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91.
Dr. André L. C. S. Nascimento Richard P. Fernandes Christian Quijia Victor H. S. Araujo Juliana Pereira Prof. Dr. Jerusa S. Garcia Prof. Dr. Marcello G. Trevisan Prof. Dr. Marlus Chorilli 《ChemMedChem》2020,15(12):1018-1029
Since the beginning of the HIV epidemic, research has been carried out to control the virus. Understanding the mechanisms of replication has given access to the various classes of drugs that over time have transformed AIDS into a manageable chronic disease. The class of protease inhibitors (PIs) gained notice in anti-retroviral therapy, once it was found that peptidomimetic molecules act by blocking the active catalytic center of the aspartic protease, which is directly related to HIV maturation. However, mutations in enzymatic internal residues are the biggest issue for these drugs, because a small change in biochemical interaction can generate resistance. Low plasma concentrations of PIs favor viral natural selection; high concentrations can inhibit even partially resistant enzymes. Food-drug/drug-drug interactions can decrease the bioavailability of PIs and are related to many side effects. Therefore, this review summarizes the pharmacokinetic properties of current PIs, the changes when pharmacological boosters are used and also lists the major mutations to help understanding of how long the continuous treatment can ensure a low viral load in patients. 相似文献
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93.
目前矿区地表单点沉陷动态预计方法主要基于传统的水准测量数据,监测方法单一,成本高,观测点易破坏,不能保证地表形变信息的实时性,且采用灰色模型进行地表沉陷预计时只针对单一模型的应用,没有结合模型自身特点分析其适用性。以袁店二矿7221工作面为试验区域,采用合成孔径雷达差分干涉测量技术监测矿区地表沉陷量,分别建立了描述沉陷量与时间关系的GM(1,1)与灰色Verhulst模型进行地表沉陷量预计,实现了矿区地表沉陷监测与动态预计一体化。通过比较、分析GM(1,1)与灰色Verhulst模型对地表沉陷量的拟合及预计结果,得出了2种灰色模型在矿区地表沉陷预计中的适用性:在矿区开采沉陷开始至活跃前期,若地表单点沉陷量曲线呈近似单峰型,则宜采用GM(1,1)进行短期预计;当矿区地表沉陷进入衰退阶段,单点沉陷量曲线呈平底饱和状态,则宜采用灰色Verhulst模型进行中长期预计。 相似文献
94.
Arianna Giacomini Sara Taranto Sara Rezzola Sara Matarazzo Elisabetta Grillo Mattia Bugatti Alessia Scotuzzi Jessica Guerra Martina Di Trani Marco Presta Roberto Ronca 《International journal of molecular sciences》2020,21(24)
Lung cancer represents an extremely diffused neoplastic disorder with different histological/molecular features. Among the different lung tumors, non-small-cell lung cancer (NSCLC) is the most represented histotype, characterized by various molecular markers, including the expression/overexpression of the fibroblast growth factor receptor-1 (FGFR1). Thus, FGF/FGFR blockade by tyrosine kinase inhibitors (TKi) or FGF-ligand inhibitors may represent a promising therapeutic approach in lung cancers. In this study we demonstrate the potential therapeutic benefit of targeting the FGF/FGFR system in FGF-dependent lung tumor cells using FGF trapping (NSC12) or TKi (erdafitinib) approaches. The results show that inhibition of FGF/FGFR by NSC12 or erdafitinib induces apoptosis in FGF-dependent human squamous cell carcinoma NCI-H1581 and NCI-H520 cells. Induction of oxidative stress is the main mechanism responsible for the therapeutic/pro-apoptotic effect exerted by both NSC12 and erdafitinib, with apoptosis being abolished by antioxidant treatments. Finally, reduction of c-Myc protein levels appears to strictly determine the onset of oxidative stress and the therapeutic response to FGF/FGFR inhibition, indicating c-Myc as a key downstream effector of FGF/FGFR signaling in FGF-dependent lung cancers. 相似文献
95.
Valentina Tedeschi Giorgia Paldino Fabiana Paladini Benedetta Mattorre Loretta Tuosto Rosa Sorrentino Maria Teresa Fiorillo 《International journal of molecular sciences》2020,21(24)
The strong association with the Major Histocompatibility Complex (MHC) class I genes represents a shared trait for a group of autoimmune/autoinflammatory disorders having in common immunopathogenetic basis as well as clinical features. Accordingly, the main risk factors for Ankylosing Spondylitis (AS), prototype of the Spondyloarthropathies (SpA), the Behçet’s disease (BD), the Psoriasis (Ps) and the Birdshot Chorioretinopathy (BSCR) are HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02, respectively. Despite the strength of the association, the HLA pathogenetic role in these diseases is far from being thoroughly understood. Furthermore, Genome-Wide Association Studies (GWAS) have highlighted other important susceptibility factors such as Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and, less frequently, ERAP2 that refine the peptidome presented by HLA class I molecules to CD8+ T cells. Mass spectrometry analysis provided considerable knowledge of HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02 immunopeptidome. However, the combined effect of several ERAP1 and ERAP2 allelic variants could generate an altered pool of peptides accounting for the “mis-immunopeptidome” that ranges from suboptimal to pathogenetic/harmful peptides able to induce non-canonical or autoreactive CD8+ T responses, activation of NK cells and/or garbling the classical functions of the HLA class I molecules. This review will focus on this class of epitopes as possible elicitors of atypical/harmful immune responses which can contribute to the pathogenesis of chronic inflammatory diseases. 相似文献
96.
目的:探讨PI3K/AKT/GSK-3β信号通路参与异丙酚对缺血再灌注损伤大鼠的脑保护作用及机制。方法:健康雄性SD大鼠72只,所有大鼠参照Zea Longa法建立局灶性脑缺血再灌注损伤的模型。随机分成6组(n=12),A-假手术组,B-模型组(MCAO),C-异丙酚组,D-异丙酚+腺苷A1R拮抗剂组(DPCPX),E-异丙酚组+PI3K特异性抑制剂(LY294002),F-异丙酚+GSK-3β抑制剂组(SB216763),观察大鼠术后24 h神经功能评分情况;LDF监测插栓前后脑血流变化;采用TTC染色法检测各组大鼠的脑梗死体积;用HE染色方法观察大鼠脑组织形态学改变;免疫组织化学法检测Bcl-2阳性细胞表达;采用TUNEL检测各组大脑脑皮质缺血周围神经元凋亡细胞的百分率。结果:与A组比较,B、C、D、E及F组大鼠行为学、脑梗死体积、细胞凋亡率、Bcl-2蛋白表达量均增加(P<0.05);与C组比较,B、D、E组大鼠行为学评分,脑梗死体积及细胞凋亡率均明显增加,Bcl-2蛋白表达量均明显减少(P<0.01),F组Bcl-2蛋白表达量却增加,细胞凋亡率降低(P<0.05),行为学评分减少、梗死体积减少(P<0.05)。 结论:腺苷A1R介导的异丙酚对缺血再灌注损伤大鼠的神经保护作用可能与PI3K/AKT/GSK-3β信号转导通路有关。 相似文献
97.
Dr. Dimitra T. Pournara Anna Durner Dr. Eftichia Kritsi Alexios Papakostas Dr. Panagiotis Zoumpoulakis Prof. Dr. Annette Nicke Dr. Maria Koufaki 《ChemMedChem》2020,15(24):2530-2543
The P2X7 receptor is a promising target for the treatment of various diseases due to its significant role in inflammation and immune cell signaling. This work describes the design, synthesis, and in vitro evaluation of a series of novel derivatives bearing diverse scaffolds as potent P2X7 antagonists. Our approach was based on structural modifications of reported (adamantan-1-yl)methylbenzamides able to inhibit the receptor activation. The adamantane moieties and the amide bond were replaced, and the replacements were evaluated by a ligand-based pharmacophore model. The antagonistic potency of the synthesized analogues was assessed by two-electrode voltage clamp experiments, using Xenopus laevis oocytes that express the human P2X7 receptor. SAR studies suggested that the replacement of the adamantane ring by an aryl-cyclohexyl moiety afforded the most potent antagonists against the activation of the P2X7 cation channel, with analogue 2-chloro-N-[1-(3-(nitrooxymethyl)phenyl)cyclohexyl)methyl]benzamide ( 56 ) exhibiting the best potency with an IC50 value of 0.39 μM. 相似文献
98.
考察了反应溶液中碱性添加剂{氨水(NH4OH)、氢氧化钠(NaOH)、碳酸钠(Na2CO3)、碳酸铵[(NH4)2CO3]和四甲基氢氧化铵(TMAOH)}及其浓度对钛硅分子筛(TS-1)催化丙烯环氧化反应性能的影响,并采用紫外拉曼光谱(UV-Raman)与气相色谱(GC)联用原位分析(Raman-GC)碱性添加剂的作用机理。结果表明:反应体系中添加碱性添加剂可有效改善TS-1催化丙烯环氧化反应的选择性。不同碱性添加剂对TS-1催化丙烯环氧化活性和稳定性影响不同,NaOH、Na2CO3和TMAOH的添加造成催化活性和稳定性降低。NH4OH或(NH4)2CO3作为添加剂改善环氧化反应选择性的同时提高了反应稳定性,其中以(NH4)2CO3效果最佳。添加(NH4)2CO3浓度为8.0×10-4mol/L时,TS-1催化丙烯环氧化在固定床反应器上连续运行336h时,X(H2O2)仍保持在90%以上。原位Raman-GC分析发现,反应体系中NH4OH和(NH4)2CO3添加可加快反应活性中间体Ti-OOH(η2)基团的生成,促进反应产物从活性中心快速扩散,从而提高丙烯环氧化反应选择性和稳定性。 相似文献
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100.