Corrales, F.J. (Fernando José)
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- In vivo regulation by glutathione of methionine adenosyltransferase S-nitrosylation in rat liver(Elsevier, 1999) Corrales, F.J. (Fernando José); Ruiz, F.A. (Félix A.); Mato, J.M. (José María)BACKGROUND/AIMS: Ethanol consumption and pathological conditions such as cirrhosis lead to a reduction of hepatic glutathione. Hepatic methionine adenosyltransferase, the enzyme that synthesizes S-adenosylmethionine, the major methylating agent, is regulated in vivo by glutathione levels. We have previously shown that nitric oxide inactivates methionine adenosyltransferase in vivo by S-nitrosylation. In this study, we aimed to investigate the regulation by glutathione of methionine adenosyltransferase S-nitrosylation in rat liver. METHODS: Rat hepatocytes and whole animals were treated with buthionine sulfoximine, an inhibitor of glutathione synthesis, and methionine adenosyltransferase S-nitrosylation and activity were determined. RESULTS: In hepatocytes, buthionine sulfoximine led to the S-nitrosylation and inactivation of methionine adenosyltransferase. Restoring glutathione levels in hepatocytes treated with buthionine sulfoximine, by the addition of glutathione monoethyl ester, a permeable derivative of glutathione, led to the denitrosylation and reactivation of methionine adenosyltransferase. In whole animals, buthionine sulfoximine led also to methionine adenosyltransferase S-nitrosylation and inactivation. S-Nitrosylation and inactivation of methionine adenosyltransferase induced by buthionine sulfoximine in whole animals was prevented by glutathione monoethyl ester. CONCLUSIONS: These results indicate that in vivo hepatic methionine adenosyltransferase exists in two forms in equilibrium, nitrosylated (inactive) and denitrosylated (active), which are regulated by both the cellular levels of nitric oxide and glutathione.
- Interaction between an adcy3 genetic variant and two weight-lowering diets affecting body fatness and body composition outcomes depending on macronutrient distribution: a randomized trial(MDPI AG, 2018) Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); Ortiz, L. (Lourdes); Corrales, F.J. (Fernando José); Goñi-Mateos, L. (Leticia); Milagro-Yoldi, F.I. (Fermín Ignacio); Cuervo, M. (Marta)The adenylate cyclase 3 (ADCY3) gene is involved in the regulation of several metabolic processes including the development and function of adipose tissue. The effects of the ADCY3 rs10182181 genetic variant on changes in body composition depending on the macronutrient distribution intake after 16 weeks of the dietary intervention were tested. The ADCY3 genetic variant was genotyped in 147 overweight or obese subjects, who were randomly assigned to one of the two diets varying in macronutrient content: a moderately-high-protein diet and a low-fat diet. Anthropometric and body composition measurements (DEXA scan) were recorded. Significant interactions between the ADCY3 genotype and dietary intervention on changes in weight, waist circumference, and body composition were found after adjustment for covariates. Thus, in the moderately-high-protein diet group, the G allele was associated with a lower decrease of fat mass, trunk and android fat, and a greater decrease in lean mass. Conversely, in the low-fat diet group carrying the G allele was associated with a greater decrease in trunk, android, gynoid, and visceral fat. Subjects carrying the G allele of the rs10182181 polymorphism may benefit more in terms of weight loss and improvement of body composition measurements when undertaking a hypocaloric low-fat diet as compared to a moderately-high-protein diet.
- Proteomic analysis of chemonaive pediatric osteosarcomas and corresponding normal bone reveals multiple altered molecular targets(American Chemical Society, 2009) Patiño-García, A. (Ana); Mora, M.I. (María I.); Folio, C. (Cecilia); Corrales, F.J. (Fernando José); Zalacain, M. (Marta); Toledo, G. (Gemma); Sierrasesumaga, L. (Luis); San-Julian, M. (Mikel); Segura, V. (Víctor)With a view to identify the proteins involved in transformation, metastasis or chemoresistance in pediatric osteosarcoma, we carried out a new experimental approach based on comparison of the proteomic profile of paired samples of osteosarcoma and normal bone tissues from the same patient. The proteomic profiles of five pairs of cell lines (normal vs tumoral) were obtained by two-dimensional difference gel electrophoresis. We detected 56 differential protein spots (t test, p < 0.05). Subsequent protein characterization by nano-LC-ESI-MS/MS enabled us to identify some of these proteins, 16 of which were chosen on the basis of the change of their relative abundance between osteosarcomas and paired normal bones and also because their involvement was supported by the genomic analysis. Two of the 16 proteins, Alpha-crystallin B chain (CRYAB) and ezrin (EZR1), were selected for further studies: an immunohistochemical analysis of a TMA (tissue microarray) and real-time PCR for a set of 14 osteosarcoma/normal-bone pairs. The results of this second tier of studies confirmed that there were significant increases in the amounts of CRYAB and ezrin, especially in advanced stages of the disease. Our overall conclusion is that proteomic profiling of paired samples of osteosarcoma and normal bone tissues from the same patient is a practicable and potentially powerful way of initiating and proceeding with a search for proteins and genes involved in pediatric osteosarcoma.
- NO, SNO and low O2(Nature Publishing Group, 2001) Corrales, F.J. (Fernando José); Avila, M.A. (Matías Antonio); Mato, J.M. (José María)
- Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma(Elsevier, 2000) Martin-Duce, A. (Antonio); Corrales, F.J. (Fernando José); Berasain, C. (Carmen); Lu, S.C. (Shelly C.); Avila, M.A. (Matías Antonio); Rodes, J. (Juan); Prieto, J. (Jesús); Torres, L. (Luis); Caballeria, J. (Juan); Yang, H. (Heping); Mato, J.M. (José María)BACKGROUND/AIMS: It has been known for at least 50 years that alterations in methionine metabolism occur in human liver cirrhosis. However, the molecular basis of this alteration is not completely understood. In order to gain more insight into the mechanisms behind this condition, mRNA levels of methionine adenosyltransferase (MAT1A), glycine methyltransferase (GNMT), methionine synthase (MS), betaine homocysteine methyltransferase (BHMT) and cystathionine beta-synthase (CBS) were examined in 26 cirrhotic livers, five hepatocellular carcinoma (HCC) tissues and ten control livers. METHODS: The expression of the above-mentioned genes was determined by quantitative RT-PCR analysis. Methylation of MAT1A promoter was assessed by methylation-sensitive restriction enzyme digestion of genomic DNA. RESULTS: When compared to normal livers MAT1A, GNMT, BHMT, CBS and MS mRNA contents were significantly reduced in liver cirrhosis. Interestingly, MAT1A promoter was hypermethylated in the cirrhotic liver. HCC tissues also showed decreased mRNA levels of these enzymes. CONCLUSIONS: These findings establish that the abundance of the mRNA of the main genes involved in methionine metabolism is markedly reduced in human cirrhosis and HCC. Hypermethylation of MAT1A promoter could participate in its reduced expression in cirrhosis. These observations help to explain the hypermethioninemia, hyperhomocysteinemia and reduced hepatic glutathione content observed in cirrhosis.
- Correlation between gene expression and GO semantic similarity(Institute of Electrical and Electronics Engineers, 2005) Sevilla, J.L. (José L.); Corrales, F.J. (Fernando José); Martinez-Cruz, L.A. (L. Alfonso); Guruceaga, E. (Elizabeth); Podhorski, A. (Adam); Segura, V. (Víctor); Mato, J.M. (José María); Rubio, A. (Ángel)This research analyzes some aspects of the relationship between gene expression, gene function, and gene annotation. Many recent studies are implicitly based on the assumption that gene products that are biologically and functionally related would maintain this similarity both in their expression profiles as well as in their Gene Ontology (GO) annotation. We analyze how accurate this assumption proves to be using real publicly available data. We also aim to validate a measure of semantic similarity for GO annotation. We use the Pearson correlation coefficient and its absolute value as a measure of similarity between expression profiles of gene products. We explore a number of semantic similarity measures (Resnik, Jiang, and Lin) and compute the similarity between gene products annotated using the GO. Finally, we compute correlation coefficients to compare gene expression similarity against GO semantic similarity. Our results suggest that the Resnik similarity measure outperforms the others and seems better suited for use in Gene Ontology. We also deduce that there seems to be correlation between semantic similarity in the GO annotation and gene expression for the three GO ontologies. We show that this correlation is negligible up to a certain semantic similarity value; then, for higher similarity values, the relationship trend becomes almost linear. These results can be used to augment the knowledge provided by clustering algorithms and in the development of bioinformatic tools for finding and characterizing gene products.
- In-depth proteomic characterization of classical and non-classical monocyte subsets(MDPI AG, 2018) García, F. (Fernando); Zarzuela, E. (Eduardo); Paradela, A. (Alberto); Corrales, F.J. (Fernando José); Fuentes, M. (Manuel); Garin-Muga, A. (Alba); Díez, P. (Paula); Orfao, A. (Alberto); Sanchez-del-Pino, M.M. (Manuel M.); Garcia-Montero, A. (A.); Beaskoetxea, J. (Javier); Cantero, L. (Laura); Arizmendi, J.M. (Jesús M.); Dégano, R.M. (Rosa M.); Navajas, R. (Rosana); Aloria, K. (Kerman); Muñoz, J. (Javier); Segura, V. (Víctor); Valero, M.L. (María L.)Monocytes are bone marrow-derived leukocytes that are part of the innate immune system. Monocytes are divided into three subsets: classical, intermediate and non-classical, which can be differentiated by their expression of some surface antigens, mainly CD14 and CD16. These cells are key players in the inflammation process underlying the mechanism of many diseases. Thus, the molecular characterization of these cells may provide very useful information for understanding their biology in health and disease. We performed a multicentric proteomic study with pure classical and non-classical populations derived from 12 healthy donors. The robust workflow used provided reproducible results among the five participating laboratories. Over 5000 proteins were identified, and about half of them were quantified using a spectral counting approach. The results represent the protein abundance catalogue of pure classical and enriched non-classical blood peripheral monocytes, and could serve as a reference dataset of the healthy population. The functional analysis of the differences between cell subsets supports the consensus roles assigned to human monocytes.
- 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.
- Identification and experimental validation of druggable epigenetic targets in hepatoblastoma(Elsevier, 2023) Indersie, E. (Emilie); Latasa, M.U. (María Ujué); Berraondo, P. (Pedro); Corrales, F.J. (Fernando José); Berasain, C. (Carmen); Arechederra, M. (María); Domingo-Sàbat, M. (Montserrat); Pineda-Lucena, A. (Antonio); Sancho-Bru, P. (Pau); Zanatto, L. (Laura); Armengol, C. (Carolina); Uriarte, I. (Iker); Ciordia, S. (Sergio); Avila, M.A. (Matías Antonio); Alaggio, R. (Rita); Alonso, C. (Cristina); Sangro, B. (Bruno); García-Fernandez-Barrena, M. (Maite); Herranz, J.M. (José M.); Cairo, S. (Stefano); García-Marin, J.J. (Jose Juan); Francalanci, P. (Paola); Prosper-Cardoso, F. (Felipe); Claveria-Cabello, A. (Alex); Martinez-Chantar, M.L. (María Luz); Zucman-Rossi, J. (Jessica)Background & Aims: Hepatoblastoma (HB) is the most frequent childhood liver cancer. Patients with aggressive tumors have limited therapeutic options; therefore, a better understanding of HB pathogenesis is needed to improve treatment. HBs have a very low mutational burden; however, epigenetic alterations are increasingly recognized. We aimed to identify epigenetic regulators consistently dysregulated in HB and to evaluate the therapeutic efficacy of their targeting in clinically relevant models. Methods: We performed a comprehensive transcriptomic analysis of 180 epigenetic genes. Data from fetal, pediatric, adult, peritumoral (n = 72) and tumoral (n = 91) tissues were integrated. Selected epigenetic drugs were tested in HB cells. The most relevant epigenetic target identified was validated in primary HB cells, HB organoids, a patient-derived xenograft model, and a genetic mouse model. Transcriptomic, proteomic and metabolomic mechanistic analyses were performed. Results: Altered expression of genes regulating DNA methylation and histone modifications was consistently observed in association with molecular and clinical features of poor prognosis. The histone methyltransferase G9a was markedly upregulated in tumors with epigenetic and transcriptomic traits of increased malignancy. Pharmacological targeting of G9a significantly inhibited growth of HB cells, organoids and patient-derived xenografts. Development of HB induced by oncogenic forms of b-catenin and YAP1 was ablated in mice with hepatocyte-specific deletion of G9a. We observed that HBs undergo significant transcriptional rewiring in genes involved in amino acid metabolism and ribosomal biogenesis. G9a inhibition counteracted these pro-tumorigenic adaptations. Mechanistically, G9a targeting potently repressed the expression of c-MYC and ATF4, master regulators of HB metabolic reprogramming. Conclusions: HBs display a profound dysregulation of the epigenetic machinery. Pharmacological targeting of key epigenetic effectors exposes metabolic vulnerabilities that can be leveraged to improve the treatment of these patients.
- Hypermethioninaemia due to methionine adenosyltransferase I/III (MAT I/III) deficiency: diagnosis in an expanded neonatal screening programme(Springer Verlag, 2008) Mora, M.I. (María I.); Corrales, F.J. (Fernando José); Boveda, M.D. (MD); Mudd, S.H. (S. Harvey); Fraga, J.M. (J. M.); Couce, M.L. (ML); Castiñeiras, D.E. (DE)The Expanded Newborn Screening Program (MS/MS) in the region of Galicia (NW Spain) was initiated in 2000 and includes the measurement of methionine levels in dried blood spots. Between June 2000 and June 2007, 140 818 newborns were analysed, and six cases of persistent hypermethioninaemia were detected: one homocystinuria due to cystathionine β-synthase (CβS) deficiency, and five methionine adenosyltransferase I/III (MAT I/III) deficiencies. The five cases of MAT I/III deficiency represent an incidence of 1/28 163 newborns. In these five patients, methionine levels in dried blood spots ranged from 50 to 147 μmol/L. At confirmation of the persistence of the hypermethioninaemia in a subsequent plasma sample, plasma methionine concentrations were moderately elevated in 4 of the 5 patients (mean 256 μmol/L), while total homocysteine (tHcy) was normal; the remaining patient showed plasma methionine of 573 μmol/L and tHcy of 22.8 μmol/L. All five patients were heterozygous for the same dominant mutation, R264H in the MAT1A gene. With a diet not exceeding recommended protein requirements for their age, all patients maintained methionine levels below 300 μmol/L. Currently, with a mean of 2.5 years since diagnosis, the patients are asymptomatic and show developmental quotients within the normal range. Our results show a rather high frequency of hypermethioninaemia due to MAT I/III deficiency in the Galician neonatal population, indicating a need for further studies to evaluate the impact of persistent isolated hypermethioninaemia in neonatal screening programmes.