Marı́a J. López-Zabalza

Universidad de Navarra

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N López-Moratalla

Clinica Universidad de Navarra

María J. Iraburu

Universidad de Navarra

Esteban Santiago

University of Rochester

Agustı́n España

Clinica Universidad de Navarra

E Santiago

Instituto Politécnico Nacional

Beatriz Pelacho

Universidad de Navarra

Teresa Mòdol

Universidad de Navarra

Juan A. Osés-Prieto

University of California, San Francisco

Eduardo Ansorena

Universidad de Navarra

Juan J. Martínez‐Irujo

Universidad de Navarra

Cooperative Institutions

Universidad de Navarra

Clinica Universidad de Navarra

Navarre Institute of Health Research

Centro de Investigación Biomédica en Red

Instituto de Salud Carlos III

Centro de Investigación Biomédica en Red de Cáncer

Icahn School of Medicine at Mount Sinai

Chartered Institute of Management Accountants

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

Universitat de Barcelona

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Amino Acid Deprivation Decreases Intracellular Levels of Reactive Oxygen Species in Hepatic Stellate Cells

Cellular Physiology and Biochemistry (2010)

Elena Arriazu María P. Pérez de Obanos Marı́a J. López-Zabalza Maite Herráiz María J. Iraburu

In eukaryotic cells amino acid deprivation triggers a response aimed to ensure cell survival in stress conditions. In the present work we analyzed the effects of amino acid deprivation on intracellular levels of reactive oxygen species (ROS) of hepatic stellate cells (HSC), a key cell type in the development of liver fibrosis. Histidine deprivation caused in the human immortalized HSC cell line LX-2 a fast decrease of intracellular ROS levels that was also observed in HSC incubated either with leucine-free or amino acid-free medium, but not with glucose-free medium. Phosphorylation of GCN2 kinase and its substrate eIF2α was induced by histidine deprivation. Reversion studies and activation of GCN2 by tRNA and the proteasome inhibitor MG-132 showed a correlation between GCN2 phosphorylation and diminished ROS levels. However, a lack of correlation between eIF2α phosphorylation and ROS levels was found using salubrinal, an inhibitor of eIF2α phosphorylation, suggesting a role for GCN2 unrelated to its activity as eIF2α kinase. LX-2 cells treated with histidine-free medium presented reduced SOD activity that could account for the decrease on ROS levels. Histidine deprivation as well as activation of GCN2 by treatment with tRNA, caused an increase in LX-2 cell viability, suggesting amino acid restriction to present a protective effect in HSC which is mediated by GCN2 activation.

Hepatic stellate cell

10.1159/000320551

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Citations (13)

3,4-Methylenedioxymethamphetamine (“Ecstasy”) induces apoptosis of cultured rat liver cells

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (2002)

Cristina Montiel‐Duarte Marta Varela‐Rey Juan A. Osés-Prieto Marı́a J. López-Zabalza Guadalupe Beitia

MDMA

Ecstasy

Hepatic stellate cell

10.1016/s0925-4439(02)00112-6

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Fibronectin Peptides as Potential Regulators of Hepatic Fibrosis Through Apoptosis of Hepatic Stellate Cells

Journal of Cellular Physiology (2014)

Teresa Mòdol Natalia Brice Marina Ruiz de Galarreta Antonia García Garzón María J. Iraburu

The turnover of extracellular matrix (ECM) components can generate signals that regulate several cellular functions such as proliferation, differentiation, and apoptosis. During liver injury, matrix metalloproteases (MMPs) production is enhanced and increased levels of peptides derived from extracellular matrix proteins can be generated. Synthetic peptides with sequences present in extracellular matrix proteins were previously found to induce both stimulating and apoptotic effects on several cell types including the inflammatory cells monocytes/macrophages. Therefore, in inflammatory liver diseases, locally accumulated peptides could be also important in regulating hepatic fibrosis by inducing apoptosis of hepatic stellate cells (HSC), the primary cellular source of extracellular matrix components. Here, we describe the apoptotic effect of fibronectin peptides on the cell line of human hepatic stellate cells LX‐2 based on oligonucleosomal DNA fragmentation, caspase‐3 and ‐9 activation, Bcl‐2 depletion, and accumulation of Bax protein. We also found that these peptides trigger the activation of Src kinase, which in turn mediated the increase of JNK and p38 activities. By the use of specific inhibitors we demonstrated the involvement of Src, JNK, and p38 in apoptosis induced by fibronectin peptides on HSC. Moreover, fibronectin peptides increased iNOS expression in human HSC, and specific inhibition of iNOS significantly reduced the sustained activity of JNK and the programmed cell death caused by these peptides. Finally, the possible regulatory effect of fibronectin peptides in liver fibrosis was further supported by the ability of these peptides to induce metalloprotease‐9 (MMP‐9) expression in human monocytes. J. Cell. Physiol. 230: 546–553, 2015. © 2014 Wiley Periodicals, Inc., A Wiley Company

Hepatic stellate cell

Hepatic fibrosis

10.1002/jcp.24714

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Citations (35)

Immunomodulation induced by synthetic peptides derived from Staphylococcus aureus protein A

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (1994)

N López-Moratalla Marı́a J. López-Zabalza María L. Subirá Francisco Borrás‐Cuesta Alberto Pérez‐Mediavilla

Alanine

Isoleucine

10.1016/0167-4889(94)90007-8

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Citations (20)

Papel de las isoformas HER y la mTOR en la acantólisis del pénfigo vulgar en un modelo murino

M. Pretel Marı́a J. López-Zabalza Agustı́n España

El penfigo vulgar (PV) es una enfermedad ampollosa autoinmune que afecta a piel y mucosas, caracterizada por la presencia de autoanticuerpos IgG frente a la desmogleina 3 (Dsg3) que provocan una ruptura intraepitelial de la epidermis llamada acantolisis. El mecanismo por el cual se produce la acantolisis no es del todo conocido. Nuestro objetivo en este trabajo fue investigar los eventos moleculares implicados en el desarrollo y la localizacion de la apoptosis y la acantolisis en el PV. Parra ello empleamos el modelo murino de tranferencia pasiva con estudios de inmunohistoquimica con un analisis cuantitativo y la tecnica TUNEL para el estudio de la apoptosis. Tanto las moleculas de senalizacion activadas analizadas como las celulas apoptoticas detectadas mostraron la misma localizacion. Hemos observado por primera vez in vivo un aumento de la expresion de las isoformas activadas de los receptores HER en la capa basal de la epidermis en las lesiones de PV. La importancia de este hallazgo se ve reforzada por el hecho de que el pretratamiento de los ratones con erlotinib (inhibidor de HER1, HER2 Y HER3) inhibio tanto la enfermedad clinica como histologica. Ademas, hemos hallado una casi nula expresion de la Akt activada comparada con un nivel mas elevado de la mTOR activada dentro de las celulas basales de la epidermis. Tras el pretratamiento de los animales con rapamicina (inhibidor de mTRO) pudimos observar como se anularon las manifestaciones clinicas e histologicas del PV. Nuestras observaciones sugieren que la acntolisis podria estar restringida a la capa basal, al menos en parte, por el aumento selectivo de las isoformas activadas de los receptores HER que ocurre en estas celulas. Despues de la forsforilacion de las isoformas de los receptores HER, se activarian vias de senalizacion intracelular en la capa basal epidermica. Ademas, el desequilibrio de Akt/mTOR que tiene lugar en las celulas de la capa basal podria aportar las senales intracelulares necesarias para el desarrollo de la apoptosis y la acantolisis

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Apoptosis of hepatic stellate cells mediated by specific protein nitration

Biochemical Pharmacology (2010)

Teresa Mòdol Cristina Natal María P. Pérez de Obanos Eduardo Domingo De Miguel María J. Iraburu

Hepatic stellate cell

LYN

10.1016/j.bcp.2010.10.017

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Citations (15)

El papel de la FAK en la acantólisis del Pénfigo vulgar en un modelo murino

M.P. Gil-Sanchez Marı́a J. López-Zabalza Agustı́n España

Pemphigus vulgaris (PV) is an autoimmune blistering skin disease characterized by suprabasal acantholysis, and autoantibodies against desmoglein 3 localized on desmosomes. In addition, caspases also seem to participate in this blistering disease. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase involved in cytoskeleton remodelling and formation and disassembly of cell adhesion structures. We have previously demonstrated that HER (human epidermal growth factor receptor related) isoforms, Src (Rous sarcoma) and mTOR (mammalian target of rapamycin), three molecules implicated in signalling processes, take part in suprabasal acantholysis and apoptosis induced by PV-IgG in a mouse model. Our aim was to investigate if upregulation of FAK is implicated in the development of PV lesions. Herein, using a mouse model, PV-IgG administration showed an increased level of FAK phosphorylated on 397 and 925 tyrosine residues in the basal layer of epidermis. When mice were pretreated with a FAK inhibitor the acantholysis of the basal layer of epidermis was absent. More interestingly, we observed that phosphorylated FAK (Y397/925) decreased when HER isoforms, Src, mTOR, and pan-caspases inhibitors were employed before PV-IgG administration. In addition, pretreatment with the FAK inhibitor before PV-IgG injection avoided the changes of both Bax and Bcl-2 expression and caspases-9 and –3 activities induced by PV-IgG. Finally, FAK inhibitor reduced expression of phosphorylated Src and mTOR in the basal cells of epidermis. In conclusion, our data reveal a novel biochemical mechanism for phosphorylated FAK (Y397/925) in PV development involving HER isoforms, Src and mTOR kinases.

Acantholysis

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Conformational changes of S-1 related to its dissociation from actin.

PubMed (1992)

S. Sanz M J Gil Marı́a J. López-Zabalza N López-Moratalla Esteban Santiago

The peptide pattern obtained after proteolysis of S-1 with trypsin was different in the absence or presence of anions. The affinity of tryptic and undigested S-1 for anions (CN-, SCN- or HCO3-) was different, as reflected by the altered values of Ki or Ka obtained from ATPase activity measurements. Anions CN-, SCN-, HCO3-, or PPi induced dissociation of actomyosin when added to acto-S-1 or acto-heavy-meromyosin. Among nucleoside di- and triphosphates, only triphosphates were effective with regard to the dissociation. The results suggest the existence of a regulatory site of cationic nature on S-1, which might be involved in the dissociation of actin from myosin.

Heavy meromyosin

Proteolysis

Cationic polymerization

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Citations (1)

Role of AGAP2 in the profibrogenic effects induced by TGFβ in LX-2 hepatic stellate cells

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (2019)

Amaia Navarro‐Corcuera Marı́a J. López-Zabalza Juan J. Martínez‐Irujo Gloria Álvarez‐Sola Matías A. Ávila

Hepatic stellate cell

10.1016/j.bbamcr.2019.01.008

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