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Biomedical subjects

M Toborek

Publications and source records attributed to M Toborek.

At least 55 records · Page 3Linked to original sources
PubMed1996

Susceptibility to hepatic oxidative stress in rabbits fed different animal and plant fats.

OBJECTIVE: This study was designed to determine the effect of diets enriched with plant and animal fats on oxidative stress and glutathione metabolism in rabbit liver tissues. This study was conducted to investigate whether the type of dietary fat will impact fatty acid composition and oxidant/antioxidant status in tissues. METHODS: Rabbits were fed diets containing 2 g corn oil/100 g diet (low fat diet, LF) and LF supplemented with 16 g/100 g diet of either corn oil (CO), CO with added cholesterol (CO + C), milk fat (MF), chicken fat (CF), beef tallow (BT), or lard (L) for 30 days. After the feeding period, livers were analyzed for total fatty acid composition, thiobarbituric acid reactive substances (TBARS), conjugated dienes, and reduced glutathione (GSH), as well as for activities of glutathione peroxidase (GP) and glutathione reductase (GR). Moreover, to fully determine the oxidative stability and free radical trapping capacity, TBARS levels were measured after additional exposure of liver homogenates to 10 mM 2,2(1)-azo-bis-amidinopropane- hydrochloride (AAPH) for up to 21 hours. RESULTS: CO and CF, but not saturated fats such as MF, increased liver conjugated diene and TBARS levels and decreased liver GSH levels and GP activity. In tissues additionally exposed to AAPH, the maximum oxidation, measured as TBARS, was reached between 6 and 7 hours of treatment, independent of dietary fat. In addition, there was a marked effect of AAPH on the maximum rate of TBARS formation with the following descending order: CO > CF > CO + C > L > MF > BT > LF. This high susceptibility to oxidative stress in liver tissues of rabbits fed the CO diet may be explained in part by the significant elevation in linoleic acid (18:2n-6). DISCUSSION: There appears to be an inverse correlation between dietary fat-mediated oxidative stress and antioxidant enzyme activities. The present data suggest that high levels of dietary unsaturated fat should be avoided if oxidative stress is a critical issue in nutrition-related diseases. In addition, these data support our hypothesis that diets rich in MF provide a lipid environment with low susceptibility to oxidative stress.

Amidines↗
PubMed1996

Nutritional implications in vascular endothelial cell metabolism.

Endothelial cells interact with blood components and the abluminal tissues, thus playing an active role in many aspects of vascular function. Numerous physiologic and pathophysiologic stimuli are often mediated by nutrients that can contribute to the overall functions of endothelial cells in the regulation of vascular tone, coagulation, cellular growth, immune and inflammatory responses. Therefore, nutrient-mediated functional changes of the endothelium and the underlying tissues may be significantly involved in disease processes such as atherosclerosis. There is evidence that individual nutrients or nutrient derivatives may either provoke or prevent metabolic and physiologic perturbations of the vascular endothelium. Diets high in fat and/or calories are considered a risk factor for the development of atherosclerosis. Our research has shown that certain diet-derived lipids and their derivatives can disrupt normal endothelial integrity, thus reducing the ability of the endothelium to act as a selectively permeable barrier to blood components. Mechanisms underlying fatty acid-mediated endothelial cell dysfunction may be related to changes in fatty acid composition as well as to an increase in cellular oxidative stress. Selective lipid accumulation and fatty acid changes in endothelial cells can modulate membrane fluidity, proteoglycan metabolism and signal transduction mechanisms. Most importantly, dietary fats rich in certain unsaturated fatty acids, may be atherogenic by enhancing the formation of reactive oxygen intermediates. A subsequent imbalance in cellular oxidative stress/antioxidant status can activate oxidative stress-responsive transcription factors, which in turn may promote cytokine production, expression of adhesion molecules on the surface of endothelial cells, and thus intensify an inflammatory response in atherosclerosis. Our data also suggest that certain nutrients, which have antioxidant and/or membrane stabilizing properties, can protect endothelial cells by interfering with lipid/cytokine-mediated endothelial cell dysfunction. These findings contribute to the understanding of the interactive role of dietary fats with inflammatory components, as well as with nutrients that exhibit antiatherogenic properties, in the development of atherosclerosis.

Antioxidants↗
PubMed1996

Linoleic acid activates nuclear transcription factor-kappa B (NF-kappa B) and induces NF-kappa B-dependent transcription in cultured endothelial cells.

High dietary intakes of unsaturated fats may be atherogenic by disrupting normal functions of the vascular endothelium, due in part to the ability of linoleic acid (18:2n-6) to contribute to an increase in cellular oxidative stress and related injurious events. Exposing endothelial cells to 90 micromol linoleic acid/L for 6 h resulted in a significant increase in lipid hydroperoxides that coincided wih an increase in intracellular calcium concentrations. Treatment with this fatty acid caused an initial decrease in glutathione concentrations, which was followed by an increase at later time points. Most importantly, a significant activation of the oxidative stress-sensitive nuclear transcription factor-kappa B (NF-kappa B) was achieved after a 6-h exposure to 18:2n-6, which is the time point at which maximal depletion of cellular glutathione was observed. The fatty acid-mediated NF-kappa B activation was accompanied by induction of NF-kappa B-dependent transcription, as measured by chloramphenicol acetyltransferase (CAT) assay of an NF-kappa B-responsive promoter construct. Pretreatment of endothelial cells with vitamin E and N-acetyl cysteine inhibited the fatty acid-induced activation of NF-kappa B and formation of lipid hydroperoxides. These data suggest that oxidative stress-induced cellular changes are critical early events in fatty acid-mediated endothelial cell dysfunction.

Animals↗
PubMed1996

Linoleic acid and TNF-alpha cross-amplify oxidative injury and dysfunction of endothelial cells.

Factors implicated in the development of atherosclerosis include metabolic alterations of the endothelium induced by certain lipids and inflammatory cytokines. To study the hypothesis that the combined presence of unsaturated fatty acids and inflammatory cytokines may cross-amplify their individual injurious effects, cultured endothelial cells were treated with 90 mu M of linoleic acid (18:2 n-6) and/or 20 ng/ml (100 U/ml) of tumor necrosis factor-alpha (TNF) for up to 24 h. Disturbances in endothelial cell metabolism were determined by measuring cellular oxidative stress, oxidative stress-inducible nuclear factor-kappa B (NF-kappa B) and NF-kappa B-related transcription, intracellular calcium levels, and endothelial barrier function reflected by transendothelial albumin movement. Both 18:2 and TNF increased cellular oxidation, intracellular calcium, and endothelial barrier permeability. These changes were cross-amplified in cells treated both with 18:2 and TNF, compared with 18:2 or TNF alone. In contrast, a combined exposure to 18:2 and TNF did not potentiate effects mediated by 18:2 or TNF alone on NF-kappa B activation or NF-kappa B-related transcription. Pretreatment with 25 mu M vitamin E attenuated 18:2 and/or TNF-mediated endothelial cell dysfunction. These results suggest that certain unsaturated fatty acids can potentiate TNF-mediated endothelial cell dysfunction and that oxidative stress may be partially responsible for these metabolic events. These findings have implications for understanding lipid-mediated inflammatory responses in atherosclerosis.

Animals↗
PubMed1995

Exposure to polychlorinated biphenyls causes endothelial cell dysfunction.

Environmental chemicals, such as polychlorinated biphenyls (PCBs), may be atherogenic by disrupting normal functions of the vascular endothelium. To investigate this hypothesis, porcine pulmonary artery-derived endothelial cells were exposed to 3,3',4,4'-tetrachlorobiphenyl (PCB 77), 2,3,4,4',5-pentachlorobiphenyl (PCB 114), or 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) for up to 24 hours. These PCBs were selected for their varying binding avidities with the aryl hydrocarbon (Ah) receptor and differences in their induction of cytochrome P450. PCB 77 and PCB 114 significantly disrupted, in a dose-dependent manner, endothelial barrier function by allowing an increase in albumin transfer across endothelial monolayers. These PCBs also contributed markedly to cellular oxidative stress, as measured by 2,7-dichlorofluorescin (DCF) fluorescence and lipid hydroperoxides, and caused a significant increase in intracellular calcium ([Ca2+]i) levels. Enhanced oxidative stress and [Ca2+]i in PCB 77- and PCB 114-treated cells were accompanied by increased activity and content of cytochrome P450 1A and by a decrease in the vitamin E content in the culture medium. In contrast to the effects of PCB 77 and PCB 114, cell exposure to PCB 153 had no effect on cellular oxidation, [Ca2+]i, or endothelial barrier function. These results suggest that certain PCBs may play a role in the development of atherosclerosis by causing endothelial cell dysfunction and a decrease in the barrier function of the vascular endothelium. It is possible that interaction of PCBs with the Ah receptor and activation of the cytochrome P450 1A subfamily are involved in this pathology.

Animals↗
PubMed1995

Increased lipid peroxidation as a mechanism of methionine-induced atherosclerosis in rabbits.

Methionine is converted by the transmethylation/transsulfuration pathway to homocysteine which may exert atherogenic effects by several mechanisms, including lipid peroxidation. Therefore, the excessive dietary methionine may induce the development of atherosclerosis. To test this hypothesis, plasma and aortic thiobarbituric acid reactive substances (TBARS), as well as activities of aortic and erythrocyte superoxide dismutase (SOD), catalase and selenium-dependent glutathione peroxidase (GPX) were measured in rabbits fed a diet enriched with 0.3% methionine for 6 or 9 months. Histological examinations of aortas also were performed. Feeding rabbits a methionine-enriched diet for 6 or 9 months resulted in significant increases in plasma and aortic TBARS levels and aortic antioxidant enzyme activities. However, a decrease in plasma antioxidant activity (AOA) was observed. In erythrocytes, SOD activity increased, catalase remained normal and GPX decreased in the treated animals. Histological examination of aortas showed typical atherosclerotic changes, such as intimal thickening, deposition of cholesterol, and calcification in methionine-fed rabbits. These results confirm that high-methionine diet may induce atherosclerosis in rabbits and indicate disturbances in lipid peroxidation and antioxidant processes as possible mechanisms of its atherogenic influence.

Animals↗
PubMed1995

Role of glutathione redox cycle in TNF-alpha-mediated endothelial cell dysfunction.

Modulation of the glutathione redox cycle may influence tumor necrosis factor-alpha (TNF)-mediated disturbances of endothelial integrity. To test this hypothesis, normal endothelial cells or cells with either increased or decreased glutathione levels were exposed to 100 ng (500 U) TNF/ml. Increased glutathione levels were achieved by exposure to 0.2 mM N-acetyl-L-cysteine (NAC) and decreased glutathione levels by exposure to 25 microM buthionine sulfoximine (BSO). Several components of the glutathione redox cycle as well as markers of endothelial integrity, such as cytoplasmic free calcium and transendothelial albumin transfer, were measured in the treated cells. Exposure to TNF for 3 and 6 h decreased total glutathione levels, which was followed by an increase at later time points. Moreover, treatment with TNF resulted in an increase in the ratio of oxidized to reduced glutathione, intracellular free calcium, albumin transfer across endothelial monolayers and lipid hydroperoxides. However, an increase in lipid hydroperoxides was seen only when endothelial cell cultures were supplemented with iron. BSO treatment increased susceptibility of endothelial cells to TNF-mediated metabolic disturbances. On the other hand, NAC partially protected against TNF-induced injury to endothelial monolayers. Our results demonstrate the important role of the glutathione redox cycle in TNF-mediated disturbances of the vascular endothelium and indicate that modulation of glutathione levels may potentiate the injurious effects of this inflammatory cytokine.

Acetylcysteine↗
PubMed1995

Animal and plant fats selectively modulate oxidizability of rabbit LDL and LDL-mediated disruption of endothelial barrier function.

Enrichment of lipoproteins with fatty acids derived from animal and/or plant fats may modify the oxidizability of lipoproteins and their effects on endothelial barrier function. To test this hypothesis, rabbits were fed for 30 days diets containing 2 g corn oil/100 g diet (low fat diet) or low fat supplemented with 16 g/100 g diet of corn oil, corn oil with added cholesterol, milk fat, chicken fat, beef tallow or lard. Compared with those fed the low fat, serum and LDL cholesterol concentrations were significantly lower in rabbits fed corn oil and greater in animals fed corn oil with added cholesterol or chicken fat. In contrast to the cholesterol data, lipid hydroperoxide levels were highest in oxidized LDL derived from rabbits fed corn oil or lard. LDL vitamin E levels were highest in rabbits fed corn oil with added cholesterol. The significant elevations in linoleic acid [18:2(n-6)] in serum and LDL may partially explain the high oxidizability of LDL in rabbits fed corn oil. LDL isolated from animals fed corn oil, lard or milk fat had significantly greater albumin transfer across cultured endothelial monolayers compared with those of the low fat diet group. Their oxidative modification further contributed to endothelial barrier dysfunction. Dietary cholesterol supplementation to the corn oil diet decreased oxidizability of LDL and partially protected the oxidized LDL-mediated endothelial cell dysfunction as compared with the corn oil diet group. These data suggest that beef tallow and chicken fat are the least atherogenic fats if oxidative modification of LDL is a critical issue in atherosclerosis.

Animals↗
PubMed1994

Influence of nutrients and cytokines on endothelial cell metabolism.

The vascular endothelium plays an active role in physiological processes such as hemostasis, regulation of vessel tone and vascular permeability. Cell injury, or any event which disrupts endothelial integrity and thus endothelial permeability properties, may be involved in the early events leading to atherosclerotic lesion formation. Because of its constant exposure to blood components, including prooxidants, diet-derived fats and their derivatives, the endothelium is susceptible to oxidative stress and to injury mediated by blood lipid components. It is likely that these events potentiate the overall inflammatory response to injury by increasing cytokine release in proximity to the endothelium, which then could further disrupt endothelial barrier function. Even though mechanisms associated with lipid/cytokine-mediated endothelial cell dysfunction are unclear, our data suggest that they may be both oxidative and non-oxidative in nature. We suggest that dietary fats, rich in certain unsaturated fatty acids are atherogenic by enhancing the formation of reactive oxygen intermediates. These intermediates can activate oxidative stress-responsive transcription factors, such as NF-kappa B, which in turn may promote cytokine production, adhesion molecule expression and ultimately endothelial barrier dysfunction. The resulting disturbances in endothelial integrity possibly allow increased penetration of cholesterol-rich lipoprotein remnants into the arterial wall, a critical event in the etiology of atherosclerosis. Data suggest that certain nutrients, which have antioxidant and/or membrane stabilizing properties, protect endothelial cells by interfering with the above proposed mechanisms of endothelial cell dysfunction.

Arteriosclerosis↗
PubMed1994

Nutrition, endothelial cell metabolism, and atherosclerosis.

The vascular endothelium that forms an interface between the blood and the surrounding tissues is continuously exposed to both physiologic and pathophysiologic stimuli. These stimuli are often mediated by nutrients that can contribute to the overall function of the endothelial cell in the regulation of vascular tone, coagulation and fibrinolysis, cellular growth and differentiation, and immune and inflammatory responses. Therefore, nutrient-mediated functional changes of the endothelium and the underlying tissues may be significantly involved in the atherosclerotic disease process. There is evidence that individual nutrients or nutrient derivatives may either provoke or prevent metabolic and physiologic perturbations of the vascular endothelium. Preservation of nutrients that exhibit antiatherogenic properties may, therefore, be a critical issue in the preparation and processing of foods. This review focuses on selected nutrients as they affect endothelial cell metabolism and their possible implications in atherosclerosis.

Amino Acids↗
PubMed1994

Fatty acid-mediated effects on the glutathione redox cycle in cultured endothelial cells.

Endothelial barrier dysfunction after exposure to fatty acids may be mediated by disturbances in antioxidant protection. To evaluate this hypothesis, components of the glutathione redox cycle such as total, reduced, and oxidized glutathione and glutathione reductase and peroxidase were measured in cultured porcine endothelial cells exposed to 90 mumol/L of stearic acid (18:0), oleic acid (18:1 omega-9), linoleic acid (18:2 omega-6), linolenic acid (18:3 omega-3), and/or buthionine sulfoximine (BSO). Treatment with fatty acids caused an initial decrease in glutathione concentrations, which was followed by an increase at later time points. The most marked changes in glutathione redox cycle components were induced by 18:2. BSO increased susceptibility of fatty acid-mediated injury to endothelial monolayers. The results indicate a fundamental role of the glutathione redox cycle in protection against fatty acid-mediated injury to the vascular endothelium.

Analysis of Variance↗
PubMed1993

Vitamin E attenuates induction of elastase-like activity by tumor necrosis factor-alpha, cholestan-3 beta,5 alpha,6 beta-triol and linoleic acid in cultured endothelial cells.

Disturbances in arterial wall elastin metabolism appear to be important factors in atherosclerosis development. To evaluate this hypothesis, elastase-like activity was determined in cultured endothelial cells and their surrounding media after exposure to tumor necrosis factor-alpha (TNF), cholestan-3 beta,5 alpha,6 beta-triol (Triol) and linoleic acid (18:2). Significant increases in elastase-like activity both in the cells and in the media were observed when subconfluent endothelial cells were treated with 12 microM Triol, 500 U TNF/ml, or 90 microM 18:2, for 72 h in the presence of 5% calf serum. Even higher activities were measured when endothelial cells were seeded directly into media enriched with 18:2, TNF or Triol and treated for 72 h. Vitamin E supplementation (25 microM) attenuated elastase-like activity in cells and media, independent of treatment. These results suggest that elastase-like enzyme induction in endothelial cells may be involved in cellular perturbations induced by certain lipids and cytokines. Vitamin E may provide a protective function by preventing the induction of elastolytic enzymes. This may have implications in elastin metabolism and atherosclerosis.

Animals↗
PubMed1993

Modulation of procainamide toxicity by selenium-enriched yeast in rats.

Free radical processes are proposed to play a crucial role in the development of procainamide adverse effects. Therefore, selenium, as a potent antioxidant, may modified procainamide toxicity. To test this hypothesis plasma and liver thiobarbituric acid-reacting substances (TBARS), plasma antioxidant activity (AOA), erythrocyte and liver superoxide dismutase (SOD), catalase, as well as selenium-dependent glutathione peroxidase (Se-GPX) were determined in the following four groups of rats: selenium-treated (Se), procainamide-treated (P), procainamide and selenium-treated (P + Se), and control (C). Morphological studies of leukocytes [tested for lupus erythematosus (LE) cells] and liver were also made. Atypical, i.e. enlarged and swollen, leukocytes resulting from procainamide and selenium treatment were observed. These changes were found in four out of five rats in the Se group, eight out of ten in the P group, and in seven out of ten in the P + Se group. LE-like cells were observed in two rats in the P + Se group. A statistically significant decrease in plasma and liver TBARS by 20% and 36%, respectively, increased activity of SOD by 20%, catalase by 48% and Se-GPX by 15% in erythrocytes, and decreased activity of liver SOD by 17% and catalase by 22% were found in the P + Se group as compared to the P group. These results indicated that selenium exerted antioxidant effects on the procainamide-treated rats. However, selenium did not prevent the development of disturbances in leukocyte morphology, on the contrary, it possibly promoted the conversion of leukocytes to LE cells.

Animals↗
PubMed1993

Increase in antioxidant activity in procainamide-treated rats.

Recent studies suggest that in vivo procainamide oxidation underlies induction of autoimmunity by this drug. Since drug metabolism may be accompanied by generation of reactive oxygen species, plasma and liver thiobarbituric acid reacting substances (TBARS), activity of erythrocyte and liver superoxide dismutase, catalase, selenium-dependent glutathione peroxidase (Se-GPX), and plasma antioxidant activity in procainamide treated rats were evaluated. Procainamide administration increased liver lipid peroxide levels, intensified the activity of liver catalase and erythrocyte superoxide dismutase, as well as plasma antioxidant activity. The remaining biochemical parameters in the treated rats were within control values, except for the decreased erythrocyte catalase activity. We conclude, that the increased activity of free radicals observed in the treated rats could contribute to the development of procainamide induced side effects.

Animals↗
PubMed1992

Effect of hemodialysis on lipid peroxidation and antioxidant system in patients with chronic renal failure.

Plasma lipid peroxidation, activity of erythrocyte superoxide dismutase (SOD) and catalase, and serum antioxidant activity (AOA) in uremic patients were examined before and after hemodialysis. An increased level of lipid peroxidation, a decreased serum AOA level, and elevated SOD and normal catalase activity before hemodialysis were observed in uremic patients compared with controls. Hemodialysis was found to produce increased lipid peroxidation, a simultaneous decrease of SOD activity, and lack of any changes in serum AOA and erythrocyte catalase. It is suggested that intensification of lipid peroxidation during hemodialysis could account for accelerated progress of atherosclerosis in patients with renal insufficiency.

Adult↗