Synthesis of bridgedhead azolo[3,2-a]pyrimidines and imidazo[2,1-b]thiazines through ring transformation of 2H-pyran-2-ones

Suitably functionalized 3-carbomethoxy/cyano-2H-pyran-2-ones are excellent synthons for the synthesis of arenes and heteroarenes of therapeutic importance. The compounds 6-aryl-3-cyano-4-methylsulfanyl-2H-pyran-2-ones have been transformed into bridgedhead azolopyrimidines and imidazothiazines through thermal and base-induced ring transformation reactions with aminoazoles and imidazolidin-2-thiones, respectively.     

Solid-State NMR Study of Phase Separation and Order of Water Molecules and Silanol Groups in Polysiloxane Networks

Homogeneity and structure of organically modified polysiloxane networks prepared by sol-gel co-condensation, as well as location and nature of water molecules and silanol groups were studied by 1D and 2D solid-state NMR. ¹H–²⁹Si and ¹H–¹H interatomic distances were estimated from variable contact-time CP/MAS experiments, ¹H NMR chemical shifts and off-resonance WISE NMR. A structure model of these networks is proposed and discussed. The fraction of proton-inaccessible units Q⁴ in the networks decreases with increasing amounts of dimethylsiloxane (D) and methylsiloxane (T) units. In contrast to systems prepared by co-condensation of tetraethoxysilane (TEOS) with dimethyl(diethoxy)silane (DMDEOS), proton-inaccessible units form essential fraction in networks prepared by co-condensation of TEOS with methyl(triethoxy)silane (MTEOS). The proton-accessible part of the networks with high O/Si ratios is nano-heterogeneous phase, which is composed of water containing Q ⁱ particles separated by copolymer domains. The overall homogeneity and uniformity of binding sites around silanol groups increases by co-condensation TEOS with DMDEOS or MTEOS, while the amount of physisorbed water as well as the hydrogen bond strength decreases, as compared with neat silica gel prepared by polycondensation of TEOS.     

Transient absorption and laser output of YAG : Nd

YAG : Nd grown under 98% Ar 2% H₂ protective atmosphere free of nitrogen or hydrocarbons showed after UV irradiation broad absorption peaked at 1·9×10⁴ cm^–1 which disappeared relatively slowly at room temperature. It was more intensive in oxygen treated samples than in those annealed in hydrogsn. Transient absorption suppresses laser output by the increase of absorption at 0·94×10⁴ cm^–1 (1064 nm) and, particularly in CW mode, by the anomalous rod deformation. YAG : Nd containing Fe ions (2·10^–4 wt%) showed no transient absorption.     

水中硝酸盐氮稳定同位素比值测定前处理方法的优化

水体中过量的硝酸盐导致会严重的水生生态恶化和环境污染问题。氮稳定同位素技术为水体污染来源的判断及水生系统氮素转化机理研究提供了强有力的工具。在前人基础上,通过开发Cu2+-Cd复合催化结合超声波辅助加速反应,优化硝酸盐氮同位素比值测定前处理方法。考察了Cu2+添加量,超声功率以及反应时间变化对NO3--N转化生成N2O气体及其氮同位素比值的影响,在单因素实验基础上采用正交实验优化得到了最佳反应条件,并采用不同15N同位素比值的KNO3标准溶液结合气体预浓缩装置与稳定同位素质谱仪联用系统对新方法进行了验证。新方法单次反应体系中氮最低量为1.0 μg,其中自然丰度和高丰度样品δ15N分析精度小于1‰,富集样品的15N分析精度可达0.1 atom%以内(CV<1%);且所有标准样品的15N测定值与参考值基本一致。将优化后的方法应用于不同来源水样中硝酸盐氮稳定同位素比值测定,均可获得较好的精度,较原方法提高了前处理效率,且精度更优。综上,建立的方法准确可靠,操作简单,耗时短,适用于水中硝酸盐氮稳定同位素比值测定的批量、快速前处理。     

Rutin Inhibits Ox-LDL-Mediated Macrophage Inflammation and Foam Cell Formation by Inducing Autophagy and Modulating PI3K/ATK Signaling

Atherosclerosis (AS) is one of the leading causes of death among the elderly, and is primarily caused by foam cell generation and macrophage inflammation. Rutin is an anti-inflammatory, anti-oxidant, anti-allergic, and antiviral flavonoid molecule, known to have anti-atherosclerotic and autophagy-inducing properties, but its biological mechanism remains poorly understood. In this study, we uncovered that rutin could suppress the generation of inflammatory factors and reactive oxygen species (ROS) in ox-LDL-induced M2 macrophages and enhance their polarization. Moreover, rutin could decrease foam cell production, as shown by oil red O staining. In addition, rutin could increase the number of autophagosomes and the LC3II/I ratio, while lowering p62 expression. Furthermore, rutin could significantly inhibit the PI3K/ATK signaling pathway. In summary, rutin inhibits ox-LDL-mediated macrophage inflammation and foam cell formation by inducing autophagy and modulating PI3K/ATK signaling, showing potential in treating atherosclerosis.     

The Pharmacokinetics in Mice and Cell Uptake of Thymus Immunosuppressive Pentapeptide Using LC-MS/MS Analysis

Thymus immunosuppressive pentapeptide (TIPP) is a novel anti-inflammatory peptide with high efficacy and low toxicity. This study aims to establish a selective LC-MS/MS method for analyzing the analyte TIPP in biological samples, laying the foundation for further PK and PD studies of TIPP. Protein precipitation was conducted in acetonitrile supplemented with 2% formic acid and 25 mg/mL dithiothreitol as a stabilizer, which was followed by backwashing the organic phase using dichloromethane. The chromatographic separation of TIPP was achieved on a C18 column with a gradient elution method. During positive electrospray ionization, TIPP was analyzed via multiple-reaction monitoring. The linear relationships between the concentration of TIPP and peak area in murine plasma cell lysates, supernatants, and the final cell rinse PBS were established within the ranges of 20–5000 ng/mL, 1–200 ng/mL, 10–200 μg/mL, and 0.1–20 ng/mL, respectively (r² > 0.99). Validated according to U.S. FDA guidelines, the proposed method was proved to be acceptable. Such a method had been successfully applied to investigate the pharmacokinetics of TIPP in mice via subcutaneous injection. The plasma half-life in mice was 5.987 ± 1.824 min, suggesting that TIPP is swiftly eliminated in vivo. The amount of TIPP uptake by RBL-2H3 cells was determined using this method, which was also visually verified by confocal. Furthermore, the effective intracellular concentration of TIPP was deduced by comparing the intracellular concentration of TIPP and degrees of inflammation, enlightening further investigation on the intracellular target and mechanism of TIPP.     

Insights into the Allosteric Effect of SENP1 Q597A Mutation on the Hydrolytic Reaction of SUMO1 via an Integrated Computational Study

Small ubiquitin-related modifier (SUMO)-specific protease 1 (SENP1) is a cysteine protease that catalyzes the cleavage of the C-terminus of SUMO1 for the processing of SUMO precursors and deSUMOylation of target proteins. SENP1 is considered to be a promising target for the treatment of hepatocellular carcinoma (HCC) and prostate cancer. SENP1 Gln597 is located at the unstructured loop connecting the helices α4 to α5. The Q597A mutation of SENP1 allosterically disrupts the hydrolytic reaction of SUMO1 through an unknown mechanism. Here, extensive multiple replicates of microsecond molecular dynamics (MD) simulations, coupled with principal component analysis, dynamic cross-correlation analysis, community network analysis, and binding free energy calculations, were performed to elucidate the detailed mechanism. Our MD simulations showed that the Q597A mutation induced marked dynamic conformational changes in SENP1, especially in the unstructured loop connecting the helices α4 to α5 which the mutation site occupies. Moreover, the Q597A mutation caused conformational changes to catalytic Cys603 and His533 at the active site, which might impair the catalytic activity of SENP1 in processing SUMO1. Moreover, binding free energy calculations revealed that the Q597A mutation had a minor effect on the binding affinity of SUMO1 to SENP1. Together, these results may broaden our understanding of the allosteric modulation of the SENP1−SUMO1 complex.     

带-NH2的嘧啶环对钌配合物与DNA相互作用的瞬态发光特性的影响

采用时间分辨的发光光谱技术,分别测量了两种新合成的钌配合物[Ru(bpy)2 (dpbpd(NH2)2)]2 和[Ru(phen)2(dpbpd(NH2)2)]2 与小牛胸腺脱氧核糖核酸(ctDNA)相互作用时的瞬态发光动力学过程,并与以往对[Ru(phen)2dppz]2 等的研究结果进行对比,从而研究带-NH2的嘧啶环对配合物与DNA作用动力学过程的影响.结果表明:这两种含有带-NH2的嘧啶环的钌配合物与DNA相互作用时的发光按双指数规律衰减,发光寿命为几十纳秒,比dppz类钌配合物与DNA作用时的发光衰变寿命(几百纳秒)小一个数量级.归因于嘧啶环上的N和-NH2可能与水分子、DNA的碱基对或磷酸骨架形成氢键,从而加快激发态的无辐射弛豫,削弱发射光强,缩短发光寿命.该结论为进一步研究配合物分子与DNA的相互作用的机理提供了一定的依据.     

Natural Products in Preventing Tumor Drug Resistance and Related Signaling Pathways

Drug resistance is still an obstacle in cancer therapy, leading to the failure of tumor treatment. The emergence of tumor drug resistance has always been a main concern of oncologists. Therefore, overcoming tumor drug resistance and looking for new strategies for tumor treatment is a major focus in the field of tumor research. Natural products serve as effective substances against drug resistance because of their diverse chemical structures and pharmacological effects. We reviewed the signaling pathways involved in the development of tumor drug resistance, including Epidermal growth factor receptor (EGFR), Renin-angiotensin system (Ras), Phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), Wnt, Notch, Transforming growth factor-beta (TGF-β), and their specific signaling pathway inhibitors derived from natural products. This can provide new ideas for the prevention of drug resistance in cancer therapy.     

Application of Two Novel Acoustic Emission Parameters on Identifying the Instability of Granite

The issue of monitoring and early warning of rock instability has received increasing critical attention in the study of rock engineering. To investigate the damage evolution process of granite under triaxial compression tests, acoustic emission (AE) tests were performed simultaneously. This study firstly introduced two novel parameters, i.e., the coefficient of variation (CoV) of the information entropy and correlation dimension of the amplitude data from the AE tests, to identify the precursor of the failure of granite. Then the relationship between the changes in these parameters and the stress-time curve was compared and analyzed. The results of this study show that: (1) There is a strong correlation between the CoV of the information entropy and the failure process of granite. The granite failed when the CoV curve raised to a plateau, which could be used as an indicator of rock instability. (2) The fluctuation of the correlation dimension indicates the different stages during the loading process, i.e., the initial compaction stage, the linear elastic stage, the yield stage, and the failure stage. Each stage contains a descending and a rising process in the correlation dimension curve, and the exhibited starting point or the bottom point at the correlation dimension curve could be selected as the indicator point for the rock instability. (3) The combined analysis of the Information entropy and Correlation dimension can improve the accuracy of rock instability prediction. This study provides new insights into the prediction of rock instability, which has theoretical implications for the stability of subsurface engineering rock masses.