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Öğe HMG-CoA reductase inhibitor rosuvastatin improves abnormal brain electrical activity via mechanisms involving eNOS(Elsevier, 2015) Şeker, Fatma Burcu; Kılıç, Ülkan; Ça?layan, Berrak; Ethemoğlu, Muhsine Sinem; Çağlayan, Ahmet Burak; Ekimci, Nur; Demirci, Selami; Do?an, Ayşegül; Öztezcan, Serdar; Şahin, Fikrettin; Yılmaz, Bayram; Kılıç, ErtuğrulApart from its repressing effect on plasma lipid levels, 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors exert neuroprotective functions in animal models of neurodegenerative disorders. In view of these promising observations, we were interested in whether HMG-CoA reductase inhibition would affect epileptiform activity in the brain. To elucidate this issue, atorvastatin, simvastatin and rosuvastatin were administered orally at a dose of 20 mg/kg each for 3 days and their anti-epileptic activities were tested and compared in rats. Epileptiform activity in the brain was induced by an intracortical penicillin G injection. Among HMG-CoA reductase inhibitors, simvastatin-treatment was less effective in terms of spike frequency as compared with atorvastatin- and rosuvastatin-treated animals. Atorvastatin treatment reduced spike frequencies and amplitudes significantly throughout the experiment. However, the most pronounced anti-epileptic effect was observed in rosuvastatin-treated animals, which was associated with improved blood-brain barrier (BBB) integrity, increased expression of endothelial nitric oxide synthase (eNOS) mRNA and decreased expressions of pro-apoptotic p53, Bax and caspase-3 mRNAs. Inhibition of eNOS activity with L-NG-Nitroarginine Methyl Ester (L-NAME) reversed the anti-epileptic effect of rosuvastatin significantly. However, L-NAME did not alter the effect of rosuvastatin on the levels of p53, Bax and caspase-3 mRNA expression. Here, we provide evidence that among HMG-CoA reductase inhibitors, rosuvastatin was the most effective statin on the reduction of epileptiform activity, which was associated with improved BBB permeability, increased expression of eNOS and decreased expressions of pro-apoptotic p53, Bax and caspase-3. Our observation also revealed that the anti-epileptic effect of rosuvastatin was dependent on the increased expression level of eNOS. The robust anti-epileptic effect encourages proof-of-concept studies with rosuvastatin in human epilepsy patients with hypercholesterolemia.Öğe Poloxamer P85 increases anticancer activity of schiff base against prostate cancer in vitro and in vivo(Lippincott Williams and Wilkins, 2017) Demirci, Selami; Doğan, Ayşegül; Türkmen Bacak, Neşe; Telci, Dilek; Çağlayan, Ahmet Burak; Beker, Mustafa Çağlar; Kılıç, Ertuğrul; Özkan, Ferda; Dede, Bülent; Şahin, FikrettinProstate cancer is the second most common cancer among men and the leading cause of death after lung cancer. Development of hormone-refractory disease is a crucial step for prostate cancer progression for which an effective treatment option is currently unavailable. Therefore, there is a need for new agents that can efficiently target cancer cells, decrease tumor growth, and thereby extend the survival of patients in late-stage castration-resistant prostate cancer. In the current study, a novel heterodinuclear copper(II)Mn(II) Schiff base complex combined with P85 was used to evaluate anticancer activity against prostate cancer in vitro and in vivo. Cell proliferation and cytotoxicity were evaluated by cell viability, gene, and protein expression assays in vitro. Results showed that the heterodinuclear copper(II)Mn(II) complex-P85 combination decreased cell proliferation by upregulating the apoptotic gene expressions and blocking the cell proliferation-related pathways. Tramp-C1-injected C57/B16 mice were used to mimic a prostate cancer model. Treatment combination of Schiff base complex and P85 significantly enhanced the cellular uptake of chemicals (by blocking the drug transporters and increased life time), suppressed tumor growth, and decreased tumor volume steadily over the course of the experiments. Overall, heterodinuclear copper(II)Mn(II) complex-P85 showed remarkable anticancer activity against prostate cancer in in vitro and in vivo.Öğe Schiff base-poloxamer p85 combination prevents prostate cancer progression in c57/bl6 mice(Wiley, 2016) Do?an, Ayşegül; Demirci, Selami; Başak Türkmen, Neşe; Çağlayan, Ahmet Burak; Aydın, Safa; Telci, Dilek; Kılıç, Ertuğrul; Şahin, Kazım; Orhan, Cemal; Tuzcu, Mehmet; Doğan Ekici, Asiye Işın; Şahin, FikrettinBACKGROUNDProstate cancer which is the second most common cause of death among men has a high incidence in recent years. Current therapeutic regimens should be improved to overcome drug resistance. At the metastatic stage, tumors become refractory to established chemotherapeutic treatments and cause serious problems at the clinics. Development of new drug molecules that are able to transport through the membrane easily and kill tumor cells rapidly is of great interest. METHODIn the current study, a novel Heterodinuclear copper(II)Mn(II) Schiff base complex combined with P85 was used for prostate cancer treatment in vivo. Tramp-C1 cells injected animals were subjected to chemotherapeutic formulation treatment and results were analyzed by toxicology analysis, tumor volume measurements, and histopathological analysis. 0.5mg/kg Schiff base was selected and combined with 0.05% P85 according to the toxicology analysis showing the enzyme levels, blood parameters, and multiple organ toxicity. RESULTSResults demonstrated that Heterodinuclear copper(II)Mn(II) complex-P85 combination decreased tumor formation and tumor volume steadily over the course of experiments. CONCLUSIONSOverall, Heterodinuclear copper(II)Mn(II) complex-P85 exerted remarkable anti-cancer activity in vivo in C57/B16 mice. Prostate 76:1454-1463, 2016.Öğe Sodium pentaborate pentahydrate and pluronic containing hydrogel increases cutaneous wound healing in vitro and in vivo(Humana Press, 2014) Do?an, Ayşegül; Demirci, Selami; Çağlayan, Ahmet Burak; Kılıç, Ertuğrul; Günal, Mehmet Yalçın; Uslu, Ünal; Cumbul, Alev; Şahin, FikrettinAfter a disruption of skin integrity, the body produces an immediate response followed by a functional and comparable regeneration period, referred to as wound healing. Although normal wounds do not need much attention during the healing period, chronic (non-healing) wounds are the major challenge of current dermatological applications. Therefore, developing new, safe, and effective wound healing drugs has always been an attractive area of international research. In the current study, sodium pentaborate pentahydrate (NaB), pluronics (Plu; F68 and F127), and their combinations were investigated for their wound healing activities, using in vitro and in vivo approaches. The results revealed that NaB significantly increased migration capacity and superoxide dismutase activity in primary human fibroblasts. Combinations of optimized concentrations for pluronic block co-polymers further increased cell migration, and the messenger RNA (mRNA) expression levels of important growth factor and cytokines (vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-ß), and tumor necrosis factor alpha (TNF-?)). NaB containing hydrogel co-formulated with pluronics was also investigated for their wound healing activities using a full thickness wound model in rats. Macroscopic and histopathological analysis confirmed that wounds in combination gel-treated groups healed faster than those of control groups. NaB/Plu gel application was found to increase wound contraction and collagen deposition in the wound area. Therefore, our results suggest that NaB, and its pluronics combination, could be used in dermatological clinics and be a future solution for chronic wounds. However, further studies should be conducted to explore its exact action of mechanism and effects of this formulation on chronic wounds.
