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Bioscavenger | Page 2

Rocío Ramírez-Jiménez, María Fernanda Martínez-Salazar, Damianys Almenares-López, Leticia Yáñez-Estrada, Antonio Monroy-Noyola
BACKGROUND: The enzymes butyrylcholinesterase (BuChE) and paraoxonase-1 (PON1) are the primary bioscavenging enzymes in serum and exhibit antioxidant and anti-inflammatory activities. PON1 has been associated with diseases caused by high oxidative stress, whereas BuChE appears to be involved in the pathophysiology of the metabolic syndrome and related disorders. It has been suggested that children from rural communities in Mexico may have a predisposition to develop obesity or type 2 diabetes during adolescence or adulthood...
March 2018: Metabolic Syndrome and related Disorders
Austen Bernardi, Karl N Kirschner, Roland Faller
Human butyrylcholinesterase (BChE) is a glycoprotein capable of bioscavenging toxic compounds such as organophosphorus (OP) nerve agents. For commercial production of BChE, it is practical to synthesize BChE in non-human expression systems, such as plants or animals. However, the glycosylation profile in these systems is significantly different from the human glycosylation profile, which could result in changes in BChE's structure and function. From our investigation, we found that the glycan attached to ASN241 is both structurally and functionally important due to its close proximity to the BChE tetramerization domain and the active site gorge...
2017: PloS One
T M Mann, M E Price, C L Whitmore, R L Perrott, T R Laws, R R McColm, E R Emery, J E H Tattersall, A C Green, H Rice
The prolonged systemic exposure that follows skin contamination with low volatility nerve agents, such as VX, requires treatment to be given over a long time due to the relatively short half-lives of the therapeutic compounds used. Bioscavengers, such as butyrylcholinesterase (BChE), have been shown to provide effective post-exposure protection against percutaneous nerve agent when given immediately on signs of poisoning and to reduce reliance on additional treatments. In order to assess the benefits of administration of bioscavenger at later times, its effectiveness was assessed when administration was delayed for 2h after the appearance of signs of poisoning in guinea-pigs challenged with VX (4×LD50 )...
September 1, 2018: Toxicology Letters
Xavier Brazzolotto, Alexandre Igert, Virginia Guillon, Gianluca Santoni, Florian Nachon
Human butyrylcholinesterase is a performant stoichiometric bioscavenger of organophosphorous nerve agents. It is either isolated from outdated plasma or functionally expressed in eukaryotic systems. Here, we report the production of active human butyrylcholinesterase in a prokaryotic system after optimization of the primary sequence through the Protein Repair One Stop Shop process, a structure- and sequence-based algorithm for soluble bacterial expression of difficult eukaryotic proteins. The mutant enzyme was purified to homogeneity...
October 27, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Katherine E Larrimore, I Can Kazan, Latha Kannan, R Player Kendle, Tameem Jamal, Matthew Barcus, Ashini Bolia, Stephen Brimijoin, Chang-Guo Zhan, S Banu Ozkan, Tsafrir S Mor
Butyrylcholinesterase (BChE) is an enzyme with broad substrate and ligand specificities and may function as a generalized bioscavenger by binding and/or hydrolyzing various xenobiotic agents and toxicants, many of which target the central and peripheral nervous systems. Variants of BChE were rationally designed to increase the enzyme's ability to hydrolyze the psychoactive enantiomer of cocaine. These variants were cloned, and then expressed using the magnICON transient expression system in plants and their enzymatic properties were investigated...
September 5, 2017: Scientific Reports
Julia Herbert, Horst Thiermann, Franz Worek, Timo Wille
Standard therapeutic options in organophosphate (OP) poisoning are limited to the administration of atropine and oximes, a regimen often lacking in efficacy and applicability. Treatment alternatives are needed, preferably covering a broad spectrum of OP intoxications. Although recent research yielded several promising compounds, e.g. bioscavengers, modulators of the muscarinic acetylcholine (ACh) receptor or bispyridinium non-oximes, these substances still need further evaluation, especially regarding effects on the potentially lethal respiratory symptoms of OP poisoning...
August 15, 2017: Toxicology
Patrick Masson, Florian Nachon
Organophosphorus agents (OPs) irreversibly inhibit acetylcholinesterase (AChE) causing a major cholinergic syndrome. The medical counter-measures of OP poisoning have not evolved for the last 30 years with carbamates for pretreatment, pyridinium oximes-based AChE reactivators, antimuscarinic drugs and neuroprotective benzodiazepines for post-exposure treatment. These drugs ensure protection of peripheral nervous system and mitigate acute effects of OP lethal doses. However, they have significant limitations...
August 2017: Journal of Neurochemistry
Hyeongseok Yun, Sungrae Lee, Sumi Kim, Jiyeon Yu, Nari Lee, Jinhee Lee, Nam Doo Kim, Chiho Yu, Jaerang Rho
BACKGROUND: Human prolidase has weak hydrolytic activity for toxic organophosphorus compounds including diisopropyl fluorophosphates (DFP), chemical warfare nerve agents and pesticides. OBJECTIVES: In order to use human prolidase as a catalytic bioscavenger against toxic organophosphorus compound exposure, protein engineering is an important issue to improve the catalytic activity of human prolidase towards the hydrolysis of toxic organophosphorus compounds. METHOD: We developed two human prolidase mutants, A252R and P365R, with a single amino acid substitution using in silico analysis based on the sequence, protein structure and stability to improve the catalytic activity of human prolidase towards DFP hydrolysis...
2017: Protein and Peptide Letters
Reed B Jacob, Kenan C Michaels, Cathy J Anderson, James M Fay, Nikolay V Dokholyan
No abstract text is available yet for this article.
April 28, 2017: Scientific Reports
Beth A Reed, Carol L Sabourin, David E Lenz
Acetylcholinesterase is vital for normal operation of many processes in the body. Following exposure to organophosphorus (OP) nerve agents, death can ensue without immediate medical intervention. Current therapies mitigate the cholinergic crisis caused by nerve agents but do not fully prevent long-term health concerns, for example, brain damage following seizures. Human butyrylcholinesterase (HuBChE) is a stoichiometric bioscavenger being investigated as an antidote for OP nerve agent poisoning. HuBChE sequesters OP nerve agent in the bloodstream preventing the nerve agent from reaching critical target organ systems...
May 2017: Journal of Biochemical and Molecular Toxicology
Reed B Jacob, Kenan C Michaels, Cathy J Anderson, James M Fay, Nikolay V Dokholyan
No abstract text is available yet for this article.
February 17, 2017: Scientific Reports
Moshe Goldsmith, Nidhi Aggarwal, Yacov Ashani, Halim Jubran, Per Jr Greisen, Sergey Ovchinnikov, Haim Leader, David Baker, Joel L Sussman, Adi Goldenzweig, Sarel J Fleishman, Dan S Tawfik
Improving an enzyme's initially low catalytic efficiency with a new target substrate by an order of magnitude or two may require only a few rounds of mutagenesis and screening or selection. However, subsequent rounds of optimization tend to yield decreasing degrees of improvement (diminishing returns) eventually leading to an optimization plateau. We aimed to optimize the catalytic efficiency of bacterial phosphotriesterase (PTE) toward V-type nerve agents. Previously, we improved the catalytic efficiency of wild-type PTE toward the nerve agent VX by 500-fold, to a catalytic efficiency (kcat/KM) of 5 × 106 M-1 min-1...
April 1, 2017: Protein Engineering, Design & Selection: PEDS
Reed B Jacob, Kenan C Michaels, Cathy J Anderson, James M Fay, Nikolay V Dokholyan
Organophosphate poisoning can occur from exposure to agricultural pesticides or chemical weapons. This exposure inhibits acetylcholinesterase resulting in increased acetylcholine levels within the synaptic cleft causing loss of muscle control, seizures, and death. Mitigating the effects of organophosphates in our bodies is critical and yet an unsolved challenge. Here, we present a computational strategy that integrates structure mining and modeling approaches, using which we identify novel candidates capable of interacting with a serine hydrolase probe (with equilibrium binding constants ranging from 4 to 120 μM)...
November 15, 2016: Scientific Reports
Hyeongseok Yun, Jiyeon Yu, Sumi Kim, Nari Lee, Jinhee Lee, Sungrae Lee, Nam Doo Kim, Chiho Yu, Jaerang Rho
Many pesticides and chemical warfare nerve agents are highly toxic organophosphorus compounds (OPs), which inhibit acetylcholinesterase activity. Human paraoxonase 1 (PON1) has demonstrated significant potential for use as a catalytic bioscavenger capable of hydrolyzing a broad range of OPs. However, there are several limitations to the use of human PON1 as a catalytic bioscavenger, including the relatively difficult purification of PON1 from human plasma and its dependence on the presence of hydrophobic binding partners to maintain stability...
March 2017: Protein Expression and Purification
Maja Katalinić, Nikolina Maček Hrvat, Krešimir Baumann, Sara Morasi Piperčić, Sandro Makarić, Srđanka Tomić, Ozren Jović, Tomica Hrenar, Ante Miličević, Dubravko Jelić, Suzana Žunec, Ines Primožič, Zrinka Kovarik
A well-considered treatment of acute nerve agents poisoning involves the exogenous administration of butyrylcholinesterase (BChE, EC as a stoichiometric bioscavenger efficient in preventing cholinergic crises caused by acetylcholinesterase (AChE, EC inhibition. An additional improvement in medical countermeasures would be to use oximes that could reactivate BChE as well to upgrade bioscavenging from stoichiometric to oxime-assisted catalytic. Therefore, in this paper we investigated the potency of 39 imidazolium and benzimidazolium oximes (36 compounds synthesized for the first time) to be considered as the reactivators specifically designed for reactivation of phosphylated human BChE...
November 1, 2016: Toxicology and Applied Pharmacology
Osvaldo Fridman, Luis Gariglio, Stephanie Riviere, Rafael Porcile, Alicia Fuchs, Miguel Potenzoni
OBJECTIVES: Oxidative stress and inflammation are important processes in development of atherosclerosis. Paraoxonase 1 (PON1) is a bioscavenger enzyme associated with inflammation and oxidative stress. We evaluate the association of two single nucleotide polymorphisms in PON1 gene, and enzyme activities with lipid profile and glycemia. METHODS: This case-control study consisted of 126 patients with coronary artery disease (CAD) and 203 healthy controls. PON Q192R and L55M polymorphisms were detected by real-time PCR...
October 2016: Archivos de Cardiología de México
Oksana Lockridge, Robert B Norgren, Rudolph C Johnson, Thomas A Blake
Acetylcholinesterase (AChE) is the physiologically important target for organophosphorus toxicants (OP) including nerve agents and pesticides. Butyrylcholinesterase (BChE) in blood serves as a bioscavenger that protects AChE in nerve synapses from inhibition by OP. Mass spectrometry methods can detect exposure to OP by measuring adducts on the active site serine of plasma BChE. Genetic variants of human AChE and BChE do exist, but loss of function mutations have been identified only in the BCHE gene. The most common AChE variant, His353Asn (H322N), also known as the Yt blood group antigen, has normal AChE activity...
September 19, 2016: Chemical Research in Toxicology
Yvonne J Rosenberg, James B Fink
In addition to the global use of organophosphate (OP) pesticides for agriculture, OP nerve agents and pesticides have been employed on battlefields and by terrorists (e.g., a recent sarin attack in Syria). These occurrences highlight the need for an effective countermeasure against OP exposure. Human butyrylcholinesterase (HuBChE) is a leading candidate, but injection of the high doses required for protection present pharmacokinetic challenges. An aerosolized recombinant form (aer-rHuBChE) that can neutralize inhaled OPs at the portal of entry has been assessed for its efficacy in protecting macaques against respiratory toxicity following inhalation exposure to the pesticide paraoxon (aer-Px)...
June 2016: Annals of the New York Academy of Sciences
Jacek Mamczarz, Joseph D Pescrille, Lisa Gavrushenko, Richard D Burke, William P Fawcett, Louis J DeTolla, Hegang Chen, Edna F R Pereira, Edson X Albuquerque
Exposure of the developing brain to chlorpyrifos (CPF), an organophosphorus (OP) pesticide used extensively in agriculture worldwide, has been associated with increased prevalence of cognitive deficits in children, particularly boys. The present study was designed to test the hypothesis that cognitive deficits induced by prenatal exposure to sub-acute doses of CPF can be reproduced in precocial small species. To address this hypothesis, pregnant guinea pigs were injected daily with CPF (25mg/kg,s.c.) or vehicle (peanut oil) for 10days starting on presumed gestation day (GD) 53-55...
September 2016: Neurotoxicology
Moshe Goldsmith, Yacov Ashani, Raanan Margalit, Abraham Nyska, David Mirelman, Dan S Tawfik
Organophosphate (OP) based pesticides are highly toxic compounds that are still widely used in agriculture around the world. According to World Health Organization (WHO) data, it is estimated that between 250,000 and 370,000 deaths occur yearly around the globe as a result of acute intoxications by pesticides. Currently available antidotal drug treatments of severe OP intoxications are symptomatic, do not reduce the level of intoxicating OP in the body and have limited ability to prevent long-term brain damage...
November 25, 2016: Chemico-biological Interactions
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