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    Celecoxib administration reduced mortality, mesenteric hypoperfusion, aortic dysfunction and multiple organ injury in septic rats
    (ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2017) Ozer, Erdem Kamil; Goktas, Mustafa Tugrul; Kilinc, Ibrahim; Bariskaner, Hulagu; Ugurluoglu, Ceyhan; Iskit, Alper Bektas
    Background: The cyclooxygenase (COX)-2 overexpression is associated with vascular injury and multiple organ failure in sepsis. However, constitutive COX-1 and basal COX-2 expressions have physiological effects. We aimed to investigate the effects of partial and selective COX-2 inhibition without affecting constitutive COX-1 and basal COX-2 activities by celecoxib on mesenteric artery blood flow (MABF), vascular reactivity, oxidative and inflammatory injuries, and survival in septic rats accomplished by cecal ligation and puncture (CLP). Methods: Wistar rats were allocated into Sham, CLP, Sham + celecoxib, CLP + celecoxib subgroups. 2 h after Sham and CLP operations, celecoxib (0.5 mg/kg) or vehicle (saline; 1 mL/kg) was administered orally to rats. 18 h after drug administrations, MABF and responses of isolated aortic rings to phenylephrine were measured. Tissue samples were obtained for biochemical and histopathological examinations. Furthermore, survival rate was monitored throughout 96 h. Results: Celecoxib ameliorated mesenteric hypoperfusion and partially improved aortic dysfunction induced by CLP. Survival rate was % 0 at 49th h in CLP group, but in CLP + celecoxib group it was 42.8% at the end of 96 h. Serum AST, ALT, LDH, BUN, Cr and inflammatory cytokine (tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6) levels were increased in CLP group that were prevented by celecoxib. The decreases in liver and spleen glutathione levels and the increases in liver, lung, spleen and kidney malondialdehyde levels in CLP group were blocked by celecoxib. The histopathological protective effects of celecoxib on organ injury due to CLP were also observed. Conclusions: Celecoxib has protective effects on sepsis due to its preservative effects on mesenteric perfusion, aortic function and its anti-inflammatory and antioxidative effects. (C) 2016 Elsevier Masson SAS. All rights reserved.
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    Coenzyme Q10 improves the survival, mesenteric perfusion, organs and vessel functions in septic rats
    (ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2017) Ozer, Erdem Kamil; Goktas, Mustafa Tugrul; Kilinc, Ibrahim; Pehlivan, Sultan; Bariskaner, Hulagu; Ugurluoglu, Ceyhan; Iskit, Alper Bektas
    Background: Coenzyme Q10 (CoQ10) is a naturally occurring, lipid-soluble antioxidant and an essential electron carrier in the mitochondrial respiratory chain. In sepsis, CoQ10 deficiency induced by mitochondrial failure can lead to hypoxia, hypoperfusion, oxidative organ damage and finally death. We aimed to investigate the effects of CoQ10 on survival, mesenteric artery blood flow (MABF), vascular reactivity, oxidative and inflammatory injuries in cecal ligation and puncture (CLP)-induced sepsis. Methods: Wistar rats were divided into Sham, CLP, Sham + CoQ10, CLP + CoQ10 subgroups. CoQ10 (10 mg/kg/day) or vehicle (olive oil; 1 mL/kg/day) was intraperitoneally injected for 15 days. At 16th day, Sham or CLP operation was performed. 20 h after the operations, MABF and phenylephrine responses of isolated aortic rings were measured. Tissue samples were obtained for histopathological and biochemical evaluations. Furthermore, survival rates were monitored throughout 96 h. Results: CoQ10 prevented mesenteric hypoperfusion and aortic dysfunction induced by CLP. Survival rate was % 0 at 46th h in CLP group, but in CLP + CoQ10 group it was 37.5% at the end of 96 h. CLP-induced elevations of serum AST, ALT, LDH, BUN, Cr and inflammatory cytokine (tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6) levels were blocked by CoQ10. CoQ10 restored the increased liver, lung, spleen and kidney malondialdehyde levels and as well as reduced liver and spleen glutathione levels. The protective effects of CoQ10 on multiple organ damage were also observed histopathologically. Conclusions: CoQ10 showed protective effects in sepsis due to its preservative effects on mesenteric perfusion, aortic function and also its anti-inflammatory and antioxidative effects. (C) 2017 Elsevier Masson SAS. All rights reserved.
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    Effects of Carvacrol on Survival, Mesenteric Blood Flow, Aortic Function and Multiple Organ Injury in a Murine Model of Polymicrobial Sepsis
    (SPRINGER/PLENUM PUBLISHERS, 2017) Ozer, Erdem Kamil; Goktas, Mustafa Tugrul; Toker, Aysun; Bariskaner, Hulagu; Ugurluoglu, Ceyhan; Iskit, Alper Bektas
    Carvacrol (CRV) has strong cytoprotective, antioxidant, and anti-inflammatory properties. We aimed to demonstrate the possible protective effects of CRV on survival, mesenteric artery blood flow (MBF), vascular reactivity, and oxidative and inflammatory injuries in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Wistar rats were allocated into the following four groups: Sham, CLP, Sham + CRV, and CLP + CRV. The animals were orally administered with CRV (80 mg/kg/day) or vehicle (corn oil; 1 mL/kg/day) for 7 days. At the eighth day, Sham or CLP procedure was applied. Twenty hours after the operations, MBF and contractile responses of isolated aortic preparations to phenylephrine were measured. Tissue samples were obtained for biochemical and histopathological assessments. Additionally, survival rates were recorded throughout 96 h. CRV administration improved the mesenteric perfusion, contractile function of aorta, and survival after CLP. CRV substantially prevented the elevations in the levels of LDH, BUN, Cr, and inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6) but could not prevent the elevations of AST and ALT after CLP. The decreased liver, kidney, and spleen glutathione levels and increased liver, kidney, lung, and spleen malondialdehyde levels induced by CLP were substantially restored by CRV. Also, histopathological protective effects of CRV on multiple organ damage due to CLP were observed. CRV possesses strong ameliorative effects on sepsis due to its protective effects on mesenteric perfusion and aortic function and its antioxidative and anti-inflammatory effects.
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    Infliximab alleviates the mortality, mesenteric hypoperfusion, aortic dysfunction, and multiple organ damage in septic rats
    (CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS, 2017) Ozer, Erdem Kamil; Goktas, Mustafa Tugrul; Kilinc, Ibrahim; Toker, Aysun; Bariskaner, Hulagu; Ugurluoglu, Ceyhan; Iskit, Alper Bektas
    Tumor necrosis factor-alpha (TNF-alpha) is a pivotal mediator that triggers inflammatory process, oxidative stress, and multiple organ injury in sepsis. We investigated the effects of infliximab on survival, mesenteric artery blood flow (MBF), vascular reactivity, and oxidative and inflammatory injuries in cecal ligation and puncture (CLP)-induced sepsis. Wistar rats were divided into Sham, CLP, Sham+infliximab, and CLP+infliximab subgroups. Twenty-four hours before the operations, rats were injected intraperitoneally with infliximab (7 mg/kg) or vehicle (saline; 1 mL/kg). Twenty hours after the operations, MBF and phenylephrine responses of isolated aortic rings were measured. Tissue damages were examined biochemically and histopathologically. Furthermore, survival rates were monitored throughout 96 h. Infliximab improved survival, mesenteric perfusion, and aortic function after CLP. Increases of serum AST, ALT, LDH, BUN, Cr, and inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6) induced by CLP were blocked by infliximab. Infliximab prevented malondialdehyde elevations in septic liver, lung, spleen, and kidney tissues, as well as glutathione reductions in septic liver, spleen, and kidney tissues. Protective effects of infliximab on multiple organ damage were also observed histopathologically. Infliximab showed protective effects in sepsis due to its improvement effects on mesenteric perfusion, aortic function, and its anti-inflammatory and antioxidative effects.
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    Investigation of 1377C/T polymorphism of the Toll-like receptor 3 among patients with chronic hepatitis B
    (CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS, 2016) Goktas, Emine Firat; Bulut, Cemal; Goktas, Mustafa Tugrul; Ozer, Erdem Kamil; Karaca, Ragip Ozgur; Kinikli, Sami; Demiroz, Ali Pekcan
    The immunopathogenesis of chronic hepatitis B (CHB) has not been clarified yet. Toll-like receptors (TLR) are a receptor family that initiates immunity with exogenous-endogenous ligands and plays a role in the pathogenesis of infections. In this study, we aimed to investigate the frequency of TLR 3 1377C/T (rs3775290) polymorphism and its role in patients with CHB. We included 50 healthy individuals as control group and 73 active and 43 inactive hepatitis B patients. All DNA samples were isolated from blood samples. For the detection of TLR 3 1377C/T single-nucleotide polymorphism, restriction fragment length polymorphism was used. A statistically significant difference was determined in Hepatitis B virus (HBV) DNA levels of CHB patients with the CC, CT, and TT genotypes (p = 0.013). The highest levels of HBV DNA were detected in individuals with TT genotypes. Additionally, the frequency of CC genotype was higher in the active CHB patients compared with that of the inactive CHB patients (p = 0.044). No statistically significant difference in TLR 3 1377C/T polymorphism was detected between healthy controls and the hepatitis B patients (p = 0.342). In conclusion, HBV DNA level was higher in the individuals with TT genotype, and CC genotype was more frequent in the active CHB patients. These results suggest a possible association between CHB and TLR 3 gene (1377C/T) polymorphism.
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    Microwave-assisted synthesis of condensed 1,4-dihydropyridines as potential calcium channel modulators
    (SCIENTIFIC TECHNICAL RESEARCH COUNCIL TURKEY-TUBITAK, 2015) Ozer, Erdem Kamil; Gunduz, Miyase Gozde; El-Khouly, Ahmed; Sara, Mehmet Yildirim; Simsek, Rahime; Iskit, Alper Bektas; Safak, Osman Cihat
    This study reports the design, synthesis, and calcium channel modulatory activity evaluation of a series of 14 novel fused 1,4-dihydropyridine derivatives. The molecular design of the compounds was based on modifications of nifedipine, which is a calcium channel blocker. The compounds were achieved by one-pot microwave-assisted reaction of 4,4-dimethyl-1,3-cyclohexanedione, 5-chlorosalicylaldehyde/3,5-dichlorosalicylaldehyde, an appropriate alkyl acetoacetate, and ammonium acetate in ethanol according to a modified Hantzsch reaction. The structures of the compounds were confirmed by spectral methods and elemental analysis. To evaluate their relaxant activities, the maximum relaxant response (E-max) and pD(2) values of the compounds and nifedipine were determined on isolated rat aorta rings. The obtained results indicated that all compounds produced concentration-dependent relaxation on the rings possibly due to the blockade of calcium channels. The E-max values (a measure of efficacy) of five compounds were higher than those of nifedipine.
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    Protective Effects of Biochanin A against Methotrexate-Induced Acute Liver Injury in Rats
    (ASSOC PHARMACEUTICAL TEACHERS INDIA, 2017) Ozer, Erdem Kamil; Goktas, Mustafa Tugrul; Toker, Aysun; Ugurluoglu, Ceyhan; Bariskaner, Hulagu
    Background: Methotrexate (MTX) is one of the most commonly used chemotherapeutic agents in the treatment of cancer patients, however its therapeutic use is limited due to dose dependent hepatotoxicity caused by oxidative damage. Biochanin A (BCA), a naturally occurring dietary isoflavone, has strong cytoprotective, anti-inflammatory, and antioxidant properties. Although protective actions of BCA against various chemical-induced hepatotoxicity including that of carbon tetrachloride and arsenic, none of the studies was made on MTX-induced acute liver injury. Methods: Wistar rats were separated into four groups; Control, MTX, Control+BCA, MTX+BCA. BCA (50 mg/kg/day) or vehicle (dimethyl sulfoxide; 1 mL/kg/day) with the same volume was intraperitoneally injected for 5 days. At sixth day, a single dose of MTX (20 mg/kg) was injected to rats. Twenty-four h after the MTX administration, rats were sacrificed and then blood and liver samples were obtained for biochemical and histopathologic analyses. Results: MTX increased the serum AST, ALT, and LDH levels. Furthermore, malondialdehyde (an indicator of oxidative injury) and myeloperoxidase (an indicator of neutrophil infiltration) levels increased, while total glutathione levels (an indicator of antioxidant status) decreased in liver. MTX-induced hepatotoxicity was also observed histopathologically. BCA substantially improved these alterations induced by MTX administration. Conclusion: These results indicate that BCA may be useful in preventing the MTX-induced acute liver injury due to its antioxidant and anti-inflammatory properties.
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    Synthesis of fused 1,4-dihydropyridines as potential calcium channel blockers
    (WALTER DE GRUYTER GMBH, 2018) Ozer, Erdem Kamil; Gunduz, Miyase Gozde; El-Khouly, Ahmed; Sara, Yildirim; Simsek, Rahime; Iskit, Alper Bektas; Safak, Cihat
    Objective: The aim of this study was to synthesize ten 1,4-dihydropyridine (DHP) derivatives in which substituted cyclohexane rings were fused to the DHP ring and to determine how different ester groups and the benzoyl substituent introduced in 4-phenyl ring affected their calcium channel blocking activity. Methods: A microwave-assisted one-pot method was applied for the synthesis of compound 1-5 according to a modified Hantzsch reaction. The benzoyl moiety was introduced in the 4-phenyl ring of these dihydropyridines by refluxing with benzoyl chloride in acetone in the presence of anhydrous potassium carbonate. Synthesized products were characterized by elemental analysis, IR, H-1-NMR and C-13-NMR spectroscopy. The inhibitory actions of compounds 1-10 on calcium channel blocking activity were tested on isolated rat aorta preparations. Results: The obtained pharmacological results showed that although all compounds are potent relaxing agents on isolated rat aorta smooth muscle, introduction of a benzoyloxy substitiuent on the phenyl ring (compound 6-10) decreased the relaxant effect of these compunds. Conclusion: The reported 1,4-DHP derivatives have calcium channel blocking activity on rat aorta smooth muscle.
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    Thymoquinone protects against the sepsis induced mortality, mesenteric hypoperfusion, aortic dysfunction and multiple organ damage in rat
    (POLISH ACAD SCIENCES INST PHARMACOLOGY, 2017) Ozer, Erdem Kamil; Goktas, Mustafa Tugrul; Toker, Aysun; Pehlivan, Sultan; Bariskaner, Hulagu; Ugurluoglu, Ceyhan; Iskit, Alper Bektas
    Background: Thymoquinone (TQ) is a potent cytoprotective, antioxidant and anti-inflammatory agent. We aimed to investigate the possible protective effects of TQ on survival, mesenteric artery blood flow (MABF), vascular reactivity, oxidative and inflammatory injuries in a murine sepsis model induced by cecal ligation and puncture (CLP).Methods: Wistar rats were divided into the following four groups: Sham, CLP, Sham + TQand CLP + TQ. TQ (1 mg/kg/day) or vehicle (dimethyl sulfoxide, 1 mL/kg/day) was intraperitoneally injected for 3 days. At 4th day Sham or CLP operation was applied. 20 h after the operations, MABF and contractile responses of isolated aortic rings to phenylephrine were measured. Tissue samples were obtained for histopathological and biochemical examinations. Also, survival rates were recorded throughout 96 h.Results: TQ ameliorated mesenteric hypoperfusion and partially attenuated aortic dysfunction induced by CLP. Survival rate was %0 at 42nd h in CLP group, but in CLP + TQ group it was 33.4% at the end of 96 h. Serum levels of AST, ALT, LDH, BUN, Cr and inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6) increased in CLP group that were prevented by TQ. The decreases in liver, spleen and kidney glutathione levels and the increases in liver, lung, kidney and spleen malondialdehyde levels induced by CLP were inhibited by TQ. The histopathological protective effects of TQ on multiple organ damage due to CLP were also observed.Conclusion: TQ has ameliorative effects on sepsis due to its protective effects on mesenteric perfusion, contractile function of aorta and its anti-inflammatory and antioxidative effects. (C) 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.