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Discovering small molecules as Wnt inhibitors that promote heart regeneration and injury repair

Journal of Molecular Cell Biology 2020年第1期12卷 42-54页

作者： Shuying Xie Wenbin Fu Guangju Yu Xueli Hu Kaa Seng Lai Xiangwen Peng Yating Zhou Xuejiao Zhu ptamen christov Leah Sawyer Terri T.Ni Gary A.Sulikowski Zhongzhou Yang Ethan Lee Chunyu Zeng Wei E.Wang Tao P.Zhong State Key Laboratory of Genetic Engineering School of Life SciencesZhongshan HospitalFudan UniversityShanghai 200438China Department of Cardiology Daping HospitalThird Military Medical UniversityChongqing 400042China Shanghai Key Laboratory of Regulatory Biology Institute of Molecular MedicineEast China Normal University School of Life SciencesShanghai 200241China Vanderbilt Institute of Chemical Biology Vanderbilt UniversityNashvilleTN 37232USA Department of Cell and Developmental Biology Vanderbilt UniversityNashvilleTN 37232USA MOE Key Laboratory of Model Animal for Disease Study Model Animal Research CenterNanjing UniversityNanjingChina

There are intense interests in discovering pro regenerative medicine leads that can promote cardiac differentiation and regeneration,as well as repair damaged heart *** have combined zebrafish embryo-based screens with cardiomyogenesis assays to discover selective small molecules that modulate heart development and regeneration with minimal adverse *** 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 *** find that Cardiomogen acts as a Wnt inhibitor by targeting p-catenin and reducing Tcf/Lef-mediated transcription in cultured *** 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 ***,Cardiomogen can alleviate the functional deterioration of mammalian hearts after myocardial *** hearts exposed to CDMG1 display increased newly formed CMs and reduced fibrotic scar tissue,which are in part attributable to the^-catenin *** 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.

关键词： small molecule screen Wnt inhibitor regeneration

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