Person: YEGEN, BERRAK
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YEGEN
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BERRAK
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Publication Metadata only Melatonin protects against oxidative organ injury in a rat model of sepsis(SPRINGER, 2005) YEGEN, BERRAK; Sener, G; Toklu, H; Kapucu, C; Ercan, F; Erkanli, G; Kacmaz, A; Tilki, M; Yegen, BCPurpose. Based on the potent antioxidant effects of melatonin, we investigated the putative protective role of melatonin against sepsis-induced oxidative organ damage in rats. Methods. Sepsis was induced by cecal ligation and puncture (CLP) in Wistar albino rats. Animals subjected to CLP and sham-operated control rats were given saline or melatonin 10 mg/kg intraperitoneally 30 min before and 6 h after the operation. The rats were killed 16 h after the operation and the biochemical changes were investigated in the liver, kidney, heart, lung, diaphragm, and brain tissues by examining malondialdehyde (MDA) and glutathione (GSH) levels, and myeloperoxidase (MPO) activity. We also examined the tissues microscopically. Results. Sepsis resulted in a significant decrease in GSH levels and a significant increase in MDA levels and MPO activity (P < 0.05-P < 0.001) showing oxidative damage, which was confirmed by histological examination. Melatonin clearly reversed these oxidant responses and the microscopic damage, demonstrating its protective effects against sepsis-induced oxidative organ injury. Conclusion. The increase in MDA levels and MPO activity and the concomitant decrease in GSH levels demonstrate the role of oxidative mechanisms in sepsis-induced tissue damage. Melatonin, by its free radical scavenging and antioxidant properties, ameliorated oxidative organ injury. Thus, supplementing antiseptic shock treatment with melatonin may be beneficial in the clinical setting.Publication Metadata only L-Carnitine ameliorates methotrexate-induced oxidative organ injury and inhibits leukocyte death(SPRINGER, 2006) YEGEN, BERRAK; Sener, G; Eksioglu-Demiralp, E; Cetiner, M; Ercan, F; Sirvanci, S; Gedik, N; Yegen, BCMethotrexate (MTX), a folic acid antagonist widely used for the treatment of a variety of tumors and inflammatory diseases, affects normal tissues that have a high rate of proliferation, including the hematopoietic cells of the bone marrow and the gastrointestinal mucosal cells. To elucidate the role of free radicals and leukocytes in MTX-induced oxidative organ damage and the putative protective effect of L-carnitine (L-Car), Wistar albino rats were administered a single dose of MTX (20 mg/kg) followed by either saline or L-Car (500 mg/kg) for 5 days. After decapitation of the rats, trunk blood was obtained, and the ileum, liver, and kidney were removed for histological examination and for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity, and collagen content. Our results showed that MTX administration increased the MDA and MPO activities and collagen content and decreased GSH levels in all tissues, while these alterations were reversed in L-Car-treated group. The elevated serum TNF-alpha level observed following MTX treatment was depressed with L-Car. The oxidative burst of neutrophils stimulated by Annexin V was reduced in the saline-treated MTX group, while L-Car abolished this inhibition. Similarly, flow cytometric measurements revealed that leukocyte apoptosis was increased in MTX-treated animals, while L-Car reversed these effects. Severe degeneration of the intestinal mucosa, liver parenchyma, and glomerular and tubular epithelium observed in the saline-treated MTX group was improved by L-Car treatment. These results suggest that L-Car, possibly via its free radical scavenging and antioxidant properties, ameliorates MTX-induced oxidative organ injury and inhibits leukocyte apoptosis. Thus, supplementation with L-Carnitine as an adjuvant therapy may be promising in alleviating the systemic side-effects of chemotherapeutics.Publication Metadata only Amelioration of sepsis-induced hepatic and ileal injury in rats by the leukotriene receptor blocker montelukast(CHURCHILL LIVINGSTONE, 2005) YEGEN, BERRAK; Sener, G; Sehirli, O; Cetinel, S; Ercan, F; Yuksel, M; Gedik, N; Yegen, BCBackground. Sepsis is a generalized inflammatory response, which involves organ systems remote from the locus of the initial infectious insult, involves the release of cytokines and the subsequent formation of reactive oxygen and nitrogen species. Objective: The aim of this study was to investigate the possible protective effect of montelukast, a leukotriene receptor blocker, against oxidative damage in the liver and ileum of septic rats. Methods: Sepsis was induced by cecal ligation and puncture method in female Wistar albino rats. Sepsis and sham operated (control) groups received either saline or montelukast (10 mg/kg, ip) immediately after the operation and at 12 h. Twenty-four hours after the surgery, rats were decapitated and malondialdehyde (MDA) content-an index of lipid peroxidation, glutathione (GSH) levels-a key antioxidant, myeloperoxidase (MPO) activity-an index of neutrophil infiltration, and collagen contents were determined in the liver and ileum. Formation of reactive oxygen species in liver and ileal tissue samples was monitored by using chemiluminescence (CL) technique with luminol and lucigenin probes. Both tissues were also analyzed histologically. Serum lactate dehydrogenase (LDH) and tumor necrosis factor-alpha (TNF-alpha) level were assessed in trunk blood. Results: Sepsis resulted in decreased GSH levels, and increased MDA levels, MPO activity, CL levels and collagen contents in both the liver and the ileum (P < 0.05 - P < 0.001) indicating the presence of the oxidative damage. Similarly, serum TNF-alpha and LDH were elevated in the sepsis group as compared to control group. On the other hand, montelukast treatment reversed all these biochemical indices, as well as histopathological alterations, which were induced by sepsis. Conclusion: Findings of the present study suggest that montelukast possesses an anti-inflammatory effect on sepsis-induced hepatic and intestinal damage and protects against oxidative injury by a neutrophil-dependent mechanism. (C) 2005 Elsevier Ltd. All rights reserved.Publication Metadata only 2-mercaptoethane sulfonate (MESNA) protects against burn-induced renal injury in rats(ELSEVIER SCI LTD, 2004) YEGEN, BERRAK; Sener, G; Sehirli, O; Erkanli, G; Cetinel, S; Gedik, N; Yegen, BAnimal models of thermal injury implicate oxygen radicals as causative agents in local wound response and distant organ injury following burn. In this study we investigated the putative protective effects of 2-mercaptoethane sulfonate (MESNA) against oxidative kidney damage in rats with thermal injury. Under ether anaesthesia, shaved dorsum of the rats was exposed to 90 degreesC bath for 10 s to induce burn injury. Rats were decapitated either 6 or 24 h after burn injury. MESNA was administered i.p. immediately after burn injury. MESNA injections were repeated once more 12 h after the first injection in the 24 h burn group. In the control group the same protocol was applied except that the dorsum was dipped in a 25 degreesC water bath for 10 s. Kidney tissues were taken for the determination of malondialdehyde (MDA) and glutathione (GSH) levels, protein oxidation (PO), myeloperoxidase (MPO) activity and collagen contents. Creatinine, urea concentrations (BUN) and lactate dehydrogenase (LDH) in blood were measured for the evaluation of renal functions and tissue damage, respectively. Tissues were also examined microscopically. Severe skin scald injury (30% of total body surface area) caused significant decrease in GSH level, significant increase in MDA level, protein oxidation (PO), MPO activity and collagen content of renal tissue. Serum creatinine was slightly increased at the early phase of thermal trauma but not changed in 24 h groups. On the other hand BUN and LDH were significantly elevated by thermal trauma in both 6 and 24 h of burn groups. Treatment of rats with MESNA significantly increased the GSH level and decreased the MDA level, PO, MPO activity, collagen contents, BUN and LDH. Since MESNA reversed the oxidant responses seen in burn injury, it seems likely that MESNA could protect against thermal trauma-induced renal damage. (C) 2004 Elsevier Ltd and ISBI. All rights reserved.Publication Metadata only Estrogen protects the liver and intestines against sepsis-induced injury in rats(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2005) YEGEN, BERRAK; Sener, G; Arbak, S; Kurtaran, P; Gedik, N; Yegen, BCBackground and aim. Sepsis is commonly associated with enhanced generation of reactive oxygen metabolites, leading to multiple organ dysfunctions. The aim of this study was to examine the putative protective role of estradiol against sepsis-induced oxidative organ damage. Materials and methods. Sepsis was induced by cecal ligation and puncture method in Wistar albino rats. Sham-operated (control) and sepsis groups received saline or estradiol propionate (10 mg/kg) intraperitoneally immediately after the operation and at 12 h. Twenty-four hours after the surgery, rats were decapitated and malondialdehyde, glutathione levels, and myeloperoxidase activity were determined in the liver and ileum, while oxidant-induced tissue fibrosis was determined by collagen contents. Tissues were also examined microscopically. Serum aspartate aminotransferase, alanine aminotransferase levels, and lactate dehydrogenase were measured for the evaluation of liver functions and tissue damage, respectively. Tumor necrosis factor-alpha was also assayed in serum samples. Results. In the saline-treated sepsis group, glutathione levels were decreased significantly, while the malondialdehyde levels, myeloperoxidase activity, and collagen content were increased in the tissues (P < 0.01 to P < 0.001), suggesting oxidative organ damage, which was also verified histologically. In the estradiol-treated sepsis group, all of these oxidant responses were reversed significantly (P < 0.05 to P < 0.01). Liver function tests and tumor necrosis factor-a levels, which were increased significantly (P < 0.001) following sepsis, were decreased (P < 0.05 to P < 0.001) with estradiol treatment. Conclusion. The results demonstrate the role of oxidative mechanisms in sepsis-induced tissue damage, and estradiol, by its antioxidant properties, ameliorates oxidative organ injury, implicating that treatment with estrogens might be applicable in clinical situations to ameliorate multiple organ damage induced by sepsis. (c) 2005 Elsevier Inc. All rights reserved.Publication Metadata only Oxytocin protects against sepsis-induced multiple organ damage: Role of neutrophils(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2005) YEGEN, BERRAK; Iseri, SO; Sener, G; Saglam, B; Gedik, N; Ercan, F; Yegen, BCBackground. Sepsis, commonly associated with enhanced generation of reactive oxygen metabolites, leads to multiple organ dysfunctions. The neurohypophyseal hormone oxytocin (OT), released during social contact, was recently shown to modulate the immune and inflammatory processes. We investigated the protective role of OT against sepsis-induced pelvic inflammation. Materials and methods. Under anesthesia, sepsis was induced in female Sprague-Dawley rats (200-250 g) by cecal ligation and perforation method. Sham-operated rats served as controls. Either saline or OT (1 mg(kg) was given subcutaneously immediately after and at the 16th hour, and rats were decapitated at the 24th hour of sepsis induction. Colon, uterus, and liver samples were obtained for the histopathological analysis of damage and for the measurement of myeloperoxidase (MPO) activity, indicating neutrophil infiltration, malondialdehyde (AIDA), indicating lipid peroxidation, and glutathione (GSH), a key antioxidant, levels. Results. Colonic, uterine and liver MDA levels in the sepsis group were significantly increased (P < 0.01-P < 0.001), while colonic and uterine GSH levels were decreased (P < 0.05-P < 0.01) when compared to the control group. OT treatment reversed the MDA and GSH levels back to the control levels, while hepatic GSH levels were not altered. MPO activity in the colon and liver was increased by sepsis (P < 0.05-P < 0.001) while OT treatment abolished the elevated MPO activity. Collagen levels in the uterus and liver were increased by sepsis (P < 0.01) and OT treatment reduced the collagen levels in both tissues (P < 0.01-P < 0.05). Serum TNF-alpha levels were significantly increased by sepsis (P < 0.001) and OT treatment abolished the sepsis-induced increase in TNF-alpha levels. Conclusions. OT protects against sepsis-induced oxidative damage by acting as an antioxidant agent and its protective effect in the colon and liver appears to be dependent on its inhibitory effect on neutrophil infiltration. Our results suggest that OT may have a therapeutic value in limiting sepsis-associated multiple organ damage. (C) 2005 Elsevier Inc. All rights reserved.Publication Metadata only Aqueous garlic extract alleviates ischaemia-reperfusion-induced oxidative hepatic injury in rats(ROYAL PHARMACEUTICAL SOC GREAT BRITAIN, 2005) YEGEN, BERRAK; Sener, G; Sehirli, O; Ipci, Y; Ercan, F; Sirvanci, S; Gedik, N; Yegen, BCThis study was designed to examine the effects of aqueous garlic extract (AGE) on hepatic ischaemia-reperfusion (I/R) injury in rats. For this purpose, Wistar albino rats were subjected to 45min of hepatic ischaemia, followed by a 60-min reperfusion period. AGE (1 mL kg(-1), i.p., corresponding to 500 mg kg(-1)) or saline was administered twice, 15 min before ischaemia and immediately before the reperfusion period. Serum aspartate aminotransferase (AST) and alanine aminotransferase.(ALT) levels were determined to assess liver functions. Liver tissues were taken for the determination of malondialdehyde (MDA) levels, an end product of lipid peroxidation; glutahione (GSP.) levels, a key antioxidant; and myeloperoxidase (MPO) activity, as an indirect index of neutrophil inifiltration Hepatic collagen content, as a fibrosis marker, was also determined. Plasma ALT and AST activities, were elevated in the I/R group as compared with the control group, while these increases significantly decreased by AGE treatment. Hepatic GSH levels, significantly, depressed by I/R were elevated back to control levels in the AGE-treated I/R group. Increases in tissue MDA levels and MPO activity due to I/R injury were reduced back to control levels by AGE treatment. Similarly,, increased hepatic collagen content in the I/R group was reduced to the control level with AGE treatment. Since AGE administration alleviated the I/R-incluced injury of the liver and improved the hepatic and function, it seems likely that AGE, with its antioxidant and oxidant-scavenging properties, may be of potential therapeutic value in protecting the liver against oxidative injury due to ischaemia-reperfusion.Publication Metadata only Protective effects of MESNA (2-mercaptoethane sulphonate) against acetaminophen-induced hepatorenal oxidative damage in mice(JOHN WILEY & SONS LTD, 2005) YEGEN, BERRAK; Sener, G; Sehirli, O; Cetinel, S; Yegen, BG; Gedik, N; Ayanoglu-Dulger, GAcetaminophen, a widely used analgesic and antipyretic, is known to cause hepatic and renal injury in humans and experimental animals when administered in high doses. It was reported that these toxic effects of acetaminophen are due to oxidative reactions that take place during its metabolism. In this study we aimed to investigate the possible beneficial effect of 2-mercaptoethane sulphonate (MESNA), an antioxidant agent, against acetaminophen toxicity in mice. Balb-c mice were injected i.p. with: vehicle (the control group); a single dose of 150 mg kg(-1) MESNA (MES group); a single dose of 900 mg kg(-1) i.p. acetaminophen (AA4h and AA24h groups); and MESNA, at a dose of 150 mg kg(-1) after acetaminophen injection (AA4h-MES and AA24h-MES groups). The MESNA injection was repeated once more 12 h after the first injection in the AA24h-MES group. Blood urea nitrogen, serum creatinine, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in blood and glutathione (GSH) and malondialdehyde (NIDA) levels, myeloperoxidase (MPO) activity and collagen contents in liver and kidney tissues were measured. Tissues also were examined microscopically. Blood urea nitrogen and serum creatinine, which were increased significantly (P < 0.001) following acetaminophen treatment were decreased significantly (P < 0.05-0.001) after treatment with MESNA. The ALT and AST levels were also increased significantly (P < 0.001) after acetaminophen treatment but were not reduced with MESNA. Acetaminophen treatment caused a significant (P < 0.05-0.001) decrease in GSH levels whereas MDA levels and MPO activity were increased in both tissues. These changes were reversed by MESNA treatment. Collagen contents of the liver and kidney tissues were increased by acetaminophen treatment (P < 0.001) and reversed back to the control levels with MESNA. Our results imply that acetaminophen causes oxidative damage in hepatic and renal tissues and that MESNA, via its antioxidant effects, protects these tissues. Therefore, its therapeutic role as a 'tissue injury-limiting agent' must be elucidated further in drug-induced oxidative damage. Copyright (C) 2005 John Wiley Sons, Ltd.Publication Metadata only Octreotide ameliorates sepsis-induced pelvic inflammation in female rats by a neutrophil-dependent mechanism(ELSEVIER SCIENCE INC, 2005) YEGEN, BERRAK; Sener, G; Cetinel, M; Erkanli, G; Gedik, N; Yegen, BCSepsis is a generalized inflammatory response, which involves organ systems remote from the locus of the initial infectious insult, accompanied by the release of cytokines and the subsequent formation of reactive oxygen and nitrogen species. The aim of this study was to investigate the possible protective effect of octreotide (OCT), a synthetic somatostatin analogue, against sepsis-induced oxidative damage in the uterine and ovarian tissues of rats. Sepsis was induced by caecal ligation and puncture method in female Wistar albino rats. Sepsis and sham operated (control) groups received either saline or OCT (50 mug/kg, i.p.; Novartis) immediately after the operation and at 12 h. Twenty-four hours after the surgery, rats were decapitated and serum TNF-alpha levels and tissue malondialdehyde (MDA) content, glutathione (GSH) levels and mycloperoxidase (MPO) activity were determined in the uterus and ovaries. Oxidant-induced tissue fibrosis was determined by tissue collagen contents. while the extent of tissue injuries was analyzed microscopically. Sepsis increased serum TNF-alpha levels and resulted in decreased GSH levels and increased MDA levels, MPO activity and collagen contents in both the uterus and the ovaries (p < 0.05-0.001) indicating the presence of the oxidative damage, as also confirmed by histological analysis. On the other hand, OCT administration reversed these oxidant responses and reduced the severity of microscopic damage (p < 0.001). In conclusion, OCT protects against sepsis-induced oxidative injury of the uterine and ovarian tissues by diminishing neutrophil infiltration, an important source of oxygen free radicals. Our results suggest that OCT may be of therapeutic value in ameliorating sepsis-associated pelvic inflammation. (C) 2004 Elsevier Inc. All rights reserved.Publication Metadata only Melatonin ameliorates ionizing radiation-induced oxidative organ damage in rats(PERGAMON-ELSEVIER SCIENCE LTD, 2003) ATASOY, BESTE MELEK; Sener, G; Jahovic, N; Tosun, O; Atasoy, BM; Yegen, BCThis study was designed to study the effects of the potential radioprotective properties of pharmacological doses of melatonin against organ damage induced by whole-body irradiation (IR) in rats. A total of 32 male Sprague-Dawley rats were exposed to irradiation performed with a LINAC producing 6 MV photons at a focus 100 cm distant from the skin. Under ketamine anaesthesia, each rat received a single whole-body dose of 800 cGy. Immediately before and after IR, rats were treated with either saline or melatonin (20 mg/kg and 10 mg/kg, ip) and decapitated at 12-h after exposure to irradiation. Another group of rats was followed for 72-h after IR, where melatonin (10 mg/kg, ip) injections were repeated once daily. Tissue levels of malondialdehyde (MDA)an index of lipid peroxidation-, glutathione (GSH)-a key to antioxidant- and myeloperoxidase (MPO) activity-an index of neutrophil infiltration-were estimated in liver, lung, colon and intestinal tissues. The results demonstrate that both 12-h and 72-h following IR, tissue leves of MDA were elevated (p<0.05-0.001), while GSH levels were reduced (p<0.05-0.001) in all organs. On the other hand, melatonin, reduced the levels of MDA and increased the GSH levels significantly, (p<0.05-0.001). MPO activity was increased significantly in the colonic tissue at the both 12-h and 72-h, and in the hepatic tissue at the 72-h following IR, which were reduced by melatonin (p<0.01-0.001). In the lung tissue enzyme activity was decreased at 72nd h of postirradiation. In conclusion, the increase in MDA levels and MPO activity and the concomitant decrease in GSH levels demonstrate the role of oxidative mechanisms in irradiation-induced tissue damage, and melatonin, by its free radical scavenging and antioxidant properties, ameliorates irradiation-induced organ injury. Thus, supplementing cancer patients with adjuvant therapy of melatonin may have some benefit for successful radiotherapy. (C) 2003 Elsevier Inc. All rights reserved.