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description Publicationkeyboard_double_arrow_right Article , Journal 1987 SpainPublisher:American Society for Clinical Investigation Authors: Fernández-Checa Torres, José Carlos; Ookhtens, Murad; Kaplowitz, Neil;Hepatocytes from rats that were fed ethanol chronically for 6-8 wk were found to have a modest decrease in cytosolic GSH (24%) and a marked decrease in mitochondrial GSH (65%) as compared with pair-fed controls. Incubation of hepatocytes from ethanol-fed rats for 4 h in modified Fisher's medium revealed a greater absolute and fractional GSH efflux rate than controls with maintenance of constant cellular GSH, indicating increased net GSH synthesis. Inhibition of gamma-glutamyltransferase had no effect on these results, which indicates that no degradation of GSH had occurred during these studies. Enhanced fractional efflux was also noted in the perfused livers from ethanol-fed rats. Incubation of hepatocytes in medium containing up to 50 mM ethanol had no effect on cellular GSH, accumulation of GSH in the medium, or cell viability. Thus, chronic ethanol feeding causes a modest fall in cytosolic and a marked fall in mitochondrial GSH. Fractional GSH efflux and therefore synthesis are increased under basal conditions by chronic ethanol feeding, whereas the cellular concentration of GSH drops to a lower steady state level. Incubation of hepatocytes with ethanol indicates that it has no direct, acute effect on hepatic GSH homeostasis.
The Journal of Clini... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticleData sources: Recolector de Ciencia Abierta, RECOLECTADiposit Digital de la Universitat de BarcelonaArticle . 1987Data sources: Diposit Digital de la Universitat de BarcelonaRecolector de Ciencia Abierta, RECOLECTAArticle . 1987Data sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1172/jci113063&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen gold 127 citations 127 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
visibility 77visibility views 77 download downloads 97 Powered bymore_vert The Journal of Clini... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticleData sources: Recolector de Ciencia Abierta, RECOLECTADiposit Digital de la Universitat de BarcelonaArticle . 1987Data sources: Diposit Digital de la Universitat de BarcelonaRecolector de Ciencia Abierta, RECOLECTAArticle . 1987Data sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1172/jci113063&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 2000Publisher:Elsevier BV Francisco J. Romero; Miguel Sans; Julià Panés; Josep M. Piqué; Esther Ardite; José C. Fernández-Checa;pmid: 10830784
Because reactive oxygen species (ROS) have been implicated as mediators of inflammatory bowel disease (IBD), the purpose of the present work was to determine the functional role of mucosal GSH in the trinitrobenzenesulfonic acid in 50% ethanol (TNBS+ethanol)-induced colitis in rats. Mucosal samples were taken to evaluate the temporal relationship between the extent of injury, the levels of glutathione (GSH) during acute colitis induced by TNBS+ethanol, and the effect of N-acetylcysteine (NAC) administration. In vitro assays revealed the interaction of TNBS with GSH leading to the almost instantaneous disappearance of GSH, while the reductive metabolism of TNBS by GSSG reductase generated ROS. Mucosal samples from TNBS+ethanol-treated rats indicated a direct correlation between GSH depletion and injury detected as soon as 30 minutes after TNBS+ethanol administration that persisted 24 hours post treatment. Although, short term depletion of mucosal GSH per se by diethylmaleate did not result in mucosal injury, the oral administration of NAC (40 mM) 4 hours after TNBS+ethanol treatment increased GSH stores (2-fold), decreasing the extent of mucosal injury (60-70%) examined at 24 hours post treatment. However, an equimolar dose of dithiothreitol failed to increase GSH levels and protect mucosa from TNBS+ethanol-induced injury. Interestingly, GSH levels in TNBS+ethanol-treated rats recovered by 1-2 weeks, an effect that was accounted for by an increase of gamma-glutamylcysteine synthetase (gamma-GCS) activity due to an induction of gamma-GCS-heavy subunit chain mRNA. Thus, TNBS promotes two independent mechanisms of injury, GSH depletion and ROS generation, both being required for the manifestation of mucosal injury as GSH limitation renders intestine susceptible to the TNBS-induced ROS overgeneration. Accordingly, in vivo administration of NAC attenuates the acute colitis through increased mucosal GSH levels, suggesting that GSH precursors may be of relevance in the acute relapse of IBD.
Laboratory Investiga... arrow_drop_down Laboratory InvestigationArticle . 2000 . Peer-reviewedLicense: Elsevier Non-CommercialData sources: Crossrefadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
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For further information contact us at helpdesk@openaire.euAccess Routesbronze 103 citations 103 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
more_vert Laboratory Investiga... arrow_drop_down Laboratory InvestigationArticle . 2000 . Peer-reviewedLicense: Elsevier Non-CommercialData sources: Crossrefadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1038/labinvest.3780077&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 2001Publisher:Ovid Technologies (Wolters Kluwer Health) Olga Coll; Neil Kaplowitz; Claudio Tiribelli; Raquel París; Carmen García-Ruiz; Anna Colell; José C. Fernández-Checa;pmid: 11679967
Mitochondrial glutathione (GSH) plays a key role against tumor necrosis factor α (TNF)-induced apoptosis because its depletion is known to sensitize hepatocytes to TNF. The present study examined the role of tauroursodeoxycholic acid (TUDCA) administration to chronic ethanol-fed rats on mitochondrial GSH levels and kinetics, mitochondrial membrane physical properties, TNF-induced peroxide formation, and subsequent hepatocyte survival. TUDCA selectively increased the levels of GSH in mitochondria without an effect on cytosolic GSH. This outcome was accompanied by improved initial rate of GSH transport examined at low (1 mmol/L) and high (10 mmol/L) GSH concentrations both in intact mitochondria and mitoplasts prepared from ethanol-fed livers. Assessment of membrane fluidity revealed an increased order parameter in mitochondria and mitoplasts from ethanol-fed rats compared with pair-fed controls, which was prevented by TUDCA administration. Compared with hepatocytes from pair-fed rats, TNF stimulated peroxide generation in hepatocytes from ethanol-fed rats, preceding TNF-induced cell death. Administration of TUDCA to ethanol-fed rats prevented TNF-induced peroxide formation and cell death, an effect that was reversed on depletion of the recovered mitochondrial GSH levels by (R,S)-3-hydroxy-4-pentenoate before TNF treatment. The protective effect of TUDCA against TNF was not because of activation of phosphatidylinositol 3-kinase, discarding a role for a survival-dependent pathway. Thus, these findings reveal a novel role of TUDCA in protecting hepatocytes in long-term ethanol-fed rats through modulation of mitochondrial membrane fluidity and subsequent normalization of mitochondrial GSH levels.
add ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1053/jhep.2001.28510&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess Routesbronze 78 citations 78 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
more_vert add ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1053/jhep.2001.28510&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 1993Publisher:Elsevier BV Neil Kaplowitz; J. C. Fernández‐Checa; J. C. Fernández‐Checa; Takeshi Hirano; Hidekazu Tsukamoto;pmid: 8123202
Alcoholic liver disease (ALD) is one the most serious consequences of chronic alcohol abuse. Liver cirrhosis, the culmination of the illness, is one of the leading causes of death in Western countries. Mitochondria are a target of ethanol intoxication mainly due to the toxic effects of acetaldehyde, a byproduct of ethanol metabolism. Morphological and functional changes in mitochondria are one of the key hallmarks of chronic ethanol exposure in both chronic alcoholics and experimental models of alcoholism. The functional changes observed in mitochondria from ethanol-treated animals are translated in an overall decrease in ATP levels resulting from a lower rate of ATP synthesis as a consequence of impaired processing at the translational level of some components of oxidative phosphorylation encoded by mitochondrial DNA genome. Mitochondrial glutathione (GSH) plays a critical role in the maintenance of cell functions and viability and in mitochondrial physiology by metabolism of oxygen free radicals generated in the respiratory chain. GSH in mitochondria originates from cytosol by a transport system which translocates GSH into the matrix. This transport system is impaired in chronic ethanol-fed rats, which translates in a selective and significant depletion of the mitochondrial GSH content resulting in the development of an increased susceptibility to oxidant stress. Using the intragastric infusion model of experimental ALD in rats, the profound and selective mitochondrial GSH depletion precedes the onset of alcoholic liver disease, mitochondrial lipid peroxidation, and progression of liver damage.(ABSTRACT TRUNCATED AT 250 WORDS)
add ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1016/0741-8329(93)90067-x&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess Routesbronze 139 citations 139 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
more_vert add ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1016/0741-8329(93)90067-x&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 2006Publisher:Wiley Authors: José C. Fernández-Checa; Carmen García-Ruiz;pmid: 16958667
AbstractSteatohepatitis represents an advanced stage of fatty liver disease that encompasses alcoholic (ASH) and non‐alcoholic steatohepatitis (NASH). The progression from steatosis to steatohepatitis is poorly understood. One of the clues to this progression is the sensitization of hepatocytes to oxidative stress and cytokine‐induced cell death. Mitochondrial glutathione (mGSH), which plays a central role in the control of mitochondrial reactive oxygen species (ROS) generation, modulates the sensitivity to cell death pathways. Mitochondrial GSH depletion due to alcohol‐mediated alteration in mitochondrial membrane dynamics underlies the susceptibility of hepatocytes from alcohol‐fed models to tumor necrosis factor (TNF), and in nutritional and genetic models of hepatic steatosis, mGSH depletion occurs due to the enrichment of mitochondria in free cholesterol, resulting in decreased mitochondrial membrane fluidity. The signaling of TNF through its membrane receptor TNFR1 from complex I to complex II is similar in hepatocytes depleted or not depleted in mGSH, yet hepatocellular susceptibility to TNF occurs if mGSH is depleted. Thus, mGSH is a critical factor in the development of steatohepatitis through sensitization of hepatocytes to inflammatory cytokines, and understanding the homeostasis of cholesterol and its trafficking to mitochondria may be of relevance in the pathophysiology of ASH and NASH.
Journal of Gastroent... arrow_drop_down Journal of Gastroenterology and HepatologyArticle . 2006 . Peer-reviewedLicense: Wiley Online Library User AgreementData sources: Crossrefadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1111/j.1440-1746.2006.04570.x&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess Routesbronze 108 citations 108 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
more_vert Journal of Gastroent... arrow_drop_down Journal of Gastroenterology and HepatologyArticle . 2006 . Peer-reviewedLicense: Wiley Online Library User AgreementData sources: Crossrefadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1111/j.1440-1746.2006.04570.x&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 1997 SpainPublisher:Ovid Technologies (Wolters Kluwer Health) Colell Riera, Anna; García-Ruiz, Carmen; Morales, Albert; Ballesta, Antonio; Ookhtens, Murad; Rodés, Joan; Kaplowitz, Neil; Fernández-Checa, José C.;Ethanol intake depletes the mitochondrial pool of reduced glutathione (GSH) by impairing the transport of GSH from cytosol into mitochondria. S-Adenosyl-L-methionine (SAM) supplementation of ethanol-fed rats restores the mitochondrial pool of GSH. The purpose of the current study was to determine the effect of ethanol feeding on the kinetic parameters of mitochondrial GSH transport, the fluidity of mitochondria, and the effect of SAM on these changes. Male Sprague-Dawley rats were fed ethanol-liquid diet for 4 weeks supplemented with either SAM or N-acetylcysteine (NAC). SAM-supplementation of ethanol-fed rats restored the mitochondrial GSH pool but NAC administration did not. Kinetic studies of GSH transport in isolated mitochondria revealed two saturable, adenosine triphosphate (ATP)-stimulated components that were affected significantly by chronic ethanol feeding: Lowering Vmax (0.22 and 1.6 in ethanol case vs. 0.44 and 2.7 nmol/15 sec/mg protein in controls) for both low and high affinity components with the latter showing an increased Km (15.5 vs. 8.9, mmol/L in ethanol vs. control). Mitochondria from SAM-supplemented ethanol-fed rats showed kinetic features of GSH transport similar to control mitochondria. Determination of membrane fluidity revealed an increased order parameter in ethanol compared with control mitochondria, which was restricted to the polar head groups of the bilayer and was prevented by SAM but not NAC supplementation of ethanol-fed rats. The changes elicited in mitochondria by ethanol were confined to the inner membrane; mitoplasts from ethanol-fed rats showed features similar to those of intact mitochondria such as impaired transport of GSH and increased order parameter. A different mitochondrial transporter, adenosine diphosphate (ADP)/ATP translocator, was unaffected by ethanol feeding. Furthermore, fluidization of mitochondria or mitoplasts from ethanol-fed rats by treatment with a fatty acid derivative restored their ability to transport GSH to control levels. Thus, ethanol-induced impaired transport of GSH into mitochondria is selective, mediated by decreased fluidity of the mitochondrial inner membrane, and prevented by SAM treatment.
Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 1997 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1002/hep.510260323&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen bronze 148 citations 148 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
visibility 13visibility views 13 download downloads 21 Powered bymore_vert Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 1997 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1002/hep.510260323&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 2009 SpainPublisher:Springer Science and Business Media LLC Carmen García-Ruiz; María Miranda; María Muriach; Jorge M. Barcia; Inmaculada Almansa; Francisco J. Romero; Anna Fernández; José C. Fernández-Checa;The aim of this study was to demonstrate the existence of alterations in glutathione and cholesterol homeostasis in brain mitochondria from alcoholic rats. Glutathione concentration decreased, whereas oxidized glutathione and cholesterol contents increased in these organelles, suggesting the ethanol-induced generation of reactive oxygen species, and the impairment of mitochondrial uptake of glutathione, possibly due to the increase in cholesterol deposition. The release of apoptogenic proteins was increased after stimulating mitochondria from the brain of alcoholic rats with atractyloside. As a conclusion, chronic alcohol consumption might sensitize brain mitochondria to apoptotic stimuli, and promote the subsequent release of apoptotic proteins.
Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 2009 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAJournal of Physiology and BiochemistryArticle . 2009 . Peer-reviewedLicense: Springer TDMData sources: Crossrefadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1007/bf03180583&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen bronze 18 citations 18 popularity Top 10% influence Average impulse Average Powered by BIP!
visibility 17visibility views 17 download downloads 35 Powered bymore_vert Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 2009 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAJournal of Physiology and BiochemistryArticle . 2009 . Peer-reviewedLicense: Springer TDMData sources: Crossrefadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1007/bf03180583&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 1998 SpainPublisher:Elsevier BV Colell Riera, Anna; García-Ruiz, Carmen; Miranda, Merge; Ardite, Esther; Marí, Montserrat; Morales, Albert; Corrales, Fernando J.; Kaplowitz, Neil; Fernández-Checa, José C.;Tumor necrosis factor (TNF)-alpha induces cell injury by generating oxidative stress from mitochondria. The purpose of this study was to determine the effect of ethanol on the sensitization of hepatocytes to TNF-alpha.Cultured hepatocytes from ethanol-fed (ethanol hepatocytes) or pair-fed (control hepatocytes) rats were exposed to TNF-alpha, and the extent of oxidative stress, gene expression, and viability were evaluated.Ethanol hepatocytes, which develop a selective deficiency of mitochondrial glutathione (mGSH), showed marked susceptibility to TNF-alpha. The susceptibility to TNF-alpha, manifested as necrosis rather than apoptosis, was accompanied by a progressive increase in hydrogen peroxide that correlated inversely with cell survival. Nuclear factor kappaB activation by TNF-alpha was significantly greater in ethanol hepatocytes than in control hepatocytes, an effect paralleled by the expression of cytokine-induced neutrophil chemoattractant. Similar sensitization of normal hepatocytes to TNF-alpha was obtained by depleting the mitochondrial pool of GSH with 3-hydroxyl-4-pentenoate. Restoration of mGSH by S-adenosyl-L-methionine or by GSH-ethyl ester prevented the increased susceptibility of ethanol hepatocytes to TNF-alpha.These results indicate that mGSH controls the fate of hepatocytes in response to TNF-alpha. Its depletion caused by alcohol consumption amplifies the power of TNF-alpha to generate reactive oxygen species, compromising mitochondrial and cellular functions that culminate in cell death.
Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 1998 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1016/s0016-5085(98)70034-4&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen bronze 331 citations 331 popularity Top 1% influence Top 1% impulse Top 1% Powered by BIP!
visibility 10visibility views 10 download downloads 37 Powered bymore_vert Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 1998 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1016/s0016-5085(98)70034-4&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 1999 SpainPublisher:Ovid Technologies (Wolters Kluwer Health) Román, Juan; Colell Riera, Anna; Blasco, Carmen; Caballería, Juan; Parés, Albert; Rodés, Joan; Fernández-Checa, José C.;The oxidative metabolism of ethanol by the cytochrome P450 2E1 (CYP2E1) has been recognized to contribute to the ethanol-induced deleterious effects through the induction of oxidative stress. This study compared the effect of ethanol and acetaldehyde in the induction of oxidative stress and activation of transcription factors nuclear factor-κB (NF-κB) and activating protein 1 (AP-1) in HepG2 cells, which do not express CYP2E1, and HepG2 cells transfected with CYP2E1 (E47 cells). Neither ethanol (80 mmol/L) nor acetaldehyde (25-200 μmol/L) caused oxidative stress in HepG2 cells, an effect that was independent of blocking reduced glutathione (GSH) synthesis with buthionine-l -sulfoximine (BSO). However, BSO preincubation caused an overproduction of peroxides and activation of NF-κB and AP-1 in E47 cells even in the absence of ethanol. Furthermore, the incubation of E47 cells with ethanol (80 mmol/L for up to 5 days) depleted cellular GSH stores in both cytosol and mitochondria, reflecting the induction of oxidative stress. Ethanol activated NF-κB and AP-1 in E47 cells, an effect that was prevented by 4-methylpyrazole, potentiated by cyanamide, and attenuated by trolox C. Interestingly, however, despite the inability of acetaldehyde to induce oxidative stress in HepG2, acetaldehyde activated NF-κB and AP-1; in contrast, ethanol failed to activate these transcription factors in HepG2. Thus, our findings indicate that activation of NF-κB and AP-1 by ethanol and acetaldehyde occurs through distinct mechanisms. CYP2E1 is indispensable in the induction of oxidative stress from ethanol, whereas the activation of NF-κB and AP-1 by acetaldehyde is independent of oxidative stress.
Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 1999 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1002/hep.510300623&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen bronze 88 citations 88 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
more_vert Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 1999 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1002/hep.510300623&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 1994 SpainPublisher:American Society for Clinical Investigation Authors: García Ruiz, Carmen; Morales Muñoz, Albert; Ballesta Gimeno, Antonio M.; Rodés, J.; +2 AuthorsGarcía Ruiz, Carmen; Morales Muñoz, Albert; Ballesta Gimeno, Antonio M.; Rodés, J.; Kaplowitz, Neil; Fernández-Checa Torres, José Carlos;Chronic ethanol feeding selectively impairs the translocation of cytosol GSH into the mitochondrial matrix. Since ethanol-induced liver cell injury is preferentially localized in the centrilobular area, we examined the hepatic acinar distribution of mitochondrial GSH transport in ethanol-fed rats. Enriched periportal (PP) and perivenous (PV) hepatocytes from pair- and ethanol-fed rats were prepared as well as mitochondria from these cells. The mitochondrial pool size of GSH was decreased in both PP and PV cells from ethanol-fed rats either as expressed per 10(6) cells or per microliter of mitochondrial matrix volume. The rate of reaccumulation of mitochondrial GSH and the linear relationship of mitochondrial to cytosol GSH from ethanol-fed mitochondria were lower for both PP and PV cells, effects observed more prominently in the PV cells. Mitochondrial functional integrity was lower in both PP and PV ethanol-fed rats, which was associated with decreased cellular ATP levels and mitochondrial membrane potential, effects which were greater in the PV cells. Mitochondrial GSH depletion by ethanol feeding preceded the onset of functional changes in mitochondria, suggesting that mitochondrial GSH is critical in maintaining a functionally competent organelle and that the greater depletion of mitochondrial GSH by ethanol feeding in PV cells could contribute to the pathogenesis of alcoholic liver disease.
The Journal of Clini... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticleData sources: Recolector de Ciencia Abierta, RECOLECTADiposit Digital de la Universitat de BarcelonaArticle . 1994Data sources: Diposit Digital de la Universitat de BarcelonaRecolector de Ciencia Abierta, RECOLECTAArticle . 1994Data sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1172/jci117306&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen gold 207 citations 207 popularity Top 10% influence Top 1% impulse Top 10% Powered by BIP!
visibility 80visibility views 80 download downloads 113 Powered bymore_vert The Journal of Clini... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticleData sources: Recolector de Ciencia Abierta, RECOLECTADiposit Digital de la Universitat de BarcelonaArticle . 1994Data sources: Diposit Digital de la Universitat de BarcelonaRecolector de Ciencia Abierta, RECOLECTAArticle . 1994Data sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
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description Publicationkeyboard_double_arrow_right Article , Journal 1987 SpainPublisher:American Society for Clinical Investigation Authors: Fernández-Checa Torres, José Carlos; Ookhtens, Murad; Kaplowitz, Neil;Hepatocytes from rats that were fed ethanol chronically for 6-8 wk were found to have a modest decrease in cytosolic GSH (24%) and a marked decrease in mitochondrial GSH (65%) as compared with pair-fed controls. Incubation of hepatocytes from ethanol-fed rats for 4 h in modified Fisher's medium revealed a greater absolute and fractional GSH efflux rate than controls with maintenance of constant cellular GSH, indicating increased net GSH synthesis. Inhibition of gamma-glutamyltransferase had no effect on these results, which indicates that no degradation of GSH had occurred during these studies. Enhanced fractional efflux was also noted in the perfused livers from ethanol-fed rats. Incubation of hepatocytes in medium containing up to 50 mM ethanol had no effect on cellular GSH, accumulation of GSH in the medium, or cell viability. Thus, chronic ethanol feeding causes a modest fall in cytosolic and a marked fall in mitochondrial GSH. Fractional GSH efflux and therefore synthesis are increased under basal conditions by chronic ethanol feeding, whereas the cellular concentration of GSH drops to a lower steady state level. Incubation of hepatocytes with ethanol indicates that it has no direct, acute effect on hepatic GSH homeostasis.
The Journal of Clini... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticleData sources: Recolector de Ciencia Abierta, RECOLECTADiposit Digital de la Universitat de BarcelonaArticle . 1987Data sources: Diposit Digital de la Universitat de BarcelonaRecolector de Ciencia Abierta, RECOLECTAArticle . 1987Data sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1172/jci113063&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen gold 127 citations 127 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
visibility 77visibility views 77 download downloads 97 Powered bymore_vert The Journal of Clini... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticleData sources: Recolector de Ciencia Abierta, RECOLECTADiposit Digital de la Universitat de BarcelonaArticle . 1987Data sources: Diposit Digital de la Universitat de BarcelonaRecolector de Ciencia Abierta, RECOLECTAArticle . 1987Data sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1172/jci113063&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 2000Publisher:Elsevier BV Francisco J. Romero; Miguel Sans; Julià Panés; Josep M. Piqué; Esther Ardite; José C. Fernández-Checa;pmid: 10830784
Because reactive oxygen species (ROS) have been implicated as mediators of inflammatory bowel disease (IBD), the purpose of the present work was to determine the functional role of mucosal GSH in the trinitrobenzenesulfonic acid in 50% ethanol (TNBS+ethanol)-induced colitis in rats. Mucosal samples were taken to evaluate the temporal relationship between the extent of injury, the levels of glutathione (GSH) during acute colitis induced by TNBS+ethanol, and the effect of N-acetylcysteine (NAC) administration. In vitro assays revealed the interaction of TNBS with GSH leading to the almost instantaneous disappearance of GSH, while the reductive metabolism of TNBS by GSSG reductase generated ROS. Mucosal samples from TNBS+ethanol-treated rats indicated a direct correlation between GSH depletion and injury detected as soon as 30 minutes after TNBS+ethanol administration that persisted 24 hours post treatment. Although, short term depletion of mucosal GSH per se by diethylmaleate did not result in mucosal injury, the oral administration of NAC (40 mM) 4 hours after TNBS+ethanol treatment increased GSH stores (2-fold), decreasing the extent of mucosal injury (60-70%) examined at 24 hours post treatment. However, an equimolar dose of dithiothreitol failed to increase GSH levels and protect mucosa from TNBS+ethanol-induced injury. Interestingly, GSH levels in TNBS+ethanol-treated rats recovered by 1-2 weeks, an effect that was accounted for by an increase of gamma-glutamylcysteine synthetase (gamma-GCS) activity due to an induction of gamma-GCS-heavy subunit chain mRNA. Thus, TNBS promotes two independent mechanisms of injury, GSH depletion and ROS generation, both being required for the manifestation of mucosal injury as GSH limitation renders intestine susceptible to the TNBS-induced ROS overgeneration. Accordingly, in vivo administration of NAC attenuates the acute colitis through increased mucosal GSH levels, suggesting that GSH precursors may be of relevance in the acute relapse of IBD.
Laboratory Investiga... arrow_drop_down Laboratory InvestigationArticle . 2000 . Peer-reviewedLicense: Elsevier Non-CommercialData sources: Crossrefadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
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For further information contact us at helpdesk@openaire.euAccess Routesbronze 103 citations 103 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
more_vert Laboratory Investiga... arrow_drop_down Laboratory InvestigationArticle . 2000 . Peer-reviewedLicense: Elsevier Non-CommercialData sources: Crossrefadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1038/labinvest.3780077&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 2001Publisher:Ovid Technologies (Wolters Kluwer Health) Olga Coll; Neil Kaplowitz; Claudio Tiribelli; Raquel París; Carmen García-Ruiz; Anna Colell; José C. Fernández-Checa;pmid: 11679967
Mitochondrial glutathione (GSH) plays a key role against tumor necrosis factor α (TNF)-induced apoptosis because its depletion is known to sensitize hepatocytes to TNF. The present study examined the role of tauroursodeoxycholic acid (TUDCA) administration to chronic ethanol-fed rats on mitochondrial GSH levels and kinetics, mitochondrial membrane physical properties, TNF-induced peroxide formation, and subsequent hepatocyte survival. TUDCA selectively increased the levels of GSH in mitochondria without an effect on cytosolic GSH. This outcome was accompanied by improved initial rate of GSH transport examined at low (1 mmol/L) and high (10 mmol/L) GSH concentrations both in intact mitochondria and mitoplasts prepared from ethanol-fed livers. Assessment of membrane fluidity revealed an increased order parameter in mitochondria and mitoplasts from ethanol-fed rats compared with pair-fed controls, which was prevented by TUDCA administration. Compared with hepatocytes from pair-fed rats, TNF stimulated peroxide generation in hepatocytes from ethanol-fed rats, preceding TNF-induced cell death. Administration of TUDCA to ethanol-fed rats prevented TNF-induced peroxide formation and cell death, an effect that was reversed on depletion of the recovered mitochondrial GSH levels by (R,S)-3-hydroxy-4-pentenoate before TNF treatment. The protective effect of TUDCA against TNF was not because of activation of phosphatidylinositol 3-kinase, discarding a role for a survival-dependent pathway. Thus, these findings reveal a novel role of TUDCA in protecting hepatocytes in long-term ethanol-fed rats through modulation of mitochondrial membrane fluidity and subsequent normalization of mitochondrial GSH levels.
add ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
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For further information contact us at helpdesk@openaire.euAccess Routesbronze 78 citations 78 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
more_vert add ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1053/jhep.2001.28510&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 1993Publisher:Elsevier BV Neil Kaplowitz; J. C. Fernández‐Checa; J. C. Fernández‐Checa; Takeshi Hirano; Hidekazu Tsukamoto;pmid: 8123202
Alcoholic liver disease (ALD) is one the most serious consequences of chronic alcohol abuse. Liver cirrhosis, the culmination of the illness, is one of the leading causes of death in Western countries. Mitochondria are a target of ethanol intoxication mainly due to the toxic effects of acetaldehyde, a byproduct of ethanol metabolism. Morphological and functional changes in mitochondria are one of the key hallmarks of chronic ethanol exposure in both chronic alcoholics and experimental models of alcoholism. The functional changes observed in mitochondria from ethanol-treated animals are translated in an overall decrease in ATP levels resulting from a lower rate of ATP synthesis as a consequence of impaired processing at the translational level of some components of oxidative phosphorylation encoded by mitochondrial DNA genome. Mitochondrial glutathione (GSH) plays a critical role in the maintenance of cell functions and viability and in mitochondrial physiology by metabolism of oxygen free radicals generated in the respiratory chain. GSH in mitochondria originates from cytosol by a transport system which translocates GSH into the matrix. This transport system is impaired in chronic ethanol-fed rats, which translates in a selective and significant depletion of the mitochondrial GSH content resulting in the development of an increased susceptibility to oxidant stress. Using the intragastric infusion model of experimental ALD in rats, the profound and selective mitochondrial GSH depletion precedes the onset of alcoholic liver disease, mitochondrial lipid peroxidation, and progression of liver damage.(ABSTRACT TRUNCATED AT 250 WORDS)
add ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1016/0741-8329(93)90067-x&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess Routesbronze 139 citations 139 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
more_vert add ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1016/0741-8329(93)90067-x&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 2006Publisher:Wiley Authors: José C. Fernández-Checa; Carmen García-Ruiz;pmid: 16958667
AbstractSteatohepatitis represents an advanced stage of fatty liver disease that encompasses alcoholic (ASH) and non‐alcoholic steatohepatitis (NASH). The progression from steatosis to steatohepatitis is poorly understood. One of the clues to this progression is the sensitization of hepatocytes to oxidative stress and cytokine‐induced cell death. Mitochondrial glutathione (mGSH), which plays a central role in the control of mitochondrial reactive oxygen species (ROS) generation, modulates the sensitivity to cell death pathways. Mitochondrial GSH depletion due to alcohol‐mediated alteration in mitochondrial membrane dynamics underlies the susceptibility of hepatocytes from alcohol‐fed models to tumor necrosis factor (TNF), and in nutritional and genetic models of hepatic steatosis, mGSH depletion occurs due to the enrichment of mitochondria in free cholesterol, resulting in decreased mitochondrial membrane fluidity. The signaling of TNF through its membrane receptor TNFR1 from complex I to complex II is similar in hepatocytes depleted or not depleted in mGSH, yet hepatocellular susceptibility to TNF occurs if mGSH is depleted. Thus, mGSH is a critical factor in the development of steatohepatitis through sensitization of hepatocytes to inflammatory cytokines, and understanding the homeostasis of cholesterol and its trafficking to mitochondria may be of relevance in the pathophysiology of ASH and NASH.
Journal of Gastroent... arrow_drop_down Journal of Gastroenterology and HepatologyArticle . 2006 . Peer-reviewedLicense: Wiley Online Library User AgreementData sources: Crossrefadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1111/j.1440-1746.2006.04570.x&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess Routesbronze 108 citations 108 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
more_vert Journal of Gastroent... arrow_drop_down Journal of Gastroenterology and HepatologyArticle . 2006 . Peer-reviewedLicense: Wiley Online Library User AgreementData sources: Crossrefadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1111/j.1440-1746.2006.04570.x&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 1997 SpainPublisher:Ovid Technologies (Wolters Kluwer Health) Colell Riera, Anna; García-Ruiz, Carmen; Morales, Albert; Ballesta, Antonio; Ookhtens, Murad; Rodés, Joan; Kaplowitz, Neil; Fernández-Checa, José C.;Ethanol intake depletes the mitochondrial pool of reduced glutathione (GSH) by impairing the transport of GSH from cytosol into mitochondria. S-Adenosyl-L-methionine (SAM) supplementation of ethanol-fed rats restores the mitochondrial pool of GSH. The purpose of the current study was to determine the effect of ethanol feeding on the kinetic parameters of mitochondrial GSH transport, the fluidity of mitochondria, and the effect of SAM on these changes. Male Sprague-Dawley rats were fed ethanol-liquid diet for 4 weeks supplemented with either SAM or N-acetylcysteine (NAC). SAM-supplementation of ethanol-fed rats restored the mitochondrial GSH pool but NAC administration did not. Kinetic studies of GSH transport in isolated mitochondria revealed two saturable, adenosine triphosphate (ATP)-stimulated components that were affected significantly by chronic ethanol feeding: Lowering Vmax (0.22 and 1.6 in ethanol case vs. 0.44 and 2.7 nmol/15 sec/mg protein in controls) for both low and high affinity components with the latter showing an increased Km (15.5 vs. 8.9, mmol/L in ethanol vs. control). Mitochondria from SAM-supplemented ethanol-fed rats showed kinetic features of GSH transport similar to control mitochondria. Determination of membrane fluidity revealed an increased order parameter in ethanol compared with control mitochondria, which was restricted to the polar head groups of the bilayer and was prevented by SAM but not NAC supplementation of ethanol-fed rats. The changes elicited in mitochondria by ethanol were confined to the inner membrane; mitoplasts from ethanol-fed rats showed features similar to those of intact mitochondria such as impaired transport of GSH and increased order parameter. A different mitochondrial transporter, adenosine diphosphate (ADP)/ATP translocator, was unaffected by ethanol feeding. Furthermore, fluidization of mitochondria or mitoplasts from ethanol-fed rats by treatment with a fatty acid derivative restored their ability to transport GSH to control levels. Thus, ethanol-induced impaired transport of GSH into mitochondria is selective, mediated by decreased fluidity of the mitochondrial inner membrane, and prevented by SAM treatment.
Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 1997 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1002/hep.510260323&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen bronze 148 citations 148 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
visibility 13visibility views 13 download downloads 21 Powered bymore_vert Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 1997 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1002/hep.510260323&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 2009 SpainPublisher:Springer Science and Business Media LLC Carmen García-Ruiz; María Miranda; María Muriach; Jorge M. Barcia; Inmaculada Almansa; Francisco J. Romero; Anna Fernández; José C. Fernández-Checa;The aim of this study was to demonstrate the existence of alterations in glutathione and cholesterol homeostasis in brain mitochondria from alcoholic rats. Glutathione concentration decreased, whereas oxidized glutathione and cholesterol contents increased in these organelles, suggesting the ethanol-induced generation of reactive oxygen species, and the impairment of mitochondrial uptake of glutathione, possibly due to the increase in cholesterol deposition. The release of apoptogenic proteins was increased after stimulating mitochondria from the brain of alcoholic rats with atractyloside. As a conclusion, chronic alcohol consumption might sensitize brain mitochondria to apoptotic stimuli, and promote the subsequent release of apoptotic proteins.
Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 2009 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAJournal of Physiology and BiochemistryArticle . 2009 . Peer-reviewedLicense: Springer TDMData sources: Crossrefadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1007/bf03180583&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen bronze 18 citations 18 popularity Top 10% influence Average impulse Average Powered by BIP!
visibility 17visibility views 17 download downloads 35 Powered bymore_vert Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 2009 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAJournal of Physiology and BiochemistryArticle . 2009 . Peer-reviewedLicense: Springer TDMData sources: Crossrefadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1007/bf03180583&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 1998 SpainPublisher:Elsevier BV Colell Riera, Anna; García-Ruiz, Carmen; Miranda, Merge; Ardite, Esther; Marí, Montserrat; Morales, Albert; Corrales, Fernando J.; Kaplowitz, Neil; Fernández-Checa, José C.;Tumor necrosis factor (TNF)-alpha induces cell injury by generating oxidative stress from mitochondria. The purpose of this study was to determine the effect of ethanol on the sensitization of hepatocytes to TNF-alpha.Cultured hepatocytes from ethanol-fed (ethanol hepatocytes) or pair-fed (control hepatocytes) rats were exposed to TNF-alpha, and the extent of oxidative stress, gene expression, and viability were evaluated.Ethanol hepatocytes, which develop a selective deficiency of mitochondrial glutathione (mGSH), showed marked susceptibility to TNF-alpha. The susceptibility to TNF-alpha, manifested as necrosis rather than apoptosis, was accompanied by a progressive increase in hydrogen peroxide that correlated inversely with cell survival. Nuclear factor kappaB activation by TNF-alpha was significantly greater in ethanol hepatocytes than in control hepatocytes, an effect paralleled by the expression of cytokine-induced neutrophil chemoattractant. Similar sensitization of normal hepatocytes to TNF-alpha was obtained by depleting the mitochondrial pool of GSH with 3-hydroxyl-4-pentenoate. Restoration of mGSH by S-adenosyl-L-methionine or by GSH-ethyl ester prevented the increased susceptibility of ethanol hepatocytes to TNF-alpha.These results indicate that mGSH controls the fate of hepatocytes in response to TNF-alpha. Its depletion caused by alcohol consumption amplifies the power of TNF-alpha to generate reactive oxygen species, compromising mitochondrial and cellular functions that culminate in cell death.
Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 1998 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1016/s0016-5085(98)70034-4&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen bronze 331 citations 331 popularity Top 1% influence Top 1% impulse Top 1% Powered by BIP!
visibility 10visibility views 10 download downloads 37 Powered bymore_vert Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 1998 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1016/s0016-5085(98)70034-4&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 1999 SpainPublisher:Ovid Technologies (Wolters Kluwer Health) Román, Juan; Colell Riera, Anna; Blasco, Carmen; Caballería, Juan; Parés, Albert; Rodés, Joan; Fernández-Checa, José C.;The oxidative metabolism of ethanol by the cytochrome P450 2E1 (CYP2E1) has been recognized to contribute to the ethanol-induced deleterious effects through the induction of oxidative stress. This study compared the effect of ethanol and acetaldehyde in the induction of oxidative stress and activation of transcription factors nuclear factor-κB (NF-κB) and activating protein 1 (AP-1) in HepG2 cells, which do not express CYP2E1, and HepG2 cells transfected with CYP2E1 (E47 cells). Neither ethanol (80 mmol/L) nor acetaldehyde (25-200 μmol/L) caused oxidative stress in HepG2 cells, an effect that was independent of blocking reduced glutathione (GSH) synthesis with buthionine-l -sulfoximine (BSO). However, BSO preincubation caused an overproduction of peroxides and activation of NF-κB and AP-1 in E47 cells even in the absence of ethanol. Furthermore, the incubation of E47 cells with ethanol (80 mmol/L for up to 5 days) depleted cellular GSH stores in both cytosol and mitochondria, reflecting the induction of oxidative stress. Ethanol activated NF-κB and AP-1 in E47 cells, an effect that was prevented by 4-methylpyrazole, potentiated by cyanamide, and attenuated by trolox C. Interestingly, however, despite the inability of acetaldehyde to induce oxidative stress in HepG2, acetaldehyde activated NF-κB and AP-1; in contrast, ethanol failed to activate these transcription factors in HepG2. Thus, our findings indicate that activation of NF-κB and AP-1 by ethanol and acetaldehyde occurs through distinct mechanisms. CYP2E1 is indispensable in the induction of oxidative stress from ethanol, whereas the activation of NF-κB and AP-1 by acetaldehyde is independent of oxidative stress.
Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 1999 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1002/hep.510300623&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen bronze 88 citations 88 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
more_vert Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 1999 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1002/hep.510300623&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 1994 SpainPublisher:American Society for Clinical Investigation Authors: García Ruiz, Carmen; Morales Muñoz, Albert; Ballesta Gimeno, Antonio M.; Rodés, J.; +2 AuthorsGarcía Ruiz, Carmen; Morales Muñoz, Albert; Ballesta Gimeno, Antonio M.; Rodés, J.; Kaplowitz, Neil; Fernández-Checa Torres, José Carlos;Chronic ethanol feeding selectively impairs the translocation of cytosol GSH into the mitochondrial matrix. Since ethanol-induced liver cell injury is preferentially localized in the centrilobular area, we examined the hepatic acinar distribution of mitochondrial GSH transport in ethanol-fed rats. Enriched periportal (PP) and perivenous (PV) hepatocytes from pair- and ethanol-fed rats were prepared as well as mitochondria from these cells. The mitochondrial pool size of GSH was decreased in both PP and PV cells from ethanol-fed rats either as expressed per 10(6) cells or per microliter of mitochondrial matrix volume. The rate of reaccumulation of mitochondrial GSH and the linear relationship of mitochondrial to cytosol GSH from ethanol-fed mitochondria were lower for both PP and PV cells, effects observed more prominently in the PV cells. Mitochondrial functional integrity was lower in both PP and PV ethanol-fed rats, which was associated with decreased cellular ATP levels and mitochondrial membrane potential, effects which were greater in the PV cells. Mitochondrial GSH depletion by ethanol feeding preceded the onset of functional changes in mitochondria, suggesting that mitochondrial GSH is critical in maintaining a functionally competent organelle and that the greater depletion of mitochondrial GSH by ethanol feeding in PV cells could contribute to the pathogenesis of alcoholic liver disease.
The Journal of Clini... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticleData sources: Recolector de Ciencia Abierta, RECOLECTADiposit Digital de la Universitat de BarcelonaArticle . 1994Data sources: Diposit Digital de la Universitat de BarcelonaRecolector de Ciencia Abierta, RECOLECTAArticle . 1994Data sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1172/jci117306&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen gold 207 citations 207 popularity Top 10% influence Top 1% impulse Top 10% Powered by BIP!
visibility 80visibility views 80 download downloads 113 Powered bymore_vert The Journal of Clini... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticleData sources: Recolector de Ciencia Abierta, RECOLECTADiposit Digital de la Universitat de BarcelonaArticle . 1994Data sources: Diposit Digital de la Universitat de BarcelonaRecolector de Ciencia Abierta, RECOLECTAArticle . 1994Data sources: Recolector de Ciencia Abierta, RECOLECTAadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://beta.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1172/jci117306&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eu