Arzu Yilmaztepe Oral

Decreased plasma levels of soluble receptor for advanced glycation endproducts (sRAGE) in patients with nonalcoholic fatty liver disease

OBJECTIVES Levels of soluble receptor for advanced glycation endproducts (sRAGE) have been linked to several components of the metabolic syndrome. We tested the hypothesis that plasma levels of sRAGE may be associated with non-alcoholic fatty liver disease. DESIGN AND METHODS We enrolled subjects with definite nonalcoholic steatohepatitis (NASH, n=40), borderline NASH (n=8), simple fatty liver (n=9) and healthy controls (n=14). Plasma levels of sRAGE were measured by ELISA. RESULTS Concentrations of sRAGE were significantly lower in patients with definite NASH (1080+/-392 pg/mL, P<0.01) and borderline NASH (1050+/-278 pg/mL, P<0.05) compared to controls (1480+/-387 pg/mL). Levels of sRAGE were significantly and inversely correlated with ALT (r=-0.30, P<0.05) and AST (r=-0.23, P<0.05). CONCLUSION Plasma levels of sRAGE are significantly reduced in definite and borderline NASH.

Serum fetuin A/α2HS-glycoprotein levels in patients with non-alcoholic fatty liver disease: relation with liver fibrosis

Background Serum concentrations of fetuin A/α2HS-glycoprotein (AHSG) have been linked to human metabolic alterations and can serve as an indicator of liver cell function. We assayed serum levels of AHSG in patients with non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome, and examined their association with clinical, biochemical and histological phenotypes. Methods Serum AHSG levels were determined by enzyme linked immunosorbent assay in 99 patients with biopsy-proven NAFLD and 75 age- and gender-matched controls. Results Serum AHSG levels were significantly higher in patients with NAFLD (940 ± 120 μg/mL) compared with healthy controls (800 ± 130 μg/mL, Students t test, P < 0.001). Bivariate analyses (Spearmans rank correlation) in patients with NAFLD showed a statistically significant association between AHSG levels and insulin resistance as assessed by the HOMA (homeostasis model assessment) index (r = 0.31, P < 0.01) and the liver fibrosis score index (r = 0.36, P < 0.001). The association between AHSG and fibrosis remained statistically significant even after adjustment for potential confounders, including the HOMA index ([beta] = 1.65, t = 2.38, P < 0.05). Conclusion Serum AHSG levels are significantly increased in adult patients with biopsy-proven NAFLD and are associated with insulin resistance. Importantly, our pilot data indicate that serum AHSG levels may identify NAFLD patients with higher fibrosis scores.

Promising anti-growth effects of palladium(II) saccharinate complex of terpyridine by inducing apoptosis on transformed fibroblasts in vitro.

Fibrosarcoma is one of the fatal cancer types and there is still not satisfactory success in its treatment despite new drugs. Therefore, the search for a new compound has been going on. It is currently known that some palladium-based anti-cancer compounds seem to have powerful apoptosis-inducing effects in cancer cells. For this purpose, a palladium(II)-saccharinate complex containing terpyridine which was synthesized by our research group was investigated in terms of its anti-tumor effects against mouse embryonic fibroblast NIH/3T3 (normal cell line) and rat embryonic fibroblast 5RP7 (H-ras transformed cell line) in vitro. The MTT and ATP viability assays were used to determine anti-growth/cytotoxic effects. Cytotoxic activity was confirmed by real time cytotoxicity analysis system. Flow cytometry analysis was further used to determine the mode of cell death (apoptosis/necrosis). Apoptosis was confirmed by triple-staining the cells with Hoechst 33342/PI/Calcein-AM triple and evaluated with fluorescence microscopy. It was found that the compound showed significant anti-growth activity by inducing apoptosis in a dose dependent manner. In conclusion, taking into account the cytotoxic activity of the compound at even relatively lower doses, in vivo experiments to elucidate its potential use for the treatment of fibrosarcoma are warranted.

Serum levels of osteoprotegerin in the spectrum of nonalcoholic fatty liver disease

Abstract Objective. Osteoprotegerin (OPG) is a member of the tumor necrosis factor superfamily with pleiotropic effects on inflammation, endocrine function and the immune system. Reduced OPG levels are related to insulin resistance. We tested the hypothesis that serum levels of OPG may be associated with nonalcoholic fatty liver disease (NAFLD). Material and methods. Four groups of patients were enrolled in the present study: subjects with definite nonalcoholic steatohepatitis (NASH, n = 56), borderline NASH (n = 26), simple fatty liver (n = 17) and healthy controls without evidence of liver disease (n = 58). Serum levels of OPG were measured by ELISA. Results. Concentrations of OPG were significantly lower in patients with definite NASH (median: 45 pg/mL, p < 0.001) and borderline NASH (57 pg/mL, p < 0.001) than in controls (92 pg/mL). The area under the ROC curve for distinguishing between steatohepatitis (definite NASH plus borderline NASH) and healthy controls using OPG was 0.82. The use of a cut-off level < 74 pg/mL for serum OPG levels yielded sensitivity and specificity values of 75.6% and 75.9%, respectively. Conclusions. Serum osteoprotegerin concentrations are reduced in patients with the more severe forms of NAFLD and may serve as a noninvasive biomarker to identify patients with NASH.

Comparative effects of pioglitazone and rosiglitazone on plasma levels of soluble receptor for advanced glycation end products in type 2 diabetes mellitus patients

Low levels of soluble receptor for advanced glycation end products (sRAGE) have been associated with the occurrence of vascular complications in patients with type 2 diabetes mellitus. Preliminary evidence has suggested that thiazolidinediones have the ability to modulate circulating levels of this molecule in the hyperglycemic milieu. The aim of this pilot study was to assess the differential effect of 2 different thiazolidinediones-pioglitazone and rosiglitazone-on plasma levels of sRAGE in type 2 diabetes mellitus patients. Sixty type 2 diabetes mellitus subjects were randomly assigned to receive pioglitazone (30 mg/d, n = 19), rosiglitazone (4 mg/d, n = 20), or placebo (medical nutrition therapy, n = 21) for 12 weeks. Changes in plasma glucose, glycosylated hemoglobin, insulin resistance (homeostasis model assessment), total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and sRAGE were evaluated at baseline and after 12 weeks. At 12 weeks, the pioglitazone (P < .001) group had a significant increase from baseline in sRAGE values that was not seen in the medical nutrition therapy and rosiglitazone groups. We conclude that, in type 2 diabetes mellitus patients, pioglitazone-but not rosiglitazone-significantly raised sRAGE, which may contribute to its antiatherogenic effects.

Can safe and long-term exposure to extremely low frequency (50 Hz) magnetic fields affect apoptosis, reproduction, and oxidative stress?

Abstract Purpose: To determine whether 50 Hz extremely low frequency-magnetic fields (ELF-MF) affects apoptotic processes, oxidative damage, and reproductive characteristics such as sperm count and morphology in rat testes. Materials and methods: Thirty male Sprague-Dawley rats were used in the present study, which were divided into three groups (sham group, n = 10, and two experimental groups, n = 10 for each group). Rats in the experimental group were exposed to 100 and 500 μT ELF-MF (2 h/day, 7 days/week, for 10 months) corresponding to exposure levels that are considered safe for humans. The same experimental procedures were applied to the sham group, but the ELF generator was turned off. Tissues from the testes were immunohistochemically stained for active (cleaved) caspase-3 in order to measure the apoptotic index by a semi-quantitative scoring system. The levels of catalase (CAT), malondialdehyde (MDA), myeloperoxidase (MPO), total antioxidative capacity (TAC), total oxidant status (TOS), and oxidative stress index (OSI) were also measured. Additionally, epididymal sperm count and sperm morphology was evaluated. Results: There were no significant differences in the reproductive and oxidative stress parameters between the sham group and the exposed groups (p > 0.05). While no difference was observed between the final apoptosis score of the sham and the 100 μT ELF-MF group (p > 0.05), the final apoptosis score was higher in the 500 μT ELF-MF exposure group than in the sham group (p < 0.05). Conclusion: Long-term exposure to 100 μT and 500 μT ELF-MF did not affect oxidative or antioxidative processes, lipid peroxidation, or reproductive components such as sperm count and morphology in testes tissue of rats. However, long-term exposure to 500 μT ELF-MF did affect active-caspase-3 activity, which is a well-known apoptotic indicator.

Chemotherapy increases caspase-cleaved cytokeratin 18 in the serum of breast cancer patients

Chemotherapy increases caspase-cleaved cytokeratin 18 in the serum of breast cancer patients Background. Apoptosis is thought to be induced by chemotherapy in cancer patients. Therefore, the measurement of its amplitude may be a useful tool to predict the effectiveness of cancer treatment sooner than conventional methods do. Patients and methods. In the study presented, apoptosis was assessed with an ELISA-based assay in which caspase-cleaved cytokeratin 18 (M30-antigen), a novel specific biomarker of apoptosis, is measured. Thirty seven patients with malignant (nonmetastatic and metastatic) breast cancer, 35 patients with benign breast disease, and 34 healthy subjects were studied. Cancer patients received neoadjuvant chemotherapy consisting of either fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin plus docetaxel (ED). Apoptosis was detected before chemotherapy, 24 and 48 h after chemotherapy in the malignant group. Results. It was found that the baseline apoptosis level in either malignant but nonmetastatic group or benign group was not statistically different from that in the control group (p>0.05). However, it was statistically significantly higher in the metastatic group than that in the control group (p<0.05). Following the drug application, M30-antigen levels significantly increased at 24 h (p<0.05). The baseline M30-antigen levels increased about 3-times in patients showing tumor regression. Conclusions. M30-antigen level is increased after chemotherapy and its measurement may help clinicians to predict the effectiveness of chemotherapy sooner in breast cancer cases although confirmative larger trials are needed.

Association between serum neopterin, obesity and daytime sleepiness in patients with obstructive sleep apnea

OBJECTIVE Obesity and obstructive sleep apnea (OSA) and systemic inflammation may interact through biochemical pathways. Neopterin (NP) is a monocyte/macrophage activation marker produced by macrophages in response to interferon-gamma secreted by activated T-lymphocytes. This study examines the association between NP, obesity and OSA. PATIENTS AND METHODS The study included 22 newly diagnosed OSA (+) patients and 18 OSA (-) patients. Subjects with history of coronary artery disease, transplant patients, history of alcohol and drug abuse, history of HIV and any other significant medical illnesses such as active infections, autoimmune disease, malignancy, liver disease, pulmonary disease (COPD, asthma,...), neuromuscular disease, patients on immunomodulating therapy or HMG-CoA reductase inhibitors were excluded. RESULTS There were no significant differences in age, body mass index (BMI), and smoking habits of the OSA (+) patients and OSA (-) patients. Serum NP levels did not show any significant difference between the OSA (+) patients and OSA (-) patients, however, NP levels were positively correlated with BMI (r=0.320, p=0.044). There was no significant correlation between NP and any of the polysomnographic parameters. The result of stepwise regression analyses (r(2)=0.320, p<0.001) showed that high serum NP levels (p=0.004) and apnea-hypopnea index (AHI) were a risk factor for elevated Epworth sleepiness score, independent of BMI. CONCLUSION We suggest that serum NP levels correlate with BMI. There was a significant relationship between serum NP levels and excessive daytime sleepiness in OSA patients.

Anti-growth effect of a novel trans-dichloridobis[2-(2-hydroxyethyl)pyridine]platinum (II) complex via induction of apoptosis on breast cancer cell lines

Breast cancer still continues to be the leading cause of cancer-related mortality in women worldwide. Although advances have been made in the treatment of this disease during the past decade, new approaches and novel compounds are urgently needed. The aim of this study was to evaluate the cytotoxic activity of trans-[PtCl2(2-hepy)2] [2-hepy=2-(2-hydroxyethyl) pyridine] on breast cancer cell lines, MCF-7 and MDA-MB-231. The platinum (II) complex was synthesized and characterized by our laboratory working group. Anti-growth effect was assayed by the MTT and ATP viability assays and also monitored real-time using xCELLigence system. The mode of cell death was evaluated by using the fluorescence microscopy (Hoechst 33342+Calcein-AM+Propidium iodide staining), Western blotting (cleaved PARP and caspase 3, total caspase 8), flow cytometry (quantitative analysis of live, early/late apoptotic, dead cells and caspase 3/7 activity) and the RT-PCR (the genes analyzed were BCL-2L10, BIK, BAX, BCL-2, FASLG, HRK, TNFRSF10B, and TNFRSF10A). The platinum (II) complex had anti-growth effect in a dose dependent manner in vitro. Cells were killed by apoptosis as evidenced by the pyknotic nuclei, cleavage of poly-(ADP-ribose) polymerase (PARP) and induction of active caspase-3. These results suggest that the complex might represent a potentially active novel drug for the breast cancer treatment and warrants further studies due to its promising cytotoxic activity.

Combination of fenretinide and indole-3-carbinol results in synergistic cytotoxic activity inducing apoptosis against human breast cancer cells in vitro.

The outcome in patients with breast cancer is not satisfactory to date, although new chemotherapy regimens have been introduced in clinics. Therefore, novel approaches are required for better management of patients with breast cancer. In this study, we tested the cytotoxic activity of a new combination of fenretinide, a synthetic retinoid, with indole-3-carbinol, a natural product present in vegetables such as broccoli and cabbage, against MCF-7 (estrogen receptor-positive) and MDA-MB-231 (estrogen receptor-negative) cell lines. It has been found that the combination resulted in more powerful cytotoxic activity, by induction of apoptosis, compared with that when they were used singly. In conclusion, this novel combination warrants in-vivo experiments to elucidate its possible use in the treatment of breast cancer.