Atilla Engin

Oxidative stress, Helicobacter pylori, and OGG1 Ser326Cys, XPC Lys939Gln, and XPD Lys751Gln polymorphisms in a Turkish population with colorectal carcinoma.

The contribution of polymorphisms of DNA repair genes OGG1 Ser326Cys, XPC Lys939Gln, and XPD Lys751Gln in developing colorectal carcinoma is controversial. Whether the group 1A carcinogen Helicobacter pylori is a risk factor or not in these patients could not be clearly elucidated. One hundred ten colorectal cancer patients and 116 cancer-free individuals constituted the test and control groups, respectively. The association of OGG1 Ser326Cys, XPC Lys939Gln, and XPD Lys751Gln polymorphisms and the susceptibility to colorectal carcinoma with or without oxidative stress were evaluated. DNA was extracted from peripheral blood cells and genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism. For serum nitric oxide and total antioxidant status assay, spectrophotometric analyses were used. Serum albumin measurements were performed using an autoanalyzer. H. pylori IgG was measured by ELISA. The serum albumin concentrations of cancer patients were significantly lower than those of the controls (p < 0.05). The carriers of the variant genotype of OGG1 (odds ratio: 0.963; 95% confidence interval: 0.446-2.079), XPC (0.789, 0.366-1.700), or XPD (0.532, 0.259-1.094) did not associate with the increased risk of cancer progression, despite the increased oxidative stress in cancer patients. Seropositivity of H. pylori IgG has been found to increase the risk of colorectal carcinoma by 2.2-fold.

Association Between XRCC1 ARG399GLN and P53 ARG72PRO Polymorphisms and the Risk of Gastric and Colorectal Cancer in Turkish Population

Association Between XRCC1 ARG399GLN and P53 ARG72PRO Polymorphisms and the Risk of Gastric and Colorectal Cancer in Turkish Population Gastric cancer is one of the most common cancers of the gastrointestinal system, and its overall five-year survival rate is still 15 % to 20 %, as it can mostly be diagnosed at an advanced stage. On the other hand, although colorectal cancer has a rather good prognosis, mortality is one half that of the incidence. As carcinogenesis is believed to involve reactive radicals that cause DNA adduct formation, impaired repair activity, and weakened tumour suppression, it would help to understand the role of the polymorphisms of nucleotide excision repair enzyme XRCC1 and of tumour suppressor gene p53 in gastric and colorectal cancers. Our study included 94 gastric cancer patients, 96 colorectal cancer patients, and 108 cancer-free individuals as control with the aim to see if there was an association between XRCC1 Arg399Gln and p53 Arg72Pro polymorphisms and cancer susceptibility. DNA was extracted from peripheral blood cells and genotypes were determined using the polymerase chain reaction-restriction fragment length polymorphism. Polymorphism p53 Arg72Pro was not associated with either gastric or colorectal carcinoma, while XRCC1 Arg399Gln was not associated with the increased risk of colorectal cancer. However, XRCC1 homozygous Gln allele at codon 399 was associated with 2.54 times higher risk of gastric cancer. Povezanost između polimorfizama XRCC1 ARG399GLN i P53 ARG72PRO s rizikom od raka želuca i debeloga crijeva u turskoj populaciji Rak želuca najčešći je oblik karcinoma probavnoga sustava, a ukupno mu je preživljenje i dalje 15 % do 20 %, budući da se većinom dijagnosticira u poodmakloj fazi razvoja. S druge pak strane, premda rak debeloga crijeva ima prilično dobru prognozu, smrtnost je i dalje 50 %. Vjeruje se da je nastanak karcinoma povezan s reaktivnim radikalima koji uzrokuju stvaranje DNA-adukata, onemogućavaju popravak DNA te slabe supresiju tumora. Stoga bi bilo korisno razumjeti ulogu polimorfizama gena za enzim XRCC1 koji sudjeluje u popravku isjecanjem nukleotida i tumor-supresorskoga gena p53 u nastanku raka želuca i debeloga crijeva. Naše je ispitivanje obuhvatilo 94 bolesnika s rakom želuca, 96 bolesnika s rakom debeloga crijeva te 108 kontrolnhih ispitanika (koji nisu oboljeli od bilo kojeg oblika raka) s ciljem da se utvrdi povezanost između polimorfizama XRCC1 Arg399Gln i p53 Arg72Pro i sklonosti nastanku raka. DNA je dobiven iz stanica periferne krvi, a genotip utvrđen s pomoću metode lančane reakcije polimerazom - polimorfizma restrikcijskih fragmenata na osnovi dužine (PCRRLFP). Polimorfizam p53 Arg72Pro nije se pokazao povezanim s povećanim rizikom od raka želuca ili debeloga crijeva niti je XRCC1 Arg399Gln bio povezan s povećanim rizikom od raka debeloga crijeva, ali je zato rizik od raka želuca u homozigotnih nositelja ovoga polimorfizma bio 2,54 puta veći.

A novel minimally invasive technique for insertion of peritoneal dialysis catheter.

The placement of a continuous ambulatory peritoneal dialysis (CAPD) catheter by conventional open surgical or trocar technique may cause a number of complications such as infection, hemorrhage, leakage, incisional hernia, and visceral organ perforation. Most complications are related to open surgery or insertion of the catheter with the guidewire without direct visualization. Insertion of the catheter laparoscopically under direct visualization has been previously described. The authors who described this technique used two or three ports for the camera and instruments. In this study we describe a laparoscopic technique for insertion of the peritoneal dialysis catheter under direct visualization with use of one-camera port and an accessory 2-mm umbilical incision. This prospective study was performed with the approval of the ethics committee of the Gazi University Hospital, in Ankara, Turkey. There were a total of eight patients: five males and three females, with an average age of 34.3 years (range, 11–54), who underwent laparoscopic CAPD insertion between 1997 and 2000. The catheter was inserted into the abdominal cavity 2 cm below the umbilicus. The subcutaneous tunnel was made with the assistance of a specially designed L-shaped trocar. All patients did well after the operation and had excellent cosmetic results. There was one leak in the early postoperative period, which was treated conservatively. The average operating time was 34.7 minutes (range, 25–45 minutes). The laparoscopic approach for peritoneal dialysis catheter insertion, for management of transmigrated CAPD catheters, and to resolve omental occlusions should be considered as an alternative to open surgery, especially for patients who have peritoneal adhesions secondary to a history of abdominal surgeries or recurrent peritonitis.

Erythrocyte Glutathione Levels in Lithium-Induced Hypothyroidism

AbstractBackground and objective: Lithium, widely used in the prophylaxis of psychiatric patients with bipolar affective disorders, is well known to induce thyroid alterations. However, a possible metabolic linkage between blood thyroxine levels and its regulatory function on erythrocyte glutathione concentration has not yet been evaluated in lithium-treated patients. The aim of this study was to assess the antioxidative capacity of erythrocytes in lithium-induced hypothyroidism before and after thyroxine replacement. Patients and methods: Thyroid ultrasound with clinical and laboratory evaluation of thyroid function and thyroid-stimulating hormone assay were performed prior to and at 6-month intervals during lithium prophylaxis in 76 patients with bipolar affective disorders. The daily lithium dosage was adjusted to 600–1200mg and the mean duration of treatment was 2.2 ± 0.4 years. Final assessment revealed that 12 patients had evidence of primary hypothyroidism, and these were assigned as the test group. Lithium prophylaxis was supplemented with thyroxine at a dosage of 100 mg/day within 6 months after thyroid dysfunction was diagnosed. Red blood cell superoxide dismutase activities and the glutathione contents were measured before and after thyroxine replacement. In order to assess the effect of long-term lithium administration on red blood cell glutathione and superoxide dismutase levels, 12 patients who had not developed hypothyroidism during the follow-up period were selected for the lithium-treated euthyroid group. Mann Whitney U-test and Wilcoxon rank sum W-test were used for comparison of data. Results: A comparison of the lithium-treated test group with healthy volunteers and their own values after thyroxine replacement revealed a significant decrease in red blood cell glutathione concentrations (p = 0.000) in the hypothyroid state. However, no clinically significant changes were observed in red blood cell superoxide dismutase activities of the test group. A statistical survey also demonstrated that there was no significant difference in the thyroid-stimulating hormone values as well as the red blood cell glutathione contents or superoxide dismutase activities between healthy controls and lithium-treated euthyroid subjects. Conclusions: It is most likely that lithium primarily inhibited hormone production in the thyroid and that this led to a compensatory increase in thyroid-stimulating hormone secretion with a significant decrease in the red blood cell glutathione content. While the red blood cell glutathione content of hypothyroid patients was reduced to 40% of the post-thyroxine level, unchanged superoxide dismutase activity might render the erythrocytes vulnerable to oxidative stress and ultimately haemolysis. Thyroxine replacement during lithium prophylaxis of psychiatric patients is advisable in order to prevent subclinical hypothyroidism and related defects of erythrocyte antioxidant capacity.

Nitric oxide-mediated liver injury in the presence of experimental bile duct obstruction.

We investigated the possible mechanism of common bile duct (CBD) obstruction-related liver cell necrosis in a guinea pig model during a 24-hour period of biliary occlusion. A total of 30 male albino guinea pigs were randomly and equally assigned to two groups. Group 1 underwent sham laparotomy (SL), and group 2 underwent common bile duct ligation (CBDL). All the animals were followed for the first 24-hours after operation. The liver antioxidant defense was examined by measuring liver total superoxide dismutase (TSOD), copper/zinc-containing superoxide dismutase (Cu-ZnSOD), manganese superoxide dismutase (MnSOD), and glutathione peroxidase (GPx) activities as well as the reduced glutathione (GSH) concentration. Severity of necrosis was assessed by blind quantitation of liver specimens using a histologic scoring system. Histologic evidence of grade +2 hepatocellular necrosis was observed in the CBDL group, as was a more than fourfold increase in plasma nitrite plus nitrate [NOx] concentrations in these animals. Although no significant difference was found between the two groups for liver Cu-ZnSOD activity, the CBDL group showed a marked decrease in MnSOD activity. Concomitant increases in liver GPx activity and the GSH level were measured in the CBDL group. These data supported the hypothesis that excessive production of [NOx] and its derivative peroxynitrite contribute to a coexisting MnSOD deficiency in the mitochondria and lead to liver cell necrosis in cholestatic animals.

Effect of the sulfonylurea glyburide on superoxide dismutase activity in alloxan-induced diabetic rat hepatocytes

In the present study we administrated glyburide (glibenclamide) to type 2 (NIDDM) diabetic rats and determined the effect of such treatment on liver superoxide dismutase (SOD) activity. Hepatic SOD activity was significantly reduced in diabetic animals. Glyburide treatment of diabetic rats for 4 weeks corrected the changes observed in diabetic liver. In addition, blood glucose levels of untreated diabetic rats decreased following glyburide treatment. Administration of glyburide to diabetic rats reversed the diabetes-induced changes, suggesting that glyburide may directly increase liver SOD enzyme activity.

Obesity-associated Breast Cancer: Analysis of risk factors

Several studies show that a significantly stronger association is obvious between increased body mass index (BMI) and higher breast cancer incidence. Furthermore, obese women are at higher risk of all-cause and breast cancer specific mortality when compared to non-obese women with breast cancer. In this context, increased levels of estrogens due to excessive aromatization activity of the adipose tissue, overexpression of pro-inflammatory cytokines, insulin resistance, hyperactivation of insulin-like growth factors (IGFs) pathways, adipocyte-derived adipokines, hypercholesterolemia and excessive oxidative stress contribute to the development of breast cancer in obese women. While higher breast cancer risk with hormone replacement therapy is particularly evident among lean women, in postmenopausal women who are not taking exogenous hormones, general obesity is a significant predictor for breast cancer. Moreover, increased plasma cholesterol leads to accelerated tumor formation and exacerbates their aggressiveness. In contrast to postmenopausal women, premenopausal women with high BMI are inversely associated with breast cancer risk. Nevertheless, life-style of women for breast cancer risk is regulated by avoiding the overweight and a high-fat diet. Estrogen-plus-progestin hormone therapy users for more than 5 years have elevated risks of both invasive ductal and lobular breast cancer. Additionally, these cases are more commonly node-positive and have a higher cancer-related mortality. Collectively, in this chapter, the impacts of obesity-related estrogen, cholesterol, saturated fatty acid, leptin and adiponectin concentrations, aromatase activity, leptin and insulin resistance on breast cancer patients are evaluated. Obesity-related prognostic factors of breast cancer also are discussed at molecular basis.

Helicobacter pylori and serum kynurenine-tryptophan ratio in patients with colorectal cancer.

AIM To evaluate how Helicobacter pylori (H. pylori) is able to evade the immune response and whether it enhances systemic immune tolerance against colorectal cancer. METHODS This prospective randomized study involved 97 consecutive colorectal cancer patients and 108 cancer-free patients with extra-digestive diseases. Colorectal cancer and cancer-free patients were assigned into subgroups according to H. pylori IgG seropositivity. Exposure to H. pylori was determined by IgG seropositivity which was detected by enzyme linked immunoassay (ELISA). Serum neopterin levels were measured by ELISA. Serum tryptophan, kynurenine, and urinary biopterin concentrations were measured by high performance liquid chromatography. Serum nitrite levels were detected spectrophotometrically. Serum indoleamine 2,3-dioxygenase activity was estimated by the kynurenine to tryptophan ratio and by assessing the correlation between serum neopterin concentrations and the kynurenine to tryptophan ratio. The frequencies of increased serum kynurenine to tryptophan ratio of H. pylori seronegative and seropositive colorectal cancer subgroups were estimated by comparing them with the average kynurenine to tryptophan ratio of H. pylori seronegative tumor-free patients. RESULTS Compared with respective controls, in both H. pylori seronegative and seropositive colorectal cancer patients, while serum tryptophan levels were decreased (controls vs patients; seronegative: 20.37 ± 0.89 μmol/L vs 15.71 ± 1.16 μmol/L, P < 0.05; seropositive: 20.71 ± 0.81 μmol/L vs 14.97 ± 0.79 μmol/L, P < 0.01) the kynurenine to tryptophan ratio was significantly increased (controls vs patients; seronegative: 52.85 ± 11.85 μmol/mmol vs 78.91 ± 8.68 μmol/mmol, P < 0.01, seropositive: 47.31 ± 5.93 μmol/mmol vs 109.65 ± 11.50 μmol/mmol, P < 0.01). Neopterin concentrations in cancer patients were significantly elevated compared with controls (P < 0.05). There was a significant correlation between serum neopterin levels and kynurenine/tryptophan in control and colorectal cancer patients groups (rs = 0.494, P = 0.0001 and rs = 0.293, P = 0.004, respectively). Serum nitrite levels of H. pylori seropositive cancer cases were significantly decreased compared with seropositive controls (controls vs patients; 26.04 ± 2.39 μmol/L vs 20.41 ± 1.48 μmol/L, P < 0.05) The decrease in the nitrite levels of H. pylori seropositive cancer patients may be attributed to excessive formation of peroxynitrite and other reactive nitrogen species. CONCLUSION A significantly high kynurenine/tryptophan suggested that H. pylori may support the immune tolerance leading to cancer development, even without an apparent upper gastrointestinal tract disease.

Effect of butylated hydroxytoluene (E321) pretreatment versus l-arginine on liver injury after sub-lethal dose of endotoxin administration

Aim of this study was to compare the effects of L-arginine (L-arg) and food-antioxidant butylated hydroxytoluene (BHT) against oxidative stress of Escherichia coli endotoxin (LPS) in liver. Ninety Wistar albino rats were assigned in three groups. Rats received one of the following pre-treatment previous to 5mg/kg LPS intraperitoneally: saline, L-arg (NO donor, 100mg/kg) or BHT (250 mg/kg/day), for 3 days. At second, fourth and sixth hours, plasma nitrite-plus-nitrate, circulating liver enzymes, glutathione levels, superoxide dismutase, glutathione peroxidase activities were measured. The most remarkable liver injury was evident in BHT pre-treated animals at all time points compared to L-arg pre-treated rats. While BHT enhanced superoxide dismutase activities following LPS, glutathione decreased simultaneously compared to L-arg group. Although the risk associated with the use of BHT alone in subthreshold doses appeared to be low, higher risk of liver toxicity should be considered when over-consuming this food additive in endotoxemic settings.

Oxidative stress-induced endothelial cell damage in thyroidectomized rat.

Patients with hypothyroidism are considered to have an increased risk of developing atherosclerosis. Uncoupling of endothelial nitric oxide synthase from tetrahyrobiopterin, an essential cofactor, leads to the decrease of nitric oxide production and increase in reactive oxygen species. Both mechanisms contribute to atherosclerotic vascular disease. The aim of this study was to investigate whether hypothyroidism influences the systemic redox-state and the structure of aortic vascular endothelium in thyroidectomized rats. Twenty-eight Sprague-Dawley rats were randomly assigned to two groups; sham thyroidectomy and near-total thyroidectomy. Three weeks after surgery, nitric oxide in plasma, homocysteine, cysteine, glutathione levels and superoxide dismutase activity were measured in serum, and biopterine and creatinine were measured in urine. Aortic endothelium samples were processed for light and transmission electron microscopy. Although superoxide dismutase activity remained constant, urine biopterin levels and serum nitric oxide levels decreased in hypothyroid rats compared to their euthyroid controls. Aortic endothelium showed early features of atherosclerosis, and transmission electron microscopy revealed budding of caveolae in endothelial cells. It is concluded that hypothyroidism might lead to systemic oxidative stress with resultant endothelial dysfunction, and subsequent occurrence of atherosclerosis.