Metaldehyde is a highly selective molluscicide with moderate water solubility. Acute metaldehyde poisoning is most commonly reported in veterinary medicine and is extremely rare in humans. Its optimal clinical management remains poorly defined and warrants further investigation.

The highly lethal organophosphorus nerve agent S-{2-[di(propan-2-yl)amino]ethyl} O-ethyl methylphosphonothioate (VX) irreversibly inhibits acetylcholinesterase (AChE), necessitating advanced bioscavengers. Herein, peptide P15 (WEIKPSSLTGKSPYFSNNHGKL) identified from a natural hydrolysate database via Python-assisted filtering and hierarchical virtual screening was prioritized by MMPBSA binding free energy (ΔGbind= -14.66 kcal/mol). Simulations reveal P15 neutralizes VX through a synergistic "scavenge-and-shield" mechanism. P15 directly sequesters free VX, while simultaneously inducing significant conformational and microenvironmental remodeling of the VX-AChE complex, selectively disrupting the electrostatic and hydrophobic networks requisite for VX accommodation. H-REMD/FEP calculations demonstrate this imposes a thermodynamic penalty (ΔΔG = +1.41 kcal/mol) on the VX-AChE complex. Steered molecular dynamics further showed P15 facilitates VX displacement, reducing the required rupture force by 53.3% (from 600 to 280 kJ/mol/nm). Supported by in vitro assays confirming P15's excellent biosafety (>100% cell viability), these computational findings indicate P15 integrates direct toxin scavenging with precise allosteric enzyme protection, serving as a promising dual-function countermeasure.

Organophosphorus compounds (OP), like pesticides and nerve agents, are potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) due to the phosphylation of their catalytic serine. Current treatment is limited, as approved oximes lack broad-spectrum efficacy and are poor reactivators of inhibited BChE. An alternative approach is pseudo-catalytic OP bioscavenging in which BChE and an efficient reactivator rapidly degrade OP in circulation, preventing it from reaching target tissues enriched with AChE. As imidazolium oximes were previously identified as potent BChE reactivators, we prepared eight novel N-substituted imidazolium oximes and tested them as reactivators of both human AChE and BChE inhibited by pesticide derivative paraoxon, and nerve warfare agents (sarin, cyclosarin, tabun VX, and five A-series agents). Oxime 3 (1,3-dibenzyl-2-hydroxy (imino)methylimidazolium bromide) was identified as the most potent reactivator, showing nanomolar affinity with native BChE and reactivation efficacy superior to standard oximes for cyclosarin-, sarin-, and tabun-BChE conjugate that was 1400-fold, 20-fold and 40-fold higher, respectively. In human whole blood, 30 μM cyclosarin was pseudo-catalytically decomposed by supplemented BChE and oxime 3, restoring 65% of total cholinesterase activity within 10 min. Although less potent, we identified two oximes capable of reactivating A-230-BChE conjugate. Furthermore, oxime 3 was not toxic to neural SH-SY5Y and hepatic HepG2 cells in concentrations relevant for biological activity. These findings highlight oxime 3 as well as the N,N'-dibenzyl imidazolium scaffold as the most potent BChE reactivators reported to date, providing a critical foundation for the advancement of bioscavenging-based therapies for OP poisoning.

Cadmium (Cd), a prevalent environmental toxin and pollutant capable of causing neurodegenerative diseases (NDs) like Alzheimer's and Parkinson's, primarily through oxidative stress, calcium imbalance, and neuroinflammation-induced mechanisms. Cd exposure increases the level of reactive oxygen species (ROS) and disrupts neurotransmitters by lowering antioxidants, leading to neuron death. Cd exposure in zebrafish results in neurodegeneration, with motor, mental, and behavioral impairments. The efficacy of the DOPA-31 intervention at varying concentrations was evaluated through the behavioral tests, biochemical assays for antioxidant enzyme activities (SOD, CAT, GSH, MDA), and histopathological analysis. Additionally, the alterations in expression levels of inflammation (tnf-α, il-1β) and neuroprotective (bdnf, syn2a) genes were also assessed. The Cd exposure exhibited the major deficits in the key behavioral parameters (motor, anxiety, and cognitive impairment). It disrupted antioxidant enzyme activity, increased lipid peroxidation, and elevated acetyl cholinesterase (AChE) activity, leading to cholinergic dysfunction. Histopathology showed extensive neuronal damage and amyloid-like protein aggregation. DOPA-31 at a 20 µM concentration, substantially exhibited antioxidant and AChE activity by reducing oxidative stress and improving motor and cognitive functions. Molecular analysis of DOPA-31 treatment showed significant downregulation of pro-inflammatory markers and upregulation of neuroprotective factors. In addition, DOPA-31 restored behavioral changes by potentially mitigating neuronal damage and protein aggregation caused by the Cd-induced neurotoxicity. This research investigation suggests the novel drug candidate DOPA-31 as a preliminary treatment for Neurodegenerative Disorder (NDD)-like features and warrants further exploration in higher animal models to assess clinical relevance.

Botulinum neurotoxin injections are used off-label to treat chronic pain, but their efficacy is limited and paralytic effects restrict clinical utility in these applications. Here, we investigated whether combining the light chain and translocation domains of botulinum neurotoxin A (BoNT/A) with the GM1-binding B subunit of cholera toxin would be beneficial in silencing pain-associated sensory neurons. Chimeric ChoBot was assembled via a coiled-coil linking technology and was shown to retain the enzymatic activity of BoNT/A in vitro and in vivo. In cultured dorsal root ganglion neurons, ChoBot cleaved SNAP25 in a calcitonin gene-related peptide (CGRP)-rich subpopulation of sensory neurons, resulting in marked inhibition of CGRP release. ChoBot had a lesser effect on the compound muscle action potentials of the rat gastrocnemius muscle than BoNT/A following subcutaneous injections. In rat models of pain, including chemotherapy-induced peripheral neuropathy, intraplantar administration of ChoBot significantly attenuated mechanical allodynia. Immunohistochemical analysis confirmed SNAP25 cleavage in NF200- and CGRP-expressing sensory fibres in the epidermis following a single injection. ChoBot also mediated SNAP25 cleavage in human neuroblastoma cells in culture. Together, these findings indicate that ChoBot enables a silencing of pain-associated sensory pathways, providing a new strategy for the development of new long-lasting analgesics for chronic pain.

Organophosphate (OP) exposure can trigger seizures within minutes and can rapidly evolve into status epilepticus (SE). Early seizure generation is plausibly driven by acetylcholinesterase inhibition, leading to central cholinergic overstimulation. With increasing seizure duration, experimental data are consistent with a time-dependent shift toward glutamatergic maintenance (NMDA/AMPA), oxidative stress, neuroinflammation, and progressive failure of GABAergic inhibition. This framework predicts a narrow window in which benzodiazepine (BDZ) monotherapy is most effective and a rising probability of BDZ non-response when seizures are prolonged, while anti-glutamatergic strategies may retain relative efficacy later in the course. This narrative review integrates clinical phenomenology, diagnostic limitations, and mechanistic evidence to propose an operational approach for OP-related seizures and SE in emergency settings. We discuss a pragmatic "Stage 1 Plus" framing for patients presenting after prolonged seizures or in non-convulsive SE with coma. Human evidence remains limited and heterogeneous, and inference is constrained by confounding due to delayed recognition, variable decontamination/resuscitation pathways, sparse EEG confirmation, and selection bias in mass-casualty reporting.

Botulinum neurotoxin serotype C (BoNT/C) exhibits therapeutic efficacy and duration of action comparable to those of BoNT/A. It has been demonstrated to effectively manage movement disorders such as dystonia and blepharospasm, making it a highly promising alternative to BoNT/A. BoNT/C is also one of the primary etiological botulinum isoforms causing animal botulism and may pose a zoonotic risk. So, it is of great need to develop antidote that can treat human iatrogenic, foodborne and animal botulism caused by BoNT/C. Currently, the approved botulism antidotes primarily are polyvalent horse serum antitoxins, which are severely limited due to insufficient supply and adverse reactions. In this study, we developed a high-affinity nanobody A2, a variable domain of a heavy-chain antibody (VHH) against BoNT/C, based on phage display library screening. Our results demonstrated that A2 effectively blocked the binding of BoNT/C to its target cell. Furthermore, A2 exhibited potent neutralizing activity and rescued BoNT/C-intoxicated mice. These findings supported nanobody A2 as a promising antitoxin candidate with therapeutic efficacy against botulism.

Nerve agents exert their toxicological effects via inhibition of acetylcholinesterase (AChE). This inhibition results in excessive cholinergic signalling, which can result in fatality through cessation of breathing. Current therapies for nerve agent poisoning antagonise the overstimulation of muscarinic acetylcholine receptors and use benzodiazepines to enhance GABAergic inhibition as a counter to increased excitability in the central nervous system. Caenorhabditis elegans (C. elegans) can be effectively used to assess the toxic effects of AChE inhibition by paraoxon-ethyl, which shares the same mode of action of AChE inhibition as organophosphate (OP) nerve agents. In particular, the C. elegans behaviours pharyngeal pumping and motility can serve as bioassays of neuromuscular function and intoxication in the intact animal. This is reinforced by measuring the OP inhibition of AChE activity from homogenates of treated worms. Here, we demonstrate that paraoxon-ethyl, sarin, soman and VX elicit an irreversible inhibition of AChE activity with an order of potency sarin>soman>paraoxon-ethyl>VX. Importantly, this order of potency is maintained when pharyngeal pumping and motility are used to assess nerve agent exposure in vivo. C. elegans neuromuscular-dependent behaviours recover following transfer to OP-free plates, which is not observed for biochemical in vitro AChE activity. Interestingly, we see recovery of extracted in vitro AChE activity following removal of the intoxicated worms to OP-free plates. These data support the use of C. elegans to model nerve agent inhibition and recovery. In particular, the molecular mechanism(s) underpinning behavioural recovery merit further investigation.

Organophosphate compounds such as dichlorvos, a widely used pesticide, account for a substantial proportion of acute poisonings globally. These agents irreversibly inhibit acetylcholinesterase, leading to cholinergic overstimulation. A subgroup of these compounds, alkyl phosphates-originally developed as nerve agents such as tabun, sarin and soman-has been increasingly implicated in intentional ingestions. Diagnosis can be challenging, particularly in the absence of classic cholinergic features such as bradycardia, bronchorrhea and miosis. We present a case of a male patient in his early 20s who was admitted to the intensive care unit with impaired consciousness, respiratory failure, tachycardia and severe metabolic acidosis following ingestion of unidentified substances. Imaging revealed chemical gastritis and aspiration pneumonia. A profoundly reduced serum cholinesterase level prompted empiric initiation of obidoxime therapy. Admission toxicology was positive for amphetamines, plausibly explaining the patient's atypical tachycardia and attenuation of classical cholinergic signs. The patient recovered following intensive supportive care and later confirmed ingestion of dichlorvos in a suicide attempt. This review discusses the clinical presentation, diagnostic challenges and current evidence-based management of alkyl phosphate intoxication. Particular emphasis is placed on the utility of serum cholinesterase measurement, the role of oximes such as obidoxime, and adjunctive interventions including seizure control, and ventilatory support. Clinicians should be aware that severe organophosphate poisoning may occur even in the absence of classical cholinergic signs, requiring a high index of suspicion and timely antidotal therapy.

Organophosphates (OPs), widely used as insecticides, exhibit severe acute toxicity and pose a significant threat to public health. Current standard therapy, which mainly relies on atropine and oxime reactivators, alleviates symptoms but fails to effectively eliminate circulating toxin or excess acetylcholine (ACh), thus representing a non-causal intervention. This study proposes a novel, efficient synergistic dual-enzyme strategy for the treatment of acute OP poisoning in a Sprague-Dawley rat model. Intravenous co-administration of organophosphorus hydrolase (OPH) from Pseudomonas diminuta, site-specifically PEGylated at its N-terminus, together with recombinant human butyrylcholinesterase (BuChE), effectively mitigated cholinergic crisis and accelerated systemic clearance of residual OPs. The hydrolysis rate of ethyl paraoxon by PEG-OPH is 90.9-fold higher than its binding rate to BuChE. This kinetic advantage enables rapid degradation of free OPs in the circulation during the early intoxication phase, thereby dominating initial toxin clearance and preventing excessive BuChE consumption. Concurrently, the administered BuChE hydrolyzes accumulated ACh due to acetylcholinesterase (AChE) inhibition, helping restore the balance of cholinergic neurotransmission. Compared with BuChE monotherapy, the synergistic regimen reduced the required BuChE dose by up to 83%, while achieving full restoration of respiratory parameters to baseline levels within 30 min post-treatment. Moreover, 24-h open-field testing revealed significantly enhanced locomotor activity in the combination group, as evidenced by a markedly greater total distance traveled compared with either PEG-OPH or BuChE monotherapy. Critically, this dual-enzyme strategy conferred complete protection against lethality, yielding a 100% 7-d survival rate. This work pioneers a therapeutic strategy using exogenous enzymes to simultaneously target both the primary toxin and its pathological downstream metabolite. Our results define a highly efficient, precise, cause-targeted approach with significant translational potential for the management of acute organophosphate poisoning.

On August 21, 2013, sarin gas was used as a weapon of war in multiple areas of Ghouta, rural Damascus, Syria, in the largest confirmed chemical weapons attack against civilians in the 21st century. Despite the scale of the attack, little is known about the long-term medical symptoms experienced by survivors. This study documents the lived experiences and the short- and long-term physical and psychological consequences of sarin exposure among civilian survivors more than a decade after the attack. We conducted a retrospective qualitative descriptive study using thematic analysis based on semi-structured narrative interviews with survivors of the 2013 Ghouta chemical attacks. Participants were selected based on confirmed exposure and willingness to provide detailed accounts of their health status, experiences, and healthcare-seeking behavior. Thematic analysis was used to identify recurrent patterns and outcomes across different domains. Participants reported several medical symptoms ranging in severity, including chronic respiratory issues, neurological complaints, fatigue, and sensory disturbances. The psychological impact was universal, with widespread reports of anxiety, nightmares, panic attacks, and social withdrawal. Most participants experienced significant disruption to their quality of life and described barriers to accessing healthcare. The long-term consequences of sarin exposure in Ghouta extend far beyond the initial event, affecting nearly every aspect of survivors' lives. These findings suggest a substantial long-term burden of self-reported physical and psychological symptoms among survivors. They highlight the need for sustained medical, psychological, and social support, and underscore the importance of integrating survivor perspectives into post-conflict recovery and health system responses.