PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection
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Article Citation - WoS: 139Granulocytic Sarcoma: a Systematic Review(e-Century Publishing Corporation, 2013) Yılmaz, Asu Fergün; Baran, Yusuf; Saydam, Güray; Şahin, Fahri; Baran, Yusuf; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyGranulocytic sarcoma also called myeloid sarcoma is an extramedullary tumor of immature granulocytic cells. It is a rare entity, and mostly accompanied by acute myeloid leukemia. It is observed during the course of myeloproliferative disorders especially in chronic myeloid leukemia and myelodysplastic syndromes. In some rare circumstances, it is detected before clinical signs of leukemia or other diseases. When the bone marrow biopsy reveals no other hematologic malignancies, the granulocytic sarcoma is described as nonleukemic, primary or isolated. It is observed at any part of the body but the most common locations are soft tissues, bone, peritoneum and lymph nodes. Presenting signs or symptoms are mainly due to mass effect of the tumor and dysfunction of the organ, or the tissue that is affected. The diagnosis is performed by biopsy of the tumor. The tumor consists of immature granulocytic cells, which could be documented by H&E, immunohistochemistry, and flow cytometric methods. Fluorescence in-situ hybridization and molecular analysis are also performed. The optimal time and type of treatment is not clear. Surgery could be an option especially for tumors, which cause organ dysfunction and/or obstruction. Systemic treatment should be considered in all patients because without systemic treatment, relapses and progression to acute myeloid leukemia is the ultimate fate of the disease in many cases. Cytarabine-containing remission-induction chemotherapies have been the most applied therapeutic strategies, but it is not clear whether the consolidation therapies are required or not, and what kind of regimens are appropriate. The role of hematopoietic stem cell transplantation (HSC) as a consolidation regimen is not clear, but, after the relapse of the disease with or without bone marrow involvement, HSC transplantation should be considered in suitable patients after the reinduction performed by AML chemotherapies. There is only limited data about the role of radiotherapy in these patients. It could be used in patients with relapsed disease, organ dysfunction which should be quickly relieved and inadequate response to chemotherapy. The effect of radiotherapy on overall survival is not known. New prospective studies and clinical trials are needed to generate guidelines for the treatment of primary granulocytic sarcomas.Article Citation - WoS: 37Mechanisms of Cellular Resistance To Imatinib in Human Chronic Myeloid Leukemia Cells(Taylor and Francis Ltd., 2007) Baran, Yusuf; Baran, Yusuf; Ural, Ali Uğur; Gündüz, Ufuk; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyA major advancement in the treatment of chronic myeloid leukemia (CML) has been the development of imatinib, which has shown striking activity in the chronic phase and the accelerated phase, but less so in the blast phase of the disease. Despite high rates of hematologic and cytogenetic responses to therapy, the emergence of resistance to imatinib has been recognized as a major problem in the treatment of patients with CML. Various cellular mechanisms may be involved in the nature of cellular resistance. Increased amount of target, alteration in structure of target proteins, decreased drug uptake and increased detoxification are well-known mechanisms of resistance. On the other hand, in some cases, even if anticancer drugs reach their sites of action, bypassing drug efflux system of the cells, some cells still may survive via the dysregulation of apoptotic signalling. In this study, mechanisms of resistance to imatinib-induced apoptosis in human Meg-01 CML cells were examined. Continuous exposure of cells to step-wise increasing concentrations of imatinib resulted in the selection of 200- and 1000 nM imatinib-resistant sub-lines referred to as Meg-01/IMA-0,2 and Meg-01/1MA-1, respectively. MTT cell proliferation, cell cycle analyses and trypan blue dye exclusion analyses showed that Meg-0l/IMA-1 cells were resistant to imatinib-induced apoptosis as compared to parental sensitive cells. There was an increased expression of BCR/ABL, Bcl-2 and an increase in mitochondrial membrane potential (MMP) detected in resistant cells comparing to parental sensitive cells. There was no mutation detected in imatinib binding site of ABL kinase region. Various diverse mechanisms have been reported for their involvement in the multidrug resistance. In this study, it has been shown that the degree of BCR/ABL expression appears to be directly proportional to the levels of imatinib resistance. In addition, there have been BCR/ABL-independent mechanisms reported for deriving resistance against imatinib. Our results revealed that besides BCR/ABL overexpression, imatinib resistance also depends on the inhibition of apoptosis as a result of up-regulation of anti-apoptotic stimuli and down-regulation of pro-apoptotic stimuli through MMP but does not depend on any mutation on imatinib binding site of ABL kinase.Article Citation - WoS: 19Citation - Scopus: 21Altered Conductance and Permeability of Cx40 Mutations Associated With Atrial Fibrillation(Rockefeller University Press, 2015) Meşe Özçivici, Gülistan; Meşe, Gülistan; Valiuniene, Laima; Brink, Peter R; White, Thomas W.; Valiunas, Virginijus; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyGap junctions ensure the rapid propagation of the action potential throughout the myocardium. Three mutant forms of connexin40 (Cx40; A96S, M163V, and G38D), the primary component of the atrial gap junction channel, are associated with atrial fibrillation and retain the ability to form functional channels. We determined the biophysical properties of these mutant gap junctions in transiently transfected HeLa and N2A cells. All three mutants showed macroscopic junctional conductances over the range of 0.5 to 40 nS, and voltage dependences comparable to those of wild-type (WT) Cx40. However, the unitary conductance of G38D channels was ~1.6-fold higher than that of WT Cx40 channels (~220 vs. ~135 pS), whereas the unitary conductances of the A96S and M163V mutants were similar to that of WT Cx40. Furthermore, the M163V and G38D channels exhibited approximately two- and approximately fivefold higher permeability to the anionic dye Lucifer yellow (LY) relative to K+ (LY/K+) compared with that of WT Cx40, whereas A96S LY transfer was similar to that of WT (G38D > M163V > A96S ? Cx40WT). In contrast, G38D channels were almost impermeable to cationic ethidium bromide (EtBr), suggesting that G38D alters channel selectivity. Conversely, A96S and M163V channels showed enhanced EtBr permeability relative to WT Cx40, with the following permeability order: M163V > A96S > Cx40WT > G38D. Altered conductive and permeability properties of mutant channels suggest an essential role for Cx40-mediated biochemical and electrical coupling in cardiac tissues. The altered properties of the three single-base substitution mutants may play a role in mechanisms of reentry arrhythmias. © 2015 Santa Cruz et al.Conference Object Suppression of STAT5A and STAT5B Chronic Myeloid Leukemia Cells Via SiRNA and Antisense-Oligonucleotide Applications With the Induction of Apoptosis(Wiley, 2014) Kaymaz, Burcin Tezcanli; Selvi, Nur; Baran, Yusuf; Adan Gökbulut, Aysun; Gunduz, Cumhur; Saydam, Guray; Kosova, Buket; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologySignal transducers and activators of transcription ( STAT) proteins function in the JAK/STAT signaling pathway and are activated by phosphorylation. As a result of this signaling event, they affect many cellular processes including cell growth, proliferation, differentiation, and survival. Increases in the expressions of STAT5A and STAT5B play a remarkable role in the development of leukemia in which leukemic cells gain uncontrolled proliferation and angiogenesis ability. At the same time, these cells acquire ability to escape from apoptosis and host immune system. In this study, we aimed to suppress STAT-5A and -5B genes in K562 CML cells by siRNA transfection and antisense oligonucleotides (ODN) targeting and then to evaluate apoptosis rate. Finally, we compared the transfection efficiencies of these approaches. Quantitative RT-PCR and Western blot results indicated that STAT expressions were downregulated at both mRNA and protein levels following siRNA transfection. However, electroporation mediated ODN transfection could only provide limited suppression rates at mRNA and protein levels. Moreover, it was displayed that apoptosis were significantly induced in siRNA treated leukemic cells as compared to ODN treated cells. As a conclusion, siRNA applications were found to be more effective in terms of gene silencing when compared to ODN treatment based on the higher apoptosis and mRNA suppression rates. siRNA application could be a new and alternative curative method as a supporting therapy in CML patients.Article Citation - WoS: 44Hesperidin Promotes Programmed Cell Death by Downregulation of Nongenomic Estrogen Receptor Signalling Pathway in Endometrial Cancer Cells(Elsevier Ltd., 2018) Cincin, Zeynep Birsu; Baran, Yusuf; Kıran, Bayram; Baran, Yusuf; Çakmakoğlu, Bedia; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyEndometrial carcinoma (EC) is the most common malignant gynecologic tumor in women. EC is thought to be caused by increasing estrogen levels relative to progesterone in the body. Hesperidin (Hsd), a biologically active flavonoid, could be extracted from Citrus species. It has been recently shown that Hsd could exert anticarcinogenic properties in different cancer types. However, the effects of Hsd and its molecular mechanisms on EC remain unclear. In this study, the antiproliferative, apoptotic and genomic effects of Hsd in EC and its underlying mechanisms were identified. We found that Hsd significantly suppressed the proliferation of EC cells in dose and time dependent manner. Mechanistic studies showed that Hsd could contribute apoptosis by inducing externalization of phosphatidyl serine (PS), caspase-3 activity and loss of mitochondrial membrane (MMP). Furthermore, we examined that Hsd could also significantly upregulate the expression of proapoptotic Bax subgroup genes (Bax and Bik) while downregulating the anti-apoptotic protein Bcl-2 in EC cell lines. According to GO enrichment and KEGG pathway analysis of differentially expressed genes in Hsd treated EC cells, we identified that Hsd could promote cell death via downregulation of estrogen receptor I (ESRI) that was directly related to ERK/MAPK pathway. Taken together, our study first showed that Hsd could be an antiestrogenic compound that could modulate nongenomic estrogen receptor signaling through inhibition of EC cell growth. Our findings may provide us a novel growth inhibitory agent for EC treatment after verifying its molecular mechanism with in vivo studies.Article Citation - WoS: 13Citation - Scopus: 15Cytotoxic Tolerance of Healthy and Cancerous Bone Cells To Anti-Microbial Phenolic Compounds Depend on Culture Conditions(Humana Press, 2019) Özçivici, Engin; Meşe Özçivici, Gülistan; Özçivici, Engin; 03.01. Department of Bioengineering; 04.03. Department of Molecular Biology and Genetics; 03. Faculty of Engineering; 04. Faculty of Science; 01. Izmir Institute of TechnologyCarnosol and carnosic acid are polyphenolic compounds found in rosemary and sage with known anti-oxidant, anti-inflammatory, and anti-microbial properties. Here, we addressed the potential use of carnosol and carnosic acid for in vitro bone tissue engineering applications, specifically depending on their cytotoxic effects on bone marrow stromal and stem cells, and osteosarcoma cells in monolayer and 3D cultures. Carnosol and carnosic acid displayed a bacteriostatic effect on Gram-positive bacteria, especially on S. aureus. The viability results indicated that bone marrow stromal cells and bone marrow stem cells were more tolerant to the presence of carnosol compared to osteosarcoma cells. 3D culture conditions increased this tolerance further for healthy cells, while not affecting the cytotoxic potential of carnosol for osteosarcoma cells. Carnosic acid was found to be more cytotoxic for all cell types used in the study. Results suggest that phenolic compounds might have potential use as anti-microbial and anti-carcinogenic agents for bone tissue engineering with further optimization for controlled release.Article Citation - WoS: 24Citation - Scopus: 23Polyethers Isolated From the Marine Actinobacterium Streptomyces Cacaoi Inhibit Autophagy and Induce Apoptosis in Cancer Cells(Elsevier, 2019) Khan, Nasar; Tosun, Çiğdem; Yılmaz, Sinem; Bedir, Erdal; Aksoy, Semiha; Yılmaz, Sinem; Uzel, Ataç; Tosun, Çiğdem; Ballar Kırmızıbayrak, Petek; Bedir, Erdal; 04.03. Department of Molecular Biology and Genetics; 03.01. Department of Bioengineering; 03. Faculty of Engineering; 04. Faculty of Science; 01. Izmir Institute of TechnologyPolyether compounds, a large group of biologically active metabolites produced by Streptomyces species have been reported to show a variety of bioactivity such as antibacterial, antifungal, antiparasitic, antiviral, and tumour cell cytotoxicity. Since some of these compounds target cancer stem cells and multi-drug resistant cancer cells, this family of compounds have become of high interest. In this study, three polyether-type metabolites (1-3), one of which was a new natural product (3), were isolated from the marine derived Streptomyces cacaoi via antimicrobial activity-guided fractionation studies. As several polyether compounds with structural similarity such as monensin have been linked with autophagy and cell death, we first assessed the cytotoxicity of these three compounds. Compounds 2 and 3, but not 1, were found to be cytotoxic in several cell lines with a higher potency towards cancer cells. Furthermore, 2 and 3 caused accumulation of both autophagy flux markers LC3-II and p62 along with cleavage of caspase-3, caspase-9 and poly (ADP-ribose) polymerase 1 (PARP-1). Interestingly, prolonged treatment of the compounds caused a dramatic downregulation of the proteins related to autophagasome formation in a dose dependent manner. Our findings provide insights on the molecular mechanisms of the polyether-type polyketides, and signify their potency as chemotherapeutic agents through inhibiting autophagy and inducing apoptosis.Article Citation - WoS: 9Citation - Scopus: 10Characterization of Long Living Yeast Deletion Mutants That Lack Mitochondrial Metabolism Genes Dss1, Ppa2 and Afg3(Elsevier, 2019) Muid, Khandaker Ashfaqul; Koç, Ahmet; Kimyon, Önder; Karakaya, Hüseyin Çağlar; Reza, Shahadat Hasan; Karakaya, Hüseyin Çağlar; Koç, Ahmet; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyMolecular mechanisms of aging and longevity are still mostly unknown. Mitochondria play central roles in cellular metabolism and aging. In this study, we identified three deletion mutants of mitochondrial metabolism genes (ppa2 Delta, dss1 Delta, and afg3 Delta) that live longer than wild-type cells. These long-lived cells harbored significantly decreased amount of mitochondria] DNA (mtDNA) and reactive oxygen species (ROS). Compared to the serpentine nature of wild-type mitochondria, a different dynamics and distribution pattern of mitochondria were observed in the mutants. Both young and old long-lived cells produced relatively low but adequate levels of ATP for cellular activities. The status of the retrograde signaling was checked by expression of CIT2 gene and found activated in long-lived mutants. The mutant cells were also profiled for their gene expression patterns, and genes that were differentially regulated were determined. All long-lived cells comprised similar pleiotropic phenotype regarding mitochondrial dynamics and functions. Thus, this study suggests that DSS1, PPA2, and AFG3 genes modulate the lifespan by altering the mitochondrial morphology and functions.Article Citation - WoS: 7Citation - Scopus: 9Genomewide Elucidation of Drug Resistance Mechanisms for Systemically Used Antifungal Drugs Amphotericin B, Caspofungin, and Voriconazole in the Budding Yeast(American Society for Microbiology, 2019) Balkan, Çiğdem; Koç, Ahmet; Ercan, İlkcan; Akdeniz, Esra Şahin; Işık, Esin; Akdeniz, Esra Şahin; Balcıoğlu, Orhan; Kodedova, Marie; Koç, Ahmet; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyThere are only a few antifungal drugs used systemically in treatment, and invasive fungal infections that are resistant to these drugs are an emerging problem in health care. In this study, we performed a high-copy-number genomic DNA (gDNA) library screening to find and characterize genes that reduce susceptibility to amphotericin B, caspofungin, and voriconazole in Saccharomyces cerevisiae. We identified the PDR16 and PMP3 genes for amphotericin B, the RMD9 and SWH1 genes for caspofungin, and the MRS3 and TRI1 genes for voriconazole. The deletion mutants for PDR16 and PMP3 were drug susceptible, but the other mutants had no apparent susceptibility. Quantitative-PCR analyses suggested that the corresponding drugs upregulated expression of the PDR16, PMP3, SWH1, and MRS3 genes. To further characterize these genes, we also profiled the global expression patterns of the cells after treatment with the antifungals and determined the genes and paths that were up-or downregulated. We also cloned Candida albicans homologs of the PDR16, PMP3, MRS3, and TRI1 genes and expressed them in S. cerevisiae. Heterologous expression of Candida homologs also provided reduced drug susceptibility to the budding yeast cells. Our analyses suggest the involvement of new genes in antifungal drug resistance.Article Citation - WoS: 27Citation - Scopus: 30Antibiotic-Resistant Staphylococcus Aureus Does Not Develop Resistance To Vanillic Acid and 2-Hydroxycinnamic Acid After Continuous Exposure in Vitro(American Chemical Society, 2019) Keman, Deniz; Keman, Deniz; Soyer, Ferda; Soyer, Ferda; 01. Izmir Institute of Technology; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of ScienceDevelopment of resistance to antibiotics is one of the major reasons of difficulties in treatments of diseases caused by antibiotic-resistant bacteria, and this resistance makes the investigation of alternative antimicrobials a key priority. Phenolic acids are plant- and fungi-originating natural antimicrobial products, and there is no known bacterial resistance after exposure to them. The purpose of this study was to investigate the resistance ability of bacteria against phenolic acids. Therefore, the ability of methicillin-resistant Staphylococcus aureus and methicillin-susceptible S. aureus to gain resistance against two phenolic acids and an antibiotic upon exposure to subinhibitory concentrations was tested. Herein, we evaluated the minimum inhibitory concentrations (MICs) of vanillic acid (VA), 2-hydroxycinnamic acid (2-HCA), and vancomycin in the beginning of the experiment and the MICs were found to be 2.5 mg/mL VA, 1.6 mg/mL 2-HCA, and 0.01 mg/mL vancomycin for both bacteria. Following continuous treatments with increasing subinhibitory concentrations, MICs were evaluated once more. Exposure to subinhibitory concentrations of vancomycin induced the development of resistance immediately; however, resistance to both phenolic acids could not be induced. These data indicated the potential of phenolic acids to be used as effective antimicrobials in the inhibition of antibiotic-resistant pathogenic bacteria.