Acetylcholinesterase (AChE) is popularly used in biological and chemical sensors since it can be inhibited or reactivated. As the inhibitor of AChE is meaningful for many neurodegenerative diseases ...caused by the lack of AChE substrate acetylcholine (ACh), and the reactivator of inhibited AChE is helpful to treat the blocked neurotransmission resulted from the excessive ACh. Therefore, it is significant to screen AChE inhibitors and reactivators for pharmaceutical application. In addition, the detection of pesticides and heavy metals is of great importance to food safety and environment. So, based on the inhibition of AChE by pesticides and heavy metals, AChE can also be used in food safety and environmental analysis. Colorimetric method is a popular strategy for AChE assay due to its low cost, practicality and simplicity. In this review, we focus on the colorimetric method for AChE assay and the corresponding applications. The basic principles, advantages and disadvantages of Ellman's method, pH indicator-, 3,3′,5,5′-tetramethylbenzidine- (TMB-), noble metal nanomaterial-, and substrate-based colorimetric method are evaluated. In addition, the applications of colorimetric AChE assays in inhibitors and reactivators screening, pesticides and heavy metals detection are reviewed. Finally, the conclusions and future perspectives are provided.
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•Different chromogenic reagent-based colorimetric method for AChE are reviewed.•The mechanism, advantage and disadvantage of colorimetric AChE assay are discussed.•The applications of colorimetric AChE assays in analysis are reviewed.•A perspective for the colorimetric AChE assay is proposed.
The incidence of postoperative residual curarisation remains unacceptably high. We assessed whether an educational intervention on perioperative neuromuscular block management can reduce it.
In this ...multicentre, cluster randomised crossover trial, centres were allocated to receive an educational intervention either in a first or a second period. The educational intervention consisted of a lecture about neuromuscular management key points, including quantitative neuromuscular monitoring and use of reversal agents. The lecture was streamed to allow repetition. Additionally, memory cards were distributed in each operating theatre. The primary outcome was postoperative residual curarisation in the PACU. Secondary outcomes were frequency of quantitative neuromuscular monitoring, use of reversal agents, and incidence of postoperative pulmonary complications during hospital stay. Measurements were performed before randomisation and after the first and the second period. The effect of the educational intervention was estimated using multivariable mixed effects logistic regression models.
We included 2314 subjects in 34 Spanish centres. Postoperative residual curarisation incidence was not affected by the educational intervention (odds ratio OR 0.90 95% confidence interval {CI}: 0.51–1.58; P=0.717 and 1.30 0.73–2.30; P=0.371 for first and second time-period interaction). The educational intervention increased the quantitative neuromuscular monitor usage (OR 2.04 95% CI: 1.31–3.19; P=0.002), the use of reversal agents was unchanged (OR 0.79 95% CI: 0.50–1.26; P=0.322), and the incidence of postoperative pulmonary complications decreased (OR 0.19 95% CI: 0.10–0.35; P<0.001).
An educational intervention on perioperative neuromuscular block management did not reduce the incidence of postoperative residual curarisation nor increase reversal, despite increased quantitative neuromuscular monitoring. Sugammadex reversal was associated with reduced postoperative residual curarisation. The educational intervention was associated with a decrease in postoperative pulmonary complications.
NCT03128151.
The bryozoan Flustra foliacea produces a range of indole alkaloids, and some have shown weak antibiotic, muscle-relaxant and cytotoxic properties; however, most of them have not been tested for ...bioactivity. Many of these alkaloids possess a physostigmine scaffold, and physostigmine is a well-known acetylcholinesterase (AChE) inhibitor. AChE inhibitors are of interest as drug leads in neurodegenerative diseases and are currently used in symptomatic treatment of Alzheimer’s disease (AD). In this study, the AChE inhibitory activity of Flustra alkaloids was studied in vitro using the colorimetric method of Ellman and AChE from Electrophorus electricus. Twenty-five compounds isolated from the Icelandic bryozoan F. foliacea were screened at a 100 µM concentration. Two of them, flustramine E and flustramine I, showed inhibition of 48%, and flustramine Q showed 82% inhibition. For flustramine Q, the IC50 was 9.6 µM. Molecular modelling and docking studies indicated that simple in silico designed derivatives of flustramine Q could have potential for increased potency. Marine natural products including brominated indole alkaloids from Flustra foliacea are an interesting new source of AChE inhibitors with potential towards central nervous system disorders, e.g., Alzheimer’s disease.
Fenitrothion is an organophosphorus insecticide usually found in aquatic ecosystems at concentrations in the range of low ng/L. In this manuscript we show that 24 h exposure to environmental ...concentrations of fenitrothion, from ng/L to low μg/L, altered basal locomotor activity, visual-motor response and acoustic/vibrational escape response of zebrafish larvae. Furthermore, fenitrothion and expression of gap43a, gfap, atp2b1a, and mbp exhibited a significant non-monotonic concentration-response relationship. Once determined that environmental concentrations of fenitrothion were neurotoxic for zebrafish larvae, a computational analysis identified potential protein targets of this compound. Some of the predictions, including interactions with acetylcholinesterase, monoamine-oxidases and androgen receptor (AR), were experimentally validated. Binding to AR was the most suitable candidate for molecular initiating event, as indicated by both the up-regulation of cyp19a1b and sult2st3 and the non-monotonic relationship found between fenitrothion and the observed responses. Finally, when the integrity of the monoaminergic system was evaluated, altered levels of L-DOPA, DOPAC, HVA and 5-HIAA were found, as well as a significant up-regulation of slc18a2 expression at the lowest concentrations of fenitrothion. These data strongly suggest that concentrations of fenitrothion commonly found in aquatic ecosystems present a significant environmental risk for fish communities.
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•Environmental concentrations of fenitrothion induce behavioral changes in zebrafish.•Fenitrothion alter the expression of neurotoxicity markers in a non-monotonic fashion.•At low environmental concentrations, fenitrothion effects are AChE-independents.•Binding to androgen receptor is the most suitable candidate to MIE.
•A reduced graphene oxide-based field-effect transistor (RGO-FET) biosensor is produced.•The device is used to recognize specific target proteins and sense pH values.•Enzymatic activities of ...acetylcholinesterase and the inhibition reactions are assessed.•The RGO-FET bioensor is a promising in situ analytical tool for studying drug effects on Alzheimer’s disease treatment.
A reduced graphene oxide-based enzyme-modified field-effect transistor (RGO-EnFET) was fabricated to study the enzymatic kinetics between acetylcholinesterase (AChE) and acetylcholine (ACh), which are related to the progression and treatment of Alzheimer’s disease (AD). The RGO-EnFET exhibited typical ambipolar transfer characteristics with a charge neutrality point (the Dirac point, VDirac) in an aqueous environment, and biological events occurring on the RGO surface were evaluated by observing the Dirac point shift (ΔVDirac) according to reactions. First, the pH sensitivity of the RGO-EnFET was measured to be 24.12 mV pH−1 for a pH range of 4–10 with excellent repeatability. Then, ACh quantification in the concentration range of 1 μM–10 mM was evaluated, with a linear slope of 13.9 mV dec−1 being obtained between ΔVDirac and the ACh concentration on a logarithmic scale. The effects of AChE inhibitors (donepezil and rivastigmine) on the AChE enzymatic activity were also investigated. The distinguishable inhibition rates were acquired for donepezil and rivastigmine at saturation levels of 90% and 75%, respectively. These results indicate that the RGO-EnFET biosensor was successfully exploited as an in vitro analytical tool and has potential of future application in the study of enzymatic kinetics and drug screening for therapeutic purposes.
•A series of new benzopyrimidinone derivatives was designed, synthesized and characterized.•All compounds were tested in vitro for their antityrosinase and anti-acetylcholinesterase ...activities.•Compounds 3g, 4b and 5f exhibited the highest tyrosinase inhibition.•Compounds 3g, 3d, and 5f displayed interesting anti-acetylcholinesterase activity amongst all compounds synthesized and tested.•Molecular docking studies confirmed the activity of some derivatives.
To discover new acetylcholinesterase and tyrosinase inhibitors, a series of dialkyl phosphonate-benzopyrimidinones 4a-b was prepared via Michaelis-Arbuzov rearrangement (Arbusov reaction) of benzopyrimidinone chloride 2 with trialkyl phosphate, as well as a series of imidazolidine-benzopyrimidinone derivatives 5a-g synthesized by Mannich reaction of 2-((arylamino)methyl) benzopyrimidin-4(3H)-one 3 with formaldehyde. The structures of the new target compounds were investigated by 1H NMR, 13C NMR and ESI-HRMS. All synthesized compounds were evaluated for their anti-acetylcholinesterase and antityrosinase activities. Compounds 5f, 3g and 4b showed the highest tyrosinase inhibition and compounds 3g, 3d and 5g were found to be the most anti-acetylcholinesterase agents. Moreover, structure activity relationship (SAR) was discussed for all synthesized compounds and the interaction modes of the most potent inhibitors were confirmed through molecular docking studies.
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Gulf War Illness (GWI) is a chronic multi-symptom disorder, characterized by symptoms such as fatigue, pain, cognitive and memory impairment, respiratory, skin and gastrointestinal problems, that is ...experienced by approximately one-third of 1991 Gulf War veterans. Over the nearly three decades since the end of the war, investigators have worked to elucidate the initiating factors and underlying causes of GWI. A significant portion of this research has indicated a strong correlation between GWI and exposure to a number of different acetycholinesterase inhibitors (AChEIs) in theater, such as sarin and cyclosarin nerve agents, chlorpyrifos and dichlorvos pesticides, and the anti-nerve agent prophylactic pyridostigmine bromide. Through studying these exposures and their relationship to the symptoms presented by ill veterans, it has become increasingly apparent that GWI is the likely result of an underlying neuroimmune disorder. While evidence indicates that AChEIs are a key exposure in the development of GWI, particularly organophosphate AChEIs, the mechanism(s) by which these chemicals instigate illness appears to be related to “off-target”, non-cholinergic effects. In this review, we will discuss the role of AChEI exposure in the development and persistence of GWI; in particular, how these chemicals, combined with other exposures, have led to a chronic neuroimmune disorder.
This article is part of the special issue entitled ‘Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield’.
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•Gulf War Illness (GWI) is associated with underlying neuroimmune dysfunction.•Veterans with GWI were exposed to several acetylcholinesterase inhibitors (AChEIs).•Organophosphate AChEIs, nerve agent and pesticides, can instigate neuroinflammation.•While associated with GWI, pyridostigmine does not cause neuroinflammation.•Lack of acute toxicity suggests GWI results from non-cholinergic actions of AChEIs.
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