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61.
Veloso MP Romeiro NC Silva GM Alves Hde M Doriguetto AC Ellena J Miranda AL Barreiro EJ Fraga CA 《Chirality》2012,24(6):463-470
This work describes the atropisomeric relationships of 3-methyl-5-(3-methyl-5-phenyl-1H-pyrazol-1-yl)-1-phenyl-1H-pyrazol-4-amine (2d), which belongs to series 4-aminobipyrazole derivatives designed as anti-inflammatory agents. The (1)H nuclear magnetic resonance spectra obtained in the presence of a chiral lanthanide shift salt associated to chiral high-performance liquid chromatography analysis, X-ray diffraction, and molecular modeling tools confirmed that ortho bis-functionalized bipyrazole 2d exists as a mixture of aR,aS-atropisomers. These results provide useful information to understand the pharmacological profile of this derivative and of other 4-aminobipyrazole analogs. 相似文献
62.
63.
Tetraspanins CD9 and CD81 modulate HIV-1-induced membrane fusion 总被引:8,自引:0,他引:8
Gordón-Alonso M Yañez-Mó M Barreiro O Alvarez S Muñoz-Fernández MA Valenzuela-Fernández A Sánchez-Madrid F 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(8):5129-5137
Protein organization on the membrane of target cells may modulate HIV-1 transmission. Since the tetraspanin CD81 is associated to CD4, the receptor of HIV-1 envelope protein (Env; gp120/gp41), we have explored the possibility that this molecule may modulate the initial steps of HIV-1 infection. On the other hand, CD81 belongs to the tetraspanin family, which has been described as organizers of protein microdomains on the plasma membrane. Therefore, the role of CD81 and other related tetraspanin, CD9, on the cell-to-cell fusion process mediated by HIV-1 was studied. We found that anti-tetraspanin Abs enhanced the syncytia formation induced by HIV-1 envelope proteins and viral entry in human T lymphoblasts. In addition, anti-CD81 Abs triggered its clustering in patches, where CD4 and CXCR4 were included. Moreover, the knocking down of CD81 and CD9 expression resulted in an increase in syncytia formation and viral entry. Accordingly, overexpression of CD81 and CD9 rendered cells less susceptible to Env-mediated syncytia formation. These data indicate that CD9 and CD81 have an important role in membrane fusion induced by HIV-1 envelope. 相似文献
64.
Busquets S Garcia-Martínez C Olivan M Barreiro E López-Soriano FJ Argilés JM 《Biochimica et biophysica acta》2006,1760(2):253-258
Overexpression of the UCP3 gene in both murine and human myotube cell cultures leads to a significant activation of the different proteolytic systems involved in muscle myofibrillar protein breakdown. Thus, lysosomal (cathepsin B) and non-lysosomal (m-calpain and ubiquitin-proteasome) mRNA content was significantly increased in the different cell culture systems used. Interestingly, the overexpression of the UCP3 gene was not associated with any changes in apoptosis. Although the function of the UCP3 protein is not completely understood (uncoupling, oxidative stress), these results suggest a possible relation between these main mechanisms involved in muscle wasting during cancer. 相似文献
65.
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
66.
In dynamical systems, configurations that permit flexible control are also prone to undesirable behavior. We study a bilateral
model of the oculomotor pre-motor network that conforms with the neuroanatomical constraint that brainstem neurons project
to cerebellar Purkinje cells on both sides, but Purkinje cells project back to brainstem neurons on the same side only. Bifurcation
analysis reveals that this network asymmetry enables flexible control by the cerebellum of brainstem network dynamics, but
small changes in connection pattern or strength lead to behavior that is unstable, oscillatory, or both. The model produces
the full range of waveform types associated with the hereditary eye movement disorder know as congenital nystagmus, and is
consistent with findings linking the disorder with abnormal connectivity or limited plasticity in the cerebellum. 相似文献
67.
Evolutionary Dynamics of Human Toll-Like Receptors and Their Different Contributions to Host Defense
Luis B. Barreiro Meriem Ben-Ali Hlne Quach Guillaume Laval Etienne Patin Joseph K. Pickrell Christiane Bouchier Magali Tichit Olivier Neyrolles Brigitte Gicquel Judith R. Kidd Kenneth K. Kidd Alexandre Alcaïs Josiane Ragimbeau Sandra Pellegrini Laurent Abel Jean-Laurent Casanova Lluís Quintana-Murci 《PLoS genetics》2009,5(7)
Infectious diseases have been paramount among the threats to health and survival throughout human evolutionary history. Natural selection is therefore expected to act strongly on host defense genes, particularly on innate immunity genes whose products mediate the direct interaction between the host and the microbial environment. In insects and mammals, the Toll-like receptors (TLRs) appear to play a major role in initiating innate immune responses against microbes. In humans, however, it has been speculated that the set of TLRs could be redundant for protective immunity. We investigated how natural selection has acted upon human TLRs, as an approach to assess their level of biological redundancy. We sequenced the ten human TLRs in a panel of 158 individuals from various populations worldwide and found that the intracellular TLRs—activated by nucleic acids and particularly specialized in viral recognition—have evolved under strong purifying selection, indicating their essential non-redundant role in host survival. Conversely, the selective constraints on the TLRs expressed on the cell surface—activated by compounds other than nucleic acids—have been much more relaxed, with higher rates of damaging nonsynonymous and stop mutations tolerated, suggesting their higher redundancy. Finally, we tested whether TLRs have experienced spatially-varying selection in human populations and found that the region encompassing TLR10-TLR1-TLR6 has been the target of recent positive selection among non-Africans. Our findings indicate that the different TLRs differ in their immunological redundancy, reflecting their distinct contributions to host defense. The insights gained in this study foster new hypotheses to be tested in clinical and epidemiological genetics of infectious disease. 相似文献
68.
Moisture sorption isotherms for oat flour and rice flour were determined at 5, 23, and 45 °C using a gravimetric technique
in an a
w range of 0.08–0.98. The results obtained showed that, for a
w values lower than around 0.75, in both flours, the sorption capacity decreased with increasing temperature, while the opposite
behavior was observed at a
w greater than this value. It was found that the experimental data in the water activity range considered were better represented
by the four-parameter Peleg equation. The monolayer water contents for both materials were determined by the BET and GAB models.
The net isosteric heats of sorption were estimated using the Clausius–Clapeyron equation. For both materials, the monolayer
water content and the isosteric heat of sorption were found to decrease with increasing temperature and increasing moisture
content, respectively. 相似文献
69.
Menegatti R Silva GM Zapata-Sudo G Raimundo JM Sudo RT Barreiro EJ Fraga CA 《Bioorganic & medicinal chemistry》2006,14(3):632-640
The present study describes the synthesis and pharmacological profiles of four novel pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives 2-5, which were structurally designed by using the sedative and analgesic drug zolpidem 1 as lead compound. The heterotricyclic system present in the target compounds 2-5 was constructed in good yields, exploiting a regioselective hetero Diels-Alder reaction of the key azabutadiene derivative 7 and functionalized N-phenylmaleimides 9-12. Additionally, we identified that 1-methyl-7-(4-nitrophenyl)-3-phenyl-3,6,7,8-tetrahydropyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8-dione derivative (LASSBio-873, 5) presented not only the most potent ability to promote sedation, which was similar to that induced by the standard benzodiazepine drug midazolam, but also potent central antinociceptive effect. 相似文献
70.
Nailton M. Nascimento-Júnior Thaiana C.F. Mendes Daniella M. Leal Claudia Maria N. Corrêa Roberto T. Sudo Gisele Zapata-Sudo Eliezer J. Barreiro Carlos A.M. Fraga 《Bioorganic & medicinal chemistry letters》2010,20(1):74-77
We described herein the optimization of the synthetic methodology exploited to obtain the pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine sedative prototype 1a and novel analogues designed by successive molecular simplifications. By applying microwave irradiation during the hetero Diels-Alder key-step to obtain the heterotricyclic scaffold, under solvent-free conditions, we were able to obtain the desired compounds in drastically shorter times and better yields. Additionally, in vivo evaluation of the sedative effects of these heterocyclic derivatives showed that 1a and the novel structurally-related analogue 1e were the most efficient compounds to impair the locomotor activity in mice at the dose of 10 μmol/kg. 相似文献