Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
Permanent URI for this collectionhttps://hdl.handle.net/11147/9
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Article Citation - WoS: 15Citation - Scopus: 13Environmentally Responsive Dual-Targeting Nanoparticles: Improving Drug Accumulation in Cancer Cells as a Way of Preventing Anticancer Drug Efflux(John Wiley and Sons Inc., 2018) Dağlıoğlu, CenkDrug targeting and stimuli-responsive drug release are 2 active areas of cancer research and hold tremendous potential in the management of cancer drug resistance. In this study, I addressed this issue and focused on the synthesis and characterization of pH-responsive Fe3O4@SiO2(FITC)-BTN/folic acid/DOX multifunctional nanoparticles aiming to increase drug accumulation in malignancies with both dual active targeting and endosomal drug release properties. Dye-doped silica magnetic-fluorescent composite was constructed by a simple coprecipitation of Fe+2/Fe+3 salts followed by sol-gel formation and dual-targeting function was obtained by conjugating folate and biotin moieties on the silica surface of nanoparticles via an esterification reaction. Doxorubicin was then successfully attached on the amine-functionalized nanoparticles using a pH-sensitive Schiff-base formation. The physicochemical characterization of the structure was performed by dynamic light scattering, zeta potential measurement, X-ray diffraction, Fourier transform infrared spectroscopy, electron microscopy techniques, and an in vitro pH-dependent release study. Cellular uptake and cytotoxicity experiments demonstrated an enhanced intracellular delivery and reduction of cancer cell viability in the cervical carcinoma HeLa cell line. Furthermore, proapoptotic studies showed that the nanoparticles increased the apoptotic rates within the same cancer cells. The preliminary cell tests confirm the potential of these multifunctional nanoparticles against the development of drug resistance in cancer cells.Article Citation - WoS: 90Citation - Scopus: 94Progesterone and Wnt4 Control Mammary Stem Cells Via Myoepithelial Crosstalk(John Wiley and Sons Inc., 2015) Rajaram, Renuga Devi; Buric, Duje; Caikovski, Marian; Ayyanan, Ayyakkannu; Rougemont, Jacques; Shan, Jingdong; Vainio, Seppo J.; Yalçın Özuysal, Özden; Brisken, CathrinOvarian hormones increase breast cancer risk by poorly understood mechanisms. We assess the role of progesterone on global stem cell function by serially transplanting mouse mammary epithelia. Progesterone receptor (PR) deletion severely reduces the regeneration capacity of the mammary epithelium. The PR target, receptor activator of Nf-κB ligand (RANKL), is not required for this function, and the deletion of Wnt4 reduces the mammary regeneration capacity even more than PR ablation. A fluorescent reporter reveals so far undetected perinatal Wnt4 expression that is independent of hormone signaling. Pubertal and adult Wnt4 expression is specific to PR+ luminal cells and requires intact PR signaling. Conditional deletion of Wnt4 reveals that this early, previously unappreciated, Wnt4 expression is functionally important. We provide genetic evidence that canonical Wnt signaling in the myoepithelium required PR and Wnt4, whereas the canonical Wnt signaling activities observed in the embryonic mammary bud and in the stroma around terminal end buds are independent of Wnt4. Thus, progesterone and Wnt4 control stem cell function through a luminal-myoepithelial crosstalk with Wnt4 acting independent of PR perinatally. Synopsis This paper ascribes a new role for Wnt4 in pre-pubertal mammary gland development while revealing luminal cells to respond to Wnt activation. During regeneration, Wnt4 interacts with progesterone receptor signaling, correcting previous notions on RANKL signaling in this context. Wnt4 is an essential control factor for mammary epithelial stem cell function. RANKL is not required for mammary gland regeneration potential. Wnt4 activates canonical Wnt signaling in the basal/myoepithelial compartment. Progesterone receptor signaling is required for mammary epithelial Wnt4 expression already during puberty. This paper ascribes a new role for Wnt4 in pre-pubertal mammary gland development while revealing luminal cells to respond to Wnt activation. During regeneration, Wnt4 interacts with progesterone receptor signaling, correcting previous notions on RANKL signaling in this context.Article Citation - WoS: 44Citation - Scopus: 42Inflammation-Mediated Abrogation of Androgen Signaling: an in Vitro Model of Prostate Cell Inflammation(John Wiley and Sons Inc., 2014) Debeleç Bütüner, Bilge; Alapınar, Cansu; Varışlı, Lokman; Erbaykent Tepedelen, Burcu; Hamid, Syed Muhammad; Gönen Korkmaz, Ceren; Korkmaz, Kemal SamiAs a link between inflammation and cancer has been reported in many studies, we established an in vitro model of prostatic inflammation to investigate the loss of androgen receptor (AR)-mediated signaling in androgen responsive prostate cell lines. First, the U937 monocyte cell line was differentiated into macrophages using phorbol acetate (PMA), and cells were induced with lipopolysaccharide (LPS) for cytokine secretion. Next, the cytokine levels (TNFα, IL-6, and IL1β) in conditioned media (CM) were analyzed. Prostate cells were then fed with CM containing varying concentrations of TNFα, and IkB degradation, nuclear factor kappa B (NFκB) translocation and transactivation, and the expression of matrix metalloproteinase-8 (MMP8) and matrix metalloproteinase-9 (MMP9) were then assessed. As a result of CM treatment, ubiquitin-mediated AR degradation, which was restored using anti-TNFα antibody neutralization, led to both a decrease in KLK4, PSA, and NKX3.1 expression levels and the upregulation of GPX2. In addition to the loss of AR, acute and chronic CM exposure resulted in p53 degradation and consequent p21 downregulation, which was also restored by either androgen administration or ectopic NKX3.1 expression via the stabilization of MDM2 levels in LNCaP cells. Additionally, CM treatment enhanced H2AX(S139) phosphorylation (a hallmark of DNA damage) and genetic heterogeneity in the absence of androgens in prostate cells without activating mitochondrial apoptosis. Thus, the data suggest that inflammatory cytokine exposure results in the loss of AR and p53 signaling in prostate cells and facilitates genetic heterogeneity via ROS accumulation to promote prostate carcinogenesis.Article Citation - WoS: 24Citation - Scopus: 26Development of Est-Ssr Markers for Diversity and Breeding Studies in Opium Poppy(John Wiley and Sons Inc., 2013) Şelale, Hatice; Çelik, İbrahim; Gültekin, Visam; Allmer, Jens; Doğanlar, Sami; Frary, AnneAll publicly available opium poppy expressed sequence tag (EST) sequences, totalling 20 885, were assembled into unigenes and examined for simple sequence repeats (SSRs). Nearly 19% of the 14 957 unigenes contained SSRs with 4% harbouring more than one SSR. Average density of the SSRs was 1 SSR per 3.6 kb of non-redundant EST sequence. Trinucleotide SSRs were most frequently identified (39%), and many of the most prevalent motifs were AT-rich. Flanking primers were designed for 86% of the SSRs and 67 primer pairs were tested on 37 opium poppy accessions and seven related species. All markers were transferable to the related species. Polymorphism information content (PIC) values for the markers were intermediate for comparisons within opium poppy (average of 0.27) and slightly higher for comparisons across species (average of 0.29). The markers were found to be useful for diversity analysis as they successfully distinguished among Turkish opium poppy accessions and land races.Article Citation - WoS: 5Citation - Scopus: 7Imatinib-Induced Apoptosis: a Possible Link To Topoisomerase Enzyme Inhibition(John Wiley and Sons Inc., 2011) Baran, Yusuf; Zencir, Sevil; Çakır, Zeynep; Öztürk, Esra; Topçu, ZekiSummary What is known and Objective: Imatinib is a specific BCR/ABL inhibitor, commonly used for the treatment of chronic myeloid leukaemia (CML), a hematological malignancy resulting from a chromosomal translocation that generates the BCR/ABL fusion protein. Recent studies showed that the imatinib has cytotoxic and apoptotic effects on many BCR/ABL-negative cancers. Numerous compounds with cytotoxic potential exert their functions by interfering with the DNA topoisomerase. In this study, we examined the effects of imatinib on tumour cell-killing in relation to DNA topoisomerase enzyme inhibition. Methods: We determined the cytotoxicity by cell proliferation assay (XTT; tetrazolium hydroxide), using the human K562 CML cells, and loss of mitochondrial membrane potential by monitoring the changes in caspase-3 enzyme activity. Type I and II topoisomerase activities were measured by supercoiled plasmid relaxation and minicircle DNA decatenation assays respectively. Results and Discussion: Imatinib-induced apoptosis and inhibited cell proliferation in a dose-dependent manner. We also found that the imatinib was effective in both type I and type II topoisomerase reactions to a varying degree between 94% and 7% for the concentration range of 1 mm-0.02 mm in a dose-dependent manner. What is new and Conclusion: Our results suggest that the inhibition of topoisomerases may be a significant factor in imatinib-induced apoptosis in CML.Article Citation - WoS: 38Citation - Scopus: 47Docetaxel/Zoledronic Acid Combination Triggers Apoptosis Synergistically Through Downregulating Antiapoptotic Bcl-2 Protein Level in Hormone-Refractory Prostate Cancer Cells(John Wiley and Sons Inc., 2009) Karabulut, B.; Erten, C.; Gül, M. K.; Cengiz, E.; Karaca, B.; Küçükzeybek, Y.; Görümlü, G.; Atmaca, H.; Uzunoğlu, S.; Şanlı, U. A.; Baran, Yusuf; Uslu, R.Docetaxel, a semi-synthetic taxane analogue, is used effectively in the treatment of metastatic prostate cancer. Zoledronic acid, the most potent member of bisphosphonates, has shown pleiotropic anti-tumoral effects on prostate cancer cells. We have explored the possible additive/synergistic effects and the apoptotic pathways induced by combination treatment of docetaxel and zoledronic acid in hormone and drug refractory, PC-3 and DU-145 prostate cancer cells. Combination of docetaxel and zoledronic acid synergistically inhibits cell growth in PC-3 and DU-145 cells. Moreover, this effect was due to downregulation of antiapoptotic protein Bcl-2 in PC-3 and DU-145 cells. In conclusion, docetaxel/zoledronic acid combination is potentially a novel and effective approach for the treatment of prostate cancer.Article Citation - WoS: 23Citation - Scopus: 29Physical Properties of Biopolymers Containing Natamycin and Rosemary Extract(John Wiley and Sons Inc., 2009) Türe, Hasan; Özen, Fatma Banu; Eroğlu, Erdal; Soyer, Ferda; Özen, Banu; Soyer, FerdaAntifungal biopolymers were prepared by incorporating natamycin (NA) and NA + rosemary extract (RE) into wheat gluten (WG) and methyl cellulose (MC) films. Interaction between antimicrobial agents and biopolymers was determined with mid-infrared spectroscopy and scanning electron microscopy (SEM). Water vapour permeability and mechanical properties of these films were also measured. Mid-infrared spectroscopy did not indicate any interaction. SEM observations showed that NA crystallises at high concentrations in biopolymers. There were no significant changes in water vapour permeabilities of biopolymers containing active agents at P < 0.05. While NA incorporation did not result in any changes in mechanical properties of WG films a reduction in tensile strength was observed for MC films containing high concentration of NA. In general, active agent incorporation into WG and MC films did not result in any considerable changes in their physical properties that could affect their application.Article Citation - WoS: 66Citation - Scopus: 81Effect of Biopolymers Containing Natamycin Against Aspergillus Niger and Penicillium Roquefortii on Fresh Kashar Cheese(John Wiley and Sons Inc., 2011) Türe, Hasan; Eroğlu, Erdal; Özen, Banu; Soyer, FerdaFungal spoilage during refrigerated storage is one of the main safety and quality-related problems for dairy products. The effect of wheat gluten (WG) and methyl cellulose (MC) biopolymers containing natamycin (NA) on the growth of Aspergillus niger and Penicillium roquefortii on the surface of fresh kashar cheese during storage at 10 C for 30 days was investigated. Wrapping of A. niger-inoculated cheese with MC films containing 5–20 mg NA per 10 g resulted in approximately 2-log reductions in spore count. Two mg NA per 10 g included into WG films was sufficient to eliminate A. niger on the surface of cheese. However, MC and WG films containing NA did not cause any significant decrease in P. roquefortii count on the cheese surface. Therefore, especially use WG films in dairy applications could be an effective way of controlling A. niger growth on these products.Article Citation - WoS: 32Citation - Scopus: 34Therapeutic Applications of Bioactive Sphingolipids in Hematological Malignancies(John Wiley and Sons Inc., 2010) Ekiz, Hüseyin Atakan; Baran, YusufSphingolipids are sphingosine-based lipid molecules that have important functions in cellular signal transduction and in a variety of cellular processes including proliferation, differentiation, programmed cell death (apoptosis) and responses to stressful conditions. Ceramides, dihydroceramide, sphingosine and sphingosine-1-phosphate are examples of those bioactive sphingolipids. They have a major impact on determination of the cell fate by contributing to the cell survival or cell death through apoptosis. Despite the number of carbon atoms in the fatty acid chain changes the physiological role; ceramides generally exert suppressive roles on the cell proliferation. There have been several enzymes identified in this pathway that are responsible for the conversion of ceramide into other sphingolipid derivatives. Those derivatives also have differential roles on those cellular processes. Sphingosine-1-phosphate is an example of such sphingolipid derivatives which has antiapoptotic effects. As they have significant impacts particularly on the cell death and survival, bioactive sphingolipids have a great potential to be targets in cancer therapy. Increasing number of studies indicates that sphingolipid derivatives are important in the progression of hematological malignancies, and they are also involved in the resistance to current chemotherapeutic options. This review compiles the current knowledge in this area for enlightening the therapeutic potentials of bioactive sphingolipids in various leukemias. © 2010 UICC.Article Citation - WoS: 29Citation - Scopus: 29Methionine Sulfoxide Reduction and the Aging Process(John Wiley and Sons Inc., 2007) Koç, Ahmet; Gladyshev, Vadim N.Aging has been described for multicellular and asymmetrically dividing organisms, but the mechanisms are poorly understood. Oxidation of proteins is considered to be one of the major factors that leads to aging. Oxidative damage to proteins results in the oxidation of certain amino acid residues, among which oxidation of sulfur-containing amino acids, methionine and cysteine, is notable because of the susceptibility of these residues to damage, and occurrence of repair mechanisms. Methionine sulfoxide reductases, MsrA and MsrB, are thioredoxin-dependent oxidoreductases that reduce oxidized forms of methionine, methionine sulfoxides, in a stereospecific manner. These enzymes are present in all cell types and have shown to be regulating life spans in mammals, insects, and yeast. Here, their roles in modulating yeast life span are discussed.