Cutaneous nerve regeneration in diabetic wounds remains a challenge for current clinical treatment.Herein,a natural protein-based functional hydrogel is developed using keratin as the sole matrix,and protocatechuic al...Cutaneous nerve regeneration in diabetic wounds remains a challenge for current clinical treatment.Herein,a natural protein-based functional hydrogel is developed using keratin as the sole matrix,and protocatechuic aldehyde(PA)and zinc ions as the building blocks through dual-dynamic crosslinking reactions of thiol-aldehyde addition and catecholzinc ions coordination.The unique structural design endows the hydrogel with excellent injectability,skin adhesion,self-healing and antibacterial ability,and biocompatibility.In addition,this hydrogel acts as a drug carrier for the loading and sustained release of phellopterin(PP),a natural compound extracted from traditional Chinese medicine Angelica dahurica.Our findings demonstrate that the PP-loaded hydrogel promotes cutaneous nerve regeneration,angiogenesis and tissue remodeling in the full-thickness wounds in both db/db and streptozotocin-induced C57BL/6 diabetic mice,notably by the synergistic effect of zinc ions and PP,showing a great potential in diabetic wound therapy.展开更多
Mutations of epigenetic regulators are pervasive in human tumors.ASXL1 is frequently mutated in myeloid malignancies.We previously found that ASXL1 forms together with BAP1 a complex that can deubiquitinylate mono-ubi...Mutations of epigenetic regulators are pervasive in human tumors.ASXL1 is frequently mutated in myeloid malignancies.We previously found that ASXL1 forms together with BAP1 a complex that can deubiquitinylate mono-ubiquitinylated lysine 119 on histone H2A(H2AK119ub1),a Polycomb repressive mark.However,a complete mechanistic understanding of ASXL1 in transcriptional regulation and tumor suppression remains to be defined.Here,we find that depletion of Asxl1 confers murine 32D cells to IL3-independent growth at least partly due to sustained activation of PI3K/AKT signaling.Consistently,Asxl1 is critical for the transcriptional activation of Pten,a key negative regulator of AKT activity.Then we confirm that Asxl1 is specifically enriched and required for H2AK119 deubiquitylation at the Pten promoter.Interestingly,ASXL1 and PTEN expression levels are positively correlated in human blood cells and ASXL1 mutations are associated with lower expression levels of PTEN in human myeloid malignancies.Furthermore,malignant cells with ASXL1 downregulation or mutations exhibit higher sensitivity to the AKT inhibitor MK2206.Collectively,this study has linked the PTEN/AKT signaling axis to deregulated epigenetic changes in myeloid malignancies.It also provides a rationale for mechanism-based therapy for patients with ASXL1 mutations.展开更多
基金supported by grants from the National Natural Science Foundation of China(Nos.82474515 and 82074428)Highlevel Chinese Medicine Key Discipline Construction Project(Integrative Chinese and Western Medicine Clinic)of National Administration of TCM(No.zyyzdxk-2023065)+1 种基金Young Qi-Huang Scholar of National Administration of Traditional Chinese Medicine,Evidence-Based Capacity Building for TCM Specialty Therapies for Skin Diseases of National Administration of TCM,and Innovative Team Projects of Shanghai Municipal Commission of Health(No.2022CX011)to Fulun Lithe National Natural Science Foundation of China(No.32371413)to Guang Yang.
文摘Cutaneous nerve regeneration in diabetic wounds remains a challenge for current clinical treatment.Herein,a natural protein-based functional hydrogel is developed using keratin as the sole matrix,and protocatechuic aldehyde(PA)and zinc ions as the building blocks through dual-dynamic crosslinking reactions of thiol-aldehyde addition and catecholzinc ions coordination.The unique structural design endows the hydrogel with excellent injectability,skin adhesion,self-healing and antibacterial ability,and biocompatibility.In addition,this hydrogel acts as a drug carrier for the loading and sustained release of phellopterin(PP),a natural compound extracted from traditional Chinese medicine Angelica dahurica.Our findings demonstrate that the PP-loaded hydrogel promotes cutaneous nerve regeneration,angiogenesis and tissue remodeling in the full-thickness wounds in both db/db and streptozotocin-induced C57BL/6 diabetic mice,notably by the synergistic effect of zinc ions and PP,showing a great potential in diabetic wound therapy.
基金This work was supported by the National Natural Science Foundation of China(31570774,31701126,and 31900464)Nati onal Key Research and Development Program(2017YFA0504102)+2 种基金Natural Science Foundation of Tianjin Municipal Science and Technology Commission(17JCZDJC352OO and 18JCQNJC82300)Open Grant from the Chinese Academy of Medical Sciences(157-Zk19-02)Talent Excellence Program from Tianjin Medical University and Research Project of Tianjin Education Commission(2018KJ075).
文摘Mutations of epigenetic regulators are pervasive in human tumors.ASXL1 is frequently mutated in myeloid malignancies.We previously found that ASXL1 forms together with BAP1 a complex that can deubiquitinylate mono-ubiquitinylated lysine 119 on histone H2A(H2AK119ub1),a Polycomb repressive mark.However,a complete mechanistic understanding of ASXL1 in transcriptional regulation and tumor suppression remains to be defined.Here,we find that depletion of Asxl1 confers murine 32D cells to IL3-independent growth at least partly due to sustained activation of PI3K/AKT signaling.Consistently,Asxl1 is critical for the transcriptional activation of Pten,a key negative regulator of AKT activity.Then we confirm that Asxl1 is specifically enriched and required for H2AK119 deubiquitylation at the Pten promoter.Interestingly,ASXL1 and PTEN expression levels are positively correlated in human blood cells and ASXL1 mutations are associated with lower expression levels of PTEN in human myeloid malignancies.Furthermore,malignant cells with ASXL1 downregulation or mutations exhibit higher sensitivity to the AKT inhibitor MK2206.Collectively,this study has linked the PTEN/AKT signaling axis to deregulated epigenetic changes in myeloid malignancies.It also provides a rationale for mechanism-based therapy for patients with ASXL1 mutations.
