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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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This study aimed to investigate the association between glutathione S-transferase (GST) M1 and T1 null genotypes and thiobarbituric acid reactive substances (TBARS), total antioxidant capacity (TAC) and nitric oxide (NO) levels in male infertility. For this purpose, semen samples were collected from fertile and infertile subjects, and then they were genotyped for GSTT1 and GSTM1 genes using multiplex-PCR. The TBARS, TAC and NO levels in seminal plasma were then measured via the ferric-reducing ability of plasma (FRAP). A significant association was observed between GSTT1 null genotype and oligozoospermia, asthenozoospermia and teratozoospermia. But, the GSTM1 null genotype was merely associated with teratozoospermia. Moreover, the GSTT1−/GSTM1+ combined genotype was associated with all subgroups of male infertility. Besides, an association was observed between GSTT1−/GSTM1− genotype and asthenozoospermia and teratozoospermia. Further analysis showed that the GSTT1 null genotype was associated with increased NO in asthenozoospermia. Also, the GSTT1 null genotype was associated with increased TBARS in oligozoospermia and asthenozoospermia. As well, GSTM1 null genotype was associated with decreased TAC and increased NO in asthenozoospermia respectively. As a preliminary conclusion, the GSTM1 and GSTT1 null genotypes could be considered as genetic risk factors for male infertility, interfering with some oxidative stress markers in infertile men. 相似文献
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Raquel Blazquez Eva Rietkötter Britta Wenske Darius Wlochowitz Daniela Sparrer Elena Vollmer Gunnar Müller Julia Seegerer Xueni Sun Katja Dettmer Alonso Barrantes-Freer Lena Stange Kirsten Utpatel Annalen Bleckmann Hannes Treiber Hanibal Bohnenberger Christof Lenz Matthias Schulz Christian Reimelt Christina Hackl Marian Grade Deram Büyüktas Laila Siam Marko Balkenhol Christine Stadelmann Dieter Kube Michael P. Krahn Martin A. Proescholdt Markus J. Riemenschneider Matthias Evert Peter J. Oefner Chistoph A. Klein Uwe K. Hanisch Claudia Binder Tobias Pukrop 《International journal of cancer. Journal international du cancer》2020,146(11):3170-3183
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目的通过对宫颈鳞状细胞癌进行顺铂(DDP)和DDP+5-氟尿嘧啶(5-FU)体外药敏检测,比较两种化疗方案的体外有效率。同时检测其耐药蛋白P糖蛋白(P-gp)、谷胱甘肽S-转移酶-π(GST-π)、DNA拓扑异构酶Ⅱ(TopoⅡ)、胸苷酸合成酶(TS)的表达,探讨DDP和DDP+5-FU体外药敏与耐药蛋白表达的关系。方法收集35例宫颈鳞状细胞癌患者的新鲜肿瘤组织,采用三磷酸腺苷生物荧光法(ATP-TCA)对DDP和DDP+5-FU进行体外药敏检测,同时采用EnVision二步法检测宫颈鳞状细胞癌组织中耐药蛋白P-gp、GST-π、TopoⅡ、TS的表达,并分析DDP和DDP+5-FU的体外药敏与耐药蛋白P-gp、GST-π、TopoⅡ、TS表达的关系。结果 35例标本均进行药敏试验,DDP的体外有效率为37.14%,与DDP+5-FU的51.43%比较,差异无统计学意义(P> 0.05)。经多因素分析发现,患者年龄、临床分期、分化程度均不为DDP、DDP+5-FU药物敏感性的影响因素(P> 0.05)。P-gp、GST-π、TopoⅡ、TS蛋白阳性表达率分别为57.14%(20/35)、51.43%(18/35)、71.43%(25/35)、57.14%(20/35)。GST-π蛋白阳性表达是宫颈鳞状细胞癌对DDP耐药的影响因素(P=0.002);TS蛋白阳性表达是宫颈鳞状细胞癌对DDP+5-FU耐药的影响因素(P=0.001)。结论 宫颈鳞状细胞癌ATP-TCA法检测DDP+5-FU与单药DDP相比,体外有效率无显著差异。GST-π、TS蛋白阳性表达可用于临床宫颈癌患者对DDP、5-FU化疗耐药的预测指标。 相似文献
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目的 探究紫草素(SK)对活性酵母诱导的血热证小鼠模型的清热凉血作用与血液氧化还原稳态调控的关系。方法 小鼠随机分为对照组、模型组、SK(10 mg/kg)组、阿司匹林(Asp,200 mg/kg)组、L-丁硫氨酸亚砜亚胺(BSO,600 mg/kg)组、N-乙酰-L-半胱氨酸(NAC,400 mg/kg)组、BSO联合SK组、NAC联合SK组。小鼠颈背部sc 0.2 g/mL活性酵母提取物(10 mL/kg),造模0.5 h后ip SK,造模8 h后ig Asp,于实验开始前ip BSO、NAC,2次/d,连续1周。考察小鼠肛温(tR)、基本活动、代谢、凝血、血细胞计数等指标,采用OPA荧光法测定小鼠血清中还原型谷胱甘肽(GSH)、氧化型谷胱甘肽(GSSG)水平。结果 与对照组相比,模型组小鼠造模4 h后tR显著升高(P<0.05),10 h达到(38.07±0.11)℃;小鼠出现烦躁、口唇色红、喜饮、碳末推进率降低、粪便含水量降低、凝血时间延长现象(P<0.05);肺组织红细胞、炎性细胞浸润;血清LPO、MDA水平显著升高、SOD活性降低、GSH/GSSG比率减小(P<0.05)。与模型组相比,SK组小鼠tR显著降低,10 h达到(37.51±0.12)℃;各指标均得到显著改善;血清LPO、MDA水平降低、SOD活性升高、GSH/GSSG比率增大(P<0.05)。BSO组可降低血清GSH/GSSG比率(P<0.05),减弱SK对血热证小鼠的治疗作用;NAC组可增加血清GSH水平,增加GSH/GSSG比率(P<0.05),增强SK对血热证小鼠的治疗效果。结论 SK通过调控血液氧化还原稳态,缓解血热证小鼠高热、出血瘀血、血液氧化损伤,从而发挥清热凉血作用。 相似文献
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Differential involvement of glutathione S‐transferase mu 1 and multidrug resistance protein 1 in melanoma acquired resistance to vinca alkaloids 下载免费PDF全文
Chaker Attaoua Laure‐Anaïs Vincent Aida Abdel Jaoued Kamel Hadj‐Kaddour Qiang Baï John De Vos Laurence Vian Pierre Cuq 《Fundamental & clinical pharmacology》2015,29(1):62-71
On account of its extreme intrinsic resistance to apoptosis and of its strong ability to become chemoresistant after a primary response to drugs, malignant melanoma (MM) is still a therapeutic challenge. We previously showed that glutathione S‐transferase mu 1 (GSTM1) acts in synergy with multidrug resistance protein 1 (MRP1) to protect GSTM1‐transfected human CAL1 melanoma cells from toxic effects of vincristine (VCR). Herein, we investigated the role of these proteins in the acquired resistance of CAL1 cells to vinca alkaloids (VAs). Resistant lines were established by continuous exposure (>1 year) of parental CAL1‐wt cells to VCR, vindesine (VDS), or vinorelbine (VRB): CAL1R‐VCR, CAL1R‐VDS, CAL1R‐VRB, respectively. All resistant lines displayed more than 10‐fold increase in resistance to their selection VA, and specifically expressed GSTM1. Suggesting a direct interaction between this protein and VAs, each VA specifically decreased the GSTM1‐mediated glutathione conjugation activity in cell lysates. Curcumin (GSTM1 inhibitor), BSO (glutathione synthesis inhibitor), and MK571 (MRP1 inhibitor) considerably reversed the acquired resistance to VCR and VDS, but not to VRB. Microarray data analysis revealed similar gene expression patterns of CAL1R‐VCR and CAL1R‐VDS, and a distinct one for CAL1R‐VRB. These data suggest a differential involvement of GSTM1 and MRP1 in acquired resistance to VAs. A coordinated expression and activity of GSTM1 and MRP1 is required to protect CAL1 cells from VCR and VDS, while the simple expression of GSTM1 is sufficient, possibly by a direct drug/protein interaction, to confer resistance against VRB. 相似文献
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Konstantina Poulianiti Christina Karatzaferi Andreas D. Flouris Ioannis G. Fatouros Yiannis Koutedakis 《Toxicology mechanisms and methods》2016,26(6):446-452
Context: It has been indicated that acute active and passive tobacco cigarette smoking may cause changes on redox status balance that may result in significant pathologies. However, no study has evaluated the effects of active and passive e-cigarette smoking on redox status of consumers.Objective: To examine the acute effects of active and passive e-cigarette and tobacco cigarette smoking on selected redox status markers.Methods: Using a randomized single-blind crossover design, 30 participants (15 smokers and 15 nonsmokers) were exposed to three different experimental conditions. Smokers underwent a control session, an active tobacco cigarette smoking session (smoked 2 cigarettes within 30-min) and an active e-cigarette smoking session (smoked a pre-determined number of puffs within 30-min using a liquid with 11?ng/ml nicotine). Similarly, nonsmokers underwent a control session, a passive tobacco cigarette smoking session (exposure of 1?h to 23?±?1?ppm of CO in a 60?m3 environmental chamber) and a passive e-cigarette smoking session (exposure of 1?h to air enriched with pre- determined number of puffs in a 60?m3 environmental chamber). Total antioxidant capacity (TAC), catalase activity (CAT) and reduced glutathione (GSH) were assessed in participants’ blood prior to, immediately after, and 1-h post-exposure.Results: TAC, CAT and GSH remained similar to baseline levels immediately after and 1-h-post exposure (p?>?0.05) in all trials.Conclusions: Tobacco and e-cigarette smoking exposure do not acutely alter the response of the antioxidant system, neither under active nor passive smoking conditions. Overall, there is not distinction between tobacco and e-cigarette active and passive smoking effects on specific redox status indices. 相似文献
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