[Objectives]This study was conducted to evaluate the protective effect of polysaccharides from Enteromorpha prolifera(PEP)on mice with hepatorenal syndrome induced by carbon tetrachloride.[Methods]A mouse hepatorenal ...[Objectives]This study was conducted to evaluate the protective effect of polysaccharides from Enteromorpha prolifera(PEP)on mice with hepatorenal syndrome induced by carbon tetrachloride.[Methods]A mouse hepatorenal syndrome model was induced by carbon tetrachloride.The serum levels of lipid,total antioxidant capacity,liver and kidney function,pathological changes of liver and kidney were selected to clarity the effectiveness of PEP on hepatorenal syndrome in mice.[Results]PEP effectively lowered the serum levels of lipid,increased total antioxidant capacity,improved liver and kidney injury,and alleviated pathological changes of liver and kidney of mice induced by carbon tetrachloride.[Conclusions]PEP has a potent preventive effect on hepatorenal syndrome induced by carbon tetrachloride in mice,which provides theoretical support for future clinical application of PEP.展开更多
Solventless mechanochemical synthesis by manual grinding was applied to grow organic proton conducting salts,imidazole-succinic acid(C_(3)H_(4)N_(2)-HOOC(CH_(2))_(2)COOH)and imidazole-glutaric acid(C_(3)H_(4)N_(2)-HOO...Solventless mechanochemical synthesis by manual grinding was applied to grow organic proton conducting salts,imidazole-succinic acid(C_(3)H_(4)N_(2)-HOOC(CH_(2))_(2)COOH)and imidazole-glutaric acid(C_(3)H_(4)N_(2)-HOOC(CH_(2))_(3)COOH).This synthesis method induces crystallization and provides the phase-pure compounds.The compounds exhibit different electric conducting behavior and activation energies Ea compared with the reported single crystals obtained from the solution method.The difference in conducting property can be related to intrinsic defects and structural disorder introduced by mechanochemical grinding,indicating that the mechanochemical method bears strong capability for tuning conductivities.Moreover,complete deuteration of the organic salts is achieved by the method.The mechanochemical synthesis of organic salts also holds high potential for the actual industrialized large-scale production.展开更多
There are intense interests in discovering pro regenerative medicine leads that can promote cardiac differentiation and regeneration,as well as repair damaged heart tissues.We have combined zebrafish embryo-based scre...There are intense interests in discovering pro regenerative medicine leads that can promote cardiac differentiation and regeneration,as well as repair damaged heart tissues.We have combined zebrafish embryo-based screens with cardiomyogenesis assays to discover selective small molecules that modulate heart development and regeneration with minimal adverse effects.Two related compounds with novel structures,named as Cardiomogen 1 and 2(CDMG1 and CDMG2),were identified for their capacity to promote myocardial hyperplasia through expansion of the cardiac progenitor cell population.We find that Cardiomogen acts as a Wnt inhibitor by targeting p-catenin and reducing Tcf/Lef-mediated transcription in cultured cells.CDMG treatment of amputated zebrafish hearts reduces nuclear p-catenin in injured heart tissue,increases cardiomyocyte(CM)proliferation,and expedites wound healing,thus accelerating cardiac muscle regeneration.Importantly,Cardiomogen can alleviate the functional deterioration of mammalian hearts after myocardial infarction.Injured hearts exposed to CDMG1 display increased newly formed CMs and reduced fibrotic scar tissue,which are in part attributable to the^-catenin reduction.Our findings indicate Cardiomogen as a Wnt inhibitor in enhancing injury-induced CM proliferation and heart regeneration,highlighting the values of embryo-based small molecule screens in discovery of effective and safe medicine leads.展开更多
Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes(CMs).However,the signaling mechanisms by which injury induces CM renewal remain incompletely understood.Here,we find that...Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes(CMs).However,the signaling mechanisms by which injury induces CM renewal remain incompletely understood.Here,we find that cardiac injury in zebrafish induces expression of the secreted Wnt inhibitors,including Dickkopf 1(Dkkl),Dkk3,secreted Frizzled-related protein 1(sFrpl),and sFrp2,in cardiac tissue adjacent to injury sites.Experimental blocking of Wnt activity via Dkkl overexpression enhances CM proliferation and heart regeneration,whereas ectopic activation of Wnt8 signaling blunts injury-induced CM dedifferentiation and proliferation.Although Wnt signaling is dampened upon injury,the cytoplasmic β-catenin is unexpectedly increased at disarrayed CM sarcomeres in myocardial wound edges.Our analyses indicated that p21-activated kinase 2(Pak2)is induced at regenerating CMs,where it phosphorylates cytoplasmic β-catenin at Ser 675 and increases its stability at disassembled sarcomeres.Myocardial-specific induction of the phospho-mimeticβ-catenin(S675E)enhances CM dedifferentiation and sarcomere disassembly in response to injury.Conversely,inactivation of Pak2 kinase activity reduces the Ser 675-phosphorylatedβ-catenin(pS675-β-catenin)and attenuates CM sarcomere disorganization and dedifferentiation・Taken together,these findings demonstrate that coordination of Wnt signaling inhibition and Pak2/pS675-βYatenin signaling enhances zebrafish heart regeneration by supporting CM dedifferentiation and proliferation.展开更多
基金Supported by Natural Science Research Fund for Colleges and Universities in Jiangsu Province(No.20KJB310026)Provincial General Project of Undergraduate Innovation and Entrepreneurship Training Program(202010324055Y).
文摘[Objectives]This study was conducted to evaluate the protective effect of polysaccharides from Enteromorpha prolifera(PEP)on mice with hepatorenal syndrome induced by carbon tetrachloride.[Methods]A mouse hepatorenal syndrome model was induced by carbon tetrachloride.The serum levels of lipid,total antioxidant capacity,liver and kidney function,pathological changes of liver and kidney were selected to clarity the effectiveness of PEP on hepatorenal syndrome in mice.[Results]PEP effectively lowered the serum levels of lipid,increased total antioxidant capacity,improved liver and kidney injury,and alleviated pathological changes of liver and kidney of mice induced by carbon tetrachloride.[Conclusions]PEP has a potent preventive effect on hepatorenal syndrome induced by carbon tetrachloride in mice,which provides theoretical support for future clinical application of PEP.
基金support of the National Natural Science Foundation of China(No.12005243,22205239,U1930102 and 11805034)Guangdong Basic and Applied Basic Research Foundation(No.2022B1515120014 and 2022A1515110210)+1 种基金China Postdoctoral Science Foundation(No.2022M721906 and 2022M721909)The neutron diffraction experiments were carried out under the fast-track proposal at Australian Nuclear Science and Technology Organisation(ANSTO)and the general user program(No.P1622061700003)at China Spallation Neutron Source(CSNS).
文摘Solventless mechanochemical synthesis by manual grinding was applied to grow organic proton conducting salts,imidazole-succinic acid(C_(3)H_(4)N_(2)-HOOC(CH_(2))_(2)COOH)and imidazole-glutaric acid(C_(3)H_(4)N_(2)-HOOC(CH_(2))_(3)COOH).This synthesis method induces crystallization and provides the phase-pure compounds.The compounds exhibit different electric conducting behavior and activation energies Ea compared with the reported single crystals obtained from the solution method.The difference in conducting property can be related to intrinsic defects and structural disorder introduced by mechanochemical grinding,indicating that the mechanochemical method bears strong capability for tuning conductivities.Moreover,complete deuteration of the organic salts is achieved by the method.The mechanochemical synthesis of organic salts also holds high potential for the actual industrialized large-scale production.
基金This research was supported in part by grants from the National Natural Science Foundation of China(NSFC315300A4,NSFC31471357,and NSFC31172173 to T.P.Z.).
文摘There are intense interests in discovering pro regenerative medicine leads that can promote cardiac differentiation and regeneration,as well as repair damaged heart tissues.We have combined zebrafish embryo-based screens with cardiomyogenesis assays to discover selective small molecules that modulate heart development and regeneration with minimal adverse effects.Two related compounds with novel structures,named as Cardiomogen 1 and 2(CDMG1 and CDMG2),were identified for their capacity to promote myocardial hyperplasia through expansion of the cardiac progenitor cell population.We find that Cardiomogen acts as a Wnt inhibitor by targeting p-catenin and reducing Tcf/Lef-mediated transcription in cultured cells.CDMG treatment of amputated zebrafish hearts reduces nuclear p-catenin in injured heart tissue,increases cardiomyocyte(CM)proliferation,and expedites wound healing,thus accelerating cardiac muscle regeneration.Importantly,Cardiomogen can alleviate the functional deterioration of mammalian hearts after myocardial infarction.Injured hearts exposed to CDMG1 display increased newly formed CMs and reduced fibrotic scar tissue,which are in part attributable to the^-catenin reduction.Our findings indicate Cardiomogen as a Wnt inhibitor in enhancing injury-induced CM proliferation and heart regeneration,highlighting the values of embryo-based small molecule screens in discovery of effective and safe medicine leads.
基金This research was supported by grants from the Ministry of Science and Technology of China(2018YFA0801004 and 2018YFA0800103)National Science Foundation of China(NSFC31530044 and NSFC31970780)We acknowledge Guozhen Wu for invaluable assistanee with fish care.We are grateful to Mark Mercola and members of TPZ laboratory for comments on the manuscript and helpful discussions.
文摘Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes(CMs).However,the signaling mechanisms by which injury induces CM renewal remain incompletely understood.Here,we find that cardiac injury in zebrafish induces expression of the secreted Wnt inhibitors,including Dickkopf 1(Dkkl),Dkk3,secreted Frizzled-related protein 1(sFrpl),and sFrp2,in cardiac tissue adjacent to injury sites.Experimental blocking of Wnt activity via Dkkl overexpression enhances CM proliferation and heart regeneration,whereas ectopic activation of Wnt8 signaling blunts injury-induced CM dedifferentiation and proliferation.Although Wnt signaling is dampened upon injury,the cytoplasmic β-catenin is unexpectedly increased at disarrayed CM sarcomeres in myocardial wound edges.Our analyses indicated that p21-activated kinase 2(Pak2)is induced at regenerating CMs,where it phosphorylates cytoplasmic β-catenin at Ser 675 and increases its stability at disassembled sarcomeres.Myocardial-specific induction of the phospho-mimeticβ-catenin(S675E)enhances CM dedifferentiation and sarcomere disassembly in response to injury.Conversely,inactivation of Pak2 kinase activity reduces the Ser 675-phosphorylatedβ-catenin(pS675-β-catenin)and attenuates CM sarcomere disorganization and dedifferentiation・Taken together,these findings demonstrate that coordination of Wnt signaling inhibition and Pak2/pS675-βYatenin signaling enhances zebrafish heart regeneration by supporting CM dedifferentiation and proliferation.