The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of ...The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.展开更多
Stem cells residing in the epidermis and skin appendages are imperative for skin homeostasis and regeneration.These stem cells also participate in the repair of the epidermis after injuries,inducing restoration of tis...Stem cells residing in the epidermis and skin appendages are imperative for skin homeostasis and regeneration.These stem cells also participate in the repair of the epidermis after injuries,inducing restoration of tissue integrity and function of damaged tissue.Unlike epidermis-derived stem cells,comprehensive knowledge about skin appendage-derived stem cells remains limited.In this review,we summarize the current knowledge of skin appendage-derived stem cells,including their fundamental characteristics,their preferentially expressed biomarkers,and their potential contribution involved in wound repair.Finally,we will also discuss current strategies,future applications,and limitations of these stem cells,attempting to provide some perspectives on optimizing the available therapy in cutaneous repair and regeneration.展开更多
The important role of lncRNAs and miRNAs in directing immune responses has become increasingly clear.Recent evidence conforms that miRNAs and lncRNAs are involved in NK cell biology and diseases through RNAeprotein,RN...The important role of lncRNAs and miRNAs in directing immune responses has become increasingly clear.Recent evidence conforms that miRNAs and lncRNAs are involved in NK cell biology and diseases through RNAeprotein,RNAeRNA,or RNAeDNA interactions.In this view,we summarize the contribution of miRNAs and lncRNAs to NK cell lineage devel-opment,activation and function,highlight the biological significance of functional miRNAs or lncRNAs in NKTL and discuss the potential of these miRNAs and lncRNAs as innovative bio-markers/targets for NKTL early diagnosis,target treatment and prognostic evaluations.展开更多
Although it has been only a couple of years since the establishment of the Epithelial Cell Biology Research Center, the first of its kind ever founded in China , the planning for the center establishment and the invol...Although it has been only a couple of years since the establishment of the Epithelial Cell Biology Research Center, the first of its kind ever founded in China , the planning for the center establishment and the involvement of the National Natural Science Foundation of China (NSFC) goes way back to more than展开更多
BACKGROUND: Uncoupling protein 2(UCP2) has been suggested to inhibit mitochondrial production of reactive oxygen species(ROS) by decreasing the mitochondrial membrane potential. Experimental acute pancreatitis is asso...BACKGROUND: Uncoupling protein 2(UCP2) has been suggested to inhibit mitochondrial production of reactive oxygen species(ROS) by decreasing the mitochondrial membrane potential. Experimental acute pancreatitis is associated with increased UCP2 expression, whereas UCP2 deficiency retards regeneration of aged mice from acute pancreatitis. Here, we have addressed biological and molecular functions of UCP2 in pancreatic stellate cells(PSCs), which are involved in pancreatic wound repair and fibrogenesis.METHODS: PSCs were isolated from 12 months old(aged) UCP2^(-/-) mice and animals of the wild-type(WT) strain C57BL/6. Proliferation and cell death were assessed by employing trypan blue staining and a 5-bromo-2'-deoxyuridine incorporation assay. Intracellular fat droplets were visualized by oil red O staining. Levels of m RNA were determined by RT-PCR, while protein expression was analyzed by immunoblotting and immunofluorescence analysis. Intracellular ROS levels were measured with 2', 7'-dichlorofluorescin diacetate. Expression of senescence-associated β-galactosidase(SA β-Gal) was used as a surrogate marker of cellular senescence.RESULTS: PSCs derived from UCP2^(-/-) mice proliferated at a lower rate than cells from WT mice. In agreement with this observation, the UCP2 inhibitor genipin displayed dosedependent inhibitory effects on WT PSC growth. Interestingly, ROS levels in PSCs did not differ between the two strains, and PSCs derived from UCP2^(-/-) mice did not senesce faster than those from corresponding WT cells. PSCs from UCP2^(-/-) mice and WT animals were also indistinguishable with respect to the activation-dependent loss of intracellular fat droplets, expression of the activation marker α-smooth muscle actin, type I collagen and the autocrine/paracrine mediators interleukin-6 and transforming growth factor-β1.CONCLUSIONS: A reduced proliferative capacity of PSC from aged UCP2^(-/-) mice may contribute to the retarded regeneration after acute pancreatitis. Apart from their slower growth, PSC of UCP2^(-/-) mice displayed no functional abnormalities. The antifibrotic potential of UCP2 inhibitors deserves further attention.展开更多
Background:Transcription factor 3(TCF3)plays pivotal roles in embryonic development,stem cell maintenance and carcinogenesis.However,its role in hepatocellular carcinoma(HCC)remains largely unknown.This study aimed to...Background:Transcription factor 3(TCF3)plays pivotal roles in embryonic development,stem cell maintenance and carcinogenesis.However,its role in hepatocellular carcinoma(HCC)remains largely unknown.This study aimed to analyze the correlation between TCF3 expression and clinicopathological features of HCC,and further explore the underlying mechanism in HCC progression.Methods:The expression of TCF3 was collected from the Cancer Genome Atlas(TCGA)and the Gene Expression Omnibus(GEO)HCC datasets,and further confirmed by immunostaining and Western blotting assays.The correlation between TCF3 expression and the clinicopathological features was evaluated.Bioinformatical analysis and in vitro experiments were conducted to explore the potential role of TCF3 in HCC development.Results:Both the mRNA and protein levels of TCF3 were significantly higher in HCC tumor tissues compared to tumor adjacent tissues(P<0.001 and P<0.01).Analysis based on TCGA datasets showed that TCF3 was positively correlated with tumor clinical stage and grade,and patients with high TCF3 expression had shorter overall survival(P=0.012),disease-specific survival(P=0.022)and progression-free survival(P=0.013).Similarly,the immunostaining results revealed that the high expression of TCF3 was closely correlated with tumor size(P=0.001)and TNM stage(P=0.002),and TCF3 was an independent risk factor of HCC.In vitro study exhibited that TCF3 knockdown dramatically suppressed cancer cell proliferation,and the underlying mechanism might be that the silencing of TCF3 reduced the expression of critical regulating proteins towards cell cycle and proteins involved in Wnt signaling pathways.Conclusions:TCF3 expression is significantly elevated in HCC and positively associated with the tumor size and TNM stage,as well as poor prognosis of HCC patients.The mechanism might be that TCF3 promotes cancer cell proliferation via activating Wnt signaling pathway.展开更多
BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is associated with obesity,insulin resistance and dyslipidaemia and currently is estimated to affect up to a third of all individuals in developed countries.Current s...BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is associated with obesity,insulin resistance and dyslipidaemia and currently is estimated to affect up to a third of all individuals in developed countries.Current standard of care for patients varies according to disease stage,but includes lifestyle interventions common insulin sensitizers,antioxidants and lipid modifiers.However,to date specific therapies have shown little histological or fibrosis stage improvement in large clinical trials,and there is still no licensed therapy for NAFLD.Given the high prevalence,limited treatment options and significant screening costs for the general population,new treatments are urgently required.AIM To assess the potential for inhibition of the amine oxidase enzyme vascular adhesion protein-1(VAP-1)to modify hepatic lipid accumulation in NAFLD.METHODS We have used immunochemical and qPCR analysis to document expression of VAP-1 and key functional proteins and transporters across the NAFLD spectrum.We then utilised hepatocytes in culture and human precision cut liver slices in concert with selective enzyme activity inhibitors to test the effects of activating the semicarbazide-sensitive amine oxidase activity of VAP-1 on hepatic lipid uptake and triglyceride export.A murine model of NAFLD was also used to determine the consequences of VAP-1 knockout and gene expression arrays were used to quantify the effects of VAP-1 activity on key lipid modifying and proinflammatory gene expression.RESULTS We confirmed that increasing severity of NAFLD and progression to cirrhosis was associated with a significant increase in hepatocellular VAP-1 expression.Hepatocytes in vitro exposed to recombinant VAP-1 and its substrate methylamine showed increased lipid accumulation as determined by quantification of Oil Red O uptake.This was recapitulated using hydrogen peroxide,and lipid accumulation was accompanied by changes in expression of the lipid transporter molecules FABP3,FATP6,insulin receptor subunits and PPARα.Human liver tissue exposed to recombinant VAP-1 or substrates for endo/exogenous VAP-1 produced less triglyceride than untreated tissue and demonstrated an increase in steatosis.This response could be inhibited by using bromoethylamine to inhibit the SSAO activity of VAP-1,and mice deficient in VAP-1/AOC3 also demonstrated reduced steatosis on high fat diet.Exposure of human liver tissue to methylamine to activate VAP-1 resulted in increased expression of FABP2 and 4,FATP3-5,caveolin-1,VLDLR,PPARGC1 and genes associated with the inflammatory response.CONCLUSION Our data confirm that the elevations in hepatic VAP-1 expression reported in nonalcoholic steatohepatitis can contribute to steatosis,metabolic disturbance and inflammation.This suggests that targeting the semicarbazide sensitive amine oxidase capacity of VAP-1 may represent a useful adjunct to other therapeutic strategies in NAFLD.展开更多
Background:Rods and cones are critical for light detection.Although there has been considerable work done in elucidating the molecular mechanisms involved in rod development,not much is known about how the cone cell f...Background:Rods and cones are critical for light detection.Although there has been considerable work done in elucidating the molecular mechanisms involved in rod development,not much is known about how the cone cell fate decision is made by the multipotent retinal progenitor cells during development.Analysis of the promoter regions of Nrl and trβ2,rod and cone differentiation factors respectively,revealed DNA binding motifs of two POU-domain containing transcription factors,Pou2f1 and Pou2f2.Preliminary experiments showed that Pou2f1/2 are expressed during the peak of cone genesis in the embryonic retina.Therefore,we hypothesize that Pou2f1/2 specify cone cell fate in the developing retina.Methods:We used immunofluorescence and in situ hybridization to establish the spatiotemporal expression of Pou2f1/2 during retinogenesis.We performed in vivo electroporation in post-natal mice to misexpress Pou2f1/2 and used antibodies specific to proteins expressed in cones such as Rxrγand S-opsin to count cones.Using ex vivo electroporation of embryonic retinal explants,we knocked out Pou2f1 and Pou2f2 using CRISPR/Cas9 gRNAs at the peak of cone production window.Finally,we transfected post-natal retinal explants with a combination of regulatory elements of Nrl or thrb with control backbone vector,Pou2f1 or Pou2f2 using electroporation.Results:We found that Pou2f1/2 are expressed in retinal progenitor cells in the developing retina and subsequently in the differentiated cones.Pou2f1/2 misexpression outside the cone genesis window led to an increase in cones at the expense of rods.Pou2f1/2 indel knockouts generated by CRISPR/Cas9 gRNAs led to a decrease in cones and a converse increase in rods.Finally,we found that Pou2f1/2 activate the cis-regulatory module(CRM)of the thrb gene and repress the activity of the CRM of Nrl.Conclusions:These results uncover novel players that establish the complex gene regulatory network for cone photoreceptor fate specification in the retinal progenitor cells.We anticipate that this work should help us devise improved replacement therapies in the future utilizing stem cells for retinal degenerative diseases such as aged-related macular degeneration(AMD)and Stargardt’s disease.展开更多
The triennial International Conference on Plant Cell Wall Biology has been held 5 times since it was initiated in the United States.PCWB2017 for the first time is organized in China.The conference was attended with mo...The triennial International Conference on Plant Cell Wall Biology has been held 5 times since it was initiated in the United States.PCWB2017 for the first time is organized in China.The conference was attended with more than 220 participants and featured with oral and poster presentations,reflecting the contemporary status of plant cell wall studies.展开更多
Since the huge success of bone marrow transplantation technology in clinical practice,hematopoietic stem cells(HSCs)have become the gold standard for defining the properties of adult stem cells(ASCs).Here,we describe ...Since the huge success of bone marrow transplantation technology in clinical practice,hematopoietic stem cells(HSCs)have become the gold standard for defining the properties of adult stem cells(ASCs).Here,we describe the“self-renewal,multilineage differentiation,apoptosis,rest,and trafficking”or“SMART”model,which has been developed based on data derived from studies of HSCs as the most well-characterized stem cell type.Given the potential therapeutic applications of ASCs,we delineate the key characteristics of HSCs using this model and speculate on the physiological relevance of stem cells identified in other tissues.Great strides are being made in understanding the biology of ASCs,and efforts are now underway to develop safe and effective ASC-based therapies in this emerging area.展开更多
Background:Dynactin(DCTN)can activate cytoplasmic dynein and drive intracellular organelle transport containing six family members(DCTN1 to DCTN6).The DCTN family has been studied as cancer-related genes or biomarkers...Background:Dynactin(DCTN)can activate cytoplasmic dynein and drive intracellular organelle transport containing six family members(DCTN1 to DCTN6).The DCTN family has been studied as cancer-related genes or biomarkers in various cancers.Nevertheless,in hepatocellular carcinoma(HCC),the functions and prognostic roles of the DCTN family have been unexplored.Methods:We evaluated the diagnostic and survival effects of DCTN subunits in HCC through bioinformatics analysis and validated the results of bioinformatics by our data to address this problem.Results:The results of bioinformatics analysis found that DCTN2 was a significant prognostic factor in HCC,and high-level DCTN2 can predict poor patient survival in HCC.Cox regression analysis also suggested that DCTN2(hazard ratio=1.748,95%confidence interval 1.190-2.568,P=0.004)is an independent prognostic factor for patient survival.Western blot and quantitative reverse transcriptionpolymerase chain reaction assays confirmed that the protein and mRNA expression levels of DCTN2 were upregulated in HCC cell lines.The proliferation,invasion,and migration were decreased and cell apoptosis was enhanced after DCTN2 was knocked down in Huh7 and Hep3B cells.DCTN2 promoted the cell cycle progression through regulating the expression of cell cycle regulatory proteins cyclindependent kinase 4,Cyclin D1,and p21.Conclusions:We propose that DCTN2 can serve as a prognostic marker for HCC.DCTN2 acts as an oncogene and promotes the cell cycle progression through the G1/S phase-related signaling pathway.展开更多
Oncogenic multidrug resistance(MDR)is a multifactorial phenotype intimately linked to deregulated expression of detoxification transporters.Drug efflux transporters,particularly the MDR P-glycoprotein ABCB1,represent ...Oncogenic multidrug resistance(MDR)is a multifactorial phenotype intimately linked to deregulated expression of detoxification transporters.Drug efflux transporters,particularly the MDR P-glycoprotein ABCB1,represent a central mechanism by which not only chemotherapeutic drugs are extruded or sequestered to prevent drug delivery to their intracellular targets,but also for inhibiting apoptotic cell death cues,such as removal of proapoptotic signals.Several cell populations exhibiting the MDR phenotype co-exist within a tumor,such as cells forming the bulk tumor cell mass,cancer stem cells,and cancer persister cells.The key to regulation of ABCB1 expression is the cellular transcriptional machinery.Developmental signaling pathways(e.g,Hedgehog,Notch,Wnt/β-catenin,TGFβ,PITX2)are pivotal in governing cell proliferation,survival,differentiation and guiding cell migration during embryogenesis,and their reactivation during carcinogenesis,which is of particular significance for tumor initiation,progression,and metastasis,also leads to the upregulation of ABCB1.These pathways also drive and maintain cancer cell stemness,for which ABCB1 is used as a marker.In this review,the contribution of canonical and non-canonical developmental signaling pathways in transcriptional regulation of ABCB1 to confer MDR in cancer is delineated.展开更多
基金supported by National Key R&D Program of China(Grant No.2017YFA0205400,China)the National Natural Science Foundation of China(Grant Nos.81530093 and 81773781,China)+43 种基金Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(Grant No.2016-I2M-1-007,China)CAMS Central Public-interest Scientific Institution Basic Research Fund(Grant No.2017PT3104,China)supported by grants of the National Natural Science Foundation of China(Grant No.81874316,China)the CAMS Innovation Fund for Medical Sciences(Grant No.2016-I2M-3-008,China)supported by grants of from the BBSRC and NWCR(Grant Nos.1088 and 1097,UK)supported by grants of NSF(Grant No.IOS-1456023,USA)NIH(Grant No.NIH R21 CA197317,USA)supported by grants of Ministry of Education,Singapore(Grant Nos.MOE2014-T2-1-012 and 2012-T1-001-036,Singapore)supported by grants from the Health Research Council of New Zealandsupported by a Rutherford Discovery Fellowship from the New Zealand government administered by the Royal Society of New Zealandsupported by Funda??o para a Ciência e a Tecnologia(FCT)Research Center Grant UID/BIM/04773/2013 Centre for Biomedical Research 1334a research grant from Liga Portuguesa Contra o Cancro–Núcleo Regional do Sul(LPCC/NRS,Portugal)a FCT 2014 research grant SFRH/BPD/100434/2014a Pro Regem grant PD/BD/114258/2016(Portugal)supported by European Marie Sklodowska Curie ITN Project TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)Innovation Network and the British Heart Foundation(PG/16/44/32146,UK)supported by grants from The Howat Foundation Ltd.(UK),Children with Cancer UK,Bloodwise and the Friends of Paul O'Gorman(UK)supported by grants of P-CREATE from Japan Agency for Medical Research and Developmentsupported by grants from the NIH(NIAID,USA),Alex's Lemonade Stand Foundation(USA)and the Samuel Waxman Cancer Research Foundation(USA)supported by European Marie Sklodowska Curie ITN Project TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)the "Fondation Centaure"(RTRS),which supports a French transplantation research network,the IHU-Cesti project,the DHU Oncogreffefinancial support managed by the National Research Agency via the"Investment into the Future" program(Grant Nos.ANR-10-IBHU-005and ANR-11-LABX-0016-01,France)supported by Nantes Métropole and Région Pays de la Loire(France)supported by grants of the British Heart Foundation(PG/16/44/32146,UK)supported by European Marie Sklodowska Curie ITN Project TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)supported by European Marie Sklodowska Curie ITN Project TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)supported by a joint Ph.D studentship beween the A*Star Institute and the University of Sheffield(UK)supported by funding from the National Institutes of Health National Heart,Lung,and Blood Institute(R01HL141745,USA)supported by European Marie Sklodowska Curie ITN Project TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)supported by European Marie Sklodowska Curie ITNProject TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)supported by the National Natural Science Foundation of China(Grant No.81503128,China)CAMS Innovation Fund for Medical Sciences(Grant No.2016-I2M-1-008,China)supported by National Institute of Health(NS R01-035546,USA)supported by the National Natural Science Foundation of China(Grant No.81400140,China)CAMS Innovation Fund for Medical Sciences(Grant No.2016-I2M-1-011,China)supported by European Marie Sklodowska Curie ITN Project TRAIN-TRIBBLES Research and Innovation Network(Grant No.721532,EU)supported by Spanish Ministry of Economy and Competitiveness(MINECO)and Fondo Europeo de desarrollo Regional(FEDER)(Grant No.INNPACTO/IPT-2012-0614-010000,Spain)supported by the National Natural Science Foundation of China(Grant Nos.81400286 and 81530093,China)the CAMS Innovation Fund for Medical Sciences(Grant No.2016-I2M-1-010,China)supported by the National Natural Science Foundation of China(Grant Nos.81472717 and 81673474,China)Beijing Natural Science Foundation(Grant No.7162133,China)the CAMS Innovation Fund for Medical Sciences(Grant No.2016-I2M-1-007,China)supported by the National Natural Science Foundation of China(Grant No.81703564,China)supported by the National Natural Science Foundation of China(Grant No.81603129,China)
文摘The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.
基金This paper was supported in part by the National Nature Science Foundation of China(81121004,81230041,81372066,81571909)the National Basic Science and Development Program(973 Program,2012CB518105)
文摘Stem cells residing in the epidermis and skin appendages are imperative for skin homeostasis and regeneration.These stem cells also participate in the repair of the epidermis after injuries,inducing restoration of tissue integrity and function of damaged tissue.Unlike epidermis-derived stem cells,comprehensive knowledge about skin appendage-derived stem cells remains limited.In this review,we summarize the current knowledge of skin appendage-derived stem cells,including their fundamental characteristics,their preferentially expressed biomarkers,and their potential contribution involved in wound repair.Finally,we will also discuss current strategies,future applications,and limitations of these stem cells,attempting to provide some perspectives on optimizing the available therapy in cutaneous repair and regeneration.
文摘The important role of lncRNAs and miRNAs in directing immune responses has become increasingly clear.Recent evidence conforms that miRNAs and lncRNAs are involved in NK cell biology and diseases through RNAeprotein,RNAeRNA,or RNAeDNA interactions.In this view,we summarize the contribution of miRNAs and lncRNAs to NK cell lineage devel-opment,activation and function,highlight the biological significance of functional miRNAs or lncRNAs in NKTL and discuss the potential of these miRNAs and lncRNAs as innovative bio-markers/targets for NKTL early diagnosis,target treatment and prognostic evaluations.
文摘Although it has been only a couple of years since the establishment of the Epithelial Cell Biology Research Center, the first of its kind ever founded in China , the planning for the center establishment and the involvement of the National Natural Science Foundation of China (NSFC) goes way back to more than
基金supported by a grant from the Bundesministerium für Bildung und Forschung(0315892A,GERONTOSYS program)
文摘BACKGROUND: Uncoupling protein 2(UCP2) has been suggested to inhibit mitochondrial production of reactive oxygen species(ROS) by decreasing the mitochondrial membrane potential. Experimental acute pancreatitis is associated with increased UCP2 expression, whereas UCP2 deficiency retards regeneration of aged mice from acute pancreatitis. Here, we have addressed biological and molecular functions of UCP2 in pancreatic stellate cells(PSCs), which are involved in pancreatic wound repair and fibrogenesis.METHODS: PSCs were isolated from 12 months old(aged) UCP2^(-/-) mice and animals of the wild-type(WT) strain C57BL/6. Proliferation and cell death were assessed by employing trypan blue staining and a 5-bromo-2'-deoxyuridine incorporation assay. Intracellular fat droplets were visualized by oil red O staining. Levels of m RNA were determined by RT-PCR, while protein expression was analyzed by immunoblotting and immunofluorescence analysis. Intracellular ROS levels were measured with 2', 7'-dichlorofluorescin diacetate. Expression of senescence-associated β-galactosidase(SA β-Gal) was used as a surrogate marker of cellular senescence.RESULTS: PSCs derived from UCP2^(-/-) mice proliferated at a lower rate than cells from WT mice. In agreement with this observation, the UCP2 inhibitor genipin displayed dosedependent inhibitory effects on WT PSC growth. Interestingly, ROS levels in PSCs did not differ between the two strains, and PSCs derived from UCP2^(-/-) mice did not senesce faster than those from corresponding WT cells. PSCs from UCP2^(-/-) mice and WT animals were also indistinguishable with respect to the activation-dependent loss of intracellular fat droplets, expression of the activation marker α-smooth muscle actin, type I collagen and the autocrine/paracrine mediators interleukin-6 and transforming growth factor-β1.CONCLUSIONS: A reduced proliferative capacity of PSC from aged UCP2^(-/-) mice may contribute to the retarded regeneration after acute pancreatitis. Apart from their slower growth, PSC of UCP2^(-/-) mice displayed no functional abnormalities. The antifibrotic potential of UCP2 inhibitors deserves further attention.
基金supported by a grant from the Key Research and Development Program of Sichuan Provincial Department of Science and Technology(2020YFS0134)。
文摘Background:Transcription factor 3(TCF3)plays pivotal roles in embryonic development,stem cell maintenance and carcinogenesis.However,its role in hepatocellular carcinoma(HCC)remains largely unknown.This study aimed to analyze the correlation between TCF3 expression and clinicopathological features of HCC,and further explore the underlying mechanism in HCC progression.Methods:The expression of TCF3 was collected from the Cancer Genome Atlas(TCGA)and the Gene Expression Omnibus(GEO)HCC datasets,and further confirmed by immunostaining and Western blotting assays.The correlation between TCF3 expression and the clinicopathological features was evaluated.Bioinformatical analysis and in vitro experiments were conducted to explore the potential role of TCF3 in HCC development.Results:Both the mRNA and protein levels of TCF3 were significantly higher in HCC tumor tissues compared to tumor adjacent tissues(P<0.001 and P<0.01).Analysis based on TCGA datasets showed that TCF3 was positively correlated with tumor clinical stage and grade,and patients with high TCF3 expression had shorter overall survival(P=0.012),disease-specific survival(P=0.022)and progression-free survival(P=0.013).Similarly,the immunostaining results revealed that the high expression of TCF3 was closely correlated with tumor size(P=0.001)and TNM stage(P=0.002),and TCF3 was an independent risk factor of HCC.In vitro study exhibited that TCF3 knockdown dramatically suppressed cancer cell proliferation,and the underlying mechanism might be that the silencing of TCF3 reduced the expression of critical regulating proteins towards cell cycle and proteins involved in Wnt signaling pathways.Conclusions:TCF3 expression is significantly elevated in HCC and positively associated with the tumor size and TNM stage,as well as poor prognosis of HCC patients.The mechanism might be that TCF3 promotes cancer cell proliferation via activating Wnt signaling pathway.
文摘BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is associated with obesity,insulin resistance and dyslipidaemia and currently is estimated to affect up to a third of all individuals in developed countries.Current standard of care for patients varies according to disease stage,but includes lifestyle interventions common insulin sensitizers,antioxidants and lipid modifiers.However,to date specific therapies have shown little histological or fibrosis stage improvement in large clinical trials,and there is still no licensed therapy for NAFLD.Given the high prevalence,limited treatment options and significant screening costs for the general population,new treatments are urgently required.AIM To assess the potential for inhibition of the amine oxidase enzyme vascular adhesion protein-1(VAP-1)to modify hepatic lipid accumulation in NAFLD.METHODS We have used immunochemical and qPCR analysis to document expression of VAP-1 and key functional proteins and transporters across the NAFLD spectrum.We then utilised hepatocytes in culture and human precision cut liver slices in concert with selective enzyme activity inhibitors to test the effects of activating the semicarbazide-sensitive amine oxidase activity of VAP-1 on hepatic lipid uptake and triglyceride export.A murine model of NAFLD was also used to determine the consequences of VAP-1 knockout and gene expression arrays were used to quantify the effects of VAP-1 activity on key lipid modifying and proinflammatory gene expression.RESULTS We confirmed that increasing severity of NAFLD and progression to cirrhosis was associated with a significant increase in hepatocellular VAP-1 expression.Hepatocytes in vitro exposed to recombinant VAP-1 and its substrate methylamine showed increased lipid accumulation as determined by quantification of Oil Red O uptake.This was recapitulated using hydrogen peroxide,and lipid accumulation was accompanied by changes in expression of the lipid transporter molecules FABP3,FATP6,insulin receptor subunits and PPARα.Human liver tissue exposed to recombinant VAP-1 or substrates for endo/exogenous VAP-1 produced less triglyceride than untreated tissue and demonstrated an increase in steatosis.This response could be inhibited by using bromoethylamine to inhibit the SSAO activity of VAP-1,and mice deficient in VAP-1/AOC3 also demonstrated reduced steatosis on high fat diet.Exposure of human liver tissue to methylamine to activate VAP-1 resulted in increased expression of FABP2 and 4,FATP3-5,caveolin-1,VLDLR,PPARGC1 and genes associated with the inflammatory response.CONCLUSION Our data confirm that the elevations in hepatic VAP-1 expression reported in nonalcoholic steatohepatitis can contribute to steatosis,metabolic disturbance and inflammation.This suggests that targeting the semicarbazide sensitive amine oxidase capacity of VAP-1 may represent a useful adjunct to other therapeutic strategies in NAFLD.
文摘Background:Rods and cones are critical for light detection.Although there has been considerable work done in elucidating the molecular mechanisms involved in rod development,not much is known about how the cone cell fate decision is made by the multipotent retinal progenitor cells during development.Analysis of the promoter regions of Nrl and trβ2,rod and cone differentiation factors respectively,revealed DNA binding motifs of two POU-domain containing transcription factors,Pou2f1 and Pou2f2.Preliminary experiments showed that Pou2f1/2 are expressed during the peak of cone genesis in the embryonic retina.Therefore,we hypothesize that Pou2f1/2 specify cone cell fate in the developing retina.Methods:We used immunofluorescence and in situ hybridization to establish the spatiotemporal expression of Pou2f1/2 during retinogenesis.We performed in vivo electroporation in post-natal mice to misexpress Pou2f1/2 and used antibodies specific to proteins expressed in cones such as Rxrγand S-opsin to count cones.Using ex vivo electroporation of embryonic retinal explants,we knocked out Pou2f1 and Pou2f2 using CRISPR/Cas9 gRNAs at the peak of cone production window.Finally,we transfected post-natal retinal explants with a combination of regulatory elements of Nrl or thrb with control backbone vector,Pou2f1 or Pou2f2 using electroporation.Results:We found that Pou2f1/2 are expressed in retinal progenitor cells in the developing retina and subsequently in the differentiated cones.Pou2f1/2 misexpression outside the cone genesis window led to an increase in cones at the expense of rods.Pou2f1/2 indel knockouts generated by CRISPR/Cas9 gRNAs led to a decrease in cones and a converse increase in rods.Finally,we found that Pou2f1/2 activate the cis-regulatory module(CRM)of the thrb gene and repress the activity of the CRM of Nrl.Conclusions:These results uncover novel players that establish the complex gene regulatory network for cone photoreceptor fate specification in the retinal progenitor cells.We anticipate that this work should help us devise improved replacement therapies in the future utilizing stem cells for retinal degenerative diseases such as aged-related macular degeneration(AMD)and Stargardt’s disease.
文摘The triennial International Conference on Plant Cell Wall Biology has been held 5 times since it was initiated in the United States.PCWB2017 for the first time is organized in China.The conference was attended with more than 220 participants and featured with oral and poster presentations,reflecting the contemporary status of plant cell wall studies.
基金supported by the Ministry of Science and Technology of China(2016YFA0100600,2017YFA0103400,2020YFE0203000)the National Natural Science Foundation of China(81922002,81730006,81890990,81870086,82070112)+1 种基金the CAMS Initiative for Innovative Medicine(2017-I2M-3-009,2016-I2M-1-017)Distinguished Young Scholars of Tianjin(19JCJQJC63400)。
文摘Since the huge success of bone marrow transplantation technology in clinical practice,hematopoietic stem cells(HSCs)have become the gold standard for defining the properties of adult stem cells(ASCs).Here,we describe the“self-renewal,multilineage differentiation,apoptosis,rest,and trafficking”or“SMART”model,which has been developed based on data derived from studies of HSCs as the most well-characterized stem cell type.Given the potential therapeutic applications of ASCs,we delineate the key characteristics of HSCs using this model and speculate on the physiological relevance of stem cells identified in other tissues.Great strides are being made in understanding the biology of ASCs,and efforts are now underway to develop safe and effective ASC-based therapies in this emerging area.
基金This work was funded by the National Natural Science Foundation of China(No.81702375)the Natural Science Foundation of Guangdong Province of China(No.2021A15150124)+1 种基金the Sun Yatsen university young teacher training program(No.19ykpy32)the Scientific Research Project of Dongguan Binhaiwan Central Hospital(No.2021001).
文摘Background:Dynactin(DCTN)can activate cytoplasmic dynein and drive intracellular organelle transport containing six family members(DCTN1 to DCTN6).The DCTN family has been studied as cancer-related genes or biomarkers in various cancers.Nevertheless,in hepatocellular carcinoma(HCC),the functions and prognostic roles of the DCTN family have been unexplored.Methods:We evaluated the diagnostic and survival effects of DCTN subunits in HCC through bioinformatics analysis and validated the results of bioinformatics by our data to address this problem.Results:The results of bioinformatics analysis found that DCTN2 was a significant prognostic factor in HCC,and high-level DCTN2 can predict poor patient survival in HCC.Cox regression analysis also suggested that DCTN2(hazard ratio=1.748,95%confidence interval 1.190-2.568,P=0.004)is an independent prognostic factor for patient survival.Western blot and quantitative reverse transcriptionpolymerase chain reaction assays confirmed that the protein and mRNA expression levels of DCTN2 were upregulated in HCC cell lines.The proliferation,invasion,and migration were decreased and cell apoptosis was enhanced after DCTN2 was knocked down in Huh7 and Hep3B cells.DCTN2 promoted the cell cycle progression through regulating the expression of cell cycle regulatory proteins cyclindependent kinase 4,Cyclin D1,and p21.Conclusions:We propose that DCTN2 can serve as a prognostic marker for HCC.DCTN2 acts as an oncogene and promotes the cell cycle progression through the G1/S phase-related signaling pathway.
基金the Intramural Research Program at Witten/Herdecke University and Westmann-Westerdorp Foundation.The research of F.T.on ABCB1 was funded by DFG(German Research Foundation)Grants TH345 and the Centre for Biomedical Education and Research(ZBAF)at Witten/Herdecke University。
文摘Oncogenic multidrug resistance(MDR)is a multifactorial phenotype intimately linked to deregulated expression of detoxification transporters.Drug efflux transporters,particularly the MDR P-glycoprotein ABCB1,represent a central mechanism by which not only chemotherapeutic drugs are extruded or sequestered to prevent drug delivery to their intracellular targets,but also for inhibiting apoptotic cell death cues,such as removal of proapoptotic signals.Several cell populations exhibiting the MDR phenotype co-exist within a tumor,such as cells forming the bulk tumor cell mass,cancer stem cells,and cancer persister cells.The key to regulation of ABCB1 expression is the cellular transcriptional machinery.Developmental signaling pathways(e.g,Hedgehog,Notch,Wnt/β-catenin,TGFβ,PITX2)are pivotal in governing cell proliferation,survival,differentiation and guiding cell migration during embryogenesis,and their reactivation during carcinogenesis,which is of particular significance for tumor initiation,progression,and metastasis,also leads to the upregulation of ABCB1.These pathways also drive and maintain cancer cell stemness,for which ABCB1 is used as a marker.In this review,the contribution of canonical and non-canonical developmental signaling pathways in transcriptional regulation of ABCB1 to confer MDR in cancer is delineated.
