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1.
《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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《Vaccine》2019,37(44):6696-6706
Live attenuated viral vaccine/vector candidates are inherently unstable and infectivity titer losses can readily occur without defining appropriate formulations, storage conditions and clinical handling practices. During initial process development of a candidate vaccine against HIV-1 using a recombinant Human Cytomegalovirus vector (rHCMV-1), large vector titer losses were observed after storage at 4 °C and after undergoing freeze-thaw. Thus, the goal of this work was to develop candidate frozen liquid formulations of rHCMV-1 with improved freeze-thaw and short-term liquid stability for potential use in early clinical trials. To this end, a virus stability screening protocol was developed including use of a rapid, in vitro cell-based immunofluorescence focus assay to quantitate viral titers. A library of ∼50 pharmaceutical excipients (from various known classes of additives) were evaluated for their effect on vector stability after freeze-thaw cycling or incubation at 4 °C for several days. Certain additives including sugars and polymers (e.g., trehalose, sucrose, sorbitol, hydrolyzed gelatin, dextran 40) as well as removal of NaCl (lower ionic strength) protected rHCMV-1 against freeze-thaw mediated losses in viral titers. Optimized solution conditions (e.g., solution pH, buffers and sugar type) slowed the rate of rHCMV-1 titer losses in the liquid state at 4 °C. After evaluating various excipient combinations, three new candidate formulations were designed and rHCMV-1 stability was benchmarked against both the currently-used and a previously reported formulation. The new candidate formulations were significantly more stable in terms of reducing rHCMV-1 titer losses after 5 freeze-thaw cycles or incubation at 4 °C for 30 days. This case study highlights the utility of semi-empirical design of frozen liquid formulations of a live viral vaccine candidate, where protection against infectivity titer losses due to freeze-thaw and short-term liquid storage are sufficient to enable more rapid initiation of early clinical trials. 相似文献
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Hui Fan Xianzhen Jin Chunyan Liao Lina Qiao Wei Zhao 《Pathology, research and practice》2019,215(11):152667
MicroRNAs (miRNAs) have been found to be aberrantly expressed and exert essential roles in the tumorigenesis and progression of gastric cancer (GC). miR-301b-3p has been recognized as a cancer-related miRNA in lung cancer, bladder cancer and hepatocellular carcinoma. However, the function of miR-301b-3p in GC progression and its underlying mechanism have not been studied yet. In this study, we found that miR-301b-3p expression was up-regulated in GC tissues compared to adjacent noncancerous tissues. Furthermore, the elevated levels of miR-301b-3p were detected in GC cell lines (SGC-7901, AGS, MKN-45 and MGC-803) as compared with GES-1 cells. Interestingly, GC tissues from patients with tumor size ≥ 5 cm and advanced tumor stages showed obvious higher levels of miR-301b-3p compared to matched controls. Functionally, miR-301b-3p knockdown prominently inhibited cell proliferation, and induced cell cycle arrest at G1 phase and apoptosis in MGC-803 cells. Meanwhile, ectopic expression of miR-301b-3p conversely regulated these biological behaviors of MKN-45 cells. Next, we found that miR-301b-3p knockdown increased, whereas miR-301b-3p overexpression reduced the expression of zinc finger and BTB domain containing 4 (ZBTB4) in GC cells. Accordingly, luciferase reporter assay identified ZBTB4 as a direct target of miR-301b-3p. ZBTB4 overexpression markedly restrained the growth of MGC-803 cells. More importantly, ZBTB4 silencing partially reversed miR-301b-3p knockdown-induced tumor suppressive effects on MGC-803 cells. In conclusion, we firstly revealed that miR-301-3p was highly expressed in GC and contributed to tumor progression via attenuating ZBTB4, which might provide a novel molecular-targeted strategy for GC treatment. 相似文献
4.
目的:探讨早期电针"百会""大椎""肾俞"穴对快速老化小鼠(SAMP8小鼠)学习记忆能力和海马磷酸化Tau蛋白表达的影响,为临床电针治疗阿尔茨海默病(AD)时间点的选择提供参考。方法:将36只3月龄SAMP8小鼠随机分为模型组、3月龄电针组、9月龄电针组,每组12只;以12只同龄正常老化SAMR1小鼠作为空白对照组。3月龄电针组及9月龄电针组分别于小鼠3月龄及9月龄时予电针"百会""大椎""肾俞"穴治疗(连续波,2 Hz,1.5~2 mA),20 min/次,每日1次,8 d为一疗程,疗程间隔2 d,共治疗3个疗程。每组小鼠在水迷宫检测学习记忆能力结束后统一于10月龄取材;免疫组织化学法、免疫蛋白印迹法(Western blot)检测小鼠海马磷酸化Tau蛋白的表达,实时荧光定量PCR法检测小鼠海马Tau mRNA表达。结果:与空白对照组比较,模型组小鼠逃避潜伏期明显延长(P<0.01),原平台象限停留时间较短,跨越平台次数减少(P<0.01),海马磷酸化Tau蛋白及Tau mRNA表达较高(P<0.01);与模型组比较,3月龄电针组及9月龄电针组小鼠逃避潜伏期缩短(P<0.05),原平台象限停留时间延长,跨越平台次数增多(P<0.05),小鼠海马磷酸化Tau蛋白及Tau mRNA表达降低(P<0.05);与9月龄电针组比较,3月龄电针组小鼠逃避潜伏期缩短(P<0.05),原平台象限停留时间延长,跨越平台次数增多(P<0.05),海马磷酸化Tau蛋白及Tau mRNA表达降低(P<0.01)。结论:早期电针干预能更有效地改善SAMP8小鼠学习记忆能力并降低其海马磷酸化Tau蛋白水平。 相似文献
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目的 探讨工娱疗法对阿尔茨海默病患者认知功能、激越行为及社会功能的影响。方法 选取从2016年10月-2018年10月我院收治的130例阿尔茨海默病患者为研究对象,采用随机抽签法将其分成对照组和观察组,各65例。对照组予以常规护理干预,观察组在对照组基础上增加工娱疗法干预。比较2组干预前后认知功能、激越行为以及社会功能的差异。结果 干预后,观察组简易智能状态检查量表评分高于对照组(t=9.517,P<0.001);激越行为量表总评分均低于对照组(t=3.307,P=0.001);社会功能评定量表总分高于对照组(t=23.091,P<0.001)。结论 工娱疗法在阿尔茨海默病患者中的应用效果明显,有利于改善患者的认知功能、激越行为以及社会行为,值得临床推广应用。 相似文献
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目的 探讨赋能心理护理对ICU患者家属心理压力及应对方式的影响。方法 选取2017年1-12月我院收治的120例ICU患者的主要照顾家属为研究对象,采用随机数字表法将其分为观察组及对照组,每组各60例。对照组行常规健康宣教,观察组在对照组基础上行赋能心理干预,比较2组心理压力、自我效能及应对方式。结果 干预后,观察组自我效能评分、积极应对方式评分均明显高于对照组(t=8.477,P<0.001;t=10.845,P<0.001),而消极应对方式评分明显低于对照组(t=8.935,P<0.001)。观察组紧张感、失控感及心理压力总评分均明显低于对照组(P<0.001)。结论 赋能心理干预能有效提高ICU重症患者家属自我效能,使家属能积极面对患者病情,减轻患者家属心理负担。 相似文献
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养精种玉汤临床多用于治疗各种不孕症、多囊卵巢综合征、月经过少、闭经溢乳综合征、体外受精-胚胎移植等疾病,疗效确切。但是记载养精种玉汤的古代文献资料较少,现代研究大部分是临床试验和基础实验研究,且存在一些不足:①有些临床试验缺乏中医辨证,治疗疾病未辨证而直接辨病论治;②缺少治疗后随访及远期疗效评价,对妊娠结局的随访亦未予以特定的描述,不便于对研究结果做进一步分析;③相关研究中应完善血清激素水平指标的监测,以增加研究结果的说服力;④大部分研究样本量偏少,影响统计学结果,降低了结果的可靠性;⑤该方的安全性研究仅仅停留在动物实验阶段。因此,今后的研究应以辨证论治为基础,增加样本量,完善相关激素水平的检测,关注随访结果,为临床用药安全性提供更可靠的依据。 相似文献
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