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1.
Anal Methods ; 16(25): 4066-4073, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38881395

RESUMO

Nerve agents have posed a huge threat to national and human security, and their sensitive detection is crucial. Herein, based on the oxidation of Ce4+ and the aggregation-induced emission (AIE) of glutathione-protected gold nanoclusters (GSH-Au NCs), a cascade reaction was designed to prepare oxidized 3,3',5,5'-tetramethylbenzidine (oxTMB) and GSH-Au NCs crosslinked by Ce3+ (Ce3+-GSH-Au NCs). oxTMB had a broad UV-visible absorption range (500-700 nm) and was capable of quenching the fluorescence of Ce3+-GSH-Au NCs at 590 nm through the internal filtration effect (IFE). Thiocholine (TCh), the hydrolysis product of acetylthiocholine chloride (ATCl) catalyzed by acetylcholinesterase (AChE), reduced oxTMB completely, resulting in a decrease in the absorption of oxTMB and the recovery of IFE-quenched fluorescence of Ce3+-GSH-Au NCs. Nerve agent sarin (GB) hindered the production of TCh and the reduction of oxTMB by inhibiting the AChE activity, leading to the fluorescence of Ce3+-GSH-Au NCs being quenched again. The dual-output sensing system (AChE + ATCl + oxTMB + Ce3+-GSH-Au NCs) exhibited a low limit of detection to GB (2.46 nM for colorimetry and 1.18 nM for fluorimetry) and excellent selectivity toward common interferences being unable to inhibit AChE. Moreover, the intelligent logic gate constructed based on the sensing system showed promising applications in the field of smart sensing of nerve agents.


Assuntos
Acetilcolinesterase , Ouro , Nanopartículas Metálicas , Agentes Neurotóxicos , Sarina , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Sarina/química , Sarina/análise , Agentes Neurotóxicos/química , Agentes Neurotóxicos/análise , Ouro/química , Nanopartículas Metálicas/química , Técnicas Biossensoriais/métodos , Cério/química , Glutationa/química , Humanos , Benzidinas/química , Espectrometria de Fluorescência/métodos , Limite de Detecção
2.
Toxicol Lett ; 397: 151-162, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38759939

RESUMO

Poisoning with organophosphorus compounds, which can lead to a cholinergic crisis due to the inhibition of acetylcholinesterase and the subsequent accumulation of acetylcholine (ACh) in the synaptic cleft, is a serious problem for which treatment options are currently insufficient. Our approach to broadening the therapeutic spectrum is to use agents that interact directly with desensitized nicotinic acetylcholine receptors (nAChRs) in order to induce functional recovery after ACh overstimulation. Although MB327, one of the most prominent compounds investigated in this context, has already shown positive properties in terms of muscle force recovery, this compound is not suitable for use as a therapeutic agent due to its insufficient potency. By means of in silico studies based on our recently presented allosteric binding pocket at the nAChR, i.e. the MB327-PAM-1 binding site, three promising MB327 analogs with a 4-aminopyridinium ion partial structure (PTM0056, PTM0062, and PTM0063) were identified. In this study, we present the synthesis and biological evaluation of a series of new analogs of the aforementioned compounds with a 4-aminopyridinium ion partial structure (PTM0064-PTM0072), as well as hydroxy-substituted analogs of MB327 (PTMD90-0012 and PTMD90-0015) designed to substitute entropically unfavorable water clusters identified during molecular dynamics simulations. The compounds were characterized in terms of their binding affinity towards the aforementioned binding site by applying the UNC0642 MS Binding Assays and in terms of their muscle force reactivation in rat diaphragm myography. More potent compounds were identified compared to MB327, as some of them showed a higher affinity towards MB327-PAM-1 and also a higher recovery of neuromuscular transmission at lower compound concentrations. To improve the treatment of organophosphate poisoning, direct targeting of nAChRs with appropriate compounds is a key step, and this study is an important contribution to this research.


Assuntos
Receptores Nicotínicos , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/efeitos dos fármacos , Animais , Masculino , Agentes Neurotóxicos/toxicidade , Ratos Wistar , Ratos , Intoxicação por Organofosfatos/tratamento farmacológico , Diafragma/efeitos dos fármacos , Diafragma/metabolismo , Relação Estrutura-Atividade , Compostos de Piridínio/farmacologia , Compostos de Piridínio/síntese química , Compostos de Piridínio/química , Contração Muscular/efeitos dos fármacos , Junção Neuromuscular/efeitos dos fármacos , Sítios de Ligação
3.
Toxicol Lett ; 397: 103-116, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38703967

RESUMO

Animal research continues to serve a critical role in the testing and development of medical countermeasures. The Göttingen minipig, developed for laboratory research, may provide many benefits for addressing research questions within chemical defense. Targeted development of the Göttingen minipig model could reduce reliance upon non-human primates, and improve study design, statistical power, and throughput to advance medical countermeasures for regulatory approval and fielding. In this vein, we completed foundational pharmacokinetics and physiological safety studies of intramuscularly administered atropine sulfate, pralidoxime chloride (2-PAM), and diazepam across a broad range of doses (1-6 autoinjector equivalent) using adult male Göttingen minipigs (n=11; n=4-8/study) surgically implanted with vascular access ports and telemetric devices to monitor cardiovascular, respiratory, arterial pressure, and temperature signals. Pharmacokinetic data were orderly and the concentration maximum mirrored available human data at comparably scaled doses clearly for atropine, moderately for 2-PAM, and poorly for diazepam. Time to peak concentration approximated 2, 7, and 20 min for atropine, 2-PAM, and diazepam, respectively, and the elimination half-life of these drugs approximated 2 hr (atropine), 3 hr (2-PAM), and 8 hr (diazepam). Atropine sulfate dose-dependently increased the magnitude and duration of tachycardia and decreased the PR and ST intervals (consistent with findings obtained from other species). Mild hypothermia was observed at the highest diazepam dose. Göttingen minipigs appear to provide a ready and appropriate large animal alternative to non-human primates, and further development and evaluation of novel nerve agent medical countermeasures and treatment strategies in this model are justified.


Assuntos
Atropina , Diazepam , Porco Miniatura , Animais , Suínos , Masculino , Diazepam/farmacocinética , Diazepam/farmacologia , Atropina/farmacocinética , Atropina/farmacologia , Agentes Neurotóxicos/farmacocinética , Agentes Neurotóxicos/toxicidade , Relação Dose-Resposta a Droga , Injeções Intramusculares , Meia-Vida , Frequência Cardíaca/efeitos dos fármacos , Telemetria , Modelos Animais , Compostos de Pralidoxima
4.
Anal Bioanal Chem ; 416(15): 3569-3584, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38698257

RESUMO

Protein adducts are important biological targets for traceability of organophosphorus nerve agents (OPNAs). Currently, the recognized biomarkers that can be used in actual samples in the field of chemical forensics only include Y411 in albumin and the active nonapeptide in butyrylcholinesterase (BChE). To explore stable and reliable protein adducts and increase the accuracy of OPNAs traceability further, we gradually expanded OPNAs-albumin adducts based on single and group adduct collection. Several stable peptides were found via LC-MS/MS analysis in human serum albumin (HSA) exposed to OPNAs in a large exposure range. These adducts were present in HSA samples exposed to OPNAs of each concentration, which provided data support for the reliability and stability of using adducts to trace OPNAs. Meanwhile, the formation mechanism of OPNAs-cysteine adduct was clarified via computer simulations. Then, these active sites found and modified peptides were used as raw materials for progressive expansion of albumin adducts. We constructed an OPNAs-HSA adducts group, in which a specific agent is the exposure source, and three or more active peptides constitute data sets for OPNAs traceability. Compared with single or scattered protein adducts, the OPNAs-HSA adduct group improves OPNAs identification by mutual verification using active peptides or by narrowing the identity range of the exposure source. We also determined the minimum detectable concentration of OPNAs for the adduct group. Two or more peptides can be detected when there is an exposure of 50 times the molar excess of OPNAs in relation to HSA. This improved the accuracy of OPNAs exposure and identity confirmation. A collection of OPNAs-albumin adducts was also examined. The collection was established by collecting, classifying, and integrating the existing albumin adducts according to the species to which each albumin belongs, the types of agents, and protease. This method can serve as a reference for discovering new albumin adducts, characteristic phosphonylated peptides, and potential biomarkers. In addition, to avoid a false negative for OPNAs traceability using albumin adducts, we explored OPNAs-cholinesterase adducts because cholinesterase is more reactive with OPNAs than albumin. Seven active peptides in red blood cell acetylcholinesterase (RBC AChE) and serum BChE can assist in OPNAs exposure and identity confirmation.


Assuntos
Agentes Neurotóxicos , Compostos Organofosforados , Albumina Sérica Humana , Espectrometria de Massas em Tandem , Humanos , Agentes Neurotóxicos/química , Agentes Neurotóxicos/análise , Compostos Organofosforados/química , Espectrometria de Massas em Tandem/métodos , Albumina Sérica Humana/química , Cromatografia Líquida/métodos , Biomarcadores/sangue , Peptídeos/química
5.
J Hazard Mater ; 471: 134400, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38691927

RESUMO

VX, a well-known organophosphorus nerve agent (OPNA), poses a significant threat to public safety if employed by terrorists. Obtaining complete metabolites is critical to unequivocally confirm its alleged use/exposure and elucidate its whole-molecular metabolism. However, the nitrogenous VX metabolites containing 2-diisopropylaminoethyl moiety from urinary excretion remain unknown. Therefore, this study applied a newly developed untargeted workflow platform to discover and identify them using VX-exposed guinea pigs as animal models. 2-(N,N-diisopropylamino)ethanesulfonic acid (DiPSA) was revealed as a novel nitrogenous VX metabolite in urine, and 2-(Diisopropylaminoethyl) methyl sulfide (DAEMS) was confirmed as another in plasma, indicating that VX metabolism differed between urine and plasma. It is the first report of a nitrogenous VX metabolite in urine and a complete elucidation of the VX metabolic pathway. DiPSA was evaluated as an excellent VX exposure biomarker. The whole-molecule VX metabolism in urine was characterized entirely for the first time via the simultaneous quantification of DiPSA and two known P-based biomarkers. About 52.1% and 32.4% of VX were excreted in urine as P-based and nitrogenous biomarkers within 24 h. These findings provide valuable insights into the unambiguous detection of OPNA exposure/intoxication and human and environmental exposure risk assessment.


Assuntos
Substâncias para a Guerra Química , Compostos Organotiofosforados , Animais , Compostos Organotiofosforados/urina , Compostos Organotiofosforados/metabolismo , Cobaias , Substâncias para a Guerra Química/metabolismo , Masculino , Biomarcadores/urina , Agentes Neurotóxicos/metabolismo
6.
Artigo em Inglês | MEDLINE | ID: mdl-38735125

RESUMO

Protein adducts are vital targets for exploring organophosphorus nerve agents (OPNAs) exposure and identification, that can be used to characterize the chemical burden and initiate chemical safety measures. However, the use of protein adducts as biomarkers of OPNA exposure has developed slowly. To further promote the development of biomarkers in chemical forensics, it is crucial to expand the range of modified peptides and active sites, and describe the characteristics of OPNA adducts at specific reaction sites. This study utilized multi-species and multi-source albumins as the protein targets. We identified 56 peptides in albumins from various species (including human, horse, rat and pig), that were modified by at least two OPNAs. Diverse modification characteristics were observed in response to certain agents: including (1) multiple sites on the same peptide modified by one or more agents, (2) different reactivities at the same site in homologous albumins, and (3) different preferences at the same active sites associated with differences in the biological matrix during exposure. Our studies provided an empirical reference with rationalized underpinnings supported by estimated conformation energetics through molecular modeling. We employed different peptide markers for detection of protein adducts, as (one would do) in forensic screening for identification and quantification of chemical damage. Three characteristic peptides were screened and analyzed in human albumin, including Y287ICENQDSISSK, K438VPQVS443TPTLVEVSR, and Y162LY164EIAR. Stable fragment ions with neutral loss were found from their tandem MS/MS spectra, which were used as characteristic ions for identification and extraction of modified peptides in enzymatic digestion mixtures. Coupling these observations with computer simulations, we found that the structural stability of albumin and albumin-adduct complexes (as well as the effective force that promotes stability of different adducts) changes in the interval before and after adduct formation. In pig albumin, five active peptides existed stably in vivo and in vitro. Most of them can be detected within 30 min after OPNA exposure, and the detection window can persist about half a month. These early findings provided the foundation and rationale for utilizing pig albumin as a sampling target for rapid analysis in future forensic work.


Assuntos
Agentes Neurotóxicos , Compostos Organofosforados , Animais , Humanos , Ratos , Compostos Organofosforados/química , Suínos , Agentes Neurotóxicos/química , Agentes Neurotóxicos/análise , Cavalos , Espectrometria de Massas em Tandem/métodos , Peptídeos/química , Peptídeos/análise , Albuminas/química , Albuminas/metabolismo , Biomarcadores/análise , Biomarcadores/química
7.
Chem Biol Interact ; 396: 111061, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38763347

RESUMO

Nerve agents pose significant threats to civilian and military populations. The reactivation of acetylcholinesterase (AChE) is critical in treating acute poisoning, but there is still lacking broad-spectrum reactivators, which presents a big challenge. Therefore, insights gained from the reactivation kinetic analysis and molecular docking are essential for understanding the behavior of reactivators towards intoxicated AChE. In this research, we present a systematic determination of the reactivation kinetics of three V agents-inhibited four human ChEs [(AChE and butyrylcholinesterase (BChE)) from either native or recombinant resources, namely, red blood cell (RBC) AChE, rhAChE, hBChE, rhBChE) reactivated by five standard oximes. We unveiled the effect of native and recombinant ChEs on the reactivation kinetics of V agents ex vitro, where the reactivation kinetics characteristic of Vs-inhibited BChE was reported for the first time. In terms of the inhibition type, all of the five oxime reactivators exhibited noncompetitive inhibition. The inhibition potency of these reactivators would not lead to the difference in the reactivation kinetics between native and recombinant ChE. Despite the significant differences between the native and recombinant ChEs observed in the inhibition, aging, and spontaneous reactivation kinetics, the reactivation kinetics of V agent-inhibited ChEs by oximes were less differentiated, which were supported by the ligand docking results. We also found differences in the reactivation efficiency between five reactivators and the phosphorylated enzyme, and molecular dynamic simulations can further explain from the perspectives of conformational stability, hydrogen bonding, binding free energies, and amino acid contributions. By Poisson-Boltzmann surface area (MM-PBSA) calculations, the total binding free energy trends aligned well with the experimental kr2 values.


Assuntos
Acetilcolinesterase , Butirilcolinesterase , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Agentes Neurotóxicos , Oximas , Humanos , Oximas/farmacologia , Oximas/química , Cinética , Agentes Neurotóxicos/química , Agentes Neurotóxicos/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Simulação de Dinâmica Molecular , Reativadores da Colinesterase/farmacologia , Reativadores da Colinesterase/química , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo
8.
J Hazard Mater ; 472: 134604, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38759283

RESUMO

Of all chemical warfare agents (CWAs), only nerve and blood agents cause massive mortality at low concentrations. To better detect and discriminate nerve and blood agents, a reliable detection method is desirable. We report a series of fluorescent probes for nerve and blood agent detection. Among the tested probes, SR-Pip detected nerve and blood agents quickly (within 10 s for nerve agents and 1 min for blood agents). SR-Pip coupled with nerve agent produced a weak orange fluorescence with good sensitivity [limit of detection (LOD)= 5.5 µM]. Upon reaction with blood agent, the fluorescence of SR-Pip changed from orange fluorescence to blue fluorescence with detection limits as low as 9.6 nM. This probe effectively visualised different concentrations of nerve agents in living cells and mice. A portable test kit using SR-Pip instantly detected nerve and blood agents. To the best of our knowledge, SR-Pip is the first fluorescent probe for nerve and blood agent detection.


Assuntos
Substâncias para a Guerra Química , Corantes Fluorescentes , Agentes Neurotóxicos , Animais , Corantes Fluorescentes/química , Agentes Neurotóxicos/análise , Agentes Neurotóxicos/toxicidade , Substâncias para a Guerra Química/análise , Camundongos , Humanos , Limite de Detecção
9.
Toxicol Lett ; 397: 42-47, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38723915

RESUMO

Organophosphate pesticide poisoning challenges health care systems worldwide. Furthermore, nerve agents remain a continuous threat. The treatment options for organophosphate poisoning have virtually been unchanged for decades, relying on symptomatic treatment and the use of oximes to indirectly restore neuromuscular function. Hence, compounds targeting directly nicotinic acetylcholine receptors (nAChRs) might substantially improve treatment options. The current study investigated a series of bispyridinium analogues with a trimethylene or 2,2'-diethyloxy linker in a rat hemidiaphragm model, using indirect field stimulation. Methyl- and ethyl-substituted bispyridinium analogues restored neuromuscular function up to 37 ± 17% (MB419, a 3-methyl analogue) at a stimulation frequency of 20 Hz. The bispyridinium analogues with a 2- or 3-methyl group, or a 2- or 3-ethyl group, tended towards a higher restoration of neuromuscular function than those with a 4-methyl or 4-ethyl group, respectively. The current data can be used for future studies to optimize structure-based molecular modeling of compounds targeting the nAChR.


Assuntos
Diafragma , Agentes Neurotóxicos , Compostos de Piridínio , Animais , Diafragma/efeitos dos fármacos , Diafragma/inervação , Agentes Neurotóxicos/toxicidade , Masculino , Compostos de Piridínio/farmacologia , Compostos de Piridínio/química , Transmissão Sináptica/efeitos dos fármacos , Relação Estrutura-Atividade , Junção Neuromuscular/efeitos dos fármacos , Ratos , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/efeitos dos fármacos , Ratos Wistar , Intoxicação por Organofosfatos/tratamento farmacológico , Oximas/farmacologia , Oximas/química , Ratos Sprague-Dawley , Estrutura Molecular
10.
Chem Biol Interact ; 395: 111001, 2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38641146

RESUMO

In recent years, various poisoning incidents have been reported, involving the alleged use of the so-called Novichok agents, resulting in their addition to the Schedule I list of the Organisation for the Prohibition of Chemical Warfare (OPCW). As the physicochemical properties of these agents are different from the 'classical' nerve agents, such as VX, research is needed to evaluate whether and to what extent existing countermeasures are effective. Here, we evaluated the therapeutic potential of RSDL® (Reactive Skin Decontamination Lotion Kit) for the neutralization of percutaneous toxicity caused by Novichok agents, both in vitro and in vivo. Experiments showed the three selected Novichok agents (A230, A232, A234) could be degraded by RSDL lotion, but at a different rate. The half-life of A234, in the presence of an excess of RSDL lotion, was 36 min, as compared to A230 (<5 min) and A232 (18 min). Following dermal exposure of guinea pigs to A234, application of the RSDL kit was highly effective in preventing intoxication, even when applied up until 30 min following exposure. Delayed use of the RSDL kit until the appearance of clinical signs of intoxication (3-4 h) was not able to prevent intoxication progression and deaths. This study determines RSDL decontamination as an effective treatment strategy for dermal exposure to the Novichok agent A234 and underscores the importance of early, forward use of skin decontamination, as rapidly as possible.


Assuntos
Descontaminação , Agentes Neurotóxicos , Pele , Animais , Cobaias , Descontaminação/métodos , Pele/efeitos dos fármacos , Agentes Neurotóxicos/toxicidade , Agentes Neurotóxicos/química , Creme para a Pele/farmacologia , Creme para a Pele/química , Masculino , Substâncias para a Guerra Química/toxicidade
11.
J Forensic Sci ; 69(4): 1256-1267, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38647068

RESUMO

Pinacolyl alcohol (PA), a key forensic marker for the nerve agent Soman (GD), is a particularly difficult analyte to detect by various analytical methods. In this work, we have explored the reaction between PA and 1,1'-carbonyldiimidazole (CDI) to yield pinacolyl 1H-imidazole-1-carboxylate (PIC), a product that can be conveniently detected by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-high-resolution mass spectrometry (LC-HRMS). Regarding its GC-MS profile, this new carbamate derivative of PA possesses favorable chromatographic features such as a sharp peak and a longer retention time (RT = 16.62 min) relative to PA (broad peak and short retention time, RT = 4.1 min). The derivative can also be detected by LC-HRMS, providing an avenue for the analysis of this chemical using this technique where PA is virtually undetectable unless present in large concentrations. From a forensic science standpoint, detection of this low molecular weight alcohol signals the past or latent presence of the nerve agent Soman (GD) in a given matrix (i.e., environmental or biological). The efficiency of the protocol was tested separately in the analysis and detection of PA by EI-GC-MS and LC-HRMS when present at a 10 µg/mL in a soil matrix featured in the 44th PT and in a glycerol-rich liquid matrix featured in the 48th Official Organization for the Prohibition of Chemical Weapons (OPCW) Proficiency Test when present at a 5 µg/mL concentration. In both scenarios, PA was successfully transformed into PIC, establishing the protocol as an additional tool for the analysis of this unnatural and unique nerve agent marker by GC-MS and LC-HRMS.


Assuntos
Cromatografia Gasosa-Espectrometria de Massas , Soman , Soman/análise , Soman/análogos & derivados , Humanos , Cromatografia Líquida , Imidazóis/química , Agentes Neurotóxicos/análise , Agentes Neurotóxicos/química , Toxicologia Forense/métodos , Substâncias para a Guerra Química/análise , Espectrometria de Massas/métodos , Propanóis/química , Propanóis/análise
12.
ACS Sens ; 9(5): 2325-2333, 2024 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-38666660

RESUMO

Organophosphorus nerve agents (OPNAs) pose a great threat to humanity. Possessing extreme toxicity, rapid lethality, and an unassuming appearance, these chemical warfare agents must be quickly and selectively identified so that treatment can be administered to those affected. Chromogenic detection is the most convenient form of OPNA detection, but current methods suffer from false positives. Here, nitrogenous base adducts of dirhodium(II,II) acetate were synthesized and used as chromogenic detectors of diethyl chlorophosphate (DCP), an OPNA simulant. UV-vis spectrophotometry was used to evaluate the sensitivity and selectivity of the complexes in the detection of DCP. Visual limits of detection (LOD) for DCP were as low as 1.5 mM DCP, while UV-vis-based LODs were as low as 0.113 µM. The dirhodium(II,II) complexes were also tested with several potential interferents, none of which produced a visual color change that could be mistaken for OPNA response. Ultimately, the Rh2(OAc)4(1,8-diazabicyclo[5.4.0]undec-7-ene)2 complex showed the best combination of detection capability and interferent resistance. These results, when taken together, show that dirhodium(II,II) paddlewheel complexes with nitrogenous base adducts can produce instant, selective, and sensitive detection of DCP. It is our aim to further explore and apply this new motif to produce even more capable OPNA sensors.


Assuntos
Agentes Neurotóxicos , Ródio , Ródio/química , Agentes Neurotóxicos/análise , Agentes Neurotóxicos/química , Complexos de Coordenação/química , Compostos Organofosforados/análise , Compostos Organofosforados/química , Limite de Detecção , Compostos Cromogênicos/química , Substâncias para a Guerra Química/análise , Substâncias para a Guerra Química/química
13.
Chem Biol Interact ; 395: 110973, 2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38574837

RESUMO

The first organophosphorus nerve agent was discovered accidently during the development of pesticides, shortly after the first use of chemical weapons (chlorine, phosgene) on the battlefield during World War I. Despite the Chemical Weapons Convention banning these substances, they have still been employed in wars, terrorist attacks or political assassinations. Characterised by their high lethality, they target the nervous system by inhibiting the acetylcholinesterase (AChE) enzyme, preventing neurotransmission, which, if not treated rapidly, inevitably leads to serious injury or the death of the person intoxicated. The limited efficacy of current antidotes, known as AChE reactivators, pushes research towards new treatments. Numerous paths have been explored, from modifying the original pyridinium oximes to developing hybrid reactivators seeking a better affinity for the inhibited AChE. Another crucial approach resides in molecules more prone to cross the blood-brain barrier: uncharged compounds, bio-conjugated reactivators or innovative formulations. Our aim is to raise awareness on the threat and toxicity of organophosphorus nerve agents and to present the main synthetic efforts deployed since the first AChE reactivator, to tackle the task of efficiently treating victims of these chemical warfare agents.


Assuntos
Agentes Neurotóxicos , Compostos Organofosforados , Humanos , Agentes Neurotóxicos/toxicidade , Compostos Organofosforados/toxicidade , Animais , Reativadores da Colinesterase/farmacologia , Reativadores da Colinesterase/uso terapêutico , Reativadores da Colinesterase/química , Contramedidas Médicas , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/toxicidade , Substâncias para a Guerra Química/toxicidade , Antídotos/farmacologia , Antídotos/uso terapêutico , Oximas/farmacologia , Oximas/uso terapêutico , Oximas/química
14.
Anal Chem ; 96(15): 6072-6078, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38577757

RESUMO

The urgent need for sensitive and accurate assays to monitor acetylcholinesterase (AChE) activity and organophosphorus pesticides (OPs) arises from the imperative to safeguard human health and protect the ecosystem. Due to its cost-effectiveness, ease of operation, and rapid response, nanozyme-based colorimetry has been widely utilized in the determination of AChE activity and OPs. However, the rational design of nanozymes with high activity and specificity remains a great challenge. Herein, trace amount of Bi-doped core-shell Pd@Pt mesoporous nanospheres (Pd@PtBi2) have been successfully synthesized, exhibiting good peroxidase-like activity and specificity. With the incorporation of trace bismuth, there is a more than 4-fold enhancement in the peroxidase-like performance of Pd@PtBi2 compared to that of Pd@Pt. Besides, no significant improvement of oxidase-like and catalase-like activities of Pd@PtBi2 was found, which prevents interference from O2 and undesirable consumption of substrate H2O2. Based on the blocking impact of thiocholine, a colorimetric detection platform utilizing Pd@PtBi2 was constructed to monitor AChE activity with sensitivity and selectivity. Given the inhibition of OPs on AChE activity, a biosensor was further developed by integrating Pd@PtBi2 with AChE to detect OPs, capitalizing on the cascade amplification strategy. The OP biosensor achieved a detection limit as low as 0.06 ng mL-1, exhibiting high sensitivity and anti-interference ability. This work is promising for the construction of nanozymes with high activity and specificity, as well as the development of nanozyme-based colorimetric biosensors.


Assuntos
Técnicas Biossensoriais , Nanosferas , Agentes Neurotóxicos , Praguicidas , Humanos , Acetilcolinesterase/metabolismo , Compostos Organofosforados , Praguicidas/análise , Peróxido de Hidrogênio , Ecossistema , Oxirredutases , Peroxidase , Colorimetria
15.
Chemosphere ; 357: 141968, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38615965

RESUMO

Understanding the fundamental physical characteristics of extremely toxic compounds and their behavior across different environments plays a crucial role in assessing their danger. Additionally, this knowledge informs the development of protocols for gathering forensic evidence related to harmful chemicals misuse. In 2018, former Russian spy Sergei Skripal and his daughter were poisoned in Salisbury, England, with a substance later identified as the unconventional nerve agent A-234. Contamination with the compound was found on items inside Skripal's home. The aim of this paper was to determine the persistence of A-234 on selected indoor surfaces. Ceramics, aluminum can, laminated chipboard, polyvinyl chloride (PVC) floor tile, polyethylene terephthalate (PET) bottle, acrylic paint and computer keyboard were used as matrices. The decrease in surface contamination and further fate of the compound was monitored for 12 weeks. Persistence determination involved optimizing the wipe sampling method. Simultaneously, evaporation from the surface and permeation of the contaminant into the matrix were closely monitored. The experimental findings indicate that the nerve agent exhibits remarkable persistence, particularly on impermeable surfaces. Notably, the process of A-234 evaporation plays a minor role in determining its fate, with detectable concentrations observed solely above solid, non-porous surfaces such as ceramics and aluminum can. The surface persistence half-life varied significantly, ranging from 12 min to 478 days, depending on the material. The article has implications for emergency response protocols, decontamination strategies, public health and crime scene investigations.


Assuntos
Agentes Neurotóxicos , Agentes Neurotóxicos/análise , Monitoramento Ambiental , Poluição do Ar em Ambientes Fechados/análise , Polietilenotereftalatos/química
16.
Luminescence ; 39(4): e4731, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38566570

RESUMO

Nerve agents are becoming serious issues for the healthy and sustainable environment of modern civilization. Therefore, its detection and degradation are of paramount importance to the scientific community. In the present contribution, we have introduced a chromo-fluorogenic pyrene-based  probe, (E)-2-methoxy-3-(pyren-1-ylimino)-3,8a-dihydro-2H-chromen-4-ol (PMCO) to detect sarin stimulant diethylchlorophosphate (DCP) in solution and gaseous phases. On inserting DCP in PMCO solution, a visual colorimetric change from yellow to clear colourless in daylight and highly intensified blue fluorescence was observed instantly under a 365 nm portable UV lamp light. PMCO has outstanding selectivity and high sensitivity with a limit of detection of 1.32 µM in dimethyl sulfoxide (DMSO) medium and 77.5 nM in 20% H2O-DMSO. A handy strained paper strip-based experiment was demonstrated to recognize DCP in a mixture of similar toxic analytes. A dip-stick experiment was performed to identify DCP vapour, and may be used as an effective photonic tool. We also demonstrated real sample analysis utilizing different DCP-spiked water samples and validating DCP detection even in various types of soils such as sand, field, and mud. Therefore, this present study provides an effective chemosensor for instant and on-site detection of toxic nerve agents in dangerous circumstances.


Assuntos
Agentes Neurotóxicos , Compostos Organofosforados , Sarina , Sarina/análise , Agentes Neurotóxicos/análise , Corantes Fluorescentes , Dimetil Sulfóxido , Gases
17.
Arch Toxicol ; 98(6): 1859-1875, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38555327

RESUMO

Poisoning with the organophosphorus nerve agent VX can be life-threatening due to limitations of the standard therapy with atropine and oximes. To date, the underlying pathomechanism of VX affecting the neuromuscular junction has not been fully elucidated structurally. Results of recent studies investigating the effects of VX were obtained from cells of animal origin or immortalized cell lines limiting their translation to humans. To overcome this limitation, motor neurons (MN) of this study were differentiated from in-house feeder- and integration-free-derived human-induced pluripotent stem cells (hiPSC) by application of standardized and antibiotic-free differentiation media with the aim to mimic human embryogenesis as closely as possible. For testing VX sensitivity, MN were initially exposed once to 400 µM, 600 µM, 800 µM, or 1000 µM VX and cultured for 5 days followed by analysis of changes in viability and neurite outgrowth as well as at the gene and protein level using µLC-ESI MS/HR MS, XTT, IncuCyte, qRT-PCR, and Western Blot. For the first time, VX was shown to trigger neuronal cell death and decline in neurite outgrowth in hiPSC-derived MN in a time- and concentration-dependent manner involving the activation of the intrinsic as well as the extrinsic pathway of apoptosis. Consistent with this, MN morphology and neurite network were altered time and concentration-dependently. Thus, MN represent a valuable tool for further investigation of the pathomechanism after VX exposure. These findings might set the course for the development of a promising human neuromuscular test model and patient-specific therapies in the future.


Assuntos
Diferenciação Celular , Sobrevivência Celular , Células-Tronco Pluripotentes Induzidas , Neurônios Motores , Agentes Neurotóxicos , Compostos Organotiofosforados , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Compostos Organotiofosforados/toxicidade , Agentes Neurotóxicos/toxicidade , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Substâncias para a Guerra Química/toxicidade , Relação Dose-Resposta a Droga , Células Cultivadas
18.
Photochem Photobiol Sci ; 23(4): 763-780, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38519812

RESUMO

Nerve agents are the most notorious substances, which can be fatal to an individual because they block the activity of acetylcholinesterase. Fighting against unpredictable terrorist assaults and wars requires the simple and quick detection of chemical warfare agent vapor. In the present contribution, we have introduced a rhodamine-based chemosensor, BDHA, for the detection of nerve gas-mimicking agents diethylchlorophosphate (DCP) and diethylcyanophosphonate (DCNP) and mustard gas-mimicking agent 2-chloroethyl ethyl sulfide (CEES), both in the liquid and vapor phase. Probe BDHA provides the ability for detection by the naked eye in terms of colorimetric and fluorometric changes. It has been revealed that the interaction between nerve agents mimics and probe BDHA facilitates spirolactam ring opening due to the phosphorylation process. Thus, the highly fluorescent and colored species developed while probe BDHA is colorless and non-fluorescent due to the intramolecular spirolactam ring. Moreover, probe BDHA can effectively recognize DCP, DCNP, and CEES in the µM range despite many toxic analytes and could be identified based on the response times and quantum yield values. Inexpensive, easily carried paper strips-based test kits were developed for the quick, on-location solid and vapor phase detection of these mustard gas imitating agents (CEES) and nerve gas mimicking agents (DCP and DCNP) without needing expensive equipment or skilled personnel. More remarkably, the test strips' color and fluorescence can be rapidly restored, exposing them to triethyl amine (TEA) for cyclic use, suggesting a potential application in the real-time identification of chemical warfare agents. To accomplish the on-location application of BDHA, we have experimented with soil samples to find traces of DCP. Therefore, the chromo-fluorogenic probe BDHA is a promising, instantaneous, and on-the-spot monitoring tool for the selective detection of DCP, DCNP, and CEES in the presence of others.


Assuntos
Substâncias para a Guerra Química , Gás de Mostarda/análogos & derivados , Agentes Neurotóxicos , Nitrofenóis , Organofosfatos , Compostos Organofosforados , Sarina , Agentes Neurotóxicos/química , Acetilcolinesterase , Corantes Fluorescentes/química , Substâncias para a Guerra Química/análise , Substâncias para a Guerra Química/química
19.
Arch Toxicol ; 98(5): 1469-1483, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38441627

RESUMO

The emergence of Novichok agents, potent organophosphorus nerve agents, has spurred the demand for advanced analytical methods and toxicity assessments as a result of their involvement in high-profile incidents. This study focuses on the degradation products of Novichok agents, particularly their potential toxic effects on biological systems. Traditional in vivo methods for toxicity evaluation face ethical and practical constraints, prompting a shift toward in silico toxicology research. In this context, we conducted a comprehensive qualitative and quantitative analysis of acute oral toxicity (AOT) for Novichok degradation products, using various in silico methods, including TEST, CATMoS, ProTox-II, ADMETlab, ACD/Labs Percepta, and QSAR Toolbox. Adopting these methodologies aligns with the 3Rs principle, emphasising Replacement, Reduction, and Refinement in the realm of toxicological studies. Qualitative assessments with STopTox and admetSAR revealed toxic profiles for all degradation products, with predicted toxicophores highlighting structural features responsible for toxicity. Quantitative predictions yielded varied estimates of acute oral toxicity, with the most toxic degradation products being EOPAA, MOPGA, MOPAA, MPGA, EOPGA, and MPAA, respectively. Structural modifications common to all examined hydrolytic degradation products involve substituting the fluorine atom with a hydroxyl group, imparting consequential effects on toxicity. The need for sophisticated analytical techniques for identifying and quantifying Novichok degradation products is underscored due to their inherent reactivity. This study represents a crucial step in unravelling the complexities of Novichok toxicity, highlighting the ongoing need for research into its degradation processes to refine analytical methodologies and fortify readiness against potential threats.


Assuntos
Agentes Neurotóxicos , Organofosfatos
20.
Anal Chim Acta ; 1299: 342421, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38499417

RESUMO

BACKGROUND: Highly toxic organophosphorus nerve agents often exist in the form of gas in the environment and can damage human neuroregulatory system by inhibiting the activity of acetylcholinesterase (AChE). However, fluorescent probes based on small organic molecules bring a secondary burden to environment, and their sensitivity and specificity for sarin simulant diethyl chlorophosphate (DCP) detection are unsatisfactory. Nanozyme cascade systems with signal amplification can be used for highly sensitive identification of analytes, but are rarely used in ratiometric analysis of DCP. Combination of enzyme cascades and ratiometric fluorescence ensures the accuracy and sensitivity of the output signal. RESULTS: We prepared a self-assembled nanohybrid (Ag-AuNCs@UiO-66-NH2) by metal-organic framework material and gold nanoclusters. On the one hand, UiO-66-NH2 with enzyme-like activity was used to hydrolyze DCP into diethyl phosphate (DEP) and chloridion (Cl-). Cl- hindered aggregation-induced enhanced emission (AIEE) of AuNCs by binding with Ag+ and decreased the fluorescence of AuNCs. On the other hand, ligand metal charge transfer effect (LMCT) of UiO-66-NH2 was blocked by DCP to enhance the fluorescence of UiO-66-NH2. Combining ratiometric analysis and nanozyme cascade reaction, an ultra-sensitive fluorescence sensor for detecting DCP was constructed, and ensured the accuracy of experimental results. In addition, Ag-AuNCs@UiO-66-NH2 was embedded into the agarose hydrogel substrate, the resulting agarose hydrogel film allowed quantitative assessment of DCP vapor and high sensitivity was demonstrated (detection limit as low as 1.02 ppb). SIGNIFICANCE: A strategy combining enzyme cascade with ratiometric fluorescence was proposed, which improved the accuracy and sensitivity of the analysis results. The soft-solid platform based on agarose hydrogel film was constructed to realize the quantitative monitoring of sarin simulant gas. The LOD value obtained in this work is much lower than the immediately life-threatening or health threatening concentration of sarin.


Assuntos
Estruturas Metalorgânicas , Agentes Neurotóxicos , Ácidos Ftálicos , Humanos , Sarina , Acetilcolinesterase , Sefarose , Limite de Detecção
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