The 8-oxoguanine DNA N-glycosylase 1 (hOGG1) Ser326Cys variant affects the susceptibility to Graves' disease.

Oxidative DNA damage, caused by either endogenous or exogenous sources of reactive oxygen species (ROS), has been linked several diseases including Graves' disease (GD). 7,8-Dihydro-8-oxoguanine (8-oxoG) is a major lesion produced by ROS and is considered a key biomarker of oxidative DNA damage. In humans, 8-oxoG is mainly repaired by 8-oxoguanine DNA N-glycosylase-1 (hOGG1), which is an essential component of the base excision repair (BER) pathway. The functional studies showed that hOGG1 Ser326Cys polymorphism is associated with the reduced DNA repair activity and increased risk for some oxidative stress-related diseases. In this study, we firstly investigated hOGG1 Ser326Cys polymorphism in GD. According to our results, Cys/Cys genotype frequency in the GD patients (23.4%) was significantly higher than the controls (9.2%). Cys/Cys genotype had an 3.5-fold [95% CI (confidence interval): 2.10-6.01, p < 0.001] the Cys allele had 1.83-fold (95% CI: 1.43-2.34, p < 0.001) increase in the risk for developing GD. Our results suggest that Ser326Cys polymorphism of the hOGG1 gene is associated with GD risk.

Preventive effect of pentoxifylline on acute radiation damage via antioxidant and anti-inflammatory pathways.

PURPOSE: The aim of the present study was to investigate whether pentoxifylline (PTX) treatment could protect against induced acute radiation enteritis. METHOD: Rats received 100 mg/kg/day PTX for 7 days before irradiation and continued on treatment for 3 days after irradiation. The intestinal myeloperoxidase (MPO) activities and malondialdehyde (MDA), glutathione (GSH), prostaglandin E2, and thromboxane B2 levels were determined. Terminal ileum tissue was evaluated for morphological changes. Also, nuclear factor kappa (NF-kappa), tumor necrosis factor-alpha (TNF-alpha), and intercellular adhesion molecule 1 (ICAM-1) expressions were analyzed with immunohistochemisty methods. RESULTS: PTX treatment was associated with increased GSH levels and decreased MPO activity and MDA, prostaglandin E2, and thromboxane B2 levels. Histopathologic examination showed that intestinal mucosal structure was preserved in the PTX-treated group while having significant decreases in NF-kappaB, TNF-a, and ICAM-1 expression. CONCLUSIONS: PTX appears to have a protective effect against radiation damage. This protective effect is mediated in part by decreasing both inflammatory reactions and oxidative stress.

Association of cholesteryl ester transfer protein -629C > A polymorphism with high-density lipoprotein cholesterol levels in coronary artery disease patients.

In Turkish population, plasma HDL-C levels were found to be lower than in any other country and it is suggested that this is associated with genetic origin. The cholesteryl ester transfer protein (CETP) -629C > A polymorphism is associated with lower plasma CETP concentration, with increased HDL-C level. In the present study, the frequency of -629C > A polymorphism in patients with coronary artery disease (CAD) was investigated and the effect of genotype on HDL-C was evaluated in a Turkish population. For this aim CETP -629C > A polymorphism was studied in angiographically documented CAD patients and healthy controls. There was no statistical significance in the distribution of genotypes between patients and controls. Although A allele carriers with CAD had significantly lower HDL-C levels than controls, plasma lipid levels showed no difference according to the genotypes. Adjustment by a logistic regression model predicting CAD status through HDL-C and including some risk factors as covariate indicated that the HDL-C doesn't have a significant association with CAD risk in CA and AA genotype carriers. Smoking, gender and hypertension were the common predictors for the HDL-C levels in CA and AA carriers. Although HDL-C appeared to be the only significant predictor of CAD in our study groups, the contribution of CETP -629C > A polymorphism to the alterations in HDL-C level appears to be weak to mention a protective effect of this polymorphism for CAD. In conclusion, the findings of the present study indicate that the CETP -629C > A polymorphism is not among the determinants of the coronary artery disease in Turks.

Polymorphisms of DNA base-excision repair genes APE/Ref-1 and XRCC1 are not associated with the risk for Graves' disease.

Oxidative stress has been implicated in etiopathogenesis of Graves' disease (GD). Increased lipid peroxidation and oxidative DNA damage have been found in GD patients. Oxidative DNA damage is mainly repaired by the base-excision repair (BER) pathway. Polymorphisms in DNA-repair genes have been associated with the increased risk of various diseases and could also be related to the etiology of GD. Therefore, we conducted a study including 197 patients with GD and age- and sex-matched 303 healthy subjects to examine the role of single-nucleotide polymorphisms of BER genes, APE/Ref-1 (codon 148) and XRCC1 (codons 194 and 399) as a risk factor for GD. These polymorphisms were determined by quantitative real-time PCR and melting curve analysis using LightCycler. No significant association was observed between the variant alleles of APE/Ref-1 codon 148 [odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.69-1.17], XRCC1 codon 194 (OR = 1.24, 95% CI = 0.79-1.94), and XRCC1 codon 399 (OR = 1.12, 95% CI = 0.86-1.46) and GD. These preliminary results suggest that APE/Ref-1 (codon 148) and XRCC1 (codons 194 and 399) polymorphisms are not significant risk factors for developing GD.

Reactive oxygen species and chemokines: are they elevated in the esophageal mucosa of children with gastroesophageal reflux disease?

AIM: To determine the role of inflammatory cytokines and reactive oxygen species (ROS) in childhood reflux esophagitis. METHODS: A total of 59 subjects who had complaints suggesting GERD underwent esophagogastroduodenoscopy. Endoscopic and histopathologic diagnosis of reflux esophagitis was established by Savary-Miller and Vandenplas grading systems, respectively. Esophageal biopsy specimens were taken from the esophagus 20% proximal above the esophagogastric junction for conventional histopathological examination and the measurements of ROS and cytokine levels. ROS were measured by chemiluminescence, whereas IL-8 and MCP-1 levels were determined with quantitative immunometric ELISA on esophageal tissue. Esophageal tissue ROS, IL-8 and MCP-1 levels were compared among groups with and without endoscopic/histo-pathologic esophagitis. RESULTS: Of 59 patients 28 (47.5%) had normal esophagus whereas 31 (52.5%) had endoscopic esophagitis. In histopathological evaluation, almost 73% of the cases had mild and 6.8% had moderate degree of esophagitis. When ROS and chemokine levels were compared among groups with and without endoscopic esophagitis, statistical difference could not be found between patients with and without esophagitis. Although the levels of ROS, IL-8 and MCP-1 were found to be higher in the group with histopathological reflux esophagitis, this difference was not statistically significant. CONCLUSION: These results suggest that the grade of esophagitis is usually mild or moderate during childhood and factors apart from ROS, IL-8 and MCP-1 may be involved in the pathogenesis of reflux esophagitis in children.

Determination of oxidative stress in thyroid tissue and plasma of patients with Graves' disease.

BACKGROUND: The aim of our study was to evaluate the oxidant/antioxidant status of thyroid tissue in Graves' disease (GD) patients and to compare the results of GD thyroid tissue with plasma of patients and healthy controls. METHODS: We studied 25 consecutive patients with GD hyperthyroidism who underwent surgical treatment. The patients were divided into groups according to the duration of antithyroid drug treatment, the type of antithyroid drugs used, the presence of ophthalmopathy, and recurrence after a complete course of antithyroid drugs. Thiobarbituric acid-reacting substances (TBARS), glutathione peroxidase (GPx) activity, superoxide dismutase (SOD) activity, and total thiol (t-SH) content of tissue and plasma samples were determined. RESULTS: TBARS concentrations were found to be significantly increased in GD patients' plasma compared with controls' plasma (0.1+/-0.02 nmol/mg protein vs. 0.062+/-0.01 nmol/mg protein). Significantly decreased t-SH concentrations were measured in GD patients' plasma compared with controls (8.26+/-1.9 nmol/mg protein vs. 13.03+/-3.3 nmol/mg protein). Tissue TBARS, t-SH, GPx, and SOD measurements in GD patients indicated significantly increased concentrations compared with the plasma levels of patients. Patients with shorter treatment duration before the operation had significantly increased plasma and tissue TBARS and decreased plasma and tissue t-SH concentrations. Patients on propylthiouracil treatment had significantly lower plasma and tissue concentrations of TBARS than patients on methimazole. Patients with recurrence had significantly higher plasma and tissue TBARS and lower plasma and tissue t-SH concentrations than patients treated for the first time. CONCLUSIONS: In euthyroid GD patients on antithyroid drugs, increased oxidative stress and a compensatory increase in the antioxidant defense system are more prominent in thyroid tissue than in plasma. Patients who relapsed had markers indicating increased oxidative stress. Thus, ongoing autoimmunity may contribute to increased oxidative stress in GD patients, even in the euthyroid state.

The predictive value of CTLA-4 and Tg polymorphisms in the recurrence of Graves' disease after antithyroid withdrawal.

Graves' disease (GD) is a multifactorial disease that develops as a result of complex interactions between genetic and environmental factors. The aim of our study is to determine the frequency of cytotoxic T-lymphocyte- associated antigen-4 (CTLA-4) A/G and TG C/T exon 33 SNPs (Tg E33SNP) in GD and to evaluate the relation between recurrence and these polymorphisms. A total of 187 subjects, including 97 previously treated GD patients and 90 age and gender matched control subjects were studied. We examined the relationship between the A/G and C/T polymorphism and various clinical and laboratory variables among patients with GD. TT genotype frequency in the GD patients was significantly higher than the controls. Number of recurrent patients was significantly higher in AG and GG carriers in comparison to AA carriers (57% and 45% vs 14%, p = 0.0001). CTLA-4 AG genotype had an eightfold (OR: 8.050; 95% CI: 2.87-22.5; p = 0.0001) and GG genotype had a sevenfold (OR: 7.025; 95% CI: 1.67-29.4; p = 0.007) increase in the risk of recurrence in the patients with GD. In conclusion, early interpretation for definitive treatment procedures (i.e., radioactive iodine or surgery) may be considered in the patients with G allele and E33SNP of Tg gene is conformed the susceptibility to GD in a Turkish population and having TT genotype increases the susceptibility to GD.

Cyclosporin A-associated changes in red blood cell membrane composition, deformability, blood and plasma viscosity in rats.

Most of the studies concerning the effects of cyclosporin A (Cs A) on red blood cell (RBC) rheology were carried out in human transplant recipients who may still have residual insufficiency and concomitant administration of other immunosuppressive and antihypertensive drugs. The aim of this study is to evaluate the effects of Cs A on red cell rheology and membrane composition in nontransplant healthy rats. Female Wistar albino rats were divided into two groups of 10 animals each. Rats received 10 mg/kg Cs A, i.p. or saline for 4 weeks. Cs A administration significantly increased the RBC deformability, and plasma and blood viscosity (p < 0.001, p < 0.01 and p < 0.01, respectively). Cs A administration to the rats increased RBC membrane cholesterol (CHO) levels and the CHO/phospholipid (PL) ratio significantly (p < 0.01 and p < 0.05, respectively) but did not change RBC membrane proteins and membrane PL levels. These results suggest that Cs A changes the rheological functions of RBC and lipid content of RBC membrane in healthy rats and thereby it may play an important role in the regulation of microcirculation.