Academic literature on the topic 'Type II topoisomerase; Enzyme'
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Journal articles on the topic "Type II topoisomerase; Enzyme"
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Kaufmann, S. H., and R. Hancock. "Topoisomerase II as a target for anticancer chemotherapy." Acta Biochimica Polonica 42, no. 4 (December 31, 1995): 381–93. http://dx.doi.org/10.18388/abp.1995_4892.
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Type II DNA topoisomerases are required for the segregation of genomic DNA at cell division in prokaryotic and eukaryotic cells, and inhibitors of these enzymes are potential cytotoxic agents in both prokaryotes and eukaryotes. The bacterial member of the topoisomerase II family, DNA gyrase, and the chemotherapeutic agents which target it are the subject of a recent review (Maxwell, A. et al., 1993, in Molecular Biology of DNA Topoisomerases, Andoh, T. et al., eds., pp. 21-30, CRC Press, Boca Raton). Here we present an overview of current knowledge of eukaryotic topoisomerase II and the anticancer agents which target this enzyme, focussing predominantly on new observations and recent reports and reviews.
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Takei, Masaya, Hideyuki Fukuda, Tokutaro Yasue, Masaki Hosaka, and Yasuo Oomori. "Inhibitory Activities of Gatifloxacin (AM-1155), a Newly Developed Fluoroquinolone, against Bacterial and Mammalian Type II Topoisomerases." Antimicrobial Agents and Chemotherapy 42, no. 10 (October 1, 1998): 2678–81. http://dx.doi.org/10.1128/aac.42.10.2678.
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ABSTRACT We determined the inhibitory activities of gatifloxacin againstStaphylococcus aureus topoisomerase IV,Escherichia coli DNA gyrase, and HeLa cell topoisomerase II and compared them with those of several quinolones. The inhibitory activities of quinolones against these type II topoisomerases significantly correlated with their antibacterial activities or cytotoxicities (correlation coefficient [r] = 0.926 forS. aureus, r = 0.972 for E. coli, and r = 0.648 for HeLa cells). Gatifloxacin possessed potent inhibitory activities against bacterial type II topoisomerases (50% inhibitory concentration [IC50] = 13.8 μg/ml for S. aureustopoisomerase IV; IC50 = 0.109 μg/ml for E. coli DNA gyrase) but the lowest activity against HeLa cell topoisomerase II (IC50 = 265 μg/ml) among the quinolones tested. There was also a significant correlation between the inhibitory activities of quinolones against S. aureustopoisomerase IV and those against E. coli DNA gyrase (r = 0.969). However, the inhibitory activity against HeLa cell topoisomerase II did not correlate with that against either bacterial enzyme. The IC50 of gatifloxacin for HeLa cell topoisomerase II was 19 and was more than 2,400 times higher than that for S. aureus topoisomerase IV and that for E. coli DNA gyrase. These ratios were higher than those for other quinolones, indicating that gatifloxacin possesses a higher selectivity for bacterial type II topoisomerases.
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Austin, Caroline, Ka Lee, Rebecca Swan, Mushtaq Khazeem, Catriona Manville, Peter Cridland, Achim Treumann, Andrew Porter, Nick Morris, and Ian Cowell. "TOP2B: The First Thirty Years." International Journal of Molecular Sciences 19, no. 9 (September 14, 2018): 2765. http://dx.doi.org/10.3390/ijms19092765.
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Type II DNA topoisomerases (EC 5.99.1.3) are enzymes that catalyse topological changes in DNA in an ATP dependent manner. Strand passage reactions involve passing one double stranded DNA duplex (transported helix) through a transient enzyme-bridged break in another (gated helix). This activity is required for a range of cellular processes including transcription. Vertebrates have two isoforms: topoisomerase IIα and β. Topoisomerase IIβ was first reported in 1987. Here we review the research on DNA topoisomerase IIβ over the 30 years since its discovery.
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Gruger, Thomas, John L. Nitiss, Anthony Maxwell, E. Lynn Zechiedrich, Peter Heisig, Siegfried Seeber, Yves Pommier, and Dirk Strumberg. "A Mutation in Escherichia coli DNA Gyrase Conferring Quinolone Resistance Results in Sensitivity to Drugs Targeting Eukaryotic Topoisomerase II." Antimicrobial Agents and Chemotherapy 48, no. 12 (December 2004): 4495–504. http://dx.doi.org/10.1128/aac.48.12.4495-4504.2004.
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ABSTRACT Fluoroquinolones are broad-spectrum antimicrobial agents that target type II topoisomerases. Many fluoroquinolones are highly specific for bacterial type II topoisomerases and act against both DNA gyrase and topoisomerase IV. In Escherichia coli, mutations causing quinolone resistance are often found in the gene that encodes the A subunit of DNA gyrase. One common site for resistance-conferring mutations alters Ser83, and mutations to Leu or Trp result in high levels of resistance to fluoroquinolones. In the present study we demonstrate that the mutation of Ser83 to Trp in DNA gyrase (GyrS83W) also results in sensitivity to agents that are potent inhibitors of eukaryotic topoisomerase II but that are normally inactive against prokaryotic enzymes. Epipodophyllotoxins, such as etoposide, teniposide and amino-azatoxin, inhibited the DNA supercoiling activity of GyrS83W, and the enzyme caused elevated levels of DNA cleavage in the presence of these agents. The DNA sequence preference for GyrS83W-induced cleavage sites in the presence of etoposide was similar to that seen with eukaryotic type II topoisomerases. Introduction of the GyrS83W mutation in E. coli strain RFM443-242 by site-directed mutagenesis sensitized it to epipodophyllotoxins and amino-azatoxin. Our results demonstrate that sensitivity to agents that target topoisomerase II is conserved between prokaryotic and eukaryotic enzymes, suggesting that drug interaction domains are also well conserved and likely occur in domains important for the biochemical activities of the enzymes.
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Blower, Tim R., Afif Bandak, Amy S. Y. Lee, Caroline A. Austin, John L. Nitiss, and James M. Berger. "A complex suite of loci and elements in eukaryotic type II topoisomerases determine selective sensitivity to distinct poisoning agents." Nucleic Acids Research 47, no. 15 (July 9, 2019): 8163–79. http://dx.doi.org/10.1093/nar/gkz579.
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AbstractType II topoisomerases catalyze essential DNA transactions and are proven drug targets. Drug discrimination by prokaryotic and eukaryotic topoisomerases is vital to therapeutic utility, but is poorly understood. We developed a next-generation sequencing (NGS) approach to identify drug-resistance mutations in eukaryotic topoisomerases. We show that alterations conferring resistance to poisons of human and yeast topoisomerase II derive from a rich mutational ‘landscape’ of amino acid substitutions broadly distributed throughout the entire enzyme. Both general and discriminatory drug-resistant behaviors are found to arise from different point mutations found at the same amino acid position and to occur far outside known drug-binding sites. Studies of selected resistant enzymes confirm the NGS data and further show that the anti-cancer quinolone vosaroxin acts solely as an intercalating poison, and that the antibacterial ciprofloxacin can poison yeast topoisomerase II. The innate drug-sensitivity of the DNA binding and cleavage region of human and yeast topoisomerases (particularly hTOP2β) is additionally revealed to be significantly regulated by the enzymes’ adenosine triphosphatase regions. Collectively, these studies highlight the utility of using NGS-based methods to rapidly map drug resistance landscapes and reveal that the nucleotide turnover elements of type II topoisomerases impact drug specificity.
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Strumberg, Dirk, John L. Nitiss, Jiaowang Dong, Jerrylaine Walker, Marc C. Nicklaus, Kurt W. Kohn, Jonathan G. Heddle, Anthony Maxwell, Siegfried Seeber, and Yves Pommier. "Importance of the Fourth Alpha-Helix within the CAP Homology Domain of Type II Topoisomerase for DNA Cleavage Site Recognition and Quinolone Action." Antimicrobial Agents and Chemotherapy 46, no. 9 (September 2002): 2735–46. http://dx.doi.org/10.1128/aac.46.9.2735-2746.2002.
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ABSTRACT We report that point mutations causing alteration of the fourth alpha-helix (α4-helix) of the CAP homology domain of eukaryotic (Saccharomyces cerevisiae) type II topoisomerases (Ser740Trp, Gln743Pro, and Thr744Pro) change the selection of type II topoisomerase-mediated DNA cleavage sites promoted by Ca2+ or produced by etoposide, the fluoroquinolone CP-115,953, or mitoxantrone. By contrast, Thr744Ala substitution had minimal effect on Ca2+- and drug-stimulated DNA cleavage sites, indicating the selectivity of single amino acid substitutions within the α4-helix on type II topoisomerase-mediated DNA cleavage. The equivalent mutation in the gene for Escherichia coli gyrase causing Ser83Trp also changed the DNA cleavage pattern generated by Ca2+ or quinolones. Finally, Thr744Pro substitution in the yeast type II topoisomerase rendered the enzyme sensitive to antibacterial quinolones. This study shows that the α4-helix within the conserved CAP homology domain of type II topoisomerases is critical for selecting the sites of DNA cleavage. It also demonstrates that selective amino acid residues in the α4-helix are important in determining the activity and possibly the binding of quinolones to the topoisomerase II-DNA complexes.
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Yi, Lanhua, and Xin Lü. "New Strategy on Antimicrobial-resistance: Inhibitors of DNA Replication Enzymes." Current Medicinal Chemistry 26, no. 10 (June 20, 2019): 1761–87. http://dx.doi.org/10.2174/0929867324666171106160326.
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Background:Antimicrobial resistance is found in all microorganisms and has become one of the biggest threats to global health. New antimicrobials with different action mechanisms are effective weapons to fight against antibiotic-resistance.Objective:This review aims to find potential drugs which can be further developed into clinic practice and provide clues for developing more effective antimicrobials.Methods:DNA replication universally exists in all living organisms and is a complicated process in which multiple enzymes are involved in. Enzymes in bacterial DNA replication of initiation and elongation phases bring abundant targets for antimicrobial development as they are conserved and indispensable. In this review, enzyme inhibitors of DNA helicase, DNA primase, topoisomerases, DNA polymerase and DNA ligase were discussed. Special attentions were paid to structures, activities and action modes of these enzyme inhibitors.Results:Among these enzymes, type II topoisomerase is the most validated target with abundant inhibitors. For type II topoisomerase inhibitors (excluding quinolones), NBTIs and benzimidazole urea derivatives are the most promising inhibitors because of their good antimicrobial activity and physicochemical properties. Simultaneously, DNA gyrase targeted drugs are particularly attractive in the treatment of tuberculosis as DNA gyrase is the sole type II topoisomerase in Mycobacterium tuberculosis. Relatively, exploitation of antimicrobial inhibitors of the other DNA replication enzymes are primeval, in which inhibitors of topo III are even blank so far.Conclusion:This review demonstrates that inhibitors of DNA replication enzymes are abundant, diverse and promising, many of which can be developed into antimicrobials to deal with antibioticresistance.
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Garinther, W. I., and M. C. Schultz. "Topoisomerase function during replication-independent chromatin assembly in yeast." Molecular and Cellular Biology 17, no. 7 (July 1997): 3520–26. http://dx.doi.org/10.1128/mcb.17.7.3520.
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DNA topoisomerases I and II are the two major nuclear enzymes capable of relieving torsional strain in DNA. Of these enzymes, topoisomerase I plays the dominant role in relieving torsional strain during chromatin assembly in cell extracts from oocytes, eggs, and early embryos. We tested if the topoisomerases are used differentially during chromatin assembly in Saccharomyces cerevisiae by a combined biochemical and pharmacological approach. As measured by plasmid supercoiling, nucleosome deposition is severely impaired in assembly extracts from a yeast mutant with no topoisomerase I and a temperature-sensitive form of topoisomerase II (strain top1-top2). Expression of wild-type topoisomerase II in strain top1-top2 fully restored assembly-driven supercoiling, and assembly was equally efficient in extracts from strains expressing either topoisomerase I or II alone. Supercoiling in top1-top2 extract was rescued by adding back either purified topoisomerase I or II. Using the topoisomerase II poison VP-16, we show that topoisomerase II activity during chromatin assembly is the same in the presence and absence of topoisomerase I. We conclude that both topoisomerases I and II can provide the DNA relaxation activity required for efficient chromatin assembly in mitotically cycling yeast cells.
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Hirsch, Jana, and Dagmar Klostermeier. "What makes a type IIA topoisomerase a gyrase or a Topo IV?" Nucleic Acids Research 49, no. 11 (April 27, 2021): 6027–42. http://dx.doi.org/10.1093/nar/gkab270.
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Abstract Type IIA topoisomerases catalyze a variety of different reactions: eukaryotic topoisomerase II relaxes DNA in an ATP-dependent reaction, whereas the bacterial representatives gyrase and topoisomerase IV (Topo IV) preferentially introduce negative supercoils into DNA (gyrase) or decatenate DNA (Topo IV). Gyrase and Topo IV perform separate, dedicated tasks during replication: gyrase removes positive supercoils in front, Topo IV removes pre-catenanes behind the replication fork. Despite their well-separated cellular functions, gyrase and Topo IV have an overlapping activity spectrum: gyrase is also able to catalyze DNA decatenation, although less efficiently than Topo IV. The balance between supercoiling and decatenation activities is different for gyrases from different organisms. Both enzymes consist of a conserved topoisomerase core and structurally divergent C-terminal domains (CTDs). Deletion of the entire CTD, mutation of a conserved motif and even by just a single point mutation within the CTD converts gyrase into a Topo IV-like enzyme, implicating the CTDs as the major determinant for function. Here, we summarize the structural and mechanistic features that make a type IIA topoisomerase a gyrase or a Topo IV, and discuss the implications for type IIA topoisomerase evolution.
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Kern, Gunther, Tiffany Palmer, David E. Ehmann, Adam B. Shapiro, Beth Andrews, Gregory S. Basarab, Peter Doig, et al. "Inhibition of Neisseria gonorrhoeae Type II Topoisomerases by the Novel Spiropyrimidinetrione AZD0914." Journal of Biological Chemistry 290, no. 34 (July 6, 2015): 20984–94. http://dx.doi.org/10.1074/jbc.m115.663534.
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We characterized the inhibition of Neisseria gonorrhoeae type II topoisomerases gyrase and topoisomerase IV by AZD0914 (AZD0914 will be henceforth known as ETX0914 (Entasis Therapeutics)), a novel spiropyrimidinetrione antibacterial compound that is currently in clinical trials for treatment of drug-resistant gonorrhea. AZD0914 has potent bactericidal activity against N. gonorrhoeae, including multidrug-resistant strains and key Gram-positive, fastidious Gram-negative, atypical, and anaerobic bacterial species (Huband, M. D., Bradford, P. A., Otterson, L. G., Basrab, G. S., Giacobe, R. A., Patey, S. A., Kutschke, A. C., Johnstone, M. R., Potter, M. E., Miller, P. F., and Mueller, J. P. (2014) In Vitro Antibacterial Activity of AZD0914: A New Spiropyrimidinetrione DNA Gyrase/Topoisomerase Inhibitor with Potent Activity against Gram-positive, Fastidious Gram-negative, and Atypical Bacteria. Antimicrob. Agents Chemother. 59, 467–474). AZD0914 inhibited DNA biosynthesis preferentially to other macromolecules in Escherichia coli and induced the SOS response to DNA damage in E. coli. AZD0914 stabilized the enzyme-DNA cleaved complex for N. gonorrhoeae gyrase and topoisomerase IV. The potency of AZD0914 for inhibition of supercoiling and the stabilization of cleaved complex by N. gonorrhoeae gyrase increased in a fluoroquinolone-resistant mutant enzyme. When a mutation, conferring mild resistance to AZD0914, was present in the fluoroquinolone-resistant mutant, the potency of ciprofloxacin for inhibition of supercoiling and stabilization of cleaved complex was increased greater than 20-fold. In contrast to ciprofloxacin, religation of the cleaved DNA did not occur in the presence of AZD0914 upon removal of magnesium from the DNA-gyrase-inhibitor complex. AZD0914 had relatively low potency for inhibition of human type II topoisomerases α and β.
Dissertations / Theses on the topic "Type II topoisomerase; Enzyme"
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Tsai, Francis T. F. "Crystallographic studies of DNA gyrase B protein." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390473.
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van, der Merwe Mariè. "Enzyme architecture and flexibility affect DNA topoisomerase I function." View the abstract Download the full-text PDF version, 2007. http://etd.utmem.edu/ABSTRACTS/2007-026-van_der_Merwe-Index.html.
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Thesis (Ph.D.)--University of Tennessee Health Science Center, 2007.Title from title page screen (viewed on July 29, 2008). Research advisor: Mary-Ann Bjornsti, Ph.D. Document formatted into pages (xiii, 175 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 161-175).
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Rodrigues, Nathalia de Campos. "Estudo estrutural das enzimas Topoisomerase II Mitocondrial e Old Yellow Enzyme de Trypanosoma cruzi." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/76/76132/tde-24032014-151614/.
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Doenças tropicais negligenciadas compartilham características que permitem que elas persistam nas condições de pobreza, onde se aglomeram e se sobrepõe frequentemente. Mais de um bilhão de pessoas sofrem de uma ou mais doenças tropicais negligenciadas. Entre estas está a doença de Chagas, resultante da infecção pelo protozoário parasito hemoflagelado Trypanosoma cruzi, tendo insetos triatomíneos como vetores. Topoisomerases são enzimas envolvidas na regulação do superespiralamento do DNA resolvendo problemas topológicos associados com replicação, transcrição, recombinação e reparo. As topoisomerases do tipo II são essenciais para tripanossomatídeos por atuarem na replicação e organização do DNA contido em uma região especializada da mitocôndria denominada cinetoplasto. O estudo da Topoisomerase II Mitocondrial (TcTopoIImit) foi realizado através de análises sequenciais e estruturais de outras topoisomerases para a determinação de construções para a clonagem. As construções para o domínio N-terminal foram clonadas no vetor pTZ57R/T e subclonadas em vetores do sistema pET para expressão proteica em E. coli. Experimentos de expressão foram realizados em diferentes cepas, vetores, soluções tampão e outros parâmetros variáveis visando a obtenção dos produtos recombinantes na forma solúvel, porém, tais resultados não foram obtidos. A flavoproteína Old Yellow Enzyme de Trypanosoma cruzi (TcOYE) é uma oxidoredutase que usa NAD(P)H como cofator. Esta enzima é clinicamente relevante devido ao seu papel no mecanismo de ação de alguns agentes tripanocidas, utilizados no tratamento da doença de Chagas, por produzirem espécies reativas de oxigênio. Neste trabalho, a enzima recombinante TcOYE foi produzida, purificada, cristalizada pelo método de difusão de vapor e sua estrutura cristalográfica, resolvida por substituição molecular e refinada. A TcOYE foi cristalizada nas formas cristalinas P212121 e P21 e os dados de difração foram coletados para o máximo de resolução de 1,27 e 2,00 Å, respectivamente. As coordenadas atômicas e fatores de estrutura das estruturas da TcOYE nas formas cristalinas P212121 e P21 foram depositados no Banco de Dados de Proteínas com os códigos de acesso 4E2B e 4E2D, respectivamente. A TcOYE apresenta um enovelamento canônico em um barril (α/β)8 com o grupo prostético localizado na cavidade maior do sítio ativo. Após a obtenção dos modelos cristalográficos análises sequenciais e estruturais foram realizadas para a TcOYE e outras OYEs. A região 141-156 do subdomínio capping em TcOYE, assim como em outras OYEs, é intrinsecamente desestruturada exibindo altos valores de fatores B. A região mais divergente entre as OYEs é o loop estendido (289-297), que pode variar em comprimento e composição mudando o volume e a acessibilidade ao sítio ativo.Neglected tropical diseases share features that allow them to persist in conditions of poverty, which clump together and frequently overlap. More than 1 billion people suffer from one or more neglected tropical diseases. Among them is the Chagas disease is an important parasitic disease resulting from infection by the flagellate protozoan parasite Trypanosoma cruzi, with triatomine insects as vectors. Topoisomerases are ubiquitous enzymes involved in the regulation of DNA supercoiling and overcoming topological barriers during replication, transcription, recombination and repair. The type II topoisomerases are essential for trypanosomatids since, in addition to their role in nuclear DNA metabolism, these enzymes might also play an important role in the replication and organization of the DNA contained in the specialized region of the mitochondrion known as the kinetoplast. The study of Mitochondrial Topoisomerase II from T. cruzi (TcTopoIImit) was performed by sequence and structural analyses into topos members for determination of domains constructions for cloning. Constructions for the N-domain were then cloned in pTZ57R/T vector and subcloned into pET system vectors for protein expression in E. coli. The protein expression experiments were performed by different strain cells, vectors, buffers solutions and others adjustable parameters for improve the solubility but recombinant products in soluble form were not obtained. The flavoprotein Old Yellow Enzyme from Trypanosoma cruzi (TcOYE) is an oxidoreductase that uses NAD(P)H as cofactor. This enzyme is clinically relevant due to its role in the action mechanism of some trypanocidal drugs used in the treatment of Chagas disease by producing reactive oxygen species. In this work, the recombinant enzyme TcOYE was produced, purified, crystallized by the vapour diffusion method and its crystallography structure was solved for molecular replacement and refined. TcOYE was crystallized in two crystalline forms, P212121 and P21 and diffraction data were collected to a maximum resolution of 1.27 and 2.00 Å, respectively. The atomic coordinates and structure factors of the TcOYE structure in P212121 and P21 crystalline forms have been deposited in the Protein Data Bank with the accession codes 4E2B and 4E2D, respectively. TcOYE displays a canonical (α/β)8-barrel fold with a FMN prosthetic group located at the large active-site cavity. Afterwards, sequential and structural analyses were carried out for TcOYE and others OYEs. The region 141-156 of the capping subdomain in TcOYE as well as in others OYEs is intrinsically flexible exhibiting high B-factor values. The most divergent region among these OYEs is the extended loop (289-297), which can vary in length and composition changing the volume and accessibility to the active site.
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Chung, In Kwon. "Reactivity of eukaryotic type II topoisomerase with unusual DNA structures /." The Ohio State University, 1991. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487758178238665.
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Gupta, Ranjan Brockman Herman E. "Effect of DNA topoisomerase II-targeting antitumor drugs in Neurospora crassa similarities to prokaryotic type II DNA topoisomerases /." Normal, Ill. Illinois State University, 1990. http://wwwlib.umi.com/cr/ilstu/fullcit?p9115225.
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Thesis (Ed. D.)--Illinois State University, 1990.Title from title page screen, viewed November 28, 2005. Dissertation Committee: Herman E. Brockman (chair), Alan J. Katz, Lynne A. Lucher, Radheshyam K. Jayaswal, David F. Weber, Anthony E. Liberta. Includes bibliographical references (leaves 114-131) and abstract. Also available in print.
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Soares, Bruno Marques. "Hellebrigenina, um BufodienolÃdeo com Potencial AÃÃo CompatÃvel de Inibidor CatalÃtico da Topoisomerase II." Universidade Federal do CearÃ, 2013. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=10367.
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CoordenaÃÃo de AperfeiÃoamento de NÃvel SuperiorOs bufodienolÃdeos sÃo esterÃides cardioativos de 24 carbonos, isolados originalmente de um extrato de pele de sapos da famÃlia Bufonidae utilizado na medicina chinesa. Os bufodienolÃdeos possuem grande variedade de atividades biolÃgicas, incluindo atividades antineoplÃsicas. Em relaÃÃo à atividade antitumoral, os bufodienolÃdeos tem demonstrado inibir o crescimento de vÃrias linhagens de cÃlulas cancerÃgenas humanas por induzir apoptose e parada do ciclo celular. O presente estudo avaliou o potencial citotÃxico e genetÃxico de seis bufodienolÃdeos em seis linhagens tumorais humanos, trÃs linhagens murinas normais e cÃlulas mononucleadas do sangue perifÃrico (CMSP) humano. Todos os seis bufodienolÃdeos foram citotÃxicos para todas as linhagens tumorais e CMSP com valores de IC50 variando entre 0,002 e 3,17 ÂM. Os bufodienolÃdeos testados nÃo apresentaram citotoxicidade para linhagens murinas normais. Desta forma, o composto hellebrigenina foi escolhido para se determinar o mecanismo de aÃÃo envolvido. Uma sequÃncia de experimentos in vitro foram realizados utilizando-se a linhagem leucÃmica HL-60. As cÃlulas foram tratadas em diferentes concentraÃÃes da amostra hellebrigenina (0,03, 0,06 e 0,12 ÂM) por 24 horas. A viabilidade das cÃlulas (nÃmero de cÃlulas viÃveis e integridade de membrana) HL-60 avaliada por citometria de fluxo, mostrou que o nÃmero de cÃlulas reduziu a partir da menor concentraÃÃo (0,03 ÂM) testada e a porcentagem de cÃlulas com membrana integra reduziu a partir da concentraÃÃo 0,06 ÂM. A anÃlise morfolÃgica por citometria de fluxo revelou aumento de cÃlulas com padrÃo apoptÃtico a partir da concentraÃÃo de 0,06 ÂM. Jà a anÃlise do conteÃdo nuclear, nos mostrou aumento de fragmentaÃÃo de DNA sub-G1 indicativo de apoptose e acÃmulo de cÃlulas na fase G2/M a partir das concentraÃÃes de 0,03 e 0,06 ÂM, respectivamente. Outros testes por citometria de fluxo revelaram que houve externalizaÃÃo da fosfatidilserina, despolarizaÃÃo mitocondrial, ativaÃÃo da caspase iniciadora 8 e consequente ativaÃÃo das caspases efetoras 3 e 7. Estes dados indicam um mecanismo citotÃxico por induÃÃo de mais de uma via apoptÃtica. Hellebrigenina nÃo foi capaz de causar danos ao DNA de HL-60 e de CMSP e nem o surgimento de aberraÃÃes cromossÃmicas em CMSP. Por meio dos estudos de docking molecular foi possÃvel predizer a ligaÃÃo entre hellebrigenina e topoisomeraseIIα humana, resultado compatÃvel com a possÃvel inibiÃÃo dessa enzima. De forma geral, os resultados apontam o potencial citotÃxico do bufodienolÃdeo hellebrigenina
Bufodienolides are cardioactive steroids of 24 carbons, originally isolated from a frogâs skin extract of the family Bufonidae used in Chinese medicine. Bufodienolides shows many biological activities, including anticancer activities. Related to antitumor activity, the bufodienolÃdeos has been shown to inhibit the growth of several human cancer cell lines by inducing apoptosis and cell cycle arrest. This study evaluated the potential cytotoxicity and genotoxicity of six bufodienolides, in six human tumor cell lines, three normal murine lineages and PBMC (peripheral blood mononuclear cells). All six bufodienolides were cytotoxic to all cell lines and tumor PBMC with IC50 values ranging from 0.002 to 3.17 ÂM. Bufodienolides showed no cytotoxicity for normal murine strains. Thus, the compound hellebrigenin was chosen to determine the action mechanism involved, a sequence of in vitro experiments were performed using HL-60 leukemia cell line. Cells were treated at different concentrations of hellebrigenin (0.03, 0.06 and 0.12 ÂM) for 24 hours. Cell viability (viable cell number and membrane integrity) HL-60 assessed by flow cytometry showed that the number of cells decreased from the lower concentration (0.03 ÂM) tested and the percentage of cells with reduced membrane integrity from 0.06 ÂM concentration. Morphological analysis by flow cytometry revealed increased apoptotic cells starting at concentrations of 0.06 ÂM. The analysis of nuclear content, showed an increase in DNA fragmentation indicative of sub-G1 apoptosis and accumulation of cells in G2 / M phase from the concentrations of 0.03 and 0.06 ÂM, respectively. Other tests by flow cytometry revealed that there was an externalization of phosphatidylserine, mitochondrial depolarization, activation of caspase 8 and initiating subsequent activation of effector caspases 3 and 7. These data indicate a cytotoxic mechanism induced by over an apoptotic pathway. Hellebrigenin was not able to cause DNA damage in HL-60 and PBMC nor the emergence of chromosomal aberrations in PBMC. Through the studies of molecular docking was possible to predict the connection between hellebrigenina and human topoisomeraseIIα, showing a result that is compatible with a possible inhibition of this enzyme. Overall, the results indicate the potential cytotoxicity of hellebrigenin
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Rance, Holly Ashlene. "Effect of quinolones which target bacterial gyrase and topoisomerase IV on mammalian type II topoisomerases." Thesis, University of Newcastle Upon Tyne, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627726.
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uinolones are a family of drugs used to treat bacterial infections by targeting bacterial type II topoisomerases (TOP2s), DNA gyrase and topoisomerase IV. Recent studies have shown that quinolones can cause genotoxicity in mammalian cells. Genotoxicity occurs when an agent causes damage to the genetic apparatus of a cell. Due to the similarities between the mammalian and bacterial TOP2 enzymes it is thought that the quinolones are targeting mammalian TOP2 to produce their genotoxic response. The aim of this study was to investigate if quinolone genotoxicity involves mammalian TOP2. Using the micronucleus assay, the genotoxicity of two quinolones ciprofloxacin and gemifloxacin was tested in three Nalm-6 cell lines containing varying amounts of TOP2. With ciprofloxacin only the Nalm-6TOP2A+/- cells showed genotoxicity, whereas for gemifloxacin only the Nalm-6 WT cells showed genotoxicity, suggesting that for gemifloxacin the removal of TOP2A or TOP2B lowers the genotoxicity of the quinolone. A selection of quinolones were tested using the Trapped in AgaRose DNA ImmunoStaining (TARDIS) assay to determine whether they stabilise the TOP2-DNA complexes in mammalian cells as known TOP2 poisons do. The analysis showed that after three hours incubation the level of complexes increased, indicating that the quinolones are able to stabilise TOP2-DNA complexes. Taken together the micronucleus and TARDIS assay data show that the quinolones are targeting mammalian TOP2 at high concentrations.
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Coelho, Raquel Autran [UNIFESP]. "Expressão de topoisomerase II alfa e de caspase-3 ativada em lesão intra-epitelial cervical escamosa de baixo grau." Universidade Federal de São Paulo (UNIFESP), 2008. http://repositorio.unifesp.br/handle/11600/9620.
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Objetivos: Estudar a expressao imuno-histoquimica de topoisomerase IIƒ¿ e de caspase-3 ativada, marcadores de proliferacao e de apoptose, respectivamente, a deteccao de DNA HPV e a evolucao da lesao cervical em mulheres portadoras de lesao intra-epitelial escamosa de baixo grau (LBG). Metodos: Foram avaliadas 40 mulheres portadoras de LBG e 32 sem neoplasia cervical, diagnosticadas por exame cito-colpo-histopatologico, quanto a imunoexpressao de topoisomerase IIƒ¿ e de caspase-3 ativada e quanto a deteccao de DNA HPV por PCR consensual (GP5+/GP6+) em material de esfregaco cervico-vaginal. Os achados foram relacionados as variaveis clinicas das pacientes e a evolucao clinica das lesoes cervicais em 12 meses. As pacientes assinaram termo de consentimento livre e esclarecido. Resultados: A media percentual de celulas imunomarcadas por topoisomerase foi de 11,71% e 4,13%, no grupo com LBG e controle, respectivamente, com diferenca estatisticamente significante. Observou-se que houve expressao de caspase-3 em 17 (42,5%) e em 5 (15,63%) pacientes com e sem LBG, respectivamente, com diferenca estatisticamente significante. Foi detectado HPV DNA em 65% das pacientes com LBG e em 59,4% das pacientes sem lesao cervical, sem relacao com a expressao de topoisomerase IIƒ¿ ou caspase-3. Na presenca de DNA-HPV, a expressao de topoisomerase IIƒ¿ no grupo com LBG foi significativamente maior do que em fragmentos sem lesao. Nao foi observada diferenca quanto a evolucao da lesao cervical em 12 meses de acordo com a imunoexpressao de topoisomerase IIƒ¿. Com relacao a caspase-3 ativada, a maioria das pacientes com imuno-histoquimica negativa teve regressao da lesao cervical. Conclusoes: A imunoexpressao de topoisomerase IIƒ¿ e de caspase-3 ativada podem ser considerados marcadores de proliferacao e de apoptose em lesao cervical de baixo grau, sem relacao com a presenca de DNA-HPV.
Purpose: To evaluate the correlation between the expression of topoisomerase II alpha, active caspase-3 and infection with human papillomavirus in low-grade cervical intraepithelial lesion and in the normal cervix, and whether they might influence susceptibility to, or evolution of, cervical lesion. Patients and methods: Forty cervical biopsies patients with low-grade cervical intraepithelial lesion and thirty-two with normal cervix were stained by immunohistochemistry for topoisomerase IIá and active caspase-3 and were investigated for the presence of HPV on exfoliated cells by general primer GP5+/6+ PCR amplification of DNA. These findings were correlated with clinicopathological features of the patients including their clinical outcome after twelve months. Subjects provided written informed consent. Results: Low-grade CIN patients as a group had a significantly higher expression of topoisomerase II alpha compared to controls, without correlation to disease outcome at 12 months. Caspase-3 was expressed in 42.5% of CIN patients and in 15.63% without disease, and most of women without caspase-3 receded cervical lesion. HPV DNA testing was positive in 65% of the patients with cervical lesion, and in 59.4% of the control group and was not associated to the expression of topoisomerase IIá or active caspase-3. In the presence of a positive HPV DNA testing, women with cervical lesion had a significantly higher expression of topoisomerase II alpha compared to controls. Conclusion: Topoisomerase II alpha and active caspase-3 might be useful diagnostic and prognostic markers in low-grade cervical lesions, delaying a better follow-up.
CNPq: 134106/2005-9
TEDE
BV UNIFESP: Teses e dissertações
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Hamdi, Haithem. "Usage des IECA / ARA II chez des aînés traités contre le diabète de type 2." Thesis, Université Laval, 2011. http://www.theses.ulaval.ca/2011/28259/28259.pdf.
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Ho, Kwun-wai. "Angiotensin converting enzyme inhibitor alone or in combination with angiotensin II type I receptor blocker in patients with chronic proteinuric nephropathies : a systemic review of clinical trials /." View the Table of Contents & Abstract, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31684038.
Full textBooks on the topic "Type II topoisomerase; Enzyme"
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Pommier, Yves. DNA Topoisomerases and Cancer. New York, NY: Springer Science+Business Media, LLC, 2012.
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(Editor), Leroy F. Liu, J. Thomas August (Series Editor), M. W. Anders (Series Editor), Ferid Murad (Series Editor), and Joseph T. Coyle (Series Editor), eds. DNA Topoisomearases: Biochemistry and Molecular Biology, Volume 29A (Advances in Pharmacology). Academic Press, 1994.
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Pommier, Yves. DNA Topoisomerases and Cancer. Humana, 2013.
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Milan, Potmesil, and Kohn Kurt W, eds. DNA topoisomerases in cancer. New York: Oxford University Press, 1991.
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Kalyuzhny, Alexander E. Handbook of ELISPOT: Methods and Protocols (Methods in Molecular Biology). Humana Press, 2005.
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E, Kalyuzhny Alexander, ed. Handbook of ELISPOT: Methods and protocols. Totowa, N.J: Humana Press, 2005.
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van der Ploeg, Ans T., and Pascal Laforêt. Pompe Disease. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0055.
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Pompe disease, also named acid maltase deficiency and glycogen storage disease type II (GSDII), is a rare autosomal recessive disorder caused by the deficiency of the glycogen-degrading lysosomal enzyme acid α-glucosidase. The clinical spectrum of this disease is broad, varying from a lethal infantile-onset generalized myopathy including cardiomyopathy, to late-onset slowly progressive muscle weakness mimicking limb-girdle muscular dystrophy. Respiratory insufficiency is a frequent complication and the main cause of death. The prognosis of Pompe disease has changed considerably with the use of enzyme replacement therapy using recombinant acid α-glucosidase (alglucosidase alfa), which has been widely available since 2006. Improvements in survival and major motor achievements can be observed in patients with infantile forms, and recent studies demonstrate improvement of walking distance and stabilization of pulmonary function in late-onset forms. A longer-term study of the safety and efficacy of ERT, based on data gathering across the complete spectrum of Pompe disease via national or international patient registries, is needed in order to formulate more precise guidelines for treatment.
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Endlich, Karlhans, and Rodger Loutzenhiser. Regulation of vasomotor tone in the afferent and efferent arterioles. Edited by Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0208.
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Pre-glomerular vessels are regulated by membrane potential alterations affecting the activity of L-type voltage-activated Ca2+ channels; whereas voltage-independent mechanisms regulate the efferent arteriole, notably influenced by angiotensin II and therefore by angiotensin converting enzyme inhibitors, and by non-steroidal anti-inflammatory drugs.These properties underlie the physiologic control of glomerular capillary pressure, for example, by prostaglandin E2, during conditions of reduced renal perfusion and the stabilization of glomerular capillary pressure when the kidney is exposed to pressure fluctuations. A wealth of hormones affects the tone of renal vessels. The chapter focuses on basic regulatory and signalling mechanisms, emphasizing the unique aspects of the renal vasculature and the underlying features that facilitate the independent regulation of pre-glomerular and post-glomerular tone.
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Dilsizian, Vasken, Ines Valenta, and Thomas H. Schindler. Myocardial Viability Assessment. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199392094.003.0021.
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Heart failure may be a consequence of ischemic or non-ischemic cardiomyopathy. Etiologies for LV systolic dysfunction in ischemic cardiomyopathy include; 1) transmural scar, 2) nontransmural scar, 3) repetitive myocardial stunning, 4) hibernating myocardium, and 5) remodeled myocardium. The LV remodeling process, which is activated by the renin-angiotensin system (RAS), stimulates toxic catecholamine actions and matrix metalloproteinases, resulting in maladaptive cellular and molecular alterations5, with a final pathway to interstitial fibrosis. These responses to LV dysfunction and interstitial fibrosis lead to progressive worsening of LV function. Established treatment options for ischemic cardiomyopathy include medical therapy, revascularization, and cardiac transplantation. While there has been continuous progress in the medical treatment of heart failure with beta-blockers, angiotensin-converting enzyme (ACE) inhibition, angiotensin II type 1 receptor (AT1R) blockers, and aldosterone to beneficially influence morbidity and mortality, the 5-years mortality rate for heart failure patients remains as high as 50%. Revascularization procedures include percutaneous transluminal coronary artery interventions (PCI) including angioplasty and endovascular stent placement and coronary artery bypass grafting (CABG). Whereas patents with heart failure due to non-coronary etiologies may best benefit from medical therapy or heart transplantation, coronary revascularization has the potential to improve ventricular function, symptoms, and long term survival, in patients with heart failure symptoms due to CAD and ischemic cardiomyopathy.
Book chapters on the topic "Type II topoisomerase; Enzyme"
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Schomburg, Dietmar, and Margit Salzmann. "Type II site-specific deoxyribonuclease." In Enzyme Handbook 3, 805–9. Berlin, Heidelberg: Springer Berlin Heidelberg, 1991. http://dx.doi.org/10.1007/978-3-642-76463-9_170.
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Beck, Michael. "TREATMENT OPTIONS FOR MUCOPOLYSACCHARIDOSIS TYPE II (HUNTER'S SYNDROME)." In Enzyme Technologies, 301–19. Hoboken, NJ: John Wiley & Sons, Inc, 2013. http://dx.doi.org/10.1002/9781118739907.ch8.
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East, Stephen P., Lloyd G. Czaplewski, and David J. Haydon. "Chapter 20. Ethyl Urea Inhibitors of the Bacterial Type II Topoisomerases DNA Gyrase (GyrB) and Topoisomerase IV (ParE)." In Drug Discovery, 335–52. Cambridge: Royal Society of Chemistry, 2012. http://dx.doi.org/10.1039/9781849734912-00335.
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Vondran, A., U. Tibes, E. Borowski, W. G. Friebe, and W. V. Scheuer. "New Type II Phospholipase A2 Inhibitors Effective in Blocking an Ongoing Enzyme Reaction: Inability of Manoalide and Scalaradial to Exert an Inhibitory Capacity." In Phospholipase A2, 130–39. Basel: KARGER, 1997. http://dx.doi.org/10.1159/000075458.
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Bensimon, David, Vincent Croquette, Jean-François Allemand, Xavier Michalet, and Terence Strick. "Topoisomerases." In Single-Molecule Studies of Nucleic Acids and Their Proteins, 177–98. Oxford University Press, 2018. http://dx.doi.org/10.1093/oso/9780198530923.003.0009.
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This chapter discusses single-molecule approaches in the study of topoisomerases. After introducing the problem posed by DNA entanglement, it describes type I and type II topoisomerases, which solve that issue. Single-molecule assays have nailed down the different mechanisms of bacterial and eukaryotic type I topoisomerases. The properties of type II topoisomerases are then described. Single-molecule experiments have shown that they relax DNA torsion by two units, passing one dsDNA segment through a break in another segment. However, while topoII relaxes positive and negative supercoils similarly, topoIV relaxes positive supercoils quickly and processively, but negative ones slowly and distributively. This chiral discrimination is compared with the activity of the enzyme on two catenated DNA molecules. After describing single-molecule assays of the activity of gyrases, in-vivo investigations of single fluorescently labelled topoIV units in single E.coli are discussed, with concluding remarks on the future of single-molecule DNA/protein studies.
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Huang, Wai Mun. "Type II DNA Topoisomerase Genes." In DNA Topoisomerases: Biochemistry and Molecular Biology, 201–25. Elsevier, 1994. http://dx.doi.org/10.1016/s1054-3589(08)60547-5.
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Mitton-Fry, Mark Joseph. "Novel Bacterial Type II Topoisomerase Inhibitors." In 2017 Medicinal Chemistry Reviews, 281–302. Medicinal Chemistry Division of the American Chemical Society, 2017. http://dx.doi.org/10.29200/acsmedchemrev-v52.ch15.
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Shirude, Pravin S., and Shahul Hameed. "Nonfluoroquinolone-Based Inhibitors of Mycobacterial Type II Topoisomerase as Potential Therapeutic Agents for TB." In Annual Reports in Medicinal Chemistry Volume 47, 319–30. Elsevier, 2012. http://dx.doi.org/10.1016/b978-0-12-396492-2.00021-7.
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Goodenow, Donna, Kiran Lalwani, and Christine Richardson. "DNA Damage and Repair Mechanisms Triggered by Exposure to Bioflavonoids and Natural Compounds." In DNA - Damages and Repair Mechanisms. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.95453.
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Eukaryotic cells use homologous recombination (HR), classical end-joining (C-NHEJ), and alternative end-joining (Alt-EJ) to repair DNA double-strand breaks (DSBs). Repair pathway choice is controlled by the activation and activity of pathways specific proteins in eukaryotes. Activity may be regulated by cell cycle stage, tissue type, and differentiation status. Bioflavonoids and other environmental agents such as pesticides have been shown to biochemically act as inhibitors of topoisomerase II (Top2). In cells, bioflavonoids directly lead to DNA double-strand breaks through both Top2-dependent and independent mechanisms, as well as induce DNA damage response (DDR) signaling, and promote alternative end-joining and chromosome alterations. This chapter will present differences in expression and activity of proteins in major DNA repair pathways, findings of Top2 inhibition by bioflavonoids and cellular response, discuss how these compounds trigger alternative end-joining, and conclude with implications for genome instability and human disease.
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Bilous, Rudolf. "Diabetes mellitus and the kidney." In Oxford Textbook of Medicine, edited by John D. Firth, 4975–87. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198746690.003.0491.
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Diabetic nephropathy is the commonest cause of endstage renal disease in the developed world. Aetiology and pathology—causation is related to glycaemic control, hypertension, inflammation, genetic factors, and dietary and other environmental factors. Pathological hallmarks in the glomerulus are thickening of the glomerular basement membrane and mesangial expansion, with or without nodule formation, secondary to an accumulation of extracellular matrix. Many patients have a varying severity of tubulointerstitial inflammation and fibrosis. Staging and natural history—is classically described in terms of urinary albumin excretion rate (UAER). Clinical features—most patients (>60%) will have a normal UAER throughout their diabetic life, but 1 to 2% of the remainder develop persistent moderately increased albuminuria each year. Once UAER exceeds 200 µg/min, there tends to be a relentless increase in proteinuria and glomerular filtration rate declines progressively at a rate that largely depends upon blood pressure control. Prevention—tight glycaemic control can prevent moderately increased albuminuria in both type 1 and type 2 diabetes. Whether intensive blood pressure control using angiotensin-converting enzyme (ACE) inhibitors can also prevent this remains controversial. In both type 1 and type 2 diabetes, intensive blood pressure control using ACE inhibitors or angiotensin II receptor blockers (ARBs) slows progression from moderately to severely increased albuminuria and also slows the rate of decline in glomerular filtration rate in those with severely increased albuminuria. Management—aims for (1) control of glycaemia, (2) control of hypertension (<130/80 mmHg) using an ACE inhibitor or an ARB as first line; and (3) other interventions, including some or all of serum lipid lowering, smoking cessation, and reduction of dietary protein and salt.
Conference papers on the topic "Type II topoisomerase; Enzyme"
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Ketron, Adam, David E. Graves, and Neil Osheroff. "Abstract 2529: Structure-activity relationship studies of the type II topoisomerase poison amsacrine." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-2529.
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Rogojina, Anna, Karin C. Nitiss, and John L. Nitiss. "Abstract 4480: New approaches to changing an enzyme into a cytotoxic agent: A novel way to stimulate DNA cleavage by topoisomerase II." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-4480.
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Sekararum, Woro Ayu, Nurfitri Bustamam, Hikmah Muktamiroh, and Harli Amir Mahmudji. "The Correlation between Secretory Phospholipase A2 Type IIA Levels and Mean Platelet Volume among Type 2 Diabetes Mellitus Patients." In The 7th International Conference on Public Health 2020. Masters Program in Public Health, Universitas Sebelas Maret, 2020. http://dx.doi.org/10.26911/the7thicph.01.09.
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Background: Platelet activity plays a role in the occurrence of diabetic angiopathy with an increase in mean platelet volume (MPV) as a marker of platelet activity. Platelet activity is influenced by phospholipase A2 type IIA (sPLA2 type IIA), which is a lipid-mediating enzyme that connects the pathogenesis of Diabetes Mellitus (DM) with complications of diabetic angiopathy. This study aimed to examine the relationship between levels of type IIA sPLA2 and MPV among type II DM patients. Subjects and Method: This was a cross-sectional study. A total of 63 patients with type II DM was selected for this study. The inclusion criteria for the study subjects were type 2 diabetes mellitus patients who did not experience an infectious disease, acute inflammation, trauma, surgery or malignancy, anemia, taking antiplatelet drugs, having abnormal platelet counts, and smoking. The dependent variable was levels of type IIA sPLA2. The independent variable was MPV. The data were obtained from the medical records of Prof. Dr. Soerojo Mental Hospital, Magelang. The data were analyzed using Spearman correlation test. Results: The study showed the median level of sPLA2 type IIA was 3841.50 ng / dL and the average MPV value was 7.36 fl. The results of the Spearman correlation analysis showed that there was no relationship between sPLA2 type IIA and MPV (p = 0.551), but there was a tendency for an increase in type IIA sPLA2 followed by an increase in MPV value (r = 0.077). There was a difference in the average MPV value in the subject group with DM ≤ 10 years and> 10 years (p = 0.009), and it was statistically significant. Conclusion: There is a tendency for an increase in type IIA sPLA2 followed by an increase in the MPV value among type II DM patients. Keywords: type II diabetes melitus, type IIA sPLA2 enzyme, mean platelet volume Correspondence: Woro Ayu Sekararum. Faculty of Medicine, Universitas Pembangunan Nasional ‘Veteran’ Jakarta. Jl, Rumah Sakit Fatmawati, Pondok Labu, South Jakarta, Indonesia. E-mail: woroayu.sekararum@gmail.com. Mobile: 0811975511 DOI: https://doi.org/10.26911/the7thicph.01.09
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Caner, Nazli, and Jeffrey W. Ruberti. "Detection of MMP-13 Activity on Intentionally Strain-Released Type-II Collagen Network in Bovine Articular Cartilage." In ASME 2011 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2011. http://dx.doi.org/10.1115/sbc2011-53913.
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Articular cartilage is a specialized avascular connective tissue found at the contact regions of diarthrodial joints. Cartilage has few cells (< 5% of the volume), though these cells can maintain the balance of turnover in healthy tissue, when the tissue is damaged, they are not able to repair the defects [1–3]. Extra cellular matrix (ECM) in cartilage comprises water, collagen (principally type II), proteoglycans and noncollagenous proteins. The type II collagen network, which is the dominant structural protein in cartilage ECM, constrains the expansion of the resident PGs and is generally held in mechanical tension. In osteoarthritis (OA), the balance of cartilage tissue production/degradation is thought to be affected by abnormal mechanical stimuli leading to net matrix resorption through production of excess degradative enzymes (e.g. matrix metalloproteinases (MMP) and aggrecanases) [4–8]. In OA tissue the amount of MMP-13 is thought to be increased relative to healthy tissue. OA typically occurs in older adults where, as cartilage ages, there is a marked decrease in the fixed charge density (FCD), the hydration and, consequently, mechanical tension on the collagen type II network [9–11]. We have hypothesized that loss of tension on the collagen network accelerates degradation by MMP. Detection of the effect of MMP on loaded, native cartilage could lead to insight about cartilage degradation kinetics in OA. However, it is quite difficult to controllably deliver MMP to cartilage, to activate the MMP during detensioning of the collagen network and to detect the effect on the cartilage mechanics (because cost limits the amount of MMP used). We have developed a transpirational enzyme loading method which is capable of precisely dosing bovine cartilage explants with a small, known quantity of MMP-13. Following enzyme insertion, we are able to detect the activity of the MMP on osmotically compressed cartilage (i.e. cartilage with a detensioned collagen network) via a simple hydration measurement.
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Zheleva, Darina, and Margarita Koleva. "Influence of type of pre-hair treatment from different types of animal sources on the degree of hydrolysis of keratin." In The 8th International Conference on Advanced Materials and Systems. INCDTP - Leather and Footwear Research Institute (ICPI), Bucharest, Romania, 2020. http://dx.doi.org/10.24264/icams-2020.ii.23.
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Keratin biomaterials have many different advantages over other biomolecules. A number of techniques have been studied to prepare keratin hydrolysates. Many of them use strong reagents and the processes take place under very drastic conditions. The present study focuses on the following aspects: producing keratin hydrolysates from various animal sources; application of various methods for extraction; comparison of the type of treatment over the degree of hydrolysis. Sheep wool samples were used, respectively native and alkaline pre-treated and samples of goat hair, respectively native and enzyme pre-treated. The methods used for the hydrolysis of keratin materials are: 1) by sulfotolysis with sodium pyrosulfate and urea; 2) with thioglycolic acid and 3) with sodium hydroxide. The obtained hydrolysates were characterized by qualitative reactions, spectrophotometric and FTIR analysis. It was found that the samples from one and the same animal source show very different properties and different degrees of hydrolysis. The highest degree of hydrolysis was achieved for the pre-treated samples. It was proved that the method of hydrolysis with NaOH is the most appropriate for sheep wool and to a much greater extent for the alkaline treated wool than for the native. The reducing agent: sodium pyrosulfate and urea is the most appropriate for enzyme pre-treated samples of goat skin. Therefore, pre-treatment of animal hair samples facilitates the hydrolysis process and makes it easier to break disulfide bonds. The disadvantage of proteins, and in particular keratins, is the difference in the structure of macromolecules, which are obtained from different animal sources. Therefore, this requires a specific approach to the hydrolysis of keratin from each individual animal source.
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Seifried, E., D. C. Rijken, B. Hoeqee, P. TansiAiell, C. Kluft, and W. Nieuwenhuizen. "FIBRIN DEGRADATION PRODUCTS (FbDP) IN HEALTHY VOLUNTEERS AFTER INFUSION OF RECOMBINANT TISSUE-TYPE PLASMINOGEN ACTIVATOR(rt-PA)." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643654.
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During thrombolytic therapy of myocardial infarction (MI) with urokinase or streptokinase (SK), levels of fibrin(ogen) degradation products in serum are often dramatically elevated as a result of a combination of systemic fibrinogenolysis and local thrombolysis. Others have measured increased levels of D-dimer in serum of MI patients after SK therapy and postulated that thrombolysis could be monitored during SK therapy by measuring D-dimer levels. In the present study rt-PA was infused into healthy volunteers to analyse if elevated FbDP levels in MI patients really reflect coronary thrombolysis or could be due to a systemic effect. Over a period of 60 min., three groups (n = 6 each) were given i.v. 0.23 mg rt-PA/'kg (group I), 0.50 mg rt-PA/kg (group II) and a placebo infusion (group III), respectively. Two blood samples were taken from an anticubital vein in the arm contralateral to the site of infusion (one on citrate/ aprotinin, the other on citrate alone) at different time points. Using a new enzyme immunoassay (EIA), based on monoclonals and development by us, we measured FbDP in plasma (not serum). Before infusion all volunteers had FbDP levels ≪ 0.5µg/ml. Upon infusion FbDP levels in groups I and II increased to average values of 1.0 ± 0.4/µg/ml and 0.8 ± 0.2/µg/ml, respectively, for the samples taken in citrate/aprotinin. The values in citrate alone did not differ significantly, and were 1.1 ± 0.5/µg/ml and 0.8 ± 0.3/µg/ml for groups I and II, respectively. FbDP levels in group III remained ≪ 0.5/µg/ml. The results show that FbDP levels increase upon rt-PA infusion, even in healthy volunteers. This suggests lysis of systemic fibrin. We conclude that lysis of systemic fibrin limits the value of FbDP levels as a measure for coronary thrombolysis.
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Finke, U., J. Schneider, E. Friderichs, L. Flohé, and H. Giertz. "MYOCARDIAL SALVAGE BY COMBINED TREATMENT WITH RECOMBINANT SINGLE-CHAIN UROKINASE-TYPE PLASMINOGEN ACTIVATOR AND RECOMBINANT HUMAN SUPEROXIDE DISMUTASE IN A CANINE CORONARY THROMBOSIS MODEL*." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643570.
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Recanalization of thrombotic coronary occlusion with fibrinolytic treatment is a promising approach to salvage jeopardized ischemic myocardium. However, the success of thrombolytic treatment of myocardial infarction may be curtailed by the risk inherent to reperfusion. Cell damage upon reoxygenation after an ischemic period is tentatively attributed to the formation of oxygen-derived free radicals. Improved myocardial salvage is therefore expected from coadministration of a free radical scavenger and fibrinolytic treatment. We tested this hypothesis in a canine model of left anterior circumflex coronary artery (LCX) thrombosis. Thrombolysis was achieved with the fibrin- selective single-chain urokinase-type plasminogen activator of recombinant origin (r-scu-PA). As enzymatic scavenger of oxygen radicals recombinant human superoxide dismu-tase (r-HSOD) was used. The three experimental groups were: group I (n=4) did not receive any treatment after LCX thrombosis; in group II (n=9) at 100 min after LCX thrombosis r-scu-PA (20 μg/kg/min i.v. for 30 min) was infused; dogs in group III (n=8) received concomitant treatment with r-scu-PA and r-HSOD (10 mg/kg i.v. for 60 min). Infarct size as percent of the risk zone was 38.2 ± 4.1 in group I, 25.3 ± 3.7 in group II (p ≤ 0.05 vs group I) and 14.9 ± 3.2 in group III (p ≤ 0.05 vs group II). Incidence of reperfusion arrhythmias and increase in plasma CK were significantly diminished by r-HSOD when compared to dogs receiving r-scu-PA only. There were no significant differences in hemodynamic parameters between the groups. In conclusion, in terms of infarct size reduction, suppression of reperfusion arrhythmias and attenuation of intracellular enzyme release the combined treatment with r-scu-PA and r-HSOD yielded a significant higher myocardial salvage versus thrombolytic treatment alone in a canine LCX thrombosis model.* This work is part of the doctoral dissertation of Miss U. Fincke
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Visser, A., I. M. A. Verhamme, D. G. Meuleman, and G. W. K. van Dedem. "AN INDIRECT KINETIC METHOD FOR ESTIMATING THE AFFINITY BETWEEN HEPARIN AND HEPARIN COFACTOR II." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644352.
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The heparin-dependent inactivation of alpha-thrombin by heparin cofactor II was studied in buffer media with a pH ranging from 6 to 9 and an ionic strength from 0.05 M to 0.80 M. We used a heparin fraction with a mean Mr of 16,000 .The log dose response curves (logarithm of the 2nd order inactivation constant vs. the logarithm of heparin concentration) display a sigmoidal behavior. The lower and upper limiting plateau and the steepness of the ascending limb are characteristic for every pH and ionic strength. Similar log dose response curves can be observed for the heparin-mediated inactivation of factor Xa and plasmin by ATIII,indicating that enhancement of the inhibition only depends on heparin-inhibitor binding despite the presence of heparin-enzyme complexes.This type of inactivation mechanism is clearly different from the one observed for the thrombin- and factor IXa - ATIII interactions which are characterized by a maximum in the log dose response curves.Therefore we can make the assumption that heparin-inhibitor binding is of major importance in the heparin-mediated thrombin-HCII interaction.Our experimental data were fit to a model which describes the dependence of the observed inactivation constant upon the concentration of heparin-HCII complex.This complex concentration is a function of the initial heparin and HCII concentrations and the dissociation constant K0 of the heparin-HCII complex.The model allows the estimation of K0 in various buffer media.A decrease of pK0 with increasing buffer concentration can be observed.The upper limiting plateau value for kobs which is often referred to as the intrinsic activity of heparin also decreases with increasing ionic strength.At pH 7 and 8 and an ionic strength of 0.4 M we-found K0 values of 1.00E-07 M.At pH 6 and an ionic strength of 0.8 M Kq eguals 4.00E-04 M indicating a markedly decreased affinity of heparin for HCII.Through a detailed analysis of the pH profile for K0 we might gain insight in the nature of the binding sites for heparin on the inhibitor.
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Kalambur, Venkat S., Ellen Longmire, and John C. Bischof. "Characterization of Cell Association and Heat Treatment Using Iron Oxide Magnetic Nanoparticles." In ASME 2007 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2007. http://dx.doi.org/10.1115/sbc2007-176216.
Full textAbstract:
Magnetic iron oxide nanoparticles (NPs) have intrinsic advantages over other NPs for various biomedical applications. These advantages include visualization under Magnetic Resonance Imaging (MRI), heating with Radiofrequency (RF), and movement in a magnetic field. There are now numerous efforts to expand the applications of these particles for non-invasive drug and adjuvant delivery, cellular imaging and in vitro cell sorting and purification. In the present study, we describe methods to (i) assess and quantify NP cell association (ii) facilitate NP heat destruction of cells after association with RF and laser. First, we show that (i) the cell association of iron oxide NPs is dependent on the surface coating (surfactant greater than dextran), time, cell-type and extracellular NP concentrations (saturation with concentration and time). Furthermore, the association fits a simple enzyme Michealis-Menten model. Second, (ii) improved heat destruction of cells can be achieved after laser irradiation compared to traditional RF treatment for similar NP associations. These results and assays show promise for cell sorting and purification applications.
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Burkhart, Collin T., Peter D. Dunning, and Michael J. Schertzer. "Electrowetting on Dielectric (EWOD) Assisted Droplet Desiccation." In ASME 2015 13th International Conference on Nanochannels, Microchannels, and Minichannels collocated with the ASME 2015 International Technical Conference and Exhibition on Packaging and Integration of Electronic and Photonic Microsystems. American Society of Mechanical Engineers, 2015. http://dx.doi.org/10.1115/icnmm2015-48498.
Full textAbstract:
Lab-on-a-chip (LOAC) devices are emerging technologies that aim to perform all of the laboratory functions of traditional diagnostic tests on single microchips. Microarrays are one promising type of LOAC device that consist of an array of droplets for testing tens to thousands of samples simultaneously. Microarrays are commonly used in gene sequencing, pathogen detection, determining microbial resistances, and conducting enzyme-linked immunosorbent assays (ELISAs). As droplets in these arrays dry, the majority of material within the droplet is deposited around the periphery. This phenomenon is referred to as the coffee stain effect. The non-uniform depositions left by this effect can result in variation of fluorescence intensity measurements in automated vision systems. A means of producing more uniform particle depositions for the microscopy analysis would allow for more accurate test results. One promising method for suppression of the coffee stain effect involves the use of electrowetting on dielectric (EWOD). EWOD devices apply an electrokinetic force at the three-phase contact line to manipulate the shape of a droplet interface. The Mugele group has already begun investigating EWOD’s effects on the coffee stain effect and found that an AC voltage applied to droplets on EWOD devices can suppress the coffee stain effect and produce smaller, more uniform droplet deposition patterns. This work presents (i) a method to characterize the deposition pattern left by a desiccated droplet as a function of radial position and (ii) a discussion of the microfabrication technique used to create devices to perform EWOD assisted desiccation for both AC and DC voltages.