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Small molecule epigenetics

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https://www.readbyqxmd.com/read/29053192/dissociation-of-nnos-from-psd-95-promotes-functional-recovery-after-cerebral-ischaemia-in-mice-through-reducing-excessive-tonic-gaba-release-from-reactive-astrocytes
#1
Yu-Hui Lin, Hai-Ying Liang, Ke Xu, Huan-Yu Ni, Jian Dong, Hui Xiao, Lei Chang, Hai-Yin Wu, Fei Li, Dong-Ya Zhu, Chun-Xia Luo
Mechanisms underlying functional recovery after stroke are little known, and effective drug intervention during the delayed stage is desirable. One potential drug target, the protein-protein interaction between neuronal nitric oxide synthase (nNOS) and postsynaptic density protein 95 (PSD-95), is critical to acute ischaemic damage and neurogenesis. We show that nNOS-PSD-95 dissociation induced by microinjection of a recombinant fusion protein Tat-nNOS-N1-133 or systemic administration of a small molecule ZL006 from days 4 to 10 after photothrombotic ischaemia in mice reduced excessive tonic inhibition in the peri-infarct cortex and ameliorated motor functional outcome...
October 20, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/29048660/canonical-and-non-canonical-wnt-signaling-in-cancer-stem-cells-and-their-niches-cellular-heterogeneity-omics-reprogramming-targeted-therapy-and-tumor-plasticity-review
#2
Masaru Katoh
Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49)...
September 19, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29032424/not-just-gene-expression-3d-implications-of-chromatin-modifications-during-sexual-plant-reproduction
#3
Stefanie Dukowic-Schulze, Chang Liu, Changbin Chen
DNA methylation and histone modifications are epigenetic changes on a DNA molecule that alter the three-dimensional (3D) structure locally as well as globally, impacting chromatin looping and packaging on a larger scale. Epigenetic marks thus inform higher-order chromosome organization and placement in the nucleus. Conventional epigenetic marks are joined by chromatin modifiers like cohesins, condensins and membrane-anchoring complexes to support particularly 3D chromosome organization. The most popular consequences of epigenetic modifications are gene expression changes, but chromatin modifications have implications beyond this, particularly in actively dividing cells and during sexual reproduction...
October 14, 2017: Plant Cell Reports
https://www.readbyqxmd.com/read/29025910/protein-arginine-methyltransferase-6-controls-erythroid-gene-expression-and-differentiation-of-human-cd34-progenitor-cells
#4
Stefanie C Herkt, Olga N Kuvardina, Julia Herglotz, Lucas Schneider, Annekarin Meyer, Claudia Pommerenke, Gabriela Salinas-Riester, Erhard Seifried, Halvard Bonig, Jörn Lausen
Hematopoietic differentiation is driven by transcription factors, which orchestrate a fine tuned transcriptional network. At bipotential branching points lineage decisions are made, where key transcription factors initiate cell type specific gene expression programs. These programs are stabilized by the epigenetic activity of recruited chromatin modifying cofactors. An example gives the association of the transcription factor RUNX1 with the protein arginine methyltransferase 6 (PRMT6) at the megakaryocytic/erythroid bifurcation...
October 12, 2017: Haematologica
https://www.readbyqxmd.com/read/29023490/network-modeling-of-kinase-inhibitor-polypharmacology-reveals-pathways-targeted-in-chemical-screens
#5
Oana Ursu, Sara J C Gosline, Neil Beeharry, Lauren Fink, Vikram Bhattacharjee, Shao-Shan Carol Huang, Yan Zhou, Tim Yen, Ernest Fraenkel
Small molecule screens are widely used to prioritize pharmaceutical development. However, determining the pathways targeted by these molecules is challenging, since the compounds are often promiscuous. We present a network strategy that takes into account the polypharmacology of small molecules in order to generate hypotheses for their broader mode of action. We report a screen for kinase inhibitors that increase the efficacy of gemcitabine, the first-line chemotherapy for pancreatic cancer. Eight kinase inhibitors emerge that are known to affect 201 kinases, of which only three kinases have been previously identified as modifiers of gemcitabine toxicity...
2017: PloS One
https://www.readbyqxmd.com/read/28992434/targeting-epigenetics-in-cancer
#6
Richard L Bennett, Jonathan D Licht
Alterations of genes regulating epigenetic processes are frequently found as cancer drivers and may cause widespread alterations of DNA methylation, histone modification patterns, or chromatin structure that disrupt normal patterns of gene expression. Because of the inherent reversibility of epigenetic changes, inhibitors targeting these processes are promising anticancer strategies. Small molecules targeting epigenetic regulators have been developed recently, and clinical trials of these agents are under way for hematologic malignancies and solid tumors...
October 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/28986582/assessing-inhibitors-of-mutant-isocitrate-dehydrogenase-using-a-suite-of-pre-clinical-discovery-assays
#7
Daniel J Urban, Natalia J Martinez, Mindy I Davis, Kyle R Brimacombe, Dorian M Cheff, Tobie D Lee, Mark J Henderson, Steven A Titus, Rajan Pragani, Jason M Rohde, Li Liu, Yuhong Fang, Surendra Karavadhi, Pranav Shah, Olivia W Lee, Amy Wang, Andrew McIver, Hongchao Zheng, Xiaodong Wang, Xin Xu, Ajit Jadhav, Anton Simeonov, Min Shen, Matthew B Boxer, Matthew D Hall
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that are mutated in a variety of cancers to confer a gain-of-function activity resulting in the accumulation of an oncometabolite, D-2-hydroxyglutarate (2-HG). Accumulation of 2-HG can result in epigenetic dysregulation and a block in cellular differentiation, suggesting these mutations play a role in neoplasia. Based on its potential as a cancer target, a number of small molecule inhibitors have been developed to specifically inhibit mutant forms of IDH (mIDH1 and mIDH2)...
October 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28978842/molecular-pathogenesis-and-its-therapeutic-implication-for-atl
#8
Kenji Ishitsuka
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type I (HTLV-1). HTLV-1 related proteins Tax and HTLV-1 bZIP factor induce immortalization and transformation of HTLV-1-infected T-lymphocytes and eventually induce clonal proliferation. One of the apparent molecular features in ATL cells is abundant genomic abnormalities targeting characteristic pathways, including T-cell receptor signaling and the NF-κB pathway, G-protein coupled-receptor, including CCR4, and transcriptional regulation...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28976073/discovery-of-a-highly-selective-cell-active-inhibitor-of-kdm2-7
#9
Philip Gerken, Jamie Wolstenhulme, Anthony Tumber, Stephanie Hatch, Yijia Zhang, Susanne Müller, Shane Chandler, Barbara Mair, Fengling Li, Sebastian Nijman, Rebecca Konietzny, Tamas Szommer, Clarence Yapp, Oleg Fedorov, Justin Benesch, Masoud Vedadi, Benedikt Kessler, Akane Kawamura, Paul Brennan, Martin Derwyn Smith
Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell-permeable inhibitors or suitable tool compounds for these enzymes. Here we describe the discovery of a new class of inhibitor that is highly selective towards the histone lysine demethylases KDM2A/7A. A modular synthetic approach was used to explore chemical space and accelerate investigation of key structure-activity relationships, leading to the development of a small molecule with ≥75-fold selectivity towards KDM2A/7A vs other KDMs, as well as cellular activity at low micromolar concentrations...
October 4, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28968981/structure-based-design-synthesis-and-activity-studies-of-small-hybrid-molecules-as-hdac-and-g9a-dual-inhibitors
#10
Lanlan Zang, Shukkoor M Kondengaden, Qing Zhang, Xiaobo Li, Dilep K Sigalapalli, Shameer M Kondengadan, Kenneth Huang, Keqin Kathy Li, Shanshan Li, Zhongying Xiao, Liuqing Wen, Hailiang Zhu, Bathini N Babu, Lijuan Wang, Fengyuan Che, Peng George Wang
Aberrant enzymatic activities or expression profiles of epigenetic regulations are therapeutic targets for cancers. Among these, histone 3 lysine 9 methylation (H3K9Me2) and global de-acetylation on histone proteins are associated with multiple cancer phenotypes including leukemia, prostatic carcinoma, hepatocellular carcinoma and pulmonary carcinoma. Here, we report the discovery of the first small molecule capable of acting as a dual inhibitor targeting both G9a and HDAC. Our structure based design, synthesis, and screening for the dual activity of the small molecules led to the discovery of compound 14 which displays promising inhibition of both G9a and HDAC in low micro-molar range in cell based assays...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28963019/an-epigenetic-bioactive-composite-scaffold-with-well-aligned-nanofibers-for-functional-tendon-tissue-engineering
#11
Can Zhang, Xianliu Wang, Erchen Zhang, Long Yang, Huihua Yuan, Wenjing Tu, Huilan Zhang, Zi Yin, Weiliang Shen, Xiao Chen, Yanzhong Zhang, Hongwei Ouyang
Poor tendon repair is often a clinical challenge due to the lack of ideal biomaterials. Electrospun aligned fibers, resembling the ultrastructure of tendon, have been previously reported to promote tenogenesis. However, the underlying mechanism is unclear and the aligned fibers alone are not capable enough to commit teno-differentiation of stem cells. Here, based on our observation of reduced expression of histone deacetylases (HDACs) in tendon stem/progenitor cells (TSPCs) cultured on aligned fibers, we proposed a strategy to enhance the tenogenesis effect of aligned fibers by using a small molecule Trichostatin A (TSA), an HDAC inhibitor...
September 26, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28962871/challenging-cancer-targets-for-aptamer-delivery
#12
REVIEW
Vittorio de Franciscis
The extraordinary boost in the understanding of the genetic and epigenetic mechanisms underlying the development and progression of different types of cancer, is offering an unprecedented hope for the development of precise therapeutics able to interfere or replace the expression of target genes. In the last decade, the design of stable, safe and effective RNA-based therapeutics has been significantly improved increasing the number of molecules now in preclinical or in clinical trials for cancer gene therapy...
September 26, 2017: Biochimie
https://www.readbyqxmd.com/read/28953875/discovery-of-a-selective-catalytic-p300-cbp-inhibitor-that-targets-lineage-specific-tumours
#13
Loren M Lasko, Clarissa G Jakob, Rohinton P Edalji, Wei Qiu, Debra Montgomery, Enrico L Digiammarino, T Matt Hansen, Roberto M Risi, Robin Frey, Vlasios Manaves, Bailin Shaw, Mikkel Algire, Paul Hessler, Lloyd T Lam, Tamar Uziel, Emily Faivre, Debra Ferguson, Fritz G Buchanan, Ruth L Martin, Maricel Torrent, Gary G Chiang, Kannan Karukurichi, J William Langston, Brian T Weinert, Chunaram Choudhary, Peter de Vries, John H Van Drie, David McElligott, Ed Kesicki, Ronen Marmorstein, Chaohong Sun, Philip A Cole, Saul H Rosenberg, Michael R Michaelides, Albert Lai, Kenneth D Bromberg
The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have also been implicated in human pathological conditions (including cancer)...
September 27, 2017: Nature
https://www.readbyqxmd.com/read/28951953/plant-small-rnas-the-essential-epigenetic-regulators-of-gene-expression-for-salt-stress-responses-and-tolerance
#14
REVIEW
Vinay Kumar, Tushar Khare, Varsha Shriram, Shabir H Wani
Saline environment cues distort the plant growth, development and crop yield. Epigenetics has emerged as one of the prime themes in plant functional genomics for molecular-stress-physiology research, as copious studies have provided new visions into the epigenetic control of stress adaptations. The epigenetic control is associated with the regulation of the expression of stress-related genes which also comprises many steady alterations inherited in next cellular generation as stress memory. These epigenetic amendments also implicate induction of small RNA (sRNA)-mediated fine-tuning of transcriptional and post-transcriptional regulations of gene expression...
September 26, 2017: Plant Cell Reports
https://www.readbyqxmd.com/read/28939121/discovery-of-novel-1-2-4-triazolo-4-3-a-quinoxaline-aminophenyl-derivatives-as-bet-inhibitors-for-cancer-treatment
#15
Imran Ali, Jooyun Lee, Areum Go, Gildon Choi, Kwangho Lee
Bromodomain and extra-terminal (BET) proteins, a class of epigenetic reader domains has emerged as a promising new target class for small molecule drug discovery for the treatment of cancer, inflammatory, and autoimmune diseases. Starting from in silico screening campaign, herein we report the discovery of novel BET inhibitors based on [1,2,4]triazolo[4,3-a]quinoxaline scaffold and their biological evaluation. The hit compound was optimized using the medicinal chemistry approach to the lead compound with excellent inhibitory activities against BRD4 in the binding assay...
October 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28923203/epigenetic-silencing-of-mirna-34a-in-human-cholangiocarcinoma-via-ezh2-and-dna-methylation-impact-on-regulation-of-notch-pathway
#16
Hyunjoo Kwon, Kyoungsub Song, Chang Han, Jinqiang Zhang, Lu Lu, Weina Chen, Tong Wu
Aberrant expression and regulation of miRNAs have been implicated in multiple stages of tumorigenic processes. The current study was designed to explore the biological function and epigenetic regulation of miR-34a in human cholangiocarcinoma (CCA). Our data show that the expression of miR-34a is decreased significantly in CCA cells compared with non-neoplastic biliary epithelial cells. Forced overexpression of miR-34a in CCA cells inhibited their proliferation and clonogenic capacity in vitro, and suppressed tumor xenograft growth in severe combined immunodeficiency mice...
October 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28921466/roles-of-hdacs-in-the-responses-of-innate-immune-cells-and-as-targets-in-inflammatory-diseases
#17
Yiqun Hu, Bandar Ali Suliman
Histone deacetylases (HDACs) are an emerging class of molecules involved in the epigenetic regulation of innate immune responses through Toll-like receptor (TLR) and interferon (IFN) signaling pathways. HDACs are also key drivers of inflammatory diseases via epigenetic regulation through chromatin DNA and histone modification by methylation and acetylation, among other mechanisms, which control innate immune cell gene expression. Importantly, these epigenetic changes are reversible, and HDACs may also be targeted by small-molecule HDAC inhibitors, which have been used in clinical settings for cancer therapy...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28915537/mta1-expression-in-human-cancers-clinical-and-pharmacological-significance
#18
REVIEW
Vijaya Lakshmi Malisetty, Vasudevarao Penugurti, Prashanth Panta, Suresh Kumar Chitta, Bramanandam Manavathi
Remarkably, majority of the cancer deaths are due to metastasis, not because of primary tumors. Metastasis is one of the important hallmarks of cancer. During metastasis invasion of primary tumor cells from the site of origin to a new organ occurs. Metastasis associated proteins (MTAs) are a small family of transcriptional coregulators that are closely associated with tumor metastasis. These proteins are integral components of nuclear remodeling and deacetylation complex (NuRD). By virtue of being integral components of NuRD, these proteins regulate the gene expression by altering the epigenetic changes such as acetylation and methylation on the target gene chromatin...
September 11, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28912274/structure-mechanism-and-regulation-of-polycomb-repressive-complex-2
#19
Lindsay E Moritz, Raymond C Trievel
Polycomb Repressive Complex 2 (PRC2) methylates lysine 27 in histone H3, a modification associated with epigenetic gene silencing. This complex plays a fundamental role in regulating cellular differentiation and development, and PRC2 overexpression and mutations have been implicated in numerous cancers. In this review, we examine recent studies elucidating the first crystal structures of the PRC2 core complex, yielding seminal insights into its catalytic mechanism, substrate specificity, allosteric regulation, and inhibition by a class of small molecules that are currently undergoing cancer clinical trials...
September 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28904640/short-term-dietary-methionine-supplementation-affects-one-carbon-metabolism-and-dna-methylation-in-the-mouse-gut-and-leads-to-altered-microbiome-profiles-barrier-function-gene-expression-and-histomorphology
#20
Isabelle R Miousse, Rupak Pathak, Sarita Garg, Charles M Skinner, Stepan Melnyk, Oleksandra Pavliv, Howard Hendrickson, Reid D Landes, Annie Lumen, Alan J Tackett, Nicolaas E P Deutz, Martin Hauer-Jensen, Igor Koturbash
BACKGROUND: Methionine, a central molecule in one-carbon metabolism, is an essential amino acid required for normal growth and development. Despite its importance to biological systems, methionine is toxic when administered at supra-physiological levels. The aim of this study was to investigate the effects of short-term methionine dietary modulation on the proximal jejunum, the section of the gut specifically responsible for amino acid absorption, in a mouse model. Eight-week-old CBA/J male mice were fed methionine-adequate (MAD; 6...
2017: Genes & Nutrition
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