Effects of combined vanadate and magnesium treatment on erythrocyte antioxidant defence system in rats

The effect of vanadate and magnesium treatment on erythrocyte defence system was studied in outbred 2-month-old, albino male Wistar rats (14 rats/each group) which daily received: Group I (Control)-deionized water to drink; Group II-water solution of sodium metavanadate (NaVO(3); SMV) at a concentration of 0.125mgV/mL; Group III-water solution of magnesium sulfate (MgSO(4); MS) at a concentration of 0.06mgMg/mL, Group IV-water solution of SMV-MS at the same concentrations over a 12-week time. The fluid intake and the concentration of reduced glutathione (GSH) as well as the activity of Cu, Zn-superoxide dismutase (Cu, Zn-SOD), catalase (CAT) and glutathione reductase (GR) were significantly decreased in the rats receiving SMV alone (Group II) or in combination with MS (Group IV) compared with Groups I and III. The cellular glutathione peroxidase (cGSH-Px) activity was unchanged in all the treated groups. The activity of glutathione S-transferase (GST) fell in the animals in Group II, compared with the rats in Groups I, III and IV; whereas in the rats in Group III its activity was higher than in the control animals. These results showed that V (as SMV) consumed by the rats with drinking water at a dose of 12mgV/kg b.w./24h for 12 weeks may attenuate defence system in rats' erythrocytes (RBCs), which is probably a consequence of vanadium pro-oxidant potential. Therefore, reactive oxygen species (ROS) are suggested to be involved in the alterations in antioxidant defence system in these cells. Mg (as MS) at the dose ingested (6mgMg/kg b.w./24h) at co-exposure to SMV was not able to counteract its deleterious effect. The results also provide evidence that V-Mg interactions may be involved in the decrease of erythrocyte GR activity and Mg concentration in the plasma under concomitant treatment with both metals at the doses of 12.6mgV and 6mgMg/kg b.w./24h.     

Failure of recovery from lead induced hepatoxicity and disruption of erythrocyte antioxidant defence system in Wistar rats

Lead acetate (PbA) is one of the major environmental contaminants with grave toxicological consequences both in the developing and developed countries. The liver and erythrocyte antioxidant status and markers of oxidative were assessed. Exposure of rats to PbA led to significant decline (p < 0.05) in hepatic and erythrocyte glutathione peroxidase (GPx), glutathione S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH) content. Similarly, malondialdehyde (MDA) and H₂O₂ concentrations were significantly (p < 0.05) elevated. Histopathology and immunohistology of liver of rats exposed to PbA showed focal areas of necrosis and COX-2 expression after 6 weeks of PbA withdrawal. Taken together, hepatic and erythrocytes antioxidant defence system failed to recover after withdrawal of the exposed PbA for the period of the study. In conclusion, experimental animals exposed to PbA did not recover from hepatotoxicity and disruption of erythrocyte antioxidant defence system via free radical generation and oxidative stress.     

Glutathione metabolism in cyclosporine A-treated rats: dose- and time-related changes in liver and kidney

1. We investigated the simultaneous effects of cyclosporine A (CsA) treatment in rats on glutathione metabolism, oxidative status and their interorgan relationship in the liver and kidney. 2. Reduced and oxidized glutathione (GSH and GSSG, respectively), lipid peroxidation and the activity of several enzymes of the glutathione cycle were evaluated in adult Wistar rats treated daily (i.p.) with saline, CsA vehicle (olive oil) or CsA (10 and 20mg/kg per day) for either 1 or 4 weeks (short- and long-term treatments, respectively). 3. Cyclosporine A treatment elicited a significant depletion in liver GSH content and a decrease in the GSH/GSSG ratio that was unrelated to either the time of treatment or the dose used; these effects were already evident after 1 week of treatment. Renal GSH levels remained unaffected or increased, while those of GSSG increased markedly in all CsA-treated rats, leading to decreases in the GSH/GSSG ratio, except in rats treated in the short term with the lower dose of CsA. These changes in the GSH/GSSG ratio were time and dose dependent. Short-term CsA treatment using the higher dose and long-term treatment with both doses of CsA progressively enhanced lipid peroxidation, which was reflected by increased levels of thiobarbituric acid-reactive substances in both hepatic and renal homogenates. Hepatic gamma-glutamylcysteine synthetase activity was increased after long-term treatment with both doses of CsA, whereas the activity of GSH hepatic peroxidase and GSH transferase was not significantly modified in any of the experimental groups. In contrast, renal gamma-glutamyl transpeptidase activity decreased in a progressive fashion, with the magnitude of this decrease being dose and time dependent. The plasma levels of total glutathione increased only in rats treated in the long term, regardless of the dose of CsA used, and remained unaltered in animals treated in the short term. 4. In summary, the data collected indicate that CsA treatment alters the interorgan homeostasis of glutathione and the oxidative status of the rat liver and kidney, which is associated with increases in lipid peroxidation in both organs, and also induces modifications in the activity of some enzyme related to the glutathione cycle.     

Changes in antioxidant defence systems induced by cyclosporine A in cultures of hepatocytes from 2- and 12-month-old rats

The in vitro effect of cyclosporine A (CsA) was studied in reference to the production of reactive oxygen species (peroxides and superoxide anion) and to cell enzyme-mediated antioxidant defence in hepatocytes isolated from rats aged 2 and 12 months. Primary cultures of hepatocytes were incubated in the presence of concentrations of cyclosporine in the range of 0 to 50 microM for 24 hr, and the release of lactate dehydrogenase into the culture medium was evaluated as a parameter of cytotoxicity and membrane lysis. Peroxides were quantified by using 2',7'-dichlorodihydrofluorescein diacetate, and superoxide anion levels were evaluated by the fluorescence of dihydroethidium. Enzyme activity and gene expression of catalase and Mn- and Cu,Zn-superoxide dismutase were also assayed. CsA cytotoxicity was significantly higher in hepatocytes from rats aged 12 months when compared to those aged 2 months. Intracellular peroxide content resulted in a dose-dependent increase, while the anion superoxide intracellular level slightly decreased as CsA increased from 0-50 microM. The progressive increase in intracellular peroxides in cell cultures in the range from 0-50 microM CsA was associated with the loss of cell viability and accompanied by significantly higher levels of Mn- and Cu, Zn-superoxide dismutase enzyme activities and mRNAs, and slight increases in catalase activity and mRNA. We conclude that, in primary hepatocyte cultures, the cytotoxicity of CsA was dose-dependent in both age groups and significantly higher in cultures from 12-month-old rats when compared to those from 2-month-old animals. The non-coordinated regulation of the gene expression of antioxidant enzyme systems, i.e. catalase and Mn- and Cu,Zn-superoxide dismutases, evidenced to a greater extent in hepatocytes from the older group of rats, could be one of the mechanisms involved in CsA toxicity.     

Brain regional responses in antioxidant system to alpha-lipoic acid in arsenic intoxicated rat

Impaired antioxidant defense mechanisms and oxidative stress are implicated in the pathogenesis of arsenic toxicity. Our study was designed to determine whether alpha-lipoic acid, which has been shown to have substantial antioxidant properties, when administered (70 mg/kg body weight) once daily for 60 days along with arsenic (100 ppm sodium arsenite mixed in drinking water) would prevent arsenic-induced changes in antioxidant defense system, superoxide dismutase (SOD-total SOD, Mn SOD, Cu/Zn SOD), catalase (CAT) and glutathione peroxidase (GSH-PX) in rat brain regions such as cortex, hypothalamus, striatum, cerebellum and hippocampus. The present study also examined the effect of alpha-lipoic acid over arsenic-induced oxidant production and lipid peroxidation level (LPO) in discrete brain regions of rats. The cortex, striatum and hippocampus showed greater decreases in GSH-Px enzyme activity than cerebellum and hypothalamus with arsenic exposure. Striatum had the greatest percentage of decreased activities of total SOD and Mn SOD, whereas cortex had the greatest percentage decrease in the activity of Cu/Zn SOD in arsenic-alone treated rats. Hypothalamus and cerebellum exhibited the lowest catalase activity among all tested regions in arsenic-only treated rats. Rate of dichlorofluorescin oxidation, an indication of reactive oxygen species and other intracellular oxidants production was increased with arsenic exposure in all brain regions studied. Cortex, hippocampus and striatum exhibited greater increase of LPO levels than cerebellum and hypothalamus. SOD, CAT, GSH-Px activities were upregulated in arsenic plus lipoic acid treated versus arsenic-only treated rats. Also, simultaneous lipoic acid treatment along with arsenic proved to be sufficient in reducing oxidant production and LPO level in all rat brain regions. Our results demonstrate that arsenic-induced deficits in antioxidant enzyme activities and increase in oxidant production and lipid peroxidation level in brain regions can be overcome through simultaneous treatment with lipoic acid.     

Protective effect of alpha-lipoic acid against chloroquine-induced hepatotoxicity in rats

Oral administration of a-lipoic acid, a metavitamin, was investigated for its possible hepatoprotective effect in Wistar rats against chloroquine-induced toxicity. Rats were treated orally with alpha-lipoic acid (10, 30 and 100 mg x kg(-1) day(-1)) for 7 days before a single oral administration of chloroquine (970 mg x kg(-1) day(-1)) and alpha-lipoic acid treatment was continued for three more days. The increased level of serum enzymes (aspartate transaminase, alanine transaminase and alkaline phosphatase), bilirubin, lipids and plasma thiobarbituric acid-reactive substances (TBARS) and hydroperoxides observed in rats treated with chloroquine were very much reduced in rats treated with alpha-lipoic acid plus chloroquine. A significant decrease in plasma antioxidants such as reduced glutathione (GSH), vitamin C and vitamin E were observed in chloroquine-treated rats when compared with control rats. Administration of alpha-lipoic acid significantly improved the levels of plasma antioxidants GSH, vitamin C and vitamin E in chloroquine-treated rats. In the case of 100 mg x kg(-1) day(-1) the effect was highly significant compared with the other doses (10 and 30 mg x kg(-1) day(-1)). The results of the study revealed that alpha-lipoic acid could offer protection against chloroquine-induced hepatotoxicity. alpha-Lipoic acid had a better protective effect when compared with silymarin, a reference drug.     

Effects of alpha-lipoic acid on deoxycorticosterone acetate-salt-induced hypertension in rats

We investigated the potential of natural occurring antioxidant alpha-lipoic acid to prevent hypertension and hypertensive tissue injury induced by deoxycorticosterone acetate (DOCA) and salt in rats. Two weeks after the start of DOCA-salt treatment, the rats were given alpha-lipoic acid (10 or 100 mg/kg/day, s.c.) or its vehicle for 2 weeks. Uninephrectomized rats without DOCA-salt treatment served as sham-operated controls. In vehicle-treated DOCA-salt rats, systolic blood pressure increased markedly after 3-4 weeks. Daily administration of 100 mg/kg alpha-lipoic acid for 2 weeks suppressed the increase in systolic blood pressure, whereas 10 mg/kg alpha-lipoic acid did not affect the progression of DOCA-salt-induced hypertension. When the degree of vascular hypertrophy of the aorta was morphometrically evaluated at 4 weeks, there were significant increases in media cross-sectional area in vehicle-treated DOCA-salt rats compared with sham-operated rats. The development of vascular hypertrophy was markedly suppressed by alpha-lipoic acid at 100 mg/kg but not at 10 mg/kg. Histopathological examination of the kidney in vehicle-treated DOCA-salt rats revealed fibrinoid-like necrosis in glomeruli and thickening of small arteries. In these animals, creatinine clearance decreased, and fractional excretion of Na(+), urinary excretion of protein and N-acetyl-beta-glucosaminidase increased. Such renal lesions and dysfunctions were ameliorated in DOCA-salt rats given alpha-lipoic acid. In addition, a marked increase in endothelin-1 content in both the aorta and kidney was evident in vehicle-treated DOCA-salt rats compared with findings in sham-operated rats. Significant attenuation of this increase occurred in alpha-lipoic acid-treated DOCA-salt rats. These results suggest that administration of alpha-lipoic acid to DOCA-salt hypertensive rats lessens the increased blood pressure and protects against renal and vascular injuries, possibly through the suppression of renal and vascular endothelin-1 overproduction.     

Altered oxidative status and integrin expression in cyclosporine A-treated oral epithelial cells

Abstract

Background and objective: Cyclosporine A (CsA) is an immunosuppressive agent administered to transplant patients. A well-known reported oral side effect of CsA consumption is gingival overgrowth (GO). Changes in the expression of integrins occurring in the gingiva following CsA treatment have been reported but these reports are mainly concerned with the connective tissue of the gingiva. In this study we targeted the alterations in the oral epithelium using KB cells, an oral epithelial cell line.

Methods: Cultured oral epithelial cells were treated with increasing concentrations of CsA (0.1, 1 and 10?µg/mL) and the molecular changes involving antioxidant enzymes [glutathione peroxidase (GPx) and glutathione reductase (GR)] and the level of reactive oxygen species (ROS) were measured. Quantitative real-time PCR was used to assess the expression of selected integrins (α₂, α₅ and β₁).

Results: At CsA concentration above 0.1?µg/mL GPx demonstrated an increase in activity while GR activity and the level of reduced glutathione were diminished (p?<?0.05). α₅ and β₁ integrin were downregulated at all treatment concentrations of CsA while α₂ integrin presented this effect at concentrations above 1?µg/mL (p?<?0.05).

Conclusion: The results suggest a possible role for oxidative stress and the altered expression of integrins in the pathology of CsA-induced gingival overgrowth.     

Combined efficacies of lipoic acid and meso-2,3-dimercaptosuccinic acid on lead-induced erythrocyte membrane lipid peroxidation and antioxidant status in rats

One of the most intriguing phenomenon observed during lead toxicity has been attributed to lead-induced oxidative stress. The combined effect of DL-alpha-lipoic acid (LA) and meso-2,3-dimercaptosuccinic acid (DMSA) on lead-induced alterations in selected parameters, which are indicators of oxidative stress in erythrocytes, have been studied. Lead acetate (Pb, 0.2%) was administered in drinking water for 5 weeks to induce toxicity. LA (25 mg/ kg body weight per day i.p.) and DMSA (20 mg/kg body weight per day i.p.) were administered individually and also in combination during week 6. Clinical evidence of toxic exposure was evident from the elevated blood lead levels (BPb) along with lowered levels of haemoglobin (Hb) and haematocrit (Ht). Lead-exposed animals showed enhanced membrane lipid peroxidation (LPO) in the erythrocytes. Damage to the erythrocyte membrane was evident from the decline in the activities of the transmembrane enzymes, viz., Na+, K(+)-ATPase, Ca(2+)-ATPase and Mg(2+)-ATPase. Lead-exposed rats also suffered an onslaught on the antioxidant defence system witnessed by lowered activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and reduced glutathione (GSH). Serum glutamic-oxoloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) were also elevated in lead-exposed rats. Treatment with either LA or DMSA reversed the lead-induced biochemical disturbances encountered by the erythrocytes, but combined treatment with LA and DMSA was very effective in mitigating all the parameters indicative of oxidative stress.     

Protective effects of L-carnitine and alpha-lipoic acid in rats with adjuvant arthritis.

Free radicals play an important role in the pathophysiology of adjuvant arthritis. The purpose of this study was to assess the efficacy of L-carnitine (LC) and alpha-lipoic acid (alpha-LA) which are known to have antioxidant effects, in the treatment of adjuvant arthritis. Arthritis model was created by the administration of complete Freund's adjuvant (CFA) in 32 of 40 male Sprague-Dawley rats. The rats were divided into five groups. Rats in Group I served as controls and received 0.1 ml kg(-1) saline. Group II received only 0.1 ml of CFA and served as the CFA-control for the other groups. Groups III-V, after being injected with CFA, were treated with LC, alpha-LA or diclofenac, respectively. Levels of malondialdehyde (MDA) and glutathione (GSH) were measured in plasma samples. Enzyme activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) were measured. The paws of rats were evaluated histopathologically to investigate the anti-inflammatory effects. TNF-alpha levels were measured for the evaluation of inflammation. In Group II plasma MDA increased, levels of glutathione decreased, enzyme activities of SOD and GPx decreased. Histopathological damage increased in the paws of the rats in this group. MDA levels decreased in Groups III-V when compared with Group II. GSH levels significantly increased in Group III and IV than Group V. SOD activity of Group IV was higher than Group III and V. TNF-alpha levels were significantly lower in Group IV and V. LC and alpha-LA seemed to have protective effects against oxidative damage in adjuvant arthritis model.     

Protective effect of alpha-lipoic acid against ischaemic acute renal failure in rats

1. In the present study, we investigated whether treatment with alpha-lipoic acid (LA), a powerful and universal anti-oxidant, has renal protective effects in rats with ischaemic acute renal failure (ARF). 2. Ischaemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Blood urea nitrogen (BUN), plasma concentrations of creatinine (Pcr) and urinary osmolality (Uosm) were measured for the assessment of renal dysfunction. Creatinine clearance (Ccr) and fractional excretion of Na+ (FENa) were used as indicators of glomerular and tubular function, respectively. 3. Renal function in ARF rats decreased markedly 24 h after reperfusion. Intraperitoneal injection of LA at a dose of 10 mg/kg before the occlusion tended to attenuate the deterioration of renal function. A higher dose of LA (100 mg/kg) significantly (P < 0.01) attenuated the ischaemia/reperfusion-induced increases in BUN (19.1 +/- 0.7 vs 7.2 +/- 0.7 mmol/L before and after treatment, respectively), Pcr (290 +/- 36 vs 78.1 +/- 4.2 micromol/L before and after treatment, respectively) and FENa (1.39 +/- 0.3 vs 0.33 +/- 0.09% before and after treatment, respectively). Treatment with 100 mg/kg LA significantly (P < 0.01) increased Ccr (0.70 +/- 0.13 vs 2.98 +/- 0.27 mL/min per kg before and after treatment, respectively) and Uosm (474 +/- 39 vs 1096 +/- 80 mOsmol/kg before and after treatment, respectively). 4. Histopathological examination of the kidney of ARF rats revealed severe lesions. Tubular necrosis (P < 0.01), proteinaceous casts in tubuli (P < 0.01) and medullary congestion (P < 0.05) were significantly suppressed by the higher dose of LA. 5. A marked increase in endothelin (ET)-1 content in the kidney after ischaemia/reperfusion was evident in ARF rats (0.43 +/- 0.02 ng/g tissue) compared with findings in sham- operated rats (0.20 +/- 0.01 ng/g tissue). Significant attenuation (P < 0.01) of this increase occurred in ARF rats treated with the higher dose of LA (0.24 +/- 0.03 ng/g tissue). 6. These results suggest that administration of LA to rats prior to development of ischaemic ARF prevents renal dysfunction and tissue injury, possibly through the suppression of overproduction of ET-1 in the postischaemic kidney.     

Effect of alpha-lipoic acid on lipid peroxidation and anti-oxidant enzyme activities in diabetic rats

1. Oxidative damage has been suggested to be a contributory factor in the development and complications of diabetes. Recently, alpha-lipoic acid (ALA) has gained considerable interest as an anti-oxidant. Various studies have indicated the anti- oxidant effects of ALA and its reduced form dihydrolipoic acid. Therefore, it appears that these compounds have important therapeutic potential in conditions where oxidative stress is involved. The aim of the present study was to investigate the effect of ALA supplementation on lipid peroxidation and anti-oxidant enzyme activities in various tissues in diabetic rats. 2. Male Wistar rats were divided into three groups. Diabetes was induced by streptozotocin (STZ) injection in the two groups of rats to be supplemented and not to be supplemented with ALA. Another group of rats, which received saline injection, formed the control group. After 5 weeks of diabetes, rats were killed. In order to assess the redox status of various organs in the diabetic and control rats, thiobarbituric acid-reactive substances (TBARS) and glutathione (GSH) levels, as well as superoxide dismutase (SOD), glutathione peroxidase (G-Px) and glutathione reductase (G-Red) activities were determined in the liver, pancreas and kidney. 3. In both diabetic groups, TBARS levels and SOD activity were increased in the liver and pancreas, G-Px and G-Red activities were increased in the kidney and GSH levels were decreased in all organs compared with controls. In the ALA- supplemented group, TBARS levels were decreased, GSH levels were increased in the liver and pancreas, SOD activity was decreased in the liver, G-Px activity remained unchanged in all tissues and G-Red activity was increased in the pancreas compared with the diabetic group that did not receive ALA supplementation. 4. In conclusion, ALA supplementation has disparate effects on the redox status of different organs. These data are not sufficient for confirmation the beneficial effects of ALA supplementation on the redox status of various organs in diabetic rats.     

Effect of alpha-lipoic acid on visual evoked potentials in rats exposed to sulfite

This study aimed to investigate the effect of alpha-lipoic acid (LA) administration on sulfite-induced alterations in visual evoked potentials (VEPs). Fifty two male albino Wistar rats were randomized into four experimental groups as follows; control (C), LA treated (L), sodium metabisulfite (Na(2)S(2)O(5)) treated (S), Na(2)S(2)O(5)+LA treated (SL). Na(2)S(2)O(5) (260 mg/kg/day) and LA (100 mg/kg/day) were given by intragastric intubation for 5 weeks. The latencies of VEP components were significantly prolonged in the S group and returned to control levels following LA administration. Thiobarbituric acid reactive substances (TBARS) levels in the S group were significantly higher than those detected in controls. LA significantly decreased brain and retina TBARS levels in the SL group compared with the S group. Sulfite caused a significant decrease in retina and brain glutathione peroxidase (GPx) activities which was restored to control levels via LA administration. Brain glutathione (GSH):glutathione disulfide (GSSG) ratio was significantly increased in rats jointly treated with sulfite and LA compared to rats treated with sulfite alone. Though not significant, a similar increase in GSH:GSSG ratio was also observed in the retina of SL group. This study showed that LA is protective against sulfite-induced VEP alterations and oxidative stress in the brain and retina.     

Effects of alpha-lipoic acid on endothelial function in aged diabetic and high-fat fed rats

BACKGROUND AND PURPOSE: This study was conducted to investigate the effects of alpha-lipoic acid (alpha-LA) on endothelial function in diabetic and high-fat fed animal models and elucidate the potential mechanism underlying the benefits of alpha-LA. EXPERIMENTAL APPROACH: Plasma metabolites reflecting glucose and lipid metabolism, endothelial function, urinary albumin excretion (UAE), plasma and aortic malondialdehyde (MDA) and urinary 8-hydroxydeoxyguanosine (8-OHdG) were assessed in non-diabetic controls (Wistar rats), untreated Goto-Kakizaki (GK) diabetic and high-fat fed GK rats (fed with atherogenic diet only, treated with alpha-LA and treated with vehicle, for 3 months). Vascular eNOS, nitrotyrosine, carbonyl groups and superoxide anion were also assessed in the different groups. KEY RESULTS: alpha-LA and soybean oil significantly reduced both total and non-HDL serum cholesterol and triglycerides induced by atherogenic diet. MDA, carbonyl groups, vascular superoxide and 8-OHdG levels were higher in GK and high-fat fed GK groups and fully reversed with alpha-LA treatment. High-fat fed GK diabetic rats showed significantly reduced endothelial function and increased UAE, effects ameliorated with alpha-LA. This endothelial dysfunction was associated with decreased NO production, decreased expression of eNOS and increased vascular superoxide production and nitrotyrosine expression. CONCLUSIONS AND IMPLICATIONS: alpha-LA restores endothelial function and significantly improves systemic and local oxidative stress in high-fat fed GK diabetic rats. Improved endothelial function due to alpha-LA was at least partially attributed to recoupling of eNOS and increased NO bioavailability and represents a pharmacological approach to prevent major complications associated with type 2 diabetes.     

Modulation of antioxidant defence system by dietary fat in rats intoxicated with o-toluidine

o-Toluidine was administered to rats in the diet for four weeks at levels approximately 40, 80 and 160 mg/kg b.w. per day. Two types of diet have been used, standard (4% fat) and high fat (14% fat). Activity of antioxidant enzymes, level of glutathione and thiobarbituric acid reactive substances were measured in liver. Glutathione peroxidase was significantly increased in all treated groups while glutathione S-transferase and glutathione reductase were elevated in rats fed high-fat diet. o-Toluidine slightly enhanced catalase activity regardless of the kind of diet. Superoxide dismutase was the only enzyme whose activity was lowered in almost all treated groups. Enzymatic and nonenzymatic microsomal lipid peroxidation was enhanced 2- to 3-fold in both diet groups. Reduced glutathione level in liver was 2.3- to 4.0-fold increased in all treated groups. Our findings indicate that free radical processes can be involved in the toxic effects of o-toluidine and dietary fat can modify the response of some antioxidant enzymes to this compound.     

Excessive dietary selenium decreases the vitamin A storage and the enzymatic antioxidant defence in the liver of rats

This study investigated the influence of selenium intake, over 8 weeks, on vitamin A level and on enzymatic antioxidant defence in the liver of young rats. Deficient animals were fed a well-balanced diet but without selenite addition; the Se content of this diet which originated from natural Se content of ingredients was 0.05 mg/kg. Controls were fed the same diet with 0.40 mg/kg added Se. The two other groups received high levels of Se, 2.05 or 4.05 mg/kg. Excessive Se intake decreased the concentrations of retinol and retinyl palmitate in the liver. The linear regression analysis indicated a significant (P < 0.001) dose-dependent vitamin A decline. As expected, Se deficit lowered glutathione peroxidase activity. The highest Se excess decreased the enzymatic antioxidation: Zn,Cu Superoxide dismutase, catalase, glutathione peroxidase activities. Data showed that high dietary Se can sometimes enhance carcinogenesis and our results suggest that it is best to be cautious in administrating Se to humans with the aim of preventing diseases.     

Design and synthesis of novel quinolinone-3-aminoamides and their alpha-lipoic acid adducts as antioxidant and anti-inflammatory agents

A series of N-substituted-quinolinone-3-aminoamides and their hybrids containing the alpha-lipoic acid functionality were designed and synthesized as potential bifunctional agents combining antioxidant and anti-inflammatory activity. The new compounds were evaluated for their antioxidant activity and for their ability to inhibit in vitro lipoxygenase as well as for their anti-inflammatory activity in vivo. In general, the derivatives were found to be potent antioxidant or anti-inflammatory agents. The results are discussed in terms of structure-activity relationships and an attempt is made to define the structural features required for activity.     

Anti-ulcerogenic effect of chitin and chitosan on mucosal antioxidant defence system in HCl-ethanol-induced ulcer in rats

The anti-ulcerogenic effect of chitin and chitosan against ulcer induced by HCl-ethanol in male Wistar rats was studied. Levels of acid output, pepsin, protein, lipid peroxides and reduced glutathione and the activity of glutathione peroxidase (GPx), glutathione-S-transferase (GST), catalase (CAT) and superoxide dismutase (SOD) were determined in the gastric mucosa of normal and experimental groups of rats. A significant increase in volume and acidity of the gastric juice was observed in the ulcer-induced group of rats. Peptic activity was significantly decreased as compared with that of normal controls. In the rats pre-treated with chitin and chitosan 2% along with feed, the volume and acid output and peptic activity of gastric mucosa were maintained at near normal levels. The level of lipid peroxidation was significantly higher in the ulcerated mucosa when compared with that of normal controls. This was paralleled by a decline in the level of reduced glutathione and in the activity of antioxidant enzymes like GPx, GST, CAT and SOD in the gastric mucosa of ulcer-induced rats. Also, the levels of mucosal proteins and glycoprotein components were significantly depleted in ulcerated mucosa. The pre-treatment with chitin and chitosan was found to exert a significant anti-ulcer effect by preventing all the HCl-ethanol-induced ulcerogenic effects in experimental rats.     

Antioxidant and prooxidant activities of alpha-lipoic acid and dihydrolipoic acid

Reactive oxygen (ROS) and nitrogen oxide (RNOS) species are produced as by-products of oxidative metabolism. A major function for ROS and RNOS is immunological host defense. Recent evidence indicate that ROS and RNOS may also function as signaling molecules. However, high levels of ROS and RNOS have been considered to potentially damage cellular macromolecules and have been implicated in the pathogenesis and progression of various chronic diseases. alpha-Lipoic acid and dihydrolipoic acid exhibit direct free radical scavenging properties and as a redox couple, with a low redox potential of -0.32 V, is a strong reductant. Several studies provided evidence that alpha-lipoic acid supplementation decreases oxidative stress and restores reduced levels of other antioxidants in vivo. However, there is also evidence indicating that alpha-lipoic acid and dihydrolipoic acid may exert prooxidant properties in vitro. alpha-Lipoic acid and dihydrolipoic acid were shown to promote the mitochondrial permeability transition in permeabilized hepatocytes and isolated rat liver mitochondria. Dihydrolipoic acid also stimulated superoxide anion production in rat liver mitochondria and submitochondrial particles. alpha-Lipoic acid was recently shown to stimulate glucose uptake into 3T3-L1 adipocytes by increasing intracellular oxidant levels and/or facilitating insulin receptor autophosphorylation presumably by oxidation of critical thiol groups present in the insulin receptor beta-subunit. Whether alpha-lipoic acid and/or dihydrolipoic acid-induced oxidative protein modifications contribute to their versatile effects observed in vivo warrants further investigation.