Purpose:To investigate the pathological changes of the synovium in mice with post-traumatic osteoarthritis(PTOA)treated with 4-octyl itaconate(4-OI)and evaluate the therapeutic effects of 4-OI.Methods:In the phenotypi...Purpose:To investigate the pathological changes of the synovium in mice with post-traumatic osteoarthritis(PTOA)treated with 4-octyl itaconate(4-OI)and evaluate the therapeutic effects of 4-OI.Methods:In the phenotypic validation experiment,the mice were randomly divided into 3 groups:wildtype(WT)group,sham group,and destabilization of the medial meniscus(DMM)group.Through MRI,micro-CT,and histological analysis,it was determined that the DMM surgery induced a mouse PTOA model with significant signs of synovitis.At 12 weeks post-DMM surgery,synovial tissues from the DMM group and WT group mice were collected for ribonucleic acid sequencing analysis.In the 4-OI treatment experiment,mice were randomly divided into the sham group,DMM group,DMM+4-OI(50 mg/kg)group,and DMM+4-OI(100 mg/kg)group.Von Frey tests and open field tests were conducted at intervals during the 12 weeks following the DMM surgery.After 12 weeks of surgery,the efficacy of 4-OI treatment on PTOA in mice was evaluated using MRI,micro-CT,histological analysis,and quantitative real-time polymerase chain reaction.Finally,we utilized network pharmacology analysis to predict the mechanism of 4-OI in treating PTOA synovitis and conducted preliminary validation.Statistical analysis was performed using one-way ANOVA and the Kruskal-Wallis test.Difference was considered statistically significant at p<0.05.Results:The DMM surgery effectively induced a PTOA mouse model,which displayed significant symptoms of synovitis.These symptoms included a notable increase in both the number of calcified tissues and osteophytes(p<0.001),an enlargement of the calcified meniscus and synovial tissue volume(p<0.001),and thickening of the synovial lining layer attributable to M1 macrophage accumulation(p=0.035).Additionally,we observed elevated histological scores for synovitis(p<0.001).Treatment with 4-OI inhibited the thickening of M1 macrophages in the synovial lining layer of PTOA mice(p<0.001)and reduced fibrosis in the synovial stroma(p=0.004).Furthermore,it reduced the histological scores of knee synovitis in PTOA mice(p=0.006)and improved the inflammatory microenvironment associated with synovitis.Consequently,this treatment alleviated pain in PTOA mice(p<0.001)and reduced spontaneous activity(p=0.003).Bioinformatics and network pharmacology analyses indicated that 4-OI may exert its therapeutic effects by inhibiting the differentiation of synovial Th17 cells.Specifically,compared to the lipopolysaccharide stimulation group,4-OI reduced the levels of positive regulatory factors of Th17 cell differentiation(IL-1:p<0.001,IL-6:p<0.001),key effector molecules(IL-17A:p<0.001,IL-17F:p=0.004),and downstream effector molecules in the IL-17 signaling pathway(CCL2:p<0.001,MMP13:p<0.001).Conclusion:4-OI is effective in inhibiting synovitis in PTOA,thereby alleviating the associated painful symptoms.展开更多
Background:Macrophage polarization anomalies and dysfunction play a crucial role in the pathogenesis of immune thrombocytopenia(ITP).Itaconate is a Krebs cycle-derived immunometabolite synthesized by myeloid cells to ...Background:Macrophage polarization anomalies and dysfunction play a crucial role in the pathogenesis of immune thrombocytopenia(ITP).Itaconate is a Krebs cycle-derived immunometabolite synthesized by myeloid cells to modulate cellular metabolism and inflammatory responses.This study aimed to evaluate the immunoregulatory effects of an itaconate derivative on macrophages in patients with ITP.Methods:Peripheral blood-derived macrophages from patients with ITP and healthy controls were treated with 4-octyl itaconate(4-OI),a derivative of itaconate that can penetrate the cell membrane.Macrophage polarization,antigen-presenting functions,and phagocytic capability were measured via flow cytometry and enzyme-linked immunosorbent assay(ELISA).Macrophage glycolysis in patients with ITP and the metabolic regulatory effect of 4-OI were detected using a Seahorse XFe96 Analyzer.An active murine model of ITP was used to evaluate the therapeutic effects of 4-OI in vivo.Results:4-OI reduced the levels of CD80 and CD86 in M1 macrophages and suppressed the release of tumor necrosis factor-α(TNF-α)and interleukin(IL)-6 pro-inflammatory cytokines,suggesting that 4-OI could hinder the polarization of macrophages toward an M1 phenotype.We found that 4-OI pretreated M1 macrophages reduced the proliferation of CD4+T cells and promoted the differentiation of regulatory T cells.In addition,after 4-OI treatment,the phagocytic capacity of M1 macrophages toward antibody-coated platelets decreased significantly in patients with ITP.In addition,the glycolytic function of M1 macrophages was elevated in individuals with ITP compared to those in healthy controls.4-OI treatment downregulated glycolysis in M1 macrophages.The glycolysis inhibitor 2-deoxy-d-glucose(2-DG)also inhibited the polarization of M1 macrophages and restored their functions.In vivo,4-OI treatment significantly increased platelet counts in the active ITP murine model.Conclusions:Itaconate derivative 4-OI inhibited M1 macrophage polarization and restored impaired functions through metabolic reprogramming.This study provides a novel therapeutic option for ITP.展开更多
Polyaspartic acid(PASP)composite,a scale inhibitor,was prepared from PASP,itaconic acid—acrylic acid—acrylic ester(IA-AA-AE)terpolymer and 2-phosphonobutane-1,2,4-tricarboxylic acid(PBTCA).The scale inhibition of PA...Polyaspartic acid(PASP)composite,a scale inhibitor,was prepared from PASP,itaconic acid—acrylic acid—acrylic ester(IA-AA-AE)terpolymer and 2-phosphonobutane-1,2,4-tricarboxylic acid(PBTCA).The scale inhibition of PASP composite and the effect of its synergism with a magnetic field on scale inhibition were investigated.Calcium carbonate crystals in scale samples were characterized by means of SEM and XRD.The static and dynamic experiments show that the chelating function of PASP composite for Ca2+can be enhanced by synergism with a magnetic field.Under Ca2+650 mg/L,HCO3-1,300 mg/L and PASPcomposite 4 mg/L,the scale inhibition rate of PASP composite in magnetic water can increase by 10%in static state and by 20%in dynamic experiments.Scanning electron microscope(SEM)and X-ray diffraction(XRD)results show that calcite and aragonite can be completely transformed into vaterite by using PASP composite.展开更多
基金supported by the Foundation of Chongqing Talents(grant no.CQYC2021059825).
文摘Purpose:To investigate the pathological changes of the synovium in mice with post-traumatic osteoarthritis(PTOA)treated with 4-octyl itaconate(4-OI)and evaluate the therapeutic effects of 4-OI.Methods:In the phenotypic validation experiment,the mice were randomly divided into 3 groups:wildtype(WT)group,sham group,and destabilization of the medial meniscus(DMM)group.Through MRI,micro-CT,and histological analysis,it was determined that the DMM surgery induced a mouse PTOA model with significant signs of synovitis.At 12 weeks post-DMM surgery,synovial tissues from the DMM group and WT group mice were collected for ribonucleic acid sequencing analysis.In the 4-OI treatment experiment,mice were randomly divided into the sham group,DMM group,DMM+4-OI(50 mg/kg)group,and DMM+4-OI(100 mg/kg)group.Von Frey tests and open field tests were conducted at intervals during the 12 weeks following the DMM surgery.After 12 weeks of surgery,the efficacy of 4-OI treatment on PTOA in mice was evaluated using MRI,micro-CT,histological analysis,and quantitative real-time polymerase chain reaction.Finally,we utilized network pharmacology analysis to predict the mechanism of 4-OI in treating PTOA synovitis and conducted preliminary validation.Statistical analysis was performed using one-way ANOVA and the Kruskal-Wallis test.Difference was considered statistically significant at p<0.05.Results:The DMM surgery effectively induced a PTOA mouse model,which displayed significant symptoms of synovitis.These symptoms included a notable increase in both the number of calcified tissues and osteophytes(p<0.001),an enlargement of the calcified meniscus and synovial tissue volume(p<0.001),and thickening of the synovial lining layer attributable to M1 macrophage accumulation(p=0.035).Additionally,we observed elevated histological scores for synovitis(p<0.001).Treatment with 4-OI inhibited the thickening of M1 macrophages in the synovial lining layer of PTOA mice(p<0.001)and reduced fibrosis in the synovial stroma(p=0.004).Furthermore,it reduced the histological scores of knee synovitis in PTOA mice(p=0.006)and improved the inflammatory microenvironment associated with synovitis.Consequently,this treatment alleviated pain in PTOA mice(p<0.001)and reduced spontaneous activity(p=0.003).Bioinformatics and network pharmacology analyses indicated that 4-OI may exert its therapeutic effects by inhibiting the differentiation of synovial Th17 cells.Specifically,compared to the lipopolysaccharide stimulation group,4-OI reduced the levels of positive regulatory factors of Th17 cell differentiation(IL-1:p<0.001,IL-6:p<0.001),key effector molecules(IL-17A:p<0.001,IL-17F:p=0.004),and downstream effector molecules in the IL-17 signaling pathway(CCL2:p<0.001,MMP13:p<0.001).Conclusion:4-OI is effective in inhibiting synovitis in PTOA,thereby alleviating the associated painful symptoms.
基金supported by grants from National Key R&D Program of China(No.2023YFC2507804)National Natural Science Foundation of China(Nos.82030005,82170124,and 82200140)+1 种基金Taishan Scholar Foundation of Shandong Province(No.tstp20221157)ECCM Program of Clinical Research Center of Shangdong University(No.2021SDUCRCB008).
文摘Background:Macrophage polarization anomalies and dysfunction play a crucial role in the pathogenesis of immune thrombocytopenia(ITP).Itaconate is a Krebs cycle-derived immunometabolite synthesized by myeloid cells to modulate cellular metabolism and inflammatory responses.This study aimed to evaluate the immunoregulatory effects of an itaconate derivative on macrophages in patients with ITP.Methods:Peripheral blood-derived macrophages from patients with ITP and healthy controls were treated with 4-octyl itaconate(4-OI),a derivative of itaconate that can penetrate the cell membrane.Macrophage polarization,antigen-presenting functions,and phagocytic capability were measured via flow cytometry and enzyme-linked immunosorbent assay(ELISA).Macrophage glycolysis in patients with ITP and the metabolic regulatory effect of 4-OI were detected using a Seahorse XFe96 Analyzer.An active murine model of ITP was used to evaluate the therapeutic effects of 4-OI in vivo.Results:4-OI reduced the levels of CD80 and CD86 in M1 macrophages and suppressed the release of tumor necrosis factor-α(TNF-α)and interleukin(IL)-6 pro-inflammatory cytokines,suggesting that 4-OI could hinder the polarization of macrophages toward an M1 phenotype.We found that 4-OI pretreated M1 macrophages reduced the proliferation of CD4+T cells and promoted the differentiation of regulatory T cells.In addition,after 4-OI treatment,the phagocytic capacity of M1 macrophages toward antibody-coated platelets decreased significantly in patients with ITP.In addition,the glycolytic function of M1 macrophages was elevated in individuals with ITP compared to those in healthy controls.4-OI treatment downregulated glycolysis in M1 macrophages.The glycolysis inhibitor 2-deoxy-d-glucose(2-DG)also inhibited the polarization of M1 macrophages and restored their functions.In vivo,4-OI treatment significantly increased platelet counts in the active ITP murine model.Conclusions:Itaconate derivative 4-OI inhibited M1 macrophage polarization and restored impaired functions through metabolic reprogramming.This study provides a novel therapeutic option for ITP.
基金supported by the Natural Science Foundation of Hebei Province of China(B2004000749).
文摘Polyaspartic acid(PASP)composite,a scale inhibitor,was prepared from PASP,itaconic acid—acrylic acid—acrylic ester(IA-AA-AE)terpolymer and 2-phosphonobutane-1,2,4-tricarboxylic acid(PBTCA).The scale inhibition of PASP composite and the effect of its synergism with a magnetic field on scale inhibition were investigated.Calcium carbonate crystals in scale samples were characterized by means of SEM and XRD.The static and dynamic experiments show that the chelating function of PASP composite for Ca2+can be enhanced by synergism with a magnetic field.Under Ca2+650 mg/L,HCO3-1,300 mg/L and PASPcomposite 4 mg/L,the scale inhibition rate of PASP composite in magnetic water can increase by 10%in static state and by 20%in dynamic experiments.Scanning electron microscope(SEM)and X-ray diffraction(XRD)results show that calcite and aragonite can be completely transformed into vaterite by using PASP composite.
