Intermittent fasting(IF)is becoming a prevailing topic worldwide,as it can cause changes in the body’s energy metabolism processes,improve health,and affect the progression of many diseases,particularly in the circum...Intermittent fasting(IF)is becoming a prevailing topic worldwide,as it can cause changes in the body’s energy metabolism processes,improve health,and affect the progression of many diseases,particularly in the circumstance of oncology.Recent research has shown that IF can alter the energy metabolism of tumor cells,thereby inhibiting tumor growth and improving antitumor immune responses.Furthermore,IF can increase cancer sensitivity to chemotherapy and radiotherapy and reduce the side effects of these traditional anticancer treatments.IF is therefore emerging as a promising approach to clinical cancer treatment.However,the balance between long-term benefits of IF compared with the harm from insufficient caloric intake is not well understood.In this article,we review the role of IF in tumorigenesis and tumor therapy,and discuss some scientific problems that remain to be clarified,which might provide some assistance in the application of IF in clinical tumor therapy.展开更多
In order to provide reference for cultivating new agricultural operators to promote the transformation and upgrading of traditional agriculture,the main practices,achievements and problems of cultivating new agricultu...In order to provide reference for cultivating new agricultural operators to promote the transformation and upgrading of traditional agriculture,the main practices,achievements and problems of cultivating new agricultural operators to promote the transformation and upgrading of traditional agriculture in Nanchong City,Sichuan Province were analyzed firstly,and then some measures were proposed.展开更多
Background:Angiogenesis plays an important role in the occurrence and development of non-small cell lung cancer(NSCLC).The atypical mitogen-activated protein kinase 4(MAPK4)has been shown to be involved in the pathoge...Background:Angiogenesis plays an important role in the occurrence and development of non-small cell lung cancer(NSCLC).The atypical mitogen-activated protein kinase 4(MAPK4)has been shown to be involved in the pathogenesis of various diseases.However,the potential role of MAPK4 in the tumor angiogenesis of NSCLC remains unclear.Methods:Adult male C57BL/6 wild-type mice were randomly divided into the control group and p-siMAPK4 intervention group,respectively.The cell proliferation was analyzed with flow cytometry and immunofluorescence staining.The vascular density in tumor mass was analyzed by immuno-fluorescence staining.The expressions of MAPK4 and related signaling molecules were detected by western blot analysis and immunofluorescence staining,and so on.Results:We found that the expression of MAPK4,which was dominantly expressed in local endothelial cells(ECs),was correlated with tumor angiogenesis of NSCLC.Furthermore,MAPK4 silencing inhibited the proliferation and migration abilities of human umbilical vein ECs(HUVECs).QKHZC-2020-4Y156,QKH-JC-2018-1428,QKH-RC-2019-5612;Collaborative Innovation Center of Chinese Ministry of Education,Grant/Award Number:2020-39;Program for Science and Technology Joint Fund Project in Zunyi Science and Technology Bureau and Zunyi Medical University,Grant/Award Numbers:ZSKH-RPT-2020-6,ZSKH-HZ-2021-193;Graduate Research Fund of Zunyi Medical University,Grant/Award Number:2023-ZYK-171 Global gene analysis showed that MAPK4 silencing altered the expression of multiple genes related to cell cycle and angiogenesis pathways,and that MAPK4 silencing increased transduction of the extracellular regulated protein kinases 1/2(ERK1/2)pathway but not Akt and c-Jun n-terminal kinase pathways.Further analysis showed that MAPK4 silencing inhibited the proliferation and migration abilities of HUVECs cultured in tumor cell supernatant,which was accompanied with increased transduction of the ERK1/2 pathway.Clinical data analysis suggested that the higher expression of MAPK4 and CD34 were associated with poor prognosis of patients with NSCLC.Targeted silencing of MAPK4 in ECs using small interfering RNA driven by the CD34 promoter effectively inhibited tumor angiogenesis and growth of NSCLC in vivo.Conclusion:Our results reveal that MAPK4 plays an important role in the angiogenesis and development of NSCLC.MAPK4 may thus represent a new target for NSCLC.展开更多
Despite advances in screening and treatment,colon cancer remains one of the leading causes of cancer-related death.Finding novel and useful drug treatment targets is also an urgent need for clinical applications.Tetra...Despite advances in screening and treatment,colon cancer remains one of the leading causes of cancer-related death.Finding novel and useful drug treatment targets is also an urgent need for clinical applications.Tetrandrine(Tet)is extracted from the Chinese medicinal herbal medicine,which is a well-known calcium blocker with a variety of pharmacological activities,including anti-cancer.In this study,we recruited cell viability assay,flow cytometry analysis,cloning formation to confirm that Tet can inhibit the proliferation of SW620 cells,and induce apoptosis.Mechanically,we confirmed that Tet up-regulates the mRNA and protein level of BMP9 in SW620 cells.Over-expression BMP9 enhances the anticancer effects of Tet in SW620 cells,but these effects can be partly reversed by silencing BMP9.Also,Tet reduces phosphorylation of Aktl/2/3 in SW620 cells,which could be elevated by overexpressed BMP9 and impaired by silencing BMP9.Furthermore,we demonstrated that Tet reduces phosphorylated PTEN,which can be promoted by overexpressed BMP9,analogously also be attenuated through silencing BMP9.Finally,we introduced a xenograft tumor model to investigate the anti-proliferative effect of Tet,further to explore the effects of BMP9 and PTEN in SW620 cells.Our findings suggested that the anti-cancer activity of Tet in SW620 cells may be mediated partly by up-regulating BMP9,followed by inactivation PI3K/Akt through up-regulating PTEN at least.展开更多
The aryl hydrocarbon receptor(AHR)plays an important role during mammalian embryo development.Inhibition of AHR signaling promotes the development of hematopoietic stem/progenitor cells.AHR also regulates the function...The aryl hydrocarbon receptor(AHR)plays an important role during mammalian embryo development.Inhibition of AHR signaling promotes the development of hematopoietic stem/progenitor cells.AHR also regulates the functional maturation of blood cells,such as T cells and megakaryocytes.However,little is known about the role of AHR modulation during the development of erythroid cells.In this study,we used the AHR antagonist StemRegenin 1(SR1)and the AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin during different stages of human erythropoiesis to elucidate the function of AHR.We found that antagonizing AHR signaling improved the production of human embryonic stem cell derived erythrocytes and enhanced erythroid terminal differentiation.RNA sequencing showed that SR1 treatment of proerythroblasts upregulated the expression of erythrocyte differentiation-related genes and downregulated actin organization-associated genes.We found that SR1 accelerated F-actin remodeling in terminally differentiated erythrocytes,favoring their maturation of the cytoskeleton and enucleation.We demonstrated that the effects of AHR inhibition on erythroid maturation were associated with F-actin remodeling.Our findings help uncover the mechanism for AHRmediated human erythroid cell differentiation.We also provide a new approach toward the large-scale production of functionally mature human pluripotent stem cell-derived erythrocytes for use in translational applications.展开更多
Dear Editor,Myelodysplastic syndromes(MDSs)are a group of clonal myeloid stem cell disorders characterized by varying degrees of cytopenias,cytogenetic and molecular genetic abnormalities,and a predisposition to acute...Dear Editor,Myelodysplastic syndromes(MDSs)are a group of clonal myeloid stem cell disorders characterized by varying degrees of cytopenias,cytogenetic and molecular genetic abnormalities,and a predisposition to acute myeloid leukemia(AML).The treatments for MDS mainly consist of cytoreductive treatment,such as traditional AML-like chemotherapy,hypomethylating agents(HMAs),allogeneic hematopoietic stem cell transplantation(alio-HSCT)and immunoregulation according to risk stratification.展开更多
The hematopoietic function of HOXC4 has not been extensively investigated.Our research indicated that induction of HOXC4 in co-culture system from D10 significantly promoted productions of most hematopoietic progenito...The hematopoietic function of HOXC4 has not been extensively investigated.Our research indicated that induction of HOXC4 in co-culture system from D10 significantly promoted productions of most hematopoietic progenitor cells.CD34−CD43+cells could be clearly classified into CD34−CD43^(low) and CD34−CD43^(high) sub-populations at D14.The former cells had greater myelogenic potential,and their production was not significantly influenced by induction of HOXC4.By contrast,the latter cells had greater potential to differentiate into megakaryocytes and erythroid cells,and thus had properties of erythroid–megakaryocyte common progenitors,which abundance was increased by∼2-fold when HOXC4 was induced from D10.For CD34−CD43^(low),CD34+CD43+,and CD34−CD43^(high) sub-populations,CD43 level served as a natural index for the tendency to undergo hematopoiesis.Induction of HOXC4 from D10 caused more CD43+cells sustain in S-phase with up-regulation of NF-κB signaling,which could be counteracted by inhibition of NF-κB signaling.These observations suggested that promotion of hematopoiesis by HOXC4 is closely related to NF-κB signaling and a change in cell-cycle status,which containing potential of clinical applications.展开更多
GATA2,a principal member of the GATA family,plays important roles in the generation and maintenance of hematopoietic stem/progenitor cells.Among the three mRNA transcripts,the distal first exon of GATA2(IS exon)is spe...GATA2,a principal member of the GATA family,plays important roles in the generation and maintenance of hematopoietic stem/progenitor cells.Among the three mRNA transcripts,the distal first exon of GATA2(IS exon)is specific for hematopoietic and neuronal cells.GATA2 mutants with abnormal expression are often present in acute myeloid leukemia-related familial diseases and myelodysplastic syndrome,indicating the crucial significance of GATA2 in the proper maintenance of blood system functions.This article offers an overview of the regulation dynamics and function of GATA2 in the generation,proliferation,and function of hematopoietic stem cells in both mouse and human models.We acknowledge the current progress in the cell fate determination mechanism by dynamic GATA2 expression.The gene modification approaches for inspecting the role of GATA2 in definitive hematopoiesis demonstrate the potential for acquiring hPSC-derived hematopoietic stem cells via manipulated GATA2 regulation.展开更多
A 52-day continuous semi-static waterborne exposure(test media renewed daily) regimen was employed to investigate the accumulation and elimination profiles of two iron oxide nanomaterials(nano-Fe2O3 and nano-Fe3O4...A 52-day continuous semi-static waterborne exposure(test media renewed daily) regimen was employed to investigate the accumulation and elimination profiles of two iron oxide nanomaterials(nano-Fe2O3 and nano-Fe3O4) in zebrafish(Danio rerio). Adult zebrafish were exposed to nanomaterial suspensions with initial concentrations of 4.0 and 10.0 mg/L for28 days and then were moved to clean water for 24 days to perform the elimination experiment. Fe content was measured in fish body and feces to provide data on accumulation and elimination of the two iron oxide nanomaterials in zebrafish. The experiment revealed that:(1) high accumulation of nano-Fe2O3 and nano-Fe3O4 were found in zebrafish, with maximum Fe contents, respectively, of 1.32 and 1.25 mg/g for 4.0 mg/L treatment groups and 1.15 and 0.90 mg/g for 10.0 mg/L treatment groups;(2) accumulated nanoparticles in zebrafish can be eliminated efficiently(the decrease of body burden of Fe conforms to a first-order decay equation) when fish were moved to nanoparticle-free water,and the elimination rates ranged from 86% to 100% by 24 days post-exposure; and(3)according to analysis of Fe content in fish excrement in the elimination phase, iron oxide nanomaterials may be adsorbed via the gastrointestinal tract, and stored for more than12 days.展开更多
Runt-related transcription factor 1(RUNX1)is required for definitive hematopoiesis;however,the functions of most human RUNX1 isoforms are unclear.In particular,the effects of RUNX1-205(a novel splice variant that lack...Runt-related transcription factor 1(RUNX1)is required for definitive hematopoiesis;however,the functions of most human RUNX1 isoforms are unclear.In particular,the effects of RUNX1-205(a novel splice variant that lacks exon 6 in comparison with RUNX1b)on human hematopoiesis are not clear.In this study,a human embryonic stem cell(hESC)line with inducible RUNX1-205 overexpression was established.Analyses of these cells revealed that induction of RUNX1-205 overexpression at early stage did not influence the induction of mesoderm but blocked the emergence of CD34+cells,and the production of hematopoietic stem/progenitor cells was significantly reduced.In addition,the expression of hematopoiesis-related factors was downregulated.However,these effects were abolished when RUNX1-205 overexpression was induced after Day 6 in co-cultures of hESCs and AGM-S3 cells,indicating that the inhibitory effect occurred prior to generation of hemogenic endothelial cells,while the promotive effect could be observed during the late stage of hematopoiesis.This is very similar to that of RUNX1b.Interestingly,the mRNA expression profile of RUNX1-205 during hematopoiesis was distinct from that of RUNX1b,and the protein stability of RUNX1-205 was much higher than that of RUNX1b.Thus,the function of RUNX1-205 in normal and diseased models should be further explored.展开更多
Targeted gene therapy has become a promising approach for lung cancer treatment.In our previous work,we reported that the targeted expression of microRNA-7(miR-7)operated by thyroid transcription factor-1(TTF-1)promot...Targeted gene therapy has become a promising approach for lung cancer treatment.In our previous work,we reported that the targeted expression of microRNA-7(miR-7)operated by thyroid transcription factor-1(TTF-1)promoter inhibited the growth of human lung cancer cells in vitro and in vivo;however,the intervention efficiency needed to be further improved.In this study,we identified the core promoter of TTF-1(from-1299 bp to-871 bp)by 5’deletion assay and screened out the putative transcription factors nuclear factor-1(NF-1)and activator protein-1(AP-1).Further analysis revealed that the expression level of NF-1,but not AP-1,was positively connected with the activation of TTF-1 core promoter in human non-small-cell lung cancer(NSCLC)cells.Moreover,the silencing of NF-1 could reduce the expression level of miR-7 operated by TTF-1 core promoter.Of note,we optimized four distinct sequences to form additional NF-1-binding sites(TGGCA)in the sequence of TTF-1 core promoter(termed asTTF-1 promoter),and verified the binding efficiency of NF-1 on theTTF-1 promoter by electrophoretic mobility shift assay(EMSA).As expected,theTTF-1 promoter could more effectively drive miR-7 expression and inhibit the growth of human NSCLC cells in vitro,accompanied by a reduced transduction of NADH dehydrogenase(ubiquinone)1αsubcomplex 4(NDUFA4)/protein kinase B(Akt)pathway.Consistently,TTF-1 promoter-driven miR-7expression could also effectively abrogate the growth and metastasis of tumor cells in a murine xenograft model of human NSCLC.Finally,no significant changes were detected in the biological indicators or the histology of some important tissues and organs,including heart,liver,and spleen.On the whole,our study revealed that the optimized TTF-1 promoter could more effectively operate miR-7 to influence the growth of human NSCLC cells,providing a new basis for the development of microRNA-based targeting gene therapy against clinical lung cancer.展开更多
Mast cells (MCs) play a pivotal role in the hypersensitivity reaction by regulating the innate and adaptive immune responses. Humans have two types of MCs. The first type, termed MCTC, is found in the skin and other c...Mast cells (MCs) play a pivotal role in the hypersensitivity reaction by regulating the innate and adaptive immune responses. Humans have two types of MCs. The first type, termed MCTC, is found in the skin and other connective tissues and expresses both tryptase and chymase, while the second, termed MCT, which only expresses tryptase, is found primarily in the mucosa. MCs induced from human adult-type CD34+ cells are reported to be of the MCT type, but the development of MCs during embryonic/fetal stages is largely unknown. Using an efficient coculture system, we identified that a CD34+c-kit+ cell population, which appeared prior to the emergence of CD34+CD45+ hematopoietic stem and progenitor cells (HSPCs), stimulated robust production of pure Tryptase+Chymase+ MCs (MCTCs). Single-cell analysis revealed dual development directions of CD34+c-kit+ progenitors, with one lineage developing into erythro-myeloid progenitors (EMP) and the other lineage developing into HSPC. Interestingly, MCTCs derived from early CD34+c-kit+ cells exhibited strong histamine release and immune response functions. Particularly, robust release of IL-17 suggested that these early developing tissue-type MCTCs could play a central role in tumor immunity. These findings could help elucidate the mechanisms controlling early development of MCTCs and have significant therapeutic implications.展开更多
基金supported by the Consultative and Research Project of the Chinese Academy of Engineering(2020-XY-19 and 2019-ZD-34)the Guangdong Basic and Applied Basic Research Foundation(2020A1515011230)the Humanities and Social Science Foundation of the Ministry of Education of China(16YJCZH162).
基金supported by the Program for Highlevel Innovative Talents in Guizhou Province(Grant No.QKH-RC-2016-4031)the National Natural Science Foundation of China(Grant No.31760258)+2 种基金the Program for New Century Excellent Talents in University,the Ministry of Education of China(Grant No.NCET-12-0661)the Program for Excellent Young Talents of Zunyi Medical University(Grant No.15ZY-001)the Project of the Guizhou Provincial Department of Science and Technology(Grant No.QKH-JC-2018-1428)。
文摘Intermittent fasting(IF)is becoming a prevailing topic worldwide,as it can cause changes in the body’s energy metabolism processes,improve health,and affect the progression of many diseases,particularly in the circumstance of oncology.Recent research has shown that IF can alter the energy metabolism of tumor cells,thereby inhibiting tumor growth and improving antitumor immune responses.Furthermore,IF can increase cancer sensitivity to chemotherapy and radiotherapy and reduce the side effects of these traditional anticancer treatments.IF is therefore emerging as a promising approach to clinical cancer treatment.However,the balance between long-term benefits of IF compared with the harm from insufficient caloric intake is not well understood.In this article,we review the role of IF in tumorigenesis and tumor therapy,and discuss some scientific problems that remain to be clarified,which might provide some assistance in the application of IF in clinical tumor therapy.
基金Supported by National Modern Agriculture Demonstration Zone Project of Ministry of Agriculture(Nong Ji Fa[2010]22)Agricultural Reform and Construction Pilot Project of National Modern Agriculture Demonstration Zone of Ministry of Agriculture and Ministry of Finance(Nong Cai Fa[2013]13)National Agricultural Science and Technology Park Project of Ministry of Science and Technology(Guo Ke Ban Nong[2015]9)
文摘In order to provide reference for cultivating new agricultural operators to promote the transformation and upgrading of traditional agriculture,the main practices,achievements and problems of cultivating new agricultural operators to promote the transformation and upgrading of traditional agriculture in Nanchong City,Sichuan Province were analyzed firstly,and then some measures were proposed.
基金National Natural Science Foundation of China,Grant/Award Numbers:82272812,81960509,32160178Program for High Level Innovative Talents in Guizhou Province,Grant/Award Number:QKH-RC-2016-4031+4 种基金Program for Excellent Young Talents of Zunyi Medical University,Grant/Award Number:15ZY-001Project of Guizhou Provincial Department of Science and Technology,Grant/Award Numbers:QKHZC-2020-4Y156,QKH-JC-2018-1428,QKH-RC-2019-5612Collaborative Innovation Center of Chinese Ministry of Education,Grant/Award Number:2020-39Program for Science and Technology Joint Fund Project in Zunyi Science and Technology Bureau and Zunyi Medical University,Grant/Award Numbers:ZSKH-RPT-2020-6,ZSKH-HZ-2021-193Graduate Research Fund of Zunyi Medical University,Grant/Award Number:2023-ZYK-171。
文摘Background:Angiogenesis plays an important role in the occurrence and development of non-small cell lung cancer(NSCLC).The atypical mitogen-activated protein kinase 4(MAPK4)has been shown to be involved in the pathogenesis of various diseases.However,the potential role of MAPK4 in the tumor angiogenesis of NSCLC remains unclear.Methods:Adult male C57BL/6 wild-type mice were randomly divided into the control group and p-siMAPK4 intervention group,respectively.The cell proliferation was analyzed with flow cytometry and immunofluorescence staining.The vascular density in tumor mass was analyzed by immuno-fluorescence staining.The expressions of MAPK4 and related signaling molecules were detected by western blot analysis and immunofluorescence staining,and so on.Results:We found that the expression of MAPK4,which was dominantly expressed in local endothelial cells(ECs),was correlated with tumor angiogenesis of NSCLC.Furthermore,MAPK4 silencing inhibited the proliferation and migration abilities of human umbilical vein ECs(HUVECs).QKHZC-2020-4Y156,QKH-JC-2018-1428,QKH-RC-2019-5612;Collaborative Innovation Center of Chinese Ministry of Education,Grant/Award Number:2020-39;Program for Science and Technology Joint Fund Project in Zunyi Science and Technology Bureau and Zunyi Medical University,Grant/Award Numbers:ZSKH-RPT-2020-6,ZSKH-HZ-2021-193;Graduate Research Fund of Zunyi Medical University,Grant/Award Number:2023-ZYK-171 Global gene analysis showed that MAPK4 silencing altered the expression of multiple genes related to cell cycle and angiogenesis pathways,and that MAPK4 silencing increased transduction of the extracellular regulated protein kinases 1/2(ERK1/2)pathway but not Akt and c-Jun n-terminal kinase pathways.Further analysis showed that MAPK4 silencing inhibited the proliferation and migration abilities of HUVECs cultured in tumor cell supernatant,which was accompanied with increased transduction of the ERK1/2 pathway.Clinical data analysis suggested that the higher expression of MAPK4 and CD34 were associated with poor prognosis of patients with NSCLC.Targeted silencing of MAPK4 in ECs using small interfering RNA driven by the CD34 promoter effectively inhibited tumor angiogenesis and growth of NSCLC in vivo.Conclusion:Our results reveal that MAPK4 plays an important role in the angiogenesis and development of NSCLC.MAPK4 may thus represent a new target for NSCLC.
基金supported by the National Natural Science Foundation of China(72242105)the National Key Research and Development Program of China(2022YFE0208700 and2022YFE0208500)the Norwegian Research Council(287690/F20)。
基金supported by the National Natural Science Foundation of China(72140001 and 41921005)Shandong Provincial Science Fund for Excellent Youth Scholars(ZR2021YQ27)+1 种基金the National Social Science Fund of China(21ZDA065)the Natural Environment Research Council(2021GRIP02COP-AQ)。
基金This work was supported by the National Program on Key Basic Research Project of China (973 Program 2015CB964902), the National Natural Science Foundation of China (NSFC H81170466 and H81370597), and the CAMS Initiatives for Innovative Medicine (2016-12M-1-018) awarded to F.M.
基金We thank Professor T.C.He(Medical Center of University of Chicago,Chicago IL,USA)for his kind provision of the recombinant adenoviruses.
文摘Despite advances in screening and treatment,colon cancer remains one of the leading causes of cancer-related death.Finding novel and useful drug treatment targets is also an urgent need for clinical applications.Tetrandrine(Tet)is extracted from the Chinese medicinal herbal medicine,which is a well-known calcium blocker with a variety of pharmacological activities,including anti-cancer.In this study,we recruited cell viability assay,flow cytometry analysis,cloning formation to confirm that Tet can inhibit the proliferation of SW620 cells,and induce apoptosis.Mechanically,we confirmed that Tet up-regulates the mRNA and protein level of BMP9 in SW620 cells.Over-expression BMP9 enhances the anticancer effects of Tet in SW620 cells,but these effects can be partly reversed by silencing BMP9.Also,Tet reduces phosphorylation of Aktl/2/3 in SW620 cells,which could be elevated by overexpressed BMP9 and impaired by silencing BMP9.Furthermore,we demonstrated that Tet reduces phosphorylated PTEN,which can be promoted by overexpressed BMP9,analogously also be attenuated through silencing BMP9.Finally,we introduced a xenograft tumor model to investigate the anti-proliferative effect of Tet,further to explore the effects of BMP9 and PTEN in SW620 cells.Our findings suggested that the anti-cancer activity of Tet in SW620 cells may be mediated partly by up-regulating BMP9,followed by inactivation PI3K/Akt through up-regulating PTEN at least.
基金supported by the National Basic Research Program(973 Program,2015CB964902)the National Natural Science Foundation of China(H81170466 and H81370597)the CAMS Initiatives for Innovative Medicine(2016-I2M-1-018,2019-I2M-1-006,and 2017-I2M-2005)to F.M.,the National Natural Science Foundation of China Youth Fund(82000119)to Yonggang Zhang.
文摘The aryl hydrocarbon receptor(AHR)plays an important role during mammalian embryo development.Inhibition of AHR signaling promotes the development of hematopoietic stem/progenitor cells.AHR also regulates the functional maturation of blood cells,such as T cells and megakaryocytes.However,little is known about the role of AHR modulation during the development of erythroid cells.In this study,we used the AHR antagonist StemRegenin 1(SR1)and the AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin during different stages of human erythropoiesis to elucidate the function of AHR.We found that antagonizing AHR signaling improved the production of human embryonic stem cell derived erythrocytes and enhanced erythroid terminal differentiation.RNA sequencing showed that SR1 treatment of proerythroblasts upregulated the expression of erythrocyte differentiation-related genes and downregulated actin organization-associated genes.We found that SR1 accelerated F-actin remodeling in terminally differentiated erythrocytes,favoring their maturation of the cytoskeleton and enucleation.We demonstrated that the effects of AHR inhibition on erythroid maturation were associated with F-actin remodeling.Our findings help uncover the mechanism for AHRmediated human erythroid cell differentiation.We also provide a new approach toward the large-scale production of functionally mature human pluripotent stem cell-derived erythrocytes for use in translational applications.
基金This work was supported by the National Key Research and Development Projects(Grant Nos.2017YFA0105500,2017YFA105504)the National Natural Science Foundation of China(Grant Nos.81770190,81970161,81500149)R&D projects in key areas of Guangdong Province(Grant No.2019B020236004).
文摘Dear Editor,Myelodysplastic syndromes(MDSs)are a group of clonal myeloid stem cell disorders characterized by varying degrees of cytopenias,cytogenetic and molecular genetic abnormalities,and a predisposition to acute myeloid leukemia(AML).The treatments for MDS mainly consist of cytoreductive treatment,such as traditional AML-like chemotherapy,hypomethylating agents(HMAs),allogeneic hematopoietic stem cell transplantation(alio-HSCT)and immunoregulation according to risk stratification.
基金This work was supported by awards from the CAMS Initiatives for Innovative Medicine(2016-I2M-1-018 to F.Ma and 2017-I2M-3-021 to J.X.Liu)Sichuan Provincial Science and Technology Department Key R&D projects(020YFSY0023 to B.Chen)the Chengdu Science and Technology Project-Technology Innovation R&D(2018-YF05-01341-SN to B.Chen).
文摘The hematopoietic function of HOXC4 has not been extensively investigated.Our research indicated that induction of HOXC4 in co-culture system from D10 significantly promoted productions of most hematopoietic progenitor cells.CD34−CD43+cells could be clearly classified into CD34−CD43^(low) and CD34−CD43^(high) sub-populations at D14.The former cells had greater myelogenic potential,and their production was not significantly influenced by induction of HOXC4.By contrast,the latter cells had greater potential to differentiate into megakaryocytes and erythroid cells,and thus had properties of erythroid–megakaryocyte common progenitors,which abundance was increased by∼2-fold when HOXC4 was induced from D10.For CD34−CD43^(low),CD34+CD43+,and CD34−CD43^(high) sub-populations,CD43 level served as a natural index for the tendency to undergo hematopoiesis.Induction of HOXC4 from D10 caused more CD43+cells sustain in S-phase with up-regulation of NF-κB signaling,which could be counteracted by inhibition of NF-κB signaling.These observations suggested that promotion of hematopoiesis by HOXC4 is closely related to NF-κB signaling and a change in cell-cycle status,which containing potential of clinical applications.
文摘GATA2,a principal member of the GATA family,plays important roles in the generation and maintenance of hematopoietic stem/progenitor cells.Among the three mRNA transcripts,the distal first exon of GATA2(IS exon)is specific for hematopoietic and neuronal cells.GATA2 mutants with abnormal expression are often present in acute myeloid leukemia-related familial diseases and myelodysplastic syndrome,indicating the crucial significance of GATA2 in the proper maintenance of blood system functions.This article offers an overview of the regulation dynamics and function of GATA2 in the generation,proliferation,and function of hematopoietic stem cells in both mouse and human models.We acknowledge the current progress in the cell fate determination mechanism by dynamic GATA2 expression.The gene modification approaches for inspecting the role of GATA2 in definitive hematopoiesis demonstrate the potential for acquiring hPSC-derived hematopoietic stem cells via manipulated GATA2 regulation.
基金supported by the Doctoral Education Funding of Education Ministry of China (No. 20070055033)
文摘A 52-day continuous semi-static waterborne exposure(test media renewed daily) regimen was employed to investigate the accumulation and elimination profiles of two iron oxide nanomaterials(nano-Fe2O3 and nano-Fe3O4) in zebrafish(Danio rerio). Adult zebrafish were exposed to nanomaterial suspensions with initial concentrations of 4.0 and 10.0 mg/L for28 days and then were moved to clean water for 24 days to perform the elimination experiment. Fe content was measured in fish body and feces to provide data on accumulation and elimination of the two iron oxide nanomaterials in zebrafish. The experiment revealed that:(1) high accumulation of nano-Fe2O3 and nano-Fe3O4 were found in zebrafish, with maximum Fe contents, respectively, of 1.32 and 1.25 mg/g for 4.0 mg/L treatment groups and 1.15 and 0.90 mg/g for 10.0 mg/L treatment groups;(2) accumulated nanoparticles in zebrafish can be eliminated efficiently(the decrease of body burden of Fe conforms to a first-order decay equation) when fish were moved to nanoparticle-free water,and the elimination rates ranged from 86% to 100% by 24 days post-exposure; and(3)according to analysis of Fe content in fish excrement in the elimination phase, iron oxide nanomaterials may be adsorbed via the gastrointestinal tract, and stored for more than12 days.
基金supported by grants from the CAMS Initiatives for Innovative Medicine(2016-I2M-1-018 to F.M.and 2017-I2M-3-021 to J.L.)the Sichuan Provincial Health and Family Planning Commissi on research project(17PJ489 to B.C.)Chengdu Science and Technology Project-Technology Innovation R&D(2018-YF05-01341-SN to B.C.).
文摘Runt-related transcription factor 1(RUNX1)is required for definitive hematopoiesis;however,the functions of most human RUNX1 isoforms are unclear.In particular,the effects of RUNX1-205(a novel splice variant that lacks exon 6 in comparison with RUNX1b)on human hematopoiesis are not clear.In this study,a human embryonic stem cell(hESC)line with inducible RUNX1-205 overexpression was established.Analyses of these cells revealed that induction of RUNX1-205 overexpression at early stage did not influence the induction of mesoderm but blocked the emergence of CD34+cells,and the production of hematopoietic stem/progenitor cells was significantly reduced.In addition,the expression of hematopoiesis-related factors was downregulated.However,these effects were abolished when RUNX1-205 overexpression was induced after Day 6 in co-cultures of hESCs and AGM-S3 cells,indicating that the inhibitory effect occurred prior to generation of hemogenic endothelial cells,while the promotive effect could be observed during the late stage of hematopoiesis.This is very similar to that of RUNX1b.Interestingly,the mRNA expression profile of RUNX1-205 during hematopoiesis was distinct from that of RUNX1b,and the protein stability of RUNX1-205 was much higher than that of RUNX1b.Thus,the function of RUNX1-205 in normal and diseased models should be further explored.
基金the National Natural Science Foundation of China(Nos.32160178,82160503,31760258,and 81960509)the Project of the Guizhou Provincial Department of Science and Technology(Nos.QKH-JC-2018-1428,QKHZC-2020-4Y156,and QKH-JC-ZK-2022-624)+1 种基金the Collaborative Innovation Center of Chinese Ministry of Education(No.2020-39)the Program for Excellent Young Talents of Zunyi Medical University(No.15ZY-001),China。
文摘Targeted gene therapy has become a promising approach for lung cancer treatment.In our previous work,we reported that the targeted expression of microRNA-7(miR-7)operated by thyroid transcription factor-1(TTF-1)promoter inhibited the growth of human lung cancer cells in vitro and in vivo;however,the intervention efficiency needed to be further improved.In this study,we identified the core promoter of TTF-1(from-1299 bp to-871 bp)by 5’deletion assay and screened out the putative transcription factors nuclear factor-1(NF-1)and activator protein-1(AP-1).Further analysis revealed that the expression level of NF-1,but not AP-1,was positively connected with the activation of TTF-1 core promoter in human non-small-cell lung cancer(NSCLC)cells.Moreover,the silencing of NF-1 could reduce the expression level of miR-7 operated by TTF-1 core promoter.Of note,we optimized four distinct sequences to form additional NF-1-binding sites(TGGCA)in the sequence of TTF-1 core promoter(termed asTTF-1 promoter),and verified the binding efficiency of NF-1 on theTTF-1 promoter by electrophoretic mobility shift assay(EMSA).As expected,theTTF-1 promoter could more effectively drive miR-7 expression and inhibit the growth of human NSCLC cells in vitro,accompanied by a reduced transduction of NADH dehydrogenase(ubiquinone)1αsubcomplex 4(NDUFA4)/protein kinase B(Akt)pathway.Consistently,TTF-1 promoter-driven miR-7expression could also effectively abrogate the growth and metastasis of tumor cells in a murine xenograft model of human NSCLC.Finally,no significant changes were detected in the biological indicators or the histology of some important tissues and organs,including heart,liver,and spleen.On the whole,our study revealed that the optimized TTF-1 promoter could more effectively operate miR-7 to influence the growth of human NSCLC cells,providing a new basis for the development of microRNA-based targeting gene therapy against clinical lung cancer.
基金This work was supported by the National Basic Research Program(973 Program2015CB96A902)+4 种基金the National Natural Science Foundation of China(H81170466 and H81370597)and the CAMS Initiatives for Innovative Medicine(2016-I2M-1-018)awarded to F.M.the CAMS Initiatives for Innovative Medicine(2017-12M-2005)the Union Youth Fund of Chinese Academy of Medical Sciences(81572089)to G.B.and the National Nature Science Foundation of China Youth Fund(81700107)to B.M.
文摘Mast cells (MCs) play a pivotal role in the hypersensitivity reaction by regulating the innate and adaptive immune responses. Humans have two types of MCs. The first type, termed MCTC, is found in the skin and other connective tissues and expresses both tryptase and chymase, while the second, termed MCT, which only expresses tryptase, is found primarily in the mucosa. MCs induced from human adult-type CD34+ cells are reported to be of the MCT type, but the development of MCs during embryonic/fetal stages is largely unknown. Using an efficient coculture system, we identified that a CD34+c-kit+ cell population, which appeared prior to the emergence of CD34+CD45+ hematopoietic stem and progenitor cells (HSPCs), stimulated robust production of pure Tryptase+Chymase+ MCs (MCTCs). Single-cell analysis revealed dual development directions of CD34+c-kit+ progenitors, with one lineage developing into erythro-myeloid progenitors (EMP) and the other lineage developing into HSPC. Interestingly, MCTCs derived from early CD34+c-kit+ cells exhibited strong histamine release and immune response functions. Particularly, robust release of IL-17 suggested that these early developing tissue-type MCTCs could play a central role in tumor immunity. These findings could help elucidate the mechanisms controlling early development of MCTCs and have significant therapeutic implications.