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https://www.readbyqxmd.com/read/28333449/epigenetic-modulation-of-endophytic-eupenicillium-sp-lg41-by-a-histone-deacetylase-inhibitor-for-production-of-decalin-containing-compounds
#1
Gang Li, Souvik Kusari, Christopher Golz, Hartmut Laatsch, Carsten Strohmann, Michael Spiteller
An endophytic fungus, Eupenicillium sp. LG41, isolated from the Chinese medicinal plant Xanthium sibiricum, was subjected to epigenetic modulation using an NAD(+)-dependent histone deacetylase (HDAC) inhibitor, nicotinamide. Epigenetic stimulation of the endophyte led to enhanced production of two new decalin-containing compounds, eupenicinicols C and D (3 and 4), along with two biosynthetically related known compounds, eujavanicol A (1) and eupenicinicol A (2). The structures and stereochemistry of the new compounds were elucidated by extensive spectroscopic analysis using LC-HRMS, NMR, optical rotation, and ECD calculations, as well as single-crystal X-ray diffraction...
March 23, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/28332716/mir-124-and-mir-9-mediated-downregulation-of-hdac5-promotes-neurite-development-through-activating-mef2c-gpm6a-pathway
#2
Xi Gu, Congcong Fu, Lifang Lin, Shuhu Liu, Xiaohong Su, Aili Li, Qiaoqi Wu, Chunhong Jia, Peidong Zhang, Lu Chen, Xinhong Zhu, Xuemin Wang
The class IIa histone deacetylases (HDACs) play important roles in the central nervous system during diverse biological processes such as synaptic plasticity, axon regeneration, cell apoptosis, and neural differentiation. Although it is known that HDAC5 regulates neuronal differentiation, neither the physiological function nor the regulation of HDAC5 in neuronal differentiation is clear. Here, we identify HDAC5 as an inhibitor of neurite elongation and show that HDAC5 is regulated by the brain enriched microRNA miR-124 and miR-9...
March 23, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28332438/quantitative-structure-activity-relationship-analysis-and-virtual-screening-studies-for-identifying-hdac2-inhibitors-from-known-hdac-bioactive-chemical-libraries
#3
H Pham-The, G Casañola-Martin, K Diéguez-Santana, N Nguyen-Hai, N T Ngoc, L Vu-Duc, H Le-Thi-Thu
Histone deacetylases (HDAC) are emerging as promising targets in cancer, neuronal diseases and immune disorders. Computational modelling approaches have been widely applied for the virtual screening and rational design of novel HDAC inhibitors. In this study, different machine learning (ML) techniques were applied for the development of models that accurately discriminate HDAC2 inhibitors form non-inhibitors. The obtained models showed encouraging results, with the global accuracy in the external set ranging from 0...
March 2017: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/28331226/the-histone-deacetylase-inhibitor-givinostat-itf2357-exhibits-potent-anti-tumor-activity-against-crlf2-rearranged-bcp-all
#4
A M Savino, J Sarno, L Trentin, M Vieri, G Fazio, M Bardini, C Bugarin, G Fossati, K Davis, G Gaipa, S Izraeli, L H Meyer, G P Nolan, A Biondi, G Te Kronnie, C Palmi, G Cazzaniga
Leukemias bearing CRLF2 and JAK2 gene alterations are characterized by aberrant JAK/STAT signaling and poor prognosis. The HDAC inhibitor givinostat/ITF2357 has been shown to exert antineoplastic activity against both systemic juvenile idiopathic arthritis and myeloproliferative neoplasms through inhibition of the JAK/STAT pathway. These findings led us to hypothesize that givinostat might also act against CRLF2-rearranged BCP-ALL, which lack effective therapies. Here, we found that givinostat inhibited proliferation and induced apoptosis of BCP-ALL CRLF2-rearranged cell lines, positive for exon 16 JAK2 mutations...
March 23, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28326839/entinostat-a-promising-treatment-option-for-patients-with-advanced-breast-cancer
#5
Roisin M Connolly, Michelle A Rudek, Richard Piekarz
Entinostat is a synthetic benzamide derivative histone deacetylase (HDAC) inhibitor, which potently and selectively inhibits class I and IV HDAC enzymes. This action promotes histone hyperacetylation and transcriptional activation of specific genes, with subsequent inhibition of cell proliferation, terminal differentiation and apoptosis. This oral HDAC inhibitor has been evaluated in Phase I and II trials in patients with advanced malignancies, and is in general well tolerated. Entinostat does not currently have regulatory approval for clinical use; however promising preclinical and clinical data exist in hormone-resistant breast cancer...
March 9, 2017: Future Oncology
https://www.readbyqxmd.com/read/28326191/global-histone-modification-fingerprinting-in-human-cells-using-epigenetic-reverse-phase-protein-array
#6
Marina Partolina, Hazel C Thoms, Kenneth G MacLeod, Giovanny Rodriguez-Blanco, Matthew N Clarke, Anuroop V Venkatasubramani, Rima Beesoo, Vladimir Larionov, Vidushi S Neergheen-Bhujun, Bryan Serrels, Hiroshi Kimura, Neil O Carragher, Alexander Kagansky
The balance between acetylation and deacetylation of histone proteins plays a critical role in the regulation of genomic functions. Aberrations in global levels of histone modifications are linked to carcinogenesis and are currently the focus of intense scrutiny and translational research investments to develop new therapies, which can modify complex disease pathophysiology through epigenetic control. However, despite significant progress in our understanding of the molecular mechanisms of epigenetic machinery in various genomic contexts and cell types, the links between epigenetic modifications and cellular phenotypes are far from being clear...
2017: Cell Death Discovery
https://www.readbyqxmd.com/read/28323005/macrophage-migration-inhibitory-factor-interacts-with-thioredoxin-interacting-protein-and-induces-nf-%C3%AE%C2%BAb-activity
#7
Mi Jeong Kim, Won Sam Kim, Dong Oh Kim, Jae-Eun Byun, Hangsak Huy, Soo Yun Lee, Hae Young Song, Young-Jun Park, Tae-Don Kim, Suk Ran Yoon, Eun-Ji Choi, Hyunjung Ha, Haiyoung Jung, Inpyo Choi
The nuclear factor kappa B (NF-κB) pathway is pivotal in controlling survival and apoptosis of cancer cells. Macrophage migration inhibitory factor (MIF), a cytokine that regulates the immune response and tumorigenesis under inflammatory conditions, is upregulated in various tumors. However, the intracellular functions of MIF are unclear. In this study, we found that MIF directly interacted with thioredoxin-interacting protein (TXNIP), a tumor suppressor and known inhibitor of NF-κB activity, and MIF significantly induced NF-κB activation...
March 17, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28321257/class-specific-histone-deacetylase-inhibitors-promote-11-beta-hydroxysteroid-dehydrogenase-type-2-expression-in-jeg-3-cells
#8
Katie L Togher, Louise C Kenny, Gerard W O'Keeffe
Exposure to maternal cortisol plays a crucial role in fetal organogenesis. However, fetal overexposure to cortisol has been linked to a range of short- and long-term adverse outcomes. Normally, this is prevented by the expression of an enzyme in the placenta called 11-beta hydroxysteroid dehydrogenase type 2 (11β-HSD2) which converts active cortisol to its inactive metabolite cortisone. Placental 11β-HSD2 is known to be reduced in a number of adverse pregnancy complications, possibly through an epigenetic mechanism...
2017: International Journal of Cell Biology
https://www.readbyqxmd.com/read/28317157/design-and-synthesis-of-novel-anti-plasmodial-histone-deacetylase-inhibitors-containing-an-alkoxyamide-connecting-unit
#9
Leandro A Alves Avelar, Jana Held, Jessica A Engel, Parichat Sureechatchaiyan, Finn K Hansen, Alexandra Hamacher, Matthias U Kassack, Benjamin Mordmüller, Katherine T Andrews, Thomas Kurz
Despite recent declines in mortality, malaria remains an important global health problem. New therapies are needed, including new drugs with novel modes of action compared to existing agents. Among new potential therapeutic targets for malaria, inhibition of parasitic histone deacetylases (HDACs) is a promising approach. Homology modeling of PfHDAC1, a known target of some anti-plasmodial HDAC inhibitors, revealed a unique threonine residue at the rim of the active site in close proximity to the location of the cap group of vorinostat-type HDAC inhibitors...
March 20, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28315487/xpln-is-modulated-by-hdac-inhibitors-and-negatively-regulates-sparc-expression-by-targeting-mtorc2-in-human-lung-fibroblasts
#10
Koichiro Kamio, Arata Azuma, Jiro Usuki, Kuniko Matsuda, Minoru Inomata, Nobuhiko Nishijima, Shioto Itakura, Hiroki Hayashi, Takeru Kashiwada, Nariaki Kokuho, Kenichiro Atsumi, Tomoyoshi Yamaguchi, Kazue Fujita, Yoshinobu Saito, Shinji Abe, Kaoru Kubota, Akihiko Gemma
Pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that participates in the assembly and turnover of the extracellular matrix, whose expression is regulated by transforming growth factor (TGF)-β1 through activation of mammalian target of rapamycin complex 2 (mTORC2). Exchange factor found in platelets, leukemic, and neuronal tissues (XPLN) is an endogenous inhibitor of mTORC2. However, whether XPLN modulates SPARC expression remains unknown...
March 14, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28315153/effects-of-histone-deacetylase-inhibitory-prodrugs-on-epigenetic-changes-and-dna-damage-response-in-tumor-and-heart-of-glioblastoma-xenograft
#11
Nataly Tarasenko, Abraham Nudelman, Gabriela Rozic, Suzanne M Cutts, Ada Rephaeli
The histone deacetylase (HDAC) inhibitory prodrugs of butyric (AN7) and valproic (AN446) acids, which release the active acids upon metabolic degradation, were studied examining their differential effects on the viability, HDAC inhibitory activity and the DNA damage response (DDR), in glioblastoma cell and normal human astrocytes (NHAs). In xenografts of glioblastoma, AN7 or AN446 given or the combination of each of them with Dox augmented the anticancer activity of Dox and protected the heart from its toxicity...
March 17, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28314773/glucocorticoid-receptor-signaling-represses-the-antioxidant-response-by-inhibiting-histone-acetylation-mediated-by-the-transcriptional-activator-nrf2
#12
Md Morshedul Alam, Keito Okazaki, Linh Thi Thao Nguyen, Nao Ota, Hiroshi Kitamura, Shohei Murakami, Hiroki Shima, Kazuhiko Igarashi, Hiroki Sekine, Hozumi Motohashi
NRF2 (nuclear factor erythroid 2-related factor 2) is a key transcriptional activator that mediates the inducible expression of antioxidant genes. NRF2 is normally ubiquitinated by KEAP1 (Kelch-like ECH-associated protein 1) and subsequently degraded by proteasomes. Inactivation of KEAP1 by oxidative stress or electrophilic chemicals allows NRF2 to activate transcription through binding to antioxidant response elements (AREs) and recruiting histone acetyltransferase CBP (CREB-binding protein). While KEAP1-dependent regulation is a major determinant of NRF2 activity, NRF2-mediated transcriptional activation varies from context to context, suggesting other intracellular signaling cascades may impact NRF2 function...
March 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28306192/histone-deacetylase-activity-mediates-acquired-resistance-towards-structurally-diverse-hsp90-inhibitors
#13
Ryan C Chai, Jessica L Vieusseux, Benjamin J Lang, Chau H Nguyen, Michelle M Kouspou, Kara L Britt, John T Price
Heat Shock Protein 90 (HSP90) regulates multiple signaling pathways critical for tumor growth. As such, HSP90 inhibitors have been shown to act as effective anticancer agents in preclinical studies but, for a number of reasons, the same effect has not been observed in the clinical trials to date. One potential reason for this may the presence of de novo or acquired resistance within the tumors. To investigate mechanisms of resistance, we generated resistant cell lines through gradual dose escalation of the HSP90 inhibitor 17-AAG...
March 17, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28302010/discovery-of-hedgehog-antagonists-for-cancer-therapy
#14
Harleen Khatra, Chandra Bose, Surajit Sinha
BACKGROUND: The evolutionarily conserved Hedgehog (Hh) signaling cascade is one of the key mediators of embryonic development of many metazoans. This pathway has been extensively targeted by small molecule inhibitors as its misregulation leads to various malignancies and developmental disorders. Thus, blocking this pathway can be a novel therapeutic avenue for the treatment of Hedgehog-dependent cancers. This review covers the mechanism of hedgehog signaling in vertebrate cells, provides an overview of reported small molecule Hh pathway inhibitors, with the synthetic routes and SAR studies of some of them discussed briefly...
March 16, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28301600/the-hdac-inhibitor-sb939-overcomes-resistance-to-bcr-abl-kinase-inhibitors-conferred-by-the-bim-deletion-polymorphism-in-chronic-myeloid-leukemia
#15
Muhammad Rauzan, Charles T H Chuah, Tun Kiat Ko, S Tiong Ong
Chronic myeloid leukemia (CML) treatment has been improved by tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM) but various factors can cause TKI resistance in patients with CML. One factor which contributes to TKI resistance is a germline intronic deletion polymorphism in the BCL2-like 11 (BIM) gene which impairs the expression of pro-apoptotic splice isoforms of BIM. SB939 (pracinostat) is a hydroxamic acid based HDAC inhibitor with favorable pharmacokinetic, physicochemical and pharmaceutical properties, and we investigated if this drug could overcome BIM deletion polymorphism-induced TKI resistance...
2017: PloS One
https://www.readbyqxmd.com/read/28288848/bcl11b-mediated-epigenetic-repression-is-a-crucial-target-for-histone-deacetylase-inhibitors-in-cutaneous-t-cell-lymphoma
#16
Wenjing Fu, Shengguo Yi, Lei Qiu, Jingru Sun, Ping Tu, Yang Wang
The treatment options for advanced cutaneous T-cell lymphoma (CTCL) are limited due to its unclear pathogenesis. HDAC inhibitors (HDACi) are recently developed therapeutics approved for refractory CTCL. However, the response rate is relatively low and unpredictable. Previously, we discovered that BCL11B, a key T-cell development regulator, was aberrantly overexpressed in mycosis fungoides (MF), the most common CTCL, as compared with benign inflammatory skin. In the current study, we identified positive correlation between BCL11B expression and the sensitivity to HDACi in CTCL lines...
March 10, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28283560/hdac7-ubiquitination-by-the-e3-ligase-cbx4-is-involved-in-contextual-fear-conditioning-memory-formation
#17
Xu Jing, Wen-Hai Sui, Shuai Wang, Xu-Feng Xu, Rong-Rong Yuan, Xiao-Rong Chen, Hui-Xian Ma, Ying-Xiao Zhu, Jin-Kai Sun, Fan Yi, Zhe-Yu Chen, Yue Wang
Histone acetylation, which comprises an epigenetic modification, plays an important role in long-term memory formation. Recently, histone deacetylase (HDAC) inhibitors were demonstrated to promote memory formation, which raises the intriguing possibility that HDAC inhibitors may be used to rescue memory deficits. However, additional research is necessary to clarify the roles of individual HDACs in memory. In this study, we demonstrated that HDAC7, within the dorsal hippocampus (DH) of C57BL6J mice, had a late and persistent decrease after contextual fear conditioning (CFC) training (4 h∼24 h), which was involved in long-term CFC memory formation...
March 10, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28273064/class-iia-hdac-inhibition-reduces-breast-tumours-and-metastases-through-anti-tumour-macrophages
#18
Jennifer L Guerriero, Alaba Sotayo, Holly E Ponichtera, Jessica A Castrillon, Alexandra L Pourzia, Sara Schad, Shawn F Johnson, Ruben D Carrasco, Suzan Lazo, Roderick T Bronson, Scott P Davis, Mercedes Lobera, Michael A Nolan, Anthony Letai
Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction and elimination. Tumour-associated macrophages often have net pro-tumour effects, but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition) or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies) tumour-associated macrophages have had some success...
March 8, 2017: Nature
https://www.readbyqxmd.com/read/28271209/tgf-%C3%AE-1-impairs-mechanosensation-of-human-osteoblasts-via-hdac6-mediated-shortening-and-distortion-of-primary-cilia
#19
Sabrina Ehnert, Vrinda Sreekumar, Romina H Aspera-Werz, Sahar O Sajadian, Elke Wintermeyer, Gunther H Sandmann, Christian Bahrs, Jan G Hengstler, Patricio Godoy, Andreas K Nussler
Transforming growth factor β (TGF-β) is a critical regulator of bone density owing to its multiple effects on cell growth and differentiation. Recently, we have shown that TGF-β1 effectively blocks bone morphogenetic protein (BMP) induced maturation of osteoblasts by upregulating histone deacetylase (HDAC) activity. The current study aimed at investigating the effect of rhTGF-β1 treatment on the expression of specific HDACs and their cellular effects, e.g., microtubule structures (primary cilia) and mechanosensation...
March 7, 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/28270022/a-phase-1-trial-of-the-hdac-inhibitor-ar-42-in-patients-with-multiple-myeloma-and-t-and-b-cell-lymphomas
#20
Douglas W Sborov, Alessandro Canella, Erinn M Hade, Xiaokui Mo, Soun Khountham, Jiang Wang, Wenjun Ni, Ming Poi, Christopher Coss, Zhongfa Liu, Mitch A Phelps, Amir Mortazavi, Leslie Andritsos, Robert A Baiocchi, Beth A Christian, Don M Benson, Joseph Flynn, Pierluigi Porcu, John C Byrd, Flavia Pichiorri, Craig C Hofmeister
Histone deacetylase inhibitors (HDACi) have proven activity in hematologic malignancies, and their FDA approval in multiple myeloma (MM) and T-cell lymphoma highlights the need for further development of this drug class. We investigated AR-42, an oral pan-HDACi, in a first-in-man phase 1 dose escalation clinical trial. Overall, treatment was well tolerated, no DLTs were evident, and the MTD was defined as 40 mg dosed three times weekly for three weeks of a 28-day cycle. One patient each with MM and mantle cell lymphoma demonstrated disease control for 19 and 27 months (ongoing), respectively...
March 7, 2017: Leukemia & Lymphoma
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