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Sigurd Lenzen - One of the best experts on this subject based on the ideXlab platform.
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effect of superoxide dismutase catalase chelating agents and free radical scavengers on the toxicity of Alloxan to isolated pancreatic islets in vitro
Free Radical Biology and Medicine, 1999Co-Authors: Anne Jorns, Markus Tiedge, Sigurd Lenzen, Rex MundayAbstract:Abstract The effect of superoxide dismutase, catalase, metal-chelating agents and hydroxyl radical scavengers on the toxicity of Alloxan to isolated ob/ob mouse pancreatic islets in vitro has been compared with the reported ability of such substances to protect against Alloxan diabetes in vivo. Superoxide dismutase and catalase protected β-cells of isolated pancreatic islets against Alloxan cytotoxicity, as did the hydroxyl radical scavengers dimethyl sulfoxide (DMSO) and butanol. However, 1,3-dimethylurea and thiourea, that are recognised as effective hydroxyl radical scavengers and that protect animals against the diabetogenic effects of Alloxan, were without effect. Similarly, desferrioxamine, that inhibits hydroxyl radical formation from Alloxan in chemically defined systems, did not protect against Alloxan toxicity. Diethylenetriamine pentaacetic acid, which does not inhibit hydroxyl radical formation from Alloxan, also gave no significant protection. The results indicate a role for superoxide radical and hydrogen peroxide in the mechanism of toxicity of Alloxan but do not support the involvement of the hydroxyl radical in this process. Alternative explanations must be sought for the ability of hydroxyl radical scavengers and metal-chelating agents to protect against Alloxan toxicity in vivo.
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comparative toxicity of Alloxan n alkylAlloxans and ninhydrin to isolated pancreatic islets in vitro
Journal of Endocrinology, 1997Co-Authors: Anne Jorns, Rex Munday, Markus Tiedge, Sigurd LenzenAbstract:The in vitro toxicity of the diabetogenic agent Alloxan as documented by the induction of beta cell necrosis was studied in isolated ob/ob mouse pancreatic islets. The effect of Alloxan has been compared with that of a number of N-alkyl Alloxan derivatives and with that of the structurally related compound, ninhydrin. Alloxan and its derivatives were selectively toxic to pancreatic beta cells, with other endocrine cells and exocrine parenchymal cells being well preserved, even at high concentration. In contrast, ninhydrin was selectively toxic to pancreatic beta cells only at comparatively low concentration, destroying all islet cell types at high concentrations. The ultrastructural changes induced by all the test compounds in pancreatic beta cells in vitro were very similar to those observed during the development of Alloxan diabetes in vivo. The relative toxicity of the various compounds to pancreatic beta cells in vitro was not, however, related to their ability to cause diabetes in vivo. Indeed, the non-diabetogenic substances ninhydrin, N-butylAlloxan and N-isobutylAlloxan were very much more toxic to isolated islets than the diabetogenic compounds Alloxan and N-methylAlloxan. These results suggest that the differences in diabetogenicity among Alloxan derivatives are not due to intrinsic differences in the susceptibility of the pancreatic beta cells to their toxicity, but may reflect differences in distribution or metabolism. High concentrations of glucose protected islets against the harmful effects of Alloxan and its derivatives, but not those of ninhydrin. Low levels of glucose, and non-carbohydrate nutrients, afforded little protection, indicating that the effect of glucose is not due to the production of reducing equivalents within the cell, 3-O-Methylglucose, which protects against alloan diabetes in vivo, did not protect against Alloxan toxicity in vitro. Since 3-O-methylglucose is known to prevent uptake of Alloxan by pancreatic beta cells, it appears that uptake of Alloxan by the cell is not a prerequisite for the induction of beta cell necrosis.
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Effects of Alloxan and ninhydrin on mitochondrial Ca2+ transport
Molecular and cellular biochemistry, 1992Co-Authors: Sigurd Lenzen, Heike Brünig, Wilfried MünsterAbstract:Alloxan at millimolar concentrations slightly inhibited the velocity of Ca2+ uptake by isolated rat liver mitochondria irrespective of the free Ca2+ concentration between 1 and 10 µM and was an effective concentration-dependent stimulator of mitochondrial Ca2+ efflux. Ninhydrin also slightly inhibited the velocity of mitochondrial Ca2+ uptake but only at free Ca2+ concentrations above 5 µM. However, ninhydrin was a strong stimulator of mitochondrial Ca2+ efflux even at micromolar concentrations, 10–50 times more potent than Alloxan. The mitochondrial membrane potential was reduced 10–20% at most by Alloxan and ninhydrin. Alloxan and ninhydrin also stimulated Ca2+ efflux from isolated permeabilized liver cells. When isolated intact liver cells had been pre-incubated with Alloxan or ninhydrin before permeabilization of the cells the ability of spermine to induce mitochondrial Ca2+ uptake was abolished. Glucose provided the typical protection against the effects of Alloxan on mitochondrial Ca2+ transport only in experiments with intact cells but not in experiments with permeabilized cells or isolated mitochondria. Therefore glucose protection is apparently due to inhibition of Alloxan uptake into the cell. Glucose provided no protection against effects of ninhydrin under any of the experimental conditions. Thus both Alloxan and ninhydrin are potent stimulators of Ca2+ efflux by isolated mitochondria but very weak inhibitors of the velocity of mitochondrial Ca2+ uptake. The direct effects of ninhydrin on mitochondrial Ca2+ efflux may contribute to the cytotoxic action of this agent whereas the direct effects of Alloxan on mitochondrial Ca2+ transport require concentrations which are too high to be of relevance for the induction of the typical pancreatic B-cell toxic effects of Alloxan. However, the effects on mitochondrial Ca2+ transport during incubation of intact cells which may result from the generation of cytotoxic intermediates during Alloxan xenobiotic metabolism may well contribute to the pancreatic B-cell toxic effect of Alloxan. Mol Cell Biochem 118: 141–151, 1992)
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Inhibition of aconitase by Alloxan and the differential modes of protection of glucose, 3-O-methylglucose, and mannoheptulose
Naunyn-Schmiedeberg's Archives of Pharmacology, 1992Co-Authors: Sigurd Lenzen, Maritta Mirzaie-petriAbstract:Alloxan inhibited aconitase with a half maximal inhibitory concentration of 0.5 mM in sonically disrupted and 2.3 mM in intact isolated liver mitochondria. For dialuric acid the half maximal inhibitory concentrations were 1.1 mM and 2.5 mM, respectively. Ninhydrin and N-ethylmaleimide (NEM) also inhibited aconitase with half maximal inhibitory concentrations in the submillimolar range and t-butylhydroperoxide (BuOOH) in the millimolar range, which, however, were not different for disrupted and intact mitochondria. Only the aconitase substrate citrate, but not glucose provided protection of the enzyme against inhibition. In intact liver cells the half maximal inhibitory concentration for Alloxan was 6.8 mM. Again, dialuric acid and BuOOH were less potent inhibitors while ninhydrin and NEM were more potent inhibitors of aconitase in intact liver cells. In intact liver cells, glucose and 3-O-methylglucose, but not mannoheptulose and citrate provided protection against Alloxan inhibition. The results show that aconitase is not an enzyme particularly sensitive towards Alloxan inhibition and thus apparently not a primary site for mediation of Alloxan toxicity as it is the glucokinase. This makes a primary site of Alloxan action in the mitochondria extremely unlikely. On the other hand the results demonstrate that both the intact mitochondrial and plasma membrane as uptake barriers provide protection against Alloxan toxicity. In addition the results clearly show, that 3-O-methylglucose provides protection against Alloxan action only at the level of the plasma membrane through inhibition of Alloxan uptake into the cell, while the site of protection of mannoheptulose is only the sugar binding site of the glucokinase. In contrast, glucose is shown here to be the only sugar with a dual protective effect both through inhibition of Alloxan uptake through the plasma membrane like 3-0methylglucose and through protection of the glucokinase sugar binding site against Alloxan inhibition of the en zyme like mannoheptulose. In the light of these results the unique protective potency of glucose as compared to that of other sugars is not surprising.
Rex Munday - One of the best experts on this subject based on the ideXlab platform.
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effect of superoxide dismutase catalase chelating agents and free radical scavengers on the toxicity of Alloxan to isolated pancreatic islets in vitro
Free Radical Biology and Medicine, 1999Co-Authors: Anne Jorns, Markus Tiedge, Sigurd Lenzen, Rex MundayAbstract:Abstract The effect of superoxide dismutase, catalase, metal-chelating agents and hydroxyl radical scavengers on the toxicity of Alloxan to isolated ob/ob mouse pancreatic islets in vitro has been compared with the reported ability of such substances to protect against Alloxan diabetes in vivo. Superoxide dismutase and catalase protected β-cells of isolated pancreatic islets against Alloxan cytotoxicity, as did the hydroxyl radical scavengers dimethyl sulfoxide (DMSO) and butanol. However, 1,3-dimethylurea and thiourea, that are recognised as effective hydroxyl radical scavengers and that protect animals against the diabetogenic effects of Alloxan, were without effect. Similarly, desferrioxamine, that inhibits hydroxyl radical formation from Alloxan in chemically defined systems, did not protect against Alloxan toxicity. Diethylenetriamine pentaacetic acid, which does not inhibit hydroxyl radical formation from Alloxan, also gave no significant protection. The results indicate a role for superoxide radical and hydrogen peroxide in the mechanism of toxicity of Alloxan but do not support the involvement of the hydroxyl radical in this process. Alternative explanations must be sought for the ability of hydroxyl radical scavengers and metal-chelating agents to protect against Alloxan toxicity in vivo.
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comparative toxicity of Alloxan n alkylAlloxans and ninhydrin to isolated pancreatic islets in vitro
Journal of Endocrinology, 1997Co-Authors: Anne Jorns, Rex Munday, Markus Tiedge, Sigurd LenzenAbstract:The in vitro toxicity of the diabetogenic agent Alloxan as documented by the induction of beta cell necrosis was studied in isolated ob/ob mouse pancreatic islets. The effect of Alloxan has been compared with that of a number of N-alkyl Alloxan derivatives and with that of the structurally related compound, ninhydrin. Alloxan and its derivatives were selectively toxic to pancreatic beta cells, with other endocrine cells and exocrine parenchymal cells being well preserved, even at high concentration. In contrast, ninhydrin was selectively toxic to pancreatic beta cells only at comparatively low concentration, destroying all islet cell types at high concentrations. The ultrastructural changes induced by all the test compounds in pancreatic beta cells in vitro were very similar to those observed during the development of Alloxan diabetes in vivo. The relative toxicity of the various compounds to pancreatic beta cells in vitro was not, however, related to their ability to cause diabetes in vivo. Indeed, the non-diabetogenic substances ninhydrin, N-butylAlloxan and N-isobutylAlloxan were very much more toxic to isolated islets than the diabetogenic compounds Alloxan and N-methylAlloxan. These results suggest that the differences in diabetogenicity among Alloxan derivatives are not due to intrinsic differences in the susceptibility of the pancreatic beta cells to their toxicity, but may reflect differences in distribution or metabolism. High concentrations of glucose protected islets against the harmful effects of Alloxan and its derivatives, but not those of ninhydrin. Low levels of glucose, and non-carbohydrate nutrients, afforded little protection, indicating that the effect of glucose is not due to the production of reducing equivalents within the cell, 3-O-Methylglucose, which protects against alloan diabetes in vivo, did not protect against Alloxan toxicity in vitro. Since 3-O-methylglucose is known to prevent uptake of Alloxan by pancreatic beta cells, it appears that uptake of Alloxan by the cell is not a prerequisite for the induction of beta cell necrosis.
Anne Jorns - One of the best experts on this subject based on the ideXlab platform.
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effect of superoxide dismutase catalase chelating agents and free radical scavengers on the toxicity of Alloxan to isolated pancreatic islets in vitro
Free Radical Biology and Medicine, 1999Co-Authors: Anne Jorns, Markus Tiedge, Sigurd Lenzen, Rex MundayAbstract:Abstract The effect of superoxide dismutase, catalase, metal-chelating agents and hydroxyl radical scavengers on the toxicity of Alloxan to isolated ob/ob mouse pancreatic islets in vitro has been compared with the reported ability of such substances to protect against Alloxan diabetes in vivo. Superoxide dismutase and catalase protected β-cells of isolated pancreatic islets against Alloxan cytotoxicity, as did the hydroxyl radical scavengers dimethyl sulfoxide (DMSO) and butanol. However, 1,3-dimethylurea and thiourea, that are recognised as effective hydroxyl radical scavengers and that protect animals against the diabetogenic effects of Alloxan, were without effect. Similarly, desferrioxamine, that inhibits hydroxyl radical formation from Alloxan in chemically defined systems, did not protect against Alloxan toxicity. Diethylenetriamine pentaacetic acid, which does not inhibit hydroxyl radical formation from Alloxan, also gave no significant protection. The results indicate a role for superoxide radical and hydrogen peroxide in the mechanism of toxicity of Alloxan but do not support the involvement of the hydroxyl radical in this process. Alternative explanations must be sought for the ability of hydroxyl radical scavengers and metal-chelating agents to protect against Alloxan toxicity in vivo.
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comparative toxicity of Alloxan n alkylAlloxans and ninhydrin to isolated pancreatic islets in vitro
Journal of Endocrinology, 1997Co-Authors: Anne Jorns, Rex Munday, Markus Tiedge, Sigurd LenzenAbstract:The in vitro toxicity of the diabetogenic agent Alloxan as documented by the induction of beta cell necrosis was studied in isolated ob/ob mouse pancreatic islets. The effect of Alloxan has been compared with that of a number of N-alkyl Alloxan derivatives and with that of the structurally related compound, ninhydrin. Alloxan and its derivatives were selectively toxic to pancreatic beta cells, with other endocrine cells and exocrine parenchymal cells being well preserved, even at high concentration. In contrast, ninhydrin was selectively toxic to pancreatic beta cells only at comparatively low concentration, destroying all islet cell types at high concentrations. The ultrastructural changes induced by all the test compounds in pancreatic beta cells in vitro were very similar to those observed during the development of Alloxan diabetes in vivo. The relative toxicity of the various compounds to pancreatic beta cells in vitro was not, however, related to their ability to cause diabetes in vivo. Indeed, the non-diabetogenic substances ninhydrin, N-butylAlloxan and N-isobutylAlloxan were very much more toxic to isolated islets than the diabetogenic compounds Alloxan and N-methylAlloxan. These results suggest that the differences in diabetogenicity among Alloxan derivatives are not due to intrinsic differences in the susceptibility of the pancreatic beta cells to their toxicity, but may reflect differences in distribution or metabolism. High concentrations of glucose protected islets against the harmful effects of Alloxan and its derivatives, but not those of ninhydrin. Low levels of glucose, and non-carbohydrate nutrients, afforded little protection, indicating that the effect of glucose is not due to the production of reducing equivalents within the cell, 3-O-Methylglucose, which protects against alloan diabetes in vivo, did not protect against Alloxan toxicity in vitro. Since 3-O-methylglucose is known to prevent uptake of Alloxan by pancreatic beta cells, it appears that uptake of Alloxan by the cell is not a prerequisite for the induction of beta cell necrosis.
Jin Woo Park - One of the best experts on this subject based on the ideXlab platform.
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Protective Effect of Amomi Semen Extract on Alloxan-induced Pancreatic β-Cell Damage
Phytotherapy Research, 2008Co-Authors: Jin Woo Park, Byung Hyun ParkAbstract:The protective effect of Amomi semen extract (ASE) on Alloxan-induced pancreatic β-cell damage was investigated in HIT T-15 cells, a Syrian hamster pancreatic β-cell line. Alloxan caused pancreatic β-cell damage through the generation of reactive oxygen species (ROS), the elevation of cytosolic free Ca2+, DNA fragmentation and the decrease of cellular NAD+ and ATP levels. All these effects of Alloxan were significantly prevented by pretreatment with a water-soluble extract of Amomi semen. Pretreatment with ASE in pancreatic islets isolated from mice, also significantly abolished the inhibition of glucose-stimulated insulin secretion by Alloxan. The results of this study provide evidence that ASE may have a protective activity on Alloxan-induced β-cell damage, and that the protective effect is primarily due to the inhibition of ROS generation by Alloxan. Copyright © 2007 John Wiley & Sons, Ltd.
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Protective mechanism of glucose against Alloxan-induced beta-cell damage: pivotal role of ATP.
Experimental and Molecular Medicine, 2000Co-Authors: Byung Hyun Park, Jin Woo ParkAbstract:Glucose prevents the development of diabetes induced by Alloxan. In the present study, the protective mechanism of glucose against Alloxan-induced β-cell damage was investigated using HIT-T 15 cell, a Syrian hamster transformed β-cell line. Alloxan caused β-cell damages with DNA fragmentation, inhibition of glucose-stimulated insulin release, and decrease of cellular ATP level, but all of these β-cell damages by Alloxan were prevented by the presence of 20 mM glucose. Oligomycin, a specific inhibitor of ATP synthase, completely abolished the protective effects of glucose against Alloxan-inudced cell damage. Furthermore, treatment of nuclei isolated from HIT-T15 cells with ATP significantly prevented the DNA fragmentation induced by Ca²?. The results indicate that ATP produced during glucose metabolism plays a pivotal role in the protection of glucose against Alloxan-induced β-cell damage.
Byung Hyun Park - One of the best experts on this subject based on the ideXlab platform.
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Protective Effect of Amomi Semen Extract on Alloxan-induced Pancreatic β-Cell Damage
Phytotherapy Research, 2008Co-Authors: Jin Woo Park, Byung Hyun ParkAbstract:The protective effect of Amomi semen extract (ASE) on Alloxan-induced pancreatic β-cell damage was investigated in HIT T-15 cells, a Syrian hamster pancreatic β-cell line. Alloxan caused pancreatic β-cell damage through the generation of reactive oxygen species (ROS), the elevation of cytosolic free Ca2+, DNA fragmentation and the decrease of cellular NAD+ and ATP levels. All these effects of Alloxan were significantly prevented by pretreatment with a water-soluble extract of Amomi semen. Pretreatment with ASE in pancreatic islets isolated from mice, also significantly abolished the inhibition of glucose-stimulated insulin secretion by Alloxan. The results of this study provide evidence that ASE may have a protective activity on Alloxan-induced β-cell damage, and that the protective effect is primarily due to the inhibition of ROS generation by Alloxan. Copyright © 2007 John Wiley & Sons, Ltd.
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Protective mechanism of glucose against Alloxan-induced beta-cell damage: pivotal role of ATP.
Experimental and Molecular Medicine, 2000Co-Authors: Byung Hyun Park, Jin Woo ParkAbstract:Glucose prevents the development of diabetes induced by Alloxan. In the present study, the protective mechanism of glucose against Alloxan-induced β-cell damage was investigated using HIT-T 15 cell, a Syrian hamster transformed β-cell line. Alloxan caused β-cell damages with DNA fragmentation, inhibition of glucose-stimulated insulin release, and decrease of cellular ATP level, but all of these β-cell damages by Alloxan were prevented by the presence of 20 mM glucose. Oligomycin, a specific inhibitor of ATP synthase, completely abolished the protective effects of glucose against Alloxan-inudced cell damage. Furthermore, treatment of nuclei isolated from HIT-T15 cells with ATP significantly prevented the DNA fragmentation induced by Ca²?. The results indicate that ATP produced during glucose metabolism plays a pivotal role in the protection of glucose against Alloxan-induced β-cell damage.