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191.
Adam Mieczkowski Tomasz Frączyk Mateusz Psurski Patrycja Wińska Paweł Siedlecki Monika Dziełak Damian Trzybiński Marcin Wilczek Maciej Bagiński Bartosz Bieszczad Krzysztof Woźniak 《化学与生物多样性》2021,18(1):e2000733
Currently available chemotherapeutic treatments for blood cancers (leukemia) usually have strong side effects. More selective, efficient, and less toxic anticancer agents are needed. We synthesized seven, new, optically pure (12aS)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione derivatives and examined their cytotoxicity towards eight cancer cell lines, including urinary bladder (TCC-SUP, UM-UC-3, KU-19-9), colon (LoVo), and breast (MCF-7, MDA-MB-231) cancer representatives, as well as two leukemic cell lines (MV-4-11, CCRF-CEM) and normal murine fibroblasts (Balb/3T3) as reference cell line. Three of the seven newly-obtained compounds ((12aS)-8-bromo-2-(3-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione, (12aS)-8,9-dimethoxy-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione and (12aS)-8-nitro-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione, showed enhanced activity and selectivity toward the leukemic MV-4-11 cell lines when compared to our previously reported compounds, with IC50 values in the range of 2.9–5.6 μM. Additionally, (12aS)-9-nitro-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione exhibited a strong cytotoxic effect against the leukemic CCRF-CEM (IC50=6.1 μM) and MV-4-11 (IC50=11.0 μM) cell lines, a moderate cytotoxic effect toward other tumor lines (IC50=31.8–55.0 μM) and very weak cytotoxic effect toward the Balb/3T3 reference cell lines. Selected compounds were further evaluated for their potential to induce apoptotic cell death in MV-4-11 cells by measuring caspase-3 activity. We also established the crystal structure of three products and investigated the effect of 22 derivatives of 1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione on the activity of the cancer-associated enzyme autotaxin. All compounds proved to be weak inhibitors of autotaxin, although some (R) and (S) enantiomers had Ki values of 10–19 μM. The obtained results showed that the tested compounds exhibited a selective antileukemic effect, which appeared not to be related directly to autotaxin. Molecular targets responsible for this effect remain to be identified. The newly obtained compounds can be used in the search for new, selective anticancer therapies. 相似文献
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Agnieszka Szala Sambor Sawicki Anna St. Swierzko Janusz Szemraj Marcin Sniadecki Mateusz Michalski Andrzej Kaluzynski Jolanta Lukasiewicz Anna Maciejewska Dariusz Wydra David C. Kilpatrick Misao Matsushita Maciej Cedzynski 《Cancer immunology, immunotherapy : CII》2013,62(8):1411-1419
Ficolins are serum pattern recognition molecules. They have opsonic properties and are able to activate complement via the lectin pathway. This paper reports investigations concerning ficolin-2 and ficolin-3 in ovarian cancer (OC). Their serum levels, single nucleotide polymorphisms of the corresponding FCN2 and FCN3 genes and specific mRNA expression in ovarian sections were investigated in 128 patients suffering from primary OC and 197 controls operated on for reasons other than malignancies. The latter consisted of two reference groups: those with benign tumours (n = 123) and those with normal ovaries (NO) (n = 74). Serum ficolin-2 and ficolin-3 concentrations were higher among patients with malignant disease when compared with either of the reference groups. A significant correlation between ficolin-2 and ficolin-3 concentrations was found, while no correlations with CA125 antigen or CRP were observed. No differences in the frequency of single nucleotide polymorphisms at sites ?64, ?4 (promoter), +6359, or +6424 (exon 8) (FCN2 gene) nor in the frame-shift mutation 1637delC (FCN3 gene) were found between investigated groups. In contrast to serum concentrations, the expression of FCN2 gene (reported for the first time in ovarian sections) was significantly lower in women with OC in comparison with patients with NO but not with benign ovarian tumours. In case of FCN3 gene, its expression levels in OC group inversely correlated with serum ficolin-3 and were lower in comparison with controls. 相似文献
195.
Danijela Popovic Hanna Panagiotopoulou Mariusz Kleszcz Mateusz Baca Robert Rutkowski Tomasz Heese Piotr Weglenski Anna Stankovic 《Ichthyological Research》2013,60(2):149-158
Until 1960s, vimba was found abundantly in Polish rivers and was an important species for the fishing industry. Overfishing, water pollution and dam constructions brought most of the vimba populations close to extinction. We analyzed the genetic variability of several remnant vimba populations in the Vistula and Oder river basins. The 305-bp fragment encompassing the 5′-end of the mtDNA control region was sequenced in a total of 202 wild specimens derived from six populations. Six different haplotypes were distinguished. The population of Barycz River was found to be the most polymorphic and was chosen as a source of breeding material for the vimba restitution program. In the years 2000–2008 fishes from this river were caught, spawned in captivity and released to the same river. The number of fishes returning to the Barycz River spawning grounds was monitored in the following years. In 2008, it was almost 70 times higher than the number of fishes recorded in 2003, when the lowest population size was observed. The haplotype and nucleotide diversities of the restored population were similar to those of the original population. 相似文献
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Monika Gawor Mateusz Śpiewak Agata Kubik Aleksandra Wróbel Anna Lutyńska Magdalena Marczak 《Biomarkers》2013,18(7):676-682
AbstractBackground: Myocardial fibrosis in hypertrophic cardiomyopathy (HCM) is associated with worse clinical outcomes. The availability of circulating biomarkers of myocardial fibrosis and hypertrophy would be helpful in clinical practice.Objective: The aim of this study was to evaluate usefulness of various biomarkers of myocardial fibrosis and hypertrophy in HCM.Methods: Levels of biomarkers: soluble ST2 (sST2), galectin-3 (Gal-3), growth differentiation factor-15 (GDF-15), NT-proBNP and high-sensitivity cardiac troponin T (hs-cTnT) were measured in 60 patients with HCM. All patients underwent cardiac magnetic resonance imaging to calculate parameters of hypertrophy and fibrosis.Results: We observed positive correlations among sST2 levels and left ventricular mass (LVM) (r?=?0.32, p?=?0.012), LV mass indexed for the body surface area (LVMI) (r?=?0.27, p?=?0.036) and maximal wall thickness (MWT) (r?=?0.31, p?=?0.015). No correlation was found between Gal-3 and GDF-15 levels and hypertrophy and fibrosis parameters. We observed positive correlations among hs-cTnT levels and LVM (r?=?0.58, p?<?0.0001), LVMI (r?=?0.48, p?=?0.0001), MWT (r?=?0.31, p?=?0.015) and late gadolinium enhancement (LGE) mass (r?=?0.37, p?=?0.003). There were positive correlations between NT-proBNP levels and LVM (r?=?0.33, p?=?0.01), LVMI (r?=?0.41, p?=?0.001), MWT (r?=?0.42, p?<?0.001) and LGE mass (r?=?0.44, p?<?0.001).Conclusions: Although no correlation between sST2 levels and myocardial fibrosis was found, sST2 may provide some additional information about hypertrophy extension. NT-proBNP and hs-cTnT are useful biomarkers in assessment of hypertrophy and fibrosis in HCM. 相似文献
197.
Mateusz Jędrzejewski Piotr Ordon Ludwik Komorowski 《Journal of molecular modeling》2013,19(10):4203-4207
The reaction force and the electronic flux, first proposed by Toro-Labbé et al. (J Phys Chem A 103:4398, 1999) have been expressed by the existing conceptual DFT apparatus. The critical points (extremes) of the chemical potential, global hardness and softness have been identified by means of the existing and computable energy derivatives: the Hellman-Feynman force, nuclear reactivity and nuclear stiffness. Specific role of atoms at the reaction center has been unveiled by indicating an alternative method of calculation of the reaction force and the reaction electronic flux. The electron dipole polarizability on the IRC has been analyzed for the model reaction HF + CO→HCOF. The electron polarizability determined on the IRC α e (ξ) was found to be reasonably parallel to the global softness curve S(ξ). The softest state on the IRC (not TS) coincides with zero electronic flux. Figure
Variation of the electronic dipole polarizability 相似文献
198.
The "fuzzy oil drop" model assuming the structure of the hydrophobic core of the form of 3-D Gauss function appeared to be verified positively. The protein 1NMF belonging to downhill proteins was found to represent the hydrophobic density distribution accordant with the assumed model. The accordance of the protein structure with the assumed model was measured using elements of theory information. This observation opens the possibility to simulate the folding process as influenced by external force field of hydrophobic character. 相似文献
199.
Mateusz Manicki Julia Majewska Szymon Ciesielski Brenda Schilke Anna Blenska Jacek Kominek Jaroslaw Marszalek Elizabeth A. Craig Rafal Dutkiewicz 《The Journal of biological chemistry》2014,289(44):30268-30278
In mitochondria FeS clusters, prosthetic groups critical for the activity of many proteins, are first assembled on Isu, a 14-kDa scaffold protein, and then transferred to recipient apoproteins. The assembly process involves interaction of Isu with both Nfs1, the cysteine desulfurase serving as a sulfur donor, and the yeast frataxin homolog (Yfh1) serving as a regulator of desulfurase activity and/or iron donor. Here, based on the results of biochemical experiments with purified wild-type and variant proteins, we report that interaction of Yfh1 with both Nfs1 and Isu are required for formation of a stable tripartite assembly complex. Disruption of either Yfh1-Isu or Nfs1-Isu interactions destabilizes the complex. Cluster transfer to recipient apoprotein is known to require the interaction of Isu with the J-protein/Hsp70 molecular chaperone pair, Jac1 and Ssq1. Here we show that the Yfh1 interaction with Isu involves the PVK sequence motif, which is also the site key for the interaction of Isu with Hsp70 Ssq1. Coupled with our previous observation that Nfs1 and Jac1 binding to Isu is mutually exclusive due to partially overlapping binding sites, we propose that such mutual exclusivity of cluster assembly factor (Nfs1/Yfh1) and cluster transfer factor (Jac1/Ssq1) binding to Isu has functional consequences for the transition from the assembly process to the transfer process, and thus regulation of the biogenesis of FeS cluster proteins. 相似文献
200.
Ewelina Stoczynska-Fidelus Sylwester Piaskowski Michal Bienkowski Mateusz Banaszczyk Krystyna Hulas-Bigoszewska Marta Winiecka-Klimek Anna Radomiak-Zaluska Waldemar Och Maciej Borowiec Jolanta Zieba Cezary Treda Piotr Rieske 《PloS one》2014,9(1)
Cell line analysis is an important element of cancer research. Despite the progress in glioblastoma cell culturing, the cells isolated from the majority of specimens cannot be propagated infinitely in vitro. The aim of this study was to identify the processes responsible for the stabilization failure. Therefore, we analyzed 56 primary GB cultures, 7 of which were stabilized. Our results indicate that senescence is primarily responsible for the glioblastoma cell line stabilization failure, while mitotic catastrophe and apoptosis play a minor role. Moreover, a new technical approach allowed for a more profound analysis of the senescent cells in primary cultures, including the distinction between tumor and normal cells. In addition, we observed that glioblastoma cells in primary cultures have a varied potential to undergo spontaneous in vitro senescence, which is often higher than that of the normal cells infiltrating the tumor. Thus, this is the first report of GB cells in primary cell cultures (including both monolayer and spheroid conditions) rapidly and spontaneously becoming senescent. Intriguingly, our data also suggest that nearly half of GB cell lines have a combination of TP53 mutation and CDKN2A homozygous deletion, which are considered as mutually exclusive in glioblastoma. Moreover, recognition of the mechanisms of senescence and mitotic catastrophe in glioblastoma cells may be a step towards a potential new therapeutic approach. 相似文献