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RSC Medicinal Chemistry Apr 2024Previously we reported two salicylaldoxime conjugates (L7R3 and L7R5) showing equal or even higher reactivating efficiency for both organophosphorus nerve agent and...
Previously we reported two salicylaldoxime conjugates (L7R3 and L7R5) showing equal or even higher reactivating efficiency for both organophosphorus nerve agent and pesticide inhibited acetylcholinesterase in comparison to obidoxime and HI-6. In this study, L7R3 and L7R5 were selected as lead compounds and refined by employing a fragment-based drug design strategy, and a total of 32 novel salicylaldoxime conjugates were constructed and screened for DFP and paraoxon inhibited acetylcholinesterase. The findings demonstrate that the conjugate L73R3, which contains a 4-nitrophenyl group, exhibited a higher reactivation efficacy against paraoxon-inhibited acetylcholinesterase compared to obidoxime and HI-6. It was confirmed that the combination of a 4-pyridinyl or 4-nitrophenyl peripheral site ligand, a piperazine linker and a methyl or chloro-substituted salicylaldoxime could construct efficient nonquaternary oxime reactivators. The results hold promise for developing a new generation of highly effective antidotes for organophosphate poisoning.
PubMed: 38665821
DOI: 10.1039/d3md00628j -
GeoHealth Apr 2024The Multi-Threat Medical Countermeasure (MTMC) technique is crucial for developing common biochemical signaling pathways, molecular mediators, and cellular processes....
The Multi-Threat Medical Countermeasure (MTMC) technique is crucial for developing common biochemical signaling pathways, molecular mediators, and cellular processes. This study revealed that the Nod-like receptor 3 (NLRP3) inflammasome pathway may be a significant contributor to the cytotoxicity induced by various organophosphorus pesticides (OPPs). The study demonstrated that exposure to six different types of OPPs (paraoxon, dichlorvos, fenthion, dipterex, dibrom, and dimethoate) led to significant cytotoxicity in BV2 cells, which was accompanied by increased expression of NLRP3 inflammasome complexes (NLRP3, ASC, Caspase-1) and downstream inflammatory cytokines (IL-1β, IL-18), in which the order of cytotoxicity was dichlorvos > dipterex > dibrom > paraoxon > fenthion > dimethoate, based on the IC values of 274, 410, 551, 585, 2,158, and 1,527,566 μM, respectively. The findings suggest that targeting the NLRP3 inflammasome pathway could be a potential approach for developing broad-spectrum antitoxic drugs to combat multi-OPPs-induced toxicity. Moreover, inhibition of NLRP3 efficiently protected the cells against cytotoxicity induced by these six OPPs, and the expression of NLRP3, ASC, Caspase-1, IL-1β, and IL-18 decreased accordingly. The order of NLRP3 affinity for OPPs was dimethoate > paraoxon > dichlorvos > dibrom > (fenthion and dipterex) based on values of 89.8, 325, 1,460, and 2,690 μM, respectively. Furthermore, the common molecular mechanism of NLRP3-OPPs was clarified by the presence of toxicity effector groups (benzene ring, nitrogen/oxygen-containing functional group); =O, -O-, or =S (active) groups; and combination residues (Gly271, Asp272). This finding provided valuable insights into exploring the common mechanisms of multiple threats and developing effective therapeutic strategies to prevent OPPs poisoning.
PubMed: 38638206
DOI: 10.1029/2023GH000888 -
ACS Chemical Neuroscience May 2024Acetylcholinesterase (AChE) inhibition by organophosphorus (OP) compounds poses a serious health risk to humans. While many therapeutics have been tested for treatment...
4-Amidophenol Quinone Methide Precursors: Effective and Broad-Scope Nonoxime Reactivators of Organophosphorus-Inhibited Cholinesterases and Resurrectors of Organophosphorus-Aged Acetylcholinesterase.
Acetylcholinesterase (AChE) inhibition by organophosphorus (OP) compounds poses a serious health risk to humans. While many therapeutics have been tested for treatment after OP exposure, there is still a need for efficient reactivation against all kinds of OP compounds, and current oxime therapeutics have poor blood-brain barrier penetration into the central nervous system, while offering no recovery in activity from the OP-aged forms of AChE. Herein, we report a novel library of 4-amidophenol quinone methide precursors (QMP) that provide effective reactivation against multiple OP-inhibited forms of AChE in addition to resurrecting the aged form of AChE after exposure to a pesticide or some phosphoramidates. Furthermore, these QMP compounds also reactivate OP-inhibited butyrylcholinesterase (BChE) which is an , endogenous scavenger of OP compounds. The efficacies of these QMP compounds were tested for reactivation and resurrection of soluble forms of human AChE and BChE and for reactivation of cholinesterases within human blood as well as blood and brain samples from a humanized mouse model. We identify compound as a lead candidate due to its broad-scope efficacy against multiple OP compounds as well as both cholinesterases. With methylphosphonates, compound (250 μM, 1 h) shows >60% recovered activity from OEt-inhibited AChE in human blood as well as mouse blood and brain, thus highlighting its potential for future analysis. For , the effective concentration (EC) is less than 25 μM for reactivation of three different methylphosphonate-inhibited forms of AChE, with a maximum reactivation yield above 80%. Similarly, for OP-inhibited BChE, has EC values that are less than 150 μM for two different methylphosphonate compounds. Furthermore, an kinetic analysis show that has a 2.2- and 92.1-fold superior reactivation efficiency against OEt-inhibited and OBu-inhibited AChE, respectively, when compared to an oxime control. In addition to being a potent reactivator of AChE and BChE, we also show that is capable of resurrecting (ethyl paraoxon)-aged AChE, which is another current limitation of oximes.
Topics: Animals; Cholinesterase Inhibitors; Humans; Acetylcholinesterase; Mice; Butyrylcholinesterase; Organophosphorus Compounds; Cholinesterase Reactivators; Indolequinones
PubMed: 38621296
DOI: 10.1021/acschemneuro.4c00011 -
Journal of Hazardous Materials May 2024Organophosphorus compounds (OPs), such as VX, pose a significant threat due to their neurotoxic and hazardous properties. Skin decontamination is essential to avoid...
Organophosphorus compounds (OPs), such as VX, pose a significant threat due to their neurotoxic and hazardous properties. Skin decontamination is essential to avoid irreversible effects. Fuller's earth (FE), a phyllosilicate conventionally employed in powder form, has demonstrated decontamination capacity against OPs. The aim of this study was to develop a formulation that forms a film on the skin, with a significant OP removal capacity (>95 %) coupled with sequestration capabilities, favorable drying time and mechanical properties to allow for easy application and removal, particularly in emergency context. Various formulations were prepared using different concentrations of polyvinyl alcohol (PVA), FE and surfactants. Their removal and sequestration capacity was tested using paraoxon-ethyl (POX), a chemical that simulates the behavior of VX. Formulations with removal capacity levels surpassing 95 % were mechanically characterized and cell viability assays were performed on Normal Human Dermal Fibroblast (NHDF). The four most promising formulations were used to assess decontamination efficacy on pig ear skin explants. These formulations showed decontamination levels ranging from 84.4 ± 4.7 % to 96.5 ± 1.3 %, which is equivalent to current decontamination methods. These results suggest that this technology could be a novel and effective tool for skin decontamination following exposure to OPs.
Topics: Decontamination; Animals; Skin; Humans; Swine; Paraoxon; Aluminum Compounds; Cell Survival; Silicates; Polyvinyl Alcohol; Magnesium Compounds; Surface-Active Agents; Fibroblasts
PubMed: 38593659
DOI: 10.1016/j.jhazmat.2024.134190 -
Pesticide Biochemistry and Physiology Mar 2024Enzymes have attracted considerable scientific attention for their crucial role in detoxifying a wide range of harmful compounds. In today's global context, the...
Enzymes have attracted considerable scientific attention for their crucial role in detoxifying a wide range of harmful compounds. In today's global context, the extensive use of insecticides has emerged as a significant threat to the environment, sparking substantial concern. Insects, including economically important pests like Helicoverpa armigera, have developed resistance to conventional pest control methods through enzymes like carboxyl/cholinesterases. This study specifically focuses on a notable carboxyl/cholinesterase enzyme from Helicoverpa armigera (Ha006a), with the goal of harnessing its potential to combat environmental toxins. A total of six insecticides belonging to two different classes displayed varying inhibitory responses towards Ha006a, thereby rendering it effective in detoxifying a broader spectrum of insecticides. The significance of this research lies in discovering the bioremediation property of Ha006a, as it hydrolyzes synthetic pyrethroids (fenvalerate, λ-cyhalothrin and deltamethrin) and sequesters organophosphate (paraoxon ethyl, profenofos, and chlorpyrifos) insecticides. Additionally, the interaction studies between organophosphate insecticides and Ha006a helped in the fabrication of a novel electroanalytical sensor using a modified carbon paste electrode (MCPE). This sensor boasts impressive sensitivity, with detection limits of 0.019 μM, 0.15 μM, and 0.025 μM for paraoxon ethyl, profenofos, and chlorpyrifos, respectively. This study provides a comprehensive biochemical and biophysical characterization of the purified esterase Ha006a, showcasing its potential to remediate different classes of insecticides.
Topics: Animals; Insecticides; Carboxylesterase; Chlorpyrifos; Helicoverpa armigera; Moths; Pyrethrins; Cholinesterases; Insecticide Resistance; Paraoxon; Organothiophosphates
PubMed: 38582571
DOI: 10.1016/j.pestbp.2024.105844 -
Carbohydrate Polymers Jun 2024The search for effective ways of paraoxon (POX) degradation becomes an extremely urgent problem, which can be solved by creating effective bioscavengers in the form of...
A supramolecular assembly of sulfobutyl ether-β-cyclodextrin and viologen calix[4]resorcinol as the master key to sustainable and eco-friendly catalyst for paraoxon hydrolysis.
The search for effective ways of paraoxon (POX) degradation becomes an extremely urgent problem, which can be solved by creating effective bioscavengers in the form of three-dimensional macrocycles. In this work, supramolecular interactions in an aqueous medium were studied between (4-sulfobutyl)-β-cyclodextrin, the hydrophobic cavity of which is capable of binding POX, and viologen calix[4]resorcinol, the cationic groups of which are able to facilitate the nucleophilic attack on the phosphorus atom of the pesticide. A complex of physicochemical methods revealed the nature of the interactions between these cyclodextrin and calix[4]resorcinol, as a result of which the spontaneous formation of nanoparticles occurs. The kinetics of POX hydrolysis reaction using these nanoparticles was studied at room temperature in aqueous Tris-buffer medium by spectrophotometric method. Pure cyclodextrin does not exhibit catalytic activity in the POX hydrolysis, but its presence in a mixture with calix[4]resorcinol leads to a fivefold increase in the hydrolysis rate constant compared to pure calix[4]resorcinol.
PubMed: 38553208
DOI: 10.1016/j.carbpol.2024.121984 -
Journal of Atherosclerosis and... Mar 2024Paraoxonase 1 (PON1) binds to high-density lipoprotein (HDL) and protects against atherosclerosis. However, the relationship between functional PON1 Q192R polymorphism,...
AIMS
Paraoxonase 1 (PON1) binds to high-density lipoprotein (HDL) and protects against atherosclerosis. However, the relationship between functional PON1 Q192R polymorphism, which is associated with the hydrolysis of paraoxon (POXase activity) and atherosclerotic cardiovascular disease (ASCVD), remains controversial. As the effect of PON1 Q192R polymorphism on the HDL function is unclear, we investigated the relationship between this polymorphism and the cholesterol efflux capacity (CEC), one of the biological functions of HDL, in association with the PON1 activity.
METHODS
The relationship between PON1 Q192R polymorphisms and CEC was investigated retrospectively in 150 subjects without ASCVD (50 with the PON1 Q/Q genotype, 50 with the Q/R genotype, and 50 with the R/R genotype) who participated in a health screening program. The POXase and arylesterase (AREase: hydrolysis of aromatic esters) activities were used as measures of the PON1 activity.
RESULTS
The AREase activity was positively correlated with CEC independent of the HDL cholesterol levels. When stratified by the PON1 Q192R genotype, the POXase activity was also positively correlated with CEC independent of HDL cholesterol. PON1 Q192R R/R genotype carriers had a lower CEC than Q/Q or Q/R genotype carriers, despite having a higher POXase activity. Moreover, in a multiple regression analysis, the PON1 Q192R genotype was associated with the degree of CEC, independent of the HDL cholesterol and POXase activity.
CONCLUSIONS
The PON1 Q192R R allele is associated with reduced CEC in Japanese people without ASCVD. Further studies on the impact of this association on the severity of atherosclerosis and ASCVD development are thus called for.
PubMed: 38508740
DOI: 10.5551/jat.64711 -
Data in Brief Apr 2024is a Gram-negative, mesophilic bacterium that thrives in aquatic environments. Here, we present the whole genome sequence of JKSF06, isolated from sediment that was...
is a Gram-negative, mesophilic bacterium that thrives in aquatic environments. Here, we present the whole genome sequence of JKSF06, isolated from sediment that was collected in La Porte, Texas, near the southern terminus of the Houston Ship Channel into the Gulf of Mexico. The JKSF06 strain harbors multiple xenobiotic gene determinants targeting environmental waste that can be found here, including petroleum hydrocarbons and n-alkanes. In addition, JKSF06 can actively degrade organophosphate phophotriesters such ethyl paraoxon. In total, the genome of JKSF06 consists of 3,462,857 bp encoding for 3173 putative proteins. The complete sequence of JKSF06 can be viewed under accession LSVD00000000.1 through the National Center for Biotechnology Information (NCBI).
PubMed: 38348316
DOI: 10.1016/j.dib.2024.110117 -
ACS Omega Jan 2024Herein, a nonenzymatic detection of paraoxon-ethyl was developed by modifying a glassy carbon electrode (GCE) with gold-silver core-shell (Au-Ag) nanoparticles combined...
Electrochemical Sensors based on Gold-Silver Core-Shell Nanoparticles Combined with a Graphene/PEDOT:PSS Composite Modified Glassy Carbon Electrode for Paraoxon-ethyl Detection.
Herein, a nonenzymatic detection of paraoxon-ethyl was developed by modifying a glassy carbon electrode (GCE) with gold-silver core-shell (Au-Ag) nanoparticles combined with the composite of graphene with poly(3,4-ethylenedioxythiophene)/poly(styrenesulfonate) (PEDOT:PSS). These core-shell nanoparticles (Au-Ag) were synthesized using a seed-growth method and characterized using UV-vis spectroscopy and high-resolution transmission electron microscopy (HR-TEM) techniques. Meanwhile, the structural properties, surface morphology and topography, and electrochemical characterization of the composite of Au-Ag core-shell/graphene/PEDOT:PSS were analyzed using infrared spectroscopy, field emission scanning electron microscopy (FE-SEM), atomic force microscopy (AFM), and electrochemical impedance spectroscopy (EIS) techniques. Moreover, the proposed sensor for paraoxon-ethyl detection based on Au-Ag core-shell/graphene/PEDOT:PSS modified GCE demonstrates good electrochemical and electroanalytical performance when investigated with cyclic voltammetry (CV), differential pulse voltammetry (DPV), and chronoamperometry techniques. It was found that the synergistic effect between Au-Ag core-shell nanoparticles and the composite of graphene/PEDOT:PSS provides a higher conductivity and enhanced electrocatalytic activity for paraoxon-ethyl detection at an optimum pH of 7. At pH 7, the proposed sensor for paraoxon-ethyl detection shows a linear range of concentrations from 0.2 to 100 μM with a limit of detection of 10 nM and high sensitivity of 3.24 μA μM cm. In addition, the proposed sensor for paraoxon-ethyl confirmed good reproducibility, with the possibility of being further developed as a disposable electrode. This sensor also displayed good selectivity in the presence of several interfering species such as diazinon, carbaryl, ascorbic acid, glucose, nitrite, sodium bicarbonate, and magnesium sulfate. For practical applications, this proposed sensor was employed for the determination of paraoxon-ethyl in real samples (fruits and vegetables) and showed no significant difference from the standard spectrophotometric technique. In conclusion, this proposed sensor might have a potential to be developed as a platform of electrochemical sensors for pesticide detection.
PubMed: 38250352
DOI: 10.1021/acsomega.3c08349 -
Frontiers in Pharmacology 2023Organophosphate-based chemical agents (OP), including nerve agents and certain pesticides such as paraoxon, are potent acetylcholinesterase inhibitors that cause severe...
Organophosphate-based chemical agents (OP), including nerve agents and certain pesticides such as paraoxon, are potent acetylcholinesterase inhibitors that cause severe convulsions and seizures, leading to permanent central nervous system (CNS) damage if not treated promptly. The current treatment regimen for OP poisoning is intramuscular injection of atropine sulfate with an oxime such as pralidoxime (2-PAM) to mitigate cholinergic over-activation of the somatic musculature and autonomic nervous system. This treatment does not provide protection against CNS cholinergic overactivation and therefore convulsions require additional medication. Benzodiazepines are the currently accepted treatment for OP-induced convulsions, but the convulsions become refractory to these GABA agonists and repeated dosing has diminishing effectiveness. As such, adjunct anticonvulsant treatments are needed to provide improved protection against recurrent and prolonged convulsions and the associated excitotoxic CNS damage that results from them. Previously we have shown that brief, 4-min administration of 3%-5% isoflurane in 100% oxygen has profound anticonvulsant and CNS protective effects when administered 30 min after a lethal dose of paraoxon. In this report we provide an extended time course of the effectiveness of 5% isoflurane delivered for 5 min, ranging from 60 to 180 min after a lethal dose of paraoxon in rats. We observed substantial effectiveness in preventing neuronal loss as shown by Fluoro-Jade B staining when isoflurane was administered 1 h after paraoxon, with diminishing effectiveness at 90, 120 and 180 min. magnetic resonance imaging (MRI) derived T2 and mean diffusivity (MD) values showed that 5-min isoflurane administration at a concentration of 5% prevents brain edema and tissue damage when administered 1 h after a lethal dose of paraoxon. We also observed reduced astrogliosis as shown by GFAP immunohistochemistry. Studies with continuous EEG monitoring are ongoing to demonstrate effectiveness in animal models of soman poisoning.
PubMed: 38230376
DOI: 10.3389/fphar.2023.1293280