Examinando por Autor "Aguayo, F."

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    Chronic restraint stress produces sex-specific behavioral and molecular outcomes in the dorsal and ventral rat hippocampus
    (Elsevier Inc., 2022-03) Olave, F.; Aguayo, F.; Román-Albasini, L.; Corrales, W.; Silva, J.; González, P.; Lagos, S.; García, M.; Alarcón-Mardones, M.; Rojas, P.; Xu, X.; Cidlowski, J.
    Stress-related disorders display differences at multiple levels according to sex. While most studies have been conducted in male rodents, less is known about comparable outcomes in females. In this study, we found that the chronic restraint stress model (2.5 h/day for 14 days) triggers different somatic responses in male and female adult rats. Chronic restraint produced a loss in sucrose preference and novel location preference in male rats. However, chronic restraint failed to produce loss of sucrose preference in females, while it improved spatial performance. We then characterized the molecular responses associated with these behaviors in the hippocampus, comparing the dorsal and ventral poles. Notably, sex- and hippocampal pole-specific transcriptional signatures were observed, along with a significant concordance between the female ventral and male dorsal profiles. Functional enrichment analysis revealed both shared and specific terms associated with each pole and sex. By looking into signaling pathways that were associated with these terms, we found an ample array of sex differences in the dorsal and, to a lesser extent, in the ventral hippocampus. These differences were mainly present in synaptic TrkB signaling, Akt pathway, and glutamatergic receptors. Unexpectedly, the effects of stress on these pathways were rather minimal and mostly dissociated from the sex-specific behavioral outcomes. Our study suggests that female rats are resilient and males susceptible to the restraint stress exposure in the sucrose preference and object location tests, while the activity of canonical signaling pathways is primarily determined by sex rather than stress in the dorsal and ventral hippocampus.
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    Phosphorylation of Endothelin-Converting Enzyme-1c at Serines 18 and 20 by CK2 Promotes Aggressiveness Traits in Colorectal Cancer Cells
    (Frontiers Media S.A., 2020-07) Pérez-Moreno, P.; Quezada-Meza, C.; Chavez-Almarza, C.; Niechi, I.; Silva-Pavez, E.; Trigo-Hidalgo, C.; Aguayo, F.; Jara, L.; Cáceres-Verschae, A.; Varas-Godoy, M.; Díaz, V.M.; García de Herreros, A.
    Endothelin-converting enzyme-1 (ECE1) activates the endothelin-1 peptide, which upregulates pathways that are related to diverse hallmarks of cancer. ECE1 is expressed as four isoforms differing in their N-terminal domains. Protein kinase CK2 phosphorylates the N-terminus of isoform ECE1c, enhancing its stability and promoting invasiveness of colorectal cancer cells. However, the specific residues in ECE1c that are phosphorylated by CK2 and how this phosphorylation promotes invasiveness was unknown. Here we demonstrate that Ser-18 and Ser-20 are the bona fide residues phosphorylated by CK2 in ECE1c. Thus, biphospho-mimetic ECE1cDD and biphospho-resistant ECE1cAA mutants were constructed and stably expressed in different colorectal cancer cells through lentiviral transduction. Biphospho-mimetic ECE1cDD displayed the highest stability in cells, even in the presence of the specific CK2 inhibitor silmitasertib. Concordantly, ECE1cDD-expressing cells showed enhanced hallmarks of cancer, such as proliferation, migration, invasiveness, and self-renewal capacities. Conversely, cells expressing the less-stable biphospho-resistant ECE1cAA showed a reduction in these features, but also displayed an important sensitization to 5-fluorouracil, an antineoplastic agent traditionally used as therapy in colorectal cancer patients. Altogether, these findings suggest that phosphorylation of ECE1c at Ser-18 and Ser-20 by CK2 promotes aggressiveness in colorectal cancer cells. Therefore, phospho-ECE1c may constitute a novel biomarker of poor prognosis and CK2 inhibition may be envisioned as a potential therapy for colorectal cancer patients. © Copyright © 2020 Pérez-Moreno, Quezada-Meza, Chavez-Almarza, Niechi, Silva-Pavez, Trigo-Hidalgo, Aguayo, Jara, Cáceres-Verschae, Varas-Godoy, Díaz, García de Herreros, Burzio and Tapia.
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    The ROCK inhibitor Fasudil prevents chronic restraint stress-induced depressive-like behaviors and dendritic spine loss in rat hippocampus
    (Oxford University Press, 2017-04) García-Rojo, G.; Fresno, C.; Vilches, N.; Díaz-Véliz, G.; Mora, S.; Aguayo, F.; Pacheco, A.; Parra-Fiedler, N.; Parra, C.S.; Rojas, P.S.; Tejos, M.; Aliaga, E.; Fiedler, J.L.
    Background: Dendritic arbor simplification and dendritic spine loss in the hippocampus, a limbic structure implicated in mood disorders, are assumed to contribute to symptoms of depression. These morphological changes imply modifications in dendritic cytoskeleton. Rho GTPases are regulators of actin dynamics through their effector Rho kinase. We have reported that chronic stress promotes depressive-like behaviors in rats along with dendritic spine loss in apical dendrites of hippocampal pyramidal neurons, changes associated with Rho kinase activation. The present study proposes that the Rho kinase inhibitor Fasudil may prevent the stress-induced behavior and dendritic spine loss. Methods: Adult male Sprague-Dawley rats were injected with saline or Fasudil (i.p., 10 mg/kg) starting 4 days prior to and maintained during the restraint stress procedure (2.5 h/d for 14 days). Nonstressed control animals were injected with saline or Fasudil for 18 days. At 24 hours after treatment, forced swimming test, Golgi-staining, and immuno-western blot were performed. Results: Fasudil prevented stress-induced immobility observed in the forced swimming test. On the other hand, Fasudiltreated control animals showed behavioral patterns similar to those of saline-treated controls. Furthermore, we observed that stress induced an increase in the phosphorylation of MYPT1 in the hippocampus, an exclusive target of Rho kinase. This change was accompanied by dendritic spine loss of apical dendrites of pyramidal hippocampal neurons. Interestingly, increased pMYPT1 levels and spine loss were both prevented by Fasudil administration. Conclusion: Our findings suggest that Fasudil may prevent the development of abnormal behavior and spine loss induced by chronic stress by blocking Rho kinase activity.