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A novel TNKS/USP25 inhibitor blocks the Wnt pathway to overcome multi-drug resistance in TNKS-overexpressing colorectal cancer

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Acta Pharmaceutica Sinica B 2024年第1期14卷 207-222页

作者： Hongrui Zhu Yamin Gao Liyun Liu Mengyu Tao Xiao Lin Yijia Cheng Yaoyao Shen Haitao Xue Li Guan Huimin Zhao Li Liu Shuping Wang Fan Yang Yongjun Zhou Hongze Liao Fan Sun Houwen Lin research Center for Marine Drugs Department of PharmacyRen Ji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127China Department of Oncology Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 200080China institute of Marine Drugs Guangxi University of Chinese MedicineNanning 530200China State Key Laboratory of New Drug and pharmaceutical Process Shanghai Professional and Technical Ser-vice Center for Biological Material Drug-ability EvaluationShanghai Institute of Pharmaceutical IndustryChina State Institute of Pharmaceutical IndustryShanghai 200437China institute of Marine Biomedicine Shenzhen PolytechnicShenzhen 518055China

Modulating Tankyrases(TNKS),interactions with USP25 to promote TNKS degradation,rather than inhibiting their enzymatic activities,is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin ***,we identified UAT-B,a novel neoantimycin analog isolated from Streptomyces conglobatus,as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction(PPI)to overcome multi-drug resistance in colorectal cancer(CRC).The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels,triggering cell apoptosis through modulation of the Wnt/β-catenin ***,UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels,as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts,as well as APC^(min/+)spontaneous CRC ***,these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment,and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

关键词： Colorectal cancer TNKSeUSP25 interaction Multi-drug resistance TNKS overexpression Wnt pathway Apoptosis Neoantimycin analog

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A high-performance lithium anode based on N-doped composite graphene

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Rare Metals 2024年第3期43卷 1030-1036页

作者： Can Jiao Hao-Bo Sun Li Zhang Shang-Qian Zhao Guo-Yao Pang Chun-Rong Zhao Shi-Gang Lu General research institute for Nonferrous Metals Beijing100088China China Automotive Battery research institute Co.Ltd Beijing101407China

Lithium(Li)metal is the most promising electrode for next-gene ration rechargeable *** order to push the commercialization of the lithium metal batteries,a kind of nitrogen(N)-doped composite graphene(NCG)adopted as the Li plating host was prepared to regulate Li metal nucleation and suppress dendrite ***,a new kind of sandwich-type composite lithium metal(STCL)electrode was developed to improve its *** STCL electrode can be used as convenient as a piece of Li foil but no dendrite *** a symmetric battery,the STCL electrode cycled for more than 4500 h with the overpotential of less than 40 *** due to the creative design,the STCL promises the Li-S battery with a prolonged cycling lifespan.

关键词： Lithium metal anode Lithiophilic N-doped composite graphene Sandwich-type composite lithium metal electrode

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In silico off-target profiling for enhanced drug safety assessment

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Acta Pharmaceutica Sinica B 2024年第7期14卷 2927-2941页

作者： Jin Liu Yike Gui Jingxin Rao Jingjing Sun Gang Wang Qun Ren Ning Qu Buying Niu Zhiyi Chene Xia Sheng Yitian Wang Mingyue Zheng Xutong Li College of pharmaceutical Sciences Zhejiang UniversityHangzhou 310058China Drug Discovery and Design Center State Key Laboratory of Drug ResearchShanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Nanjing University of Chinese Medicine Nanjing 210023China School of pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyHangzhou 330106China

Ensuring drug safety in the early stages of drug development is crucial to avoid costly failures in subsequent ***,the economic burden associated with detecting drug off-targets and potential side effects through in vitro safety screening and animal testing is *** off-target interactions,along with the adverse drug reactions they induce,are significant factors affecting drug *** assess the liability of candidate drugs,we developed an artificial intelligence model for the precise prediction of compound off-target interactions,leveraging multi-task graph neural *** outcomes of off-target predictions can serve as representations for compounds,enabling the differentiation of drugs under various ATC codes and the classification of compound ***,the predicted off-target profiles are employed in adverse drug reaction(ADR)enrichment analysis,facilitating the inference of potential ADRs for a *** the withdrawn drug Pergolide as an example,we elucidate the mechanisms underlying ADRs at the target level,contributing to the exploration of the potential clinical relevance of newly predicted off-target ***,our work facilitates the early assessment of compound safety/toxicity based on off-target identification,deduces potential ADRs of drugs,and ultimately promotes the secure development of drugs.

关键词： Drug safety Off-target prediction Adverse drug reactions Toxicity Molecular representation Artificial intelligence

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Natural polysaccharide-based smart CXCR4-targeted nano-system for magnified liver fibrosis therapy

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Chinese Chemical Letters 2024年第2期35卷 341-346页

作者： Liqiong Sun Xinping Luo Chenxi Zhou Zhanwei Zhou Minjie Sun College of Horticulture Nanjing Agricultural UniversityNanjing 210095China NMPA Key Laboratory for research and Evaluation of pharmaceutical Preparations and Excipients State Key Laboratory of Natural MedicinesDepartment of PharmaceuticsChina Pharmaceutical UniversityNanjing 210009China

Activated hepatic stellate cells(aHSCs),the main source of extracellular matrix deposition,are key targets in liver ***,no effective drug specific to aHSCs has been clinically applied due to poor drug delivery ***,we designed a CXC chemokine receptor 4(CXCR4)-targeted reactive oxygen species(ROS)-responsive platform AMD-Dex-ROS-responsive-sorafenib(ARS)based on natural polysaccharide and thioctic acid frame,which can deliver anti-fibrosis drug represented by sorafenib specifically to aHSCs on account of CXCR4 over-expression on aHSCs,and smartly disassemble via ROS-responsive thioketal rupture relying on high intracellular ROS in HSCs,realized on-demand drug release and effective liver fibrosis ***,in this platform,the CXCR4 antagonist AMD3100 not only enhanced aHSCs targeting efficiency of sorafenib but also effectively magnified the aHSCs elimination of sorafenib by blocking stroma cell derived factor-1(SDF-1)/CXCR4-induced aHSCs protection,resulting in synergistic anti-fibrosis *** platform provided a new approach for drug delivery system design and liver fibrosis treatment.

关键词： Nanoparticle CXCR4 antagonism ROS-responsive Hepatic stellate cells Liver fibrosis

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Pr-Tb synergistic strengthening on coercivity of Nd-Ce-Fe-B magnets grain boundary diffused with Pr-Tb-Al-Ga alloys

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Journal of Rare Earths 2024年第9期42卷 1704-1709,I0003页

作者： Ruifang Song Hang Zhao Haibo Feng institute of Functional Materials Central Iron&Steel Research InstituteBeijing100081China

Sintered Nd-Ce-Fe-B magnets were grain boundary diffused(GBDed) with Pr_(x)Tb_(80-x)Al_(10)Ga_(10)(at%)(x=0,20,40,60,80) *** effect of Pr/Tb content in diffusion source on magnetic properties,microstructure and elements distribution of GBDed magnets was *** Pr is used to substitute for 75% Tb in diffusion source,Tb consumption per unit coercivity improvement of GBDed magnet reduces by 77%,compared with the Tb_(80)Al_(10)Ga_(10) diffused *** element diffuses into magnets and then forms Tb-rich shell with high magneto-crystalline anisotropy field surrounding main phase grains,resulting in substantial coercivity *** with low melting point diffuses deeply along liquid grain boundary phase during GBD *** can eliminate some sharp defects of main phase grains and make grain boundaries smooth,which provides diffusion channels for further diffusion of Tb ***,there are more diffusion channels for Tb and less Tb enriched at surface region,making Tb diffuse more deeply and improving Tb utilization *** method significantly improves the coercivity,and realizes the green,efficient and high-quality utilization of heavy rare earth(HRE)elements.

关键词： Grain boundary diffusion Rare earths Microstructure Synergistic strengthening

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Deciphering the Shared and Specific Drug Resistance Mechanisms of Anaplastic Lymphoma Kinase via Binding Free Energy Computation

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research 2024年第1期2023卷 663-674页

作者： Yang Yu Zhe Wang Lingling Wang Qinghua Wang Rongfan Tang Sutong Xiang Qirui Deng Tingjun Hou Huiyong Sun Department of Medicinal Chemistry China Pharmaceutical UniversityNanjing 210009JiangsuP.R.China Innovation institute for Artificial Intelligence in Medicine of Zhejiang University College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058ZhejiangP.R.China

Anaplastic lymphoma kinase(ALK),a tyrosine receptor kinase,has been proven to be associated with the occurrence of numerous *** there have been already at least 3 generations of ALK inhibitors approved by FDA or in clinical trials,the occurrence of various mutations seriously attenuates the effectiveness of the ***,most of the drug resistance mechanisms still remain ***,it is necessary to reveal the bottom reasons of the drug resistance mechanisms caused by the *** this work,on the basis of verifying the accuracy of 2 main kinds of binding free energy calculation methodologies[end-point method of Molecular Mechanics with Poisson-Boltzmann/Generalized Born and Surface Area(MM/PB(GB)SA)and alchemical method of Thermodynamic Integration(TI)],we performed a systematic analysis on the ALK systems to explore the underlying shared and specific drug resistance mechanisms,covering the one-drug-multiple-mutation and multiple-drug-onemutation cases.

关键词： drugs Anaplastic clinical

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Mechanism of reduction-diffusion reaction in Sm-Fe binary system at low temperature using molten salts

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Journal of Rare Earths 2024年第10期42卷 1889-1894页

作者： Jungryang Kim Shusuke Okada Kenta Takagi Kimihiro Ozaki Innovative Functional Materials research institute National Institute of Advanced Industrial Science and Technology (AIST)

In this study,the mechanism of the reduction-diffusion reaction in a Sm-Fe binary system at low temperature was studied to investigate the possibility of synthesis of a Fe-rich TbCu7-type SmFex（x>9）by the low-temperature diffusion-reduction（LTRD） process using LiCl-KCl eutectic molten ***,the Sm-Fe phase transformation depending on the Sm-Fe composition,the LTRD temperature,and time was investigated,and it is found that the obtained metastable phase is only TbCu7-type SmFe～8.5,which is not a Fe-rich *** Fe content does not change even after an expended LTRD process,and the metastable TbCu7-type SmFe～8.5tends to transform to the stable *** addition,it is found that the Sm-Fe phase starts to synthesize from the Sm-rich phase in the order of SmFe2,SmFe3,and SmFe8.5as the LTRD temperature increases（when the time was 10 h） or the LTRD time increases（when the temperature was 550℃）.Core-shell-like particles are observed in the case of a short LTRD time,and the core and the shell are Fe and the Sm-rich Sm-Fe phase,respectively,indicating that the Sm-rich phase begins to produce on the surface of the Fe *** is difficult to synthesize a Fe-rich TbCu7-type SmFex（x>9） phase with the Sm-Fe binary system,suggesting that a different approach,such as addition of other elements,will be necessary.

关键词： Low-temperature synthesis Molten salts Rare earths Reduction-diffusion process Sm–Fe compounds Synthesis mechanism

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Amide naphthotubes:Biomimetic macrocycles for selective molecular recognition

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Chinese Chemical Letters 2024年第4期35卷 124-131页

作者： Cheng-Da Zhao Huan Yao Shi-Yao Li Fangfang Du Li-Li Wang Liu-Pan Yang School of pharmaceutical Science Postdoctoral Research Station of Basic MedicineHengyang Medical SchoolUniversity of South ChinaHengyang 421001China

Selective molecular recognition in water is routine for bioreceptors,but remains challenging for synthetic *** is principally because noncovalent interactions are usually less efficient in aqueous *** mimicking the cavity feature of bioreceptors,*** Jiang proposed and clarified the concept of“endo-functionalized cavity”.Through situating polar binding sites into a deep hydrophobic cavity,we designed and synthesized several macrocyclic hosts,among which amide naphthotubes are the most *** hosts can selectively recognize various polar molecules including organic micropollutants,drug molecules,and chiral molecules in water by employing the hydrophobic effect and shielded hydrogen *** addition,these biomimetic hosts have been applied in spectroscopic analysis,adsorptive separation and *** this review,we provide an overview of recent advances on amide naphthotubes with special emphasis on the efforts of Jiang's *** are convinced that these biomimetic macrocycles will make further contributions to supramolecular chemistry and beyond.

关键词： Molecular recognition Supramolecular chemistry Amide naphthotube Endo-functionalized cavity Biomimetic macrocycle

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Cancer cell membrane-coated bacterial ghosts for highly efficient paclitaxel delivery against metastatic lung cancer

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Acta Pharmaceutica Sinica B 2024年第1期14卷 365-377页

作者： Dandan Ling Xueli Jia Ke Wang Qiucheng Yan Bochuan Yuan Lina Du Miao Li Yiguang Jin Anhui Medical University Hefei 230032China Department of pharmaceutical Sciences Beijing Institute of Radiation MedicineBeijing 100850China

Chemotherapy is one of the major approaches for the treatment of metastatic lung cancer,although it is limited by the low tumor delivery efficacy of anticancer *** therapy is emerging for cancer treatment due to its high immune stimulation effect;however,excessively generated immunogenicity will cause serious inflammatory response ***,we prepared cancer cell membrane-coated liposomal paclitaxel-loaded bacterial ghosts(LP@BG@CCM)by layer-by-layer encapsulation for the treatment of metastatic lung *** preparation processes were simple,only involving film formation,electroporation,and pore ***@BG@CCM owned much higher 4T1 cancer cell toxicity than LP@BG due to its faster fusion with cancer *** the 4T1 breast cancer metastatic lung cancer mouse models,the remarkably higher lung targeting of intravenously injected LP@BG@CCM was observed with the almost normalized lung appearance,the reduced lung weight,the clear lung tissue structure,and the enhanced cancer cell apoptosis compared to its ***,several major immune factors were improved after administration of LP@BG@CCM,including the CD4^(+)/CD8a^(+)T cells in the spleen and the TNF-α,IFN-γ,and IL-4 in the ***@BG@CCM exhibits the optimal synergistic chemo-immunotherapy,which is a promising medication for the treatment of metastatic lung cancer.

关键词： Apoptosis Bacterial ghost Cancer cell membrane Immune stimulation Liposome Lung targeting Metastatic lung cancer Paclitaxel

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Multi-UAVs Collaborative Path Planning in the Cramped Environment

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IEEE/CAA Journal of Automatica Sinica 2024年第2期11卷 529-538页

作者： Siyuan Feng Linzhi Zeng Jining Liu Yi Yang Wenjie Song School of Automation Beijing Institute of TechnologyNanjing 210039China Nanjing research institute of Electronics Technology Nanjing 210039China Yichang Testing Technique research institute Yichang 443003China IEEE

Due to its flexibility and complementarity, the multiUAVs system is well adapted to complex and cramped workspaces, with great application potential in the search and rescue(SAR) and indoor goods delivery fields. However, safe and effective path planning of multiple unmanned aerial vehicles(UAVs)in the cramped environment is always challenging: conflicts with each other are frequent because of high-density flight paths, collision probability increases because of space constraints, and the search space increases significantly, including time scale, 3D scale and model scale. Thus, this paper proposes a hierarchical collaborative planning framework with a conflict avoidance module at the high level and a path generation module at the low level. The enhanced conflict-base search(ECBS) in our framework is improved to handle the conflicts in the global path planning and avoid the occurrence of local deadlock. And both the collision and kinematic models of UAVs are considered to improve path smoothness and flight safety. Moreover, we specifically designed and published the cramped environment test set containing various unique obstacles to evaluating our framework performance thoroughly. Experiments are carried out relying on Rviz, with multiple flight missions: random, opposite, and staggered, which showed that the proposed method can generate smooth cooperative paths without conflict for at least 60 UAVs in a few *** benchmark and source code are released in https://***/inin-xingtian/multi-UAVs-path-planner.

关键词： Collision avoidance conflict resolution multi-unmanned aerial vehicles(UAVs)system path planning

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