ABSTRACT:The repair of large-scale bone defects is still a challenge in clinical orthopedics.Especially,excessive reactive oxygen species(ROS)-induced oxidative stress injury greatly affected bone healing.In this stud...ABSTRACT:The repair of large-scale bone defects is still a challenge in clinical orthopedics.Especially,excessive reactive oxygen species(ROS)-induced oxidative stress injury greatly affected bone healing.In this study,we innovatively developed an antioxidant three-dimensional(3D)-bioprinted MMn_(3)O_(4)@Gel by integrating M-Mn_(3)O_(4) nanozyme into photocrosslinked gelatin methacryloyl(GelMA)for the therapy of bone defects.Results showed that the incorporation of MMn_(3)O_(4) not only enhanced the mechanical properties of the nanocomposite hydrogel with the compressive modulus 141.79%higher than that of pure GelMA,but also maintained excellent 3D printability.In vitro studies confirmed that the 3Dprinted M-Mn_(3)O_(4)@Gel exhibited favorable biocompatibility and cell adhesion.It significantly reduced oxidative stress through efficient ROS scavenging,restored mitochondrial function,and ultimately demonstrated remarkable osteogenic capacity,highlighting the efficacy of control-released nanozymes.More importantly,under near-infrared(NIR)irradiation,MMn_(3)O_(4)@Gel demonstrated further enhanced ROS-scavenging capacity and bone regeneration potential.Mechanistically,MMn_(3)O_(4)@Gel promoted osteogenesis by upregulating heat shock protein 40 kDa(HSP40)and HSP70 expression,effectively mitigating the overactivation of the Nrf2 pathway.This study innovatively combines nanozyme technology with 3D-printed hydrogel materials,offering a novel strategy to address the challenge of oxidative stress in bone regeneration.展开更多
Developing dedicated nanomedicines to improve delivery efficacy of anti-inflammatory drugs is still a formidable challenge.In this study,we present an extremely simple yet efficient approach to obtain hybrid nanodrugs...Developing dedicated nanomedicines to improve delivery efficacy of anti-inflammatory drugs is still a formidable challenge.In this study,we present an extremely simple yet efficient approach to obtain hybrid nanodrugs through metal-drug coordination-driven self-assembly for carrier-free drug delivery.The resulting metallo-nanodrugs exhibit well-defined morphology and high drug encapsulation capability,allowing for the combination of magnetic resonance imaging and anti-inflammatory therapy.In the case of osteoarthritis(OA),the metallo-nanodrugs remarkably alleviate synovial inflammation,preventing cartilage destruction and extracellular matrix loss.In addition,it led to significantly improved therapeutic efficacy compared with intra-articular administration of the same dose of free drugs in OA mouse model.This work provides a very simple approach for the development of anti-inflammatory nanoformulations by exploiting coordination-driven self-assembly.展开更多
Background Colorectal cancer(CRC)is a type of malignant gastroenteric tumors associated with a high mortal-ity rate worldwide.Calycosin,a natural phytoestrogen,possesses potent anti-cancer properties.We structurally m...Background Colorectal cancer(CRC)is a type of malignant gastroenteric tumors associated with a high mortal-ity rate worldwide.Calycosin,a natural phytoestrogen,possesses potent anti-cancer properties.We structurally modified calycosin to improve its physicochemical properties,and generated a novel small molecule termed CA028.Methods By using network pharmacology,followed by gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis and molecular docking,we aimed to predict and disclose the biological functions and mechanism of CA028 in the treatment of CRC through bioinformatic analyses.Results By searching the online Swiss Target Prediction and TargetNet databases,we identified 150 genes shared by CA028 and CRC.Using the Search Tool for the Retrieval of Interacting Genes(STRING)database and Cytoscape software,we identified 14 hub-functional genes,namely the FYN proto-oncogene,a Src family tyrosine kinase(F YN),mitogen-activated protein kinase 1(MAPK1),MAPK8,MAPK14,Rac family small GTPase 1(RAC1),epi-dermal growth factor receptor(EGFR),protein tyrosine kinase 2(PTK2),sphingosine-1-phosphate receptor 1(S1PR1),S1PR2,Janus kinase 1(JAK1),JAK2,the RELA proto-oncogene NF-𝜅B subunit(RELA),bradykinin re-ceptor B1(BDKRB1),and BDKRB2.Additionally,biological docking analysis using the Autodock Vina software revealed that FYN and MAPK1 were the main pharmacological proteins of CA028 against CRC.The gene ontol-ogy analysis using R-language packages further revealed the anti-CRC functions of CA028,including biological processes,cell components,and molecular pathways.Conclusion CA028 exhibits effective pharmacological activity against CRC by suppressing the proliferation of CRC cells and improving the tumor microenvironment.Importantly,certain predicted genes(e.g.,FYN and MAPK1)may be the pharmacological targets of CA028 in the treatment of CRC.展开更多
基金financially supported by the Guangxi Natural Science Foundation(No.2025GXNSFBA069100)the National Natural Science Foundation of China(Nos.52573316 and 82360426)the Basic ability enhancement project for young and middle-aged teachers of universities in Guangxi(No.2024KY0105).
文摘ABSTRACT:The repair of large-scale bone defects is still a challenge in clinical orthopedics.Especially,excessive reactive oxygen species(ROS)-induced oxidative stress injury greatly affected bone healing.In this study,we innovatively developed an antioxidant three-dimensional(3D)-bioprinted MMn_(3)O_(4)@Gel by integrating M-Mn_(3)O_(4) nanozyme into photocrosslinked gelatin methacryloyl(GelMA)for the therapy of bone defects.Results showed that the incorporation of MMn_(3)O_(4) not only enhanced the mechanical properties of the nanocomposite hydrogel with the compressive modulus 141.79%higher than that of pure GelMA,but also maintained excellent 3D printability.In vitro studies confirmed that the 3Dprinted M-Mn_(3)O_(4)@Gel exhibited favorable biocompatibility and cell adhesion.It significantly reduced oxidative stress through efficient ROS scavenging,restored mitochondrial function,and ultimately demonstrated remarkable osteogenic capacity,highlighting the efficacy of control-released nanozymes.More importantly,under near-infrared(NIR)irradiation,MMn_(3)O_(4)@Gel demonstrated further enhanced ROS-scavenging capacity and bone regeneration potential.Mechanistically,MMn_(3)O_(4)@Gel promoted osteogenesis by upregulating heat shock protein 40 kDa(HSP40)and HSP70 expression,effectively mitigating the overactivation of the Nrf2 pathway.This study innovatively combines nanozyme technology with 3D-printed hydrogel materials,offering a novel strategy to address the challenge of oxidative stress in bone regeneration.
基金funded by the Beijing Natural Science Foundation(No.JQ20005)Guangxi Science and Technology Major Project(No.GuikeAA19254002).
文摘Developing dedicated nanomedicines to improve delivery efficacy of anti-inflammatory drugs is still a formidable challenge.In this study,we present an extremely simple yet efficient approach to obtain hybrid nanodrugs through metal-drug coordination-driven self-assembly for carrier-free drug delivery.The resulting metallo-nanodrugs exhibit well-defined morphology and high drug encapsulation capability,allowing for the combination of magnetic resonance imaging and anti-inflammatory therapy.In the case of osteoarthritis(OA),the metallo-nanodrugs remarkably alleviate synovial inflammation,preventing cartilage destruction and extracellular matrix loss.In addition,it led to significantly improved therapeutic efficacy compared with intra-articular administration of the same dose of free drugs in OA mouse model.This work provides a very simple approach for the development of anti-inflammatory nanoformulations by exploiting coordination-driven self-assembly.
基金the National Natural Science Founda-tion of China(Grant Nos.81973574,82174082,and 82060736)Guangxi Natural Science Foundation(Grant Nos.2019GXNSFFA245001 and 2018GXNSFAA281334)Innovation Project of Guangxi Graduate Education(Grant No.YCSW2021253).
文摘Background Colorectal cancer(CRC)is a type of malignant gastroenteric tumors associated with a high mortal-ity rate worldwide.Calycosin,a natural phytoestrogen,possesses potent anti-cancer properties.We structurally modified calycosin to improve its physicochemical properties,and generated a novel small molecule termed CA028.Methods By using network pharmacology,followed by gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis and molecular docking,we aimed to predict and disclose the biological functions and mechanism of CA028 in the treatment of CRC through bioinformatic analyses.Results By searching the online Swiss Target Prediction and TargetNet databases,we identified 150 genes shared by CA028 and CRC.Using the Search Tool for the Retrieval of Interacting Genes(STRING)database and Cytoscape software,we identified 14 hub-functional genes,namely the FYN proto-oncogene,a Src family tyrosine kinase(F YN),mitogen-activated protein kinase 1(MAPK1),MAPK8,MAPK14,Rac family small GTPase 1(RAC1),epi-dermal growth factor receptor(EGFR),protein tyrosine kinase 2(PTK2),sphingosine-1-phosphate receptor 1(S1PR1),S1PR2,Janus kinase 1(JAK1),JAK2,the RELA proto-oncogene NF-𝜅B subunit(RELA),bradykinin re-ceptor B1(BDKRB1),and BDKRB2.Additionally,biological docking analysis using the Autodock Vina software revealed that FYN and MAPK1 were the main pharmacological proteins of CA028 against CRC.The gene ontol-ogy analysis using R-language packages further revealed the anti-CRC functions of CA028,including biological processes,cell components,and molecular pathways.Conclusion CA028 exhibits effective pharmacological activity against CRC by suppressing the proliferation of CRC cells and improving the tumor microenvironment.Importantly,certain predicted genes(e.g.,FYN and MAPK1)may be the pharmacological targets of CA028 in the treatment of CRC.
