Biomedical subjects

B Finckh

Publications and source records attributed to B Finckh.

28 records · Page 2Linked to original sources

PubMed1996

Antioxidant and prooxidant activity of alpha-tocopherol in human plasma and low density lipoprotein.

Alpha-Tocopherol is a classical lipophilic antioxidant well known as a scavenger of free radicals in a hydrophobic milieu. However, it can develop both anti- and prooxidant activity in isolated low density lipoprotein (LDL). It is unknown how these activities are balanced in vivo in human plasma. We studied oxidation of plasma and LDL isolated from healthy donors or from a patient with familial isolated vitamin E deficiency and supplemented with alpha-tocopherol in vivo or in vitro. We found that alpha-tocopherol supplementation decreased plasma and LDL oxidizability under strong oxidative conditions when oxidation was initiated by high amounts of Cu2+ or 2,2'-azobis-(2-amidinopropane) hydrochloride (AAPH). The effect was independent of the presence of ascorbate in the samples. Under conditions of mild oxidation by low amounts of Cu2+ or AAPH, alpha-tocopherol supplementation decreased plasma oxidizability only in the presence of physiological amounts of ascorbate. A prooxidant effect of alpha-tocopherol was found under mild oxidative conditions in highly diluted (150-fold) plasma and in isolated LDL. These results indicate that the level of oxidative stress and concentration of co-antioxidants, such as ascorbate, capable of regenerating alpha-tocopherol in the oxidizing lipoprotein particle, appear to represent major factors determining alpha-tocopherol activity towards oxidation both in human plasma and LDL. In vivo, in the presence of high concentrations of co-antioxidants and under mild oxidative conditions, alpha-tocopherol should normally behave as an antioxidant. This antioxidant activity is also expected to prevail under strong oxidative conditions independently of the presence of co-antioxidants but it may evolve into prooxidant, when the co-antioxidants are exhausted under conditions of mild oxidation. It remains to be shown whether such a transformation is physiologically relevant and can occur in vivo.

Adult↗

PubMed1995

Monitoring of ubiquinol-10, ubiquinone-10, carotenoids, and tocopherols in neonatal plasma microsamples using high-performance liquid chromatography with coulometric electrochemical detection.

A method for measuring the lipophilic antioxidants alpha-tocopherol, gamma-tocopherol, ubiquinol-10, ubiquinone-10, beta-cryptoxanthin, and beta-carotene in 5 or 10 microliters neonatal plasma is presented. First lipid extraction together with the internal standards gamma-tocotrienol, ubiquinone-7, ubiquinol-9, ubiquinone-9, and ethyl beta-apo-8'-carotenoate was carried out. Then the components were separated on a RPC2/C18 column. Coulometric electrochemical detection was performed using the reduction-oxidation mode (-0.60 V; -0.15 V; +0.60 V). Detection limits for all components were between 21 and 60 fmol, corresponding to 0.004 and 0.012 mumol/liter plasma; the within-day precision (coefficient of variation) was between 3 and 14% for all measured substances. Reference values are given for healthy newborn children from the second to the sixth day of life. Using the presented HPLC technique it is possible to monitor the concentrations of lipophilic antioxidants in plasma of sick immature newborn children in order to study effects of oxidative stress.

Antioxidants↗

PubMed1995

Antioxidative activity of ubiquinol-10 at physiologic concentrations in human low density lipoprotein.

Ubiquinol-10 is a powerful lipid-soluble antioxidant found in cell membranes and lipoproteins in vivo. Its mechanism of action on lipid peroxidation has been determined in model and biological systems. Data concerning antioxidative activity of ubiquinol-10 in lipoproteins, however, are still controversial. The present work examines its role in the prevention of low density lipoprotein (LDL) oxidation, specifically its influence on a copper-mediated oxidative modification of human LDL in vitro. We found that ubiquinol-10 incorporated in LDL in subnormal concentrations (0.05-0.13 mol/mol LDL incorporated in comparison with 0.10-1.20 mol/mol LDL reported as normally in human LDL) slightly but not significantly decreased production of lipid peroxidation products (lipid peroxides, conjugated dienes, thiobarbituric acid-reactive substances) during the first hours of oxidation. The extent of apolipoprotein B modification (LDL fluorescence at 360/430 nm) was also decreased. Increasing the ubiquinol-10 concentration in LDL to 0.55-1.48 mol/mol LDL made it significantly more resistant to copper-mediated oxidation than native LDL. Adding the same amounts of either ubiquinone-10 or alpha-tocopherol to the LDL suspension had almost no effect on its oxidation. Ubiquinol-10 decreased alpha-tocopherol consumption during LDL oxidation and was consumed more rapidly than the latter. These results demonstrate that LDL ubiquinol-10 content is an important factor influencing LDL susceptibility to oxidation by copper and suggest that it represents the first line of defense against oxidative modification in human LDL.

Antioxidants↗

PubMed1995

Deteriorating free radical-trapping capacity and antioxidant status in plasma during bone marrow transplantation.

Organ toxicity in BMT may in part be due to free radical damage. Therefore the 'Total Radical-trapping Antioxidant Parameter of plasma' (TRAP), individual plasma antioxidants, serum iron and linoleic acid, a main substrate of lipid peroxidation, were monitored before and after BMT, and they were compared with values obtained from healthy controls. Seven patients (3 AML, 3 CML, 1 multiple myeloma) receiving 16 mg/kg busulfan, 30-45 mg VP-16 and 120 mg/kg cyclophosphamide were investigated. TRAP values declined during chemotherapy by about 40% (day -9: 1019 +/- 245 mumol/l, mean +/- s.d.; day 0: 660 +/- 164 mumol/l; P < 0.05). The concentration of uric acid, one of the main antioxidants in plasma, decreased markedly (day -9: 339 +/- 108 mumol/l, day 0: 148 +/- 61 mumol/l; P < 0.05) and paralleled TRAP values. Vitamin E and bilirubin did not change from day -9 to 0 whereas vitamin C increased (day -9: 46 +/- 16 mumol/l, day 0: 89 +/- 44 mumol/l; P < 0.05). Serum iron rapidly increased within the pre-transplantation period, reaching values normally seen only in iron overload (day -9: 11.8 +/- 5.2 mumol/l, day 0: 40.6 +/- 6.5 mumol/l; P < 0.05). Linoleic acid levels were normal at the start and decreased substantially (27.0 +/- 1.6 wt% at day -9; 15.7 +/- 4.9 wt% at day 0; P < 0.05), indicating possible lipid peroxidation during high-dose chemotherapy. In conclusion, complex monitoring of the antioxidant status before and after BMT revealed a breakdown of plasma antioxidant defence and of radical-vulnerable lipids, which was associated with high circulating levels of iron.

Adult↗

PubMed1994

Low density lipoprotein oxidizability by copper correlates to its initial ubiquinol-10 and polyunsaturated fatty acid content.

At an early stage of oxidation induced by Cu2+, the rate of oxidative modification of human low density lipoprotein (LDL) from healthy donors correlated negatively to its ubiquinol-10 (r = -0.58, P < 0.01) and positively to its polyunsaturated fatty acid (PUFA) (r = 0.53, P < 0.05) content. The PUFA/ubiquinol-10 ratio was the best predictor of LDL susceptibility to oxidation (r = 0.68, P < 0.01). No significant correlation between LDL oxidizability and its alpha-tocopherol content was found at any oxidation stage. It is suggested that ubiquinol-10 plays a central role in the early protection of LDL PUFAs against Cu(2+)-induced oxidation whereas alpha-tocopherol posesses both pro- and antioxidant activity.

Adult↗

PubMed1993

Decreased plasma ubiquinone-10 concentration in patients with mevalonate kinase deficiency.

Patients with mevalonate kinase deficiency suffer from psychomotor retardation, ataxia with progredient cerebellar atrophy, and myopathy. The pathophysiology of the disease remains unclear. The mevalonate kinase product, cholesterol, is within the normal range in patient plasma and fibroblasts. In search of the pathophysiology of this disorder, another mevalonate kinase product, ubiquinone-10, was studied. The concentrations of ubiquinone-10 in patient plasma (n = 6) and ubiquinol-10 in patient LDL (n = 2) and the synthesis of ubiquinone-10 in patient fibroblasts (n = 4) were determined. After oxidative modification of LDL by copper in vitro, the concentrations of alpha-tocopherol and polyunsaturated fatty acids in LDL and the relative electrophoretic mobility of LDL were measured to determine the antioxidant capacity of LDL samples of two affected siblings. The ubiquinone-10 concentrations in plasma samples (median = 508 micrograms/L, range = 488-642 micrograms/L) versus controls (median = 613 micrograms/L, range = 564-809 micrograms/L; p < 0.005) were decreased. In LDL samples of two affected siblings, the concentration of ubiquinol-10 and the resistance to oxidation in vitro were found decreased during intercurrent patient crisis condition. In patient fibroblasts (median = 533 dpm/mg protein, range = 399-1,047 dpm/mg protein) versus controls (median = 40,731 dpm/mg protein, range = 12,774-54,739 dpm/mg protein), the synthesis of ubiquinone was found to be decreased. We conclude that mevalonate kinase deficiency leads to a decreased synthesis of ubiquinone-10 and that ubiquinone-10 deficiency is responsible for the clinical progression of this disease characterized by increased lipid peroxidation, cerebellar atrophy, cataract development, and myopathy with increased creatine kinase activity.

Cells, Cultured↗

PubMed1991

Oxidatively modified human low-density lipoprotein stimulates leukocyte adherence to the microvascular endothelium in vivo.

In vitro studies indicate that oxidatively modified low-density lipoprotein (oxLDL) promotes leukocyte sticking to the vascular endothelium, a constant feature of early atherogenesis. Using intravital fluorescence microscopy in the dorsal skinfold chamber model in hamsters, we investigated whether systemic administration of human LDL, oxidized by Cu2+, elicited leukocyte/endothelium interaction in vivo. While no effect was seen after injection of native LDL, oxLDL administration resulted in an immediate induction of leukocyte rolling along the microvascular endothelium and subsequent firm sticking to the wall of postcapillary venules as well as arterioles. The presented model may provide an alternative experimental approach to long-term feeding studies with atherogenic diets for the in vivo investigation of leukocyte/endothelium interaction in early atherogenesis.

Adult↗

PubMed1991

Dietary fish oil reduces leukocyte/endothelium interaction following systemic administration of oxidatively modified low density lipoprotein.

BACKGROUND: In vitro and in vivo experiments have demonstrated the role of oxidatively modified low density lipoprotein (oxLDL) in eliciting leukocyte/endothelium interaction during early atherogenesis. METHODS AND RESULTS: In the present study we investigated the effect of dietary fish oil on oxLDL-induced leukocyte/endothelium interaction using intravital fluorescence microscopy in the dorsal skinfold chamber model in awake Syrian golden hamsters. Hamsters were fed for 4 weeks prior to the experiments with either standard laboratory chow or a diet supplemented with 5% of a fish oil concentrate (18% eicosapentaenoate, 12% docosahexaenoate). The efficacy of the fish oil diet was demonstrated by the incorporation of fish oil-derived omega-3 fatty acids into plasma, leukocyte, and erythrocyte lipids. In control hamsters (n = 7) and fish oil-fed hamsters (n = 7), leukocyte/endothelium interaction was assessed in the time course after intravenous injection of human LDL (4 mg/kg), oxidized by 7.5 microM Cu2+ (6 hours, 37 degrees C). In control hamsters, injection of oxLDL elicited the rolling and sticking of leukocytes to the endothelium of arterioles and postcapillary venules with a maximum 15 minutes after injection (arterioles: from 3 +/- 1 to 91 +/- 25 cells/mm2 at 15 minutes; venules: from 13 +/- 6 to 150 +/- 46 cells/mm2 at 15 minutes; mean +/- SD). This phenomenon was significantly reduced in fish oil-fed hamsters, where 15 minutes after injection of oxLDL leukocyte sticking reached a maximum of only 15 +/- 7 and 20 +/- 5 cells/mm2 in arterioles and postcapillary venules, respectively (p less than 0.01 versus control animals). CONCLUSIONS: The results of the present study suggest that inhibition of leukocyte/endothelium interaction may be one of the mechanisms by which dietary fish oil exerts its protective effects on experimental and clinical atherogenesis.

Animals↗

PubMed1991

Role of leukotrienes in leukocyte adhesion following systemic administration of oxidatively modified human low density lipoprotein in hamsters.

In vitro studies indicate that oxidatively modified low density lipoprotein (oxLDL) promotes leukocyte adhesion to the vascular endothelium, a constant feature of early atherogenesis. Using intravital fluorescence microscopy in the dorsal skinfold chamber model in awake Syrian golden hamsters, we studied whether (a) oxLDL elicits leukocyte/endothelium interaction in vivo, and whether (b) leukotrienes play a mediator role in this event. Leukocyte/endothelium interaction was assessed in the time course after intravenous injection of native human LDL (4 mg/kg body wt) and of oxLDL (7.5 microM Cu++, 6 h, 37 degrees C) into control hamsters and into hamsters, pretreated with the selective leukotriene biosynthesis inhibitor MK-886 (20 mumol/kg, i.v.). While no effect was seen after injection of native LDL, oxLDL elicited an immediate induction of leukocyte adhesion to the endothelium of arterioles and postcapillary venules. Total and differential leukocyte counts suggest that all leukocyte subsets were likewise affected by oxLDL with no specific preference for monocytes. Stimulation of leukocyte adhesion was entirely prevented in inhibitor-treated animals, suggesting the important mediator role of leukotrienes in oxLDL-induced leukocyte/endothelium interaction.

Adult↗

PubMed1991

Antiatherosclerotic effect of probucol in WHHL rabbits: are there plasma parameters to evaluate this effect?

Probucol has been used as a lipid-lowering agent for over 10 years. Lately it has been found that its antiatherogenic action is due mainly to its antioxidative capacity, in addition to its known lipid-lowering effect. To study the antioxidative capability of probucol and its influence on plaque development we used the animal model of the LDL-receptor-defective Watanabe heritable hyperlipidemic (WHHL) rabbit. In this study we measured all lipid values before and after probucol feeding and compared them with corresponding values in untreated controls. Probucol levels were determined, as were the physiological antioxidants alpha and gamma tocopherol (vitamin E). Thiobarbituric reactive substances were measured in plasma as a parameter for lipid peroxidation. In addition to the biochemical measurements the plaque area was analyzed macroscopically and microscopically to check the antiatherosclerotic effect and correlate it with the biochemical parameters. In four experiments we showed that probucol treatment in WHHL rabbits decreases the progression of atherosclerotic plaques by way of a combined lipid-lowering and antioxidative effect.

Animals↗