases (MAO) in the brain of 263K scrapie-infected hamsters during the development of this experimental prion disease. Indeed, MAO activity modifications which have already been related in aging and neurodegenerations is suspected to be involved in the neuron loss process by elevated hydrogen peroxide formation. Monoamine oxidase type A (MAO-A) and B (MAO-B) activities were followed in the brain at different stages of the disease. MAO-A activity did not change significantly during the evolution of the disease. However, concerning the MAO-B activity, a significant increase was observed from 50 days post-infection and through the course of the disease and reached 42.9+/-5.3% at its ultimate stage. Regarding these results, MAO-B could be a potential therapeutic target then we have performed a pre-clinical treatment with irreversible (Selegiline or L-deprenyl) or and reversible (MS-9510) MAO-B inhibitors used alone or in association with an anti-scrapie drug such as MS-8209, an amphotericin B derivative. Our results show that none of the MAO-B inhibitors used was able to delay the onset of the disease. Neither these MAO-B inhibitors nor R-NMDA inhibitors (MK-801) can enhance the effects of MS-8209. The present findings clearly indicate a significant increase of cerebral MAO-B activity in scrapie-infected hamsters. Furthermore, inhibitors of MAO-B do not have any curative or palliative effect on this experimental model indicating that the raise of this activity is probably more a consequence rather than a causal event of the neurodegenerative process.


Asunto(s)
Monoaminas Biogénicas/metabolismo , Encéfalo/enzimología , Monoaminooxidasa/metabolismo , Proteínas PrPSc/metabolismo , Scrapie/enzimología , Anfotericina B/análogos & derivados , Anfotericina B/farmacología , Animales , Encéfalo/fisiopatología , Cricetinae , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Mesocricetus , Inhibidores de la Monoaminooxidasa/farmacología , Degeneración Nerviosa/enzimología , Degeneración Nerviosa/fisiopatología , Scrapie/fisiopatología
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