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1.
Mater Sci Eng C Mater Biol Appl ; 117: 111349, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32919694

ABSTRACT

Oxidative stress is caused by the accumulation of reactive oxygen and nitrogen species (ROS and RNS) in the cellular microenvironment. These ROS and RNS damage important cell structures leading to cell apoptosis and senescence, thus causing a detrimental effect on numerous disease pathologies such as osteoarthritis, neurodegeneration and cardiovascular diseases. For this reason, there is a growing interest in the development of antioxidant biomaterials that can eventually regulate the levels of ROS/RNS and prevent oxidative stress. The encapsulation of antioxidant enzymes (e.g., catalase or superoxide dismutase) on polymer microcapsules fabricated via the layer-by-layer (LbL) approach represents a promising strategy within this context. The diffusion of reagents and by-products through the shell of these microcapsules is timely and spatially controlled, allowing the bio-chemical reaction between ROS/RNS and the encapsulated enzyme. However, natural enzymes usually present low stability, high cost and difficult storage, which could limit their potential application in the biomedical field. Hence, nanomaterials with intrinsic enzyme-like characteristics (i.e., nanozymes) have been considered as inorganic alternatives. In the present work, manganese dioxide nanoparticles were encapsulated into LbL polymer microcapsules to yield synthetic antioxidant microreactors. These microreactors efficiently scavenged hydrogen peroxide (H2O2) from solution and protected cells from oxidative stress in an in vitro model. The versatility of the synthetic procedure presented herein allows the fabrication of capsules with either positive or negative surface charge, which has a direct impact on the cytotoxicity and cell interaction. This study represents accordingly a novel strategy to obtain antioxidant polymer microreactors based on synthetic (nano)materials for the treatment of oxidative stress.


Subject(s)
Antioxidants , Nanoparticles , Capsules , Hydrogen Peroxide , Manganese Compounds , Oxidative Stress , Oxides , Polymers , Reactive Oxygen Species
2.
J Biol Regul Homeost Agents ; 29(2): 357-65, 2015.
Article in English | MEDLINE | ID: mdl-26122223

ABSTRACT

Multidrug resistance (MDR) mediated by P-glycoprotein (Pgp) remains one of the major obstacles to effective cancer chemotherapy. Several chemosensitizers have been used in vivo and in vitro to reverse MDR but have exhibited several unwanted side effects. Antipsychotics are often administered to treat psychiatric disorders such as delirium, anxiety and sleep disorders in cancer patients during chemotherapy. The present in vitro study, examined the effects of two common antipsychotic compounds, haloperidol and risperidone, and a natural compound such as theobromine on reversing MDR Pgp-mediated, to evaluate their potential use as chemosensitizing agents. The human doxorubicin (doxo) resistant uterine sarcoma cells (MES-SA/Dx5) that overexpress Pgp (100-fold), were treated with the antipsychotic alone (1, 10 and 20 µM) or in combination with different concentrations of doxo (2, 4 and 8 µM). The accumulation and cytotoxicity of doxo (MTT assay) and cellular GSH content (GSH assay) in comparison with verapamil, a well-known Pgp inhibitor, used as reference molecule were examined. It was found that the three compounds significantly enhanced the intracellular accumulation of doxo in resistant cancer cells, when compared with cells receiving doxo alone (p<0.05). Furthermore, compounds showed strong potency to increase doxo cytotoxicity toward resistant MES-SA/Dx5 cells, when compared with untreated control cells. The antipsychotic compounds also significantly increased GSH content at all concentrations (> 30%) in resistant cells, when compared to untreated control cells (p<0.05). These findings suggest that the antipsychotics or their derivatives might represent a novel class of reversal agents for overcoming MDR in cancer therapy, in particular theobromine showed to be an effective Pgp inhibitor with the lowest toxicity.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Antimetabolites, Antineoplastic/therapeutic use , Antipsychotic Agents/pharmacology , Doxorubicin/therapeutic use , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Haloperidol/pharmacology , Neoplasm Proteins/antagonists & inhibitors , Risperidone/pharmacology , Sarcoma/pathology , Theobromine/pharmacology , Uterine Neoplasms/pathology , ATP Binding Cassette Transporter, Subfamily B, Member 1/physiology , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/metabolism , Cell Line, Tumor , Doxorubicin/administration & dosage , Doxorubicin/metabolism , Drug Screening Assays, Antitumor , Female , Glutathione/analysis , Humans , Neoplasm Proteins/physiology , Verapamil/pharmacology
3.
J Biol Regul Homeost Agents ; 27(4): 1029-37, 2013.
Article in English | MEDLINE | ID: mdl-24382184

ABSTRACT

Multidrug resistance (MDR) in cancer cells is often caused by the high expression of the plasma membrane drug transporter P-glycoprotein (Pgp) associated with an elevated intracellular glutathione (GSH) content in various human tumors. Several chemosensitizers reverse MDR but have significant toxicities. Antiemetic medications are often used for controlling chemotherapy-induced nausea and vomiting in cancer patient. In this in vitro study we investigated if the effects of two common antiemetic drugs such as dimenhydrinate (dime) and ondansentron (onda) and a natural compound (6)-gingerol (ginger), the active principle of ginger root, interfere on Pgp activity and intracellular GSH content in order to evaluate their potential use as chemosensitizing agents in anticancer chemotherapy. The human doxorubicin (doxo) resistant uterine sarcoma cells (MES-SA/Dx5) that overexpress Pgp, were treated with each antiemetic alone (1, 10 and 20 microM) or in combination with different doxo concentrations (2, 4, and 8 microM). We measured the intracellular accumulation and cytotoxicity of doxo (MTT assay), the cellular GSH content (GSH assay) and ROS production (DFC-DA assay), in comparison with verapamil (Ver), a specific inhibitor for Pgp, used as reference molecule. We found that exposure at 2, 4 and 8 microM doxo concentrations in the presence of dime, onda and ginger enhanced significantly doxo accumulation and cytotoxicity on resistant MES-SA/Dx5 cells when compared with doxo alone. Moreover, treatment with ginger (20 microM) increased cellular GSH content (greater than 10 percent) in resistant cells, while ROS production remained below the control values for all antiemetic compounds at all concentrations. These findings provide the rationale for innovative clinical trials of antiemetics or their derivatives as a new potential generation of chemosensitizers to improve effectiveness of the anticancer drugs in MDR human tumours.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/analysis , Antibiotics, Antineoplastic/pharmacology , Antiemetics/pharmacology , Doxorubicin/pharmacology , Sarcoma/drug therapy , Cell Line, Tumor , Doxorubicin/pharmacokinetics , Drug Resistance, Neoplasm , Glutathione/metabolism , Humans , Reactive Oxygen Species/metabolism , Sarcoma/pathology
4.
Appl Radiat Isot ; 69(12): 1725-7, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21398132

ABSTRACT

The applicability of boron nitride nanotubes (BNNTs) containing Fe paramagnetic impurities as contrast agents in magnetic resonance imaging (MRI) was investigated. The measurement of longitudinal and transverse relaxation times of water protons in homogeneous aqueous dispersions of BNNTs wrapped with poly(L-lysine) at different concentrations allowed longitudinal (r(1)) and transverse (r(2)) relaxivities to be determined at 3T. The r(2) value was comparable to those of commercial superparamagnetic iron oxide nanoparticles, indicating that Fe-containing BNNTs have the potential to be used as T(2) contrast-enhancement agents in MRI at 3T.


Subject(s)
Boron Neutron Capture Therapy , Contrast Media , Magnetic Resonance Imaging/methods , Cell Line , Humans
5.
Int J Nanomedicine ; 5: 285-98, 2010 Apr 15.
Article in English | MEDLINE | ID: mdl-20463944

ABSTRACT

Boron nitride nanotubes (BNNTs) have generated considerable interest within the scientific community by virtue of their unique physical properties, which can be exploited in the biomedical field. In the present in vitro study, we investigated the interactions of poly-l-lysine-coated BNNTs with C2C12 cells, as a model of muscle cells, in terms of cytocompatibility and BNNT internalization. The latter was performed using both confocal and transmission electron microscopy. Finally, we investigated myoblast differentiation in the presence of BNNTs, evaluating the protein synthesis of differentiating cells, myotube formation, and expression of some constitutive myoblastic markers, such as MyoD and Cx43, by reverse transcription - polymerase chain reaction and Western blot analysis. We demonstrated that BNNTs are highly internalized by C2C12 cells, with neither adversely affecting C2C12 myoblast viability nor significantly interfering with myotube formation.


Subject(s)
Boron Compounds/administration & dosage , Boron Compounds/chemistry , Coated Materials, Biocompatible/administration & dosage , Coated Materials, Biocompatible/chemistry , Muscle Fibers, Skeletal/cytology , Muscle Fibers, Skeletal/drug effects , Nanotubes/chemistry , Polylysine/administration & dosage , Animals , Cell Differentiation/drug effects , Cell Line , Materials Testing , Muscle Fibers, Skeletal/chemistry , Nanotubes/ultrastructure , Polylysine/chemistry , Rats
6.
Colloids Surf B Biointerfaces ; 76(2): 535-43, 2010 Apr 01.
Article in English | MEDLINE | ID: mdl-20060274

ABSTRACT

Nanoscale structures and materials have been explored in many biological applications because of their extraordinary novel properties. Here we propose a study of cellular interactions with barium titanate nanoparticles, an interesting ceramic material that has received a lot of interest in the nanotechnology research, but without any attention about its biological potential. We introduced for the first time an efficient method for the preparation of stable aqueous dispersions of barium titanate nanoparticles, characterized with FIB, TEM and AFM imaging, light scattering, Z-potential and UV/vis analysis. Finally, we presented a systematic study of short-term cytotoxicity of the prepared dispersion based both on quantitative (metabolism, proliferation) and qualitative (apoptosis, viability, differentiation) assays.


Subject(s)
Barium Compounds/chemical synthesis , Barium Compounds/pharmacology , Biomedical Research , Nanoparticles/chemistry , Titanium/pharmacology , Animals , Apoptosis/drug effects , Barium Compounds/chemistry , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Particle Size , Rats , Surface Properties , Titanium/chemistry
7.
Nanotechnology ; 20(7): 075104, 2009 Feb 18.
Article in English | MEDLINE | ID: mdl-19417408

ABSTRACT

Boron nitride nanotubes (BNNTs) are a structural analogue of carbon nanotubes (CNTs), with alternating B and N atoms which entirely substitute for C atoms in a graphitic-like sheet with almost no change in atomic spacing. BNNTs have generated considerable interest within the scientific community by virtue of their unique properties. Very recently, biomedical applications of BNNTs have also been proposed. In the present in vitro study, we demonstrate that BNNTs can be used as nanotools to enable cell electropermeabilization with very low electric fields (40-60 V cm(-1)). An explanation of this behaviour based on the dielectric response of BNNTs to static electric fields is proposed.


Subject(s)
Boron Compounds , Cell Membrane Permeability/drug effects , Electroporation/methods , Nanotubes/chemistry , Cell Line, Tumor , Humans
8.
Nanoscale Res Lett ; 5(1): 257-62, 2009 Oct 27.
Article in English | MEDLINE | ID: mdl-20651914

ABSTRACT

Carbon nanotubes (CNTs) are tubular nanostructures that exhibit magnetic properties due to the metal catalyst impurities entrapped at their extremities during fabrication. When mammalian cells are cultured in a CNT-containing medium, the nanotubes interact with the cells, as a result of which, on exposure to a magnetic field, they are able to move cells towards the magnetic source. In the present paper, we report on a model that describes the dynamics of this mammalian cell movement in a magnetic field consequent on CNT attachment. The model is based on Bell's theory of unbinding dynamics of receptor-ligand bonds modified and validated by experimental data of the movement dynamics of mammalian cells cultured with nanotubes and exposed to a magnetic field, generated by a permanent magnet, in the vicinity of the cell culture wells. We demonstrate that when the applied magnetic force is below a critical value (about Fc ≈ 10-11 N), the cell 'creeps' very slowly on the culture dish at a very low velocity (10-20 nm/s) but becomes detached from the substrate when this critical magnetic force is exceeded and then move towards the magnetic source.

9.
Free Radic Biol Med ; 31(3): 331-5, 2001 Aug 01.
Article in English | MEDLINE | ID: mdl-11461770

ABSTRACT

The thiobarbituric acid (TBA) reactivity of human plasma was studied to evaluate its adequacy in quantifying lipid peroxidation as an index of systemic oxidative stress. Two spectrophotometric TBA tests based on the use of either phosphoric acid (pH 2.0, method A) or trichloroacetic plus hydrochloric acid (pH 0.9, method B) were employed with and without sodium sulfate (SS) to inhibit sialic acid (SA) reactivity with TBA. To correct for background absorption, the absorbance values at 572 nm were subtracted from those at 532 nm, which represent the absorption maximum of the TBA:MDA adduct. Method B gave values of TBA-reactive substances (TBARS) 2-fold higher than those detected with method A. SS lowered TBARS by about 50% with both methods, indicating a significant involvement of SA in plasma TBA reactivity. Standard SA, at a physiologically relevant concentration of 1.5 mM, reacted with TBA, creating interference problems, which were substantially eliminated by SS plus correction for background absorbance. When method B was carried out in the lipid and protein fraction of plasma, SS inhibited by 65% TBARS formation only in the latter. Protein TBARS may be largely ascribed to SA-containing glycoproteins and, to a minor extent, protein-bound MDA. Indeed, EDTA did not affect protein TBARS assessed in the presence of SS. TBA reactivity of whole plasma and of its lipid fraction was instead inhibited by EDTA, suggesting that lipoperoxides (and possibly monofunctional lipoperoxidation aldehydes) are involved as MDA precursors in the TBA test. Pretreatment of plasma with KI, a specific reductant of hydroperoxides, decreased TBARS by about 27%. Moreover, aspirin administration to humans to inhibit prostaglandin endoperoxide generation reduced plasma TBARS by 40%. In conclusion, reaction conditions affect the relationship between TBA reactivity and lipid peroxidation in human plasma. After correction for the interfering effects of SA in the TBA test, 40% of plasma TBARS appears related to in vivo generated prostaglandin endoperoxides and only about 60% to lipoperoxidation products. Thus, the TBA test is not totally specific to oxidant-driven lipid peroxidation in human plasma.


Subject(s)
Lipid Peroxidation , Lipid Peroxides/blood , Thiobarbituric Acid Reactive Substances/analysis , Biomarkers/blood , Edetic Acid , Humans , Hydrogen-Ion Concentration , Indicators and Reagents , Oxidative Stress , Phosphoric Acids , Reproducibility of Results , Spectrophotometry/methods , Sulfates
10.
Br J Pharmacol ; 133(5): 739-45, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11429399

ABSTRACT

Lipoprotein oxidation is crucial in atherogenic processes. Amiodarone is a lipophilic antiarrhythmic/antianginal drug which is able to influence the physicochemical status of biological lipid components. Since oxidation of lipids is affected by their physicochemical state and amiodarone binds to lipoproteins, we hypothesized that the drug may exert an antioxidant activity on human lipoprotein oxidation. Dose-dependent effects of therapeutically achievable amiodarone concentrations (1.5, 3, 5, 7 and 10 microM) were studied on copper-catalysed oxidation of the non-HDL fraction in vitro. Amiodarone inhibited oxidation as judged by generation of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH) and fluorescent products of lipoperoxidation (FPL) as well as from the kinetics of conjugated diene formation. This antioxidant activity was significant at 1.5 microM with total inhibition at 10 microM and an IC(50) of 4 microM. The primary in vivo metabolite of amiodarone, namely desethylamiodarone, also exhibited specific antioxidant properties although it was less effective than amiodarone with an IC(50) of 7 microM. In further in vivo experiments, susceptibility to copper-mediated oxidation of the non-HDL fraction was investigated before and 4 weeks after oral amiodarone administration to humans. Following treatment, significant inhibition of TBARS, LOOH and FPL generation was observed in comparison with baseline levels and a placebo-treated control group, highlighting an effective antioxidant capacity of amiodarone in vivo. Amiodarone did not change lipoprotein vitamin E and phospholipid content in vivo and did not show scavenging effects on oxidizing species involved in lipoprotein oxidation, such as peroxyl radicals, nor metal-binding/inactivating properties, suggesting that physicochemical modifications of lipoprotein lipids induced by the lipophilic drug may be involved in its antioxidant activity. In conclusion, amiodarone, and its primary metabolite desethylamiodarone, show previously unrecognized antioxidant activity on human lipoprotein oxidation. This effect is also evident in vivo and at therapeutically achievable drug concentrations. Thus, amiodarone may act as an antioxidant/antiatherosclerotic agent in humans, although this issue warrants further clinical study.


Subject(s)
Amiodarone/pharmacology , Antioxidants/pharmacology , Lipoproteins/drug effects , Adult , Aged , Amiodarone/chemistry , Anti-Arrhythmia Agents/pharmacology , Copper/chemistry , Copper/pharmacology , Dose-Response Relationship, Drug , Female , Free Radical Scavengers/pharmacology , Humans , Lipid Peroxidation , Lipid Peroxides/metabolism , Lipoproteins/metabolism , Middle Aged , Oxidation-Reduction/drug effects , Spectrometry, Fluorescence , Thiobarbituric Acid Reactive Substances/metabolism , Time Factors
11.
Free Radic Res ; 31(6): 487-91, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10630672

ABSTRACT

Abstract-cell-mediated lipoprotein oxidation may be due to generation of non-protein thiols (NP-SH) from cystine with formation of oxidizing species. However, NP-SH, especially GSH, may also exert antioxidant effects in vitro and in vivo. To further investigate whether vascular NP-SH could be prooxidants or antioxidants in atherosclerosis, we have correlated the aortic content of NP-SH with that of lipoperoxides in 10 rabbits fed on a fat-enriched atherogenic diet for 9 weeks. As compared to 7 control rabbits, aortic NP-SH and lipoperoxides were significantly increased in the fat-fed animals. The levels of NP-SH were strongly and inversely correlated with those of lipid peroxidation in the atherosclerotic aorta (r(s) -0.92, P < 0.0001 for thiobarbituric acid reactive substances, and r(s) -0.80, P < 0.01 for fluorescent damage products of lipid peroxidation). A similar trend was evident also in the control rabbits (r(s) -0.60 for both indices of lipid peroxidation). Thus, the present data suggest that vascular NP-SH exert significant antioxidant-antilipoperoxidative effects in vivo especially in fat diet-related atherogenic conditions.


Subject(s)
Arteriosclerosis/metabolism , Lipid Peroxidation , Sulfhydryl Compounds/metabolism , Animals , Antioxidants/metabolism , Aorta/physiology , Cholesterol/blood , Diet, Atherogenic , Disease Models, Animal , Male , Rabbits
12.
FEBS Lett ; 436(3): 357-60, 1998 Oct 09.
Article in English | MEDLINE | ID: mdl-9801148

ABSTRACT

We found that ticlopidine, at therapeutically relevant concentrations (2.5-10 microM), but not aspirin nor salicylate, significantly counteracted copper-driven human LDL oxidation. Ticlopidine, at 5 and 10 microM, was also antioxidant on peroxyl radical-induced LDL oxidation; yet it was ineffectual on thiol and ascorbate oxidation mediated by peroxyl radicals themselves, suggesting that drug antioxidant capacity is somehow related to the lipoprotein nature of the oxidizable substrate, but not to radical scavenging. The drug could not indeed react with the stable free radical 1,1-diphenyl-2-pycrylhydrazyl, nor had apparent metal complexing-inactivating activity. Thus, ticlopidine has antioxidant effects on LDL oxidation, which, together with its anti-platelet activity, could confer peculiar antiatherogenic properties to the drug in vivo.


Subject(s)
Antioxidants/pharmacology , Lipoproteins, LDL/drug effects , Lipoproteins, LDL/metabolism , Ticlopidine/pharmacology , Amidines/pharmacology , Ascorbic Acid/metabolism , Aspirin/pharmacology , Free Radical Scavengers/pharmacology , Free Radicals , Humans , Kinetics , Lipoproteins, LDL/blood , Oxidants/pharmacology , Oxidation-Reduction , Peroxides/pharmacology
13.
Circulation ; 97(19): 1930-4, 1998 May 19.
Article in English | MEDLINE | ID: mdl-9609086

ABSTRACT

BACKGROUND: Oxidative stress, resulting from an antioxidant/prooxidant imbalance, seems to be crucial in atherogenesis. Recent evidence has emerged, however, of a surprisingly high content of low-molecular-weight antioxidants in human atherosclerotic plaques, although other antioxidant systems have not been investigated in these lesions. METHODS AND RESULTS: We studied glutathione-related antioxidant defenses (which play a key role in tissue antioxidant protection) in carotid atherosclerotic plaques of 13 patients subjected to endarterectomy and in normal internal mammary arteries of 13 patients undergoing coronary artery bypass surgery. Selenium-dependent glutathione peroxidase activity was undetectable in the plaques of 7 patients; the other 6 patients with plaques showed a mean enzymatic activity approximately 3.5-fold lower than that of mammary arteries. Glutathione reductase activity was also markedly lower in the plaques than in the arteries. Glutathione transferase instead had comparable activity in the two tissues. Remarkably, 5 of the 7 patients with an undetectable selenium-dependent glutathione peroxidase activity but none of the 6 with a detectable one were characterized by multivascular atherosclerotic involvement (3 patients) or stenosis of the contralateral carotid artery (2 patients). CONCLUSIONS: A weak glutathione-related enzymatic antioxidant shield is present in human atherosclerotic lesions. Although the cause of this phenomenon remains to be determined, the present data suggest that a specific antioxidant/prooxidant imbalance operative in the vascular wall may be involved in atherogenic processes in humans.


Subject(s)
Arteriosclerosis/enzymology , Carotid Stenosis/enzymology , Glutathione Peroxidase/metabolism , Glutathione Reductase/metabolism , Glutathione Transferase/metabolism , Glutathione/metabolism , Mammary Arteries/enzymology , Antioxidants/metabolism , Arteriosclerosis/pathology , Arteriosclerosis/surgery , Carotid Stenosis/pathology , Carotid Stenosis/surgery , Endarterectomy, Carotid , Female , Glutathione Disulfide/metabolism , Humans , Male , Middle Aged , Muscle, Smooth, Vascular/enzymology
14.
FEBS Lett ; 409(2): 265-8, 1997 Jun 09.
Article in English | MEDLINE | ID: mdl-9202158

ABSTRACT

We found that allopurinol, at therapeutically relevant concentrations (9-58 microM), significantly counteracted copper-catalysed human non-HDL lipoprotein oxidation, as assessed by thiobarbituric acid reactant content and kinetics of conjugated diene formation. Oxypurinol was ineffectual. Both drugs had no activity on metal-independent, peroxyl radical-induced lipoprotein oxidation. Specific fluorescence-quenching experiments revealed that only allopurinol could interact with copper antagonizing metal binding to lipoproteins. Thus, therapeutic allopurinol concentrations can inhibit copper-catalysed lipoprotein oxidation through metal complexation, suggesting some antioxidant-antiatherogenic activity of the drug in vivo.


Subject(s)
Allopurinol/pharmacology , Antioxidants/pharmacology , Copper/pharmacology , Lipoproteins/metabolism , Adult , Allopurinol/chemistry , Allopurinol/metabolism , Antioxidants/chemistry , Antioxidants/metabolism , Catalysis , Copper/metabolism , Humans , Lipid Peroxidation/drug effects , Lipoproteins, HDL/metabolism , Male , Middle Aged , Oxypurinol/pharmacology
15.
Br J Clin Pharmacol ; 42(4): 451-6, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8904616

ABSTRACT

1. Captopril has been reported to possess hydroxyl radical (OH.) and hypochlorous acid (HOCl) scavenging effects, which could contribute to its therapeutic activity in the clinical setting. 2. The objective of the present study was to determine whether therapeutically achievable captopril concentrations could augment antioxidant properties of human plasma and protect it against OH.- and HOCl-driven oxidant injury in vitro. Possible drug influences on systemic oxidative stress status in vivo were also investigated in subjects taking 50 mg captopril orally by measuring plasma and red blood cell peroxidation, as well as plasma protein thiols. 3. The results show that captopril is incapable of enhancing antioxidant properties of human plasma, of protecting it against specific oxidative attack and of decreasing systemic oxidant load in vivo. 4. The present data, therefore, do not support the contention of a beneficial action of captopril through systemic antiradical-antioxidant effects in human beings.


Subject(s)
Antioxidants/pharmacology , Captopril/pharmacology , Adult , Blood Pressure/drug effects , Captopril/blood , Free Radical Scavengers , Humans , Male , Middle Aged , Oxidative Stress
16.
FEBS Lett ; 391(1-2): 76-8, 1996 Aug 05.
Article in English | MEDLINE | ID: mdl-8706934

ABSTRACT

Non-protein thiols (NP-SH) and the activities of the glutathione status-regulating enzymes gamma-glutamylcysteine synthetase (G-GCS), gamma-glutamyl transpeptidase (G-GT) and glutathione reductase (GR) were assessed in perfused rabbit hearts subjected to severe (60 min) or mild (7 min) total ischemia and 30 min reperfusion. Severe ischemia significantly decreased NP-SH, which were further depressed on reperfusion together with a significant decline in G-GCS activity; G-GT and GR activities were unchanged. Specific analytes were unaffected by mild ischemia-reperfusion. Thus, impaired enzymatic biosynthesis of GSH is operative in the reperfused rabbit myocardium after 60 min ischemia. This phenomenon may favour myocardial GSH depression and oxidative reperfusion injury after severe ischemia.


Subject(s)
Glutathione/biosynthesis , Myocardial Reperfusion , Myocardium/metabolism , Animals , Glutamate-Cysteine Ligase/metabolism , Glutathione Reductase/metabolism , In Vitro Techniques , Kinetics , Myocardial Ischemia/metabolism , Rabbits , Reference Values , Sulfhydryl Compounds/metabolism , Time Factors , gamma-Glutamyltransferase/metabolism
17.
FEBS Lett ; 382(1-2): 189-92, 1996 Mar 11.
Article in English | MEDLINE | ID: mdl-8612750

ABSTRACT

Potential antioxidant properties of therapeutically achievable concentrations of the protonated, active form of omeprazole (OM) were investigated in vitro at specific acidic pH values to mimic intragastric conditions in the clinical setting. We found that OM is a powerful scavenger of hypochlorous acid (HOCl) even at a drug concentration of 10 microM at pH 5.3 or 3.5. This effect is also evident in the presence of the physiological HOCl scavenger ascorbate. Moreover, 10 and 50 microM OM inhibit significantly both iron- and copper-driven oxidant damage at pH 5.3 and 3.5, respectively. Since oxidative stress is involved the gastric injury of peptic ulcer and gastritis, it may be hypothesized that some therapeutical effects of OM could also be related to its antioxidant properties.


Subject(s)
Anti-Ulcer Agents/pharmacology , Antioxidants/pharmacology , Omeprazole/pharmacology , Ascorbic Acid/pharmacology , Carotenoids/metabolism , Chlorides , Copper/pharmacology , Deoxyribose/metabolism , Ferric Compounds/pharmacology , Hydrogen-Ion Concentration , Hypochlorous Acid/pharmacology , Oxidation-Reduction/drug effects , beta Carotene
18.
Eur J Clin Invest ; 25(7): 464-70, 1995 Jul.
Article in English | MEDLINE | ID: mdl-7556363

ABSTRACT

Potential antioxidant properties of aminophylline and theophylline were investigated. We have found that these drugs, though ineffective against superoxide anion and hydrogen peroxide, are scavengers of hydroxyl radical (OH.). Indeed, second-order rate constants (k) of aminophylline and theophylline with OH. are about 1.9 x 10(10) mol-1 s-1 and 4.5 x 10(9) mol-1 s-1, respectively. Ethylenediamine, which is present in the aminophylline molecule, significantly contributes to this marked OH. scavenging activity, since it is characterized by a high k value, i.e. about 8 x 10(9) mol-1 s-1. However, when using therapeutically relevant concentrations of the methylxanthines (9 and 13 micrograms mL-1), significant antioxidant effects against OH.-induced oxidant injury are evident only with aminophylline. Although all three substances can apparently bind and inactivate iron, only aminophylline is effective at 9 and 13 micrograms mL-1; also this action is favoured by ethylenediamine. Moreover, therapeutic concentrations of aminophylline, but not of theophylline, are capable of antagonizing hypochlorous acid (HOCl); this effect is entirely due to the presence of ethylenediamine. Oxidant species, such as OH. and HOCl, have been implicated in the pathophysiology of asthma; it could be hypothesized, therefore, that some therapeutic effects of aminophylline may be related to its antioxidant properties, which are partly or totally attributable to ethylenediamine, depending on the chemical identity of the prooxidant antagonized (e.g. iron/OH. or HOCl). Aminophylline antioxidant capacity should be taken into account when investigating the lung epithelial lining fluid antioxidant capacity and oxidative stress indices in humans.


Subject(s)
Aminophylline , Antioxidants , Hydroxyl Radical , Theophylline , Aminophylline/pharmacology , Antioxidants/pharmacology , Deoxyribose , Epithelium/drug effects , Epithelium/physiology , Free Radical Scavengers , Humans , Hypochlorous Acid , Lung/drug effects , Lung/physiology , Oxidative Stress , Reactive Oxygen Species , Sensitivity and Specificity , Theophylline/pharmacology , Thiobarbituric Acid Reactive Substances
19.
Biochem Pharmacol ; 50(1): 27-32, 1995 Jun 29.
Article in English | MEDLINE | ID: mdl-7605341

ABSTRACT

The thiol drug captopril has been reported to possess reducing and transition metal-binding properties, which could result in specific changes in iron and copper prooxidant capacity. Thus, the effects of captopril on iron- and copper-induced oxidative injury were evaluated using deoxyribose as the oxidizable substrate in the presence of physiological phosphate concentrations but in the absence of the non-physiological chelator EDTA. In an iron(III)/H2O2/ascorbate oxidant system, captopril enhanced deoxyribose oxidation only when it was pre-mixed with iron, whereas it did not influence sugar degradation when not pre-mixed with the metal or when ascorbate was omitted. The physiological thiol GSH acted in a similar manner, whereas the SH-lacking angiotensin-converting enzyme inhibitor ramiprilat did not influence iron-induced deoxyribose oxidation, indicating that the thiol group is crucial in favouring enhanced iron reactivity due to 'malignant' chelation. Further specific experiments designed to evaluate possible thiol-dependent iron(III) reduction failed to demonstrate ferric to ferrous reduction by either captopril or reduced glutathione (GSH). When iron(III) was replaced by copper(II) to induce deoxyribose oxidation, captopril was prooxidant both in the presence and absence of ascorbate, and when pre-mixed or not with copper. On the other hand, GSH was prooxidant up to 2:1 molar ratio with respect to copper but markedly inhibited copper-dependent sugar oxidation beginning at molar ratio of 4:1. Ramiprilat did not significantly influence copper-induced deoxyribose oxidation. Moreover, unlike the experiments performed with iron, captopril, as well as GSH, readily reduced copper(II) to copper(I). Hence, captopril can act as prooxidant in the presence of iron or copper. In the former case, only 'malignant' iron chelation by the drug is involved in oxidant injury, whereas in the latter both copper chelation and reduction are operative, although specific chelating mechanisms are crucial in enhancing copper-induced oxidant injury. Captopril, therefore, cannot be considered simply as an 'antioxidant drug', and its catalytic transition metal-related prooxidant capacity should be taken into account in experimental and clinical investigations.


Subject(s)
Captopril/pharmacology , Reactive Oxygen Species/pharmacology , Captopril/chemistry , Copper/chemistry , Deoxyribose/chemistry , Iron/chemistry , Oxidation-Reduction , Reactive Oxygen Species/chemistry
20.
Biochem Pharmacol ; 49(9): 1249-54, 1995 May 11.
Article in English | MEDLINE | ID: mdl-7763305

ABSTRACT

Potential scavenging properties of cephalosporins (i.e. cefamandole, cefotaxime and ceftriaxone) towards hypochlorous acid (HOCl) as well as the antibacterial activity of control and HOCl-reacted antibiotics were investigated. We found that these drugs, at therapeutically relevant concentrations, are indeed scavengers of HOCl, with ceftriaxone showing the highest anti-HOCl capacity. However, the efficiency of cephalosporins in protecting biological molecules is also related to the chemical identity of such molecules. Indeed, the polyenoic compound beta-carotene is much better protected that the thiol compound GSH against HOCl attack. Moreover, the drugs do not appear to form chloramine derivatives as a result of their reaction with HOCl, and they inhibit taurine-chloramine formation. After HOCl challenge, the antibacterial activity of cefamandole, cefotaxime and ceftriaxone (tested against the standard strain Escherichia coli ATCC 25922) is approx. 8-, 5- and 4-fold lower, respectively, than that of the HOCl-unreacted antibiotics. The depression of the antibacterial activity of cephalosporins appears inversely related to their HOCl scavenging capacity, suggesting that the drug antioxidant groups may protect the beta-lactam ring against HOCl attack. In conclusion, physiological biomolecules are protected by cephalosporins against HOCl-driven oxidative injury with varying efficiency, this antioxidant defence being a consequence of a direct drug scavenging capacity towards HOCl. The interaction of cephalosporins with HOCl, however, results in a depression of their antibacterial activity.


Subject(s)
Antioxidants/chemistry , Cephalosporins/chemistry , Hypochlorous Acid/chemistry , Carotenoids/chemistry , Glutathione/chemistry , Microbial Sensitivity Tests , Oxidation-Reduction , beta Carotene
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