Regenerative endodontics(RE)therapy means physiologically replacing damaged pulp tissue and regaining functional dentin–pulp complex.Current clinical RE procedures recruit endogenous stem cells from the apical papill...Regenerative endodontics(RE)therapy means physiologically replacing damaged pulp tissue and regaining functional dentin–pulp complex.Current clinical RE procedures recruit endogenous stem cells from the apical papilla,periodontal tissue,bone marrow and peripheral blood,with or without application of scaffolds and growth factors in the root canal space,resulting in cementum-like and bone-like tissue formation.Without the involvement of dental pulp stem cells(DPSCs),it is unlikely that functional pulp regeneration can be achieved,even though acceptable repair can be acquired.DPSCs,due to their specific odontogenic potential,high proliferation,neurovascular property,and easy accessibility,are considered as the most eligible cell source for dentin–pulp regeneration.The regenerative potential of DPSCs has been demonstrated by recent clinical progress.DPSC transplantation following pulpectomy has successfully reconstructed neurovascularized pulp that simulates the physiological structure of natural pulp.The self-renewal,proliferation,and odontogenic differentiation of DPSCs are under the control of a cascade of transcription factors.Over recent decades,epigenetic modulations implicating histone modifications,DNA methylation,and noncoding(nc)RNAs have manifested as a new layer of gene regulation.These modulations exhibit a profound effect on the cellular activities of DPSCs.In this review,we offer an overview about epigenetic regulation of the fate of DPSCs;in particular,on the proliferation,odontogenic differentiation,angiogenesis,and neurogenesis.We emphasize recent discoveries of epigenetic molecules that can alter DPSC status and promote pulp regeneration through manipulation over epigenetic profiles.展开更多
Multiple histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) have been developed for cancer therapy. However, the research on their mechanisms of action is not sophisticated enough. In ...Multiple histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) have been developed for cancer therapy. However, the research on their mechanisms of action is not sophisticated enough. In this study, we reported a dual HDAC and DNMT inhibitor 208 and found it induced G1 cell cycle arrest and apoptosis in U937 cells. Proteome and bioinformatic analyses revealed that the combined inhibition of DNMT1 and HDAC by 208 affected the expression of a series of proteins involved in many biological processes. We observed that several proteins associated with G1 cell cycle arrest and apoptosis were down regulated after 208 treatment, including p85α, MEK, and CDK4, suggesting that 208 induces cell cycle arrest and apoptosis through the p85α/MEK-mediated pathway in U937 cells. Moreover, biological function analysis showed that the combined epigenetic inhibition influenced various processes, including the synthesis and processing of RNA, translation, protein transport, and DNA repair. These findings provide novel insight into the potential mechanisms of multifunctional epigenetic inhibitors, which supports their further improvement and development.展开更多
Epigenetic modifications alter chromatin structures and consequently affect transcription and cellular functions.Major epigenetic markers include DNA methylation and histone acetylation and methylation.The modificatio...Epigenetic modifications alter chromatin structures and consequently affect transcription and cellular functions.Major epigenetic markers include DNA methylation and histone acetylation and methylation.The modifications are reversible and are achieved in aid of relative enzymes.Much effort has been directed at the understanding of the chemical mechanisms of individual catalytic reactions,which can serve as a foundation for inhibitor development.Among the many methods deployed,structural studies have proven the most effective for understanding enzyme-mediated modifications and have provided support for the development of lead-candidate drug inhibitors.This review briefly summarizes the existing knowledge on the catalytic mechanisms of the major epigenetic modification enzymes,with an emphasis on the structural information and inhibitors of these enzymes.展开更多
BRPF(bromodomain and PHD finger containing)蛋白作为表观遗传"reader"结构域,能特异性地识别组蛋白"尾部"乙酰化的赖氨酸残基以促进靶基因的转录。本文综述了BPRF蛋白如何识别和结合乙酰赖氨酸标记,讨论了乙酰...BRPF(bromodomain and PHD finger containing)蛋白作为表观遗传"reader"结构域,能特异性地识别组蛋白"尾部"乙酰化的赖氨酸残基以促进靶基因的转录。本文综述了BPRF蛋白如何识别和结合乙酰赖氨酸标记,讨论了乙酰化组蛋白识别对其生物学功能的重要性,以及总结了BRPF bromodomain抑制剂的研究进展。展开更多
Epigenetic modifications have been proved to be a powerful way to activate silent gene clusters and lead to diverse secondary metabolites in fungi. Previously, inactivation of a histone H3 deacetylase in Calcarisporiu...Epigenetic modifications have been proved to be a powerful way to activate silent gene clusters and lead to diverse secondary metabolites in fungi. Previously, inactivation of a histone H3 deacetylase in Calcarisporium arbuscula had led to pleiotropic activation and overexpression of more than 75% of the biosynthetic genes and isolation of ten compounds. Further investigation of the crude extract of C. arbuscula Δhda A strain resulted in the isolation of twelve new diterpenoids including three cassanes(1-3), one cleistanthane(4), six pimaranes(5-10), and two isopimaranes(11 and 12) along with two know cleistanthane analogues. Their structures were elucidated by extensive NMR spectroscopic data analysis. Compounds 2 and 4 showed potent inhibitory effects on the expression of MMP1 and MMP2(matrix metalloproteinases family) in human breast cancer(MCF-7) cells.展开更多
Targeting bromodomain-containing protein 4(BRD4) has been proved to be an effective strategy for cancer therapy.To date,numerous BRD4 inhibitors and degraders have been identified,some of which have advanced into clin...Targeting bromodomain-containing protein 4(BRD4) has been proved to be an effective strategy for cancer therapy.To date,numerous BRD4 inhibitors and degraders have been identified,some of which have advanced into clinical trials.In this work,a focused library of new [1,2,4]triazolo [1,5-a]pyrimidine derivatives were discovered to be able to inhibit BRD4.WS-722 inactivated BRD4(BD1/BD2),BRD2(BD1/BD2) and BRD3(BD1/BD2) broadly with the IC_(50) values less than 5 μmol/L.Besides,WS-722 inhibited growth of THP-1 cells with an IC_(50) value of 3.86 μmol/L.Like(+)-JQ1,WS-722 inhibited BRD4 in a reversible manner and enhanced protein stability.Docking studies showed that WS-722 occupied the central acetyl-lysine(Kac) binding cavity and formed a hydrogen bond with Asn140.In THP-1 cells,WS-722 showed target engagement to BRD4.Cellular effects of WS-722 on THP-1 cells were also examined,showing that WS-722 could block c-MYC expression,induce G0/G1 phase arrest and p21 up-regulation,and promote differentiation of THP-1 cells.BRD4 inhibition by WS-722 resulted in cell apoptosis and upregulated expression of cleaved caspased-3/7 and PARP in THP-1 cell lines.The [1,2,4]triazolo[1,5-a]pyrimidine is a new template for the development of new BRD4 inhibitors.展开更多
基金Supported by National Natural Science Foundation of China,No.81800929 and No.81771033Sichuan Science and Technology Program,No.2019JDRC0096and Research and Develop Program,West China Hospital of Stomatology Sichuan University,No.LCYJ2019-24.
文摘Regenerative endodontics(RE)therapy means physiologically replacing damaged pulp tissue and regaining functional dentin–pulp complex.Current clinical RE procedures recruit endogenous stem cells from the apical papilla,periodontal tissue,bone marrow and peripheral blood,with or without application of scaffolds and growth factors in the root canal space,resulting in cementum-like and bone-like tissue formation.Without the involvement of dental pulp stem cells(DPSCs),it is unlikely that functional pulp regeneration can be achieved,even though acceptable repair can be acquired.DPSCs,due to their specific odontogenic potential,high proliferation,neurovascular property,and easy accessibility,are considered as the most eligible cell source for dentin–pulp regeneration.The regenerative potential of DPSCs has been demonstrated by recent clinical progress.DPSC transplantation following pulpectomy has successfully reconstructed neurovascularized pulp that simulates the physiological structure of natural pulp.The self-renewal,proliferation,and odontogenic differentiation of DPSCs are under the control of a cascade of transcription factors.Over recent decades,epigenetic modulations implicating histone modifications,DNA methylation,and noncoding(nc)RNAs have manifested as a new layer of gene regulation.These modulations exhibit a profound effect on the cellular activities of DPSCs.In this review,we offer an overview about epigenetic regulation of the fate of DPSCs;in particular,on the proliferation,odontogenic differentiation,angiogenesis,and neurogenesis.We emphasize recent discoveries of epigenetic molecules that can alter DPSC status and promote pulp regeneration through manipulation over epigenetic profiles.
基金financial supports from Shenzhen Development and Reform Committee(No. 20151961)China Postdoctoral Science Foundation(No. 2018M631825)Department of Science and Technology of Guangdong Province (No. 2017B030314083)
文摘Multiple histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) have been developed for cancer therapy. However, the research on their mechanisms of action is not sophisticated enough. In this study, we reported a dual HDAC and DNMT inhibitor 208 and found it induced G1 cell cycle arrest and apoptosis in U937 cells. Proteome and bioinformatic analyses revealed that the combined inhibition of DNMT1 and HDAC by 208 affected the expression of a series of proteins involved in many biological processes. We observed that several proteins associated with G1 cell cycle arrest and apoptosis were down regulated after 208 treatment, including p85α, MEK, and CDK4, suggesting that 208 induces cell cycle arrest and apoptosis through the p85α/MEK-mediated pathway in U937 cells. Moreover, biological function analysis showed that the combined epigenetic inhibition influenced various processes, including the synthesis and processing of RNA, translation, protein transport, and DNA repair. These findings provide novel insight into the potential mechanisms of multifunctional epigenetic inhibitors, which supports their further improvement and development.
文摘Epigenetic modifications alter chromatin structures and consequently affect transcription and cellular functions.Major epigenetic markers include DNA methylation and histone acetylation and methylation.The modifications are reversible and are achieved in aid of relative enzymes.Much effort has been directed at the understanding of the chemical mechanisms of individual catalytic reactions,which can serve as a foundation for inhibitor development.Among the many methods deployed,structural studies have proven the most effective for understanding enzyme-mediated modifications and have provided support for the development of lead-candidate drug inhibitors.This review briefly summarizes the existing knowledge on the catalytic mechanisms of the major epigenetic modification enzymes,with an emphasis on the structural information and inhibitors of these enzymes.
基金supported financially by National Natural Science Foundation of China (Nos. 21502233 and 81522043)CAMS Initiative for Innovative Medicine (CAMS-I2M-1-010)+1 种基金the PUMC Youth Fund (33320140175)the State Key Laboratory Fund for Excellent Young Scientists to Youcai Hu (GTZB201401)
文摘Epigenetic modifications have been proved to be a powerful way to activate silent gene clusters and lead to diverse secondary metabolites in fungi. Previously, inactivation of a histone H3 deacetylase in Calcarisporium arbuscula had led to pleiotropic activation and overexpression of more than 75% of the biosynthetic genes and isolation of ten compounds. Further investigation of the crude extract of C. arbuscula Δhda A strain resulted in the isolation of twelve new diterpenoids including three cassanes(1-3), one cleistanthane(4), six pimaranes(5-10), and two isopimaranes(11 and 12) along with two know cleistanthane analogues. Their structures were elucidated by extensive NMR spectroscopic data analysis. Compounds 2 and 4 showed potent inhibitory effects on the expression of MMP1 and MMP2(matrix metalloproteinases family) in human breast cancer(MCF-7) cells.
基金supported by the National Natural Science Foundation of China(Nos.81703326,81773562,81602961 and 81430085)Scientific Program of Henan Province(No.182102310123)China Postdoctoral Science Foundation(Nos.2018M630840 and 2019T120641)。
文摘Targeting bromodomain-containing protein 4(BRD4) has been proved to be an effective strategy for cancer therapy.To date,numerous BRD4 inhibitors and degraders have been identified,some of which have advanced into clinical trials.In this work,a focused library of new [1,2,4]triazolo [1,5-a]pyrimidine derivatives were discovered to be able to inhibit BRD4.WS-722 inactivated BRD4(BD1/BD2),BRD2(BD1/BD2) and BRD3(BD1/BD2) broadly with the IC_(50) values less than 5 μmol/L.Besides,WS-722 inhibited growth of THP-1 cells with an IC_(50) value of 3.86 μmol/L.Like(+)-JQ1,WS-722 inhibited BRD4 in a reversible manner and enhanced protein stability.Docking studies showed that WS-722 occupied the central acetyl-lysine(Kac) binding cavity and formed a hydrogen bond with Asn140.In THP-1 cells,WS-722 showed target engagement to BRD4.Cellular effects of WS-722 on THP-1 cells were also examined,showing that WS-722 could block c-MYC expression,induce G0/G1 phase arrest and p21 up-regulation,and promote differentiation of THP-1 cells.BRD4 inhibition by WS-722 resulted in cell apoptosis and upregulated expression of cleaved caspased-3/7 and PARP in THP-1 cell lines.The [1,2,4]triazolo[1,5-a]pyrimidine is a new template for the development of new BRD4 inhibitors.
