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51.
David A. Ellis Julie K. Blazel Chinh V. Tran Frank Ruebsam Douglas E. Murphy Lian-Sheng Li Jingjing Zhao Yuefen Zhou Helen M. McGuire Alan X. Xiang Stephen E. Webber Qiang Zhao Qing Han Charles R. Kissinger Matthew Lardy Alberto Gobbi Richard E. Showalter Amit M. Shah Mei Tsan Rupal A. Patel Leo Kirkovsky 《Bioorganic & medicinal chemistry letters》2009,19(21):6047-6052
The discovery of 5,5′- and 6,6′-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 <0.10 μM). In vitro DMPK data for selected compounds as well as crystal structures of representative inhibitors complexed with the NS5B protein are also disclosed. 相似文献
52.
Benghezal M Fauvarque MO Tournebize R Froquet R Marchetti A Bergeret E Lardy B Klein G Sansonetti P Charette SJ Cosson P 《Cellular microbiology》2006,8(1):139-148
The amoeba Dictyostelium discoideum shares many traits with mammalian macrophages, in particular the ability to phagocytose and kill bacteria. In response, pathogenic bacteria use conserved mechanisms to fight amoebae and mammalian phagocytes. Here we developed an assay using Dictyostelium to monitor phagocyte-bacteria interactions. Genetic analysis revealed that the virulence of Klebsiella pneumoniae measured by this test is very similar to that observed in a mouse pneumonia model. Using this assay, two new host resistance genes (PHG1 and KIL1) were identified and shown to be involved in intracellular killing of K. pneumoniae by phagocytes. Phg1 is a member of the 9TM family of proteins, and Kil1 is a sulphotransferase. The loss of PHG1 resulted in Dictyostelium susceptibility to a small subset of bacterial species including K. pneumoniae. Remarkably, Drosophila mutants deficient for PHG1 also exhibited a specific susceptibility to K. pneumoniae infections. Systematic analysis of several additional Dictyostelium mutants created a two-dimensional virulence array, where the complex interactions between host and bacteria are visualized. 相似文献
53.
Capacitation (modifications required for gamete fusion) is produced by incubating guinea-pig spermatozoa in vitro in a chemically defined medium. It is shown that during such incubation a net uptake of Ca2+ by the sperm occurs in two distinguishable phases. An initial loose association of Ca2+, possibly to surface sites, is unaffected by agents (Mg2+, inhibitors of mitochondiral function) that prevent or delay the exocytotic spermatozoal acrosome reaction. The time course of a secondary Ca2+ uptake parallels or slightly precedes the time course of the acrosome reaction. This parallelism is maintained during a variety of treatments that either expedite (local anaesthetics, ionophore A23187, Triton X-100) or delay (Mg2+, low external Ca2+) the acrosome reaction. We conclude that the secondary Ca2+ influx described herein apparently serves to link alterations of the spermatozoal membrane to subsequent contractile and secretory components of the capacitation sequence. 相似文献
54.
The two-phase extraction technique has been used to study the equilibrium between A23187, metal cations, and H+. Under these conditions the ionophore forms charge neutral isostoichiometric complexes with divalent cations in which both carboxylate groups of the 2:1 A23187:M2+ complexes are deprotonated. In ethanol, however, the methyl ester of A23187 also binds divalent cations indicating that protonated complexes between A23187 and cations should also exist. With monovalent cations, A23187 forms two charge-neutral complexes of stoichiometries and relative stabilities: A2HM greater than AM. Examination of energy utilization K+ and H+ movements, and light scattering capacity of mitochondria in the presence of divalent cation chelators, A23187, and valinomycin demonstrates that A23187 can act as a nigericin type K+ ionophore under appropriate conditions. Formation constants for the A2HM complexes with monovalent cations indicate that with appropriate conditions transport of Li+ and Na+ mediated by A23187 would also be expected. The binding constant data and associated free energies of complex formation are compared as a function of ionic radius and of cation charge. The data indicate that lack of conformational mobility in A23187 is responsible for the high cation size selectivity of this compound. To explain the transport selectivity of A23187 for divalent cations, it is proposed that this ionophore forms a family of five complexes, isostoichiometric between cations of different valence but of which only charge-neutral species are permeant to membranes. The charge of a given complex is in turn determined by that of the cation. The concept is consistent with the divalent cation transport specificity of A23187, explains the observed monovalent cation transport, and is useful in rationalizing the differences in charge selectivity between A23187 and X-537A. 相似文献
55.
Calcium uptake into bovine epididymal spermatozoa is enhanced by introducing phosphate in the suspending medium (Babcock et al. (1975) J. Biol. Chem. 250, 6488-6495). This effect of phosphate is found even at a low extracellular Ca2+ concentrations (i.e., 5 microM) suggesting that phosphate is involved in calcium transport via the plasma membrane. Bicarbonate (2 mM) cannot substitute for phosphate, and a relatively high bicarbonate concentration (20 mM) causes partial inhibition of calcium uptake in absence of Pi. In the presence of 1-2 mM phosphate, 20 mM bicarbonate enhances Ca2+ uptake. The data indicate that the plasma membrane of bovine spermatozoa contains two carriers for Ca2+ transport: a phosphate-independent Ca2+ carrier that is stimulated by bicarbonate and a phosphate-dependent Ca2+ carrier that is inhibited by bicarbonate. Higher phosphate concentrations (i.e., 10 mM) inhibit Ca2+ uptake into intact cells (compared to 1.0 mM phosphate) and this inhibition can be relieved partially by 20 mM bicarbonate. This effect of bicarbonate is inhibited by mersalyl. Calcium uptake into the cells is enhanced by adding exogenous substrates to the medium. There is no correlation between ATP levels in the cells and Ca2+ transport into the cell. ATP levels are high even without added exogenous substrate and this ATP level is almost completely reduced by oligomycin, suggesting that ATP can be synthesized in the mitochondria in the absence of exogenous substrate. Calcium transport into the sperm mitochondria (washed filipin-treated cells) is absolutely dependent upon the presence of phosphate and mitochondrial substrate. Bicarbonate cannot support Ca2+ transport into sperm mitochondria. There is good correlation between Ca2+ uptake into intact epididymal sperm and into sperm mitochondria with the various substrates used. This indicates that the rate of calcium transport into the cells is determined by the rate of mitochondrial Ca2+ uptake and respiration with the various substrates. 相似文献
56.
Certain amiloride analogues 3',4'-dichlorobenzamil 2',4'-dimethylbenzamil and alpha',2'-benzobenzamil hydrochloride (ATBB) stimulate calcium accumulation and motility by epididymal bovine spermatozoa. This stimulation can be seen at a range of 0.1-0.4 mM, while at higher concentration there is inhibition of calcium uptake by these amiloride analogues. The amiloride derivative 5-(4-chlorobenzyl)-2',4'-dimethylbenzamil (CBDMB), which bears a 4-chlorobenzyl substituent on the 5-amino nitrogen atom, did not stimulate calcium uptake. The amiloride analogue 3',4'-dichlorobenzamil inhibits the Na+/Ca2(+)-exchange activity in isolated plasma membrane vesicles, and the stimulatory effect of 3',4'-dichlorobenzamil on calcium uptake into epididymal sperm could be seen in Na(+)-free medium. Thus, the stimulation of Ca2+ accumulation in the cells caused by 3',4'-dichlorobenzamil is not a result of inhibiting the Na(+)-dependent Ca2+ clearance. There is no stimulation of Ca2+ uptake into ejaculated cells by adding 3',4'-dichlorobenzamil, which is not due to the presence of the calcium-transport inhibitor (caltrin) in these cells [Rufo, G.A., Schoff, P.K. & Lardy, H.A. (1984) J. Biol. Chem. 259, 2547-2552]. The stimulatory effect of 3',4'-dichlorobenzamil on Ca2+ uptake is inhibited by the voltage-dependent Ca2(+)-channel blockers nifedipin and diltiazem. This indicates that the stimulation of Ca2+ uptake by the amiloride analogues is due to the activation of a voltage-dependent Ca2+ channel of the plasma membrane. 相似文献
57.
Lardy B Bof M Aubry L Paclet MH Morel F Satre M Klein G 《Biochimica et biophysica acta》2005,1744(2):199-212
Membrane-associated NADPH oxidase complexes catalyse the production of the superoxide anion radical from oxygen and NADPH. In mammalian systems, NADPH oxidases form a family of at least seven isoforms that participate in host defence and signalling pathways. We report here the cloning and the characterisation of slime mould Dictyostelium discoideum homologs of the mammalian heme-containing subunit of flavocytochrome b (gp91(phox)) (NoxA, NoxB and NoxC), of the small subunit of flavocytochrome b (p22(phox)) and of the cytosolic factor p67(phox). Null-mutants of either noxA, noxB, noxC or p22(phox) show aberrant starvation-induced development and are unable to produce spores. The overexpression of NoxA(myc2) in noxA null strain restores spore formation. Remarkably, the gene alg-2B, coding for one of the two penta EF-hand proteins in Dictyostelium, acts as a suppressor in noxA, noxB, and p22(phox) null-mutant strains. Knockout of alg-2B allows noxA, noxB or p22(phox) null-mutants to return to normal development. However, the knockout of gene encoding NoxC, which contains two penta EF-hands, is not rescued by the invalidation of alg-2B. These data are consistent with a hypothesis connecting superoxide and calcium signalling during Dictyostelium development. 相似文献
58.
7-Oxo-dehydroepiandrosterone, which can be formed from dehydroepiandrosterone (DHEA) by several mammalian tissues, is more effective than its parent steroid as an inducer of thermogenic enzymes when administered to rats. Using the Morris water maze procedure, we tested DHEA and its 7-oxo-derivative for their ability to reverse the memory abolition induced by scopolamine in young C57BL/6 mice, and for their effect on memory in old mice. A single dose of 7-oxo-DHEA-acetate at 24 mg/kg b.w. completely reversed the impairment caused by 1 mg of scopolamine per kg b.w. (P < 0.001). DHEA (20 mg/kg) was also effective (P < 0.01). In old mice given the same single doses followed by feeding 0.05% of the respective steroid in the diet, memory of the water maze training was retained through a four week test period in mice receiving 7-oxo-DHEA-acetate (P < 0.05) but not in the control or DHEA-treated groups. When old mice were not tested until five weeks after being trained 7-oxo-DHEA exerted a slight, but statistically insignificant, improvement in memory retention. The possible effect of 7-oxo-DHEA in human memory problems deserves investigation. 相似文献
59.
The 7-oxo derivative of dehydroepiandrosterone is more active than the parent steroid and is devoid of adverse side effects in rats, monkeys and humans. In anticipation of possible therapeutic use we have sought more active, longer lasting forms of 7-oxo- and 7beta-hydroxydehydroepiandrosterones. The 7-oxo- and 7-hydroxy steroids have been converted to glucuronides, ethers and carbonate esters. The syntheses of these compounds are described and their ability to induce the formation of liver thermogenic enzymes when fed to rats is reported. Some of the new derivatives were found to be somewhat more effective than the equimolar amounts of 7-oxo-DHEA with which they were compared in each experiment. 相似文献
60.
P E Hughes V Bobyleva-Guarriero H A Lardy 《Comparative biochemistry and physiology. B, Comparative biochemistry》1984,78(3):621-625
When chickens are fasted, the liver becomes dark, whereas the spleen is bleached. Microscopic and spectrophotometric analysis indicated the colour resulted from red blood cells accumulating in enlarged sinusoids of the liver. In birds fasted for 48 hr the hematocrit increases 30%. Blood volume and red cell volume are not altered; the extra cells are not newly synthesised. The extra cells arise from the spleen, possibly under alpha-adrenergic control if given epinephrine by injection and under beta-adrenergic control during fasting as indicated by experiments with alpha and beta-receptor blocking agents. 相似文献