7 results on '"Joaquín Fernández-Irigoyen"'
Search Results
2. Host tau genotype specifically designs and regulates tau seeding and spreading and host tau transformation following intrahippocampal injection of identical tau AD inoculum
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Pol Andrés-Benito, Margarita Carmona, Mónica Jordán, Joaquín Fernández-Irigoyen, Enrique Santamaría, José Antoni del Rio, Isidro Ferrer, Universidad Pública de Navarra. Departamento de Ciencias de la Salud, and Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila
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Genotype ,QH301-705.5 ,Fluorescent Antibody Technique ,Mice, Transgenic ,tau Proteins ,Hippocampus ,Catalysis ,Article ,Inorganic Chemistry ,Host tau ,Mice ,3Rtau and 4Rtau ,Alzheimer Disease ,host tau ,mental disorders ,Animals ,Humans ,Physical and Theoretical Chemistry ,Biology (General) ,Molecular Biology ,QD1-999 ,Spectroscopy ,Mice, Knockout ,Neurons ,Seeding and spreading ,seeding and spreading ,tauopathies ,hTau ,Alzheimer’s disease ,Organic Chemistry ,Brain ,General Medicine ,Alzheimer's disease ,Immunohistochemistry ,Metabolisme ,Computer Science Applications ,Disease Models, Animal ,Chemistry ,Malaltia d'Alzheimer ,Metabolism ,Tauopathies ,Mutation ,Disease Susceptibility ,HTau ,Biomarkers - Abstract
Several studies have demonstrated the different characteristics of tau seeding and spreading following intracerebral inoculation in murine models of tau-enriched fractions of brain homogenates from AD and other tauopathies. The present study is centered on the importance of host tau in tau seeding and the molecular changes associated with the transformation of host tau into abnormal tau. The brains of three adult murine genotypes expressing different forms of tau—WT (murine 4Rtau), hTau (homozygous transgenic mice knock-out for murine tau protein and heterozygous expressing human forms of 3Rtau and 4Rtau proteins), and mtWT (homozygous transgenic mice knock-out for murine tau protein)—were analyzed following unilateral hippocampal inoculation of sarkosyl-insoluble tau fractions from the same AD and control cases. The present study reveals that (a) host tau is mandatory for tau seeding and spreading following tau inoculation from sarkosyl-insoluble fractions obtained from AD brains; (b) tau seeding does not occur following intracerebral inoculation of sarkosyl-insoluble fractions from controls; (c) tau seeding and spreading are characterized by variable genotype-dependent tau phosphorylation and tau nitration, MAP2 phosphorylation, and variable activation of kinases that co-localize with abnormal tau deposits; (d) transformation of host tau into abnormal tau is an active process associated with the activation of specific kinases; (e) tau seeding is accompanied by modifications in tau splicing, resulting in the expression of new 3Rtau and 4Rtau isoforms, thus indicating that inoculated tau seeds have the capacity to model exon 10 splicing of the host mapt or MAPT with a genotype-dependent pattern; (e) selective regional and cellular vulnerabilities, and different molecular compositions of the deposits, are dependent on the host tau of mice injected with identical AD tau inocula. The project leading to these results received funding from the La Caixa Foundation (ID 100010434) under the agreement LCF/PR/HR19/52160007 to IF; it was also supported by the Ministry of Economy and Competitiveness, Institute of Health Carlos III (ISCIII) (co-funded by European Regional Development Fund, ERDF, a way to build Europe): FISPI17/000809 to IF; and the IntraCIBERNED 2019 collaborative project to IF and JADR. This work was also co-financed by ERDF under the program Interreg Poctefa: RedPrion 148/16; ERDF [148/16]. We thank CERCA Programme/Generalitat de Catalunya for institutional support.
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- 2022
3. Olfactory Bulb Proteomics Reveals Widespread Proteostatic Disturbances in Mixed Dementia and Guides for Potential Serum Biomarkers to Discriminate Alzheimer Disease and Mixed Dementia Phenotypes
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Enrique Santamaría, Ignacio Iñigo-Marco, Mercedes Lachén-Montes, Paz Cartas-Cejudo, Joaquín Fernández-Irigoyen, Universidad Pública de Navarra. Departamento de Ciencias de la Salud, Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila, and Gobierno de Navarra / Nafarroako Gobernua
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Proteomics ,Medicine (miscellaneous) ,Biology ,Vascular dementia ,Article ,mixed dementia ,03 medical and health sciences ,Olfactory bulb ,0302 clinical medicine ,proteomics ,medicine ,anatomy_morphology ,030304 developmental biology ,Synucleinopathies ,0303 health sciences ,vascular dementia ,Neuron projection regeneration ,medicine.disease ,LRP1 ,Proteostasis ,Mixed dementia ,olfactory bulb ,Medicine ,Alzheimer's disease ,Neuroscience ,Alzheimer’s disease ,030217 neurology & neurosurgery - Abstract
The most common form of mixed dementia (MixD) is constituted by abnormal protein deposits associated with Alzheimer's disease (AD) that coexist with vascular disease. Although olfactory dysfunction is considered a clinical sign of AD-related dementias, little is known about the impact of this sensorial impairment in MixD at the molecular level. To address this gap in knowledge, we assessed olfactory bulb (OB) proteome-wide expression in MixD subjects (n = 6) respect to neurologically intact controls (n = 7). Around 9% of the quantified proteins were differentially expressed, pinpointing aberrant proteostasis involved in synaptic transmission, nucleoside monophosphate and carbohydrate metabolism, and neuron projection regeneration. In addition, network-driven proteomics revealed a modulation in cell-survival related pathways such as ERK, AKT, and the PDK1-PKC axis. Part of the differential OB protein set was not specific of MixD, also being deregulated across different tauopathies, synucleinopathies, and tardopathies. However, the comparative functional analysis of OB proteome data between MixD and pure AD pathologies deciphered commonalities and differences between both related phenotypes. Finally, olfactory pro-teomics allowed to propose serum Prolow-density lipoprotein receptor-related protein 1 (LRP1) as a candidate marker to differentiate AD from MixD phenotypes. This work was funded by grants from the Spanish Ministry of Science, Innovation and Universities (Ref. PID2019-110356RB-I00/AEI/10.13039/501100011033) and the Department of Economic and Business Development from Government of Navarra (Ref. 0011-1411-2020-000028 to E.S.).
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- 2021
4. Maraviroc prevents hcc development by suppressing macrophages and the liver progenitor cell response in a murine chronic liver disease model
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Joaquín Fernández-Irigoyen, Sarah B. McSpadden, Luke A. Diepeveen, Janina E.E. Tirnitz-Parker, Alfredo Martínez, Bernard A. Callus, Weihao Zhao, Enrique Santamaría, Caryn L. Elsegood, Hyerin Park, Ken H. Woo, Andy Chevigné, Adam M. Passman, Laura Ochoa-Callejero, Roslyn London, George C.T. Yeoh, José Ramón Blanco, Martyna Szpakowska, Robyn P. Strauss, Laura Medina-Ruiz, Megan Finch-Edmondson, Rodrigo Carlessi, Murray V. Baker, Neil Andrewartha, Universidad Pública de Navarra. Departamento de Ciencias de la Salud, and Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila
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Cancer Research ,Hepatocellular carcinoma ,CCL5 chemokine ,CCR5 receptor antagonist ,Biology ,Chronic liver disease ,Article ,Maraviroc ,Liver progenitor cells ,chemistry.chemical_compound ,medicine ,Macrophage ,Progenitor cell ,Receptor ,STAT3 ,Protein kinase B ,RC254-282 ,Macrophages ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,musculoskeletal system ,Mara-viroc ,body regions ,Oncology ,chemistry ,biology.protein ,Cancer research ,human activities - Abstract
Maraviroc (MVC), a CCR5 antagonist, reduces liver fibrosis, injury and tumour burden in mice fed a hepatocarcinogenic diet, suggesting it has potential as a cancer therapeutic. We investigated the effect of MVC on liver progenitor cells (LPCs) and macrophages as both have a role in hepatocarcinogenesis. Mice were fed the hepatocarcinogenic choline-deficient, ethionine-supplemented diet (CDE) ± MVC, and immunohistochemistry, RNA and protein expression were used to determine LPC and macrophage abundance, migration and related molecular mechanisms. MVC reduced LPC numbers in CDE mice by 54%, with a smaller reduction seen in macrophages. Transcript and protein abundance of LPC-associated markers correlated with this reduction. The CDE diet activated phosphorylation of AKT and STAT3 and was inhibited by MVC. LPCs did not express Ccr5 in our model, in contrast, macrophages expressed high levels of this receptor, suggesting the effect of MVC is mediated by targeting macrophages. MVC reduced CD45+ cells and macrophage migration in liver and blocked the CDE-induced transition of liver macrophages from an M1- to M2-tumour-associated macrophage (TAM) phenotype. These findings suggest MVC has potential as a re-purposed therapeutic agent for treating chronic liver diseases where M2-TAM and LPC numbers are increased, and the incidence of HCC is enhanced.
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- 2021
5. Amyotrophic Lateral Sclerosis Is Accompanied by Protein Derangements in the Olfactory Bulb-Tract Axis
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Naroa Mendizuri, Karina Ausín, Isidro Ferrer, Pol Andrés-Benito, Joaquín Fernández-Irigoyen, Mercedes Lachén-Montes, Enrique Santamaría, Universidad Pública de Navarra. Departamento de Ciencias de la Salud, Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila, and Gobierno de Navarra / Nafarroako Gobernua, Ref. 0011-1411-2020-000028
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Male ,Proteomics ,Proteome ,lcsh:Chemistry ,Olfaction Disorders ,Olfactory bulb ,Olfactory tract ,Axon ,Amyotrophic lateral sclerosis ,lcsh:QH301-705.5 ,Spectroscopy ,Inclusion Bodies ,Motor Neurons ,Glial fibrillary acidic protein ,General Medicine ,Frontotemporal lobar degeneration ,Middle Aged ,Computer Science Applications ,DNA-Binding Proteins ,medicine.anatomical_structure ,olfactory bulb ,Disease Progression ,TDP-43 proteinopathy ,Female ,signaling ,Signal Transduction ,olfactory tract ,Biology ,Proteòmica ,Catalysis ,Article ,Inorganic Chemistry ,proteomics ,Glial Fibrillary Acidic Protein ,medicine ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,Gliogenesis ,Aged ,Organic Chemistry ,medicine.disease ,Signaling ,lcsh:Biology (General) ,lcsh:QD1-999 ,biology.protein ,Frontotemporal Lobar Degeneration ,Neuroscience ,Olfactory marker protein ,Esclerosi lateral amiotròfica - Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by progressive muscle paralysis due to the degeneration of upper and lower motor neurons. Recent studies point out an involvement of the non-motor axis during disease progression. Despite smell impairment being considered a potential non-motor finding in ALS, the pathobiochemistry at the olfactory level remains unknown. Here, we applied an olfactory quantitative proteotyping approach to analyze the magnitude of the olfactory bulb (OB) proteostatic imbalance in ALS subjects (n = 12) with respect to controls (n = 8). Around 3% of the quantified OB proteome was differentially expressed, pinpointing aberrant protein expression involved in vesicle-mediated transport, macroautophagy, axon development and gliogenesis in ALS subjects. The overproduction of olfactory marker protein (OMP) points out an imbalance in the olfactory signal transduction in ALS. Accompanying the specific overexpression of glial fibrillary acidic protein (GFAP) and Bcl-xL in the olfactory tract (OT), a tangled disruption of signaling routes was evidenced across the OB&ndash, OT axis in ALS. In particular, the OB survival signaling dynamics clearly differ between ALS and frontotemporal lobar degeneration (FTLD), two faces of TDP-43 proteinopathy. To the best of our knowledge, this is the first report on high-throughput molecular characterization of the olfactory proteostasis in ALS.
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- 2020
6. Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervix
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Karina Ausín, David Guerrero-Setas, Saioa Mendaza, José Santos-Salas, Joaquín Fernández-Irigoyen, Xavier Matias-Guiu, Enrique Santamaría, August Vidal, María José Díaz de Cerio, Rosa Guarch, Tamara Zudaire, Esperanza Martín-Sánchez, Universidad Pública de Navarra. Departamento de Ciencias de la Salud, Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila, Gobierno de Navarra / Nafarroako Gobernua, and Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa
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nuclear p16 ,Cancer cells ,cervical cancer ,Cell ,subcellular location ,Uterine Cervical Neoplasms ,cytoplasmic p16 ,Nuclear p16 ,lcsh:Chemistry ,Diagnòstic ,Cervix cancer ,Diagnosis ,predictive biomarker ,lcsh:QH301-705.5 ,Spectroscopy ,Cervical cancer ,General Medicine ,Middle Aged ,Prognosis ,Immunohistochemistry ,Computer Science Applications ,Predictive biomarker ,medicine.anatomical_structure ,High-grade squamous intraepithelial lesion ,Carcinoma, Squamous Cell ,Biomarker (medicine) ,Female ,Cèl·lules canceroses ,high-grade squamous intraepithelial lesion ,Càncer de coll uterí ,Sensitivity and Specificity ,Article ,Catalysis ,Inorganic Chemistry ,Gentamicin protection assay ,Cell Line, Tumor ,Biomarkers, Tumor ,medicine ,Humans ,Cytoplasmic p16 ,Physical and Theoretical Chemistry ,Molecular Biology ,Cervix ,Cyclin-Dependent Kinase Inhibitor p16 ,Cell Nucleus ,business.industry ,Cell growth ,Organic Chemistry ,Colocalization ,Squamous cell carcinoma of the cervix ,medicine.disease ,Subcellular location ,Survival Analysis ,lcsh:Biology (General) ,lcsh:QD1-999 ,Cancer research ,squamous cell carcinoma of the cervix ,business ,HeLa Cells - Abstract
The tumor-suppressor protein p16 is paradoxically overexpressed in cervical cancer (CC). Despite its potential as a biomarker, its clinical value and the reasons for its failure in tumor suppression remain unclear. Our purpose was to determine p16 clinical and biological significance in CC. p16 expression pattern was examined by immunohistochemistry in 78 CC cases (high-grade squamous intraepithelial lesions (HSILs) and squamous cell carcinomas of the cervix &ndash, SCCCs). CC cell proliferation and invasion were monitored by real-time cell analysis and Transwell®, invasion assay, respectively. Cytoplasmic p16 interactors were identified from immunoprecipitated extracts by liquid chromatography-tandem mass spectrometry, and colocalization was confirmed by double-immunofluorescence. We observed that SCCCs showed significantly more cytoplasmic than nuclear p16 expression than HSILs. Importantly, nuclear p16 absence significantly predicted poor outcome in SCCC patients irrespective of other clinical parameters. Moreover, we demonstrated that cytoplasmic p16 interacted with CDK4 and other unreported proteins, such as BANF1, AKAP8 and AGTRAP, which could sequester p16 to avoid nuclear translocation, and then, impair its anti-tumor function. Our results suggest that the absence of nuclear p16 could be a diagnostic biomarker between HSIL and SCCC, and an independent prognostic biomarker in SCCC, and explain why p16 overexpression fails to stop CC growth.
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- 2020
7. Profound reprogramming towards stemness in pancreatic cancer cells as adaptation to AKT inhibition
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Grazyna Kochan, C. Rodriguez, Maria Gato, Ruth Vera, Enrique Santamaría, Ana Bocanegra, Idoia Blanco-Luquin, Miren Zuazo, Carlos Hernandez, Karina Ausín, Luisa Chocarro, Hugo Arasanz, Joaquín Fernández-Irigoyen, David Escors, Gonzalo Fernandez, Eva Santamaría, Universidad Pública de Navarra. Departamento de Ciencias de la Salud, Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila, Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa, and Gobierno de Navarra / Nafarroako Gobernua
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0301 basic medicine ,Homeobox protein NANOG ,Cancer Research ,Cancer stem cell ,AKT ,AKT1 ,Pancreatic cancer ,Biology ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Mitochondrial biogenesis ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,medicine ,Protein kinase B ,PI3K/AKT/mTOR pathway - Abstract
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. This research was supported by: Asociación Española Contra el Cáncer (AECC, PROYE16001ESCO); Instituto de Salud Carlos III, Spain (FIS project grant PI17/02119); 'Precipita' Crowdfunding grant (FECYT); Crowdfunding grant from Sociedad Española de Inmunología (SEI); and Government of Navarre project grant in biomedicine (BMED 050-2019). D.E. is funded by a Miguel Servet Fellowship (ISC III, CP12/03114, Spain); H.A. is supported by the Clinico Junior 2019 scholarship from AECC; M.Z. is supported by a scholarship from Universidad Pública de Navarra; M.G. is supported by a scholarship from the Government of Navarre; and L.C.D is supported by a DESCARTHES project grant (Industry department, Government of Navarre).
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- 2020
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