Toxins最新文献

While tropical regions have traditionally been the focus of studies on natural bioactive products, works published within the last decade demonstrate that cyanobacteria from the Baltic Sea also possess significant biotechnological and pharmaceutical potential. The Baltic Pseudanabaena galeata CCNP1313 previously demonstrated activity against breast cancer cell lines (MCF7 and T47D) and several viruses. In the present study, the cytotoxicity of cellular extract and flash chromatography fractions from the strain were evaluated against a wider panel of cancer cells (A549, C-33A, CaSki, DoTC2, HeLa, PC3, SiHa, and T47D). To gain better insight into the compounds potentially responsible for the observed effects, high-resolution mass spectrometry was combined with bioactivity-based molecular networking. Both the extract and hydrophobic fractions showed strong cytotoxicity, particularly against breast cancer cells and selected cervical cancer cells. While HRMS analyses confirmed the production of previously characterised peptides by CCNP1313 (Pseudanabaena galeata peptides and galeapeptins), neither of them was found to be responsible for the activity. Instead, the molecular networking approach linked the cytotoxicity to specific lipid classes, including diacylglycerols (DAGs) and monogalactosyldiacylglycerols (MGDGs). This study highlights the necessity of integrating traditional methods with advanced bioinformatics for the successful discovery of bioactive natural products, especially when complex samples, such as extract or chromatographically separated fractions, are analysed.

Snake venoms are rich sources of bioactive molecules that modulate hemostasis and, among these, anticoagulant snake venom phospholipases A₂ (sPLA₂) are found in a range of snake venoms. Crotoxin (CTX), from the Crotalus durissus rattlesnake, is a heterodimeric PLA₂ complex, and literature has reported its mechanisms in anticoagulant activity. The present review revisits the biological roles of anticoagulant sPLA₂ and critically examines evidence on CTX in hemostatic regulation, aiming to clarify its mechanisms and therapeutic promise. CTX exerts anticoagulant activity via enzymatic hydrolysis of procoagulant phospholipids and direct interaction with coagulation factors, disrupting key complex assembly. It also counteracts inflammation-induced coagulation by modulating leukocyte- and endothelial-derived mediators, restoring balance among anticoagulant, procoagulant, and fibrinolytic pathways. Effects on platelet function appear comparatively modest, ranging from less potent pro-aggregatory activity to negligible aggregation. The dual anticoagulant and anti-inflammatory properties of CTX highlight its potential as a model for novel antithrombotic agents in hypercoagulable and inflammation-driven disorders, despite toxicological concerns that necessitate cautious pharmacological exploration.

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Animal venoms are valuable resources for drug discovery. They offer a wide variety of bioactive molecules with significant biotechnological potential. Venom composition shows extensive diversity not only between and within species, but also across the lifetime of an individual. This natural variation further enhances the biotechnological potential of venoms, supporting the development and optimization of venom-derived drugs. Despite numerous studies highlighting the variability of venom, many lack a coherent framework to explain the underlying causes of this diversity. In this review, we explore the molecular and evolutionary mechanisms driving variations in venom composition and the evolution of venom systems, including gene regulation, point mutations, gene duplication events, modulation by miRNAs, alternative splicing and post-translational modifications as driving forces of venom component diversity. We also discuss the critical role of omics technologies and comparative studies in advancing our understanding of the diversity of venom and their contribution to the identification, development, and refinement of venom-based product candidates. The aspects reviewed here are relevant for future omics study designs to advance venom research and biodiscovery.

The increasing occurrence of harmful cyanobacterial blooms in freshwater ecosystems poses important risks to aquatic organisms and human health due to the production of bioactive secondary metabolites such as cyanopeptides. While analytical methods for microcystins are well developed, there is a notable lack of validated protocols for the broader spectrum of cyanopeptides in biota. This study presents the development and validation of a robust UHPLC-QqQ-MS method for the simultaneous extraction, cleanup, and quantification of 27 cyanopeptides, including microcystins, anabaenopeptins, microginins, aeruginosins, aeruginoguanidine, and nodularin, in fish muscle, liver, and whole fish tissues. Comprehensive optimization was conducted to minimize matrix effects and analyte losses during every step of sample preparation. The method demonstrated generally high recoveries (28-98%), good precision (RSD < 20%), and sensitivity, with MQLs below 0.5 ng g^-1 for most analytes. Microginins posed analytical challenges due to their amphiphilic structure, which contributed to significant losses during filtration and extraction; the reasoning is discussed. Application to wild fish collected after a mass mortality event revealed no detectable cyanopeptide contamination but confirmed the method's suitability for comprehensive detection. This represents an important advancement in cyanopeptide analysis, offering a valuable tool for environmental risk assessment and food safety evaluation related to harmful cyanobacteria.

Toxins as channel probes, small guanidinium alkaloids, such as tetrodotoxin and saxitoxin, canonical pore occlusion in voltage-gated Na⁺ channels. Cystine-rich peptides from spiders, scorpions, cone snails, and sea anemones, which act as pore blockers or gating modifiers targeting voltage-sensing domains. Recent structural and electrophysiological studies have identified specific binding sites on ion channels, including the S5-S6 pore loops, outer vestibule and turret regions, and S3-S4 "paddle" motifs in NaV, Kv, and CaV channels. These discrete binding epitopes are recognized by different peptide toxins, enabling isoform- and state-specific modulation; for example, μ-conotoxins bind the NaV pore, whereas charybdotoxin and agitoxin target the Kv outer vestibule. Beyond mechanistic insights, peptide toxins inspire translational strategies, including emerging therapies for retinal degenerative diseases. Photopharmacology using chemical photoswitches allows reversible, light-controlled modulation of ion channels in retinal ganglion cells without genetic manipulation or cell transplantation. Although BENAQ was discovered by small-molecule screening rather than toxin-guided design, its ion channel control demonstrates the potential of toxin-based molecular determinants for engineering synthetic compounds. This review thus integrates structural, functional, and translational perspectives, emphasizing the versatility of animal-derived peptide toxins as molecular probes and as blueprints for precision ion channel modulation in health and disease.

Nephrotoxin-mediated kidney injury is an important clinical problem, as it can lead to acute kidney injury and chronic kidney disease. Both entities are associated with significant morbidity, increased hospitalisation, healthcare utilisation, and cardiovascular mortality. With the loss of kidney function, there is an accumulation of uraemic toxins, of which the protein-bound toxins-indoxyl sulphate and p-cresyl sulphate-can further inflict damage to the kidneys and the cardiovascular system, culminating in a vicious cycle. Therefore, it is imperative that clinicians have a firm understanding of the common causes and mechanisms of toxin-mediated kidney injury, as well as their clinical presentations and histopathologic features, in order to reduce the prevalence of this pernicious condition.

Although ochratoxin A (OTA) contamination has been previously reported in Lebanon, this study is the first worldwide to assess its potential impact on renal health among adolescents aged 10 to 18 years. In this cross-sectional study, the aim was to evaluate the levels of OTA, OTα, and kidney injury biomarkers, as well as creatinuria and total proteinuria, while correlating these findings with dietary patterns. Urinary concentrations of OTA, its main metabolite ochratoxin α (OTa), the three renal injury biomarkers (N-acetyl-β-D-glucosaminidase [NAG], Kidney Injury Molecule-1 [KIM-1], and human lipocalin-2 [NGAL]), and two renal function indicators (creatinine and total protein) were quantified. Associations between biomarker levels and dietary intake patterns were also evaluated. OTA and OTα were detected in 14.2% and 59.5% of urine samples, respectively. NGAL and NAG were found in all participants at low concentrations, with the NAG-to-creatinine ratio exceeding the clinical threshold in 1.5% of samples, while KIM-1 was detected in 86% of participants. A weak positive correlation between urinary OTα and NAG suggests subtle renal alterations possibly linked to OTA exposure. Correlations between biomarker levels and food consumption were generally weak and positive. Estimated dietary intake (EDI) of OTA generated from consumption patterns was shown to be less than the probable dietary intake (PDI) calculated from urinary OTA. However, this presented a limitation, as EDI was calculated from previous contamination data in Lebanon. Overall, these findings indicate that while renal injury biomarkers were present at low levels, they may reflect early kidney stress not yet manifesting as overt pathology and highlight the need for strengthened regulatory measures to limit OTA contamination in foods available on the Lebanese market and for longitudinal studies to confirm these preliminary findings.

Amanita exitialis is a lethal mushroom species found in southern China. Its amatoxins can cause acute liver injury with a high case-fatality rate. However, reports combining toxin detection in clinical specimens with autopsy pathology remain limited. We conducted a retrospective analysis of A. exitialis poisoning events treated at Chuxiong Yi Autonomous Prefecture People's Hospital from 2019 to 2024. Toxins were measured in collected mushrooms, patient blood, and urine. Clinical data included demographics, complications, laboratory parameters, and autopsy findings. Associations between a time-weighted urinary amatoxin exposure metric and laboratory indices were assessed. Ten poisoning incidents involving 27 individuals were identified, including five deaths. We collected 10 mushroom samples, 120 urine samples, and 108 blood samples. α-amanitin, β-amanitin, phallacidin, and phallisacin were detected in mushrooms and urine. The detection rates of α-AMA, β-AMA, PCD, and PSC in urine samples were 31.67%, 5.00%, 38.33%, and 49.17%, respectively. Only three blood samples tested positive for α-AMA. The time-weighted urinary amatoxin exposure metric was positively correlated with total bilirubin (TBIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), creatinine (Cr), creatine kinase (CK), creatine kinase isoenzymes (CK-MB), prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized ratio (INR). Early symptoms included nausea, vomiting, diarrhea, abdominal pain, and distention; later findings involved injury to the liver, kidneys, intestines, heart, and lungs. On the fourth day following ingestion, there was a marked increase in bilirubin levels and a concurrent decrease in liver enzymes, indicating severe damage to the hepatocytes. Platelet count, white blood cell count, hemoglobin, and red blood cell count decreased over time. Autopsies demonstrated hepatic, renal, and myocardial injury, gastrointestinal mucosal exfoliation, and multiorgan hemorrhage. In summary, A. exitialis poisoning is primarily characterized by liver damage, accompanied by injuries to the kidneys, myocardium, and intestines, as well as multiorgan hemorrhaging, which may lead to blood toxicity. The detection rate of toxins in urine samples is relatively high, and early urine toxin testing can help clarify the diagnosis and guide treatment.

Mirabilis antiviral protein (MAP) is the type I ribosome-inactivating protein (RIP), which consists of an RNA N-glycosylase domain with no carbohydrate-binding domain. Unlike many RIPs, such as ricin or trichosanthin, which inactivate eukaryotic ribosomes, MAP also inactivates the E. coli ribosome by cleaving the N-glycosidic bond at A2660 of 23S ribosomal RNA. The structure of the wild-type MAP has not been revealed yet. Here, we expressed, purified, and crystallized the plural recombinant MAPs, including both E168Q and R171Q mutations (MAP-EQRQ) in E. coli, and determined the crystal structure of MAP-EQRQ at 2.1 Å resolution. According to the predicted structure with RNA (sarcin-ricin loop) and the mutant protein's activities using quantitative RT-PCR, we showed that residue R171 at the active site of MAP is a key residue to form the stable complex with target adenine. Furthermore, we showed that MAP bound the C-terminal domains of eukaryotic P2-stalk as well as E. coli L12-stalk.