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Biomedical subjects

A Bast

Publications and source records attributed to A Bast.

At least 73 records · Page 4Linked to original sources
PubMed1998

Effects of dihydrolipoic acid on peptide methionine sulfoxide reductase. Implications for antioxidant drugs.

By showing that dihydrolipoic acid (DHLA) reactivates oxidatively damaged alpha-1 antiprotease (alpha 1-AP), a new antioxidant property of DHLA is described. For the first time, it is shown that a drug is able to reverse oxidative damage of physiologically essential macromolecules. Until now, only antioxidant properties have been reported that prevent oxidative stress. Repair of oxidized alpha 1-AP is catalysed by peptide methionine sulfoxide reductase (PMSR, EC 1.8.4.6). It is found that DHLA acts as a reducing cofactor for PMSR. Oxidized alpha 1-AP has been implicated in the etiology of certain lung diseases. Generally, by stimulating PMSR, DHLA may exert a curative effect in diseases accompanied by oxidative stress.

Animals↗
PubMed1998

Antioxidant effects of carotenoids.

Surprisingly, neither the precise pharmacological effect nor the toxicological profile is usually established for food components. Carotenoids are no exception in this regard. Only limited insight into the pharmacology and toxicology of carotenoids exists. It is known that the antioxidant action of carotenoids is determined by 1. electron transfer reactions and the stability of the antioxidant free radical, 2. the interplay with other antioxidants and 3. the reaction with active oxygen. Numerous metabolites of carotenoids are formed upon their action as an antioxidant. Most of these metabolites have an unknown biological activity. It is concluded that a severe lack of knowledge hampers adequate suggestions for human supplementation.

Antioxidants↗
PubMed1997

Peroxynitrite scavenging by flavonoids.

The peroxynitrite scavenging activity of a series of structurally related flavonoids was tested. It was found that flavonoids are excellent scavengers of peroxynitrite. Compared to the known peroxynitrite scavenger ebselen, the most active flavonoids proved to be 10 times more effective. Indications were found that the catechol group (ring B) and the hydroxyl group at position 3 give the highest contribution to the peroxynitrite scavenging effect. The peroxynitrite scavenging is discussed in relation to the beneficial effect of flavonoid intake on the incidence of coronary heart disease.

Flavonoids↗
PubMed1997

Changes in neuroreceptor function of tracheal smooth muscle following acute ozone exposure of guinea pigs.

We studied the effect of in vivo ozone inhalation (3 ppm, 2 h) on neuroreceptor function in guinea pig tracheal smooth muscle in vitro and the role of the epithelial layer in this process. Changes in smooth muscle tension after stimulation of the muscarinic- and beta-adrenergic receptor were recorded isometrically and stained tracheal tissue sections were histologically evaluated for changes in the epithelial and smooth muscle layer. Ozone exposure resulted in an increase in maximal contraction following stimulation of the muscarinic receptor, whereas pD2 values remained unchanged. After stimulation of the beta-adrenergic receptor no increase in maximal relaxation but only an increase in pD2 value was observed after correction for differences in precontraction level in control- and ozone-exposed situations. Mechanical removal of the epithelial layer resulted in a slight increase of the maximal contraction level after stimulation with methacholine in the control situation, whereas exposure to ozone resulted in a strong decrease of the maximal contraction level under these conditions. Histological stainings showed a slight and focal influx of neutrophilic granulocytes in the epithelial layer, submucosal layer and airway lumen after exposure to ozone. These data support the idea that ozone is able to increase the maximal degree of airway narrowing upon muscarinergic stimulation, i.e. a hyperreactivity response. The results also suggest that functionally altered epithelium plays an important role in the process of ozone-induced hyperreactivity, possibly linked with an early inflammatory response.

Animals↗
PubMed1997

Acute exposure to ozone does not influence neuroreceptor density and sensitivity in guinea pig lung.

The effects of acute exposure of guinea pigs to 3 ppm of ozone for 2 h on the receptor density and sensitivity of the muscarinergic-, the histaminergic- and the beta-adrenergic receptor systems were studied, in order to provide more insight in the complex mechanisms underlying the well known ozone-induced changes in receptor functionality. The exposure to ozone did not change either the total amount of receptors present in lung tissue, nor the receptor sensitivity of the systems studied. Although no effects were observed, this does not yet fully exclude the receptor system for being a target of ozone exposure. The receptor function can be changed after exposure to ozone, e.g., the coupling with the G-protein can be influenced. Furthermore, the G-protein itself may have been altered or changes can occur at lower levels in the receptor signal transmission route leading to functional changes after stimulation of the receptor with an agonist.

Animals↗
PubMed1997

Antioxidant levels in the nasal mucosa of patients with chronic sinusitis and healthy controls.

BACKGROUND: Imbalances between oxidant formation and antioxidative defense are associated with the pathogenesis of several chronic inflammatory disorders of the respiratory tract. Therefore, a role of oxidative stress in chronic upper airway tract infections can be anticipated. OBJECTIVE: To determine if patients with chronic sinusitis demonstrate a reduced antioxidative tissue status. DESIGN: The levels of 3 biologically important antioxidants, reduced glutathione and oxidized glutathione, uric acid, and vitamin E, were determined biochemically in mucosal biopsy specimens from the uncinate process of patients with chronic sinusitis and healthy controls. SUBJECTS: Inflamed mucosa samples were obtained from 9 patients with chronic sinusitis during functional endoscopic sinus surgery. Normal mucosa samples were collected from 10 healthy controls during surgery for nasal obstruction. RESULTS: The data (presented as mean +/- SD) show a significant reduction (P < or = .05) of reduced glutathione levels (0.3 +/- 0.1 mumol/g wet weight) and uric acid levels (2.7 +/- 0.4 mumol/g wet weight) in mucosa samples obtained from patients with chronic sinusitis compared with healthy controls (0.6 +/- 0.2 and 3.4 +/- 0.6 mumol/g wet weight, respectively). No difference was found in oxidized glutathione (24 +/- 8 vs 25 +/- 15 nmol/g wet weight) and vitamin E (20.5 +/- 7.9 vs 22.5 +/- 6.9 nmol/g wet weight) levels between both groups. CONCLUSIONS: Decreased levels of both reduced glutathione and uric acid in patients with chronic sinusitis lead to a diminished antioxidant defense, which may be associated with the pathogenesis of upper respiratory tract disorders. The vitamin E level seems less important. This finding may offer perspectives for pharmacotherapeutic intervention with antioxidants.

Case-Control Studies↗
PubMed1997

The pharmacology of the antioxidant lipoic acid.

1. Lipoic acid is an example of an existing drug whose therapeutic effect has been related to its antioxidant activity. 2. Antioxidant activity is a relative concept: it depends on the kind of oxidative stress and the kind of oxidizable substrate (e.g., DNA, lipid, protein). 3. In vitro, the final antioxidant activity of lipoic acid is determined by its concentration and by its antioxidant properties. Four antioxidant properties of lipoic acid have been studied: its metal chelating capacity, its ability to scavenge reactive oxygen species (ROS), its ability to regenerate endogenous antioxidants and its ability to repair oxidative damage. 4. Dihydrolipoic acid (DHLA), formed by reduction of lipoic acid, has more antioxidant properties than does lipoic acid. Both DHLA and lipoic acid have metal-chelating capacity and scavenge ROS, whereas only DHLA is able to regenerate endogenous antioxidants and to repair oxidative damage. 5. As a metal chelator, lipoic acid was shown to provide antioxidant activity by chelating Fe2+ and Cu2+; DHLA can do so by chelating Cd2+. 6. As scavengers of ROS, lipoic acid and DHLA display antioxidant activity in most experiments, whereas, in particular cases, pro-oxidant activity has been observed. However, lipoic acid can act as an antioxidant against the pro-oxidant activity produced by DHLA. 7. DHLA has the capacity to regenerate the endogenous antioxidants vitamin E, vitamin C and glutathione. 8. DHLA can provide peptide methionine sulfoxide reductase with reducing equivalents. This enhances the repair of oxidatively damaged proteins such as alpha-1 antiprotease. 9. Through the lipoamide dehydrogenase-dependent reduction of lipoic acid, the cell can draw on its NADH pool for antioxidant activity additionally to its NADPH pool, which is usually consumed during oxidative stress. 10. Within drug-related antioxidant pharmacology, lipoic acid is a model compound that enhances understanding of the mode of action of antioxidants in drug therapy.

Animals↗
PubMed1997

Effect of phospholipase A2 activation on the receptor function in the rat left atrium: unmasking of a positive inotropic effect of methacholine.

1. To elucidate the functional consequence of endogenous phospholipase A2 activation, the effect of pretreatment with melittin on (-)-isoprenaline, forskolin and methacholine inotropic responses in isolated rat left atria was studied. 2. Melittin pretreatment resulted in a significant decrease of the positive inotropic response of (-)-isoprenaline, whereas no significant change in the forskolin response was seen. 3. A more prominent negative inotropic effect of methacholine could be perceived after melittin pretreatment. These effects of melittin were not simply reversed by mepacrine, a phospholipase A2 inhibitor. 4. After combined mepacrine/melittin pretreatment, a positive inotropic response was elicited by methacholine, which could be blocked by atropine but not by (+/-)-propranolol. 5. It is suggested that the combination of mepacrine/melittin abolishes the activity of an inhibitory G protein.

Adrenergic beta-Agonists↗
PubMed1997

A method for measuring nitric oxide radical scavenging activity. Scavenging properties of sulfur-containing compounds.

A new method for the quantification of the nitric oxide (.NO) scavenging activity of compounds in aqueous solutions is described using an amperometric .NO sensor. After correction for the spontaneous degradation of .NO, second-order rate kinetics of the scavenging reaction are observe. The rate constant for hemoglobin found with this method is comparable with that found with an established spectrophotometric method. To demonstrate the capability of the method, several sulfur-containing compounds were tested (GSH, GSSG, S-methyl glutathione, N-acetyl cysteine, lipoic acid and dihydrolipoic acid). Of these compounds, only those that contained a thiol group displayed a considerable .NO scavenging activity.

Electrochemistry↗
PubMed1997

Decreased first trimester uric acid production in future preeclamptic patients.

The relationship between first trimester uric acid production and later development of pregnancy induced hypertensive disorders (PIHD) was investigated. An anti-oxidant role for uric acid has been mentioned. Since uric acid and fibronectin (PF) are both markers of preeclampsia, the relationship between these two substances was also studied. Controls (n = 72) and patients with PIHD (n = 120) were selected. Uric acid was measured in serum and 24-hours urine samples (uric acid excretion) and PF in blood plasma in 270 nulliparous women at 13 +/- 2 weeks of gestation. Uric acid excretion was significantly lower in the first trimester in a group of patients who later develop PIHD as compared to patients who remain normotensive (p < 0.05), especially when corrected for body weight (p < 0.01). Patients with elevated PF levels in the first trimester showed a significantly lower uric acid excretion than patients with normal PF levels (p < 0.05). The data show diminished uric acid production in patients who will likely develop preeclampsia suggesting an impaired anti-oxidant production in the first trimester. This observation fits well with the hypothesis that an imbalance between anti-oxidant and oxidants plays an important role in the pathogenesis of preeclampsia.

Acids↗
PubMed1997

Pitfalls in a method for assessment of total antioxidant capacity.

A relatively simple and widely applied method for quantitating the total antioxidant capacity of body fluids and drug solutions based on the absorbance of the ABTS radical cation was evaluated. In this assay, the end-point is an antioxidant-induced decrease in absorbance at a fixed time. This decrease is used as an index of total antioxidant capacity. It is shown that Trolox, potassium cyanide and quercetin all decrease the absorbance of ABTS radical cations at a fixed time, but by different mechanisms. Trolox scavenges the ABTS radical, potassium cyanide inhibits radical formation, while quercetin acts by both mechanisms. Using this method antioxidant capacity may be overestimated, due to both a scavenger effect and an effect on the rate of ABTS oxidation. To distinguish between these effects, a post-addition assay was used in which the sample is added when the formation of radicals is stable. Using post- addition assay conditions enables discrimination between effects on radical scavenging and on the radical formation, two major mechanisms for antioxidant action. In extrapolating the results to an in vivo situation it should be questioned: (i) whether the peroxidase process does indeed mimic the process of radical formation in vivo, and (ii) whether the ABTS radicals do resemble the radical species involved in an in vivo situation. Results obtained in the ABTS radical-based methods should therefore be reviewed critically before the antioxidant capacity can be assessed.

Antioxidants↗
PubMed1997

Monohydroxyethylrutoside, a dose-dependent cardioprotective agent, does not affect the antitumor activity of doxorubicin.

The cumulative dose-related cardiotoxicity of doxorubicin is believed to be caused by the production of oxygen- free radicals. 7-Monohydroxyethylrutoside (monoHER), a semisynthetic flavonoid and powerful antioxidant, was investigated with respect to the prevention of doxorubicin-induced cardiotoxicity in mice and to its influence on the antitumor activity of doxorubicin in vitro and in vivo. Non-tumor-bearing mice were equipped with a telemeter in the peritoneal cavity. They were given six weekly doses of 4 mg/kg doxorubicin i.v., alone or in combination with either 100 or 250 mg/kg monoHER i.p., 1 h prior to doxorubicin administration and for the following 4 days. Cardiotoxic effects were measured from electrocardiogram changes up to 2 weeks after treatment. Protection against cardiotoxicity was found to be dose dependent, with 53 and 75% protection, respectively, as calculated from the reduction in the increase in the ST interval. MonoHER and several other flavonoids with good antioxidant properties were tested for their antiproliferative effects in the absence or the presence of doxorubicin in A2780 and OVCAR-3 human ovarian cancer cells and MCF-7 human breast cancer cells in vitro. Some flavonoids were directly toxic at 50 and 100 microM, whereas others, including monoHER, did not influence the antiproliferative effects of doxorubicin at these concentrations. The influence of monoHER was further tested on the growth-inhibitory effect of 8 mg/kg doxorubicin i.v., given twice with an interval of 1 week in A2780 and OVCAR-3 cells that were grown as s.c. xenografts in nude mice. MonoHER, administered 1 h before doxorubicin in a dose schedule of 500 mg/kg i.p. 2 or 5 days per week, was not toxic and did not decrease the antitumor activity of doxorubicin. It can be concluded that monoHER showed a dose-dependent protection against chronic cardiotoxicity and did not influence the antitumor activity of doxorubicin in vitro or in vivo.

Animals↗
PubMed1996

Reduction of lipoic acid by lipoamide dehydrogenase.

Racemic lipoic acid is therapeutically applied in pathologies in which free radicals are involved. The in vivo reduction of lipoic acid may play an essential role in its antioxidant effect. It was found that mitochondrial lipoamide dehydrogenase (LipDH, EC 1.8.1.4.) reduces the R-enantiomer 28 times faster than the S-enantiomer of lipoic acid. Moreover, it was observed that the metabolites of lipoic acid, bisnor-, tetranor-, and beta-lipoic acid are poor substrates of LipDH. S-lipoic acid inhibits the reduction of the R enantiomer only at relatively high concentrations. The reduction of R-lipoic acid by mitochondria-rich tissues may proceed smoothly, even if the racemic mixture is applied. This is of importance in elucidating the molecular mechanism of the pharmacotherapeutic effect of lipoic acid.

Animals↗
PubMed1996

Doxorubicin-induced cardiotoxicity monitored by ECG in freely moving mice. A new model to test potential protectors.

In laboratory animals, histology is most commonly used to study doxorubicin-induced cardiotoxicity. However, for monitoring during treatment, large numbers of animals are needed. Recently we developed a new method to measure ECG values in freely moving mice by telemetry. With this model we investigated the effect of chronic doxorubicin administration on the ECG of freely moving BALB/c mice and the efficacy of ICRF-187 as a protective agent. The ST interval significantly widened from 15.0 +/- 1.5 to 56.8 +/- 11.8 ms in week 10 (7 weekly doses of 4 mg/kg doxorubicin given i.v. plus 3 weeks of observation). The ECG of the control animals did not change during the entire study. After sacrifice the hearts of doxorubicin-treated animals were enlarged and the atria were hypertrophic. As this schedule exerted more toxicity than needed to investigate protective agents, the protection of ICRF-187 was determined using a dose schedule with lower general toxicity (6 weekly doses of 4 mg/kg doxorubicin given i.v. plus 2 weeks of observation). On this schedule, the animals' hearts appeared normal after sacrifice and ICRF-187 (50 mg/kg given i.p. 1 h before doxorubicin) provided almost full protection. These data were confirmed by histology. The results indicate that this new model is very sensitive and enables monitoring of the development of cardiotoxicity with time. These findings result in a model that allows the testing of protectors against doxorubicin-induced cardiotoxicity as demonstrated by the protection provided by ICRF-187.

Analysis of Variance↗
PubMed1996

Structural aspects of antioxidant activity of flavonoids.

Flavonoids, a group of naturally occurring antioxidants and iron chelators, might be used as cardioprotective agents in doxorubicin-induced cardiotoxicity, which is believed to be caused by the formation of oxygen free radicals. To investigate the underlying molecular mechanism, we tested a large group of flavonoids from all major structural subclasses on their ability to inhibit doxorubicin (enzymatically)-induced and Fe2+/ascorbate (nonenzymatically)-induced microsomal lipid peroxidation (LPO) and to chelate Fe2+. In addition, we measured half peak oxidation potentials (Ep/2). LPO inhibition data gave a good qualitative correlation with the oxidation potentials. Most flavonoids tested chelated Fe2+, but there were large differences in the chelating capacity. For good scavenging activity, a catechol moiety on ring B is required. The 3-OH moiety can function as a chelation site and can also be oxidized. The 3-OH group in combination with a C2 C3 double bond, increases the scavenging activity. Fe2+ chelation only plays a role in the LPO inhibition by less active scavengers. Chelation can then raise the activity to the level of the most active scavengers, possibly by site-specific scavenging. It can be concluded that Ep/2 values and iron chelating activity can almost completely describe the LPO inhibiting behaviour of the flavonoids.

Animals↗
PubMed1996

Relationship between the tumour tissue pharmacokinetics and the antiproliferative effects of anthracyclines and their metabolites.

The intrinsic activity of anthracyclines and their metabolites was measured in order to determine whether the tumour exposure to the compounds reflects the difference in their ability to inhibit tumour growth. (Dox), 4'-epidoxorubicin (Epi-Dox), daunorubicin (Dauno), N-1-leucyl-doxorubicin (Leu-Dox) and their metabolites were analysed for their antiproliferative effects in three human malignant cell lines: MCF7, RPMI 8226 and A2780. The antitumour efficacy of equitoxic, maximum tolerated doses of the present drugs was assessed in nude mice bearing subcutaneous (s.c.) well-established A2780 doses of the parent drugs was assessed in nude mice bearing subcutaneous (s.c.) well-established A2780 human ovarian cancer xenografts. The same doses were given to tumour-bearing mice to determine the distribution of the anthracyclines and their metabolites in A2780 tumour tissue during the first 48 h after injection. In vitro antiproliferative effects of the anthracyclines and their metabolites revealed a comparable activity for the parent drugs and daunorubicinol, whereas the other metabolites were at least 10-fold less active. The growth inhibition obtained in A2780 xenografts was 87% for Dox, 82% for Epi-Dox, 74% for Dauno and 97% for Leu-Dox. In vivo, the exposure of tumour tissue to the drug, calculated as the area under the concentration-time curve (AUC), was related to the extent of growth inhibition after correction of the AUC values for the intrinsic activity of the anthracycline. For each of the anthracyclines, the sum of the corrected AUC values (nmol/g/min) of the active compounds was calculated as 8812 for Dauno; 9320 for Epi-Dox; 10 986 for Dox and 15 163 for Leu-Dox. The sequence of increasing AUC values corresponded with the sequence of increasing growth inhibition by the four anthracyclines observed in A2780 xenografts.

Animals↗