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DNMT and HDAC are closely related to each other and involved in various human diseases especially cancer. These two enzymes have been widely recognized as antitumor targets for drug discovery. Besides, research has indicated that combination therapy consisting of DNMT and HDAC inhibitors exhibited therapeutic advantages. We have reported a DNMT and HDAC dual inhibitor 15a of which the DNMT enzymatic inhibitory potency needs to be improved. Herein we reported the development of a novel dual DNMT and HDAC inhibitor C02S which showed potent enzymatic inhibitory activities against DNMT1, DNMT3A, DNMT3B and HDAC1 with IC50 values of 2.05, 0.93, 1.32, and 4.16 µM, respectively. Further evaluations indicated that C02S could inhibit DNMT and HDAC at cellular levels, thereby inversing mutated methylation and acetylation and increasing expression of tumor suppressor proteins. Moreover, C02S regulated multiple biological processes including inducing apoptosis and G0/G1 cell cycle arrest, inhibiting angiogenesis, blocking migration and invasion, and finally suppressing tumor cells proliferation in vitro and tumor growth in vivo. 相似文献
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Responsible for interpreting histone post-translational modifications, epigenetic reader proteins have emerged as novel therapeutic targets for a wide range of diseases. Chemical probes have been critical in enabling target validation studies and have led to translational advances in cancer and inflammation-related pathologies. Here, we present the most recently reported probes of reader proteins that recognize acylated and methylated lysine. We will discuss challenges associated with achieving potent antagonism of reader domains and review ongoing efforts to overcome these hurdles, focusing on targeting strategies including the use of peptidomimetic ligands, allosteric modulators, and protein degraders. 相似文献
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为了解加勒比松(Pinus caribaea)种源的遗传多样性,利用甲基化敏感扩增多态性技术对加勒比松3个变种17个种源的DNA甲基化多样性进行了研究。结果表明,56对引物组合共扩增出425条谱带,其中多态性谱带422条,多态性百分率为99.25%。加勒比松种源幼苗半甲基化比率比全甲基化比率稍高,洪都拉斯加勒比松、古巴加勒比松和巴哈马加勒比松的DNA甲基化率分别为22.39%、22.29%和22.35%,差异不显著。加勒比松的DNA序列遗传多样性(H=0.4376)高于DNA甲基化多样性(H=0.3274),Mantel检验表明,基因组遗传变异与表观遗传变异不存在相关性(r=-0.171,P=0.16)。表观聚类与遗传聚类间存在较大差异,两种聚类分析结果均未将3个加勒比松变种分开。这表明加勒比松变种间的表观遗传变异极为丰富,能为加勒比松遗传改良提供优良种质资源。 相似文献
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The use of the computer metaphor has led to the proposal of mind architecture (Pylyshyn 1984; Newell 1990) as a model of the organization of the mind. The dualist computational model, however, has, since the earliest days of psychological functionalism, required that the concepts mind architecture and brain architecture be remote from each other. The development of both connectionism and neurocomputational science, has sought to dispense with this dualism and provide general models of consciousness – a uniform cognitive architecture –, which is in general reductionist, but which retains the computer metaphor. This paper examines, in the first place, the concepts of mind architecture and brain architecture, in order to evaluate the syntheses which have recently been offered. It then moves on to show how modifications which have been made to classical functionalist mind architectures, with the aim of making them compatible with brain architectures, are unable to resolve some of the most serious problems of functionalism. Some suggestions are given as to why it is not possible to relate mind structures and brain structures by using neurocomputational approaches, and finally the question is raised of the validity of reductionism in a theory which sets out to unite mind and brain architectures. 相似文献
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The density-dependent phase polyphenism in locusts offers an excellent model to investigate the epigenetic regulatory mechanisms underlying phenotypic plasticity. In this study, we identified histone-modifying enzymes mediating histone post-translational modifications, which serve as a major regulatory mechanism of epigenetic processes, on the basis of the whole genome sequence of the migratory locust, Locusta migratoria. We confirmed the existence of various functional histone modifications in the locusts. Compared with other sequenced insect genomes, the locust genome contains a richer repertoire of histone-modifying enzymes. Several locust histone-modifying enzymes display vertebrate-like characteristics, such as the presence of a Sirt3-like gene and multiple alternative splicing of GCN5 gene. Most histone-modifying enzymes are highly expressed in the eggs or in the testis tissues of male adults. Several histone deacetylases and H3K4-specific methyltransferases exhibit differential expression patterns in brain tissues between solitarious and gregarious locusts. These results reveal the main characteristics of histone-modifying enzymes and provide important cues for understanding the epigenetic mechanisms underlying phase polyphenism in locusts. 相似文献
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Angela Picerno Alessandra Stasi Rossana Franzin Claudia Curci Ighli di Bari Loreto Gesualdo Fabio Sallustio 《World journal of stem cells》2021,13(11):1714-1732
Nowadays, it is clear that adult stem cells, also called as tissue stem cells, play a central role to repair and maintain the tissue in which they reside by their self-renewal ability and capacity of differentiating into distinct and specialized cells. As stem cells age, their renewal ability declines and their capacity to maintain organ homeostasis and regeneration is impaired. From a molecular perspective, these changes in stem cells properties can be due to several types of cell intrinsic injury and DNA aberrant alteration (i.e epigenomic profile) as well as changes in the tissue microenviroment, both into the niche and by systemic circulating factors. Strikingly, it has been suggested that aging-induced deterioration of stem cell functions may play a key role in the pathophysiology of the various aging-associated disorders. Therefore, understanding how resident stem cell age and affects near and distant tissues is fundamental. Here, we examine the current knowledge about aging mechanisms in several kinds of adult stem cells under physiological and pathological conditions and the principal aging-related changes in number, function and phenotype that determine the loss of tissue renewal properties. Furthermore, we examine the possible cell rejuvenation strategies. Stem cell rejuvenation may reverse the aging phenotype and the discovery of effective methods for inducing and differentiating pluripotent stem cells for cell replacement therapies could open up new possibilities for treating age-related diseases. 相似文献