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description 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.
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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 88 citations 88 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
visibility 42visibility views 42 download downloads 36 Powered bymore_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 1995Publisher:Ovid Technologies (Wolters Kluwer Health) Anna Colell; Joan Rodés; Neil Kaplowitz; Albert Morales; Carmen García-Ruiz; José C. Fernández-Checa; Antonio M. Ballesta;pmid: 7806156
Mitochondrial glutathione plays an important role in maintaining a functionally competent organelle. Previous studies have shown that ethanol feeding selectively depletes the mitochondrial glutathione pool, more predominantly in mitochondria from perivenous hepatocytes. Because S-adenosyl-L-methionine (SAM) is a glutathione precursor and maintains the structure and function of biological membranes, the purpose of the present study was to determine the effects of SAM on glutathione and function of perivenous (PV) and periportal (PP) mitochondria from chronic ethanol-fed rats. SAM administration resulted in a significant increase in the basal cytosol and mitochondrial glutathione in both PP and PV cells from both pair-fed or ethanol-fed groups. When hepatocytes from ethanol-fed rats supplemented with SAM were incubated with methionine plus serine or N-acetylcysteine, mitochondrial glutathione increased in parallel with cytosol, an effect not observed in cells from ethanol-fed rats without SAM. Feeding equimolar N-acetylcysteine raised cytosol glutathione but did not prevent the mitochondrial glutathione defect. In addition, SAM feeding resulted in significant preservation of cellular adenosine triphosphate (ATP) levels (23% to 43%), mitochondrial membrane potential (17% to 25%), and the uncoupler control ratio (UCR) of respiration (from 5.1 ± 0.7 to 7.3 ± 0.6 and 2.1 ± 0.3 to 6.1 ± 0.7) for PP and PV mitochondria, respectively. Thus, these effects of SAM suggest that it may be a useful agent to preserve the disturbed mitochondrial integrity in liver disease caused by alcoholism through maintenance of mitochondrial glutathione transport. (Hepatology 1995;21:207-214).
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=10.1002/hep.1840210133&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eu192 citations 192 popularity Top 10% influence Top 1% impulse Top 1% 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=10.1002/hep.1840210133&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 2005Publisher:Wiley Authors: Montserrat Marí; Carmen García-Ruiz; José C. Fernández-Checa; Anna Colell;pmid: 16344602
Abstract: Background: The pathogenesis of alcohol‐induced liver disease (ALD) is incompletely known. One of the key processes mediating the progression of ALD involved the overproduction of tumor necrosis factor (TNF) and the susceptibility of hepatocytes to TNF‐induced apoptosis by alcohol intake.Methods: Analyze the apoptotic signaling of TNF resulting in the targeting and subsequent recruitment of mitochondria to death pathways.Results: Studies in experimental animal models of the disease have provided evidence for the role of ceramide generated from acidic sphingomyelinase in the apoptotic signaling of TNF through recruitment of mitochondria. The mitochondrial pool of glutathione (mGSH) is a vital line of defense against oxidative stress by precluding the accumulation peroxides generated endogenously within mitochondria and as a cofactor of mitochondrial antioxidant enzymes. The depletion of mGSH by alcohol has been described to determine the susceptibility of hepatocytes to TNF‐mediated cell death.Conclusions: The level of mGSH determines the fate of hepatocytes to acidic sphingomyelinase activation by TNF and hence strategies aimed to replenish mGSH or to antagonize the generation of ceramide from acidic sphingomyelinase may be of therapeutic value for ALD.
Alcoholism Clinical ... arrow_drop_down Alcoholism Clinical and Experimental ResearchArticle . 2005 . 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.
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For further information contact us at helpdesk@openaire.eu22 citations 22 popularity Average influence Average impulse Average Powered by BIP!
more_vert Alcoholism Clinical ... arrow_drop_down Alcoholism Clinical and Experimental ResearchArticle . 2005 . 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=10.1097/01.alc.0000189285.04059.b3&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 2009 SpainPublisher:Wiley Francisco Caballero; Carmen García-Ruiz; Nuria Matías; Anna Colell; Anna Fernández; José C. Fernández-Checa;Background: Alcohol‐induced liver injury is associated with decreasedS‐adenosyl‐l‐methionine (SAM)/S‐adenosyl‐l‐homocysteine (SAH) ratio and mitochondrial glutathione (mGSH) depletion, which has been shown to sensitize hepatocytes to tumor necrosis factor (TNF).Aims: As the effect of alcohol on mitochondrial SAM (mSAM) has been poorly characterized, our aim was to examine the status and transport of mSAM in relation to that of mGSH during alcohol intake.Methods: Sprague–Dawley rats were pair fed Lieber–DeCarli diets containing alcohol for 1 to 4 weeks and liver fractionated into cytosol and mitochondria to examine the mSAM transport and its sensitivity to membrane dynamics.Results: We found that cytosol SAM was depleted from the first week of alcohol feeding, with mSAM levels paralleling these changes. Cytosol SAH, however, increased during the first 3 weeks of alcohol intake, whereas its mitochondrial levels remained unchanged. mGSH depletion occurred by 3 to 4 weeks of alcohol intake due to cholesterol‐mediated impaired transport from the cytosol. In contrast to this outcome, the transport of SAM into hepatic mitochondria was unaffected by alcohol intake and resistant to cholesterol‐mediated perturbations in membrane dynamics; furthermore cytosolic SAH accumulation in primary hepatocytes by SAH hydrolase inhibition reproduced the mSAM depletion by alcohol due to the competition of SAH with SAM for mitochondrial transport. However, alcohol feeding did not potentiate the sensitivity to inhibition by SAH accumulation.Conclusions: Alcohol‐induced mSAM depletion precedes that of mGSH and occurs independently of alcohol‐mediated perturbations in membrane dynamics, disproving an inherent defect in the mSAM transport by alcohol. These findings suggest that the early mSAM depletion may contribute to the alterations of mitochondrial membrane dynamics and the subsequent mGSH down‐regulation induced by alcohol feeding.
Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 2009 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAAlcoholism Clinical and Experimental ResearchArticle . 2009 . 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.
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For further information contact us at helpdesk@openaire.euAccess RoutesGreen 27 citations 27 popularity Top 10% influence Average impulse Top 10% Powered by BIP!
visibility 27visibility views 27 download downloads 15 Powered bymore_vert Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 2009 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAAlcoholism Clinical and Experimental ResearchArticle . 2009 . 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.1530-0277.2009.00940.x&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 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 146 citations 146 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
visibility 25visibility views 25 download downloads 36 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 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.
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For further information contact us at helpdesk@openaire.euAccess RoutesGreen 331 citations 331 popularity Top 1% influence Top 1% impulse Top 1% Powered by BIP!
visibility 25visibility views 25 download downloads 46 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 1998 SpainPublisher:Georg Thieme Verlag KG Authors: Fernández-Checa, José C.; Kaplowitz, Neil; García-Ruiz, Carmen; Colell Riera, Anna;Accumulating evidence pointing to mitochondria as critical participants in the control of apoptotic and necrotic cell death and in the development of specific disease states has led to a renaissance on the study of these organelles. Because mitochondria are the major consumers of molecular oxygen within cells, they stand as one of the most important generators of reactive oxygen species and therefore constitute potential targets of therapeutic intervention in pathologic states in which oxidative stress originates from these organelles. In this regard, mitochondria are specific targets of ethanol intoxication, thereby leading to reported morphologic and functional alterations of mitochondria. Because mitochondria are also indispensable for the maintenance of cell functions, their dysfunction induced by ethanol may be a key event in the development of alcoholic liver disease. Indeed, chronic ethanol feeding in experimental animals has been reported to cause a selective deficiency in the availability of reduced glutathione (GSH) in mitochondria due to the impaired functioning of the specific mitochondrial carrier that translocates GSH from cytosol into the mitochondrial matrix. Such a selective depletion sensitizes hepatocytes from chronic ethanol-fed animals to the oxidative effects of cytokines, e.g., tumor necrosis factor (TNF). Restoration of mitochondrial GSH by the in vivo administration of S-adenosyl-L-methionine or the in vitro use of GSH ethyl ester prevents the susceptibility of hepatocytes to TNF. Although the nature of this specific carrier has not yet been uncovered, the elucidation of the mechanisms whereby ethanol leads to its impaired activity may provide important clues as to its function and mechanism of action, which in turn may be useful toward the definitive characterization and identification of this important carrier.
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=10.1055/s-2007-1007172&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen 204 citations 204 popularity Top 10% influence Top 1% impulse Top 10% Powered by BIP!
visibility 31visibility views 31 download downloads 35 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=10.1055/s-2007-1007172&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 1998 SpainPublisher:Elsevier BV Authors: Bosch Morell, Francisco; Martínez-Soriano, Francisco; Colell Riera, Anna; Fernández-Checa, José C.; +1 AuthorsBosch Morell, Francisco; Martínez-Soriano, Francisco; Colell Riera, Anna; Fernández-Checa, José C.; Romero, Francisco. J.;Chronic ethanol feeding promotes oxidative stress in rat peripheral nerve. Malondialdehyde, a lipid peroxidation product, content increases in sciatic nerves of rats fed an ethanol-containing diet, when compared with pair-fed animals. Moreover, glutathione content and glutathione peroxidase activity in this same tissue decrease in ethanol-fed vs. pair-fed rats. S-Adenosyl-L-methionine and N-acetyl-L-cysteine, both with possible therapeutic action on alcoholism, were tested in this animal model. Only N-acetyl-L-cysteine was able to normalize malondialdehyde content and to restore glutathione content and glutathione peroxidase activity, to values not significantly different from those of sciatic nerves from pair-fed animals. The reasons for the different effect of both substances tested is also discussed.
Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 1998 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAFree Radical Biology and MedicineArticle . 1998 . Peer-reviewedLicense: Elsevier 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=10.1016/s0891-5849(98)00036-7&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen 44 citations 44 popularity Average influence Top 10% impulse Top 10% Powered by BIP!
visibility 28visibility views 28 download downloads 31 Powered bymore_vert Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 1998 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAFree Radical Biology and MedicineArticle . 1998 . Peer-reviewedLicense: Elsevier 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.
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For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 1997Publisher:American Physiological Society Albert Morales; Neil Kaplowitz; Montserrat Marí; Esther Ardite; Carmen García-Ruiz; Merce Miranda; José C. Fernández-Checa; Anna Colell;pmid: 9252504
Mitochondria generate reactive oxygen species (ROS) as byproducts of molecular oxygen consumption in the electron transport chain. Most cellular oxygen is consumed in the cytochrome-c oxidase complex of the respiratory chain, which does not generate reactive species. The ubiquinone pool of complex III of respiration is the major site within the respiratory chain that generates superoxide anion as a result of a single electron transfer to molecular oxygen. Superoxide anion and hydrogen peroxide, derived from the former by superoxide dismutase, are precursor of hydroxyl radical through the participation of transition metals. Glutathione (GSH) in mitochondria is the only defense available to metabolize hydrogen peroxide. A small fraction of the total cellular GSH pool is sequestered in mitochondria by the action of a carrier that transports GSH from the cytosol to the mitochondrial matrix. Mitochondria are not only one of the main cellular sources of ROS, they also are a key target of ROS. Mitochondria are subcellular targets of cytokines, especially tumor necrosis factor (TNF); depletion of GSH in this organelle renders the cell more susceptible to oxidative stress originating in mitochondria. Ceramide generated during TNF signaling leads to increased production of ROS in mitochondria. Chronic ethanol-fed hepatocytes are selectively depleted of GSH in mitochondria due to a defective operation of the carrier responsible for transport of GSH from the cytosol into the mitochondrial matrix. Under these conditions, limitation of the mitochondrial GSH pool represents a critical contributory factor that sensitizes alcoholic hepatocytes to the prooxidant effects of cytokines and prooxidants generated by oxidative metabolism of ethanol. S-adenosyl-L-methionine prevents development of the ethanol-induced defect. The mitochondrial GSH carrier has been functionally expressed in Xenopus laevis oocytes microinjected with mRNA from rat liver. This critical carrier displays functional characteristics distinct from other plasma membrane GSH carriers, such as its ATP dependency, inhibitor specificity, and the size class of mRNA that encode the corresponding carrier, suggesting that the mitochondrial carrier of GSH is a gene product distinct from the plasma membrane transporters.
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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=10.1152/ajpgi.1997.273.1.g7&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eu333 citations 333 popularity Top 1% influence Top 1% impulse Top 1% 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.
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description 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 88 citations 88 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
visibility 42visibility views 42 download downloads 36 Powered bymore_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 1995Publisher:Ovid Technologies (Wolters Kluwer Health) Anna Colell; Joan Rodés; Neil Kaplowitz; Albert Morales; Carmen García-Ruiz; José C. Fernández-Checa; Antonio M. Ballesta;pmid: 7806156
Mitochondrial glutathione plays an important role in maintaining a functionally competent organelle. Previous studies have shown that ethanol feeding selectively depletes the mitochondrial glutathione pool, more predominantly in mitochondria from perivenous hepatocytes. Because S-adenosyl-L-methionine (SAM) is a glutathione precursor and maintains the structure and function of biological membranes, the purpose of the present study was to determine the effects of SAM on glutathione and function of perivenous (PV) and periportal (PP) mitochondria from chronic ethanol-fed rats. SAM administration resulted in a significant increase in the basal cytosol and mitochondrial glutathione in both PP and PV cells from both pair-fed or ethanol-fed groups. When hepatocytes from ethanol-fed rats supplemented with SAM were incubated with methionine plus serine or N-acetylcysteine, mitochondrial glutathione increased in parallel with cytosol, an effect not observed in cells from ethanol-fed rats without SAM. Feeding equimolar N-acetylcysteine raised cytosol glutathione but did not prevent the mitochondrial glutathione defect. In addition, SAM feeding resulted in significant preservation of cellular adenosine triphosphate (ATP) levels (23% to 43%), mitochondrial membrane potential (17% to 25%), and the uncoupler control ratio (UCR) of respiration (from 5.1 ± 0.7 to 7.3 ± 0.6 and 2.1 ± 0.3 to 6.1 ± 0.7) for PP and PV mitochondria, respectively. Thus, these effects of SAM suggest that it may be a useful agent to preserve the disturbed mitochondrial integrity in liver disease caused by alcoholism through maintenance of mitochondrial glutathione transport. (Hepatology 1995;21:207-214).
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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.1840210133&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eu192 citations 192 popularity Top 10% influence Top 1% impulse Top 1% 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=10.1002/hep.1840210133&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 2005Publisher:Wiley Authors: Montserrat Marí; Carmen García-Ruiz; José C. Fernández-Checa; Anna Colell;pmid: 16344602
Abstract: Background: The pathogenesis of alcohol‐induced liver disease (ALD) is incompletely known. One of the key processes mediating the progression of ALD involved the overproduction of tumor necrosis factor (TNF) and the susceptibility of hepatocytes to TNF‐induced apoptosis by alcohol intake.Methods: Analyze the apoptotic signaling of TNF resulting in the targeting and subsequent recruitment of mitochondria to death pathways.Results: Studies in experimental animal models of the disease have provided evidence for the role of ceramide generated from acidic sphingomyelinase in the apoptotic signaling of TNF through recruitment of mitochondria. The mitochondrial pool of glutathione (mGSH) is a vital line of defense against oxidative stress by precluding the accumulation peroxides generated endogenously within mitochondria and as a cofactor of mitochondrial antioxidant enzymes. The depletion of mGSH by alcohol has been described to determine the susceptibility of hepatocytes to TNF‐mediated cell death.Conclusions: The level of mGSH determines the fate of hepatocytes to acidic sphingomyelinase activation by TNF and hence strategies aimed to replenish mGSH or to antagonize the generation of ceramide from acidic sphingomyelinase may be of therapeutic value for ALD.
Alcoholism Clinical ... arrow_drop_down Alcoholism Clinical and Experimental ResearchArticle . 2005 . 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.
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For further information contact us at helpdesk@openaire.eu22 citations 22 popularity Average influence Average impulse Average Powered by BIP!
more_vert Alcoholism Clinical ... arrow_drop_down Alcoholism Clinical and Experimental ResearchArticle . 2005 . 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=10.1097/01.alc.0000189285.04059.b3&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 2009 SpainPublisher:Wiley Francisco Caballero; Carmen García-Ruiz; Nuria Matías; Anna Colell; Anna Fernández; José C. Fernández-Checa;Background: Alcohol‐induced liver injury is associated with decreasedS‐adenosyl‐l‐methionine (SAM)/S‐adenosyl‐l‐homocysteine (SAH) ratio and mitochondrial glutathione (mGSH) depletion, which has been shown to sensitize hepatocytes to tumor necrosis factor (TNF).Aims: As the effect of alcohol on mitochondrial SAM (mSAM) has been poorly characterized, our aim was to examine the status and transport of mSAM in relation to that of mGSH during alcohol intake.Methods: Sprague–Dawley rats were pair fed Lieber–DeCarli diets containing alcohol for 1 to 4 weeks and liver fractionated into cytosol and mitochondria to examine the mSAM transport and its sensitivity to membrane dynamics.Results: We found that cytosol SAM was depleted from the first week of alcohol feeding, with mSAM levels paralleling these changes. Cytosol SAH, however, increased during the first 3 weeks of alcohol intake, whereas its mitochondrial levels remained unchanged. mGSH depletion occurred by 3 to 4 weeks of alcohol intake due to cholesterol‐mediated impaired transport from the cytosol. In contrast to this outcome, the transport of SAM into hepatic mitochondria was unaffected by alcohol intake and resistant to cholesterol‐mediated perturbations in membrane dynamics; furthermore cytosolic SAH accumulation in primary hepatocytes by SAH hydrolase inhibition reproduced the mSAM depletion by alcohol due to the competition of SAH with SAM for mitochondrial transport. However, alcohol feeding did not potentiate the sensitivity to inhibition by SAH accumulation.Conclusions: Alcohol‐induced mSAM depletion precedes that of mGSH and occurs independently of alcohol‐mediated perturbations in membrane dynamics, disproving an inherent defect in the mSAM transport by alcohol. These findings suggest that the early mSAM depletion may contribute to the alterations of mitochondrial membrane dynamics and the subsequent mGSH down‐regulation induced by alcohol feeding.
Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 2009 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAAlcoholism Clinical and Experimental ResearchArticle . 2009 . 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.
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For further information contact us at helpdesk@openaire.euAccess RoutesGreen 27 citations 27 popularity Top 10% influence Average impulse Top 10% Powered by BIP!
visibility 27visibility views 27 download downloads 15 Powered bymore_vert Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 2009 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAAlcoholism Clinical and Experimental ResearchArticle . 2009 . 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.1530-0277.2009.00940.x&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.
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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 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 146 citations 146 popularity Top 10% influence Top 10% impulse Top 10% Powered by BIP!
visibility 25visibility views 25 download downloads 36 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.
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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.
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For further information contact us at helpdesk@openaire.euAccess RoutesGreen 331 citations 331 popularity Top 1% influence Top 1% impulse Top 1% Powered by BIP!
visibility 25visibility views 25 download downloads 46 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 1998 SpainPublisher:Georg Thieme Verlag KG Authors: Fernández-Checa, José C.; Kaplowitz, Neil; García-Ruiz, Carmen; Colell Riera, Anna;Accumulating evidence pointing to mitochondria as critical participants in the control of apoptotic and necrotic cell death and in the development of specific disease states has led to a renaissance on the study of these organelles. Because mitochondria are the major consumers of molecular oxygen within cells, they stand as one of the most important generators of reactive oxygen species and therefore constitute potential targets of therapeutic intervention in pathologic states in which oxidative stress originates from these organelles. In this regard, mitochondria are specific targets of ethanol intoxication, thereby leading to reported morphologic and functional alterations of mitochondria. Because mitochondria are also indispensable for the maintenance of cell functions, their dysfunction induced by ethanol may be a key event in the development of alcoholic liver disease. Indeed, chronic ethanol feeding in experimental animals has been reported to cause a selective deficiency in the availability of reduced glutathione (GSH) in mitochondria due to the impaired functioning of the specific mitochondrial carrier that translocates GSH from cytosol into the mitochondrial matrix. Such a selective depletion sensitizes hepatocytes from chronic ethanol-fed animals to the oxidative effects of cytokines, e.g., tumor necrosis factor (TNF). Restoration of mitochondrial GSH by the in vivo administration of S-adenosyl-L-methionine or the in vitro use of GSH ethyl ester prevents the susceptibility of hepatocytes to TNF. Although the nature of this specific carrier has not yet been uncovered, the elucidation of the mechanisms whereby ethanol leads to its impaired activity may provide important clues as to its function and mechanism of action, which in turn may be useful toward the definitive characterization and identification of this important carrier.
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=10.1055/s-2007-1007172&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen 204 citations 204 popularity Top 10% influence Top 1% impulse Top 10% Powered by BIP!
visibility 31visibility views 31 download downloads 35 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=10.1055/s-2007-1007172&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 1998 SpainPublisher:Elsevier BV Authors: Bosch Morell, Francisco; Martínez-Soriano, Francisco; Colell Riera, Anna; Fernández-Checa, José C.; +1 AuthorsBosch Morell, Francisco; Martínez-Soriano, Francisco; Colell Riera, Anna; Fernández-Checa, José C.; Romero, Francisco. J.;Chronic ethanol feeding promotes oxidative stress in rat peripheral nerve. Malondialdehyde, a lipid peroxidation product, content increases in sciatic nerves of rats fed an ethanol-containing diet, when compared with pair-fed animals. Moreover, glutathione content and glutathione peroxidase activity in this same tissue decrease in ethanol-fed vs. pair-fed rats. S-Adenosyl-L-methionine and N-acetyl-L-cysteine, both with possible therapeutic action on alcoholism, were tested in this animal model. Only N-acetyl-L-cysteine was able to normalize malondialdehyde content and to restore glutathione content and glutathione peroxidase activity, to values not significantly different from those of sciatic nerves from pair-fed animals. The reasons for the different effect of both substances tested is also discussed.
Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 1998 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAFree Radical Biology and MedicineArticle . 1998 . Peer-reviewedLicense: Elsevier 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=10.1016/s0891-5849(98)00036-7&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen 44 citations 44 popularity Average influence Top 10% impulse Top 10% Powered by BIP!
visibility 28visibility views 28 download downloads 31 Powered bymore_vert Recolector de Cienci... arrow_drop_down Recolector de Ciencia Abierta, RECOLECTAArticle . 1998 . Peer-reviewedData sources: Recolector de Ciencia Abierta, RECOLECTAFree Radical Biology and MedicineArticle . 1998 . Peer-reviewedLicense: Elsevier 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=10.1016/s0891-5849(98)00036-7&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eudescription Publicationkeyboard_double_arrow_right Article , Journal 1997Publisher:American Physiological Society Albert Morales; Neil Kaplowitz; Montserrat Marí; Esther Ardite; Carmen García-Ruiz; Merce Miranda; José C. Fernández-Checa; Anna Colell;pmid: 9252504
Mitochondria generate reactive oxygen species (ROS) as byproducts of molecular oxygen consumption in the electron transport chain. Most cellular oxygen is consumed in the cytochrome-c oxidase complex of the respiratory chain, which does not generate reactive species. The ubiquinone pool of complex III of respiration is the major site within the respiratory chain that generates superoxide anion as a result of a single electron transfer to molecular oxygen. Superoxide anion and hydrogen peroxide, derived from the former by superoxide dismutase, are precursor of hydroxyl radical through the participation of transition metals. Glutathione (GSH) in mitochondria is the only defense available to metabolize hydrogen peroxide. A small fraction of the total cellular GSH pool is sequestered in mitochondria by the action of a carrier that transports GSH from the cytosol to the mitochondrial matrix. Mitochondria are not only one of the main cellular sources of ROS, they also are a key target of ROS. Mitochondria are subcellular targets of cytokines, especially tumor necrosis factor (TNF); depletion of GSH in this organelle renders the cell more susceptible to oxidative stress originating in mitochondria. Ceramide generated during TNF signaling leads to increased production of ROS in mitochondria. Chronic ethanol-fed hepatocytes are selectively depleted of GSH in mitochondria due to a defective operation of the carrier responsible for transport of GSH from the cytosol into the mitochondrial matrix. Under these conditions, limitation of the mitochondrial GSH pool represents a critical contributory factor that sensitizes alcoholic hepatocytes to the prooxidant effects of cytokines and prooxidants generated by oxidative metabolism of ethanol. S-adenosyl-L-methionine prevents development of the ethanol-induced defect. The mitochondrial GSH carrier has been functionally expressed in Xenopus laevis oocytes microinjected with mRNA from rat liver. This critical carrier displays functional characteristics distinct from other plasma membrane GSH carriers, such as its ATP dependency, inhibitor specificity, and the size class of mRNA that encode the corresponding carrier, suggesting that the mitochondrial carrier of GSH is a gene product distinct from the plasma membrane transporters.
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=10.1152/ajpgi.1997.273.1.g7&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eu333 citations 333 popularity Top 1% influence Top 1% impulse Top 1% 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=10.1152/ajpgi.1997.273.1.g7&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.eu