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Thomas George Back, Kai N Sands, Tyler A Tuck
Selenium compounds play an important role in redox homeostasis in living organisms. One of their major functions is to suppress the harmful effects of hydrogen peroxide, hydroperoxides and downstream reactive oxygen species that lead to oxidative stress, which has in turn been implicated in many diseases and degenerative conditions. The glutathione peroxidase (GPx) family of selenoenzymes plays a key protective role by catalyzing the reduction of peroxides with glutathione. Considerable effort has been expended toward the discovery of small-molecule selenium compounds that mimic GPx...
March 14, 2018: Chemistry: a European Journal
Danny C Lenstra, Abbas H K Al Temimi, Jasmin Mecinović
Histone lysine methyltransferases G9a and GLP are validated targets for the development of new epigenetic drugs. Most, if not all, inhibitors of G9a and GLP target the histone substrate binding site or/and the S-adenosylmethionine cosubstrate binding site. Here, we report an alternative approach for inhibiting the methyltransferase activity of G9a and GLP. For proper folding and enzymatic activity, G9a and GLP contain structural zinc fingers, one of them being adjacent to the S-adenosylmethionine binding site...
February 24, 2018: Bioorganic & Medicinal Chemistry Letters
Walaa M El-Hady, Azza A A Galal
The neurological effects of manganese (Mn) exposure on adults consuming contaminated water remain unclear. Accordingly, the current experiment was planned to explore the neurotoxic consequences of subchronic Mn exposure via contaminated water and to examine whether ebselen (Ebs) improved these outcomes. Rats exposed to oral MnCl2 (50 mg/kg body weight) for 30 successive days exhibited reduced rearing and ambulation. Furthermore, Mn administration increased brain Mn concentrations and induced superoxide dismutase, catalase, and glutathione depletion...
March 7, 2018: Biological Trace Element Research
Ling Xu, Changguo Gong, Guangming Li, Jue Wei, Ting Wang, Wenying Meng, Min Shi, Yugang Wang
Ebselen is a seleno-organic compound that has been demonstrated to have antioxidant and anti-inflammatory properties. A previous study determined that ebselen inhibits airway inflammation induced by inhalational lipopolysaccharide (LPS), however, the underlying molecular mechanism remains to be elucidated. The present study investigated the effect of ebselen on the glutathione peroxidase (GPX)‑reactive oxygen species (ROS) pathway and interleukin‑8 (IL‑8) expression induced by Helicobacter pylori LPS in gastric cancer (GC) cells...
February 27, 2018: Molecular Medicine Reports
I Antoniadou, M Kouskou, T Arsiwala, N Singh, S R Vasudevan, T Fowler, E Cadirci, G C Churchill, T Sharp
BACKGROUND AND PURPOSE: Lithium's antidepressant action may be mediated by inhibition of inositol monophosphatase (IMPase), a key enzyme in Gq protein coupled receptor signalling. Recently, the antioxidant agent ebselen was identified as an IMPase inhibitor. Here we investigated both ebselen and lithium in models of the 5-HT2A receptor, a Gq protein coupled receptor implicated in lithium's actions. EXPERIMENTAL APPROACH: 5-HT2A receptor function was modelled in mice by measuring the behavioural (head-twitches) and cortical immediate early gene (IEG; Arc, c-fos and Erg2 mRNA) responses to 5-HT2A receptor agonist administration...
February 27, 2018: British Journal of Pharmacology
Yanhong Jin, Di Li, Shiying Lu, Han Zhao, Zhao Chen, Wei Hou, Benfang Helen Ruan
Human glutamate dehydrogenase (GDH) plays an important role in neurological diseases, tumor metabolism, and hyperinsulinism-hyperammonemia syndrome (HHS). However, there are very few inhibitors known for human GDH. Recently, Ebselen was reported to crosslink with Escherichia coli GDH at the active site cysteine residue (Cys321), but the sequence alignment showed that the corresponding residue is Ala329 in human GDH. To investigate whether Ebselen could be an inhibitor for human GDH, we cloned and expressed an N-terminal His-tagged human GDH in E...
February 22, 2018: Assay and Drug Development Technologies
Yogy Simanjuntak, Jian-Jong Liang, Si-Yu Chen, Jin-Kun Li, Yi-Ling Lee, Han-Chung Wu, Yi-Ling Lin
Despite the low case fatality, Zika virus (ZIKV) infection has been associated with microcephaly in infants and Guillain-Barré syndrome. Antiviral and vaccine developments against ZIKV are still ongoing; therefore, in the meantime, preventing the disease transmission is critical. Primarily transmitted by Aedes species mosquitoes, ZIKV also can be sexually transmitted. We used AG129 mice lacking interferon-α/β and -γ receptors to study the testicular pathogenesis and sexual transmission of ZIKV. Infection of ZIKV progressively damaged mouse testes, increased testicular oxidative stress as indicated by the levels of reactive oxygen species, nitric oxide, glutathione peroxidase 4, spermatogenesis-associated-18 homolog in sperm and pro-inflammatory cytokines including IL-1β, IL-6, and G-CSF...
February 2018: PLoS Pathogens
Rana Eltahan, Fengguang Guo, Haili Zhang, Lixin Xiang, Guan Zhu
Cryptosporidium parvum is a water-borne and food-borne apicomplexan pathogen. It is one of the top four diarrheal-causing pathogens in children under the age of five in developing countries, and an opportunistic pathogen in immunocompromised individuals. Unlike other apicomplexans, C. parvum lacks Kreb's cycle and cytochrome-based respiration, thus relying mainly on glycolysis to produce ATP. In this study, we characterized the primary biochemical features of the C. parvum glucose-6-phosphate isomerase (CpGPI) and determined its Michaelis constant towards fructose-6-phosphate (Km = 0...
January 25, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Franciele Martini, Ana Paula Pesarico, César Augusto Brüning, Gilson Zeni, Cristina Wayne Nogueira
There is a well-known relationship between the cholinergic system and learning, memory and other common cognitive processes. The process for researching and developing new drugs has lead researchers to repurpose older ones. This study investigated the effects of ebselen on the activity of acethylcholinesterase (AChE) isoforms in vitro and in an amnesia model induced by scopolamine in Swiss mice. In vitro, ebselen at concentrations equal or higher than 10 µM inhibited the activity of cortical and hippocampal G4/AChE, but not G1/AChE isoform...
February 5, 2018: Journal of Cellular Biochemistry
Samuel O Adeosun, Kyle H Moore, David M Lang, Assumpta C Nwaneri, Terry D Hinds, David E Stec
Biliverdin reductase (BVR) is the enzyme responsible for the last step in the production of bilirubin from the breakdown of heme. Bilirubin is one of the most potent antioxidant molecules in the body. Monitoring BVR activity is essential in studying the antioxidant capacity of cells and tissues. Traditional methods of determining BVR activity have relied on the measurement of bilirubin converted from biliverdin using absorbance spectroscopy. The approach has limited sensitivity and requires large quantities of cells or tissues...
2018: Reactive Oxygen Species (Apex, N.C.)
Paul Pang, Molly Abbott, Malyun Abdi, Quynh-Anh Fucci, Nikita Chauhan, Murti Mistri, Brandon Proctor, Matthew Chin, Bin Wang, Wenqing Yin, Tzong-Shi Lu, Arvin Halim, Kenneth Lim, Diane E Handy, Joseph Loscalzo, Andrew M Siedlecki
Background: Chronic kidney disease (CKD) patients have deficient levels of glutathione peroxidase-3 (GPx3). We hypothesized that GPx3 deficiency may lead to cardiovascular disease in the presence of chronic kidney disease due to an accumulation of reactive oxygen species and decreased microvascular perfusion of the myocardium. Methods: To isolate the exclusive effect of GPx3 deficiency in kidney disease-induced cardiac disease, we studied the GPx3 knockout mouse strain (GPx3-/-) in the setting of surgery-induced CKD...
December 13, 2017: Nephrology, Dialysis, Transplantation
Ramesh Kheirabadi, Mohammad Izadyar, Mohammad Reza Housaindokht
The catalytic cycle of a new derivative of ebselen, 1, was elucidated via three steps by the density functional theory and solvent-assisted proton exchange procedure involving indirect proton exchange through a hydrogen-bonded transfer network. Different behaviors of the aromatic and aliphatic thiols were investigated in the reduction of selenoxide (step 2 → 3) and selenurane (step 3 → 1) based on their nucleophilicity. The reduction of selenoxide in the presence of thiophenol (ΔG‡ = 15.9 kcal·mol-1 ) is faster than that of methanethiol (ΔG‡ = 29...
January 11, 2018: Journal of Physical Chemistry. A
Shannon M Dunn, Robert H Hilgers, Kumuda C Das
High-fat sucrose (HFS) diet in aged individuals causes severe weight gain (obesity) with much higher risk of cardiovascular diseases such as hypertension or atherosclerosis. Endothelial dysfunction is a major contributor for these vascular disorders. We hypothesize that prolonged ingestion of HFS diet by aged mice would accentuate endothelial dysfunction in the small resistance arteries. Male C57BL/6J mice at 12 weeks of age were divided into four groups and fed either normal chow (NC) or high-fat sucrose diet (HFS)...
December 2017: Physiological Reports
Anna Cebrián-Prats, Tiffani Rovira, Patricia Saura, Àngels González-Lafont, José M Lluch
Ebselen is a potent competitive inhibitor of the active form of rabbit 15-lipoxygenase, an enzyme involved in many inflammatory diseases. Light-induced Z-to-E isomerization of the ebselen-like 2-(3-benzylidene)-3-oxo-2,3-dihydrobenzo[b]thiophene-7-carboxylic acid methyl ester (BODTCM) molecule was used to convert the weak (Z)-BOTDCM inhibitor into the (E)-isomer with much higher inhibitory capacity. In this study, the binding modes of ebselen, (E)-BOTDCM and (Z)-BOTDCM, have been analyzed to provide molecular insights on the inhibitory potency of ebselen and on the geometric-isomer specificity of (E)- and (Z)-BOTDCM inhibitors...
December 28, 2017: Journal of Physical Chemistry. A
Nilda V Barbosa, Cristina W Nogueira, Pablo A Nogara, Andreza F de Bem, Michael Aschner, João B T Rocha
Selenium is an essential trace element for animals and its role in the chemistry of life relies on a unique functional group: the selenol (-SeH) group. The selenol group participates in critical redox reactions. The antioxidant enzymes glutathione peroxidase (GPx) and thioredoxin reductase (TrxR) exemplify important selenoproteins. The selenol group shares several chemical properties with the thiol group (-SH), but it is much more reactive than the sulfur analogue. The substitution of S by Se has been exploited in organic synthesis for a long time, but in the last 4 decades the re-discovery of ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) and the demonstration that it has antioxidant and therapeutic properties has renovated interest in the field...
November 23, 2017: Metallomics: Integrated Biometal Science
Yan Yu, Yanhong Jin, Jie Zhou, Haoqiang Ruan, Han Zhao, Shiying Lu, Yue Zhang, Di Li, Xiaoyun Ji, Benfang Helen Ruan
Ebselen modulates target proteins through redox reactions with selenocysteine/cysteine residues, or through binding to the zinc finger domains. However, a recent contradiction in ebselen inhibition of kidney type glutaminase (KGA) stimulated our interest in investigating its inhibition mechanism with glutamate dehydrogenase (GDH), KGA, thioredoxin reductase (TrxR), and glutathione S-transferase. Fluorescein- or biotin-labeled ebselen derivatives were synthesized for mechanistic analyses. Biomolecular interaction analyses showed that only GDH, KGA, and TrxR proteins can bind to the ebselen derivative, and the binding to GDH and KGA could be competed off by glutamine or glutamate...
November 7, 2017: ACS Chemical Biology
C S Oliveira, B C Piccoli, M Aschner, J B T Rocha
The antagonism of mercury toxicity by selenium has been well documented. Mercury is a toxic metal, widespread in the environment. The main target organs (kidneys, lungs, or brain) of mercury vary depending on its chemical forms (inorganic or organic). Selenium is a semimetal essential to mammalian life as part of the amino acid selenocysteine, which is required to the synthesis of the selenoproteins. This chapter has the aim of disclosing the role of selenide or hydrogen selenide (Se-2 or HSe- ) as central metabolite of selenium and as an important antidote of the electrophilic mercury forms (particularly, Hg2+ and MeHg)...
2017: Advances in Neurobiology
A B Niculescu, H Le-Niculescu, D F Levey, P L Phalen, H L Dainton, K Roseberry, E M Niculescu, J O Niezer, A Williams, D L Graham, T J Jones, V Venugopal, A Ballew, M Yard, T Gelbart, S M Kurian, A Shekhar, N J Schork, G E Sandusky, D R Salomon
Suicide remains a clear, present and increasing public health problem, despite being a potentially preventable tragedy. Its incidence is particularly high in people with overt or un(der)diagnosed psychiatric disorders. Objective and precise identification of individuals at risk, ways of monitoring response to treatments and novel preventive therapeutics need to be discovered, employed and widely deployed. We sought to investigate whether blood gene expression biomarkers for suicide (that is, a 'liquid biopsy' approach) can be identified that are more universal in nature, working across psychiatric diagnoses and genders, using larger cohorts than in previous studies...
September 2017: Molecular Psychiatry
Taro Sakamoto, Hirotaka Imai
Superoxide dismutase (SOD) is a ubiquitous antioxidant enzyme that catalytically converts the superoxide radical to hydrogen peroxide (H2O2). In mammals, high SOD activity is detectable in sperm and seminal plasma, and loss of SOD activity has been correlated with male infertility; however, the underlying mechanisms of sperm infertility remain to be clarified. Here we report that the deletion of two major SOD genes in Caenorhabditis elegans, sod-1 and sod-2, causes sperm activation defects, leading to a significant reduction in brood size...
September 8, 2017: Journal of Biological Chemistry
Jonathan Kil, Edward Lobarinas, Christopher Spankovich, Scott K Griffiths, Patrick J Antonelli, Eric D Lynch, Colleen G Le Prell
BACKGROUND: Noise-induced hearing loss is a leading cause of occupational and recreational injury and disease, and a major determinant of age-related hearing loss. No therapeutic agent has been approved for the prevention or treatment of this disorder. In animal models, glutathione peroxidase 1 (GPx1) activity is reduced after acute noise exposure. Ebselen, a novel GPx1 mimic, has been shown to reduce both temporary and permanent noise-induced hearing loss in preclinical studies. We assessed the safety and efficacy of ebselen for the prevention of noise-induced hearing loss in young adults in a phase 2 clinical trial...
July 14, 2017: Lancet
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