Pulmonary fibrosis(PF)is a devastating lung disease with limited treatment options.During this pathological process,the profibrogenic macrophage subpopulation plays a crucial role,making the characterization of this s...Pulmonary fibrosis(PF)is a devastating lung disease with limited treatment options.During this pathological process,the profibrogenic macrophage subpopulation plays a crucial role,making the characterization of this subpopulation fundamentally important.The present study revealed a positive correlation between pulmonary macrophages with higher mitochondrial mass(Mø^(mitohigh))and fibrosis.Among the Mø^(mitohigh)subpopulation of CD206^(+)M2,characterized by higher expression of dynamin 1-like(Drp1),as determined by flow cytometry and RNA-seq analysis,a therapeutic intervention was developed using an exosome-based formula composed of pathfinder and therapeutics.A pathfinder exosome called“exosome^(MMP19)(Exo^(MMP19))”,was constructed to display matrix metalloproteinase-19(^(MMP19))on the surface to locally break down the excessive extracellular matrix(ECM)in the fibrotic lung.A therapeutic exosome called“exosome therapeutics(Exo^(Tx))”,was engineered to display D-mannose on the surface while encapsulating siDrp1 inside.Prior delivery of Exo^(MMP19)degraded excessive ECM and thus paved the way for Exo^(Tx)to be delivered into Mø^(mitohigh),where Exo^(Tx)inhibited mitochondrial fission and alleviated PF.This study has not only identified Mø^(mitohigh)as profibrotic macrophages but it has also provided a potent strategy to reverse PF via a combination of formulated exosomes.展开更多
Atherosclerosis is characterized by inflammation in the arterial wall,which is known to be exacerbated by diabetes.Therapeutic repression of inflammation is a promising strategy for treating atherosclerosis.In this st...Atherosclerosis is characterized by inflammation in the arterial wall,which is known to be exacerbated by diabetes.Therapeutic repression of inflammation is a promising strategy for treating atherosclerosis.In this study,we showed that diabetes aggravated atherosclerosis in apolipoproteinE knockout(ApoE^(-/-))mice,in which increased expression of long-chain acyl-CoA synthetase 1(Acsl1)in macrophages played an important role.Knockdown of Acsl1 in macrophages(Mφ^(shAcsl1))reprogrammed macrophages to an anti-inflammatory phenotype,especially under hyperglycemic conditions.Injection of Mφ^(shAcsl1) reprogrammed macrophages into streptozotocin(STZ)-induced diabetic ApoE^(-/-) mice(ApoE^(-/-)+STZ)alleviated inflammation locally in the plaque,liver and spleen.Consistent with the reduction in inflammation,plaques became smaller and more stable after the adoptive transfer of reprogrammed macrophages.Taken together,our findings indicate that increased Acsl1 expression in macrophages play a key role in aggravated atherosclerosis of diabetic mice,possibly by promoting inflammation.Adoptive transfer of Acsl1 silenced macrophages may serve as a potential therapeutic strategy for atherosclerosis.展开更多
Immune suppressive microenvironment in tumor emerges as the main obstacle for cancer immunotherapy.In this study,we identified that HIF1α was activated in the tumor associated macrophages and acted as an important fa...Immune suppressive microenvironment in tumor emerges as the main obstacle for cancer immunotherapy.In this study,we identified that HIF1α was activated in the tumor associated macrophages and acted as an important factor for the immune suppressive microenvironment.Epigenetically silencing of Hif1αvia histone H3 methylation in the promoter region was achieved by CRISPR/dCas9-EZH2 system,in which histone H3 methylase EZH2 was recruited to the promoter region specifically.The Hif1αsilenced macrophage,namely HERM(Hif1αEpigenetically Repressed Macrophage)manifested as inheritable tumor suppressing phenotype.In the subcutaneous B16-F10 melanoma syngeneic model,intratumoral injection of HERMs reprogrammed the immune suppressive microenvironment to the active one,reducing tumor burden and prolonging overall survival.Additionally,HERMs therapy remarkably inhibited tumor angiogenesis.Together,our study has not only identified a promising cellular and molecular target for reverting immune suppressive microenvironment,but also provided a potent strategy for reprogramming tumor microenvironment via epigenetically reprogrammed macrophages.展开更多
Cationic gold nanoparticles(cAuNPs)have been regarded as promising candidates for antibacterial applications due to their high surface charge density,favorable biocompatibility,and controllable surface chemistry.Never...Cationic gold nanoparticles(cAuNPs)have been regarded as promising candidates for antibacterial applications due to their high surface charge density,favorable biocompatibility,and controllable surface chemistry.Nevertheless,the complicated fabrication process and unclear antibacterial mechanism have greatly hindered the further biomedical application of cAuNPs.Herein,we have developed a simple and controllable strategy for synthesizing cAuNPs with tailored size and antibacterial behavior by kinetically modulating the reaction process.Specifically,a functional ligand,(11-mercaptoundecyl)-N,N,Ntrimethylammonium bromide(MUTAB),was chosen to chemically manipulate the positive surface charge of cAuNPs via a one-step strategy.The size of cAuNPs could be flexibly adjusted from 1.1 to 14.8 nm by simply elevating the stirring speed of the reaction from 0 to 1500 rpm.Further studies revealed that the antibacterial effect of cAuNPs was strongly correlated with the particle size.MUTAB-protected ultrasmall gold nanoclusters(MUTAB-AuNCs)were able to eradicate E.coli at a concentration as low as 1.25μg mL^(-1),while the minimum inhibitory concentration of MUTAB-AuNPs with a large size for E.coli was 5μg mL^(-1).Mechanistic investigation revealed that MUTAB-AuNPs were able to damage the bacterial membrane and stimulate the production of reactive oxygen species more effectively than MUTAB-AuNCs.Conversely,MUTAB-AuNCs were more active in inducing membrane depolarization in contrast to MUTAB-AuNPs,suggesting the unique size-dependent antibacterial manner of cAuNPs.This study presents a new strategy for the controlled preparation of cAuNPs with distinct sizes and antibacterial behavior,laying a valuable foundation for developing efficient cationic NP-based bactericidal agents.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.NSFC 81970076)Key R&D Program of Shaanxi Province,China(2022ZDLSF01-10)。
文摘Pulmonary fibrosis(PF)is a devastating lung disease with limited treatment options.During this pathological process,the profibrogenic macrophage subpopulation plays a crucial role,making the characterization of this subpopulation fundamentally important.The present study revealed a positive correlation between pulmonary macrophages with higher mitochondrial mass(Mø^(mitohigh))and fibrosis.Among the Mø^(mitohigh)subpopulation of CD206^(+)M2,characterized by higher expression of dynamin 1-like(Drp1),as determined by flow cytometry and RNA-seq analysis,a therapeutic intervention was developed using an exosome-based formula composed of pathfinder and therapeutics.A pathfinder exosome called“exosome^(MMP19)(Exo^(MMP19))”,was constructed to display matrix metalloproteinase-19(^(MMP19))on the surface to locally break down the excessive extracellular matrix(ECM)in the fibrotic lung.A therapeutic exosome called“exosome therapeutics(Exo^(Tx))”,was engineered to display D-mannose on the surface while encapsulating siDrp1 inside.Prior delivery of Exo^(MMP19)degraded excessive ECM and thus paved the way for Exo^(Tx)to be delivered into Mø^(mitohigh),where Exo^(Tx)inhibited mitochondrial fission and alleviated PF.This study has not only identified Mø^(mitohigh)as profibrotic macrophages but it has also provided a potent strategy to reverse PF via a combination of formulated exosomes.
基金funded by the National Natural Science Foundation of China(No,81671910 to X Yang)Shanxi Province Foundation of China(No.2021SF-341 to X Yang).
文摘Atherosclerosis is characterized by inflammation in the arterial wall,which is known to be exacerbated by diabetes.Therapeutic repression of inflammation is a promising strategy for treating atherosclerosis.In this study,we showed that diabetes aggravated atherosclerosis in apolipoproteinE knockout(ApoE^(-/-))mice,in which increased expression of long-chain acyl-CoA synthetase 1(Acsl1)in macrophages played an important role.Knockdown of Acsl1 in macrophages(Mφ^(shAcsl1))reprogrammed macrophages to an anti-inflammatory phenotype,especially under hyperglycemic conditions.Injection of Mφ^(shAcsl1) reprogrammed macrophages into streptozotocin(STZ)-induced diabetic ApoE^(-/-) mice(ApoE^(-/-)+STZ)alleviated inflammation locally in the plaque,liver and spleen.Consistent with the reduction in inflammation,plaques became smaller and more stable after the adoptive transfer of reprogrammed macrophages.Taken together,our findings indicate that increased Acsl1 expression in macrophages play a key role in aggravated atherosclerosis of diabetic mice,possibly by promoting inflammation.Adoptive transfer of Acsl1 silenced macrophages may serve as a potential therapeutic strategy for atherosclerosis.
基金This work was funded by the National Natural Science Foundation of China(NSFC31573244 to L Liu,NSFC31771507 and NSFC81970737 to G Yang)Key Projects of Shaanxi Province(2018ZDXM-SF-063 to L Liu).
文摘Immune suppressive microenvironment in tumor emerges as the main obstacle for cancer immunotherapy.In this study,we identified that HIF1α was activated in the tumor associated macrophages and acted as an important factor for the immune suppressive microenvironment.Epigenetically silencing of Hif1αvia histone H3 methylation in the promoter region was achieved by CRISPR/dCas9-EZH2 system,in which histone H3 methylase EZH2 was recruited to the promoter region specifically.The Hif1αsilenced macrophage,namely HERM(Hif1αEpigenetically Repressed Macrophage)manifested as inheritable tumor suppressing phenotype.In the subcutaneous B16-F10 melanoma syngeneic model,intratumoral injection of HERMs reprogrammed the immune suppressive microenvironment to the active one,reducing tumor burden and prolonging overall survival.Additionally,HERMs therapy remarkably inhibited tumor angiogenesis.Together,our study has not only identified a promising cellular and molecular target for reverting immune suppressive microenvironment,but also provided a potent strategy for reprogramming tumor microenvironment via epigenetically reprogrammed macrophages.
基金supported by the National Natural Science Foundation of China(No.52103320)the Fundamental Research Funds for the Central Universities(No.G2021KY05102)the Key Research and Development Projects of Shaanxi Province(No.2023-YBSF-163).
文摘Cationic gold nanoparticles(cAuNPs)have been regarded as promising candidates for antibacterial applications due to their high surface charge density,favorable biocompatibility,and controllable surface chemistry.Nevertheless,the complicated fabrication process and unclear antibacterial mechanism have greatly hindered the further biomedical application of cAuNPs.Herein,we have developed a simple and controllable strategy for synthesizing cAuNPs with tailored size and antibacterial behavior by kinetically modulating the reaction process.Specifically,a functional ligand,(11-mercaptoundecyl)-N,N,Ntrimethylammonium bromide(MUTAB),was chosen to chemically manipulate the positive surface charge of cAuNPs via a one-step strategy.The size of cAuNPs could be flexibly adjusted from 1.1 to 14.8 nm by simply elevating the stirring speed of the reaction from 0 to 1500 rpm.Further studies revealed that the antibacterial effect of cAuNPs was strongly correlated with the particle size.MUTAB-protected ultrasmall gold nanoclusters(MUTAB-AuNCs)were able to eradicate E.coli at a concentration as low as 1.25μg mL^(-1),while the minimum inhibitory concentration of MUTAB-AuNPs with a large size for E.coli was 5μg mL^(-1).Mechanistic investigation revealed that MUTAB-AuNPs were able to damage the bacterial membrane and stimulate the production of reactive oxygen species more effectively than MUTAB-AuNCs.Conversely,MUTAB-AuNCs were more active in inducing membrane depolarization in contrast to MUTAB-AuNPs,suggesting the unique size-dependent antibacterial manner of cAuNPs.This study presents a new strategy for the controlled preparation of cAuNPs with distinct sizes and antibacterial behavior,laying a valuable foundation for developing efficient cationic NP-based bactericidal agents.