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Equilibrative nucleoside transporter 3 supports microglial functions and protects against the progression of Huntington's disease in the mouse model

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Brain, Behavior, and Immunity 2024年 120卷 413-429页

作者： Lu, Ying-Sui Hung, Wei-Chien Hsieh, Yu-Ting Tsai, Pei-Yuan Tsai, Tsai-Hsien Fan, Hsiu-Han Chang, Ya-Gin Cheng, Hui-Kuei Huang, Shen-Yan Lin, Hsin-Chuan Lee, Yan-Hua Shen, Tzu-Hsiang Hung, Bing-Yu Tsai, Jin-Wu Dzhagalov, Ivan Cheng, Irene Han-Juo Lin, Chun-Jung Chern, Yijuang Hsu, Chia-Lin Institute of Microbiology and Immunology National Yang Ming Chiao Tung University Taipei Taiwan Taiwan International Graduate Program in Molecular Medicine National Yang Ming Chiao Tung University and Academia Sinica Taipei Taiwan Institute of Brain Science National Yang Ming Chiao Tung University Taipei Taiwan Institute of Biomedical Sciences Academia Sinica Taipei Taiwan Taiwan International Graduate Program in Interdisciplinary Neuroscience National Yang Ming Chiao Tung University and Academia Sinica Taipei Taiwan Biomedical Industry Ph.D. Program National Yang Ming Chiao Tung University Taipei Taiwan Brain Research Center National Yang Ming Chiao Tung University Taipei Taiwan School of Pharmacy College of Medicine National Taiwan University Taipei Taiwan

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by involuntary movements, cognitive deficits, and psychiatric symptoms. Currently, there is no cure, and only limited treatments are available to manage the symptoms and to slow down the disease's progression. The molecular and cellular mechanisms of HD's pathogenesis are complex, involving immune cell activation, altered protein turnover, and disturbance in brain energy homeostasis. Microglia have been known to play a dual role in HD, contributing to neurodegeneration through inflammation but also enacting neuroprotective effects by clearing mHTT aggregates. However, little is known about the contribution of microglial metabolism to HD progression. This study explores the impact of a microglial metabolite transporter, equilibrative nucleoside transporter 3 (ENT3), in HD. Known as a lysosomal membrane transporter protein, ENT3 is highly enriched in microglia, with its expression correlated with HD severity. Using the R6/2 ENT3^−/− mouse model, we found that the deletion of ENT3 increases microglia numbers yet worsens HD progression, leading to mHTT accumulation, cell death, and disturbed energy metabolism. These results suggest that the delicate balance between microglial metabolism and function is crucial for maintaining brain homeostasis and that ENT3 has a protective role in ameliorating neurodegenerative processes. © 2024 The Authors

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Association of computed variables with anthropometric indices in north indian children exposed to Bisphenol-A and heavy metals

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Discover Epidemics 2025年第1期2卷 1-17页

作者： Malik, Vivek Singh Attri, Savita Verma Dayal, Devi Ravindra, Khaiwal Department of Community Medicine and School of Public Health Post Graduate Institute of Medical Education and Research (PGIMER) Chandigarh India Department of Pediatrics Post Graduate Institute of Medical Education and Research (PGIMER) Chandigarh India Department of Telemedicine and Biomedical Informatics All India Institute of Medical Sciences (AIIMS) Rishikesh India

Obesity and underweight-associated environmental risk factors pose significant health challenges for the public, especially among children at an early stage of life. This study evaluates the association and potential role of combined exposure to Bisphenol-A (BPA) and heavy metals with anthropometric indices among North Indian children. This study also demonstrates the possibility of reverse causality, where obesity or underweight may result from BPA and heavy metals exposure among children. A total of 301 children were enrolled, grouped into obese, non-obese, and underweight. Urinary BPA and blood heavy metal levels were measured using LC–MS/MS and ICP-MS. Both quantitative variables, BPA and metals, were combined using the computed feature of SPSS, followed by linear regression analysis to identify the association with anthropometric indices (height, weight, BMI, waist and hip circumference, waist-to-stature ratio, and waist-to-hip ratio). A positive association was found among obese children for computed variables of combined exposure to BPA*Zn (WB) and a negative association with BPA*Fe (WB) for weight, height, and BMI. Similarly, a positive association was observed among underweight children for the computed variable of BPA*U (WB) with weight, height, and BMI. Significant negative associations were also observed for the BPA*Mg (WB) and BPA*Hg (WB) with WHR among obese and BPA*Cu (WB) with weight and BPA*Hg (WB) with WHR among underweight children. This study found a positive association for BPA*Se (WB) and BPA*Cd (S) with WC and WHR, respectively, among non-obese children. Our analysis suggests that BPA, combined with metals, is associated with both obesity and underweight. Both BPA and heavy metals are endocrine disruptive pollutants that may affect the metabolic pathways by substituting vital metals and inducing oxidative stress. This extends the scope for future research to address obesity and underweight among children. However, these results should be inter

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Overcoming the Blood-Brain Tumor Barrier with Docetaxel-Loaded Mesoporous Silica Nanoparticles for Treatment of Temozolomide-Resistant Glioblastoma

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ACS Applied Materials and Interfaces 2024年第17期16卷 21722-21735页

作者： Hsu, Tsung-I Chen, Yi-Ping Zhang, Rong-Lin Chen, Zih-An Wu, Cheng-Hsun Chang, Wen-Chang Mou, Chung-Yuan Chan, Hardy Wai-Hong Wu, Si-Han Ph.D. Program in Medical Neuroscience College of Medical Science and Technology Taipei Medical University and National Health Research Institutes Taipei110 Taiwan International Master Program in Medical Neuroscience College of Medical Science and Technology Taipei Medical University Taipei110 Taiwan Graduate Institute of Nanomedicine and Medical Engineering Taipei Medical University Taipei110 Taiwan International Ph.D. Program in Biomedical Engineering College of Biomedical Engineering Taipei Medical University Taipei110 Taiwan Nano Targeting & Therapy Biopharma Inc. Taipei110 Taiwan Graduate Institute of Medical Sciences College of Medicine Taipei Medical University Taipei110 Taiwan Department of Chemistry National Taiwan University Taipei106 Taiwan

While temozolomide (TMZ) has been a cornerstone in the treatment of newly diagnosed glioblastoma (GBM), a significant challenge has been the emergence of resistance to TMZ, which compromises its clinical benefits. Additionally, the nonspecificity of TMZ can lead to detrimental side effects. Although TMZ is capable of penetrating the blood-brain barrier (BBB), our research addresses the need for targeted therapy to circumvent resistance mechanisms and reduce off-target effects. This study introduces the use of PEGylated mesoporous silica nanoparticles (MSN) with octyl group modifications (C8-MSN) as a nanocarrier system for the delivery of docetaxel (DTX), providing a novel approach for treating TMZ-resistant GBM. Our findings reveal that C8-MSN is biocompatible in vitro, and DTX@C8-MSN shows no hemolytic activity at therapeutic concentrations, maintaining efficacy against GBM cells. Crucially, in vivo imaging demonstrates preferential accumulation of C8-MSN within the tumor region, suggesting enhanced permeability across the blood-brain tumor barrier (BBTB). When administered to orthotopic glioma mouse models, DTX@C8-MSN notably prolongs survival by over 50%, significantly reduces tumor volume, and decreases side effects compared to free DTX, indicating a targeted and effective approach to treatment. The apoptotic pathways activated by DTX@C8-MSN, evidenced by the increased levels of cleaved caspase-3 and PARP, point to a potent therapeutic mechanism. Collectively, the results advocate DTX@C8-MSN as a promising candidate for targeted therapy in TMZ-resistant GBM, optimizing drug delivery and bioavailability to overcome current therapeutic limitations. © 2024 The Authors. Published by American Chemical Society.

关键词： Tumors

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Synthesis of Methotrexate-Loaded Dumbbell-Shaped Titanium Dioxide/Gold Nanorods Coated with Mesoporous Silica and Decorated with Upconversion Nanoparticles for Near-Infrared-Driven Trimodal Cancer Treatment

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ACS Applied Materials and Interfaces 2023年第28期15卷 33335-33347页

作者： Dash, Pranjyan Thirumurugan, Senthilkumar Tseng, Ching-Li Lin, Yu-Chien Chen, Sung-Lung Dhawan, Udesh Chung, Ren-Jei Taipei10608 Taiwan Graduate Institute of Biomedical Materials and Tissue Engineering College of Biomedical Engineering Taipei Medical University Taipei110 Taiwan International Ph.D. Program in Biomedical Engineering College of Biomedical Engineering Taipei Medical University Taipei110 Taiwan Research Center of Biomedical Device College of Biomedical Engineering Taipei Medical University Taipei110 Taiwan International Ph.D. Program in Cell Therapy and Regenerative Medicine College of Medicine Taipei Medical University Taipei110 Taiwan Centre for the Cellular Microenvironment Division of Biomedical Engineering James Watt School of Engineering Mazumdar-Shaw Advanced Research Centre University of Glasgow GlasgowG116EW United Kingdom Taipei10608 Taiwan

This study prepared dumbbell-shaped titanium dioxide (TiO2)/gold nanorods (AuNRs) coated with mesoporous silica shells (mS) (AuNRs-TiO2@mS). Methotrexate (MTX) was further loaded into the AuNRs-TiO2@mS, and then upconversion nanoparticles (UCNPs) were decorated to form AuNRs-TiO2@mS-MTX: UCNP nanocomposites. TiO2 is used as an intense photosensitizer (PS) to produce cytotoxic reactive oxygen species (ROS), leading to photodynamic therapy (PDT). Concurrently, AuNRs exhibited intense photothermal therapy (PTT) effects and photothermal conversion efficiency. In vitro results suggested that these nanocomposites can kill oral cancer cells (HSC-3) without toxicity through irradiation of NIR laser, owing to the synergistic effect. The in vivo studies indicated that these nanocomposites exhibited excellent antitumor effects through synergistic PDT/PTT/chemotherapy under a near-infrared (NIR) 808 nm laser irradiation. Thus, these AuNRs-TiO2@mS: UCNP nanocomposites have great potential to undergo deep tissue penetration with enhanced synergistic effects through NIR-triggered light for cancer treatment. © 2023 American Chemical Society

关键词： Titanium dioxide

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Nano-modified viruses prime the tumor microenvironment and promote the photodynamic virotherapy in liver cancer

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Journal of biomedical Science 2024年第1期31卷 1页

作者： Ou, Da-Liang Liao, Zi-Xian Kempson, Ivan M. Li, Lin Yang, Pan-Chyr Tseng, S.-Ja Graduate Institute of Oncology National Taiwan University College of Medicine Taipei 10051 Taiwan National Taiwan University YongLin Institute of Health National Taiwan University Taipei 10051 Taiwan Institute of Medical Science and Technology National Sun Yat-Sen University Kaohsiung 80424 Taiwan Future Industries Institute University of South Australia Mawson Lakes 5095 SA Australia Department of Internal Medicine National Taiwan University College of Medicine Taipei 10051 Taiwan Institute of Biomedical Sciences Academia Sinica Taipei 11529 Taiwan Program in Precision Health and Intelligent Medicine Graduate School of Advanced Technology National Taiwan University Taipei 10051 Taiwan

Background: As of 2020, hepatocellular carcinoma (HCC), a form of liver cancer, stood as the third most prominent contributor to global cancer-related mortality. Combining immune checkpoint inhibitors (ICI) with other therapies has shown promising results for treating unresectable HCC, offering new opportunities. Recombinant adeno-associated viral type 2 (AAV2) virotherapy has been approved for clinical use but it efficacy is stifled through systemic administration. On the other hand, iron oxide nanoparticles (ION) can be cleared via the liver and enhance macrophage polarization, promoting infiltration of CD8⁺ T cells and creating a more favorable tumor microenvironment for immunotherapy. Methods: To enhance the efficacy of virotherapy and promote macrophage polarization towards the M1-type in the liver, ION-AAV2 were prepared through the coupling of ION-carboxyl and AAV2-amine using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)/N-hydroxysulfosuccinimide (Sulfo-NHS). Efficacy after systemic delivery of ION-AAV2 in an orthotopic HCC model was evaluated. Results: After 28 days, the tumor weight in mice treated with ION-AAV2 was significantly reduced by 0.56-fold compared to the control group. The ION-AAV2 treatment led to an approximate 1.80-fold increase in the level of tumor associated M1-type macrophages, while the number of M2-type macrophages was reduced by 0.88-fold. Moreover, a proinflammatory response increased the population of tumor-infiltrating CD8⁺ T cells in the ION-AAV2 group. This transformation converted cold tumors into hot tumors. Conclusions: Our findings suggest that the conjugation of ION with AAV2 could be utilized in virotherapy while simultaneously exploiting macrophage-modulating cancer immunotherapies to effectively suppress HCC growth. © 2023, The Author(s).

关键词： Adeno-associated virus Immune-promoting effect Iron oxide nanoparticles Macrophage Orthotopic hepatocellular carcinoma Photodynamic virotherapy

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A multi-trait GWAS identifies novel genes influencing albuminuria

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Nephrology Dialysis Transplantation 2025年第1期40卷 123-132页

作者： Tsao, Hsiao-Mei Lai, Tai-Shuan Chang, Yi-Cheng Hsiung, Chia-Ni Tsai, I-Jung Chou, Yu-Hsiang Wu, Vin-Cent Lin, Shuei-Liong Chen, Yung-Ming Division of Nephrology Department of Internal Medicine National Taiwan University Hospital Taipei Taiwan Department of Internal Medicine College of Medicine National Taiwan University Taipei Taiwan Graduate Institute of Medical Genomics and Proteomics College of Medicine National Taiwan University Taipei Taiwan Department of Internal Medicine National Taiwan University Hospital Taipei Taiwan Institute of Biomedical Sciences Academia Sinica Taipei Taiwan Program in Precision Medicine National Tsing Hua University Hsinchu Taiwan Institute of Molecular Medicine National Tsing Hua University Hsinchu Taiwan Department of Pediatrics National Taiwan University Children's Hospital Taipei Taiwan Graduate Institute of Physiology College of Medicine National Taiwan University Taipei Taiwan Department of Internal Medicine National Taiwan University Hospital Bei-Hu branch Taipei Taiwan

BACKGROUND: Albuminuria is common and is associated with increased risks of end-stage kidney disease and cardiovascular diseases, yet its underlying mechanism remains obscure. Previous genome-wide association studies (GWAS) for albuminuria did not consider gene pleiotropy and primarily focused on European ancestry populations. This study adopted a multi-trait analysis of GWAS (MTAG) approach to jointly analyze two vital kidney traits, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) to identify and prioritize the genes associated with UACR. METHODS: Data from the Taiwan Biobank from 2012 to 2023 were analyzed. GWAS of UACR and eGFR were performed separately and the summary statistics from these GWAS were jointly analyzed using MTAG. The polygenic risk scores (PRS) of UACR were constructed for validation. The UACR-associated loci were further fine-mapped and prioritized based on their deleteriousness, eQTL associations and relatedness to Mendelian kidney diseases. RESULTS: MTAG analysis of the UACR revealed 15 genetic loci, including 12 novel loci. The PRS for UACR was significantly associated with urinary albumin level (P < .001) and microalbuminuria (P = .001-.045). A list of priority genes was generated. Twelve genes with high priority included the albumin endocytic receptor gene LRP2 and ciliary gene IFT172. CONCLUSIONS: The findings of this multi-trait GWAS suggest that primary cilia play a role in sensing mechanical stimuli, leading to albumin endocytosis. The priority list of genes warrants further translational investigation to reduce albuminuria. © The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.

关键词： albumin endocytosis albuminuria GWAS multi-trait analysis of GWAS primary cilia

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NIR-Responsive Methotrexate-Modified Iron Selenide Nanorods for Synergistic Magnetic Hyperthermic, Photothermal, and Chemodynamic Therapy

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ACS Applied Materials and Interfaces 2024年第20期16卷 25622-25636页

作者： Thirumurugan, Senthilkumar Muthiah, Kayalvizhi Samuvel Lin, Yu-Chien Dhawan, Udesh Liu, Wai-Ching Wang, An-Ni Liu, Xinke Hsiao, Michael Tseng, Ching-Li Chung, Ren-Jei No. 1 Section 3 Zhongxiao East Road Taipei10608 Taiwan Centre for the Cellular Microenvironment Division of Biomedical Engineering James Watt School of Engineering Mazumdar-Shaw Advanced Research Centre University of Glasgow GlasgowG116EW United Kingdom Faculty of Science and Technology Technological and Higher Education Institute of Hong Kong Hong Kong New Territories999077 Hong Kong Scrona AG Grubenstrasse 9 Zürich8045 Switzerland College of Materials Science and Engineering Chinese Engineering and Research Institute of Microelectronics Shenzhen University Shenzhen518060 China Department of Electrical and Computer Engineering National University of Singapore Singapore117583 Singapore Genomics Research Center Academia Sinica Taipei115 Taiwan Department and Graduate Institute of Veterinary Medicine School of Veterinary Medicine National Taiwan University Taipei10617 Taiwan Graduate Institute of Biomedical Materials and Tissue Engineering College of Biomedical Engineering Taipei Medical University Taipei11031 Taiwan International Ph.D. Program in Biomedical Engineering College of Biomedical Engineering Taipei Medical University Taipei11031 Taiwan Research Center of Biomedical Device College of Biomedical Engineering Taipei Medical University Taipei11031 Taiwan International Ph.D. Program in Cell Therapy and Regenerative Medicine College of Medicine Taipei Medical University Taipei11031 Taiwan Taipei10608 Taiwan

Breast cancer is a malignant tumor with a high mortality rate among women. Therefore, it is necessary to develop novel therapies to effectively treat this disease. In this study, iron selenide nanorods (FeSe2 NRs) were designed for use in magnetic hyperthermic, photothermal, and chemodynamic therapy (MHT/PTT/CDT) for breast cancer. To illustrate their efficacy, FeSe2 NRs were modified with the chemotherapeutic agent methotrexate (MTX). MTX-modified FeSe2 (FeSe2-MTX) exhibited excellent controlled drug release properties. Fe2+ released from FeSe2 NRs induced the release of •OH from H2O2 via a Fenton/Fenton-like reaction, enhancing the efficacy of CDT. Under alternating magnetic field (AMF) stimulation and 808 nm laser irradiation, FeSe2-MTX exerted potent hyperthermic and photothermal effects by suppressing tumor growth in a breast cancer nude mouse model. In addition, FeSe2 NRs can be used for magnetic resonance imaging in vivo by incorporating their superparamagnetic characteristics into a single nanomaterial. Overall, we presented a novel technique for the precise delivery of functional nanosystems to tumors that can enhance the efficacy of breast cancer treatment. © 2024 The Authors. Published by American Chemical Society

关键词： Magnetic resonance imaging

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McSNAC:A software to approximate first-order signaling networks from mass cytometry data

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Quantitative Biology 2023年第1期11卷 59-71页

作者： Darren Wethington Sayak Mukherjee Jayajit Das Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research InstituteNationwide Children’s HospitalColumbusOhio 43205United States Biomedical Sciences Graduate Program College of MedicineThe Ohio State UniversityColumbusOhio 43210United States Department of Pediatrics College of MedicineThe Ohio State UniversityColumbusOhio 43210United States Pelotonia Institute for Immuno-Oncology College of MedicineThe Ohio State UniversityColumbusOhio 43210United States DepartmentofBiomedicalInformatics CollegeofMedicineTheOhioStateUniversityColumbusOhio43210United States Biophysics Graduate Program The Ohio State UniversityColumbusOhio 43210United States Battelle Memorial Institute ColumbusOhio 43201United States

Background:Mass cytometry(CyTOF)gives unprecedented opportunity to simultaneously measure up to 40 proteins in single cells,with a theoretical potential to reach 100 *** high-dimensional single-cell information can be very useful in dissecting mechanisms of cellular *** particular,measuring abundances of signaling proteins like phospho-proteins can provide detailed information on the dynamics of single-cell signaling ***,computational analysis is required to reconstruct such networks with a mechanistic ***:We propose our Mass cytometry Signaling Network Analysis Code(McSNAC),a new software capable of reconstructing signaling networks and estimating their kinetic parameters from CyTOF *** approximates signaling networks as a network of first-order reactions between *** assumption often breaks down as signaling reactions can involve binding and unbinding,enzymatic reactions,and other nonlinear ***,McSNAC may be limited to approximating indirect interactions between protein species,as cytometry experiments are only able to assay a small fraction of protein species involved in ***:We carry out a series of in silico experiments here to show(1)McSNAC is capable of accurately estimating the ground-truth model in a scalable manner when given data originating from a first-order system;(2)McSNAC is capable of qualitatively predicting outcomes to perturbations of species abundances in simple second-order reaction models and in a complex in silico nonlinear signaling network in which some proteins are ***:These findings demonstrate that McSNAC can be a valuable screening tool for generating models of signaling networks from time-stamped CyTOF data.

关键词： single-cell CyTOF data signaling network kinetics ODE McSNAC

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deCS:A Tool for Systematic Cell Type Annotations of Single-cell RNA Sequencing Data among Human Tissues

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Genomics, Proteomics & Bioinformatics 2023年第2期21卷 370-384页

作者： Guangsheng Pei Fangfang Yan Lukas M.Simon Yulin Dai Peilin Jia Zhongming Zhao Center for Precision Health School of Biomedical InformaticsThe University of Texas Health Science Center at HoustonHoustonTX 77030USA Therapeutic Innovation Center Baylor College of MedicineHoustonTX 77030USA Human Genetics Center School of Public HealthThe University of Texas Health Science Center at HoustonHoustonTX 77030USA MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences HoustonTX 77030USA Department of Biomedical Informatics Vanderbilt University Medical CenterNashvilleTN 37203USA CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China

Single-cell RNA sequencing(scRNA-seq)is revolutionizing the study of complex and dynamic cellular ***,cell type annotation remains a main challenge as it largely relies on a priori knowledge and manual curation,which is cumbersome and *** increasing number of scRNA-seq datasets,as well as numerous published genetic studies,has motivated us to build a comprehensive human cell type reference ***,we present decoding Cell type Specificity(deCS),an automatic cell type annotation method augmented by a comprehensive collection of human cell type expression profiles and marker *** used deCS to annotate scRNAseq data from various tissue types and systematically evaluated the annotation accuracy under different conditions,including reference panels,sequencing depth,and feature selection *** results demonstrate that expanding the references is critical for improving annotation *** to many existing state-of-the-art annotation tools,deCS significantly reduced computation time and increased *** can be integrated into the standard scRNA-seq analytical pipeline to enhance cell type ***,we demonstrated the broad utility of deCS to identify trait-cell type associations in 51 human complex traits,providing deep insights into the cellular mechanisms underlying disease pathogenesis.

关键词： Cell type-specific enrichment analysis scRNA-seq Cell type annotation Trait-cell type association Cell typemarkergene

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Targeted PERK inhibition with biomimetic nanoclusters confers preventative and interventional benefits to elastase-induced abdominal aortic aneurysms

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Bioactive Materials 2023年第8期26卷 52-63页

作者： Nisakorn Yodsanit Takuro Shirasu Yitao Huang Li Yin Zain Husain Islam Alexander Christopher Gregg Alessandra Marie Riccio Runze Tang Eric William Kent Yuyuan Wang Ruosen Xie Yi Zhao Mingzhou Ye Jingcheng Zhu Yi Huang Nicholas Hoyt Mengxue Zhang John A.Hossack Morgan Salmon K.Craig Kent Lian-Wang Guo Shaoqin Gong Bowen Wang Department of Biomedical Engineering Wisconsin Institute for DiscoveryUniversity of Wisconsin-MadisonMadisonWI53715USA Department of Ophthalmology and Visual Sciences University of Wisconsin-MadisonMadisonWI53715USA Department of Surgery School of MedicineUniversity of VirginiaCharlottesvilleVA22908USA The Biomedical Sciences Graduate Program(BIMS) School of MedicineUniversity of VirginiaCharlottesvilleVA22908USA Department of Biomedical Engineering School of EngineeringUniversity of VirginiaCharlottesvilleVA22908USA School of Medicine and Health Sciences George Washington UniversityWashingtonDC20052USA Department of Cardiac Surgery Michigan MedicineUniversity of MichiganAnn ArborMI48109USA

Abdominal aortic aneurysm(AAA)is a progressive aortic dilatation,causing~80%mortality upon ***,there is no approved drug therapy for *** repairs are invasive and risky and thus not recommended to patients with small AAAs which,however,account for~90%of the newly diagnosed *** is therefore a compelling unmet clinical need to discover effective non-invasive strategies to prevent or slow down AAA *** contend that the first AAA drug therapy will only arise through discoveries of both effective drug targets and innovative delivery *** is substantial evidence that degenerative smooth muscle cells(SMCs)orchestrate AAA pathogenesis and *** this study,we made an exciting finding that PERK,the endoplasmic reticulum(ER)stress Protein Kinase R-like ER Kinase,is a potent driver of SMC degeneration and hence a potential therapeutic ***,local knockdown of PERK in elastase-challenged aorta significantly attenuated AAA lesions in *** parallel,we also conceived a biomimetic nanocluster(NC)design uniquely tailored to AAA-targeting drug *** NC demonstrated excellent AAA homing via a platelet-derived biomembrane coating;and when loaded with a selective PERK inhibitor(PERKi,GSK2656157),the NC therapy conferred remarkable benefits in both preventing aneurysm development and halting the progression of pre-existing aneurysmal lesions in two distinct rodent models of *** summary,our current study not only establishes a new intervention target for mitigating SMC degeneration and aneurysmal pathogenesis,but also provides a powerful tool to facilitate the development of effective drug therapy of AAA.

关键词： Abdominal aortic aneurysm ER stress PERK Biomimetic nanomedicine Targeted delivery

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