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A multidimensional platform of patient-derived tumors identifies drug susceptibilities for clinical lenvatinib resistance

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Acta Pharmaceutica Sinica B 2024年第1期14卷 223-240页

作者： Lei Sun Arabella H.Wan Shijia Yan Ruonian Liu Jiarui Li Zhuolong Zhou Ruirui Wu Dongshi Chen Xianzhang Bu Jingxing Ou Kai Li Xiongbin Lu Guohui Wan Zunfu Ke Department of Pathology the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China national-Local Joint Engineering laboratory of druggability and New drug Evaluation National Engineering Research Center for New Drug and Druggability(Cultivation)Guangdong Province Key Laboratory of New Drug Design and EvaluationSchool of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China Department of Medical and Molecular Genetics Indiana University School of MedicineIndianapolisIN 46202USA Department of Medicine Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90033USA Department of Hepatic Surgery and Liver Transplantation center Third Affiliated HospitalOrgan Transplantation InstituteSun Yat-sen UniversityOrgan Transplantation Research Center of Guangdong ProvinceGuangdong Province Engineering Laboratory for Transplantation MedicineGuangzhou 510630China Guangdong Provincial key laboratory of Liver Disease research Guangzhou 510630China Department of Ultrasound Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630China Melvin and Bren Simon Comprehensive Cancer center Indiana UniversityIndianapolisIN 46202USA

Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug ***,we applied a multidimensional,high-throughput screening platform comprising patient-derived resistant liver tumor cells(PDCs),organoids(PDOs),and xenografts(PDXs)to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant *** and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment,expediting drug repurposing *** screening identified romidepsin,YM155,apitolisib,NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO ***,romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway.A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX ***,our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer,providing a feasible multidimensional platform for personalized medicine.

关键词： Lenvatinib drug resistance High-throughput screening drug discovery Patient-derived model Romidepsin EGFR Liver cancer

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Nanomedicine integrating the lipidic derivative of 5-fluorouracil,miriplatin and PD-L1 si RNA for enhancing tumor therapy

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Chinese Chemical Letters 2024年第6期35卷 385-391页

作者： An Lu Yuhao Guo Yi Yan Lin Zhai Xiangyu Wang Weiran Cao Zijie Li Zhixia Zhao Yujie Shi Yuanjun Zhu Xiaoyan Liu Huining He Zhiyu Wang Jian-Cheng Wang Beijing key laboratory of Molecular Pharmaceutics and New drug Delivery Systems State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China Tianjin key laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics School of PharmacyTianjin Medical UniversityTianjin 300070China Department of Immuno-oncology The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050011China Department of Pharmacy Clinical Trial Research CenterChina-Japan Friendship HospitalBeijing 100029China laboratory of innovative formulations and pharmaceutical excipients Ningbo Institute of Marine MedicinePeking UniversityNingbo 315832China

Immunosuppressive microenvironments present critical problems in clinical *** regulate the tumor immune microenvironment for enhancing antitumor effect,a combination of immune checkpoint inhibitors(ICIs)with chemotherapeutics has been applied *** this study,miriplatin(MiPt),the lipidic derivative of 5-fluorouracil(Fu-OA),as well as the programmed death ligand 1(PD-L1)target si RNA(siPD-L1)were integrated into Lip-Pt/Fu@siPD-L1 nanoparticles(NPs)for *** vitro results showed that Lip-Pt/Fu@siPD-L1 NPs could exhibit effective siRNA gene silencing and promote the phagocytosis of tumor cells by ***,in vivo results revealed that LipPt/Fu@siPD-L1 NPs showed significantly higher anti-tumor efficiency than that of the physical mixing of Mi Pt,5-fluorouracil,and Lip@siPD-L1 NPs(delivery of siPD-L1 by liposomes).The best anti-tumor efficiency of Lip-Pt/Fu@siPD-L1 NPs resulted from the synergistic immunotherapeutic effects of Mi Pt and siPD-L1 based on the inhibition of CD47 expression and the downregulation of PD-L1 in tumor cells,which elicited a robust anti-tumor immune response through the activation of macrophage phagocytosis and immune checkpoint *** Lip-Pt/Fu@siPD-L1 NPs provide a potential strategy for tumor chemo-immunotherapy.

关键词： Chemo-immunotherapy Immune checkpoint inhibition Gene silencing Miriplatin Macrophage phagocytosis Nanotechnology

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Timp1 Deletion Induces Anxiety-like Behavior in Mice

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Neuroscience Bulletin 2024年第6期40卷 732-742页

作者： Xiaotong Wang Wei Zheng Ziyi Zhu Biyu Xing Weijie Yan Ke Zhu Lingli Xiao Chaojuan Yang Mengping Wei Lei Yang Zi-Bing Jin Xueyun Bi Chen Zhang state key laboratory of Neurology and Oncology drug Development Nanjing210000China School of Basic Medical Sciences Wenzhou Medical UniversityWenzhou325035China School of Basic Medical Sciences Beijing Key Laboratory of Neural Regeneration and RepairAdvanced Innovation Center for Human Brain ProtectionBeijing Laboratory of Oral HealthCapital Medical UniversityBeijing100069China Beijing Institute of Ophthalmology Beijing Tongren Eye CenterBeijing Tongren HospitalCapital Medical UniversityBeijing100005China Chinese Institute for Brain research Beijing102206China key laboratory for Biomechanics and Mechanobiology of the Ministry of Education Beijing Advanced Innovation Center for Biomedical EngineeringSchool of Engineering MedicineBeihang UniversityBeijing100191China

The hippocampus is essential for learning and memory,but it also plays an important role in regulating emotional behavior,as hippocampal excitability and plasticity affect anxiety and *** synaptic plasticity may be regulated by tissue inhibitor of matrix metalloproteinase 1(TIMP1),a known protein inhibitor of extracellular matrix(ECM),and the expression of TIMP1 in the hippocampus can be induced by neuronal excitation and various ***,the involvement of Timp1 in fear learning,anxiety,and hippocampal synaptic function remains to be *** study of Timp1 function in vivo revealed that Timp1 knockout mice exhibit anxiety-like behavior but normal fear *** results suggested that Timp1 knockout mice showed hyperactivity in the ventral CA1 region,but the basic synaptic transmission and plasticity were normal in the Schaffer collateral *** together,our results suggest that deletion of Timp1 in vivo leads to the occurrence of anxiety behaviors,but that Timp1 is not crucial for fear learning.

关键词： Timp1 Anxiety Fear Synaptic transmission Synaptic plasticity

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Effect of microstructure on lipolysis behavior of milk fat globules during gastrointestinal digestion

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Food Science and Human Wellness 2024年

作者： Xinyun Zhou Ting Guo Chen Chen Hadiatullah Hadiatullah Yunping Yao Changmo Li Xingguo Wang state key laboratory of Food Nutrition and Safety key laboratory of Food Nutrition and Safety Ministry of Education College of Food Science and Engineering Tianjin University of Science & Technology Tianjin key laboratory for Modern drug Delivery & High-Efficiency Collaborative Innovation center of Chemical Science and Engineering School of Pharmaceutical Science and Technology Tianjin University Collaborative Innovation center of Food Safety and Quality Control in Jiangsu Province national Engineering research center for Functional Food School of Food Science and Technology Jiangnan University

Milk fat globules (MFG) are the primary source of energy and functional factor in dairy-based products. To evaluate the suitability of commercial MFG substitutes for infant and adult consumers， the lipolysis properties and regulatory factors in digesting bovine， caprine， and human MFG were compared. The lipolysis kinetic models of bovine and caprine MFG are comparable， with bovine MFG displaying the highest degree of lipolysis (50.21%) during gastric digestion in infants， resulting in the production short-chain saturated fatty acids. Caprine MFG has a high rate of lipolysis due to its weak phospholipid-glycoprotein layer， which is prominent in both infants’ and adults’ digestion. The effects of consuming bovine and caprine MFG for adults are comparable in terms of lipolysis properties and nutritional value of fatty acid. After gastrointestinal digestion， human MFG has the highest digestibility (93.98%). The advantages of human MFG include its phospholipid structure， exogenous lipase， and lipolysis-regulating proteins. This study provides recommendation for the selection of milk fat substitutes and improvements in commercial dairy.

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Astragaloside IV Alleviates Acute Liver Failure Induced by D-GalN/LPS by Upregulating Autophagy and Reducing Inflammation

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Infectious Microbes & Diseases 2024年第1期6卷 20-28页

作者： Meng Hong Wenwen Lian Ying Yang Zhi Chen state key laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina

Acute liver failure(ALF)is a life-threatening condition that manifests in an extremely serious manner and progresses *** following study investigated the protective effect of astragaloside IV(AS-IV),a traditional Chinese drug,on ALF,and its underlying mechanisms,focusing on autophagy and inflammation *** were randomly divided into a saline group,a D-galactosamine and lipopolysac-charide(D-GalN/LPS)group and an AS-IV *** analysis,immunohistochemistry,cytometric bead array,high-throughput quantitative PCR,flow cytometry and Western analysis were used to assess inflammation and liver damage 5 hours after D-GalN/LPS *** IV treatment reduced mortality by alleviating D-GalN/LPS–induced hepatic damage and decreasing inflammation(decreasing Ly6c+monocyte levels,reducing inflammatory cytokines and increasing anti-inflammatory factors)as well as upregulating ***,PCR array was used to detect expression of autophagy-related genes,which demonstrated a Log2 fold change in gene expression between the AS-IV and D-GalN/LPS groups ranging from 1.19 to-3.53,with Tnfsf10 showing the largest alteration be-tween the two *** data suggest that AS-IV may alleviate ALF by upregulating autophagy and reducing inflammation,and it may therefore be an interesting drug for alleviating ALF.

关键词： astragaloside IV acute liver failure inflammation autophagy

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Screened peptides from one-bead one-compound technique extend half-life of peptide drugs in circulation through binding to albumin

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Chinese Chemical Letters 2024年第3期35卷 384-388页

作者： Yi-Jing Li Lingze Zhang Ming-Hao Pang Pei-Pei Yang Lu-Ming Guo Kuo Zhang Da-Yong Hou Lei Wang Hao Wang Hui Cao state key laboratory for Advanced Metals and Materials School of Materials Science and EngineeringUniversity of Science and Technology BeijingBeijing 100083China CAS center for Excellence in Nanoscience CAS Key Laboratory for Biomedical Effects of Nanomaterials NanosafetyNational Center for Nanoscience and Technology(NCNST)Beijing 100190China

Peptide drugs are known for their high biological ***,compared with small molecule drugs,peptide drugs are easily oxidized and hydrolyzed as well as short in ***,inspired by the long circulation of albumin in blood,we screened albumin binding peptides(ABPs)from a one-bead one-compound(OBOC)peptide library to increase the half-life of peptide *** displaying random peptides were screened using fluorescent labeled human serum *** beads with specific binding to albumin were isolated for *** selected ABPs can effectively bind to albumin,thus possessing the long circulation of *** dissociation constant(K_(D))of ABPs to albumin is up to 1×10^(-8)mol/*** one of ABPs(ABP2)was coupled to triptorelin,the circulation half-life of triptorelin in mice was significantly prolonged to 263.50 h much longer than that of triptorelin alone(179.07 h).In addition,the combination therapy using ABP-conjugated triptorelin and doxorubicin(DOX)can effectively inhibit the proliferation of tumor cells in *** OBOC screening strategy and resulting ABPs showed great potential for enhancing the delivery efficiency of peptide drugs.

关键词： One-bead one-compound Combinatorial library Albumin binding drug delivery Triptorelin

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Ciclopirox inhibits SARS-CoV-2 replication by promoting the degradation of the nucleocapsid protein

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2505-2519页

作者： Xiafei Wei Yuzheng Zhou Xiaotong Shen Lujie Fan Donglan Liu Xiang Gao Jian Zhou Yezi Wu Yunfei Li Wei Feng Zheng Zhang Institute for Hepatology National Clinical Research Center for Infectious DiseaseShenzhen Third People's HospitalSouthern University of Science and TechnologyShenzhen 518112China Guangzhou laboratory Guangzhou Medical UniversityGuangzhou 511495China state key laboratory of Respiratory Disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120China

The nucleocapsid protein(NP)plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long *** its vital role in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)assembly and host inflammatory response,it remains an unexplored target for drug *** this study,we identified a small-molecule compound(ciclopirox)that promotes NP degradation using an FDA-approved library and a drug-screening cell *** significantly inhibited SARS-CoV-2 replication both in vitro and in vivo by inducing NP *** induced abnormal NP aggregation through indirect interaction,leading to the formation of condensates with higher viscosity and lower *** condensates were subsequently degraded via the autophagy-lysosomal pathway,ultimately resulting in a shortened NP half-life and reduced NP *** results suggest that NP is a potential drug target,and that ciclopirox holds substantial promise for further development to combat SARS-CoV-2 replication.

关键词： SARS-CoV-2 Nucleocapsid protein Viral replication Ciclopirox Abnormal aggregation Protein degradation Autophagy-lysosome drug target

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Rapid and sensitive detection of Epstein-Barr virus antibodies in nasopharyngeal carcinoma by chemiluminescence strips based on iron-porphyrin single atom nanozyme

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Nano research 2024年第3期17卷 1827-1836页

作者： Daji Wang Jie Wang Dan Liu Jiuyang He Meiying Wang Haibing Huang Guohui Nie Hui Ding Xiyun Yan Nanozyme Synthesis center Shenzhen Institute of Synthetic BiologyShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China center for drug Evaluation National Medical Products AdministrationBeijing 100022China Shenzhen key laboratory of nanozymes and Translational Cancer research Department of Otolaryngologyand Shenzhen Institute of Translational MedicineShenzhen Second People’s Hospital/the First Affiliated Hospital of Shenzhen University Health Science CenterShenzhen 518035China CAS Engineering laboratory for Nanozyme Key Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China Department of Rheumatology and Immunology Shenzhen Second People’s HospitalThe First Affiliated Hospital of Shenzhen UniversityShenzhen 518055China

The correlation between Epstein-Barr virus(EBV)infection and nasopharyngeal carcinoma(NPC)risk has been extensively *** continual monitoring of EBV-IgAs provides a promising approach of NPC screening in its early *** this study,we successfully synthesized a single-atom nanozyme(SANzyme)through the application of iron-porphyrin based metal organic framework(MOF-FeP).The MOF-FeP possesses precisely-defined electronic and geometric structures that accurately mimic highly-evolved catalytic site of natural *** peroxidase-like activity of MOF-FeP enables it to catalyze the chemiluminescence of luminol *** integrating MOF-FeP into a traditional strip,we created a rapid and highly-sensitive evaluation tool for detecting ***,the MOF-FeP strip enables the simultaneous detection of three EBV-IgAs,greatly improving the accuracy of EBV-associated NPC *** sensitivities of the MOF-FeP strip(75.56%–93.30%)surpass those of current enzyme-linked immunosorbent assay(ELISA)methods(64.44%–82.22%).This test takes only 16 min to perform as opposed to the customary 1–2 h required for standard ***,the MOF-FeP strip is suitable for whole blood samples,thereby significantly simplifying the sample preparation and detection *** conclusion,the MOF-FeP strip combines the simplicity of traditional strip with the high catalytic activity of *** innovative MOF-FeP strip offers a new point-of-care strategy for EBV-IgAs detection,which is expected to markedly facilitate early screening for EBV-associated diseases.

关键词： iron-porphyrin single-atom nanozyme(SANzyme) chemiluminescence strips Epstein-Barr virus(EBV) nasopharyngeal carcinoma(NPC) antibody detection

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High expression of GPR160 in prostate cancer is unrelated to CARTp-mediated signaling pathways

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1467-1471页

作者： Chenyu Ye Qingtong Zhou Shi Lin Wensheng Yang Xiaoqing Cai Yiting Mai Yanyan Chen Dehua Yang Ming-Wei Wang Department of Pharmacology School of Basic Medical SciencesFudan UniversityShanghai 200032China research center for Deepsea Bioresources Sanya 572025China Department of Pharmacy Children’s Hospital of Fudan UniversityNational Children’s Medical CenterShanghai 201102China state key laboratory of Chemical Biology Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China The national center for drug screening Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Department of Chemistry School of Sciencethe University of TokyoTokyo 113-0033Japan School of Pharmacy Hainan Medical UniversityHaikou 571199China

To the Editor:G protein-coupled receptors(GPCRs)are the largest group of membrane proteins with over 800 members,characteristic of a seven transmembrane *** playing crucial roles in regulation of various physiological processes,GPCRs have been implicated in many diseases including diabetes,obesity,depression and *** initiate different intracellular responses,GPCRs mainly interact with three families of effector proteins upon agonist binding:the heterotrimeric G proteins,G protein-coupled receptor kinases(GRKs)and arrestins1.

关键词： GPR160 CARTp Prostate cancer Signaling pathway

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Allogenic microglia replacement:A novel therapeutic strategy for neurological disorders

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Fundamental research 2024年第2期4卷 237-245页

作者： Yanxia Rao Bo Peng Department of laboratory Animal Science MOE Frontiers Center for Brain ScienceFudan UniversityShanghai 200032China Department of Neurosurgery Huashan HospitalInstitute for Translational Brain ResearchState Key Laboratory of Medical NeurobiologyMOE Frontiers Center for Brain ScienceMOE Innovative Center for New Drug Development of Immune Inflammatory DiseasesFudan UniversityShanghai 200000China Co-Innovation center of Neuroregeneration Nantong UniversityNantongJiangsu 226001China

Microglia are resident immune cells in the central nervous system(CNS)that play vital roles in CNS development,homeostasis and disease *** defects in microglia lead to microglial dysfunction,which in turn leads to neurological *** correction of the specific genetic defects in microglia in these disorders can lead to therapeutic *** genetic defect correction approaches are dependent on viral vectorbased genetic defect ***,the viruses used in these approaches,including adeno-associated viruses,lentiviruses and retroviruses,do not primarily target microglia;therefore,viral vector-based genetic defect corrections are ineffective in *** replacement is a novel approach to correct microglial genetic defects via replacing microglia of genetic defects with allogenic healthy *** this paper,we systematically review the history,rationale and therapeutic perspectives of microglia replacement,which would be a novel strategy for treating CNS disorders.

关键词： Microglia Replacement Microglia replacement Microglia depletion Microglia-free niche CSF1R

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