HMG-CoA reductase inhibitor rosuvastatin improves abnormal brain electrical activity via mechanisms involving eNOS.

Apart from its repressing effect on plasma lipid levels, 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors exert neuroprotective functions in animal models of neurodegenerative disorders. In view of these promising observations, we were interested in whether HMG-CoA reductase inhibition would affect epileptiform activity in the brain. To elucidate this issue, atorvastatin, simvastatin and rosuvastatin were administered orally at a dose of 20 mg/kg each for 3 days and their anti-epileptic activities were tested and compared in rats. Epileptiform activity in the brain was induced by an intracortical penicillin G injection. Among HMG-CoA reductase inhibitors, simvastatin-treatment was less effective in terms of spike frequency as compared with atorvastatin- and rosuvastatin-treated animals. Atorvastatin treatment reduced spike frequencies and amplitudes significantly throughout the experiment. However, the most pronounced anti-epileptic effect was observed in rosuvastatin-treated animals, which was associated with improved blood-brain barrier (BBB) integrity, increased expression of endothelial nitric oxide synthase (eNOS) mRNA and decreased expressions of pro-apoptotic p53, Bax and caspase-3 mRNAs. Inhibition of eNOS activity with L-NG-Nitroarginine Methyl Ester (L-NAME) reversed the anti-epileptic effect of rosuvastatin significantly. However, L-NAME did not alter the effect of rosuvastatin on the levels of p53, Bax and caspase-3 mRNA expression. Here, we provide evidence that among HMG-CoA reductase inhibitors, rosuvastatin was the most effective statin on the reduction of epileptiform activity, which was associated with improved BBB permeability, increased expression of eNOS and decreased expressions of pro-apoptotic p53, Bax and caspase-3. Our observation also revealed that the anti-epileptic effect of rosuvastatin was dependent on the increased expression level of eNOS. The robust anti-epileptic effect encourages proof-of-concept studies with rosuvastatin in human epilepsy patients with hypercholesterolemia.

Predictors of atopic dermatitis phenotypes and severity: roles of serum immunoglobulins and filaggrin gene mutation R501X.

BACKGROUND: Atopic dermatitis (AD), the most common chronic relapsing skin condition of infancy and childhood, is a complex multifactorial disease, which arises from the interaction between strong genetic and environmental factors. OBJECTIVE: To investigate the roles of several factors on the severity of AD including FLG R501X gene mutation, serum immunoglobulin (Ig) levels, atopy and accompanying allergic disorders. METHOD: Children were genotyped for the mutation in FLG R501X gene. Serum levels of major Ig isotypes, atopy and accompanying allergic disorders were assessed. RESULTS: Study group consisted of 49 patients (M: 26, F: 23) with a mean age of 4.9±3.6 years and control group consisted of 50 children (M: 30, F: 20) with a mean age of 3.8±2.8 years. Genotyping of R501X mutation revealed risk alleles in none of the children in study group or control group. IgG z-scores were significantly higher in patients with AD compared to controls (-0.97±1.13 vs 1.48±1.02, p=0.026). There was a positive trend in IgG z-scores and a negative trend in IgA z-scores across the severity of AD. History of recurrent infections was significantly associated with asthma and/or AR (47.8% in patients with asthma/AR vs 3.8% in those without). Children with low IgG or IgA levels presented at an earlier age with lower rates of atopy and mild type AD. CONCLUSION: In a sample of Turkish children, FLG R501X genotyping revealed no risk alleles in variable severities of AD or healthy controls. Our data suggest that IgG and IgA levels might have a role in phenotypic features of AD in terms of severity and atopic sensitisation.

An increase in lipoprotein oxidation and endogenous lipid peroxides in serum of obese women.

Endogenous malondialdehyde and diene conjugate levels, the susceptibility of apolipoprotein B-containing lipoproteins to copper-induced lipid peroxidation, and antibody titer against oxidized low-density lipoproteins were increased, but serum antioxidant activity was unchanged in obese women. Serum cholesterol, low-density lipoproteincholesterol, and trigliceride levels were also elevated, but high-density lipoprotein-cholesterol levels remained unchanged in obese women. In vitro, oxidation of apolipoprotein B-containing lipoproteins and levels of antibody against oxidized low-density lipoprotein correlated with body mass index, serum total cholesterol, and low-density lipoproteincholesterol levels in obese women. These results indicate that obesity is associated with increases in endogenous lipid peroxides, oxidation of low-density lipoproteins, and lipids in serum.

The effect of selenium and/or vitamin E treatments on radiation-induced intestinal injury in rats.

Cytotoxic effects of ionizing radiation on gastrointestinal epithelium may be related to oxidative stress. In this study, we wanted to investigate the effects of selenium, vitamin E and selenium plus vitamin E pretreatments prior to whole abdominal irradiation on intestinal injury. Irradiation caused increased lipid peroxide and decreased GSH levels in the intestine. Intestinal superoxide dismutase and glutathione peroxidase activities were increased, but glutathione transferase activity decreased following irradiation. Selenium and/or vitamin E pretreatments ameliorated these disturbances in prooxidant-antioxidant balance. This amelioriation has been verified with histopathological findings. These results indicate that antioxidant pretreatments prior to irradiation may have some beneficial effects against irradiation-induced intestinal injury.

The role of stimulated lipid peroxidation and impaired calcium sequestration in the enhancement of cocaine induced hepatotoxicity by ethanol.

The purpose of this study was to investigate possible mechanism of cocaine-induced hepatotoxicity and its potentiation by ethanol in mice. Ethanol (2 g/kg) and/or cocaine (25 mg/kg) injections were given as binge model (five injections in 3 days). Cocaine administration with or without ethanol caused an increase in lipid peroxidation in liver homogenate and its subcellular fractions. The greatest increases were observed in mitochondrial fraction following cocaine plus ethanol treatment. Also, glutathione (GSH) levels were increased in liver homogenate and its mitochondrial fractions after cocaine and cocaine plus ethanol treatment. Microsomal calcium sequestration was found to decrease in all treatments. These results suggest that increased lipid peroxidation and decreased microsomal calcium sequestration in the liver may play a possible role cocaine-induced hepatotoxicity and its potentiation by ethanol.

In vitro effects of peroxynitrite on human spermatozoa.

In the present study, the in vitro effects of peroxynitrite on sperm motility, lipid peroxidation and sulfhydryl content were examined. Sperm percentage motility and movement characteristics were assessed by a computer-assisted system. Lipid peroxidation was measured by determining malondialdehyde levels using the thiobarbituric acid (TBA) method. Sperm sulfhydryl content was measured by a spectrophotometric method based on reduction of 5,5'-dithiobis-(2-nitrobenzoic acid) by sulfhydryl groups. Percentage motility, movement characteristics and sulfhydryl content decreased significantly in peroxynitrite-treated samples compared to decomposed peroxynitrite-treated samples. Lipid peroxidation in peroxynitrite-treated samples was significantly higher than in decomposed peroxynitrite-treated samples. These results indicate that peroxynitrite anion may cause sperm dysfunction through lipid peroxidation stimulation and total SH depletion.

Antioxidant role of alpha-lipoic acid in lead toxicity.

The assumption of oxidative stress as a mechanism in lead toxicity suggests that antioxidants might play a role in the treatment of lead poisoning. The present study was designed to investigate the efficacy of lipoic acid (LA) in rebalancing the increased prooxidant/antioxidant ratio in lead-exposed Chinese hamster ovary (CHO) cells and Fischer 344 rats. Furthermore, LA's ability to decrease lead levels in the blood and tissues of lead-treated rats was examined. LA administration resulted in a significant improvement in the thiol capacity of cells via increasing glutathione levels and reducing malondialdehyde levels in the lead-exposed cells and animals, indicating a strong antioxidant shift on lead-induced oxidative stress. Furthermore, administration of LA after lead treatment significantly decreased catalase and red blood cell glucose-6-phosphate dehydrogenase activity. In vitro administration of LA to cultures of CHO cells significantly increased cell survival, that was inhibited by lead treatment in a concentration-dependent manner. Administration of LA was not effective in decreasing blood or tissue lead levels compared to a well-known chelator, succimer, that was able to reduce them to control levels. Hence, LA seems to be a good candidate for therapeutic intervention of lead poisoning, in combination with a chelator, rather than as a sole agent.

Captopril as an antioxidant in lead-exposed Fischer 344 rats.

Recent studies suggest that lead induces oxidative stress in various tissues. Captopril ([2S]-1-[3-mercapto-2-methylpropionyl]-L-proline), an angiotensin-converting enzyme inhibitor, is a well-known antihypertensive agent and is also believed to function as an antioxidant. In the present study the antioxidant effect of captopril on lead-induced oxidative stress was studied in Fischer 344 rats. Their liver, brain and kidneys were assayed for glutathione (GSH), glutathione disulfide (GSSG), malondialdehyde concentrations, and catalase activities. The results from animals treated with captopril were compared to results of control and lead-exposed non-treated groups. The captopril-treated samples showed higher GSH:GSSG ratios in the liver, brain and kidneys, as well as slightly decreased malondialdehyde concentrations. The catalase activity was not significantly affected.

Peroxidation status of erythrocytes and apolipoprotein B containing lipoproteins in hypercholesterolemic subjects.

Erythrocyte diene conjugate levels and glutathione peroxidase and superoxide dismutase activities were found unchanged in hypercholesterolemic subjects with plasma cholesterol levels of 240 mg/dl as compared to normocholesterolemics (below 200 mg/dl). However, the susceptibility of VLDL + LDL, apolipoprotein B containing lipoproteins to copper-induced peroxidation and plasma endogenous malondialdehyde levels were increased in hypercholesterolemics. These results indicate that hypercholesterolemia is associated with increased susceptibility of VLDL + LDL to lipid peroxidation.

Fluoride concentration and profile in different cementum surfaces.

This study was performed to determine the fluoride concentration of the various cementum surfaces in different tooth groups to find out the most proper teeth and tooth surfaces for different cementum studies. For this purpose, direct measurements of phosphorus and fluoride were carried out in an acid etch biopsy solution. The findings indicate that incisors with exposed cementum are the most inappropriate teeth in comparison with the other groups. According to the results obtained it may be recommended that the studies related to fluoride uptake for cementum should be performed on teeth with no gingival recession or on the unerupted teeth.

High-performance liquid chromatography assay for N-acetylcysteine in biological samples following derivatization with N-(1-pyrenyl)maleimide.

N-Acetylcysteine is a thiol antioxidant with expanding clinical importance. A sensitive, rapid method for determining reduced N-acetylcysteine (NAC) concentration in biological samples has been developed which uses a modified reversed-phase high-performance liquid chromatography (HPLC) technique in conjunction with the derivatizing agent N-(1-pyrenyl)maleimide (NPM). The NAC-NPM adduct was analyzed by HPLC with fluorescence detection. The calibration curve for NAC was linear over the range 8-2500 nM and the coefficient of variation obtained for the within-run precision and the between-run precision for 0.5 mM NAC was 1.5% and 2.7%, respectively. Relative recovery of NAC from biological materials ranged between 86% and 96% and the limit of quantitation from biological samples was 32 nM. These results suggest practical advantages relative to other widely-accepted methods of NAC measurement.

Peroxidation potential and antioxidant activity of serum in patients with diabetes mellitus and myocard infarction.

Endogen malondialdehyde (MDA), diene conjugate levels, the susceptibility to copper-induced lipid peroxidation and antioxidant activity of serum were determined in patients with atherosclerotic diseases such as diabetes mellitus and myocard infarction. Lipid peroxidation susceptibility and antioxidant activity did not change, however, an increase in endogen MDA and diene conjugate levels was observed in serum of these patients. These results indicate the presence of oxidative stress in diabetes mellitus and myocard infarction.