Delayed wound healing in diabetes is a global challenge,and the development of related drugs is a clinical problem to be solved.In this study,purpurolide C(PC),a small-molecule secondary metabolite of the endophytic f...Delayed wound healing in diabetes is a global challenge,and the development of related drugs is a clinical problem to be solved.In this study,purpurolide C(PC),a small-molecule secondary metabolite of the endophytic fungus Penicillium purpurogenum,was found to promote diabetic wound healing.To investigate the key regulation targets of PC,in vitro RNA-seq,molecular docking calcula-tions,TLR4-MD2 dimerization SDS-PAGE detection,and surface plasmon resonance(SPR)were per-formed,indicating that PC inhibited inflammatory macrophage activation by inhibiting both TLR4-MD2 dimerization and MYD88 phosphorylation.Tlr4 knockout in vivo attenuated the promotion effect of PC on wound healing.Furthermore,a delivery system consisting of macrophage liposome and GelMA-based microneedle patches combined with PC(PC@MLIP MN)was developed,which overcame the poor water solubility and weak skin permeability of PC,so that successfully punctured the skin and delivered PC to local tissues,and accurately regulated macrophage polarization in diabetic wound management.Overall,PC is an anti-inflammatory small molecule compound with a well-defined structure and dualtarget regulation,and the PC@MLIP MN is a promising novel biomaterial for the management of diabetic wound.展开更多
基金supported by grants from National Key R&D Program of China(Grant NO.2022YFC2504200 to Yi Liu)the National Nature Science Foundation of China(81991504 and 81974149 to Yi Liu,82073978 to Sheng Lin,82201053 to Yitong Liu,81803397 to Guiyang Xia,82122015 to Junji Xu)+6 种基金the Innovation Research Team Project of Beijing Stomatological Hospital,Capital Medical University(CXTD202202 to Yi Liu,China)the Innovation Foundation of Beijing Stomatological Hospital,Capital Medical University(21-09-18 to Lijia Guo,China)the Beijing Stomatological Hospital,Capital Medical University Young Scientist Program(YSP202105 to Yitong Liu,China)the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support(ZYLX202121 to Yi Liu,China)Beijing Municipal Administration of Hospitals'Ascent Plan(DFL20181501 to Yi Liu,China)Beijing Municipal Administration of Hospitals'Youth Programme(QML20181501 to Lijia Guo,QML20231506 to Yitong Liu,China)Beijing Municipal Administration of Hospitals Incubating Program(PX2023054 to Lijia Guo,China).
文摘Delayed wound healing in diabetes is a global challenge,and the development of related drugs is a clinical problem to be solved.In this study,purpurolide C(PC),a small-molecule secondary metabolite of the endophytic fungus Penicillium purpurogenum,was found to promote diabetic wound healing.To investigate the key regulation targets of PC,in vitro RNA-seq,molecular docking calcula-tions,TLR4-MD2 dimerization SDS-PAGE detection,and surface plasmon resonance(SPR)were per-formed,indicating that PC inhibited inflammatory macrophage activation by inhibiting both TLR4-MD2 dimerization and MYD88 phosphorylation.Tlr4 knockout in vivo attenuated the promotion effect of PC on wound healing.Furthermore,a delivery system consisting of macrophage liposome and GelMA-based microneedle patches combined with PC(PC@MLIP MN)was developed,which overcame the poor water solubility and weak skin permeability of PC,so that successfully punctured the skin and delivered PC to local tissues,and accurately regulated macrophage polarization in diabetic wound management.Overall,PC is an anti-inflammatory small molecule compound with a well-defined structure and dualtarget regulation,and the PC@MLIP MN is a promising novel biomaterial for the management of diabetic wound.
