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International Journal of Nanomedicine 2024Organophosphates are among the deadliest of known chemicals based on their ability to inactivate acetylcholinesterase in neuromuscular junctions and synapses of the...
A Pralidoxime Nanocomplex Formulation Targeting Transferrin Receptors for Reactivation of Brain Acetylcholinesterase After Exposure of Mice to an Anticholinesterase Organophosphate.
INTRODUCTION
Organophosphates are among the deadliest of known chemicals based on their ability to inactivate acetylcholinesterase in neuromuscular junctions and synapses of the central and peripheral nervous systems. The consequent accumulation of acetylcholine can produce severe acute toxicities and death. Oxime antidotes act by reactivating acetylcholinesterase with the only such reactivator approved for use in the United States being 2-pyridine aldoxime methyl chloride (., pralidoxime or 2-PAM). However, this compound does not cross the blood-brain barrier readily and so is limited in its ability to reactivate acetylcholinesterase in the brain.
METHODS
We have developed a novel formulation of 2-PAM by encapsulating it within a nanocomplex designed to cross the blood-brain barrier via transferrin receptor-mediated transcytosis. This nanocomplex (termed scL-2PAM) has been subjected to head-to-head comparisons with unencapsulated 2-PAM in mice exposed to paraoxon, an organophosphate with anticholinesterase activity.
RESULTS AND DISCUSSION
In mice exposed to a sublethal dose of paraoxon, scL-2PAM reduced the extent and duration of cholinergic symptoms more effectively than did unencapsulated 2-PAM. The scL-2PAM formulation was also more effective than unencapsulated 2-PAM in rescuing mice from death after exposure to otherwise-lethal levels of paraoxon. Improved survival rates in paraoxon-exposed mice were accompanied by a higher degree of reactivation of brain acetylcholinesterase.
CONCLUSION
Our data indicate that scL-2PAM is superior to the currently used form of 2-PAM in terms of both mitigating paraoxon toxicity in mice and reactivating acetylcholinesterase in their brains.
Topics: Animals; Mice; Acetylcholinesterase; Brain; Cholinesterase Inhibitors; Cholinesterase Reactivators; Organophosphates; Oximes; Paraoxon; Pralidoxime Compounds
PubMed: 38229703
DOI: 10.2147/IJN.S443498 -
Journal of Environmental Management Feb 2024Sulfate radical (SO), formed by persulfate (PS) activation during advanced oxidation process (AOPs), can be used for the remediation of organic contaminated soil....
Sulfate radical (SO), formed by persulfate (PS) activation during advanced oxidation process (AOPs), can be used for the remediation of organic contaminated soil. However, the role of biochar and microwave (MW) in the activation of PS is not fully understood, especially the corresponding mechanism. Herein, biochar combined with MW was used to activate PS for the remediation of ethyl-parathion (PTH)-polluted soil. The dynamic evolutions of PTH under different conditions, such as biochar content, particle size, reaction temperature, and the degradation mechanisms of PTH were also systematically investigated. Significant enhancement performance on PTH removal was observed after adding biochar, which was 88.78% within 80 min. Meanwhile, activating temperature exhibited remarkable abilities to activate PS for PTH removal. The higher content of adsorption sites in nano-biochar facilitated the removal of PTH. Furthermore, chemical probe tests coupled with quenching experiments confirmed that the decomposition of PS into active species, such as SO, •OH, O and O, contributed to the removal of PTH in biochar combined with MW system, which could oxidize PTH into oxidative products, including paraoxon, 4-ethylphenol, and hydroquinone. The results of this study provide valuable insights into the synergistic effects of biochar and MW in the PS activation, which is helpful for the potential application of biochar materials combined with MW-activated PS in the remediation of pesticide-polluted soils.
Topics: Parathion; Soil; Microwaves; Environmental Pollution; Charcoal; Oxidation-Reduction; Water Pollutants, Chemical
PubMed: 38160544
DOI: 10.1016/j.jenvman.2023.119930 -
Biochemia Medica Feb 2024Paraoxonase 1 (PON1) is the enzyme that removes carcinogenic radicals from lipids. The aim of the study was to investigate the differences in PON1 activity and oxidation...
INTRODUCTION
Paraoxonase 1 (PON1) is the enzyme that removes carcinogenic radicals from lipids. The aim of the study was to investigate the differences in PON1 activity and oxidation stress parameters between patients with cervical intraepithelial neoplasia (CIN) and healthy controls.
MATERIALS AND METHODS
The study included 65 women with CIN and 109 healthy women. Lipid parameters were determined on Cobas Integra 400 plus (Roche, Mannheim, Germany). Tiols and reduced glutathione (GSH) were determined spectrophotometric using Eliman reagent. Activity of PON1 was assessed with two substrates, paraoxon and phenylacetate by spectrophotometric method. Malondialdehyde (MDA) was determined by high performance liquid chromatography (Shimadzu Corporation, Kyoto, Japan). Mann-Whitney-test, t-test, χ2-test, correlation and logistic regression was used in statistical analysis. P < 0.05 was considered statistically significant.
RESULTS
The basal (P = 0.929) and NaCl-stimulated (P = 0.985) PON1 activity and activities standardised on the concentration of high-density lipoprotein (HDL; P = 0.076; P = 0.065, respectively) and apolipoprotein AI (apo AI; P = 0.444; P = 0.499, respectively) as well as PON1 phenotypes (P = 0.842) did not differ significantly between the groups. The PON1 arylesterase activity (53±19 kU/L vs. 77±17 kU/L; P < 0.001) and HDL-standardized activity (37 (28-44) kU/mmol . 43 (37-50) kU/mmol; P < 0.001) and apoAI (29±11 kU/g . 44±11 kU/g; P < 0.001) was significantly reduced in the CIN group. The concentration of the thiol groups was similar (P = 0.519), of MDA was lower (0.39 (0.27-0.55) µmol/L . 0.76 (0.57-1.15) µmol/L; P < 0.001) and of GSH was higher (112.0 (66.0-129.6) µg/mL . 53.4 (34.8-134.4) µg/mL; P < 0.001) in the CIN group.
CONCLUSION
Reduced PON1 arylesterase activity, lower MDA and higher GSH concentration were observed in CIN patients.
Topics: Humans; Female; Aryldialkylphosphatase; Carboxylic Ester Hydrolases; Oxidative Stress; Uterine Cervical Dysplasia
PubMed: 38125616
DOI: 10.11613/BM.2024.010701 -
Biosensors & Bioelectronics: X Dec 2023Organophosphate (OP) pesticides remain a worldwide health concern due to their acute or chronic poisoning and widespread use in agriculture around the world. There is a...
Organophosphate (OP) pesticides remain a worldwide health concern due to their acute or chronic poisoning and widespread use in agriculture around the world. There is a need for robust and field-deployable tools for onsite detection of OP pesticides in food and water. Herein, we present an integrated smartphone/resistive biosensor for simple, rapid, reagentless, and sensitive monitoring of OP pesticides in food and environmental water. The biosensor leverages the hydrolytic activity of acetylcholinesterase (AChE) to its substrate, acetylcholine (ACh), and unique transport properties of polyaniline nanofibers (PAnNFs) of chitosan/AChE/PAnNF/carbon nanotube (CNT) nanocomposite film on a gold interdigitated electrode. The principle of the sensor relies on OP inhibiting AChE, thus, reducing the rate of ACh hydrolysis and consequently decreasing the rate of protons doping the PAnNFs. Such resulted decrease in conductance of PAnNF can be used to quantify OP pesticides in a sample. A mobile app for the biosensor was developed for analyzing measurement data and displaying and sharing testing results. Under optimal conditions, the biosensor demonstrated a wide linear range (1 ppt-100 ppb) with a low detection limit (0.304 ppt) and high reproducibility (RSD <5%) for Paraoxon-Methyl (PM), a model analyte. Furthermore, the biosensor was successfully applied for analyzing PM spiked food/water samples with an average recovery rate of 98.3% and provided comparable results with liquid chromatography-mass spectrometry. As such, the nanosensing platform provides a promising tool for onsite rapid and sensitive detection of OP pesticides in food and environmental water.
PubMed: 38124900
DOI: 10.1016/j.biosx.2023.100402 -
Langmuir : the ACS Journal of Surfaces... Jan 2024The surface of nanocrystalline cerium oxide (CeO) was treated with various chemical agents by a simple postmodification method at 25 °C and atmospheric pressure....
The surface of nanocrystalline cerium oxide (CeO) was treated with various chemical agents by a simple postmodification method at 25 °C and atmospheric pressure. Hydrogen peroxide, ammonium persulfate, deionized water, ascorbic acid, and ortho-phosphoric acid were used in order to study and evaluate their effect on surface materials, such as surface area, crystallite size, number of surface hydroxyl groups, particle morphology, and Ce/Ce ratio. Paraoxon-methyl (PO) decomposition and inorganic phosphate adsorption were used to evaluate the effect of surface treatment on catalytic and adsorption properties. CeO surface was studied by Fourier transform infrared spectroscopy, Raman spectroscopy, X-ray photoelectron spectroscopy, and acid-base titration. While the treatment procedure affected the number of surface hydroxyl groups and the amount of bulk surface oxygen vacancies, only negligible changes were observed in the Ce/Ce ratio. Interestingly, surface treatment affected the ability to decompose PO, but only a small effect on inorganic phosphate adsorption was observed, indicating the robustness of CeO for the latter. A mechanism for possible interaction of the used chemicals with the CeO surface was proposed.
PubMed: 38117753
DOI: 10.1021/acs.langmuir.3c02576 -
Environmental Research Feb 2024Organophosphates pesticide (OP) toxicity through water resources is a large concern globally among all the emerging pollutants. Detection of OPs is a challenge which...
Recombinant Organophosphorus acid anhydrolase (OPAA) enzyme-carbon quantum dot (CQDs)-immobilized thin film biosensors for the specific detection of Ethyl Paraoxon and Methyl Parathion in water resources.
Organophosphates pesticide (OP) toxicity through water resources is a large concern globally among all the emerging pollutants. Detection of OPs is a challenge which needs to be addressed considering the hazardous effects on the health of human beings. In the current research thin film biosensors of recombinant, Organophosphorus acid anhydrolase (OPAA) enzyme along with carbon quantum dots (CQDs) immobilized in thin films were developed. OPAA-CQDs thin film biosensors were used for the specific detection of two OPs Ethyl Paraoxon (EP) and Methyl Parathion (MP) in river water and household water supply. Recombinant OPAA enzyme was expressed in E. Coli, purified and immobilized on the CQD containing chitosan thin films. The CQDs used for this purpose were developed by a one-pot hydrothermal method from phthalic acid and Tri ethylene diamine. The properties of CQDs, OPAA and thin films were characterized using techniques like XPS, TEM, XRD, enzyme activity and CLSM measurements. Biosensing studies of EP and MP were performed by taking fluorescence measurements using a fiber optic spectrometer. The analytical parameters of biosensing were compared against an estimation carried out using the HPLC method. The biosensing performance indicates that the OPAA-CQDs thin film-based biosensors were able to detect both EP and MP in a range of 0-100 μM having a detection limit of 0.18 ppm/0.69 ppm for EP/MP, respectively with a response time of 5 min. The accuracy of estimation of EP/MP when spiked in water resources lie in the range of ∼100-102% which clearly indicates the OPAA-CQD based thin film biosensors can function as a point-of-use method for the detection of OP pesticides in complex water resources.
Topics: Humans; Paraoxon; Aryldialkylphosphatase; Methyl Parathion; Quantum Dots; Carbon; Water Resources; Escherichia coli; Pesticides; Parathion; Biosensing Techniques
PubMed: 38070850
DOI: 10.1016/j.envres.2023.117855 -
International Journal of Biological... Feb 2024Properties of paraoxon, such as poor water solubility, low rate of natural decomposition, ability to accumulate in soil and wastewater, lead to the fact that paraoxon is...
Properties of paraoxon, such as poor water solubility, low rate of natural decomposition, ability to accumulate in soil and wastewater, lead to the fact that paraoxon is found in various agricultural products and textiles. In this regard, the search for effective ways of paraoxon degradation becomes an extremely urgent problem, which can be solved by creating catalysts by mimicking paraxonase. In this work, a complex of physicochemical methods was used to study the supramolecular interactions of sodium alginate, which has a calcium-binding ability similar to paraxonase, with viologen calix[4]resorcinol and to reveal the nature of the intermolecular interactions between them resulting in the spontaneous formation of nanoparticles. Before proceeding to the investigation of the binding ability of obtained nanoparticles to paraoxon, the encapsulating effect of nanoparticles on a number of model substrates of different solubility (doxorubicin hydrochloride, quercetin and oleic acid) was studied. The kinetics of paraoxon hydrolysis reaction using these nanoparticles was studied at room temperature in an aqueous medium by spectrophotometric method. The rate of this reaction increases with increasing concentration of stable nanoparticles having hydrophobic domains that ensure paraoxon immobilization. The results obtained allow considering the supramolecular polysaccharide/calixarene system as an effective biomimetic catalyst.
Topics: Paraoxon; Hydrolysis; Temperature; Alginates; Resorcinols
PubMed: 38048928
DOI: 10.1016/j.ijbiomac.2023.128578 -
Biosensors & Bioelectronics Feb 2024Hydrolase-mimicking nanozymes have received increasing attention in recent years, but the effective rational design and development of these materials has not been...
Hydrolase-mimicking nanozymes have received increasing attention in recent years, but the effective rational design and development of these materials has not been realized, as they are not at present considered a critical research target. Herein, we report that Zn-doped mesoporous ceria (Zn-m-ceria) engineered to have an abundance of two different active sites with different functions-one that allows both co-adsorption binding of organophosphate (OP) and water and another that serves as a general base-has significant organophosphorus hydrolase (OPH)-like catalytic activity. Specifically, Zn-m-ceria exhibits a catalytic efficiency over 75- and 25-fold higher than those of m-ceria and natural OPH, respectively. First-principles calculations reveal the importance of Zn for the OPH-mimicking activity of the material, promoting substrate adsorption and proton-binding. The OPH-like Zn-m-ceria catalyst is successfully applied to detect a model OP, methyl paraoxon, in spiked tap water samples with excellent sensitivity, stability, and detection precision. We expect that these findings will promote research based on the rational engineering of the active site of nanozymes and efficient strategies for obtaining a diverse range of catalysts that mimic natural enzymes, and hence the utilization in real-world applications of enzyme-mimicking catalysts with properties superior to their natural analogs should follow.
Topics: Aryldialkylphosphatase; Catalytic Domain; Biosensing Techniques; Organophosphates; Water; Zinc
PubMed: 38043302
DOI: 10.1016/j.bios.2023.115882 -
Scientific Reports Nov 2023Organophosphorus poisoning kills individuals by causing central apnea; however, the underlying cause of death remains unclear. Following findings that the pre-Bötzinger...
Organophosphorus poisoning kills individuals by causing central apnea; however, the underlying cause of death remains unclear. Following findings that the pre-Bötzinger complex impairment alone does not account for central apnea, we analyzed the effect of paraoxon on the brainstem-spinal cord preparation, spanning the lower medulla oblongata to phrenic nucleus. Respiratory bursts were recorded by connecting electrodes to the ventral 4th cervical nerve root of excised brainstem-spinal cord preparations obtained from 6-day-old Sprague-Dawley rats. We observed changes in respiratory bursts when paraoxon, neostigmine, atropine, and 2-pyridine aldoxime methiodide were administered via bath application. The percentage of burst extinction in the paraoxon-poisoning group was 50% compared with 0% and 18.2% in the atropine and 2-pyridine aldoxime methiodide treatment groups, respectively. Both treatments notably mitigated the paraoxon-induced reduction in respiratory bursts. In the neostigmine group, similar to paraoxon, bursts stopped in 66.7% of cases but were fully reversed by atropine. This indicates that the primary cause of central apnea is muscarinic receptor-mediated in response to acetylcholine excess. Paraoxon-induced central apnea is hypothesized to result from neural abnormalities within the inferior medulla oblongata to the phrenic nucleus, excluding pre-Bötzinger complex. These antidotes antagonize central apnea, suggesting that they may be beneficial therapeutic agents.
Topics: Rats; Animals; Antidotes; Paraoxon; Rats, Sprague-Dawley; Neostigmine; Sleep Apnea, Central; Atropine; Pralidoxime Compounds; Pyridines
PubMed: 37990100
DOI: 10.1038/s41598-023-47745-x -
Carbohydrate Polymers Jan 2024Developing appropriate disposal of stockpiles of chemical warfare agents (CWAs) has gained significant attention as their lethal toxicity seriously harms humanity. In...
Robust and highly reactive membranes for continuous disposal of chemical warfare agents: Effects of nanostructure and functionality in MOF and nanochitin aerogel composites.
Developing appropriate disposal of stockpiles of chemical warfare agents (CWAs) has gained significant attention as their lethal toxicity seriously harms humanity. In this study, a novel green-fabrication method with UiO-66 catalysts and amine-functionalized chitin nanofibers (ChNFs) was suggested to prepare durable and highly reactive membranes for decomposing chemical warfare agents (CWAs) in the continuous flow system. The strong interaction between ChNFs and the UiO-66 led to stable loading of the UiO-66 on the continuous nano-porous channel of the ChNF reactive membrane even with high loading of UiO-66 (70 wt% of UiO-66 in the ChNF substrate). In addition, the Brønsted base functionalities (-NH and -NHCOCH) of the ChNF enhanced the catalytic activity and recyclability of the UiO-66. The resulting 70-ChNF composites can effectively decompose a nerve agent simulant (methyl paraoxon) even after 7 repeatable cycles, which has been not obtained in the previous UiO-66 catalyst. The ChNF/UiO-66 reactive membranes with 1 m of the area decomposed 130 g of CWAs within an hour in a continuous flow system. We believe these robust and highly reactive membranes can provide a sustainable and efficient solution for the massive CWA disposal and also contribute to the advancement of functional membrane material science.
PubMed: 37985045
DOI: 10.1016/j.carbpol.2023.121489