The growing concern over bacterial multidrug resistance has led to a heightened interest in antimicrobial peptides(AMPs)known for their strong efficacy,albeit with high toxicity.In order to retain the potent antibacte...The growing concern over bacterial multidrug resistance has led to a heightened interest in antimicrobial peptides(AMPs)known for their strong efficacy,albeit with high toxicity.In order to retain the potent antibacterial activity of AMPs while minimizing their systemic toxicity,we introduce a conjugate strategy with selective infection-activatable and bacteria-targeting capabilities.A series of colistin prodrugs with well-defined structures were developed by attaching a reactive oxygen species-responsive phenylboronic acid linker to all amines of colistin,followed by covalent linkage to sugars through the reaction of boronic acid and a diol moiety.Among these prodrugs,a lactosyl-functionalized colistin prodrug,LaP-Col,was identified because of its minimal toxicity toward normal tissues and ability to target bacteria.It exhibits a maximum tolerated dose over 20 times greater than colistin and minimal nephrotoxicity.In a mouse model of bacterial pneumonia,intravenous administration of LaP-Col led to its accumulation in the infected lung.It effectively killed bacteria,significantly improving the therapeutic efficacy and mouse survival rates.Overall,this study presents a prodrug strategy that effectively reduces the inherent high toxicity of colistin and enhances its therapeutic targeting efficacy,which has promising implications for modifying other potent but toxic AMPs.展开更多
To the Editor:Segmentectomy is an effective surgical method to cure early lung cancer.Segmentectomy which is designed precisely can preserve the pulmonary function to the maximal level with comparable post-operative s...To the Editor:Segmentectomy is an effective surgical method to cure early lung cancer.Segmentectomy which is designed precisely can preserve the pulmonary function to the maximal level with comparable post-operative survival rate.However,there are still some factors such as surgical experience,anatomy familiarity,and intersegmental plane identification,influencing the application of segmentectomy.Identifying the intersegmental plane is an important intra-operative procedure for successful lung segmentectomy.Currently,there are several methods used by surgeons,including(1)inflation-deflation:displaying the border between inflated and deflated lung segments;(2)injection of indocyanine green by an intravenous or intrabronchial route.These methods have obvious shortcomings:the"inflation-deflation"method needs about 10 to 15 minutes of intra-operative time,which reduces operation efficiency and increases patient risk;injection of indocyanine helps to identify the intersegmental plane but there are risks of toxicity and allergies associated with indocyanine.展开更多
基金supported by the Shandong Provincial Higher Edu-cation Institutions“Youth Innovation Team Plan”Project(No.2022KJ280)“Stomatology+X”University and Hospital Integration Innovation Project of Binzhou Medical University(No.KQRH2024MS003)Initial Scientific Research Fund of Young Teachers in Binzhou Medical University(No.BY2021KYQD23).
文摘Critical-sized calvarial defects remain a formidable clinical challenge due to dyssynchronous immunomodulation-osteogenesis coupling and unregulated growth factor release.Here,a bioinspired porous core-shell microsphere system(GCI@HPPS)is developed,integrating hydroxyapatite(HA)-loaded shell,surfaceimmobilized SDF-1α,and IGF-1-encapsulated cores to immunomodulate osteoimmune microenvironment and osteogenesis promotion.The hierarchical architecture achieved spatiotemporally programmed release:HA degradation-dependent mineralization,SDF-1α-mediated BMSC chemotaxis,and sustained IGF-1 delivery,mimicking natural bone repair cascades.Dual covalent/vip-host crosslinking(GelMA/Ac-β-CD)enhanced compressive strength,while polydopamine functionalization of microspheres conferred electroactivity,hydro-philicity,ROS/RNS scavenging(97.29%ABTS•+elimination),antibacterial efficacy(>99.8%)and hemostasis.In vitro,GCI@HPPS mitigates oxidative stress,induces M2 macrophage polarization,and suppresses inflamma-tory cascades while concomitantly enhancing endogenous BMSC recruitment,proliferation,and osteogenic differentiation.Proteomics revealed a tetradic anti-inflammatory mechanisms of GCI@HPPS:NF-κB/P-JNK suppression,pro-inflammatory cytokines downregulation,mitochondrial oxidative modulation,and STAT6-driven M2 polarization.In vivo,GCI@HPPS achieved calvarial defect closure at 8 weeks through porous matrix-guided cellular infiltration,and SDF-1α/IGF-1-mediated chemotaxis,Rho/MAPK signaling pathway activation balancing osteoclast-osteoblast dynamics,stage-specific osteogenic induction and AGE-RAGE/VEGFcoupled angiogenesis-osteogenesis.This work pioneers a spatiotemporal delivery paradigm that coordinates inflammation modulation,stem cell recruitment,osteogenic differentiation,and mineralization phases,offering a promising approach for complex cranial reconstruction.
基金supported by the National Key R&D Program of China(2023YFB3809904)the National Natural Science Foundation of China(U22A20156,52073102,51873070,32171319,52203165,52403183)+4 种基金the Guangdong Provincial Pearl River Talents Program(2019QN01Y090)the Guangdong Basic and Applied Basic Research Foundation(2023B1515020086)the Science and Technology Planning Project of Guangdong Province(2023B1212060013)the Guangzhou Innovation and Entrepreneurship Team Projects(2024A03J1055)the Guangdong Provincial Key Laboratory of Cancer Pathogenesis and Precision Diagnosis and Treatment(2024B1212030002)。
文摘The growing concern over bacterial multidrug resistance has led to a heightened interest in antimicrobial peptides(AMPs)known for their strong efficacy,albeit with high toxicity.In order to retain the potent antibacterial activity of AMPs while minimizing their systemic toxicity,we introduce a conjugate strategy with selective infection-activatable and bacteria-targeting capabilities.A series of colistin prodrugs with well-defined structures were developed by attaching a reactive oxygen species-responsive phenylboronic acid linker to all amines of colistin,followed by covalent linkage to sugars through the reaction of boronic acid and a diol moiety.Among these prodrugs,a lactosyl-functionalized colistin prodrug,LaP-Col,was identified because of its minimal toxicity toward normal tissues and ability to target bacteria.It exhibits a maximum tolerated dose over 20 times greater than colistin and minimal nephrotoxicity.In a mouse model of bacterial pneumonia,intravenous administration of LaP-Col led to its accumulation in the infected lung.It effectively killed bacteria,significantly improving the therapeutic efficacy and mouse survival rates.Overall,this study presents a prodrug strategy that effectively reduces the inherent high toxicity of colistin and enhances its therapeutic targeting efficacy,which has promising implications for modifying other potent but toxic AMPs.
基金This study was supported by the First Medical Center of the General Hospital of the People’s Liberation Army Medical Big Data Research Project(No.2019MBD-034)。
文摘To the Editor:Segmentectomy is an effective surgical method to cure early lung cancer.Segmentectomy which is designed precisely can preserve the pulmonary function to the maximal level with comparable post-operative survival rate.However,there are still some factors such as surgical experience,anatomy familiarity,and intersegmental plane identification,influencing the application of segmentectomy.Identifying the intersegmental plane is an important intra-operative procedure for successful lung segmentectomy.Currently,there are several methods used by surgeons,including(1)inflation-deflation:displaying the border between inflated and deflated lung segments;(2)injection of indocyanine green by an intravenous or intrabronchial route.These methods have obvious shortcomings:the"inflation-deflation"method needs about 10 to 15 minutes of intra-operative time,which reduces operation efficiency and increases patient risk;injection of indocyanine helps to identify the intersegmental plane but there are risks of toxicity and allergies associated with indocyanine.
