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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
Maria Lorenzo Pisarello, Tatyana V Masyuk, Sergio A Gradilone, Anatoliy I Masyuk, Jingyi Francess Ding, Pui-Yuen Lee, Nicholas F LaRusso
Hepatic cystogenesis in polycystic liver disease (PLD) is associated with abnormalities in multiple cellular processes, including elevated cAMP and overexpression of histone deacetylase 6 (HDAC6). Disease progression in polycystic kidney (PCK) rats (an animal model of PLD) is attenuated by inhibition of either cAMP production or HDAC6. Therefore, we hypothesized that concurrent targeting of HDAC6 and cAMP would synergistically reduce cyst growth. Changes in hepatorenal cystogenesis were examined in PCK rats treated with a pan-HDAC inhibitor, panobinostat; three specific HDAC6 inhibitors, ACY-1215, ACY-738, and ACY-241; and a combination of ACY-1215 and the somatostatin receptor analogue, pasireotide...
January 31, 2018: American Journal of Pathology
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 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
Ruimin Liu, Cong Men, Wenwen Yu, Fei Xu, Qingrui Wang, Zhenyao Shen
To examine the variabilities of source contributions in the Yangtze River Estuary (YRE), the uncertainty based on the positive matrix factorization (PMF) was applied to the source apportionment of the 16 priority PAHs in 120 surface sediment samples from four seasons. Based on the signal-to-noise ratios, the PAHs categorized as "Bad" might drop out of the estimation of bootstrap. Next, the spatial variability of residuals was applied to determine which species with non-normal curves should be excluded...
January 2018: Chemosphere
Wen-Bin Zhang, Hai-Yue Zhang, Fang-Zhou Jiao, Lu-Wen Wang, Hong Zhang, Zuo-Jiong Gong
Histone deacetylase 6 (HDAC6) is considered a new target for anticancer, anti-inflammatory, and neurodegenerative treatment. ACY-1215 is a selective histone deacetylase 6 inhibitor, and it has been recognized as a potential anticancer and anti-inflammation drug. The aim of our study was to investigate whether ACY-1215 has protective effects on acute liver failure (ALF) in mice and explore its potential mechanism. Male C57/BL6 mice were divided into normal, model, and ACY-1215 groups. ACY-1215 (25mg/kg) and same amounts of saline were given to mice...
January 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Hyun-Wook Ryu, Dong-Hee Shin, Dong Hoon Lee, Hye-Rim Won, So Hee Kwon
HDAC6-selective inhibitors are novel epigenetic anticancer agents. However, their precise mechanisms of action are incompletely understood. We investigated the anticancer mechanisms of the novel potent and selective HDAC6 inhibitor A452 compared with current clinically tested HDAC6 inhibitor ACY-1215. We demonstrate that A452 effectively inhibits the cell growth and viability of various cancer cell types, irrespective of p53 status. A452 induced apoptosis as evidenced by activated caspase 3 and PARP, increased Bak and Bax, and decreased Bcl-xL...
November 2, 2017: Carcinogenesis
A Ray, D S Das, Y Song, T Hideshima, Y-T Tai, D Chauhan, K C Anderson
Leukemia accepted article preview online, 06 November 2017. doi:10.1038/leu.2017.322.
November 6, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Ze-Nan Lin, Jie Chen, Qi Zhang, Qian Li, Min-Yun Cai, Hai Yang, Hong-Ping Cui
AIM: To identify the 100 most cited papers in cataract surgery, we performed a comprehensive bibliometric analysis basing on the literature search on the Thomson Reuters Web of Knowledge. METHODS: The number of citations, including the total citations, latest 5y citations and average citation number per year (ACY), authorship, year of publication, major topics, journal of publication, country and institution of origin of each paper were recorded and then analyzed...
2017: International Journal of Ophthalmology
Liz Gutiérrez-Quequezana, Anssi L Vuorinen, Heikki Kallio, Baoru Yang
Methods were optimized for extraction and quantification of anthocyanins (ACY) and vitamin C in potatoes. Acidified aqueous methanol (70%) was the optimal extraction solvent and freeze-drying significantly improved the extraction yield of ACY. The content of ACY varied widely in five potato cultivars from 0.42 to 3.18mg/g dry weight, with the latter being the highest value found in the Finnish cultivar 'Synkeä Sakari'. Compared with dithiothreitol (DTT), tris(2-carboxyethyl) phosphine hydrochloride (TCEP) was more efficient in reducing dehydroascorbic acid (DHA) to ascorbic acid (AA) and for quantifying the content of total ascorbic acid (TAA)...
March 1, 2018: Food Chemistry
J Ren, X Liao, M D Vieson, M Chen, R Scott, J Kazmierczak, X M Luo, C M Reilly
We have demonstrated previously that histone deacetylase (HDAC6) expression is increased in animal models of systemic lupus erythematosus (SLE) and that inhibition of HDAC6 decreased disease. In our current studies, we tested if an orally active selective HDAC6 inhibitor would decrease disease pathogenesis in a lupus mouse model with established early disease. Additionally, we sought to delineate the cellular and molecular mechanism(s) of action of a selective HDAC6 inhibitor in SLE. We treated 20-week-old (early-disease) New Zealand Black (NZB)/White F1 female mice with two different doses of the selective HDAC6 inhibitor (ACY-738) for 5 weeks...
January 2018: Clinical and Experimental Immunology
Qian Cheng, Shaohua Gu, Zewen Liu, Chen-Zhu Wang, Xianchun Li
How FACs-producing generalist and specialist herbivores regulate their FACs-hydrolyzing enzyme L-ACY-1 to balance FACs' beneficial vs. detrimental effects remains unknown. To address this question, we compared L-ACY-1 expression in Helicoverpa armigera and Helicoverpa assulta, a pair of closely related sibling species differing mainly in their host range, by the same sets of hostplants, protein to digestible carbohydrate (P:C) ratios, or allelochemical. L-ACY-1 expression remained low/unchanged in H. armigera, but was induced by hot pepper fruits and repressed by cotton bolls in H...
August 18, 2017: Scientific Reports
Chuan-Xi Mao, Xue Wen, Shan Jin, Yong Q Zhang
Tau normally associates with and stabilizes microtubules (MTs), but is hyperphosphorylated and aggregated into neurofibrillary tangles in Alzheimer's disease and related neurodegenerative diseases, which are collectively known as tauopathies. MTs are regulated by different forms of post-translational modification, including acetylation; acetylated MTs represent a more stable microtubule population. In our previous study, we showed that inhibition of histone deacetylase 6 (HDAC6), which deacetylates tubulin at lysine 40, rescues defects in MTs and in neuromuscular junction growth caused by tau overexpression...
October 1, 2017: Disease Models & Mechanisms
Gajanand Sharma, Kanika Thakur, Arvind Setia, Basant Amarji, Mini P Singh, Kaisar Raza, Om Prakash Katare
The present investigation focuses on the development and evaluation of acyclovir-loaded flexible membrane vesicles (ACY-FMVs) and evaluates their targeting potential to localize the drug into skin layers. The drug-loaded FMVs were prepared by thin-film hydration method and characterized for various attributes including micromeritics, entrapment efficiency, vesicle shape, size, and degree of deformability. The values of particle size and zeta potential of the developed carrier system were found to be 453.7 nm and - 11...
October 2017: Drug Delivery and Translational Research
Joanna Poluszyńska, Elżbieta Jarosz-Krzemińska, Edeltrauda Helios-Rybicka
The research comprised of studying the effect composting sewage sludge with sawdust and vermicomposting with earthworm Eisenia fetida has on the degradation of 16 polycyclic aromatic hydrocarbons (PAHs). Raw rural sewage sludge prior composting was more contaminated with PAHs than urban sewage sludge, in both cases exceeding EU cutoff limits of 6 mg/kg established for land application. Dibenzo[a,h]anthracene (DBahAnt), acenaphtylene (Acy) and indeno[1,2,3-c,d]pyrene (IPyr) were predominant in rural sewage sludge, whilst the urban sewage sludge contained the highest concentrations of benzo[b]fluoranthene (BbFl), benzo[k]fluoranthene (BkFl) and indeno[1,2,3-c,d]pyrene (IPyr)...
2017: Water, Air, and Soil Pollution
Murali K Yanda, Qiangni Liu, Liudmila Cebotaru
Adult-onset autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in either the PKD1 or PKD2 gene, leading to malfunction of their gene products, polycystin 1 or 2. Histone deacetylase 6 (HDAC6) expression and activity are increased in PKD1 mutant renal epithelial cells. Here we studied the effect of ACY-1215, a specific HDAC6 inhibitor, on cyst growth in ADPKD. Treatment with ACY-1215 slowed cyst growth in a mouse model of ADPKD that forms massive cysts within 3 wk after knockout of polycystin 1 function...
October 1, 2017: American Journal of Physiology. Renal Physiology
Danilo Russo, Antonietta Siciliano, Marco Guida, Emilia Galdiero, Angela Amoresano, Roberto Andreozzi, Nuno M Reis, Gianluca Li Puma, Raffaele Marotta
The photochemical and ecotoxicological fate of acyclovir (ACY) through UV254 direct photolysis and in the presence of hydroxyl radicals (UV254 /H2 O2 process) were investigated in a microcapillary film (MCF) array photoreactor, which provided ultrarapid and accurate photochemical reaction kinetics. The UVC phototransformation of ACY was found to be unaffected by pH in the range from 4.5 to 8.0 and resembled an apparent autocatalytic reaction. The proposed mechanism included the formation of a photochemical intermediate (ϕACY  = (1...
October 1, 2017: Water Research
Olivia S Chao, Tim C Chang, Maria A Di Bella, Riccardo Alessandro, Fabio Anzanello, Germana Rappa, Oscar B Goodman, Aurelio Lorico
Tumor-derived extracellular vesicles (EVs) are emerging as an important mode of intercellular communication, capable of transferring biologically active molecules that facilitate the malignant growth and metastatic process. CD133 (Prominin-1), a stem cell marker implicated in tumor initiation, differentiation and resistance to anti-cancer therapy, is reportedly associated with EVs in various types of cancer. However, little is known about the factors that regulate the release of these CD133(+) EVs. Here, we report that the HDAC6 inhibitor tubacin promoted the extracellular release of CD133(+) EVs from human FEMX-I metastatic melanoma and Caco-2 colorectal carcinoma cells, with a concomitant downregulation of intracellular CD133...
December 2017: Journal of Cellular Biochemistry
Deepika Sharma Das, Abhishek Das, Arghya Ray, Yan Song, Mehmet Kemal Samur, Nikhil C Munshi, Dharminder Chauhan, Kenneth C Anderson
Purpose: The ubiquitin proteasome pathway is a validated therapeutic target in multiple myeloma. Deubiquitylating enzyme USP1 participates in DNA damage response and cellular differentiation pathways. To date, the role of USP1 in multiple myeloma biology is not defined. In the present study, we investigated the functional significance of USP1 in multiple myeloma using genetic and biochemical approaches.Experimental Design: To investigate the role of USP1 in myeloma, we utilized USP1 inhibitor SJB3-019A (SJB) for studies in myeloma cell lines and patient multiple myeloma cells...
August 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Karen Krukowski, Jiacheng Ma, Olga Golonzhka, Geoffroy O Laumet, Tanuja Gutti, John H van Duzer, Ralph Mazitschek, Matthew B Jarpe, Cobi J Heijnen, Annemieke Kavelaars
Chemotherapy-induced peripheral neuropathy is one of the most common dose-limiting side effects of cancer treatment. Currently, there is no Food and Drug Administration-approved treatment available. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase whose function includes regulation of α-tubulin-dependent intracellular mitochondrial transport. Here, we examined the effect of HDAC6 inhibition on established cisplatin-induced peripheral neuropathy. We used a novel HDAC6 inhibitor ACY-1083, which shows 260-fold selectivity towards HDAC6 vs other HDACs...
June 2017: Pain
Brian J North, Ingrid Almeciga-Pinto, David Tamang, Min Yang, Simon S Jones, Steven N Quayle
Thalidomide-based Immunomodulatory Drugs (IMiDs®), including lenalidomide and pomalidomide, are effective therapeutics for multiple myeloma. These agents have been approved with, or are under clinical development with, other targeted therapies including proteasome inhibitors, αCD38 monoclonal antibodies, as well as histone deacetylase (HDAC) inhibitors for combination therapy. HDAC inhibitors broadly targeting Class I and IIb HDACs have shown potent preclinical efficacy but have frequently demonstrated an undesirable safety profile in combination therapy approaches in clinical studies...
2017: PloS One
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