Heavy alcohol consumption is a known risk factor for various forms of dementia and the developmen... more Heavy alcohol consumption is a known risk factor for various forms of dementia and the development of Alzheimer’s disease (AD). In this work, we investigated how intragastric alcohol feeding may alter the liver-to-brain axis to induce and/or promote AD pathology. Four weeks of intragastric alcohol feeding to mice, which causes significant fatty liver (steatosis) and liver injury, caused no changes in AD pathology markers in the brain [amyloid precursor protein (APP), presenilin], except for a decrease in microglial cell number in the cortex of the brain. Interestingly, the decline in microglial numbers correlated with serum alanine transaminase (ALT) levels, suggesting a potential link between liver injury and microglial loss in the brain. Intragastric alcohol feeding significantly affected two hepatic proteins important in amyloid-beta (Aβ) processing by the liver: 1) alcohol feeding downregulated lipoprotein receptor-related protein 1 (LRP1, ∼46%), the major receptor in the liver ...
Background and PurposeAcetaminophen‐induced acute liver injury (AILI) is the most frequent cause ... more Background and PurposeAcetaminophen‐induced acute liver injury (AILI) is the most frequent cause of acute liver failure in developed countries. Given the significant limitations associated with N‐acetyl cysteine, the only antidote used to treat AILI, the development of novel therapeutic approaches that can offer a wide range of therapeutic time‐windows is clearly needed. Glycycoumarin (GCM), a natural coumarin purified from liquorice, has been previously demonstrated to possess potent hepatoprotective effects. In the present study, we aimed to investigate the therapeutic potential of GCM against AILI.Experimental ApproachAcetaminophen (300 mg·kg−1) was administered to male C57BL/6 mice, with and without GCM. Serum transaminases, haematoxylin and eosin staining and Western blot were used to assess hepatic damage.Key ResultsGCM (50 mg·kg−1) was highly effective against acetaminophen‐induced hepatotoxicity. Moreover, GCM was superior to N‐acetyl cysteine, in terms of the dosage and the...
Acetaminophen (APAP) induced hepatotoxicity is a leading cause of acute liver failure worldwide. ... more Acetaminophen (APAP) induced hepatotoxicity is a leading cause of acute liver failure worldwide. It is well established that the liver damage induced by acetaminophen exhibits diurnal variation. However, the detailed mechanism for the hepatotoxic variation is not clear. Here we aimed to determine the relative contributions of gut microbiota in modulating the diurnal variation of hepatotoxicity induced by APAP. Male Balb/C mice were treated with or without antibiotics and orally administrated a single dose of APAP (300 mg/kg) at ZT0 (when the light is on-start of resting period) and ZT12 (when the light is off-start of active period). In agreement with previous findings, hepatic injury was markedly enhanced at ZT12 compared with ZT0. Interestingly, upon antibiotics treatment, ZT12 displayed protection against APAP hepatotoxicity similar to ZT0. Moreover, mice that received the cecal content from ZT12 showed more severe liver damage than mice that received the cecal content from ZT0. ...
In the past decade our understanding of idiosyncratic drug induced liver injury (IDILI) and the c... more In the past decade our understanding of idiosyncratic drug induced liver injury (IDILI) and the contribution of genetic susceptibility and the adaptive immune system to the pathogenesis of this disease process has grown tremendously. One of the characteristics of IDILI is that it occurs rarely and only in a subset of individuals with a presumed susceptibility to the drug. Despite a clear association between single nucleotide polymorphisms in human leukocyte antigen (HLA) genes and certain drugs that cause IDILI, not all individuals with susceptible HLA genotypes develop clinically significant liver injury when exposed to drugs. The adaptation hypothesis has been put forth as an explanation for why only a small percentage of susceptible individuals develop overt IDILI and severe injury, while the majority with susceptible genotypes develop only mild abnormalities that resolve spontaneously upon continuation of the drug. This spontaneous resolution is referred to as clinical adaptatio...
This report is a summary of a symposium on the role of S-adenosylmethionine (SAM), betaine, and f... more This report is a summary of a symposium on the role of S-adenosylmethionine (SAM), betaine, and folate in the treatment of alcoholic liver disease (ALD), which was organized by the National Institute on Alcohol Abuse and Alcoholism in collaboration with the Office of Dietary Supplements and the National Center for Complementary and Alternative Medicine of the National Institutes of Health (Bethesda, MD) and held on 3 October 2005. SAM supplementation may attenuate ALD by decreasing oxidative stress through the up-regulation of glutathione synthesis, reducing inflammation via the down-regulation of tumor necrosis factor-alpha and the up-regulation of interleukin-10 synthesis, increasing the ratio of SAM to S-adenosylhomocysteine (SAH), and inhibiting the apoptosis of normal hepatocytes and stimulating the apoptosis of liver cancer cells. Folate deficiency may accelerate or promote ALD by increasing hepatic homocysteine and SAH concentrations; decreasing hepatic SAM and glutathione co...
P309 PROGNOSTIC MODEL FOR PREDICTING DRUG-INDUCED ACUTE LIVER FAILURE R.J. Andrade, M. Robles-Dia... more P309 PROGNOSTIC MODEL FOR PREDICTING DRUG-INDUCED ACUTE LIVER FAILURE R.J. Andrade, M. Robles-Diaz, C. Stephens, I. MedinaCaliz, A. Gonzalez-Jimenez, A.F. Gonzalez, N. Kaplowitz, M.C. Fernandez, M. Romero-Gomez, M. Jimenez-Perez, M. Bruguera, M. Prieto, F. Bessone, N. Hernandez, M. Arrese, M.I. Lucena, Spanish-Latin DILI Registry. Unidad de Gestion Cĺinica de Enfermedades Digestivas, Servicio de Farmacoloǵia Cĺinica, Hospital Universitario Virgen de la Victoria, Instituto de Investigacion Biomedica de Malaga-IBIMA, Universidad de Malaga. CIBERehd, Malaga, Spain; USC Research Center for Liver Diseases, Keck School of Medicine, Los Angeles, CA, United States; Servicio de Farmacia, Hospital de Torrecardenas, Almeŕia, Unidad de Gestion Cĺinica de Enfermedades Digestivas, Hospital Universitario de Valme, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Sevilla, Unidad de Gestion Cĺinica de Enfermedades Digestivas, Hospital Regional Universitario Carlos Haya, IBIMA, Malaga, Instituto de Enfermedades Digestivas y Metabolismo, Hospital Clinic, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Barcelona, Unidad de Gestion Cĺinica de Enfermedades Digestivas, Hospital La Fe. Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Valencia, Spain; Facultad de Ciencias Medicas, Servicio de Gastroenteroloǵia y Hepatoloǵia, Hospital Provincial del Centenario. Universidad Nacional de Rosario, Rosario, Argentina; Hospital de Cĺinicas, Cĺinica de Gastroenteroloǵia, Facultad de Medicina, Universidad de la Republica, Montevideo, Uruguay; Departamento de Gastroenteroloǵia, Facultad de Medicina Pontificia. Universidad Catolica de Chile, Santiago, Chile E-mail: mrobles@uma.es
Heavy alcohol consumption is a known risk factor for various forms of dementia and the developmen... more Heavy alcohol consumption is a known risk factor for various forms of dementia and the development of Alzheimer’s disease (AD). In this work, we investigated how intragastric alcohol feeding may alter the liver-to-brain axis to induce and/or promote AD pathology. Four weeks of intragastric alcohol feeding to mice, which causes significant fatty liver (steatosis) and liver injury, caused no changes in AD pathology markers in the brain [amyloid precursor protein (APP), presenilin], except for a decrease in microglial cell number in the cortex of the brain. Interestingly, the decline in microglial numbers correlated with serum alanine transaminase (ALT) levels, suggesting a potential link between liver injury and microglial loss in the brain. Intragastric alcohol feeding significantly affected two hepatic proteins important in amyloid-beta (Aβ) processing by the liver: 1) alcohol feeding downregulated lipoprotein receptor-related protein 1 (LRP1, ∼46%), the major receptor in the liver ...
Background and PurposeAcetaminophen‐induced acute liver injury (AILI) is the most frequent cause ... more Background and PurposeAcetaminophen‐induced acute liver injury (AILI) is the most frequent cause of acute liver failure in developed countries. Given the significant limitations associated with N‐acetyl cysteine, the only antidote used to treat AILI, the development of novel therapeutic approaches that can offer a wide range of therapeutic time‐windows is clearly needed. Glycycoumarin (GCM), a natural coumarin purified from liquorice, has been previously demonstrated to possess potent hepatoprotective effects. In the present study, we aimed to investigate the therapeutic potential of GCM against AILI.Experimental ApproachAcetaminophen (300 mg·kg−1) was administered to male C57BL/6 mice, with and without GCM. Serum transaminases, haematoxylin and eosin staining and Western blot were used to assess hepatic damage.Key ResultsGCM (50 mg·kg−1) was highly effective against acetaminophen‐induced hepatotoxicity. Moreover, GCM was superior to N‐acetyl cysteine, in terms of the dosage and the...
Acetaminophen (APAP) induced hepatotoxicity is a leading cause of acute liver failure worldwide. ... more Acetaminophen (APAP) induced hepatotoxicity is a leading cause of acute liver failure worldwide. It is well established that the liver damage induced by acetaminophen exhibits diurnal variation. However, the detailed mechanism for the hepatotoxic variation is not clear. Here we aimed to determine the relative contributions of gut microbiota in modulating the diurnal variation of hepatotoxicity induced by APAP. Male Balb/C mice were treated with or without antibiotics and orally administrated a single dose of APAP (300 mg/kg) at ZT0 (when the light is on-start of resting period) and ZT12 (when the light is off-start of active period). In agreement with previous findings, hepatic injury was markedly enhanced at ZT12 compared with ZT0. Interestingly, upon antibiotics treatment, ZT12 displayed protection against APAP hepatotoxicity similar to ZT0. Moreover, mice that received the cecal content from ZT12 showed more severe liver damage than mice that received the cecal content from ZT0. ...
In the past decade our understanding of idiosyncratic drug induced liver injury (IDILI) and the c... more In the past decade our understanding of idiosyncratic drug induced liver injury (IDILI) and the contribution of genetic susceptibility and the adaptive immune system to the pathogenesis of this disease process has grown tremendously. One of the characteristics of IDILI is that it occurs rarely and only in a subset of individuals with a presumed susceptibility to the drug. Despite a clear association between single nucleotide polymorphisms in human leukocyte antigen (HLA) genes and certain drugs that cause IDILI, not all individuals with susceptible HLA genotypes develop clinically significant liver injury when exposed to drugs. The adaptation hypothesis has been put forth as an explanation for why only a small percentage of susceptible individuals develop overt IDILI and severe injury, while the majority with susceptible genotypes develop only mild abnormalities that resolve spontaneously upon continuation of the drug. This spontaneous resolution is referred to as clinical adaptatio...
This report is a summary of a symposium on the role of S-adenosylmethionine (SAM), betaine, and f... more This report is a summary of a symposium on the role of S-adenosylmethionine (SAM), betaine, and folate in the treatment of alcoholic liver disease (ALD), which was organized by the National Institute on Alcohol Abuse and Alcoholism in collaboration with the Office of Dietary Supplements and the National Center for Complementary and Alternative Medicine of the National Institutes of Health (Bethesda, MD) and held on 3 October 2005. SAM supplementation may attenuate ALD by decreasing oxidative stress through the up-regulation of glutathione synthesis, reducing inflammation via the down-regulation of tumor necrosis factor-alpha and the up-regulation of interleukin-10 synthesis, increasing the ratio of SAM to S-adenosylhomocysteine (SAH), and inhibiting the apoptosis of normal hepatocytes and stimulating the apoptosis of liver cancer cells. Folate deficiency may accelerate or promote ALD by increasing hepatic homocysteine and SAH concentrations; decreasing hepatic SAM and glutathione co...
P309 PROGNOSTIC MODEL FOR PREDICTING DRUG-INDUCED ACUTE LIVER FAILURE R.J. Andrade, M. Robles-Dia... more P309 PROGNOSTIC MODEL FOR PREDICTING DRUG-INDUCED ACUTE LIVER FAILURE R.J. Andrade, M. Robles-Diaz, C. Stephens, I. MedinaCaliz, A. Gonzalez-Jimenez, A.F. Gonzalez, N. Kaplowitz, M.C. Fernandez, M. Romero-Gomez, M. Jimenez-Perez, M. Bruguera, M. Prieto, F. Bessone, N. Hernandez, M. Arrese, M.I. Lucena, Spanish-Latin DILI Registry. Unidad de Gestion Cĺinica de Enfermedades Digestivas, Servicio de Farmacoloǵia Cĺinica, Hospital Universitario Virgen de la Victoria, Instituto de Investigacion Biomedica de Malaga-IBIMA, Universidad de Malaga. CIBERehd, Malaga, Spain; USC Research Center for Liver Diseases, Keck School of Medicine, Los Angeles, CA, United States; Servicio de Farmacia, Hospital de Torrecardenas, Almeŕia, Unidad de Gestion Cĺinica de Enfermedades Digestivas, Hospital Universitario de Valme, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Sevilla, Unidad de Gestion Cĺinica de Enfermedades Digestivas, Hospital Regional Universitario Carlos Haya, IBIMA, Malaga, Instituto de Enfermedades Digestivas y Metabolismo, Hospital Clinic, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Barcelona, Unidad de Gestion Cĺinica de Enfermedades Digestivas, Hospital La Fe. Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Valencia, Spain; Facultad de Ciencias Medicas, Servicio de Gastroenteroloǵia y Hepatoloǵia, Hospital Provincial del Centenario. Universidad Nacional de Rosario, Rosario, Argentina; Hospital de Cĺinicas, Cĺinica de Gastroenteroloǵia, Facultad de Medicina, Universidad de la Republica, Montevideo, Uruguay; Departamento de Gastroenteroloǵia, Facultad de Medicina Pontificia. Universidad Catolica de Chile, Santiago, Chile E-mail: mrobles@uma.es
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