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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
Linbo Gao, David Cheng, Jie Yang, Renyi Wu, Wenji Li, Ah-Ng Kong
Increasing evidence suggests that epigenetic aberrations contribute to the development and progression of cancers such as lung cancer. The promoter region of miR-9-3 was recently found to be hypermethylated in lung cancer, resulting in down-regulation of miR-9-3 and poor patient prognosis. Sulforaphane (SFN), a natural compound that is obtained from cruciferous vegetables, has potent anticancer activities. In this study, we aimed to investigate the effect of SFN on restoring the miR-9-3 level in lung cancer A549 cells through epigenetic regulation...
February 9, 2018: Journal of Nutritional Biochemistry
Xiaolei Wang, Yanhua Wu, Jin Jiao, Qing Huang
Mycobacterium tuberculosis (MTB) infection is a significant contributor to dysregulated T cell-mediated immune response. Here we aimed to evaluate the mechanism of MTB infection in promoting interleukin-10 (IL-10) upregulation. The IL-10 levels in MTB infected THP-1 cells were evaluated with enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (qRT-PCR). In challenged THP-1 cells, the HDAC6 and HDAC11 mRNA and protein levels were monitored at varied duration after MTB infection. Further, chromatin immunoprecipitation (ChIP) analysis was used to investigate the interaction between IL-10 expression and HDAC6 or HDAC11...
January 2018: Tuberculosis
Alanna Sedgwick, M Olivia Balmert, Crislyn D'Souza-Schorey
Aberrant cellular cholesterol accumulation contributes to the pathophysiology of many diseases including neurodegenerative disorders such as Niemann-Pick Type C (NPC) and Alzheimer's Disease1-4 . Many aspects of cholesterol efflux from cells remain elusive. Here we describe the utility of cholesterol-rich giant plasma membrane vesicles (GPMVs) as a means to monitor cholesterol that is translocated to the plasma membrane for secretion. We demonstrate that small molecules known to enhance lipid efflux, including those in clinical trials for lipid storage disorders, enhance this GPMV formation...
March 6, 2018: Experimental Cell Research
Zhongying Mo, Xiaobei Zhao, Huaqing Liu, Qinghua Hu, Xu-Qiao Chen, Jessica Pham, Na Wei, Ze Liu, Jiadong Zhou, Robert W Burgess, Samuel L Pfaff, C Thomas Caskey, Chengbiao Wu, Ge Bai, Xiang-Lei Yang
Dominant mutations in glycyl-tRNA synthetase (GlyRS) cause a subtype of Charcot-Marie-Tooth neuropathy (CMT2D). Although previous studies have shown that GlyRS mutants aberrantly interact with Nrp1, giving insight into the disease's specific effects on motor neurons, these cannot explain length-dependent axonal degeneration. Here, we report that GlyRS mutants interact aberrantly with HDAC6 and stimulate its deacetylase activity on α-tubulin. A decrease in α-tubulin acetylation and deficits in axonal transport are observed in mice peripheral nerves prior to disease onset...
March 8, 2018: Nature Communications
Mitsuaki Yamashita, Teruyuki Tahara, Shinya Hayakawa, Hironobu Matsumoto, Shun-Ichi Wada, Kiyoshi Tomioka, Akira Iida
HDAC inhibitors enable histones to maintain a high degree of acetylation. The resulting looser state of chromatin DNA may increase the accessibility of DNA drug targets and consequently improve the efficiency of anticancer drugs targeting DNA, such as Topo II inhibitors. A novel class of nucleoside-SAHA derivatives has been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities toward histone deacetylases and Topo II, and their cytotoxicities in cancer cell lines, were evaluated...
February 27, 2018: Bioorganic & Medicinal Chemistry
Sandrine Herbelet, Elly De Vlieghere, Amanda Gonçalves, Boel De Paepe, Karsten Schmidt, Eline Nys, Laurens Weynants, Joachim Weis, Gert Van Peer, Jo Vandesompele, Jens Schmidt, Olivier De Wever, Jan L De Bleecker
Aims: Regeneration in skeletal muscle relies on regulated myoblast migration and differentiation, in which the transcription factor nuclear factor of activated T-cells 5 (NFAT5) participates. Impaired muscle regeneration and chronic inflammation are prevalent in myositis. Little is known about the impact of inflammation on NFAT5 localization and expression in this group of diseases. The goal of this study was to investigate NFAT5 physiology in unaffected myoblasts exposed to cytokine or hyperosmolar stress and in myositis...
2018: Frontiers in Physiology
Jinyu Yang, Gaoliang Cheng, Qihao Xu, Shenglin Luan, Shuxiang Wang, Dan Liu, Linxiang Zhao
In recent years, inhibition of HDAC6 became a promising therapeutic strategy for the treatment of cancer and HDAC6 inhibitors were considered to be potent anti-cancer agents. In this work, celecoxib showed moderate degree of HDAC6 inhibition activity and selectivity in preliminary enzyme inhibition activity assay. A series of hydroxamic acid derivatives bearing phenylpyrazol moiety were designed and synthesized as HDAC6 inhibitors. Most compounds showed potent HDAC6 inhibition activity. 11i was the most selective compound against HDAC6 with IC50 values of 0...
August 19, 2017: Bioorganic & Medicinal Chemistry
Xiaoyang Li, Yuri K Peterson, Elizabeth S Inks, Richard Himes, Jiaying Li, Yingjie Zhang, Xiujie Kong, C James Chou
Previously we designed and synthesized a series of o-aminobenzamide-based HDAC inhibitors, among which the representative compound 11a exhibited potent inhibitory activity against class I HDACs. In this study, we report the development of more potent hydrazide-based class I selective HDAC inhibitors using 11a as a lead. Representative compound 13b showed a mixed, slow, and tight binding inhibition mechanism for HDAC1, 2 and 3. The most potent compound 13e exhibited low nano-molar IC50s toward HDAC1, 2 and 3, and could down-regulate HDAC6 in acute myeloid leukemia MV4-11 cells...
March 2, 2018: Journal of Medicinal Chemistry
Victor S C Wong, Cristina Picci, Michelle Swift, Max Levinson, Dianna Willis, Brett Langley
Damage to the CNS results in neuronal and axonal degeneration, and subsequent neurological dysfunction. Endogenous repair in the CNS is impeded by inhibitory chemical and physical barriers, such as chondroitin sulfate proteoglycans (CSPGs) and myelin-associated glycoprotein (MAG), which prevent axon regeneration. Previously, it has been demonstrated that the inhibition of axonal histone deacetylase-6 (HDAC6) can promote microtubule α-tubulin acetylation and restore the growth of CSPGs- and MAG-inhibited axons...
January 2018: ENeuro
Jooeun Bae, Teru Hideshima, Yu-Tzu Tai, Yan Song, Paul Richardson, Noopur Raje, Nikhil C Munshi, Kenneth C Anderson
Histone deacetylases (HDAC) are therapeutic targets in multiple cancers. ACY241, an HDAC6 selective inhibitor, has shown anti-multiple myeloma (MM) activity in combination with immunomodulatory drugs and proteasome inhibitors. Here we show ACY241 significantly reduces the frequency of CD138+ MM cells, CD4+ CD25+ FoxP3+ regulatory T cells, and HLA-DRLow/- CD11b+ CD33+ myeloid-derived suppressor cells; and decreases expression of PD1/PD-L1 on CD8+ T cells and of immune checkpoints in bone marrow cells from myeloma patients...
February 22, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Nicholas Forsythe, Alaa Refaat, Arman Javadi, Hajrah Khawaja, Jessica-Anne Weir, Heba Emam, Wendy L Allen, Frank Burkamp, Vlad Popovici, Puthen V Jithesh, Claudio Isella, Melissa J LaBonte, Ian G Mills, Patrick G Johnston, Sandra Van Schaeybroeck
BRAFV600E mutations occur in 10% of colorectal cancer (CRC) cases, are associated with poor survival and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT CRC. We have used differential gene expression and pathway analyses of untreated stage II and stage III BRAFMT (discovery set: n=31; validation set: n=26) CRC and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome...
February 26, 2018: Molecular Cancer Therapeutics
Sin Young Choi, Hae Jin Kee, Li Jin, Yuhee Ryu, Simei Sun, Gwi Ran Kim, Myung Ho Jeong
Histone deacetylase (HDAC) inhibitors are gaining increasing attention as potential therapeutics for cardiovascular diseases as well as cancer. We recently reported that the class II HDAC inhibitor, MC1568, and the phytochemical, gallic acid, lowered high blood pressure in mouse models of hypertension. We hypothesized that class II HDACs may be involved in the regulation of hypertension. The aim of this study was to determine and compare the effects of well-known HDAC inhibitors (TMP269, panobinostat, and MC1568), phytochemicals (gallic acid, sulforaphane, and piceatannol), and anti-hypertensive drugs (losartan, carvedilol, and furosemide) on activities of class IIa HDACs (HDAC4, 5, 7, and 9)...
February 23, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Jie Xia, Huabin Hu, Wenjie Xue, Xiang Simon Wang, Song Wu
Histone deacetylase 3 (HDAC3) is a potential target for the treatment of human diseases such as cancers, diabetes, chronic inflammation and neurodegenerative diseases. Previously, we proposed a virtual screening (VS) pipeline named "Hypo1_FRED_SAHA-3" for the discovery of HDAC3 inhibitors (HDAC3Is) and had thoroughly validated it by theoretical calculations. In this study, we attempted to explore its practical utility in a large-scale VS campaign. To this end, we used the VS pipeline to hierarchically screen the Specs chemical library...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Harinder Singh, Nathan Wray, Jeffrey M Schappi, Mark M Rasenick
Current antidepressant therapies meet with variable therapeutic success and there is increasing interest in therapeutic approaches not based on monoamine signaling. Histone deacetylase 6 (HDAC6), which also deacetylates α-tubulin shows altered expression in mood disorders and HDAC6 knockout mice mimic traditional antidepressant treatments. Nonetheless, a mechanistic understanding for HDAC6 inhibitors in the treatment of depression remains elusive. Previously, we have shown that sustained treatment of rats or glioma cells with several antidepressants translocates Gαs from lipid rafts toward increased association with adenylyl cyclase (AC)...
February 5, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Mitsutake Yano, Masanori Yasuda, Mika Sakaki, Koji Nagata, Takashi Fujino, Eiichi Arai, Takahiro Hasebe, Masaki Miyazawa, Mariko Miyazawa, Naoki Ogane, Kosei Hasegawa, Hisashi Narahara
Histone deacetylase (HDAC) inhibitor is known to have a cytotoxic effect on ovarian cancer cell lines. The present study analyzed the association between immunohistochemical HDAC expression and clinicopathological findings, in particular, the association with histological type and effect of chemotherapy. The histology of the 201 ovarian cancers addressed was as follows: Serous carcinoma (SEC), 100 cases; clear cell carcinoma (CCC), 56 cases; endometrioid carcinoma (EMC), 36 cases; and mucinous carcinoma (MUC), 9 cases...
March 2018: Oncology Letters
Angela S Brijmohan, Sri N Batchu, Syamantak Majumder, Tamadher A Alghamdi, Karina Thieme, Sarah McGaugh, Youan Liu, Suzanne L Advani, Bridgit B Bowskill, M Golam Kabir, Laurette Geldenhuys, Ferhan S Siddiqi, Andrew Advani
To contend with the deleterious effects of accumulating misfolded protein aggregates or damaged organelles cells rely on a system of quality control processes, among them the autophagy-lysosome pathway. This pathway is itself controlled by a master regulator transcription factor termed transcription factor EB (TFEB). When TFEB localizes to the cell nucleus it promotes the expression of a number of genes involved in protein clearance. Here, we set out to determine (1) whether TFEB expression is altered in chronic kidney disease (CKD); (2) whether inhibition of the cytosolic deacetylase histone deacetylase 6 (HDAC6) affects TFEB acetylation and nuclear localization; and (3) whether HDAC6 inhibition, in turn, alters the natural history of experimental CKD...
2018: Frontiers in Pharmacology
Ji-Young Choi, Jun-Hyeok Ko, Sangmee Ahn Jo
Our previous study showed that the level of glutamate carboxypeptidase II (GCPII) protein is regulated by valproic acid, a histone deacetylase (HDAC) inhibitor, through acetylation of lysine residue in the GCPII protein in human astrocytes, U-87MG. The present study further investigated which HDAC subtype is involved in the acetylation of GCPII. The results revealed that GCPII interacted with HDAC1 but not with HDAC2, HDAC3, HDAC4, HDAC5, and HDAC6. Overexpression of catalytic domain (1-56 aa)-deleted HDAC1, which poorly binds to GCPII, enhanced lysine acetylation in GCPII and increased the level of GCPII protein when compared with that of the wild-type HDAC1...
February 12, 2018: Biochemical and Biophysical Research Communications
Martin Dom, Fritz Offner, Wim Vanden Berghe, Xaveer Van Ostade
Withaferin A (WA), a natural steroid lactone from the plant Withania somnifera, is often studied because of its antitumor properties. Although many in vitro and in vivo studies have been performed, the identification of Withaferin A protein targets and its mechanism of antitumor action remain incomplete. We used quantitative chemoproteomics and differential protein expression analysis to characterize the WA antitumor effects on a multiple myeloma cell model. Identified relevant targets were further validated by Ingenuity Pathway Analysis and Western blot and indicate that WA targets protein networks that are specific for monoclonal gammopathy of undetermined significance (MGUS) and other closely related disorders, such as multiple myeloma (MM) and Waldenström macroglobulinemia (WM)...
February 12, 2018: Journal of Proteomics
Svenja Memmert, A V B Nogueira, A Damanaki, M Nokhbehsaim, S Eick, T Divnic-Resnik, A Spahr, B Rath-Deschner, A Till, W Götz, J A Cirelli, A Jäger, J Deschner
OBJECTIVES: Damage-regulated autophagy modulator (DRAM) 1 is a p53 target gene with possible involvement in oral inflammation and infection. This study sought to examine the presence and regulation of DRAM1 in periodontal diseases. MATERIAL AND METHODS: In vitro, human periodontal ligament fibroblasts were exposed to interleukin (IL)-1β and Fusobacterium nucleatum for up to 2 days. The DRAM1 synthesis and its regulation were analyzed by real-time PCR, immunocytochemistry, and ELISA...
February 13, 2018: Clinical Oral Investigations
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