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71.
Myriam Gonzlez María Ovejero-Snchez Alba Vicente-Blzquez Raquel lvarez Ana B. Herrero Manuel Medarde Rogelio Gonzlez-Sarmiento Rafael Pelez 《International journal of molecular sciences》2021,22(4)
Pan-Gyn cancers entail 1 in 5 cancer cases worldwide, breast cancer being the most commonly diagnosed and responsible for most cancer deaths in women. The high incidence and mortality of these malignancies, together with the handicaps of taxanes—first-line treatments—turn the development of alternative therapeutics into an urgency. Taxanes exhibit low water solubility that require formulations that involve side effects. These drugs are often associated with dose-limiting toxicities and with the appearance of multi-drug resistance (MDR). Here, we propose targeting tubulin with compounds directed to the colchicine site, as their smaller size offer pharmacokinetic advantages and make them less prone to MDR efflux. We have prepared 52 new Microtubule Destabilizing Sulfonamides (MDS) that mostly avoid MDR-mediated resistance and with improved aqueous solubility. The most potent compounds, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methylaminobenzenesulfonamide 38, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 42, and N-benzyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 45 show nanomolar antiproliferative potencies against ovarian, breast, and cervix carcinoma cells, similar or even better than paclitaxel. Compounds behave as tubulin-binding agents, causing an evident disruption of the microtubule network, in vitro Tubulin Polymerization Inhibition (TPI), and mitotic catastrophe followed by apoptosis. Our results suggest that these novel MDS may be promising alternatives to taxane-based chemotherapy in chemoresistant Pan-Gyn cancers. 相似文献
72.
Dr. Maria L. Di Paolo Dr. Michael S. Christodoulou Dr. Alessandra M. Calogero Dr. Luca Pinzi Prof. Giulio Rastelli Prof. Daniele Passarella Prof. Graziella Cappelletti Prof. Lisa Dalla Via 《ChemMedChem》2019,14(18):1641-1652
A series of 2-phenyloxazoles bearing an amide group at position 4 were designed and synthesized for evaluation as potential inhibitors of human recombinant monoamine oxidases (hrMAOs). Results of kinetics experiments demonstrated that all compounds behave as competitive MAO inhibitors, with good selectivity toward the MAO-B isoform. The most potent and selective derivatives are characterized by inhibition constant (Ki) values in the sub-micromolar range and a good selectivity index (Ki MAO-A/Ki MAO-B>50). Some derivatives were also found to be able to inhibit MAO activity in nerve growth factor (NGF)-differentiated PC12 cells, taken as a model of neuronal cells. In particular, 2-(2-hydroxyphenyl)-N-phenyloxazole-4-carboxamide (compound 4 a ) may be a promising new scaffold, exerting the highest selectivity and inhibitory effect toward MAOs in NGF-differentiated PC12 cell lysates, without compromising cell viability. Molecular docking analysis allowed a rationalization of the experimentally observed binding affinity and selectivity. 相似文献
73.
针对模拟电路健康管理的特点,提出了一种基于PSO优化多核RVM的模拟电路故障预测方法。利用参数分析得到电路的输出频域响应作为特征,计算其与电路无故障标准响应的欧氏距离来表征电路元件健康值,将多个核函数线性组合,并用PSO优化多核RVM参数后的模型实现对各个时间点元件的健康值变化轨迹进行预测。仿真结果表明,该方法在小样本情况下,预测效果优于单一核函数的RVM模型,适用于健康管理中实时预测,具有较好的实用性。 相似文献
74.
This research is concerned with the problem of 4 degrees of freedom (DOF) ship manoeuvring identification modelling with the full-scale trial data. To avoid the multi-innovation matrix inversion in the conventional multi-innovation least squares (MILS) algorithm, a new transformed multi-innovation least squares (TMILS) algorithm is first developed by virtue of the coupling identification concept. And much effort is made to guarantee the uniformly ultimate convergence. Furthermore, the auto-constructed TMILS scheme is derived for the ship manoeuvring motion identification by combination with a statistic index. Comparing with the existing results, the proposed scheme has the significant computational advantage and is able to estimate the model structure. The illustrative examples demonstrate the effectiveness of the proposed algorithm, especially including the identification application with full-scale trial data. 相似文献
75.
For the first time, we present the unique features exhibited by power 4H–SiC UMOSFET in which N and P type columns (NPC) in the drift region are incorporated to improve the breakdown voltage, the specific on-resistance, and the total lateral cell pitch. The P-type column creates a potential barrier in the drift region of the proposed structure for increasing the breakdown voltage and the N-type column reduces the specific on-resistance. Also, the JFET effects reduce and so the total lateral cell pitch will decrease. In the NPC-UMOSFET, the electric field crowding reduces due to the created potential barrier by the NPC regions and causes more uniform electric field distribution in the structure. Using two dimensional simulations, the breakdown voltage and the specific on-resistance of the proposed structure are investigated for the columns parameters in comparison with a conventional UMOSFET (C-UMOSFET) and an accumulation layer UMOSFET (AL-UMOSFET) structures. For the NPC-UMOSFET with 10 µm drift region length the maximum breakdown voltage of 1274 V is obtained, while at the same drift region length, the maximum breakdown voltages of the C-UMOSFET and the AL-UMOSFET structures are 534 and 703 V, respectively. Moreover, the proposed structure exhibits a superior specific on-resistance (Ron,sp) of 2 mΩ cm2, which shows that the on-resistance of the optimized NPC-UMOSFET are decreased by 56% and 58% in comparison with the C-UMOSFET and the AL-UMOSFET, respectively. 相似文献
76.
Martin Michálek Monika Michálková Gurdial Blugan Jakob Kuebler 《Ceramics International》2018,44(3):3255-3260
Up to now, commercially available alumina ceramics were claimed to have strength between 400 and 550 MPa. However, our study shows strength ~ 2 times higher for commercially available alumina than commonly believed. The average and characteristic strength, measured on 31 pure alumina ceramic discs by ball on three balls (B3B) test, were 1205 ± 93 MPa and 1257 MPa, respectively, with a Weibull modulus of m = 11.8. Tested specimens were in form of discs with a diameter of 5 mm and thickness 0.5 mm. The grain size distribution of the alumina is bimodal with an average grain size of ~ 850 nm measured at the surface. The fracture reveals a mixed transgranular / intergranular failure mode. To avoid incorporation of additional flaws, the discs were tested as sintered. The characteristic flexural strength measured in B3B was recalculated according to Weibull theory for standard 4-point bending bars of size 3 × 4 × 45 mm as bend 856 MPa. The measured strength of nearly 900 MPa shows the potential of strength for high purity alumina ceramics. 相似文献
77.
Mri Miczi Mria Golda Balzs Kunkli Tibor Nagy Jzsef Tzsr Jnos Andrs Mtyn 《International journal of molecular sciences》2020,21(24)
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease-19 (COVID-19) being associated with severe pneumonia. Like with other viruses, the interaction of SARS-CoV-2 with host cell proteins is necessary for successful replication, and cleavage of cellular targets by the viral protease also may contribute to the pathogenesis, but knowledge about the human proteins that are processed by the main protease (3CLpro) of SARS-CoV-2 is still limited. We tested the prediction potentials of two different in silico methods for the identification of SARS-CoV-2 3CLpro cleavage sites in human proteins. Short stretches of homologous host-pathogen protein sequences (SSHHPS) that are present in SARS-CoV-2 polyprotein and human proteins were identified using BLAST analysis, and the NetCorona 1.0 webserver was used to successfully predict cleavage sites, although this method was primarily developed for SARS-CoV. Human C-terminal-binding protein 1 (CTBP1) was found to be cleaved in vitro by SARS-CoV-2 3CLpro, the existence of the cleavage site was proved experimentally by using a His6-MBP-mEYFP recombinant substrate containing the predicted target sequence. Our results highlight both potentials and limitations of the tested algorithms. The identification of candidate host substrates of 3CLpro may help better develop an understanding of the molecular mechanisms behind the replication and pathogenesis of SARS-CoV-2. 相似文献
78.
Cecilia Arriagada Viviana A. Cavieres Charlotte Luchsinger Alexis E. Gonzlez Vanessa C. Muoz Jorge Cancino Patricia V. Burgos Gonzalo A. Mardones 《International journal of molecular sciences》2020,21(22)
Protein trafficking is altered when normal cells acquire a tumor phenotype. A key subcellular compartment in regulating protein trafficking is the Golgi apparatus, but its role in carcinogenesis is still not well defined. Golgi phosphoprotein 3 (GOLPH3), a peripheral membrane protein mostly localized at the trans-Golgi network, is overexpressed in several tumor types including glioblastoma multiforme (GBM), the most lethal primary brain tumor. Moreover, GOLPH3 is currently considered an oncoprotein, however its precise function in GBM is not fully understood. Here, we analyzed in T98G cells of GBM, which express high levels of epidermal growth factor receptor (EGFR), the effect of stable RNAi-mediated knockdown of GOLPH3. We found that silencing GOLPH3 caused a significant reduction in the proliferation of T98G cells and an unexpected increase in total EGFR levels, even at the cell surface, which was however less prone to ligand-induced autophosphorylation. Furthermore, silencing GOLPH3 decreased EGFR sialylation and fucosylation, which correlated with delayed ligand-induced EGFR downregulation and its accumulation at endo-lysosomal compartments. Finally, we found that EGF failed at promoting EGFR ubiquitylation when the levels of GOLPH3 were reduced. Altogether, our results show that GOLPH3 in T98G cells regulates the endocytic trafficking and activation of EGFR likely by affecting its extent of glycosylation and ubiquitylation. 相似文献
79.
樟芝多糖通过降低NLRP3 Caspase1炎性小体表达改善帕金森小鼠神经行为学的机制研究 总被引:1,自引:0,他引:1
目的:研究樟芝多糖通过降低NLRP3-Caspase1炎性小体表达改善6-OHDA构建的帕金森小鼠模型的行为学机制。方法:利用6-OHDA脑内注射构建帕金森小鼠模型,通过酪氨酸羟化酶(TH)免疫组化染色和行为学判定小鼠模型的构建成功。利用樟芝多糖进行干预,分别在干预前、干预后的第1、3、7天4个时间点进行神经行为学实验,分别采用转棒实验、爬杆实验检测小鼠自主行为能力以及协调能力,4个时间点取小鼠尾静脉外周血采用ELISA法检测外周血中Caspase1和IL-1β的表达,樟芝多糖干预第7天时待进行完行为学实验后小鼠断颈处死,取小鼠脑组织-纹状体,Western blot法检测纹状体中Caspase1、proCaspase1、NLRP3的表达,高效液相色谱检测纹状体中单胺类神经递质的表达,RT-QPCR检测Caspase1、NLRP3、IL-1β、IL-4、IL-6的mRNA表达。NISSl染色检测小鼠脑组织神经细胞凋亡情况。 结果:6-OHDA脑内注射可以造成小鼠帕金森样病变,且TH蛋白表达显著下调,樟芝多糖干预后小鼠的行为学得到显著改善(P<0.05),纹状体中Caspase1、proCaspase1、NLRP3的表达显著下调,与模型小鼠相比具有统计学差异(P<0.05),且相关炎症因子Caspase1、NLRP3、IL-1β、IL-4、IL-6的mRNA表达下调(P<0.05),纹状体中单胺类神经递质表达上升(P<0.05)。结论:樟芝多糖可以通过下调NLRP3-Caspase1炎性小体表达来改善6-OHDA构建的帕金森小鼠模型行为改善,这可能是樟芝多糖治疗帕金森的机制之一。 相似文献
80.
Gina Cavaliere Giovanna Trinchese Nadia Musco Federico Infascelli Chiara De Filippo Vincenzo Mastellone Valeria Maria Morittu Pietro Lombardi Raffaella Tudisco Micaela Grossi Vincenzo Monda Monica I. Cutrignelli Antonietta Messina Serena Calabrò Heleena B. Moni Luigi Stradella Giovanni Messina Marcellino Monda Maria Pina Mollica 《Journal of dairy science》2018,101(3):1843-1851
Excessive energy intake may evoke complex biochemical processes characterized by inflammation, oxidative stress, and impairment of mitochondrial function that represent the main factors underlying noncommunicable diseases. Because cow milk is widely used for human nutrition and in food industry processing, the nutritional quality of milk is of special interest with respect to human health. In our study, we analyzed milk produced by dairy cows fed a diet characterized by a high forage:concentrate ratio (high forage milk, HFM). In view of the low n-6:n-3 ratio and high content of conjugated linoleic acid of HFM, we studied the effects of this milk on lipid metabolism, inflammation, mitochondrial function, and oxidative stress in a rat model. To this end, we supplemented for 4 wk the diet of male Wistar rats with HFM and with an isocaloric amount (82 kJ, 22 mL/d) of milk obtained from cows fed a diet with low forage:concentrate ratio, and analyzed the metabolic parameters of the animals. Our results indicate that HFM may positively affect lipid metabolism, leptin:adiponectin ratio, inflammation, mitochondrial function, and oxidative stress, providing the first evidence of the beneficial effects of HFM on rat metabolism. 相似文献