Envenomation by Deinagkistrodon acutus (D. acutus) often results in severe limb damage, but therapeutic strategies to counteract the damage are limited. Botulinum neurotoxin A (BoNT/A) has shown protective effects in various models of tissue damage. The present study employed a rabbit model of D. acutus-induced limb damage to investigate the potential therapeutic use and underlying mechanisms of BoNT/A.

Spider venoms are primarily composed of small neurotoxic peptides. However, recent studies suggested a hitherto overlooked diversity of spider venom enzymes, although their functional space still remains largely unexplored. We tested 10 spider venoms for enzymatic activities covering six enzyme classes and found that all tested enzymatic activities can be detected in at least some of the venoms and that hyaluronidases exhibit particularly high enzymatic activities. With this, our study provides functional evidence for the proposed biological significance of enzymes in spider venoms, but more detailed investigations are required.

We aimed to determine the effects of linear cyanobacterial oligopeptides: microginin-FR1 (MG-FR1), anabaenopeptin-B (ANA-B), aeruginosin 98A (AER-A), aeruginosin 98B (AER-B) and their binary and quaternary mixtures on RTgill-W1 cell line. The following cellular parameters were determined after 48-h exposure: propapoptotic caspase 3/7, heat shock protein 70 kDa (HSP70) level, cAMP level as an indicator of interaction with G protein-coupled receptors (GPCRs) and tyrosine phosphatase level. The study showed that caspase 3/7 level was increased in cells exposed to the tested single (MG-FR1 was the most potent stimulator) and mixtures of the oligopeptides (the most potent was ANA-B + AER-A), mostly with synergistic interactions. Single MG-FR1, AER-A, AER-B and AER-B increased the level of HSP70 The highest augmentation was noted in cells exposed to AER-A and AER-B. On the other hand, ANA-B and the mixture of MG-FR1+ANA-B induced a concentration-dependent inhibition but the other binary mixtures increased this parameter. The quaternary mixture was the most effective stimulator of HSP70 production. Both single cyanobacterial metabolites and their mixtures decreased the level of cAMP at the highest concentrations. The single tested oligopeptides and their mixtures had poor effects on tyrosine phosphatases. Only ANA-B and the binary mixture of MG-FR1+ANA-B reduced this parameter. The results show that cyanobacterial oligopeptides should be considered as stressful agents to fish gills and may contribute to various biochemical alterations and physiological disorders in these aquatic vertebrates.

This study analyzes 26 years of European Union Rapid Alert System for Food and Feed (RASFF) notifications concerning mycotoxins (354 notifications), pathogenic microorganisms (311), and pesticide residues (300) in organic products from 1999 to 2024. Analysis of notification classifications revealed that mycotoxins dominated border rejections (42.94 %), pathogenic microorganisms dominated information notifications (59.49 %), and pesticide residues led alerts (55.33 %). The countries of origin most frequently associated with notifications were Turkey for mycotoxins (26.27 %), Italy for pathogenic microorganisms (20.26 %), and India for pesticide residues (37.33 %). Nuts, nut products, and seeds were the most frequently reported product categories associated with mycotoxin (35.88 %) and pesticide residue (38.00 %) notifications, while feed materials were predominant in pathogenic microorganisms (45.34 %). Peanuts (24.29 %) and figs (19.21 %) were frequently implicated in mycotoxin notifications, while sesame seeds (37.33 %) and soybeans (24.12 %) were commonly associated with pesticide residues and pathogenic microorganism notifications, respectively. Aflatoxin B1, Salmonella, and ethylene oxide were the most frequently reported mycotoxin (49.15 %), pathogenic microorganism (89.71 %), and pesticide residue (48.67 %), respectively, in RASFF notifications. A high percentage of mycotoxin (75.42 %), pathogenic microorganism (42.77 %), and pesticide residue (56.33 %) notifications were classified as serious, emphasizing the need for robust quality control measures to ensure the safety and integrity of organic products.

OnabotulinumtoxinA (onabotA) is approved for the treatment of various therapeutic indications, which require retreatment. In clinical practice, many patients receive onabotA for multiple therapeutic indications concomitantly over extended time periods; however, there is limited long-term utilization and safety data for treating comorbid indications. SYNCHRONIZE, a 2-year, multicenter, retrospective observational chart review study in 10 US clinics, describes onabotA real-world utilization and safety in adults treated for ≥2 therapeutic indications within repeating 3-month periods for up to 7 treatments. This analysis assessed the long-term onabotA safety profile for multiple therapeutic indications by analyzing the incidence of treatment-emergent adverse events (TEAEs). Of 279 patients treated for ≥2 different therapeutic indications across all treatment combination groups in Period1, there was a gradual decrease to 80 patients at the last treatment period. The overall mean onabotA treatments over the study period was 9.3 (range: 2-48). Across treatment periods, most patients had a treatment interval between different indications of ≤24 h (range: 62-98 %) and received ≥200-<400U of cumulative 3-month dosages for multiple indications (range: 43 %-50 %) with a mean 3-month dose from 231.8 to 287.0 U. In total, 28.7 % of patients reported ≥1 TEAE after Period1; this proportion remained broadly constant across treatments (range: 28.3-31.8 %). Overall, the most common TEAEs across treatments were UTIs (range: 0.7-5.7 %), neck pain (range: 3.7-9.1 %), headache (range: 2.9-6.5 %), and migraine (range: 2.5-6.4 %). There was no apparent trend between TEAE incidence and treatment intervals nor cumulative 3-month dose categories for multiple indications. No patients were determined to have lack of effect based on clinical objective measurement. OnabotA showed a safety profile with no new signals in patients treated concomitantly for ≥2 therapeutic indications over repeat treatments up to 2 years. TEAEs across treatment periods were commonly related to the site of injection and were consistent with those previously reported for individual indications.

In 2018, the World Health Organization (WHO) acknowledged Snakebite Envenoming (SBE) as a Neglected Tropical Disease (NTD). The WHO set a target for 2030 to halve the number of snakebite victims and published a roadmap to assist affected countries with drafting national SBE policies. These national SBE policies define the course of action to reach country specific and global goals. In order to review the policy environment needed to reduce the burden, we studied if SBE policy was included in national NTD programmes and if it included the four WHO SBE policy aims and a vision for the integration of NTDs. National NTD masterplans were reviewed and combined with in-depth interviews focusing on stakeholders' experience with the integration of SBE in NTD programmes, and the influence of the inclusion of SBE on the NTD list. Only 18 % (2 out of 11) of 2015-2020 NTD masterplans mentioned SBE whereas all twelve countries who published masterplans for 2020-2025 included SBE and the need for an integrated approach between NTD programmes. Information on the type of activities allowing integration or the organizational aspects of an integrated approach was often missing. The extent to which the core policy aims of the WHO SBE roadmap has been elaborated differs considerably from country to country. In the interviews, several stakeholders raised the importance of improving the quality of epidemiological data to convince policy makers of its importance, to base antivenom distribution and to facilitate overall policy making. The path of improvement that has been taken since the recognition of SBE as an NTD must be continued and benefits from a closer collaboration between policymakers, researchers and healthcare workers to reduce the evidence gap and, ultimately, to improve care.

Scorpion envenomation is a common acute life-threatening health problem in developing countries as Morocco, where is considered as the first cause of intoxication. The present study was designed to investigate scorpionism in three provinces located in central Morocco, namely Beni Mellal, Fquih Ben Salah, and Khouribga.

Fructus Gardeniae, a widely used traditional Chinese medicine that also serves as food, contains geniposide as its active ingredient. Current research indicates that high doses of geniposide can cause nephrotoxicity in rats. This study investigates the nephrotoxicity induced by geniposide and preliminarily explores its underlying mechanisms. Male SD rats were orally administered geniposide (200 mg/kg), geniposide (400 mg/kg), and geniposide + obeticholic acid (OCA) (25 mg/kg) for 1 week consecutively. The results indicate that geniposide induces nephrotoxicity, manifested by elevated levels of blood urea nitrogen, creatinine, KIM-1, and NGAL, along with increased renal histopathological damage. Additionally, in all geniposide dose groups, the mRNA and protein expression levels of FXR were significantly downregulated, while those of NLRP3 and Caspase-1 were upregulated. The addition of the FXR receptor agonist OCA alleviated the nephrotoxicity induced by geniposide, as evidenced by reduced levels of urea nitrogen, creatinine, KIM-1, and NGAL, as well as mitigated renal histopathological damage. The protein expression levels of ASC, cleaved IL-1β and cleaved Caspase-1 were detected by Western Blot. RT-qPCR and Western blot experiments revealed a significant upregulation of FXR mRNA and protein levels, while the mRNA and protein expression of endoplasmic reticulum stress-related proteins PERK and TXNIP, NLRP3 and Caspase-1, were downregulated. These results confirm that geniposide can induce nephrotoxicity, and the FXR/PERK/TXNIP/NLRP3 signaling pathway is involved.

This report is built on insights gathered during the European Venom Network (EUVEN) workshop on the patentability of natural compounds, with a particular focus on venom-derived molecules, held online on June 10, 2022. The program explored key aspects of Intellectual Property (IP) rights relevant to the development of therapeutic agents derived from natural sources, including animal venoms and toxins. Topics included IP considerations in biotechnology, strategies for building and managing IP portfolios, and licensing pathways from academic research to industry. The review further discusses the specific challenges and opportunities in patenting venom-based compounds, and outlines recommended practices for IP sharing within collaborative research consortia such as EUVEN. Finally, it incorporates perspectives from industry on fostering academic partnerships to advance the translational potential of venom-derived therapeutics. This document aims to serve as a practical guide for researchers at all career stages working in life sciences, particularly those engaged in the discovery and development of natural product-based innovations.

MC-LR, a potent cyanotoxin produced by specific kinds of cyanobacteria, is widely acknowledged for its cytotoxic effects; however, its role in mitochondrial-mediated epigenetic regulation remains poorly characterized. This study examined the mitochondrial integrated stress response and associated epigenetic changes following exposure to varying concentrations of MC-LR. Elevated mitochondrial reactive oxygen species (mtROS) indicated disrupted mitochondrial function and dynamics, potentially contributing to reduced cell viability. Gene expression profiling revealed dose-dependent upregulation of key regulators of mitochondrial fission and fusion (Drp1, Fis1, MFN1, MFN2), integrated stress response mediators (OMA1, DELE1, HRI), and epigenetic modifiers (DNMTs, TFAM, TET). Significant shifts were also observed in DNA and RNA methylation levels, along with increased pro-inflammatory cytokine expression. Correlation and regression analyses revealed a clear dose-dependent activation of several gene pathways, with DNA repair enzymes and DNMTs exhibiting the highest EC values. To assess preliminary insight into potential structural interactions, we conducted exploratory molecular docking using the Schrödinger Suite, focusing on the interaction of MC-LR fragments with the catalytic subunit of protein phosphatase 2A (PP2A; PDB: 3DW8). The results suggested favorable binding energies for specific fragments, indicating PP2A as a possible target of MC-LR, which may contribute to its mitochondrial effects. Overall, these findings provide new insights into the mitochondrial-associated epigenetic consequences of MC-LR exposure and suggest possible structural interactions with PP2A. This work enhances the understanding of the mito-epigenetic disruptions caused by MC-LR. It points to structural mechanisms that need further experimental investigation, which may also help inform future environmental toxicity evaluations.

Avermectin (AVM), as one of the most important members of the biopesticide family, is widely used in the fields of agriculture and forestry production. An increasing number of reports indicate the toxic effects of avermectin in environmental exposure. Sophocarpine (SPC) is known to exhibit anti-inflammatory function. The effect of SPC on AVM-induced kidney injury in carp were investigated. The carps were received AVM for 30 days and SPC was given 1 h after AVM treatment. Then, kidney injury was tested by detecting kidney pathological change and myeloperoxidase (MPO) activity. Inflammatory cytokine production and signaling pathway were also detected. SPC significantly alleviated AVM-induced kidney histopathological changes and MPO activity. TNF-α and IL-1β production and nuclear factor kappa-B (NF-κB) activation were also inhibited by the treatment of SPC. Meanwhile, AVM-induced malondialdehyde (MDA) and Fe contents were prevented by SPC. And SPC increased GPX4 and SLC7A11 expression, as well as GSH level decreased by AVM. Furthermore, SPC markedly increased nuclear factor erythroid-2 related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) expression. These results indicated SPC may have protective effects against AVM-induced kidney injury through inhibiting inflammation and ferroptosis via Nrf2/SLC7A11/GPX4 signal pathway.

Botulinum neurotoxin type A formulations all contain the same 150 kDa core protein, yet they behave as if they were different drugs. Clinicians routinely observe differences in onset, spread, duration, and immunogenicity, despite the fact that accessory proteins dissociate quickly after injection. If dissociation were the full story, these products should act identically. They do not. Using a multiscale in silico AesthetiSIM™ platform and a 10,000-patient digital twin cohort. Simulations were performed under physiologic temperature (37 °C) and pH 7.4, with sensitivity analyses evaluating these conditions. Our simulations confirmed that dissociation alone cannot account for divergent clinical profiles. Instead, excipients and microenvironmental factors create distinct pharmacokinetic and immunologic landscapes that persist even when the neurotoxin core is identical. Lactose drove broader diffusion, sucrose stabilized local confinement, sodium chloride altered electrostatic spread, and the peptide RTP004 prolonged residence by binding extracellular proteoglycans. These formulation-specific interactions shaped receptor engagement, clearance, and immunogenicity, overturning the assumption that dissociation explains everything. The findings demand a shift in perspective: botulinum toxins are not defined solely by their neurotoxin, but by the excipient ecosystem in which they are delivered. This mechanistic framework explains why products remain "non-interchangeable" and shows that the paradox of dissociation is not a paradox at all; it is the predictable outcome of pharmacology embedded in formulation. As these outcomes are derived from computational modelling, they should be viewed as predictive and require confirmation through targeted biochemical, biophysical, and cell-based assays.

Despite the widespread use of Crotonis Fructus (derived from Croton tiglium L.) in traditional medicine, its reproductive toxicity remains poorly characterized. Here, we investigated its potential mechanisms using Caenorhabditis elegans, network toxicology, molecular docking, and multi-model validation. Exposure to croton extract (CE) impaired reproductive capacity and shortened lifespan in C. elegans. Network toxicology identified 21 putative toxic compounds and 88 female reproductive dysfunction-related targets. Molecular docking revealed strong binding affinities of phorbol diesters, among others (key Crotonis Fructus components) to critical targets, including AKT1 and MMP9. In vitro (RAW264.7 cells) and in vivo (SD rats) experiments demonstrated CE-induced dysregulation of PI3K/Akt signaling pathway genes. Our findings establish that Crotonis Fructus induces female reproductive toxicity by regulating the release of inflammatory factors and activating the PI3K/Akt pathway, providing critical insights for refining its clinical safety guidelines.

Scorpion stings by members of the genus Parabuthus (Buthidae) can lead to life-threatening envenoming. Namibia harbours a rich diversity of scorpions, including seventeen species of the highly venomous genus Parabuthus, although the biology and medical relevance of most species are poorly documented. Severe envenoming is caused by at least P. granulatus, P. villosus, P. kraepelini and P. schlechteri, which are considered to be of particular importance. Data on epidemiology, venom composition and variation, and clinical effects remain scarce. A lack of effective antivenom and long distances to hospitals in rural areas complicate clinical management and compromise patient outcomes.

Comparative evaluation of botulinum neurotoxin type A (BoNT/A) formulations is limited by short clinical trials and lack of long-term safety data. This study applied a validated multiscale computational model (AesthetiSIM™) to simulate 20 years of repeated treatment with eight BoNT/A formulations, integrating receptor binding kinetics, tissue diffusion, pharmacodynamic response, and HLA-weighted immunogenicity. Model parameters were calibrated against published biochemical, imaging, and randomized clinical trial data, and uncertainty was quantified through 10,000 Monte Carlo iterations. Each virtual patient underwent standardized five-site glabellar injections with clinically equivalent doses. LetibotulinumtoxinA and PrabotulinumtoxinA predicted the most balanced profiles, combining high efficacy (mean peak strain reduction 72 % and 68 %, respectively), rapid onset (2.7-3.1 days), and minimal predicted neutralizing antibody incidence over 20 years (0.4-0.6 %). DaxibotulinumtoxinA showed the longest modelled duration of effect (median 142 days), whereas AbobotulinumtoxinA and Relatox exhibited broader diffusion and higher immunogenicity risk. Overall ranking stability remained high (ρ = 0.92) across all uncertainty scenarios. These simulations align closely with available empirical data and suggest that formulation-specific differences in protein structure, diffusion behaviour, and antigenicity may contribute to observed clinical variability. Model-informed comparative analysis can complement real-world and prospective studies to optimize product selection and dosing strategies in aesthetic and therapeutic applications.

Deoxynivalenol (DON) is a mycotoxin widely present in grain crops and feed materials and exhibits a relatively high contamination rate. It is most commonly found in grains such as wheat, barley, and corn. DepA, a pyrroloquinoline-quinone (PQQ)-dependent enzyme isolated from Devosia mutans 17-2-E-8, catalyzes the conversion of DON to 3-keto-DON. Following the synthesis and cloning of the DepA gene, the deoxynivalenol epimerization enzyme (DepA) was produced using a cell-free Escherichia coli synthesis system. DepA has a molecular weight of 63 kDa, with optimal activity at pH 7.0 and 35 °C. The coenzyme PQQ is essential for the activity of both crude and purified DepA. Metal ions Ca enhance DepA activity, while Co,Cu and Zn inhibit. Three-dimensional structural simulation of the DepA protein (covering 90.88 % of the gene sequence) identified a PQQ binding site and a Ca binding site. This indicates that PQQ influences the binding of DON to DepA. In the presence of the coenzyme PQQ, the type and strength of interactions between PQQ and DON changed: the interaction distance with the hydrogen atom of the C3-OH group decreased, while the interaction with the hydrogen atom at the C3 position increased. This alteration may be an important factor underlying PQQ's influence on DepA activity. This study provides a novel method for producing DepA using a cell-free system and elucidates a mechanistic pathway for DepA-catalyzed biotransformation of DON into 3-keto-DON.

Snake venoms exert profound effects on blood coagulation, mostly associated with consumption coagulopathy due to the procoagulant activity of venom proteinases, which result in drastic alterations of laboratory clotting tests. In addition, snake venoms contain enzymes [mostly phospholipases A (PLAs) and metalloproteinases (SVMPs)] that have strong anticoagulant activity in vitro. However, their actual effect on coagulation parameters in vivo has not been studied in detail. In the present work, we evaluated the alterations in standard clotting tests (prothrombin time, activated partial thromboplastin time and fibrinogen concentration) and in rotational thromboelastometry parameters after the administration of venoms (Naja nigricollis and Pseudechis papuanus) and enzymes (P-I and P-III fibrinogenolytic SVMPs and an anticoagulant PLA) that exert anticoagulant effect in vitro. For comparative purposes the venom of Bothrops asper, which is procoagulant in vitro and induces defibrinogenation in vivo, was also studied. Venoms and enzymes were administered intravenously in mice using sublethal doses to assess their in vivo effects on clotting parameters. Despite their anticoagulant effect on mouse plasma in vitro, the alterations of the clotting tests in vivo were generally limited, being more pronounced in the case of P. papuanus venom and in some Intem and Fibtem parameters. In contrast, the venom of B. asper induced a consumption coagulopathy associated with drastic alterations in all clotting parameters examined. Our observations suggest that venom components that induce anticoagulation in vitro do not necessarily exert major alterations in clotting parameters in vivo.

Abamectin (ABM) is synthesised by Streptomyces avermitilis and is used for the treatment of Onchocerca volvulus in humans and also in the veterinary and agricultural areas. The study employed 48 male Wistar Albino rats, aged 2-3 months and weighed 150-200 g, 8 per group. Control animals received corn oil. The experimental groups received 100 mg/kg.bw baicalin (BAI), 100 mg/kg.bw vitamin E (VIT E), 2 mg/kg.bw ABM, 2 mg/kg.bw ABM combined with 100 mg/kg.bw BAI, and 2 mg/kg.bw ABM combined with 100 mg/kg.bw VIT E for 28 days. Oxidative stress parameters of MDA, NO, GSH, GPx, GR, GST, SOD, and CAT, liver expression levels of caspase 3, 8, 9, Bcl-2, Bax, Fas, and p53, and biochemical parameters of triglyceride, cholesterol, total protein, albumin, LDH, AST, ALT and ALP were measured. ABM alone caused significant variations in the investigated parameters, but the combinations of ABM plus BAI or VIT E corresponded more closely to the control values. ABM altered the oxidant-antioxidant equilibrium, increasing oxidation and apoptosis. VIT E and BAI was regressed this pathological process to some extent. Toxic impact mitigation was similar for both compounds. VIT E and BAI may serve as additional treatments in cases of ABM toxicity.

Toad poison is composed of a range of molecules, such as alkaloids, bufotoxin, proteins, and peptides, including phospholipases A (PLA). PLAs are responsible for catalyzing the hydrolysis of the ester bonds of phospholipids, which are one of the main compounds of the cellular membrane. PLAs may have hemolytic, myotoxic, and antimicrobial functions. However, the function of this protein in Rhinella's poison is still unknown. In this study, Rhinella diptycha mucous poison was fractionated using reversed-phase chromatography, and fraction 16, which contained a PLA-sized protein, was subjected to a phospholipase assay, N-terminal sequencing, and an agar diffusion antimicrobial assay against Escherichia coli. Molecular modeling and in-silico analysis of PLA were performed to identify potential antimicrobial peptides encoded in its sequence. Selected peptides were subjected to solid-phase peptide synthesis and analyzed using minimum inhibitory concentration and minimum bactericidal concentration assays against Staphylococcus aureus and E. coli. PLA was successfully isolated, showing enzymatic activity. N-terminal sequencing confirmed its identity as RsPLA from the R. diptycha skin transcriptome. The antimicrobial assay revealed no growth inhibition of E. coli at the RsPLA tested concentrations. In-silico analysis identified three potential antimicrobial peptides, two of which were synthesized and tested against E. coli and S. aureus, showing limited antimicrobial activity. Further investigations are required to assess its potential against other microorganisms. This study enhances our understanding of toad poisons and their potential biotechnological applications.

Venom composition and gene expression in the habu snake Protobothrops flavoviridis (P. flavoviridis), native to the southwestern islands of Japan, vary by habitat and may reflect regional dietary differences. Because juveniles and adults feed on different prey, we hypothesized that venom composition undergoes age-dependent changes during growth. To test this hypothesis, we compared venom proteins from juvenile and adult snakes by two-dimensional gel electrophoresis (2-DE) and identified a protein spot uniquely present in juvenile venom. Mass spectrometry revealed that this protein is encoded by the phospholipase A (PLA) gene pgPLA1b/2b, previously regarded as a pseudogene because its product is absent from adult venom. Reverse transcription-PCR (RT-PCR) analysis of venom glands from snakes of different ages showed that pgPLA1b/2b is expressed in 0- and 1-year-old individuals, barely detectable at age 2, and absent in adults, whereas other PLA isozyme genes remain constitutively expressed regardless of age. These findings demonstrate that pgPLA1b/2b is the only venom PLA isozyme gene exhibiting ontogenetic regulation. Since PLA isozyme genes form gene clusters in the P. flavoviridis genome, the age-dependent expression of only pgPLA1b/2b is of particular interest. Our study provides molecular evidence that venom composition in P. flavoviridis is developmentally regulated through juvenile-specific expression of a venom gene, likely reflecting ecological and dietary transitions during growth. Future studies should elucidate the transcriptional mechanisms underlying this regulation.

Cancer remains a significant global health challenge, prompting the search for novel therapeutic strategies that minimize the limitations of current treatments. Crotamine, a cationic myotoxin isolated from the venom of Crotalus durissus spp., has emerged as a promising anticancer candidate due to its selective cytotoxicity toward tumor cells and multifaceted biological activities. This review examines the structural and functional characteristics of crotamine, emphasizing its mechanisms of action, such as disruption of ionic homeostasis through calcium influx, inhibition of voltage-gated potassium channels (Kv), and its preferential uptake by proliferating cells as a cell-penetrating peptide (CPP). Moreover, crotamine facilitates the intracellular delivery of bioactive compounds, enhancing drug selectivity and efficacy. Preclinical studies have demonstrated its ability to inhibit tumor growth both in vitro and in vivo, with minimal toxicity to normal tissues and low immunogenicity. These features position crotamine as a strong candidate for anticancer drug development. However, further investigation is essential to fully elucidate its molecular targets and mechanisms and to support its clinical translation.