OPCIONES TERAPEUTICAS DE LA CICLOOXIGENASA 2 EN LA ENFERMEDAD DEL HIGADO GRASO NO ALCOHOLICO: UNA APROXIMACION A LA NANOTECNOLOGIA

PID2019-108977RB-I00

Nombre agencia financiadora Agencia Estatal de Investigación
Acrónimo agencia financiadora AEI
Programa Programa Estatal de Generación de Conocimiento y Fortalecimiento Científico y Tecnológico del Sistema de I+D+i
Subprograma Subprograma Estatal de Generación de Conocimiento
Convocatoria Proyectos I+D
Año convocatoria 2019
Unidad de gestión Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020
Centro beneficiario AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS (CSIC)
Identificador persistente http://dx.doi.org/10.13039/501100011033

Publicaciones

Found(s) 14 result(s)
Found(s) 2 page(s)

Metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in Chronic Myeloid Leukemia

Digital.CSIC. Repositorio Institucional del CSIC
  • Contreras Mostazo, Miriam G.
  • Kurrle, Nina
  • Casado, Marta
  • Fuhrmann, Dominik
  • Alshamleh, Islam
  • Häupl, Björn
  • Martín-Sanz, Paloma
  • Brüne, Bernhard
  • Serve, Hubert
  • Schwalbe, Harald
  • Schnütgen, Frank
  • Marín, Silvia
  • Cascante, Marta
© 2020 by the authors., Tyrosine kinase inhibitors (TKIs) are currently the standard chemotherapeutic agents for the treatment of chronic myeloid leukemia (CML). However, due to TKI resistance acquisition in CML patients, identification of new vulnerabilities is urgently required for a sustained response to therapy. In this study, we have investigated metabolic reprogramming induced by TKIs independent of BCR-ABL1 alterations. Proteomics and metabolomics profiling of imatinib-resistant CML cells (ImaR) was performed. KU812 ImaR cells enhanced pentose phosphate pathway, glycogen synthesis, serine-glycine-one-carbon metabolism, proline synthesis and mitochondrial respiration compared with their respective syngeneic parental counterparts. Moreover, the fact that only 36% of the main carbon sources were utilized for mitochondrial respiration pointed to glycerol-phosphate shuttle as mainly contributors to mitochondrial respiration. In conclusion, CML cells that acquire TKIs resistance present a severe metabolic reprogramming associated with an increase in metabolic plasticity needed to overcome TKI-induced cell death. Moreover, this study unveils that KU812 Parental and ImaR cells viability can be targeted with metabolic inhibitors paving the way to propose novel and promising therapeutic opportunities to overcome TKI resistance in CML., M.G. Contreras Mostazo and I. Alshamleh were supported by the EU grant HaemMetabolome H2020-MSCA-ITN-2015-675790. H. Schwalbe, H. Serve, F. Schnütgen, S. Marin and M. Cascante acknowledge support from the European Commission (HaemMetabolome [EC-675790]). M. Cascante and S. Marin acknowledge the Spanish Ministerio de Economia y Competitividad (MINECO)-European Commission FEDER funds—“Una manera de hacer Europa” (SAF2017-89673-R), the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) Generalitat de Catalunya (2017SGR1033) and CIBERehd (CB17/04/00023) (ISCIII, Spain). M. Cascante also received support through the prize “ICREA Academia” for excellence in research, funded by ICREA foundation–Generalitat de Catalunya. F. Schnütgen was supported by the Wilhelm Sander-Foundation (2015.138.1) and the Deutsche Forschungsgemeinschaft (SCHN1166/4-1). H. Schwalbe acknowledges support for the Center for Biomolecular Magnetic Resonance (BMRZ) by state of Hesse. M. Casado and P. Martín-Sanz acknowledge support from SAF2016-75004-R (MINECO, Spain, AEI/FEDER, UE), PID2019-108977RB-I00 (MICINN, Spain,AEI/FEDER, UE), and CIBERehd (CB06/04/1069) (ISCIII, Spain). D. Fuhrmann, B. Brüne, N. Kurrle and H. Serve acknowledge Deutsche Forschungsgemeinschaft (SFB 815, TP A08, TP A10).




Role of cyclooxygenase 2 (COX-2) in liver mitochondrial function after ischemia-reperfusion injury

Digital.CSIC. Repositorio Institucional del CSIC
  • Fuertes-Agudo, Marina
  • Cucarella, Carme
  • Brea, Rocío
  • Boscá, Lisardo
  • Martín-Sanz, Paloma
  • Casado, Marta
Póster presentado al: Liver Meeting AASLD 2021: American Association fort eh Study of Liver Diseases. (Anaheim, CA, USA and virtual), 12-15 de novembre 2021 Abstract: 470, pag. 293A, In this work, we analyzed different aspects in order to characterize the impact of COX-2 in mitochondrial function after IRI., This work was supported by SAF2016-75004-R (MINECO, Spain) and PID2019-108977RB-I00 (MICINN, Spain), CIBERehd (ISCIII, Spain). M F-A. is recipient of FPI fellowship from MINECO (BES-2017-081928), Peer reviewed




Beyond classic concepts in thyroid homeostasis: Immune system and microbiota

Digital.CSIC. Repositorio Institucional del CSIC
  • Fernández-García, Victoria
  • González-Ramos, Silvia
  • Martín-Sanz, Paloma
  • Laparra, José Moisés
  • Boscá, Lisardo
© 2022 The Authors., It has long been known that thyroid hormones have implications for multiple physiological processes and can lead to serious illness when there is an imbalance in its metabolism. The connections between thyroid hormone metabolism and the immune system have been extensively described, as they can participate in inflammation, autoimmunity, or cancer progression. In addition, changes in the normal intestinal microbiota involve the activation of the immune system while triggering different pathophysiological disorders. Recent studies have linked the microbiota and certain bacterial fragments or metabolites to the regulation of thyroid hormones and the general response in the endocrine system. Even if the biology and function of the thyroid gland has attracted more attention due to its pathophysiological importance, there are essential mechanisms and issues related to it that are related to the interplay between the intestinal microbiota and the immune system and must be further investigated. Here we summarize additional information to uncover these relationships, the knowledge of which would help establish new personalized medical strategies., The review was written by authors that work in a laboratory where projects are supported by: Ministerio de Economía, Industria y Competitividad (RTI2018-094727-B-100, SAF2017-82436-R, RYC-2015-18083, PID2019-107650RB-C22 and PID2019-108977RB-100), Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CB16/11/00222), Consorcio de Investigación en Red de la Comunidad de Madrid, S2017/BMD-3686 and Fondo Europeo de Desarrollo Regional.




NOD1 in the interplay between microbiota and gastrointestinal immune adaptations

Digital.CSIC. Repositorio Institucional del CSIC
  • Fernández-García, Victoria
  • González-Ramos, Silvia
  • Martín-Sanz, Paloma
  • García del Portillo, Francisco
  • Moisés Laparra, José
  • Boscá, Lisardo
© 2021 The Author(s)., Nucleotide-binding oligomerization domain 1 (NOD1), a pattern recognition receptor (PRR) that detects bacterial peptidoglycan fragments and other danger signals, has been linked to inflammatory pathologies. NOD1, which is expressed by immune and non-immune cells, is activated after recognizing microbe-associated molecular patterns (MAMPs). This recognition triggers host defense responses and both immune memory and tolerance can also be achieved during these processes. Since the gut microbiota is currently considered a master regulator of human physiology central in health and disease and the intestine metabolizes a wide range of nutrients, drugs and hormones, it is a fact that dysbiosis can alter tissues and organs homeostasis. These systemic alterations occur in response to gastrointestinal immune adaptations that are not yet fully understood. Even if previous evidence confirms the connection between the microbiota, the immune system and metabolic disorders, much remains to be discovered about the contribution of NOD1 to low-grade inflammatory pathologies such as obesity, diabetes and cardiovascular diseases. This review compiles the most recent findings in this area, while providing a dynamic and practical framework with future approaches for research and clinical applications on targeting NOD1. This knowledge can help to rate the consequences of the disease and to stratify the patients for therapeutic interventions., The review was written by authors that work in a laboratory where projects are supported by: Ministerio de Economía, Industria y Competitividad/Agencia Estatal de Investigación 10.13039/501100011033 (RTI2018-094727-B100, SAF2017-82436-R, BIO2016-77639-P, PID2019-108977-RBI00 and PID2020-113238-RBI00), Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CB16/11/00222), Consorcio de Investigación en Red de la Comunidad de Madrid, S2017/BMD-3686 and Fondo Europeo de Desarrollo Regional.




Liver spheroids: a robust human in vitro system for testing the therapeutic options of cyclooxygenase 2 in NAFLD/NASH

Digital.CSIC. Repositorio Institucional del CSIC
  • Huete, Javier
  • Fuertes-Agudo, Marina
  • Brea, Rocío
  • Luque-Tévar, María
  • Cucarella, Carme
  • Martín-Sanz, Paloma
  • Casado, Marta
Trabajo presentado en las XV Jornadas CIBER Enfermedades Hepáticas y Digestivas: Jornades científiques del CIBERehd, celebradas en modalidad virtual y de forma presencial en Barcelona (España) del 08 al 09 de noviembre de 2021., Cyclooxygenase (COX) is a key enzyme in the biosynthesis of prostanoids. Prostaglandins are involved in multiple homeostatic processes, as well as playing an important role in the onset of inflammation. COX-2 is an isoform that is expressed and induced by different stimuli in various tissues and cell types; however, in liver, COX-2 expression is restricted to those situations where proliferation and dedifferentiation occur (1). Our previous results have shown that COX-2 expression in hepatocytes protects against hyperglycemia-induced liver damage, peripheral insulin resistance and adiposity in mice fed a high-fat diet (2), and also protects against experimental non-alcoholic steatohepatitis and fibrosis (3)., This work was supported by SAF2016-75004-R and PID2019-108977RB-I00 (MINECO, Spain) and CIBERehd (ISCIII, Spain). M F-A. and M L-T are recipient of FPI fellowship from MINECO (BES-2017-081928 and PRE2020-094885, respectively). We thank FEDER for financial support.




A Very Rare Variant in SREBF2, a Possible Cause of Hypercholesterolemia and Increased Glycemic Levels

Digital.CSIC. Repositorio Institucional del CSIC
  • García-García, Ana-Barbara
  • Martinez-Hervás, Sergio
  • Vernia, Santiago
  • Ivorra, Carmen
  • Pulido, Ines
  • Martin-Escudero, Juan-Carlos
  • Casado, Marta
  • Carretero, Julián
  • Real, Jose T.
  • Chaves, Felipe Javier
10 páginas, 2 figuras, 2 tablas. This article belongs to the Special Issue Molecular Research of Genes Involved in Metabolic Diseases.
The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/biomedicines10051178/s1, Figure S1: Comparison of the c.-
405A>G position in SREBF2 gene in five Hominidae species; Table S1: Sequences of primers used in
this work., Patients with high cholesterol and glucose levels are at high risk for cardiovascular disease. The Sterol Regulatory Element Binding Protein (SREBP) system regulates genes involved in lipid, cholesterol and glucose pathways. Autosomal Dominant Hypercholesterolemias (ADHs) are a group of diseases with increased cholesterol levels. They affect 1 out of every 500 individuals. About 20-30% of patients do not present any mutation in the known genes (LDLR, APOB and PCSK9). ADHs constitute a good model to identify the genes involved in the alteration of lipid levels or possible therapeutic targets. In this paper, we studied whether a mutation in the SREBP system could be responsible for ADH and other metabolic alterations present in these patients. Forty-one ADH patients without mutations in the main responsible genes were screened by direct sequencing of SREBP system genes. A luciferase reporter assay of the found mutation and an oral glucose tolerance test in carriers and non-carriers were performed. We found a novel mutation in the SREBF2 gene that increases transcription levels and cosegregates with hypercholesterolemia, and we found increased glucose levels in one family. SREBP2 is known to be involved in cholesterol synthesis, plasma levels and glucose metabolism in humans. The found mutation may involve the SREBF2 gene in hypercholesterolemia combined with hyperglycemia., This work was funded by the CIBER of Diabetes and Associated Metabolic Diseases
(CIBERDEM, which is an initiative of the Instituto de Salud Carlos III, Madrid, Spain), research grants
PI17/0497 and PI21/00506 from FIS to F.J.C., grant AP11-091 from Generalitat Valenciana to F.J.C.
and grant PID2019-108977RB-I00 from the Spanish Ministry of Science and Innovation to M.C., Peer reviewed




COX-2 Expression in Hepatocytes Improves Mitochondrial Function after Hepatic Ischemia-Reperfusion Injury

Digital.CSIC. Repositorio Institucional del CSIC
  • Fuertes-Agudo, Marina
  • Luque-Tévar, María
  • Cucarella, Carme
  • Brea, Rocío
  • Boscá, Lisardo
  • Quintana-Cabrera, Ruben
  • Martín-Sanz, Paloma
  • Casado, Marta
18 páginas, 7 figuras, Cyclooxygenase 2 (COX-2) is a key enzyme in prostanoid biosynthesis. The constitutive hepatocyte expression of COX-2 has a protective role in hepatic ischemia-reperfusion (I/R) injury (IRI), decreasing necrosis, reducing reactive oxygen species (ROS) levels, and increasing autophagy and antioxidant and anti-inflammatory response. The physiopathology of IRI directly impacts mitochondrial activity, causing ATP depletion and being the main source of ROS. Using genetically modified mice expressing human COX-2 (h-COX-2 Tg) specifically in hepatocytes, and performing I/R surgery on the liver, we demonstrate that COX-2 expression has a beneficial effect at the mitochondrial level. Mitochondria derived from h-COX-2 Tg mice livers have an increased respiratory rate associated with complex I electron-feeding pathways compared to Wild-type (Wt) littermates, without affecting complex I expression or assembly. Furthermore, Wt-derived mitochondria show a loss of mitochondrial membrane potential (ΔΨm) that correlates to increased proteolysis of fusion-related OPA1 through OMA1 protease activity. All these effects are not observed in h-COX-2 Tg mitochondria, which behave similarly to the Sham condition. These results suggest that COX-2 attenuates IRI at a mitochondrial level, preserving the proteolytic processing of OPA1, in addition to the maintenance of mitochondrial respiration., The experiments were performed in laboratories where projects are supported by: Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación 10.13039/501100011033 (SAF2016-
75004-R and PID2019-108977RB-I00), Centro de Investigación Biomédica en Red en Enfermedades
Hepáticas y Digestivas (CB06/04/1069), Centro de Investigación Biomédica en Red de Enfermedades
Cardiovasculares (CB/11/00222), Consorcio de Investigación en Red de la Comunidad de Madrid,
S2017/BMD-3686,and Fondo Europeo de Desarrollo Regional. M.F.-A. and M.L.-T. are recipient of
FPI fellowship from MINECO (BES-2017-081928 and PRE2020-094885, respectively)., Peer reviewed




Total data_BA

Digital.CSIC. Repositorio Institucional del CSIC
  • Casado, Marta
Methods

20 μL of plasma samples were spiked with deuterated internal standards stock solution. Then proteins were precipitated and supernatants were dried and reconstituted in methanol:water (50:50, V/V). Besides, approximately 50 mg of each tissue were placed in 2 ml tubes containing CK14 ceramic beads (Precellys). For each 50 mg of tissue, 300 μl of methanol and the deuterated internal standards were added and tissues were homogenized in a Precellys 24 Dual system equipped with a Criolys cooler (Precellys). Samples were analyzed using an Acquity UPLC system (Waters, UK) equipped with an Acquity UPLC BEH C18 column (1.7μm, 2.1 x 100 mm; Waters). The MS analysis was performed using a Waters Xevo TQ-XS mass spectrometer (Waters) with an ESI source working in the negative-ion mode., Cyclooxygenase-2 (COX-2) is involved in different liver diseases, but little is known about the significance of COX-2 or its metabolites in cholestatic injury. This study was designed to elucidate the role of COX-2 expression during the pathogenesis of cholestasis. Thus, we investigated the mechanisms underlying the role of COX-2 and its derived prostaglandins in modulating cell survival, inflammation, oxidative stress status and the synthesis and excretion of bile acids (BA) in response to cholestatic liver injury. We used genetically modified mice constitutively expressing human COX-2 (hCOX-2-Tg) specifically in hepatocytes. Transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were either subjected to a common bile duct ligation (BDL) to establish an experimental model of obstructive cholestasis. We performed an exhaustive analysis of the different types of bile acids (total, primary, secondary, conjugated, non-conjugated and hydrophilic, α-, β- and ω-muricholic acid) in plasma and in liver tissue from Wt and h-COX-2 Tg mice. Samples were analyzed at Instituto de Investigación Sanitaria La Fe (Valencia, Spain) detecting a total of 31 analytes., Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación 10.13039/501100011033 (PID2019-108977RB-I00), No




Quantitative Proteomics Analysis Reveals That Cyclooxygenase-2 Modulates Mitochondrial Respiratory Chain Complex IV in Cardiomyocytes

Digital.CSIC. Repositorio Institucional del CSIC
  • Alvarez, María Soledad
  • Núñez, Estefanía
  • Fuertes-Agudo, Marina
  • Cucarella, Carme
  • Fernández-Velasco, María
  • Boscá, Lisardo
  • Vázquez, Jesús
  • Rossignol, Rodrigue
  • Martín-Sanz, Paloma
  • Casado, Marta
19 páginas, 9 figuras, 1 tabla, The biochemical mechanisms of cell injury and myocardial cell death after myocardial infarction remain unresolved. Cyclooxygenase 2 (COX-2), a key enzyme in prostanoid synthesis, is expressed in human ischemic myocardium and dilated cardiomyopathy, but it is absent in healthy hearts. To assess the role of COX-2 in cardiovascular physiopathology, we developed transgenic mice that constitutively express functional human COX-2 in cardiomyocytes under the control of the α-myosin heavy chain promoter. These animals had no apparent phenotype but were protected against ischemia-reperfusion injury in isolated hearts, with enhanced functional recovery and diminished cellular necrosis. To further explore the phenotype of this animal model, we carried out a differential proteome analysis of wild-type vs. transgenic cardiomyocytes. The results revealed a tissue-specific proteomic profile dominated by mitochondrial proteins. In particular, an increased expression of respiratory chain complex IV proteins was observed. This correlated with increased catalytic activity, enhanced respiratory capacity, and increased ATP levels in the heart of COX-2 transgenic mice. These data suggest a new link between COX-2 and mitochondria, which might contribute to the protective cardiac effects of COX-2 against ischemia-reperfusion injury., This work was supported by Ministerio de Economia y Competitividad (BIO2012-37926),
Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación 10.13039/501100011033 (PID2019-
108977RB-I00; PID2020-113238RB-I00), by Generalitat Valenciana (ACOMP/2011/120), by grant PRB2
(IPT13/0001—ISCIII-SGEFI/FEDER, ProteoRed), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CB06/04/1069) and Centro de Investigación Biomédica en Red de
Enfermedades Cardiovasculares (CB/11/00222). M.S.A. was supported by a fellowship from CSIC
(Spanish National Research Council) (JAE-predoc). M.F.-A. is a recipient of the FPI fellowship from
MINECO (BES-2017-081928)., Peer reviewed




High-fat diet activates splenic NOD1 and enhances neutrophil recruitment and neutrophil extracellular traps release in the spleen of ApoE-deficient mice

Digital.CSIC. Repositorio Institucional del CSIC
  • Fernández-García, Victoria
  • González-Ramos, Silvia
  • Avendaño-Ortiz, José
  • Martín-Sanz, Paloma
  • Gómez-Coronado, Diego
  • Delgado, Carmen
  • Castrillo, Antonio
  • Boscá, Lisardo
In the course of atherogenesis, the spleen plays an important role in the regulation of extramedullary hematopoiesis, and in the control of circulating immune cells, which contributes to plaque progression. Here, we have investigated the role of splenic nucleotide-binding oligomerization domain 1 (NOD1) in the recruitment of circulating immune cells, as well as the involvement of this immune organ in extramedullary hematopoiesis in mice fed on a high-fat high-cholesterol diet (HFD). Under HFD conditions, the absence of NOD1 enhances the mobilization of immune cells, mainly neutrophils, from the bone marrow to the blood. To determine the effect of NOD1-dependent mobilization of immune cells under pro-atherogenic conditions, Apoe−/− and Apoe−/−Nod1−/− mice fed on HFD for 4 weeks were used. Splenic NOD1 from Apoe−/− mice was activated after feeding HFD as inferred by the phosphorylation of the NOD1 downstream targets RIPK2 and TAK1. Moreover, this activation was accompanied by the release of neutrophil extracellular traps (NETs), as determined by the increase in the expression of peptidyl arginine deiminase 4, and the identification of citrullinated histone H3 in this organ. This formation of NETs was significantly reduced in Apoe−/−Nod1−/− mice. Indeed, the presence of Ly6G+ cells and the lipidic content in the spleen of mice deficient in Apoe and Nod1 was reduced when compared to the Apoe−/− counterparts, which suggests that the mobilization and activation of circulating immune cells are altered in the absence of NOD1. Furthermore, confirming previous studies, Apoe−/−Nod1−/− mice showed a reduced atherogenic disease, and diminished recruitment of neutrophils in the spleen, compared to Apoe−/− mice. However, splenic artery ligation reduced the atherogenic burden in Apoe−/− mice an effect that, unexpectedly was lost in Apoe−/−Nod1−/− mice. Together, these results suggest that neutrophil accumulation and activity in the spleen are driven in part by NOD1 activation in mice fed on HFD, contributing in this way to regulating atherogenic progression., This work has been supported by: Ministerio de Ciencia, Investigación y Universidades, Agencia Estatal de Investigación *** (PID2019-104284RB-I00, PID2020-113238RB-I00, RTI2018-098113B-I00, PID2019-108977RB-I00), Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CB16/11/00222) and Consorcio de Investigación en Red de la Comunidad de Madrid, S2017/BMD-3686, Fondo Social Europeo and Fondo Europeo de Desarrollo Regional.