A Potent,Selective CBX2 Chromodomain Ligand and Its Cellular Activity During Prostate Cancer Neuroendocrine Differentiation

Polycomb group (PcG) proteins are epigenetic regulators that facilitate both embryonic development and cancer progression. PcG proteins form Polycomb repressive complexes 1 and 2 (PRC1 and PRC2). PRC2 trimethylates histone H3 lysine 27 (H3K27me3), a histone mark recognized by the N-terminal chromodomain (ChD) of the CBX subunit of canonical PRC1. There are five PcG CBX paralogs in humans. CBX2 in particular is upregulated in a variety of cancers, particularly in advanced prostate cancers. Using CBX2 inhibitors to understand and target CBX2 in prostate cancer is highly desirable; however, high structural similarity among the CBX ChDs has been challenging for developing selective CBX ChD inhibitors. Here, we utilize selections of focused DNA encoded libraries (DELs) for the discovery of a selective CBX2 chromodomain probe, SW2_152F. SW2_152F binds to CBX2 ChD with a K_d of 80 nM and displays 24-1000-fold selectivity for CBX2 ChD over other CBX paralogs in vitro. SW2_152F is cell permeable, selectively inhibits CBX2 chromatin binding in cells, and blocks neuroendocrine differentiation of prostate cancer cell lines in response to androgen deprivation.     

Characterization,in vitro bioactivity and biological studies of sol-gel-derived TiO2 substituted 58S bioactive glass

Bioactive glasses (BGs) have been used for bone formation and bone repair processes in recent years. This study investigated the titanium substitution effect on 58S BGs (Ti-BGs) 60SiO₂-(36 − X)CaO-4P₂O₅-XTiO₂ (X = 0, 3, and 5 mol.%) prepared by the sol-gel technique, and the main goal was to find the optimum amount of titanium in Ti-BGs. Synthesized BGs, which were investigated after immersion in simulated body fluid (SBF), were tested by X-ray diffraction (XRD) analysis, Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy. Moreover alkaline phosphate (ALP) activity, 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and antibacterial studies were employed to investigate the biological properties of Ti-BGs. According to the FTIR and XRD test results, hydroxyapatite (HA) formation on Ti-BGs surfaces was confirmed. Meanwhile, the presence of 5 mol.% compared to 3 mol.% increased the HA grain distribution and their size on the Ti-BGs surface. Additionally, MTT and ALP results confirmed that the optimal amount of titanium substitution in BG was 5 mol.%. Since 5 mol.% Ti incorporated BG (BG-5) had the highest biocompatibility level, antibacterial properties, maximum cell proliferation, and ALP activity among the synthesized Ti-BGs, it is presented as the best candidate for further in vivo investigations.     

Transmittance Measurements in Non-alternating Magnetic Field as Reliable Method for Determining of Heating Properties of Phosphate and Phosphonate Coated Fe3O4 Magnetic Nanoparticles

Different phosphates and phosphonates have shown excellent coating ability toward magnetic nanoparticles, improving their stability and biocompatibility which enables their biomedical application. The magnetic hyperthermia efficiency of phosphates (IDP and IHP) and phosphonates (MDP and HEDP) coated Fe₃O₄ magnetic nanoparticles (MNPs) were evaluated in an alternating magnetic field. For a deeper understanding of hyperthermia, the behavior of investigated MNPs in the non-alternating magnetic field was monitored by measuring the transparency of the sample. To investigate their theranostic potential coated Fe₃O₄-MNPs were radiolabeled with radionuclide ¹⁷⁷Lu. Phosphate coated MNPs were radiolabeled in high radiolabeling yield (>?99%) while phosphonate coated MNPs reached maximum radiolabeling yield of 78%. Regardless lower radiolabeling yield both radiolabeled phosphonate MNPs may be further purified reaching radiochemical purity of more than 95%. In vitro stabile radiolabeled nanoparticles in saline and HSA were obtained. The high heating ability of phosphates and phosphonates coated MNPs as sine qua non for efficient in vivo hyperthermia treatment and satisfactory radiolabeling yield justifies their further research in order to develop new theranostic agents.

     

并流控速沉淀法制备纳米α-Bi2O3及其光催化降解苯酚性能研究

以五水合硝酸铋为铋源,氢氧化钠为沉淀剂,通过简单易操作的并流控速沉淀法合成了α-Bi2O3纳米颗粒.同时,利用XRD和SEM分析了所获产品的结构与表面形貌.并选用苯酚作为模拟污染物,利用LC3000型高效液相色谱仪对其进行色谱分析,探究了所合成的纳米α-Bi2O3光催化剂的催化性能.当苯酚的质量分数为100μg·g?1、pH=8、α-Bi2O3投加量为60 mg·L?1时,可见光照射180 min,降解率可达92.6％.通过自由基捕获实验发现,在α-Bi2O3光催化降解苯酚体系中主要活性物种为羟基自由基.     

N-苄氧羰基甘氨酰-L-脯氨酸与4'-去甲基表鬼臼毒素的拼接合成及其抗肿瘤活性评价

以4'-去甲基表鬼臼毒素和N-苄氧羰基甘氨酰-L-脯氨酸为原料,通过酯化反应首次得到两种不同构型的拼接产物(3a、3b),其结构经1HNMR、13C NMR和ESI-MS确认.利用MTT法考察化合物3a、3b对HepG2、THP-1、Hela、MCF-7细胞的抑制活性.结果表明,化合物3a、3b对四种细胞都具有抑制作用,以化合物3b对THP-1细胞的作用最突出,其抑制强度是依托泊苷的16.5倍.     

Synthesis and Properties of New Cleavable Cationic Surfactants Containing Carbonate Groups

A novel series of cleavable alkyltrimethylammonium surfactants with different hydrocarbon chain lengths (C8–16) were synthesized. A carbonate break site inserted between the polar head and the hydrocarbon chain makes these compounds hydrolyzable. The reagents used are renewable, (bio)degradable, or reusable. The hydrolysis of these cleavable surfactants will lead to the generation of fatty alcohols and choline, which is an essential biological nutrient. The surface activities in aqueous solution of the synthesized carbonates fulfill the requirement of being good surfactants. In addition, the cleavable compounds containing n-decyl and n-dodecyl chains showed similar or higher antimicrobial activities when compared to a non-cleavable analog.     

The Age-Sensitive Efficacy of Calorie Restriction on Mitochondrial Biogenesis and mtDNA Damage in Rat Liver

Calorie restriction (CR) is the most efficacious treatment to delay the onset of age-related changes such as mitochondrial dysfunction. However, the sensitivity of mitochondrial markers to CR and the age-related boundaries of CR efficacy are not fully elucidated. We used liver samples from ad libitum-fed (AL) rats divided in: 18-month-old (AL-18), 28-month-old (AL-28), and 32-month-old (AL-32) groups, and from CR-treated (CR) 28-month-old (CR-28) and 32-month-old (CR-32) counterparts to assay the effect of CR on several mitochondrial markers. The age-related decreases in citrate synthase activity, in TFAM, MFN2, and DRP1 protein amounts and in the mtDNA content in the AL-28 group were prevented in CR-28 counterparts. Accordingly, CR reduced oxidative mtDNA damage assessed through the incidence of oxidized purines at specific mtDNA regions in CR-28 animals. These findings support the anti-aging effect of CR up to 28 months. Conversely, the protein amounts of LonP1, Cyt c, OGG1, and APE1 and the 4.8 Kb mtDNA deletion content were not affected in CR-28 rats. The absence of significant differences between the AL-32 values and the CR-32 counterparts suggests an age-related boundary of CR efficacy at this age. However, this only partially curtails the CR benefits in counteracting the generalized aging decline and the related mitochondrial involvement.     

Chloroquine-Induced Accumulation of Autophagosomes and Lipids in the Endothelium

Chloroquine (CQ) is an antimalarial drug known to inhibit autophagy flux by impairing autophagosome–lysosome fusion. We hypothesized that autophagy flux altered by CQ has a considerable influence on the lipid composition of endothelial cells. Thus, we investigated endothelial responses induced by CQ on human microvascular endothelial cells (HMEC-1). HMEC-1 cells after CQ exposure were measured using a combined methodology based on label-free Raman and fluorescence imaging. Raman spectroscopy was applied to characterize subtle chemical changes in lipid contents and their distribution in the cells, while the fluorescence staining (LipidTox, LysoTracker and LC3) was used as a reference method. The results showed that CQ was not toxic to endothelial cells and did not result in the endothelial inflammation at concentrations of 1–30 µM. Notwithstanding, it yielded an increased intensity of LipidTox, LysoTracker, and LC3 staining, suggesting changes in the content of neutral lipids, lysosomotropism, and autophagy inhibition, respectively. The CQ-induced endothelial response was associated with lipid accumulation and was characterized by Raman spectroscopy. CQ-induced autophagosome accumulation in the endothelium is featured by a pronounced alteration in the lipid profile, but not in the endothelial inflammation. Raman-based assessment of CQ-induced biochemical changes offers a better understanding of the autophagy mechanism in the endothelial cells.     

基于数值模拟的嘉兴城区河网水文特征

基于MIKE 11河网水动力模型,利用2010年—2019年实测气象水文资料,分析了嘉兴城区大包围圈内外主要河流的入流和出流特征.结果显示:嘉兴城区主要来流河道是苏州塘和杭州塘,出流河道主要为长纤塘、嘉善塘和平湖塘;平均来流量为88.2 m3/s,出流量为93.3 m3/s;年均和月均来流量变化较大,最枯月的平均来流量为50.1 m3/s,90％保证率枯水月的平均来流量为59.3 m3/s;大包围圈内部河道的平均流量为28.3 m3/s,平均出流量为19.1 m3/s,这表明大量外部来水未进入大包围圈内部河道,而是通过环郊河"短路"绕过嘉兴城区,流向东北;大包围圈内部河道的最枯月平均入流量为14.5 m3/s,90％保证率枯水月的平均入流量为18.3 m3/s.研究结果可为嘉兴城区河网综合规划和生态治理提供科学依据.