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TREM-1 mediates interaction between substantia nigra microglia and peripheral neutrophils

Neural Regeneration Research 2024年第6期19卷 1375-1384页

作者： Tong Shen Guiyun Cui Hao Chen Long Huang Wei Song Jie Zu Wei Zhang Chuanying Xu Liguo Dong Yongmei Zhang Jiangsu Province key laboratory of Anesthesiology Xuzhou Medical University Jiangsu Province key laboratory of Anesthesia and Analgesia Application Technology Xuzhou Medical University NMPA key laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs Department of Neurology The Affiliated Hospital of Xuzhou Medical University

Microglia-mediated neuroinflammation is considered a pathological feature of Parkinson’s disease. Triggering receptor expressed on myeloid cell-1(TREM-1) can amplify the inherent immune response, and crucially, regulate inflammation. In this study, we found marked elevation of serum soluble TREM-1 in patients with Parkinson’s disease that positively correlated with Parkinson’s disease severity and dyskinesia. In a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease, we found that microglial TREM-1 expression also increased in the substantia nigra. Further, TREM-1 knockout alleviated dyskinesia in a mouse model of Parkinson’s disease and reduced dopaminergic neuronal injury. Meanwhile, TREM-1 knockout attenuated the neuroinflammatory response, dopaminergic neuronal injury, and neutrophil migration. Next, we established an in vitro 1-methyl-4-phenyl-pyridine-induced BV2 microglia model of Parkinson’s disease and treated the cells with the TREM-1 inhibitory peptide LP17. We found that LP17 treatment reduced apoptosis of dopaminergic neurons and neutrophil migration. Moreover, inhibition of neutrophil TREM-1 activation diminished dopaminergic neuronal apoptosis induced by lipopolysaccharide. TREM-1 can activate the downstream CARD9/NF-κB proinflammatory pathway via interaction with SYK. These findings suggest that TREM-1 may play a key role in mediating the damage to dopaminergic neurons in Parkinson’s disease by regulating the interaction between microglia and peripheral neutrophils.

关键词： 1-methyl-4-phenylpyridiniumion dopaminergic neurons infiltration 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine microglia neutrophils neuroinflammation Parkinson's disease SYK TREM-1

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Scalable synthesis of lipid nanoparticles for nucleic acid drug delivery using an isometric channel-size enlarging strategy

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Nano Research 2024年第4期17卷 2899-2907页

作者： Zesen Ma Haiyang Tong Sijin Lin Li Zhou Demeng Sun Baoqing Li Changlin Tian Jiaru Chu Department of Precision Machinery and Precision Instrumentation University of Science and Technology of ChinaHefei 230027China key laboratory of Precision Scientific Instrumentation of Anhui Higher Education Institutes University of Science and Technology of ChinaHefei 230027China Science Island Branch Graduate SchoolUniversity of Science and Technology of ChinaHefei 230026China Anhui Provincial key laboratory of High Field Magnetic Resonance Imaging High Magnetic Field LaboratoryHefei Institute of Physical ScienceChinese Academy of SciencesHefei 230031China Anhui Provincial Engineering laboratory of peptide Drugs University of Science and Technology of ChinaHefei 230027China School of Biomedical Engineering Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaSuzhou 215127China

Lipid nanoparticles(LNPs)have emerged as highly effective delivery systems for nucleic acid-based ***,the broad clinical translation of LNP-based drugs is hampered by the lack of robust and scalable synthesis techniques that can consistently produce formulations from early development to clinical *** this work,we proposed a method to achieve scalable synthesis of LNPs by scaling inertial microfluidic mixers isometrically in three ***,a theoretical predictive method,which controls the mixing time to be equal across different chips,is developed to ensure consistent particle size and size distribution of the synthesized *** loaded with small interfering RNA(siRNA)were synthesized at different flow rates,exhibiting consistent physical properties,including particle size,size distribution and encapsulation *** work provides a practical approach for scalable synthesis of LNPs consistently,offering the potential to accelerate the transition of nucleic acid drug development into clinical application.

关键词： lipid nanoparticles nucleic acid delivery microfluidics scalable synthesis consistent particle size

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CA IX-targeted Ag_(2)S quantum dots bioprobe for NIR-II imaging-guided hypoxia tumor chemo-photothermal therapy

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Journal of Pharmaceutical Analysis 2024年第6期14卷 878-888页

作者： Xinyue Cui Zhuang Hu Ruihan Li Peng Jiang Yongchang Wei Zilin Chen Department of Radiation and Medical Oncology Zhongnan Hospital of Wuhan University and School of Pharmaceutical SciencesWuhan UniversityWuhan430071China key laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of EducationHubei Province Engineering and Technology Research Center for Fluorinated PharmaceuticalsWuhan430071China

Hypoxia is the common characteristic of almost all solid tumors,which prevents therapeutic drugs from reaching the ***,the development of new targeted agents for the accurate diagnosis of hypoxia tumors is widely *** carbonic anhydrase IX(CA IX)is abundantly distributed on the hypoxia tumor cells,it is considered as a potential tumor biomarker.4-(2-Aminoethyl)benzenesulfonamide(ABS)as a CA IX inhibitor has inherent inhibitory activity and good targeting *** this study,Ag_(2)S quantum dots(QDs)were used as the carrier to prepare a novel diagnostic and therapeutic bioprobe(Ag_(2)S@polyethylene glycol(PEG)-ABS)through ligand exchange and amide condensation ***_(2)S@PEG-ABS can selectively target tumors by surface-modified ABS and achieve accurate tumor imaging by the near infrared-II(NIR-II)fluorescence characteristics of Ag_(2)S *** modification of Ag_(2)S QDs greatly improves its water solubility and stability,and therefore achieves high photothermal stability and high photothermal conversion efficiency(PCE)of 45.17%.Under laser irradiation,Ag_(2)S@PEG-ABS has powerful photothermal and inherent antitumor combinations on colon cancer cells(CT-26)in *** also has been proved that Ag_(2)S@PEG-ABS can realize the effective treatment of hypoxia tumors in vivo and show good ***,it is a new efficient integrated platform for the diagnosis and treatment of hypoxia tumors.

关键词： CA IX-targeted Hypoxia tumor combination therapy NIR-II imaging Photothermal effect

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Intake of tobacco nitrosamines of smokers in various provinces of China and their cancer risk:A meta-analysis

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Journal of Environmental Sciences 2024年第7期141卷 249-260页

作者： Xiao Li Zhiwei Ye Jun Wang Pengfei Lin Xiaojin Zhang Shuguang Xie Chao Chen Research Institute for Environmental Innovation(Suzhou) TsinghuaSuzhouJiangsu 215163China State key Joint laboratory of Environmental Simulation and Pollution Control School of EnvironmentTsinghua UniversityBeijing 100084China Shenzhen key laboratory of Organic Pollution Prevention and Control State Key Laboratory of Urban Water Resource and EnvironmentHarbin Institute of TechnologyShenzhen 518055China State key Joint laboratory of Environmental Simulation and Pollution Control College of Environmental Science and EngineeringPeking UniversityBeijing 100871China

Nitrosamines are a class of carcinogens which have been detected widely in food,water,some pharmaceuticals as well as *** objectives of this paper include reviewing the basic information on tobacco consumption and nitrosamine contents,and assessing the health risks of tobacco nitrosamines exposure to Chinese *** searched the publications in English from“Web of Science”and those in Chinese from the“China National Knowledge Infrastructure”in 2022 and collected 151 literatures with valid *** content of main nitrosamines in tobacco,including 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone(NNK),N-nitrosonornicotine(NNN),N-nitrosoanatabine(NAT),N-nitrosoanabasine(NAB),total tobacco-specific nitrosamines(TSNA),and N-nitrosodimethylamine(NDMA)were *** information of daily tobacco consumption of smokers in 30 provinces of China was also ***,the intakes of NNN,NNK,NAT,NAB,TSNAs,and NDMA via tobacco smoke were estimated as 1534ng/day,591 ng/day,685 ng/day,81 ng/day,2543 ng/day,and 484 ng/day by adult smokers in30 provinces,*** cancer risk(CR)values for NNN and NNK inhalation intake were further calculated as 1.44×10^(-5)and 1.95×10^(-4).The CR value for NDMA intake via tobacco smoke(inhalation:1.66×10^(-4))indicates that NDMA is similarly dangerous in tobacco smoke when compared with the *** China,the CR values caused by average nitrosamines intake via various exposures and their order can be estimated as the following:smoke(3.75×10^(-4))>food(1.74×10^(-4))>drinking water(1.38×10^(-5)).Smokers in China averagely suffer 200%of extra cancer risk caused by nitrosamines in tobacco when compared with non-smokers.

关键词： N-nitrosamine Tobacco Cancer risk Tobacco specific nitrosamines(TSNAs) N-nitrosodimethylamine(NDMA)

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Design of pH-responsive antimicrobial peptide melittin analog-camptothecin conjugates for tumor therapy

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Asian Journal of Pharmaceutical Sciences 2024年第1期19卷 135-146页

作者： Sujie Huang Yuxuan Gao Ling Ma Bo Jia Wenhao Zhao Yufan Yao Wenyuan Li Tongyi Lin Rui Wang Jingjing Song Wei Zhang Institute of Pharmacology School of Basic Medical SciencesLanzhou UniversityLanzhou 730000China key laboratory of Preclinical Study for New Drugs of Gansu Province School of Basic Medical Sciences&Research Unit of Peptide ScienceChinese Academy of Medical SciencesLanzhou UniversityLanzhou 730000China State key laboratory of Veterinary Etiological Biology College of Veterinary MedicineLanzhou UniversityLanzhou 730000China Lanzhou University Second Hospital Lanzhou UniversityLanzhou 730000China

Melittin,a classical antimicrobial peptide,is a highly potent antitumor ***,its significant toxicity seriously hampers its application in tumor *** this study,we developed novel melittin analogs with pH-responsive,cell-penetrating and membranelytic activities by replacing arginine and lysine with *** conjugation with camptothecin(CPT),CPT-AAM-1 and CPT-AAM-2 were capable of killing tumor cells by releasing CPT at low concentrations and disrupting cell membranes at high concentrations under acidic ***,we found that the C-terminus of the melittin analogs was more suitable for drug conjugation than the ***-AAM-1 significantly suppressed melanoma growth in vivo with relatively low ***,the present study demonstrates that the development of antitumor drugs based on pH-responsive antimicrobial peptide-drug conjugates is a promising strategy.

关键词： Antimicrobial peptide peptide-drug conjugate Cell-penetrating activity Membrane disruption Antitumor activity

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Synthesis of poly(thiourethane-alt-thioester)by alternating ring-opening copolymerization of N-thiocarboxyanhydrides and episulfides

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Science China Chemistry 2024年第9期67卷 3091-3097页

作者： Wei Xiong Tianjun Yue Haiwang Lai Chunyan Lyu Weimin Ren Hua Lu Beijing National laboratory for Molecular Sciences Center for Soft Matter Science and EngineeringKey Laboratory of Polymer Chemistry and Physics of Ministry of EducationCollege of Chemistry and Molecular EngineeringPeking UniversityBeijing 100871China State key laboratory of Fine Chemicals Dalian University of TechnologyDalian 116081China

Polythiourethanes(PTU)and polythioesters(PTE)derived from renewable sources are emerging sustainable polymers for their excellent degradability and ***,P(TU-alt-TE)copolymers have been rare and challenging to ***,we report the efficient synthesis of novel P(TU-alt-TE)copolymers via the alternating copolymerization of N-thiocarboxyanhydrides(NTA)/episufides(ES)and provide mechanistic insight into the alternating chain propagation process via density functional theory(DFT)*** incorporation of ESs into traditional peptide backbone is capable of adjusting the glass transition temperature below thermal decomposition temperature,which confers better thermal processability by regulating the rigidity of the backbone and the hydrogen bond interaction among the polymer *** PTUs with tailored properties are accessible by altering the feeding ratio of NTAs and(bifunctional)***,the thiourethane in the backbone can endow interesting underwater adhesion properties to the *** the broad scope of NTA and ES monomers,this method is expected to provide a promising and general route to a wide range of P(TU-alt-TE)copolymers with diverse properties.

关键词： poly(thiourethane-alt-thioester) alternating ring-opening copolymerization N-thiocarboxyanhydrides episulfides

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Electrochemical chemoselective thiocarbamylation of late-stage Tyr-containing drugs and peptides

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Science China Chemistry 2024年第10期67卷 3382-3388页

作者： Wan-Jie Wei Xin-Yu Wang Hai-Tao Tang Fei-Hu Cui Yun-Qi Wu Ying-Ming Pan State key laboratory for Chemistry and Molecular Engineering of Medicinal Resources Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China)Collaborative Innovation Center for Guangxi Ethnic MedicineSchool of Chemistry and Pharmaceutical SciencesGuangxi Normal University

The synthesis and modification of peptides occupy a unique position in the field of drug development, and the functionalization of amino acids is a valuable strategy as an alternative to peptide modification. Currently, the development of tyrosine(Tyr) as a target amino acid is a major challenge in the field of chemistry. Herein, we report an electrochemical radical coupling reaction of labeling tyrosine-containing active drugs and peptides with thiocarbamate derivatives for the first time. This tri-component, onepot reaction can be performed smoothly under simple, gentle, and clean electrochemical conditions and is suitable for the functionalization of various Tyr-containing drug molecular derivatives and peptides.

关键词： tyrosine electrochemical radical coupling chemical modification peptides

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OsNPF3.1,a nitrate,abscisic acid and gibberellin transporter gene,is essential for rice tillering and nitrogen utilization efficiency

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Journal of Integrative Agriculture 2024年第4期23卷 1087-1104页

作者： Junnan Hang Bowen Wu Diyang Qiu Guo Yang Zhongming Fang Mingyong Zhang Institute of Rice Industry Technology Research/key laboratory of Functional Agriculture Guizhou Provincial Department of Education/Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous RegionMinistry of Education/Key Laboratory of Molecular Breeding for Grain and Oil Crops in Guizhou Province/College of Agricultural SciencesGuizhou UniversityGuiyang 550025China key laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement/Guangdong Provincial key laboratory of Applied Botany/South China Botanical Garden Chinese Academy of SciencesGuangzhou 510650China Institute of Fruit Tree Research Guangdong Academy of Agricultural SciencesGuangzhou 510640China

Low-affinity nitrate transporter genes have been identified in subfamilies 4-8 of the rice nitrate transporter 1(NRT1)/peptide transporter family(NPF),but the OsNPF3 subfamily responsible for nitrate and phytohormone transport and rice growth and development remains *** this study,we described OsNPF3.1 as an essential nitrate and phytohormone transporter gene for rice tillering and nitrogen utilization efficiency(NUtE).OsNPF3.1 possesses four major haplotypes of its promoter sequence in 517 cultivars,and its expression is positively associated with tiller *** expression was higher in the basal part,culm,and leaf blade than in other parts of the plant,and was strongly induced by nitrate,abscisic acid(ABA)and gibberellin 3(GA_3)in the root and shoot of *** experiments demonstrated that OsNPF3.1 is a pH-dependent low-affinity nitrate transporter,with rice protoplast uptake assays showing it to be an ABA and GA_3 ***3.1 overexpression significantly promoted ABA accumulation in the roots and GA accumulation in the basal part of the plant which inhibited axillary bud outgrowth and rice tillering,especially at high nitrate *** NUtE of OsNPF3.1-overexpressing plants was enhanced under low and medium nitrate concentrations,whereas the NUtE of OsNPF3.1 clustered regularly interspaced short palindromic repeats(CRISPR)plants was increased under high nitrate *** results indicate that OsNPF3.1 transports nitrate and phytohormones in different rice tissues under different nitrate *** altered OsNPF3.1 expression improves NUtE in the OsNPF3.1-overexpressing and CRISPR lines at low and high nitrate concentrations,respectively.

关键词： rice tillering grain yield phytohormone nitrate transporter nitrogen utilization efficiency

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Engineered extracellular vesicles efficiently deliver CRISPR-Cas9 ribonucleoprotein(RNP)to inhibit herpes simplex virus1 infection in vitro and in vivo

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1362-1379页

作者： Yuanda Wan Liren Li Ruilin Chen Jiajia Han Qiyun Lei Zhipeng Chen Xiaodong Tang Wenyu Wu Shuwen Liu Xingang Yao NMPA key laboratory for Research and Evaluation of Drug Metabolism Guangdong Provincial Key Laboratory of New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Center of Clinical Pharmacy Nanfang HospitalSouthern Medical UniversityGuangzhou 510515China State key laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-sen UniversityGuangzhou 510060China key laboratory of Infectious Diseases Research in South China(Southern Medical University) Ministry of EducationGuangzhou 510515China

Extracellular vesicles(EVs)have recently emerged as a promising delivery platform for CRISPR/Cas9 ribonucleoproteins(RNPs),owing to their ability to minimize off-target effects and immune ***,enhancements are required to boost the efficiency and safety of Cas9 RNP enrichment within *** response,we employed the Fc/Spa interaction system,in which the human Fc domain was fused to the intracellular domain of PTGFRN-Δ687 and anchored to the EV ***,the B domain of the Spa protein was fused to the C domain of cargos such as Cre or *** to the robust interaction between Fc and Spa,this method enriched nearly twice the amount of cargo within the *** loaded with spCas9 RNP targeting the HSV1 genome exhibited significant inhibition of viral replication in vitro and in ***,following neuron-targeting peptide RVG modification,the in vivo dosage in neural tissues substantially increased,contributing to the clearance of the HSV1 virus in neural tissues and exhibiting a lower off-target *** findings establish a robust platform for efficient EV-based SpCas9 delivery,offering potential therapeutic advantages for HSV1 infections and other neurological disorders.

关键词： Extracellular vesicles CRISPR/Cas9 Ribonucleoproteins PTGFRN Fc/Spa HSV1 Neuron-targeting Delivery

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MMAE-loaded PLGA nanomedicine with improved biosafety to achieve efficient antitumor treatment

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Journal of Innovative Optical Health Sciences 2024年第2期17卷 79-93页

作者： Changqiang Xie Yan Wang Zhenzhen Cai Jianghai Du Zhengyu Chen Junjie Wang Xingzhou Peng State key laboratory of Digital Medical Engineering School of Biomedical Engineering Hainan University Haikou 570228P.R.China key laboratory of Biomedical Engineering of Hainan Province One Health Institute Hainan University Haikou 570228P.R.China key laboratory of Hainan Trauma and Disaster Rescue The First Affiliated Hospital of Hainan Medical University Hainan Medical University Haikou 571199P.R.China Engineering Research Center for Hainan Bio.Smart Materials and Bio-Medical Devices Key Laboratory of Emergency and Trauma Ministry of EducationKey Laboratory of Hainan Functional Materials and Molecular ImagingCollege of Emergency and Trauma Hainan Medical UniversityHaikou 571199P.R.China

Monomethyl auristatin E(MMAE)is a derivative of the marine peptide Dolastatin 10,which has therapeutic effects against various cancers according to its antimitotic activity in multiple clinical *** antibody drug conjugate(ADC)of MMAE is currently used in clinical ***,the safety issues of MMAE-based ADC,such as high drug toxicity and poor bioavailability,still exist when using it for anticancer therapy.A sustained release of drug delivery approach should be used to reduce toxicity and achieve sufficient anticancer ***,PLGA-b-PEG 2000 with excellent biocompatibility and slow degradation ability was adopted to construct MMAE-loaded nanoparticles for safe and effective *** sustained release effect and the immunogenic cell death(ICD)effect of PLGA-MMAE nanoparticles were assessed by in vitro *** PLGA-MMAE nanoparticles effectively accumulated in the tumor through the enhanced permeability and retention(EPR)effect,inducing cell apoptosis and causing a certain degree of immune *** sustained drug release of PLGA-MMAE improved the bioavailability and effectively reduced the toxicity and development of the tumor compared to the effect of free MMAE or ***,this study provides a safe and effective chemotherapeutic approach,as well as a simple and effective synthetic process for MMAE-based nanoparticles,improving their therapeutic efficacy and safety.

关键词： Monomethyl auristatin E poly(lactic-co-glycolic acid)nanoparticles sustained release chemotherapy immunogenic cell death

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