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https://www.readbyqxmd.com/read/28097234/kruppel-like-factor4-regulates-prdm1-expression-through-binding-to-an-autoimmune-risk-allele
#1
Su Hwa Jang, Helen Chen, Peter K Gregersen, Betty Diamond, Sun Jung Kim
A SNP identified as rs548234, which is found in PRDM1, the gene that encodes BLIMP1, is a risk allele associated with systemic lupus erythematosus (SLE). BLIMP1 expression was reported to be decreased in women with the PRDM1 rs548234 risk allele compared with women with the nonrisk allele in monocyte-derived DCs (MO-DCs). In this study, we demonstrate that BLIMP1 expression is regulated by the binding of Kruppel-like factor 4 (KLF4) to the risk SNP. KLF4 is highly expressed in MO-DCs but undetectable in B cells, consistent with the lack of altered expression of BLIMP1 in B cells from risk SNP carriers...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28092474/novel-histone-deacetylase-6-hdac6-selective-inhibitors-a-patent-evaluation-wo2014181137
#2
Claudia A Simões-Pires, Philippe Bertrand, Muriel Cuendet
The invention described in this patent (WO2014181137) is related to hydroxamic acid derivatives with inhibitory activity towards histone deacetylases (HDACs), their synthetic process and pharmaceutical formulations, as well as a method for treating patients suffering from a list of selected tumoral, inflammatory, cardiac and chronic disorders. HDACs are known to deacetylate histones and other proteins, which makes HDAC inhibitors able to affect cell survival, cell signaling, transport, and gene expression. Those effects have been associated to the therapeutic success of HDAC inhibitors...
January 16, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28078999/hdacs-and-hdac-inhibitors-in-urothelial-carcinoma-perspectives-for-an-antineoplastic-treatment
#3
Maria Pinkerneil, Michèle J Hoffmann, Wolfgang A Schulz, Günter Niegisch
Histone deacetylases (HDACs) influence diverse cellular processes and may contribute to tumor development and progression by multiple mechanisms. Class I HDACs are often overexpressed in cancers contributing to a genome-wide epigenetic state permitting increased proliferation, and diminished apoptosis and cell differentiation. Class IIA and IIB isoenzymes may likewise contribute to tumorigenesis as components of specific intranuclear repressor complexes or regulators of posttranslational protein modifications...
January 11, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28076695/deacetylase-inhibitors-an-advance-in-myeloma-therapy
#4
Jacob P Laubach, Jesus F San-Miguel, Vania Hungria, Jian Hou, Philippe Moreau, Sagar Lonial, Jae Hoon Lee, Hermann Einsele, Melissa Alsina, Paul G Richardson
A significant unmet need exists in patients with relapsed or refractory multiple myeloma (MM), which remains an incurable disease despite recent advances in the field. One such development was the use of deacetylase inhibitors (DACi), which exert unique antimyeloma effects through targeting of epigenetic and protein metabolism pathways. The pan-DACi panobinostat was recently approved in combination with bortezomib and dexamethasone for use in patients with relapsed or relapsed and refractory MM. Results of a phase 3 trial showed that the panobinostat-containing regimen improved the overall response rate and progression-free survival...
January 11, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28053023/ricolinostat-the-first-selective-histone-deacetylase-6-inhibitor-in-combination-with-bortezomib-and-dexamethasone-for-relapsed-or-refractory-multiple-myeloma
#5
Dan T Vogl, Noopur S Raje, Sundar Jagannath, Paul G Richardson, Parameswaran Hari, Robert Z Orlowski, Jeffrey G Supko, David Tamang, Min Yang, Simon S Jones, Catherine Wheeler, Robert J Markelewicz, Sagar Lonial
PURPOSE: Histone deacetylase (HDAC) inhibition improves the efficacy of proteasome inhibition for multiple myeloma but adds substantial toxicity. Preclinical models suggest that the observed synergy is due to the role of HDAC6 in mediating resistance to proteasome inhibition via the aggresome/autophagy pathway of protein degradation. EXPERIMENTAL DESIGN: We conducted a phase 1/2 trial of the HDAC6-selective inhibitor ricolinostat to define the safety, preliminary efficacy, and recommended phase 2 dose in combination with standard proteasome inhibitor therapy...
January 4, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28052874/inhibition-of-hdac6-protects-against-rhabdomyolysis-induced-acute-kidney-injury
#6
Shi Yingfeng, Xu Liuqing, Tang Jinhua, Fang Lu, Ma Shuchen, Ma Xiaoyan, Nie Jing, Pi Xiaoling, Qiu Andong, Zhuang Shougang, Liu Na
Histone deacetylase 6 (HDAC6) inhibition has been reported to protect against ischemic stroke and prolong survival after sepsis in animal models. However, it remains unknown whether HDAC6 inhibition offers a renoprotective effect after acute kidney injury (AKI). In this study, we examined the therapeutic effect of tubastatin A (TA), a highly selective inhibitor of HDAC6, on AKI in a murine model of glycerol (GL) injection-induced rhabdomyolysis. Following GL injection, the mice developed severe acute tubular injury as indicated by renal dysfunction, expression of neutrophil gelatinase-associated lipocalin (NGAL), an injury marker of renal tubules and increase of TUNEL positive tubular cells...
January 4, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28052127/overexpression-of-histone-deacetylase-6-enhances-resistance-to-porcine-reproductive-and-respiratory-syndrome-virus-in-pigs
#7
Tianyu Lu, Zhiyuan Song, Qiuyan Li, Zhiguo Li, Meng Wang, Lin Liu, Kegong Tian, Ning Li
Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically relevant viral pathogens in pigs and causes substantial losses in the pig industry worldwide each year. At present, PRRSV vaccines do not effectively prevent and control this disease. Consequently, it is necessary to develop new antiviral strategies to compensate for the inefficacy of the available vaccines. Histone deacetylase 6 (HDAC6) is an important member of the histone deacetylase family that is responsible for regulating many important biological processes...
2017: PloS One
https://www.readbyqxmd.com/read/28044941/design-synthesis-and-biological-evaluation-of-a-phenyl-butyric-acid-derivative-n-4-chlorophenyl-4-phenylbutanamide-a-hdac6-inhibitor-with-anti-proliferative-activity-on-cervix-cancer-and-leukemia-cells
#8
Rodríguez-Fonseca Rolando Alberto, Sixto-López Yudibeth, Fragoso-Vázquez M Jonathan, Flores-Mejía Raúl, Cabrera-Pérez Laura Cristina, Vázquez-Moctezuma Ismael, Rosales-Hernández Martha Cecilia, Bello Martiniano, M Martínez-Archundia, Trujillo-Ferrara José Guadalupe, Becerra-Martínez Elvia, Correa-Basurto José
The epigenetic regulation of genes in cancer could be targeted by inhibiting Histone deacetylase 6 (HDAC6), an enzyme involved in several types of cancer such as lymphoma, leukemia, ovarian cancer, etc. Through in silico methods, a set of Phenyl butyric acid derivatives with possible HDAC6 inhibitory activity were designed, rendering monophenylamides and biphenylamides using tubacin (HDAC6 selective inhibitor) as reference. The target compounds were submitted to theoretical ADMET analyses and their binding properties on different HDAC6 conformers were evaluated through docking calculations...
January 2, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28038324/ring-opened-tetrahydro-%C3%AE-carbolines-display-cytotoxicity-and-selectivity-with-histone-deacetylase-isoforms
#9
Kunal Nepali, Hsueh-Yun Lee, Mei-Jung Lai, Ritu Ojha, Tung-Yun Wu, Gu-Xian Wu, Mei-Chuan Chen, Jing-Ping Liou
This study is focused on modification of the indole moiety and the N1-zinc binding domain of tubastatin A, and the effects of such changes on biological activity. Fourteen N-substituted indoles (5-18) were synthesized and structure-activity relationship studies indicated that the change of the tetrahydro-γ-carboline in tubastatin A led to substituted indoles (compounds 7, 11, and 15) which showed significant improvements of selective inhibition for HDAC6 over HDAC1 and HDAC2 in comparison to ACY1215, a compound undergoing clinical trials...
December 21, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28035401/acy-1215-accelerates-vemurafenib-induced-cell-death-of-braf-mutant-melanoma-cells-via-induction-of-er-stress-and-inhibition-of-erk-activation
#10
Ueihuei Peng, Zhihao Wang, Sa Pei, Yunchao Ou, Pengchao Hu, Wanhong Liu, Jiquan Song
BRAFV600E mutation is found in ~50% of melanoma patients and BRAFV600E kinase activity inhibitor, vemurafenib, has achieved a remarkable clinical response rate. However, most patients treated with vemurafenib eventually develop resistance. Overcoming primary and secondary resistance to selective BRAF inhibitors remains one of the most critically compelling challenges for these patients. HDAC6 has been shown to confer resistance to chemotherapy in several types of cancer. Few studies focused on the role of HDAC6 in vemurafenib resistance...
February 2017: Oncology Reports
https://www.readbyqxmd.com/read/27997532/phosphatidylserine-ameliorates-neurodegenerative-symptoms-and-enhances-axonal-transport-in-a-mouse-model-of-familial-dysautonomia
#11
Shiran Naftelberg, Ziv Abramovitch, Shani Gluska, Sivan Yannai, Yuvraj Joshi, Maya Donyo, Keren Ben-Yaakov, Tal Gradus, Jonathan Zonszain, Chen Farhy, Ruth Ashery-Padan, Eran Perlson, Gil Ast
Familial Dysautonomia (FD) is a neurodegenerative disease in which aberrant tissue-specific splicing of IKBKAP exon 20 leads to reduction of IKAP protein levels in neuronal tissues. Here we generated a conditional knockout (CKO) mouse in which exon 20 of IKBKAP is deleted in the nervous system. The CKO FD mice exhibit developmental delays, sensory abnormalities, and less organized dorsal root ganglia (DRGs) with attenuated axons compared to wild-type mice. Furthermore, the CKO FD DRGs show elevated HDAC6 levels, reduced acetylated α-tubulin, unstable microtubules, and impairment of axonal retrograde transport of nerve growth factor (NGF)...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27993968/mechanisms-of-acquired-drug-resistance-to-the-hdac6-selective-inhibitor-ricolinostat-reveals-rational-drug-drug-combination-with-ibrutinib
#12
Jennifer E Amengual, Sathyen A Prabhu, Maximilian Lombardo, Kelly M Zullo, Paul M Johannet, Yulissa Gonzalez, Luigi Scotto, Xavier Jirau-Serrano, Ying Wei, Jimmy K Duong, Renu Nandakumar, Serge Cremers, Akanksha Verma, Olivier Elemento, Owen A O'Connor
PURPOSE: Pan-class I/II histone deacetylase (HDAC) inhibitors are effective treatments for select lymphomas. Isoform-selective HDAC inhibitors are emerging as potentially more targeted agents. ACY-1215 (ricolinostat) is a first in class selective HDAC6 inhibitor. To better understand the discrete function of HDAC6 and its role in lymphoma, we developed a lymphoma cell line resistant to ACY-1215. EXPERIMENTAL DESIGN: The diffuse large B-cell lymphoma cell line OCI-Ly10 was exposed to increasing concentrations of ACY-1215 over an extended period of time, leading to the development of a resistant cell line...
December 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27959772/cellular-defense-or-viral-assist-the-dilemma-of-hdac6
#13
Kai Zheng, Yingchun Jiang, Zhendan He, Kaio Kitazato, Yifei Wang
AbstractHistone deacetylase 6 (HDAC6) is an unique cytoplasmic deacetylase that regulates various important biological processes via preventing protein aggregation and deacetylating different non-histone substrates including tubulin, heat shock protein 90 (Hsp90), cortactin, retinoic acid inducible gene I (RIG-1) and β-catenin. Growing evidences have indicated a dual role for HDAC6 in viral infection and pathogenesis: HDAC6 may represent a host defense mechanism against viral infection through modulating microtubule, triggering antiviral immune response and stimulating protective autophagy, or it may be hijacked by the virus to enhance proinflammatory response...
December 12, 2016: Journal of General Virology
https://www.readbyqxmd.com/read/27957719/development-of-improved-hdac6-inhibitors-as-pharmacological-therapy-for-axonal-charcot-marie-tooth-disease
#14
Veronick Benoy, Pieter Vanden Berghe, Matthew Jarpe, Philip Van Damme, Wim Robberecht, Ludo Van Den Bosch
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy, with an estimated prevalence of 1 in 2500. The degeneration of motor and sensory nerve axons leads to motor and sensory symptoms that progress over time and have an important impact on the daily life of these patients. Currently, there is no curative treatment available. Recently, we identified histone deacetylase 6 (HDAC6), which deacetylates α-tubulin, as a potential therapeutic target in axonal CMT (CMT2). Pharmacological inhibition of the deacetylating function of HDAC6 reversed the motor and sensory deficits in a mouse model for mutant "small heat shock protein B1" (HSPB1)-induced CMT2 at the behavioral and electrophysiological level...
December 12, 2016: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
https://www.readbyqxmd.com/read/27926524/selective-hdac-inhibition-by-acy-241-enhances-the-activity-of-paclitaxel-in-solid-tumor-models
#15
Pengyu Huang, Ingrid Almeciga-Pinto, Matthew Jarpe, John H van Duzer, Ralph Mazitschek, Min Yang, Simon S Jones, Steven N Quayle
ACY-241 is a novel, orally available and selective histone deacetylase (HDAC) 6 inhibitor in Phase 1b clinical development in multiple myeloma (NCT 02400242). Like the structurally related drug ACY-1215 (ricolinostat), ACY-241 has the potential for a substantially reduced side effect profile versus current nonselective HDAC inhibitor drug candidates due to reduced potency against Class I HDACs while retaining the potential for anticancer effectiveness. We now show that combination treatment of xenograft models with paclitaxel and either ricolinostat or ACY-241 significantly suppresses solid tumor growth...
December 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27921344/uhplc-ms-based-hdac-assay-applied-to-bio-guided-microfractionation-of-fungal-extracts
#16
Vincent Zwick, Pierre-Marie Allard, Lucie Ory, Claudia A Simões-Pires, Laurence Marcourt, Katia Gindro, Jean-Luc Wolfender, Muriel Cuendet
INTRODUCTION: Histone deacetylases (HDAC) are considered as promising targets for cancer treatment. Today, four HDAC inhibitors, vorinostat, romidepsin, belinostat, and panobinostat, have been approved by the Food and Drug Administration (FDA) for cancer treatment, while others are in clinical trials. Among them, several are naturally occurring fungal metabolites. OBJECTIVE: To develop and optimise an enzyme assay for bio-guided identification of HDAC inhibitors in fungal strains...
December 5, 2016: Phytochemical Analysis: PCA
https://www.readbyqxmd.com/read/27902771/piceatannol-attenuates-renal-fibrosis-induced-by-unilateral-ureteral-obstruction-via-downregulation-of-histone-deacetylase-4-5-or-p38-mapk-signaling
#17
Sin Young Choi, Zhe Hao Piao, Li Jin, Jung Ha Kim, Gwi Ran Kim, Yuhee Ryu, Ming Quan Lin, Hyung-Seok Kim, Hae Jin Kee, Myung Ho Jeong
Piceatannol, a resveratrol metabolite, is a phenolic compound found in red wine and grapes. We investigated the effect of piceatannol on renal fibrosis and histone deacetylase (HDAC) expression in a mouse model of unilateral ureteral obstruction (UUO). Fibrosis was established by UUO and piceatannol was intraperitoneally injected for 2 weeks. Piceatannol suppressed extracellular matrix (ECM) protein deposition including collagen type I and fibronectin as well as connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA) in UUO kidneys...
2016: PloS One
https://www.readbyqxmd.com/read/27901049/glucocorticoid-receptor-and-histone-deacetylase-6-mediate-the-differential-effect-of-dexamethasone-during-osteogenesis-of-mesenchymal-stromal-cells-mscs
#18
Marilyn G Rimando, Hao-Hsiang Wu, Yu-An Liu, Chien-Wei Lee, Shu-Wen Kuo, Yin-Ping Lo, Kuo-Fung Tseng, Yi-Shiuan Liu, Oscar Kuang-Sheng Lee
Lineage commitment and differentiation of mesenchymal stromal cells (MSCs) into osteoblasts in vitro is enhanced by a potent synthetic form of glucocorticoid (GC), dexamethasone (Dex). Paradoxically, when used chronically in patients, GCs exert negative effects on bone, a phenomenon known as glucocorticoid-induced osteoporosis in clinical practice. The mechanism on how GC differentially affects bone precursor cells to become mature osteoblasts during osteogenesis remains elusive. In this study, the dose and temporal regulation of Dex on MSC differentiation into osteoblasts were investigated...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27900262/impaired-histone-deacetylases-5-and-6-expression-mimics-the-effects-of-obesity-and-hypoxia-on-adipocyte-function
#19
Julien Bricambert, Dimitri Favre, Saška Brajkovic, Amélie Bonnefond, Raphael Boutry, Roberto Salvi, Valérie Plaisance, Mohamed Chikri, Giulia Chinetti-Gbaguidi, Bart Staels, Vittorio Giusti, Robert Caiazzo, François Pattou, Gérard Waeber, Philippe Froguel, Amar Abderrahmani
OBJECTIVE: The goal of the study was to investigate the role of histone deacetylases (HDACs) in adipocyte function associated with obesity and hypoxia. METHODS: Total proteins and RNA were prepared from human visceral adipose tissues (VAT) of human obese and normal weight subjects and from white adipose tissue (WAT) of C57Bl6-Rj mice fed a normal or high fat diet (HFD) for 16 weeks. HDAC activity was measured by colorimetric assay whereas the gene and protein expression were monitored by real-time PCR and by western blotting, respectively...
December 2016: Molecular Metabolism
https://www.readbyqxmd.com/read/27886544/3-aroylindoles-display-antitumor-activity-in%C3%A2-vitro-and-in%C3%A2-vivo-effects-of-n1-substituents-on-biological-activity
#20
Hsueh-Yun Lee, Jiann-Fong Lee, Sunil Kumar, Yi-Wen Wu, Wei-Chun HuangFu, Mei-Jung Lai, Yu-Hsuan Li, Hsiang-Ling Huang, Fei-Chiao Kuo, Che-Jen Hsiao, Chun-Chun Cheng, Chia-Ron Yang, Jing-Ping Liou
A series of 3-aroylindole hydroxamic acids (10-17) were developed based on the concept of a structural combination of tubulin and histone deacetylase (HDAC) inhibitors. This was accomplished by introducing hydroxamic acid-containing moieties at the N1 position of the tubulin assembly inhibitor, compound 9 (SCB01A, BPR0L075, phase II trial). Most of synthetic compounds produced in this way displayed comparable HDAC inhibitory activity, and four (10, 12-14) of them also inhibit tubulin assembly. Notably, compound 12 possesses not only tubulin and HDAC inhibitory activity but also shows HDAC6 selectivity over other HDAC isoforms...
January 5, 2017: European Journal of Medicinal Chemistry
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