Protein neddylation is a post-translational modification which transfers the ubiquitin-like protein NEDD8 to a lysine residue of the target substrate through a three-step enzymatic cascade.The bestknown substrates of ...Protein neddylation is a post-translational modification which transfers the ubiquitin-like protein NEDD8 to a lysine residue of the target substrate through a three-step enzymatic cascade.The bestknown substrates of neddylation are cullin family proteins,which are the core component of Cullin-RING E3 ubiquitin ligases(CRLs).Given that cullin neddylation is required for CRL activity,and CRLs control the turn-over of a variety of key signal proteins and are often abnormally activated in cancers,targeting neddylation becomes a promising approach for discovery of novel anti-cancer therapeutics.In the past decade,we have witnessed significant progress in the field of protein neddylation from preclinical target validation,to drug screening,then to the clinical trials of neddylation inhibitors.In this review,we first briefly introduced the nature of protein neddylation and the regulation of neddylation cascade,followed by a summary of all reported chemical inhibitors of neddylation enzymes.We then discussed the structure-based targeting of protein-protein interaction in neddylation cascade,and finally the available approaches for the discovery of new neddylation inhibitors.This review will provide a focused,up-to-date and yet comprehensive overview on the discovery effort of neddylation inhibitors.展开更多
背景:乳腺癌是女性最常见的恶性肿瘤之一,其发病率逐年上升且趋于年轻化,严重威胁女性生命健康,因此建立一个能够准确模拟体内肿瘤情况的理想乳腺癌模型显得尤为重要。类器官与体内来源的组织或器官高度相似,是一种新型的体外三维培养模...背景:乳腺癌是女性最常见的恶性肿瘤之一,其发病率逐年上升且趋于年轻化,严重威胁女性生命健康,因此建立一个能够准确模拟体内肿瘤情况的理想乳腺癌模型显得尤为重要。类器官与体内来源的组织或器官高度相似,是一种新型的体外三维培养模型,近年来在各种恶性肿瘤的研究中备受研究人员的青睐。目的:综述乳腺癌类器官的研究进展及应用,以期为乳腺癌的个性化治疗提供新的研究途径。方法:第一作者以“类器官、乳腺癌类器官、肿瘤类器官、乳腺球、3D培养”“organoid,breast cancer organoids,cancer organoids,mammosphere,three-dimensional culture”为检索词,检索1980年1月至2020年2月CNKI、万方、PubMed数据库相关文献,文献类型不限,排除与文章研究目的无关及重复性的文献,最终纳入66篇文献进行综述分析。结果与结论:文章简要介绍了类器官技术,回顾了构建乳腺癌类器官模型的过程,总结了乳腺癌类器官最新研究进展及应用。乳腺癌类器官在疾病建模、肿瘤发生机制、药物筛选等方面有广泛应用前景,为乳腺癌研究和治疗提供了可靠的模型,特别是为乳腺癌个性化治疗开辟了新的视野。展开更多
Glucose transporter 1(GLUT1)overexpression in tumor cells is a potential target for drug therapy,but few studies have reported screening GLUT1 inhibitors from natural or synthetic compounds.With current analysis techn...Glucose transporter 1(GLUT1)overexpression in tumor cells is a potential target for drug therapy,but few studies have reported screening GLUT1 inhibitors from natural or synthetic compounds.With current analysis techniques,it is difficult to accurately monitor the GLUT1 inhibitory effect of drug molecules in real-time.We developed a cell membrane-based glucose sensor(CMGS)that integrated a hydrogel electrode with tumor cell membranes to monitor GLUT1 transmembrane transport and screen for GLUT1 inhibitors in traditional Chinese medicines(TCMs).CMGS is compatible with cell membranes of various origins,including different types of tumors and cell lines with GLUT1 expression knocked down by small interfering RNA or small molecules.Based on CMGS continuous monitoring technique,we investigated the glucose transport kinetics of cell membranes with varying levels of GLUT1 expression.We used CMGS to determine the GLUT1-inhibitory effects of drug monomers with similar structures from Scutellaria baicalensis and catechins families.Results were consistent with those of the cellular glucose uptake test and molecular-docking simulation.CMGS could accurately screen drug molecules in TCMs that inhibit GLUT1,providing a new strategy for studying transmembrane protein-receptor interactions.展开更多
The ongoing coronavirus disease 2019(COVID-19) pandemic has boosted the development of antiviral research.Microfluidic technologies offer powerful platforms for diagnosis and drug discovery for severe acute respirator...The ongoing coronavirus disease 2019(COVID-19) pandemic has boosted the development of antiviral research.Microfluidic technologies offer powerful platforms for diagnosis and drug discovery for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) diagnosis and drug discovery.In this review,we introduce the structure of SARS-CoV-2 and the basic knowledge of microfluidic design.We discuss the application of microfluidic devices in SARS-CoV-2 diagnosis based on detecting viral nucleic acid,antibodies,and antigens.We highlight the contribution of lab-on-a-chip to manufacturing point-ofcare equipment of accurate,sensitive,low-cost,and user-friendly virus-detection devices.We then investigate the efforts in organ-on-a-chip and lipid nanoparticles(LNPs) synthesizing chips in antiviral drug screening and mRNA vaccine preparation.Microfluidic technologies contribute to the ongoing SARSCoV-2 research efforts and provide tools for future viral outbreaks.展开更多
核磁共振(nuclear magnetic resonance,NMR)是以原子核自旋的共振跃迁为探测对象的谱学方法.当自旋量子数不为零的原子核处于外磁场中时,会引起能级的Zeeman分裂.若再施加能量等于Zeeman能级差的射频场,则会诱发原子核自旋的共振跃迁,...核磁共振(nuclear magnetic resonance,NMR)是以原子核自旋的共振跃迁为探测对象的谱学方法.当自旋量子数不为零的原子核处于外磁场中时,会引起能级的Zeeman分裂.若再施加能量等于Zeeman能级差的射频场,则会诱发原子核自旋的共振跃迁,这种现象即为核磁共振.核自旋的共振频率与原子的类型有关,且受原子所处化学和物理环境的影响.此外,NMR能量较低,不会影响探测对象(常为分子)的状态.因此,NMR能够在无损条件下提供多种具有原子和分子分辨的物质组成、结构、形态、动态变化等丰富信息.展开更多
Background:The detection of drug-resistant tuberculosis(DR-TB)is a major health concern in China.We aim to summarize interventions related to the screening and detection of DR-TB in Jiangsu Province,analyse their impa...Background:The detection of drug-resistant tuberculosis(DR-TB)is a major health concern in China.We aim to summarize interventions related to the screening and detection of DR-TB in Jiangsu Province,analyse their impact,and highlight policy implications for improving the prevention and control of DR-TB.Methods:We selected six prefectures from south,central and no「th Jiangsu Province.We reviewed policy documents between 2008 and 2019,and extracted routineTB patient registration data from theTB Information Management System(TBIMS)between 2013 and 2019.We used the High-quality Health System Framework to structure the analysis.We performed statistical analysis and logistic regression to assess the impact of different policy interventions on DR-TB detection.Results:Three prefectures in Jiangsu introduced DR-TB related interventions between 2008 and 2010 in partnership with the Global Fund to Fight AIDS,Tuberculosis and Malaria(the Global Fund)and the Bill&Melinda Gates Foundation(Gates Foundation).By 2017,all prefectures in Jiangsu had implemented provincial level DR-TB policies,such as use of rapid molecular tests(RMT),and expanded drug susceptibility testing(DST)for populations at risk of DR-TB.The percentage of pulmonary TB cases con firmed by bacteriology in creased from 30.0%in 2013 to over 50.0%in all prefectures by 2019,indicating that the implementation of new diagnostics has provided more sensitive testing results than the traditional smear microscopy.At the same time,the proportion of bacteriologically confirmed cases tested for drug resistance has increased substantially,indicating that the intervention of expanding the coverage of DST has reached more of the population at risk of DR-TB.Prefectures that implemented interventions with support from the Global Fund and the Gates Foundation had better detection performance of DR-TB patiens compared to those did not receive external support.However,the disparities in DR-TB detection across prefectures significantly narrowed after the implementation of provinci展开更多
基金the financial support by the National Key R&D Program of China(2016YFA0501800 to YS)
文摘Protein neddylation is a post-translational modification which transfers the ubiquitin-like protein NEDD8 to a lysine residue of the target substrate through a three-step enzymatic cascade.The bestknown substrates of neddylation are cullin family proteins,which are the core component of Cullin-RING E3 ubiquitin ligases(CRLs).Given that cullin neddylation is required for CRL activity,and CRLs control the turn-over of a variety of key signal proteins and are often abnormally activated in cancers,targeting neddylation becomes a promising approach for discovery of novel anti-cancer therapeutics.In the past decade,we have witnessed significant progress in the field of protein neddylation from preclinical target validation,to drug screening,then to the clinical trials of neddylation inhibitors.In this review,we first briefly introduced the nature of protein neddylation and the regulation of neddylation cascade,followed by a summary of all reported chemical inhibitors of neddylation enzymes.We then discussed the structure-based targeting of protein-protein interaction in neddylation cascade,and finally the available approaches for the discovery of new neddylation inhibitors.This review will provide a focused,up-to-date and yet comprehensive overview on the discovery effort of neddylation inhibitors.
文摘背景:乳腺癌是女性最常见的恶性肿瘤之一,其发病率逐年上升且趋于年轻化,严重威胁女性生命健康,因此建立一个能够准确模拟体内肿瘤情况的理想乳腺癌模型显得尤为重要。类器官与体内来源的组织或器官高度相似,是一种新型的体外三维培养模型,近年来在各种恶性肿瘤的研究中备受研究人员的青睐。目的:综述乳腺癌类器官的研究进展及应用,以期为乳腺癌的个性化治疗提供新的研究途径。方法:第一作者以“类器官、乳腺癌类器官、肿瘤类器官、乳腺球、3D培养”“organoid,breast cancer organoids,cancer organoids,mammosphere,three-dimensional culture”为检索词,检索1980年1月至2020年2月CNKI、万方、PubMed数据库相关文献,文献类型不限,排除与文章研究目的无关及重复性的文献,最终纳入66篇文献进行综述分析。结果与结论:文章简要介绍了类器官技术,回顾了构建乳腺癌类器官模型的过程,总结了乳腺癌类器官最新研究进展及应用。乳腺癌类器官在疾病建模、肿瘤发生机制、药物筛选等方面有广泛应用前景,为乳腺癌研究和治疗提供了可靠的模型,特别是为乳腺癌个性化治疗开辟了新的视野。
基金supported by the National Natural Science Foundation of China,China(Grant Nos.:61801160 and 81730108).
文摘Glucose transporter 1(GLUT1)overexpression in tumor cells is a potential target for drug therapy,but few studies have reported screening GLUT1 inhibitors from natural or synthetic compounds.With current analysis techniques,it is difficult to accurately monitor the GLUT1 inhibitory effect of drug molecules in real-time.We developed a cell membrane-based glucose sensor(CMGS)that integrated a hydrogel electrode with tumor cell membranes to monitor GLUT1 transmembrane transport and screen for GLUT1 inhibitors in traditional Chinese medicines(TCMs).CMGS is compatible with cell membranes of various origins,including different types of tumors and cell lines with GLUT1 expression knocked down by small interfering RNA or small molecules.Based on CMGS continuous monitoring technique,we investigated the glucose transport kinetics of cell membranes with varying levels of GLUT1 expression.We used CMGS to determine the GLUT1-inhibitory effects of drug monomers with similar structures from Scutellaria baicalensis and catechins families.Results were consistent with those of the cellular glucose uptake test and molecular-docking simulation.CMGS could accurately screen drug molecules in TCMs that inhibit GLUT1,providing a new strategy for studying transmembrane protein-receptor interactions.
基金support from the National Natural Science Foundation of China(82072087,31970893,32270976)funding by Science and Technology Projects in Guangzhou(202206010087,China)。
文摘The ongoing coronavirus disease 2019(COVID-19) pandemic has boosted the development of antiviral research.Microfluidic technologies offer powerful platforms for diagnosis and drug discovery for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) diagnosis and drug discovery.In this review,we introduce the structure of SARS-CoV-2 and the basic knowledge of microfluidic design.We discuss the application of microfluidic devices in SARS-CoV-2 diagnosis based on detecting viral nucleic acid,antibodies,and antigens.We highlight the contribution of lab-on-a-chip to manufacturing point-ofcare equipment of accurate,sensitive,low-cost,and user-friendly virus-detection devices.We then investigate the efforts in organ-on-a-chip and lipid nanoparticles(LNPs) synthesizing chips in antiviral drug screening and mRNA vaccine preparation.Microfluidic technologies contribute to the ongoing SARSCoV-2 research efforts and provide tools for future viral outbreaks.
文摘核磁共振(nuclear magnetic resonance,NMR)是以原子核自旋的共振跃迁为探测对象的谱学方法.当自旋量子数不为零的原子核处于外磁场中时,会引起能级的Zeeman分裂.若再施加能量等于Zeeman能级差的射频场,则会诱发原子核自旋的共振跃迁,这种现象即为核磁共振.核自旋的共振频率与原子的类型有关,且受原子所处化学和物理环境的影响.此外,NMR能量较低,不会影响探测对象(常为分子)的状态.因此,NMR能够在无损条件下提供多种具有原子和分子分辨的物质组成、结构、形态、动态变化等丰富信息.
基金The study was partially funded by a research grant from Jiangsu Provincial Health Commissi on to support the tale nted researchers in the health sector.Dr.Xiao-Yan Ding,supported by the Jiangsu Health International Exchange Program,was a visiting fellow at Duke Global Health Institute,when she was working on this manuscript.
文摘Background:The detection of drug-resistant tuberculosis(DR-TB)is a major health concern in China.We aim to summarize interventions related to the screening and detection of DR-TB in Jiangsu Province,analyse their impact,and highlight policy implications for improving the prevention and control of DR-TB.Methods:We selected six prefectures from south,central and no「th Jiangsu Province.We reviewed policy documents between 2008 and 2019,and extracted routineTB patient registration data from theTB Information Management System(TBIMS)between 2013 and 2019.We used the High-quality Health System Framework to structure the analysis.We performed statistical analysis and logistic regression to assess the impact of different policy interventions on DR-TB detection.Results:Three prefectures in Jiangsu introduced DR-TB related interventions between 2008 and 2010 in partnership with the Global Fund to Fight AIDS,Tuberculosis and Malaria(the Global Fund)and the Bill&Melinda Gates Foundation(Gates Foundation).By 2017,all prefectures in Jiangsu had implemented provincial level DR-TB policies,such as use of rapid molecular tests(RMT),and expanded drug susceptibility testing(DST)for populations at risk of DR-TB.The percentage of pulmonary TB cases con firmed by bacteriology in creased from 30.0%in 2013 to over 50.0%in all prefectures by 2019,indicating that the implementation of new diagnostics has provided more sensitive testing results than the traditional smear microscopy.At the same time,the proportion of bacteriologically confirmed cases tested for drug resistance has increased substantially,indicating that the intervention of expanding the coverage of DST has reached more of the population at risk of DR-TB.Prefectures that implemented interventions with support from the Global Fund and the Gates Foundation had better detection performance of DR-TB patiens compared to those did not receive external support.However,the disparities in DR-TB detection across prefectures significantly narrowed after the implementation of provinci
