Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow mesenchymal stem ce...Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow mesenchymal stem cells(BMSCs) is lost upon aging is still unclear. Here, we found that the RNA-binding protein Musashi2(Msi2) regulates BMSC lineage commitment. Msi2 is commonly enriched in stem cells and tumor cells. We found that its expression was downregulated during adipogenic differentiation and upregulated during osteogenic differentiation of BMSCs. Msi2 knockout mice exhibited decreased bone mass with substantial accumulation of marrow adipocytes, similar to aging-induced osteoporosis. Depletion of Msi2 in BMSCs led to increased adipocyte commitment. Transcriptional profiling analysis revealed that Msi2 deficiency led to increased PPARγ signaling.RNA-interacting protein immunoprecipitation assays demonstrated that Msi2 could inhibit the translation of the key adipogenic factor Cebpα, thereby inhibiting PPAR signaling. Furthermore, the expression of Msi2 decreased significantly during the aging process of mice, indicating that decreased Msi2 function during aging contributes to abnormal accumulation of adipocytes in bone marrow and osteoporosis. Thus, our results provide a putative biochemical mechanism for aging-related osteoporosis, suggesting that modulating Msi2 function may benefit the treatment of bone aging.展开更多
Sustainable energy conversion and storage technologies are a vital prerequisite for neutral future carbon.To this end,carbon materials with attractive features,such as tunable pore architecture,good electrical conduct...Sustainable energy conversion and storage technologies are a vital prerequisite for neutral future carbon.To this end,carbon materials with attractive features,such as tunable pore architecture,good electrical conductivity,outstanding physicochemical stability,abundant resource,and low cost,have used as promising electrode materials for energy conversion and storage.Defect engineering could modulate the structures of carbon materials,thereby affecting their electronic properties.The presence of defects on carbons may lead to asymmetric charge distribution,change in geometrical configuration,and distortion of the electronic structure that may result in unexpected electrochemical performances.In this review,recent advances in defects of carbons used for energy conversion and storage were examined in terms of types,regulation strategies,and fine characterization means of defects.The applications of such carbons in supercapacitors,rechargeable batteries,and electrocatalysis were also discussed.The perspectives toward the development of defect engineering carbons were proposed.In all,novel insights related to improvement in high-performance carbon materials for future energy conversion and storage applications were provided.展开更多
Inhibitors that target diabetes pathology-related signaling pathways have great therapeutic potential for diabetic wound healing.Metal–organic frameworks(MOFs)are increasingly popular drug delivery systems that have ...Inhibitors that target diabetes pathology-related signaling pathways have great therapeutic potential for diabetic wound healing.Metal–organic frameworks(MOFs)are increasingly popular drug delivery systems that have high loading capacity and can release their intrinsic metal ions to act as bioactive agents.In light of this,a receptor for advanced glycation end products(RAGE)inhibitor,4-chloro-N-cyclohexyl-N-(phenylmethyl)-benzamide(FPS-ZM1),was loaded into a cobalt(Co)-based MOF(zeolitic imidazolate framework-67,ZIF-67)to fabricate FPS-ZM1 encapsulated ZIF-67(FZ@ZIF-67)nanoparticles(NPs).As a result,FZ@ZIF-67 NPs could dually deliver Co ions and FPS-ZM1 in a controlled manner for over 14 days.Our in vitro study showed that FZ@ZIF-67 NPs not only enhanced angiogenesis by delivering Co ions but also released FPS-ZM1 to promote M2 macrophage polarization and attenuated high glucose(HG)-and/or inflammation-induced impairment of angiogenesis through RAGE inhibition.Moreover,in an in vivo study,FZ@ZIF-67 NPs markedly improved re-epithelialization,collagen deposition,neovascularization,and relieved inflammation in diabetic wounds in rats.This study not only provides a low-cost,effective,and synergistic proangiogenic bioactive agent but also demonstrates that targeting diabetes-related pathological signaling pathways is necessary to ameliorate vascularization impairment during diabetic wound healing.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 the National Natural Science Foundation of China(NSFC)[81672119 and 81725010 to W.Z.]W Z is a scholar of‘the National Science Fund for Distinguished Young Scholars’(NSFC)[81725010]+4 种基金the Strategic Priority Research Program of the Chinese Academy of Science(XDA16020400 to P.H.)Ministry of Science and Technology of China(2017YFA0102700 to P.H.)National Natural Science Foundation of China(32170804 to PH)P.H.the fellowship of China Postdoctoral Science Foundation(2021TQ0207,2021M702184 to J.S.)the‘Basic research project of Shanghai Sixth People’s Hospital’(ynqn202102 to J.S.)。
文摘Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow mesenchymal stem cells(BMSCs) is lost upon aging is still unclear. Here, we found that the RNA-binding protein Musashi2(Msi2) regulates BMSC lineage commitment. Msi2 is commonly enriched in stem cells and tumor cells. We found that its expression was downregulated during adipogenic differentiation and upregulated during osteogenic differentiation of BMSCs. Msi2 knockout mice exhibited decreased bone mass with substantial accumulation of marrow adipocytes, similar to aging-induced osteoporosis. Depletion of Msi2 in BMSCs led to increased adipocyte commitment. Transcriptional profiling analysis revealed that Msi2 deficiency led to increased PPARγ signaling.RNA-interacting protein immunoprecipitation assays demonstrated that Msi2 could inhibit the translation of the key adipogenic factor Cebpα, thereby inhibiting PPAR signaling. Furthermore, the expression of Msi2 decreased significantly during the aging process of mice, indicating that decreased Msi2 function during aging contributes to abnormal accumulation of adipocytes in bone marrow and osteoporosis. Thus, our results provide a putative biochemical mechanism for aging-related osteoporosis, suggesting that modulating Msi2 function may benefit the treatment of bone aging.
基金the National Natural Science Foundation of China(52062012)Key Science&Technology Project of Hainan Province(ZDYF2020028)+2 种基金Key-Area Research and Development Program of Guangdong Province(2019B1102109003)the Innovation Team of Universities of Guangdong Province(2020KCXTD011)Guangdong Province Key Discipline Construction Project(2021ZDJS102).
文摘Sustainable energy conversion and storage technologies are a vital prerequisite for neutral future carbon.To this end,carbon materials with attractive features,such as tunable pore architecture,good electrical conductivity,outstanding physicochemical stability,abundant resource,and low cost,have used as promising electrode materials for energy conversion and storage.Defect engineering could modulate the structures of carbon materials,thereby affecting their electronic properties.The presence of defects on carbons may lead to asymmetric charge distribution,change in geometrical configuration,and distortion of the electronic structure that may result in unexpected electrochemical performances.In this review,recent advances in defects of carbons used for energy conversion and storage were examined in terms of types,regulation strategies,and fine characterization means of defects.The applications of such carbons in supercapacitors,rechargeable batteries,and electrocatalysis were also discussed.The perspectives toward the development of defect engineering carbons were proposed.In all,novel insights related to improvement in high-performance carbon materials for future energy conversion and storage applications were provided.
基金supported by grants from the National Natural Science Foundation of China(Nos.81930069,81772338,81974331,and 81802156)supported by the Major Scientific Research and Innovation Project of Shanghai Municipal Education Commission(No.2019-01-07-00-02-E00043).
文摘Inhibitors that target diabetes pathology-related signaling pathways have great therapeutic potential for diabetic wound healing.Metal–organic frameworks(MOFs)are increasingly popular drug delivery systems that have high loading capacity and can release their intrinsic metal ions to act as bioactive agents.In light of this,a receptor for advanced glycation end products(RAGE)inhibitor,4-chloro-N-cyclohexyl-N-(phenylmethyl)-benzamide(FPS-ZM1),was loaded into a cobalt(Co)-based MOF(zeolitic imidazolate framework-67,ZIF-67)to fabricate FPS-ZM1 encapsulated ZIF-67(FZ@ZIF-67)nanoparticles(NPs).As a result,FZ@ZIF-67 NPs could dually deliver Co ions and FPS-ZM1 in a controlled manner for over 14 days.Our in vitro study showed that FZ@ZIF-67 NPs not only enhanced angiogenesis by delivering Co ions but also released FPS-ZM1 to promote M2 macrophage polarization and attenuated high glucose(HG)-and/or inflammation-induced impairment of angiogenesis through RAGE inhibition.Moreover,in an in vivo study,FZ@ZIF-67 NPs markedly improved re-epithelialization,collagen deposition,neovascularization,and relieved inflammation in diabetic wounds in rats.This study not only provides a low-cost,effective,and synergistic proangiogenic bioactive agent but also demonstrates that targeting diabetes-related pathological signaling pathways is necessary to ameliorate vascularization impairment during diabetic wound healing.
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.
