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《Drug discovery today》2022,27(6):1733-1742
Compounds that exhibit assay interference or undesirable mechanisms of bioactivity are routinely encountered in assays at various stages of drug discovery. We observed that assays for the investigation of thiol-reactive and redox-active compounds have not been collected in a comprehensive review. Here, we review these assays and subject them to experimental optimization to improve their reliability. We demonstrate the usefulness of our assay cascade by assaying a library of bioactive compounds, chemical probes, and a set of approved drugs. These high-throughput assays should complement the array of wet-lab and in silico assays during the initial stages of hit discovery campaigns to pursue only hit compounds with tractable mechanisms of action. 相似文献
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背景 随着血糖监测技术的发展,近些年来人们开始使用扫描式葡萄糖监测系统(FGMS)"全景式"地观察2型糖尿病(T2DM)患者的血糖水平,明确FGMS指标与T2DM并发症之间的关系有助于提高其临床应用价值,但目前相关研究较少。 目的 探究佩戴FGMS的T2DM患者葡萄糖在目标范围内时间(TIR)等指标与尿白蛋白/肌酐比值(UACR)的相关性。 方法 选取2019年1月至2021年10月于北京大学人民医院老年科就诊并佩戴FGMS的T2DM患者79例,以尿液检查中UACR是否<30 mg/g将患者分为无白蛋白尿组(n=50)和白蛋白尿组(n=29)。比较两组患者的临床特征、实验室检查指标及FGMS指标等。采用Pearson相关、Spearman秩相关分析探讨TIR、高血糖时间(TAR)与糖化血红蛋白(HbA1c)的相关性。分别采用Pearson相关、Spearman秩相关、偏相关分析探讨FGMS指标与lnUACR的相关性。使用多因素Logistic回归分析探究T2DM患者发生白蛋白尿的影响因素,采用受试者工作特征(ROC)曲线评估TIR对白蛋白尿的预测价值。 结果 白蛋白尿组T2DM病程长于无白蛋白尿组,三酰甘油(TG)、HbA1c、平均血糖(MBG)、TAR、平均血糖标准差(SDBG)、最大葡萄糖波动幅度(LAGE)、平均葡萄糖波动幅度(MAGE)、连续每隔2 h血糖净作用(CONGA2)高于无白蛋白尿组,TIR低于无白蛋白尿组(P<0.05)。Pearson相关、Spearman秩相关分析结果显示,TIR与HbA1c呈负相关(P<0.001),TAR与HbA1c呈正相关(P<0.001)。Pearson相关、Spearman秩相关、偏相关分析结果均表明,TIR与lnUACR呈负相关(P<0.001),MBG、TAR、SDBG、LAGE、MAGE、CONGA2与lnUACR呈正相关(P<0.001)。多因素Logistic回归分析结果显示,TIR>70%〔OR=0.038,95%CI(0.003,0.467)〕是T2DM患者出现白蛋白尿的保护因素(P<0.05),TAR升高〔OR=1.046,95%CI(1.000,1.094)〕是T2DM患者出现白蛋白尿的危险因素(P<0.05)。TIR预测T2DM患者出现白蛋白尿的ROC曲线下面积(AUC)为0.784〔95%CI(0.674,0.894)〕(P=0.003),灵敏度为78%,特异度为83%,最佳切点为69.71%。 结论 在FGMS指标中,TIR>70%是T2DM患者出现白蛋白尿的保护因素,TAR升高是T2DM患者出现白蛋白尿的危险因素。同时,SDBG、LAGE、MAGE、CONGA2等多种反映血糖波动的指标也与UACR密切相关。对TIR水平较低及TAR、SDBG、LAGE、MAGE、CONGA2水平较高的T2DM患者进行FGMS筛查有助于早期识别及预防白蛋白尿的发生、发展。 相似文献
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《Vaccine》2022,40(13):1996-2002
ChAdOx1 nCoV-19 adenoviral vector vaccine (ChAd) against coronavirus disease 2019 has been associated with vaccine-induced thrombosis and thrombocytopenia (VITT), especially in young women who have presented with unusual localized thrombosis after receiving the vaccine. The pathogenesis of VITT remains incompletely understood. We tried to provide new insights into mechanisms underlying this phenomenon in the model of arterial thrombosis electrically induced in the carotid artery of female rats. At 28 days post-vaccination, ChAd induced SARS-CoV-2-specific neutralizing antibody responses in all animals. The analysis of the blood vessel/thrombus area showed slight luminal narrowing of the carotid artery with extravasation of blood in vaccinated rats. These small changes were not accompanied by differences in thrombus weight and composition. The vaccinated animals presented a slight increase (by around 14–24%) in platelet aggregation. ChAd did not significantly affect blood coagulation, platelet counts, and their activation markers. Unaffected thrombus formation, the lack of thrombocytopenia and all the measured blood and hemostasis parameters that predominantly stayed unchanged, indicate that the ChAd does not increase the risk of arterial thrombosis development in female rats. 相似文献
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《Saudi Pharmaceutical Journal》2022,30(2):108-111
Linezolid is an oxazolidinone antibiotic. Linezolid-associated lactic acidosis has been reported in 6.8% of linezolid-treated patients. Lactic acidosis is associated with poor clinical outcomes, with high blood lactate levels resulting in organ dysfunction and mortality. This case report describes the development of lactic acidosis in a 64-year-old Chinese woman who had received 33 days of treatment with antituberculosis drugs and 28 days of treatment with oral linezolid for tuberculous meningitis. Severe lactic acidosis was reversed by withdrawing antituberculosis drugs and using continuous venovenous hemodiafiltration (CVVH). When the patient's condition was stable, she was transferred to the infectious disease department, and antituberculosis drugs, with the exception of linezolid, were reintroduced. This did not result in recurrence of lactic acidosis. The causal relationship between lactic acidosis and linezolid was categorized as ‘probable’ on the Adverse Drug Reaction Probability Scale. This case demonstrates that CVVH has potential as an alternative to discontinuation of linezolid alone for rapid reversal of linezolid-associated severe lactic acidosis. 相似文献
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ObjectiveTo investigate the feasibility of transnasal heated humidified high flow nasal cannula oxygen therapy (HFNC) in the treatment of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) with respiratory failure in elderly patients. MethodsA total of 176 elderly patients with AECOPD complicated with respiratory failure who were hospitalized at Peking University Shougang Hospital from December 2016 to January 2022 were enrolled, including 82 patients in an HFNC group and 94 patients in an NPPV group. After treatment, pulse oxygen saturation (SPO2), arterial partial pressure of carbon dioxide (PaCO2), oxygenation index (OI), respiratory rate (RR), heart rate (HR), mean arterial pressure (MAP), comfort score, discharge rate, rate of endotracheal intubation, rate of transfer to intensive care unit (ICU), and mortality were compared between the two groups. The independent sample t-test was used for comparison between the two groups. Statistical data are expressed in percentage or number of cases and the χ2 test was used for their comparisons. ResultsThe SPO2 values at 30 min, 1 h, and 6 h were significantly higher in the HFNC group than in the NPPV group (t=-2.049,-2.618, and -3.314, P=0.043, 0.010, and 0.001, respectively). SPO2 before discharge was significantly lower than that of the NPPV group (t=2.162, P=0.033), but OI at each time point and before discharge had no statistical significance (P>0.05). MAP at 6 h was significantly higher in the HFNC group than in the NPPV group (t=-2.209, P=0.029), but within the normal range. HRs at 2 h and 3 h in the HFNC group were significantly higher than those of the NPPV group (t=-2.199 and -2.336, P=0.030 and 0.021, respectively). There were no significant differences in RR, HR, or MAP between the two groups at other time points and before discharge (P>0.05). There was no significant difference in PaCO2 between the two groups (P>0.05). Comfort score in the HFNC group was significantly higher than that of the NPPV group (t=-46.807, P<0.001). There were no significant differences in discharge rate, ICU transfer rate, endotracheal intubation rate, and mortality between the two groups (P>0.05). ConclusionHFNC is as effective as NPPV in treating elderly patients with AECOPD complicated with type Ⅰ or mild type Ⅱ respiratory failure, and HFNC is more comfortable than NPPV. 相似文献
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《Saudi Pharmaceutical Journal》2022,30(11):1665-1671
5-fluorouracil (5FU) is widely used to treat colorectal cancer (CC) and its main mechanisms of anticancer action are through generation of ROS which often result in inflammation. Here, we test the effect of Lycopene against 5FU in Caco2 cell line. Caco2 cells were exposed to 3 µg/ml of 5FU alone or with 60, 90, 120 µg/ml of lycopene. This was followed by assessment of cytotoxicity, oxidative stress, and gene expression of inflammatory genes. Our findings showed that Lycopene and 5FU co-exposure induced dose-dependent cytotoxic effect without compromising the membrane integrity based on the LDH assay. Lycopene also significantly enhanced 5FU-induced SOD activity and GSH level compared to control for all mixture concentrations (p < 0.01). Lycopene alone and combination with 5FU-induced expression of IL-1β, TNF-α, and IL-6. Furthermore, IFN-γ expression was significantly enhanced by only mixture of lycopene (90 µg/ml) and 5FU (p < 0.05). In conclusion, Lycopene supplementation with 5FU therapy resulted in improvement in antioxidant parameters such as catalase and GSH levels giving the cell capacity to cope with 5FU-mediated oxidative stress. Lycopene also enhanced IFN-γ expression in the presence of 5FU, which may activate antitumor effects further enhancing the cancer killing effect of 5FU. 相似文献