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https://www.readbyqxmd.com/read/29317150/design-synthesis-and-evaluate-of-novel-dual-fgfr1-and-hdac-inhibitors-bearing-an-indazole-scaffold
#1
Jian Liu, Chengbo Qian, Yehua Zhu, Jianguo Cai, Yufang He, Jie Li, Tianlin Wang, Haohao Zhu, Zhi Li, Wei Li, Lihong Hu
Both histone deacetylase (HDAC) and fibroblast growth factor receptor (FGFR) are important targets for cancer therapy. Although combining dual HDAC pharmacophore with tyrosine kinase inhibitors (TKIs) had achieved a successful progress, dual HDAC/FGFR1 inhibitors haven't been reported yet. Herein, we designed a series of hybrids bearing 1H-indazol-3-amine and benzohydroxamic acids scaffold with scaffold hopping and molecular hybridization strategies. Among them, compound 7j showed the most potent inhibitory activity against HDAC6 with IC50 of 34 nM and exhibited the great inhibitory activities against a human breast cancer cell line MCF-7 with IC50 of 9 μM in vitro...
December 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29304284/-n-hydroxycarbonylbenylamino-quinolines-as-selective-histone-deacetylase-6-inhibitors-suppress-growth-of-multiple-myeloma-in-vitro-and-in-vivo
#2
Hsueh-Yun Lee, Kunal Nepali, Fang-I Huang, Chih-Yi Chang, Mei-Jung Lai, Yu-Hsuan Li, Hsiang-Ling Huang, Chia-Ron Yang, Jing-Ping Liou
A series of bicyclic arylamino/heteroarylamino hydroxamic acids (7-31) have been examined as novel histone deacetylase 6 (HDAC6) inhibitors. One compound (13) exhibits remarkable inhibitory activity of HDAC6 with an IC50 value of 0.29 nM, which is 4000-43000 times more selective over other HDAC isoforms. Compound 13 was shown to have antiproliferative activity against human multiple myeloma RPMI 8226, U266, and NCI-H929 cells with no effect on normal bone marrow cells. Compound 13, as a single drug, suppresses the growth of tumors by a %TGI factor of 60...
January 5, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29301535/inhibition-of-histone-deacetylase-activity-rescues-inflammatory-cystic-fibrosis-lung-disease-by-modulating-innate-and-adaptive-immune-responses
#3
Manish Bodas, Steven Mazur, Taehong Min, Neeraj Vij
BACKGROUND: Chronic lung disease resulting from dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) and NFκB-mediated neutrophilic-inflammation forms the basis of CF-related mortality. Here we aimed to evaluate if HDAC inhibition controls Pseudomonas-aeruginosa-lipopolysaccharide (Pa-LPS) induced airway inflammation and CF-lung disease. METHODS: For in vitro experiments, HEK293-cells were transfected with IL-8 or NFκB-firefly luciferase, and SV40-renilla- luciferase reporter constructs or ΔF508-CFTR-pCEP, followed by treatment with suberoylanilide hydroxamic acid (SAHA), Trichostatin-A (TSA) and/or TNFα...
January 4, 2018: Respiratory Research
https://www.readbyqxmd.com/read/29286621/quasi-stem-cells-derived-from-human-somatic-cells-by-chemically-modified-carbon-nanotubes
#4
Jae-Hyeok Lee, Hyuk-Kwon Kwon, Hyeon-Jun Shin, Gwang-Hyeon Nam, Jae-Ho Kim, Sangdun Choi
Surface modification of micro- and nanotopography has been employed to alter the surface properties of scaffolds for controlling cell attachment, proliferation, and differentiation. This study reports a method for generating multinucleated colonies as evidenced by spherical colony formation through nanotopography-induced expression of reprogramming factors in human dermal fibroblasts. Colony formation is achieved by subjecting the cells to specific environments, such as culturing with single-walled carbon nanotubes and poly-L-lysine (PLL-SWCNTs)...
December 29, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/29286587/designing-novel-dual-transglutaminase-2-histone-deacetylase-inhibitors-effective-in-halting-neuronal-death
#5
Manuela Basso, Huan Huan Chen, Debasmita Tripathy, Mariarosaria Conte, Kim Y P Apperley, Angela De Simone, Jeffrey W Keillor, Rajiv Ratan, Angela Nebbioso, Federica Sarno, Lucia Altucci, Andrea Milelli
In recent years there has been a clear consensus that neurodegenerative conditions can be better treated through concurrent modulation of different targets. Herein, we report that combined inhibition of Transglutaminase 2 (TG2) and Histone Deacetylases (HDACs) protects synergistically against toxic stimuli mediated by glutamate. Based on these findings, we designed and synthesized a series of novel dual TG2-HDAC binding agents. Compound 3 emerges as the most interesting of the series being able to inhibit TG2 and HDACs both in vitro (TG2, IC50 = 13...
December 29, 2017: ChemMedChem
https://www.readbyqxmd.com/read/29281743/hdac6-controls-innate-immune-and-autophagy-responses-to-tlr-mediated-signalling-by-the-intracellular-bacteria-listeria-monocytogenes
#6
Olga Moreno-Gonzalo, Marta Ramírez-Huesca, Noelia Blas-Rus, Danay Cibrián, María Laura Saíz, Inmaculada Jorge, Emilio Camafeita, Jesús Vázquez, Francisco Sánchez-Madrid
Recent evidence on HDAC6 function underlines its role as a key protein in the innate immune response to viral infection. However, whether HDAC6 regulates innate immunity during bacterial infection remains unexplored. To assess the role of HDAC6 in the regulation of defence mechanisms against intracellular bacteria, we used the Listeria monocytogenes (Lm) infection model. Our data show that Hdac6-/- bone marrow-derived dendritic cells (BMDCs) have a higher bacterial load than Hdac6+/+ cells, correlating with weaker induction of IFN-related genes, pro-inflammatory cytokines and nitrite production after bacterial infection...
December 27, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29278704/hdac6-interacts-with-ptpn1-to-enhance-melanoma-cells-progression
#7
Jiaqi Liu, Wenjie Luan, Yong Zhang, Jianying Gu, Yuedong Shi, Yanwen Yang, Zihao Feng, Fazhi Qi
Histone deacetylase 6 (HDAC6) plays an important role in oncogenic transformation and cancer metastasis. Our previous study has demonstrated that HDAC6 was highly expressed in melanoma cells, and contributed to the proliferation and metastasis of melanoma cells. However, the underlying mechanism of HDAC6 in melanoma metastasis and progression remains largely unclear. In this study, we reported that HDAC6 directly interacted with Tyrosine-protein phosphatase non-receptor type 1 (PTPN1) by performing co-immunoprecipitation (Co-IP) combined with liquid chromatography tandem mass spectrometry (LC-MS/MS)...
December 23, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29259132/histone-deacetylase-6-hdac6-deacetylates-extracellular-signal-regulated-kinase-1-erk1-and-thereby-stimulates-erk1-activity
#8
Jheng-Yu Wu, Shengyan Xiang, Mu Zhang, Bin Fang, He Huang, Oh Kwang Kwon, Yingming Zhao, Zhe Yang, Wenlong Bai, Gerold Bepler, Xiaohong Mary Zhang
Histone deacetylase 6 (HDAC6), a class IIb HDAC, plays an important role in many biological and pathological processes. Previously, we found that ERK1, a downstream kinase in the MAPK signaling pathway, phosphorylates HDAC6, thereby increasing HDAC6-mediated deacetylation of α-tubulin. However, whether HDAC6 reciprocally modulates ERK1 activity is unknown. Here, we report that both ERK1 and 2 are acetylated and that HDAC6 promotes ERK1 activity via deacetylation. Briefly, we found that both ERK1 and 2 physically interact with HDAC6...
December 19, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29222038/hdac6-inhibition-induces-glioma-stem-cells-differentiation-and-enhances-cellular-radiation-sensitivity-through-the-shh-gli1-signaling-pathway
#9
Wei Yang, Yingying Liu, Ruoling Gao, Hongquan Yu, Ting Sun
The existence of small numbers of stem-like cells, called glioma stem cells (GSCs), in human glioblastoma multiforme (GBM) is responsible for recurrence due to resistance to radiotherapy and chemotherapy. Inhibition of histone deacetylase 6 (HDAC6) enhanced radiosensitivity of cancer cells. However, the effect of inhibiting HDAC6 on stemness and radioresistance of GSCs and its molecular mechanism are largely unknown. In the present study, we found that HDAC6 was upregulated in GSCs comparing to non-stem tumor cells...
December 5, 2017: Cancer Letters
https://www.readbyqxmd.com/read/29203661/unusual-zinc-binding-mode-of-hdac6-selective-hydroxamate-inhibitors
#10
Nicholas J Porter, Adaickapillai Mahendran, Ronald Breslow, David W Christianson
Histone deacetylases (HDACs) regulate myriad cellular processes by catalyzing the hydrolysis of acetyl-l-lysine residues in histone and nonhistone proteins. The Zn2+-dependent class IIb enzyme HDAC6 regulates microtubule function by deacetylating α-tubulin, which suppresses microtubule dynamics and leads to cell cycle arrest and apoptosis. Accordingly, HDAC6 is a target for the development of selective inhibitors that might be useful in new therapeutic approaches for the treatment of cancer, neurodegenerative diseases, and other disorders...
December 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29201907/developmental-testicular-expression-cloning-and-characterization-of-rat-hdac6-in-silico
#11
Pratibha Verma, Omshree Shetty, Sweta Parab, Karen Menezes, Priyanka Parte
We had previously reported presence of histone deacetylase 6 (HDAC6) in sperm and demonstrated its tubulin deacetylase activity and role in sperm motility in rat. In the present study we report its abundant expression in testis, epididymis, accessory sex organs, brain, and adrenal. In the testis, HDAC6 transcript and protein were observed throughout development. We therefore cloned the gene from rat testis using primers for hdac6 (accession number XM_228753.8) in order to determine the role of acetylation/deacetylation in spermatogenesis...
2017: BioMed Research International
https://www.readbyqxmd.com/read/29197621/inhibition-of-histone-deacetylase-6-hdac6-protects-against-vincristine-induced-peripheral-neuropathies-and-inhibits-tumor-growth
#12
Lawrence Van Helleputte, Mandy Kater, Dana P Cook, Caroline Eykens, Elisabeth Rossaert, Wanda Haeck, Tom Jaspers, Natasja Geens, Pieter Vanden Berghe, Conny Gysemans, Chantal Mathieu, Wim Robberecht, Philip Van Damme, Guido Cavaletti, Matthew Jarpe, Ludo Van Den Bosch
As cancer is becoming more and more a chronic disease, a large proportion of patients is confronted with devastating side effects of certain anti-cancer drugs. The most common neurological complications are painful peripheral neuropathies. Chemotherapeutics that interfere with microtubules, including plant-derived vinca-alkaloids such as vincristine, can cause these chemotherapy-induced peripheral neuropathies (CIPN). Available treatments focus on symptom alleviation and pain reduction rather than prevention of the neuropathy...
November 29, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29180246/the-immunohistochemical-expression-and-potential-prognostic-value-of-hdac6-ar-in-invasive-breast-cancer
#13
Congying Li, Lu Cao, Cong Xu, Fang Liu, Guomin Xiang, Xiaozhen Liu, Jiao Jiao, Yun Niu
Previous studies have investigated the role of histone deacetylase 6 (HDAC6) in the regulation of androgen receptor (AR) in prostate cancer; however, the role of HDAC6 has not yet been clearly identified in breast cancer. The aim of this study was to examine the expression of HDAC6 and AR, determine the correlation between HDAC6 and AR, and assess the prognostic value of HDAC6 and AR in breast cancer. A total of 228 cases of invasive breast cancer were randomly selected. The expression of HDAC6 and AR was analyzed by immunohistochemistry...
November 24, 2017: Human Pathology
https://www.readbyqxmd.com/read/29179471/histone-deacetylase-6-inhibition-counteracts-the-epithelial-mesenchymal-transition-of-peritoneal-mesothelial-cells-and-prevents-peritoneal-fibrosis
#14
Liuqing Xu, Na Liu, Hongwei Gu, Hongrui Wang, Yingfeng Shi, Xiaoyan Ma, Shuchen Ma, Jun Ni, Min Tao, Andong Qiu, Shougang Zhuang
The role of histone deacetylase 6 (HDAC6) in peritoneal fibrosis remains unknown. In this study, we examined the effect of HDAC6 inhibition on the epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells and development of peritoneal fibrosis. Treatment with tubastatin A, a highly selective HDAC6 inhibitor, or silencing of HDAC6 with siRNA inhibited transforming growth factor β1-induced EMT, as evidenced by decreased expression of α-smooth muscle actin, collagen I and preserved expression of E-cadherin in cultured human peritoneal mesothelial cells...
October 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/29176689/critical-role-of-the-hdac6-cortactin-axis-in-human-megakaryocyte-maturation-leading-to-a-proplatelet-formation-defect
#15
Kahia Messaoudi, Ashfaq Ali, Rameez Ishaq, Alberta Palazzo, Dominika Sliwa, Olivier Bluteau, Sylvie Souquère, Delphine Muller, Khadija M Diop, Philippe Rameau, Valérie Lapierre, Jean-Pierre Marolleau, Patrick Matthias, Isabelle Godin, Gérard Pierron, Steven G Thomas, Stephen P Watson, Nathalie Droin, William Vainchenker, Isabelle Plo, Hana Raslova, Najet Debili
Thrombocytopenia is a major side effect of a new class of anticancer agents that target histone deacetylase (HDAC). Their mechanism is poorly understood. Here, we show that HDAC6 inhibition and genetic knockdown lead to a strong decrease in human proplatelet formation (PPF). Unexpectedly, HDAC6 inhibition-induced tubulin hyperacetylation has no effect on PPF. The PPF decrease induced by HDAC6 inhibition is related to cortactin (CTTN) hyperacetylation associated with actin disorganization inducing important changes in the distribution of megakaryocyte (MK) organelles...
November 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/29162325/scriptaid-improves-the-reprogramming-of-donor-cells-and-enhances-canine-porcine-interspecies-embryo-development
#16
Jin-Gu No, Tai-Young Hur, Minghui Zhao, Seunghoon Lee, Mi-Kyung Choi, Yoon-Seok Nam, Dong-Hyun Yeom, Gi-Sun Im, Dong-Hoon Kim
Histone methylation, histone acetylation, and DNA methylation are the important factors for somatic cell nuclear transfer (SCNT). Histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) have been used to improve cloning efficiency. In particular, scriptaid, an HDACi, has been shown to improve SCNT efficiency. However, no studies have been performed on canines. Here, we evaluated the effects of scriptaid on histone modification in canine ear fibroblasts (cEFs) and cloned canine embryos derived from cEFs...
November 18, 2017: Reproductive Biology
https://www.readbyqxmd.com/read/29161966/altered-downstream-target-gene-expression-of-the-placental-vitamin-d-receptor-in-human-idiopathic-fetal-growth-restriction
#17
Thy Ph Nguyen, Hannah Ej Yong, Tejasvy Chollangi, Shaun P Brennecke, Susan J Fisher, Euan M Wallace, Peter R Ebeling, Padma Murthi
Fetal growth restriction (FGR) affects up to 5% of pregnancies and is associated with significant perinatal complications. Maternal deficiency of vitamin D, a secosteroid hormone, is common in FGR-affected pregnancies. We recently demonstrated that decreased expression of the vitamin D receptor (VDR) in idiopathic FGR placentae could impair trophoblast growth. As strict regulation of cell-cycle genes in trophoblast cells is critical for optimal feto-placental growth, we hypothesised that pathologically decreased placental VDR contributes to aberrant regulation of cell-cycle genes...
November 22, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29151164/correction-to-hdac6-deacetylates-alpha-tubulin-in-sperm-and-modulates-sperm-motility-in-holtzman-rat
#18
Sweta Parab, Omshree Shetty, Reshma Gaonkar, Nafisa Balasinor, Vrinda Khole, Priyanka Parte
The published online version contains mistake. The chimeric peptide should read as 'DPSVLYVSLHRYGGYMNEGELRV'. It was inadvertently written as 'DPSVLYVSLYVSLHRYGGYMNEGELR' a mistake which we missed during proof reading.
November 18, 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/29150330/the-structural-requirements-of-histone-deacetylase-inhibitors-c4-modified-saha-analogs-display-dual-hdac6-hdac8-selectivity
#19
Ahmed T Negmeldin, Joseph R Knoff, Mary Kay H Pflum
Histone deacetylase (HDAC) enzymes govern the post-translational acetylation state of lysine residues on protein substrates, leading to regulatory changes in cell function. Due to their role in cancers, HDAC proteins have emerged as promising targets for cancer treatment. Four HDAC inhibitors have been approved as anti-cancer therapeutics, including SAHA (Suberoylanilide hydroxamic acid, Vorinostat, Zolinza). SAHA is a nonselective HDAC inhibitor that targets most of the eleven HDAC isoforms. The nonselectivity of SAHA might account for its clinical side effects, but certainly limits its use as a chemical tool to study cancer-related HDAC cell biology...
October 31, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29137331/hdac-inhibitors-enhance-the-immunotherapy-response-of-melanoma-cells
#20
Laurence Booth, Jane L Roberts, Andrew Poklepovic, John Kirkwood, Paul Dent
We focused on the ability of the pan-histone deacetylase (HDAC) inhibitors AR42 and sodium valproate to alter the immunogenicity of melanoma cells. Treatment of melanoma cells with HDAC inhibitors rapidly reduced the expression of multiple HDAC proteins as well as the levels of PD-L1, PD-L2 and ODC, and increased expression of MHCA. In a cell-specific fashion, melanoma isolates released the immunogenic protein HMGB1 into the extracellular environment. Very similar data were obtained in ovarian and H&NSCC PDX isolates, and in established tumor cell lines from the lung and kidney...
October 10, 2017: Oncotarget
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