Novel selenylated imidazo[1,2-a]pyridines for breast cancer chemotherapy: Inhibition of cell proliferation by Akt-mediated regulation, DNA cleavage and apoptosis.

A novel series of selenylated imidazo[1,2-a]pyridines were designed and synthesized with a view to a promising activity against breast cancer cell. The compounds, 7-methyl-3-(naphthalene-1-ylselanyl)-2-phenylimidazo[1,2-a]pyridine, named IP-Se-05, and 3-((2-methoxyphenyl)selanyl)-7-methyl-2-phenylimidazo[1,2-a]pyridine, named IP-Se-06, showed high cytotoxicity for MCF-7 cells (IC50 = 26.0 µM and 12.5 µM, respectively). Both the compounds inhibited the cell proliferation and caused decrease in the number of cells in the G2/M phase of cell cycle. IP-Se-05 and IP-Se-06 were also evaluated for effects on CT-DNA and DNA of MCF-7 cells. The compounds intercalated into CT-DNA and both treatments caused cleavage of DNA in cells. In addition, the compounds induced cell death by apoptosis. However, the presence of (2-methoxyphenyl) selenyl moiety at the imidazo[1,2-a]pyridine (IP-Se-06) appears to have a better antitumor effect with higher cytotoxicity at a lower concentration and caused less necrosis. Overall, the current study established IP-Se-06 more than IP-Se-05 as a potential prototype compound to be employed as an antiproliferative agent for the treatment of breast cancer.

Anticancer activity of flavonol and flavan-3-ol rich extracts from Croton celtidifolius latex.

CONTEXT: Croton celtidifolius Baill (Euphorbiaceae) is a tree found in the Atlantic Forest in Southern Brazil, where it is commonly known as "Sangue-de-Dragão". Its red latex is used traditionally for treating ulcers, diabetes and cancer. OBJECTIVE: To evaluate antitumor activities of Croton celtififolius latex in vitro and in vivo. MATERIAL AND METHODS: Phytochemical analyses were conducted using HPLC-DAD-MS. Cytotoxic, nuclease and pro-apoptotic properties were determined using the tetrazolium salt assay (MTT), plasmid DNA damage assay and ethidium bromide (EB)/acridine orange methods, respectively, and antitumor activity was determined in the Ehrlich ascites carcinoma (EAC) mouse model. RESULTS: Phytochemical studies indicated a high phenol content of flavonols (45.67 ± 0.24 and 18.01 ± 0.23 mg/mL of myricetin and quercetin, respectively) and flavan-3-ols (114.12 ± 1.84 and 1527.41 ± 16.42 mg/L of epicatechin and epigallocatechin, respectively) in latex. These compounds reduced MCF-7 and EAC cell viability in the MTT assay (IC50 = 169.0 ± 1.8 and 187.0 ± 2.2 µg/mL, respectively). Latex compounds caused significant DNA fragmentation and increased the number of apoptotic cells (negative control (NC), 12%; latex, 41%) as indicated by differential staining in the EB/acridine orange assay. The in vivo latex treatment at 3.12 mg/kg/day reduced the body weight by 7.57 ± 2.04 g and increased median survival time to 17.5 days when compared to the NC group (13.0 days). In addition, the highest latex concentration inhibited tumor growth by 56%. DISCUSSION AND CONCLUSION: These results agree with ethno-pharmacological reports showing cytotoxicity and antitumor activity of C. celtidifolius latex. The mechanism of antitumor action may be related to direct DNA fragmentation that reduces survival and induces apoptosis.

Docking and molecular dynamics predicted B-DNA and dihydropyrimidinone selenoesters interactions elucidating antiproliferative effects on breast adenocarcinoma cells.

Dihydropyrimidinones have demonstrated different biological activities including anticancer properties. Cytotoxic potential and antiproliferative potential of new dihydropyrimidinone-derived selenoesters (Se-DHPM) compounds were assessed in vitro against the breast adenocarcinoma cells (MCF-7). Among the eight Se-DHPM compounds tested just 49A and 49F were the most cytotoxic for MCF-7 and the most selective for the non-tumor strain (McCoy) and reduced cell viability in a time- and concentration-dependent manner. Compounds 49A and 49F increased the rate of cell death due to apoptosis and necrosis comparatively to the control, however only the 49F showed antiproliferative potential, reducing the number of colonies formed. In the molecular assay 49A interacts with CT-DNA and caused hyperchromism while 49F caused a hypochromic effect. The intercalation test revealed that the two compounds caused destabilization in the CT-DNA molecule. This effect was evidenced by the loss of fluorescence when the compounds competed and caused the displacement of propidium iodide. Simulations (docking and molecular dynamics) using B-DNA brought a greater understanding of ligand-B-DNA interactions. Furthermore, they predicted that the compounds act as minor groove ligands that are stabilized through hydrogen bonds and hydrophobic interactions. However, the form of interaction foreseen for 49A was more energetically favorable and had more stable hydrogen bonds during the simulation time. Despite some violations foreseen in the ADMET for 49F, the set of other results point to this Se-DHPM as a promising leader compound with anti-tumor potential for breast cancer.Communicated by Ramaswamy H. Sarma.

The 2',4',6'-trihydroxyacetophenone isolated from Myrcia multiflora has antiobesity and mixed hypolipidemic effects with the reduction of lipid intestinal absorption.

This study evaluated the hypolipidemic and antiobesity effects of phloroacetophenone (2',4',6'-trihydroxyacetophenone, THA) isolated from Myrcia multiflora and their relationship with triglyceride (TG) intestinal absorption and pancreatic lipase activity inhibition. The hypolipidemic effect of THA was evaluated by acute (Triton WR-1339 treatment) and chronic assay (high-fat diet treatment), the antiobesity effect was evaluated by chronic assay (high-fat diet treatment), while the inhibition of enzymatic activity of pancreatic lipase was measured in the intestinal tissue of mice treated with high olive oil concentration. In the acute assay, THA caused greater total cholesterol (37 %) and triglyceride (46 %) serum level reduction than lovastatin (32 and 1 %), a HMG-CoA reductase inhibitor or orlistat (26 and 34 %), a gastrointestinal lipase inhibitor. In addition, in the chronic assay with a high-fat diet, THA reduced cholesterol and triglyceride levels (32 and 61 %, respectively) while lovastatin showed a decrease of 35 and 49 %, respectively. THA also caused a reduction in weight gain very similar to orlistat (40 and 38 %, respectively) when the animals were submitted to a high-fat diet. Moreover, THA showed a stronger and continuous pancreatic lipase inhibitory activity when compared with orlistat, causing inhibition of this enzyme during 6 hours associated to a significant reduction of triglyceride serum levels. The IN VIVO antiobesity and hypolipidemic effects of THA may be partly mediated by delaying the intestinal absorption of dietary fat by inhibiting pancreatic lipase activity.

Study of the antitumor potential of Bidens pilosa (Asteraceae) used in Brazilian folk medicine.

AIM OF THE STUDY: Bidens pilosa (L.) (Asteraceae) is a medicinal plant traditionally used in Brazil for treating conditions that can be related to cancer. Therefore the present study was carried out to evaluate the antitumor activity of extracts obtained from the aerial parts of this plant species. MATERIALS AND METHODS: The crude hydroalcoholic extract (HAE) (water:alcohol, 6:4) and solvent fractions (chloroform=CHCl3,ethyl acetate=EtOAc, methanol=MeOH) were assessed for cytotoxicity assay by the brine shrimp and hemolytic, MTT and NRU assays. The antiproliferative potential of the crude extract and fractions was investigated in vivo using the Ehrlich ascites carcinoma (EAC) in isogenic Balb/c mice that were administered intraperitoneally 150 and 300 mg/kg body weight per day for nine days beginning 24 h after tumor inoculation. RESULTS: In in vitro cytotoxicity using Ehrlich ascites carcinoma cell line assay CHCl3 extract proved to be more toxic than the crude HAE with an IC(50) of 97+/-7.2 and 83+/-5.2 microg/mL to NRU and MTT, respectively. Histomorphological evaluations indicated that the treatment with CHCl3 and HAE extracts significantly reduced (P<0.05) body weight, abdominal circumference, tumor volume, packed cell volume and viable cell count, when compared to EAC control group. Furthermore, nonviable tumor cell count increased significantly (P<0.01) only under treatment with CHCl3 or HAE, and this was accompanied by a marked percentage increase in life span (54.2 and 41.7%, respectively). Biochemical assays revealed that CHCl3 and HAE extracts were also able to decrease serum LDH activity (39.5 and 30.6%) and GSH concentration (94.6 and 50.7%) in ascitic fluid, respectively. CONCLUSION: The chloroform fraction showed the best and methanolic the worst antitumor activity.

In vivo antitumor activity of by-products of Passiflora edulis f. flavicarpa Deg. Rich in medium and long chain fatty acids evaluated through oxidative stress markers, cell cycle arrest and apoptosis induction.

Antiinflammatory and antitumor activity has been reported in Passiflora edulis (yellow passion fruit) nevertheless the intrinsic mechanisms of action are not fully elucidated. The present study aimeds to perform a comparison between the antitumor activity involving the crude extract (HCE) and the supercritical fluid extract with ethanol as co-solvent (SFEtOH) from P. edulis f. flavicarpa Deg. The in vitro cytotoxicity was evaluated in MCF-7 cells, while the in vivo antitumor activity was assessed in male Balb/c mice inoculated with Ehrlich carcinoma cells. SFEtOH exhibited higher antitumor activity compared to HCE. Wherein, SFEtOH showed an EC50 of 264.6 µg/mL against MCF-7 cells as well as an increased inhibition of tumor growth of 48.5% (p < 0.001) in male Balb/c mice, thereby promoting an increased mice lifespan to approximately 42%. Moreover, SFEtOH caused lipid (p < 0.001) and protein (p < 0.001) oxidation by increasing glutathione redox cycle activity while decreased the thioredoxin reductase activity (p < 0.001). SFEtOH also induced oxidative DNA damage in Ehrlich ascites carcinoma (EAC) cells leading to G2/M cycle arrest and has increased apoptotic cells up to 48.2%. These data suggest that the probable mechanisms of antitumor effect are associated to the lipid, protein and DNA damage, leading to cell cycle arrest and triggering apoptosis via mitochondrial pathway, should be probable due to the presence of medium and long chain fatty acids such as lauric acid.

Exercise through a cardiac rehabilitation program attenuates oxidative stress in patients submitted to coronary artery bypass grafting.

BACKGROUND: Cardiovascular disease is the main cause of morbidity and mortality in the world and oxidative stress has been implicated in the pathogenesis. Cardiac rehabilitation in patients with coronary artery disease submitted to coronary artery bypass grafting may prevent cardiovascular events probably through the attenuation of oxidative stress. The aim of this study was to evaluate the benefits of a cardiac rehabilitation program in the control of the systemic oxidative stress. METHODS: The studied population consisted of 40 patients, with chronic stable coronary artery disease submitted to coronary artery bypass grafting, who attended a cardiac rehabilitation program. Biomarkers of oxidative stress were evaluated in the blood of these patients at different moments. RESULTS: After the onset of cardiac rehabilitation, there was a significant and progressive decrease in thiobarbituric acid reactive substances levels and protein carbonyls, an initial increase and subsequent decrease in superoxide dismutase, catalase and glutathione peroxidase activities. Also, a progressive increase of uric acid, while ferric reducing antioxidant power levels increased only at the end of the cardiac rehabilitation and a tendency to increase of glutathione contents. CONCLUSIONS: The results suggest that regular exercise through a cardiac rehabilitation program can attenuate oxidative stress in chronic coronary artery disease patients submitted to coronary artery bypass grafting.

Hyperthyroidism in the developing rat testis is associated with oxidative stress and hyperphosphorylated vimentin accumulation.

Hyperthyroidism was induced in rats and somatic indices and metabolic parameters were analyzed in testis. In addition, the morphological analysis evidenced testes maturation and intense protein synthesis and processing, supporting the enhancement in vimentin synthesis in hyperthyroid testis. Furthermore, vimentin phosphorylation was increased, indicating an accumulation of phosphorylated vimentin associated to the cytoskeleton, which could be a consequence of the extracellular-regulated kinase (ERK) activation regulating the cytoskeleton. Biomarkers of oxidative stress demonstrated an increased basal metabolic rate measured by tissue oxygen consumption, as well as, increased TBARS levels. In addition, the enzymatic and non-enzymatic antioxidant defences appeared to respond according to the augmented oxygen consumption. We observed decreased total glutathione levels, with enhancement of reduced glutathione, whereas most of the antioxidant enzyme activities were induced. Otherwise, superoxide dismutase activity was inhibited. These results support the idea that an increase in mitochondrial ROS generation, underlying cellular oxidative damage, is a side effect of hyperthyroid-induced biochemical changes by which rat testis increase their metabolic capacity.

Developmental exposure to glyphosate-based herbicide and depressive-like behavior in adult offspring: Implication of glutamate excitotoxicity and oxidative stress.

We have previously demonstrated that maternal exposure to glyphosate-based herbicide (GBH) leads to glutamate excitotoxicity in 15-day-old rat hippocampus. The present study was conducted in order to investigate the effects of subchronic exposure to GBH on some neurochemical and behavioral parameters in immature and adult offspring. Rats were exposed to 1% GBH in drinking water (corresponding to 0.36% of glyphosate) from gestational day 5 until postnatal day (PND)-15 or PND60. Results showed that GBH exposure during both prenatal and postnatal periods causes oxidative stress, affects cholinergic and glutamatergic neurotransmission in offspring hippocampus from immature and adult rats. The subchronic exposure to the pesticide decreased L-[14C]-glutamate uptake and increased 45Ca2+ influx in 60-day-old rat hippocampus, suggesting a persistent glutamate excitotoxicity from developmental period (PND15) to adulthood (PND60). Moreover, GBH exposure alters the serum levels of the astrocytic protein S100B. The effects of GBH exposure were associated with oxidative stress and depressive-like behavior in offspring on PND60, as demonstrated by the prolonged immobility time and decreased time of climbing observed in forced swimming test. The mechanisms underlying the GBH-induced neurotoxicity involve the NMDA receptor activation, impairment of cholinergic transmission, astrocyte dysfunction, ERK1/2 overactivation, decreased p65 NF-κB phosphorylation, which are associated with oxidative stress and glutamate excitotoxicity. These neurochemical events may contribute, at least in part, to the depressive-like behavior observed in adult offspring.

Effects of diet energy level and tomato powder consumption on antioxidant status in rats.

BACKGROUND AND AIMS: Evaluate the influence of tomato powder in diets differing in energy level on antioxidant status in blood and liver of rats. METHODS: Twenty-four adult male Wistar rats weighing 150-180 g were placed four groups (n=6). For 28 days, animals were fed a diet that was either hyper energetic or hypo energetic. Some diets were supplemented with tomato powder. Liver and blood were collected for analysis of antioxidant enzymes, non-enzymatic antioxidants, thiobarbituric acid reactive species, ubiquinol 9, alpha-tocopherol, lycopene and beta-carotene. Data were analysed by two-way ANOVA. RESULTS: Food intake and thiobarbituric acid-reactive substances contents in liver and plasma were significantly decreased by tomato powder at both energy levels. After tomato powder supplementation, the hepatic levels of ubiquinol 9, alpha-tocopherol, lycopene and beta-carotene were significantly enhanced. In plasma, only the contents of lycopene and beta-carotene were enhanced. The erythrocytic and hepatic activities of catalase were lower, while those of glutathione peroxidase were higher after the ingestion of tomato powder. Total and reduced glutathione contents in liver showed lower levels in cafeteria-fed rats compared to the hypo energetic diet. CONCLUSIONS: The data suggest that the lycopene and beta-carotene component in the tomato power supplement might be beneficial for the prevention of oxidative damage in rats fed both types of energetic diets.

Persistence of the benefit of an antioxidant therapy in children and teenagers with Down syndrome.

This study examined the effect of an antioxidant intervention in biomarkers of inflammation and oxidative stress (OS) in the blood of Down syndrome (DS) children and teenagers during four different stages. A control group was composed by healthy children (n=18), assessed once, and a Down group composed by DS patients (n=21) assessed at the basal period (t0), as well as after 6 months of antioxidant supplementation (t1), after 12 months (after interruption of the antioxidant intervention for 6 months) (t2), and again after further 6 months of antioxidant supplementation (t3). Biomarkers of inflammation (myeloperoxidase activity - MPO and levels of IL-1ß and TNF-α) and OS (thiobarbituric acid reactive substances - TBARS, protein carbonyls - PC), reduced glutathione (GSH), uric acid (UA) and vitamin E levels, as well as antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST) and gamma-glutamyltransferase (GGT) activities, were measured after each period. After the antioxidant supplementation, the activities of SOD, CAT, GPx, GR, GGT and MPO were downregulated, while TBARS contents were strongly decreased, the contents of GSH and vitamin E were significantly increased, and no changes in G6PD and GST activity as well as in UA and PC levels were detected. After the interruption of the antioxidant therapy for 6 months, DS patients showed elevated GPx and GGT activities and also elevated UA and TBARS levels. No changes in SOD, CAT, GR, GST, G6PD and MPO activities as well as in GSH, vitamin E, PC, TNF-α and IL-1ß levels were detected. The results showed that the antioxidant intervention persistently attenuated the systemic oxidative damage in DS patients even after a relatively long period of cessation of the antioxidant intervention.

Spermatic cord torsion, reactive oxygen and nitrogen species and ischemia-reperfusion injury.

Mammalian testes are highly sensitive to oxidative free radical damage. Acute scrotum is a clinical syndrome mainly caused by torsion of the spermatic cord that constitutes a surgical emergence affecting newborns, children and adolescents. This syndrome often leads to infertility of the ipsilateral (torted) and contralateral (not torted) testis, an outcome that makes surgical intervention mandatory. There is a controversy involving the effects of ischemia and reperfusion on ipsilateral and contralateral testes after unilateral torsion and detorsion of the spermatic cord. Conflicting reports have led to two distinct and opposite recommendations regarding surgical intervention: detortion and preservation of the ipsilateral testis, or ipsilateral orchiectomy to preserve contralateral fertility. Early detortion surgery in humans preserves fertility, but after prolonged torsion periods followed by preservation of the ipsilateral fertility of both testis is jeopardized. Lowered contralateral blood flow after unilateral testicular torsion is associated with reactive oxygen species (ROS) overgeneration and therefore with the corresponding tissue damage. Reperfusion time appears to be determinant of contralateral testes damage due to the consequent oxidative insult that accompanies the rise in ROS following ischemia-reperfusion. Nevertheless, more investigations on the molecular mechanisms and the antioxidant status in testis are necessary to ascertain the contribution of ROS to the tissue damage produced by spermatic cord torsion in experimental animals and humans.

Oxidative stress in the mussel Mytella guyanensis from polluted mangroves on Santa Catarina Island, Brazil.

Digestive glands of the mangrove mussel Mytella guyanensis, collected at one non-polluted site (site 1) and two polluted sites (sites 2 and 3), were analysed for different antioxidant defenses, lipid peroxidation and DNA damage. Thiobarbituric acid-reactive substance (TBARS) and 8-oxo-7,8-dihydro-2'-deoxyguanosine levels were enhanced at the polluted sites. With the exception of superoxide dismutase, the activities of catalase and glutathione peroxidase were also higher at the polluted sites. Greater increases were observed in glutathione reductase, glutathione S-transferase and etoxyresorufine-O-deethylase activities at the polluted sites. Conversely, reduced glutathione content was higher at the control site. Trace metal contents in mussels collected at polluted sites were increased compared to the control site, and there were strong positive correlations between TBARS and Cu and Pb contents. M. guyanensis is routinely exposed to an oxidative stress condition at both polluted sites, and considering xenobiotic bioaccumulation in bivalve molluscs, the mangrove mussel represents an excellent bioindicator for environmental monitoring studies.

Stilbenes and tyrosol as target compounds in the assessment of antioxidant and hypolipidemic activity of Vitis vinifera red wines from southern Brazil.

The contents of stilbene monomers, cis-resveratrol, trans-resveratrol, cis-piceid, trans-piceid, and tyrosol, were quantified in Vitis vinifera red wines, cvs. Cabernet Franc, Merlot, Sangiovese, and Syrah, 2006 and 2007 vintages, from the São Joaquim region, a new grape-growing region at southern Brazil. Moreover, the effect of chronic consumption of these wines on the antioxidant and hypolipidemic activities was monitored in C57BL6 LDL receptor knockout mice and treated with a hypercholesterolemic diet. Red wines from this region had substantial levels of resveratrols (the predominant forms were glycoside and trans) and tyrosol. Biomonitoring of antioxidant and hypolipidemic activities in vivo revealed that consumption of these wines increased the antioxidant capacity and reduced the hypercholesterolemia and hypertriglyceridemia promoted by the hypercholesterolemic diet. Significant correlations were found between the increase of antioxidant capacity markers, the decrease of lipid levels promoted by wine consumption, and the contents of stilbenes and tyrosol, supporting the important biological activity of these compounds.

Brazilian Bidens pilosa Linné yields fraction containing quercetin-derived flavonoid with free radical scavenger activity and hepatoprotective effects.

Bidens pilosa is a plant used by Amazonian and Asian folks for some hepatopathies. The hydroethanol crude extract and three fractions were assessed for antioxidant and hepatoprotective effects. Higher levels of scavenger activity on the 1,1-diphenyl-2-picrylhydrazyl radical, inhibition of deoxyribose oxidation and lipid peroxidation in vitro were detected for the ethyl acetate fraction (IC(50)~4.3-32.3 µg/ml) followed by the crude extract (IC(50)~14.2-98.0 µg/ml). The ethyl acetate fraction, again followed by the crude extract, showed high contents of total soluble polyphenols (3.6±0.2 and 2.1±0.2 GAE/mg, respectively) and presence of a quercetin-derived flavonoid identified as quercetin 3,3'-dimethyl ether 7-O-ß-D-glycopyranoside. Both products were assayed for hepatoprotector effects against CCl(4)-induced liver injury in mice. Markers of oxidative stress and hepatic injury were evaluated. The results showed that the 10-day pretreatments (15 mg/kg, p.o.) protected the livers against injury by blocking CCl(4)-induced lipid peroxidation and protein carbonylation and the DNA fragmentation was decreased (~60%). The pretreatments avoided the loss of the plasma ferric reducing/antioxidant power and the elevation of serum transaminases and lactate dehydrogenase activities. The results suggest that the main constituents responsible for the hepatoprotective effects with free radical scavenger power associated are well extracted by performing fractionation with ethyl acetate. The findings support the Brazilian traditional use of this plant and justify further evaluations for the therapeutic efficacy and safety of the constituents of the ethyl acetate fraction to treat some liver diseases.

Antioxidant intervention compensates oxidative stress in blood of subjects exposed to emissions from a coal electric-power plant in South Brazil.

In the process of energy generation, particulate matter (PM) emissions derived from coal combustion expose humans to serious occupational diseases, which are associated with overgeneration of reactive oxygen species (ROS). The purpose of the present study is to better understand the relations between PM exposure derived from a coal electric-power plant and the oxidative damage in subjects (n=20 each group) directly (working at the burning area) or indirectly (working at the office or living in the vicinity of the electric-power plant=group of residents) exposed to airborne contamination, before and after daily supplementation with vitamins C (500mg) and E (800mg) during six months, which were compared to non-exposed subjects (control group). Several biomarkers of oxidative stress were examined such as levels of thiobarbituric acid reactive substances (TBARS), protein carbonyls (PC), protein thiols (PT) and vitamin E in plasma, levels of reduced glutathione (GSH) in whole blood, and of activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST) in red cells. Before supplementation, TBARS and PC levels were significantly increased, levels of GSH and vitamin E were decreased, while the activities of SOD and CAT were increased in workers groups and GST were increased in all groups in compared to controls. After the antioxidant supplementation essentially all these biomarkers were normalized to control levels. The antioxidant intervention was able to confer a protective effect of vitamins C and E against the oxidative insult associated with airborne contamination derived from coal burning of an electric-power plant.

Antioxidant therapy attenuates oxidative insult caused by benzonidazole in chronic Chagas' heart disease.

Chronic chagasic cardiac patients are exposed to oxidative stress that apparently contributes to disease progression. Benznidazole (BZN) is the main drug used for the treatment of chagasic patients and its action involves the generation of reactive species. 41 patients with Chagas' heart disease were selected and biomarkers of oxidative stress were measured before and after 2 months of BZN treatment (5 mg/kg/day) and the subsequent antioxidant supplementation with vitamin E (800 UI/day) and C (500 mg/day) during 6 months. Patients were classified according to the modified Los Andes clinical hemodynamic classification in groups IA, IB, II and III, and the activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST) and glutathione reductase (GR), as well as the contents of reduced glutathione (GSH), thiobarbituric acid reactive species (TBARS), protein carbonyl (PC), vitamin E and C and nitric oxide (NO), myeloperoxidase (MPO) and adenosine deaminase (ADA) activities were measured in their blood. Excepting in group III, after BZN treatment SOD, CAT, GPx and GST activities as well as PC levels were enhanced while vitamin E levels were decreased in these groups. After antioxidant supplementation the activities of SOD, GPx and GR were decreased whereas PC, TBARS, NO, and GSH levels were decreased. In conclusion, BZN treatment promoted an oxidative insult in such patients while the antioxidant supplementation was able to attenuate this effect by increasing vitamin E levels, decreasing PC and TBARS levels, inhibiting SOD, GPx and GR activities as well as inflammatory markers, mainly in stages with less cardiac involvement.

Supplementation of vitamin E, vitamin C, and zinc attenuates oxidative stress in burned children: a randomized, double-blind, placebo-controlled pilot study.

The aim of this study was to investigate the effect of supplementation of vitamin E, vitamin C, and zinc on the oxidative stress in burned children. In a prospective double-blind placebo controlled pilot study, 32 patients were randomized as no supplementation (n = 15) or antioxidant supplementation (n = 17) groups. Supplementation consisted of the antioxidant mixture of vitamin C (1.5 times upper intake level), vitamin E (1.35 times upper intake level), and zinc (2.0 times recommended dietary allowance) administered during 7 days starting on the second day of admittance into the hospital. Energy requirement was calculated by the Curreri equation, and protein input was 3.0 g/kg of ideal body mass index (percentile 50). Total antioxidant capacity of plasma and malondialdehyde were used to monitor oxidative stress. The time of wound healing was evaluated as the main clinical feature. Patients (age 54.2 +/- 48.9 months, 65.6% males), who exhibited 15.5 +/- 6.7% of total burn area, showed no differences in age and sex, when compared with controls. Intake of the administered antioxidants was obviously higher in treated subjects (P = .005), and serum differences were confirmed for vitamin E and C, but not for zinc (P = .180). There was a decrease in lipid peroxidation (malondialdehyde level) (P = .006) and an increase in vitamin E concentrations in the antioxidant supplementation group (P = .016). The time of wound healing was lower in the supplemented group (P < .001). The antioxidant supplementation through vitamin E and C and the mineral zinc apparently enhanced antioxidant protection against oxidative stress and allowed less time for wound healing.

Propylthiouracil-induced congenital hypothyroidism upregulates vimentin phosphorylation and depletes antioxidant defenses in immature rat testis.

Congenital hypothyroidism was induced in rats by adding 0.05% 6-propyl-2-thiouracil in the drinking water from day 9 of gestation, and continually up to postnatal day 15. Structural alterations observed by light microscopy of seminiferous tubules and by transmission electron microscopy of Sertoli cells of treated animals were consistent with hypothyroid condition. Hypothyroidism was also associated with high phospho-p38 mitogen-activated protein kinase and decreased phospho-extracellular signal-regulated kinase 1/2 levels. Furthermore, the phosphorylation and the immunoreactivity of cytoskeletal-associated vimentin were increased without altering vimentin expression, suggesting an accumulation of insoluble and phosphorylated vimentin. These alterations in intermediate filament dynamics could result in loss of Sertoli cell cytoskeletal integrity and be somewhat related to the deleterious effects of hypothyroidism in testis. In addition, the mitochondrial alterations observed could also be related to defective cytoskeletal dynamics implying in cell damage. Moreover, we observed decreased oxygen consumption and unaltered lipid peroxidation in hypothyroid testis. However, we demonstrated decreased enzymatic and non-enzymatic antioxidant defenses, supporting an increased mitochondrial reactive oxygen species (ROS) generation, contributing to biochemical changes in hypothyroid testis. In addition, the changes in the testis histoarchitecture could be ascribed to cytoskeletal alterations, decreased antioxidant defenses, and increased ROS generation, leading to oxidative stress in the organ.

Oxidative stress in chronic cardiopathy associated with Chagas disease.

BACKGROUND: Chagas disease is characterized by chronic inflammation similar to autoimmune diseases. The imbalance between prooxidant and antioxidant defenses is known as oxidative stress, and is often associated with inflammatory processes of many diseases. METHODS: The present work measured some components of the antioxidant system present in the blood of four groups of patients in different stages of chronic Chagas heart disease (n=10 each group), according to the modified Los Andes clinical-hemodynamic classification. Each group of chagasic patients was compared with four groups of healthy subjects, and chagasic group IV was compared to group V, characterized by rheumatic cardiac disease, giving a total of 90 subjects. Antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), and the contents of reduced (GSH), oxidized (GSSG) and total glutathione (TG) were assayed. RESULTS: SOD, CAT and GR activities showed essentially no differences among the four groups, however, intraerythrocytic GSH concentrations showed decreased values parallel to the progression of the disease. In addition, the glutathione peroxidase (GPx) activities were higher in groups III and V and lower in groups I, II and IV, also suggesting an antioxidant depletion with progression of the disease. In contrast, except for SOD and CAT activities, patients from group V showed a generally higher antioxidant capacity compared to the chagasic group IV. CONCLUSION: The results indicate a general increase of oxidative stress parallel to the progression of Chagas disease.