The role of hepcidin, GDF15, and mitoferrin-1 in iron metabolism of polycythemia vera and essential thrombocytosis patients

Background/aim: GDF15, hepcidin and mitoferrin-1 (mfrn-1) are proteins involved in systemic iron regulation. There are no studies in the literature demonstrating the serum mfrn-1 levels in polycythemia vera (PV) and essential thrombocythemia (ET) patients. The aim of this study was to investigate GDF15, hepcidin and mfrn-1 levels in PV and ET patients. Materials and methods: Ten PV, 17 ET patients, and 27 healthy controls (HCs) were enrolled. GDF15, hepcidin and mfrn-1 values were measured with enzyme-linked immunosorbent assay (ELISA). Results: GDF15 levels were higher in the myeloproliferative neoplasm (MPN) group (P = 0.002). Hepcidin levels were not different between MPN patients and HCs. The mfrn-1 levels were lower in MPN patients (P = 0.039). Hepcidin, GDF15, and mfrn-1 levels were not different between PV and ET patients. mfrn-1 levels were lower in ET patients than HCs (P = 0.038). Conclusion: Increased erythropoiesis in MPNs may lead to high GDF15 levels in these patients. However, hepcidin was not suppressed despite the increased GDF15 levels and erythropoiesis in these patients. Decrease in mfrn-1 in MPNs can be the result of its increased turnover due to increased myelopoiesis. It can be hypothesized that similar hepcidin levels in patients and controls and low mfrn-1 levels in patients may be a defense mechanism against erythroid activity and thromboembolic complications.

Evaluation of the efficacy of Hypericum perforatum (St. John's wort) oil in the prevention of stricture due to esophageal corrosive burns.

BACKGROUND/PURPOSE: The inflammatory response that follows the caustic burns results in fibrosis on the esophageal wall leading to esophageal stricture, dysphagia, and malnutrition. The controversy over the use of corticosteroids warrants alternative therapeutic interventions. We investigated the effect of extracts from St. John's wort (SJW) with known wound-healing activity on stricture formation in rat esophageal injury models. METHODS: Five experimental groups were involved: sham group with no injury, control group with injury without treatment, and three different treatment groups (methylprednisolone, SJW extract, and combination of the two). Histopathological examination of esophageal damage and collagen accumulation, stenosis index, and tissue hydroxyproline levels were used to assess stricture and the effect of treatments. RESULTS: There was a significant weight loss in all groups except for those without injury and those treated with SJW extract, the latter gained weight albeit not significant. Stenosis index was increased in all groups compared to sham but not significantly in those treated with SJW extract. Histopathological and biochemical analyses produced mixed results. CONCLUSIONS: Some of the experimental indicators such as weight gain and stenosis index suggested the treatment of esophageal injury models using extracts of St. John's wort effective while other histopathological indicators show no significant benefit.

Beneficial effects of Oltipraz, nuclear factor - erythroid - 2 - related factor 2 (Nrf2), on renal damage in unilateral ureteral obstruction rat model.

INTRODUCTION: We investigated whether Oltipraz (OPZ) attenuated renal fibrosis in a unilateral ureteral obstruction (UUO) rat model. MATERIALS AND METHODS: We randomly divided 32 rats into four groups, each consisting of eight animals as follows: Rats in group 1 underwent a sham operation and received no treatment. Rats in group 2 underwent a sham operation and received OPZ. Rats in group 3 underwent unilateral ureteral ligation and received no treatment. Group 4 rats were subjected to unilateral ureteral ligation plus OPZ administration. Transforming growth factor beta-1 (TGF-ß1), E-cadherin, nitric oxide (NO) and hydroxyproline levels were measured. Histopathological and immunohistochemical examinations were carried out. RESULTS: TGF-ß1, NO and E-cadherin levels in the UUO group were significantly higher than the sham group and these values were significantly different in treated groups compared to the UUO group. In rats treated with UUO + OPZ, despite the presence of mild tubular degeneration and less severe tubular necrosis, glomeruli maintained a better morphology when compared to the UUO group. Expressions of α-SMA in immunohistochemistry showed that the staining positivity decreased in the tubules of the OPZ-treated group. CONCLUSIONS: While the precise mechanism of action remains unknown, our results demonstrated that OPZ exerted a protective role in the UUO-mediated renal fibrosis rat model highlighting a promising therapeutic potency of Nrf2-activators for alleviating the detrimental effects of unilateral obstruction in kidneys.

Effects of Tadalafil 5 mg Dosed Once Daily in Men with Premature Ejaculation.

PURPOSE: In this study, we evaluated the effect of 5 mg tadalafil once daily in men with premature ejaculation (PE). METHODS: Thirty married men with lifelong PE and 30 healthy men as control group were included in this study. All the patients received 5 mg tadalafil once a day for a month. The international index of erectile function questionnaire and intravaginal ejaculatory latency times (IELTs) and PE profile were recorded before and after treatment. Plasma samples were collected before and after treatment. RESULTS: The mean baseline IELTs was 40.8 ± 8.1 s in the PE group and 196.5 ± 26.2 s in the control group. After treatment in the PE group, the mean IELTs values showed a statistically significant improvement from the baseline values. At the end of 4 weeks, in the PE group, the mean IELT values showed a statistically significant improvement from the baseline values. Baseline serum nitric oxide (NO) levels were 27.3 ± 1.7 in the PE group and in the 31.1 ± 1.4 healthy control groups. After treatment, NO levels were increased from baseline. CONCLUSION: We consider that 5 mg tadalafil once daily is safety and effective for the treatment of PE.

Effects of chronic kidney disease and type of dialysis on serum levels of adiponectin, TNF-alpha and high sensitive C-reactive protein.

BACKGROUND: In uremic patients, depending on their type, the T-cells produce a range of pro-inflammatory and anti-inflammatory cytokines. The aim of this study was to compare the effects of chronic kidney disease (CKD) and two different therapy methods of dialysis [hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD)] on adiponectin, TNF-alpha, and hs-CRP levels in human serum. METHODS: We measured the serum levels of hs-CRP, adiponectin, and TNF-alpha in 37 patients with CKD on conservative treatment, 34 patients maintained on CAPD, 35 HD patients, and 25 healthy volunteers. The statistical analysis of the obtained results was performed by commercial statistics PC software. RESULTS: The mean TNF-alpha levels were found to be significantly higher in patients in the predialysis, CAPD, and the HD groups, than in the control group (17.24 +/- 9.22, 31.57 +/- 10.56, 24.34 +/- 5.32, 7.64 +/- 4.12 pg/mL, respectively, p < 0.001). The mean TNF-alpha levels in the predialysis group were significantly lower than in both the CAPD and the HD group (p < 0.001). The mean TNF-alpha levels in the CAPD group were significantly higher than in the HD group (p = 0.001). The mean adiponectin levels in the control group were significantly lower than in the predialysis, CAPD, and HD groups (2.54 +/- 2.30, 4.10 +/- 3.12, 7.69 +/- 8.35, 5.97 +/- 6.20 ng/mL, respectively, p < 0.05). Furthermore, the mean adiponectin levels in the predialysis groups were significantly lower than in the CAPD group (p < 0.05). The mean hs-CRP levels were found to be significantly higher in patients in the predialysis, CAPD, and HD groups than in the control group (0.65 +/- 0.57, 0.82 +/- 0.71, 1.14 +/- 1.45, 0.30 +/- 0.19 mg/dL, respectively, p < 0.05). CONCLUSIONS: According to the results of this study, the levels of adiponectin, hs-CRP, and TNF-alpha were increased for all patients with chronic renal failure (CRF). Along with this, the highest level of increase in TNF-alpha levels were observed in patients with CAPD.

Antioxidant Effect of Thioredoxin and Vitamin D3 in Peritoneal Dialysis Patients.

Background: Among the chronic diseases, chronic kidney failure is one of diseases that have the most difficulty in coping with oxidative stress due to the deterioration of the antioxidant system balance in the body. Beyond being a vitamin, 1α,25-dihydroxycholecalciferol (vitamin D3) is a molecule that positively or negatively affects many enzymes which are in protein structures. Thioredoxin (TRX), which has an important role in the antioxidant system, is one of these proteins. By conducting this study, we wanted to emphasize the role of vitamin D3 in reducing the oxidative stress load on patients undergoing peritoneal dialysis (PD) via serum TRX level measurement. Methods: In this study, we evaluated the medical treatments of 69 PD patients who were followed up routinely. The patients were divided into 2 groups according to whether they used vitamin D3 or not. 49 of our patients were using vitamin D3. While requesting routine laboratory tests, we reserved a separate serum sample to measure serum TRX levels by double-antibody sandwich enzyme-linked immunosorbent assay for all patients. Results: Only one parameter has a significant statistical relationship with serum TRX level and the treatment protocol. The serum TRX level was significantly higher (211,62 U/l ± 314,46) in the group receiving vitamin D3 compared to the group which is not using Vitamin D3 (101,63 U/l ± 215,03) (p < 0,006). Conclusion: This study highlights the importance of appropriate dose of vitamin D3 replacement especially in PD patients who are under intense oxidative stress compared to healthy individuals.

Protective effects of rectal ozone administration on colon anastomoses following radiotherapy.

BACKGROUND: Anastomotic leakage (AL) following rectal surgery is associated with increased mortality and morbidity. Neoadjuvant radiotherapy disrupts the wound healing process in rectal surgery. OBJECTIVES: To evaluate the effects of intra-rectal ozone application on rectal anastomoses after radiotherapy. MATERIAL AND METHODS: This study was performed on animals. Thirty-two male Wistar rats were randomly divided into 4 groups: control group, ozone group, radiotherapy group, and radiotherapy/ozone group. Ozone was administered intrarectally in the ozone group and water was administered intrarectally in rthe control group for 5 days. The radiotherapy group received 20 Gy of pelvic radiotherapy. The radiotherapy/ozone group received 20 Gy of pelvic radiotherapy after the administration of ozone. Afterward, colon resection followed by an anastomosis were performed under general anesthesia in all groups. Anastomotic segments were resected to evaluate tissue hydroxyproline (HYP) and myeloperoxidase (MPO) levels, perform a histological evaluation, and measure bursting pressure. RESULTS: There were no statistically significant differences between groups regarding tissue MPO levels (p = 0.55). Tissue HYP levels were significantly decreased in the radiotherapy group (p = 0.04). Bursting pressure was found to be significantly lower in the radiotherapy group (p < 0.05). No significant differences were found between adhesion scores in the control and ozone groups. Exudate formation was significantly lower in the radiotherapy group (p < 0.05). The lowest macrophage scores were found in the radiotherapy group (p < 0.05). Fibroblast scores were the highest in the control group and the lowest in the radiotherapy group (p < 0.05). CONCLUSIONS: Intra-rectal ozone application significantly improved the anastomotic healing process after radiation exposure.

Effects of melatonin on ovarian reserve in cigarette smoking: an experimental study.

INTRODUCTION: The aim of the study was to investigate whether melatonin has a protective effect against diminished ovarian reserve induced by smoking. MATERIAL AND METHODS: Seventy-two female Wistar-Albino rats were divided into 6 groups: group I (room air), group II (chronic cigarette smoking), group III (room air + 10 mg/kg subcutaneous melatonin), group IV (room air + 20 mg/kg subcutaneous melatonin), group V (chronic cigarette smoking + 10 mg/kg subcutaneous melatonin), group VI (chronic cigarette smoking + 20 mg/kg subcutaneous melatonin). For 45 days, rats were exposed to cigarette smoke through a smoking machine, then subcutaneous melatonin was administered. Apoptotic index, immunohistochemical scoring, ovarian follicle counting, ovarian tissue and serum malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) analyses were carried out. RESULTS: All of the primordial, primary, secondary and mature follicle numbers were found to be significantly lowered in study groups. Increased HSCORE with anti-caspase-3 staining and a high follicular apoptotic index were demonstrated in the smoking group. Serum and ovarian tissue levels of MDA were found to be elevated with smoke exposure whereas lower MDA levels were determined in melatonin treated groups. Serum and tissue levels of SOD, GPx and CAT were shown to be reduced in the smoking group in comparison with melatonin treated and control groups. 20 mg/kg melatonin administration in the smoking group revealed significantly decreased HSCOREs and apoptotic indices. CONCLUSIONS: Cigarette smoking has been definitely shown to be associated with impaired ovarian reserve with respect to significantly diminished numbers of primordial, primary, secondary and mature follicles. Dose-related treatment of melatonin in smokers may provide an evidently reduced apoptotic index and improved antioxidant activity in tissue.

Serum fetuin--a concentrations are inversely related to cytokine concentrations in patients with chronic renal failure.

BACKGROUND/AIMS: A close relationship exists between inflammation and vascular calcification. Although fetuin-A is known to be an inhibitor of calcification, studies correlating levels of this glycoprotein to markers of inflammation are limited. To understand these relationships, we investigated the relationship between serum fetuin-A and proinflammatory cytokine levels in patients with chronic renal failure (CRF). METHODS: Thirty-two patients on haemodialysis (HD), 32 conservatively managed chronic kidney disease (CKD) patients and a control group of 25 subjects with normal renal function were enrolled in this study. Serum fetuin-A, IL-1beta, IL-6 and TNF-alpha levels were measured by ELISA. Correlations between serum fetuin-A and IL-1beta, IL-6 and TNF-alpha concentrations were investigated by the Spearman correlation test. RESULTS: In 64 CRF patients (on HD and with CKD), serum fetuin-A was significantly and inversely related to IL-1beta (P<0.001), IL-6 (P=0.025) and TNF-alpha levels (P=0.007), respectively. The serum fetuin-A levels of the control subjects were not significantly correlated to levels of the inflammatory markers IL-1beta, IL-6 and TNF-alpha (P=0.551, 0.985 and 0.984, respectively). CONCLUSION: The negative correlation between serum fetuin-A and cytokine concentrations in CRF patients supports the hypothesis of inflammation-dependent down-regulation of fetuin-A expression.

Depressive symptoms and proinflammatory cytokine levels in chronic renal failure patients.

BACKGROUND/AIMS: Cytokine secretion is known to play an important role in the pathophysiology of depression, and levels of proinflammatory cytokines are increased in chronic renal failure (CRF) patients. The objective of this study was to examine the correlation between levels of proinflammatory cytokines in CRF patients and degree of depression. METHODS: 31 patients on hemodialysis, 31 patients on continuous ambulatory peritoneal dialysis, and 31 conservatively managed chronic kidney disease (CKD) patients were enrolled in this study. Depressive symptoms were measured with the Beck Depression Inventory (BDI), and 'elevated symptoms of depression' were defined as a BDI score > or =17. IL-6 and TNFalpha cytokine levels were measured by ELISA. RESULTS: 'Elevated symptoms of depression' occurred in 37 of 93 patients (40%). IL-6 and TNFalpha levels were not significantly different among CRF patients with and without elevated depressive symptoms (p = 0.937 and p = 0.414, respectively). When analyzed by treatment subgroup, proinflammatory cytokine levels were not significantly different in patients with and without elevated symptoms of depression. CONCLUSION: In patients with CRF, elevated symptoms of depression were not associated with increased cytokine levels.

Adipocytokines leptin and adiponectin, and measures of malnutrition-inflammation in chronic renal failure: is there a relationship?

BACKGROUND: Serum levels of adipocytokines such as leptin and adiponectin are significantly elevated in patients with chronic renal failure (CRF). The effect of such adipocytokines on malnutrition in the CRF population has been of substantial interest. We sought to determine the relationship between plasma leptin and adiponectin levels and malnutrition-inflammation status in end-stage renal disease patients. METHODS: Thirty patients (15 women and 15 men; mean [+/-SD] age, 50 +/- 14 years) on hemodialysis, and 30 patients (12 women and 18 men; mean [+/-SD] age, 47 +/- 16) on continuous ambulatory peritoneal dialysis, were enrolled in this study. Adipocytokine levels were measured by enzyme-linked immunosorbent assay. Inflammatory markers, such as high-sensitivity serum C-reactive protein (hs-CRP), ferritin, and a nutritional inflammatory scoring system known as the malnutrition-inflammation score (MIS), were also measured in all patients. RESULTS: Serum leptin had negative correlations with ferritin (r = -0.33, P = .016) and MIS (r = -0.39, P = .003). Adiponectin had a weak positive correlation with MIS (r = 0.26, P = .050), indicating that an increased level of serum adiponectin was associated with a worse nutritional status. Levels of hs-CRP, serum albumin, cholesterol, and triglycerides did not correlate with nutritional status. CONCLUSIONS: Serum leptin concentration seems to be a marker of good nutritional status, rather than an appetite-suppressing uremic toxin, in patients with CRF. However, the positive correlation between serum adiponectin and worse nutritional-inflammatory status suggests that elevated adiponectin levels may contribute to the pathogenesis of malnutrition in such patients.

Effect of resveratrol and metformin on ovarian reserve and ultrastructure in PCOS: an experimental study.

BACKGROUND: PCOS is a reproductive hormonal abnormality and a metabolic disorder. It is frequently associated with insulin resistance, hyperandrogenism, chronic inflammation, and oxidative stress. We aim to investigate the potential therapeutic effects of combined therapy of resveratrol and metformin on polycystic ovaries via SIRT1 and AMPK activation. METHODS: Wistar albino rats were divided into control and experimental (PCOS) groups. DHEA-induced PCOS rats were given resveratrol (20 mg/kg/day), metformin (300 mg/kg/day) and combined therapy. At the end of the experiment, the body and ovarian weight of rats were measured and blood samples were analyzed for FSH, LH, testosterone, AMH, TNF-α and MDA levels. Histopathological evaluation of ovaries were carried out by light and electron microscopy. SIRT1 and AMPK immunreactivity and TUNEL assay were scored. Data were statistically analyzed by SPSS programme. RESULTS: Metformin and combined treatment groups reduced the body and ovary weights compared to the PCOS group. Serum testosterone levels were significantly higher in the PCOS group than in the control group and this was reduced when PCOS was treated with all but especially resveratrol. All the treatment groups decreased LH, LH/FSH, TNF-α and tissue AMH levels which were induced in the PCOS group, whereas metformin was unable to improve the increased MDA and plasma AMH levels. Treatment with resveratrol and/or metformin ameliorated the elevated number of secondary and atretic follicles and the decreased number of Graafian follicles in the PCOS group, which indicates the effect of the treatments on the maintenance of folliculogenesis. Light and electron microscopic findings supported the analysis of follicular count. Increased number of TUNEL (+) granulosa cells in the PCOS group were reduced significantly in the treatment groups. Resveratrol and metformin increased SIRT1 and AMPK immunreactivity, respectively, compared to the PCOS group. CONCLUSIONS: The results suggest that combined therapy of metformin and resveratrol may improve the weight gain, hormone profile and ovarian follicular cell architecture by inducing antioxidant and antiinflammatory systems via SIRT1 and AMPK activation in PCOS.

The Relationship between Adiponectin and Breast Cancer.

OBJECTIVE: Breast cancer is the most common type of cancer in women worldwide. It is indicated that increased body mass index elevates the risk of developing breast cancer, worsens prognosis, and decreases survival. Several polymorphisms of adiponectin have been shown to affect serum levels of adiponectin and their association with breast cancer. The aim of this study was to investigate the relationship between the adiponectin 45T/G and 276 G/T gene polymorphism and breast cancer in the East Marmara region. MATERIALS AND METHODS: A case-control study was performed in 97 patients with breast cancer and 101 controls in East Marmara in order to evaluate the prevalence of adiponectin gene polymorphism at positions 45 and 276. Patients with familial breast cancer and those who had received chemotherapy or radiotherapy were excluded from the study. Adiponectin gene polymorphisms were investigated using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP). RESULTS: Adiponectin 45T/G gene genotype frequencies of TT, TG, and GG were 61.9%, 37.1%, and 1% in patients with breast cancer, and 67.3%, 30.7%, and 2% in the control group, respectively. Adiponectin 276G/T gene genotype frequencies of GG, GT, and TT were 45.4%, 45.4%, and 9.3% in patients with breast cancer and 55.4%, 39.6%, and 5.0% in the control group, respectively. CONCLUSION: Our study showed that adiponectin 45T/G and 276 G/T gene polymorphism is not associated with breast cancer risk in patients from the East Marmara region.

Beneficial effects of Oltipraz, nuclear factor - erythroid - 2 - related factor 2 (Nrf2), on renal damage in unilateral ureteral obstruction rat model

ABSTRACT Introduction: We investigated whether Oltipraz (OPZ) attenuated renal fibrosis in a unilateral ureteral obstruction (UUO) rat model. Materials and Methods: We randomly divided 32 rats into four groups, each consisting of eight animals as follows: Rats in group 1 underwent a sham operation and received no treatment. Rats in group 2 underwent a sham operation and received OPZ. Rats in group 3 underwent unilateral ureteral ligation and received no treatment. Group 4 rats were subjected to unilateral ureteral ligation plus OPZ administration. Transforming growth factor beta-1 (TGF-β1), E-cadherin, nitric oxide (NO) and hydroxyproline levels were measured. Histopathological and immunohistochemical examinations were carried out. Results: TGF-β1, NO and E-cadherin levels in the UUO group were significantly higher than the sham group and these values were significantly different in treated groups compared to the UUO group. In rats treated with UUO + OPZ, despite the presence of mild tubular degeneration and less severe tubular necrosis, glomeruli maintained a better morphology when compared to the UUO group. Expressions of α-SMA in immunohistochemistry showed that the staining positivity decreased in the tubules of the OPZ-treated group. Conclusions: While the precise mechanism of action remains unknown, our results demonstrated that OPZ exerted a protective role in the UUO-mediated renal fibrosis rat model highlighting a promising therapeutic potency of Nrf2-activators for alleviating the detrimental effects of unilateral obstruction in kidneys.

Effects of vitamins E, A and D on MDA, GSH, NO levels and SOD activities in 5/6 nephrectomized rats.

BACKGROUND: Excessive generation of reactive oxygen species (ROS) contributes to the process of progressive renal injury in a variety of clinical and experimental renal diseases. The present study was designed to test the hypothesis that treatment with vitamins decreases renal injury in chronic renal failure (CRF). METHODS: Forty male Sprague-Dawley rats were divided into 5 groups: group 1, control; group 2, 5/6 nephrectomy (CRF); other groups 5/6 nephrectomy and injected vitamins (E, A, D). After 8 weeks, urea, creatinine and renal tissue malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO) levels and superoxide dismutase (SOD) activities were determined. RESULTS: Renal tissue MDA levels were significantly lower in the control and Vit E groups compared to that of the CRF, Vit A and Vit D groups. GSH levels were significantly higher in the control group compared to that of other groups. However, GSH levels were significantly lower in the control group than those in the other groups. SOD activities of the control group were significantly higher than those in the other groups. SOD activities were significantly decreased in the Vit E group compared to the Vit A and Vit D groups. Tissue NO levels of control group were significantly increased compared to the other groups. CONCLUSION: According to this study, Vit E may at least in part prevent tissue injury by acting as a free radical scavenger.