The Experts below are selected from a list of 2418 Experts worldwide ranked by ideXlab platform
Daniel J. Müller - One of the best experts on this subject based on the ideXlab platform.
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Probing the interactions of carboxy-Atractyloside and Atractyloside with the yeast mitochondrial ADP/ATP carrier.
Structure (London England : 1993), 2010Co-Authors: Alexej Kedrov, Alex M. Hellawell, Adam Klosin, R. Bill Broadhurst, Edmund R. S. Kunji, Daniel J. MüllerAbstract:Summary Mitochondrial ADP/ATP carriers are inhibited by two natural compounds, Atractyloside (ATR) or carboxy-Atractyloside (CATR), which differ by one carboxylate group. The interactions of the inhibitors with the carrier were investigated by single-molecule force spectroscopy. Transmembrane α helices of the ATR-inhibited carrier displayed heterogeneous mechanical and kinetic properties. Whereas α helix H2 showed the most brittle mechanical properties and lowest kinetic stability, α helix H5 was mechanically the most flexible and possessed a kinetic stability 9 orders of magnitude greater than that of α helix H2. In contrast, CATR-binding substantially increased the kinetic stability of α helix H2 and tuned the mechanical flexibility of α helices H5 and H6. NMR spectroscopy confirmed that the additional carboxylate group of CATR binds to the sixth α helix, indicating that the enhanced stability of H2 is mediated via interactions between CATR and H6.
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probing the interactions of carboxy Atractyloside and Atractyloside with the yeast mitochondrial adp atp carrier
Structure, 2010Co-Authors: Alexej Kedrov, Alex M. Hellawell, Adam Klosin, Edmund R. S. Kunji, Daniel J. Müller, Bill R BroadhurstAbstract:Summary Mitochondrial ADP/ATP carriers are inhibited by two natural compounds, Atractyloside (ATR) or carboxy-Atractyloside (CATR), which differ by one carboxylate group. The interactions of the inhibitors with the carrier were investigated by single-molecule force spectroscopy. Transmembrane α helices of the ATR-inhibited carrier displayed heterogeneous mechanical and kinetic properties. Whereas α helix H2 showed the most brittle mechanical properties and lowest kinetic stability, α helix H5 was mechanically the most flexible and possessed a kinetic stability 9 orders of magnitude greater than that of α helix H2. In contrast, CATR-binding substantially increased the kinetic stability of α helix H2 and tuned the mechanical flexibility of α helices H5 and H6. NMR spectroscopy confirmed that the additional carboxylate group of CATR binds to the sixth α helix, indicating that the enhanced stability of H2 is mediated via interactions between CATR and H6.
Peter H. Bach - One of the best experts on this subject based on the ideXlab platform.
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Adenine nucleotide and calpain inhibitor I protect against Atractyloside-induced toxicity in rat renal cortical slices in vitro.
Archives of toxicology, 2001Co-Authors: David K. Obatomi, Richard Blackburn, Peter H. BachAbstract:Atractyloside is a compound with a documented nephrotoxicity. It induces renal tubular necrosis at high doses and apoptosis at lower doses. This study investigates the potential protective effect of some chemical agents against Atractyloside-induced nephrotoxicity in vitro using the precision-cut rat renal cortical slices obtained from kidneys of Wistar rats. For co-incubation experiments, slices were incubated for 3 h at 37°C on a rocker platform with various chemical agents: ADP (5 mM), calpain inhibitor I (CPI, 1 mM), stevioside (STV, 2.5 mM) or probenecid (PRB, 2.5 mM) in the presence or absence of Atractyloside (2 mM). For pre-incubation experiments, slices were incubated with the same chemical agents for 1 h before exposure to Atractyloside. The nephrotoxic effects of Atractyloside (2 mM) alone were manifested in several ways: by a marked increase in lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) leakage, significant inhibition of p-aminohippurate (PAH) accumulation, marked depletion of intracellular ATP and reduced glutathione (GSH), and a significant reduction in pyruvate-stimulated gluconeogenesis. Co-incubation of slices with ADP or CPI and Atractyloside completely blocked Atractyloside-induced increase in LDH leakage, but not ALP leakage. Atractyloside-induced depletion of ATP and reduced gluconeogenesis was prevented by co-incubation with ADP or CPI. Furthermore, co-incubation of slices with STV and Atractyloside, but not PRB, completely abolished Atractyloside-induced depletion of ATP and decreased gluconeogenesis in the slices. Pre-incubation of slices with either ADP or CPI protected against Atractyloside-induced increase in LDH leakage, reduced ATP and decreased gluconeogenesis. PAH uptake in the slices was inhibited by Atractyloside and PRB in a time-dependent manner. While ADP and CPI were found to exert complete protection against Atractyloside-induced toxicity irrespective of treatment schedule, STV is effective only under certain conditions, and PRB offer no protection at all. The results of this study demonstrate the usefulness of renal cortical slices as toxicology tool for evaluating and screening compounds for their potential protective effects, and are supportive of a role of adeninine nucleotide (ADP) and protease inhibitor (CPI) in protecting against Atractyloside-induced cell injury.
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The toxic mechanism and metabolic effects of Atractyloside in precision-cut pig kidney and liver slices
Archives of toxicology, 1998Co-Authors: David K. Obatomi, Nguyen T. K. Thanh, Stephen Brant, Peter H. BachAbstract:The toxic and cellular metabolic eAects of at- ractyloside, a diterpenoid glycoside, which causes fatal renal and hepatic necrosis in vivo in animals and hu- mans, have been investigated in tissue slices prepared from male domestic pig kidney and liver. Precision-cut slices (200 lm thick) were incubated with Atractyloside at concentrations of 200 lM, 500 lM, 1.0 mM and 2.0 mM for 3 h at 37 ∞C and changes in lipid profile and pyruvate-stimulated gluconeogenesis investigated. Lipid peroxidative changes, reduced glutathione (GSH) and ATP content, the release of lactate dehydrogenase (LDH), alkaline phosphatase (ALP), alanine and aspartate aminotransferase (ALT/AST) were also as- sessed. After 3 h of incubation, Atractyloside caused a significant (P< 0.01) and concentration-dependent leakage of LDH and ALP from kidney slices. Only LDH leakage was significantly elevated in liver slices while ALT and AST leakage showed marginal increase. At- ractyloside at concentrations of ‡200 lM caused a sig- nificant increase in lipid peroxidation, but only in liver slices. However, Atractyloside at concentrations of ‡200 lM caused a marked depletion of GSH and ATP content in both kidney and liver slices. There was a marked decrease in total and individual phospholipid in kidney but not in liver slices. However, cholesterol and triacylglycerol levels were not aAected by Atractyloside in both kidney and liver slices. Renal and hepatic pyruvate-stimulated gluconeogenesis were significantly (P < 0.05) inhibited at Atractyloside concentrations of ‡500 lM. Accumulation of organic anion p-amino- hippuric acid (PAH) was also inhibited in renal cortical slices at Atractyloside concentrations of ‡500 lM. These results suggest that the observable in vivo eAect of at- ractyloside can be reproduced in slices and that basic mechanistic diAerences exist in the mode of toxicity in liver and kidney tissues. The data also raise the possi- bility that the mechanistic basis of metabolic alterations in these tissues following treatment with Atractyloside may be relevant to target selective toxicity.
David K. Obatomi - One of the best experts on this subject based on the ideXlab platform.
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Adenine nucleotide and calpain inhibitor I protect against Atractyloside-induced toxicity in rat renal cortical slices in vitro.
Archives of toxicology, 2001Co-Authors: David K. Obatomi, Richard Blackburn, Peter H. BachAbstract:Atractyloside is a compound with a documented nephrotoxicity. It induces renal tubular necrosis at high doses and apoptosis at lower doses. This study investigates the potential protective effect of some chemical agents against Atractyloside-induced nephrotoxicity in vitro using the precision-cut rat renal cortical slices obtained from kidneys of Wistar rats. For co-incubation experiments, slices were incubated for 3 h at 37°C on a rocker platform with various chemical agents: ADP (5 mM), calpain inhibitor I (CPI, 1 mM), stevioside (STV, 2.5 mM) or probenecid (PRB, 2.5 mM) in the presence or absence of Atractyloside (2 mM). For pre-incubation experiments, slices were incubated with the same chemical agents for 1 h before exposure to Atractyloside. The nephrotoxic effects of Atractyloside (2 mM) alone were manifested in several ways: by a marked increase in lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) leakage, significant inhibition of p-aminohippurate (PAH) accumulation, marked depletion of intracellular ATP and reduced glutathione (GSH), and a significant reduction in pyruvate-stimulated gluconeogenesis. Co-incubation of slices with ADP or CPI and Atractyloside completely blocked Atractyloside-induced increase in LDH leakage, but not ALP leakage. Atractyloside-induced depletion of ATP and reduced gluconeogenesis was prevented by co-incubation with ADP or CPI. Furthermore, co-incubation of slices with STV and Atractyloside, but not PRB, completely abolished Atractyloside-induced depletion of ATP and decreased gluconeogenesis in the slices. Pre-incubation of slices with either ADP or CPI protected against Atractyloside-induced increase in LDH leakage, reduced ATP and decreased gluconeogenesis. PAH uptake in the slices was inhibited by Atractyloside and PRB in a time-dependent manner. While ADP and CPI were found to exert complete protection against Atractyloside-induced toxicity irrespective of treatment schedule, STV is effective only under certain conditions, and PRB offer no protection at all. The results of this study demonstrate the usefulness of renal cortical slices as toxicology tool for evaluating and screening compounds for their potential protective effects, and are supportive of a role of adeninine nucleotide (ADP) and protease inhibitor (CPI) in protecting against Atractyloside-induced cell injury.
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The toxic mechanism and metabolic effects of Atractyloside in precision-cut pig kidney and liver slices
Archives of toxicology, 1998Co-Authors: David K. Obatomi, Nguyen T. K. Thanh, Stephen Brant, Peter H. BachAbstract:The toxic and cellular metabolic eAects of at- ractyloside, a diterpenoid glycoside, which causes fatal renal and hepatic necrosis in vivo in animals and hu- mans, have been investigated in tissue slices prepared from male domestic pig kidney and liver. Precision-cut slices (200 lm thick) were incubated with Atractyloside at concentrations of 200 lM, 500 lM, 1.0 mM and 2.0 mM for 3 h at 37 ∞C and changes in lipid profile and pyruvate-stimulated gluconeogenesis investigated. Lipid peroxidative changes, reduced glutathione (GSH) and ATP content, the release of lactate dehydrogenase (LDH), alkaline phosphatase (ALP), alanine and aspartate aminotransferase (ALT/AST) were also as- sessed. After 3 h of incubation, Atractyloside caused a significant (P< 0.01) and concentration-dependent leakage of LDH and ALP from kidney slices. Only LDH leakage was significantly elevated in liver slices while ALT and AST leakage showed marginal increase. At- ractyloside at concentrations of ‡200 lM caused a sig- nificant increase in lipid peroxidation, but only in liver slices. However, Atractyloside at concentrations of ‡200 lM caused a marked depletion of GSH and ATP content in both kidney and liver slices. There was a marked decrease in total and individual phospholipid in kidney but not in liver slices. However, cholesterol and triacylglycerol levels were not aAected by Atractyloside in both kidney and liver slices. Renal and hepatic pyruvate-stimulated gluconeogenesis were significantly (P < 0.05) inhibited at Atractyloside concentrations of ‡500 lM. Accumulation of organic anion p-amino- hippuric acid (PAH) was also inhibited in renal cortical slices at Atractyloside concentrations of ‡500 lM. These results suggest that the observable in vivo eAect of at- ractyloside can be reproduced in slices and that basic mechanistic diAerences exist in the mode of toxicity in liver and kidney tissues. The data also raise the possi- bility that the mechanistic basis of metabolic alterations in these tissues following treatment with Atractyloside may be relevant to target selective toxicity.
Rudolf Bauer - One of the best experts on this subject based on the ideXlab platform.
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influence of processing on the content of toxic carboxyAtractyloside and Atractyloside and the microbiological status of xanthium sibiricum fruits cang erzi
Planta Medica, 2015Co-Authors: Stefanie Nikles, Eberhard Hilsdorf, Robert Schmucker, Rebecca Seidenberger, Heidi Heuberger, Rudolf BauerAbstract:The dried ripe fruits of Xanthium sibiricum (Cangʼerzi) are used in traditional Chinese medicine for the treatment of nasal congestion, nasal discharge, allergic rhinitis, sinusitis, and wind-cold headaches. CarboxyAtractyloside and Atractyloside are important constituents of the fruits because these diterpenoid glycosides are responsible for their toxicity. In order to evaluate procedures for reducing the amount of the more toxic carboxyAtractyloside, the fruits were dried and heated with different methods. CarboxyAtractyloside and Atractyloside were analysed by a new reversed-phase high-performance liquid chromatographic method using liquid chromatography-diode array detector-tandem mass spectrometry analysis. The results revealed that temperature and drying methods have a strong influence on the content of carboxyAtractyloside and Atractyloside. Fruits which were treated at higher temperatures showed a lower content of carboxyAtractyloside and an increased content of Atractyloside, which is 50 times less toxic. This indicates that the roasting process can reduce toxicity effectively. The microbiological colonisation of Xanthium fruits is also reduced by roasting and by drying above 100 °C. For the safe use of Cangʼerzi, the effect of processing should be monitored and analysis of carboxyAtractyloside and Atractyloside should be obligatory in quality control.
Brian Herman - One of the best experts on this subject based on the ideXlab platform.
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Human papillomavirus (HPV) 16 E6 sensitizes cells to Atractyloside‐induced apoptosis: Role of p53, ICE‐like proteases and the mitochondrial permeability transition
Journal of cellular biochemistry, 1997Co-Authors: Jacqueline Brown, Hiromi Higo, Ann Mckalip, Brian HermanAbstract:Infection of cervical epithelial cells with certain high risk HPV genotypes is thought to play an etiologic role in the development of cervical cancer. In particular, HPV type 16 and 18 early protein 6 (E6) is thought to contribute to epithelial transformation by binding to the tumor suppressor protein p53, targeting it for rapid proteolysis, resulting in loss of its cell cycle arrest and apoptosis-inducing activities. Recent data indicate that factors responsible for triggering apoptosis reside in the cytoplasm of cells, and not in the nucleus. In particular, the findings that mitochondria are required in certain cell-free models for induction of apoptosis and that bcl-2 is localized to mitochondria have focused attention on the role of the mitochondrial membrane permeability transition (MPT) in apoptosis. Here we present data to indicate that HPV 16 E6 expression sensitizes cells to MPT-induced apoptosis. We also report that HPV 16 E6 sensitization of cells to MPT-induced apoptosis occurs only in the presence of wildtype (wt) p53 expression. The extent of apoptosis induced by Atractyloside (an inducer of the MPT) in normal, temperature-sensitive (ts) p53, and HPV-16 E6 transfected J2-3T3 cells, and the HPV expressing cervical carcinoma cell lines SiHa, Hela and CaSki was determined. C33A cells, which express mutant p53 but not HPV, were also exposed to Atractyloside in the presence or absence of HPV 16 E6 expression. Dose-dependent apoptosis induced by Atractyloside in normal J2-3T3 cells and cervical carcinoma cells was measured by loss of cell viability, nuclear fragmentation and DNA laddering. The sensitivity of cells to Atractyloside-induced apoptosis was found to be: HPV 16 E6-J2-3T3 > CaSki > normal-J2-3T3 cells ≈ ts p53-J2-3T3 ≈ vector-J2-3T3 cells > Hela > SiHa > C33A ≈ C33A 16 E6. Cyclosporin A (CsA), an inhibitor of the MPT, and ICE-I, a protease inhibitor, provided protection against Atractyloside-induced apoptosis. These findings indicate that: 1) high risk HPV 16 E6 protein is capable of sensitizing cells to apoptosis; 2) HPV 16 E6 sensitization of cells to Atractyloside-induced apoptosis occurs in a p53-dependent fashion; 3) the target of HPV 16 E6 sensitization of cells to Atractyloside-induced apoptosis is the mitochondria; and 4) HPV 16 E6 sensitization of cells to atroctycoside-induced apoptosis involves an ICE-like protease-sensitive mechanism, regulating the onset of the MPT. These findings constitute the first evidence that mitochondria play a role in HPV 16 E6 modulation of apoptosis. J. Cell. Biochem. 66:245-255. © 1997 Wiley-Liss, Inc.
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human papillomavirus hpv 16 e6 sensitizes cells to Atractyloside induced apoptosis role of p53 ice like proteases and the mitochondrial permeability transition
Journal of Cellular Biochemistry, 1997Co-Authors: Jacqueline Brown, Hiromi Higo, Ann Mckalip, Brian HermanAbstract:Infection of cervical epithelial cells with certain high risk HPV genotypes is thought to play an etiologic role in the development of cervical cancer. In particular, HPV type 16 and 18 early protein 6 (E6) is thought to contribute to epithelial transformation by binding to the tumor suppressor protein p53, targeting it for rapid proteolysis, resulting in loss of its cell cycle arrest and apoptosis-inducing activities. Recent data indicate that factors responsible for triggering apoptosis reside in the cytoplasm of cells, and not in the nucleus. In particular, the findings that mitochondria are required in certain cell-free models for induction of apoptosis and that bcl-2 is localized to mitochondria have focused attention on the role of the mitochondrial membrane permeability transition (MPT) in apoptosis. Here we present data to indicate that HPV 16 E6 expression sensitizes cells to MPT-induced apoptosis. We also report that HPV 16 E6 sensitization of cells to MPT-induced apoptosis occurs only in the presence of wildtype (wt) p53 expression. The extent of apoptosis induced by Atractyloside (an inducer of the MPT) in normal, temperature-sensitive (ts) p53, and HPV-16 E6 transfected J2-3T3 cells, and the HPV expressing cervical carcinoma cell lines SiHa, Hela and CaSki was determined. C33A cells, which express mutant p53 but not HPV, were also exposed to Atractyloside in the presence or absence of HPV 16 E6 expression. Dose-dependent apoptosis induced by Atractyloside in normal J2-3T3 cells and cervical carcinoma cells was measured by loss of cell viability, nuclear fragmentation and DNA laddering. The sensitivity of cells to Atractyloside-induced apoptosis was found to be: HPV 16 E6-J2-3T3 > CaSki > normal-J2-3T3 cells ≈ ts p53-J2-3T3 ≈ vector-J2-3T3 cells > Hela > SiHa > C33A ≈ C33A 16 E6. Cyclosporin A (CsA), an inhibitor of the MPT, and ICE-I, a protease inhibitor, provided protection against Atractyloside-induced apoptosis. These findings indicate that: 1) high risk HPV 16 E6 protein is capable of sensitizing cells to apoptosis; 2) HPV 16 E6 sensitization of cells to Atractyloside-induced apoptosis occurs in a p53-dependent fashion; 3) the target of HPV 16 E6 sensitization of cells to Atractyloside-induced apoptosis is the mitochondria; and 4) HPV 16 E6 sensitization of cells to atroctycoside-induced apoptosis involves an ICE-like protease-sensitive mechanism, regulating the onset of the MPT. These findings constitute the first evidence that mitochondria play a role in HPV 16 E6 modulation of apoptosis. J. Cell. Biochem. 66:245-255. © 1997 Wiley-Liss, Inc.
