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Joshua A Beckman, Allison B Goldfine, Jane A Leopold, Mark A Creager
Oxidative stress is a key driver of vascular dysfunction in diabetes mellitus. Ebselen is a glutathione-peroxidase mimetic. A single-site, randomized, double-masked, placebo-controlled crossover trial in 26 subjects with either type 1 or type 2 diabetes to evaluate effects of high-dose ebselen (150 mg orally twice daily) administration on oxidative stress and endothelium-dependent vasodilation. Treatment periods were in random order of 4 weeks duration, with a 4 week washout between. Measures of oxidative stress included nitrotyrosine, plasma 8-isoprostanes, and the ratio of reduced-to-oxidized glutathione...
October 7, 2016: American Journal of Physiology. Heart and Circulatory Physiology
Jyothi Padiadpu, Priyanka Baloni, Kushi Anand, MohamedHusen Munshi, Chandrani Thakur, Abhilash Mohan, Amit Singh, Nagasuma Chandra
The global mechanisms and associated molecular alterations that occur in drug-resistant mycobacteria are poorly understood. To address this, we obtain genomics data and then construct a genome-scale response network in isoniazid-resistant Mycobacterium smegmatis and apply a network-mining algorithm. Through this, we decipher global alterations in an unbiased manner and identify emergent vulnerabilities in resistant bacilli, of which redox response was prominent. Using phenotypic profiling, we find that resistant bacilli exhibit collateral sensitivity to several compounds that block antioxidant responses...
September 9, 2016: ACS Infectious Diseases
Jie Dai, Jun Zhou, Hongmei Liu, Kaixun Huang
Selenite and ebselen supplementation has been shown to possess anti-cataract potential in some experimental animal models of cataract, however, the underlying mechanisms remain unclear. The present study was designed to evaluate the anti-cataract effects and the underlying mechanisms of selenite and ebselen supplementation on galactose induced cataract in rats, a common animal model of sugar cataract. Transmission electron microscopy images of lens fiber cells (LFC) and lens epithelial cells (LEC) were observed in D-galactose-induced experimental cataractous rats treated with or without selenite and ebselen, also redox homeostasis and expression of proteins such as selenoprotein R (SELR), 15kD selenoprotein (SEP15), superoxide dismutase 1 (SOD1), catalase (CAT), β-crystallin protein, aldose reductase (AR) and glucose-regulated protein 78 (GRP78) were estimated in the lenses...
October 17, 2016: Journal of Biological Inorganic Chemistry: JBIC
Francieli Chassot, Tarcieli Pozzebon Venturini, Fernanda Baldissera Piasentin, Janio Morais Santurio, Terezinha Inez Estivalet Svidzinski, Sydney Hartz Alves
We evaluated the in vitro antifungal activity of diphenyl diselenide and ebselen against echinocandin-susceptible and -resistant strains of Candida parapsilosis using the broth microdilution method. Diphenyl diselenide (MIC range=1-8μg/mL) and ebselen (MIC range=0.25-4μg/mL) showed in vitro activity against echinocandin-susceptible isolates. However, ebselen also showed the highest antifungal activity against echinocandin-resistant strains (MIC range=0.06-4μg/mL). This study demonstrated that the antifungal potential of diphenyl diselenide and ebselen deserves further investigation using in vivo experimental protocols...
September 13, 2016: New Microbiologica
Shankar Thangamani, Hassan E Eldesouky, Haroon Mohammad, Pete E Pascuzzi, Larisa Avramova, Tony R Hazbun, Mohamed N Seleem
BACKGROUND: Ebselen, an organoselenium compound and a clinically safe molecule has been reported to possess potent antifungal activity, but its antifungal mechanism of action and in vivo antifungal activity remain unclear. METHODS: The antifungal effect of ebselen was tested against Candida albicans, C. glabrata, C. tropicalis, C. parapsilosis, Cryptococcus neoformans, and C. gattii clinical isolates. Chemogenomic profiling and biochemical assays were employed to identify the antifungal target of ebselen...
October 3, 2016: Biochimica et Biophysica Acta
Ewelina Węglarz-Tomczak, Małgorzata Burda-Grabowska, Mirosław Giurg, Artur Mucha
A collection of twenty-six organoselenium compounds, ebselen and its structural analogues, provided a novel approach for inhibiting the activity of human methionine aminopeptidase 2 (MetAP2). This metalloprotease, being responsible for the removal of the amino-terminal methionine from newly synthesized proteins, plays a key role in angiogenesis, which is essential for the progression of diseases, including solid tumor cancers. In this work, we discovered that ebselen, a synthetic organoselenium drug molecule with anti-inflammatory, anti-oxidant and cytoprotective activity, inhibits one of the main enzymes in the tumor progression pathway...
September 20, 2016: Bioorganic & Medicinal Chemistry Letters
Michael J Parnham
INTRODUCTION: Discussion of the relevance of suitable experimental models for the effective translation of drug effects to clinical inflammatory diseases has a long history. Much emphasis is placed these days on genetically transformed mice, which may have developmental drawbacks. But are established models redundant? FINDINGS: Drawn from personal experience, examples are provided of the success of tinkering with technology in the context of inflammation. These include the use of specific dietary deficiency conditions, the development of new applications for established drugs and the introduction of a variety of readouts to assess outcome in studies on established disease models...
September 28, 2016: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
Claudia Pisanu, Carla Melis, Alessio Squassina
Preclinical Research Bipolar disorder (BPD) is a chronic and disabling psychiatric disorder with a prevalence of 0.8-1.2% in the general population. Although lithium is considered the first-line treatment, a large percentage of patients do not respond sufficiently. Moreover, lithium can induce severe side effects and has poor tolerance and a narrow therapeutic index. The genetics of lithium response has been largely investigated, but findings have so far failed to identify reliable biomarkers to predict clinical response...
September 16, 2016: Drug Development Research
Ramesh Kheirabadi, Mohammad Izadyar, Mohammad Reza Housiandokht
Density functional theory and solvent-assisted proton exchange methods have been applied for computational modeling of the catalytic cycle of selenol zwitterion anion from the kinetic and thermodynamic viewpoints. Selenol zwitterion anion has been represented as an effective glutathione peroxidase nanomimic. It reduces peroxides through a three-step pathway. In the first step, seleninic acid is produced through deprotonating of the selenol zwitterion anion in the presence of the hydrogen peroxide. Seleninic acid reacts with a thiol to form selenylsulfide in the second step...
November 21, 2016: Journal of Theoretical Biology
Katarzyna Macegoniuk, Ewa Grela, Jerzy Palus, Ewa Rudzińska-Szostak, Agnieszka Grabowiecka, Monika Biernat, Łukasz Berlicki
Urease inhibitors are considered promising compounds for the treatment of ureolytic bacterial infections, particularly infections resulting from Helicobacter pylori in the gastric tract. Herein, we present the synthesis and the inhibitory activity of novel and highly effective organoselenium compounds as inhibitors of Sporosarcina pasteurii and Helicobacter pylori ureases. These studied compounds represent a class of competitive reversible urease inhibitors. The most active compound, 2-phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen), displayed Ki values equal to 2...
September 8, 2016: Journal of Medicinal Chemistry
Fabricia Petronilho, Monique Michels, Lucinéia G Danielski, Mariana Pereira Goldim, Drielly Florentino, Andriele Vieira, Mariana G Mendonça, Moema Tournier, Bárbara Piacentini, Amanda Della Giustina, Daniela D Leffa, Gregório W Pereira, Volnei D Pereira, João Batista Teixeira Da Rocha
OBJETIVE: The aim of this study was to evaluate the effects of diphenyl diselenide (PhSe)2 and ebselen (EB) in ulcerative colitis (UC) induced by dextran sulfate sodium (DSS) in rats. METHODS: The effects of (PhSe)2 and EB in rats submitted to DSS-induced colitis were determined by measurement of oxidative stress parameters, inflammatory response and bowel histopathological alterations. RESULTS: Animals developed moderate to severe neutrophil infiltration in histopathology assay in DSS rats and (PhSe)2 improved this response...
September 2016: Pathology, Research and Practice
Jacob Ingemar Olsen, Gabriela B Plata, José M Padrón, Óscar López, Mikael Bols, José G Fernández-Bolaños
Herein we report the synthesis of N-alkylated deoxynojirimycin derivatives decorated with a selenoureido motif at the hydrocarbon tether as an example of unprecedented multitarget agents. Title compounds were designed as dual drugs for tackling simultaneously the Gaucher disease (by selective inhibition of β-glucosidase, Ki = 1.6-5.5 μM, with improved potency and selectivity compared to deoxynojirimycin) and its neurological complications (by inhibiting AChE, Ki up to 5.8 μM). Moreover, an excellent mimicry of the selenoenzyme glutathione peroxidase was also found for the catalytic scavenging of H2O2 (Kcat/Kuncat up to 640) using PhSH as a cofactor, with improved activity compared to known positive controls, like (PhSe)2 and ebselen; therefore, such compounds are also excellent scavengers of peroxides, an example of reactive oxygen species present at high concentrations in patients of Gaucher disease and neurological disorders...
November 10, 2016: European Journal of Medicinal Chemistry
Qianqian Jiang, Yu Pan, Yupeng Cheng, Huiling Li, Hui Li
Hepatic ischemia-reperfusion (I-R) injury causes acute organ damage or dysfunction, and remains a problem for liver transplantation. In the I-R phase, the generation of reactive oxygen species aggravates the injury. In the current study, a novel selenocysteine-containing 7‑mer peptide (H-Arg-Sec-Gly-Arg-Asn-Ala-Gln-OH) was constructed to imitate the active site of an antioxidant enzyme, glutathione peroxidase (GPX). The 7‑mer peptide which has a lower molecular weight, and improved water‑solubility, higher stability and improved cell membrane permeability compared with other GPX mimics...
September 2016: Molecular Medicine Reports
Jim Küppers, Anna Christina Schulz-Fincke, Jerzy Palus, Mirosław Giurg, Jacek Skarżewski, Michael Gütschow
The organo-seleniumdrug ebselen exhibits a wide range of pharmacological effects that are predominantly due to its interference with redox systems catalyzed by seleno enzymes, e.g., glutathione peroxidase and thioredoxin reductase. Moreover, ebselen can covalently interact with thiol groups of several enzymes. According to its pleiotropic mode of action, ebselen has been investigated in clinical trials for the prevention and treatment of different ailments. Fluorescence-labeled probes containing ebselen are expected to be suitable for further biological and medicinal studies...
2016: Pharmaceuticals
Wei Zhang, Min Zhu, Feng Wang, Danhui Cao, Jennifer Jin Ruan, Weike Su, Benfang Helen Ruan
Glutamate dehydrogenase (GDH) catalyzes the oxidative deamination of L-glutamate and is important for several biological processes. For GDH inhibitor screening, we developed a novel mono-sulfonated tetrazolium salt (EZMTT), which can be synthesized using H2O2 oxidation and purified easily on silica gel in large quantities. The EZMTT detection method showed linear dose responses to NAD(P)H, dehydrogenase concentration and cell numbers. In E. coli GDH assay, the EZMTT method showed excellent assay reproducibility with a Z factor of 0...
September 15, 2016: Analytical Biochemistry
Saad Shaaban, Amr Negm, Abeer M Ashmawy, Dalia M Ahmed, Ludger A Wessjohann
Novel tetrazole-based diselenides and selenoquinones were synthesized via azido-Ugi and sequential nucleophilic substitution (SN) strategy. Molecular docking study into mammalian TrxR1 was used to predict the anticancer potential of the newly synthesized compounds. The cytotoxic activity of the compounds was evaluated using hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7) cancer cells and compared with their cytotoxicity in normal fibroblast (WI-38) cells. The corresponding redox properties of the synthesized compounds were assessed employing 2,2-diphenyl-1-picrylhydrazyl (DPPH), glutathione peroxidase (GPx)-like activity and bleomycin dependent DNA damage...
October 21, 2016: European Journal of Medicinal Chemistry
Huy X Ngo, Sanjib K Shrestha, Sylvie Garneau-Tsodikova
Invasive fungal infections are on the rise due to an increased population of critically ill patients as a result of HIV infections, chemotherapies, and organ transplantations. Current antifungal drugs are helpful, but are insufficient in addressing the problem of drug-resistant fungal infections. Thus, there is a growing need for novel antimycotics that are safe and effective. The ebselen scaffold has been evaluated in clinical trials and has been shown to be safe in humans. This makes ebselen an attractive scaffold for facile translation from bench to bedside...
July 19, 2016: ChemMedChem
Patricia Santofimia-Castaño, Alicia Izquierdo-Alvarez, Irene de la Casa-Resino, Antonio Martinez-Ruiz, Marcos Perez-Lopez, Juan C Portilla, Gines M Salido, Antonio Gonzalez
Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) is an organoselenium radical scavenger compound, which has strong antioxidant and anti-inflammatory effects. Because of its properties, it may be protective against injury to the nervous tissue. However, evidence suggests that its glutathione peroxidase activity could underlie certain deleterious actions on cell physiology. In this study we have analyzed the effect of ebselen on rat hippocampal astrocytes in culture. Cellular oxidative status, cytosolic free-Ca(2+) concentration ([Ca(2+)]c), setting of endoplasmic reticulum stress and phosphorylation of glial fibrillary acidic protein and major mitogen-activated protein kinases were analyzed...
May 16, 2016: Toxicology
Charles Masaki, Ann L Sharpley, Charlotte M Cooper, Beata R Godlewska, Nisha Singh, Sridhar R Vasudevan, Catherine J Harmer, Grant C Churchill, Trevor Sharp, Robert D Rogers, Philip J Cowen
RATIONALE: Lithium remains the most effective treatment for bipolar disorder and also has important effects to lower suicidal behaviour, a property that may be linked to its ability to diminish impulsive, aggressive behaviour. The antioxidant drug, ebselen, has been proposed as a possible lithium-mimetic based on its ability in animals to inhibit inositol monophosphatase (IMPase), an action which it shares with lithium. OBJECTIVES: The aim of the study was to determine whether treatment with ebselen altered emotional processing and diminished measures of risk-taking behaviour...
July 2016: Psychopharmacology
Holger Steinbrenner, Esra Bilgic, Antonio Pinto, Melanie Engels, Lena Wollschläger, Laura Döhrn, Kristine Kellermann, Udo Boeken, Payam Akhyari, Artur Lichtenberg
Ischemia/reperfusion injury (IRI) contributes to morbidity and mortality after cardiovascular surgery requiring cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). Multi-organ damage is associated with substantial decreases of blood selenium (Se) levels in patients undergoing cardiac surgery with CPB. We compared the influence of a dietary surplus of Se and pretreatment with ebselen, a mimic of the selenoenzyme glutathione peroxidase, on IRI-induced tissue damage and inflammation. Male Wistar rats were fed either a Se-adequate diet containing 0...
August 2016: Inflammation
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