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Jun Ren - One of the best experts on this subject based on the ideXlab platform.

  • amp dependent kinase and autophagic flux are involved in aldehyde dehydrogenase 2 induced protection against cardiac Toxicity of Ethanol
    Free Radical Biology and Medicine, 2011
    Co-Authors: Rui Guo, Jun Ren
    Abstract:

    Mitochondrial aldehyde dehydrogenase-2 (ALDH2) alleviates Ethanol Toxicity although the precise mechanism is unclear. This study was designed to evaluate the effect of ALDH2 on Ethanol-induced myocardial damage with a focus on autophagy. Wild-type FVB and transgenic mice overexpressing ALDH2 were challenged with Ethanol (3g/kg/day, ip) for 3days and cardiac mechanical function was assessed using the echocardiographic and IonOptix systems. Western blot analysis was used to evaluate essential autophagy markers, Akt and AMPK, and the downstream signal mTOR. Ethanol challenge altered cardiac geometry and function as evidenced by enlarged ventricular end systolic and diastolic diameters, decreased cell shortening and intracellular Ca(2+) rise, prolonged relengthening and intracellular Ca(2+) decay, as well as reduced SERCA Ca(2+) uptake, which effects were mitigated by ALDH2. Ethanol challenge facilitated myocardial autophagy as evidenced by enhanced expression of Beclin, ATG7, and LC3B II, as well as mTOR dephosphorylation, which was alleviated by ALDH2. Ethanol challenge-induced cardiac defect and apoptosis were reversed by the ALDH2 agonist Alda-1, the autophagy inhibitor 3-MA, and the AMPK inhibitor compound C, whereas the autophagy inducer rapamycin and the AMPK activator AICAR mimicked or exacerbated Ethanol-induced cell injury. Ethanol promoted or suppressed phosphorylation of AMPK and Akt, respectively, in FVB but not ALDH2 murine hearts. Moreover, AICAR nullified Alda-1-induced protection against Ethanol-triggered autophagic and functional changes. Ethanol increased GFP-LC3 puncta in H9c2 cells, the effect of which was ablated by Alda-1 and 3-MA. Lysosomal inhibition using bafilomycin A1, E64D, and pepstatin A obliterated Alda-1- but not Ethanol-induced responses in GFP-LC3 puncta. Our results suggest that ALDH2 protects against Ethanol Toxicity through altered Akt and AMPK signaling and regulation of autophagic flux.

  • aldehyde dehydrogenase 2 ameliorates acute cardiac Toxicity of Ethanol role of protein phosphatase and forkhead transcription factor
    Journal of the American College of Cardiology, 2009
    Co-Authors: F Gao, Jun Ren
    Abstract:

    Objectives This study was designed to evaluate the role of facilitated detoxification of acetaldehyde, the main metabolic product of Ethanol, through systemic overexpression of mitochondrial aldehyde dehydrogenase-2 (ALDH2) on acute Ethanol exposure-induced myocardial damage. Background Binge drinking may exert cardiac Toxicity and interfere with heart function, manifested as impaired ventricular contractility, although the underlying mechanism remains poorly defined. Methods ALDH2 transgenic mice were produced using the chicken beta-actin promoter. Wild-type FVB (friend virus B) and ALDH2 mice were challenged with Ethanol (3 g/kg, intraperitoneally), and cardiac function was assessed 24 h later using the Langendroff and cardiomyocyte edge-detection systems. Western blot analysis was used to evaluate protein phosphatase 2A and 2C (PP2A and PP2C), phosphorylation of Akt, AMP-activated protein kinase (AMPK), and the transcription factors Foxo3 (Thr32 and Ser413). Results ALDH2 reduced Ethanol-induced elevation in cardiac acetaldehyde levels. Acute Ethanol challenge deteriorated myocardial and cardiomyocyte contractile function evidenced by reduction in maximal velocity of pressure development and decline (±dP/dt), left ventricular developed pressure, cell shortening, and prolonged relengthening duration, the effects of which were alleviated by ALDH2. Ethanol treatment dampened phosphorylation of Akt and AMPK associated with up-regulated PP2A and PP2C, which was abrogated by ALDH2. ALDH2 significantly attenuated Ethanol-induced decrease in Akt- and AMPK-stimulated phosphorylation of Foxo3 at Thr32 and Ser413, respectively. Consistently, ALDH2 rescued Ethanol-induced myocardial apoptosis, protein damage, and mitochondrial membrane potential depolarization. Conclusions Our results suggest that ALDH2 is cardioprotective against acute Ethanol Toxicity, possibly through inhibition of protein phosphatases, leading to enhanced Akt and AMPK activation, and subsequently, inhibition of Foxo3, apoptosis, and mitochondrial dysfunction.

Frederic Lallemand - One of the best experts on this subject based on the ideXlab platform.

  • binge drinking chronic nicotine administration alters extracellular glutamate and arginine levels in the nucleus accumbens of adult male and female wistar rats
    Alcohol and Alcoholism, 2011
    Co-Authors: Frederic Lallemand, Roberta J Ward, Philippe De Witte, Paul Verbanck
    Abstract:

    The effect of ‘binge drinking’ coupled or not with chronic nicotine administration on nucleus accumbens (NAc) glutamate, arginine, taurine and hydroxyl radical levels has been investigated in these present studies. Methods and Results: Ethanol, 2 or 3 g/kg, has been administered to male or female adult rats in a ‘binge-type’ regime for 3 weeks, +/– nicotine, and changes in glutamate, arginine and taurine content in the NAc, assayed by microdialysis after a further dose of Ethanol. The basal concentration of NAc glutamate increased 8-fold in the female adult rats but did not change significantly after further doses of Ethanol. In contrast, the male adult rats showed no changes in basal glutamate content but exhibited a dose-dependent increase in NAc glutamate after further doses of Ethanol. NAc arginine basal levels decreased significantly in both male and female adult rats after further doses of Ethanol. Co-administration of nicotine modified the Toxicity of Ethanol as exemplified by diminishment of both the basal NAc glutamate release as well as modifying the release of this excitatory amino acid after further Ethanol doses, particularly in female rats. In addition, the marked changes in arginine release after further Ethanol doses were less evident. There was no evidence for increased hydroxyl radical production in the NAc after ‘binge drinking’ +/– nicotine. Conclusion: There appeared to be a greater vulnerability to Ethanol Toxicity in female adult rats after ‘binge drinking’. It remains unclear whether the increased release of glutamate during the microdialysis evokes activation of inducible nitric oxide synthase (iNOS), which would utilize arginine in the formation of nitric oxide.

  • pharmacology and cell metabolism binge drinking chronic nicotine administration alters extracellular glutamate and arginine levels in the nucleus accumbens of adult male and female wistar rats
    2011
    Co-Authors: Frederic Lallemand, Roberta J Ward, Philippe De Witte, Paul Verbanck
    Abstract:

    Aims: The effect of 'binge drinking' coupled or not with chronic nicotine administration on nucleus accumbens (NAc) glutamate, arginine, taurine and hydroxyl radical levels has been investigated in these present studies. Methods and Results: Ethanol, 2 or 3 g/kg, has been administered to male or female adult rats in a 'binge-type' regime for 3 weeks, +/- nicotine, and changes in glutamate, arginine and taurine content in the NAc, assayed by microdialysis after a further dose of Ethanol. The basal concentration of NAc glutamate increased 8-fold in the female adult rats but did not change significantly after further doses of Ethanol. In contrast, the male adult rats showed no changes in basal glutamate content but exhibited a dose-dependent increase in NAc glutamate after further doses of Ethanol. NAc arginine basal levels decreased significantly in both male and female adult rats after further doses of Ethanol. Co-administration of nicotine modified the Toxicity of Ethanol as exemplified by diminishment of both the basal NAc glutamate release as well as modifying the release of this excitatory amino acid after further Ethanol doses, particularly in female rats. In addition, the marked changes in arginine release after further Ethanol doses were less evident. There was no evi- dence for increased hydroxyl radical production in the NAc after 'binge drinking' +/- nicotine. Conclusion: There appeared to be a greater vulnerability to Ethanol Toxicity in female adult rats after 'binge drinking'. It remains unclear whether the increased release of glutamate during the microdialysis evokes activation of inducible nitric oxide synthase (iNOS), which would utilize arginine in the formation of nitric oxide.

Paul Verbanck - One of the best experts on this subject based on the ideXlab platform.

  • binge drinking chronic nicotine administration alters extracellular glutamate and arginine levels in the nucleus accumbens of adult male and female wistar rats
    Alcohol and Alcoholism, 2011
    Co-Authors: Frederic Lallemand, Roberta J Ward, Philippe De Witte, Paul Verbanck
    Abstract:

    The effect of ‘binge drinking’ coupled or not with chronic nicotine administration on nucleus accumbens (NAc) glutamate, arginine, taurine and hydroxyl radical levels has been investigated in these present studies. Methods and Results: Ethanol, 2 or 3 g/kg, has been administered to male or female adult rats in a ‘binge-type’ regime for 3 weeks, +/– nicotine, and changes in glutamate, arginine and taurine content in the NAc, assayed by microdialysis after a further dose of Ethanol. The basal concentration of NAc glutamate increased 8-fold in the female adult rats but did not change significantly after further doses of Ethanol. In contrast, the male adult rats showed no changes in basal glutamate content but exhibited a dose-dependent increase in NAc glutamate after further doses of Ethanol. NAc arginine basal levels decreased significantly in both male and female adult rats after further doses of Ethanol. Co-administration of nicotine modified the Toxicity of Ethanol as exemplified by diminishment of both the basal NAc glutamate release as well as modifying the release of this excitatory amino acid after further Ethanol doses, particularly in female rats. In addition, the marked changes in arginine release after further Ethanol doses were less evident. There was no evidence for increased hydroxyl radical production in the NAc after ‘binge drinking’ +/– nicotine. Conclusion: There appeared to be a greater vulnerability to Ethanol Toxicity in female adult rats after ‘binge drinking’. It remains unclear whether the increased release of glutamate during the microdialysis evokes activation of inducible nitric oxide synthase (iNOS), which would utilize arginine in the formation of nitric oxide.

  • pharmacology and cell metabolism binge drinking chronic nicotine administration alters extracellular glutamate and arginine levels in the nucleus accumbens of adult male and female wistar rats
    2011
    Co-Authors: Frederic Lallemand, Roberta J Ward, Philippe De Witte, Paul Verbanck
    Abstract:

    Aims: The effect of 'binge drinking' coupled or not with chronic nicotine administration on nucleus accumbens (NAc) glutamate, arginine, taurine and hydroxyl radical levels has been investigated in these present studies. Methods and Results: Ethanol, 2 or 3 g/kg, has been administered to male or female adult rats in a 'binge-type' regime for 3 weeks, +/- nicotine, and changes in glutamate, arginine and taurine content in the NAc, assayed by microdialysis after a further dose of Ethanol. The basal concentration of NAc glutamate increased 8-fold in the female adult rats but did not change significantly after further doses of Ethanol. In contrast, the male adult rats showed no changes in basal glutamate content but exhibited a dose-dependent increase in NAc glutamate after further doses of Ethanol. NAc arginine basal levels decreased significantly in both male and female adult rats after further doses of Ethanol. Co-administration of nicotine modified the Toxicity of Ethanol as exemplified by diminishment of both the basal NAc glutamate release as well as modifying the release of this excitatory amino acid after further Ethanol doses, particularly in female rats. In addition, the marked changes in arginine release after further Ethanol doses were less evident. There was no evi- dence for increased hydroxyl radical production in the NAc after 'binge drinking' +/- nicotine. Conclusion: There appeared to be a greater vulnerability to Ethanol Toxicity in female adult rats after 'binge drinking'. It remains unclear whether the increased release of glutamate during the microdialysis evokes activation of inducible nitric oxide synthase (iNOS), which would utilize arginine in the formation of nitric oxide.

Arthur I. Cederbaum - One of the best experts on this subject based on the ideXlab platform.

  • inhibition of autophagy promotes cyp2e1 dependent Toxicity in hepg2 cells via elevated oxidative stress mitochondria dysfunction and activation of p38 and jnk mapk
    Redox biology, 2013
    Co-Authors: Arthur I. Cederbaum
    Abstract:

    Autophagy has been shown to be protective against drug and alcohol-induced liver injury. CYP2E1 plays a role in the Toxicity of Ethanol, carcinogens and certain drugs. Inhibition of autophagy increased Ethanol-Toxicity and accumulation of fat in wild type and CYP2E1 knockin mice but not in CYP2E1 knockout mice as well as in HepG2 cells expressing CYP2E1 (E47 cells) but not HepG2 cells lacking CYP2E1 (C34 cells). The goal of the current study was to evaluate whether modulation of autophagy can affect CYP2E1-dependent cytoToxicity in the E47 cells. The agents used to promote CYP2E1 -dependent Toxicity were a polyunsaturated fatty acid, arachidonic acid (AA), buthionine sulfoximine (BSO), which depletes GSH, and CCl4, which is metabolized to the CCl3 radical. These three agents produced a decrease in E47 cell viability which was enhanced upon inhibition of autophagy by 3-methyladenine (3-MA) or Atg 7 siRNA. Toxicity was lowered by rapamycin which increased autophagy and was much lower to the C34 cells which do not express CYP2E1. Toxicity was mainly necrotic and was associated with an increase in reactive oxygen production and oxidative stress; 3-MA increased while rapamycin blunted the oxidative stress. The enhanced Toxicity and ROS formation produced when autophagy was inhibited was prevented by the antioxidant N-Acetyl cysteine. AA, BSO and CCl4 produced mitochondrial dysfunction, lowered cellular ATP levels and elevated mitochondrial production of ROS. This mitochondrial dysfunction was enhanced by inhibition of autophagy with 3-MA but decreased when autophagy was increased by rapamycin. The mitogen activated protein kinases p38 MAPK and JNK were activated by AA especially when autophagy was inhibited and chemical inhibitors of p38 MAPK and JNK lowered the elevated Toxicity of AA produced by 3-MA. These results show that autophagy was protective against the Toxicity produced by several agents known to be activated by CYP2E1. Since CYP2E1 plays an important role in the Toxicity of Ethanol, drugs and carcinogens and is activated under various pathophysiological conditions such as diabetes, NASH and obesity, attempts to stimulate autophagy may be beneficial in preventing/lowering CYP2E1/Ethanol liver injury.

  • oxidative stress and cytoToxicity induced by ferric nitrilotriacetate in hepg2 cells that express cytochrome p450 2e1
    Molecular Pharmacology, 1998
    Co-Authors: Koichi Sakurai, Arthur I. Cederbaum
    Abstract:

    Iron can potentiate the Toxicity of Ethanol. Ethanol increases the content of cytochrome P450 2E1 (CYP2E1), which generates reactive oxygen species, and transition metals such as iron are powerful catalysts of hydroxyl radical formation and lipid peroxidation. Experiments were carried out to attempt to link CYP2E1, iron, and oxidative stress as a potential mechanism by which iron increases Ethanol Toxicity. The addition of ferric-nitrilotriacetate (Fe-NTA) to a HepG2 cell line expressing CYP2E1 decreased cell viability, whereas little effect was observed in control cells not expressing CYP2E1. Toxicity in the CYP2E1-expressing cells was markedly enhanced after the depletion of glutathione. Lipid peroxidation was increased by Fe-NTA, especially in cell extracts and medium from the CYP2E1-expressing cells. Toxicity was completely prevented by vitamin E or by 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, which also decreased the lipid peroxidation. Levels of ATP were lowered by Fe-NTA, and this was associated with a decreased rate of oxygen consumption by permeabilized cells with substrates donating electrons to complexes I, II, and IV of the respiratory chain. This mitochondrial damage was prevented by vitamin E. Toxicity was accompanied by DNA fragmentation, and this fragmentation was prevented by antioxidants. Overexpression of bcl-2 decreased the Toxicity and DNA fragmentation produced by the combination of CYP2E1 plus Fe-NTA, as did a peptide inhibitor of caspase 3. These results suggest that elevated generation of reactive oxygen species in HepG2 cells expressing CYP2E1 leads to lipid peroxidation in the presence of iron, and the ensuing prooxidative state damages mitochondria, releasing factors that activate caspase 3, leading to a loss in cell viability and DNA fragmentation.

  • Oxidative Stress and CytoToxicity Induced by Ferric-Nitrilotriacetate in HepG2 Cells That Express
    1998
    Co-Authors: Cytochrome P E, Koichi Sakurai, Arthur I. Cederbaum
    Abstract:

    Iron can potentiate the Toxicity of Ethanol. Ethanol increases the content of cytochrome P450 2E1 (CYP2E1), which generates reactive oxygen species, and transition metals such as iron are powerful catalysts of hydroxyl radical formation and lipid per-oxidation. Experiments were carried out to attempt to link CYP2E1, iron, and oxidative stress as a potential mechanism by which iron increases Ethanol Toxicity. The addition of ferric-nitrilotriacetate (Fe-NTA) to a HepG2 cell line expressing CYP2E1 decreased cell viability, whereas little effect was ob-served in control cells not expressing CYP2E1. Toxicity in the CYP2E1-expressing cells was markedly enhanced after the depletion of glutathione. Lipid peroxidation was increased by Fe-NTA, especially in cell extracts and medium from the CYP2E1-expressing cells. Toxicity was completely prevente

Roberta J Ward - One of the best experts on this subject based on the ideXlab platform.

  • binge drinking chronic nicotine administration alters extracellular glutamate and arginine levels in the nucleus accumbens of adult male and female wistar rats
    Alcohol and Alcoholism, 2011
    Co-Authors: Frederic Lallemand, Roberta J Ward, Philippe De Witte, Paul Verbanck
    Abstract:

    The effect of ‘binge drinking’ coupled or not with chronic nicotine administration on nucleus accumbens (NAc) glutamate, arginine, taurine and hydroxyl radical levels has been investigated in these present studies. Methods and Results: Ethanol, 2 or 3 g/kg, has been administered to male or female adult rats in a ‘binge-type’ regime for 3 weeks, +/– nicotine, and changes in glutamate, arginine and taurine content in the NAc, assayed by microdialysis after a further dose of Ethanol. The basal concentration of NAc glutamate increased 8-fold in the female adult rats but did not change significantly after further doses of Ethanol. In contrast, the male adult rats showed no changes in basal glutamate content but exhibited a dose-dependent increase in NAc glutamate after further doses of Ethanol. NAc arginine basal levels decreased significantly in both male and female adult rats after further doses of Ethanol. Co-administration of nicotine modified the Toxicity of Ethanol as exemplified by diminishment of both the basal NAc glutamate release as well as modifying the release of this excitatory amino acid after further Ethanol doses, particularly in female rats. In addition, the marked changes in arginine release after further Ethanol doses were less evident. There was no evidence for increased hydroxyl radical production in the NAc after ‘binge drinking’ +/– nicotine. Conclusion: There appeared to be a greater vulnerability to Ethanol Toxicity in female adult rats after ‘binge drinking’. It remains unclear whether the increased release of glutamate during the microdialysis evokes activation of inducible nitric oxide synthase (iNOS), which would utilize arginine in the formation of nitric oxide.

  • pharmacology and cell metabolism binge drinking chronic nicotine administration alters extracellular glutamate and arginine levels in the nucleus accumbens of adult male and female wistar rats
    2011
    Co-Authors: Frederic Lallemand, Roberta J Ward, Philippe De Witte, Paul Verbanck
    Abstract:

    Aims: The effect of 'binge drinking' coupled or not with chronic nicotine administration on nucleus accumbens (NAc) glutamate, arginine, taurine and hydroxyl radical levels has been investigated in these present studies. Methods and Results: Ethanol, 2 or 3 g/kg, has been administered to male or female adult rats in a 'binge-type' regime for 3 weeks, +/- nicotine, and changes in glutamate, arginine and taurine content in the NAc, assayed by microdialysis after a further dose of Ethanol. The basal concentration of NAc glutamate increased 8-fold in the female adult rats but did not change significantly after further doses of Ethanol. In contrast, the male adult rats showed no changes in basal glutamate content but exhibited a dose-dependent increase in NAc glutamate after further doses of Ethanol. NAc arginine basal levels decreased significantly in both male and female adult rats after further doses of Ethanol. Co-administration of nicotine modified the Toxicity of Ethanol as exemplified by diminishment of both the basal NAc glutamate release as well as modifying the release of this excitatory amino acid after further Ethanol doses, particularly in female rats. In addition, the marked changes in arginine release after further Ethanol doses were less evident. There was no evi- dence for increased hydroxyl radical production in the NAc after 'binge drinking' +/- nicotine. Conclusion: There appeared to be a greater vulnerability to Ethanol Toxicity in female adult rats after 'binge drinking'. It remains unclear whether the increased release of glutamate during the microdialysis evokes activation of inducible nitric oxide synthase (iNOS), which would utilize arginine in the formation of nitric oxide.