Person: Cubero Palero, Francisco Javier
Universidad Complutense de Madrid
Faculty / Institute
Inmunología, Oftalmología y ORL
Now showing 1 - 10 of 10
- PublicationMitogen-Activated Protein Kinases (MAPKs) and Cholangiocarcinoma: The Missing Link(MDPI, 2019-09-28) Chen, Chaobo; Nelson, L. J.; Ávila, M. A.; Cubero Palero, Francisco JavierIn recent years, the incidence of both liver and biliary tract cancer has increased. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common types of hepatic malignancies. Whereas HCC is the fifth most common malignant tumor in Western countries, the prevalence of CCA has taken an alarming increase from 0.3 to 2.1 cases per 100,000 people. The lack of specific biomarkers makes diagnosis very difficult in the early stages of this fatal cancer. Thus, the prognosis of CCA is dismal and surgery is the only effective treatment, whilst recurrence after resection is common. Even though chemotherapy and radiotherapy may prolong survival in patients with CCA, the 5-year survival rate is still very low—a significant global problem in clinical diagnosis and therapy. The mitogen-activated protein kinase (MAPK) pathway plays an important role in signal transduction by converting extracellular stimuli into a wide range of cellular responses including inflammatory response, stress response, differentiation, survival, and tumorigenesis. Dysregulation of the MAPK cascade involves key signaling components and phosphorylation events that play an important role in tumorigenesis. In this review, we discuss the pathophysiological role of MAPK, current therapeutic options, and the current situation of MAPK-targeted therapies in CCA.
- PublicationAbnormal liver function test in patients infected with Coronavirus (SARS-CoV-2): a retrospective Single-Center Study from Spain(MDPI, 2021-03-03) Benedé Ubieto, Raquel; Estevez Vázquez, Olga; Flores-Perojo, Vicente; Macías-Rodríguez, Ricardo U.; Ruiz-Margáin, Astrid; Martinez Naves, Eduardo; Regueiro González-Barros, José Ramón; Avila, Matías A.; Trautwein, Christian; Bañares, Rafael; Bosch, J.; Cubero Palero, Francisco Javier; Nevzorova, Yulia A.The outbreak of the novel coronavirus SARS-CoV-2 epidemic has rapidly spread and still poses a serious threat to healthcare systems worldwide. In the present study, electronic medical records containing clinical indicators related to liver injury in 799 COVID-19-confirmed patients admitted to a hospital in Madrid (Spain) were extracted and analyzed. Correlation between liver injury and disease outcome was also evaluated. Serum levels of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma-glutamyltransferase (GGT), Alkaline phosphatase (ALP), Lactate dehydrogenase (LDH) and AST/ALT ratio were elevated above the Upper Limit of Normal (ULN) in 25.73%, 49.17%, 34.62%, 24.21%, 55.84% and 75% of patients, respectively. Interestingly, significant positive correlation between LDH levels and the AST/ALT ratio with disease outcome was found. Our data showed that SARS-CoV-2 virus infection leads to mild, but significant changes in serum markers of liver injury. The upregulated LDH levels as well as AST/ALT ratios upon admission may be used as additional diagnostic characteristic for COVID-19 patients.
- PublicationAlcohol and Hepatocellular Carcinoma: Adding Fuel to the Flame(MDPI, 2017-09-25) Ramadori, Pierluigi; Cubero Palero, Francisco Javier; Liedtke, Christian; Trautwein, Christian; Nevzorova, Yulia AlexandrownaPrimary tumors of the liver represent the fifth most common type of cancer in the world and the third leading cause of cancer-related death. Case-control studies from different countries report that chronic ethanol consumption is associated with an approximately 2-fold increased odds ratio for hepatocellular carcinoma (HCC). Despite the substantial epidemiologic data in humans demonstrating that chronic alcohol consumption is a major risk factor for HCC development, the pathways causing alcohol-induced liver cancer are poorly understood. In this overview, we summarize the epidemiological evidence for the association between alcohol and liver cancer, review the genetic, oncogenic, and epigenetic factors that drive HCC development synergistically with ethanol intake and discuss the essential molecular and metabolic pathways involved in alcohol-induced liver tumorigenesis.
- Publicationc-MYC—Making Liver Sick: Role of c-MYC in Hepatic Cell Function, Homeostasis and Disease(MDPI, 2017-04-19) Zheng, Kang; Cubero Palero, Francisco Javier; Nevzorova, Yulia AlexandrownaOver 35 years ago, c-MYC, a highly pleiotropic transcription factor that regulates hepatic cell function, was identified. In recent years, a considerable increment in the number of publications has significantly shifted the way that the c-MYC function is perceived. Overexpression of c-MYC alters a wide range of roles including cell proliferation, growth, metabolism, DNA replication, cell cycle progression, cell adhesion and differentiation. The purpose of this review is to broaden the understanding of the general functions of c-MYC, to focus on c-MYC-driven pathogenesis in the liver, explain its mode of action under basal conditions and during disease, and discuss efforts to target c-MYC as a plausible therapy for liver disease.
- PublicationFat: Quality, or Quantity? What Matters Most for the Progression of Metabolic Associated Fatty Liver Disease (MAFLD)(MDPI, 2021-09-22) Estévez-Vázquez, Olga; Benedé-Ubieto, Raquel; Guo, Feifei; Gómez-Santos, Beatriz; Aspichueta, Patricia; Reissing, Johanna; Bruns, Tony; Sanz-García, Carlos; Sydor, Svenja; Bechmann, Lars P; Maranillo Alcaide, Eva; Sañudo Tejero, José Ramón; Vázquez Osorio, María Teresa; Lamas-Paz, Arantza; Morán, Laura; Mazariegos, Marina S; Ciudin, Andreea; Pericàs, Juan M.; Peligros, María Isabel; Vaquero, Javier; Martínez-Naves, Eduardo; Liedtke, Christian; Regueiro González-Barros, José Ramón; Trautwein, Christian; Bañares Cañizares, Rafael; Cubero Palero, Francisco Javier; Nevzorova, Yulia A.Objectives: Lately, many countries have restricted or even banned transfat, and palm oil has become a preferred replacement for food manufacturers. Whether palm oil is potentially an unhealthy food mainly due to its high content of saturated Palmitic Acid (PA) is a matter of debate. The aim of this study was to test whether qualitative aspects of diet such as levels of PA and the fat source are risk factors for Metabolic Syndrome (MS) and Metabolic Associated Fatty Liver Disease (MAFLD). Methods: C57BL/6 male mice were fed for 14 weeks with three types of Western diet (WD): 1. LP-WD—low concentration of PA (main fat source—corn and soybean oils); 2. HP-WD—high concentration of PA (main fat source—palm oil); 3. HP-Trans-WD—high concentration of PA (mainly transfat). Results: All types of WD caused weight gain, adipocyte enlargement, hepatomegaly, lipid metabolism alterations, and steatohepatitis. Feeding with HP diets led to more prominent obesity, hypercholesterolemia, stronger hepatic injury, and fibrosis. Only the feeding with HP-Trans-WD resulted in glucose intolerance and elevation of serum transaminases. Brief withdrawal of WDs reversed MS and signs of MAFLD. However, mild hepatic inflammation was still detectable in HP groups. Conclusions: HP and HP-Trans-WD play a crucial role in the genesis of MS and MAFLD.
- PublicationThe Space of Disse: The Liver Hub in Health and Disease(MDPI, 2021) Sanz García, Carlos; Fernández Iglesias, Anabel; Gracia Sancho, Jordi; Arráez Aybar, Luis Alfonso; Nevzorova, Yulia A.; Cubero Palero, Francisco JavierSince it was first described by the German anatomist and histologist, Joseph Hugo Vincenz Disse, the structure and functions of the space of Disse, a thin perisinusoidal area between the endothelial cells and hepatocytes filled with blood plasma, have acquired great importance in liver disease. The space of Disse is home for the hepatic stellate cells (HSCs), the major fibrogenic players in the liver. Quiescent HSCs (qHSCs) store vitamin A, and upon activation they lose their retinol reservoir and become activated. Activated HSCs (aHSCs) are responsible for secretion of extracellular matrix (ECM) into the space of Disse. This early event in hepatic injury is accompanied by loss of the pores—known as fenestrations—of the endothelial cells, triggering loss of balance between the blood flow and the hepatocyte, and underlies the link between fibrosis and organ dysfunction. If the imbalance persists, the expansion of the fibrotic scar followed by the vascularized septae leads to cirrhosis and/or end-stage hepatocellular carcinoma (HCC). Thus, researchers have been focused on finding therapeutic targets that reduce fibrosis. The space of Disse provides the perfect microenvironment for the stem cells niche in the liver and the interchange of nutrients between cells. In the present review article, we focused on the space of Disse, its components and its leading role in liver disease development.
- PublicationPilot Multi-Omic Analysis of Human Bile from Benign and Malignant Biliary Strictures: A Machine-Learning Approach(MDPI, 2020-06-21) Urman, Jesús M.; Herranz, José M.; Uriarte, Iker; Rullán, María; Oyón, Daniel; González, Belén; Fernandez-Urién, Ignacio; Carrascosa, Juan; Bolado, Federico; Zabalza, Lucía; Arechederra, María; Alvarez-Sola, Gloria; Colyn, Leticia; Latasa, María U.; Puchades-Carrasco, Leonor; Pineda-Lucena, Antonio; Iraburu, María J.; Iruarrizaga-Lejarreta, Marta; Alonso, Cristina; Sangro, Bruno; Purroy, Ana; Gil, Isabel; Carmona, Lorena; Cubero Palero, Francisco Javier; Martínez-Chantar, María L.; Banales, Jesús M.; Romero, Marta R.; Macias, Rocio I.R.; Monte, Maria J.; Marín, Jose J. G.; Vila, Juan J.; Corrales, Fernando J.; Berasain, Carmen; Fernández-Barrena, Maite G.; Avila, Matías A.Cholangiocarcinoma (CCA) and pancreatic adenocarcinoma (PDAC) may lead to the development of extrahepatic obstructive cholestasis. However, biliary stenoses can also be caused by benign conditions, and the identification of their etiology still remains a clinical challenge. We performed metabolomic and proteomic analyses of bile from patients with benign (n = 36) and malignant conditions, CCA (n = 36) or PDAC (n = 57), undergoing endoscopic retrograde cholangiopancreatography with the aim of characterizing bile composition in biliopancreatic disease and identifying biomarkers for the differential diagnosis of biliary strictures. Comprehensive analyses of lipids, bile acids and small molecules were carried out using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (1H-NMR) in all patients. MS analysis of bile proteome was performed in five patients per group. We implemented artificial intelligence tools for the selection of biomarkers and algorithms with predictive capacity. Our machine-learning pipeline included the generation of synthetic data with properties of real data, the selection of potential biomarkers (metabolites or proteins) and their analysis with neural networks (NN). Selected biomarkers were then validated with real data. We identified panels of lipids (n = 10) and proteins (n = 5) that when analyzed with NN algorithms discriminated between patients with and without cancer with an unprecedented accuracy.
- PublicationA Shortcut from Metabolic-Associated Fatty Liver Disease (MAFLD) to Hepatocellular Carcinoma (HCC): c-MYC a Promising Target for Preventative Strategies and Individualized Therapy(MDPI, 2021-12-31) Guo, Feifei; Estevez Vázquez, Olga; Benedé Ubieto, Raquel; Maya Mile, Douglas; Zheng, Kang; Gallego Durán, Rocío; Rojas Ávalos, Ángela; Ampuero, Javier; Romero Gómez, Manuel; Philip, Kaye; Egbuniwe, Isioma U.; Chen, Chaobo; Simon, Jorge; Delgado, Teresa C.; Martínez Chantar, Maria L.; Sun, Jie; Reissing, Johanna; Bruns, Tony; Lamas Paz, Arantza; Gómez del Moral Martín-Consuegra, Manuel María; Woitok, Marius Maximilian; Vaquero Martín, Javier; Regueiro, José R.; Liedtke, Christian; Trautwein, Christian; Bañares Cañizares, Rafael; Cubero Palero, Francisco Javier; Nevzorova, Yulia A.Background: Metabolic-associated fatty liver disease (MAFLD) has risen as one of the leading etiologies for hepatocellular carcinoma (HCC). Oncogenes have been suggested to be responsible for the high risk of MAFLD-related HCC. We analyzed the impact of the proto-oncogene c-MYC in the development of human and murine MAFLD and MAFLD-associated HCC. Methods: alb-myctg mice were studied at baseline conditions and after administration of Western diet (WD) in comparison to WT littermates. c-MYC expression was analyzed in biopsies of patients with MAFLD and MAFLD-associated HCC by immunohistochemistry. Results: Mild obesity, spontaneous hyperlipidaemia, glucose intolerance and insulin resistance were characteristic of 36-week-old alb-myctg mice. Middle-aged alb-myctg exhibited liver steatosis and increased triglyceride content. Liver injury and inflammation were associated with elevated ALT, an upregulation of ER-stress response and increased ROS production, collagen deposition and compensatory proliferation. At 52 weeks, 20% of transgenic mice developed HCC. WD feeding exacerbated metabolic abnormalities, steatohepatitis, fibrogenesis and tumor prevalence. Therapeutic use of metformin partly attenuated the spontaneous MAFLD phenotype of alb-myctg mice. Importantly, upregulation and nuclear localization of c-MYC were characteristic of patients with MAFLD and MAFLD-related HCC. Conclusions: A novel function of c-MYC in MAFLD progression was identified opening new avenues for preventative strategies.
- PublicationOxidative Stress in Drug-Induced Liver Injury (DILI): From Mechanisms to Biomarkers for Use in Clinical Practice(MDPI, 2021-03-05) Villanueva Paz, Marina; Morán, Laura; López Alcántara, Nuria; Freixo, Cristiana; Andrade, Raúl J.; Lucena, M Isabel; Cubero Palero, Francisco JavierIdiosyncratic drug-induced liver injury (DILI) is a type of hepatic injury caused by an uncommon drug adverse reaction that can develop to conditions spanning from asymptomatic liver laboratory abnormalities to acute liver failure (ALF) and death. The cellular and molecular mechanisms involved in DILI are poorly understood. Hepatocyte damage can be caused by the metabolic activation of chemically active intermediate metabolites that covalently bind to macromolecules (e.g., proteins, DNA), forming protein adducts—neoantigens—that lead to the generation of oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, which can eventually lead to cell death. In parallel, damage-associated molecular patterns (DAMPs) stimulate the immune response, whereby inflammasomes play a pivotal role, and neoantigen presentation on specific human leukocyte antigen (HLA) molecules trigger the adaptive immune response. A wide array of antioxidant mechanisms exists to counterbalance the effect of oxidants, including glutathione (GSH), superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX), which are pivotal in detoxification. These get compromised during DILI, triggering an imbalance between oxidants and antioxidants defense systems, generating oxidative stress. As a result of exacerbated oxidative stress, several danger signals, including mitochondrial damage, cell death, and inflammatory markers, and microRNAs (miRNAs) related to extracellular vesicles (EVs) have already been reported as mechanistic biomarkers. Here, the status quo and the future directions in DILI are thoroughly discussed, with a special focus on the role of oxidative stress and the development of new biomarkers.
- PublicationHacia una estrategia de internalización común en la Facultad de Medicina en particular y en la UCM en general(2021-06) Cubero Palero, Francisco Javier; Nevzorova, Yulia; Sanz García, Carlos; Martinez Naves, Eduardo; Martín Adrados, Beatriz; Estevez Vázquez, Olga; Roda Navarro, Pedro; Aguilar Sopeña, ÓscarEste 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.