Protein tyrosine phosphatase 1B inhibitors from natural sources

Since PTP1B enzyme was discovered in 1988, it has captured the research community’s attention. This landmark discovery has stimulated numerous research studies on a variety of human diseases, including cancer, inflammation, and diabetes. Tremendous progress has been made in finding PTP1B inhibitors and exploring PTP1B regulatory mechanisms. This review investigates for the natural PTP1B inhibitors, and focuses on the common characteristics of the discovered structures and structure–activity relationships. To facilitate understanding, all the natural compounds are here divided into five different classes (fatty acids, phenolics, terpenoids, steroids, and alkaloids), according to their skeletons. These PTP1B inhibitors of scaffold structures could serve as a theoretical basis for new concept drug discovery and design.     

Contribution of equilibrative nucleoside transporters 1 and 2 to gemcitabine uptake in pancreatic cancer cells

Hepatic arterial infusion (HAI) chemotherapy is expected to be a more effective and safer method to treat the hepatic metastasis of pancreatic cancer than intravenous (iv) administration because of higher tumor exposure and lower systemic exposure. To clarify the uptake mechanism of nucleoside anticancer drugs, including gemcitabine (GEM), in pancreatic cancer, we investigated the uptakes of radiolabeled uridine (a general substrate of nucleoside transporters) and GEM in pancreatic cancer cell lines MIA‐PaCa2 and As‐PC1. Uridine uptake was inhibited by non‐labeled GEM and also by S‐(4‐nitrobenzyl)‐6‐thioinosine (NBMPR; an inhibitor of equilibrative nucleoside transporters, ENTs) in a concentration‐dependent manner, suggesting that ENTs contribute to uridine uptake in pancreatic cancer cells. As for GEM, saturable uptake was mediated by high‐ and low‐affinity components with K_m values of micromolar and millimolar orders, respectively. Uptake was inhibited in a concentration‐dependent manner by NBMPR and was sodium ion‐independent. Moreover, the concentration dependence of uptake in the presence of 0.1 μM NBMPR showed a single low‐affinity site. These results indicated that the high‐ and low‐affinity sites correspond to hENT1 and hENT2, respectively. The results indicated that at clinically relevant hepatic concentrations of GEM in GEM‐HAI therapy, the metastatic tumor exposure of GEM is predominantly determined by hENT2 under unsaturated conditions, suggesting that hENT2 expression in metastatic tumor would be a candidate biomarker for indicating anticancer therapy with GEM‐HAI.     

贫困、疾病及精准健康扶贫政策:基于贫困居民生命质量评价

目的:将生命质量评价引入精准健康识别与干预政策中,通过比较不同类别贫困居民生命质量特征,揭示扶贫对象各维度现状,为完善精准健康扶贫政策提供参考。方法:评价工具采用WHOQOL-BREF量表,通过入户调查方式收集数据,采用t检验分析与中国常模数据进行比较。结果:贫困居民其人群分布表现为男性(71.7%)多于女性,年龄普遍偏大(平均55岁)。贫困居民与中国常模比较,健康组和疾病组的生命质量评价评分均显著低于中国常模的对照组,说明贫困对于居民生命质量评价的负面影响十分显著。不论处于何种收入水平,健康贫困居民总体评价均高于患病贫困居民。对于患病贫困居民而言,收入越高、其心理和总体评价越好;反之亦然。结论:健康对于贫困居民总体评价具有显著正影响、而患病对于贫困居民总体评价具有显著负影响。收入提高对于患病贫困居民的心理和总体评价改善有效。     

Membrane Loaded Copper Oleate PEGylated Liposome Combined with Disulfiram for Improving Synergistic Antitumor Effect <Emphasis Type="BoldItalic">In Vivo</Emphasis>

Purpose

This work aims to create a novel Cu²⁺ liposome with excellent loading stability and develop synergistic effect with disulfiram (DSF) for the treatment of tumor.

Methods

Copper oleate was incorporated into the liposome membrane via alcohol injection method in this work. In vitro release test was applied to evaluate the release profile of the liposomes. Pharmacokinetic studies were performed in rats and the antitumor efficacy was assessed in mice bearing hepatoma xenografts.

Results

The copper oleate liposome (Cu(OI)₂-L) was formulated and the loading efficiency were more than 85%. TEM images confirmed that the Cu(OI)₂-L had a spherical morphology with an average diameter of 100 nm. Cu(OI)₂-L displayed a biphasic release profile, with >70% retained drug over 8 h incubation in PBS at pH 7.4. Pharmacokinetic studies demonstrated that Cu(OI)₂-L had a prolonged circulation time and increased AUC when compared to the injection of copper oleate solution. The antitumor efficacy test demonstrated an enhanced tumor inhibition rate with the treatment of Cu(OI)₂-L and DSF nanoparticles, indicating an improved synergistic antitumor effect.

Conclusions

The Cu(OI)₂-L was suitable to be employed in combination with disulfiram for tumor treatment and can also open up opportunities for targeted delivery of copper.

     

Effects of squalene on expression of LDLR in HepG2 cells and its mechanism北大核心CSCD

Aim To investigate the effect of squalene on LDLR expression in HepG2 cells and its mechanism of down-regulated cholesterol. Methods The proliferation of HepG2 cells exposed to squalene at different concentrations was measured by MTT assay. The effect of squalene on the expression of LDLR in HepG2 cells was measured by flow cytometry and fluorescence mi-croscopy. The effect of different concentrations of squalene on the interaction between SCAP and Insig2, two key protein molecules of SREBP pathway, was assayed by FRET technology. Results MTT results showed that squalene had inhibitory effect on the proliferation of HepG2 cells in a dose-dependent manner. Flow cytometry and fluorescence microscopy results showed that squalene enhanced LDLR expression in HepG2 cells compared with the control group. The results of FRET technology revealed that compared with model control group, the YFP fluorescence value in Squalene group dramatically declined, and the YFP fluorescence value of each drug group decreased with the range of 5-25 |xmol L1 squalene concentration. Conclusions Squalene may promote the expression of LDLR in HepG2 cells through inhibiting the interaction between SCAP and Insig2 proteins in SREBP pathway, which may confirm that squalene is a potential novel drug for the down-regulation of cholesterol level. © 2018 Publication Centre of Anhui Medical University. All rights reserved.     

Similar pyridinone compounds with different activities of anti-HIV-1 reverse transcriptase

Among the structurally diverse NNRTIs, pyridinone scaffolds demonstrate high potency against HIV-1 wild type and drug-resistant strains. During the optimization of our pyridinone compound 1 (LAM-trans),we found that the introduction of the N atoms in the C-4 position could dramatically improve the water solubility (7b), whereas protonation of the piperidine N atom resulted in a decrease in its hydrophobic interaction with the binding pocket. In particular, protonation altered the orientation of the alicyclic rings in the hydrophobic pocket, thus impeding the formation of key halogen bond and eventually leading to a huge change in anti-HIV-1 RT activity. These results provided theoretical and experimental basis for the subsequent structural modification of pyridinone compounds.     

Development and validation of a sensitive LC/MS-MS method for the determination of letrozole in nude mice plasma and its application to a pharmacokinetic study

A sensitive, rapid and simple liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of letrozole (LTZ) in nude mouse plasma in the current study, which was successfully applied to a pharmacokinetic study. Using anastrozole as internal standard (IS), plasma samples went through a one-step protein precipitation with acetonitrile before determination. The analyte and IS were analyzed on a reversed-phase ZORBAX-SB-C₁₈column (4.6 mm×250 mm, 5 μm) with an isocratic mobile phase consisting of acetonitrile and water containing 0.1% formic acid (v/v) at a flow rate of 1.0 mL/min. The analyte and IS were detected by a triple-quadrupole tandem mass spectrometer, and electrospray and multiple reaction monitoring (MRM) were employed to select LTZ at m/z 286.4/217.1 and IS at m/z 294.1/225.3 simultaneously in the positive ion mode. The calibration curve showed good linearity ranging from 0.8–2000.0 ng/mL (r>0.99). The intra-day and inter-day precisions of LTZ were 4.0%–8.4%, with an accuracy of 98.6%–104.9%. Using this method, we successfully characterized the pharmacokinetics (PK) of LTZ by a one-compartment model with first-order absorption in female BALB/c nude mice.     

An indoor air quality evaluation in a residential retrofit project using spray polyurethane foam

Understanding of indoor air quality (IAQ) during and after spray polyurethane foam (SPF) application is essential to protect the health of both workers and building occupants. Previous efforts such as field monitoring, micro-chamber/spray booth emission studies, and fate/transport modeling have been conducted to understand the chemical exposure of SPF and guide risk mitigation strategies. However, each type of research has its limitation and can only reveal partial information on the relationship between SPF and IAQ. A comprehensive study is truly needed to integrate the experimental design and analytical testing methods in the field/chamber studies with the mathematical tools employed in the modeling studies. This study aims to bridge this gap and provide a more comprehensive understanding on the impact of SPF to IAQ. The field sampling plan of this research aims to evaluate the airborne concentrations of methylene diphenyl diisocyanate (MDI), formaldehyde, acetaldehyde, propionaldehyde, tris(1-chlor-2-propyl)phosphate (TCPP), trans-1-chloro-3,3,3-trifluoropropene (Solstice^TM), and airborne particles. Modifications to existing MDI sampling and analytical methods were made so that level of quantification was improved. In addition, key fate and transport modeling input parameters such as air changes per hour and airborne particle size distribution were measured. More importantly, TCPP accumulation onto materials was evaluated, which is important to study the fate and transport of semi-volatile organic compounds. The IAQ results showed that after spray application was completed in the entire building, airborne concentrations decreased for all chemicals monitored. However, it is our recommendation that during SPF application, no one should return to the application site without proper personal protection equipment as long as there are active spray activities in the building. The comparison between this field study and a recent chamber study proved surface sorption and particle deposition is an important factor in determining the fate of airborne TCPP. The study also suggests the need for further evaluation by employing mathematical models, proving the data generated in this work as informative to industry and the broader scientific community.     

基于临床参考及基因因素建立华法林稳定维持剂量预测模型

目的 探讨华法林应用的临床参考因素及基因因素与华法林稳定维持剂量的相关性,并尝试构建适用于非瓣膜病心房纤颤（non-valvular-disease atrial fibrillation,NVAF）患者华法林稳定维持剂量的预测模型。方法 按照纳入标准共纳入126例患者,应用测序反应通用试剂盒及荧光检测仪检测细胞色素P450 2C9和维生素K环氧化物还原酶基因多态性,同时记录华法林应用的临床参考因素：年龄、体质量、房颤栓塞风险评分系统（CHA₂DS₂-VASc）评分、房颤出血风险评分系统（HAS-BLED）评分、谷丙转氨酶（glutamic-pyruvic transaminase,ALT）、肾小球滤过率（glomerular filtration rate,GFR）、左心室射血分数（left ventricular ejection fraction,LVEF）、二尖瓣环水平左室侧壁组织多普勒S波;采用相关性分析探讨临床参考因素及基因多态性与华法林稳定维持剂量的相关性,并通过多元线性回归建立了华法林稳定维持剂量预测模型。结果 体质量、ALT水平、二尖瓣环水平左室侧壁组织多普勒S波与华法林稳定维持剂量成正相关,年龄、CHA₂DS₂-VASc评分、HAS-BLED评分则成负相关,而LVEF、GFR未显示明显的相关性。建立的预测模型对已有样本验证准确率达55.6%。结论 该模型可用于预测NVAF患者华法林稳定维持剂量。