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L Gille

Publications and source records attributed to L Gille.

24 records · Page 2Linked to original sources
PubMed1995

Effect of alpha-lipoic acid and dihydrolipoic acid on ischemia/reperfusion injury of the heart and heart mitochondria.

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.

Animals↗
PubMed1987

Quantitative neutron capture radiography for studying the biodistribution of tumor-seeking boron-containing compounds.

Biodistribution of two compounds presently considered for use in neutron capture therapy has been studied in mice carrying a transplantable Harding-Passey melanoma. A method is described by which quantitative assessment can be made of the boron distribution in whole-body sections of such animals. An alpha-particle-sensitive film is placed in close contact with a freeze-dried section of an animal and exposed to neutrons. The tracks visible after etching are analyzed optoelectronically in fields of 0.6 X 0.6 mm2 and compared to standards of boron homogeneously distributed in liver homogenates. The dynamic range of this method is about two orders of magnitude in concentration, with a lower detection limit of 0.1 to 0.01 ppm 10B, depending on the rate of induction of spurious tracks by fast neutrons present in the neutron beam chosen. In a transplantable Harding-Passey melanoma in mice, it was found that the sulfhydryl boron hydride Na2B12H11SH presently used for therapy of glioblastoma clears blood, muscle, and brain very rapidly. Its accumulation in tumors was persistent for more than three days. A higher tumor accumulation was observed with its disulfide, which has been suggested for neutron capture therapy. For both compounds, a marked heterogeneity of boron distribution within one tumor was found.

Animals↗
PubMedDate not supplied

Imbalance of oxygen activation and energy metabolism as a consequence or mediator of aging.

Ever increasing numbers of aging theories suggest that free radicals are only one factor among others that may initiate stochastic disorders finally terminating life. It is therefore compelling not only to demonstrate the existence of increasing steady-state concentrations of free oxygen radicals during senescence, but it is essential to show that they act in concert with other postulated triggering factors of aging. We have recently shown that various factors may have a life-long influence and challenge oxygen homeostasis of cell respiration. Among these factors are environmental pollutants, therapeutics, and transient hypoxia. Although the nature of these "hits" is different, mitochondrial respiration was found to respond in a similar manner to each of them. The major derangement was an univalent electron leak to oxygen giving rise to the establishment of oxidative stress. Associated with this transformation, oxidative phosphorylation was impaired with the resultant reduction of cellular ATP. Mitochondria from senescent rats exhibited similar alterations of all cell parameters found when adult animals were exposed to "environmental stress" or transient ischemia. Age-related stimulation of mitochondrial oxygen radical generation is therefore suggested to result from accumulation of minihits during life. Based on our data, together with those from other laboratories, it is possible to assess the ranking order of oxygen radicals in the development of stochastic events associated with (or causing) aging.

Aging↗
PubMedDate not supplied

Evaluation of the antioxidant capacity of ubiquinol and dihydrolipoic acid.

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.

Antioxidants↗
PubMedDate not supplied

The exogenous NADH dehydrogenase of heart mitochondria is the key enzyme responsible for selective cardiotoxicity of anthracyclines.

The molecular mechanism of the anthracycline-dependent development of cardiotoxicity is still far from being clear. However, it is generally accepted, that mitochondria play a significant role in triggering this organ specific injury. The results presented in this study demonstrate that, in contrast to liver mitochondria, isolated heart mitochondria shuttle single electrons to adriamycin, giving rise to oxygen radical formation via autoxidation of adriamycin semiquinones. This one electron reduction of anthracyclines is catalyzed by the exogenous NADH dehydrogenase associated with complex I of heart mitochondria, an enzyme which is lacking in liver mitochondria. Upon addition of NADH heart mitochondria generate significant amounts of adriamycin semiquinones while liver mitochondria were ineffective. Adriamycin semiquinones undergo both autoxidation leading to superoxide radical release and complex reactions under formation of adriamycin aglycone. Due to the high lipophilicity adriamycin aglycones accumulate in the inner mitochondrial membrane where they interfere with electron carriers of the respiratory chain. Adriamycin aglycone semiquinones emerging from an interaction with complex I were found to trigger homolytic cleavage of H2O2 which results in the formation of hydroxyl radicals. As demonstrated in this study the activation of adriamycin by the exogenous NADH dehydrogenase of cardiac mitochondria initiates a cascade of reaction steps leading to the establishment of oxidative stress. Our experiments suggest the exogenous NADH dehydrogenase of heart mitochondria to play a key role in the cardiotoxicity of adriamycin. This organ-specific enzyme initiates a sequence of one electron transfer reactions ending up in the establishment of oxidative stress.

Animals↗