Muntane, J. (Jordi)

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    Serum metabolites as diagnostic biomarkers for cholangiocarcinoma, hepatocellular carcinoma and primary sclerosing cholangitis
    (Wiley, 2019) Banales, J.M. (Jesús M.); Muñoz-Bellvis, L. (Luis); Martínez-Arranz, I. (Ibon); Arbelaiz, A. (Ander); Flores-González, L.M. (Luis Manuel); Muntane, J. (Jordi); Avila, M.A. (Matías Antonio); Alonso, C. (Cristina); Lapitz, A. (Ainhoa); La-Casta-Muñoa, A. (Adelaida); Sangro, B. (Bruno); Arretxe, A. (Anere); Iñarrairaegui, M. (Mercedes); Bujanda, L. (Luis); Milkiewicz, P. (Piotr); Macias, R. (Rocío); Santos-Laso, A. (Alvaro); Martinez-Chantar, M.L. (María Luz); Marin, J.J.G (Jose J.G.)
    Early and differential diagnosis of intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) by noninvasive methods represents a current clinical challenge. The analysis of low-molecular-weight metabolites by new high-throughput techniques is a strategy for identifying biomarkers. Here, we have investigated whether serum metabolome can provide useful biomarkers in the diagnosis of iCCA and HCC and could discriminate iCCA from HCC. Because primary sclerosing cholangitis (PSC) is a risk factor for CCA, serum metabolic profiles of PSC and CCA have also been compared. The analysis of the levels of lipids and amino acids in the serum of patients with iCCA, HCC, and PSC and healthy individuals (n = 20/group) showed differential profiles. Several metabolites presented high diagnostic value for iCCA versus control, HCC versus control, and PSC versus control, with areas under the receiver operating characteristic curve (AUC) greater than those found in serum for the nonspecific tumor markers carbohydrate antigen 19-9 (CA 19-9) and alpha-fetoprotein (AFP), commonly used to help in the diagnosis of iCCA and HCC, respectively. The development of an algorithm combining glycine, aspartic acid, SM(42:3), and SM(43:2) permitted to accurately differentiate in the diagnosis of both types of tumors (biopsy-proven). The proposed model yielded 0.890 AUC, 75% sensitivity, and 90% specificity. Another algorithm by combination of PC(34:3) and histidine accurately permitted to differentiate PSC from iCCA, with an AUC of 0.990, 100% sensitivity, and 70% specificity. These results were validated in independent cohorts of 14-15 patients per group and compared with profiles found in patients with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Conclusion: Specific changes in serum concentrations of certain metabolites are useful to differentiate iCCA from HCC or PSC, and could help in the early diagnosis of these diseases.
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    S-Nitrosation of proteins during D-galactosamine-induced cell death in human hepatocytes
    (Informa Healthcare, 2007) Rodriguez-Ariza, A. (Antonio); Corrales, F.J. (Fernando José); Muntane, J. (Jordi); Fraga, E. (Enrique); Lopez-Sanchez, L.M. (Laura M.); Montero, J.L. (José L.); Collado, J.A. (Juan A.); Serrano, J. (Juan); Lopez-Cillero, P. (Pedro); Mata, M. (Manuel) de la
    Nitric oxide (NO) participates in the cell death induced by d-Galactosamine (d-GalN) in hepatocytes, and NO-derived reactive oxygen intermediates are critical contributors to protein modification and hepatocellular injury. It is anticipated that S-nitrosation of proteins will participate in the mechanisms leading to cell death in d-GalN-treated human hepatocytes. In the present study, d-GalN-induced cell death was related to augmented levels of NO production and S-nitrosothiol (SNO) content. The biotin switch assay confirmed that d-GalN increased the levels of S-nitrosated proteins in human hepatocytes. S-nitrosocysteine (CSNO) enhanced protein S-nitrosation and altered cell death parameters that were related to S-nitrosation of the executioner caspase-3. Fifteen S-nitrosated proteins participating in metabolism, antioxidative defense and cellular homeostasis were identified in human hepatocytes treated with CSNO. Among them, seven were also identified in d-GalN-treated hepatocytes. The results here reported underline the importance of the alteration of SNO homeostasis during d-GalN-induced cell death in human hepatocytes
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    Detection and proteomic identification of S-nitrosated proteins in human hepatocytes
    (Elsevier, 2008) Rodriguez-Ariza, A. (Antonio); Corrales, F.J. (Fernando José); Muntane, J. (Jordi); Lopez-Sanchez, L.M. (Laura M.); Mata, M. (Manuel) de la
    The S-nitrosation of protein thiols is a redox-based posttranslational modification that modulates protein function and cell phenotype. Although the detection of S-nitrosated proteins is problematical because of the lability of S-nitrosothiols, an increasing range of proteins has been shown to undergo S-nitrosation with the improvement of molecular tools. This chapter describes the methodology used to identify potential targets of S-nitrosation in cultured primary human hepatocytes using proteomic approaches. This methodology is based on the biotin switch method, which labels S-nitrosated proteins with an affinity tag, allowing their selective detection and proteomic identification.
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    Altered protein expression and protein nitration pattern during d-galactosamine-induced cell death in human hepatocytes: a proteomic analysis
    (John Wiley and Sons, 2005) Rodriguez-Ariza, A. (Antonio); Corrales, F.J. (Fernando José); Muntane, J. (Jordi); Lopez-Sanchez, L.M. (Laura M.); Bernardos, A. (Angel); Gonzalez, R. (Raúl); Lopez-Casas, P. (Pedro)
    BACKGROUND/AIMS: Hepatic injury by d-galactosamine (d-GalN) is a suitable experimental model of hepatocellular injury. The induction of oxidative and nitrosative stress participates during d-GalN-induced cell death in cultured rat hepatocytes. This study aimed to identify protein expression changes during the induction of apoptosis and necrosis by d-GalN in cultured human hepatocytes. METHODS: A proteomic approach was used to identify the proteins involved and those altered by tyrosine nitration. A high dose of d-GalN (40 mM) was used to induce apoptosis and necrosis in primary culture of human hepatocytes. Cellular lysates prepared at different times after addition of d-GalN were separated by two-dimensional electrophoresis. Gel spots with an altered expression and those matching nitrotyrosine-immunopositive proteins were excised and analyzed by mass spectrometry. RESULTS: d-GalN treatment upregulated microsomal cytochrome b5, fatty acid binding protein and manganese superoxide dismutase, and enhanced annexin degradation. d-GalN increased tyrosine nitration of four cytosolic (Hsc70, Hsp70, annexin A4 and carbonyl reductase) and three mitochondrial (glycine amidinotransferase, ATP synthase beta chain, and thiosulfate sulfurtransferase) proteins in human hepatocytes. CONCLUSIONS: The results provide evidences that oxidative stress and nitric oxide-derived reactive oxygen intermediates induce specific alterations in protein expression that may be critical for the induction of apoptosis and necrosis by d-GalN in cultured human hepatocytes.
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    Alteration of S-nitrosothiol homeostasis and targets for protein S-nitrosation in human hepatocytes
    (Wiley-VCH Verlag Berlin, 2008) Briceño, J. (Javier); Rodriguez-Ariza, A. (Antonio); Corrales, F.J. (Fernando José); Ranchal, I. (Isidora); Muntane, J. (Jordi); Ferrin, G. (Gustavo); Lopez-Sanchez, L.M. (Laura M.); Gonzalez, R. (Raúl); Hidalgo, A.B. (Ana B.); Muñoz-Castañeda, J.R. (Juan R.); Gomez, M.A. (Miguel A.); Lopez-Cillero, P. (Pedro); Mata, M. (Manuel) de la
    The liver is one organ clearly influenced by nitric oxide (NO), and acute and chronic exposure to this substance has been associated with distinct patterns of liver disease. Disruption or deregulation of S-nitrosothiol (SNO) signalling leads to impairment of cellular function and disease, and this study was aimed to identify potential targets for protein S-nitrosation during alteration of SNO homeostasis in human hepatocytes. Cells were treated with S-nitroso-L-cysteine (CSNO), an effective physiological nitrosothiol for delivering NO bioactivity to cells. Treatment with CSNO augmented the levels of S-nitrosoproteins detected both by chemiluminescence and the biotin switch method. CSNO treatment also increased S-nitrosoglutathione reductase (GSNOR) activity that returned SNO content to basal levels. This increased enzymatic activity was related to augmented levels of ADH-5 mRNA, the gene encoding for GSNOR in humans. In addition, the treatment with the SNO also increased cell death. Twenty S-nitrosoproteins were identified in CSNO-treated hepatocytes, including mitochondrial aldehyde dehydrogenase, protein disulphide isomerase, Hsp60, GRP75 and Raf kinase inhibitor protein. The identification in the S-nitrosatable proteome of proteins involved in metabolism, maintenance of cellular homeostasis and signalling points to the relevance of protein S-nitrosation to the physiology and pathophysiology of human hepatocytes.