Person:
Martín Adrados, Beatriz

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First Name
Beatriz
Last Name
Martín Adrados
URI
https://hdl.handle.net/20.500.14352/86251
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Medicina
Department
Inmunología, Oftalmología y ORL
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2020 - 20225
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Author: Nevzorova, Yulia ×

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Now showing 1 - 5 of 5
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    Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy
    (Cell Death and Disease, 2022) Hui, Ye; Chaobo, Chen; Hanghang, Wu; Kang, Zheng; Martín Adrados, Beatriz; Caparros, Esther; Francés, Rubén; Nelson, Leonard J.; Gómez Del Moral Martín-Consuegra, Manuel María; Asensio, Iris; Javier Vaquero; Bañares Cañizares, Rafael; Ávila, Matías A.; Andrade, Raúl J.; Lucena, María Isabel; Martínez Chantar, Maria Luz; Reeves, Helen L.; Masson, Steven; Blumberg, Richard S.; Gracia Sancho, Jordi; Nevzorova, Yulia; Martínez Naves, Eduardo; Cubero Palero, Francisco Javier
    Acetaminophen (APAP) hepatotoxicity induces endoplasmic reticulum (ER) stress which triggers the unfolded protein response (UPR) in hepatocytes. However, the mechanisms underlying ER stress remain poorly understood, thus reducing the options for exploring new pharmacological therapies for patients with hyperacute liver injury. Eight-to-twelve-week-old C57BL/6J Xbp1-floxed (Xbp1f/f) and hepatocyte-specific knockout Xbp1 mice (Xbp1∆hepa) were challenged with either high dose APAP [500 mg/kg] and sacrificed at early (1–2 h) and late (24 h) stages of hepatotoxicity. Histopathological examination of livers, immunofluorescence and immunohistochemistry, Western blot, real time (RT)-qPCR studies and transmission electron microscopy (TEM) were performed. Pharmacological inhibition of XBP1 using pre-treatment with STF-083010 [STF, 75 mg/kg] and autophagy induction with Rapamycin [RAPA, 8 mg/kg] or blockade with Chloroquine [CQ, 60 mg/kg] was also undertaken in vivo. Cytoplasmic expression of XBP1 coincided with severity of human and murine hyperacute liver injury. Transcriptional and translational activation of the UPR and sustained activation of JNK1/2 were major events in APAP hepatotoxicity, both in a human hepatocytic cell line and in a preclinical model. Xbp1∆hepa livers showed decreased UPR and JNK1/2 activation but enhanced autophagy in response to high dose APAP. Additionally, blockade of XBP1 splicing by STF, mitigated APAP-induced liver injury and without non-specific off-target effects (e.g., CYP2E1 activity). Furthermore, enhanced autophagy might be responsible for modulating CYP2E1 activity in Xbp1∆hepa animals. Genetic and pharmacological inhibition of Xbp1 specifically in hepatocytes ameliorated APAP-induced liver injury by enhancing autophagy and decreasing CYP2E1 expression. These findings provide the basis for the therapeutic restoration of ER stress and/or induction of autophagy in patients with hyperacute liver injury.
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    Intestinal Epithelial Cell-Derived Extracellular Vesicles Modulate Hepatic Injury via the Gut-Liver Axis During Acute Alcohol Injury
    (Frontiers in Pharmacology, 2020) Lamas Paz, Arantza; Morán, Laura; Salinas Rodríguez, Beatriz; López Alcántara, Nuria; Asensio, Iris; Fengjie, Hao; Kang, Zheng; Martín Adrados, Beatriz; Moreno Gutiérrez, Laura; Cogolludo Torralba, Ángel Luis; Gómez Del Moral Martín-Consuegra, Manuel María; Martínez Naves, Eduardo; Vaquero Martín, Francisco Javier; Bañares Cañizares, Rafael; Nevzorova, Yulia; Cubero Palero, Francisco Javier
    Binge drinking, i.e., heavy episodic drinking in a short time, has recently become an alarming societal problem with negative health impact. However, the harmful effects of acute alcohol injury in the gut-liver axis remain elusive. Hence, we focused on the physiological and pathological changes and the underlying mechanisms of experimental binge drinking in the context of the gut-liver axis. Eight-week-old mice with a C57BL/6 background received a single dose (p.o.) of ethanol (EtOH) [6 g/kg b.w.] as a preclinical model of acute alcohol injury. Controls received a single dose of PBS. Mice were sacrificed 8 h later. In parallel, HepaRGs and Caco-2 cells, human cell lines of differentiated hepatocytes and intestinal epithelial cells intestinal epithelial cells (IECs), respectively, were challenged in the presence or absence of EtOH [0-100 mM]. Extracellular vesicles (EVs) isolated by ultracentrifugation from culture media of IECs were added to hepatocyte cell cultures. Increased intestinal permeability, loss of zonula occludens-1 (ZO-1) and MUCIN-2 expression, and alterations in microbiota-increased Lactobacillus and decreased Lachnospiraceae species-were found in the large intestine of mice exposed to EtOH. Increased TUNEL-positive cells, infiltration of CD11b-positive immune cells, pro-inflammatory cytokines (e.g., tlr4, tnf, il1β), and markers of lipid accumulation (Oil Red O, srbep1) were evident in livers of mice exposed to EtOH, particularly in females. In vitro experiments indicated that EVs released by IECs in response to ethanol exerted a deleterious effect on hepatocyte viability and lipid accumulation. Overall, our data identified a novel mechanism responsible for driving hepatic injury in the gut-liver axis, opening novel avenues for therapy
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    Project number: 415
    Hacia una estrategia de internalización común en la Facultad de Medicina en particular y en la UCM en general
    (2021) Cubero Palero, Francisco Javier; Nevzorova, Yulia; Sanz García, Carlos; Martínez Naves, Eduardo; Martín Adrados, Beatriz; Estévez Vázquez, Olga; Roda Navarro, Pedro; Aguilar Sopeña, Óscar
    Este proyecto se basa en diseñar una estrategia para la internalización de las asignaturas de grado y posgrado de la Facultad de Medicina, especialmente los impartidos por el Departamento de Inmunología, Oftalmología y ORL.
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    Project number: 288
    Internalización de la Inmunología en la Facultad de Medicina
    (2022) Cubero Palero, Francisco Javier; Nevzorova, Yulia; Martínez Naves, Eduardo; Sanz García, Carlos; Estévez Vázquez, Olga; Benede Ubieto, Raquel; Martín Adrados, Beatriz; Mazariegos, Marina S.
    Este proyecto se basa en diseñar una estrategia para la internalización de las asignaturas de grado y posgrado de la Facultad de Medicina, especialmente los impartidos por el área de Inmunología del Departamento de Inmunología, Oftalmología y Otorrinolaringología. La actividad propuesta pretende crear un entorno que favorezca la implantación de la docencia bilingüe mediante la diseminación de los procedimientos disponibles para el personal PAS, PDI o estudiantes (movilidad, idiomas y cooperación internacional) actualmente en la UCM así como el desarrollo de capacidades del alumnado en el proceso de aprendizaje bilingüe. De esta manera, no sólo el Departamento y el Centro sino que también el Alumnado saldrán favorecidos en el proceso de internacionalización de la educación superior.
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    Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy
    (Cell death diseases, 2022) Ye, Hui; Wu, Hanghang; Martín Adrados, Beatriz; Gómez Del Moral Martín-Consuegra, Manuel María; Bañares Cañizares, Rafael; Nevzorova, Yulia; Martínez Naves, Eduardo; Cubero Palero, Francisco Javier
    Acetaminophen (APAP) hepatotoxicity induces endoplasmic reticulum (ER) stress which triggers the unfolded protein response (UPR) in hepatocytes. However, the mechanisms underlying ER stress remain poorly understood, thus reducing the options for exploring new pharmacological therapies for patients with hyperacute liver injury. Eight-to-twelve-week-old C57BL/6J Xbp1-floxed (Xbp1f/f) and hepatocyte-specific knockout Xbp1 mice (Xbp1∆hepa) were challenged with either high dose APAP [500 mg/kg] and sacrificed at early (1-2 h) and late (24 h) stages of hepatotoxicity. Histopathological examination of livers, immunofluorescence and immunohistochemistry, Western blot, real time (RT)-qPCR studies and transmission electron microscopy (TEM) were performed. Pharmacological inhibition of XBP1 using pre-treatment with STF-083010 [STF, 75 mg/kg] and autophagy induction with Rapamycin [RAPA, 8 mg/kg] or blockade with Chloroquine [CQ, 60 mg/kg] was also undertaken in vivo. Cytoplasmic expression of XBP1 coincided with severity of human and murine hyperacute liver injury. Transcriptional and translational activation of the UPR and sustained activation of JNK1/2 were major events in APAP hepatotoxicity, both in a human hepatocytic cell line and in a preclinical model. Xbp1∆hepa livers showed decreased UPR and JNK1/2 activation but enhanced autophagy in response to high dose APAP. Additionally, blockade of XBP1 splicing by STF, mitigated APAP-induced liver injury and without non-specific off-target effects (e.g., CYP2E1 activity). Furthermore, enhanced autophagy might be responsible for modulating CYP2E1 activity in Xbp1∆hepa animals. Genetic and pharmacological inhibition of Xbp1 specifically in hepatocytes ameliorated APAP-induced liver injury by enhancing autophagy and decreasing CYP2E1 expression. These findings provide the basis for the therapeutic restoration of ER stress and/or induction of autophagy in patients with hyperacute liver injury.