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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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《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
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D. R. Frei R. Beasley D. Campbell A. Forbes K. Leslie D. Mackle C. Martin A. Merry M. R. Moore P. S. Myles L. Ruawai-Hamilton T. G. Short P. J. Young 《Anaesthesia》2023,78(10):1272-1284
International recommendations encourage liberal administration of oxygen to patients having surgery under general anaesthesia, ostensibly to reduce surgical site infection. However, the optimal oxygen regimen to minimise postoperative complications and enhance recovery from surgery remains uncertain. The hospital operating theatre randomised oxygen (HOT-ROX) trial is a multicentre, patient- and assessor-blinded, parallel-group, randomised clinical trial designed to assess the effect of a restricted, standard care, or liberal peri-operative oxygen therapy regimen on days alive and at home after surgery in adults undergoing prolonged non-cardiac surgery under general anaesthesia. Here, we report the findings of the internal vanguard feasibility phase of the trial undertaken in four large metropolitan hospitals in Australia and New Zealand that included the first 210 patients of a planned overall 2640 trial sample, with eight pre-specified endpoints evaluating protocol implementation and safety. We screened a total of 956 participants between 1 September 2019 and 26 January 2021, with data from 210 participants included in the analysis. Median (IQR [range]) time-weighted average intra-operative FiO2 was 0.30 (0.26–0.35 [0.20–0.59]) and 0.47 (0.44–0.51 [0.37–0.68]) for restricted and standard care, respectively (mean difference (95%CI) 0.17 (0.14–0.20), p < 0.001). Median time-weighted average intra-operative FiO2 was 0.83 (0.80–0.85 [0.70–0.91]) for liberal oxygen therapy (mean difference (95%CI) compared with standard care 0.36 (0.33–0.39), p < 0.001). All feasibility endpoints were met. There were no significant patient adverse events. These data support the feasibility of proceeding with the HOT-ROX trial without major protocol modifications. 相似文献
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目的 探讨扶正化瘀方含药血清对肝星状细胞(HSC)激活素A(activinA)/smad信号通路活化的影响。方法 20只SD大鼠按照随机数字表法分为对照组及扶正化瘀(Fzhy)-低、中、高剂量含药血清组,每组5只,分别以蒸馏水,0.75、1.5、3.0 g/kg扶正化瘀溶液(扶正化瘀胶囊药物粉末与蒸馏水配制)灌胃1次/d,连续3 d,取血制备空白血清(对照组)和含药血清。以大鼠HSC-T6细胞为研究对象,分别用5%、10%、20%体积分数的各组含药血清培养细胞。CCK-8检测细胞存活率,选取细胞存活率在50%左右的体积分数重新分为对照组及Fzhy-低、中、高剂量组。流式细胞术检测细胞周期及凋亡率、线粒体膜电位变化和活性氧(ROS)水平;实时荧光定量聚合酶链反应检测细胞中activinA、smad3、samd7、核因子(NF)-κB的mRNA水平;蛋白质印迹法检测细胞中activinⅡA受体(ActRⅡA)、smad3、NF-κB p65、胱天蛋白酶(caspase)-3的蛋白水平。结果 各扶正化瘀含药血清组的细胞存活率均低于对照组(P<0.05),选择体积分数为10%的含药血清进行后续实验。对照组和各扶正化瘀方含药血清组细胞周期和凋亡率差异均无统计学意义。对照组及Fzhy-低、中、高剂量组细胞内ROS水平及线粒体膜电位水平降低比例逐次升高(P<0.05)。与对照组比较,Fzhy-中、高剂量组smad3 mRNA表达水平降低,smad7 mRNA升高,Fzhy-低、中、高剂量组NF-κB、activinA mRNA,smad3、NF-κB p65、ActRⅡA蛋白表达水平降低,Fzhy-低剂量组、中剂量组caspase-3蛋白表达水平升高(P<0.05);与Fzhy-低剂量组相比,Fzhy-中、高剂量组smad3 mRNA表达水平降低,Fzhy-中剂量组activinA及smad7 mRNA升高(P<0.05)。结论 扶正化瘀方含药血清可通过影响HSC-T6细胞增殖、参与细胞的氧化应激以及调节细胞activinA/smad信号转导通路来实现抗纤维化作用。 相似文献
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目的:探讨脑出血对酵母沉默信息调节因子2(Sirt2)和炎症的影响。方法:将胶原酶Ⅳ注入SD大鼠右侧
纹状体中建立脑出血模型,通过免疫印迹和ELISA 等方法测定大鼠脑出血后48 h 的Sirt2 的表达及炎症变化。利
用Hemin 诱导PC12 细胞损伤模拟体外脑出血模型,并检测Sirt2 及炎症变化;采用短发夹RNA(shRNA)-Sirt2 沉
默Sirt2 在PC12 细胞中的表达及对炎症的影响。结果:手术后48 h 脑出血行为学评分最低。脑出血组Sirt2 的表达
显著高于假手术组。脑出血组IL-6、IL-1β 表达显著升高。结论:脑出血可以促进Sirt2 的表达和炎症反应,降低
Sirt2 的表达可减缓炎症反应。
关键词 脑出血;沉默信息调节 相似文献