Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
Permanent URI for this collectionhttps://hdl.handle.net/11147/9
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Conference Object Targeting Sphingosine Kinase-1/Spingosine-1-phosphate Receptor 2 Signalling Pathway To Overcome T315i Mutation in 32dcl3 Cells(Elsevier Ltd., 2014) Adan Gökbulut, Aysun; Öğretmen, Besim; Baran, YusufThe main problem in chronic myeloid leukemia patients is the development of resistance against tyrosine kinase inhibitors. The expression of BCR-ABL1 having T315 mutation is responsible for the development of nilotinib resistance. The alterations in sphingolipid signalling pathway is a significant BCR-ABL1-dependent resistance mechanism. Recently, we showed that sphingosine kinase-1 (SK-1)/sphingosine-1 phosphate (S1P)-mediated drug resistance is transduced via sphingosine-1 phosphate receptor 2 (S1P2) that inhibits protein phosphatase 2A (PP2A), causing increased stability of BCR-ABL1. However, specific signaling cascade involved in this process remain unkown. In this study, BCR-ABL1 expressing 32Dcl3 cells, 32D-p210Bcr-Abl(wt) and 32D-p210Bcr-Abl (T315I) were used. The antiproliferative effects of nilotinib, SK-1 inhibitor (PF-543), S1P2 inhibitor (JTE-013), phospholipase C inhibitor (U-73122) and nilotinib/PF-543 and nilotinib/JTE-013 combinations on wt and resistant cells were determined by MTT assay. Isobologram analysis was performed using CompuSyn program.Conference Object Therapeutic Potential of Fisetin, Vitexin and Hesperetin on Chronic Myeloid Leukemia Cells(Elsevier Ltd., 2014) Adan Gökbulut, Aysun; Baran, YusufIn Chronic Myeloid Leukemia (CML) treatment, despite therapeutic efficacy of tyrosine kinase inhibitors, resistance development and side effects cause problems. Fisetin, vitexin and hesperetin are plant-derived flavonoids. In this study, therapeutic potentials of fisetin, vitexin and hesperetin were determined in CML cells. Cytotoxic effects of flavonoids were determined by MTT assay while apoptotic effects were determined by changes in caspase- 3 activity, loss of mitochondrial membrane potential (MMP) and Annexin V/PI double staining. Cytostatic effects of the flavonoids were evaluated by propidium iodide staining using flow cytometry.Conference Object A Novel Biomarker for Drug Resistance in Chronic Myeloid Leukemia: Microrna-17(Elsevier Ltd., 2014) Baran, Yusuf; Fıratlıgil, Burcu; Kartal Yandım, Melis; Kiraz, Yağmur; Kozanoğlu, İlknur; Özdoğu, Hakan; Ünal, AlimiRNAs are single stranded small RNA molecules (20–22 nt), which do not have ability to code for proteins. These types of RNAs play significant roles on gene regulation through inhibition of their target genes. In animals, most of miRNAs show their translational inhibitor effect on target mRNAs by semi-complementation to 3’UTR sequences of mRNAs and deadenylation that cause degradation of these mRNAs. The importance of miRNAs is increasing in cancer diagnosis and treatment since they are one of the major regulators of genes such as oncogenes, tumor suppressor genes. miR-17 is an oncogenic miRNA that suppress the activation of tumor suppressor genes like CDKN1A, p21 and E2F1. Based on previous information, we aimed to determine the correlation between expression levels of miR-17 microRNA in newly diagnosed, tyrosine kinase inhibitors treated and drug resistant CML patients.Conference Object Cytotoxic and Apoptotic Effects of Fisetin, Hesperetin and Vitexinon Acute Promyelocytic Leukemia Cells(Elsevier Ltd., 2014) Adan Gökbulut, Aysun; Baran, YusufAcute Promyelocytic Leukaemia (APL) is characterized by abnormal accumulation of immature granulocytes in the bone marrow and the blood stream. To date, there is no definitive treatment strategy. Fisetin, hesperetin and vitexin are flavanoids found in fruits and vegetables. Their anticancer properties have been studied on several cancer types. In this study, we aimed to examine the cytotoxic, cytostatic and apoptotic effects of fisetin, hesperetin and vitexin on Acute Promyelocytic Leukaemia cells. Cytotoxic effects were evaluated by MTT assay while apoptotic effects of these flavonoids were examined by changes in caspase-3 activity, loss of mitochondrial membrane potential (MMP) and Annexin V/PI double staining. Cytostatic effects of the flavonoids were evaluated by propidium iodide staining using flow cytometry.Article Citation - WoS: 8Citation - Scopus: 7Secreted Wnt Antagonists in Leukemia: a Road Yet To Be Paved(Elsevier Ltd., 2018) Pehlivan, Melek; Çalışkan, Ceyda; Yüce, Zeynep; Sercan, Hakkı OgünWnt signaling has been a topic of research for many years for its diverse and fundamental functions in physiological (such as embryogenesis, organogenesis, proliferation, tissue repair and cellular differentiation) and pathological (carcinogenesis, congenital/genetic diseases, and tissue degeneration) processes. Wnt signaling pathway aberrations are associated with both solid tumors and hematological malignancies. Unregulated Wnt signaling observed in malignancies may be due to a wide spectrum of abnormalities, from mutations in the genes of key players to epigenetic modifications of Wnt antagonists. Of these, Wnt antagonists are gaining significant attention for their potential of being targets for treatment and inhibition of Wnt signaling. In this review, we discuss and summarize the significance of Wnt signaling antagonists in the pathogenesis and treatment of hematological malignancies.Article Citation - WoS: 51Citation - Scopus: 58Synthesis, Cytotoxic and Antimicrobial Activities of Novel Cobalt and Zinc Complexes of Benzimidazole Derivatives(Elsevier Ltd., 2017) Apohan, Elif; Yılmaz, Ülkü; Yılmaz, Özgür; Serindağ, Ayfer; Küçükbay, Hasan; Yeşilada, Özfer; Baran, YusufIn this study fourteen novel cobalt (II) or zinc (II) complexes of benzimidazoles were synthesized from the 1-(4-substitutedbenzyl)-1H-benzimidazoles and CoCl2·6H2O or ZnCl2. Cytotoxic activities of novel complexes were investigated against lung cancer cells (A549) and BEAS-2B. Three of the examined compounds (1, 4 and 5) showed high cytotoxic activity against A549. While the IC50 of the cisplatin was 2.56 μg/mL for A549 cells at 72 h, the IC50 values of compounds 1, 4 and 5 were 1.97, 1.87 and 1.9 μg/mL, respectively. IC50 values of these compounds for BEAS-2B cells were higher than the IC50 values for A549. While the IC50 values for BEAS-2B cells were 59.8, 24.5 and 32.67 μg/mL, respectively, the IC50 of the cisplatin was determined as 2.53 μg/mL in the present work. Three of the compounds have also high antimicrobial activity against all the microorganisms used.Article Citation - WoS: 14Citation - Scopus: 15Neuraminidase-1 Contributes Significantly To the Degradation of Neuronal B-Series Gangliosides but Not To the Bypass of the Catabolic Block in Tay-Sachs Mouse Models(Elsevier Ltd., 2015) Timur, Zehra Kevser; Akyıldız Demir, Seçil; Marsching, C.; Sandhoff, R.; Seyrantepe, VolkanTaySachs disease is a severe lysosomal storage disorder caused bymutations in the HEXA gene coding for? subunit of lysosomal β-Hexosaminidase A enzyme, which converts GM2 to GM3 ganglioside. HexA mice, depleted of the β-Hexosaminidase A iso-enzyme, remain asymptomatic up to 1 year of age because of a metabolic bypass by neuraminidase(s). These enzymes remove a sialic acid residue converting GM2 to GA2,which is further degraded by the still intact β-Hexosaminidase B iso-enzyme into lactosylceramide. A previously identified ganglioside metabolizing neuraminidase, Neu4, is abundantly expressed in the mouse brain and has activity against gangliosides like GM2 in vitro. Neu4 mice showed increased GD1a and decreased GM1 ganglioside in the brain suggesting the importance of the Neu4 in ganglioside catabolism. Mice with targeted disruption of both HexA and Neu4 genes showed accumulating GM2 ganglioside and epileptic seizures with 40% penetrance, indicating that the neuraminidase Neu4 is a modulatory gene, but may not be the only neuraminidase contributing to the metabolic bypass in HexA mice. Therefore, we elucidated the biological role of neuraminidase-1 in ganglioside degradation in mouse. Analysis of HexANeu1 and HexANeu4Neu1 mice models showed significant contribution of neuraminidase-1 on B-series ganglioside degradation in the brain. Therefore, we speculate that other neuraminidase/neuraminidases such as Neu2 and/or Neu3 might be also involved in the ganglioside degradation pathway in HexA mice.Article Citation - WoS: 3Citation - Scopus: 3Genetic relationships among Eurasian Puccinellia distans genotypes(Elsevier Ltd., 2015) Bar, Cantuğ; Doğanlar, Sami; Frary, AnnePuccinellia distans (Jacq.) Parl. is a common grass species found throughout the world. It can grow in arid and saline environments as well as under toxic boron concentrations. In this work we performed sequence related amplified polymorphism (SRAP) marker analysis on 20 wild P. distans genotypes to understand the genetic relationships among different genotypes and subspecies. We tested 119 SRAP primer pairs and found that 43 were polymorphic. The molecular data were then analyzed to determine the genetic relationships and population structure of the genotypes. We were able to trace the origin of genotypes that were carried to distant locations or gathered for research purposes. We also found that geographical distance between genotypes was not an important determinant of genetic relationships as even distantly located Puccinellia genotypes were closely related. As P. distans is known to be tolerant to salinity stress and toxic mineral concentrations, the findings of this work can be used as a starting point for selection of genotypes that should be tested under such conditions.Article Citation - WoS: 5Citation - Scopus: 5Targeting Foxm1 Transcription Factor in T-Cell Acute Lymphoblastic Leukemia Cell Line(Elsevier Ltd., 2015) Tüfekçi, Özlem; Kartal Yandım, Melis; Ören, Hale; İrken, Gülersu; Baran, YusufThe Forkhead box protein M1 (FoxM1) is an important transcription factor having significant roles in various cellular events. FoxM1 overexpression has been reported to be related with many types of cancer. However, it is not known whether it contributes to oncogenesis of acute lymphoblastic leukemia. Siomycin A, a thiazol antibiotic, is known to inhibit FoxM1 transcriptional activity. In this study, we aimed to determine gene expression levels of FoxM1 in Jurkat cells (T-cell acute lymphoblastic leukemia cell line) and therapeutic potential of targeting FoxM1 by siomycin A alone and in combination with dexamethasone which improves the survival of children with T-cell acute lymphoblastic leukemia (ALL). We also examined the molecular mechanisms of siomycin A and dexamethasone-induced cell death in Jurkat cells. We demonstrated that FoxM1 mRNA is highly expressed in Jurkat cells. Dexamethasone and siomycin A caused a significant reduction in gene expression levels of FoxM1 in Jurkat cells. Targeting FoxM1 by siomycin A and dexamethasone caused a significant decrease in T-ALL cell line proliferation through induction of G1 cell cycle arrest. All these findings suggest a possible role of FoxM1 in T-cell ALL pathogenesis and represent FoxM1 as an attractive target for T-cell ALL therapy. © 2014 Elsevier Ltd.Article Citation - WoS: 34Citation - Scopus: 41Autologous Rabbit Adipose Tissue-Derived Mesenchymal Stromal Cells for the Treatment of Bone Injuries With Distraction Osteogenesis(Elsevier Ltd., 2013) Sunay, Özgür; Can, Geylani; Çakır, Zeynep; Denek, Ziya; Kozanoglu, İlknur; Erbil, Güven; Yılmaz, Mustafa; Baran, YusufBackground aims: Adipose tissue-derived mesenchymal stromal cells (MSCs) have a higher capacity for proliferation and differentiation compared with other cell lineages. Although distraction osteogenesis is the most important therapy for treating bone defects, this treatment is restricted in many situations. The aim of this study was to examine the therapeutic potential of adipose tissue-derived MSCs and osteoblasts differentiated from adipose tissue-derived MSCs in the treatment of bone defects. Methods: Bone defects were produced in the tibias of New Zealand rabbits that had previously undergone adipose tissue extraction. Tibial osteotomy was performed, and a distractor was placed on the right leg of the rabbits. The rabbits were placed in control (group I), stem cell (group II) and osteoblast-differentiated stem cell (group III) treatment groups. The rabbits were sacrificed, and the defect area was evaluated by radiologic, biomechanical and histopathologic tests to examine the therapeutic effects of adipose tissue-derived MSCs. Results: Radiologic analyses revealed that callus density and the ossification rate increased in group III compared with group I and group II. In biomechanical tests, the highest ossification rate was observed in group III. Histopathologic studies showed that the quality of newly formed bone and the number of cells active in bone formation were significantly higher in group III rabbits compared with group I and group II rabbits. Conclusions: These data reveal that osteoblasts differentiated from adipose tissue-derived MSCs shorten the consolidation period of distraction osteogenesis. Stem cells could be used as an effective treatment for bone defects.