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B S van Asbeck

Publications and source records attributed to B S van Asbeck.

At least 37 records · Page 2Linked to original sources
PubMed1998

Nerve function and oxidative stress in diabetic and vitamin E-deficient rats.

Nerve dysfunction in diabetes is associated with increased oxidative stress. Vitamin E depletion also leads to enhanced presence of reactive oxygen species (ROS). We compared systemic and endoneurial ROS activity and nerve conduction in vitamin E-depleted control and streptozotocin-diabetic rats (CE- and DE-), and in normally fed control and diabetic animals (CE+ and DE+). Nerve conduction was reduced in both diabetic groups. Vitamin E depletion caused a small further nerve conduction deficit in the diabetic, but not in the control animals. The combination of vitamin E deficiency and streptozotocin-diabetes (group DE-) appeared to be lethal. In the remaining groups, an important rise in sciatic nerve malondialdehyde (MDA) was observed in the vitamin E-depleted control rats. In contrast, plasma MDA levels were elevated in group DE+ only, whereas hydrogen peroxide levels were increased in group CE-. Endoneurial total and oxidized glutathione and catalase were predominantly elevated in group DE+. These data show that nerve lipid peroxidation induced by vitamin E depletion does not lead to reduced nerve conduction or changes in antioxidant concentrations as observed in STZ-diabetes. The marked systemic changes in MDA and antioxidants suggest that nerve dysfunction in experimental hyperglycemia is rather a consequence of systemic than direct nerve damage.

Animals↗
PubMed1998

Low-dose N-acetylcysteine protects rats against endotoxin-mediated oxidative stress, but high-dose increases mortality.

We evaluated the effect of the antioxidant N-acetylcysteine (NAC) on oxidative stress, lung damage, and mortality induced by an endotoxin (lipopolysaccharide, or LPS) in the rat. Continuous intravenous infusion of 275 mg NAC/kg in 48 h, starting 24 h before LPS challenge, decreased hydrogen peroxide (H2O2) concentrations in whole blood (p < 0.01). This decrease was accompanied by fewer histologic abnormalities of the lung and decreased mortality (p < 0.025), compared with rats receiving LPS alone. N-Acetylserine, which has no sulfhydryl group, did not protect rats against LPS toxicity. Improved survival was not associated with an increase in pulmonary reduced glutathione, nor with inhibition of serum tumor necrosis factor (TNF) activity. In vitro, TNF production and DNA binding of nuclear factor kappa B (NF-kappaB) in human Mono Mac 6 cells was only inhibited at concentrations of NAC above 20 mM. High-dose NAC treatment (550 and 950 mg/kg in 48 h) decreased lung GSH (p < 0.05) and resulted in a significantly smaller number of surviving animals when compared with the low-dose NAC group (p < 0.025). In vitro, NAC increased hydroxyl radical generation in a system with Fe(III)-citrate and H2O2 by reducing ferric iron to its catalytic, active Fe2+ form. We conclude that low-dose NAC protects against LPS toxicity by scavenging H2O2, while higher doses may have the opposite effect.

Acetylcysteine↗
PubMed1998

Hydrogen peroxide modulation of the superoxide anion production by stimulated neutrophils.

Hydrogen peroxide (H2O2) pretreatment of human neutrophils results in a suppression of the superoxide anion (O2) production in response to surface-acting stimulants such as lipopolysaccharide (LPS) and opsonized zymosan. This effect was not observed when phorbol myristate acetate (PMA), formyl-methionyl-leucyl-phenylalanine (fMLP) or tumor necrosis factor alpha (TNF alpha) were used as a stimuli. Since the response to PMA and other stimuli was unimpaired by preincubation with H2O2, we assume that the H2O2 modulated O2 production is probably due to alteration of the LPS receptor conformation rather than effecting directly NADPH-oxidase. The balance of reactive oxygen species (ROS) produced by neutrophils in the state of sepsis may thus be autoregulated by negative feedback phenomena of locally produced H202.

Humans↗
PubMed1997

Dimethylthiourea protects rats against gram-negative sepsis and decreases tumor necrosis factor and nuclear factor kappaB activity.

The thiol-containing compound dimethylthiourea (DMTU) is a known protectant in various models of oxidant-mediated tissue damage. Protective effects of DMTU have also been reported in studies on endotoxin-induced (LPS-induced) tissue injury. DMTU may exert this protective effect by reducing oxidative stress. In this study we investigated the effect of DMTU on survival, oxidative stress, and tumor necrosis factor (TNF) activity in two rat models of gram-negative bacterial sepsis. Intraperitoneal injection of 500 mg DMTU/kg protected against the lethal effects of intraperitoneally injected LPS (5 mg/kg) and live Salmonella typhimurium (3.3 x 10(10) CFU/kg). LPS injection resulted in oxidative stress, as indicated by an elevated concentration of hydrogen peroxide (H(2)O(2)) in normal and carbon monoxide-treated deproteinized blood. We also observed increased H(2)O(2) levels in animals injected with live Salmonella typhimurium. Although DMTU improved survival in both models, H(2)O(2) concentrations were not affected by it. This is consistent with our in vitro observation that DMTU is a weak H(2)O(2) scavenger. Serum TNF activity, however, was substantially decreased by DMTU, and this was associated with a reduced activation of nuclear factor kappaB in the peritoneal cells of LPS-treated rats. In addition, LPS-induced TNF production in vitro by rat peritoneal macrophages was inhibited by DMTU (p < 0.05). These results suggest that the protective effect of DMTU in gram-negative bacterial sepsis may be the result of a reduction in TNF activity. DMTU does not exert this effect by H(2)O(2) scavenging but may inactivate toxic H(2)O(2) metabolites.

Animals↗
PubMed1996

Effects of insulin treatment on endoneurial and systemic oxidative stress in relation to nerve conduction in streptozotocin-diabetic rats.

As increased oxidative stress is probably a pathogenetic factor in the development of diabetic complications, we studied nerve function and endogenous antioxidants in plasma, erythrocytes and sciatic nerve of untreated and insulin-treated streptozotocin-diabetic rats. After 18 weeks, the diabetes-induced sciatic nerve conduction velocity deficits were approximately 65% improved by insulin (P < 0.001). Plasma superoxide dismutase was significantly reduced in diabetes (P < 0.01); smaller decreases in plasma catalase and glutathione levels were observed. These changes were corrected by insulin treatment. In erythrocytes, decreased superoxide dismutase (P < 0.05) and increased total glutathione levels (P < 0.05) were found. All effects of diabetes, including a rise in plasma malonyldialdehyde (P < 0.05), were partially reversed by insulin treatment. In nervous tissue, diabetes caused increased catalase activity, uninfluenced by insulin (P < 0.05). Nerve superoxide dismutase and glutathione did not change. The data suggest that in diabetes, changes in systemic rather than endoneurial oxidative stress lead to nerve dysfunction.

Animals↗
PubMed1996

Use of iron chelators in preventing hydroxyl radical damage: adult respiratory distress syndrome as an experimental model for the pathophysiology and treatment of oxygen-radical-mediated tissue damage.

Tissue damage in many diseases is caused by hydroxyl radicals, generated during single electron reduction of oxygen. The first step is usually the formation of the superoxide radical. This radical is constantly formed in all living cells, and in particular during activation of phagocytes or during reoxygenation following ischaemia. Damage, however, only occurs in the presence of catalytic transition metals of which iron is the most important in human pathology. Oxygen-radical-mediated damage can be prevented by iron chelators, as has been demonstrated in numerous in vitro and in vivo experiments. A description is given as to how toxic oxygen products are formed in biological systems, and how organisms succeed in preventing autodestruction by scavenger molecules. The use of iron chelators to prevent oxygen radical damage is reviewed with emphasis on possible clinical applications. The adult respiratory distress syndrome is described in more detail as a model for oxygen-radical-mediated damage that can be successfully prevented with iron chelators.

Free Radical Scavengers↗
PubMed1994

Copper, zinc-superoxide dismutase and hydrogen peroxide: a hydroxyl radical generating system.

Because superoxide (O2-.) is a mediator of inflammation, Cu,Zn-superoxide dismutase (Cu,Zn-SOD) has been employed as an anti-inflammatory compound. However, Cu,Zn-SOD can increase intra- and extracellular H2O2. This may react with the Cu atom of SOD in a Fenton-type reaction producing the hydroxyl radical (.OH). With a non-physiological concentration of H2O2 (0.8 mmol/l) to stimulate chemiluminescence (CL) at a level < 2 mV, it was observed that the addition of Cu,Zn-SOD (100 micrograms/ml) yielded an increase of 204.7 +/- 78.2 mV (P < 0.05). This increase in CL depended on the concentrations of H2O2 and Cu,Zn-SOD and was only seen with luminol (reacts with O2-. and .OH) but not with lucigenin (reacts with O2-.). No CL was observed when Cu,Zn-SOD was heat inactivated, or when Mn-SOD was used. Dissipators of H2O2, copper chelators and .OH scavengers attenuated this CL. In electron paramagnetic resonance, with the use of the spin-trap dimethylpyrroline-N-oxide (DMPO), it was demonstrated that, in the reaction between H2O2 and Cu,Zn-SOD, .OH was generated. The oxidation of keto-methylthiobutyric acid (KMB) to ethylene, assessed by gas chromatography, demonstrated that H2O2/Cu,Zn-SOD-generated .OH can react with KMB and not only with the SOD molecule itself. We conclude that H2O2 reduces SOD-bound Cu2+ to Cu1+ which, in reaction with H2O2 catalyses its reduction to OH. Whether this 'pro-inflammatory' reaction occurs in vivo remains to be established.

Acridines↗
PubMed1994

Role for oxygen radicals in self-sustained HIV-1 replication in monocyte-derived macrophages: enhanced HIV-1 replication by N-acetyl-L-cysteine.

N-acetyl-L-cysteine (NAC) has been proposed as a therapeutic agent for AIDS patients because it reduces human immunodeficiency virus type 1 (HIV-1) replication in stimulated T cells. However, NAC and glutathione enhanced acute HIV-1 replication in monocyte-derived macrophages. Buthionine sulfoximine did not affect NAC-mediated enhanced HIV-1 replication, indicating that the NAC-mediated effects are glutathione-independent. Superoxide dismutase and the hydroxyl radical scavengers dimethylthiourea and thiourea, but not urea, inhibited acute HIV-1 replication in macrophages. NAC reduced ferricytochrome c and increased dose-dependently Fe(III)-citrate and Fe(III)-EDTA-catalyzed hydroxyl radical formation in a system using glucose and glucose oxidase. Dimethylthiourea and thiourea, but not urea and superoxide dismutase, dose-dependently inhibited NAC-mediated enhancement of HIV-1 replication. These data suggest that oxygen radicals play an important role in self-sustained HIV-1 replication in macrophages and that oxygen radical scavengers other than NAC should be considered as therapeutic agents for AIDS patients.

Acetylcysteine↗
PubMed1994

Comparison of different iron chelators as protective agents against acute doxorubicin-induced cardiotoxicity.

Doxorubicin (Dox) is a widely used antineoplastic agent. Irreversible cardiomyopathy is a serious and dose-limiting side effect after chronic administration. The iron chelating bispiperazinedione ICRF-187 is currently the only drug which affords protection against Dox-induced cardiotoxicity. To compare the protective value of structurally unrelated iron chelators, isolated mice atria were exposed to Dox (30 microM) and either the hydroxamate desferrioxamine (DFO, 200 and 500 microM), EDTA (200 microM) or the hydroxypridones CP44 (200 microM), CP51 (200 microM), and CP93 (200 microM) and ICRF-187 (200 and 500 microM). The nitroxide TEMPO (5 mM) lacks iron chelating properties but was used to prevent redox cycling or iron and scavenge superoxide. All iron chelators, except EDTA. CP93 and CP44, were modestly protective against a Dox-induced decrease in contractile force. As a single agent the hydroxypridones decreased atrial contractile force. At a concentration of 200 microM, DFO was the most effective protector of the chelators tested. However, this effect disappeared when a concentration of 500 microM was used. This in contrast to ICRF-187 for which a concentration-dependent inhibition of Dox-induced decrease in contractile force was observed. TEMPO exerted a biphasic response consisting of a two-fold increase in contractile force, followed by a decrease in force and irregular contractions. In this model TEMPO lacked any perspective as a cardioprotectant. We conclude that at 200 microM. DFO was the most effective agent to afford protection against Dox-mediated atrial malfunction. However, at 500 microM, DFO was not effective whereas ICRF-187 afforded partial protection. Hydroxipyridones were found to be of limited value because of a negative inotropic effect on the isolated atria.

Animals↗
PubMed1993

Phase I study using desferrioxamine and iron sorbitol citrate in an attempt to modulate the iron status of tumor cells to enhance doxorubicin activity.

A novel approach to enhance the activity of doxorubicin is to increase the availability of cellular "chelatable" iron to participate in doxorubicin-mediated free-radical generation. To achieve this, we designed a regimen consisting of desferrioxamine (DFO, 50 mg/kg daily given as an i.v. infusion over 72 h) to increase cellular iron uptake. Thereafter, the combination of iron sorbitol citrate (ISC) and doxorubicin (as a single agent or as part of the CHOP regimen) was given. In a phase I study we investigated the toxicity of this regimen in nine patients with refractory malignant disease. Severe but reversible ocular toxicity (i.e., acute maculopathy) was observed in two patients. As these patients were the only ones who were pretreated with cisplatin, we caution against the use of DFO in cisplatin-pretreated patients. Severe phlebitis was encountered in five of nine patients. A partial remission was observed in two of four patients with refractory Non-Hodgkin's lymphoma who were treated with DFO, ISC, and doxorubicin as part of the CHOP regimen. We conclude that pretreatment with DFO and iron sorbitol citrate may be of benefit in the treatment of malignancies with doxorubicin-containing regimens, but ocular toxicity and severe phlebitis limits the use of DFO in this approach. The attachment of DFO to biocompatible polymers may be a method of overcoming the observed toxicity and warrants further study.

Adult↗
PubMed1993

The in vitro response of human tumour cells to desferrioxamine is growth medium dependent.

Iron chelating agents have been demonstrated to inhibit tumour cell growth. However, in vitro and in vivo results using desferrioxamine a hexadentate iron chelating agent, for anti-cancer treatment are not always in agreement. Therefore, we have studied the response of three human tumour cell lines (HL-60 promyelocytic leukaemia, MCF-7 breast cancer and HepG2 hepatoma), grown in culture medium supplemented with either human pooled (HPS) or fetal bovine serum (FBS), to desferrioxamine. Desferrioxamine, at micromolar concentrations, induced severe cytotoxicity in all tumour cell lines grown in FBS medium. When grown in HPS medium, comparable desferrioxamine cytotoxicity was observed in the millimolar range. The addition of 50% saturated human transferrin to FBS medium resulted in protection against desferrioxamine cytotoxicity. HL-60 cells were further studied for iron metabolism characteristics. HL-60 cells, grown in medium with FBS, were found to have an 8.4 fold increase in surface transferrin receptor (TfR) expression (P < 0.001) as compared with HL-60 cells grown in medium with HPS. However, iron uptake of HPS cultured HL-60 cells, after incubation with saturated human transferrin, was higher, resulting in a higher concentration of iron in HPS cultured HL-60 cells as compared with FBS cultured cells (1.72 +/- 0.02 mumol/g protein v. 1.32 +/- 0.14 mumol/g protein; P < 0.001). Using desferrioxamine it was shown that TfR expression is dependent on the biological availability of iron in the cell. Consistent with the lower iron content in FBS cultured cells, we conclude that the cytotoxicity of desferrioxamine is dependent on the ability of cells to replenish cellular iron stores from the culture medium. Cells grown in FBS medium lack this ability and are therefore more susceptible to desferrioxamine.

Biological Availability↗
PubMed1992

Increased hydrogen peroxide concentration in human tumor cells due to a nitroxide free radical.

Evidence is presented that the nitroxide free radical, TEMPO, at concentrations commonly used to prevent oxidative damage, increases the intracellular hydrogen peroxide concentration. To investigate the origin of this increased hydrogen peroxide concentration, we have incubated various human tumor cell lines with compounds interfering with the generation of active oxygen metabolites. Sodium azide, inhibitor of the respiratory chain, the iron-chelating agent desferrioxamine, superoxide dismutase and catalase had no effect on the hydrogen peroxide concentration. Metyrapone, inhibitor of the cytochrome P450 system, was demonstrated to decrease, but not completely prevent, the hydrogen peroxide production. N-ethylmaleimide, a sulphydryl-bond alkylating agent, was able to completely prevent the increased hydrogen peroxide production. We conclude that, by increasing the cellular hydrogen peroxide concentration, TEMPO exerts a pro-oxidant effect. This increase in hydrogen peroxide production seems to be mediated by the induction of oxidase activity in the cytochrome P450 system, but other cellular systems involved in electron transport may also play a role.

Catalase↗
PubMed1992

Effect of iron chelators on paraquat toxicity in rats and alveolar type II cells.

There is general agreement that the lung damage seen in paraquat poisoning is due to the generation of free radicals in alveolar epithelial cells. We have recently shown that the iron chelator and antioxidant deferoxamine (DF) reduces the mortality caused by paraquat in vitamin-E-deficient rats. In the present study we investigated the effect of DF and the lipid soluble iron chelator compound 51 (CP51) of the hydroxypyridin-4-one family on paraquat poisoning in rats with a normal vitamin E status and on isolated alveolar type II cells (ATTC). Adult rats were intravenously injected with a lethal dose of paraquat (40 mg/kg) while concurrent treatment with a continuous intravenous infusion of DF or CP51 was started. Survival of rats receiving DF at 25 and 50 mg/kg/24 h was not significantly increased compared with PBS-treated control animals. CP51, however, significantly (p less than 0.01) reduced the mortality caused by paraquat. When rats were treated with 25 mg/kg/24 h, eight of 15 rats survived the study period of 35 days compared with three in the PBS-treated control group (n = 27). In ancillary in vitro studies radiolabeled [51Cr]ATTC were incubated in a medium containing 100 microM paraquat in the absence or presence of DF and CP51. Paraquat-induced ATTC lysis increased to approximately 25% after 7 h of incubation. At the highest tested concentration (500 microM) of chelator, injury decreased markedly (80%), whereas at the lowest tested concentration (50 microM) cytotoxicity was not prevented.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Exercise-induced muscle damage in the rat: the effect of vitamin E deficiency.

Rats, fed a vitamin-E-deficient diet for 6 weeks, performed treadmill exercise for 2 h. Muscle damage was assessed by measuring the creatine kinase (CK) activity in plasma before and after exercise, and by studying semi-thin longitudinal sections of the soleus muscle 48 h after running. Vitamin-E-deficient male and female rats showed an increased post-exercise CK activity when compared to matched controls, but male rats showed a larger CK response than females. This rise in plasma CK activity was caused mainly by an increased activity of the muscle-specific CK-isoenzyme, CK-MM (males + 1238%; females + 540%, P less than 0.05). In a parallel histological study we observed in vitamin-E-deficient male rats a dramatic and significant disturbance of the normal cyto-architecture of the muscle fibres after exercise (focal necrosis, phagocytosis and cellular infiltrates), whereas in females only minor, non-significant, changes were seen. We conclude that vitamin E deficiency enhances the susceptibility to exercise-induced muscle damage in male rats more than in female rats. This difference between the sexes is attributed to the protective effect of oestradiol that remains operative in female rats when the vitamin E status is disturbed: male rats lack such hormonal protection.

Animals↗
PubMed1990

Mechanism of protection of alveolar type II cells against paraquat-induced cytotoxicity by deferoxamine.

Paraquat toxicity has been associated with the generation of free radicals in alveolar epithelial cells in which paraquat specifically accumulates via a polyamine uptake system. In the present study we investigated whether deferoxamine (DF), an iron chelator that has antioxidant capacity and that also has a polyamine-like structure, could protect alveolar type II cells (ATTC) against injury by paraquat. Radiolabeled [3H]adenine ATTC were incubated in a medium containing 75 microM paraquat in the absence or presence of DF (500 microM). After 3 hr of incubation paraquat-mediated cytotoxicity of ATTC, as measured by [3H]adenine release, was significantly (P less than 0.005) decreased by addition of DF (26.6 +/- 2.6% vs 7.4 +/- 1.7%). Accumulation of radiolabeled [14C]paraquat at a concentration of 75 microM was also decreased (70%) by 500 microM DF from 94.8 +/- 2.1 to 28.9 +/- 6.7 nmoles paraquat/2.5 x 10(5) ATTC. This effect of DF was dose dependent and comparable with the protective effect of equimolar concentrations of putrescine. However, per cent uptake of paraquat at a concentration of 500 microM was not significantly inhibited by DF (1 mM), whereas paraquat-induced injury was still markedly reduced (36.2 +/- 2.5% vs 2.6 +/- 4.2%). This indicated that the protective effect of DF could not be explained by its competition with paraquat on uptake alone. In the same series of experiments using another iron chelator, pyridoxal benzoyl hydrazone (PBH), which has antioxidant properties similar to DF but does not show its polyamine-like structure, ATTC lysis was also prevented although paraquat uptake was not reduced. These in vitro data indicate that the mechanism of protection by DF against paraquat toxicity in lung epithelial type II cells is two-fold: inhibition of paraquat uptake through its compliance with the structural requirements necessary for transport, and inhibition of paraquat-induced iron-catalysed free radical generation.

Animals↗