Publications (13)38.31 Total impact
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Article: Cytoprotective properties of rifampicin are related to the regulation of detoxification system and bile acid transporter expression during hepatocellular injury induced by hydrophobic bile acids.
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ABSTRACT: Rifampicin has been used for the treatment of patients with jaundice and pruritus. This study evaluated the effect of rifampicin on the expression of different detoxification systems and bile acid transporters during in-vivo and in-vitro experimental models of cholestasis. Rifampicin was administered to glycochenodeoxycholic acid (GCDCA)-treated human hepatocytes and bile duct-obstructed rats. Different parameters related to cell death, and the expression of phase I and II drug metabolizing enzymes (DME) and bile acid transporters were determined. The induction of hepatocellular injury induced by cholestasis was associated with a reduction in cytochrome P4503A4 (CYP3A4), CYP7A1, and UDP-glucuronosyltransferase 2B4 (UGT2B4) expression, as well as an increase in import (Na(+)-taurocholate co-transporting polypeptide, NTCP) system expression. The beneficial properties of rifampicin were associated with an increase in DME and export bile acid systems (multidrug resistance-associated protein 4, MRP4, and bile acid export pump to bile duct, BSEP) expression, as well as a reduction in NTCP expression. The beneficial effect of rifampicin in cholestasis is associated with an increase in DME expression involved in toxic, bile acid and cholesterol metabolism, as well as a reduction in the bile acid importing system in hepatocytes.Journal of hepato-biliary-pancreatic sciences. 04/2011; 18(5):740-50. -
Article: Nitric oxide mimics transcriptional and post-translational regulation during α-tocopherol cytoprotection against glycochenodeoxycholate-induced cell death in hepatocytes.
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ABSTRACT: Reactive oxygen species (ROS) and nitric oxide (NO) exert a relevant role during bile acid-induced hepatotoxicity. Whether α-Tocopherol regulates oxidative and nitrosative stress, bile acid transporter expression and their NO-dependent post-translational modifications, and cell death were assessed in vitro and in vivo. α-Tocopherol and/or NO donors (DETA-NONOate or CSNO, and V-PYRRO/NO) were administered to glycochenodeoxycholic acid (GCDCA)-treated cultured human hepatocytes or to bile duct obstructed rats. Cell injury, superoxide anion (O⁻₂) production, as well as inducible nitric oxide synthase (NOS-2), cytochrome P4507A1 (CYP7A1), heme oxygenase-1, (HO-1) and bile acid transporter expression were determined. Cysteine S-nitrosylation and tyrosine nitration of Na(+)-taurocholate co-transporting polypeptide (NTCP), as well as taurocholic acid (TC) uptake were also evaluated. GCDCA-induced cell death was associated with increased (O⁻₂) production, NTCP and HO-1 expression, and with a reduction of CYP7A1 and NOS-2 expression. α-Tocopherol reduced cell death, (O⁻₂) production, CYP7A1, NTCP, and HO-1 expression, as well as increased NOS-2 expression and NO production in GCDCA-treated hepatocytes. α-Tocopherol and NO donors increased NTCP cysteine S-nitrosylation and tyrosine nitration, and reduced TC uptake in hepatocytes. α-Tocopherol and V-PYRRO/NO reduced liver injury and NTCP expression in obstructed rats. The regulation of CYP7A1, NTCP, and HO-1 expression may be relevant for the cytoprotective properties of α-Tocopherol and NO against mitochondrial dysfunction, oxidative stress and cell death in GCDCA-treated hepatocytes. The regulation of NO-dependent post-translational modifications of NTCP by α-Tocopherol and NO donors reduces the uptake of toxic bile acids by hepatocytes.Journal of Hepatology 11/2010; 55(1):133-44. · 9.26 Impact Factor -
Article: Does fecal calprotectin predict relapse in patients with Crohn's disease and ulcerative colitis?
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ABSTRACT: An evaluation is made of the utility of fecal calprotectin in predicting relapse in patients with inflammatory bowel disease (IBD). The possible differences in its predictive capacity in Crohn's disease (CD) versus ulcerative colitis (UC), and the different phenotypes, are also examined. This is a prospective study with 135 patients diagnosed with IBD in clinical remission for at least 3 months. The patients submitted a stool sample within 24 hours after the baseline visit, for the measurement of fecal calprotectin. All patients were followed-up on for one year. Sixty-six patients had CD and 69 UC. Thirty-nine (30%) suffered from relapse. The fecal calprotectin concentration was higher among the patients with relapse than in those that remained in remission: 444 µg/g (95% CI 34-983) versus 112 µg/g (95% CI 22-996); p<0.01. Patients with CD and calprotectin>200 µg/g relapsed 4 times more often than those with lower marker concentrations. In UC, calprotectin>120 µg/g was associated with a 6-fold increase in the probability of disease activity outbreak. The predictive value was similar in UC and CD with colon involvement and inflammatory pattern. In this group, calprotectin>120 µg/g predicted relapse risk with a sensitivity of 80% and a specificity of 60%. Relapse predictive capacity was lower in patients with ileal disease. Fecal calprotectin may be a useful marker for predicting relapse in patients with IBD. Its predictive value is greater in UC and CD with colon involvement and inflammatory pattern, compared with ileal CD.Journal of Crohn s and Colitis 06/2010; 4(2):144-52. · 2.57 Impact Factor -
Article: Interleukin-6 is associated with liver lipid homeostasis but not with cell death in experimental hepatic steatosis.
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ABSTRACT: Hepatic steatosis is a risk factor for the progression of non-alcoholic fatty liver disease. The role of pro-inflammatory interleukin (IL)-6 in hepatic steatosis etiology is controversial. We investigated in vivo and in primary hepatocyte cultures whether IL-6 has a modulator role in liver and mitochondria lipid composition and cell death in a choline-deficient (CD) diet rat model of hepatic steatosis. Dietary choline deficiency increased triglycerides and cholesterol, and reduced phosphatidylcholine (PC), phosphatidylethanolamine (PE) and the membrane integrity marker PC:PE ratio in liver. Choline-deficient diet enhanced systemic IL-6, and IL-6 receptor expression and cell death vulnerability in hepatocytes. Derangement of the mitochondrial electron transport chain and of its phospholipid environment was found in CD rat liver mitochondria, which exhibited elevated concentrations of triglycerides, cardiolipin and PC and elevated PC:PE ratio. The cell treatment with IL-6, but not PC, eliminated much of the CD-promoted lipid imbalance in mitochondria but not tumor-necrosis factor (TNF)-alpha-induced cell death. However, PC supplementation prevented the TNF-alpha-induced DNA fragmentation, cytochrome-c release and caspase-3 activity in control and CD hepatocytes. In conclusion, IL-6 ameliorated the mitochondria lipid disturbance in hepatocytes isolated from steatotic animals. Furthermore, PC is identified as a new survival agent that reverses several TNFalpha-inducible responses that are likely to promote steatosis and necrosis.Innate Immunity 09/2009; 15(6):337-49. · 4.00 Impact Factor -
Article: N-acetylcysteine, coenzyme Q10 and superoxide dismutase mimetic prevent mitochondrial cell dysfunction and cell death induced by d-galactosamine in primary culture of human hepatocytes.
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ABSTRACT: D-Galactosamine (D-GalN) induces reactive oxygen species (ROS) generation and cell death in cultured hepatocytes. The aim of the study was to evaluate the cytoprotective properties of N-acetylcysteine (NAC), coenzyme Q(10) (Q(10)) and the superoxide dismutase (SOD) mimetic against the mitochondrial dysfunction and cell death in D-GalN-treated hepatocytes. Hepatocytes were isolated from liver resections. NAC (0.5 mM), Q(10) (30 microM) or MnTBAP (Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (1mg/mL) were co-administered with D-GalN (40 mM) in hepatocytes. Cell death, oxidative stress, mitochondrial transmembrane potential (MTP), ATP, mitochondrial oxidized/reduced glutathione (GSH) and Q(10) ratios, electronic transport chain (ETC) activity, and nuclear- and mitochondria-encoded expression of complex I subunits were determined in hepatocytes. d-GalN induced a transient increase of mitochondrial hyperpolarization and oxidative stress, followed by an increase of oxidized/reduced GSH and Q(10) ratios, mitochondrial dysfunction and cell death in hepatocytes. The cytoprotective properties of NAC supplementation were related to a reduction of ROS generation and oxidized/reduced GSH and Q(10) ratios, and a recovery of mitochondrial complexes I+III and II+III activities and cellular ATP content. The co-administration of Q(10) or MnTBAP recovered oxidized/reduced GSH ratio, and reduced ROS generation, ETC dysfunction and cell death induced by D-GalN. The cytoprotective properties of studied antioxidants were related to an increase of the protein expression of nuclear- and mitochondrial-encoded subunits of complex I. In conclusion, the co-administration of NAC, Q(10) and MnTBAP enhanced the expression of complex I subunits, and reduced ROS production, oxidized/reduced GSH ratio, mitochondrial dysfunction and cell death induced by D-GalN in cultured hepatocytes.Chemico-biological interactions 07/2009; 181(1):95-106. · 2.46 Impact Factor -
Article: The reduction of cell death and proliferation by p27(Kip1) minimizes DNA damage in an experimental model of genotoxicity.
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ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth most commonly occurring cancer worldwide. The expression of p27 has been related to reduced severity of tumor grade and recurrence of HCC. The study assessed the role of p27 on the cell proliferation and death, and DNA mutagenesis in experimental genotoxicity induced by aflatoxin B1 (AFB(1)) in cultured hepatocytes obtained from control and p27(Kip1) deficient mice. The overexpression of p27 was assessed with wild type p27(Kip1) expression vector in HepG2 cells. The expression of p27, p21 and p53 was assessed in well and poorly-differentiated liver tumors. DNA damage and cell death induced by AFB(1) were related to a reduction of p27 and p21 expression in cultured hepatocytes. AFB(1)-induced nuclear phosphorylated (Ser 10) p27 degradation was related to a rise of nuclear KIST, Rsk-1 and Rsk-2 expression and cytoplasm phosphorylated (Thr 198) p27 expression. The overexpression of p27 reduced cell proliferation, cell death and DNA damage in AFB(1)-treated hepatocytes. The enhanced survival of patients with well differentiated compared to poorly-differentiated tumors was related to high expression of p27, p21 and p53 in liver sections. The study showed that the p27 reduced cell proliferation and death, as well as the accumulation of DNA damage in hepatocarcinogenesis.International Journal of Cancer 07/2009; 125(10):2270-80. · 5.44 Impact Factor -
Article: Alteration of S-nitrosothiol homeostasis and targets for protein S-nitrosation in human hepatocytes.
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ABSTRACT: 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.Proteomics 11/2008; 8(22):4709-20. · 4.43 Impact Factor -
Article: Melatonin exerts a more potent effect than S-adenosyl-l-methionine against iron metabolism disturbances, oxidative stress and tissue injury induced by obstructive jaundice in rats.
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ABSTRACT: Melatonin and S-adenosyl-l-methionine (SAMe) prevent oxidative stress and tissue dysfunction in obstructive jaundice (OJ). Lipid peroxidation is exacerbated in the presence of trace amounts of iron (Fe). The study investigated the regulation by melatonin and SAMe the induction of oxidative stress, iron metabolism disturbances and tissue injury in an experimental model of OJ. Different parameters of lipid peroxidation, antioxidant status, tissue injury and Fe metabolism were determined in liver and blood. OJ induced Fe accumulation in liver, and increased transferrin (Tf) saturation and loosely bound Fe content in blood. Melatonin, and SAMe at lesser extent, enhanced protein Tf content in liver and blood, that reduced loosely bound Fe content in blood. Melatonin and SAMe did not affect ferritin (FT) and Tf mRNA expression, but reduced Tf receptor (TfR) mRNA expression in liver. In conclusion, the effect of melatonin and SAMe on Fe metabolism may be included in the beneficial properties of these agents on lipid peroxidation and tissue injury induced by OJ.Chemico-Biological Interactions 08/2008; 174(2):79-87. · 2.46 Impact Factor -
Article: [Diagnostic value of fecal calprotectin in predicting an abnormal colonoscopy].
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ABSTRACT: Abdominal pain and diarrhoea are common symptoms in the general population. The colonoscopy is the gold standard method of detecting an organic pathology in the colon. However, it is invasive; it can not be repeated frecuently; it is expensive; and the system is overloaded. Fecal calprotectin (FCP) is a marker that may detect organic pathologies of the colon. The aims of this study were to analyze the usefulness of FCP to predict an abnormal colonoscopy and to correlate the levels of FCP with the degree of activity in inflammatory bowel disease (IBD). 190 people were included in the study. All of them underwent a colonoscopy and a stool sample. People were divided in: normal colonoscopy: 117 people, and 28 colon adenomas, 20 colorectal cancer (CRC) and 25 IBD. The mean (SD) FCP concentration was 2,171.1 (2,133.6) mg/kgin patients with IBD and 726.6 mg/kg (533) in CRC. Both results were significantly elevated compared with those of healthy controls [114 (113)] mg/kg In patients with IBD, their levels correlated directly with the activity of the inflammation. 217 mg/kg was the best cut-off for discriminating patients with organic colon disorders. The sensibility was 85% and NPV was 93%. NSAIDs use was a clinical variable which was connected with a high FCP concentration in patients with normal colonoscopy. The higher levels of FCP were found in people with IBD and CRC. The measurement of FCP is a non-invasive, inexpensive, reliable and easily measured test. Among people with abdominal pain and diarrhoea, testing for FCP allows us to select those who must undergo a colonoscopy. NSAIDs can raise the levels of FCP in people with normal colonoscopies.Medicina Clínica 07/2006; 127(2):41-6. · 1.38 Impact Factor -
Article: The differential effect of PGE(1) on d-galactosamine-induced nitrosative stress and cell death in primary culture of human hepatocytes.
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ABSTRACT: The pre-administration of PGE(1) reduced inducible nitric oxide synthase (NOS-2) expression and cell death induced by d-galactosamine (d-GalN) in cultured rat hepatocytes. The present study evaluated the role of nitric oxide (NO) during PGE(1) treatment in fully established d-GalN-induced cytotoxicity in cultured human hepatocytes. Human hepatocytes were isolated from liver resections by classic collagenase perfusion. PGE(1) (1 microM) was administered at 2 h before d-GalN (40 mM), or 2 or 10 h after d-GalN in cultured hepatocytes. The production of NO was inhibited by N-omega-nitroso-l-arginine methyl ester (l-NAME) (0.5 mM). Various parameters related to oxidative and nitrosative stress, mitochondrial dysfunction, NF-kappaB activation, NOS-2 expression and cell death were evaluated in hepatocytes. NO mediated mitochondrial disturbances, nitrosative stress and cell death in d-GalN-treated hepatocytes. The administration of PGE(1) 10 h after d-GalN enhanced NF-kappaB activation, NOS-2 expression and nitrosative stress. Although PGE(1) administered at 2 h before or 2h after d-GalN reduced apoptosis and necrosis, its administration 10 h after d-GalN had no beneficial effect on cell death. In conclusion, the administration of PGE(1) during advanced d-GalN cytotoxicity induced nitrosative stress and lost its cytoprotective properties in cultured human hepatocytes.Prostaglandins & other lipid mediators 06/2006; 79(3-4):245-59. · 2.70 Impact Factor -
Article: Dual effect of ethanol on cell death in primary culture of human and rat hepatocytes.
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ABSTRACT: In-vivo and in-vitro studies have shown that ethanol induces hepatocyte damage. The aim of the present study was to evaluate the effect of a broad range of ethanol concentrations on apoptosis and necrosis in primary culture of human and rat hepatocytes. Human and rat hepatocytes were isolated from human hepatectomies and male Wistar rats (200-250 g) using the classical collagenase perfusion method. After stabilization of cell culture, ethanol (0-10 mmol/l) was administered and the parameters were measured 24 h after ethanol addition. Apoptosis was studied by DNA fragmentation, iodide propidium-DNA staining, caspase-3 activity and annexin V binding in hepatocytes. Necrosis was evaluated by lactate dehydrogenase (LDH) release. Malondialdehyde (MDA) and GSH/GSSG were used as parameters of oxidative stress. Ethanol enhanced dose-dependently all the parameters associated with apoptosis in human and rat hepatocytes. Low or high ethanol concentrations induced an opposite action against cell necrosis in cultured hepatocytes. Low concentrations of ethanol (1-2 mmol/l) reduced LDH release from human and rat hepatocytes. However, the highest ethanol concentration (10 mmol/l) induced a sharp increase in cell necrosis. The effect of ethanol on cell necrosis was related to lipid peroxidation in hepatocytes. Ethanol differentially regulates apoptosis or necrosis in cultured hepatocytes. Although ethanol exerted a dose-dependent induction of apoptosis, low ethanol concentrations were able to reduce basal lipid peroxidation and necrosis in hepatocytes. The highest ethanol concentration (10 mmol/l) induced apoptosis and necrosis in human and rat cultured hepatocytes.Alcohol and Alcoholism 39(4):290-6. · 2.95 Impact Factor -
Article: Can systemic cytokines predict relapse of inflammatory bowel disease?
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ABSTRACT: To determine the value of systemic cytokines as predictors of relapse in inflammatory bowel disease (IBD). A prospective study with 135 patients in clinical remission for at least 3 months. At enrollment, a venous blood was drawn in order to measure, by an ELISA test, the following cytokines: TNFalpha, TNFalpha-R1 and R2, IL-16, IL-1beta, IL 2, IL-R2, IL-6, IL-10, and IFNgamma. All patients were followed-up for one year. Sixty-six patients had Crohn's disease (CD) and 69 had ulcerative colitis (UC). Thirty-nine (30%) had a relapse. Forty-four percent were receiving immunomodulatory therapy. No differences were found regarding detection and baseline concentration of the various cytokines between patients with CD and UC, or between patients with or without ongoing use of immunomodulators. The detection and concentration levels of cytokines were not associated with the risk of relapse of IBD. Systemic cytokines are of little value to predict IBD relapse.Hepato-gastroenterology 57(99-100):524-30. · 0.66 Impact Factor -
Article: The differential effect of PGE1 on d-galactosamine-induced nitrosative stress and cell death in primary culture of human hepatocytes
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ABSTRACT: The pre-administration of PGE1 reduced inducible nitric oxide synthase (NOS-2) expression and cell death induced by d-galactosamine (d-GalN) in cultured rat hepatocytes. The present study evaluated the role of nitric oxide (NO) during PGE1 treatment in fully established d-GalN-induced cytotoxicity in cultured human hepatocytes. Human hepatocytes were isolated from liver resections by classic collagenase perfusion. PGE1 (1 μM) was administered at 2 h before d-GalN (40 mM), or 2 or 10 h after d-GalN in cultured hepatocytes. The production of NO was inhibited by N-ω-nitroso-l-arginine methyl ester (l-NAME) (0.5 mM). Various parameters related to oxidative and nitrosative stress, mitochondrial dysfunction, NF-κB activation, NOS-2 expression and cell death were evaluated in hepatocytes. NO mediated mitochondrial disturbances, nitrosative stress and cell death in d-GalN-treated hepatocytes. The administration of PGE1 10 h after d-GalN enhanced NF-κB activation, NOS-2 expression and nitrosative stress. Although PGE1 administered at 2 h before or 2 h after d-GalN reduced apoptosis and necrosis, its administration 10 h after d-GalN had no beneficial effect on cell death. In conclusion, the administration of PGE1 during advanced d-GalN cytotoxicity induced nitrosative stress and lost its cytoprotective properties in cultured human hepatocytes.Prostaglandins & Other Lipid Mediators.
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Institutions
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2008–2011
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Hospital Universitario Reina Sofía
Córdoba, Andalusia, Spain
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