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Journal Article 2008; 29(5): 802-805 PubMed PMID: 18987580 Citation  Keywords:  Adenosine Triphosphate:metabolism, Antioxidants:pharmacology, Cell Survival:drug effects, Dose-Response Relationship, Drug, Humans, Luminescence, Neutrophils:drug effects, Reactive Oxygen Species:metabolism, Stilbenes:pharmacology, Structure-Activity Rela.   

OBJECTIVES: Oxidative stress is related to a number of autoimmune diseases, e.g. rheumatoid arthritis, cancer, etc. The main source of pathologically working reactive oxygen species (ROS) are activated polymorphonuclear leukocytes (PMNL).

OBJECTIVE: There are some papers comparing structure - pharmacological efficiency relationship of vegetal substances from the stilbenoid group. We compared the effect of trans-resveratrol, which is well-known by its antioxidative activity, with the effect of pinosylvin and pterostilbene.

METHODS: Luminol-enhanced chemiluminescence (CL) was used to study the antioxidative action. The effect was observed in whole blood and in isolated PMNL. The concentrations of substances tested were 0.01-100 microM. Due to the different abilities of luminol and isoluminol to pass through the cell membrane, we studied the effect of the substances tested on intracellular and extracellular ROS. To stimulate the production of ROS we used phorbol-myristate-acetate (PMA), which activates PMNL via protein kinase C.

RESULTS: Resveratrol, pinosylvin and pterostilbene inhibited significantly the CL of whole blood and extra- and intracellular CL of isolated PMNL in a dosedependent manner. Depending on different functional groups of the stilbene molecule, resveratrol inhibited CL of whole blood and isolated PMNL, whereas pinosylvin influenced mainly intracellular CL and pterostilbene extracellular CL.

CONCLUSION: The presence of different functional groups in the molecules of stilbenoids influence their antioxidative effect. Modification of these functional groups may result in derivatives with required antioxidative properties, targeting mainly extracellular ROS which are responsible for tissue damage during chronic inflammation....

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Journal Article 2008; 29(5): 614-619 PubMed PMID: 18987575 Citation  Keywords:  Animals, Antioxidants:pharmacology, Bioterrorism, Chemical Warfare Agents:toxicity, Humans, Melatonin:pharmacology, Mustard Gas:toxicity, Neurotoxicity Syndromes:prevention & control,.   

: Among the most readily available chemical warfare agents, sulfur mustard (SM) has been the most widely used chemical weapon. The toxicity of SM as an incapacitating agent is of much greater importance than its ability to cause lethality. Oxidative stress is the first and key event in the pathogenesis of SM toxicity. The involvement of inducible nitric oxide (iNOS) in SM toxicity, however, also leads to elevated nitrosative stress; thus, the damage caused by SM is nitro-oxidative stress because of peroxynitrite (ONOO-) production. Once ONOO- is formed, it activates nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) leading to pro-inflammatory gene expression thereby promoting inflammation; additionally, ONOO- directly exerts harmful effects by damaging all biomolecules including lipids, proteins and DNA within cells. DNA damage is sensed by an important DNA repair enzyme, poly (ADP-ribose) polymerase (PARP); this enzyme repairs molecular damage by using nicotinamide adenine dinucleotide (NAD+) as a substrate. Over-activation of PARP, due to severe DNA damage, consumes vast amounts of the respiratory coenzyme NAD+ leading to a cellular energy crisis. This pathophysiologic mechanism eventually results in cellular dysfunction, apoptosis or necrosis. Therefore, classic antioxidants may have limited beneficial effects on SM toxicity. Melatonin is a multifunctional indolamine which counteracts virtually all pathophysiologic steps and displays significant beneficial effects against ONOO--induced cellular toxicity. Melatonin has the capability of scavenging both oxygen and nitrogen-based reactants including ONOO- and blocking transcriptional factors which induce pro-inflammatory cytokines. The delayed toxicity of SM, however, currently has no mechanistic explanation. We propose that epigenetic aberrations may be responsible for delayed detrimental effects of mustard poisoning. Therefore, as a putative epigenetic modulator, melatonin may also be beneficial to subjects with delayed toxicity of SM....

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Journal Article 2007; 28(Suppl 4): 4-6 PubMed PMID: 18030259 Citation  Keywords:  Animals, Antioxidants:pharmacology, Catalase:metabolism, Ethanol:pharmacology, Intestinal Absorption:drug effects, Longevity:drug effects, Male, Progeria:chemically induced, Rats, Rats, Wistar, Specific Pathogen-Free Organisms, Superoxide Dismutase:metabo.   

: Whole-life consumption of the pure Tokaj wine (The Furmint variety) with documented antioxidative activity significantly elongated (p<0.05) the life of laboratory animals in comparison to the control group consuming water and in comparison to group consuming ethanol (10%). Whole-life intake of ethanol (10%) diluted with water neither shortened nor elongated life of laboratory animals in comparison to control group consuming water. An increased dosing of the Tokaj wine combined with water shortened life expectation (p<0.001). Obviously mixing of wine and water increases the absorption of toxic elements influenced by an acid medium through the change of anions to cations, but also increased appetite resulting into obesity on the basis of hyperphagia....

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Journal Article 2006; 27(Suppl 2): 164-167 PubMed PMID: 17159806 Citation  Keywords:  Animals, Antioxidants:pharmacology, Calcium:metabolism, Female, Flavonoids:pharmacology, Muscle, Skeletal:drug effects, Rabbits, Sarcoplasmic Reticulum Calcium-Transporting ATPases:metabolism,.   

OBJECTIVES: Effects of phenolic antioxidants, synthetized (trolox, pyridoindole stobadine) and plant extracts (EGb 761 and Pycnogenol) were investigated on the activity of Ca(2+)-ATPase from sarcoplasmic reticulum (SR) of rabbit skeletal muscle to examine their potency to modulate the activity of this calcium level regulating enzyme.

METHODS: SR vesicles and pure Ca(2+)-ATPase were isolated by ultracentrifugation. Ca(2+)-ATPase activity was measured spectrophotometrically by enzyme-coupled assay.

RESULTS: Pycnogenol (Pyc) significantly decreased the activity of Ca(2+)-ATPase incorporated into SR vesicles as well as the activity of purified Ca(2+)-ATPase, the latter with respect to both enzyme substrates, Ca(2+) and ATP. Trolox, stobadine and EGb 761 did not influence significantly the activity SR- vesicle incorporated or pure Ca(2+)-ATPase, the latter with respect to either substrate, in spite of alterations of kinetic parameters in some cases.

CONCLUSIONS: The decrease of SR Ca(2+)-ATPase activity induced by Pyc may be associated with its proapoptotic and anticancerogenic properties....

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Clinical Trial 2006; 27(Suppl 2): 138-140 PubMed PMID: 17159799 Citation  Keywords:  Adrenergic beta-Antagonists:pharmacology, Aged, Antihypertensive Agents:therapeutic use, Antioxidants:pharmacology, Carbazoles:pharmacology, Diabetes Mellitus, Type 2:blood, Diabetic Angiopathies:blood, Female, Heart Failure:blood, Humans, In Vitro Techni.   

OBJECTIVES: In the present study we investigated whether the beta-adrenoceptor antagonist carvedilol (CARV) [Dilatrend] prevented reactive oxygen metabolite (ROM) production in human polymorphonuclear leukocytes (PMNL) or interfered with ROM already generated. To specify the site of action of CARV, we evaluated its effect on extra- and intracellular ROM generation. In addition, we studied the effect of CARV therapy on ROM production in whole blood obtained from patients with congestive heart failure (CHF) combined with type II diabetes mellitus.

METHODS: ROM generation in whole blood and isolated PMNL was determined after phorbol 12-myristate-13-acetate (PMA-0.05 micromol/l) stimulation by luminol/isoluminol-enhanced chemiluminescence (CL) in the microplate luminometer Immunotech LM-01T.

RESULTS: CARV significantly decreased CL of human whole blood in the concentrations of 10, 20, 50 and 100 micromol/l, both when applied simultaneously and after stimulation. In isolated PMNL, CARV significantly decreased extracellular CL in the concentrations of 50 and 100 micromol/l, intracellular CL was decreased in the concentrations of 20, 50 and 100 micromol/l. The nonstimulated and PMA stimulated CL of whole blood was increased in patients before therapy in comparison with healthy controls. After CARV therapy, 25 mg/day and 50 mg/day, there was a trend to reduce CL as compared to values before therapy.

CONCLUSIONS: In human PMNL, CARV interfered in vitro and ex vivo with ROM generation as well as with already generated ROM, suggestive of its both "preventive" and "therapeutic" effect....

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Comparative Study 2006; 27(5): 595-599 PubMed PMID: 17159816 Citation  Keywords:  Animals, Antioxidants:pharmacology, Antithyroid Agents:pharmacology, Diet, Dose-Response Relationship, Drug, Kidney:chemistry, Liver:chemistry, Lung:chemistry, Male, Oxidative Stress:drug effects, Potassium Iodide:administration & dosage, Propylthiouracil.   

OBJECTIVES: Iodide administration to animals, living in iodine-deficient areas, can induce oxidative processes in the thyroid gland and increase concentration of lipid peroxidation (LPO). Propylthiouracil (PTU)--a well-known antithyroid drug--may also act as an antioxidant. There are some reports, which consider the protective ability of this drug against LPO. The goal of the study was to evaluate oxidative processes and the protective role of PTU in three rat organs during treatment with pharmacological doses of iodide.

MATERIAL AND METHODS: Schiff's bases (SB) concentrations (a parameter of oxidative stress) were measured in liver, lung and kidney homogenates of male Wistar rats. For 2 weeks the animals received iodides in their diet in the following concentrations: Group 1--Controls (standard diet, approx. 0.7 mg of potassium iodide per kg; KI/kg); Group 2--diet containing 0.25 mg KI/kg; Group 3--diet with 4.0 mg KI/kg; Group 4--diet with 8.0 mg KI/kg. Group 5--standard diet with 0.1% of PTU in drinking water for two weeks. Subsequent tree groups (6-8) received KI in their diet in doses as above, respectively, together with PTU.

RESULTS: We noted increased SB levels in the lungs and in the liver, compared to those observed in the control group. We also found decreased SB concentrations in liver and lung homogenates after the administration of PTU but, unexpectedly, the level of SB increased in kidney homogenates of all the groups.

CONCLUSIONS: The results of this study indicate that iodine is involved in oxidative processes in different organs and PTU protects against iodine-induced oxidative stress....

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Journal Article 2006; 27(1-2): 81-84 PubMed PMID: 16648798 Citation  Keywords:  Aflatoxin B1:antagonists & inhibitors, Animals, Antioxidants:pharmacology, Apoptosis:drug effects, Cell Death:drug effects, Injections, Intraperitoneal, Male, Melatonin:pharmacology, Rats, Rats, Wistar, Thyroid Gland:cytology,.   

OBJECTIVES: Apoptosis, or programmed cell death, is a normal component in the development of multicellular organisms and is essential for many physiological processes. Apoptosis is a process in which cells play an active role in their own death (apoptosis is often referred to as "cell suicide"). Disturbances of apoptosis regulation can result in many diseases. Certain substances (for example--aflatoxin B1; AFB1) can induce apoptosis in various organs and tissues. Melatonin (Mel) is a hormone (indoleamine) which has antioxidant, antiproliferative and, potentially, anticancerogenic activities. The aim of our study was to examine the influence of late-afternoon (1600-1800) intraperitoneal (i.p.) Mel injections, administered for 3 weeks, on the process of apoptosis in male Wistar rat thyroid follicular cells (TFC); Mel was injected alone or together with AFB1 (i.p., also once daily for 3 weeks).

METHODS: In order to assess the process of apoptosis, evaluated in microscopic preparations of rat thyroids, an In Situ Cell Death Detection, POD Kit [Roche, GER] and the DAKO Liquid DAB Substrate-Chromogen System [DakoCytomation, USA] were employed.

RESULTS: Aflatoxin B1 increased the apoptotic index (I(apopt)) in rat TFC, in comparison to controls (p<0.001). The I(apopt) value in the rats, receiving Mel and AFB1 injections, was statistically lower, as compared to the value of the examined index in the group of AFB1-treated animals (p<0.001). No statistically significant differences of I(apopt) value were observed between the Mel-treated group of animals and the controls.

CONCLUSION: Melatonin can assumingly regulate the growth of cells and tissues by influencing the process of apoptosis....

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Comparative Study 2005; 26(6): 704-708 PubMed PMID: 16380675 Citation  Keywords:  Analysis of Variance, Animals, Antioxidants:pharmacology, Antithyroid Agents:pharmacology, Brain:metabolism, Hydrocarbons:metabolism, Lipid Peroxidation:physiology, Male, Malondialdehyde:metabolism, Melatonin:metabolism, Neuroprotective Agents:metabolism,.   

OBJECTIVE: It is known that thyrotoxicosis induces lipid peroxidation (LPO). In contrast, propylthiouracil (PTU), a thyrostatic drug is a well-known antioxidant. Also melatonin has been shown to protect against free radical-induced neuronal destruction. At the same time, it is generally accepted that the brain is the most vulnerable tissue to oxidative stress.

METHODS: The goal of the study was to examine the components of LPO, i.e., conjugated dienes (CD), malondialdehyde (MDA) and Schiff's bases (SB), in the brain of male Wistar rats. Two experiments were performed, with two control groups created for each experiment: Group 1--intact animals and Group 2--animals injected with 0.9% NaCl. In Experiment I, the animals received L-thyroxine (L-T4) in a dose of 100 microg/kg BW, i.p., daily, for two weeks (Groups 3-5). After one week of L-T4 treatment, the following agents were added during a subsequent week: Group 4--PTU in drinking water (45 mg/kg BW/day); Group 5--melatonin (5 mg/kg BW, daily). In Experiment II, lasting 7 days, the animals were divided into the following groups: Group 1--intact animals; Group 2--animals injected with 0.9% NaCl; Group 3--PTU in drinking water (45 mg/kg BW/day); Group 4--melatonin (5 mg/kg BW, daily).

RESULTS: In Experiment I, we observed a significantly higher SB level in saline treated animals and a significant increase in both CD and SB levels in rats treated with L-T4, compared to those in non treated control. CD levels were also elevated in rats treated with L-T4, compared to values in the saline only treated animals. Melatonin and PTU reduced CD levels and melatonin diminished SB levels, as compared to those in L-T4-treated rats. In Experiment II, we observed significantly higher CD, SB and MDA levels in saline treated rats, when compared to respective values in non treated control. Melatonin decreased CD levels, when compared to CD levels in both the non treated and saline injected controls. Additionally, melatonin reduced SB levels relative to change in the brains of saline treated rats. Furthermore, PTU decreased CD levels in brain homogenates compared to non-treated animals.

CONCLUSIONS: (1) L-thyroxine administration stimulates LPO in the rat brain; (2) All the examined antioxidants decrease LPO in L-T4-administered animals; (3) All the examined antioxidants reduce the basal LPO; 4) Stress, when induced by handling, intensifies oxidative processes in the organism....

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