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Absence of Tau triggers age‐dependent sciatic nerve morphofunctional deficits and motor impairment 下载免费PDF全文
Sofia Lopes André Lopes Vítor Pinto Marco R. Guimarães Vanessa Morais Sardinha Sara Duarte‐Silva Sara Pinheiro João Pizarro João Filipe Oliveira Nuno Sousa Hugo Leite‐Almeida Ioannis Sotiropoulos 《Aging cell》2016,15(2):208-216
Dementia is the cardinal feature of Alzheimer's disease (AD), yet the clinical symptoms of this disorder also include a marked loss of motor function. Tau abnormal hyperphosphorylation and malfunction are well‐established key events in AD neuropathology but the impact of the loss of normal Tau function in neuronal degeneration and subsequent behavioral deficits is still debated. While Tau reduction has been increasingly suggested as therapeutic strategy against neurodegeneration, particularly in AD, there is controversial evidence about whether loss of Tau progressively impacts on motor function arguing about damage of CNS motor components. Using a variety of motor‐related tests, we herein provide evidence of an age‐dependent motor impairment in Tau?/? animals that is accompanied by ultrastructural and functional impairments of the efferent fibers that convey motor‐related information. Specifically, we show that the sciatic nerve of old (17–22‐months) Tau?/? mice displays increased degenerating myelinated fibers and diminished conduction properties, as compared to age‐matched wild‐type (Tau+/+) littermates and younger (4–6 months) Tau?/? and Tau+/+ mice. In addition, the sciatic nerves of Tau?/? mice exhibit a progressive hypomyelination (assessed by g‐ratio) specifically affecting large‐diameter, motor‐related axons in old animals. These findings suggest that loss of Tau protein may progressively impact on peripheral motor system. 相似文献
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Andrea Pinto Lucia Tamborini Eugenia Pennacchietti Antonio Coluccia Romano Silvestri Gregorio Cullia 《Journal of enzyme inhibition and medicinal chemistry》2016,31(2):295-301
The γ-aminobutyrate (GABA)-degradative enzyme GABA aminotransferase (GABA-AT) is regarded as an attractive target to control GABA levels in the central nervous system: this has important implications in the treatment of several neurological disorders and drug dependencies. We have investigated the ability of newly synthesized compounds to act as GABA-AT inhibitors. These compounds have a unique bicyclic structure: the carbocyclic ring bears the GABA skeleton, while the fused 3-Br-isoxazoline ring contains an electrophilic warhead susceptible of nucleophilic attack by an active site residue of the target enzyme. Out of the four compounds tested, only the one named (+)-3 was found to significantly inhibit mammalian GABA-AT in vitro. Docking studies, performed on the available structures of GABA-AT, support the experimental findings: out of the four tested compounds, only (+)-3 suitably orients the electrophilic 3-Br-isoxazoline warhead towards the active site nucleophilic residue Lys329, thereby explaining the irreversible inhibition of GABA-AT observed experimentally. 相似文献
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Elaine da Conceição Petronilho Magdalena do Nascimento Rennó Newton Gonçalves Castro Fernanda Motta R. da Silva Angelo da Cunha Pinto 《Journal of enzyme inhibition and medicinal chemistry》2016,31(6):1069-1078
Analogs of pralidoxime, which is a commercial antidote for intoxication from neurotoxic organophosphorus compounds, were designed, synthesized, characterized, and tested as potential inhibitors or reactivators of acetylcholinesterase (AChE) using the Ellman’s test, nuclear magnetic resonance, and molecular modeling. These analogs include 1-methylpyridine-2-carboxaldehyde hydrazone, 1-methylpyridine-2-carboxaldehyde guanylhydrazone, and six other guanylhydrazones obtained from different benzaldehydes. The results indicate that all compounds are weak AChE reactivators but relatively good AChE inhibitors. The most effective AChE inhibitor discovered was the guanylhydrazone derived from 2,4-dinitrobenzaldehyde and was compared with tacrine, displaying similar activity to this reference material. These results indicate that guanylhydrazones as well as future similar derivatives may function as drugs for the treatment of Alzheimer's disease. 相似文献
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Oliveira Sílvia Ardais Ana Paula Bastos Clarissa Ribeiro Gazal Marta Jansen Karen de Mattos Souza Luciano da Silva Ricardo Azevedo Kaster Manuella Pinto Lara Diogo Rizzato Ghisleni Gabriele 《Purinergic signalling》2019,15(1):37-44
Purinergic Signalling - Genetic variants involved in adenosine metabolism and its receptors were associated with increased risk for psychiatric disorders, including anxiety, depression, and... 相似文献
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Pinto José de Azevedo Cristiana Rodrigues Oliveira Rui von Stosch Moritz 《Bioprocess and biosystems engineering》2019,42(11):1853-1865
Bioprocess and Biosystems Engineering - Hybrid semi-parametric modeling, combining mechanistic and machine-learning methods, has proven to be a powerful method for process development. This paper... 相似文献
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Jessica Tauany Andrade Geisa Fantini de Figueiredo Luisa Ferreira Cruz Sarah Eliza de Morais Carla Daiane Ferreira Souza Flávia Carmo Horta Pinto Jaqueline Maria Siqueira Ferreira Marcelo Gonzaga de Freitas Araújo 《Revista iberoamericana de micología》2019,36(4):192-199
BackgroundCandida albicans is the main agent that causes vulvovaginal candidiasis. Resistance among isolates to azole antifungal agents has been reported.AimsDue to the well-known antifungal potential of curcumin, the purpose of this work was to evaluate the in vitro anticandidal activity of curcumin and its effect in the treatment of experimental vulvovaginal candidiasis.MethodsThe anticandidal activity of curcumin was investigated against eight Candida strains by the broth microdilution assay, and its mechanism of action was evaluated by testing the binding to ergosterol. Then, the effect of curcumin in the treatment of vulvovaginal candidiasis was evaluated in an immunosuppressed, estrogen treated rat model.ResultsCurcumin showed minimum inhibitory concentration values of 125–1000 μg/ml, and the best result was observed against Candida glabrata. The compound was shown to be able to bind to the ergosterol present in the membrane, event that may be the mechanism of action. In addition, in the in vivo model of vulvovaginal candidiasis with C. albicans, treatments reduced the vaginal fungal burden in infected rats after seven days of treatment with different doses.ConclusionsCurcumin could be considered a promising effective antifungal agent in the treatment of vulvovaginal candidiasis. 相似文献
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