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Targeting the organelle for radiosensitization in cancer radiotherapy

Asian Journal of Pharmaceutical Sciences 2024年第2期19卷 52-71页

作者： Xiaoyan Sun Linjie Wu Lina Du Wenhong Xu Min Han institute of Pharmaceutics College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Department of Pharmaceutical Sciences Beijing Institute of Radiation MedicineBeijing 100850China Department of Radiation Oncology Key Laboratory of Cancer Prevention and InterventionThe Second Afliated HospitalCollege of MedicineZhejiang UniversityHangzhou 310058China Hangzhou institute of innovative Medicine Zhejiang UniversityHangzhou 310058China Jinhua institute of Zhejiang University Jinhua 321299China National Key Laboratory of Advanced drug Delivery and Release Systems Zhejiang UniversityHangzhou 310058China

Radiotherapy is a well-established cytotoxic therapy for local solid cancers, utilizing high-energy ionizing radiation to destroy cancer cells. However, this method has several limitations, including low radiation energy deposition, severe damage to surrounding normal cells, and high tumor resistance to radiation. Among various radiotherapy methods, boron neutron capture therapy (BNCT) has emerged as a principal approach to improve the therapeutic ratio of malignancies and reduce lethality to surrounding normal tissue, but it remains deficient in terms of insufficient boron accumulation as well as short retention time, which limits the curative effect. Recently, a series of radiosensitizers that can selectively accumulate in specific organelles of cancer cells have been developed to precisely target radiotherapy, thereby reducing side effects of normal tissue damage, overcoming radioresistance, and improving radiosensitivity. In this review, we mainly focus on the field of nanomedicine-based cancer radiotherapy and discuss the organelle-targeted radiosensitizers, specifically including nucleus, mitochondria, endoplasmic reticulum and lysosomes. Furthermore, the organelle-targeted boron carriers used in BNCT are particularly presented. Through demonstrating recent developments in organelle-targeted radiosensitization, we hope to provide insight into the design of organelle-targeted radiosensitizers for clinical cancer treatment.

关键词： Cancer radiotherapy Organelle-target Radiosensitization Boron neutron capture therapy Nanomedicines

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A proteomic landscape of pharmacologic perturbations for functional relevance

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Journal of Pharmaceutical Analysis 2024年第1期14卷 128-139页

作者： Zhiwei Liu Shangwen Jiang Bingbing Hao Shuyu Xie Yingluo Liu Yuqi Huang Heng Xu Cheng Luo Min Huang Minjia Tan Jun-Yu Xu State Key Laboratory of drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing210023China Zhongshan institute for drug Discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshanGuangdong528400China State Key Laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing210023China

Pharmacological perturbation studies based on protein-level signatures are fundamental for drug discovery. In the present study, we used a mass spectrometry (MS)-based proteomic platform to profile the whole proteome of the breast cancer MCF7 cell line under stress induced by 78 bioactive compounds. The integrated analysis of perturbed signal abundance revealed the connectivity between phenotypic behaviors and molecular features in cancer cells. Our data showed functional relevance in exploring the novel pharmacological activity of phenolic xanthohumol, as well as the noncanonical targets of clinically approved tamoxifen, lovastatin, and their derivatives. Furthermore, the rational design of synergistic inhibition using a combination of histone methyltransferase and topoisomerase was identified based on their complementary drug fingerprints. This study provides rich resources for the proteomic landscape of drug responses for precision therapeutic medicine.

关键词： Proteomics drug Perturbation drug target drug combination

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Phase separation of Nur77 mediates XS561-induced apoptosis by promoting the formation of Nur77/Bcl-2 condensates

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1204-1221页

作者： Xiaohui Chen Meichun Gao Yongzhen Xia Xin Wang Jingbo Qin Hongying He Weirong Liu Xiaowei Zhang Shuangzhou Peng Zhiping Zeng Ying Su Xiaokun Zhang School of Pharmaceutical Science Fujian Provincial Key Laboratory of Innovative Drug Target ResearchXiamen UniversityXiamen 361002China NucMito Pharmaceuticals Co. Ltd.Xiamen 361000China Department of Clinical Laboratory the Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhai 519000China

The orphan nuclear receptor Nur77 is a critical regulator of the survival and death of tumor *** pro-death effect of Nur77 can be regulated by its interaction with Bcl-2,resulting in conversion of Bcl-2 from a survival to *** Bcl-2 is overexpressed in various cancers preventing them from apoptosis and promoting their resistance to chemotherapy,targeting the apoptotic pathway of Nur77/Bcl-2 may lead to new cancer ***,we report our identification of XS561 as a novel Nur77 ligand that induces apoptosis of tumor cells by activating the Nur77/Bcl-2 *** vitro and animal studies revealed an apoptotic effect of XS561 in a range of tumor cell lines including MDA-MB-231 triple-negative breast cancer(TNBC)and MCF-7/LCC2 tamoxifen-resistant breast cancer(TAMR)in a Nur77-dependent *** studies showed XS561 potently induced the translocation of Nur77 from the nucleus to mitochondria,resulting in mitochondria-related ***,XS561-induced accumulation of Nur77 at mitochondria was associated with XS561 induction of Nur77 phase separation and the formation of Nur77/Bcl-2 ***,our studies identify XS561 as a new activator of the Nur77/Bcl-2 apoptotic pathway and reveal a role of phase separation in mediating the apoptotic effect of Nur77 at mitochondria.

关键词： XS561 Nur77 Bcl-2 Apoptosis Mitochondria Phase separation TNBC TAMR

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Ti_(3)C_(2)T_(x)/SnO_(2)P–N heterostructure construction boosts room-temperature detecting formaldehyde

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Rare Metals 2024年第1期43卷 267-279页

作者： Yue Zhang Ming-Yue Wang Xiao-Guang San Yan-Bai Shen Guo-Sheng Wang Lei Zhang Dan Meng College of Chemical Engineering Shenyang University of Chemical TechnologyShenyang 110142China institute for Superconducting and Electronic Materials(ISEM) Australian Institute for Innovative Materials(AIIM)University ofWollongongWollongongNSW2500Australia College of Resources and Civil Engineering Northeastern UniversityShenyang 110819China

Formaldehyde is a common atmospheric pollutant produced in industrial production and daily ***,the traditional semiconductor formaldehyde gas sensor cannot work at room temperature,which limits its practical ***,developing high-performance gas sensors for rapidly and accurately detecting formaldehyde at room temperature is an important *** this study,Ti_(3)C_(2)Tx/SnO_(2)heterostructures were constructed,which could selectively detect formaldehyde at room temperature with a response value of 29.16%(10×10^(-6)).In addition,the sensor shows a remarkable theoretical detection limit of 5.09×10^(-9)and good longterm *** functional theory(DFT)simulations reveal that SnO_(2)nano spheres provide the majority of adsorption sites that strongly interact with ***,Ti_(3)C_(2)T_(x)acting as a conductive layer facilitates the transfer of charge carriers so that they show a sensing response to formaldehyde at room ***,the formation of p-n heterostructures between SnO_(2)and Ti_(3)C_(2)T_(x)boosts the Schottky barrier at the interface,which is the critical factor in enhancing the sensing properties by turning the Schottky barrier upon introducing formaldehyde *** perspective is expected to provide instructive guidance for utilizing MXene/metal oxide nanocomposites to improve the gas sensing performance at room temperature.

关键词： Ti_(3)C_(2)T_(x)/SnO_(2)nanocomposites p-n heterostructures Formaldehyde sensing Room temperature DFT calculations

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How topography and neighbor shape the fate of trees in subtropical forest restoration:Environmental filtering and resource competition drive natural regeneration

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Forest Ecosystems 2024年第1期11卷 73-86页

作者： Haonan Zhang Xingshuo Zhang Yingying Lv Yanyan Ni Baokun Xu Xiangnan Han Xiao Cao Qingpei Yang Wanggu Xu Zhedong Qian innovative Research Team for Forest Restoration Mechanisms Nanjing Institute of Environmental SciencesMinistry of Ecology and Environment(MEE)Nanjing 210042China College of Forestry Jiangxi Agricultural UniversityNanchang 330045China

The structure of plant communities at local scales depends on both the spatial heterogeneity of abiotic environmental factors and the biotic interactions within the ***,although environmental filtering due to microtopographic heterogeneity and resource competition among plants caused by spatial variation in tree density and size are considered to be very important in explaining the mechanisms of community assembly,their effects on the processes of individual mortality and recruitment in natural forest regeneration,as well as their relative contributions,are still poorly *** address this,we established a 12-ha permanent plot in a subtropical evergreen broad-leaved forest area and measured microtopographic variables such as elevation,slope,aspect,and terrain position index(TPI)using a total *** monitored the individual mortality and recruitment in forest natural regeneration through repeated surveys at 5-year *** fitted spatial covariance models to jointly use multiple factors from three groups of variables(microtopographic effect,neighborhood density effects,neighborhood size effects)as explanatory variables to analyze their roles in driving the mortality and recruitment of all individual and 12 dominant species in forest natural regeneration at the neighborhood *** results show that:(1)In the crucial early stages of secondary forest restoration,natural regeneration is influenced by a synergy of environmental filtering,due to microtopographic heterogeneity,and resource competition among plants.(2)For distinct species responses,evergreen dominant species'mortality is largely explained by neighborhood effects,while deciduous species are more affected by topographic ***,the adverse effects of larger conspecific trees on younger trees indicate a pattern of competitive pressure leading to mortality among regenerating trees,such pattern emphasis the influence of parent trees on natural regeneration.(3)As trees g

关键词： Natural regeneration Microtopography Neighborhood effects Mortality and recruitment

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AI enhances drug discovery and development

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National Science Review 2024年第3期11卷 52-54页

作者： Fang Bai Shiliang Li Honglin Li Shanghai institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech University Lingang Laboratory Innovation Center for AI and drug Discovery East China Normal University

The advent of the third wave of artificial intelligence(AI) heralds a new era in drug discovery. AI-powered techniques can be characteristic of identifying features that are difficult for humans to interpret from big ...

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Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy

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Asian Journal of Pharmaceutical Sciences 2024年第2期19卷 188-203页

作者： Mingyang Zhang Yifan Miao Can Zhao Tong Liu Xiyan Wang Zixuan Wang Wenxin Zhong Zhonggui He Chutong Tian Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Key Laboratory of Advanced drug Delivery Systems of Zhejiang Province Hangzhou 310058China Joint International Research Laboratory of Intelligent drug Delivery Systems Ministry of EducationShenyang 110016China Liaoning Provincial institute of drug Inspection and Testing Shenyang 110036China

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

关键词： Steric disulfide bond Triglyceride-like pr odrugs Cabazitaxel Lymphatic transport Oral chemotherapy

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Macrophage senescence in health and diseases

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1508-1524页

作者： Longling Wang Wenxiang Hong Hong Zhu Qiaojun He Bo Yang Jiajia Wang Qinjie Weng Center for drug Safety Evaluation and Research Zhejiang Province Key Laboratory of Anti-Cancer Drug ResearchCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Nanhu Brain-Computer Interface institute Hangzhou 311100China Taizhou institute of Zhejiang University Taizhou 318000China The Second Affiliated Hospital Zhejiang University School of MedicineHangzhou 310009China

Macrophage senescence,manifested by the special form of durable cell cycle arrest and chronic low-grade inflammation like senescence-associated secretory phenotype,has long been consid-ered *** senescence of macrophages may lead to maladaptation,immune dysfunction,and finally the development of age-related diseases,infections,autoimmune diseases,and ***,it is a ubiquitous,multi-factorial,and dynamic complex phenomenon that also plays roles in remodeled processes,including wound repair and *** this review,we summarize some general molecular changes and several specific biomarkers during macrophage senescence,which may bring new sight to recognize senescent macrophages in different ***,we take an in-depth look at the functional changes in senescent macrophages,including metabolism,autophagy,polarization,phagocytosis,antigen presentation,and infiltration or ***,some degenerations and diseases associated with senescent macrophages as well as the mechanisms or relevant genetic regulations of senescent macrophages are integrated,not only emphasizing the possibility of regulating macrophage senescence to benefit age-associated diseases but also has an implication on the finding of potential tar-gets ordrugs clinically.

关键词： Macrophages Senescence Molecular changes Functional alterations Aging tissues Age-associated diseases drug treatment Genetic regulation

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Recent advances in the synthesis and application of N-heterocyclic carbene-based molecular cages

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Science China Chemistry 2024年第5期67卷 1510-1523页

作者： Qiongjie Chai Lixin Duan Yanzhe Ma Tianheng Hou Tao Tu Shanghai Key Laboratory of Molecular Catalysis and innovative Materials Department of ChemistryFudan UniversityShanghai 200438China State Key Laboratory of Organometallic Chemistry Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 200032China

N-Heterocyclic carbene(NHC)-based cages have emerged as a prominent and dynamic research area within the research field of chemistry. Leveraging the distinctive electronic and steric properties of NHC ligands, the design, synthesis, and application of these corresponding cages have garnered substantial scholarly interest. In recent years, we have witnessed the successful fabrication of diverse NHC-based cages through a range of synthetic methodologies, which hold significant potential for applications in molecular recognition and catalysis. In this review, we delve into the foundational synthetic strategies that underlie the creation of NHC-based cages, employing approaches encompassing metal–NHC chelation, coordination assembly,and covalent bonding. Additionally, we compile the diverse applications of these cages within catalytic processes and molecular recognition. Lastly, we shed light on the current limitations of synthesis and outline future trends in the development of NHCbased cages.

关键词： N-heterocyclic carbene molecular cages supramolecular chemistry synthetic strategies applications

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Prevalence of Cannabis Use around the World:A Systematic Review and Meta-Analysis,2000-2024

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China CDC weekly 2024年第25期6卷 597-604,I0013,I0014页

作者： Qianning Wang Zhen Qin Xing Xing He Zhu Zhongwei Jia National institute of Health Data Science Center for Drug Abuse Prevention and ControlPeking UniversityBeijingChina School of Public Health Peking UniversityBeijingChina

This study aims to perform a systematic review and meta-analysis on the global prevalence of cannabis use to inform drug prevention strategies,policy-making,and resource *** study initially screened 177,843 studies published between January 1,2000,and January 15,2024,using peer-reviewed databases including Web of Science,PubMed,Scopus,Embase,and Cochrane ***,595 studies were identified for data extraction,and 39 of these were selected as country-representative *** among the selected studies was assessed using the chi-squared test and I2 statistic,while sensitivity analysis was conducted to evaluate the robustness of the *** prevalence of cannabis use varied between 0.42%and 43.90%across 33 European countries,1.40%to 38.12%across 15 North and South American countries,0.30%to 19.10%across 16 Asian countries,and 1.30%to 48.70%across 18 Oceania and African *** pooled prevalence of cannabis use was 12.0%[95%confidence interval(CI):10.0,14.3]in countries where cannabis is legalized,compared to 5.4%(95%CI:4.3,6.9)in non-legalized *** findings indicate that the prevalence of cannabis use has disproportionately increased in most countries with the implementation of medical or recreational cannabis legalization policies and relevant geographic *** efforts are needed to monitor newly cannabis-legalized countries and prevent initial use.

关键词： prevention legal initially

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