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Resolving the geometric structure of trastuzumab by mobility capillary electrophoresis and native mass spectrometry

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Chinese Chemical Letters 2024年第3期35卷 221-225页

作者： Wenjing Zhang Jie Hong Lei Yang Zuqiang Xu Yu Xiang Wei Xu School of life science Beijing Institute of TechnologyBeijing 100081China

Available online Immunoglobulins G(IgGs)are Y-shaped globular proteins,however,their high flexibility and heterogeneity pose great challenges to their structure and conformation determinations.Geometric structure of IgG closely correlates to its biofunctions,such as the antibody escape of human immunodeficiency virus(HIV)could attribute to the distance mismatch between the ends of two Fab arms(antigen-binding sites)and envelope glycoprotein spikes on virion surface.Herein,we report the first use of mobility capillary electrophoresis(MCE)and native mass spectrometry(nMS)to resolve the internal geometric structure and conformation of an IgG(trastuzumab)in solution phase.After proteolysis,the ellipsoid dimensions of IgG and its subunits were measured by MCE-nMS experiments.IgG was then reconstructed,in which the sizes and relative positions of these three subunits in three-dimensional space were characterized.It was found that the two Fab arms have an angle of~102.1°and a distance of~11.0 nm between the two antigen-binding sites under native condition,and the Fc arm was tilted~16.0°towards one of the Fab arms.Fc was not on the plane of Fab-Fab,but has an angle of no larger than 103.1°.Under acidic environment(pH 3.0),each subunit of the IgG would unfold into larger dimensions,and the angles between these subunits also change.With great potential for tumor imaging and therapy,the structure of F(ab')_(2)fragments was also measured and validated by molecular dynamic simulation.It was found that the electrostatic force among these three subunits and steric hindrance stemming from Fc help maintaining the angle between two Fab arms.

关键词： Native mass spectrometry Mobility capillary electrophoresis Trastuzumab Protein structure Geometric structure

A novel alternative for pyrogen detection based on a transgenic cell line

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1221-1229页

作者： Qing He Chuan-Fei Yu Gang Wu Kai-Qin Wang Yong-Bo Ni Xiao Guo Zhi-Hao Fu Lan Wang De-Jiang Tan Hua Gao Can Wang Gang Chen Xu-Hong Chen Bo Chen Jun-Zhi Wang National institutes for Food and Drug Control BeijingChina School of life science and Biopharmaceutics Shenyang Pharmaceutical UniversityShenyangChina Shanghai Institute for Food and Drug Control ShanghaiChina KeyMed Biosciences Inc. ChengduChina

Pyrogen,often as a contaminant,is a key indicator affecting the safety of almost all parenteral drugs(including biologicals,chemicals,traditional Chinese medicines and medical devices).It has become a goal to completely replace the in vivo rabbit pyrogen test by using the in vitro pyrogen test based on the promoted‘reduction,replacement and refinement’principle,which has been highly considered by regulatory agencies from different countries.We used NF-κB,a central signalling molecule mediating inflammatory responses,as a pyrogenic marker and the monocyte line THP-1 transfected with a luciferase reporter gene regulated by NF-κB as an in vitro model to detect pyrogens by measuring the intensity of a fluorescence signal.Here,we show that this test can quantitatively and sensitively detect endotoxin(lipopolysaccharide from different strains)and nonendotoxin(lipoteichoic acid,zymosan,peptidoglycan,lectin and glucan),has good stability in terms of NF-κB activity and cell phenotypes at 39 cell passages and can be applied to detect pyrogens in biologicals(group A&C meningococcal polysaccharide vaccine;basiliximab;rabies vaccine(Vero cells)for human use,freeze-dried;Japanese encephalitis vaccine(Vero cells),inactivated;insulin aspart injection;human albumin;recombinant human erythropoietin injection(CHO Cell)).The within-laboratory reproducibility of the test in three independent laboratories was 85%,80%and 80%and the interlaboratory reproducibility among laboratories was 83.3%,95.6%and 86.7%.The sensitivity(true positive rate)and specificity(true negative rate)of the test were 89.9%and 90.9%,respectively.In summary,the test provides a novel alternative for pyrogen detection.

关键词： pyrogen rabbit replace

A mix & act liposomes of phospholipase A2-phosphatidylserine for acute brain detoxification by blood‒brain barrier selective-opening

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1827-1844页

作者： Zinan Zhang Wenbin Cao Huanchun Xing Shuai Guo Lijuan Huang Lin Wang Xin Sui Kui Lu Yuan Luo Yongan Wang Jun Yang State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institutes of Pharmacology and ToxicologyBeijing 100850China Tianjin University of science and Technology Tianjin 300222China Hebei University of science and Technology Shijiazhuang 050018China

In the treatment of central nervous system disease,the blood-brain barrier(BBB)is a major obstruction to drug delivery that must be overcome.In this study,we propose a brain-targeted delivery strat-egy based on selective opening of the BBB.This strategy allows some simple bare nanoparticles to enter the brain when mixed with special opening material;however,the BBB still maintains the ability to completely block molecules from passing through.Based on the screening of BBB opening and matrix delivery mate-rials,we determined that phospholipase A2-catalyzed 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine li-posomes can efficiently carry drugs into the brain immediately.At an effective dose,this delivery system is safe,especially with its effect on the BBB being reversible.This mix&act delivery system has a simple structure and rapid preparation,making it a strong potential candidate for drug delivery across the BBB.

关键词： Liposomes Phospholipase A2 Phosphoserine Blood-brainbarrier Selectively open Mix&act

Applications and grants of the National Natural science Foundation of China's General Program and Young Scientists Fund in immunology research:a 10-year review(2013–2022)

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science China(life sciences) 2024年第6期67卷 1321-1324页

作者： Baoman Li Yanyan Tian Puyue Wang Department of life sciences National Natural Science Foundation of ChinaBeijing 100085China

Immunology,a biomedical discipline with an ancient history of maintaining thriving research vitality to date,refers to the study of the structure and function of the immune system of the body,the pathogenesis of immune-related diseases,immunological diagnoses,and prevention mechanisms(National Natural science Foundation of China,2023).Immunological research is the foundation of research in biology,as well as basic and clinical medicine(Kubli et al.,2021).

关键词： prevention Foundation Natural

A neural m^(6)A pathway regulates behavioral aggregation in migratory locusts

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science China(life sciences) 2024年第6期67卷 1242-1254页

作者： Xianliang Huang Qing Li Yanan Xu Ang Li Shanzheng Wang Yusheng Chen Chunrui Zhang Xia Zhang Hailin Wang Cong Lv Baofa Sun Shaoqin Li Le Kang Bing Chen School of life science Institutes of Life Science and Green DevelopmentHebei UniversityBaoding 071002China College of Plant science and Technology Huazhong Agricultural UniversityWuhan 430070China State Key Laboratory of Integrated Management of Pest Insects and Rodents Institute of ZoologyChinese Academy of SciencesBeijing 100101China Institute of Health sciences Anhui UniversityHefei 230601China beijing Institute of Genomics Chinese Academy of SciencesBeijing 100101China State Key Laboratory of Environmental Chemistry and Ecotoxicology Research Center for Eco-Environmental SciencesChinese Academy of SciencesBeijing100101China

RNA N6-methyladenosine(m^(6)A),as the most abundant modification of messenger RNA,can modulate insect behaviors,but its specific roles in aggregation behaviors remain unexplored.Here,we conducted a comprehensive molecular and physiological characterization of the individual components of the methyltransferase and demethylase in the migratory locust Locusta migratoria.Our results demonstrated that METTL3,METTL14 and ALKBH5 were dominantly expressed in the brain and exhibited remarkable responses to crowding or isolation.The individual knockdown of methyltransferases(i.e.,METTL3 and METTL14)promoted locust movement and conspecific attraction,whereas ALKBH5 knockdown induced a behavioral shift toward the solitary phase.Furthermore,global transcriptome profiles revealed that m^(6)A modification could regulate the orchestration of gene expression to fine tune the behavioral aggregation of locusts.In summary,our in vivo characterization of the m^(6)A functions in migratory locusts clearly demonstrated the crucial roles of the m^(6)A pathway in effectively modulating aggregation behaviors.

关键词： RNA methylation N^(6)-methyladenosine transcriptional orchestration aggregation behavior Locusta migratoria

Determining an optimal control strategy for anthropogenic VOC emissions in China based on source emissions and reactivity

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Journal of Environmental sciences 2024年第2期136卷 248-260页

作者： Ruipeng Wang Xiaoqi Wang Shuiyuan Cheng Jiaxian Zhu Xinyu Zhang Long Cheng Kai Wang Key Laboratory of beijing on Regional Air Pollution Control Faculty of Environment and LifeBeijing University of TechnologyBeijing 100124China

An evidence-based control strategy for emission reduction of VOC sources can effectively solve the regional PM2.5and O3compound pollution in China.We estimated the anthropogenic VOC emission inventory in China in 2018 and established a source profile database containing 129 sources based on localized detection and the latest research results.Then,the distribution of the ozone formation potential(OFP)and secondary organic aerosol formation potential(SOAFP)for emission sources was analyzed.Moreover,priority control routes for VOC emission sources were proposed for different periods.Anthropogenic VOC emissions in China reached 27,211.8 Gg in 2018,and small passenger cars,industrial protective coatings,biomass burning,heavy trucks,printing,asphalt paving,oil storage and transportation,coking,and oil refining were the main contributors.Industrial protective coatings,small passenger cars,and biomass burning all contributed significantly to OFP and SOAFP.Priority in emission reduction control should be given to industrial protective coatings,small passenger cars,heavy trucks,coking,printing,asphalt paving,chemical fibers,and basic organic chemical sources over the medium and long term in China.In addition,the priority control route for VOC emission sources should be adjusted according to the variations in VOC emission characteristics and regional differences,so as to obtain the maximum environmental benefits.

关键词： Volatile organic compounds Anthropogenic emission inventory Reactivity Emission projection Priority control route

Lactate metabolism in neurodegenerative diseases

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Neural Regeneration Research 2024年第1期19卷 69-74页

作者： Chaoguang Yang Rui-Yuan Pan Fangxia Guan Zengqiang Yuan The Brain science Center Beijing Institute of Basic Medical SciencesBeijingChina School of life sciences Zhengzhou UniversityZhengzhouHenan ProvinceChina

Lactate,a byproduct of glycolysis,was thought to be a metabolic waste until the discovery of the Warburg effect.Lactate not only functions as a metabolic substrate to provide energy but can also function as a signaling molecule to modulate cellular functions under pathophysiological conditions.The Astrocyte-Neuron Lactate Shuttle has cla rified that lactate plays a pivotal role in the central nervous system.Moreover,protein lactylation highlights the novel role of lactate in regulating transcription,cellular functions,and disease development.This review summarizes the recent advances in lactate metabolism and its role in neurodegenerative diseases,thus providing optimal pers pectives for future research.

关键词： Alzheimer's disease Astrocyte-Neuron Lactate Shuttle brain central nervous system glucose metabolism glycolysis neuroinflammation Parkinson's disease protein lactylation signaling molecule

The autophagy protein Atg9 functions in glia and contributes to parkinsonian symptoms in a Drosophila model of Parkinson’s disease

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Neural Regeneration Research 2024年第5期19卷 1150-1155页

作者： Shuanglong Yi Linfang Wang Margaret S.Ho Shiping Zhang School of life science and Technology ShanghaiTech UniversityShanghaiChina College of life sciences University of Chinese Academy of SciencesBeijingChina

Parkinson’s disease is a progressive neurodegenerative disease characterized by motor deficits,dopaminergic neuron loss,and brain accumulation ofα-synuclein aggregates called Lewy bodies.Dysfunction in protein degradation pathways,such as autophagy,has been demonstrated in neurons as a critical mechanism for eliminating protein aggregates in Parkinson’s disease.However,it is less well understood how protein aggregates are eliminated in glia,the other cell type in the brain.In the present study,we show that autophagy-related gene 9(Atg9),the only transmembrane protein in the autophagy machinery,is highly expressed in Drosophila glia from adult brain.Results from immunostaining and live cell imaging analysis reveal that a portion of Atg9 localizes to the trans-Golgi network,autophagosomes,and lysosomes in glia.Atg9 is persistently in contact with these organelles.Lacking glial atg9 reduces the number of omegasomes and autophagosomes,and impairs autophagic substrate degradation.This suggests that glial Atg9 participates in the early steps of autophagy,and hence the control of autophagic degradation.Importantly,loss of glial atg9 induces parkinsonian symptoms in Drosophila including progressive loss of dopaminergic neurons,locomotion deficits,and glial activation.Our findings identify a functional role of Atg9 in glial autophagy and establish a potential link between glial autophagy and Parkinson’s disease.These results may provide new insights on the underlying mechanism of Parkinson’s disease.

关键词： Atg9 autophagy glia Parkinson’s disease

Overexpression of wild-type HRAS drives non-alcoholic steatohepatitis to hepatocellular carcinoma in mice

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Zoological Research 2024年第3期45卷 551-566页

作者： Chen Ling Su-Su Liu Yu-Ya Wang Gui-Tao Huo Yan-Wei Yang Nan Xu Hong Wang Yong Wu Yu-Fa Miao Rui Fu Yu-Wei Zhao Chang-Fa Fan College of life sciences Northwest UniversityProvincial Key Laboratory of Biotechnology of Shaanxi ProvinceXi’anShaanxi 710069China Division of Animal Model Research Institute for Laboratory Animal ResourcesNational Institutes for Food and Drug Control(NIFDC)Beijing 102629China National Center for Safety Evaluation of Drugs National Institutes for Food and Drug Control(NIFDC)Beijing 100176China Division of HIV/AIDS and Sexually Transmitted Virus Vaccines Institute for Biological Products ControlNational Institutes for Food and Drug Control(NIFDC)Beijing 102629China Division of Laboratory Animal Monitoring Institute for Laboratory Animal ResourcesNational Institutes for Food and Drug Control(NIFDC)Beijing 102629China

Hepatocellular carcinoma(HCC),a prevalent solid carcinoma of significant concern,is an aggressive and often fatal disease with increasing global incidence rates and poor therapeutic outcomes.The etiology and pathological progression of non-alcoholic steatohepatitis(NASH)-related HCC is multifactorial and multistage.However,no single animal model can accurately mimic the full NASH-related HCC pathological progression,posing considerable challenges to transition and mechanistic studies.Herein,a novel conditional inducible wild-type human HRAS overexpressed mouse model(HRAS-HCC)was established,demonstrating 100%morbidity and mortality within approximately one month under normal dietary and lifestyle conditions.Advanced symptoms of HCC such as ascites,thrombus,internal hemorrhage,jaundice,and lung metastasis were successfully replicated in mice.In-depth pathological features of NASH-related HCC were demonstrated by pathological staining,biochemical analyses,and typical marker gene detections.Combined murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival,further confirming the accuracy and reliability of the model.Based on protein-protein interaction(PPI)network and RNA sequencing analyses,we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis,with subsequent progression to HCC.Collectively,our study successfully duplicated natural sequential progression in a single murine model over a very short period,providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.

关键词： HRAS THBS1 HCC driver factor NASH Fibrosis Cirrhosis HCC Treatment evaluation