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21.
Pierce RJ Dubois-Abdesselem F Caby S Trolet J Lancelot J Oger F Bertheaume N Roger E 《Memórias do Instituto Oswaldo Cruz》2011,106(7):794-801
Only one drug is currently available for the treatment and control of schistosomiasis and the increasing risk of selecting strains of schistosome that are resistant to praziquantel means that the development of new drugs is urgent. With this objective we have chosen to target the enzymes modifying histones and in particular the histone acetyltransferases and histone deacetylases (HDAC). Inhibitors of HDACs (HDACi) are under intense study as potential anti-cancer drugs and act via the induction of cell cycle arrest and/or apoptosis. Schistosomes like other parasites can be considered as similar to tumours in that they maintain an intense metabolic activity and rate of cell division that is outside the control of the host. We have shown that HDACi can induce apoptosis and death of schistosomes maintained in culture and have set up a consortium (Schistosome Epigenetics: Targets, Regulation, New Drugs) funded by the European Commission with the aim of developing inhibitors specific for schistosome histone modifying enzymes as novel lead compounds for drug development. 相似文献
22.
miR-124-1 is a tumour suppressor microRNA (miR). Epigenetic deregulation of miRs is implicated in carcinogenesis. Promoter DNA methylation and histone modification of miR-124-1 was studied in 5 normal marrow controls, 4 lymphoma, 8 multiple myeloma (MM) cell lines, 230 diagnostic primary samples of acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), MM, and non-Hodgkin's lymphoma (NHL), and 53 MM samples at stable disease or relapse. Promoter of miR-124-1 was unmethylated in normal controls but homozygously methylated in 4 of 4 lymphoma and 4 of 8 myeloma cell lines. Treatment of 5-Aza-2'-deoxycytidine led to miR-124-1 demethylation and re-expression of mature miR-124, which also associated with emergence of euchromatic trimethyl H3K4 and consequent downregulation of CDK6 in myeloma cells harboring homozygous miR-124-1 methylation. In primary samples at diagnosis, miR-124-1 methylation was absent in CML but detected in 2% each of MM at diagnosis and relapse/progression, 5% ALL, 15% AML, 14% CLL and 58.1% of NHL (p<0.001). Amongst lymphoid malignancies, miR-124-1 was preferentially methylated in NHL than MM, CLL or ALL. In primary lymphoma samples, miR-124-1 was preferentially hypermethylated in B- or NK/T-cell lymphomas and associated with reduced miR-124 expression. In conclusion, miR-124-1 was hypermethylated in a tumour-specific manner, with a heterochromatic histone configuration. Hypomethylation led to partial restoration of euchromatic histone code and miR re-expression. Infrequent miR-124-1 methylation detected in diagnostic and relapse MM samples showed an unimportant role in MM pathogenesis, despite frequent methylation found in cell lines. Amongst haematological cancers, miR-124-1 was more frequently hypermethylated in NHL, and hence warrants further study. 相似文献
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24.
Lucie Guetzoyan Xiao-Min Yu Florence Ramiandrasoa Stéphanie Pethe Christophe Rogier Bruno Pradines Thierry Cresteil Martine Perrée-Fauvet Jean-Pierre Mahy 《Bioorganic & medicinal chemistry》2009,17(23):8032-8039
A series of acridine derivatives were synthesised and their in vitro antimalarial activity was evaluated against one chloroquine-susceptible strain (3D7) and three chloroquine-resistant strains (W2, Bre1 and FCR3) of Plasmodium falciparum. Structure–activity relationship showed that two positives charges as well as 6-chloro and 2-methoxy substituents on the acridine ring were required to exert a good antimalarial activity. The best compounds possessing these features inhibited the growth of the chloroquine-susceptible strain with an IC50 ? 0.07 μM, close to that of chloroquine itself, and that of the three chloroquine-resistant strains better than chloroquine with IC50 ? 0.3 μM. These acridine derivatives inhibited the formation of β-hematin, suggesting that, like CQ, they act on the haem crystallization process. Finally, in vitro cytotoxicity was also evaluated upon human KB cells, which showed that one of them 9-(6-ammonioethylamino)-6-chloro-2-methoxyacridinium dichloride 1 displayed a promising antimalarial activity in vitro with a quite good selectivity index versus mammalian cell on the CQ-susceptible strain and promising selectivity on other strains. 相似文献
25.
Berthier S Paclet MH Lerouge S Roux F Vergnaud S Coleman AW Morel F 《The Journal of biological chemistry》2003,278(28):25499-25508
Phagocyte NADPH oxidase generates O2. for defense mechanisms and cellular signaling. Myeloid-related proteins MRP8 and MRP14 of the S100 family are EF-hand calcium-binding proteins. MRP8 and MRP14 were co-isolated from neutrophils on an anti-p47phox matrix with oxidase cytosolic factors and identified by mass spectrometry. MRP8 and MRP14 are absent from Epstein-Barr virus-immortalized B lymphocytes, and, coincidentally, these cells display weak oxidase activity compared with neutrophils. MRP8/MRP14 that was purified from neutrophils enhanced oxidase turnover of B cells in vitro, suggesting that MRP8/MRP14 is involved in the activation process. This was confirmed ex vivo by co-transfection of Epstein-Barr virus-transformed B lymphocytes with genes encoding MRP8 and MRP14. In a semi-recombinant cell-free assay, recombinant MRP8/MRP14 increased the affinity of p67phox for cytochrome b558 synergistically with p47phox. Moreover, MRP8/MRP14 initiated oxidase activation on its own, through a calcium-dependent specific interaction with cytochrome b558 as shown by atomic force microscopy and a structure-function relationship investigation. The data suggest that the change of conformation in cytochrome b558, which initiates the electron transfer, can be mediated by effectors other than oxidase cytosolic factors p67phox and p47phox. Moreover, MRP8/MRP14 dimer behaves as a positive mediator of phagocyte NADPH oxidase regulation. 相似文献
26.
The crystallographic three-dimensional structure of the Escherichia coli maa gene product, previously identified as a maltose O-acetyltransferase (MAT) [Brand, B., and Boos, W. (1991) J. Biol. Chem. 266, 14113-14118] has been determined to 2.15 A resolution by the single anomalous dispersion method using data from a crystal cocrystallized with trimethyllead acetate. It is shown here that MAT acetylates glucose exclusively at the C6 position and maltose at the C6 position of the nonreducing end glucosyl moiety. Furthermore, MAT shows higher affinity toward artificial substrates containing an alkyl or hydrophobic chain as well as a glucosyl unit. The presence of a long hydrophobic patch near the acceptor site provides the structural explanation for this preference. The three-dimensional structure reveals the expected trimeric left-handed parallel beta-helix structure found in all other known hexapeptide repeat enzymes. In particular, the structure shows similarities both overall and at the putative active site to the recently determined structure of galactoside acetyltransferase (GAT), the lacA gene product [Wang, X.-G., Olsen, L. R., and Roderick, S. L. (2002) Structure 10, 581-588]. The structure, together with the new biochemical data, suggests that GAT and MAT are more closely related than previously thought and might have similar cellular functions. However, while GAT is specific for acetylation of galactosyl units, MAT is specific for glucosyl units and is able to acetylate maltooligosaccharides, an important property for biotechnological applications. Structural differences at the acceptor site reflect the differences in substrate specificity. 相似文献
27.
Daoud Z Moubareck C Hakime N Doucet-Populaire F 《The Journal of General and Applied Microbiology》2006,52(3):169-178
Our study aims to investigate and describe the epidemiology of the intestinal carriage of ESBL-PS in intensive care units of five Lebanese hospitals and to analyze the potential risk factors for the acquisition of these strains. At the same time, we intend to determine the patterns of susceptibility of these strains, exploring therefore the availability of alternative treatment. One thousand, four hundred forty-two fecal samples were collected between January 1, 2003 and March 31, 2003 from 378 patients admitted to the ICUs of five Lebanese tertiary care general hospitals located in different areas of Lebanon. ESBL production was detected by the double disk synergy test and antibiotic susceptibility of ESBL-producing strains as well as minimum inhibitory concentrations were determined. A paired case-control study was undertaken to identify risk factors for carriage of ESBL-PS. One hundred eighteen strains isolated from 72 subjects were identified as ESBL producers, including 95 (80.5%) E. coli, 16 (13.6%) Klebsiella pneumoniae, and 7 (5.6%) Enterobacter cloacae. A higher rate of multiple ESBL-PS carriage was described among these acquisition cases (21 double carriages and 3 triple carriages of ESBL-PS compared to only 1 double carriage of ESBL-PS at admission). In general, similar trends of susceptibility were observed in the different hospitals. As expected, the lowest MIC was observed with imipenem for all E. coli, Klebsiella, and Enterobacter isolates. Ciprofloxacin, followed by trimethoprim-sulfamethoxazole seem to be associated with the lowest susceptibility. In vitro susceptibility to cefoxitin for all isolates was 74.6%; more resistance was associated to ceftazidime (90.7%) than to cefotaxime (69.7%). Our data agree with other national and international reports showing the increase in ESBL-PS carriage in ICU patients. They demonstrate the endemic character of this carriage in Lebanese hospitals and the important risk factors including immunosuppression and evidence of ESBL infection. The highly resistant profile of ESBL-PS to antimicrobial agents available for treatment reflects the severity of this issue. The significance of this study resides in the direct correlation between our results and the nationwide increase in multi-drug resistant bacteria and the continuous change in bacterial resistance epidemiology. Our data may have an important impact on infection control policies in hospitals and on treatment of infectious diseases. 相似文献
28.
Summary Calcium alginate gel-entrapped cells ofCatharanthus roseus were used to study the production of indole alkaloids in a flow through process. The bioreactor was functional for more than two months and product recovery was analyzed under various operating conditions. 相似文献
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30.
Evaluating the Ribosomal Internal Transcribed Spacer (ITS) as a Candidate Dinoflagellate Barcode Marker 总被引:4,自引:0,他引:4
RF Stern RA Andersen I Jameson FC Küpper MA Coffroth D Vaulot F Le Gall B Véron JJ Brand H Skelton F Kasai EL Lilly PJ Keeling 《PloS one》2012,7(8):e42780