Centro de Investigación en Nutrición (CIN)
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61 results
Results
- Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function(2023) Nogueiras, R. (Rubén); Heras, V. (Violeta); Bravo, S. (Susana B.); Ameneiro, C. (Cristina); Gonzalez-Rellan, M.J. (María J.); Fondevila, M.F. (Marcos F.); Parracho, T. (Tamara); Frühbeck, G. (Gema); Iruzubieta, P. (Paula); Novoa, E. (Eva); Crespo, J. (Javier); Prevot, V. (Vincent); Varela-Rey, M. (Marta); da-Silva-Lima, N. (Natalia); Dieguez, C. (Carlos); Lopitz-Otsoa, F. (Fernando); Rodriguez, A. (Amaia); Bernardo, G. (Ganeko); Millet, O. (Oscar); Fernández-Ramos, D. (David); Guallar, D. (Diana); Fidalgo, M. (Miguel); Schwaninger, M. (Markus); Bilbao, J. (Jon); Mato, J.M. (José María); Chantada-Vazquez, P. (Pilar); Martinez-Chantar, M.L. (María Luz); Senra, A. (Ana)Objective: O-GlcNAcylation is a post-translational modification that directly couples the processes of nutrient sensing, metabolism, and signal transduction, affecting protein function and localization, since the O-linked N-acetylglucosamine moiety comes directly from the metabolism of glucose, lipids, and amino acids. The addition and removal of O-GlcNAc of target proteins are mediated by two highly conserved enzymes: O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase (OGA), respectively. Deregulation of O-GlcNAcylation has been reported to be associated with various human diseases such as cancer, diabetes, and cardiovascular diseases. The contribution of deregulated O-GlcNAcylation to the progression and pathogenesis of NAFLD remains intriguing, and a better understanding of its roles in this pathophysiological context is required to uncover novel avenues for therapeutic intervention. By using a translational approach, our aim is to describe the role of OGT and O-GlcNAcylation in the pathogenesis of NAFLD. Methods: We used primary mouse hepatocytes, human hepatic cell lines and in vivo mouse models of steatohepatitis to manipulate O-GlcNAc transferase (OGT). We also studied OGT and O-GlcNAcylation in liver samples from different cohorts of people with NAFLD. Results: O-GlcNAcylation was upregulated in the liver of people and animal models with steatohepatitis. Downregulation of OGT in NAFLD-hepatocytes improved diet-induced liver injury in both in vivo and in vitro models. Proteomics studies revealed that mitochondrial proteins were hyper-O-GlcNAcylated in the liver of mice with steatohepatitis. Inhibition of OGT is able to restore mitochondrial oxidation and decrease hepatic lipid content in in vitro and in vivo models of NAFLD. Conclusions: These results demonstrate that deregulated hyper-O-GlcNAcylation favors NAFLD progression by reducing mitochondrial oxidation and promoting hepatic lipid accumulation.
- Demonstration of a peptidoglycan-linked lipoprotein and characterization of its trypsin fragment in the outer membrane of Brucella spp(1986) Gomez-Miguel, M.J. (María J.); Moriyon, I. (Ignacio)The sodium dodecyl sulfate (SDS) extraction-trypsin digestion protocol used by Braun and Sieglin (V. Braun and U. Sieglin, Eur. J. Biochem. 13:336-346, 1970) to show the peptidoglycan-linked lipoprotein of Escherichia coli was applied to both Brucella abortus and E. coli. Whereas a single polypeptide of 8,000 molecular weight was obtained from E. coli, several proteins of apparent molecular weight lower than 35,000 were demonstrated by SDS-polyacrylamide gel electrophoresis in B. abortus. These results did not change when the trypsin digestion conditions were modified. On the other hand, when the SDS extractions were performed under conditions more stringent than those used for other gram-negative bacteria, only a polypeptide fragment of apparent molecular weight of 8,000 was obtained from B. abortus. This polypeptide was similar to the trypsin fragment of the E. coli lipoprotein with respect to its behavior in SDS-polyacrylamide gels, isoelectric point in urea, molecular weight, and presence of both ester- and amide-linked fatty acids. Moreover, the amino acid analysis showed an overall similarity with respect to the amino acid composition of E. coli lipoprotein. A polypeptide of the same molecular weight, isoelectric point, and amino acid composition was also obtained from Brucella ovis by the same method. These results demonstrated that B. abortus and B. ovis cell envelopes contain a lipoprotein and strongly support the hypothesis that it is the only major protein covalently linked to the peptidoglycan.
- Prevalencia de diabesidad en España: depende de cómo se defina la obesidad(Gobierno de Navarra, 2022) Catalan, V. (Victoria); Gomez-Ambrosi, J. (Javier)La obesidad representa la enfermedad metabólica más prevalente a nivel mundial, conllevando un aumento de la morbi-mortalidad y la consiguiente disminución en la esperanza de vida1. A pesar de la magnitud del problema y de la atención que recibe en las publicaciones científicas, la pandemia sigue creciendo de forma imparable. Según un estudio reciente llevado a cabo en 200 países, la prevalencia de la obesidad en el mundo se ha multiplicado por seis en los últimos 40 años4. La prevalencia de obesidad en Europa varía entre el 12 y el 26%5, rango dentro del cual se encuentran también las cifras en la población adulta española, entorno al 22%6. La obesidad se ha convertido en una de las principales causas de muerte, ya que constituye el principal factor de riesgo para una serie de enfermedades no transmisibles, en particular la diabetes tipo 2 (DT2)7,8. Esta estrecha relación llevó hace unos años a acuñar el término diabesidad, destacando el hecho de que la mayoría de las personas con DT2 tienen obesidad.
- Decreased Levels of Microfibril-Associated Glycoprotein (MAGP)-1 in Patients with Colon Cancer and Obesity Are Associated with Changes in Extracellular Matrix Remodelling(2021) Unamuno, X. (Xabier); Valenti, V. (Víctor); Baixauli-Fons, J. (Jorge); Ramirez, B. (Beatriz); Catalan, V. (Victoria); Ahechu-Garayoa, P. (Patricia); Mentxaka, A. (Amaia); Gómez-de-Segura, I. (Iranzu); Becerril, S. (Sara); Frühbeck, G. (Gema); Moncada, R. (Rafael); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia)Objective: The protein microfibril-associated glycoprotein (MAGP)-1 constitutes a crucial extracellular matrix protein. We aimed to determine its impact on visceral adipose tissue (VAT) remodelling during obesity-associated colon cancer (CC). Methods: Samples obtained from 79 subjects (29 normoponderal (NP) (17 with CC) and 50 patients with obesity (OB) (19 with CC)) were used in the study. Circulating concentrations of MAGP-1 and its gene expression levels (MFAP2) in VAT were analysed. The impact of inflammation-related factors and adipocyte-conditioned media (ACM) on MFAP2 mRNA levels in colon adenocarcinoma HT-29 cells were further analysed. The effects of MAGP-1 in the expression of genes involved in the extracellular matrix (ECM) remodelling and tumorigenesis in HT-29 cells was also explored. Results: Obesity (p < 0.01) and CC (p < 0.001) significantly decreased MFAP2 gene expression levels in VAT whereas an opposite trend in TGFB1 mRNA levels was observed. Increased mRNA levels of MFAP2 after the stimulation of HT-29 cells with lipopolysaccharide (LPS) (p < 0.01) and interleukin (IL)-4 (p < 0.01) together with a downregulation (p < 0.05) after hypoxia mimicked by CoCl2 treatment was observed. MAGP-1 treatment significantly enhanced the mRNA levels of the ECM-remodelling genes collagen type 6 alpha 3 chain (COL6A3) (p < 0.05), decorin (DCN) (p < 0.01), osteopontin (SPP1) (p < 0.05) and TGFB1 (p < 0.05). Furthermore, MAGP-1 significantly reduced (p < 0.05) the gene expression levels of prostaglandin-endoperoxide synthase 2 (COX2/PTGS2), a key gene controlling cell proliferation, growth and adhesion in CC. Interestingly, a significant decrease (p < 0.01) in the mRNA levels of MFAP2 in HT-29 cells preincubated with ACM from volunteers with obesity compared with control media was observed. Conclusion: The decreased levels of MAGP-1 in patients with obesity and CC together with its capacity to modulate key genes involved in ECM remodelling and tumorigenesis suggest MAGP-1 as a link between AT excess and obesity-associated CC development.
- Adiponectin-leptin Ratio is a Functional Biomarker of Adipose Tissue Inflammation(MDPI AG, 2019) Colina, I. (Inmaculada); Ramirez, B. (Beatriz); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Gomez-Ambrosi, J. (Javier); Salvador, J. (Javier); Rodriguez, A. (Amaia)Obesity favors the development of cardiometabolic alterations such as type 2 diabetes (T2D) and the metabolic syndrome (MS). Obesity and the MS are distinguished by an increase in circulating leptin concentrations, in parallel to a drop in the levels of adiponectin. Consequently, the Adpn/Lep ratio has been suggested as a maker of dysfunctional adipose tissue. We aimed to investigate in humans (n = 292) the reliability of the Adpn/Lep ratio as a biomarker of adipose tissue dysfunction. We considered that an Adpn/Lep ratio of ≥1.0 can be considered normal, a ratio of ≥0.5 <1.0 suggests moderate-medium increased risk, and a ratio of <0.5 indicates a severe increase in cardiometabolic risk. Using these cut-offs, 5%, 54% and 48% of the lean, normoglycemic and without-MS subjects, respectively, fall within the group with an Adpn/Lep ratio below 0.5; while 89%, 86% and 90% of the obese, with T2D and with MS patients fall within the same group (p < 0.001). A significant negative correlation (r = -0.21, p = 0.005) between the Adpn/Lep ratio and serum amyloid A (SAA) concentrations, a marker of adipose tissue dysfunction, was found. We concluded that the Adpn/Lep ratio is a good indicator of a dysfunctional adipose tissue that may be a useful estimator of obesity- and MS-associated cardiometabolic risk, allowing the identification of a higher number of subjects at risk.
- Anti-leishmanial and structure-activity relationship of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives(Instituto Oswaldo Cruz, Ministério da Saúde, 2008) Aldana, I. (Ignacio); Deharo, E. (Eric); Vicente, E. (Esther); Sauvain, M. (Michel); Burguete, A. (Asunción); Pérez-Silanes, S. (Silvia); Monge, A. (Antonio); Castillo, D. (Denis); Solano, B. (Beatriz); Raquel; Estevez, Y. (Yannick); Gonzalez, G. (Germán)A series of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives were synthesized and tested for in vitro leishmanicidal activity against amastigotes of Leishmania amazonensis in axenical cultures and murine infected macrophages. Structure-activity relationships demonstrated the importance of a radical methoxy at position R3', R4' and R5'. (2E)-3-(3,4,5-trimethoxy-phenyl)-1-(3,6,7-trimethyl-1,4-dioxy-quinoxalin-2-yl)-propenone was the most active. Cytotoxicity on macrophages revealed that this product was almost six times more active than toxic.
- Novel quinoxaline 1,4-di-N-oxide derivatives as new potential antichagasic agents(Elsevier, 2013-05-30) Devarapally, G. (Goutham); Aldana, I. (Ignacio); Torres, E. (Enrique); Gonzalez, M. (Mercedes); Varela, J. (Javier); Di-Maio, R. (Rossanna); Birriel, E. (Estefanía); Arbillaga, L. (Leire); Pérez-Silanes, S. (Silvia); Galiano, S. (Silvia); Monge, A. (Antonio); Moreno-de-Viguri, E. (Elsa); Cerecetto, H. (Hugo); Azqueta, A. (Amaya); Crawford, P.W. (Philip W.)As a continuation of our research and with the aim of obtaining new agents against Chagas disease, an extremely neglected disease which threatens 100 million people, eighteen new quinoxaline 1,4-di-Noxide derivatives have been synthesized following the Beirut reaction. The synthesis of the new derivatives was optimized through the use of a new and more efficient microwave-assisted organic synthetic method. The new derivatives showed excellent in vitro biological activity against Trypanosoma cruzi. Compound 17, which was substituted with fluoro groups at the 6- and 7-positions of the quinoxaline ring, was the most active and selective in the cytotoxicity assay. The electrochemical study showed that the most active compounds, which were substituted by electron-withdrawing groups,possessed a greater ease of reduction of the N-oxide groups
- Synthesis and antimycobacterial activity of new quinoxaline-2- carboxamide 1,4-di-N-oxide derivatives.(Elsevier, 2010-07-03) Aldana, I. (Ignacio); Ancizu, S. (Saioa); Torres, E. (Enrique); Pérez-Silanes, S. (Silvia); Monge, A. (Antonio); Moreno-de-Viguri, E. (Elsa)As a continuation of our research and with the aim of obtaining new anti-tuberculosis agents which can improve the current chemotherapeutic anti-tuberculosis treatments, forty-three new quinoxaline-2-carboxamide 1,4-di-N-oxide derivatives were synthesized and evaluated for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis strain H37Rv. Active compounds were also screened to assess toxicity to a VERO cell line. Results indicate that compounds with a methyl moiety substituted in position 3 and unsubstituted benzyl substituted on the carboxamide group provide an efficient approach for further development of anti-tuberculosis agents.
- Cyclic voltammetric study of some anti-Chagas-active 1,4-dioxidoquinoxalin-2-yl ketone derivatives(Wiley, 2013-02) Devarapally, G. (Goutham); Aldana, I. (Ignacio); Torres, E. (Enrique); Monge, A. (Antonio); Moreno-de-Viguri, E. (Elsa); Peres-Silanes, S. (Silvia); Crawford, P.W. (Philip W.)The electrochemical properties of 24 1,4-dioxidoquinoxalin-2-yl ketone derivatives with varying degrees of anti-Chagas activity were investigated in the aprotic solvent dimethylformamide (DMF) by cyclic voltammetry and first-derivative cyclic voltammetry. For this group of compounds, the first reduction in DMF was either reversible or quasireversible and consistent with reduction of the N-oxide functionality to form the radical anion. The second reduction process for these compounds was irreversible under the conditions used. The reduction potentials correlated well with molecular structure. Substitution in the 3-, 6-, and 7- positions of the quinoxaline ring by electron-withdrawing substituents directly affected the ease of reduction and improved the biological activities of these compounds, whereas substitution by electron-donating groups had the opposite effect. The electrochemical results, when combined with previous work on their mechanism of action against Chagas disease and their measured anti-Chagas activities, indicated that the quinoxaline 1,4-dioxide system serves as a promising starting point for chemical modifications aimed at improving the T. cruzi activity via a possible bioreduction mechanism.
- New quinoxaline 1,4-di-N-oxide derivatives: Trypanosomaticidal activities and enzyme docking simulation(Elsevier, 2011-01-25) Quiliano, M. (Miguel); Aldana, I. (Ignacio); Deharo, E. (Eric); Zimic, M. (Mirko); Cabanillas, B. (Billy); Burguete, A. (Asunción); Malaga, E. (Edith); Pérez-Silanes, S. (Silvia); Monge, A. (Antonio); Castillo, D. (Denis); Verastegui, M. (Manuela); Estevez, Y. (Yannick)Two series of pyrazol and propenone quinoxaline derivatives were tested for parasiticidal activity (against amastigotes of Leishmania peruviana and trypomastigotes of Trypanosoma cruzi) and for toxicity against proliferative and non-proliferative cells. The pyrazol series was almost inactive against T. cruzi but, 2,6-Dimethyl-3-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-1H-pyrazol-3-yl] - quinoxaline 1,4-dioxide inhibited 50% of Leishmania growth at 8.9 µM with no impact against proliferative kidney cells and low toxicity against Thp-1 and murine macrophages. The compounds of the propenone series were moderately active against T. cruzi. Among them, 2 compounds were particularly interesting: (2E)-1-(7-Fluoro-3-methyl-quinoxalin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propenone, that showed a selective activity against proliferative cells (cancer and parasites), being inactive against normal murine peritoneal macrophages and (2E)-3-(3,4,5-Trimethoxy-phenyl)-1-(3,6,7-trimethyl-quinoxalin-2-yl)-propenone that was only active against Leishmania and inactive against the other tested cells. Furthermore in silico studies were performed for ADME properties and docking studies, both series of compounds respected the Lipinski’s rules and show linear correlation between tripanosomaticidal activities and LogP. Docking studies revealed that compounds of the second series could interact with the poly (ADP-ribose) polymerase protein of Trypanosoma cruzi.