Person: Roncero Romero, Cesáreo
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First Name
Cesáreo
Last Name
Roncero Romero
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Bioquímica y Biología Molecular
Area
Bioquímica y Biología Molecular
Identifiers
14 results
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Item Lack of EGFR catalytic activity in hepatocytes improves liver regeneration following DDC‐induced cholestatic injury by promoting a pro‐restorative inflammatory response(Journal of Pathology, 2022) Lazcanoiturburu, Nerea; García‐Sáez, Juan; González‐Corralejo, Carlos; Roncero Romero, Cesáreo; Sanz Ortega, Julián; Martín‐Rodríguez, Carlos; Valdecantos, M Pilar; Martínez‐Palacián, Adoración; Almale Del Barrio, Laura; Bragado Domingo, Paloma; Calero‐Pérez, Silvia; Fernández, Almudena; García‐Bravo, María; Guerra, Carmen; Montoliu, Lluis; Segovia, José Carlos; Martínez Valverde, Ángela María; Fabregat Romero, María Isabel; Herrera González, Blanca María; Sánchez Muñoz, AranzazuDespite the well‐known hepatoprotective role of the epidermal growth factor receptor (EGFR) pathway upon acute damage, its specific actions during chronic liver disease, particularly cholestatic injury, remain ambiguous and unresolved. Here, we analyzed the consequences of inactivating EGFR signaling in the liver on the regenerative response following cholestatic injury. For that, transgenic mice overexpressing a dominant negative mutant human EGFR lacking tyrosine kinase activity (ΔEGFR) in albumin‐positive cells were submitted to liver damage induced by 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC), an experimental model resembling human primary sclerosing cholangitis. Our results show an early activation of EGFR after 1–2 days of a DDC‐supplemented diet, followed by a signaling switch‐off. Furthermore, ΔEGFR mice showed less liver damage and a more efficient regeneration following DDC injury. Analysis of the mechanisms driving this effect revealed an enhanced activation of mitogenic/survival signals, AKT and ERK1/2‐MAPKs, and changes in cell turnover consistent with a quicker resolution of damage in response to DDC. These changes were concomitant with profound differences in the profile of intrahepatic immune cells, consisting of a shift in the M1/M2 balance towards M2 polarity, and the Cd4/Cd8 ratio in favor of Cd4 lymphocytes, overall supporting an immune cell switch into a pro‐restorative phenotype. Interestingly, ΔEGFR livers also displayed an amplified ductular reaction, with increased expression of EPCAM and an increased number of CK19‐positive ductular structures in portal areas, demonstrating an overexpansion of ductular progenitor cells. In summary, our work supports the notion that hepatocyte‐specific EGFR activity acts as a key player in the crosstalk between parenchymal and non‐parenchymal hepatic cells, promoting the pro‐inflammatory response activated during cholestatic injury and therefore contributing to the pathogenesis of cholestatic liver disease. © 2022 The Pathological Society of Great Britain and Ireland.Item Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms(Antioxidants, 2020) Abbruzzese, Giuseppe; Morón Oset, Javier; Díaz Castroverde, Sabela; García Font, Nuria; Roncero Romero, Cesáreo; López Muñoz, Francisco; Marco Contelles, José Luis; Oset Gasque, María JesúsPhytoestrogens can have a neuroprotective effect towards ischemia-reperfusion-induced neuronal damage. However, their mechanism of action has not been well described. In this work, we investigate the type of neuronal cell death induced by oxygen and glucose deprivation (OGD) and resupply (OGDR) and pinpoint some of the signaling mechanisms whereby the neuroprotective effects of phytoestrogens occur in these conditions. First, we found that autophagy initiation affords neuronal protection upon neuronal damage induced by OGD and OGDR. The mammalian target of rapamycin/ribosomal S6 kinase (mTOR/S6K) pathway is blocked in these conditions, and we provide evidence that this is mediated by modulation of both the 50 AMP-activated protein kinase (AMPK) and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. These are dampened up or down, respectively, under OGDR-induced neuronal damage. In contrast, the MAPK-Erk kinase/extracellular signal-regulated kinase (MEK/ERK) pathway is increased under these conditions. Regarding the pathways affected by phytoestrogens, we show that their protective properties require autophagy initiation, but at later stages, they decrease mitogen-activated protein kinase (MAPK) and AMPK activation and increase mTOR/S6K activation. Collectively, our results put forward a novel mode of action where phytoestrogens play a dual role in the regulation of autophagy by acting as autophagy initiation enhancers when autophagy is a neuroprotective and pro-survival mechanism, and as autophagy initiation inhibitors when autophagy is a pro-death mechanism. Finally, our results support the therapeutic potential of phytoestrogens in brain ischemia by modulating autophagy.Item c-Met Signaling Is Essential for Mouse Adult Liver Progenitor Cells Expansion After Transforming Growth Factor-β-Induced Epithelial–Mesenchymal Transition and Regulates Cell Phenotypic Switch(Stem Cells, 2019) Almale Del Barrio, Laura; García-Álvaro, María; Martínez-Palacián, Adoración; García-Bravo, María; Lazcanoiturburu, Nerea; Addante, Annalisa; Roncero Romero, Cesáreo; Sanz Ortega, Julián; López, María de la O; Bragado Domingo, Paloma; Mikulits, Wolfgang; Factor, Valentina M.; Thorgeirsson, Snorri S.; Ignacio, Casal, J.; Segovia, José-Carlos; Rial, Eduardo; Fabregat Romero, María Isabel; Herrera González, Blanca María; Sánchez Muñoz, AranzazuAdult hepatic progenitor cells (HPCs)/oval cells are bipotential progenitors that participate in liver repair responses upon chronic injury. Recent findings highlight HPCs plasticity and importance of the HPCs niche signals to determine their fate during the regenerative process, favoring either fibrogenesis or damage resolution. Transforming growth factor-β (TGF-β) and hepatocyte growth factor (HGF) are among the key signals involved in liver regeneration and as component of HPCs niche regulates HPCs biology. Here, we characterize the TGF-β-triggered epithelial–mesenchymal transition (EMT) response in oval cells, its effects on cell fate in vivo, and the regulatory effect of the HGF/c-Met signaling. Our data show that chronic treatment with TGF-β triggers a partial EMT in oval cells based on coexpression of epithelial and mesenchymal markers. The phenotypic and functional profiling indicates that TGF-β-induced EMT is not associated with stemness but rather represents a step forward along hepatic lineage. This phenotypic transition confers advantageous traits to HPCs including survival, migratory/invasive and metabolic benefit, overall enhancing the regenerative potential of oval cells upon transplantation into a carbon tetrachloride-damaged liver. We further uncover a key contribution of the HGF/c-Met pathway to modulate the TGF-β-mediated EMT response. It allows oval cells expansion after EMT by controlling oxidative stress and apoptosis, likely via Twist regulation, and it counterbalances EMT by maintaining epithelial properties. Our work provides evidence that a coordinated and balanced action of TGF-β and HGF are critical for achievement of the optimal regenerative potential of HPCs, opening new therapeutic perspectives.Item Glutamate triggers neurosecretion and apoptosis in bovine chromaffin cells through a mechanism involving NO production by neuronal NO synthase activation(Free Radical Biology and Medicine, 2014) Pérez Rodríguez, Rocío; Oliván, A. M.; Roncero Romero, Cesáreo; Morón Oset, J.; González Prieto, María Del Pilar; Oset Gasque, María JesúsPrevious work from our group stated that nitric oxide (NO), via cytokines, induces apoptosis in chromaffin cells by a mechanism involving iNOS, nNOS, and NF-κB. In this paper the involvement of glutamate as a possible intracellular trigger of neurosecretion and NO-mediated apoptosis has been evaluated. We show that chromaffin cells express different ionotropic and metabotropic glutamate receptors, this exerting different effects on the regulation of basal and glutamate-induced catecholamine secretion, via NO/cGMP. In addition, we studied the effects of endogenously generated NO, both basal and glutamate-stimulated, on apoptosis of chromaffin cells. Our results show that glutamate agonists are able to induce cell death and apoptosis in bovine chromaffin cells, parallel to an increase in NO production. Such effects were reversed by NOS inhibitors and glutamate receptor antagonists. Under basal conditions, iNOS inhibitors did not have any effect on apoptosis, whereas nNOS inhibitors induced apoptosis, indicating a neuroprotective effect of constitutive nNOS-generated NO. In contrast, glutamate-induced apoptosis was strongly reversed by nNOS inhibitors and weakly by iNOS inhibitors, thus indicating nNOS involvement in glutamate-mediated apoptosis. These results were confirmed by the fact that nNOS expression, but not iNOS, is specifically activated by glutamate. Finally, our results suggest the participation of PKG, PKA, PKC, and MAPK pathways in glutamate-mediated nNOS activation in chromaffin cells and point out the involvement of both PKA and PKC signaling pathways in the apoptotic effect of glutamate.- Project number: 237
Item Mejora de la docencia en Bioquímica Aplicada y Clínica: desarrollo de una revista digital sobre investigación en Medicina Molecular elaborado por los alumnos y puesta en marcha de la metodología didáctica mediante clases invertidas(2020) Oset Gasque, María Jesús; Escrivá Pons, Fernando; Iniesta Serrano, María Pilar; Gómez Hernández, María De La Almudena; Escribano Illanes, Óscar; García Redondo, Alberto; Martínez Ruiz, Antonio; Roncero Romero, Cesáreo; Álvarez Escolá, Carmen; Juan Chocano, María Del Carmen De Item BMP9-Induced Survival Effect in Liver Tumor Cells Requires p38MAPK Activation(International Journal of Molecular Sciences, 2015) García Álvaro, María; Addante, Annalisa; Roncero Romero, Cesáreo; Fernández Mier, Margarita; Fabregat, Isabel; Sánchez Muñoz, Aranzazu; Herrera González, Blanca MaríaThe study of bone morphogenetic proteins (BMPs) role in tumorigenic processes, and specifically in the liver, has gathered importance in the last few years. Previous studies have shown that BMP9 is overexpressed in about 40% of hepatocellular carcinoma (HCC) patients. In vitro data have also shown evidence that BMP9 has a pro-tumorigenic action, not only by inducing epithelial to mesenchymal transition (EMT) and migration, but also by promoting proliferation and survival in liver cancer cells. However, the precise mechanisms driving these effects have not yet been established. In the present work, we deepened our studies into the intracellular mechanisms implicated in the BMP9 proliferative and pro-survival effect on liver tumor cells. In HepG2 cells, BMP9 induces both Smad and non-Smad signaling cascades, specifically PI3K/AKT and p38MAPK. However, only the p38MAPK pathway contributes to the BMP9 growth-promoting effect on these cells. Using genetic and pharmacological approaches, we demonstrate that p38MAPK activation, although dispensable for the BMP9 proliferative activity, is required for the BMP9 protective effect on serum withdrawal-induced apoptosis. These findings contribute to a better understanding of the signaling pathways involved in the BMP9 pro-tumorigenic role in liver tumor cells.Item Bone morphogenetic protein 9 as a key regulator of liver progenitor cells in DDC‐induced cholestatic liver injury(Liver International, 2018) Addante, Annalisa; Roncero Romero, Cesáreo; Almale Del Barrio, Laura; Lazcanoiturburu, Nerea; García‐Álvaro, María; Fernández García De Castro, Margarita; Sanz Ortega, Julián; Hammad, Seddik; Nwosu, Zeribe C.; Lee, Se‐Jin; Fabregat Romero, María Isabel; Dooley, Steven; Dijke, Peter ten; Herrera González, Blanca María; Sánchez Muñoz, AranzazuBackground & Aims: Bone morphogenetic protein 9 (BMP9) interferes with liver regeneration upon acute injury, while promoting fibrosis upon carbon tetrachlorideinduced chronic injury. We have now addressed the role of BMP9 in 3,5 diethoxicarbonyl-1,4 dihydrocollidine (DDC)-induced cholestatic liver injury, a model of liver regeneration mediated by hepatic progenitor cell (known as oval cell), exemplified as ductular reaction and oval cell expansion. Methods: WT and BMP9KO mice were submitted to DDC diet. Livers were examined for liver injury, fibrosis, inflammation and oval cell expansion by serum biochemistry, histology, RT-qPCR and western blot. BMP9 signalling and effects in oval cells were studied in vitro using western blot and transcriptional assays, plus functional assays of DNA synthesis, cell viability and apoptosis. Crosslinking assays and short hairpin RNA approaches were used to identify the receptors mediating BMP9 effects. Results: Deletion of BMP9 reduces liver damage and fibrosis, but enhances inflammation upon DDC feeding. Molecularly, absence of BMP9 results in overactivation of PI3K/AKT, ERK-MAPKs and c-Met signalling pathways, which together with an enhanced ductular reaction and oval cell expansion evidence an improved regenerative response and decreased damage in response to DDC feeding. Importantly, BMP9 directly targets oval cells, it activates SMAD1,5,8, decreases cell growth and promotes apoptosis, effects that are mediated by Activin Receptor-Like Kinase 2 (ALK2) type I receptor. Conclusions: We identify BMP9 as a negative regulator of oval cell expansion in cholestatic injury, its deletion enhancing liver regeneration. Likewise, our work further supports BMP9 as an attractive therapeutic target for chronic liver diseases.Item HGF/c-Met signaling promotes liver progenitor cell migration and invasion by an epithelial-mesenchymal transition-independent, phosphatidyl inositol-3 kinase-dependent pathway in an in vitro model(BBA - Molecular Cell Research, 2015) Suárez Causado, Amileth; Caballero Díaz, D.; Bertrán, E.; Roncero Romero, Cesáreo; Addante, Annalisa; García Álvaro, M.; Fernández García De Castro, Margarita; Herrera González, Blanca María; Porras Gallo, María Almudena; Fabregat, I.; Sánchez Muñoz, AranzazuOval cells constitute an interesting hepatic cell population. They contribute to sustain liver regeneration during chronic liver damage, but in doing this they can be target of malignant conversion and become tumor-initiating cells and drive hepatocarcinogenesis. The molecular mechanisms beneath either their pro-regenerative or pro-tumorigenic potential are still poorly understood. In this study, we have investigated the role of the HGF/c-Met pathway in regulation of oval cell migratory and invasive properties. Our results show that HGF induces c-Met-dependent oval cell migration both in normal culture conditions and after in vitro wounding. HGF-triggered migration involves Factin cytoskeleton reorganization, which is also evidenced by activation of Rac1. Furthermore, HGF causes ZO-1 translocation from cell-cell contact sites to cytoplasm and its concomitant activation by phosphorylation. However, no loss of expression of cell-cell adhesion proteins, including E-cadherin, ZO-1 and Occludin-1, is observed. Additionally, migration does not lead to cell dispersal but to a characteristic organized pattern in rows, in turn associated with Golgi compaction, providing strong evidence of a morphogenic collective migration. Besides migration, HGF increases oval cell invasion through extracellular matrix, process that requires PI3K activation and is at least partly mediated by expression and activation of metalloproteases. Altogether, our findings provide novel insights into the cellular and molecular mechanisms mediating the essential role of HGF/c-Met signaling during oval cell-mediated mouse liver regeneration.- Project number: 335
Item Innovación Docente en la enseñanza de la Bioquímica y la Biología Molecular: Revistas digitales, clases invertidas y recursos didácticos para la enseñanza “en línea”(2021) Oset Gasque, María Jesús; Bragado Domingo, Paloma; Escribano Illanes, Óscar; Escrivá Pons, Fernando; Fernández Millán, Elisa; García Redondo, Alberto; Gómez Hernández, María De La Almudena; Herrera González, Blanca María; Iniesta Serrano, María Pilar; Juan Chocano, María Del Carmen De; Linares Gómez, María; Martínez Ruiz, Antonio; Pacheco González, Beatriz; Roncero Romero, Cesáreo; Sánchez Muñoz, AranzazuEn este Proyecto de Innovación Docente (PID 335/20) se han realizado tres tipos de actividades: 1. Elaboración de revistas digitales 2. Implantación de la metodología de clase invertida 3. Desarrollo de materiales docentes par la implantación de la enseñanza "en línea" y formación del profesorado. En ella han participado 15 profesores del Dpto. de Bioquímica y Biología Molecular (Sección Farmacia), de 4 asignaturas diferentes: Bioquímica Aplicada y Clínica, Bioquímica, Biología Molecular y Genética. Los resultados han sido muy satisfactorios, ya que se ha conseguido la participación de un enorme número de alumnos de todas estas asignaturas, los cuales han quedado muy contentos y satisfechos, ya que ha fomentado su autoaprendizaje, su trabajo en grupo, su conocimiento del método científico y sus habilidades como divulgadores de ciencia. Item A Signaling Crosstalk between BMP9 and HGF/c-Met Regulates Mouse Adult Liver Progenitor Cell Survival(Cells, 2020) Addante, Annalisa; Roncero Romero, Cesáreo; Lazcanoiturburu, Nerea; Méndez, Rebeca; Almale Del Barrio, Laura; García Álvaro, María; Ten Dijke, Peter; Fabregat, Isabel; Herrera González, Blanca María; Sánchez Muñoz, AranzazuDuring chronic liver disease, hepatic progenitor cells (HPC, oval cells in rodents) become activated, proliferate, and differentiate into cholangiocytes and/or hepatocytes contributing to the final outcome of the regenerative process in a context-dependent fashion. Here, we analyze the crosstalk between the hepatocyte growth factor (HGF)/c-Met signaling axis, key for liver regeneration, and bone morphogenetic protein (BMP)9, a BMP family ligand that has emerged as a critical regulator of liver pathology. Our results show that HGF/c-Met signaling blocks BMP9-mediated apoptotic cell death, while it potentiates small mothers against decapentaplegic (SMAD)1 signaling triggered by BMP9 in oval cells. Interestingly, HGF-induced overactivation of SMAD1, -5, -8 requires the upregulation of TGF-β type receptor activin receptor-like kinase (ALK)1, and both ALK1 and SMAD1 are required for the counteracting effect of HGF on BMP9 apoptotic activity. On the other hand, we also prove that BMP9 triggers the activation of p38MAPK in oval cells, which drives BMP9-apoptotic cell death. Therefore, our data support a model in which BMP9 and HGF/c-Met signaling axes establish a signaling crosstalk via ALK1 that modulates the balance between the two pathways with opposing activities, SMAD1 (pro-survival) and p38 mitogen-activated protein kinases (p38MAPK; pro-apoptotic), which determines oval cell fate. These data help delineate the complex signaling network established during chronic liver injury and its impact on the oval cell regenerative response.