Repetitive implant-related infections(IRIs)are devastating complications in orthopedic surgery,threatening implant survival and even the life of the host.Biofilms conceal bacterial-associated antigens(BAAs)and result ...Repetitive implant-related infections(IRIs)are devastating complications in orthopedic surgery,threatening implant survival and even the life of the host.Biofilms conceal bacterial-associated antigens(BAAs)and result in a"cold tumor"-like immune silent microenvironment,allowing the persistence of IRIs.To address this challenge,an iron-based covalent organic framed nanoadjuvant doped with curcumin and platinum(CFCP)was designed in the present study to achieve efficient treatment of IRIs by inducing a systemic immune response.Specifically,enhanced sonodynamic therapy(SDT)from CFCP combined with iron ion metabolic interference increased the release of bacterial-associated double-stranded DNA(dsDNA).Immunogenic dsDNA promoted dendritic cell(DC)maturation through activation of the stimulator of interferon gene(STING)and amplified the immune stimulation of neutrophils via interferon-β(IFN-β).At the same time,enhanced BAA presentation aroused humoral immunity in B and T cells,creating long-term resistance to repetitive infections.Encouragingly,CFCP served as neoadjuvant immunotherapy for sustained antibacterial protection on implants and was expected to guide clinical IRI treatment and relapse prevention.展开更多
Self-assembling carrier-free nanodrugs are attractive agents because they accumulate at tumor by an enhanced permeability and retention(EPR) effect without introduction of inactive substances,and some nanodrugs can al...Self-assembling carrier-free nanodrugs are attractive agents because they accumulate at tumor by an enhanced permeability and retention(EPR) effect without introduction of inactive substances,and some nanodrugs can alter the immune environment. We synthesized a peptidyl arginine deiminase 4(PAD4) molecular inhibitor, ZD-E-1 M. It could self-assembled into nanodrug ZD-E-1. Using confocal laser scanning microscopy, we observed its cellular colocalization, PAD4 activity and neutrophil extracellular traps(NETs) formation. The populations of immune cells and expression of immune-related proteins were determined by single-cell mass cytometry. ZD-E-1 formed nanoflowers in an acidic environment, whereas it formed nanospheres at pH 7.4. Accumulation of ZD-E-1 at tumor was pHresponsive because of its pH-dependent differences in the size and shape. It could enter the nucleus and bind to PAD4 to prolong the intracellular retention time. In mice, ZD-E-1 inhibited tumor growth and metastasis by inhibiting PAD4 activity and NETs formation. Besides, ZD-E-1 could regulate the ratio of immune cells in LLC tumor-bearing mice. Immunosuppressive proteins like LAG3 were suppressed,while IFN-γ and TNF-a as stimulators of tumor immune response were upregulated. Overall, ZD-E-1 is a self-assembling carrier-free nanodrug that responds to pH, inhibits PAD4 activity, blocks neutrophil extracellular traps formation, and improves the tumor immune microenvironment.展开更多
To investigate the effect of neutrophil activation on pathogenesis of pre eclampsia, neutrophil activation was examined by using flow cytometry to assess the CD11b expression and the levels of plasma endothelin 1 (E...To investigate the effect of neutrophil activation on pathogenesis of pre eclampsia, neutrophil activation was examined by using flow cytometry to assess the CD11b expression and the levels of plasma endothelin 1 (ET 1) and serum NO - 2 were also measured by using non equilibrium radioimmunoassay and by Griess assay in 29 pregnant women with pre eclampsia and 31 normal pregnant women at third trimester. The expression of neutrophil CD11b was significantly elevated in women with pre eclampsia as compared with that of normal pregnant women at third trimester. The mean fluorescence index of CD11b was 438.38±179.91 and 326.97±170.14 respectively ( P < 0.05). The plasma ET 1 level and serum NO 2 concentration in pre eclampsic women (63.69±48.33 pg/ml and 20.03±4.77 μmol/L, respectively) were both significantly increased as compared with those in the normal pregnancy women (29.98±20.25 pg/ml and 15.47±5.47 μmol/L, respectively, P <0.01). The neutrophil CD11b expression was significantly elevated in pre eclampsia. The increased neutrophil activation may cause the damage of vascular endothelium and result in NO release compensatory increase in endothelial cells, suggesting that the neutrophil activation may play a key role in pathogenesis of pre eclampsia.展开更多
基金supported by the National Natural Science Foundation of China(82272512,82102586)the Natural Science Foundation of Anhui Province,Distinguishing Youth Project(2108085J40)+1 种基金Anhui Provincial Scientific Research Compilation Project(2022AH051251,2022AH010076)Research Funds of Centre for Leading Medicine and Advanced Technologies of IHM(2023IHM01070,2023IHM01074).
文摘Repetitive implant-related infections(IRIs)are devastating complications in orthopedic surgery,threatening implant survival and even the life of the host.Biofilms conceal bacterial-associated antigens(BAAs)and result in a"cold tumor"-like immune silent microenvironment,allowing the persistence of IRIs.To address this challenge,an iron-based covalent organic framed nanoadjuvant doped with curcumin and platinum(CFCP)was designed in the present study to achieve efficient treatment of IRIs by inducing a systemic immune response.Specifically,enhanced sonodynamic therapy(SDT)from CFCP combined with iron ion metabolic interference increased the release of bacterial-associated double-stranded DNA(dsDNA).Immunogenic dsDNA promoted dendritic cell(DC)maturation through activation of the stimulator of interferon gene(STING)and amplified the immune stimulation of neutrophils via interferon-β(IFN-β).At the same time,enhanced BAA presentation aroused humoral immunity in B and T cells,creating long-term resistance to repetitive infections.Encouragingly,CFCP served as neoadjuvant immunotherapy for sustained antibacterial protection on implants and was expected to guide clinical IRI treatment and relapse prevention.
基金supported by the Beijing Municipal Colleges and Universities High Level Talents Introduction and Cultivate Project-Beijing Great Wall Scholar Program (CIT&TCD 20180332,China)。
文摘Self-assembling carrier-free nanodrugs are attractive agents because they accumulate at tumor by an enhanced permeability and retention(EPR) effect without introduction of inactive substances,and some nanodrugs can alter the immune environment. We synthesized a peptidyl arginine deiminase 4(PAD4) molecular inhibitor, ZD-E-1 M. It could self-assembled into nanodrug ZD-E-1. Using confocal laser scanning microscopy, we observed its cellular colocalization, PAD4 activity and neutrophil extracellular traps(NETs) formation. The populations of immune cells and expression of immune-related proteins were determined by single-cell mass cytometry. ZD-E-1 formed nanoflowers in an acidic environment, whereas it formed nanospheres at pH 7.4. Accumulation of ZD-E-1 at tumor was pHresponsive because of its pH-dependent differences in the size and shape. It could enter the nucleus and bind to PAD4 to prolong the intracellular retention time. In mice, ZD-E-1 inhibited tumor growth and metastasis by inhibiting PAD4 activity and NETs formation. Besides, ZD-E-1 could regulate the ratio of immune cells in LLC tumor-bearing mice. Immunosuppressive proteins like LAG3 were suppressed,while IFN-γ and TNF-a as stimulators of tumor immune response were upregulated. Overall, ZD-E-1 is a self-assembling carrier-free nanodrug that responds to pH, inhibits PAD4 activity, blocks neutrophil extracellular traps formation, and improves the tumor immune microenvironment.
文摘To investigate the effect of neutrophil activation on pathogenesis of pre eclampsia, neutrophil activation was examined by using flow cytometry to assess the CD11b expression and the levels of plasma endothelin 1 (ET 1) and serum NO - 2 were also measured by using non equilibrium radioimmunoassay and by Griess assay in 29 pregnant women with pre eclampsia and 31 normal pregnant women at third trimester. The expression of neutrophil CD11b was significantly elevated in women with pre eclampsia as compared with that of normal pregnant women at third trimester. The mean fluorescence index of CD11b was 438.38±179.91 and 326.97±170.14 respectively ( P < 0.05). The plasma ET 1 level and serum NO 2 concentration in pre eclampsic women (63.69±48.33 pg/ml and 20.03±4.77 μmol/L, respectively) were both significantly increased as compared with those in the normal pregnancy women (29.98±20.25 pg/ml and 15.47±5.47 μmol/L, respectively, P <0.01). The neutrophil CD11b expression was significantly elevated in pre eclampsia. The increased neutrophil activation may cause the damage of vascular endothelium and result in NO release compensatory increase in endothelial cells, suggesting that the neutrophil activation may play a key role in pathogenesis of pre eclampsia.
