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https://www.readbyqxmd.com/read/28720877/role-of-the-histone-deacetylase-inhibitor-valproic-acid-in-high-fat-diet-induced-hypertension-via-inhibition-of-hdac1-angiotensin-ii-axis
#1
J Choi, S Y Park, T K Kwon, S-I Sohn, K M Park, J I Kim
BACKGROUND: Obesity is known as an epidemic worldwide because of consumption of westernized high-fat diets and one of the major risk factors of hypertension. Histone deacetylases (HDACs) control gene expression by regulating histone/non-histone protein deacetylation. HDAC inhibitors exert anti-cancer and anti-inflammatory effects and play a protective role in cardiovascular diseases. In the present study, we tested the effect of an FDA-approved pan-HDAC inhibitor valproic acid (VPA) on high-fat diet (HFD)-induced hypertension in mice...
July 19, 2017: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/28720543/involvement-of-the-bh3-only-pro-apoptotic-bik-nbk-in-braf-mek-inhibitor-induced-apoptosis-in-melanoma-cell-lines
#2
Andreas Borst, Sebastian Haferkamp, Johannes Grimm, Manuel Rösch, Guannan Zhu, Sen Guo, Chunying Li, Tianwen Gao, Svenja Meierjohann, David Schrama, Roland Houben
In patients with BRAF-mutated melanoma specific inhibitors of BRAF(V600E) and MEK1/2 frequently induce initial tumor reduction, frequently followed by relapse. As demonstrated previously, BRAF(V600E)-inhibition induces apoptosis only in a fraction of treated cells, while the remaining arrest and survive providing a source or a niche for relapse. To identify factors contributing to the differential initial response towards BRAF/MEK inhibition, we established M14 melanoma cell line-derived single cell clones responding to treatment with BRAF inhibitor vemurafenib and MEK inhibitor trametinib predominantly with either cell cycle arrest (CCA-cells) or apoptosis (A-cells)...
July 15, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28718331/entinostat-for-the-treatment-of-breast-cancer
#3
Dario Trapani, Angela Esposito, Carmen Criscitiello, Luca Mazzarella, Marzia Locatelli, Ida Minchella, Saverio Minucci, Giuseppe Curigliano
Breast cancer accounts for 29% of malignant tumors. It is an heterogenous disease covering a spectrum of different molecular subtypes. Epigenetic aberrations may affect gene expression through DNA and histone proteins modifications thus promoting tumor progression and resistance to anti- tumor treatment. Area covered: This article explores the potential role of entinostat in the treatment of breast cancer. The clinical trials evaluating entinostat are discussed, highlighting preclinical data and early-phase clinical studies results...
July 18, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28716899/hdac1-upregulation-by-nanog-promotes-multidrug-resistance-and-a-stem-like-phenotype-in-immune-edited-tumor-cells
#4
Kwon-Ho Song, Chel Hun Choi, Hyo-Jung Lee, Se Jin Oh, Seon Rang Woo, Soon-Oh Hong, Kyung Hee Noh, Hanbyoul Cho, Eun Joo Chung, Jae-Hoon Kim, Joon-Yong Chung, Stephen M Hewitt, Seungki Baek, Kyung-Mi Lee, Cassian Yee, Minjoo Son, Chih-Ping Mao, T-C Wu, Tae Woo Kim
Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Immunoediting driven by antigen (Ag)-specific T cells enriches NANOG expression in tumor cells, resulting in a stem-like phenotype and immune resistance. Here we identify HDAC1 as a key mediator of the NANOG-associated phenotype. NANOG upregulated HDAC1 through promoter occupancy, thereby decreasing histone H3 acetylation on K14 and K27. NANOG-dependent, HDAC1-driven epigenetic silencing of cell cycle inhibitor CDKN2D and CDKN1B induced stem-like features...
July 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28714868/interval-dosing-with-the-hdac-inhibitor-vorinostat-effectively-reverses-hiv-latency
#5
Nancie M Archin, Jennifer L Kirchherr, Julia Am Sung, Genevieve Clutton, Katherine Sholtis, Yinyan Xu, Brigitte Allard, Erin Stuelke, Angela D Kashuba, Joann D Kuruc, Joseph Eron, Cynthia L Gay, Nilu Goonetilleke, David M Margolis
BACKGROUND: The histone deacetylase (HDAC) inhibitor vorinostat (VOR) can increase HIV RNA expression in vivo within resting CD4+ T cells of aviremic HIV+ individuals. However, while studies of VOR or other HDAC inhibitors have reported reversal of latency, none has demonstrated clearance of latent infection. We sought to identify the optimal dosing of VOR for effective serial reversal of HIV latency. METHODS: In a study of 16 HIV-infected, aviremic individuals, we measured resting CD4+ T cell-associated HIV RNA ex vivo and in vivo following a single exposure to VOR, and then in vivo after a pair of doses separated by 48 or 72 hours, and finally following a series of 10 doses given at 72-hour intervals...
July 17, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28713892/trichostatin%C3%A2-a-induces-bladder-cancer-cell-death-via-intrinsic-apoptosis-at-the-early%C3%A2-phase-and-sp1%C3%A2-survivin-downregulation-at-the-late%C3%A2-phase-of-treatment
#6
Shou-Chieh Wang, Shou-Tsung Wang, Hung-Te Liu, Xiang-Yu Wang, She-Ching Wu, Lei-Chin Chen, Yi-Wen Liu
Histone deacetylase (HDAC) inhibitors have been widely shown to result in cancer cell death. The present study investigated the mechanisms underlying the antitumor effects of the phytochemical trichostatin A (TSA), a classic pan-HDAC inhibitor, in 5,637 urinary bladder cancer cells. It was found that TSA caused cell cycle arrest at the G2/M and G1 phase accompanied by reduced expression of cyclin D1 and upregulated induction of p21. In addition, TSA induced morphological changes, reduced cell viability and apoptotic cell death in 5,637 cells through caspase-3 activation followed by PARP cleavage...
July 6, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28712747/selectivity-and-kinetic-requirements-of-hdac-inhibitors-as-progranulin-enhancers-for-treating-frontotemporal-dementia
#7
Angela She, Iren Kurtser, Surya A Reis, Krista Hennig, Jenny Lai, Audrey Lang, Wen-Ning Zhao, Ralph Mazitschek, Bradford C Dickerson, Joachim Herz, Stephen J Haggarty
Frontotemporal dementia (FTD) arises from neurodegeneration in the frontal, insular, and anterior temporal lobes. Autosomal dominant causes of FTD include heterozygous mutations in the GRN gene causing haploinsufficiency of progranulin (PGRN) protein. Recently, histone deacetylase (HDAC) inhibitors have been identified as enhancers of PGRN expression, although the mechanisms through which GRN is epigenetically regulated remain poorly understood. Using a chemogenomic toolkit, including optoepigenetic probes, we show that inhibition of class I HDACs is sufficient to upregulate PGRN in human neurons, and only inhibitors with apparent fast binding to their target HDAC complexes are capable of enhancing PGRN expression...
July 11, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28708596/hdac6-inhibitor-wt161-downregulates-growth-factor-receptors-in-breast-cancer
#8
Teru Hideshima, Ralph Mazitschek, Jun Qi, Naoya Mimura, Jen-Chieh Tseng, Andrew L Kung, James E Bradner, Kenneth C Anderson
We have shown that WT-161, a histone deacetylase 6 (HDAC6) inhibitor, shows remarkable anti-tumor activity in multiple myeloma (MM) in preclinical models. However, its activity in other type of cancers has not yet been shown. In this study, we further evaluated the biologic sequelae of WT161 in breast cancer cell lines. WT161 triggers apoptotic cell death in MCF7, T47D, BT474, and MDA-MB231 cells, associated with decreased expression of EGFR, HER2, and ERα and downstream signaling. However, HDAC6 knockdown shows that cytotoxicity and destabilization of these receptors triggered by WT161 are not dependent on HDAC6 inhibition...
July 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28706131/structure-based-design-synthesis-and-activity-studies-of-small-hybrid-molecules-as-hdac-and-g9a-dual-inhibitors
#9
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...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28705738/identification-of-novel-potential-scaffold-for-class-i-hdacs-inhibition-an-in-silico-protocol-based-on-virtual-screening-molecular-dynamics-mathematical-analysis-and-machine-learning
#10
Cong Fan, Yanxin Huang
Histone deacetylases (HDACs) family has been widely reported as an important class of enzyme targets for cancer therapy. Much effort has been made in discovery of novel scaffolds for HDACs inhibition besides existing hydroxamic acids, cyclic peptides, benzamides, and short-chain fatty acids. Herein we set up an in-silico protocol which not only could detect potential Zn(2+) chelation bonds but also still adopted non-bonded model to be effective in discovery of Class I HDACs inhibitors, with little human's subjective visual judgment involved...
July 10, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28702178/the-development-prospection-of-hdac-inhibitors-as-a-potential-therapeutic-direction-in-alzheimer-s-disease
#11
REVIEW
Shuang-Shuang Yang, Rui Zhang, Gang Wang, Yong-Fang Zhang
Alzheimer's disease (AD) is a chronic neurodegenerative disease, which is associated with learning and memory impairment in the elderly. Recent studies have found that treating AD in the way of chromatin remodeling via histone acetylation is a promising therapeutic regimen. In a number of recent studies, inhibitors of histone deacetylase (HDACs) have been found to be a novel promising therapeutic agents for neurological disorders, particularly for AD and other neurodegenerative diseases. Although HDAC inhibitors have the ability to ameliorate cognitive impairment, successful treatments in the classic AD animal model are rarely translated into clinical trials...
2017: Translational Neurodegeneration
https://www.readbyqxmd.com/read/28701956/administration-of-a-histone-deacetylase-inhibitor-into-the-basolateral-amygdala-enhances-memory-consolidation-delays-extinction-and-increases-hippocampal-bdnf-levels
#12
Fernanda E Valiati, Mailton Vasconcelos, Martina Lichtenfels, Fernanda S Petry, Rosa M M de Almeida, Gilberto Schwartsmann, Nadja Schröder, Caroline B de Farias, Rafael Roesler
Gene expression related to the formation and modification of memories is regulated epigenetically by chromatin remodeling through histone acetylation. Memory formation and extinction can be enhanced by treatment with inhibitors of histone deacetylases (HDACs). The basolateral amygdala (BLA) is a brain area critically involved in regulating memory for inhibitory avoidance (IA). However, previous studies have not examined the effects of HDAC inhibition in the amygdala on memory for IA. Here we show that infusion of an HDAC inhibitor (HDACi), trichostatin A (TSA), into the BLA, enhanced consolidation of IA memory in rats when given at 1...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28697338/hdac-inhibitors-finally-open-up-chromatin-accessibility-signatures-of-ctcl
#13
Christopher J Ott, Catherine J Wu
In this issue of Cancer Cell, Qu et al. describe the chromatin accessibility profiles of cutaneous T cell lymphoma, with dynamic assessments of response and resistance to histone deacetylase inhibitor therapy. Their "personal regulome" analysis framework reveals chromatin features that may be predictive of clinical response to epigenetic therapy.
July 10, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28693431/the-attenuation-of-renal-fibrosis-by-histone-deacetylase-inhibitors-is-associated-with-the-plasticity-of-foxp3-il-17-t-cells
#14
Wen-Pyng Wu, Yi-Giien Tsai, Tze-Yi Lin, Ming-Ju Wu, Ching-Yuang Lin
BACKGROUND: The histone deacetylase (HDAC) inhibitor, which has potential effects on epigenetic modifications, had been reported to attenuate renal fibrosis. CD4(+) forkhead box P3 (FOXP3)(+) T regulatory (Treg) cells may be converted to inflammation-associated T helper 17 cells (Th17) with tissue fibrosis properties. The association between FOXP3(+)IL-17(+) T cells and the attenuation of renal fibrosis by the HDAC inhibitor is not clear. METHODS: This study evaluated the roles of the HDAC inhibitor, Treg cells and their differentiation into Th17 cells, which aggravate chronic inflammation and renal fibrosis in a unilateral ureteral obstruction (UUO) mouse model...
July 10, 2017: BMC Nephrology
https://www.readbyqxmd.com/read/28690313/the-hdac-inhibitor-panobinostat-lbh589-exerts-in-vivo-anti-leukaemic-activity-against-mll-rearranged-acute-lymphoblastic-leukaemia-and-involves-the-rnf20-rnf40-wac-h2b-ubiquitination-axis
#15
P G Castro, E H J van Roon, S S M Pinhanços, L Trentin, P Schneider, M Kerstjens, G Te Kronnie, O Heidenreich, R Pieters, R W Stam
MLL-rearranged acute lymphoblastic leukaemia (ALL) represents an aggressive malignancy in infants (<1 year of age), associated with poor outcome. Current treatment intensification is not further possible, and novel therapy strategies are needed. Notably, MLL-rearranged ALL is characterised by a strongly deregulated epigenome and shows sensitivity to epigenetic perturbators. Here, we demonstrate the in vivo efficacy of the histone deacetylase inhibitor Panobinostat (LHB589) using xenograft mouse models of MLL-rearranged ALL...
July 10, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28687272/interstrand-crosslink-repair-as-a-target-for-hdac-inhibition
#16
REVIEW
Teodora Nikolova, Nicole Kiweler, Oliver H Krämer
DNA interstrand crosslinks (ICLs) covalently connect complementary DNA strands. Consequently, DNA replication and transcription are hampered, DNA damage responses (DDR) are initiated, and cell death is triggered. Therefore, drugs inducing ICLs are effective against rapidly growing cancer cells. However, tumors engage a complicated enzymatic machinery to repair and survive ICLs. Several factors, including the post-translational acetylation/deacetylation of lysine residues within proteins, control this network...
July 4, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28686912/antiproliferative-and-apoptotic-activities-of-sequence-specific-histone-acetyltransferase-inhibitors
#17
Zutao Yu, Junichi Taniguchi, Yulei Wei, Ganesh N Pandian, Kaori Hashiya, Toshikazu Bando, Hiroshi Sugiyama
In parallel to monomeric epigenetic regulators, sequence-specific epigenetic regulators represent versatile synthetic dual-target ligands that achieve regulatory control over multi-gene networks. Development of DNA-binding domain (DBD)-HDAC inhibitors and DBD-HAT activators, which result in increased histone acetylation, has become one promising research field. However, there is no report regarding the gene regulatory pattern by sequence-specific epigenetic repressor. We report here for the first time, the synthesis of DBD-HAT inhibitors and demonstrate that these conjugates could retain their dual-target activity using predicted working model of thermal stability assay and in vitro HAT activity assay...
June 23, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28685689/arylurea-derivatives-a-class-of-potential-cancer-targeting-agents
#18
Jia-Nian Chen, De-Wen Wu, Ting Li, Kang-Jian Yang, Li Cheng, Zu-Ping Zhou, Shi-Ming Pu, Wan-Hua Lin
Arylurea derivatives, an important class of small molecules, have received considerable attention in recent years due to their wide range of biological applications. Various molecular targeted agents with arylurea scaffold as potential enzyme/receptor inhibitors were constructed with the successful development of sorafenib and regorafenib. This review focuses on those arylureas possessing anti-cancer activities from 2010 to date. According to their different mechanisms of action, these arylureas are divided into the following six categories: (1) Ras/Raf/MEK/ERK signaling pathway inhibitors; (2) tumor angiogenesis inhibitors, their targets include vascular endothelial growth factor receptors (VEGFRs), fibroblast growth factor receptors (FGFRs), platelet-derived growth factor receptors (PDGFRs), epidermal growth factor receptors (EGFRs), insulin-like growth factor 1 receptor (IGF-1R), Fms-like tyrosine kinase 3 (FLT3), c-Kit, MET, and Smoothened (Smo); (3) PI3K/AKT/mTOR signaling pathway inhibitors; (4) cell cycle inhibitors, their targets include checkpoint kinases (Chks), cyclin-dependent kinases (CDKs), Aurora, SUMO activating enzyme 1 (SUMO E1), tubulin, and DNA; (5) tumor differentiation, migration, and invasion inhibitors, their targets include matrix metalloproteinases (MMPs), LIM kinase (Limk), nicotinamide phosphoribosyltransferase (Nampt), and histone deacetylase (HDAC); (6) arylureas from the rational modification of natural products...
July 7, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28682229/-epigenetic-mechanisms-and-alcohol-use-disorders-a-potential-therapeutic-target
#19
Rémi Legastelois, Jérôme Jeanblanc, Catherine Vilpoux, Erika Bourguet, Mickael Naassila
Alcohol use disorder is a devastating illness with a profound health impact, and its development is dependent on both genetic and environmental factors. This disease occurs over time and requires changes in brain gene expression. There is converging evidence suggesting that the epigenetic processes may play a role in the alcohol-induced gene regulations and behavior such as the intervention of DNA methylation and histone acetylation. Histone acetylation, like histone methylation, is a highly dynamic process regulated by two classes of enzymes: histone acetyltransferases and histone deacetylases (HDACs)...
2017: Biologie Aujourd'hui
https://www.readbyqxmd.com/read/28677817/inhibition-of-the-hdac-suv39-g9a-pathway-restores-the-expression-of-dna-damage-dependent-major-histocompatibility-complex-class%C3%A2-i-related-chain%C3%A2-a%C3%A2-and%C3%A2-b-in-cancer-cells
#20
Nakako Izumi Nakajima, Atsuko Niimi, Mayu Isono, Takahiro Oike, Hiro Sato, Takashi Nakano, Atsushi Shibata
Immunotherapy is expected to be promising as a next generation cancer therapy. Immunoreceptors are often activated constitutively in cancer cells, however, such levels of ligand expression are not effectively recognized by the native immune system due to tumor microenvironmental adaptation. Studies have demonstrated that natural-killer group 2, member D (NKG2D), a major activating immunoreceptor, responds to DNA damage. The upregulation of major histocompatibility complex class I-related chain A and B (MICA/B) (members of NKG2D ligands) expression after DNA damage is associated with NK cell-mediated killing of cancer cells...
June 30, 2017: Oncology Reports
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