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排序方式: 共有143条查询结果,搜索用时 46 毫秒
1.
Alexey E. Machulkin Dmitry A. Skvortsov Yan A. Ivanenkov Anton P. Ber Mikhail V. Kavalchuk Anastasia V. Aladinskaya Anastasia A. Uspenskaya Radik R. Shafikov Ekaterina A. Plotnikova Raisa I. Yakubovskaya Ekaterina A. Nimenko Nikolay U. Zyk Elena K. Beloglazkina Nikolay V. Zyk Victor E Koteliansky Alexander G. Majouga 《Bioorganic & medicinal chemistry letters》2019,29(16):2229-2235
Prostate cancer (PC) is the second most commonly occurring cancer in men. Conventional chemotherapy has wide variety of disadvantages such as high systemic toxicity and low selectivity. Targeted drug delivery is a promising approach to decrease side effects of therapy. Prostate specific membrane antigen (PSMA) is overexpressed in prostate cancer cells while low level of expression is observed in normal cells. In this study we describe the development of Glu-urea-Lys based PSMA-targeting conjugates with paclitaxel. A series of new PSMA targeting conjugates with paclitaxel was designed and synthesized. The cytotoxicity of conjugates was evaluated against prostate (LNCaP, 22Rv1 and PC-3) and non-prostate (Hek293T, VA13, A549 and MCF-7) cell lines. The most promising conjugate 21 was examined in vivo using 22Rv1 xenograft mice model. It demonstrated good efficiency comparable with paclitaxel, while reduced toxicity. 3D molecular docking study was also performed to understand underlying mechanism of binding and further optimization of the linker substructure and conjugates structure for improving the target affinity. These conjugates may be useful for further design of novel PSMA targeting delivery systems for PC. 相似文献
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Bacterial populations and environmental factors controlling cellulose degradation in an acidic Sphagnum peat 总被引:5,自引:0,他引:5
Northern peatlands represent a major global carbon store harbouring approximately one-third of the global reserves of soil organic carbon. A large proportion of these peatlands consists of acidic Sphagnum-dominated ombrotrophic bogs, which are characterized by extremely low rates of plant debris decomposition. The degradation of cellulose, the major component of Sphagnum-derived litter, was monitored in long-term incubation experiments with acidic (pH 4.0) peat extracts. This process was almost undetectable at 10°C and occurred at low rates at 20°C, while it was significantly accelerated at both temperature regimes by the addition of available nitrogen. Cellulose breakdown was only partially inhibited in the presence of cycloheximide, suggesting that bacteria participated in this process. We aimed to identify these bacteria by a combination of molecular and cultivation approaches and to determine the factors that limit their activity in situ. The indigenous bacterial community in peat was dominated by Alphaproteobacteria and Acidobacteria. The addition of cellulose induced a clear shift in the community structure towards an increase in the relative abundance of the Bacteroidetes. Increasing temperature and nitrogen availability resulted in a selective development of bacteria phylogenetically related to Cytophaga hutchinsonii (94-95% 16S rRNA gene sequence similarity), which densely colonized microfibrils of cellulose. Among isolates obtained from this community only some subdivision 1 Acidobacteria were capable of degrading cellulose, albeit at a very slow rate. These Acidobacteria represent indigenous cellulolytic members of the microbial community in acidic peat and are easily out-competed by Cytophaga-like bacteria under conditions of increased nitrogen availability. Members of the phylum Firmicutes, known to be key players in cellulose degradation in neutral habitats, were not detected in the cellulolytic community enriched at low pH. 相似文献
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Using an immunohistochemical technique and densitometric analysis in experiments on rats, we examined the expression of an
early-response protein, c-Fos, in the medial parvicellular subnucleus of the hypothalamic paraventricular nucleus (mpcPVN).
During 7 days, the animals were kept under conditions of (i) normal photoperiod (group LD), (ii) continuous illumination (group
LL), and (iii) continuous darkness (light deprivation, group DD). It was found that both normal photoperiodicity and artificial
modifications of the latter result in significant changes of c-Fos immunopositivity in the nuclei of mpcPVN neurons (cells
that synthesize corticotropin-releasing factor). Changes in the indices of concentration and amount of c-Fos in mpcPVN neurons
were, from some aspects, similar to those observed under analogous experimental conditions in neurons of a leading pacemaker
of the circadian periodicity, the suprachiasmatic nuclei (SChNs) of the hypothalamus [10], but, at the same time, demonstrated noticeable specificity from other aspects. In all experimental groups, the concentration
and amount of c-Fos in mpcPVN neurons were greater during daytime than at night. Dramatic increases in the above parameters
observed at daytime in rats subjected to light deprivation were the most significant effect of modifications of the photoperiod.
Both continuous illumination and light deprivation resulted in some increase of the number (density) of c-Fos-immunopositive
units in the mpcPVN. The nuclei of neurons of this structure demonstrated the phenomenon found earlier in SChN neuron; geometrical
dimensions of the cell nuclei of these structures depended noticeably on both illumination conditions and periodicity. Probable
mechanisms of the dependence of c-Fos expression in the hypothalamic nuclei on the photoperiod and its modifications, interdependence
of such changes observed in the circadian pacemaker (SChN) and an important component of the system controlling the stress
reactions (mpcPVN), and the relation of the above phenomena to the level of melatonin produced by the epiphysis cerebri (main neuroendocrine intermediator organizing the above-mentioned periodicity) are discussed. 相似文献
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Do HT Tselykh TV Mäkelä J Ho TH Olkkonen VM Bornhauser BC Korhonen L Zelcer N Lindholm D 《The Journal of biological chemistry》2012,287(16):12602-12611
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The paper presents a method for syndromic surveillance of an epidemic outbreak due to an emerging disease, formulated in the context of stochastic nonlinear filtering. The dynamics of the epidemic is modeled using a stochastic compartmental epidemiological model with inhomogeneous mixing. The syndromic (typically non-medical) observations of the number of infected people (e.g. visits to pharmacies, sale of certain products, absenteeism from work/study, etc.) are assumed available for monitoring and prediction of the epidemic. The state of the epidemic, including the number of infected people and the unknown parameters of the model, are estimated via a particle filter. The numerical results indicate that the proposed framework can provide useful early prediction of the epidemic peak if the uncertainty in prior knowledge of model parameters is not excessive. 相似文献
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Rostislav A. Petrov Svetlana Yu. Maklakova Yan A. Ivanenkov Stanislav A. Petrov Olga V. Sergeeva Emil Yu. Yamansarov Irina V. Saltykova Igor I. Kireev Irina B. Alieva Ekaterina V. Deyneka Alina A. Sofronova Anastasiia V. Aladinskaia Alexandre V. Trofimenko Renat S. Yamidanov Sergey V. Kovalev Victor E. Kotelianski Timofey S. Zatsepin Elena K. Beloglazkina Alexander G. Majouga 《Bioorganic & medicinal chemistry letters》2018,28(3):382-387
Asialoglycoprotein receptor (ASGP-R) is a promising biological target for drug delivery into hepatoma cells. Nevertheless, there are only few examples of small-molecule conjugates of ASGP-R selective ligand equipped by a therapeutic agent for the treatment of hepatocellular carcinoma (HCC). In the present work, we describe a convenient and versatile synthetic approach to novel mono- and multivalent drug-conjugates containing N-acetyl-2-deoxy-2-aminogalactopyranose and anticancer drug – paclitaxel (PTX). Several molecules have demonstrated high affinity towards ASGP-R and good stability under physiological conditions, significant in vitro anticancer activity comparable to PTX, as well as good internalization via ASGP-R-mediated endocytosis. Therefore, the conjugates with the highest potency can be regarded as a promising therapeutic option against HCC. 相似文献
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