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Unmodified methodologies in target discovery for small molecule drugs:A rising star

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Chinese Chemical Letters 2022年第12期33卷 4980-4988页

作者： Jiayue Tang Meng Ou qiuling zheng Ya Ding Key Laboratory of Drug Quality Control and Pharmacovigilance Ministry of EducationChina Pharmaceutical UniversityNanjing 210009China State Key Laboratory of Natural Medicines Department of Pharmaceutical AnalysisCollege of PharmacyChina Pharmaceutical UniversityNanjing 210009China

Target discovery,involving target identification and validation,is the prerequisite for drug discovery and *** methodologies and technologies for the precise discovery and confirmation of drug targets are powerful tools in understanding the disease,looking for a drug and elucidating the mechanism of drug *** the common target identification and confirmation methods,the modified method is time-consuming and laborious,which may reduce or change the activity of natural *** unmodified methods developed in recent years without chemical modification have gradually become an important means of studying drug targets.A wide range of unmodified approaches have been reported,introducing and analyzing the recent emerging methodologies and *** review highlights the advantages and limitations of these methods for the application of drug target discovery and presents an overview of their contributions to the target discovery of small molecule *** application and future development trends of methodologies in target discovery are also prospected to provide a reference for drug target research.

关键词： Target discovery Target identification Small molecule drug Methodologies Unmodified

Drug target discovery by magnetic nanoparticles coupled mass spectrometry

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Journal of Pharmaceutical Analysis 2021年第1期11卷 122-127页

作者： Dandan Xia Baoling Liu Xiaowei Xu Ya Ding qiuling zheng Department of Pharmaceutical Analysis School of PharmacyChina Pharmaceutical UniversityNanjing210009China State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing210009China Key Laboratory of Drug Metabolism and Pharmacokinetics China Pharmaceutical UniversityNanjing210009China

Drug target discovery is the basis of drug *** elucidates the cause of disease and the mechanism of drug action,which is the essential of drug *** discovery performed in biological systems is complicated as proteins are in low abundance and endogenous compounds may interfere with drug ***,methods to track drug-target interactions in biological matrices are urgently *** this work,a Fe_(3)O_(4) nanoparticle-based approach was developed for drug-target screening in biofluids.A known ligand-protein complex was selected as a principle-to-proof example to validate the *** incubation in cell lysates,ligand-modified Fe_(3)O_(4) nanoparticles bound to the target protein and formed complexes that were separated from the lysates by a magnet for further *** large surface-to-volume ratio of the nanoparticles provides more active sites for the modification of chemical *** enhances the opportunity for ligand-protein interactions,which is beneficial for capturing target proteins,especially for those with low ***,a one-step magnetic separation simplifies the pre-processing of ligand-protein complexes,so it effectively reduces the endogenous ***,the present nanoparticle-based approach has the potential to be used for drug target screening in biological systems.

关键词： Drug-target discovery Nanoparticle Mass spectrometry

Hydrogen selenide,a vital metabolite of sodium selenite,uncouples the sulfilimine bond and promotes the reversal of liver fibrosis

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Science China(Life Sciences) 2021年第3期64卷 443-451页

作者： Dongrui Luan Zengteng Zhao Dandan Xia qiuling zheng Xiaonan Gao Kehua Xu Bo Tang College of Chemistry Chemical Engineering and Materials ScienceCollaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of ShandongKey Laboratory of Molecular and Nano ProbesMinistry of EducationInstitute of Molecular and Nano ScienceShandong Normal UniversityJinan 250014China Department of Pharmaceutical Analysis School of PharmacyState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China

Sodium selenite has alleviating effects on liver fibrosis;however,its therapeutic molecular mechanism remains ***,hydrogen selenide,a major metabolite of Na_(2)SeO_(3),was tested to uncouple the sulfilimine bond in collagen IV,the biomarker of liver fibrosis.A mouse model of liver fibrosis was constructed via a CCl_(4)-induced method,followed by the administration of 0.2 mg kg−1 Na_(2)SeO_(3)via gavage three times per week for 4 *** in H2Se,NADPH,and H_(2)O_(2)levels were monitored in real time by using NIR-H2Se,DCI-MQ-NADPH,and H_(2)O_(2)probes in vivo,respectively.H_(2)Se continuously accumulated in the liver throughout the Na_(2)SeO_(3)treatment period,but the levels of NADPH and H_(2)O_(2)*** expression of collagen IV was analyzed through Western blot and liquid chromatography-mass *** confirmed that the sulfilimine bond of collagen IV in the fibrotic mouse livers could be broken by H2Se with the Na_(2)SeO_(3)***,the therapeutic effect of Na_(2)SeO_(3)on liver fibrosis could be mainly attributed to H_(2)Se that uncoupled the sulfilimine bond to induce collagen IV *** study provided a reasonable explanation for the molecular mechanism of the in vivo function of Na_(2)SeO_(3)and the prevention of liver fibrosis by administering inorganic selenium.

关键词： hydrogen selenide sodium selenite sulfilimine bond liver fibrosis reversal collagen IV

Protocatechuic aldehyde protects cardiomycoytes against ischemic injury via regulation of nuclear pyruvate kinase M2

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Acta Pharmaceutica Sinica B 2021年第11期11卷 3553-3566页

作者： Xunxun Wu Lian Liu qiuling zheng Haiping Hao Hui Ye Ping Li Hua Yang State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China College of Pharmacy China Pharmaceutical UniversityNanjing 210009China Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics China Pharmaceutical UniversityNanjing 210009China

Rescuing cells from stress damage emerges a potential therapeutic strategy to combat myocardial *** aldehyde(PCA)is a major phenolic acid in Chinese herb Danshen(Salvia miltiorrhiza root).This study investigated whether PCA regulated nuclear pyruvate kinase isoform M2(PKM2)function to protect *** rats subjected to isoprenaline,PCA attenuated heart injury and protected cardiomyocytes from *** DARTS and CETSA assays,we identified that PCA bound and promoted PKM2 nuclear translocation in cardiomyocytes exposed to oxygen/glucose deprivation(OGD).In the nucleus,PCA increased the binding of PKM2 to β-Catenin via preserving PKM2 acetylation,and the complex,in cooperation with T-cell factor 4(TCF4),was required for transcriptional induction of genes encoding anti-apoptotic proteins,contributing to rescuing cardiomyocyte *** addition,PCA ameliorated mitochondrial dysfunction and prevented mitochondrial apoptosis dependent on ***,PCA increased the binding of PKM2 to β-Catenin,improved heart contractive function,normalized heart structure and attenuated oxidative damage in mice subjected to artery ligation,but the protective effects were lost in Pkm2-deficient ***,we showed that PCA regulated nuclear PKM2 function to rescue cardiomyocyte survival via β-Catenin/TCF4 signaling cascade,suggesting the potential of pharmacological intervention of PKM2 shuttle to protect the heart.

关键词： Protocatechuic aldehyde PKM2 β-Catenin TCF4 Heart ischemia Myocardial infarction Apoptosis Mitochondrial damage Nuclear translocation

Dihydrotanshinone I preconditions myocardium against ischemic injury via PKM2 glutathionylation sensitive to ROS

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Acta Pharmaceutica Sinica B 2023年第1期13卷 113-127页

作者： Xunxun Wu Lian Liu qiuling zheng Hui Ye Hua Yang Haiping Hao Ping Li State Key Laboratory of Natural Medicines Department of PharmacognosySchool of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjing 210009China College of Pharmacy China Pharmaceutical UniversityNanjing 210009China State Key Laboratory of Natural Medicines Jiangsu Provincial Key Laboratory of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjing 210009China

Ischemic preconditioning(IPC)is a potential intervention known to protect the heart against ischemia/reperfusion injury,but its role in the no-reflow phenomenon that follows reperfusion is *** I(DT)is a natural compound and this study illustrates its role in cardiac ischemic injury from the aspect of *** with DT induced modest ROS production and protected cardiomyocytes against oxygen and glucose deprivation(OGD),but the protection was prevented by a ROS *** addition,DT administration protected the heart against isoprenaline ***,PKM2 reacted to transient ROS via oxidization at Cys423/Cys424,leading to glutathionylation and nuclear translocation in dimer *** the nucleus,PKM2 served as a co-factor to promote HIF-1a-dependent gene induction,contributing to adaptive *** mice subjected to permanent coronary ligation,cardiac-specific knockdown of Pkm2 blocked DT-mediated preconditioning protection,which was rescued by overexpression of wild-type Pkm2,rather than Cys423/424-mutated *** conclusion,PKM2 is sensitive to oxidation,and subsequent glutathionylation promotes its nuclear *** IPC has been viewed as a protective means against reperfusion injury,our study reveals its potential role in protection of the heart from no-reflow ischemia.

关键词： Dihydrotanshinone I Ischemic preconditioning PKM2 Glutathionylation Myocardial ischemia ROS Oxidation modification Nuclear translocation

The haplotype-resolved T2T genome of teinturier cultivar Yan73 reveals the genetic basis of anthocyanin biosynthesis in grapes

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Horticulture Research 2023年第11期10卷 180-192页

作者： Kekun Zhang Mengrui Du Hongyan Zhang Xiaoqian Zhang Shuo Cao Xu Wang Wenrui Wang Xueqiang Guan Penghui Zhou Jin Li Wenguang Jiang Meiling Tang qiuling zheng Muming Cao Yongfeng Zhou Keqin Chen Zhongjie Liu Yulin Fang College of Enology Heyang Viti-Viniculture StationNingxia Helan Mountain’s East Foothill Wine Experiment and Demonstration StationNorthwest A&F UniversityYangling 712100China National Key Laboratory of Tropical Crop Breeding Shenzhen BranchGuangdong Laboratory of Lingnan Modern AgricultureKey Laboratory of Synthetic BiologyMinistry of Agriculture and Rural AffairsAgricultural Genomics Institute at ShenzhenChinese Academy of Agricultural SciencesShenzhen518120China College of Agriculture Shanxi Agricultural UniversityTaigu 030801China Shandong Grape Research Institute Shanda South RoadJinan 250199China Shandong Technology Innovation Center of Wine Grape and Wine COFCO Great Wall Wine(Penglai)Co.Ltd.Yantai 265600China Yantai Changyu Group Co. Ltd.Yantai 264001China Yantai Academy of Agricultural Sciences Gangcheng West StreetYantai 264000China Viticulture and Wine Research Institute Guangxi Academy of Agricultural SciencesNanning 530007China National Key Laboratory of Tropical Crop Breeding Tropical Crops Genetic Resources InstituteChinese Academy of Tropical Agricultural SciencesHaikou 570100China

Teinturier grapes are characterized by the typical accumulation of anthocyanins in grape skin,flesh,and vegetative tissues,endowing them with high utility value in red wine blending and nutrient-enriched foods ***,due to the lack of genome information,the mechanism involved in regulating teinturier grape coloring has not yet been elucidated and their genetic utilization research is still ***,the cultivar‘Yan73’was used for assembling the telomere-to-telomere(T2T)genome of teinturier grapes by combining the High Fidelity(HiFi),Hi-C and ultralong Oxford Nanopore Technologies(ONT)*** haplotype genomes were assembled,at the sizes of 501.68 Mb and 493.38 Mb,*** the haplotype 1 genome,the transposable elements(TEs)contained 32.77%of long terminal repeats(LTRs),while in the haplotype 2 genome,31.53%of LTRs were detected in ***,obvious inversions were identified in chromosome 18 between the two *** profiling suggested that the gene expression patterns in‘Cabernet Sauvignon’and‘Yan73’were diverse depending on tissues,developmental stages,and *** transcription program of genes in the anthocyanins biosynthesis pathway between the two cultivars exhibited high similarity in different tissues and developmental stages,whereas the expression levels of numerous genes showed significant *** with other genes,the expression levels of VvMYBA1 and VvUFGT4 in all samples,VvCHS2 except in young shoots and VvPAL9 except in the E-L23 stage of‘Yan73’were higher than those of‘Cabernet Sauvignon’.Further sequence alignments revealed potential variant gene loci and structure variations of anthocyanins biosynthesis related genes and a 816 bp sequence insertion was found in the promoter of VvMYBA1 of‘Yan73’haplotype 2 ***‘Yan73’T2T genome assembly and comparative analysis provided valuable foundations for further revealing the coloring mechanism of teinturier grapes and the genetic imp

关键词： coloring resolved similarity

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开展转供电加价清理的工作举措分析

大众用电 2021年第4期37卷 15-16页

作者：段妤郑秋菱国网长沙供电公司

1当前的政策形势转供电加价清理是2021年政府工作报告中明确的推进一般工商业降价的重要举措,纳入营商环境整治项目,是今年各级价格监管部门监控检查的重点。从3月起,湖南省各级市场监管局对转供电主体开展检查,7月湖南省将迎接国家市... 详细信息

1当前的政策形势转供电加价清理是2021年政府工作报告中明确的推进一般工商业降价的重要举措,纳入营商环境整治项目,是今年各级价格监管部门监控检查的重点。从3月起,湖南省各级市场监管局对转供电主体开展检查,7月湖南省将迎接国家市场监管局的水电气专项检查,转供电加价清理也在其中。2存在的突出问题2.1突出问题从一线员工、班组长至管理层对转供电加价清理工作存在认识偏差。

关键词：一线员工转供电营商环境政府工作报告认识偏差整治项目专项检查班组长

棚架下垂叶幕与水平叶幕对香百川葡萄叶片光合特性的影响

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果树学报 2022年第2期39卷 193-202页

作者：范东英王浩傅彩琦郑秋玲高振康慧杜远鹏山东农业大学园艺科学与工程学院·作物生物学国家重点实验室·山东果蔬优质高效生产协同创新中心山东泰安271018

【目的】比较棚架下垂叶幕和水平叶幕下葡萄叶片臭氧伤害状况以及对光合性能的影响。【方法】以5年生的葡萄品种香百川为试材,利用臭氧监测仪监测7—9月份栽培环境中臭氧浓度,采用CIRAS-3便携式光合作用测定仪和Handy PEA测定2种叶幕叶... 详细信息

【目的】比较棚架下垂叶幕和水平叶幕下葡萄叶片臭氧伤害状况以及对光合性能的影响。【方法】以5年生的葡萄品种香百川为试材,利用臭氧监测仪监测7—9月份栽培环境中臭氧浓度,采用CIRAS-3便携式光合作用测定仪和Handy PEA测定2种叶幕叶片的净光合速率和荧光特性。【结果】下垂叶幕缓解了臭氧伤害情况,其主梢叶片发生臭氧伤害的比例在6月和7月均低于水平叶幕。成熟期时下垂叶幕主副梢叶片叶绿素总含量均显著高于水平叶幕。下垂叶幕主梢中部功能叶片净光合速率在转色期和成熟期分别高于水平叶幕13%~56%和28%~99%。水平叶幕的PSⅡ最大光化学量子产量(F_(v)/F_(m))在转色期时比下垂叶幕低3.08%;水平叶幕叶片单位面积内有活性反应中心的数量(RC/CS_(m))与反应中心吸收的光能用于电子传递的量子产额(φ_(Eo))在转色期和成熟期均显著低于下垂叶幕;水平叶幕J点相对可变荧光(V_(j))与用(F_(m)–F_(o))进行标准化后K点相对可变荧光(W_(k))在转色期和成熟期时均高于下垂叶幕,其PSⅡ受体侧及放氧复合体受到的伤害程度更高。【结论】棚架下垂叶幕减少了强光直射时间,从而缓解了臭氧对PSⅡ的伤害,增加了叶片的叶绿素含量和叶片净光合速率。

关键词：葡萄叶幕类型臭氧光合特性

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论“理解教育”的价值及应用策略

江苏教育研究 2019年第31期 8-11页

作者：韩加强郑秋玲天府第七中学成都610200 成都市龙泉驿区柏合九年制学校成都610100

“理解教育”是一种以“理解”为教育基础并以“理解”为教育目的的教育方法,是提升教育教学效果的重要手段,是构建和谐师生关系的重要纽带,是建设社会主义和谐社会的重要基石。地位平等是理解教育的基本原则,相互信任是理解教育的基本... 详细信息

“理解教育”是一种以“理解”为教育基础并以“理解”为教育目的的教育方法,是提升教育教学效果的重要手段,是构建和谐师生关系的重要纽带,是建设社会主义和谐社会的重要基石。地位平等是理解教育的基本原则,相互信任是理解教育的基本前提,耐心陪伴是理解教育的重要过程,善于倾听是理解教育的基本习惯,家校合作是理解教育的基本保障,行为示范是理解教育的基本手段。

关键词：理解教育师生关系全面发展核心素养