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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.
Neruoprotection is considered as one of important therapeutic approaches for ischemic stroke. Inflammation plays an important role in the pathogenesis of ischemic stroke, and the inhibition of inflammation in the ischemic brain tissue may provide neuroprotective effect. In this study, we observed the influence of permanent middle cerebral artery occlussion (pMCAO) and transient MCAO (tMCAO) on NF-κB level and production of several inflammatory cytokines in injured hemisphere in mice, investigated the regulative effect of a new compound W026B on these influences in the two MCAO models. In pMCAO model, 10 μg/kg and 100 μg/kg of W026B (i.v.) significantly reduced infarct volumes, 100 μg/kg of W026B significantly decreased neurologic deficit scores and brain water contents, and 10 μg/kg and 100 μg/kg of W026B reduced Evans blue exudation from ischemic brain tissue. The level of NF-κB was elevated by 17.6 times in injured hemisphere, and the levels of TNF-α, IL-1β and IL-17 were elevated by 2.3 times, 2.2 times and 3.8 times compared with the sham operation group, respectively, 100 μg/kg of W026B significantly reduced these inflammatory cytokines. In tMCAO model, the elevation of NF-κB, TNF-α, IL-1β and IL-17 was 2.3 times, 1.4 times, 1.5 times and 1.4 times compared with the sham operation group, respectively. Moreover, 100 μg/kg of W026B significantly decreased the levels of these inflammatory cytokines. In embolic MCAO mice model, W026B alone significantly reduced infarct volumes, and combined application with tPA further reduced infarct volume. In conclusion, W026B displayed significant protecive effect on three brain ischemia models. It could protect brain against injury induced by ischmia and ischemia-reperfusion through inhibiting the production of NF-κB, TNF-α, IL-1β and IL-17. These results suggest that W026B has a value for further study.
Previous studies have shown that Ras/Raf/MEK/ERK signaling pathway is up-regulated in almost all cancer cells. Blocking of this pathway by MEK inhibition is an efficient therapeutic approach of cancer. In the present study, we described the discovery of 5-benzyl-2-phenylpyrimidin-4(3H)-one as a novel skeleton of allosteric MEK inhibitor. All acquired target compounds exhibited modest potency to inhibit MEK1 in Raf-MEK cascading assay, and docking studies revealed that the binding mode of the most potent compound (SJ3) was very similar to that of the well known diarylamine-based inhibitor (PD0325901). The results provided valuable guidance for further optimizations on this novel scaffold to achieve druggable molecules.
Cancer is one of the leading causes of death both in developing countries and across the globe. In Indonesia, cancer ranks as the fifth primary cause of death following heart disease, stroke, respiratory tract and diarrhea. Therefore, studies on thiourea derivative compounds as anticancer agents have been profoundly conducted but still require further continuous development. In the present study, we aimed tosynthesize new anticancer compounds of N-(phenylcarbamothioyl)-benzamide derivatives, namely N-(phenylcarbamothioyl)-4-bromobenzamide and N-(phenylcarbamothioyl)-4-fluorobenzamide compounds and assess their activities against MCF-7 breast cancer cells. The initial step was to predict the drug-receptor activity through docking between the tested compounds using epidermal growth factor receptor (EGFR) (PDB code: 1M17). The compounds were futher synthesized from the reactions between benzoyl chloride derivatives and N-phenylthiourea. The structures of the new compounds were identified using FTIR, 1H NMR, 13C NMR and mass spectra. The cytotoxic activities (IC50) to breast cancer cells of MCF-7 N-(phenylcarbamothioyl)-4-bromobenzamide compound and N-(phenylcarbamothioyl)-4-fluorobenzamide were 0.27 mM and 0.31 mM, respectively. These two new compounds had better cytotoxic activities than those of the currenthydroxyurea-based anticancer drugs (the reference compound) with an IC50 value of 9.76 mM. Furthermore, these two newcompounds were not toxic to Vero normal cells. Therefore, they possessedtremendous potentials as the candidates for new drugs against breastcancer.
Asa traditional Chinese herbal medicine exhibiting analgesic, fever-reducing and anti-inflammatory effects, Radix Bupleuri (Chai-Hu) is commonly used for the treatment of influenza, which is derived from the dried roots of Bupleurum chinense DC. and Bupleurum scorzonerifolium Willd. Among of diverse chemical components, saikosaponins are the key active components of the herb medicine. In the present study, we established a method of high performance liquid chromatography (HPLC) coupled with evaporative light scattering detection (ELSD) for simultaneous determination of saikosaponin a, c and d in root, stem, leaf and flower of Bupleurumchinense (B chinense) collected from different areas of Shanxi Province, China. The results from 16 samples of root, stem, leaf and flower of B chinense demonstrated that the total contents of the three saikosaponins in the root of B chinense collected from Dongshan Taiyuan, Xishan, Tianlongshan and Pangquangou were 4.26 mg/g, 3.22 mg/g, 4.23 mg/g and 3.05 mg/g, respectively. However, there was scarcely any saikosaponins in the stem, leaf and flower of B chinensecollected from above-mentioned areas. The method of HPLC coupled with ELSD was suitable for quality control of Radix Bupleuri. The result also confirmed that the root of B chinense was the best medicinal part.
A total of 13 types of endophytic fungi, classified into six genera, were isolated from Hosta. ventricosa based on 18S rDNA sequencing of ITS region and microscopic examination. The antioxidant activities of the crude extracts were investigated by T-AOC, DPPH and ABTS+ methods. The results showed that the crude extracts from Fusarium oxysporum (HoV1) and Epicoccum (HoV4), which presented higher phenol levels (1.90±0.03 mg/g, and 2.41±0.01 mg/g, respectively), exhibited stronger comprehensive antioxidant activities, with higher T-AOC values (63.46±0.26 U/g, and 66.05±0.71 U/g, respectively), lower EC50 values against ABTS+ (30.25±0.05 μg/mL, and 24.66±0.65 μg/mL, respectively)and DPPH radicals (83.42±0.24 μg/mL, and 59.136 μg/mL, respectively). Moreover, Fusarium oxysporum (HoV8) showed excellent scavenging activity against DPPH radicals (EC50 = 16.02 μg/mL), which was better than BHT. All of them could be useful in the developing of new natural antioxidant agents.
A new monoterpenoid, 4,5,8-trihydroxy-6(7)-en-decenoic acid γ-lactone (1) and six known compounds, 3,7-dimethyloct-1-ene-3,6,7-triol (2), 2,8-bornanediol (3), 1-(4-hydroxyphenyl)ethane-1,2-diol (4),2-(3-methoxy-4-hydroxyphenyl)-propane-1,3-diol(5), indole-3-carboxylic acid (6), and 3-hydroxy-benzenemethanol (7) were isolated from the whole parts of Teucrium viscidum. Their structures were established by a combination of spectroscopic data analysis, besides comparison with literature data. Compounds 2–7 described above were isolated from this genus for the first time.
Vaccines have contributed to a significant reduction in many childhood infectious diseases, such as diphtheria, measles, and Haemophilus influenzae type b (Hib). Some infectious diseases, such as polio and smallpox, have been eliminated in the United States due to effective vaccines. It is now rare for children in the United States to experience the devastating and often deadly effects of these diseases that were once common in the United States and other countries with high vaccination coverage.
2018年9月25日, 美国化学会Journal of the American Chemical Society(JACS)期刊在线刊登了我院刘涛研究员团队的最新研究成果: “Proteomic identification of protein tyrosine phosphatase and substrate interactions in living mammalian cells by genetic encoding of irreversible enzyme inhibitors”。酪氨酸磷酸化修饰是常见的蛋白翻译后修饰方式之一, 在细胞信号转导中起着重要作用, 当该修饰发生异常时, 则会导致相关疾病的产生。酪氨酸磷酸化修饰具有可逆性, 由蛋白酪氨酸激酶(Protein Tyrosine Kinases, 简称PTKs)负责添加磷酸基团, 由蛋白酪氨酸磷酸酶(Protein Tyrosine Phosphatases, 简称PTPs)催化去掉磷酸基团。迄今为止, 研究者们广泛地研究PTKs催化机理以及其在相关疾病诱发中的作用, 目前已经有20多种基于PTKs的药物在临床上应用。相比之下, 虽然有个别PTP的抑制剂在临床研究阶段, 由于研究技术的瓶颈, 对PTPs功能的阐述以及其与底物相互作用的研究仍然处于初级阶段。