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Lester Packer - One of the best experts on this subject based on the ideXlab platform.
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Antioxidant and prooxidant activities of alpha-lipoic Acid and Dihydrolipoic Acid.
Toxicology and applied pharmacology, 2002Co-Authors: Hadi Moini, Lester Packer, Nils-erik L. SarisAbstract:Reactive oxygen (ROS) and nitrogen oxide (RNOS) species are produced as by-products of oxidative metabolism. A major function for ROS and RNOS is immunological host defense. Recent evidence indicate that ROS and RNOS may also function as signaling molecules. However, high levels of ROS and RNOS have been considered to potentially damage cellular macromolecules and have been implicated in the pathogenesis and progression of various chronic diseases. alpha-Lipoic Acid and Dihydrolipoic Acid exhibit direct free radical scavenging properties and as a redox couple, with a low redox potential of -0.32 V, is a strong reductant. Several studies provided evidence that alpha-lipoic Acid supplementation decreases oxidative stress and restores reduced levels of other antioxidants in vivo. However, there is also evidence indicating that alpha-lipoic Acid and Dihydrolipoic Acid may exert prooxidant properties in vitro. alpha-Lipoic Acid and Dihydrolipoic Acid were shown to promote the mitochondrial permeability transition in permeabilized hepatocytes and isolated rat liver mitochondria. Dihydrolipoic Acid also stimulated superoxide anion production in rat liver mitochondria and submitochondrial particles. alpha-Lipoic Acid was recently shown to stimulate glucose uptake into 3T3-L1 adipocytes by increasing intracellular oxidant levels and/or facilitating insulin receptor autophosphorylation presumably by oxidation of critical thiol groups present in the insulin receptor beta-subunit. Whether alpha-lipoic Acid and/or Dihydrolipoic Acid-induced oxidative protein modifications contribute to their versatile effects observed in vivo warrants further investigation.
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thiol chelation of cu2 by Dihydrolipoic Acid prevents human low density lipoprotein peroxidation
Free Radical Biology and Medicine, 1998Co-Authors: John K. Lodge, Maret G. Traber, Lester PackerAbstract:Mono-thiols can act either as pro- or anti-oxidants during metal-catalyzed low density lipoprotein (LDL) peroxidation, however investigation of the role of vicinal thiols has been neglected. Therefore Dihydrolipoic Acid (DHLA), a vicinal dithiol, and lipoic Acid, its oxidized form, were used to investigate Cu2+-mediated LDL peroxidation. We demonstrate here that DHLA inhibited Cu2+-dependent LDL peroxidation by chelating copper. DHLA (0–20 μM) increased lag-times of conjugated diene formation in LDL (100 μg/ml) oxidized with 5 μM Cu2+ in a concentration dependent manner, and this effect was saturated after 5 μM DHLA; enough to chelate all of the added Cu2+. In a similar fashion DHLA prevented LDL-mediated reduction of Cu2+ to Cu+. Lipoic Acid had no effect in these systems. DHLA alone also reduced Cu2+, however this was inhibited when DHLA was in excess of the copper concentration. Hence there is complex formation between the two species. Copper:DHLA complex formation was further investigated and found to be dependent upon pH and the presence of oxygen. At low pH (<6), or in the absence of oxygen, the complex is stable, presumably due to vicinal thiol chelation. As the pH is increased, the carboxylate group also participates in copper chelation, this results in a less stable complex which is susceptible to oxidation, and copper is eventually released. Electron spin resonance studies demonstrate the formation of hydroxyl, but not superoxide, radicals during Cu2+-catalyzed DHLA oxidation. Thus in our LDL experiments at physiological pH, DHLA is able to either reductively inactivate Cu2+ when Cu2+ is in excess, or effectively chelate Cu2+ when DHLA is in excess. The Cu2+:DHLA complex eventually undergoes copper-catalyzed oxidation, copper is released and LDL peroxidation proceeds. DHLA, thus, has both pro- and antioxidant properties depending upon the ratio of Cu2+:DHLA and the pH. These results provide an additional mechanism of thiol-mediated formation of radicals and metal chelation.
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Thiol chelation of Cu2+ by Dihydrolipoic Acid prevents human low density lipoprotein peroxidation.
Free radical biology & medicine, 1998Co-Authors: John K. Lodge, Maret G. Traber, Lester PackerAbstract:Mono-thiols can act either as pro- or anti-oxidants during metal-catalyzed low density lipoprotein (LDL) peroxidation, however investigation of the role of vicinal thiols has been neglected. Therefore Dihydrolipoic Acid (DHLA), a vicinal dithiol, and lipoic Acid, its oxidized form, were used to investigate Cu2+-mediated LDL peroxidation. We demonstrate here that DHLA inhibited Cu2+-dependent LDL peroxidation by chelating copper. DHLA (0–20 μM) increased lag-times of conjugated diene formation in LDL (100 μg/ml) oxidized with 5 μM Cu2+ in a concentration dependent manner, and this effect was saturated after 5 μM DHLA; enough to chelate all of the added Cu2+. In a similar fashion DHLA prevented LDL-mediated reduction of Cu2+ to Cu+. Lipoic Acid had no effect in these systems. DHLA alone also reduced Cu2+, however this was inhibited when DHLA was in excess of the copper concentration. Hence there is complex formation between the two species. Copper:DHLA complex formation was further investigated and found to be dependent upon pH and the presence of oxygen. At low pH (
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Cigarette smoke induced oxidation of human plasma proteins, lipids, and antioxidants; selective protection by the biothiols Dihydrolipoic Acid and glutathione.
Redox report : communications in free radical research, 1997Co-Authors: A. Z. Reznick, D. Han, Lester PackerAbstract:SummaryExposure of human plasma to gas-phase cigarette smoke (CS) causes loss of human plasma antioxidants, protein modification (Frei et al, Biochem J, 1991 277:133–138; Reznick et al, Biochem J, 1992 286: 607–611) and a minimal amount of lipid oxidation. Ascorbic Acid was found to prevent CS-induced lipid peroxidation and glutathione (GSH) partially protected against protein modification, as determined by loss of protein -SH groups and by increases in carbonyl content as a measure of protein oxidation. In the present study we demonstrate that Dihydrolipoic Acid (0.25–1.0 mM) decreases CS-induced protein carbonyls, α-tocopherol loss, and lipid hydroperoxide formation in plasma. In contrast GSH (1 mM) failed to influence CS-induced loss of α-tocopherol, and was 50% as effective as dihydrolipoate in protecting against CS-induced protein carbonyl formation. On the other hand, lipoic Acid (oxidized form of Dihydrolipoic Acid) and oxidized glutathione (GSSG) had minimal effect in protecting against the CS-ind...
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Reevaluation of Superoxide Scavenging Activity of Dihydrolipoic Acid and Its Analogues by Chemiluminescent Method Using 2-Methyl-6-[p-methoxyphenyl]-3,7-dihydroimidazo-[1,2-a]pyrazine-3-one (MCLA ) as a Superoxide Probe
Biochemical and biophysical research communications, 1996Co-Authors: S. Matsugo, Hans J. Tritschler, Tetsuya Konishi, Daisuke Matsuo, Lester PackerAbstract:The superoxide scavenging activity of Dihydrolipoic Acid and its analogues has been reevaluated by a chemiluminescence method using MCLA as a superoxide indicator. The results demonstrated that all the compounds having the thiol chromophore in the molecule showed scavenging activity toward superoxide. The short-chain analogue, tetranor-Dihydrolipoic Acid, showed almost the same scavenging activity as that of Dihydrolipoic Acid; however, bisnor-Dihydrolipoic Acid showed weaker scavenging activity than that of Dihydrolipoic Acid. The reaction rates of Dihydrolipoic Acid, bisnor-Dihydrolipoic Acid, and tetranor-Dihydrolipoic Acid were calculated from the competitive inhibition of MCLA-superoxide reaction. Thus, it was concluded that Dihydrolipoic Acid and the analogues are good scavengers of superoxide radical anion.
Hans Nohl - One of the best experts on this subject based on the ideXlab platform.
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Dihydrolipoic Acid maintains ubiquinone in the antioxidant active form by two-electron reduction of ubiquinone and one-electron reduction of ubisemiquinone.
Archives of biochemistry and biophysics, 1999Co-Authors: Andrey V. Kozlov, Katrin Staniek, Lars Gille, Hans NohlAbstract:Dihydrolipoic Acid (DHLA) is a constituent of cellular energy metabolism, where it cycles between the oxidized and reduced form. The two thiol residues of DHLA make this biomolecule susceptible to most radical species and prevent Fenton-type reactions by chelating free iron. In this study we present a novel mode of action by which DHLA exerts antioxidant function in combination with coenzyme Q (ubiquinone). DHLA was found to reduce ubiquinone to ubiquinol by the transfer of a pair of electrons, thereby increasing the antioxidant capacity of coenzyme Q in biomembranes. In addition, ubisemiquinone, which was earlier shown to be an active oxygen radical source when existing in the anionic form, is removed from equilibrium by the addition of a single electron from DHLA. The high reactivity of DHLA with this potentially deleterious ubisemiquinone species not only prevents the formation of prooxidants, it also keeps ubiquinone in its antioxidant active form. Experimental data of this study demonstrate a superadditive effect of ubiquinone in combination with DHLA in preventing peroxidation of biomembranes.
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Evaluation of the antioxidant capacity of ubiquinol and Dihydrolipoic Acid.
Zeitschrift fur Naturforschung. C Journal of biosciences, 1998Co-Authors: Hans Nohl, Lars GilleAbstract:Ubiquinone and alpha-lipoic Acid are natural constituents which are involved in mitochondrial energy metabolism. Their bioenergetic activities require redox-cycling. In the case of alpha-lipoic Acid redox-cycling leads to Dihydrolipoic Acid which occurs in multienzyme complexes involved in the citric Acid cycle while UQ recycles through semi- and divalently reduced ubiquinones in the respiratory chain. We have proved the validity of the concept about the antioxidant function of these natural compounds in their reduced form. Ubiquinol was found to interfere with lipid peroxidation of liposomal membranes being itself degradated by two consecutive oxidation steps. Dihydrolipoic Acid was found to totally recycle ubiquinone to the antioxidant active divalently reduced form. In contrast to the antioxidative derived reaction products of ubiquinols which in turn promoted lipid peroxidation, the antioxidant derived reaction product of Dihydrolipoic Acid was the unreactive two electron oxidation product alpha-lipoic Acid. Our experiments demonstrate the existence of an Dihydrolipoic Acid driven recycling of UQ to the antioxidative-active UQH2. The efficiency of the antioxidative capacity of the latter was found to be diminished through prooxidant activities of the antioxidant-derived metabolites.
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Dihydrolipoic Acid and Coenzyme Q, Two Natural Compounds with Pro- and Antioxidation Function
Free Radicals in Biology and Environment, 1997Co-Authors: Hans Nohl, Lars Gille, Katrin StaniekAbstract:Mitochondrial ubiquinone (Coenzyme Q) is essentially involved in energy-linked respiration. Apart from this classical function this electron carrier was also suggested to account for \({{\text{O}}_2}^{\bar \bullet }\) radical formation of normal cell respiration assuming the existence of a direct redox couple between ubisemiquinone (\({\text{S}}{{\text{Q}}^{\bar \bullet }}\)) and dioxygen (Fig. 1). Electron deviation out of sequence is considered to involve also ubihydroquinone (QH2) which was shown to interact with chromanoxyl radicals [1,2,3,4]. Furthermore, Dihydrolipoic Acid (DHLA) which is part of several mitochondrial multienzyme complexes was reported to exert antioxidant function like ubihydroquinone [5,6,7,8].
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Effect of alpha-lipoic Acid and Dihydrolipoic Acid on ischemia/reperfusion injury of the heart and heart mitochondria.
Biochimica et biophysica acta, 1995Co-Authors: Katrin Schönheit, Lars Gille, Hans NohlAbstract:The aim of the present study was to evaluate a possible interference of alpha-lipoic Acid (LA) or its reduced form (dithiol Dihydrolipoic Acid = DHLA) in the cardiac ischemia/reperfusion injury both at the level of the intact organ and at the subcellular level of mitochondria. In order to follow the effect of LA on the ischemia/reperfusion injury of the heart the isolated perfused organ was subjected to total global ischemia and reperfusion in the presence and absence of different concentrations of LA. Treatment with 0.5 microM LA improved the recovery of hemodynamic parameters; electrophysiological parameters were not influenced. However, application of 10 microM LA to rat hearts further impaired the recovery of hemodynamic functions and prolonged the duration of severe rhythm disturbances in comparison to reperfusion of control hearts. Treatment of isolated mitochondria with any concentration of DHLA could not prevent the impairment of respiratory-linked energy conservation caused by the exposure of mitochondria to 'reperfusion' conditions. However, DHLA was effective in decreasing the formation and the existence of mitochondrial superoxide radicals (O2.-). Apart from its direct O(2.-)-scavenging activities DHLA was also found to control mitochondrial O2.- formation indirectly by regulating redox-cycling ubiquinone. It is suggested that impairment of this mitochondrial O2.- generator mitigates postischemic oxidative stress which in turn reduces damage to hemodynamic heart function.
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effect of alpha lipoic Acid and Dihydrolipoic Acid on ischemia reperfusion injury of the heart and heart mitochondria
Biochimica et Biophysica Acta, 1995Co-Authors: Katrin Schönheit, Lars Gille, Hans NohlAbstract:The aim of the present study was to evaluate a possible interference of alpha-lipoic Acid (LA) or its reduced form (dithiol Dihydrolipoic Acid = DHLA) in the cardiac ischemia/reperfusion injury both at the level of the intact organ and at the subcellular level of mitochondria. In order to follow the effect of LA on the ischemia/reperfusion injury of the heart the isolated perfused organ was subjected to total global ischemia and reperfusion in the presence and absence of different concentrations of LA. Treatment with 0.5 microM LA improved the recovery of hemodynamic parameters; electrophysiological parameters were not influenced. However, application of 10 microM LA to rat hearts further impaired the recovery of hemodynamic functions and prolonged the duration of severe rhythm disturbances in comparison to reperfusion of control hearts. Treatment of isolated mitochondria with any concentration of DHLA could not prevent the impairment of respiratory-linked energy conservation caused by the exposure of mitochondria to 'reperfusion' conditions. However, DHLA was effective in decreasing the formation and the existence of mitochondrial superoxide radicals (O2.-). Apart from its direct O(2.-)-scavenging activities DHLA was also found to control mitochondrial O2.- formation indirectly by regulating redox-cycling ubiquinone. It is suggested that impairment of this mitochondrial O2.- generator mitigates postischemic oxidative stress which in turn reduces damage to hemodynamic heart function.
Baiyun Wang - One of the best experts on this subject based on the ideXlab platform.
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Aldehyde dehydrogenase 1A1 increases NADH levels and promotes tumor growth via glutathione/Dihydrolipoic Acid-dependent NAD+ reduction.
Oncotarget, 2017Co-Authors: Baiyun Wang, Xue Chen, Zixi Wang, Wei Xiong, Xinyuan Zhao, Yang Cao, Yanru Guo, She ChenAbstract:Aldehyde dehydrogenase 1A1 (ALDH1A1) is a member of the aldehyde dehydrogenase superfamily that oxidizes aldehydes to their corresponding Acids, reactions that are coupled to the reduction of NAD+ to NADH. We report here that ALDH1A1 can also use glutathione (GSH) and Dihydrolipoic Acid (DHLA) as electron donors to reduce NAD+ to NADH. The GSH/DHLA-dependent NAD+-reduction activity of ALDH1A1 is not affected by the aldehyde dehydrogenase inhibitor or by mutation of the residues in its aldehyde-binding pocket. It is thus a distinct biochemical reaction from the classic aldehyde-dehydrogenase activity catalyzed by ALDH1A1. We also found that the ectopic expression of ALDH1A1 decreased the intracellular NAD+/NADH ratio, while knockout of ALDH1A1 increased the NAD+/NADH ratio. Simultaneous knockout of ALDH1A1 and its isozyme ALDH3A1 in lung cancer cell line NCI-H460 inhibited tumor growth in a xenograft model. Moreover, the ALDH1A1 mutants that retained their GSH/DHLA-dependent NAD+ reduction activity but lost their aldehyde-dehydrogenase activity were able to decrease the NAD+/NADH ratio and to rescue the impaired growth of ALDH1A1/3A1 double knockout tumor cells. Collectively, these results suggest that this newly characterized GSH/DHLA-dependent NAD+-reduction activity of ALDH1A1 can decrease cellular NAD+/NADH ratio and promote tumor growth.
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aldehyde dehydrogenase 1a1 increases nadh levels and promotes tumor growth via glutathione Dihydrolipoic Acid dependent nad reduction
Oncotarget, 2017Co-Authors: Baiyun Wang, Xue Chen, Zixi Wang, Wei Xiong, Xinyuan Zhao, Yang Cao, Yanru Guo, She Chen, Song HuangAbstract:Aldehyde dehydrogenase 1A1 (ALDH1A1) is a member of the aldehyde dehydrogenase superfamily that oxidizes aldehydes to their corresponding Acids, reactions that are coupled to the reduction of NAD+ to NADH. We report here that ALDH1A1 can also use glutathione (GSH) and Dihydrolipoic Acid (DHLA) as electron donors to reduce NAD+ to NADH. The GSH/DHLA-dependent NAD+-reduction activity of ALDH1A1 is not affected by the aldehyde dehydrogenase inhibitor or by mutation of the residues in its aldehyde-binding pocket. It is thus a distinct biochemical reaction from the classic aldehyde-dehydrogenase activity catalyzed by ALDH1A1. We also found that the ectopic expression of ALDH1A1 decreased the intracellular NAD+/NADH ratio, while knockout of ALDH1A1 increased the NAD+/NADH ratio. Simultaneous knockout of ALDH1A1 and its isozyme ALDH3A1 in lung cancer cell line NCI-H460 inhibited tumor growth in a xenograft model. Moreover, the ALDH1A1 mutants that retained their GSH/DHLA-dependent NAD+ reduction activity but lost their aldehyde-dehydrogenase activity were able to decrease the NAD+/NADH ratio and to rescue the impaired growth of ALDH1A1/3A1 double knockout tumor cells. Collectively, these results suggest that this newly characterized GSH/DHLA-dependent NAD+-reduction activity of ALDH1A1 can decrease cellular NAD+/NADH ratio and promote tumor growth.
Peter H. Seeberger - One of the best experts on this subject based on the ideXlab platform.
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Continuous-flow reactor–based synthesis of carbohydrate and Dihydrolipoic Acid–capped quantum dots
Nature Protocols, 2011Co-Authors: Paola Laurino, Raghavendra Kikkeri, Peter H. SeebergerAbstract:A detailed protocol for the large-scale synthesis of carbohydrate and Dihydrolipoic Acid (DHLA)-coated CdSe/ZnS and CdTe/ZnS nanoparticles using continuous flow reactors is described here. Three continuous flow microreaction systems, operating at three different temperatures, are used for the synthesis of mannose-, galactose- or DHLA-functionalized quantum dots (QDs). In the first step of synthesis, the CdSe and CdTe nanoparticles are prepared. The size and spectral properties of the CdSe core of the nanoparticles are controlled by adjustment of the residence time and the temperature. As a second step, the zinc sulfide capping under homogenous conditions is carried out at a substantially lower temperature than is required for nanoparticle growth in batch processes. Finally, the trioctylphosphine/oleic Acid ligand is effectively replaced with either carbohydrate PEG-thiol moieties or DHLA at 60 °C. This new protocol allows the synthesis of biologically active fluorescent QDs in 4 d.
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Continuous-flow reactor-based synthesis of carbohydrate and Dihydrolipoic Acid-capped quantum dots
Nature Protocols, 2011Co-Authors: Paola Laurino, Raghavendra Kikkeri, Peter H. SeebergerAbstract:Continuous-flow reactor–based synthesis of carbohydrate and Dihydrolipoic Acid–capped quantum dots
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Continuous-flow reactor-based synthesis of carbohydrate and Dihydrolipoic Acid-capped quantum dots
Nature protocols, 2011Co-Authors: Paola Laurino, Raghavendra Kikkeri, Peter H. SeebergerAbstract:A detailed protocol for the large-scale synthesis of carbohydrate and Dihydrolipoic Acid (DHLA)-coated CdSe/ZnS and CdTe/ZnS nanoparticles using continuous flow reactors is described here. Three continuous flow microreaction systems, operating at three different temperatures, are used for the synthesis of mannose-, galactose- or DHLA-functionalized quantum dots (QDs). In the first step of synthesis, the CdSe and CdTe nanoparticles are prepared. The size and spectral properties of the CdSe core of the nanoparticles are controlled by adjustment of the residence time and the temperature. As a second step, the zinc sulfide capping under homogenous conditions is carried out at a substantially lower temperature than is required for nanoparticle growth in batch processes. Finally, the trioctylphosphine/oleic Acid ligand is effectively replaced with either carbohydrate PEG-thiol moieties or DHLA at 60 °C. This new protocol allows the synthesis of biologically active fluorescent QDs in 4 d.
Guido Zimmer - One of the best experts on this subject based on the ideXlab platform.
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The influence of vitamin E and Dihydrolipoic Acid on cardiac energy and glutathione status under hypoxia-reoxygenation.
Biochemistry and molecular biology international, 1995Co-Authors: Nobuya Haramaki, Guido Zimmer, Hasaan Assadnazari, Victor Schepkin, Lester PackerAbstract:The combination of vitamin E supplementation with Dihydrolipoic Acid perfusion synergistically improves cardiac functional recovery during post-ischemic reperfusion or post-hypoxic reoxygenation of the rat heart. To elucidate the mechanism of this effect, isolated rat hearts were perfused using a working heart system. In hearts perfused with a buffer containing Dihydrolipoic Acid, ATP levels were significantly higher than those of hearts perfused without addition of Dihydrolipoic Acid during 90 min of reoxygenation following 30 min of hypoxia. Cardiac tissue glutathione status measured in hearts after perfusion experiments showed significant elevation of reduced glutathione in vitamin E supplemented normoxic rat hearts without hypoxia. Significant elevation of oxidized glutathione was observed in Dihydrolipoic Acid perfused heart after hypoxia-reoxygenation. It is concluded that vitamin E and Dihydrolipoic Acid exert separate and synergistic effects in the protection of the hypoxic-reoxygenated heart.
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Cardiac Recovery during Postischemic Reperfusion Is Improved by Combination of Vitamin E with Dihydrolipoic Acid
Biochemical and biophysical research communications, 1993Co-Authors: Nobuya Haramaki, Lester Packer, Hasaan Assadnazari, Guido ZimmerAbstract:Effects of dietary vitamin E supplementation in rats were studied to determine whether or not they have a higher tolerance against cardiac ischemia-reperfusion injury using the working or Langendorff heart systems. Also, Dihydrolipoic Acid, recently reported to have potent antioxidant properties and accelerate vitamin E recycling of membrane in vitro, was perfused into the heart model systems to investigate its in vivo relationship with vitamin E. Tissue vitamin E content was increased by vitamin E feeding, but heart preparations did not show any improved functional recovery. Control hearts perfused with Dihydrolipoic Acid also did not show any improvement. However, a synergistic response is observed with the combination of Dihydrolipoic Acid perfusion and high dietary vitamin E using both perfusion systems in improvement of cardiac recovery. These results indicate that a high concentration of myocardial vitamin E does not increase tolerance to ischemia-reperfusion injury by itself, but, the combination of exogenous Dihydrolipoic Acid and high endogenous vitamin E can produce synergistic protective effects on recovery from ischemia during reperfusion.
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Dihydrolipoic Acid activates oligomycin-sensitive thiol groups and increases ATP synthesis in mitochondria.
Archives of biochemistry and biophysics, 1991Co-Authors: Guido Zimmer, Luise Mainka, Erika KrügerAbstract:Abstract Investigations with Dihydrolipoic Acid in rat heart mitochondria and mitoplasts reveal an activation of ATP-synthase up to 45%, whereas ATPase activities decrease by 36%. In parallel with an increase in ATP synthesis oligomycin-sensitive mitochondrial SH groups are activated at 2–4 nmol Dihydrolipoic Acid/mg protein. ATPase activation by the uncouplers carbonylcyanide- p -trifluoromethoxyphenylhydrazone and oleate is diminished by Dihydrolipoic Acid, and ATP synthesis depressed by oleate is partially restored. No such efficiency of Dihydrolipoic Acid is seen with palmitate-induced ATPase activation or decrease of ATP synthesis. This indicates different interference of oleate and palmitate with mitochondria. In addition to its known coenzymatic properties Dihydrolipoic Acid may act as a substitute for coenzyme A, thereby diminishing the uncoupling efficiency of oleate. Furthermore, Dihydrolipoic Acid is a very potent antioxidant, shifting the SHSS equilibrium in mitochondria to the reduced state and improving the energetic state of cells.