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1.
Biomolecules ; 13(5)2023 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-37238612

RESUMEN

Neutrophils are the most abundant leukocyte in circulation and are the first line of defense after an infection or injury. Neutrophils have a broad spectrum of functions, including phagocytosis of microorganisms, the release of pro-inflammatory cytokines and chemokines, oxidative burst, and the formation of neutrophil extracellular traps. Traditionally, neutrophils were thought to be most important for acute inflammatory responses, with a short half-life and a more static response to infections and injury. However, this view has changed in recent years showing neutrophil heterogeneity and dynamics, indicating a much more regulated and flexible response. Here we will discuss the role of neutrophils in aging and neurological disorders; specifically, we focus on recent data indicating the impact of neutrophils in chronic inflammatory processes and their contribution to neurological diseases. Lastly, we aim to conclude that reactive neutrophils directly contribute to increased vascular inflammation and age-related diseases.


Asunto(s)
Trampas Extracelulares , Enfermedades del Sistema Nervioso , Humanos , Neutrófilos , Citocinas , Fagocitosis , Inflamación
2.
EMBO Rep ; 21(9): e50446, 2020 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-32749065

RESUMEN

Melanoma progression is generally associated with increased transcriptional activity mediated by the Yes-associated protein (YAP). Mechanical signals from the extracellular matrix are sensed by YAP, which then activates the expression of proliferative genes, promoting melanoma progression and drug resistance. Which extracellular signals induce mechanotransduction, and how this is mediated, is not completely understood. Here, using secretome analyses, we reveal the extracellular accumulation of amyloidogenic proteins, i.e. premelanosome protein (PMEL), in metastatic melanoma, together with proteins that assist amyloid maturation into fibrils. We also confirm the accumulation of amyloid-like aggregates, similar to those detected in Alzheimer disease, in metastatic cell lines, as well as in human melanoma biopsies. Mechanistically, beta-secretase 2 (BACE2) regulates the maturation of these aggregates, which in turn induce YAP activity. We also demonstrate that recombinant PMEL fibrils are sufficient to induce mechanotransduction, triggering YAP signaling. Finally, we demonstrate that BACE inhibition affects cell proliferation and increases drug sensitivity, highlighting the importance of amyloids for melanoma survival, and the use of beta-secretase inhibitors as potential therapeutic approach for metastatic melanoma.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Melanoma , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Amiloidogénicas , Humanos , Mecanotransducción Celular , Melanoma/tratamiento farmacológico , Melanoma/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
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