Alzheimer＇s disease, the leading cause of dementia in the elderly, is a complex neurodegenerative disorder which leads to a progressive decline in cognitive functions. A rapid screening model is highly demanded for i...Alzheimer＇s disease, the leading cause of dementia in the elderly, is a complex neurodegenerative disorder which leads to a progressive decline in cognitive functions. A rapid screening model is highly demanded for identification and evaluation of novel anti-Alzheimer＇s disease drugs from a large numbers of compounds. Until now, numerous studies utilized zebrafish model for drug discovery. Since aluminum can induce a similar biological activity in zebrafish as in Alzheimer patients, in this study, we developed a novel animal model using 3 to 5 day post-fertilization larval zebrafish by optimizing the doses and duration of aluminum chloride exposure. Six anti-Alzheimer＇s disease drugs with a variety of mechanisms were tested to validate the newly developed zebrafish model. Importantly, Rivastigmine, ThT, Flurbiprofen and AM-117 could increase the value of Dyskinesia Recovery Rate by 53.4-64%, 169.4-200%, 54.5-96% and 70.9-121%, respectively. Rivastigmine, Memantine, ThT, Flurbiprofen, Rosiglitazone and AM-117 improved the value of Response Efficiency by 86.6-175.1%, 28.2-66.6%, 127.2-236.5%, 118.3-323.7%, 26.6-140.8% and 70.2-161.4%, respectively. Our results suggest that the zebrafish model developed in this study could be a useful tool for high throughput screening of potential novel anti-Alzheimer＇s disease leading compounds targeting acetylcholinesterase, N-methyl-D-aspartic acid receptor, γ-secretase, peroxisome proliferator-activated receptor-γand amyloid-β.展开更多
Tau oligomers are recognized for their critical role in causing neuronal toxicity and synaptic dysfunction in a diverse array of neurodegenerative diseases collectively referred to as tauopathies.However,the discovery...Tau oligomers are recognized for their critical role in causing neuronal toxicity and synaptic dysfunction in a diverse array of neurodegenerative diseases collectively referred to as tauopathies.However,the discovery of drugs that specifically target tau oligomers has been impeded by the absence of appropriate screening methods.Here,we suggest a drug screening platform based on tau amyloid corona-shelled nanoparticles(TACONs)to assess the efficacy of tau oligomer-degrading agents through aggregation-induced colorimetric responses of TACONs.TACONs were engineered via the encapsulation of gold nanoparticles(AuNPs)with homogeneous tau oligomers by leveraging heparin as a co-factor.Our TACON-based strategy harnesses two primary functions of AuNPs:(i)catalytic activators for the selective isolation of tau oligomers and(ii)optical reporters for quantifying colorimetric responses induced by tau oligomer-degrading agents.To validate this approach,we employed proteases that can degrade tau oligomers(protease XIV and plasmin)along with various small molecules known to aid in the treatment of tauopathies.Furthermore,we significantly enhanced screening efficiency by integrating a time-series deep learning architecture,enabling rapid identification of effective agents within 1 h.These results highlight the great potential of a deep learning-assisted TACON-based drug screening platform as a powerful strategy for streamlining drug discovery in tauopathies.展开更多
Articular cartilage,which is mainly composed of collagen Ⅱ,enables smooth skeletal movement.Degeneration of collagen Ⅱ can be caused by various events,such as injury,but degeneration especially increases over the co...Articular cartilage,which is mainly composed of collagen Ⅱ,enables smooth skeletal movement.Degeneration of collagen Ⅱ can be caused by various events,such as injury,but degeneration especially increases over the course of normal aging.Unfortunately,the body does not fully repair itself from this type of degeneration,resulting in impaired movement.Microfracture,an articular cartilage repair surgical technique,has been commonly used in the clinic to induce the repair of tissue at damage sites.Mesenchymal stem cells(MSC)have also been used as cell therapy to repair degenerated cartilage.However,the therapeutic outcomes of all these techniques vary in different patients depending on their age,health,lesion size and the extent of damage to the cartilage.The repairing tissues either form fibrocartilage or go into a hypertrophic stage,both of which do not reproduce the equivalent functionality of endogenous hyaline cartilage.One of the reasons for this is inefficient chondrogenesis by endogenous and exogenous MSC.Drugs that promote chondrogenesis could be used to induce self-repair of damaged cartilage as a non-invasive approach alone,or combined with other techniques to greatly assist the therapeutic outcomes.The recent development of human induced pluripotent stem cell(iPSCs),which are able to self-renew and differentiate into multiple cell types,provides a potentially valuable cell resource for drug screening in a“more relevant”cell type.Here we report a screening platform using human iPSCs in a multi-well plate format to identify compounds that could promote chondrogenesis.展开更多
Cardiac fibrosis has emerged as the primary cause of morbidity,disability,and even mortality in numerous nations.In light of the advancements in precision medicine strategies,substantial attention has been directed to...Cardiac fibrosis has emerged as the primary cause of morbidity,disability,and even mortality in numerous nations.In light of the advancements in precision medicine strategies,substantial attention has been directed toward the development of a practical and precise drug screening platform customized for individual patients.In this study,we introduce a biomimetic cardiac fibrosis-on-a-chip incorporating structural color hydrogels(SCHs)to enable optical high-throughput drug screening.By cocultivating a substantial proportion of cardiac fibroblasts(CFBs)with cardiomyocytes on the SCH,this biomimetic fibrotic microtissue successfully replicates the structural components and biomechanical properties associated with cardiac fibrosis.More importantly,the structural color shift observed in the SCH can be indicative of cardiac contraction and relaxation,making it a valuable tool for evaluating fibrosis progression.By incorporating such fibrotic microtissue into a microfluidic gradient chip,we develop a biomimetic optical cardiac fibrosis-on-a-chip platform that accurately and efficiently screens potential anti-fibrotic drugs.These characteristics suggest that this microphysiological platform possesses the capability to establish a preclinical framework for screening cardiac drugs,and may even contribute to the advancement ofprecisionmedicine.展开更多
基金Acknowledgments The authors thank the National Natural Science Foundation of China （81302646）, Natural Science Foundation of Zhejiang Province （LQ13H300002）, Science Technology Department of Zhejiang Province （2015F50015） and Health and Family Planning commission of Zhejiang Province （XKQ-010-001 and 2013KYB070） for financial support.
文摘Alzheimer＇s disease, the leading cause of dementia in the elderly, is a complex neurodegenerative disorder which leads to a progressive decline in cognitive functions. A rapid screening model is highly demanded for identification and evaluation of novel anti-Alzheimer＇s disease drugs from a large numbers of compounds. Until now, numerous studies utilized zebrafish model for drug discovery. Since aluminum can induce a similar biological activity in zebrafish as in Alzheimer patients, in this study, we developed a novel animal model using 3 to 5 day post-fertilization larval zebrafish by optimizing the doses and duration of aluminum chloride exposure. Six anti-Alzheimer＇s disease drugs with a variety of mechanisms were tested to validate the newly developed zebrafish model. Importantly, Rivastigmine, ThT, Flurbiprofen and AM-117 could increase the value of Dyskinesia Recovery Rate by 53.4-64%, 169.4-200%, 54.5-96% and 70.9-121%, respectively. Rivastigmine, Memantine, ThT, Flurbiprofen, Rosiglitazone and AM-117 improved the value of Response Efficiency by 86.6-175.1%, 28.2-66.6%, 127.2-236.5%, 118.3-323.7%, 26.6-140.8% and 70.2-161.4%, respectively. Our results suggest that the zebrafish model developed in this study could be a useful tool for high throughput screening of potential novel anti-Alzheimer＇s disease leading compounds targeting acetylcholinesterase, N-methyl-D-aspartic acid receptor, γ-secretase, peroxisome proliferator-activated receptor-γand amyloid-β.
基金supported by National Research Foundation of Korea(NRF)grants funded by the Korean Government(MSIP)(Grant Numbers:RS-2025-00553786,RS-2024-00400563,RS-2024-00409958,RS-2025-02263504,RS-2025-02263404,and RS-2025-00519761)the BK21 FOUR Institute of Precision Public Health,the Science and Technology Commercialization Agency(Grant Number:RS-2024-00423580)+1 种基金Soseon Foundationsupported by Korea Health Industry Development Institute(KHIDI),funded by the Ministry of Health and Welfare(Grant Numbers:RS-2023-00274152 and RS-2023-00265159).
文摘Tau oligomers are recognized for their critical role in causing neuronal toxicity and synaptic dysfunction in a diverse array of neurodegenerative diseases collectively referred to as tauopathies.However,the discovery of drugs that specifically target tau oligomers has been impeded by the absence of appropriate screening methods.Here,we suggest a drug screening platform based on tau amyloid corona-shelled nanoparticles(TACONs)to assess the efficacy of tau oligomer-degrading agents through aggregation-induced colorimetric responses of TACONs.TACONs were engineered via the encapsulation of gold nanoparticles(AuNPs)with homogeneous tau oligomers by leveraging heparin as a co-factor.Our TACON-based strategy harnesses two primary functions of AuNPs:(i)catalytic activators for the selective isolation of tau oligomers and(ii)optical reporters for quantifying colorimetric responses induced by tau oligomer-degrading agents.To validate this approach,we employed proteases that can degrade tau oligomers(protease XIV and plasmin)along with various small molecules known to aid in the treatment of tauopathies.Furthermore,we significantly enhanced screening efficiency by integrating a time-series deep learning architecture,enabling rapid identification of effective agents within 1 h.These results highlight the great potential of a deep learning-assisted TACON-based drug screening platform as a powerful strategy for streamlining drug discovery in tauopathies.
文摘Articular cartilage,which is mainly composed of collagen Ⅱ,enables smooth skeletal movement.Degeneration of collagen Ⅱ can be caused by various events,such as injury,but degeneration especially increases over the course of normal aging.Unfortunately,the body does not fully repair itself from this type of degeneration,resulting in impaired movement.Microfracture,an articular cartilage repair surgical technique,has been commonly used in the clinic to induce the repair of tissue at damage sites.Mesenchymal stem cells(MSC)have also been used as cell therapy to repair degenerated cartilage.However,the therapeutic outcomes of all these techniques vary in different patients depending on their age,health,lesion size and the extent of damage to the cartilage.The repairing tissues either form fibrocartilage or go into a hypertrophic stage,both of which do not reproduce the equivalent functionality of endogenous hyaline cartilage.One of the reasons for this is inefficient chondrogenesis by endogenous and exogenous MSC.Drugs that promote chondrogenesis could be used to induce self-repair of damaged cartilage as a non-invasive approach alone,or combined with other techniques to greatly assist the therapeutic outcomes.The recent development of human induced pluripotent stem cell(iPSCs),which are able to self-renew and differentiate into multiple cell types,provides a potentially valuable cell resource for drug screening in a“more relevant”cell type.Here we report a screening platform using human iPSCs in a multi-well plate format to identify compounds that could promote chondrogenesis.
基金supported by the National Key Research and Development Program of China(2020YFA0710800 and 2020YFA0908200)the Key Program of the National Natural Science Foundation of China(81930043 and 82330055)+2 种基金the National Natural Science Foundation of China(T2225003,82001719,52073060,and 61927805)the Nanjing Medical Science and Technique Development Foundation(ZKX21019)the Clinical Trials from Nanjing Drum Tower Hospital(2022-LCYJ-ZD-01).
文摘Cardiac fibrosis has emerged as the primary cause of morbidity,disability,and even mortality in numerous nations.In light of the advancements in precision medicine strategies,substantial attention has been directed toward the development of a practical and precise drug screening platform customized for individual patients.In this study,we introduce a biomimetic cardiac fibrosis-on-a-chip incorporating structural color hydrogels(SCHs)to enable optical high-throughput drug screening.By cocultivating a substantial proportion of cardiac fibroblasts(CFBs)with cardiomyocytes on the SCH,this biomimetic fibrotic microtissue successfully replicates the structural components and biomechanical properties associated with cardiac fibrosis.More importantly,the structural color shift observed in the SCH can be indicative of cardiac contraction and relaxation,making it a valuable tool for evaluating fibrosis progression.By incorporating such fibrotic microtissue into a microfluidic gradient chip,we develop a biomimetic optical cardiac fibrosis-on-a-chip platform that accurately and efficiently screens potential anti-fibrotic drugs.These characteristics suggest that this microphysiological platform possesses the capability to establish a preclinical framework for screening cardiac drugs,and may even contribute to the advancement ofprecisionmedicine.
