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Aalt Bast

Publications and source records attributed to Aalt Bast.

At least 37 records · Page 2Linked to original sources
PubMed2004

Possible (enzymatic) routes and biological sites for metabolic reduction of BNP7787, a new protector against cisplatin-induced side-effects.

Disodium 2,2'-dithio-bis-ethane sulfonate (BNP7787) is under investigation as a potential new chemoprotector against cisplatin-induced nephrotoxicity. The selective protection of BNP7787 appears to arise from the preferential uptake of the drug in the kidneys, where BNP7787 would undergo intracellular conversion into mesna (2-mercapto ethane sulfonate), which in turn can prevent cisplatin induced toxicities. In the present study, we have investigated whether the reduction of BNP7787 into the reactive compound mesna is restricted to the kidney or whether it can also occur in other organs, cells and physiological compartments, including the cytosolic fraction of the renal cortex, plasma, red blood cells (RBCs), liver and small intestine from rats and several tumors (OVCAR-3, MRI-H-207 and WARD). We also determined whether the endogenous thiols glutathione (GSH) and cysteine and the enzyme systems glutaredoxin and thioredoxin, which are all present in the kidney, can be involved in the BNP7787 reduction. UV detection and micro-HPLC with dual electrochemical detection were used to analyze the various incubation mixtures. Our observations are that, in contrast to plasma, a very large reductive conversion of BNP7787 to mesna was measured in RBC lysate. Intact RBCs, however, did not take up BNP7787. Although BNP7787 could be reduced in cytosol of liver and several tumors, this reduction will not be relevant in vivo, since these tissues do not take up large amounts of BNP7787. Kidney cortex cytosol was, similar to the small intestine cytosol, able to substantially reduce BNP7787 to mesna. The ability to reduce BNP7787 in the presence of the endogenous thiols GSH and cysteine, the glutaredoxin system as well as the thioredoxin system, could at least in part explain the high BNP7787 reductive activity of the kidney cortex cytosol. In conclusion, the high reduction of BNP7787 into mesna in the kidney as well as our earlier observation that the distribution of BNP7787 and mesna was mainly restricted to rat kidney are strong arguments in favor of selective protection of the kidney by BNP7787.

Animals↗
PubMed2004

The extraordinary antioxidant activity of vitamin E phosphate.

The antioxidant activities of RRR-vitamin E (VE), all-rac-vitamin E (all-rac-VE), trolox, RRR-vitamin E acetate (VEA), all-rac-vitamin E phosphate (VEP) and RRR-vitamin E succinate (VES) were compared. In this study, the rank order in the inhibition of lipid peroxidation (LPO) of VE and its derivatives was trolox>VE approximately all-rac-VE>VEA>VES. VE and trolox inhibited LPO in non-heated and heated rat liver microsomes. It has generally been accepted that this is due to scavenging of free radicals by these antioxidants, and during this protection the antioxidants are oxidized. VEA and VES have to be converted into VE by esterases to obtain antioxidant activity against LPO. VEP, however, had a potent antioxidant effect of its own without conversion to VE. In contrast to VE, VEP is not consumed during this protection. Of the compounds tested, VEP is the most potent in induction of hemolysis of erythrocytes. EPR experiments using the spin label 16-doxylstearic acid showed that VEP reduces membrane fluidity, in contrast to VE. This indicates that VEP acts as a detergent and forms a barrier that might inhibit the transfer of radicals from one polyunsaturated fatty acid to another. This new mechanism may form the basis for a new class of antioxidants.

Animals↗
PubMed2004

Sustained protective effects of 7-monohydroxyethylrutoside in an in vivo model of cardiac ischemia-reperfusion.

Earlier studies have shown that 7-monohydroxyethylrutoside (monoHER), an antioxidant flavonoid, protects against doxorubicin-induced cardiotoxicity. In this study, we investigated potential sustained cardioprotective effects of monoHER in a model of ischemia-reperfusion (I/R) in mice. Ischemia was induced for 30 min by ligating the left anterior descending coronary artery. Afterwards, the ligature was removed and reperfusion was allowed for 6 or 24 h or 2 weeks. MonoHER (500 mg/kg) was given intraperitoneally (i.p.) one hour before ischemia. Treatment with monoHER significantly attenuated myocardial neutrophil influx both at 6 and 24 h after reperfusion by 77% and 76%, respectively. Infarct size was also significantly reduced, 24 h and 2 weeks after reperfusion by 58% and 49%, respectively. Whereas ischemia-reperfusion had no influence on basal levels of cardiac contractility (+dp/dt), responses to dobutamine were blunted 24 h and 2 weeks after reperfusion. In mice treated with monoHER, cardiac contractility response was significantly restored. These results indicate that monoHER exerts a sustained cardioprotective effect on ischemia-reperfusion injury and prevents deterioration of cardiac contractility.

Animals↗
PubMed2004

Lecithinized copper,zinc-superoxide dismutase as a protector against doxorubicin-induced cardiotoxicity in mice.

Production of superoxide radicals from doxorubicin is widely accepted to be the cause of the cardiotoxicity induced by this antitumor agent. Pretreatment with superoxide dismutase could improve the therapeutic application. Aim of the present study was to determine whether lecithinized superoxide dismutase (PC-SOD) can serve as a cardioprotective drug during doxorubicin treatment. The protective potential of PC-SOD on doxorubicin-induced cardiotoxicity was investigated in BALB/c mice. The possible influence of PC-SOD on the antitumor activity of doxorubicin was investigated in vitro as well as in vivo. Mice were treated intravenously with doxorubicin (4 mg x kg(-1)) or doxorubicin and PC-SOD (5000, 20000 or 80000 U x kg(-1)) weekly x 6 and appropriate controls were included. Cardiotoxicity was monitored for 8 weeks by ECG measurement. The influence of PC-SOD on the antitumor activity of doxorubicin was evaluated in three human malignant cell lines. Nude mice bearing OVCAR-3 human ovarian cancer xenografts were treated intravenously with doxorubicin (8 mg x kg(-1)) alone or preceded by PC-SOD 20000 or 80000 U x kg(-1) weekly x 2 and appropriate controls were included. PC-SOD prevented doxorubicin-induced cardiotoxicity already at 5000 U x kg(-1) whereas 20000 and 80000 U x kg(-1) were equally protective. No toxicity was observed in mice treated with PC-SOD. PC-SOD did not interfere with the antiproliferative effects of doxorubicin in vitro. In vivo, PC-SOD had no negative effect on the inhibition of xenograft growth induced by doxorubicin. It can be concluded that PC-SOD protects the heart, but not the tumor against doxorubicin. These data suggest that PC-SOD may be a suitable cardioprotector during doxorubicin treatment.

Animals↗
PubMed2004

Antioxidant capacity of reaction products limits the applicability of the Trolox Equivalent Antioxidant Capacity (TEAC) assay.

The Trolox Equivalent Antioxidant Capacity (TEAC) assay is based on the scavenging of the 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical (ABTS(*)) converting it into a colorless product. The degree of decolorization induced by a compound is related to that induced by trolox, giving the TEAC value. The assay is frequently used for constructing structure activity relationships (SARs). HPLC analysis of the reaction mixture, obtained after scavenging of ABTS(*) by the flavonoid chrysin, shows that a product is formed that also reacts with ABTS(*). The product has a higher antioxidant capacity and reacts faster with ABTS(*) than the parent compound, chrysin. In contrast to the reaction product of chrysin, the reaction product of trolox, which is formed during scavenging of ABTS(*), i.e. trolox quinone, does not react with ABTS(*). The experiments show that the TEAC is the antioxidant capacity of the parent compound plus the potential antioxidant capacity of the reaction product(s). This means that the TEAC assay does not necessarily reflect the antioxidant effect of only one structure. This hampers the applicability of the assay for the construction of SARs and for ranking antioxidants.

Antioxidants↗
PubMed2004

Relaxant effects of estradiol through non-genomic pathways in male and female pig bladder smooth muscle.

The precise effect of low estrogen levels on urinary bladder contractility remains controversial. The present study was designed to analyze the effect of 17beta-estradiol in bladder smooth muscle contractility and the involvement of specific estrogen receptor stimulation in this effect. Castrated male and female pig detrusor strips were mounted for tension recording in an organ bath, superfused with Krebs solution at 37 degrees C and stimulated electrically and pharmacologically. In order to verify the acute effect of 17beta-estradiol on muscle contractility, the strips were incubated with different concentrations of the hormone. Muscle contractions were induced by potassium chloride, acetylcholine chloride and electrical field stimulation. The involvement of the estrogen receptor in the effects of 17beta-estradiol was assessed by incubation of some strips with the selective estrogen receptor antagonist ICI 182.780 before estradiol was applied. Estradiol at a dose of 30 micromol/l elicited a lower amplitude of contractions induced by EFS, Ach and KCl in female as well as in castrated male pig bladder smooth muscle strips. The effects of 17beta-estradiol were stronger in contractions induced by potassium chloride than those induced by other forms of stimulation. Pre-treatment with the pure estrogen receptor antagonist had no effect on 17beta-estradiol-induced inhibition of muscle contractility. These observations suggest that 17beta-estradiol induces lower amplitude of contraction of female as well as castrated male pig detrusor which is not mediated by the classic estrogen receptor. Furthermore, we can conclude that estradiol has a stronger inhibitory effect on the depolarization of muscle cell membrane compared to a muscarinic receptor-induced contraction.

Acetylcholine↗
PubMed2004

In vivo reduction of erythrocyte oxidant stress in a murine model of beta-thalassemia.

BACKGROUND AND OBJECTIVES: Oxidant damage is an important contributor to the premature destruction of erythrocytes and anemia in thalassemias. To assess the extent of oxidant damage of circulating erythrocytes and the effects of antioxidant therapy on erythrocyte characteristics and anemia, we used a mouse model of human beta-thalassemia intermedia (b1/b2 deletion). DESIGN AND METHODS: Several parameters indicative of oxidant damage were measured at baseline and following administration of the semi-synthetic flavonoid antioxidant, 7-monohydroxyethylrutoside (monoHER), to beta-thalassemic mice at a dose of either 500 mg/kg i.p. once a day (n=6) or 250 mg/kg i.p. twice a day (n=6) for 21 days. RESULTS: Significant erythrocyte oxidant damage at baseline was indicated by: (i) dehydration, reduced cell K content, and up-regulated K-Cl co-transport; (ii) marked membrane externalization of phosphatidylserine; (iii) reduced plasma and membrane content of vitamin E; and (iv) increased membrane bound IgG. MonoHER treatment increased erythrocyte K content, and markedly improved all cellular indicators of oxidant stress and of lipid membrane peroxidation. While anemia did not improve, monoHER therapy reduced reticulocyte counts, improved survival of a fraction of red cells, and reduced ineffective erythropoiesis with decreased total bilirubin, lactate dehydrogenase and plasma iron. INTERPRETATION AND CONCLUSIONS: Antioxidant therapy reverses several indicators of oxidant damage in vivo. These promising antioxidant effects of monoHER should be investigated further.

Animals↗
PubMed2003

Lipoic acid protects efficiently only against a specific form of peroxynitrite-induced damage.

The ability of the sulfur-containing compounds glutathione (GSH), glutathione disulphide (GSSG), S-methylglutathione (GSMe), lipoic acid (LA), and dihydrolipoic acid (DHLA) to protect against hypochlorous acid (HOCl)-mediated damage and peroxynitrite (ONOOH)-induced damage has been compared. Protective activity was assessed in competition assays by monitoring several detectors, i.e. dihydrorhodamine-123 (DHR-123) oxidation, alpha(1)-antiproteinase (alpha(1)-AP) inactivation, and glutathione S-transferase P1-1 (GST-P1-1) inactivation. In addition, nitration of tyrosine was measured to assess protection of the sulfur-containing compounds against ONOOH. For protection against HOCl, the efficacy of the antioxidant was controlled by the ratio of the reaction rates of the antioxidant and the detector molecule with the oxidant. The rank order of the activity of the antioxidants (GSH > DHLA approximately LA approximately GSMe > GSSG) appeared to be independent of the detector used. However, the rank order of the antioxidants against ONOOH-induced damage is strongly dependent on the detector. LA was 40 times less active than GSH in the inhibition of ONOOH-induced DHR-123 oxidation, whereas LA was 20 times more active than GSH in preventing the inhibition of GST-P1-1 by ONOOH. This points to different molecular mechanisms of ONOOH damage to DHR-123 compared with ONOOH damage to GST-P1-1. LA is a poor antioxidant in protecting against the form of ONOOH damage involved in DHR-123 oxidation. In the form of ONOOH toxicity involved in GST-P1-1 inhibition, LA is the most potent sulfur-containing antioxidant in our series. It is proposed that an intermediate product in which both sulfur atoms of LA have reacted is involved in the reaction of ONOOH with LA. The high potency of LA to protect GST-P1-1 against ONOOH might be of therapeutic interest.

Antioxidants↗
PubMed2003

Tetrahydrofolate and 5-methyltetrahydrofolate are folates with high antioxidant activity. Identification of the antioxidant pharmacophore.

The presumed protective effect of folic acid on the pathogenesis of cardiovascular, hematological and neurological diseases and cancer has been associated with the antioxidant activity of folic acid. Peroxynitrite (PON) scavenging activity and inhibition of lipid peroxidation (LPO) of the physiological forms of folate and of structurally related compounds were tested. It was found that the fully reduced forms of folate, i.e. tetrahydrofolate (THF) and 5-methyltetrahydrofolate (5-MTHF), had the most prominent antioxidant activity. It appeared that their protection against LPO is less pronounced than their PON scavenging activity. The antioxidant activity of these forms of folic acid resides in the pterin core, the antioxidant pharmacophore is 4-hydroxy-2,5,6-triaminopyrimidine. It is suggested that an electron donating effect of the 5-amino group is of major importance for the antioxidant activity of 4-hydroxy-2,5,6-triaminopyrimidine. A similar electron donating effect is probably important for the antioxidant activity of THF and 5-MTHF.

Animals↗
PubMed2003

Oxidized quercetin reacts with thiols rather than with ascorbate: implication for quercetin supplementation.

When an antioxidant scavenges a reactive species, i.e., when it exerts its antioxidant activity, the antioxidant is converted into potentially harmful oxidation products. In this way, the antioxidant quercetin might yield an ortho-quinone, denoted as QQ, which has four tautomeric forms, i.e., the ortho-quinone and three quinonmethides. We evaluated the interaction of QQ with ascorbate or glutathione (GSH). Ascorbate recycles QQ to the parent compound quercetin, while GSH forms two adducts with QQ, i.e., 6-GSQ and 8-GSQ. When both GSH and ascorbate are present, QQ is converted exclusively into GSQ. In the absence of GSH, protein thiols will be arylated by QQ. This protein arylation is not prevented by ascorbate. Thiol arylation by quinones and quinonmethides can impair several vital enzymes. This implies that the product formed when quercetin displays its antioxidant scavenging effect is toxic in the absence of GSH. Therefore, an adequate GSH level should be maintained when quercetin is supplemented.

Antioxidants↗
PubMed2003

Bioavailability and pharmacokinetics of the cardioprotecting flavonoid 7-monohydroxyethylrutoside in mice.

PURPOSE: The pharmacokinetics and bioavailability of monoHER, a promising protector against doxorubicin-induced cardiotoxicity, were determined after different routes of administration. METHODS: Mice were treated with 500 mg.kg(-1) monoHER intraperitoneally (i.p.), subcutaneously (s.c.) or intravenously (i.v.) or with 1000 mg.kg(-1) orally. Heart tissue and plasma were collected 24 h after administration. In addition liver and kidney tissues were collected after s.c. administration. The levels of monoHER were measured by HPLC with electrochemical detection. RESULTS: After i.v. administration the AUC(0-120 min) values of monoHER in plasma and heart tissue were 20.5+/-5.3 micromol.min.ml(-1) and 4.9+/-1.3 micromol.min.g(-1) wet tissue, respectively. After i.p. administration, a mean peak plasma concentration of about 130 microM monoHER was maintained from 5 to 15 min after administration. The AUC(0-120 min) values of monoHER were 6.1+/-1.1 micromol.min.ml(-1) and 1.6+/-0.4 micromol.min.g(-1) wet tissue in plasma and heart tissue, respectively. After s.c. administration, monoHER levels in plasma reached a maximum (about 230 microM) between 10 and 20 min after administration. The AUC(0-120 min) values of monoHER in plasma, heart, liver and kidney tissues were 8.0+/-0.6 micromol.min.ml(-1), 2.0+/-0.1, 22.4+/-2.0 and 20.5+/-5.7 micromol.min.g(-1), respectively. The i.p. and s.c. bioavailabilities were about 30% and 40%, respectively. After oral administration, monoHER could not be detected in plasma, indicating that monoHER had a very poor oral bioavailability. CONCLUSIONS: MonoHER was amply taken up by the drug elimination organs liver and kidney and less by the target organ heart. Under cardioprotective conditions (500 mg/kg, i.p.), the Cmax was 131 microM and the AUC(infinity) was 6.3 microM.min. These values will be considered endpoints for the clinical phase I study of monoHER.

Administration, Oral↗
PubMed2003

Systemic poly(ADP-ribose) polymerase-1 activation, chronic inflammation, and oxidative stress in COPD patients.

Oxidative stress and systemic inflammation in chronic obstructive pulmonary disease (COPD) strongly suggest a role for the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1, E.C.2.4.2.30) in the disease pathophysiology. PARP-1 is highly activated by reactive oxygen species-induced DNA strand breaks, upon which it forms extensive poly(ADP-ribose) (PAR) polymers from its substrate NAD(+). We hypothesized that in COPD, chronic inflammation and oxidative stress would lead to systemic PARP-1 activation and to a reduced NAD(+) status. In a patient-control study, systemic PARP-1 activation was assessed by immunofluorescent detection of PAR polymers in peripheral blood lymphocytes. The percentage of PAR polymer-positive lymphocytes appeared to be higher in COPD patients (27 +/- 3%) than in healthy age-matched controls (17 +/- 2%, p <.05). Trolox equivalent antioxidant capacity (TEAC) of deproteinized plasma (p <.001), plasma uric acid (p <.05), as well as blood NAD(+) (p <.01) of stable COPD patients were significantly reduced when compared to controls. In addition, levels of proinflammatory cytokines IL-6, IL-8, and sICAM-1 were increased (p <.005) in COPD patients. In this study, evidence was found for the presence of systemic inflammation, chronic oxidative stress, and systemic PARP-1 activation in stable COPD patients. These data support a contribution of oxidative stress-induced PARP-1 activation to the pathophysiology of COPD.

Antioxidants↗
PubMed2003

Role of superoxide anion on basal and stimulated nitric oxide activity in neonatal piglet pulmonary vessels.

The superoxide anion (O2*-) appears to be an important modulator of nitric oxide bioavailability. Enzymatic scavenging of O2*- is carried out by superoxide dismutase (SOD). The present study was designed to characterize the developmental changes on pulmonary vascular reactivity induced by 1) exogenous Cu/Zn SOD, 2) several putative SOD mimetics, and 3) endogenous SOD inhibition. We also analyzed age-related changes on pulmonary SOD activity and vascular O2*- levels. SOD (1-300 U/mL) produced endothelium-dependent relaxation of U46619-contracted intrapulmonary arteries (fourth branch) and veins from 12- to 24-h-old and 2-wk-old piglets. SOD-induced relaxation was greater in pulmonary arteries and was abolished by the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester. SOD induced a greater pulmonary artery relaxation in the 2-wk-old than in the 12- to 24-h-old piglet. SOD (100 U/mL) did not modify acetylcholine-induced relaxation in pulmonary arteries. In contrast, endogenous SOD inhibition by diethyldithiocarbamate (3 mM) impaired acetylcholine-induced relaxation in pulmonary arteries from newborn but not from 2-wk-old piglets. Total SOD activity in lung tissue did not change with postnatal age. With the use of dihydroethidium, an oxidant-sensitive fluorescent probe, we did not find significant age- or vessel-related differences in O2*- presence. From the putative SOD mimetics tested, only the metal salts MnCl2 and CuSO4 reproduced the vascular effects of SOD. In summary, SOD produces endothelium-dependent pulmonary vascular relaxation by protecting nitric oxide from destruction by O2*-. This effect was less marked in newborns than in 2-wk-old piglets. In contrast, pulmonary arteries from newborn piglets are more sensitive to the inhibition of endogenous SOD.

Acetylcholine↗
PubMed2003

New method to study oxidative damage and antioxidants in the human small bowel: effects of iron application.

Iron may induce oxidative damage to the intestinal mucosa by its catalyzing role in the formation of highly reactive hydroxyl radicals. This study aimed to determine iron-induced oxidative damage provoked by a single clinical dosage of ferrous sulfate and to elucidate the antioxidant defense mechanisms in the human small intestine in vivo. A double-lumen perfusion tube was positioned orogastrically into a 40-cm segment of the proximal small intestine in six healthy volunteers (25 +/- 5 yr). The segment was perfused with saline and subsequently with saline containing 80 mg iron as ferrous sulfate at a rate of 10 ml/min. Intestinal fluid samples were collected at 15-min intervals. Thiobarbituric acid reactive substances concentrations as an indicator of lipid peroxidation increased significantly from 0.07 microM (range, 0-0.33 microM) during saline perfusion to 3.35 microM (range, 1.19-7.27 microM) during iron perfusion (P < 0.05). Nonprotein antioxidant capacity increased significantly from 474 microM (range, 162-748 microM) to 1,314 microM (range, 674-1,542 microM) (P < 0.05). These data show that a single dosage of ferrous sulfate induces oxidative damage and the subsequent release of an antioxidant in the small intestine in vivo in healthy volunteers.

Adult↗
PubMed2003

The cardioprotector monoHER does not interfere with the pharmacokinetics or the metabolism of the cardiotoxic agent doxorubicin in mice.

PURPOSE: Monohydroxyethylrutoside (monoHER) has proved to be a good protector against doxorubicin-induced cardiotoxicity without interfering with the antitumor effect of doxorubicin. The aim of the present study was to determine whether there is a pharmacokinetic interaction between monoHER and doxorubicin which may be involved in monoHER cardioprotection. METHODS: Mice were treated with monoHER (500 mg x kg(-1) i.v.) alone, monoHER 5 min after doxorubicin (10 mg x kg(-1) i.v.), doxorubicin alone and doxorubicin 5 min after monoHER. The levels of monoHER and doxorubicin(ol) in plasma and heart tissue were measured by HPLC 24 h and 48 h after monoHER and doxorubicin administration, respectively. RESULTS: The areas under the concentration-time curves (AUCs) of monoHER and doxorubicin(ol) were not affected by the coadministered drug. No changes were observed in pharmacokinetic parameters such as initial and final half-lives, mean residence time, clearance and volume of distribution of monoHER and doxorubicin(ol) after single or combined administration. CONCLUSION: The cardioprotection of monoHER in mice is not caused by a pharmacokinetic interaction between monoHER and doxorubicin.

Animals↗
PubMed2003

Superoxide dismutase: the balance between prevention and induction of oxidative damage.

Cu,Zn-superoxide dismutase (SOD1) has been shown to be effective in several free radical mediated diseases, although some studies have pointed toward SOD1 toxicity at a high concentrations. In the present study, the balance between prevention and induction of damage by SOD1 has been investigated both in vitro and in vivo. In vitro superoxide was generated using xanthine/xanthine oxidase. In vivo superoxide was generated using the redox cycling compound doxorubicin. Furthermore, we determined the pharmacokinetics of lecithinized SOD1 (PC-SOD) in order to compare the results obtained in vivo with those obtained in vitro. It was found that in vitro high concentrations of SOD1 induce hydroxylation of coumarin 3-carboxylic acid (3-CCA). This could be caused by a peroxidative action of SOD1 or formation of the highly reactive hydroxyl radicals. Any signs of toxicity are absent in vivo because these concentrations are not reached. It can be concluded that SOD1 possesses a large therapeutic window and application of SOD1 or its derivatives for strengthening the body's defenses against oxidative stress in a variety of pathologies seems safe.

Animals↗