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.

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.

Sarcosphaera crassa is an edible but deadly mushroom that is poisonous in its raw form. In this study, fatty acids profiles, total phenolic, along with in vitro antioxidant and anticholinesterase activities of baked and raw forms of S. crassa were reported for the first time. Linoleic acid (53.6%), oleic acid (24.2%), and palmitic acid (11.5%) were present in the highest amount in the baked sample, while oleic acid (50.5%), palmitic acid (22.4%) and linoleic acid (16.6%) were found in the raw petroleum ether extract (in phenolic equivalents, PEs). PE extracts of raw and baked samples exhibited high phenolic content i.e. 18.8 ± 0.99 μg PEs/mg extract samples and 8.6 ± 0.22 μg PEs/mg extract samples. Similarly, water extract (WE) of baked [12.9 ± 0.03 μg quercetin equivalents (QEs)/mg extract, respectively] and raw (11.4 ± 0.12 μg QEs/mg extract respectively) samples had high flavonoid contents. Acetone extract (AE), methanol extract (ME), and WE of raw and baked S. crassa showed antioxidant activity in β-carotene-linoleic acid, DPPH·, ABTS+·, Fe2+-Ferrin, and CUPRAC assays. Acetone extract (IC50: 256.0 ± 2.0 μg/mL) and PE (IC50: 317.3 ± 1.5 μg/mL) of raw samples also showed moderate inhibitory activity against butyrylcholinesterase (BChE). This mushroom can be used to prevent rancidity in lipids due to peroxidation and may be helpful in healthy food products and as a food additive after cooking.

Alternariol (AOH), alternariol monomethyl ether (AME), and tenuazonic acid (TeA) are three major emerging Alternaria toxins in food. In this lncRNA-mRNA omics-based study, we first decrypt the blueprint: how emerging Alternaria toxins induce hepatic stellate cell LX-2 transdifferentiation for liver fibrosis. AOH and AME caused the fibrotic marker α-smooth muscle actin, extracellular matrix collagen expression, and cell contraction, while TeA had no significant effect. Mechanistically, AOH, AME, and AAT (their combination) activated the NF-κB pathway and induced ferroptosis and AMPK/AKT/m-TOR-related autophagy. Meanwhile, lncRNAs associated with hepatotoxicity were analyzed, and core LncRNAs associated with transdifferentiation were identified. Furthermore, we also proposed a CotA degradation strategy to eliminate the AOH hepatotoxicity. In summary, the present study identifies the potential hepatotoxicity of Alternaria toxins, introduces a CotA laccase-mediated detoxification approach, and lays a foundation for subsequent research and control strategies targeting hepatotoxicity.

Botulism is a neuroparalytic disease caused by exposure to botulinum neurotoxins produced by anaerobic spore-forming bacteria of the genus Clostridium. This disease occurs in both humans and wild and domestic animals, and is currently becoming an increasingly serious problem worldwide due to high animal mortality and economic losses. The clinical signs observed during the progression of botulism are nonspecific and difficult to unequivocally associate with this disease entity. The aim of this study is to present laboratory diagnostics of suspected botulism cases reported in Poland in 2022-2024, as well as to present the challenges encountered during laboratory investigations. The material for the study consisted of samples of liver, serum, digestive tract, feed, feces, straw, and water from drinking lines, sent to the National Veterinary Research Institute (NVRI) in relation to thirteen suspected cases of botulism, predominantly reported in poultry, but also in mink and cattle farms. The samples were analyzed using a mouse bioassay and conventional culture methods, as well as real-time PCR methods aimed at detecting the ntnh and bont genes, which determine the production of botulinum neurotoxins. Of the thirteen suspected cases analyzed, ten were confirmed by the detection of botulinum toxin (BoNTs) and/or the presence of the ntnh and bont genes in the tested material. Based on the results obtained, it was concluded that botulinum toxin type C was the etiological factor of botulism poisoning in most of the analyzed cases. In one case reported in cattle, poisoning occurred as a result of the mosaic variant of BoNT D/C. Due to the nonspecific signs of botulism and the time required for them to appear, laboratory diagnostics play a key role in detecting the disease. However, this process is complicated due to the high heterogeneity observed among Clostridium spp. strains, as well as difficulties encountered during the isolation of the microorganism and the possibility of loss of toxin-producing capacity at later stages of analysis.

The recent use of low volatile nerve agents for assassination attempts has shown that nerve agent poisoning is an ongoing challenge. Immediate decontamination of exposed patients is crucial to prevent systemic effects from skin exposure and to facilitate survival. Currently used skin models to study penetration rates rely on animal or human skin, that has most often been stored in a frozen state (obvious impairement of epidermal tight junction barrier in frozen thawed skin). Thus, we investigated a bioartificial three-dimensional model of human skin which allows the study of decontamination procedures on viable skin. In the Franz diffusion cell, we investigated the effectiveness of different decontamination lotions (RSDL; AHAK; sodium hypochlorite 2% and tap water) by calculating the amount of penetrated VX in the acceptor chamber over 5 h, as a surrogate parameter of decontamination efficacy. The FDA approved RSDL (Reactive Skin Decontamination Lotion) and the AHAK lotion (potassium salt of the acetohydroxamic acid) showed a substantial decontamination efficacy. The penetrated amount of VX in the acceptor chamber (Franz diffusion cell) after 5 h was reduced by 99.97% for AHAK and by 96.57% for RSDL. Sodium hypochlorite (2%) and tap water showed a significantly lower efficacy compared to the lipophilic decontamination agents (RSDL and AHAK). AHAK was also tested as application prior to exposure and showed substantial results. In summary, the results demonstrate that the FT (full-thickness) skin model is a suitable model for investigating the decontamination efficacy of various decontamination solutions against the highly toxic nerve agent VX.