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71.
Daniel Stubba Dr. Dennis Bensinger Janika Steinbacher Lilia Proskurjakov Álvaro Salcedo Gómez Dr. Uwe Schmidt Prof. Dr. Stefan Roth Prof. Dr. Katja Schmitz Prof. Dr. Boris Schmidt 《ChemMedChem》2019,14(23):2005-2022
The ubiquitin-proteasome system (UPS) is an established therapeutic target for approved drugs to treat selected hematologic malignancies. While drug discovery targeting the UPS focuses on irreversibly binding epoxyketones and slowly-reversibly binding boronates, optimization of novel covalent-reversibly binding warheads remains largely unattended. We previously reported α-ketoamides to be a promising reversible lead motif, yet the cytotoxic activity required further optimization. This work focuses on the lead optimization of phenoxy-substituted α-ketoamides combining the structure-activity relationships from the primed and the non-primed site of the proteasome β5 subunit. Our optimization strategy is accompanied by molecular modeling, suggesting occupation of P1′ by a 3-phenoxy group to increase β5 inhibition and cytotoxic activity in leukemia cell lines. Key compounds were further profiled for time-dependent inhibition of cellular substrate conversion. Furthermore, the α-ketoamide lead structure 27 does not affect escape response behavior in Danio rerio embryos, in contrast to bortezomib, which suggests increased target specificity. 相似文献
72.
RAGHDA A. SOLIMAN RANA A. YOUNESS TAMER M. MANIE EMAD KHALLAF MOHAMED EL-SHAZLY MONA ABDELMOHSEN HEBA HANDOUSSA MOHAMED Z. GAD 《Biocell》2022,46(3):769-783
Triple Negative Breast Cancer (TNBC) immunotherapy has recently shown promising approach. However, some TNBC patients presented with resistance. One of the reasons was attributed to the excessive release of cytokines at the tumor microenvironment (TME) such as Tumor necrosis factor alpha (TNF-α) and Interleukin-10 (IL-10). Fine regulation of these cytokines’ levels via non-coding RNAs (ncRNAs) might alleviate the immune quiescent nature of TME at TNBC tumors. However, the extrapolation of ncRNAs as therapeutic tools is highly challenging. Therefore, disentanglement the nature for the isolation of natural compounds that could modulate the ncRNAs and their respective targets is an applicable translational therapeutic approach. Hence, this study aimed to targeting the chief immune suppressive cytokines at the TME (TNF-α and IL-10) via ncRNAs and to examine the effects of Rosemary aerial parts extract on the expression levels of these ncRNAs in TNBC. Results revealed miR-17-5p as a dual regulator of TNF-α and IL-10. Moreover, an intricate interaction has been shown between miR-17-5p and the oncogenic lncRNAs: MALAT1 and H19. Knocking down of MALAT1 and/or H19 caused an induction in miR-17-5p and reduction in TNF-α and IL-10 expression levels. miR-17-5p was found to be down-regulated, while TNF-α, IL-10, MALAT1 and H19 were up-regulated in BC patients. Forced expression of miR-17-5p in MDA-MB-231 cells reduced TNF-α, IL-10, MALAT1 and H19 expression levels, as well as several BC hallmarks. In a translational approach, ursolic acid (UA) isolated from rosemary induced the expression of miR-17-5p, MALAT1 and decreased H19 expression levels. In conclusion, this study suggests miR-17-5p as a tumor suppressor and an immune-activator miRNA in BC through tuning up the immunological targets TNF-α, IL-10 at the TME and the oncological mediators MALAT1 and H19 lncRNAs. 相似文献
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人类所受辐射照射主要来源于天然辐射。本工作分析了长江沿岸部分NORM行业水中210Po的浓度。结果表明,燃煤电厂、水泥厂、钢铁厂、铁矿排出水口中210Po的活度浓度分别为(0.93~4.76)×10-3 Bq/L、(1.12±0.07)×10-2 Bq/L、(9.89±0.78)×10-3 Bq/L、(2.17±0.21)×10-3 Bq/L,均在长江水系210Po的波动范围之内。稀土加工排放的废水和雨水中210Po的活度浓度分别为(1.03~1.40)×10-1Bq/L、(3.05±0.04)×10-1Bq/L,比本底水平高两个数量级,需要引起特别关注,有待于进一步研究。 相似文献
76.
The Ca,Eu-α-sialon powders with the mixed solid solution composition have been manufactured via the solid-state reaction process in flowing nitrogen in a graphite furnace at a relatively low temperature of 1650 °C without an external overpressure. XRD data with Rielveld refinement and XPS measurements were used for characterization of the lattice constants and the surface chemical composition. The monophase Ca-Eu-α-sialon was obtained with the nominal composition of Eu0.048Ca0.702Si7.75Al2.25O0.75N15.25. The highest emission intensity in a yellow-orange region at 590 nm and quantum efficiency of 66% was found for this pure Ca,Eu-α-sialon. Estimation of m,n values from the lattice constant and EDS results showed a small deviation from the nominal composition of designed α-sialon. XPS results demonstrated significant changes of the chemical composition in the oxidized surface of phosphor particles. Possible reasons of emission redshift and relationship between the actual solid solution composition and luminescence properties are discussed in terms of simultaneous presence of Eu2+ and Eu3+ ions in the sialon crystal lattice and residual oxynitride glass. 相似文献
77.
为了实现在工业化生产中对α钛富氧层厚度预测和控制,通过实验研究α钛富氧层在高温空气环境中的形成及增厚过程,讨论热处理温度和时间的影响作用,建立高温(750~850℃)空气环境下关于温度、时间的富氧层增厚动力学模型。结果表明:当恒温热处理温度为750~850℃时,α钛富氧层厚度x与保温时间t0.5呈正比例关系,且升高热处理温度可显著提高富氧层增厚速度。在此温度范围内,氧原子的扩散激活能约为203473 J/mol,计算曲线与实验数据吻合性较好。结合文献中已有的扩散系数方程和实验测得的富氧层厚度数据,推导得到5个富氧层增厚动力学方程,其中3个方程的计算曲线与实验数据吻合性较好,可为实际生产中预估富氧层厚度提供理论支持。 相似文献
78.
《International Journal of Hydrogen Energy》2019,44(51):27876-27884
Evaluation of hydrogen diffusion in structural materials is essential to predict the leakage and embrittlement of hydrogen storage applications. In this work, we investigate the atomic-scale diffusion of interstitial hydrogen (H) in α-iron (Fe) over a temperature range from 350 to 900 K with different H concentrations (0.01–5%), employing classical molecular dynamics (MD) simulations. The self-diffusivity of H atoms increases with increasing temperature and decreasing concentration. With low concentrations, the calculated diffusion properties agree well with prior experiments. However, with a higher concentration (≥1%), the H diffusivity at low temperatures deviates from a high-temperature Arrhenius behavior. Through the energetic and structural analysis, we suggest that this deviation is attributed to a reduced mobility due to increased energy barrier by other H interstitials. This work contributes to the effective design of H storage applications by identifying temperature and concentration effects on permeability and addressing possible microstructural transformation. 相似文献
79.
Mohamed Abdin Yahya Saud Hamed Hafiz Muhammad Saleem Akhtar Dan Chen Shanza Mukhtar Peng Wan Asad Riaz Xiaoxiong Zeng 《International Journal of Food Science & Technology》2019,54(6):2084-2093
The objectives of this study were to determine the optimal extraction conditions of polyphenols from Syzygium cumini seeds by response surface methodology and investigate their antioxidant activity and inhibition on α-amylase and pancreatic lipase. As results, the optimal extraction conditions in the ultrasonic extraction process which maximised total polyphenols content, minimised the IC50 values of α-amylase and pancreatic lipase were determined as follows: extraction time 60 min, ethanol concentration 63% and solvent/solid ratio 44 mL g−1. The main phenolic compounds in partially purified fraction of Syzygium cumini seeds were catechin, epicatechin, kaempferol, gallic, 5-caffeoylquinic, caffeic and ferulic acids. In addition, the partially purified fraction inhibited 87.66 ± 5.55 and 86.61 ± 3.15% of α-amylase and pancreatic lipase, respectively. The results suggested that Syzygium cumini seeds could be explored as a natural antioxidant and could be used as a source of highly antidiabetic and anti-obesity bioactive compounds. 相似文献
80.
Faezeh Sharifi M. T. Hamed Mosavian Camellia Zarei 《Chemical Engineering Communications》2016,203(1):64-74
α-Tocopherol (α-Toc) has valuable biological activity, but its activity is limited when exposed to environmental factors. Nanocapsules can be used to overcome this problem. Using nanocapsules in the range of 100–200 nm is more beneficial. A 24 full factorial design was carried out to optimize the size of nanocapsules using the complex coacervation method. The four factors were the amount of the wall material, the ratio of core material to wall material, the pH of the solution, and the speed of the homogenizer. The smallest nanocapsules (176 nm) were obtained at a wall content (gelatine and pectin) of 0.8 mg, a percentage of core material (α-Toc) to wall material of 20%, a pH = 4.5, and a homogenizer speed of 12,000 rpm. The encapsulation efficiency was 90.6 ± 1.1%, and the encapsulation yield was 83.4 ± 1.6%. Assessment of the stability of α-Toc after 1 month showed that encapsulation could improve its stability in the presence of three influential factors: humidity, light, and temperature. 相似文献