The Experts below are selected from a list of 48 Experts worldwide ranked by ideXlab platform
Jasmohan S Bajaj - One of the best experts on this subject based on the ideXlab platform.
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Alcohol Liver Disease and the gut microbiota
Nature Reviews Gastroenterology & Hepatology, 2019Co-Authors: Jasmohan S BajajAbstract:Alcoholic Liver Disease, which ranges from mild Disease to Alcoholic hepatitis and cirrhosis, is a leading cause of morbidity and mortality worldwide. Alcohol intake can lead to changes in gut microbiota composition, even before Liver Disease development. These alterations worsen with advancing Disease and could be complicit in Disease progression. Microbial function, especially related to bile acid metabolism, can modulate Alcohol-associated injury even in the presence of cirrhosis and Alcoholic hepatitis. Microbiota changes might also alter brain function, and the gut-brain axis might be a potential target to reduce Alcoholic relapse risk. Gut microbiota manipulation including probiotics, faecal microbial transplant and antibiotics has been studied in Alcoholic Liver Disease with varying success. Further investigation of the modulation of the gut-Liver axis is relevant, as most of these patients are not candidates for Liver transplantation. This Review focuses on clinical studies involving the gut microbiota in patients with Alcoholic Liver Disease across the spectrum from Alcoholic fatty Liver to cirrhosis and Alcoholic hepatitis. Specific alterations in the gut-Liver-brain axis that are complicit in the interactions between the gut microbiota and Alcohol addiction are also reviewed.
Arthur I Cederbaum - One of the best experts on this subject based on the ideXlab platform.
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overexpression of cyp2e1 in mitochondria sensitizes hepg2 cells to the toxicity caused by depletion of glutathione
Journal of Biological Chemistry, 2006Co-Authors: Jingxiang Bai, Arthur I CederbaumAbstract:Induction of CYP2E1 by ethanol is one mechanism by which ethanol causes oxidative stress and Alcohol Liver Disease. Although CYP2E1 is predominantly found in the endoplasmic reticulum, it is also located in rat hepatic mitochondria. In the current study, chronic Alcohol consumption induced rat hepatic mitochondrial CYP2E1. To study the role of mitochondrial targeted CYP2E1 in generating oxidative stress and causing damage to mitochondria, HepG2 lines overexpressing CYP2E1 in mitochondria (mE10 and mE27 cells) were established by transfecting a plasmid containing human CYP2E1 cDNA lacking the hydrophobic endoplasmic reticulum targeting signal sequence into HepG2 cells followed by G418 selection. A 40-kDa catalytically active NH2-terminally truncated form of CYP2E1 (mtCYP2E1) was detected in the mitochondrial compartment in these cells by Western blot analysis. Cell death caused by depletion of GSH by buthionine sulfoximine (BSO) was increased in mE10 and mE27 cells as compared with cells transfected with empty vector (pCI-neo). Antioxidants were able to abolish the loss of cell viability. Increased levels of reactive oxygen species and mitochondrial 3-nitrotyrosine and 4-hydroxynonenal protein adducts and decreased mitochondrial aconitase activity and mitochondrial membrane potential were observed in mE10 and mE27 cells treated with BSO. The mitochondrial membrane stabilizer, cyclosporine A, was also able to protect these cells from BSO toxicity. These results revealed that CYP2E1 in the mitochondrial compartment could induce oxidative stress in the mitochondria, damage mitochondria membrane potential, and cause a loss of cell viability. The accumulation of CYP2E1 in hepatic mitochondria induced by ethanol consumption might play an important role in Alcohol Liver Disease.
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adenovirus mediated overexpression of catalase in the cytosolic or mitochondrial compartment protects against cytochrome p450 2e1 dependent toxicity in hepg2 cells
Journal of Biological Chemistry, 2001Co-Authors: Jingxiang Bai, Arthur I CederbaumAbstract:Cytochrome P450 2E1 (CYP2E1) is an effective producer of reactive oxygen species such as superoxide radical and hydrogen peroxide, which may contribute to the development of Alcohol Liver Disease or cytotoxicity. To investigate the protective role of catalase against CYP2E1-dependent cytotoxicity, E47 cells, a transfected HepG2 cell line overexpressing CYP2E1, were infected with adenoviral vectors containing human catalase cDNA (AdCat) and catalase cDNA with a mitochondrial leader sequence (AdmCat). Forty-eight hours after infection with AdCat or AdmCat at a multiplicity of infection of 100, intracellular catalase protein was increased >2-fold compared with uninfected E47 cells and E47 cells infected with empty adenoviral vector (AdNull) as determined by Western blotting and catalase activity measurements. Overexpression of catalase in the cytosol (AdCat) and in mitochondria (AdmCat) was confirmed by confocal microscopy. Cell death caused by arachidonic acid plus iron was considerably suppressed in both AdCat- and AdmCat-infected E47 cells as determined by assays of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide absorbance, lactate dehydrogenase release, and morphology changes. AdCat- and AdmCat-infected cells were also more resistant to the loss of mitochondrial membrane potential and to the increase in lipid peroxidation induced by arachidonic acid and iron. This study indicates that catalase in the cytosol and catalase in mitochondria are capable of protecting HepG2 cells expressing CYP2E1 against cytotoxicity induced by oxidants that promote lipid peroxidation and suggests the possibility that such agents may be useful in protecting against the development of Alcohol Liver injury.
Jingxiang Bai - One of the best experts on this subject based on the ideXlab platform.
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overexpression of cyp2e1 in mitochondria sensitizes hepg2 cells to the toxicity caused by depletion of glutathione
Journal of Biological Chemistry, 2006Co-Authors: Jingxiang Bai, Arthur I CederbaumAbstract:Induction of CYP2E1 by ethanol is one mechanism by which ethanol causes oxidative stress and Alcohol Liver Disease. Although CYP2E1 is predominantly found in the endoplasmic reticulum, it is also located in rat hepatic mitochondria. In the current study, chronic Alcohol consumption induced rat hepatic mitochondrial CYP2E1. To study the role of mitochondrial targeted CYP2E1 in generating oxidative stress and causing damage to mitochondria, HepG2 lines overexpressing CYP2E1 in mitochondria (mE10 and mE27 cells) were established by transfecting a plasmid containing human CYP2E1 cDNA lacking the hydrophobic endoplasmic reticulum targeting signal sequence into HepG2 cells followed by G418 selection. A 40-kDa catalytically active NH2-terminally truncated form of CYP2E1 (mtCYP2E1) was detected in the mitochondrial compartment in these cells by Western blot analysis. Cell death caused by depletion of GSH by buthionine sulfoximine (BSO) was increased in mE10 and mE27 cells as compared with cells transfected with empty vector (pCI-neo). Antioxidants were able to abolish the loss of cell viability. Increased levels of reactive oxygen species and mitochondrial 3-nitrotyrosine and 4-hydroxynonenal protein adducts and decreased mitochondrial aconitase activity and mitochondrial membrane potential were observed in mE10 and mE27 cells treated with BSO. The mitochondrial membrane stabilizer, cyclosporine A, was also able to protect these cells from BSO toxicity. These results revealed that CYP2E1 in the mitochondrial compartment could induce oxidative stress in the mitochondria, damage mitochondria membrane potential, and cause a loss of cell viability. The accumulation of CYP2E1 in hepatic mitochondria induced by ethanol consumption might play an important role in Alcohol Liver Disease.
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adenovirus mediated overexpression of catalase in the cytosolic or mitochondrial compartment protects against cytochrome p450 2e1 dependent toxicity in hepg2 cells
Journal of Biological Chemistry, 2001Co-Authors: Jingxiang Bai, Arthur I CederbaumAbstract:Cytochrome P450 2E1 (CYP2E1) is an effective producer of reactive oxygen species such as superoxide radical and hydrogen peroxide, which may contribute to the development of Alcohol Liver Disease or cytotoxicity. To investigate the protective role of catalase against CYP2E1-dependent cytotoxicity, E47 cells, a transfected HepG2 cell line overexpressing CYP2E1, were infected with adenoviral vectors containing human catalase cDNA (AdCat) and catalase cDNA with a mitochondrial leader sequence (AdmCat). Forty-eight hours after infection with AdCat or AdmCat at a multiplicity of infection of 100, intracellular catalase protein was increased >2-fold compared with uninfected E47 cells and E47 cells infected with empty adenoviral vector (AdNull) as determined by Western blotting and catalase activity measurements. Overexpression of catalase in the cytosol (AdCat) and in mitochondria (AdmCat) was confirmed by confocal microscopy. Cell death caused by arachidonic acid plus iron was considerably suppressed in both AdCat- and AdmCat-infected E47 cells as determined by assays of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide absorbance, lactate dehydrogenase release, and morphology changes. AdCat- and AdmCat-infected cells were also more resistant to the loss of mitochondrial membrane potential and to the increase in lipid peroxidation induced by arachidonic acid and iron. This study indicates that catalase in the cytosol and catalase in mitochondria are capable of protecting HepG2 cells expressing CYP2E1 against cytotoxicity induced by oxidants that promote lipid peroxidation and suggests the possibility that such agents may be useful in protecting against the development of Alcohol Liver injury.
Alba Diaz - One of the best experts on this subject based on the ideXlab platform.
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integrative microrna profiling in Alcoholic hepatitis reveals a role for microrna 182 in Liver injury and inflammation
Gut, 2016Co-Authors: Delia Blaya, Lizbeth Perea, Daniel Rodrigotorres, Maria Vilacasadesus, Isabel Graupera, Beatriz Aguilarbravo, Marta Llopis, Mar Coll, José Altamirano, Alba DiazAbstract:Objective MicroRNAs (miRNAs) are well-known regulators of Disease pathogenesis and have great potential as biomarkers and therapeutic targets. We aimed at profiling miRNAs in Alcoholic hepatitis (AH) and identifying miRNAs potentially involved in Liver injury. Design MiRNA profiling was performed in Liver samples from patients with AH, Alcohol Liver Disease, non-Alcoholic steatohepatitis, HCV Disease and normal Liver tissue. Expression of miRNAs was assessed in Liver and serum from patients with AH and animal models. Mimic and decoy miR-182 were used in vitro and in vivo to evaluate miR-1829s biological functions. Results MiRNA expression profile in Liver was highly altered in AH and distinctive from Alcohol-induced cirrhotic Livers. Moreover, we identified a set of 18 miRNAs predominantly expressed in AH as compared with other chronic Liver conditions. Integrative miRNA-mRNA functional analysis revealed the association of AH-altered miRNAs with nuclear receptors, IGF-1 signalling and cholestasis. Interestingly, miR-182 was the most highly expressed miRNA in AH, which correlated with degree of ductular reaction, Disease severity and short-term mortality. MiR-182 mimic induced an upregulation of inflammatory mediators in biliary cells. At experimental level, miR-182 was increased in biliary cells in mice fed with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet but not upregulated by Alcohol intake or fibrosis. Inhibition of miR-182 in DDC-fed mice reduced Liver damage, bile acid accumulation and inflammatory response. Conclusions AH is characterised by a deregulated miRNA profile, including miR-182, which is associated with Disease severity and Liver injury. These results highlight the potential of miRNAs as therapeutic targets and biomarkers in AH.
Delia Blaya - One of the best experts on this subject based on the ideXlab platform.
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integrative microrna profiling in Alcoholic hepatitis reveals a role for microrna 182 in Liver injury and inflammation
Gut, 2016Co-Authors: Delia Blaya, Lizbeth Perea, Daniel Rodrigotorres, Maria Vilacasadesus, Isabel Graupera, Beatriz Aguilarbravo, Marta Llopis, Mar Coll, José Altamirano, Alba DiazAbstract:Objective MicroRNAs (miRNAs) are well-known regulators of Disease pathogenesis and have great potential as biomarkers and therapeutic targets. We aimed at profiling miRNAs in Alcoholic hepatitis (AH) and identifying miRNAs potentially involved in Liver injury. Design MiRNA profiling was performed in Liver samples from patients with AH, Alcohol Liver Disease, non-Alcoholic steatohepatitis, HCV Disease and normal Liver tissue. Expression of miRNAs was assessed in Liver and serum from patients with AH and animal models. Mimic and decoy miR-182 were used in vitro and in vivo to evaluate miR-1829s biological functions. Results MiRNA expression profile in Liver was highly altered in AH and distinctive from Alcohol-induced cirrhotic Livers. Moreover, we identified a set of 18 miRNAs predominantly expressed in AH as compared with other chronic Liver conditions. Integrative miRNA-mRNA functional analysis revealed the association of AH-altered miRNAs with nuclear receptors, IGF-1 signalling and cholestasis. Interestingly, miR-182 was the most highly expressed miRNA in AH, which correlated with degree of ductular reaction, Disease severity and short-term mortality. MiR-182 mimic induced an upregulation of inflammatory mediators in biliary cells. At experimental level, miR-182 was increased in biliary cells in mice fed with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet but not upregulated by Alcohol intake or fibrosis. Inhibition of miR-182 in DDC-fed mice reduced Liver damage, bile acid accumulation and inflammatory response. Conclusions AH is characterised by a deregulated miRNA profile, including miR-182, which is associated with Disease severity and Liver injury. These results highlight the potential of miRNAs as therapeutic targets and biomarkers in AH.