Browsing by Author "Amigo, Julio"

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    Imatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann-Pick type C disease
    (WILEY, 2008) Alvarez, Alejandra R.; Klein, Andres; Castro, Juan; Cancino, Gonzalo I.; Amigo, Julio; Mosqueira, Matias; Vargas, Lina M.; Yevenes, L. Fernanda; Bronfman, Francisca C.; Zanlungo, Silvana
    Niemann-Pick type C (NPC) disease is a fatal autosomal recessive disorder characterized by the accumulation of free cholesterol and glycosphingo-lipids in the endosomal-lysosomal system. Patients with NPC disease have markedly progressive neuronal loss, mainly of cerebellar Purkinje neurons. There is strong evidence indicating that cholesterol accumulation and trafficking defects activate apoptosis in NPC brains. The purpose of this study was to analyze the relevance of apoptosis and particularly the proapoptotic c-Abl/p73 system in cerebellar neuron degeneration in NPC disease. We used the NPC1 mouse model to evaluate c-Abl/p73 expression and activation in the cerebellum and the effect of therapy with the c-Abl-specific inhibitor imatinib. The proapoptotic c-Abl/p73 system and the p73 target genes are expressed in the cerebellums of NPC mice. Furthermore, inhibition of c-Abl with imatinib preserved Purkinje neurons and reduced general cell apoptosis in the cerebellum, improved neurological symptoms, and increased the survival of NPC mice. Moreover, this prosurvival effect correlated with reduced mRNA levels of p73 proapoptotic target genes. Our results suggest that the c-Abl/p73 pathway is involved in NPC neurodegeneration and show that treatment with c-Abl inhibitors is useful in delaying progressive neurodegeneration, supporting the use of imatinib for clinical treatment of patients with NPC disease.
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    Mecanismos de activación y coordinación de las señales de Ca2+ involucradas en la migración de las células endoteliales y la angiogénesis
    (2020) Espinoza Amador, Hilda Andrea; Figueroa, Xavier; Amigo, Julio; Pontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas
    La migración endotelial es clave para la angiogénesis y depende de un incremento en la [Ca2+]i. El intercambiador Na+-Ca2+ (NCX) es crítico en el control del Ca2+ y podría contribuir al aumento en la [Ca2+]i de las células endoteliales a través de la activación de su modo reverso mediante el acoplamiento con los canales de Na+ dependientes de voltaje (Nav). La comunicación vía uniones comunicantes coordina los cambios en la [Ca2+]i, pero no se ha evaluado la participación de los hemicanales en este proceso. En esta tesis se descubrió un nuevo mecanismo de regulación de la señalización de Ca2+ endotelial durante la angiogénesis, el cual depende de la activación secuencial de los canales Nav sensibles a TTX, Nav1.2 y Nav1.6, del modo reverso del NCX y los hemicanales formados por Cx43. La activación del modo reverso del NCX mediada por los canales Nav sensibles a TTX lleva a un aumento inicial de la [Ca2+]i, la cual induce la producción de NO y la apertura de los hemicanales formados por Cx43 a través de la S-nitrosilación de esta Cx. Además, este mecanismo depende de la redistribución celular de los canales Nav1.2 y los hemicanales formados por Cx43 junto a las caveolas hacia la parte posterior de las células endoteliales, concentrando de esta forma la señalización de Ca2+ en esta región celular. Estos resultados demuestran que los canales Nav sensibles a TTX y los hemicanales formados por Cx43 son fundamentales en el desarrollo de la migración endotelial y la angiogénesis.
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    The Differential Paracrine Role of the Endothelium in Prostate Cancer Cells
    (2022) Torres-Estay, Veronica; Mastri, Michalis; Rosario, Spencer; Fuenzalida, Patricia; Echeverria, Carolina E.; Flores, Emilia; Watts, Anica; Cerda-Infante, Javier; Montecinos, Viviana P.; Sotomayor, Paula C.; Amigo, Julio; Escudero, Carlos; Nualart, Francisco; Ebos, John M. L.; Smiraglia, Dominic J.; Godoy, Alejandro S.
    Simple Summary A growing body of literature supports the concept that a tumor mass is under the strict control of the microvascular endothelium and that the perfusion of oxygen and nutrients by capillary vessels to the tumor mass is reinforced by potent paracrine activity from the vascular endothelial cells. In our study, we investigate the biological and molecular implications of the paracrine crosstalk between vascular endothelial cells and prostate cancer cells. Our results indicate that the endothelial cells were able to secrete molecular signals that promote the proliferation and growth of low and highly aggressive prostate cancer cells and selectively increased the migration, invasion and metastatic potential of highly aggressive prostate cancer cells. The molecular analyses indicated that endothelial cells induced a differential effect on gene expression profile when comparing low versus highly aggressive prostate cancer cells, causing an enrichment of epigenetic changes in migratory pathways in highly aggressive prostate cancer cells. In conclusion, our results indicate that endothelial cells release signals that favor tumor growth and aggressiveness and that this interaction may play an important role in the progression of prostate cancer. The survival of patients with solid tumors, such as prostate cancer (PCa), has been limited and fleeting with anti-angiogenic therapies. It was previously thought that the mechanism by which the vasculature regulates tumor growth was driven by a passive movement of oxygen and nutrients to the tumor tissue. However, previous evidence suggests that endothelial cells have an alternative role in changing the behavior of tumor cells and contributing to cancer progression. Determining the impact of molecular signals/growth factors released by endothelial cells (ECs) on established PCa cell lines in vitro and in vivo could help to explain the mechanism by which ECs regulate tumor growth. Using cell-conditioned media collected from HUVEC (HUVEC-CM), our data show the stimulated proliferation of all the PCa cell lines tested. However, in more aggressive PCa cell lines, HUVEC-CM selectively promoted migration and invasion in vitro and in vivo. Using a PCa-cell-line-derived xenograft model co-injected with HUVEC or preincubated with HUVEC-CM, our results are consistent with the in vitro data, showing enhanced tumor growth, increased tumor microvasculature and promoted metastasis. Gene set enrichment analyses from RNA-Seq gene expression profiles showed that HUVEC-CM induced a differential effect on gene expression when comparing low versus highly aggressive PCa cell lines, demonstrating epigenetic and migratory pathway enrichments in highly aggressive PCa cells. In summary, paracrine stimulation by HUVEC increased PCa cell proliferation and tumor growth and selectively promoted migration and metastatic potential in more aggressive PCa cell lines.
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    The Reprimo gene family member, reprimo-like (rprml), is required for blood development in embryonic zebrafish
    (2019) Stanic, Karen; Reig, German; Figueroa, Ricardo J.; Retamal, PedroA.; Wichmann Pérez, Ignacio Alberto; Opazo, JuanC.; Owen, Gareth Ivor; Corvalán R., Alejandro; Concha, Miguel L.; Amigo, Julio
    The Reprimo gene family comprises a group of sing le-exon genes for which their physiological function remains poorly understood. Heretofore, mammalian Reprimo (RPRM) has been described as a putative p53-dependent tumor suppressor gene that functions at the G2/M cell cycle checkpoint. Another family member, Reprimo-like (RPRML), has not yet an established role in physiology or pathology. Importantly, RPRML expression pattern is conserved between zebrafish and human species. Here, using CRISPR-Cas9 and antisense morpholino oligonucleotides, we disrupt the expression of rprml in zebrafish and demonstrate that its loss leads to impaired definitive hematopoiesis. The formation of hemangioblasts and the primitive wave of hematopoiesis occur normally in absence of rprml Later in development there is a significant reduction in erythroid-myeloid precursors (EMP) at the posterior blood island (PBI) and a significant decline of definitive hematopoietic stem/progenitor cells (HSPCs). Furthermore, loss of rprml also increases the activity of caspase-3 in endothelial cells within the caudal hematopoietic tissue (CHT), the first perivascular niche where HSPCs reside during zebrafish embryonic development. Herein, we report an essential role for rprml during hematovascular development in zebrafish embryos, specifically during the definitive waves of hematopoiesis, indicating for the first time a physiological role for the rprml gene.
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    The reprimo-like gene is an epigenetic-mediated tumor suppressor and a candidate biomarker for the non-invasive detection of gastric cancer
    (2020) Alarcón Alarcón, María Alejandra; Olivares, W.; Córdova Delgado, M.; Wichmann Pérez, Ignacio Alberto; Amigo, Julio; Norero Muñoz, Enrique; Riquelme Pérez, Arnoldo; Garrido S., Marcelo; Owen, Gareth Ivor; Corvalán R., Alejandro; Muñoz-Medel, M.; Mayo, T. de; Carrasco-Aviño, G.; Landeros, N.; Villarroel Espíndola, F.