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Paul G Richardson, Philippe Moreau, Jacob P Laubach, Michelle E Maglio, Sagar Lonial, Jesus San-Miguel
Deacetylase enzymes remove acetyl groups from histone and nonhistone proteins. Dysregulation of deacetylase activity is a hallmark of malignancy, including multiple myeloma (MM). Deacetylase inhibitors (DACi) cause epigenetic modification and inhibition of the aggresome pathway, resulting in death of MM cells. Panobinostat, a pan-DACi, has shown significant clinical benefit and is the first DACi approved for the treatment of MM. It is approved for use in combination with bortezomib and dexamethasone for the treatment of patients with relapsed or relapsed and refractory MM who have received ≥2 prior regimens including bortezomib and an immunomodulatory drug...
November 21, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Andrew J Yee, William I Bensinger, Jeffrey G Supko, Peter M Voorhees, Jesus G Berdeja, Paul G Richardson, Edward N Libby, Ellen E Wallace, Nicole E Birrer, Jill N Burke, David L Tamang, Min Yang, Simon S Jones, Catherine A Wheeler, Robert J Markelewicz, Noopur S Raje
BACKGROUND: Histone deacetylase (HDAC) inhibitors are an important new class of therapeutics for treating multiple myeloma. Ricolinostat (ACY-1215) is the first oral selective HDAC6 inhibitor with reduced class I HDAC activity to be studied clinically. Motivated by findings from preclinical studies showing potent synergistic activity with ricolinostat and lenalidomide, our goal was to assess the safety and preliminary activity of the combination of ricolinostat with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma...
September 16, 2016: Lancet Oncology
Binghui Zheng, Yingqun Ma, Yanwen Qin, Lei Zhang, Yanmin Zhao, Wei Cao, Chenchen Yang, Chaonan Han
Water samples were collected from wastewater treatment plant (WWTP), drain water (DW), major tributaries (MT), and main course of the Yangtze River (MY) in areas of three industrial parks (IPs) in Chongqing city in the Three Gorges Reservoir (TGR). Sixteen EPA priority polycyclic aromatic hydrocarbon (PAH) pollutants were quantified to identify the effects of industrial activities on water quality of the TGR. The results showed that 11 individual PAHs were quantified and 5 PAHs (naphthalene (Nap), acenaphthylene (Acy), benzo[k]fluoranthene (BkF), indeno[1,2,3-cd]pyrene (InP), and benzo[g,h,i]perylene (BgP)) were under detection limits in all of the water samples...
December 2016: Environmental Science and Pollution Research International
Acy Quixada, Pedro Aurio Maia Filho, Tarcísio Paulo Almeida Filho, Fernando Barroso Duarte, Caroline Aquino Moreira-Nunes, Romélia Pinheiro Gonçalves Lemes
BACKGROUND: Visceral leishmaniasis is a zoonosis characterized by chronic evolution of symptoms; it usually appears 2 to 4 months after the initial infection, with multiple cutaneous lesions and systemic involvement, which if left untreated results in death in 90 % of cases. CASE PRESENTATION: We present a case of 29-year-old white male farmer, with chronic myeloid leukemia treated with imatinib who developed significant pancytopenia, leading to discontinuation of treatment...
July 27, 2016: Journal of Medical Case Reports
Sunisa Roidoung, Kirk D Dolan, Muhammad Siddiq
The objective of this study was to evaluate different antioxidants for anthocyanin (ACY) retention in vitamin C fortified cranberry juice and assess its quality. Cranberry juice was fortified with 40-80mg/100mL vitamin C and added hesperidin, catechin, and gallic acid at different concentrations. Juice was pasteurized at 85°C for 1min and stored at 23°C for 16days. ACYs, vitamin C, color intensity, and browning index (BI) were evaluated at 2-day intervals. Gallic acid was found to be the most effective antioxidant against ACYs degradation and significantly (p<0...
November 1, 2016: Food Chemistry
Mihwa Seo, Sangsoon Park, Hong Gil Nam, Seung-Jae V Lee
RNA helicases, which unwind RNAs, are essential for RNA metabolism and homeostasis. However, the roles of RNA helicases in specific physiological processes remain poorly understood. We recently reported that an RNA helicase, HEL-1, promotes long lifespan conferred by reduced insulin/insulin-like growth factor-1 (IGF-1) signaling (IIS) in Caenorhabditis elegans. We also showed that HEL-1 induces the expression of longevity genes by physically interacting with Forkhead box O (FOXO) transcription factor. Thus, the HEL-1 RNA helicase appears to regulate lifespan by specifically activating FOXO in IIS...
July 17, 2016: Cell Cycle
Jeffrey R Shearstone, Olga Golonzhka, Apurva Chonkar, David Tamang, John H van Duzer, Simon S Jones, Matthew B Jarpe
Therapeutic intervention aimed at reactivation of fetal hemoglobin protein (HbF) is a promising approach for ameliorating sickle cell disease (SCD) and β-thalassemia. Previous studies showed genetic knockdown of histone deacetylase (HDAC) 1 or 2 is sufficient to induce HbF. Here we show that ACY-957, a selective chemical inhibitor of HDAC1 and 2 (HDAC1/2), elicits a dose and time dependent induction of γ-globin mRNA (HBG) and HbF in cultured primary cells derived from healthy individuals and sickle cell patients...
2016: PloS One
Nicole L Regna, Miranda D Vieson, Xin M Luo, Cristen B Chafin, Abdul Gafoor Puthiyaveetil, Sarah E Hammond, David L Caudell, Matthew B Jarpe, Christopher M Reilly
We sought to determine if a selective HDAC6 inhibitor (ACY-738) decreases disease in NZB/W mice. From 22 to 38weeks-of-age, mice were injected intraperitoneally with 5 or 20mg/kg of ACY-738, or vehicle control. Body weight and proteinuria were measured every 2weeks, while sera anti-dsDNA, Ig isotypes, and cytokine levels were measured every 4weeks. Kidney disease was determined by evaluation of sera, urine, immune complex deposition, and renal pathology. Flow cytometric analysis assessed thymic, splenic, bone marrow, and peripheral lymphocyte differentiation patterns...
January 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Nicole L Regna, Miranda D Vieson, Alexander M Gojmerac, Xin M Luo, David L Caudell, Christopher M Reilly
Prior studies have shown that pan-HDAC inhibition can decrease disease in lupus mice; however, the mechanisms(s) remain to be elucidated. MRL/MpJ-Fas(lpr) (MRL/lpr) mice develop a lupus-like disease characterized by anti-dsDNA production, lymphoproliferation, and immune complex-mediated glomerulonephritis. Early- and late-disease (12 and 20weeks-of-age respectively) female MRL/lpr mice were compared to age-matched, healthy C57BL/6 mice for HDAC expression and activity in bone marrow (BM) B cells, splenic B and T cells, and glomerular cells...
December 2015: International Immunopharmacology
Zhuang Yang, Taijin Wang, Fang Wang, Ting Niu, Zhuowei Liu, Xiaoxin Chen, Chaofeng Long, Minghai Tang, Dong Cao, Xiaoyan Wang, Wei Xiang, Yuyao Yi, Liang Ma, Jingsong You, Lijuan Chen
Novel selective histone deacetylase 6 (HDAC6) inhibitors using the quinazoline as the cap were designed, synthesized, and evaluated for HDAC enzymatic assays. N-Hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)butanamide, 23bb, was the most potent selective inhibitor for HDAC6 with an IC50 of 17 nM and showed 25-fold and 200-fold selectivity relative to HDAC1 and HDAC8, respectively. In vitro, 23bb presented low nanomolar antiproliferative effects against panel of cancer cell lines. Western blot analysis further confirmed that 23bb increased acetylation level of α-tubulin in vitro...
February 25, 2016: Journal of Medicinal Chemistry
Dorothy E Vatner, Lin Yan, Lo Lai, Chujun Yuan, Laurent Mouchiroud, Ronald E Pachon, Jie Zhang, Jean-Guillaume Dillinger, Riekelt H Houtkooper, Johan Auwerx, Stephen F Vatner
The most important physiological mechanism mediating enhanced exercise performance is increased sympathetic, beta adrenergic receptor (β-AR), and adenylyl cyclase (AC) activity. This is the first report of decreased AC activity mediating increased exercise performance. We demonstrated that AC5 disruption, that is, knock out (KO) mice, a longevity model, increases exercise performance. Importantly for its relation to longevity, exercise was also improved in old AC5 KO. The mechanism resided in skeletal muscle rather than in the heart, as confirmed by cardiac- and skeletal muscle-specific AC5 KO's, where exercise performance was no longer improved by the cardiac-specific AC5 KO, but was by the skeletal muscle-specific AC5 KO, and there was no difference in cardiac output during exercise in AC5 KO vs...
December 2015: Aging Cell
Vivian Caetano Bochi, Milene Teixeira Barcia, Daniele Rodrigues, Helena Teixeira Godoy
UNLABELLED: Dovyalis hebecarpa, which is also known as the Ceylon gooseberry, is an attractive exotic purple berry that is produced in the southwest of Brazil with high yields. Current literature lacks information about the nutritional composition and antioxidant capacity of this fruit. As such, this work aimed to evaluate and compare the proximate composition, phytochemical content, and antioxidant capacity of D. hebecarpa over two seasons through the application of a range of different methods, including FRAP, ABTS, and ORAC assays...
October 2015: Journal of Food Science
Sonia Pedotti, Venerando Pistarà, Carmela Cannavà, Claudia Carbone, Felisa Cilurzo, Antonino Corsaro, Giovanni Puglisi, Cinzia Anna Ventura
We report the synthesis of an oligomeric prodrug of the antiviral agent Acyclovir (Acy) conjugated to β-cyclodextrin (β-CyD). The drug was selectively linked through a succinic spacer to one of the primary hydroxyl groups of β-CyD by ester linkage in a 1:1 molar ratio. The conjugate was purified by semipreparative reverse-phase chromatography and characterized by FAB mass spectrometry and NMR experiments. The release of Acy from the conjugate was evaluated both in acidic and in neutral conditions and in the presence of porcine liver esterase...
October 20, 2015: Carbohydrate Polymers
Karishma Hussain, S Balachandran, Raza Rafiqul Hoque
Analysis of riverine sediments offers important information regarding anthropogenic activities in the adjacent watershed. In this study, we provide polycyclic aromatic hydrocarbon (PAH) levels, their possible sources and potential hazards in the Bharalu tributary of the Brahmaputra River flowing through Guwahati city in India. The USEPA's 16 priority PAHs were determined in river bank sediments during two distinct seasons viz. pre- and post-monsoon. The ∑PAHs concentrations varied between 338 and 23,100 ng g(-1) during post-monsoon and between 609 and 8620 ng g(-1) during pre-monsoon...
December 2015: Ecotoxicology and Environmental Safety
Ping Li, Xiaoping Diao, Yu Zhang, Yanli Xie, Fei Yang, Hailong Zhou, Qian Han, Fuqiang Wang, Huamin Cheng, Haihua Wang
The study investigated the occurrence of polycyclic aromatic hydrocarbons (PAHs) in the surface sediment from eleven sites in Yangpu Bay, China in December 2013 (winter) and July 2014 (summer). The 16 US EPA priority PAHs were found in the range of 1583.2-5701.7 ng/g dry weights with an average of 3134.7 ± 1241.3 ng/g in winter and ranged from 2161.8 to 4527.2 ng/g with an average of 3016.6 ± 748.0 ng/g in summer, respectively. The concentrations of the PAHs tended to be relatively high in comparison with other areas from the literatures...
October 15, 2015: Marine Pollution Bulletin
D Murawa, P Nowaczyk, A Spychała, M Hünerbein, M Michał
BACKGROUND: The aim of this study was to assess sentinel node biopsy (SNB) results in colon cancer (CC) regarding intraoperative staging of the disease and pathological cancer features. MATERIAL AND METHODS: The study was conducted on the basis of 132 SNBs in CC. The elements of intraoperative staging of the disease and pathological cancer features were compared with accuracy, sensitivity and false negative results of SNB in CC by means of ROC curves and the tests for population proportions...
May 2015: Acta Chirurgica Belgica
Shun Li, Xiao Liu, Xiangrong Chen, Liu Zhang, Xiangyu Wang
Histone deacetylases (HDACs) play a role in the tumorigenesis of glioblastoma multiforme (GBM), whereas the underlying mechanism has not been elucidated. Here, we reported significantly higher HDAC6 levels in GBM from the patients. GBM cell growth was significantly inhibited by ACY-1215, a specific HDAC6 inhibitor. Further analyses show that HDAC6 may promote growth of GBM cells through inhibition of SMAD2 phosphorylation to downregulate p21. Thus, our data demonstrate a previously unrecognized regulation pathway in that HDAC6 increases GBM growth through attenuating transforming growth factor β (TGFβ) receptor signaling...
December 2015: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Jennifer E Amengual, Paul Johannet, Maximilian Lombardo, Kelly Zullo, Daniela Hoehn, Govind Bhagat, Luigi Scotto, Xavier Jirau-Serrano, Dejan Radeski, Jennifer Heinen, Hongfeng Jiang, Serge Cremers, Yuan Zhang, Simon Jones, Owen A O'Connor
PURPOSE: Pan-class histone deacetylase (HDAC) inhibitors are effective treatments for select lymphomas. Isoform-selective HDAC inhibitors are emerging as potentially more targeted agents. HDAC6 is a class IIb deacetylase that facilitates misfolded protein transport to the aggresome for degradation. We investigated the mechanism and therapeutic impact of the selective HDAC6 inhibitor ACY-1215 alone and in combination with bortezomib in preclinical models of lymphoma. EXPERIMENTAL DESIGN: Concentration-effect relationships were defined for ACY-1215 across 16 lymphoma cell lines and for synergy with bortezomib...
October 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Rey Gutiérrez, Salvador Vega, Rutilio Ortiz, José Jesús Pérez, Beatriz Schettino
The objective of this study was to determine the concentrations of polycyclic aromatic hydrocarbons (PAHs) in cow's milk from industrial farms that are located near an industrial park in Hidalgo, Mexico. It was found that the concentrations of PAHs in the raw milk of cattle from industrial farms have increased in recent years. Composite samples were collected between 2008 and 2010 and analysis carried out according to 8100 EPA procedures and analyzed by gas chromatography with FID detection. The results show that combustion PAHs were mostly Ace, Acy, and Fla (0...
2015: Journal of Environmental Science and Health. Part. B, Pesticides, Food Contaminants, and Agricultural Wastes
Yuko Mishima, Loredana Santo, Homare Eda, Diana Cirstea, Neeharika Nemani, Andrew J Yee, Elizabeth O'Donnell, Martin Karl Selig, Steven N Quayle, Shirin Arastu-Kapur, Christopher Kirk, Lawrence H Boise, Simon S Jones, Noopur Raje
Proteasome inhibition induces the accumulation of aggregated misfolded/ubiquitinated proteins in the aggresome; conversely, histone deacetylase 6 (HDAC6) inhibition blocks aggresome formation. Although this rationale has been the basis of proteasome inhibitor (PI) and HDAC6 inhibitor combination studies, the role of disruption of aggresome formation by HDAC6 inhibition has not yet been studied in multiple myeloma (MM). The present study aimed to evaluate the impact of carfilzomib (CFZ) in combination with a selective HDAC6 inhibitor (ricolinostat) in MM cells with respect to the aggresome-proteolysis pathway...
May 2015: British Journal of Haematology
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