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https://www.readbyqxmd.com/read/29457866/epigenetic-effects-of-metformin-from-molecular-mechanisms-to-clinical-implications
#1
REVIEW
S C Bridgeman, G C Ellison, P E Melton, P Newsholme, Cds Mamotte
There is a growing body of evidence that links epigenetic modifications to type 2 diabetes. Researchers have more recently investigated effects of commonly used medications, including those prescribed for diabetes, on epigenetic processes. This work reviews the influence of the widely used antidiabetic drug metformin on epigenomics, microRNA levels and subsequent gene expression and potential clinical implications. Metformin may influence the activity of numerous epigenetic modifying enzymes, mostly via modulating the activation of AMP-activated protein kinase (AMPK)...
February 19, 2018: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/29452350/extra-virgin-olive-oil-contains-a-metabolo-epigenetic-inhibitor-of-cancer-stem-cells
#2
Bruna Corominas-Faja, Elisabet Cuyàs, Jesús Lozano-Sánchez, Sílvia Cufí, Sara Verdura, Salvador Fernández-Arroyo, Isabel Borrás-Linares, Begoña Martin-Castillo, Ángel G Martin, Ruth Lupu, Alfons Nonell-Canals, Melchor Sanchez-Martinez, Vicente Micol, Jorge Joven, Antonio Segura-Carretero, Javier A Menendez
Targeting tumor-initiating, drug-resistant populations of cancer stem cells (CSC) with phytochemicals is a novel paradigm for cancer prevention and treatment. We herein employed a phenotypic drug discovery approach coupled to mechanism-of-action profiling and target deconvolution to identify phenolic components of extra virgin olive oil (EVOO) capable of suppressing the functional traits of CSC in breast cancer (BC). In vitro screening revealed that the secoiridoid decarboxymethyl oleuropein aglycone (DOA) could selectively target sub-populations of epithelial-like, aldehyde dehydrogenase (ALDH)-positive and mesenchymal-like, CD44+CD24-/low CSC...
February 14, 2018: Carcinogenesis
https://www.readbyqxmd.com/read/29449903/specific-or-not-specific-recruitment-of-dnmts-for-dna-methylation-an-epigenetic-dilemma
#3
REVIEW
Eric Hervouet, Paul Peixoto, Régis Delage-Mourroux, Michaël Boyer-Guittaut, Pierre-François Cartron
Our current view of DNA methylation processes is strongly moving: First, even if it was generally admitted that DNMT3A and DNMT3B are associated with de novo methylation and DNMT1 is associated with inheritance DNA methylation, these distinctions are now not so clear. Secondly, since one decade, many partners of DNMTs have been involved in both the regulation of DNA methylation activity and DNMT recruitment on DNA. The high diversity of interactions and the combination of these interactions let us to subclass the different DNMT-including complexes...
2018: Clinical Epigenetics
https://www.readbyqxmd.com/read/29435016/cranial-irradiation-inhibits-hippocampal-neurogenesis-via-dnmt1-and-dnmt3a
#4
Shengjun Ji, Xin Ding, Jiang Ji, Haohao Wu, Rui Sun, Xiaoyang Li, Liyuan Zhang, Ye Tian
Impairment of neurogenesis in the hippocampus following whole-brain irradiation is the most important mechanism of radiation-induced cognitive dysfunction. However, the underlying mechanism remains obscure, meaning an ideal therapeutic target has not been identified. Evidence indicates that DNA methylation in neurons regulates synaptic plasticity and neuronal network activity. In the present study, the expression of DNA methyltransferases (DNMTs) in the hippocampus was analyzed to investigate their potential function in radiation-induced neurogenesis impairment...
March 2018: Oncology Letters
https://www.readbyqxmd.com/read/29392812/mechanism-based-inhibitor-of-dna-cytosine-5-methyltransferase-dnmt-via-a-snar-reaction-with-an-oligodeoxyribonucleotide-containing-2-amino-4-halopyridine-c-nucleoside-dxp
#5
Kousuke Sato, Yuma Kunitomo, Yukiko Kasai, Shohei Utsumi, Isao Suetake, Shoji Tajima, Satoshi Ichikawa, Akira Matsuda
In chromatin, 5-methylcytosine (mC), which represents the 5th nucleobase in genomic DNA, plays a role as an inducer of epigenetic changes. Tumor cells exhibit aberrant DNA methylation patterns, and inhibition of human DNA cytosine-5 methyltransferase (DNMT), which is responsible for generating mC in CpG sequences, is an effective strategy to treat various cancers. Here, we describe the design, synthesis, and evaluation of the properties of 2-amino-4-halopyridine-C-nucleosides (dXP) and oligodeoxyribonucleotides (ODNs) containing dXP as a novel mechanism-based inhibitor of DNMTs...
February 2, 2018: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29383100/sirt1-regulates-mxd1-during-malignant-melanoma-progression
#6
Fabiana M Meliso, Danilo Micali, Camila T Silva, Thaís S Sabedot, Simon G Coetzee, Adrian Koch, Fabian B Fahlbusch, Houtan Noushmehr, Regine Schneider-Stock, Miriam G Jasiulionis
In a murine melanoma model, malignant transformation promoted by a sustained stress condition was causally related to increased levels of reactive oxygen species resulting in DNA damage and massive epigenetic alterations. Since the chromatin modifier Sirtuin-1 (SIRT1) is a protein attracted to double-stranded DNA break (DSB) sites and can recruit other components of the epigenetic machinery, we aimed to define the role of SIRT1 in melanomagenesis through our melanoma model. The DNA damage marker, γH2AX was found increased in melanocytes after 24 hours of deadhesion, accompanied by increased SIRT1 expression and decreased levels of its target, H4K16ac...
December 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29381856/biochemical-studies-and-molecular-dynamic-simulations-reveal-the-molecular-basis-of-conformational-changes-in-dna-methyltransferase-1-dnmt1
#7
Fei Ye, Xiangqian Kong, Hao Zhang, Yan Liu, Zhiyuan Shao, Jia Jin, Yi Cai, Rukang Zhang, Linjuan Li, Yang W Zhang, Yu-Chih Liu, Chenhua Zhang, Wenbing Xie, Kunqian Yu, Hong Ding, Kehao Zhao, Shijie Chen, Hualiang Jiang, Stephen B Baylin, Cheng Luo
DNA methyltransferase-1 (DNMT1) plays a crucial role in the maintenance of genomic methylation patterns. The crystal structure of DNMT1 was determined in two different states, in which the helix that follows the catalytic loop was either kinked (designated helix-kinked) or well folded (designated helix-straight state). Here, we show that the proper structural transition between these two states is required for DNMT1 activity. The mutations of N1248A and R1279D, which didn't affect interactions between DNMT1 and substrates or cofactors, allosterically reduced enzymatic activities in vitro by decreasing kcat/Km for AdoMet...
January 30, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29379364/dna-cytosine-5-methyltransferase-3b-dnmt-3b-polymorphism-and-risk-of-down-syndrome-offspring
#8
Cláudia Melo de Moura, Pedro Ribeiro Bastos, Julyana S V Ribeiro, Márcia Gonçalves Ribeiro, Márcia Rodrigues Amorim, Marcelo Aguiar Costa-Lima
Down syndrome (DS) is the most common form of human genetic mental retardation. Several polymorphisms in genes coding folic acid cycle enzymes have been associated to the risk of bearing a DS child; however, the results are controversial. S-adenosyl-l-methionine (SAM) is an important intermediate of folic acid pathway and acts as methyl donor and substrate for DNA (cytosine-5)-methyltransferase 3B (DNMT3B - EC 2.1.1.37) de novo methylation processes during embryogenesis. Recent studies suggest that a functional polymorphism of DNMT 3B in maternal genotype may be associated with a decreased risk of having a DS child...
January 2018: Saudi Journal of Biological Sciences
https://www.readbyqxmd.com/read/29378471/nanaomycin-a-treatment-promotes-hepatoblast-differentiation-from-human-induced-pluripotent-stem-cells
#9
Soichiro Nakamae, Yukiko Toba, Kazuo Takayama, Fuminori Sakurai, Hiroyuki Mizuguchi
Human induced pluripotent stem cell-derived hepatocyte-like cells are expected to be utilized in pharmaceutical research, including drug screening. However, the hepatocyte functions of the hepatocyte-like cells are still lower than those of human hepatocytes. Therefore, we attempted to improve the hepatocyte differentiation method by modulating the DNA epigenetic status. We first examined the expression profiles of the maintenance DNA methyltransferase (DNMT) 1 and the de novo DNA methyltransferases DNMT3A and DNMT3B, all of which are essential for mammalian development...
January 29, 2018: Stem Cells and Development
https://www.readbyqxmd.com/read/29378290/antidepressant-administration-modulates-stress-induced-dna-methylation-and-dna-methyltransferase-expression-in-rat-prefrontal-cortex-and-hippocampus
#10
Amanda J Sales, Sâmia R L Joca
Stress and antidepressant treatment can modulate DNA methylation in promoter region of genes related to neuroplasticity and mood regulation, thus implicating this epigenetic mechanism in depression neurobiology and treatment. Accordingly, systemic administration of DNA methyltransferase (DNMT) inhibitors induces antidepressant-like effects in rodents. DNA methylation is conveyed by DNMT 1, 3a and 3b isoforms, which are differentially expressed in the brain. In order to investigate if the behavioral effects of antidepressants could be associated with changes in DNA methylation and DNMT expression, we investigated the effects induced by acute and repeated antidepressant treatment on DNA methylation and DNMT expression (1, 3a and 3b isoforms) in different brain regions of rats exposed to a stress model of depression, the learned helplessness (LH)...
January 26, 2018: Behavioural Brain Research
https://www.readbyqxmd.com/read/29363667/curcumol-controls-choriocarcinoma-stem-like-cells-self-renewal-via-repression-of-dna-methyltransferase-dnmt-and-histone-deacetylase-hdac-mediated-epigenetic-regulation
#11
Zheng Peng, Wenjun Zhou, Chun Zhang, Huining Liu, Yi Zhang
BACKGROUND Cancer stem cells (CSCs), in choriocarcinoma and other carcinomas, possess the ability of self-renewal and multilineage differentiation potential. We previous isolated choriocarcinoma cancer stem-like cells (CSLCs), which hold the stemness characteristics of CSCs. Epigenetic modifications have emerged as drivers in tumorigenesis, but the mechanisms of CSCs are largely unknown, and new drug therapies are needed to break the persistence of CSCs. MATERIAL AND METHODS Quantitative real-time PCR (qRT-PCR) and Western blot analysis were performed to detect the expression of DNMTs, HDACs, and stemness-genes...
January 24, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29344166/identification-and-functional-analysis-of-risk-related-micrornas-for-the-prognosis-of-patients-with-bladder-urothelial-carcinoma
#12
Ji Gao, Hongyan Li, Lei Liu, Lide Song, Yanting Lv, Yuping Han
The aim of the present study was to investigate risk-related microRNAs (miRs) for bladder urothelial carcinoma (BUC) prognosis. Clinical and microRNA expression data downloaded from the Cancer Genome Atlas were utilized for survival analysis. Risk factor estimation was performed using Cox's proportional regression analysis. A microRNA-regulated target gene network was constructed and presented using Cytoscape. In addition, the Database for Annotation, Visualization and Integrated Discovery was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment, followed by protein-protein interaction (PPI) network analysis...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29336230/alterations-of-global-dna-methylation-and-dnmt-expression-in-t-and-b-lymphocytes-from-patients-with-newly-diagnosed-aitd-after-treatment-a-follow-up-study
#13
Qingling Guo, Dan Wu, Huixin Yu, Jiandong Bao, Shiqiao Peng, Zhongyan Shan, Haixia Guan, Weiping Teng
BACKGROUND: Dysregulated DNA methylation in lymphocytes has been linked to autoimmune disorders. The aims of this study were to identify global DNA methylation patterns in patients with autoimmune thyroid diseases (AITDs) and to observe methylation changes after treatment for these conditions. METHODS: We conducted a cross-sectional study design including the following patients: 51 with newly diagnosed Graves' disease (GD), 28 with autoimmune hypothyroidism (AIT), 29 with positive thyroid autoantibodies (pTAb) and 39 matched healthy volunteers...
January 16, 2018: Thyroid: Official Journal of the American Thyroid Association
https://www.readbyqxmd.com/read/29323674/can-5-methylcytosine-analogues-with-extended-alkyl-side-chains-guide-dna-methylation
#14
D Kotandeniya, C L Seiler, J Fernandez, S S Pujari, L Curwick, K Murphy, S Wickramaratne, S Yan, D Murphy, Yuk Y Sham, N Y Tretyakova
5-Methylcytosine (MeC) is an endogenous modification of DNA that plays a crucial role in DNA-protein interactions, chromatin structure, epigenetic regulation, and DNA repair. MeC is produced via enzymatic methylation of the C-5 position of cytosine by DNA-methyltransferases (DNMT) which use S-adenosylmethionine (SAM) as a cofactor. Hemimethylated CG dinucleotides generated as a result of DNA replication are specifically recognized and methylated by maintenance DNA methyltransferase 1 (DNMT1). The accuracy of DNMT1-mediated methylation is essential for preserving tissue-specific DNA methylation and thus gene expression patterns...
January 11, 2018: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/29303998/linking-dna-damage-and-age-related-promoter-dna-hyper-methylation-in-the-intestine
#15
Torsten Thalheim, Maria Herberg, Joerg Galle
Aberrant DNA methylation in stem cells is a hallmark of aging and tumor development. Here, we explore whether and how DNA damage repair might impact on these time-dependent changes, in particular in proliferative intestinal stem cells. We introduce a 3D multiscale computer model of intestinal crypts enabling simulation of aberrant DNA and histone methylation of gene promoters during aging. We assume histone state-dependent activity of de novo DNA methyltransferases (DNMTs) and methylation-dependent binding of maintenance DNMTs to CpGs...
January 5, 2018: Genes
https://www.readbyqxmd.com/read/29282690/targeting-the-epigenome-as-a-novel-therapeutic-approach-for-breast-cancer
#16
Sumin Oh, Je Yeong Ko, Chaeun Oh, Kyung Hyun Yoo
Breast cancer is one of complex diseases that are influenced by environment. Various genetic and epigenetic alterations are provoking causes of breast carcinogenesis. Dynamic epigenetic regulation including DNA methylation and histone modification induces dysregulation of genes related to proliferation, apoptosis, and metastasis in breast cancer. DNA methylation is strongly associated with the repression of transcription through adding to the methyl group by DNA methyltransferases (DNMTs), and tumor suppressor genes such as CCND2 and RUNX3 have been investigated to undergo hypermethylation at promoter region in breast cancer...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29281720/reversible-dual-inhibitor-against-g9a-and-dnmt1-improves-human-ipsc-derivation-enhancing-met-and-facilitating-transcription-factor-engagement-to-the-genome
#17
Juan Roberto Rodriguez-Madoz, Edurne San Jose-Eneriz, Obdulia Rabal, Natalia Zapata-Linares, Estibaliz Miranda, Saray Rodriguez, Angelo Porciuncula, Amaia Vilas-Zornoza, Leire Garate, Victor Segura, Elizabeth Guruceaga, Xabier Agirre, Julen Oyarzabal, Felipe Prosper
The combination of defined factors with small molecules targeting epigenetic factors is a strategy that has been shown to enhance optimal derivation of iPSCs and could be used for disease modelling, high throughput screenings and/or regenerative medicine applications. In this study, we showed that a new first-in-class reversible dual G9a/DNMT1 inhibitor compound (CM272) improves the efficiency of human cell reprogramming and iPSC generation from primary cells of healthy donors and patient samples, using both integrative and non-integrative methods...
2017: PloS One
https://www.readbyqxmd.com/read/29261667/increased-lipid-availability-for-three-days-reduces-whole-body-glucose-uptake-impairs-muscle-mitochondrial-function-and-initiates-opposing-effects-on-pgc-1%C3%AE-promoter-methylation-in-healthy-subjects
#18
Roy Eldor, Luke Norton, Marcel Fourcaudot, Cynthia Galindo, Ralph A DeFronzo, Muhammad Abdul-Ghani
AIMS: FFA and FFA metabolites cause insulin resistance and impair beta cell function. The goal of our research was to examine whether elevation of plasma FFA impairs mitochondrial function and alters PGC-1α promoter methylation. METHODS: In this uncontrolled, change from baseline study design, insulin sensitivity and glucose-stimulated insulin secretion were measured in 9 normal glucose tolerant subjects before and after 3 day lipid infusion to elevate plasma FFA concentration...
2017: PloS One
https://www.readbyqxmd.com/read/29245974/chondroitin-sulfatases-differentially-regulate-wnt-signaling-in-prostate-stem-cells-through-effects-on-shp2-phospho-erk1-2-and-dickkopf-wnt-signaling-pathway-inhibitor-dkk3
#19
Sumit Bhattacharyya, Leo Feferman, Joanne K Tobacman
The chondroitin sulfatases N-acetylgalactosamine-4-sulfatase (ARSB) and galactosamine-N-acetyl-6-sulfatase (GALNS) remove either the 4-sulfate group at the non-reducing end of chondroitin 4-sulfate (C4S) and dermatan sulfate, or the 6-sulfate group of chondroitin 6-sulfate, chondroitin 4,6-disulfate (chondroitin sulfate E), or keratan sulfate. In human prostate cancer tissues, the ARSB activity was reduced and the GALNS activity was increased, compared to normal prostate tissue. In human prostate stem cells, when ARSB was reduced by silencing or GALNS was increased by overexpression, activity of SHP2, the ubiquitous non-receptor tyrosine phosphatase, declined, attributable to increased binding of SHP2 with C4S...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29230671/incorporating-dna-methyltransferase-inhibitors-dnmtis-in-the-treatment-of-genitourinary-malignancies-a-systematic-review
#20
Michal Chovanec, Fadi Taza, Maitri Kalra, Noah Hahn, Kenneth P Nephew, Michael J Spinella, Costantine Albany
Inhibition of DNA methyltransferases (DNMTs) has emerged as a novel treatment strategy in solid tumors. Aberrant hypermethylation in promoters of critical tumor suppressor genes is the basis for the idea that treatment with hypomethylating agents may lead to the restoration of a "normal" epigenome and produce clinically meaningful therapeutic outcomes. The aim of this review article is to summarize the current state of knowledge of DNMT inhibitors in the treatment of genitourinary malignancies. The efficacy of these agents in genitourinary malignancies was reported in a number of studies and suggests a role of induced DNA hypomethylation in overcoming resistance to conventional cytotoxic treatments...
December 11, 2017: Targeted Oncology
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