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Protease-Activatable Porphyrin Molecular Beacon for Osteoarthritis Management

Chemical & Biomedical Imaging 2023年第1期1卷 66-80页

作者： Connor Walsh Maneesha A.Rajora Lili Ding Sayaka Nakamura Helal Endisha jason rockel Juan Chen Mohit Kapoor Gang Zheng Princess Margaret Cancer Centre University Health NetworkTorontoON M5G 1L7Canada Institute of Biomedical Engineering University of TorontoTorontoON M5S 3G9Canada Schroeder Arthritis Institute University Health NetworkTorontoON M5T 0S8Canada Krembil Research Institute University Health NetworkTorontoON M5T 0S8Canada Department of Medical Biophysics University of TorontoTorontoON M5G 1L7Canada

Despite the substantial burden posed by osteoarthritis(OA)globally,difffcult challenges remain in achieving early OA diagnosis and adopting effective disease-modifying *** this study,we use a biomolecular approach to address these limitations by creating an inherently theranostic molecular beacon whose imaging and therapeutic capabilities are activated by early pathological changes in *** platform comprised(1)a peptide linker substrate for metalloproteinase-13(MMP-13),a pathological protease upregulated in OA,which was conjugated to(2)a porphyrin moiety with inherent multimodal imaging,photodynamic therapy,and drug delivery capabilities,and(3)a quencher that silences the porphyrin’s endogenous ffuorescence and photoreactivity when the beacon is *** diseased OA tissue with upregulated MMP-13 expression,this porphyrin molecular beacon(PP_(MMP13B))was expected to undergo sequence-speciffc cleavage,yielding porphyrin fragments with restored ffuorescence and photoreactivity that could,respectively,be used as a readout of MMP13 activity within the joint for early OA imaging and disease-targeted photodynamic *** study focused on the synthesis and characterization of PPMMP13B,followed by a proof-of-concept evaluation of its OA imaging and drug delivery *** solution,PP_(MMP13B)demonstrated 90%photoactivity quenching in its intact form and robust MMP-13 activation,yielding a 13-fold increase in ffuorescence *** vitro,PP_(MMP13B)was readily uptaken and activated in an MMP-13 cell expressiondependent manner in primary OA synoviocytes without exuding signiffcant *** translated into effective intra-articular cartilage(to a 50μm depth)and synovial uptake and activation of PP_(MMP13B)in a destabilization of the medial meniscus OA mouse model,yielding strong ffuorescence contrast(7-fold higher signal than background)at the diseased joint *** results provide the foundation for further exploration of porphyrin mol

关键词： Molecular Beacon Porphyrin Osteoarthritis Photodynamic Therapy Molecular Imaging Fluorescence Drug Delivery

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HIF-1α and MIF enhance neutrophil-driven type 3 immunity and chondrogenesis in a murine spondyloarthritis model

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Cellular & Molecular Immunology 2024年第7期21卷 770-786页

作者： Akihiro Nakamura Sungsin Jo Sayaka Nakamura Mansi K.Aparnathi Shaghayegh Foroozan Boroojeni Mariia Korshko Ye-Soo Park Himanshi Gupta Sandra Vijayan jason S.rockel Mohit Kapoor Igor Jurisica Tae-Hwan Kim Nigil Haroon Schroeder Arthritis Institute University Health NetworkTorontoONM5T 0S8Canada Krembil Research Institute University Health NetworkTorontoONM5T 0S8Canada Institute of Medical Science Temerty Faculty of Medicine of MedicineUniversity of TorontoTorontoONM5S 1A8Canada Department of Medicine Division of RheumatologyQueen’s UniversityKingstonONK7L2V6Canada Translational Institute of Medicine School of MedicineQueen’s UniversityKingstonONK7L 2V6Canada Division of Rheumatology Kingston Health Science CentreKingstonONK7L 2V6Canada Hanyang University Institute for Rheumatology Research(HYIRR) Seoul04763Republic of Korea Department of Biology College of Natural SciencesSoonchunhyang UniversityAsan31538Republic of Korea Department of Orthopedic Surgery Guri HospitalHanyang University College of MedicineGuri11293Republic of Korea Department of Surgery and Department of Laboratory Medicine and Pathobiology University of TorontoTorontoONM5T 1P5Canada Departments of Medical Biophysics and Comp.Science and Faculty of Dentistry University of TorontoTorontoONM5G 1L7Canada Institute of Neuroimmunology Slovak Academy of Sciences85410BratislavaSlovakia Department of Rheumatology Hanyang University Hospital for Rheumatic DiseasesSeoul04763Republic of Korea

The hallmarks of spondyloarthritis(SpA)are type 3 immunity-driven inflammation and new bone formation(NBF).Macrophage migration inhibitory factor(MIF)was found to be a key driver of the pathogenesis of SpA by amplifying type 3 immunity,yet MIF-interacting molecules and networks remain ***,we identified hypoxia-inducible factor-1 alpha(HIF1A)as an interacting partner molecule of MIF that drives SpA pathologies,including inflammation and ***1A expression was increased in the joint tissues and synovial fluid of SpA patients and curdlan-injected SKG(curdlan-SKG)mice compared to the respective *** hypoxic conditions in which HIF1A was stabilized,human and mouse neutrophils exhibited substantially increased expression of MIF and IL-23,an upstream type 3 immunity-related *** to MIF,systemic overexpression of IL-23 induced SpA pathology in SKG mice,while the injection of a HIF1A-selective inhibitor(PX-478)into curdlan-SKG mice prevented or attenuated SpA pathology,as indicated by a marked reduction in the expression of MIF and ***,genetic deletion of MIF or HIF1A inhibition with PX-478 in IL-23-overexpressing SKG mice did not induce evident arthritis or NBF,despite the presence of psoriasis-like dermatitis and *** also found that MIF-and IL-23-expressing neutrophils infiltrated areas of the NBF in curdlan-SKG *** neutrophils potentially increased chondrogenesis and cell proliferation via the upregulation of STAT3 in periosteal cells and ligamental cells during endochondral ***,these results provide supporting evidence for an MIF/HIF1A regulatory network,and inhibition of HIF1A may be a novel therapeutic approach for SpA by suppressing type 3 immunity-mediated inflammation and NBF.

关键词： Endochondral ossification Hypoxia-inducible factor-1 alpha Interleukin-23 Macrophage migration inhibitory factor Neutrophil Spondyloarthritis

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