Toxins最新文献

Antivenom administration is currently the only therapy for snakebite envenoming. However, in sub-Saharan Africa, inadequate quality control systems have led to deficits in the availability, accessibility, efficacy and safety of regionally available antivenoms, which, in turn, hinder snakebite treatment and management in the region. To address this impediment to snakebite treatment in Kenya, this study aimed to assess the preclinical neutralising potencies of four different antivenoms previously or currently available in Kenya (SAIMR polyvalent, AFRIVEN, PANAF-Premium^TM and Inoserp^TM) against key snakes of medical importance in the region, towards establishing a national antivenom quality control laboratory. Venoms were extracted from the Kenyan "big five" medically important snake species: Naja ashei, Naja pallida, Naja nigricollis, Dendroaspis polylepis and Bitis arietans, and their lethal potencies were determined using a murine median lethal dose (LD₅₀) assay. In vitro immunological assays (ELISAs and immunoblotting) and an established preclinical murine in vivo neutralisation assay (median effective dose [ED₅₀]) were used to assess the immunoglobulin-binding and venom-neutralising efficacies of the test antivenoms. In vitro assays revealed high venom-binding titres of SAIMR polyvalent, AFRIVEN and PANAF-Premium^TM, and reactivity to a wide range of venom proteins across the different snake venoms. Contrastingly, Inoserp^TM antivenom had low binding titres and poor reactivity to the snake venom proteins. These findings were aligned with the in vivo results, where SAIMR polyvalent, AFRIVEN and PANAF-Premium^TM showed potent venom-neutralising efficacies against all the tested snake venoms, while Inoserp^TM had low potency and failed to neutralise the lethal effects of N. ashei, N. pallida and D. polylepis venoms at the manufacture-claimed doses. Based on these robust preclinical results, we conclude that SAIMR polyvalent, AFRIVEN and PANAF-Premium^TM antivenoms offer considerable potential for the treatment of envenoming by diverse medically important snakes in Kenya. The observed deficiencies with the Inoserp^TM product highlight the importance of (i) robust, independent preclinical antivenom efficacy testing and (ii) the value of establishing a quality control laboratory to inform local regulatory and procurement decision making.

Aflatoxin M1 (AFM₁) is a carcinogenic milk contaminant and a persistent food safety concern in Serbia, especially under changing climate conditions that exacerbate contamination risks. This review synthesizes national research conducted between 2012 and 2024, covering more than thirty thousand analyzed milk and dairy samples, to evaluate AFM1 contamination, public health risks, and the need for structured risk ranking and prioritization frameworks recommended by the Food and Agriculture Organization (FAO) and the European Food Safety Authority (EFSA). A systematic analysis of Serbian studies explored AFM₁ occurrence, dietary exposure, and health risk estimates across population groups. The evidence reveals persistent AFM1 contamination with pronounced seasonal peaks during drought years and winter months, frequently exceeding the EU maximum limit of 0.05 µg/kg. Recent multi-year studies confirm that climate-driven AFB1 contamination in maize and compound feed remains a significant and recurring source of AFM1 in milk, highlighting the necessity of structured risk prioritization frameworks. Exposure assessments highlight children and students as the most vulnerable groups, displaying the highest estimated daily intake. Although current margin of exposure (MOE) values remain within acceptable limits, the persistence of contamination underscores a need for proactive risk management. Adoption of FAO and EFSA risk-ranking methodologies would enhance monitoring efficiency, protect high-risk populations, and support alignment with EU standards. Implementing structured risk prioritization is crucial for strengthening Serbia's food safety governance, guiding policy decisions, and reducing the health burden of AFM₁ in the dairy sector.

Skeletal muscle is the largest metabolic demanding organ in human body. Alterations of skeletal muscle in shape and size significantly affect its biological functions. Botulinum neurotoxin type A1 (BoNT/A1) has been successfully used in clinics to treat masseter, trapezius and gastrocnemius hypertrophy. Here, we used a healthy rat-based skeletal muscle hypertrophy model to evaluate the muscle-reducing activity of recombinant BoNT/A1 (rBoNT/A1) with genetically fused cell-penetrating peptides (CPPs), which was previously reported to increase the cellular uptake of BoNT/A1. Analyses of treated muscle sections using hematoxylin-eosin and immunofluorescence staining showed that both wild-type rBoNT/A1 without modification (WT-rBoNT/A1) and rBoNT/A1 with CPP fusion (CPP-rBoNT/A1) could induce myocomma atrophy and altered gastrocnemius muscle fiber proportions as a result of denervation and reinnervation. Importantly, rBoNT/A1 with the fusion of a specific CPP, zinc finger protein (ZFP), resulted in the highest degree of muscle atrophy and greatest increase in the ratio of type I muscle fibers over type II fibers. An examination of gastrocnemius muscle cells at the subcellular levels using TEM staining revealed swelled mitochondria and diminished mitochondrial crista upon rBoNT/A1 administration. Transcriptomic RNA sequencing (RNA-Seq) analysis followed by RT-qPCR validation showed that rBoNT/A1 treatment also caused changes in mitochondrial biogenesis and mitophagy. Collectively, our results demonstrated that rBoNT/A1 proteins could alleviate skeletal muscle hypertrophy, with associated alterations of mitochondrial homeostasis.

Zearalenone (ZEA) is a prevalent non-steroidal estrogenic mycotoxin in feed and feedstuffs. This study investigated the effects of graded dietary purified ZEA standard (0, 0.2, 0.5, 1, 2, and 4 mg/kg) on growth performance, blood biochemistry, oxidative stress, immune response, intestinal morphology, histopathology, and gut microbiota in broilers. The use of purified ZEA standard eliminates confounding effects from co-occurring contaminants and the reduced nutritional quality of naturally contaminated feed, allowing an accurate assessment of ZEA-specific effects. A total of 216 one-day-old Arbor Acres male broilers were randomly allocated into six treatment groups, each with six replicates of six birds, for a 42-day trial. At the regulatory limit (0.5 mg/kg) and below, no overt toxic effects were observed on growth performance, hematology, or serum biochemistry. Although alterations in oxidative stress markers, specifically decreased liver superoxide dismutase (SOD) activity and reduced ileal glutathione peroxidase (GSH-Px) activity, and in immune markers, including increased interleukin-2 (IL-2) levels in the jejunum and ileum and decreased ileal interleukin-10 (IL-10) levels, were observed at 0.2-0.5 mg/kg, these changes did not cause tissue damage or functional impairment. Toxicological alterations emerged only at higher doses (1-4 mg/kg), comprising impaired jejunal morphology and moderate lung secretory cell metaplasia. The highest dose (4 mg/kg) further induced severe renal tubular degeneration and necrosis, accompanied by significant disruption of the jejunal microbiota. In conclusion, these findings indicate that purified ZEA at the regulatory limit exhibits no overt toxicity in broilers, although higher contamination levels pose clear risks to intestinal, pulmonary, and renal health.

Ochratoxin A (OTA) is a globally distributed mycotoxin that poses serious threats to food safety and human health due to its nephrotoxic, hepatotoxic, and carcinogenic properties. Previous enzymatic detoxification strategies for OTA have been constrained by low degradation efficiency or poor soluble expression of highly active enzymes. In this study, a bacterial strain with strong OTA-degrading activity was isolated and identified as Acinetobacter kookii AK4, which degraded 95.44% of 1 μg/mL OTA within 6 h. The predominant OTA-degrading activity was derived from intracellular enzymes. Through genome mining and experimental validation, gene2102 was identified as encoding an amidohydrolase. The enzyme was designated AMH2102 and was heterologously expressed in Escherichia coli. Codon optimization combined with fusion of an N-terminal SUMO tag increased the soluble expression of AMH2102 by 14.81-fold, enabling complete (100%) OTA degradation within 3 min. Overall, this study achieved the identification of an efficient OTA-degrading strain and enzyme and explored strategies for improving enzyme expression, yielding effective outcomes that provide useful references for future studies on strain mining and enzyme engineering.

Patients with cerebral palsy (CP) experience complex gait disorders that change with age, leading to reduced activity and social participation. This study aimed to analyse how gait patterns developed over five years and to examine the relationships between the Observational Gait Scale (OGS), Amsterdam Gait Classification (AGC), Gross Motor Function Classification System (GMFCS), and the Functional Mobility Scale (FMS) at 5 and 50 m (FMS 5/50) during treatment. This retrospective, single-centre observational study involved annual assessments over a five-year period, which were analysed. Patients underwent a rehabilitation programme including physiotherapy, orthotics, multilevel botulinum toxin type A injections (BoNT-A), and serial casting. Data regarding BoNT-A treatment, casting, physiotherapy, orthoses, GMFCS levels, and FMS 5/50 scores were obtained from medical records. OGS and AGC were evaluated through two-plane clinical video recordings conducted in the same gait laboratory for all children. A cohort of 200 pediatric subjects (120 boys and 80 girls) diagnosed with bilateral cerebral palsy, predominantly classified as GMFCS II (48%) and III (36%), was analyzed. The average initial age was 32.23 months (±6.96), and GMFCS levels improved in 33. 5% of children and worsened in 2% (p < 0.001). Improvements were observed in 50% of children with GMFCS III and 40% with GMFCS IV levels. FMS 5 and 50 improved by 54% and 52%, respectively. OGS scores showed improvement in 74% and 76% of patients, respectively, while deterioration was observed in 5% and 7% for the right and left lower limbs, respectively. Most changes in OGS scores ranged from 1 to 4 points. A negative correlation was found between OGS and GMFCS (p < 0.001), and a positive correlation was found between OGS scores and FMS 5 and FMS 50 (p < 0.001). Additionally, significant relationships were identified between AGC and GMFCS, as well as FMS at 5 and 50 m. Complex gait disorders identified by the AGC are associated with higher GMFCS E&R scores and lower FMS scores. During the five-year follow-up, relationships were observed among GMFCS, FMS, OGS, and AGC. Our findings indicate that integrated treatment has a positive effect on functional mobility and gait patterns in patients with CP.

The rising incidence of colorectal cancer (CRC) in modernized societies is linked to diet-induced dysbiosis, characterized by a critical metabolic divergence: the depletion of protective indole-3-acetic acid (IAA) concurrent with the accumulation of toxic skatole (3-methylindole). However, the molecular mechanisms by which high concentrations of skatole drive malignancy-and whether IAA can counteract this toxicity-remain elusive. Here, we demonstrate that physiologically relevant concentrations of skatole (500 µM) significantly promote the proliferation of HCT-116 CRC cells through a "dual-hit" mechanism involving both aryl hydrocarbon receptor (AhR)-dependent genomic activity and AhR-independent activation of the ERK MAPK pathway. Notably, co-treatment with IAA (250 µM) effectively abrogated skatole-induced proliferation, restoring cell growth to baseline levels while sparing upstream MAPK phosphorylation. Mechanistic analysis indicates that IAA acts not merely as a competitor, but as a functional antagonist. Specifically, our findings suggest that IAA functions as a putative selective AhR modulator (SAhRM) that qualitatively reprograms AhR signaling. This modulation uncouples upstream MAPK phosphorylation from downstream cell cycle progression, effectively impeding the proliferative program even in the presence of skatole-induced stress. Furthermore, we propose a theoretical model of counter-balancing metabolic activation, hypothesizing that the oxidative environment associated with skatole metabolism may trigger the bioactivation of IAA into highly active anti-tumor derivatives. These findings suggest that restoring the gut IAA/skatole balance-either by targeting the bacterial enzyme indoleacetate decarboxylase (IAD) or via dietary resistant starch-may offer a promising precision nutrition strategy for CRC prevention.

Botulinum toxin type A (BoNT/A) formulations differ in their content of non-toxic accessory proteins, also known as complexing proteins (CPs), which may influence immunogenicity. Some BoNT/A products share structurally similar CPs, potentially leading to antibody cross-reactivity among formulations. This prospective study investigated whether patients treated with different BoNT/A products develop cross-reactive anti-CP antibody responses. One hundred participants were allocated into five treatment groups, each receiving a single BoNT/A formulation: incobotulinumtoxinA (IncoA), onabotulinumtoxinA (OnaA), abobotulinumtoxinA (AboA), letibotulinumtoxinA (LetiA), or prabotulinumtoxinA (PraboA). Each participant received 50 units or equivalent dosing. Serum samples were collected 180 days post-injection, and anti-CP antibodies were quantified using an absorption ELISA and compared with a toxin-naïve control group. IncoA did not induce significant anti-CP antibody responses. In contrast, higher antibody levels were observed in the OnaA, LetiA, and PraboA groups against multiple CPs, suggesting structural similarity and cross-reactivity. AboA primarily induced antibodies directed against its own CPs and those of PraboA. These findings demonstrate that CP-containing formulations can induce cross-reactive antibody responses, whereas CP-free incobotulinumtoxinA exhibits minimal immunogenicity. This study highlights the importance of CP composition in guiding clinical product selection, particularly in patients requiring repeated BoNT/A administration.

It is with both excitement and sorrow that I now write this brief introduction and overview to this Special Edition of Toxins [...].

Blooms of the marine dinoflagellate Vulcanodinium rugosum have been associated with skin lesion outbreaks in Cuba and elsewhere. In this study, cell growth and toxin production were investigated under laboratory-controlled conditions in two strains isolated from Cienfuegos Bay, Cuba. Strains were cultured with and without a mechanical agitation and toxins were analyzed at two stages of the culture growth (exponential and stationary). Although blooms in Cienfuegos Bay occur in a semi-enclosed system characterized by calm waters with no agitation, the results of this study suggest that V. rugosum cells may also exhibit growth capacity under agitated conditions, or in open waters, comparable to that observed in systems with low hydrodynamic energy. Higher toxin levels, as determined by liquid chromatography with mass spectrometry (LC-MS/MS), were detected after exponential growth. Portimine-A and pinnatoxin-F (PnTX-F) were the dominant toxins (up to 1.75 and 1.0 pg·cell^-1, respectively). PnTX-E, -D and Portimine-B were also detected at minor concentrations. This study contributes the first data necessary for a proper interpretation of monitoring programs aiming to assess the impact of V. rugosum blooms, particularly when used alongside forecasting models.