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    Design, Synthesis, and Evaluation of Heat Shock Protein 90 Inhibitors in Human Breast Cancer and Its Metastasis
    (BENTHAM SCIENCE PUBL LTD, 2016) Gumus, Mehmet; Ozgur, Aykut; Tutar, Lutfi; Disli, Ali; Koca, Irfan; Tutar, Yusuf
    Background: Despite development of novel cancer drugs, invasive ductal breast carcinoma and its metastasis are still highly morbid. Therefore, new therapeutic approaches are being developed and Hsp90 is an important target for drug design. For this purpose, a series of benzodiazepine derivatives were designed and synthesized as novel Hsp90 inhibitor. Methods: Benzodiazepine derivatives anticancer activities were determined by XTT cell proliferation assay against human breast cancer cell line (MCF-7). Effects of the compounds on endothelial function were monitored on human vascular endothelium (HUVEC) cell line as well. In order to determine the anti-proliferative mechanism of the compounds, in silico molecular docking studies were performed between Hsp90 ATPase domain and the benzodiazepine derivatives. Further, these compounds perturbation on Hsp90 ATPase function were tested. Fluorescence binding experiments showed that the derivatives bind Hsp90 effectively. Expression analysis of known cancer drug target genes by PCR array experiments suggest that the benzodiazepine derivatives have remarkable anticancer activity. Results: A representative Benzodiazepine derivative D5 binds Hsp90 with Kd value of 3,93 mu M and with estimated free energy of binding -7.99 (kcal/mol). The compound decreases Hsp90 ATPase function and inhibit Hsp90 client protein folding activity. The compound inhibits expression of both Hsp90 isoforms and key proteins (cell cycle receptors; PLK2 and TERT, kinases; PI3KC3 and PRKCE, and growth factors; IGF1, IGF2, KDR, and PDGFRA) on oncogenic pathways. Conclusion: Benzodiazepine derivatives presented here display anticancer activity. The compounds effect on both breast cancer and endothelial cell lines show their potential as drug templates to inhibit breast cancer and its metastasis.
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    Heat Shock Proteins; An Overview
    (BENTHAM SCIENCE PUBL LTD, 2010) Tutar, Lutfi; Tutar, Yusuf
    Heat shock proteins (Hsps) protect protein substrates against conformational damage to promote the function of the proteins, prevent aggregation and prevent formation of toxic inclusion bodies. Protein aggregates and fibrils have been associated with neurodegenerative diseases and with inclusion bodies. High-level expression of recombinant protein for biotechnological purposes often leads to insoluble inclusion bodies. Therefore, misfolded proteins must be properly folded or must be degraded through heat shock protein action. This function protects cells against cytotoxic outcomes. In addition to their cytoprotective roles, Hsps are involved in other functions since Hsps exist in all types of cells and tissues. Therefore, several diseases are associated with alterations of these biochemical functions. This first review of the theme issue will discuss general properties of Hsps concisely along with their potential use in pharmaceutical and biotechnological applications.
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    Heat, pH Induced Aggregation and Surface Hydrophobicity of S. cerevesiae Ssa1 Protein
    (SPRINGER, 2010) Tutar, Yusuf; Arslan, Derya; Tutar, Lutfi
    Heat shock protein 70 is a conserved protein among organisms. Hsp70 helps substrate proteins to fold correctly. Unfolded substrate proteins increase the probability of the aggregate formation. High level recombinant protein expression in biotechnology often leads insoluble inclusion bodies. To prevent aggregation and to obtain high levels of soluble proteins, Hsp co-expression with desired recombinant protein in yeast becomes a popular method. For this purpose, S. cerevesiae cytosolic Hsp70 (Ssa1) biochemical properties were characterized. Alteration of Ssa1 structure between ATP- and ADP-bound states regulates its function. Therefore, conformation-dependent Ssa1 hydrophobicity and as a result aggregation may also play a key role in Ssa1 function. Therefore, a combination of FTIR, acrylamide quenching, and ANS was used to investigate the effect of nucleotide binding on the structure of Ssa1. Ssa1 secondary structure alterations and hydrophobic properties in aqueous solutions with differing ionic strengths and temperature were also studied.
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    Isolation and Identification of Free-Living Amoebae from Tap Water in Sivas, Turkey
    (HINDAWI PUBLISHING CORPORATION, 2013) Coskun, Kubra Acikalin; Ozcelik, Semra; Tutar, Lutfi; Elaldi, Nazif; Tutar, Yusuf
    The present work focuses on a local survey of free-living amoebae (FLA) that cause opportunistic and nonopportunistic infections in humans. Determining the prevalence of FLA in water sources can shine a light on the need to prevent FLA related illnesses. A total of 150 samples of tap water were collected from six districts of Sivas province. The samples were filtered and seeded on nonnutrient agar containing Escherichia coli spread. Thirty-three (22%) out of 150 samples were found to be positive for FLA. The FLA were identified by morphology and by PCR using 18S rDNA gene. The morphological analysis and partial sequencing of the 18S rDNA gene revealed the presence of three different species, Acanthamoeba castellanii, Acanthamoeba polyphaga, and Hartmannella vermiformis. Naegleria fowleri, Balamuthia mandrillaris, or Sappinia sp. was not isolated during the study. All A. castellanii and A. polyphaga sequence types were found to be genotype T4 that contains most of the pathogenic Acanthamoeba strains. The results indicated the occurrence and distribution of FLA species in tap water in these localities of Sivas, Turkey. Furthermore, the presence of temperature tolerant Acanthamoeba genotype T4 in tap water in the region must be taken into account for health risks.
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    MicroRNAs and Cancer; an Overview
    (BENTHAM SCIENCE PUBL LTD, 2014) Tutar, Lutfi; Tutar, Esen; Tutar, Yusuf
    MiRNAs are a family of small, endogenous, and evolutionarily conserved non-coding ribonucleic acids that have been involved in the regulation of several essential, cellular, and functional processes. MicroRNAs are known to play key roles in all types of cancer and function as oncogenes (oncomirs) or tumour-suppressors in up-regulation or down-regulation processes respectively. MiRNAs have potential power to be examined as prognostic and diagnostic biomarkers. Modulating miRNAs, based on two major approaches (miRNA mimics and miRNA antagonists), is used for clinical development of therapeutic miRNAs. This review emphasizes the latest discovery in the field of miRNA research involved in cancer, biomarkers, and therapeutics.
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    Pyrazolyl-Benzoxazinone Derivatives as Dual Hsp Inhibitors in Human Breast Cancer
    (Wiley-V C H Verlag Gmbh, 2022) Koca, Irfan; Kamaci, Volkan; Ozsoy, Ceylan; Sert, Yusuf; Kani, Ibrahim; Tutar, Lutfi; Tutar, Yusuf
    Heat Shock Proteins (Hsps) play major role on the onset of several cancers. Metabolic rates of cancer cells are higher compared to that of untransformed cells. This accelerated rate force functional substrate proteins to fold faster than normal folding rate. Although, the process leads cell cycle halting and eventually induces apoptosis, Hsps help cell survival and inhibit apoptosis and fold substrate proteins especially signaling proteins. When cancer cells accelerate the metabolism for invasion and metastasis, substrate proteins must fold to their native state rapidly. Since, functional forms of the proteins must be folded properly, cancer cells overexpress Hsps to fold substrate proteins and avoid apoptosis. Hsp90 and Hsp70 play key role in these processes. Inhibition of either Hsp90 or Hsp70 display complementary function. Therefore, dual inhibition of Hsp70 and Hsp90 potentially provides anticancer affect. In silico studies showed that pyrazolyl-benzoxazine derivatives display binding activity for both Hsps. For this purpose, pyrazole-3-carbonyl chloride were converted to pyrazolyl-benzoxazine derivatives via reactions of anthranilic acids in good yields (68-83 %). The structures of the newly synthesized compounds were elucidated by IR-NMR spectroscopy, elemental analysis, and single-crystal X-ray diffraction. Binding of the compounds inhibit function of Hsps and cause cytotoxic effect over MCF-7 cells. The compounds display potential anticancer effects.
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    Regulation of oncogenic genes by MicroRNAs and pseudogenes in human lung cancer
    (ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2016) Tutar, Yusuf; Ozgur, Aykut; Tutar, Esen; Tutar, Lutfi; Pulliero, Alessandra; Izzotti, Alberto
    Lung cancer is one of the most common mortal cancer types both for men and women. Several different biomarkers have been analyzed to reveal lung cancer prognosis pathways for developing efficient therapeutics and diagnostic agents. microRNAs (miRNAs) and pseudogenes are critical biomarkers in lung cancer and alteration of their expression levels has been identified in each step of lung cancer tumorigenesis. miRNAs and pseudogenes are crucial gene regulators in normal cells as well as in lung cancer cells, and they have both oncogenic and tumor-suppressive roles in lung cancer tumorigenesis. In this study, we have determined the relationship between lung cancer related oncogenes and miRNAs along with pseudogenes in lung cancer, and the results indicate their potential as biological markers for diagnostic and therapeutic purposes. (C) 2016 Elsevier Masson SAS. All rights reserved.
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    Therapeutic Targeting of microRNAs in Cancer: Future Perspectives
    (WILEY-BLACKWELL, 2015) Tutar, Lutfi; Tutar, Esen; Ozgur, Aykut; Tutar, Yusuf
    The discovery of microRNAs (miRNAs) and their link with cancer has opened a new era in cancer therapeutics. Approximately, 18-24 nucleotides long, miRNAs can up-regulate or down-regulate gene expression in many cancer types and are respectively categorized as oncogenes (oncomirs) or tumor suppressors. Expression profiles of miRNAs with biomarker potential can be used for the classification, diagnosis, therapeutic treatment, and prognosis of different cancer types. miRNA mimics and miRNA antagonists are the two main approaches to miRNA-based cancer therapies that respectively inhibit oncomirs or restore the expression of tumor suppressive miRNAs. This review serves to provide some general insight into miRNA biogenesis, cancer related miRNAs, and miRNA therapeutics. Drug Dev Res 76 : 382-388, 2015. (c) 2015 Wiley Periodicals, Inc.
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    Tumor Targeting of Polymeric Nanoparticles Conjugated with Peptides, Saccharides, and Small Molecules for Anticancer Drugs
    (BENTHAM SCIENCE PUBL LTD, 2017) Bayram, Banu; Ozgur, Aykut; Tutar, Lutfi; Tutar, Yusuf
    Targeting drugs or pharmaceutical compounds to tumor site increases cancer treatment efficiency and therapeutic outcome. Nanoparticles are unique delivery systems for site-targeting within an organism. Many novel technologies have been established in drug research and development area. Nanotechnology now offers nanometer size polymeric nanoparticles and these particles direct drugs to their targets, protect drugs against degradation, and release the drug in a controlled manner. Modification of nanoparticle surface by molecules leads to prolonged retention and accumulation in the target area of the organism. Current efforts of designing polymeric nanoparticles include drug activation in the target area, controlled drug release at the site upon stimulation, and increased drug loading capacity of drug polymer conjugates. Recent progress in molecular mechanism elucidation of cancer cell and rising research in nanoparticle designs may provide efficient cancer treatment modality and innovative nanoparticle designs in the near future. Recent years have seen many developments in the field of innovative peptide based drug nanoparticles. Although none of them approved to be used in clinics yet, peptides are promising structures due to their simple and non-antigenic nature. Biodegradable materials are also preferred materials in drug delivery. Polysaccharide-based micelle systems improve hydrophobic drug and protein delivery. Ease of saccharide structure modification improves pharmacokinetic and pharmacodynamic properties of drug molecules as well as their delivery to a specific site in a controlled manner and sustained rate. Small molecules, especially drugs, conjugated to nanoparticles and several nanoparticles of this type are in the clinical trials and at the market. This review provides recent developments of polymeric nanoparticles conjugated with peptides, saccharides, and small molecules in cancer theraphy.
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    Ydj1 but not Sis1 stabilizes Hsp70 protein under prolonged stress in vitro
    (JOHN WILEY & SONS INC, 2008) Tutar, Lutfi; Tutar, Yusuf
    Yeast cytosol has two important co-chaperons; Ydj1 and Sis1. Genetic experiments showed that Ydj1 is not I essential for viability; however, cells lacking it grow very poorly at 30 degrees C or unable to grow at extreme temperatures. On the other hand, Sis1 is an essential protein and apparently plays a functional role at assembly or disassembly of protein complexes. Stability experiments revealed that only Ydj1-protected Hsp70 proteins can hydrolyze ATP under prolonged stress. (c) 2007 Wiley Periodicals, Inc.