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961.
Insights into the molecular mechanism of action of Celastraceae sesquiterpenes as specific, non-transported inhibitors of human P-glycoprotein 总被引:1,自引:0,他引:1
Muñoz-Martínez F Reyes CP Pérez-Lomas AL Jiménez IA Gamarro F Castanys S 《Biochimica et biophysica acta》2006,1758(1):98-110
Dihydro-beta-agarofuran sesquiterpenes from Celastraceae have been recently shown to bind to human P-glycoprotein (Pgp), functioning as specific, mixed-type inhibitors of its drug transport activity, as well as multidrug resistance (MDR) modulators in vitro. However, nothing is known about whether such compounds are themselves transported by Pgp, or whether they affect Pgp expression as well as its activity, or about the location of their binding site within the protein. We performed transport experiments with a newly synthesized fluorescent sesquiterpene derivative, which retains the anti-Pgp activity of its natural precursor. This probe was poorly transported by Pgp, MRP1, MRP2 and BCRP transporters, compared with classical MDR substrates. Moreover, Pgp did not confer cross-resistance to the most potent dihydro-beta-agarofurans, which did not affect Pgp expression levels in several MDR cell lines. Finally, we observed competitive and non-competitive interactions between one of such dihydro-beta-agarofurans (Mama12) and classical Pgp modulators such as cyclosporin A, verapamil, progesterone, vinblastine and GF120918. These findings suggest that multidrug ABC transporters do not confer resistance to dihydro-beta-agarofurans and could not affect their absorption and biodistribution in the body. Moreover, we mapped their binding site(s) within Pgp, which may prove useful for the rational design of improved modulators based on the structure of dihydro-beta-agarofurans. 相似文献
962.
Iñiguez AM Reinhard K Carvalho Gonçalves ML Ferreira LF Araújo A Paulo Vicente AC 《International journal for parasitology》2006,36(13):1419-1425
Enterobius vermicularis, pinworm, is one of the most common helminths worldwide, infecting nearly a billion people at all socio-economic levels. In prehistoric populations the paleoparasitological findings show a pinworm homogeneous distribution among hunter-gatherers in North America, intensified with the advent of agriculture. This same increase also occurred in the transition from nomad hunter-gatherers to sedentary farmers in South America, although E. vermicularis infection encompasses only the ancient Andean peoples, with no record among the pre-Colombian populations in the South American lowlands. However, the outline of pinworm paleoepidemiology has been supported by microscopic finding of eggs recovered from coprolites. Since molecular techniques are precise and sensitive in detecting pathogen ancient DNA (aDNA), and also could provide insights into the parasite evolutionary history, in this work we have performed a molecular paleoparasitological study of E. vermicularis. aDNA was recovered and pinworm 5S rRNA spacer sequences were determined from pre-Columbian coprolites (4110 BC-AD 900) from four different North and South American archaeological sites. The sequence analysis confirmed E. vermicularis identity and revealed a similarity among ancient and modern sequences. Moreover, polymorphisms were identified at the relative positions 160, 173 and 180, in independent coprolite samples from Tulán, San Pedro de Atacama, Chile (1080-950 BC). We also verified the presence of peculiarities (Splicing leader (SL1) RNA sequence, spliced donor site, the Sm antigen biding site, and RNA secondary structure) which characterise the SL1 RNA gene. The analysis shows that the SL1 RNA gene of contemporary pinworms was present in pre-Columbian E. vermicularis by 6110 years ago. We were successful in detecting E. vermicularis aDNA even in coprolites without direct microscopic evidence of the eggs, improving the diagnosis of helminth infections in the past and further pinworm paleoepidemiological studies. 相似文献
963.
Sohn M Tan Y Wang B Klein RL Trojanowska M Jaffa AA 《American journal of physiology. Heart and circulatory physiology》2006,290(4):H1624-H1634
Hyperlipidemia is a recognized risk factor for atherosclerotic vascular disease. The underlying mechanisms that link lipoproteins and vascular disease are undefined. Connective tissue growth factor (CTGF) is emerging as a key determinant of progressive fibrotic diseases, and its expression is upregulated by diabetes. To define the mechanisms through which low-density lipoproteins (LDL) promote vascular injury, we evaluated whether LDL can modulate the expression of CTGF and collagen IV in human aortic endothelial cells (HAECs). Treatment of HAECs with LDL (50 microg/ml) for 24 h produced a significant increase in the mRNA and the protein levels of CTGF and collagen IV compared with unstimulated controls. To explore the mechanisms by which LDL regulates CTGF and collagen IV expression in HAECs, we determined first if CTGF and collagen IV are downstream targets for regulation by transforming growth factor-beta (TGF-beta). The results demonstrated that TGF-beta produced a concentration-dependent increase in the protein levels of CTGF. To assess whether the induction of CTGF in response to LDL is mediated via autocrine activation of TGF-beta, HAECs were treated with LDL for 24 h in the presence and absence of anti-TGF-beta neutralizing antibodies (anti-TGF-beta NA). The results demonstrated that the increase in CTGF induced by LDL was significantly inhibited by the anti-TGF-beta NA. To investigate the upstream mediators of TGF-beta on activity of CTGF in response to LDL, HAECs were treated with LDL for 24 h in the presence and absence of cell-permeable MAPK inhibitors. Inhibition of p38(mapk) activities did not affect LDL-induced TGF-beta1, CTGF, and collagen IV expression. On the other hand, SP-600125, a specific inhibitor of c-Jun NH(2)-terminal kinase, suppressed LDL-induced TGF-beta, CTGF, and collagen IV expression, and PD-98059, a selective inhibitor of p44/42(mapk), suppressed LDL-induced TGF-beta and CTGF expression. These findings are the first to implicate the MAPK pathway and TGF-beta as key players in LDL signaling, leading to CTGF and collagen IV expression in HAECs. The data also point to a potential mechanistic pathway through which lipoproteins may promote vascular injury. 相似文献
964.
Albareda M Dardanelli MS Sousa C Megías M Temprano F Rodríguez-Navarro DN 《FEMS microbiology letters》2006,259(1):67-73
The plant rhizosphere is an important soil ecological environment for plant-microorganism interactions, which include colonization by a variety of microorganisms in and around the roots that may result in symbiotic, endophytic, associative, or parasitic relationships within the plant, depending on the type of microorganisms, soil nutrient status, and soil environment. Rhizosphere competence may be attributable to the differences in the extent of bacterial attachment to the root surface. We present results of the effect of various factors on the attachment to bean (Phaseolus vulgaris) and soybean (Glycine max) roots of some bacterial species of agronomic importance, such as Rhizobium tropici, Rhizobium etli, Ensifer fredii (homotypic synonym Sinorhizobium fredii), and Azospirillum brasilense; as well as the attachment capability of the plant growth promoting rhizobacteria Pseudomonas fluorescens and Chryseobacterium balustinum. Additionally, we have studied various bacterial traits, such as autoaggregation and flagella movements, which have been postulated to be important properties for bacterial adhesion to surfaces. The lack of mutual incompatibility between rhizobial strains and C. balustinum has been demonstrated in coinoculation assays. 相似文献
965.
Macedo MC Deschamps JC Lucia T Bordignon J Serret CG Rambo G Pivato I Schmitt E 《Animal reproduction science》2006,92(3-4):334-348
The present study consisted of two experiments. In the first one, ejaculates from four boars were used to compare in vitro penetration (IVP) rates of fresh and vitrified swine oocytes by homologous spermatozoa in four treatments: fresh oocytes in conventional incubation (CO2 incubator) (FC), vitrified oocytes in conventional incubation (VC), fresh oocytes in submarine (bag) incubation (FS) and vitrified oocytes in submarine incubation (VS). The IVP rates for FC, VC, FS and VS were 46.5, 44.3, 36.9 and 33.1%, respectively. Analysis through Chi-square tests identified no differences in IVP rates between FC and VC and between FS and VS (P > 0.05), but IVP rate for FC was greater (P < 0.05) than those for both FS and VS. Besides IVP rate for VC did not differ (P > 0.05) from those for FC and FS, but it was greater than that for VS (P < 0.05). Logistic regression analysis identified differential effects of treatments dependant on individual boars. The second experiment evaluated the influence of semen storage period on the semen quality of the two boars associated with greater IVP rate in the first experiment. Semen quality was estimated by IVP rate using the VC treatment and by the following methods: sperm motility, sperm morphology, hypoosmotic swelling test (HOST) and thermal stress test (TST). According to analysis using Chi-square tests, IVP rate did not differ (P > 0.05), for the first boar, between 0 (100.0%) and 24 h of semen storage (98.1%) nor after 48 and 72 h (66.0 and 59.3%, respectively), but IVP rates were greater during the 0-24 h period compared with the 48-72 h period (P < 0.05). For the second boar, IVP rate at 0 h (50.6%) was greater (P < 0.05) than at 24, 48 and 72 h of semen storage (34.3, 28.3 and 24.0%, respectively), with no further differences observed after 24 h (P > 0.05). Logistic regression analysis identified that the effect of storage on IVP rate was influenced by the effect of individual boars. No differences in semen quality during the storage period were identified by conventional methods of semen evaluation, for either boar (P > 0.05) using analysis of variance with repeated measures. These results indicate that IVP test can be used to estimate boar fertility, even when vitrified oocytes are used (if using conventional CO2 incubators) or using an alternative submarine incubation system (if using fresh oocytes). The IVP test was the only method of semen evaluation that identified the reduction in semen quality up to 72 h of storage. 相似文献
966.
Quantitative genetic analysis of biomass and wood chemistry of Populus under different nitrogen levels 总被引:2,自引:1,他引:1
967.
Saccharomyces cerevisiae phosphoenolpyruvate (PEP) carboxykinase mutant Ser252Ala, affecting the conserved Walker A serine residue, was characterized to elucidate the role of this serine residue. The substitution did not result in changes in the protein structure, as indicated by circular dichroism, intrinsic fluorescence spectroscopy, and gel-exclusion chromatography. Kinetic analysis of the mutated enzyme in both directions of the main reaction and in the two secondary reactions showed an approximately 50-fold increase in apparent K(m) for oxaloacetate with minor alterations in the other kinetic parameters. These results show that the hydroxyl group of serine 252 is required for proper oxaloacetate interaction. 相似文献
968.
969.
Gabriela Ecco Javier Vernal Guilherme Razzera Carolina Tavares Viviane Isabel Serpa Santiago Arias Fabricio Klerynton Marchini Marco Aurlio Krieger Samuel Goldenberg Hernn Terenzi 《Gene》2009,448(1):1-6
Kynureninase has been described in bacteria, fungi and animals as an enzyme involved in the catabolic degradation pathway of l-tryptophan. This pyridoxal 5′-phosphate (PLP)-dependent enzyme catalyzes the hydrolytic cleavage of l-kynurenine and 3-hydroxy-l-kynurenine to yield l-alanine and either anthranilic or 3-hydroxyanthranilic acid, respectively. We identified a putative kynureninase gene from a Trypanosoma cruzi project aiming at the structural and functional characterization of more than 100 proteins differentially expressed during metacyclogenesis. This gene encodes a protein similar in size and sequence to kynureninases from other sources. This open reading frame was cloned and the recombinant enzyme was overexpressed. Recombinant T. cruzi kynureninase was purified to homogeneity and its identity was confirmed by mass spectrometry. The apparent molecular mass of the native T. cruzi kynureninase was estimated by gel filtration, suggesting that the protein is a homodimer. Circular dichroism spectrum indicated a mixture of α-helix and β-sheet structure, expected for an aminotransferase fold. l-kynurenine, preferentially hydrolyzed by prokaryotic inducible kynureninases, and 3-hydroxy-l-kynurenine, the preferred substrate in fungi and vertebrates, are both catabolized equally well by T. cruzi kynureninase. Further experimental assays will be performed to fully understand the importance of this enzyme for T. cruzi metabolism. 相似文献
970.
Carolina M. Avila Nelilma C. Romeiro Carlos M.R. Sant’Anna Eliezer J. Barreiro Carlos A.M. Fraga 《Bioorganic & medicinal chemistry letters》2009,19(24):6907-6910
This Letter describes the results of two combined approaches: homology modeling and molecular docking studies, in order to propose the molecular basis of IKKβ inhibition by staurosporine and quercetin as ATP-competitive inhibitors. The results provides a rationale and structural frameworks for designing potent ATP binding-site inhibitors of IKKβ, which is an attractive drug target for inflammatory diseases and has been found to be responsible for some of the already observed pharmacological effects for marketed drugs. 相似文献