Fernandez-Irigoyen, J. (Joaquín)

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    NADPH oxidase 5 (NOX5) overexpression promotes endothelial dysfunction via cell apoptosis, migration, and metabolic alterations in human brain microvascular endothelial cells (hCMEC/D3)
    (2022) Martínez-Azcona, M. (María); Ainzúa-Pérez, E. (Elena); Orbe, J. (Josune); Fernandez-Irigoyen, J. (Joaquín); Marqués-Cantero, J. (Javier); Cortés-Jiménez, A. (Adriana); Roncal, C. (Carmen); Zalba, G. (Guillermo); Santamaria, E. (Enrique)
    NADPH oxidases (NOX) constitute the main reactive oxygen species (ROS) source in blood vessels. An oxidative stress situation due to ROS overproduction can lead into endothelial dysfunction, a molecular mechanism that precedes cardiovascular diseases (CVDs) such as atherosclerosis, myocardial infarction, and stroke. NOX5 is the last discovered member of the NOX family, studied in a lesser extent due to its absence in the rodent genome. Our objective was to describe the phenotypic alterations produced by an oxidative stress situation derived from NOX5 overexpression in an endothelial in vitro model. The in vitro model consists of the hCMEC/D3 cell line, derived from brain microvascular endothelium, infected with a recombinant NOX5-beta adenovirus. After an initial proteomic analysis, three phenotypic alterations detected in silico were studied: cell proliferation and apoptosis, general and mitochondrial metabolism, and migration capacity. NOX5 infection of hCMEC/D3 generates a functional protein and an increase in ROS production. This model produced changes in the whole cell proteome. The in silico analysis together with in vitro validations demonstrated that NOX5 overexpression inhibits proliferation and promotes apoptosis, metabolic alterations and cell migration in hCMEC/D3 cells. NOX5 overexpression in endothelial cells leads to phenotypic changes that can lead to endothelial dysfunction, the onset of atherosclerosis, myocardial infarction, and stroke.
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    Biomarkers of delirium risk in older adults: a systematic review and meta-analysis
    (2023) Martínez-Velilla, N. (Nicolás); García-Hermoso, A. (Antonio); Romero-Ortuno, R. (Román); Sáez-de-Asteasu, M.L. (Mikel L.); Lozano-Vicario, L. (Lucía); Muñoz-Vázquez, Á.J. (Ángel Javier); Fernandez-Irigoyen, J. (Joaquín); Cedeño-Veloz, B.A. (Bernardo Abel); Zambom-Ferraresi, F. (Fabricio); Izquierdo, M. (Mikel); Santamaria, E. (Enrique)
    Delirium is a neuropsychiatric syndrome associated with increased morbidity and mortality in older patients. The aim of this study was to review predictive biomarkers of delirium in older patients to gain insights into the pathophysiology of this syndrome and provide guidance for future studies. Two authors independently and systematically searched MEDLINE, Embase, Cochrane Library, Web of Science and Scopus databases up to August 2021. A total of 32 studies were included. Only 6 studies were eligible for the meta-analysis, pooled results showed a significant increase in some serum biomarkers (C-reactive protein [CRP], tumour necrosis factor alpha [TNF-alpha] and interleukin-6 [IL-6]) among patients with delirium (odds ratio = 1.88, 95% CI 1.01 to 1.637; I2 = 76.75%). Although current evidence does not favour the use of any particular biomarker, serum CRP, TNF-alpha, and IL-6 were the most consistent biomarkers of delirium in older patients.
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    Profound reprogramming towards stemness in pancreatic cancer cells as adaptation to AKT inhibition
    (MDPI AG, 2020) Kochan, G. (Grazyna); Chocarro, L. (Luisa); Gato-Cañas, M. (María); Blanco-Luquin, I. (Idoia); Bocanegra, A. (Ana); Hernández, C. (Carlos); Fernandez-Irigoyen, J. (Joaquín); Zuazo, M. (Miren); Arasanz, H. (Hugo); Santamaría, E. (Eva); Fernandez, G. (Gonzalo); Escors, D. (David); Rodríguez, C. (Carlos); Santamaria, E. (Enrique); Ausin, K. (Karina); Vera, R. (Ruth)
    Cancer cells acquire resistance to cytotoxic therapies targeting major survival pathways by adapting their metabolism. The AKT pathway is a major regulator of human pancreatic adenocarcinoma progression and a key pharmacological target. The mechanisms of adaptation to long-term silencing of AKT isoforms of human and mouse pancreatic adenocarcinoma cancer cells were studied. Following silencing, cancer cells remained quiescent for long periods of time, after which they recovered proliferative capacities. Adaptation caused profound proteomic changes largely affecting mitochondrial biogenesis, energy metabolism and acquisition of a number of distinct cancer stem cell (CSC) characteristics depending on the AKT isoform that was silenced. The adaptation to AKT1 silencing drove most de-differentiation and acquisition of stemness through C-MYC down-modulation and NANOG upregulation, which were required for survival of adapted CSCs. The changes associated to adaptation sensitized cancer cells to inhibitors targeting regulators of oxidative respiration and mitochondrial biogenesis. In vivo pharmacological co-inhibition of AKT and mitochondrial metabolism effectively controlled pancreatic adenocarcinoma growth in pre-clinical models.
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    Omics approaches in pancreatic adenocarcinoma
    (MDPI AG, 2019) Sayar, O. (Onintza); García, E. (Estefania); Arévalo, S. (Sara); Viudez, A. (Antonio); Zarate, R. (Ruth); Gonzalez, I. (Iranzu); Hernández-García, I. (Irene); Fernandez-Irigoyen, J. (Joaquín); Goñi, S. (Saioa); Arrazubi, V. (Virginia); Sala-Elarre, P. (Pablo); Pérez-Sanz, J. (Jairo); Oyaga-Iriarte, E. (Esther); Santamaria, E. (Enrique); Vera, R. (Ruth)
    Pancreatic ductal adenocarcinoma, which represents 80% of pancreatic cancers, is mainly diagnosed when treatment with curative intent is not possible. Consequently, the overall five-year survival rate is extremely dismal—around 5% to 7%. In addition, pancreatic cancer is expected to become the second leading cause of cancer-related death by 2030. Therefore, advances in screening, prevention and treatment are urgently needed. Fortunately, a wide range of approaches could help shed light in this area. Beyond the use of cytological or histological samples focusing in diagnosis, a plethora of new approaches are currently being used for a deeper characterization of pancreatic ductal adenocarcinoma, including genetic, epigenetic, and/or proteo-transcriptomic techniques. Accordingly, the development of new analytical technologies using body fluids (blood, bile, urine, etc.) to analyze tumor derived molecules has become a priority in pancreatic ductal adenocarcinoma due to the hard accessibility to tumor samples. These types of technologies will lead us to improve the outcome of pancreatic ductal adenocarcinoma patients.
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    Regulation of stathmin phosphorylation in mouse liver progenitor-29 cells during proteasome inhibition
    (Wiley-VCH Verlag Berlin, 2009) Mora, M.I. (María I.); Corrales, F.J. (Fernando José); Sanchez-Quiles, V. (Virginia); Fernandez-Irigoyen, J. (Joaquín); Prieto, J. (Jesús); Muñoz, J. (Javier); Santamaria, E. (Enrique)
    Proteasome inhibitors are potential therapeutic agents in the treatment of hepatocarcinoma and other liver diseases. The analysis of alternative protein phosphorylation states might contribute to elucidate the underlying mechanisms of proteasome inhibitor-induced apoptosis. We have investigated the response of mouse liver progenitor-29 (MLP-29) cells to MG132 using a combination of phosphoprotein affinity chromatography, DIGE, and nano LC-MS/MS. Thirteen unique deregulated phosphoproteins involved in chaperone activity, stress response, mRNA processing and cell cycle control were unambiguously identified. Alterations in NDRG1 and stathmin suggest new mechanisms associated to proteasome inhibitor-induced apoptosis in MLP-29 cells. Particularly, a transient modification of the phosphorylation state of Ser(16), Ser(25) and Ser(38), which are involved in the regulation of stathmin activity, was detected in three distinct isoforms upon proteasome inhibition. The parallel deregulation of calcium/calmodulin-activated protein kinase II, extracellular regulated kinase-1/2 and cyclin-dependent kinase-2, might explain the modified phosphorylation pattern of stathmin. Interestingly, stathmin phosphorylation profile was also modified in response to epoxomicin treatment, a more specific proteasome inhibitor. In summary, we report here data supporting that regulation of NDRG1 and stathmin by phosphorylation at specific Ser/Thr residues may participate in the cellular response induced by proteasome inhibitors.
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    Identification of replication-competent HSV-1 Cgal+ strain signaling targets in human hepatoma cells by functional organelle proteomics
    (American Society for Biochemistry and Molecular Biology, 2009) Mora, M.I. (María I.); Corrales, F.J. (Fernando José); Epstein, A.L. (Alberto L.); Potel, C. (Corinne); Fernandez-Irigoyen, J. (Joaquín); Carro-Roldan, E. (Elvira); Prieto, J. (Jesús); Hernandez-Alcoceba, R. (Rubén); Santamaria, E. (Enrique)
    In the present work, we have attempted a comprehensive analysis of cytosolic and microsomal proteomes to elucidate the signaling pathways impaired in human hepatoma (Huh7) cells upon herpes simplex virus type 1 (HSV-1; Cgal(+)) infection. Using a combination of differential in-gel electrophoresis and nano liquid chromatography/tandem mass spectrometry, 18 spots corresponding to 16 unique deregulated cellular proteins were unambiguously identified, which were involved in the regulation of essential processes such as apoptosis, mRNA processing, cellular structure and integrity, signal transduction, and endoplasmic-reticulum-associated degradation pathway. Based on our proteomic data and additional functional studies target proteins were identified indicating a late activation of apoptotic pathways in Huh7 cells upon HSV-1 Cgal(+) infection. Additionally to changes on RuvB-like 2 and Bif-1, down-regulation of Erlin-2 suggests stimulation of Ca(2+)-dependent apoptosis. Moreover, activation of the mitochondrial apoptotic pathway results from a time-dependent multi-factorial impairment as inferred from the stepwise characterization of constitutive pro- and anti-apoptotic factors. Activation of serine-threonine protein phosphatase 2A (PP2A) was also found in Huh7 cells upon HSV-1 Cgal(+) infection. In addition, PP2A activation paralleled dephosphorylation and inactivation of downstream mitogen-activated protein (MAP) kinase pathway (MEK(1/2), ERK(1/2)) critical to cell survival and activation of proapoptotic Bad by dephosphorylation of Ser-112. Taken together, our results provide novel molecular information that contributes to define in detail the apoptotic mechanisms triggered by HSV-1 Cgal(+) in the host cell and lead to the implication of PP2A in the transduction of cell death signals and cell survival pathway arrest.
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    Olfactory characterization and training in older adults: protocol study
    (2021) Martínez-Velilla, N. (Nicolás); Uzcanga-Lacabe, M.(M.); Cartas-Cejudo, P. (Paz); Maraví-Aznar, E. (Enrique); Fernández-González, S. (Secundino); Fernandez-Irigoyen, J. (Joaquín); Zambom-Ferraresi, F. (Fabiola); Cedeño-Veloz, B.A. (Bernardo Abel); Casares, N. (Noelia); Zambom-Ferraresi, F. (Fabricio); Lachén-Montes, M. (Mercedes); Galbete, A. (Arkaitz); Santamaria, E. (Enrique); Lasarte, J.J. (Juan José)
    The aim of this article is to present the research protocol for a prospective cohort study that will assess the olfactory function and the effect of an intervention based on olfactory training in healthy very old adults (>= 75 years old). A convenience sample of 180 older people (50% female) will be recruited in three different environments: hospitalized control group (CH) with stable acute illness (n = 60); ambulatory control group (CA) of community-based living (n = 60); and an experimental odor training group (EOT) from nursing homes (n = 60). The odor training (OT) intervention will last 12 weeks. All the volunteers will be assessed at baseline; CA and EOT groups will also be assessed after 12 weeks. The primary end point will be change in olfactory capacity from baseline to 12 weeks period of intervention or control. The intervention effects will be assessed with the overall score achieved in Sniffin Sticks Test (SST) - Threshold, Discrimination, and Identification (TDI) extended version. Secondary end points will be changes in cognitive tasks, quality of life, mood, immune status, and functional capacity. All these measurements will be complemented with an immune fitness characterization and a deep proteome profiling of the olfactory epithelium (OE) cultured ex vivo. The current study will provide additional evidence to support the implementation of olfactory precision medicine and the development of immunomodulatory nasal therapies based on non-invasive procedures. The proposed intervention will also intend to increase the knowledge about the olfactory function in very elderly people, improve function and quality of life, and promote the recovery of the health.
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    Proteomic analysis of liver diseases: molecular mechanisms and biomarker discovery
    (Bentham Science Publishers, 2008) Corrales, F.J. (Fernando José); Odriozola, L. (Leticia); Fernandez-Irigoyen, J. (Joaquín); Sesma, L. (Laura); Muñoz, J. (Javier); Santamaria, E. (Enrique)
    Liver diseases afflict more than 10% of the world population. Although the main risk factors are known and the population at risk is monitored, new biomarkers are urgently needed to allow early diagnosis and hence more effective therapeutic interventions. Here, we revise the contribution of proteomics to the study of liver diseases and its potential impact in the clinical practice is evaluated.
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    Proteomic analysis of human hepatoma cells expressing methionine adenosyltransferase I/III Characterization of DDX3X as a target of S-adenosylmethionine
    (Elsevier, 2012) Corrales, F.J. (Fernando José); Lu, S.C. (Shelly C.); Schröder, P.C. (Paul C.); Fernandez-Irigoyen, J. (Joaquín); Serna, A. (Antonio); Prieto, J. (Jesús); Hernandez-Alcoceba, R. (Rubén); Mato, J.M. (José María); Bigaud, E. (Emilie)
    Methionine adenosyltransferase I/III (MATI/III) synthesizes S-adenosylmethionine (SAM) in quiescent hepatocytes. Its activity is compromised in most liver diseases including liver cancer. Since SAM is a driver of hepatocytes fate we have studied the effect of re-expressing MAT1A in hepatoma Huh7 cells using proteomics. MAT1A expression leads to SAM levels close to those found in quiescent hepatocytes and induced apoptosis. Normalization of intracellular SAM induced alteration of 128 proteins identified by 2D-DIGE and gel-free methods, accounting for deregulation of central cellular functions including apoptosis, cell proliferation and survival. Human Dead-box protein 3 (DDX3X), a RNA helicase regulating RNA splicing, export, transcription and translation was down-regulated upon MAT1A expression. Our data support the regulation of DDX3X levels by SAM in a concentration and time dependent manner. Consistently, DDX3X arises as a primary target of SAM and a principal intermediate of its antitumoral effect. Based on the parallelism between SAM and DDX3X along the progression of liver disorders, and the results reported here, it is tempting to suggest that reduced SAM in the liver may lead to DDX3X up-regulation contributing to the pathogenic process and that replenishment of SAM might prove to have beneficial effects, at least in part by reducing DDX3X levels. This article is part of a Special Issue entitled: Clinical Proteomics.
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    Redox regulation of methylthioadenosine phosphorylase in liver cells: molecular mechanism and functional implications
    (Portland Press, 2008) Latasa, M.U. (María Ujué); Corrales, F.J. (Fernando José); Sanchez-del-Pino, M.M. (Manuel M.); Avila, M.A. (Matías Antonio); Sanchez-Quiles, V. (Virginia); Fernandez-Irigoyen, J. (Joaquín); Prieto, J. (Jesús); Muñoz, J. (Javier); Santamaria, M. (Mónica); Santamaria, E. (Enrique); Valero, M.L. (María L.)
    MTAP (5'-methylthioadenosine phosphorylase) catalyses the reversible phosphorolytic cleavage of methylthioadenosine leading to the production of methylthioribose-1-phosphate and adenine. Deficient MTAP activity has been correlated with human diseases including cirrhosis and hepatocellular carcinoma. In the present study we have investigated the regulation of MTAP by ROS (reactive oxygen species). The results of the present study support the inactivation of MTAP in the liver of bacterial LPS (lipopolysaccharide)-challenged mice as well as in HepG2 cells after exposure to t-butyl hydroperoxide. Reversible inactivation of purified MTAP by hydrogen peroxide results from a reduction of V(max) and involves the specific oxidation of Cys(136) and Cys(223) thiols to sulfenic acid that may be further stabilized to sulfenyl amide intermediates. Additionally, we found that Cys(145) and Cys(211) were disulfide bonded upon hydrogen peroxide exposure. However, this modification is not relevant to the mediation of the loss of MTAP activity as assessed by site-directed mutagenesis. Regulation of MTAP by ROS might participate in the redox regulation of the methionine catabolic pathway in the liver. Reduced MTA (5'-deoxy-5'-methylthioadenosine)-degrading activity may compensate for the deficient production of the precursor S-adenosylmethionine, allowing maintenance of intracellular MTA levels that may be critical to ensure cellular adaptation to physiopathological conditions such as inflammation.