OBJECTIVE Refractory wounds in diabetic patients constitute a serious complication that often leads to amputation with limited treatment regimens.Recent studies have shown that the imbalance of mitochondrial dynamics ...OBJECTIVE Refractory wounds in diabetic patients constitute a serious complication that often leads to amputation with limited treatment regimens.Recent studies have shown that the imbalance of mitochondrial dynamics was associated with the increased reactive oxygen species(ROS)production in endothelial cells,which is a significant contributor to the microvascular complications of diabetes.The present study was designed to determine the involvement of transcription factor FOXO1in diabetic wound healing and investigate underlying mechanisms.METHODS&RESULTS Impaired mitochondrial networks and increased phosphorylation of dynaminrelated protein-1(Drp1)at ser616,a protein required for mitochondrial fission,were observed in human umbilical vein endothelial cells(HUVECs)24 h after exposure to high concentrations of glucose.Inhibition of FOXO1 by si RNA or by FOXO1 selective inhibitor AS1842856 abrogated high glucos-induced alterations in mitochondrial networks and phosphorylation of Drp1.Treatment with AS1842856 or si RNA of FOXO1 could significantly increase the mitochondrial membrane potential and suppress the overproduction of ROS induced by high glucose.Addition of AS1842856 inhibited glucoseinduced apoptosis,ameliorated capillary tube formation in HUVECs.In vivo,AS1842856 dose-dependently rescued the delay of wound closure in diabetic mice,and5 mg·kg-1of AS1842856 treatment significantly increased the mean perfusion rate.CONCLUSION These findings suggested that FOXO1 is critical to preserve mitochondrial quantity and function in endothelial cells,inhibition of FOXO1 rescued the delayed wound healing and improved wound angiogenesis in diabetic mice.展开更多
OBJECTIVE Prostate cancer is the most commonly diagnosed malignancy and the sixth leading cause of cancer death in men.Aberrant upregulation of enhancer of Zeste homolog2(EZH2)occur frequently in human cancers,includi...OBJECTIVE Prostate cancer is the most commonly diagnosed malignancy and the sixth leading cause of cancer death in men.Aberrant upregulation of enhancer of Zeste homolog2(EZH2)occur frequently in human cancers,including prostate adenocarcinoma,it′s a bona fide oncogene,yet clinical benefits of EZH2 inhibitor(EZH2i)remain unsatis⁃factory and limited to certain hematological malignancies.AD20 is a natural product which is extracted from creosote bush.Our previous study has demonstrated that AD20 could inhibit the growth and metastasis in prostate cancer by inhibiting NRP1,however,the mechanisms still need to be clarified.METHODS PC3 cell were cultured in DMEM/F12 supplemented with 10%fetal bovine serum.The proliferation and migration were measured by MTS,wound healing assay and tran⁃swell assay.The expression of the protein was observed by Western blot.The mRNA levels were detected by real-time PCR.LC-MS/MS-based proteomic assay,CoIP-MS and network pharmacology are used to construct the PPI network and identify related proteins.RESULTS AD20(10-20μmol·L^-1)can regulate EZH2 expression from transcription,trans⁃lation,degradation levels.AD20 downregulates EZH2-H3K27me3 signaling dramatically and activates many down⁃stream tumor suppressor genes,such as CDH1,GATA6,CDKN2A.In vitro,AD20(10-40μmol·L^-1)suppresses PC3 cell proliferation and migration in a dose-dependent manner.And interestingly,the combination with AD20 significantly improved the efficacy of EZH2 inhibitors(GSK126 and EPZ-6438)in PC3 cell line.CONCLUSION AD20 can suppress PC3 cell proliferation by targeting EZH2-H3K27me3-p16INK4a signaling and inhibit PC3 cell migration by inhibiting NRP1.展开更多
基金The project supported by National Natural Science Foundation of China(81373405,30901803)Beijing Higher Education Young Elite Teacher Project(YETP0053)
文摘OBJECTIVE Refractory wounds in diabetic patients constitute a serious complication that often leads to amputation with limited treatment regimens.Recent studies have shown that the imbalance of mitochondrial dynamics was associated with the increased reactive oxygen species(ROS)production in endothelial cells,which is a significant contributor to the microvascular complications of diabetes.The present study was designed to determine the involvement of transcription factor FOXO1in diabetic wound healing and investigate underlying mechanisms.METHODS&RESULTS Impaired mitochondrial networks and increased phosphorylation of dynaminrelated protein-1(Drp1)at ser616,a protein required for mitochondrial fission,were observed in human umbilical vein endothelial cells(HUVECs)24 h after exposure to high concentrations of glucose.Inhibition of FOXO1 by si RNA or by FOXO1 selective inhibitor AS1842856 abrogated high glucos-induced alterations in mitochondrial networks and phosphorylation of Drp1.Treatment with AS1842856 or si RNA of FOXO1 could significantly increase the mitochondrial membrane potential and suppress the overproduction of ROS induced by high glucose.Addition of AS1842856 inhibited glucoseinduced apoptosis,ameliorated capillary tube formation in HUVECs.In vivo,AS1842856 dose-dependently rescued the delay of wound closure in diabetic mice,and5 mg·kg-1of AS1842856 treatment significantly increased the mean perfusion rate.CONCLUSION These findings suggested that FOXO1 is critical to preserve mitochondrial quantity and function in endothelial cells,inhibition of FOXO1 rescued the delayed wound healing and improved wound angiogenesis in diabetic mice.
文摘OBJECTIVE Prostate cancer is the most commonly diagnosed malignancy and the sixth leading cause of cancer death in men.Aberrant upregulation of enhancer of Zeste homolog2(EZH2)occur frequently in human cancers,including prostate adenocarcinoma,it′s a bona fide oncogene,yet clinical benefits of EZH2 inhibitor(EZH2i)remain unsatis⁃factory and limited to certain hematological malignancies.AD20 is a natural product which is extracted from creosote bush.Our previous study has demonstrated that AD20 could inhibit the growth and metastasis in prostate cancer by inhibiting NRP1,however,the mechanisms still need to be clarified.METHODS PC3 cell were cultured in DMEM/F12 supplemented with 10%fetal bovine serum.The proliferation and migration were measured by MTS,wound healing assay and tran⁃swell assay.The expression of the protein was observed by Western blot.The mRNA levels were detected by real-time PCR.LC-MS/MS-based proteomic assay,CoIP-MS and network pharmacology are used to construct the PPI network and identify related proteins.RESULTS AD20(10-20μmol·L^-1)can regulate EZH2 expression from transcription,trans⁃lation,degradation levels.AD20 downregulates EZH2-H3K27me3 signaling dramatically and activates many down⁃stream tumor suppressor genes,such as CDH1,GATA6,CDKN2A.In vitro,AD20(10-40μmol·L^-1)suppresses PC3 cell proliferation and migration in a dose-dependent manner.And interestingly,the combination with AD20 significantly improved the efficacy of EZH2 inhibitors(GSK126 and EPZ-6438)in PC3 cell line.CONCLUSION AD20 can suppress PC3 cell proliferation by targeting EZH2-H3K27me3-p16INK4a signaling and inhibit PC3 cell migration by inhibiting NRP1.
