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Histone 3

Lisa Menegazzo, Valentina Scattolini, Roberta Cappellari, Benedetta Maria Bonora, Mattia Albiero, Mario Bortolozzi, Filippo Romanato, Giulio Ceolotto, Saula Vigili de Kreutzeberg, Angelo Avogaro, Gian Paolo Fadini
AIMS: Diabetes is associated with an excess release of neutrophil extracellular traps (NETs) and an enhanced NETosis, a neutrophil cell death programme instrumental to anti-microbial defences, but also involved in tissue damage. We herein investigated whether the antidiabetic drug metformin protects against NETosis. METHODS: We measured NET components in the plasma of patients with pre-diabetes who were randomized to receive metformin or placebo for 2 months. To control for the effect on glucose, we also measured NET components in the plasma of patients with type 2 diabetes before and after treatment with insulin or dapagliflozin...
March 15, 2018: Acta Diabetologica
Lianbin Yao, Sten Ohlson, Brian W Dymock
Inhibition of multiple signaling pathways in a cancer cell with a single molecule could result in better therapies that are simpler to administer. Efficacy may be achieved with reduced potency against individual targets if there is synergy through multiple pathway inhibition. To achieve this, it is necessary to be able to build multi-component ligands by joining together key pharmacophores in a way which maintains sufficient activity against the individual pathways. In this work, designed triple inhibiting ligands are explored aiming to block three completely different target types: a kinase (JAK2), an epigenetic target (HDAC) and a chaperone (HSP90)...
March 3, 2018: Bioorganic & Medicinal Chemistry Letters
Yunan Zheng, Martin J Gilgenast, Sacha Hauc, Abhishek Chatterjee
Reversible post-translational modification (PTM) is a powerful and ubiquitous mechanism to regulate protein function. The mechanistic basis of the associated functional regulation by PTMs often involves the recruitment of interaction partners that selectively binds the modified protein. Identifying such functionally important protein-protein interactions that are uniquely triggered by PTMs remains difficult due to several technical challenges. To address this, here we develop technology to site-specifically incorporate two distinct noncanonical amino acids into recombinant proteins: one modeling a PTM of interest and the second harboring a photoaffinity probe...
March 15, 2018: ACS Chemical Biology
Jinxu Gao, Adelphe Mfuh, Yuka Amako, Christina M Woo
Many therapeutics elicit cell-type specific polypharmacology that is executed by a network of molecular recognition events between a small molecule and the whole proteome. However, measurement of the structures that underpin the molecular associations between the proteome and even common therapeutics, such as the nonsteroidal anti-inflammatory drugs (NSAIDs), is limited by the inability to map the small molecule interactome. To address this gap, we developed a platform termed small molecule interactome mapping by photoaffinity labeling (SIM-PAL) and applied it to the in cellulo direct characterization of specific NSAID binding sites...
March 15, 2018: Journal of the American Chemical Society
Xiao-Fen Ruan, Yong-Jun Li, Cheng-Wei Ju, Yan Shen, Wei Lei, Can Chen, Yang Li, Hong Yu, Yu-Tao Liu, Il-Man Kim, Xiao-Long Wang, Neal L Weintraub, Yao-Liang Tang
Suxiao Jiuxin Pill (SJP) is a traditional Chinese medicine for the treatment of acute coronary syndrome in China, which contains two principal components, tetramethylpyrazine (TMP) and borneol (BOR). Thus far, however, the molecular mechanisms underlying the beneficial effects of SJP on the cardiac microenvironment are unknown. Cardiac mesenchymal stem cells (C-MSCs) communicate with cardiomyocytes (CMs) through the release of microvesicles (exosomes) to restore cardiac homeostasis and elicit repair, in part through epigenetic regulatory mechanisms...
March 15, 2018: Acta Pharmacologica Sinica
Li Huang, Wei-Hong Lai, Lei Zhu, Wei Li, Lei Wei, Kuo-Hsiung Lee, Lan Xie, Chin-Ho Chen
We have previously reported gnidimacrin (GM), a protein kinase C (PKC) agonist, significantly reduces the frequency of HIV-1 latently infected cells in peripheral blood mononuclear cells (PBMCs) from patients undergoing successful antiretroviral therapy at low picomolar concentrations ex vivo , which is distinct from other latency reversing agents. In this study, we demonstrate that strong viral reactivation by GM is a mechanism for elimination of latently infected cells, and a histone deacetylase inhibitor (HDACI), a thiophenyl benzamide (TPB), further potentiated the efficacy of GM against latent HIV-1...
March 8, 2018: ACS Medicinal Chemistry Letters
Bipin Balan, Ana M Ibáñez, Abhaya M Dandekar, Tiziano Caruso, Federico Martinelli
A bioinformatic analysis of previously published RNA-Seq studies on Huanglongbing (HLB) response and tolerance in leaf tissues was performed. The aim was to identify genes commonly modulated between studies and genes, pathways and gene set categories strongly associated with this devastating Citrus disease. Bioinformatic analysis of expression data of four datasets present in NCBI provided 46-68 million reads with an alignment percentage of 72.95-86.76%. Only 16 HLB-regulated genes were commonly identified between the three leaf datasets...
2018: Frontiers in Plant Science
Xu-Feng Lu, Xiao-Yue Cao, Yong-Jie Zhu, Zhen-Ru Wu, Xiang Zhuang, Ming-Yang Shao, Qing Xu, Yong-Jie Zhou, Hong-Jie Ji, Qing-Richard Lu, Yu-Jun Shi, Yong Zeng, Hong Bu
Histone deacetylase 3 (HDAC3) plays pivotal roles in cell cycle regulation and is often aberrantly expressed in various cancers including hepatocellular carcinoma (HCC), but little is known about its role in liver regeneration and liver cancer cells proliferation. Using an inducible hepatocyte-selective HDAC3 knockout mouse, we find that lack of HDAC3 dramatically impaired liver regeneration and blocked hepatocyte proliferation in the G1 phase entry. HDAC3 inactivation robustly disrupted the signal transducer and activator of transcription 3 (STAT3) cascade...
March 14, 2018: Cell Death & Disease
John R Horton, Xu Liu, Lizhen Wu, Kai Zhang, John Shanks, Xing Zhang, Ganesha Rai, Bryan T Mott, Daniel J Jansen, Stephen C Kales, Mark J Henderson, Katherine Pohida, Yuhong Fang, Xin Hu, Ajit Jadhav, David J Maloney, Matthew D Hall, Anton Simeonov, Haian Fu, Paula M Vertino, Qin Yan, Xiaodong Cheng
Isomers of chiral drugs can exhibit marked differences in biological activities. We studied the binding and inhibitory activities of 12 compounds against KDM5A. Among them are two pairs of enantiomers representing two distinct inhibitor chemotypes, namely (R)- and (S)-2-((2-chlorophenyl)(2-(piperidin-1-yl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (compounds N51 and N52) and (R)- and (S)-N-(1-(3-isopropyl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl)cyclopropane-carboxamide (compounds N54 and N55)...
March 14, 2018: Journal of Medicinal Chemistry
Miguel Fontecha-Barriuso, Diego Martin-Sanchez, Olga Ruiz-Andres, Jonay Poveda, Maria Dolores Sanchez-Niño, Lara Valiño-Rivas, Marta Ruiz-Ortega, Alberto Ortiz, Ana Belén Sanz
Epigenetics refers to heritable changes in gene expression patterns not caused by an altered nucleotide sequence, and includes non-coding RNAs and covalent modifications of DNA and histones. This review focuses on functional evidence for the involvement of DNA and histone epigenetic modifications in the pathogenesis of kidney disease and the potential therapeutic implications. There is evidence of activation of epigenetic regulatory mechanisms in acute kidney injury (AKI), chronic kidney disease (CKD) and the AKI-to-CKD transition of diverse aetiologies, including ischaemia-reperfusion injury, nephrotoxicity, ureteral obstruction, diabetes, glomerulonephritis and polycystic kidney disease...
March 9, 2018: Nephrology, Dialysis, Transplantation
Laurie Galvan, Laetitia Francelle, Marie-Claude Gaillard, Lucie de Longprez, Maria-Angeles Carrillo-de Sauvage, Géraldine Liot, Karine Cambon, Lev Stimmer, Sophie Luccantoni, Julien Flament, Julien Valette, Michel de Chaldée, Gwenaelle Auregan, Martine Guillermier, Charlène Joséphine, Fanny Petit, Caroline Jan, Margot Jarrige, Noëlle Dufour, Gilles Bonvento, Sandrine Humbert, Frédéric Saudou, Philippe Hantraye, Karine Merienne, Alexis-Pierre Bemelmans, Anselme L Perrier, Nicole Déglon, Emmanuel Brouillet
The neurobiological functions of a number of kinases expressed in the brain are unknown. Here, we report new findings on DCLK3 (doublecortin like kinase 3), which is preferentially expressed in neurons in the striatum and dentate gyrus. Its function has never been investigated. DCLK3 expression is markedly reduced in Huntington's disease. Recent data obtained in studies related to cancer suggest DCLK3 could have an anti-apoptotic effect. Thus, we hypothesized that early loss of DCLK3 in Huntington's disease may render striatal neurons more susceptible to mutant huntingtin (mHtt)...
March 9, 2018: Brain: a Journal of Neurology
Chunlong Zhao, Jie Zang, Qin'ge Ding, Elizabeth S Inks, Wenfang Xu, C James Chou, Yingjie Zhang
In the past decade, although research and development of histone deacetylase (HDAC) inhibitors as therapeutic agents have achieved great accomplishments, especially in oncology field, there is still an urgent need for the discovery of isoform-selective HDAC inhibitors considering the side effects caused by nonselective HDAC inhibitors. HDAC8, a unique class I zinc-dependent HDAC, is becoming a potential target in cancer and other diseases. In the current study, a novel series of N-hydroxy-3-sulfamoylbenzamide-based HDAC8 selective inhibitors (12a-12p) were designed and synthesized, among which compounds 12a, 12b and 12c exhibited potent HDAC8 inhibition with two-digit nanomolar IC50 values, and considerable selectivity over HDAC2 (>180-fold) and HDAC6 (∼30-fold) which was confirmed by western blot analysis...
March 6, 2018: European Journal of Medicinal Chemistry
Weiqing Qian, Yan Su, Yajie Zhang, Nianwei Yao, Nin Gu, Xu Zhang, Hong Yin
Osteoporosis is a serious public health problem and icariin (ICA) is the active component of the Epimedium sagittatum, a traditional Chinese medicinal herb. The present study aimed to investigate the effects and underlying mechanisms of ICA as a potential therapy for osteoporosis. Calvaria osteoblasts were isolated from newborn rats and treated with ICA. Cell viability, apoptosis, alkaline phosphatase activity and calcium deposition were analyzed. Bioinformatics analyses were performed to identify differentially expressed proteins (DEPs) in response to ICA treatment...
March 9, 2018: Molecular Medicine Reports
Matteo Vecellio, Adrian Cortes, Amity R Roberts, Jonathan Ellis, Carla Jayne Cohen, Julian C Knight, Matthew A Brown, Paul Bowness, Bryan Paul Wordsworth
Objectives: To explore the functions of RUNX3 single nucleotide polymorphisms (SNPs) associated with ankylosing spondylitis (AS). Methods: Individual SNP associations were evaluated in 4230 UK cases. Their effects on transcription factor (TF) binding, transcription regulation, chromatin modifications, gene expression and gene interactions were tested by database interrogation, luciferase reporter assays, electrophoretic mobility gel shifts, chromatin immunoprecipitation and real-time PCR...
2018: RMD Open
Qiang Zhuang, Wenjuan Li, Christina Benda, Zhijian Huang, Tanveer Ahmed, Ping Liu, Xiangpeng Guo, David P Ibañez, Zhiwei Luo, Meng Zhang, Mazid Md Abdul, Zhongzhou Yang, Jiayin Yang, Yinghua Huang, Hui Zhang, Dehao Huang, Jianguo Zhou, Xiaofen Zhong, Xihua Zhu, Xiuling Fu, Wenxia Fan, Yulin Liu, Yan Xu, Carl Ward, Muhammad Jadoon Khan, Shahzina Kanwal, Bushra Mirza, Micky D Tortorella, Hung-Fat Tse, Jiayu Chen, Baoming Qin, Xichen Bao, Shaorong Gao, Andrew P Hutchins, Miguel A Esteban
Somatic cell reprogramming by exogenous factors requires cooperation with transcriptional co-activators and co-repressors to effectively remodel the epigenetic environment. How this interplay is regulated remains poorly understood. Here, we demonstrate that NCoR/SMRT co-repressors bind to pluripotency loci to create a barrier to reprogramming with the four Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC), and consequently, suppressing NCoR/SMRT significantly enhances reprogramming efficiency and kinetics. The core epigenetic subunit of the NCoR/SMRT complex, histone deacetylase 3 (HDAC3), contributes to the effects of NCoR/SMRT by inducing histone deacetylation at pluripotency loci...
March 12, 2018: Nature Cell Biology
Charles J Underwood, Kyuha Choi, Christophe Lambing, Xiaohui Zhao, Heïdi Serra, Filipe Borges, Joe Simorowski, Evan Ernst, Yannick Jacob, Ian R Henderson, Robert A Martienssen
Eukaryotic centromeres contain the kinetochore, which connects chromosomes to the spindle allowing segregation. During meiosis, centromeres are suppressed for inter-homolog crossover, as recombination in these regions can cause chromosome missegregation and aneuploidy. Plant centromeres are surrounded by transposon-dense pericentromeric heterochromatin that is epigenetically silenced by histone 3 lysine 9 dimethylation (H3K9me2), and DNA methylation in CG and non-CG sequence contexts. However, the role of these chromatin modifications in control of meiotic recombination in the pericentromeres is not fully understood...
March 12, 2018: Genome Research
Werner Giehl Glanzner, Vitor Braga Rissi, Mariana Priotto de Macedo, Lady Katerine Serrano Mujica, Karina Gutierrez, Alessandra Bridi, João Ricardo Malheiros de Souza, Paulo Bayard Dias Gonçalves, Vilceu Bordignon
Epigenetic modifications in the C-terminal domain of histones coordinate important events during early development including embryo genome activation (EGA) and cell differentiation. In this study, the mRNA expression profile of the main lysine demethylases (KDMs) acting on the lysine 4 (H3K4), 9 (H3K9) and 27 (H3K27) of the histone H3 was determined at pre-, during and post- EGA stages of bovine and porcine embryos produced by in vitro fertilization (IVF) and somatic cell nuclear transfer (SCNT). In IVF embryos, mRNA abundance of most KDMs revealed a bell-shaped profile with peak expression around the EGA period, i...
March 8, 2018: Biology of Reproduction
S-S Dong, Y-J Zhang, Y-X Chen, S Yao, R-H Hao, Y Rong, H-M Niu, J-B Chen, Y Guo, T-L Yang
We aimed to summarize the results of genetic association studies for obesity and provide a comprehensive annotation of all susceptibility single nucleotide polymorphisms (SNPs). A total of 72 studies were summarized, resulting in 90,361 susceptibility SNPs (738 index SNPs and 89,623 linkage disequilibrium SNPs). Over 90% of the susceptibility SNPs are located in non-coding regions, and it is challenging to understand their functional significance. Therefore, we annotated these SNPs by using various functional databases...
March 12, 2018: Obesity Reviews: An Official Journal of the International Association for the Study of Obesity
Tokihiro Ro, Naoki Nakayama, Hiroyuki Achiwa, Tomoko Ohtsu
Romidepsin (Brand name: ISTODAX® for Injection 10 mg) is a novel antitumor drug that inhibits histone deacetylase (HDAC). Romidepsin strongly inhibited class I HDAC activity in vitro and demonstrated a strong antitumor activity against human tumor cell line xenograft in vivo. Based on its demonstrated efficacy against T-cell lymphoma in early clinical studies, multicenter phase II clinical studies in overseas with romidepsin were conducted in patients with cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), followed by approval for the treatment of CTCL and PTCL in the U...
2018: Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica
Silvia D Visonà, Onno J de Boer, Claire Mackaaij, Hans H de Boer, Kartika R Pertiwi, Ruben W de Winter, Antonio Osculati, Allard C van der Wal
Acute medial dissection of aorta can occur in the context of a sudden and unexpected death. For medico-legal reasons it is important to estimate as accurately the histological age of dissections. We evaluated the additional value of a systematic application of immunohistochemistry, compared with conventional histology only, in determining chronological steps of injury and repair. Thirty two paraffin embedded specimens of aortic dissection were retrospectively allocated to one of four defined stages: acute (I), subacute (II), early organizing (III) and scarring (IV) using Hematoxylin and Eosin and Elastica van Gieson stained sections...
February 10, 2018: Cardiovascular Pathology: the Official Journal of the Society for Cardiovascular Pathology
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