Toxins最新文献

The ribbon worms of the closely related species Cephalothrix simula, Cephalothrix cf. simula, and Cephalothrix mokievskii, representing the C. simula species complex, possess high concentrations of tetrodotoxin (TTX) and its analogues in all developmental stages from eggs to adults. It has recently been suggested that the eggs and larvae of these animals can be a source of tetrodotoxins (TTXs) for other aquatic organisms. In the current study, TTXs in mature and post-spawning individuals and in the eggs of C. mokievskii were identified using high-performance liquid chromatography-tandem mass spectrometry. For the first time, the quantity and profile of TTXs that these nemerteans released into the environment during spawning were estimated. We showed that the spawning C. mokievskii females released significant amounts of TTX and 5,6,11-trideoxyTTX with their eggs; these levels were sufficient for the potential toxification of marine bioresources. The issues surrounding the monitoring of TTXs in commercial marine animals, and collecting at the sites of the spawning of nemerteans from the C. simula species complex, are discussed.

Food contamination with mycotoxin-producing fungi increases the risk of many diseases, including neurological diseases closely related to the neurotoxicity of these toxins. Based on the latest literature data, we presented the association of common Fusarium mycotoxins with neurological diseases. Articles from 2001 to 2024 were analyzed. The mechanisms underlying the neurotoxicity of the described mycotoxins were presented. They are mainly related to the increase in oxidative stress in neuronal cells, which leads to higher levels of pro-inflammatory cytokines as IL-1β, IL-6 and TNF-α, enzymatic activity as GST, GPx, CAT and SOD and neurotransmitter dysfunction (5-HT, serotonin, dopamine and GABA). At the end of the article, based on the literature data, we attempted to present ways to mitigate mycotoxin neurotoxicity using mainly natural substances of plant origin. The data in this review focus on the Fusarium mycotoxins most frequently found in food and will be useful as comparative information for future studies. It is important to conduct further studies to mitigate the neurotoxic effects of Fusarium mycotoxins in order to reduce the development of diseases of the nervous system.

Coagulation factor XIa is a new serine-protease family drug target for next-generation anticoagulants. With the snake venom Kunitz-type peptide BF9 as the scaffold, we obtained a highly active XIa inhibitor BF9-N17K in our previous work, but it also inhibited the hemostatic target plasmin. Here, in order to enhance the selectivity of BF9-N17K toward XIa, four mutants, BF9-N17K-L19A, BF9-N17K-L19S, BF9-N17K-L19D, and BF9-N17K-L19K, were further designed using the P2' amino acid classification scanning strategy. The anticoagulation assay showed that the four P2' single-point mutants still had apparent inhibitory anticoagulation activity that selectively inhibited the human intrinsic coagulation pathway and had no influence on the extrinsic coagulation pathway or common coagulation pathway, which indicated that the single-point mutants had minimal effects on the anticoagulation activity of BF9-N17K. Interestingly, the enzyme inhibitor assay experiments showed that the XIa and plasmin inhibitory activities were significantly changed by the P2' amino acid replacements. The XIa inhibitory activity of BF9-N17K-L19D was apparently enhanced, with an IC₅₀ of 19.28 ± 2.53 nM, and its plasmin inhibitory was significantly weakened, with an IC₅₀ of 459.33 ± 337.40 nM. BF9-N17K-L19K was the opposite to BF9-N17K-L19D, which had enhanced plasmin inhibitory activity and reduced XIa inhibitory activity. For BF9-N17K-L19A and BF9-N17K-L19S, no apparent changes were found in the serine protease inhibitory activity, and they had similar XIa and plasmin inhibitory activities to the template peptide BF9-N17K. These results suggested that the characteristics of the charge of the P2' site might be associated with the drug selectivity between the anticoagulant target XIa and hemostatic target plasmin. In addition, according to the molecular diversity and sequence conservation, a common motif GR/PCR/KA/SXIP-XYGGC is proposed in the XIa-inhibitory Kunitz-type peptides, which might provide a new clue for further peptide engineering. In conclusion, through P2' amino acid classification scanning with the snake venom Kunitz-type peptide scaffold, a new potent and selective XIa inhibitor, BF9-N17K-L19D, was discovered, which provides a new XIa-targeting lead drug template for the treatment of thrombotic-related diseases.

Leukocidins of Staphylococcus (S.) aureus are bicomponent toxins that form polymeric pores in host leukocyte membranes, leading to cell death and/or triggering apoptosis. Some of these toxin genes are located on prophages and are associated with specific hosts. The genes lukP/Q have been described from equine S. aureus isolates. We examined the genomes, including the lukP/Q prophages, of S. aureus strains belonging to clonal complexes CC1, CC350, CC816, and CC8115. In addition to sequencing, phages were characterised by mitomycin C induction and transmission electron microscopy (TEM). All lukP/Q prophages integrated into the lip2=geh gene, and all included also the gene scn-eq encoding an equine staphylococcal complement inhibitor. The lukP/Q prophages clustered, based on gene content and allelic variants, into three groups. One was found in CC1 and CC97 sequences; one was present mainly in CC350 but also in other lineages (CC1, CC97, CC133, CC398); and a third one was exclusively observed in CC816 and CC8115. Prophages of the latter group additionally included a rare enterotoxin A allele (sea_320E). Moreover, a prophage from a CC522 goat isolate was found to harbour lukP. Its lukF component could be regarded as chimaera comprising parts of lukQ and of lukF-P83. A putative kinase gene of 1095 basepairs was found to be associated with equine strains of S. aureus. It was also localised on prophages. However, these prophages were different from the ones that carried lukP/Q, and three different integration sites of kinase-carrying phages were identified. These observations confirmed the presence of prophage-located important virulence-associated genes in equine S. aureus and that certain prophages might determine the host specificity of the staphylococcal strains they reside in.

Bacillus microorganisms play an important role in the zearalenone (ZEA) biotransformation process in natural environments. The phosphotransferase pathway in Bacillus is both widespread and relatively well conserved. However, the reaction kinetics of these phosphotransferases remain poorly understood, and their catalytic activities are suboptimal. In this study, a ZEA phosphotransferase, ZPH1101, was identified from Bacillus subtilis 1101 using genome sequencing. The product transformed by ZPH1101 was identified as phosphorylated ZEA (ZEA-P) through LC-TOF-MS/MS analysis. The experiments conducted on MCF-7 cells demonstrated that ZEA-P exhibited a lower level of estrogenic toxicity than ZEA. The optimal reaction conditions for ZPH1101 were determined to be 45 °C and pH 8.0. The maximum velocity (V_max), Michaelis constant (K_m), and catalytic constant (k_cat) were calculated through fitting to be 16.40 μM·s^-1·mg^-1, 18.18 μM, and 54.69 s^-1, respectively. Furthermore, adding 1 mmol/L Fe²⁺ or Fe³⁺ to the reaction system increased the efficiency of ZPH1101 in converting ZEA by 100% relative to the system containing solely 1 mmol/L ATP and 1 mmol/L Mg²⁺, suggesting that low concentrations of Fe²⁺ or Fe³⁺ can improve the ZPH1101-mediated transformation of ZEA. This study contributes to the enzymatic removal of ZEA and broadens the spectrum of strain and enzyme options available to researchers for ZEA detoxification efforts.

Snakebites caused by Bothrops snakes are the most prevalent in the Amazon region, causing local and systemic complications. Local complications are mostly represented by necrosis, secondary bacterial infection and compartment syndrome. There are reports of long-term disabilities, but their burden is poorly investigated. This study aims to describe and estimate the frequency of physical and sensory long-term disabilities from Bothrops snakebites in the Manaus Region, in the western Brazilian Amazon region. Participants were >18-years individuals that accepted to return to the hospital 3-12 months (average follow-up time of 195 days) after the discharge for neuromusculoskeletal, chronic pain and sensory assessments. Assessment of disability was also performed using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). Factors associated with summary disability using WHODAS 2.0 were identified. Fifty participants were enrolled. A frequency of 20% of the participants reported difficulty in moving the affected limb (20%), and 23.7% reported difficulty in walking. Limitations of daily activities were reported by 26% of the patients. Decreased strength of the affected limb was observed in 22% of the patients. Decreased range of joint motion was seen in 20% of the patients. Chronic pain was reported in 48% of the patients. Tactile sensibility was decreased in 30%, thermal sensibility in 14%, painful sensibility (hypoalgesia) in 12%, kinetic-postural sensibility (hypokinesthesia) in 4% and vibratory sensibility was decreased or abolished in 16% of the participants. Cognition and mobility domains were those with the highest frequencies of participants with any degree of disability, each with 57%. The summary WHODAS 2.0 disability rate was 59%. Age > 59 years (p = 0.02)] was associated with protection against disability. Difficulty in moving the limb (p = 0.05), pain at the affected limb (p < 0.01), limitations of daily activities (p < 0.01) and decreased thermal sensibility (p = 0.05) were significantly associated with disability. The present study consists of the first follow-up investigation involving Bothrops snakebite patients related to long-term disabilities. These findings represent important data on Bothrops snakebites causing clinically significant long-term neuromusculoskeletal and sensory disabilities, resulting in reduced quality of life of the patients.

Chinese coral snakes (Sinomicrurus) are highly neglected regarding their venom profiles and harm to humans, which impedes our ability to deeply understand their biological properties and explore their medicinal potential. In this study, we performed a comparative analysis to reveal the venom profiles of two Chinese coral snakes in terms of their venom yields, proteomic profiles, and immunorecognition by commercial antivenoms. The results showed that Sinomicrurus kelloggi expels more venom (lyophilized venom mass) than Sinomicrurus maccelellandi but possesses a similar solid venom content. These interspecific differences in venom yield were influenced by the snout-vent length. The venoms of these two species varied in their electrophoretic profiles, as well as in the presence or absence and relative abundance of protein families. They exhibited a 3-FTx-predominant phenotype, where the S. maccelellandi venom was dominated by 3-FTx (32.43%), SVMP (23.63%), PLA₂ (19.88%), and SVSP (12.61%), while the S. kelloggi venom was dominated by 3-FTx (65.81%), LAAO (11.35%), and AMP (10.09%). While both the commercial Naja atra and Bungarus multicinctus antivenoms could immunorecognize these two Chinese coral snake venoms, the N. atra antivenom possessed a higher neutralization capability than the B. multicinctus antivenom for both species of coral snakes. Our findings show significant interspecific variations in the venom profiles of these Sinomicrurus snakes for the first time. We suggest screening or preparing specific antivenoms with high efficiency for the clinical treatment of envenomation caused by these snakes.

Hyperalgesia is a condition marked by an abnormal increase in pain sensitivity, often occurring in response to tissue injury, inflammation, or prolonged exposure to certain medications. Inflammatory mediators, such as cytokines IL-1β, IL-6, and TNF-α, play a central role in this process, amplifying pain perception. Developing effective treatments that address the underlying mechanisms of hyperalgesia is an active field of research. Apis mellifera syriaca venom demonstrated potential immunomodulatory activity associated with cytokine release in vivo. Therefore, the aim of this study is to evaluate the effect of Apis mellifera syriaca bee venom (AmsBV) on pain sensitivity in a formalin-induced hyperalgesia mice model and to evaluate the potential role of cytokines associated with the nociception of pain. The hotplate test, used to measure pain latency, showed that hypersensitivity to pain was induced in formalin-injected male mice only, with no changes in females, suggesting a sex-based response to formalin. When applied, AmsBV reduced pain sensitivity in males, suggesting pain relief potential. At the molecular level, AmsBV was able to reduce pro-inflammatory interleukin IL-4 and cytokine IFN-γ, emphasizing its immunomodulatory potential. Interestingly, the venom restored anti-inflammatory IL-10 levels that were significantly decreased in hyperalgesia males. Together, these findings highlight the therapeutic potential for AmsBV in managing inflammation and reducing pain, particularly hyperalgesia.

Epidemiological studies suggest an increased risk of colorectal cancer (CRC) aggravation in patients with chronic kidney disease (CKD). Our previous study demonstrated that indoxyl sulfate, a uremic toxin whose concentration increases with CKD progression, exacerbates CRC through activation of the AhR and Akt pathways. Consequently, indoxyl sulfate has been proposed to be a significant link between CKD progression and CRC aggravation. The present study aimed to investigate the roles of c-Myc and β-Catenin, which are hypothesized to be downstream factors of indoxyl sulfate-induced AhR and Akt activation, in CRC cell proliferation and EGF sensitivity in HCT-116 CRC cells. Indoxyl sulfate significantly induced CRC cell proliferation at concentrations exceeding 62.5 µM, a process suppressed by the c-Myc inhibitor 10058-F4. Indoxyl sulfate activated the Akt/β-Catenin/c-Myc pathway as evidenced by the Akt inhibitor MK2206, which decreased both β-Catenin and c-Myc protein levels, and the β-Catenin inhibitor XAV-939, which reduced c-Myc protein levels. The AhR antagonist CH223191 also inhibited c-Myc upregulation, indicating involvement of the AhR/c-Myc pathway. MK2206 partially attenuated the indoxyl sulfate-induced AhR transcriptional activity, suggesting that Akt activation influences the AhR/c-Myc pathway. MK2206, CH223191, and 10058-F4 suppressed the increase in EGFR protein levels induced by indoxyl sulfate, indicating that the Akt/β-Catenin/c-Myc and AhR/c-Myc pathways enhance the sensitivity of HCT-116 CRC cells to EGF. These findings indicate that the elevation of indoxyl sulfate levels in the blood, due to CKD progression, could worsen CRC by promoting the proliferation of CRC cells and enhancing EGF signaling. Therefore, indoxyl sulfate could potentially serve as a therapeutic target for CRC aggravation in patients with CKD.

Fusarium mycotoxins often co-occur in broiler feed, and their presence negatively impacts health even at subclinical concentrations, so there is a need to identify the concentrations of these toxins that do not adversely affect chickens health and performance. The study was conducted to evaluate the least toxic effects of combined mycotoxins fumonisins (FUM), deoxynivalenol (DON), and zearalenone (ZEA) on the production performance, immune response, intestinal morphology, and nutrient digestibility of broiler chickens. A total of 960 one-day-old broilers were distributed into eight dietary treatments: T1 (Control); T2: 33.0 FUM + 3.0 DON + 0.8 ZEA; T3: 14.0 FUM + 3.5 DON + 0.7 ZEA; T4: 26.0 FUM + 1.0 DON + 0.2 ZEA; T5: 7.7 FUM + 0.4 DON + 0.1 ZEA; T6: 3.6 FUM + 2.5 DON + 0.9 ZEA; T7: 0.8 FUM + 1.0 DON + 0.3 ZEA; T8: 1.0 FUM + 0.5 DON + 0.1 ZEA, all in mg/kg diet. The results showed that exposure to higher mycotoxin concentrations, T2 and T3, had significantly reduced body weight gain (BWG) by 17% on d35 (p < 0.05). The T2, T3, and T4 groups had a significant decrease in villi length in the jejunum and ileum (p < 0.05) and disruption of tight junction proteins, occludin, and claudin-4 (p < 0.05). Higher mycotoxin groups T2 to T6 had a reduction in the digestibility of amino acids methionine (p < 0.05), aspartate (p < 0.05), and serine (p < 0.05); a reduction in CD4+, CD8+ T-cell populations (p < 0.05) and an increase in T regulatory cell percentages in the spleen (p < 0.05); a decrease in splenic macrophage nitric oxide production and total IgA production (p < 0.05); and upregulated cytochrome P450-1A1 and 1A4 gene expression (p < 0.05). Birds fed the lower mycotoxin concentration groups, T7 and T8, did not have a significant effect on performance, intestinal health, and immune responses, suggesting that these concentrations pose the least negative effects in broiler chickens. These findings are essential for developing acceptable thresholds for combined mycotoxin exposure and efficient feed management strategies to improve broiler performance.