Abstract：
:Pyridinium oximes are strong nucleophiles and many are effective reactivators of organophosphate-inhibited cholinesterase (ChE). However, the current oxime reactivators are ineffective at crossing the blood-brain barrier and reactivating brain ChE in the intact organism. Our laboratories have developed a series of substituted phenoxyalkyl pyridinium oximes (US patent 9,227,937 B2) with the goal of identifying reactivators effective in crossing the blood-brain barrier. The first 35 of the series were found to have similar in vitro efficacy as reactivators of ChE inhibited by a sarin surrogate (phthalimidyl isopropyl methylphosphonate, PIMP) or a VX surrogate (nitrophenyl ethyl methylphosphonate, NEMP) in bovine brain preparations as previously observed in rat brain preparations. A number of these novel oximes have shown the ability to decrease the level of ChE inhibition in the brains of rats treated with a high sublethal dosage of either a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) or the VX surrogate NEMP. Levels of reactivation at 2 h after oxime administration were up to 35% while the currently approved therapeutic, 2-PAM, yielded no reduction in brain ChE inhibition. In addition, there was evidence of attenuation of seizure-like behavior with several of the more effective novel oximes, but not 2-PAM. Therefore these novel oximes have demonstrated an ability to reactivate inhibited ChE in brain preparations from two species and in vivo data support their ability to enter the brain and provide a therapeutic action. These novel oximes have the potential to be developed into improved antidotes for nerve agent therapy.
journal_name
Chem Biol Interactjournal_title
Chemico-biological interactionsauthors
Chambers JE,Chambers HW,Funck KE,Meek EC,Pringle RB,Ross MKdoi
10.1016/j.cbi.2016.07.004subject
Has Abstractpub_date
2016-11-25 00:00:00pages
154-159issue
Pt Beissn
0009-2797issn
1872-7786pii
S0009-2797(16)30278-2journal_volume
259pub_type
杂志文章abstract：:Bis(12)-hupyridone (B12H), derived from the Chinese medicinal component huperzine A, was originally designed as a novel acetylcholinesterase (AChE) inhibitor. In this paper, we report that B12H (24-h pretreatment) effectively blocked glutamate-induced neuronal excitotoxicity in cerebellar granule neurons (CGNs). Howev...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2012.10.003
更新日期：2013-03-25 00:00:00
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2004.05.006
更新日期：2004-08-10 00:00:00
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(76)90036-3
更新日期：1976-07-01 00:00:00
abstract：:Inhibition of microtubule assembly by arenastatin A (1) and five synthetic analogs (3-7) was examined. Arenastatin A and the triamide 6 showed potent and moderately strong inhibitory activities, respectively (IC50; 2.3 microM for 1, 7.8 microM for 6) and also depolymerized preformed microtubules. The other analogs tes...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/s0009-2797(96)03743-x
更新日期：1996-12-20 00:00:00
abstract：:The general features of the reduction of nitroblue tetrazolium chloride (NBT) by NADH and phenazine methosulphate (PMS) have been studied under aerobic and anaerobic conditions. Under aerobic condition the reduction appears to be mediated through the intermediate formation of the superoxide anion radical O2-.; this re...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(78)90090-x
更新日期：1978-12-01 00:00:00
abstract：:We investigated the permeabilities of lipid bilayers to the neurotoxin methylmercuric chloride (MMC). This mercurial is an efficient collisional quencher of the fluorescence of N-alkyl carbazole derivatives. Quenching of the fluorescence of beta-(3-(9-carbazole)-propionyl-L-alpha-phosphatidylcholine (CPA-PC) in vesicl...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(80)90054-x
更新日期：1980-06-01 00:00:00
abstract：:The relationship between dimethylnitrosamine (DMN) demethylase activity and DMN-induced mutagenesis was investigated in Drosophila melanogaster. The activity of DMN-demethylase was at least 10-fold greater in the Hikone-R strain than in three other Drosophila strains. However, the sex-linked recessive lethal (SLRL) mu...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(83)90006-6
更新日期：1983-08-15 00:00:00
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(78)90051-0
更新日期：1978-02-01 00:00:00
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2017.03.002
更新日期：2017-10-01 00:00:00
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journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2010.06.013
更新日期：2010-10-06 00:00:00
abstract：:Repair synthesis has been followed in P388F cell DNA following treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) using 5-iodo-deoxyuridine (IUdR) and [3H] thymidine combination. A pattern of repair synthesis was obtained, similar in its timing to the initial and medial stages of single-strand break formation ...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(76)90023-5
更新日期：1976-07-01 00:00:00
abstract：:Chronic pancreatitis is characterized by pancreatic fibrosis, associated with excessive activation of pancreatic stellate cells (PSCs) and increased expression of transforming growth factor-β1 (TGF-β1). Recently, our studies have shown that autophagy inhibitor could inhibit PSCs activation and reduce collagen secretio...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2019.01.005
更新日期：2019-02-25 00:00:00
abstract：:Thiol oxidation by diphenyl ditelluride is a favorable reaction and may be responsible for alteration in regulatory or signaling pathways. We have measured rate constants for reactions of diphenyl ditelluride with cysteine, dimercaptosuccinic acid, glutathione and dithiothreitol in phosphate buffer. The relative react...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2008.12.013
更新日期：2009-06-15 00:00:00
abstract：:Zinc oxide (ZnO) nanoparticles are one of the important industrial nanoparticles. The production of ZnO nanoparticles is increasing every year. On the other hand, it is known that ZnO nanoparticles have strong cytotoxicity. In vitro studies using culture cells revealed that ZnO nanoparticles induce severe oxidative st...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2012.04.007
更新日期：2012-06-25 00:00:00
abstract：:2,4,6-Triphenyldioxane-1,3 (TPD) is a highly effective species-specific inducer of CYP2В in rats. Several analogs of TPD were synthesized to verify a hypothesis that minor changes in the inducer structure can cause changes in induction abilities (R=H, cisTPD and transTPD; R=N(CH(3))(2), transpDMA; R=NO(2), transpNO(2)...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2011.03.005
更新日期：2011-07-15 00:00:00
abstract：:The pathogenesis of hepatic fibrosis involves significant deposition of fibrilar collagen and other extracellular matrix proteins. It is a rather dynamic process of wound healing in response to a variety of persistent liver injury caused by factors such as ethanol intake, viral infection, drugs, toxins, cholestasis, a...
journal_title：Chemico-biological interactions
pub_type： 杂志文章,评审
doi：10.1016/j.cbi.2011.07.001
更新日期：2011-09-30 00:00:00
abstract：:Excision repair was measured in normal human and xeroderma pigmentosum group C fibroblasts treated with ultraviolet radiation and the carcinogens acridine mustard (ICR-170) or 4-nitroquinoline 1-oxide (4NQO) by the techniques of unscheduled synthesis, photolysis of bromodeoxyuridine incorporated into parental DNA duri...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(80)90084-8
更新日期：1980-01-01 00:00:00
abstract：:The functional genetic polymorphism of aldehyde dehydrogenase 2 (ALDH2) influences the enzymatic activities of its wild type (Glu504 encoded by ALDH2*1) and mutant type (Lys504 encoded by ALDH2*2) proteins. The enzymatic activities of mutant-type ALDH2 are limited compared with those of the wild type. ALDH2 has been s...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2017.03.012
更新日期：2017-10-01 00:00:00
abstract：:The effect of puromycin has been investigated on protein and glycoprotein synthesis and on ultrastructure of the Golgi complex from rat liver. Incorporation of [14C]leucine into protein in Golgi fractions and into serum proteins was depressed rapidly after puromycin treatment. In the serum proteins, incorporation retu...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(75)90100-3
更新日期：1975-09-01 00:00:00
abstract：:The toxicity of halogenated alkanes originates from their metabolism by cytochrome P-450 which leads to the formation of reactive intermediates. In particular, peroxyl radicals derived from the halogenated compounds are believed to induce peroxidative chain degradation of lipids. To examine this hypothesis, radical re...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/s0009-2797(85)80170-8
更新日期：1985-08-01 00:00:00
abstract：:The hydrolysis of paraoxon (POX), phenylacetate (PA) and beta-naphthylacetate (BNA) was studied in human serum. Based upon correlations between enzyme activities, upon reversible inhibition by EDTA and upon progressive inhibition by iso-OMPA, tabun, eserine and bis-4 nitrophenylphosphate, the following conclusions wer...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(93)90027-v
更新日期：1993-06-01 00:00:00
abstract：:Two homogenous fractions of hepatic metallothioneins ((Cd,Zn) MT-1 and (Cd,Zn) MT-2) and renal metal binding proteins ((Bi,Cu) BP-1 and (Bi,Cu) BP-2) were isolated from rats exposed to heavy metals and specific antisera to them were produced in rabbits. These antisera were tested by immunodiffusion and immunoelectroph...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(80)90048-4
更新日期：1980-12-01 00:00:00
abstract：:Exposure of mice to 14C-labelled ethene or ethene oxide gave rise to hydroxyethylations of nucleophilic sites in hemoglobin and DNA. The relative amounts of alkylation products of different amino acids in hemoglobin were the same for the two compounds. Furthermore, the ratio between the degree of alkylation of DNA in ...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(83)90064-9
更新日期：1983-07-15 00:00:00
abstract：:The ability of lysolipids to enter into a membrane bi-layer and disturb the membrane structure was used to study the behavior of K562 erythroleukemic cells, K562 wild type (K562wt) as well as the multidrug resistant cells K562adr. Both types of cells, when analyzed by proton NMR spectroscopy exhibit the high resolutio...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2004.12.005
更新日期：2005-01-15 00:00:00
abstract：:Studies were undertaken to investigate the mechanism of bioactivation and covalent binding of TNT. Incubation of [14C]TNT with rat liver microsomes in the presence of an NADPH generating system resulted in metabolism and covalent binding to microsomal proteins. Time-dependence studies showed that TNT was rapidly reduc...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(94)03606-9
更新日期：1995-06-30 00:00:00
abstract：:Previously we reported that methylsulphonyl-2,6-dichlorobenzene, 2, 6-(diCl-MeSO(2)-B), was irreversibly bound to the olfactory mucosa of mice and induced necrosis of the Bowman's glands with subsequent neuroepithelial degeneration and detachment. In this study, autoradiography and histopathology were used to determin...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/s0009-2797(00)00187-3
更新日期：2000-10-16 00:00:00
abstract：:Formic acid is a common organic acid used in many industrial processes. There is a paucity of research on the direct toxicity of formic acid and how it might affect the cardiovascular system. This study aimed to understand the effect of formic acid on vascular tension in an animal model and the underlying mechanism. R...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2019.06.023
更新日期：2019-08-25 00:00:00
abstract：:Recently, it has been shown that drimane-type sesquiterpenoids isolated from Zygogynum pancheri, a species native to New Caledonia, possessed significant α-amylase inhibitory activities. To further explore their antidiabetic potential, we investigated the effect of 1β-O-(E-cinnamoyl)-6α-hydroxy-9epi-polygodial (D) and...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2020.109167
更新日期：2020-10-01 00:00:00
abstract：:Mammalian steroid 5β-reductases belong to the Aldo-Keto Reductase 1D sub-family and are essential for the formation of A-ring 5β-reduced steroids. Steroid 5β-reduction is required for the biosynthesis of bile-acids and the metabolism of all steroid hormones that contain a Δ4-3-ketosteroid functionally to yield the 5β-...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/j.cbi.2019.03.025
更新日期：2019-05-25 00:00:00
abstract：:Vitamin A-deficient male mice were treated for 10 days with 0.02% perfluorooctanoic acid (PFOA) in their diet. The effects of this highly potent peroxisome proliferator on peroxisomal palmitoyl-CoA oxidation and lauroyl-CoA oxidase activities were reduced by 3.1-7.5 times in comparison to the values obtained with mice...
journal_title：Chemico-biological interactions
pub_type： 杂志文章
doi：10.1016/0009-2797(95)03630-5
更新日期：1995-10-20 00:00:00
