Toxins

20 pages, 1159 KiB

Open AccessEditor’s ChoiceArticle

Assessing Alternaria Species and Related Mycotoxin Contamination in Wheat in Algeria: A Food Safety Risk

by Meriem Barkahoum Daichi, Mario Masiello, Miriam Haidukowski, Annalisa De Girolamo, Antonio Moretti, Amor Bencheikh, Noureddine Rouag and Stefania Somma

Toxins 2025, 17(6), 309; https://doi.org/10.3390/toxins17060309 - 18 Jun 2025

Viewed by 851

Abstract

Alternaria species are important fungal pathogens occurring worldwide in wheat, causing both productive and qualitative losses, and posing a toxicological risk to human health due to the production of their mycotoxins in kernels. This study aimed to investigate the occurrence of Alternaria species [...] Read more.

Alternaria species are important fungal pathogens occurring worldwide in wheat, causing both productive and qualitative losses, and posing a toxicological risk to human health due to the production of their mycotoxins in kernels. This study aimed to investigate the occurrence of Alternaria species and their mycotoxins in 48 wheat grain samples collected from the northeast to the southeast of Algeria. Seventy-two representative Alternaria strains were molecularly analyzed using a multi-locus sequence approach and evaluated for their capability to produce mycotoxins under in vitro conditions. Alternaria alternata, representing 42% of the strains, was the dominant species, followed to a lesser extent by species included in the Infectoriae section (26%). In addition, three species not previously reported in Algerian wheat, A. eureka, A. consortialis and A. tellustris, were identified, accounting for 5% of the total strains. Mycotoxin analyses showed high contamination of grains with alternariol monomethyl ether, alternariol and tenuazonic acid, occurring in 75, 69 and 35% of the samples, respectively. Moreover, 41 out of 48 samples showed the co-occurrence of multiple Alternaria mycotoxins. This study provides, for the first, time a clear picture of the occurrence and the distribution of Alternaria species on wheat in Algeria. Finally, the extensive monitoring activities carried out revealed the great biodiversity of Alternaria species able to colonize wheat grains. Moreover, findings on mycotoxin contamination raise concerns about the significant mycotoxigenic risk in Algerian wheat, emphasizing the need for strict monitoring and regulatory measures on Alternaria mycotoxins in food and feed. Full article

(This article belongs to the Section Mycotoxins)

► Show Figures

Graphical abstract

18 pages, 4121 KiB

Open AccessEditor’s ChoiceArticle

Defence Against Desiccation and Predation in Lophyohylini Casque-Headed Tree Frogs

by César Alexandre, Pedro L. Mailho-Fontana, Bianca C. L. F. Távora, Marta M. Antoniazzi and Carlos Jared

Toxins 2025, 17(6), 303; https://doi.org/10.3390/toxins17060303 - 16 Jun 2025

Viewed by 1208

Abstract

Casque-headed tree frogs (Lophyohylini) can have a very large and distinctive head characterised by hyperossification of their cranial skin. This type of skull was primarily associated with phragmosis, a behaviour in which the frog enters holes backwards and seals them with its head [...] Read more.

Casque-headed tree frogs (Lophyohylini) can have a very large and distinctive head characterised by hyperossification of their cranial skin. This type of skull was primarily associated with phragmosis, a behaviour in which the frog enters holes backwards and seals them with its head to prevent water loss in challenging environments. Further investigations revealed that hyperossification also gives rise to bony spines interspersed with skin poison glands. These peculiar anatomical features of the head make it challenging for predators to prey on the frogs in phragmosis. When bitten on the head, the bite pressure causes the spines to cross the poison glands, allowing the injection of toxins into the predator’s mouth. We studied the head morphology of different Lophyohylini species along with some characteristics of their cutaneous poison, both in the field and in the laboratory. These frogs exemplify distinct chemical defence strategies, highlighting the differences between venom and poison. Notably, some species can cause self-poisoning in predators by injecting poison (in this case, venom) through their head spines, similar to the use of fangs by snakes. Full article

(This article belongs to the Collection Evolution of Venom Systems)

► Show Figures

Figure 1

21 pages, 7088 KiB

Open AccessEditor’s ChoiceReview

The Biological Role of Conoporins, Actinoporin-like Pore-Forming Toxins from Cone Snails

by Matija Ruparčič, Gašper Šolinc, Simon Caserman, Juan Carlos Garcia Galindo, Manuel Jimenez Tenorio and Gregor Anderluh

Toxins 2025, 17(6), 291; https://doi.org/10.3390/toxins17060291 - 7 Jun 2025

Viewed by 1320

Abstract

Cone snails are a large group of marine gastropods that produce a complex mixture of toxic compounds to hunt prey and defend against predators. The majority of the venom comprises small toxic peptides named conotoxins, which target membrane receptors. In contrast, a smaller [...] Read more.

Cone snails are a large group of marine gastropods that produce a complex mixture of toxic compounds to hunt prey and defend against predators. The majority of the venom comprises small toxic peptides named conotoxins, which target membrane receptors. In contrast, a smaller part of the venom contains larger proteins and conoproteins, which are thought to be involved in conotoxin maturation and the envenomation process, respectively. Interestingly, many species of cone snails contain conoporins, which are similar to actinoporins—pore-forming toxins found in sea anemones. These actinoporin-like proteins (ALPs) have recently been detected in many molluscan species, and only a few have been experimentally characterized. Due to being highly expressed in the venom gland of many cone snail species, conoporins are thought to play an important part in the envenomation process. Despite this, the exact function of conoporins is currently unknown. We propose several hypotheses aiming to elucidate their biological role. Full article

(This article belongs to the Special Issue Structure, Function and Evolution of Conotoxins)

► Show Figures

Figure 1

14 pages, 263 KiB

Open AccessEditor’s ChoiceArticle

Evaluating Bias in Self-Reported Symptoms During a Cyanobacterial Algal Bloom

by John S. Reif, Rebecca Koszalinski, Malcolm M. McFarland, Michael L. Parsons, Rachael Schinbeckler, Judyta Kociolek, Alex Rockenstyre and Adam M. Schaefer

Toxins 2025, 17(6), 287; https://doi.org/10.3390/toxins17060287 - 6 Jun 2025

Viewed by 550

Abstract

Algal blooms produced by cyanobacteria liberate microcystins and other toxins that create a public health hazard. During the 2018 bloom of Microcystis aeruginosa in Florida, USA, residential and recreational exposures were associated with an increased risk of self-reporting respiratory, gastrointestinal, or ocular symptoms [...] Read more.

Algal blooms produced by cyanobacteria liberate microcystins and other toxins that create a public health hazard. During the 2018 bloom of Microcystis aeruginosa in Florida, USA, residential and recreational exposures were associated with an increased risk of self-reporting respiratory, gastrointestinal, or ocular symptoms for 125 participants. Subsequently, 207 persons were interviewed between 2019 and 2024 in the absence of large-scale algal blooms and were considered non-exposed. Analyses of cyanotoxins and brevetoxins in water and air showed only intermittent, background levels of toxins during the non-bloom period. The purpose of this report was to compare symptom reporting between active bloom and non-bloom periods. The assessment of information bias from self-reported symptoms is an important issue in epidemiologic studies of harmful algal blooms. During the non-bloom period, no statistically significant associations with residential, recreational, or occupational exposures were found for any symptom group. Estimated risks for respiratory, gastrointestinal, and ocular symptoms, headache, and skin rash were significantly higher for persons sampled during the bloom than the non-bloom period with odds ratios (ORs) of 2.3 to 8.3. ORs for specific respiratory symptoms were also significantly elevated. After adjustment for confounders and multiple exposures in multivariable analyses, the differences in symptom reporting between bloom and non-bloom periods remained statistically significant. In summary, the use of self-reported symptoms in this epidemiologic study of exposure to a cyanobacterial algal bloom did not appear to introduce substantial information bias. Full article

(This article belongs to the Special Issue Prospective Studies on Harmful Cyanobacteria and Cyanotoxins)

15 pages, 2495 KiB

Open AccessEditor’s ChoiceArticle

Palytoxin Signal in LC-MS and UV: Preliminary Investigation on the Effect of Solvent and Temperature

by Chiara Melchiorre, Michela Varra, Valeria Tegola, Valentina Miele and Carmela Dell’Aversano

Toxins 2025, 17(6), 286; https://doi.org/10.3390/toxins17060286 - 6 Jun 2025

Viewed by 611

Abstract

Palytoxins (PLTXs) and ovatoxins (OVTXs) are a group of highly potent marine toxins that pose significant health risks through seafood contamination and environmental exposure. OVTX-producing algae have been linked to dermatitis and respiratory distress in Mediterranean beachgoers, while serious public health concerns are [...] Read more.

Palytoxins (PLTXs) and ovatoxins (OVTXs) are a group of highly potent marine toxins that pose significant health risks through seafood contamination and environmental exposure. OVTX-producing algae have been linked to dermatitis and respiratory distress in Mediterranean beachgoers, while serious public health concerns are related to PLTX accumulation in seafood. In 2009, the European Food Safety Authority highlighted the need for analytical detection methods of the PLTX group of toxins and for the preparation of reference materials. This study investigates the stability of the palytoxin signal using liquid chromatography tandem mass spectrometry (LC-MRM-MS) and UV-Vis spectrophotometry under different experimental conditions: three concentrations (10, 1, and 0.5 µg/mL), three methanol–water mixtures (10%, 50%, and 90%), and two temperatures (6 °C and 25 °C). The results showed that the PLTX signal response is significantly influenced by the experimental conditions used. LC-MRM-MS analysis revealed the optimal response of PLTX in 50% and 90% MeOH at 25 °C, with minimal signal loss occurring over 16 h (9% and 6%). UV-Vis data indicated reduced absorbance in 10% MeOH, but a stable spectral intensity over 21 h in all the tested solvent mixtures. These results underscore the necessity of carefully controlled experimental conditions to ensure accurate and reproducible PLTX detection in environmental and food safety monitoring. Full article

(This article belongs to the Section Marine and Freshwater Toxins)

► Show Figures

Figure 1

28 pages, 4731 KiB

Open AccessEditor’s ChoiceArticle

Time-Resolved Visualization of Cyanotoxin Synthesis via Labeling by the Click Reaction in the Bloom-Forming Cyanobacteria Microcystis aeruginosa and Planktothrix agardhii

by Rainer Kurmayer and Rubén Morón Asensio

Toxins 2025, 17(6), 278; https://doi.org/10.3390/toxins17060278 - 3 Jun 2025

Viewed by 852

Abstract

In non-ribosomal peptide synthesis of cyanobacteria, promiscuous adenylation domains allow the incorporation of clickable non-natural amino acids into peptide products—namely into microcystins (MCs) or into anabaenopeptins (APs): 4-azidophenylalanine (Phe-Az), N-propargyloxy-carbonyl-L-lysine (Prop-Lys), or O-propargyl-L-tyrosine (Prop-Tyr). Subsequently, chemo-selective labeling is used to visualize [...] Read more.

In non-ribosomal peptide synthesis of cyanobacteria, promiscuous adenylation domains allow the incorporation of clickable non-natural amino acids into peptide products—namely into microcystins (MCs) or into anabaenopeptins (APs): 4-azidophenylalanine (Phe-Az), N-propargyloxy-carbonyl-L-lysine (Prop-Lys), or O-propargyl-L-tyrosine (Prop-Tyr). Subsequently, chemo-selective labeling is used to visualize the clickable cyanopeptides using Alexa Fluor 488 (A488). In this study, the time-lapse build up or decline of azide- or alkyne-modified MCs or APs was visualized during maximum growth, specifically MC biosynthesis in Microcystis aeruginosa and AP biosynthesis in Planktothrix agardhii. Throughout the time-lapse build up or decline, the A488 signal occurred with heterogeneous intracellular distribution. There was a fast increase or decrease in the A488 signal for either Prop-Tyr or Prop-Lys, while a delayed or unobservable A488 signal for Phe-Az was related to increased cell size as well as a reduction in growth and autofluorescence. The proportion of clickable MC/AP in peptide extracts as recorded by a chemical–analytical technique correlated positively with A488 labeling intensity quantified via laser-scanning confocal microscopy for individual cells or via flow cytometry at the population level. It is concluded that chemical modification of MC/AP can be used to track intracellular dynamics in biosynthesis using both analytical chemistry and high-resolution imaging. Full article

(This article belongs to the Special Issue Harmful Algae in a Changing World: Where Did We Come from and Where Are We Going?)

► Show Figures

Graphical abstract

28 pages, 7518 KiB

Open AccessEditor’s ChoiceArticle

Probing Bacterial Interactions with the Schistosoma mansoni-Killing Toxin Biomphalysin via Atomic Force Microscopy and Single Molecule Force Spectroscopy

by Jihen Zouaoui, Pierre Poteaux, Audrey Beaussart, Nicolas Lesniewska, David Duval and Jérôme F. L. Duval

Toxins 2025, 17(6), 269; https://doi.org/10.3390/toxins17060269 - 27 May 2025

Viewed by 1196

Abstract

Recent work has identified biomphalysin (BM) protein from the snail Biomphalaria glabrata as a cytolytic toxin against the Schistosoma mansoni parasite. Ex vivo interactome studies further evidenced BM’s ability to bind bacterial outer membrane proteins, but its specific antibacterial mechanisms and selectivity remain [...] Read more.

Recent work has identified biomphalysin (BM) protein from the snail Biomphalaria glabrata as a cytolytic toxin against the Schistosoma mansoni parasite. Ex vivo interactome studies further evidenced BM’s ability to bind bacterial outer membrane proteins, but its specific antibacterial mechanisms and selectivity remain unclear. Accordingly, this study aims to elucidate the interaction between BM and two model bacteria with distinct cell surface architectures: Escherichia coli (Gram−) and Micrococcus luteus (Gram+). Employing a multiscale approach, we used in vivo single-molecule force spectroscopy (SMFS) to probe molecular interactions at the single cell level. Combined with cell aggregation assays, immunoblotting and Atomic Force Microscopy (AFM) imaging, SMFS results evidenced a selective interaction of BM from snail plasma with M. luteus but not E. coli. Exposure of M. luteus to BM compromised cell surface integrity and induced cell aggregation. These effects correlated with a patch-like distribution of BM on M. luteus reminiscent of pore-forming toxins, as revealed by the anti-BM antibody-functionalized AFM tip. Overall, this work highlights the utility of SMFS in dissecting host–pathogen molecular dialogs. It reveals BM’s selective action against M. luteus, potentially via surface clustering, and it shows spatially heterogeneous responses to the toxin within and between individual cells. Full article

(This article belongs to the Section Marine and Freshwater Toxins)

► Show Figures

Graphical abstract

24 pages, 3342 KiB

Open AccessEditor’s ChoiceReview

Unveiling the Neurotoxic Effects of Ochratoxin A and Its Impact on Neuroinflammation

by María Ángeles García-Esparza, Eva María Mateo, José Antonio Robles, Michela Capoferri, Misericordia Jiménez and José Miguel Soria

Toxins 2025, 17(6), 264; https://doi.org/10.3390/toxins17060264 - 23 May 2025

Viewed by 801

Abstract

Ochratoxin A (OTA), a toxic compound generated by Aspergillus and Penicillium fungi, is a common contaminant in different food and animal feed sources, thereby posing possible dangers to human well-being. Although OTA is widely recognized for its kidney-damaging properties, new findings have also [...] Read more.

Ochratoxin A (OTA), a toxic compound generated by Aspergillus and Penicillium fungi, is a common contaminant in different food and animal feed sources, thereby posing possible dangers to human well-being. Although OTA is widely recognized for its kidney-damaging properties, new findings have also indicated its potential to harm the nervous system. Current research trends have increasingly examined the part played by environmental poisons, such as mycotoxins, in the development of diseases. This systematic review gathers and assesses the features of OTA along with the insights acquired from studies on its neurotoxicity. This work presents recent research that demonstrates some mechanisms by which OTA crosses the intestinal and blood–brain barriers, penetrating neural structures. In addition, it discusses the effect of OTA on several types of neural cells and its roles in apoptosis, neuroinflammation, and neurogenesis defects, while also determining the effects of antioxidant systems that neutralize the effects of OTA. This paper identifies crucial gaps in the research and highlights the necessity for further in-depth studies into how OTA affects the processes underlying neurodegeneration. Filling these knowledge gaps could provide valuable insights into the neurotoxic potential of OTA and its relevance to neurological disorders. Full article

(This article belongs to the Special Issue Biomonitoring of Mycotoxins the Silent Invaders, Their Subtle Assault on Human and Animal Health)

► Show Figures

Figure 1

16 pages, 4520 KiB

Open AccessEditor’s ChoiceArticle

StingReady: A Novel Device for Controlled Insect Sting Challenge—From Field Capture to Clinical Application

by Xesús Feás, Margarita Armisén, Sara López-Freire, Manuela Alonso-Sampedro and Carmen Vidal

Toxins 2025, 17(6), 260; https://doi.org/10.3390/toxins17060260 - 22 May 2025

Viewed by 2701

Abstract

Reliable assessment of protection in venom immunotherapy (VIT) patients remains a clinical challenge, especially due to the limitations of conventional sting challenge tests (SCTs), which require complex insect handling and may compromise test accuracy. This study introduces StingReady, a novel, user-friendly device designed [...] Read more.

Reliable assessment of protection in venom immunotherapy (VIT) patients remains a clinical challenge, especially due to the limitations of conventional sting challenge tests (SCTs), which require complex insect handling and may compromise test accuracy. This study introduces StingReady, a novel, user-friendly device designed to streamline the SCT process by enabling safe, efficient, and minimally manipulative exposure to hymenopteran stings. For the first time, StingReady was applied to conduct SCTs with Vespa velutina, an invasive hornet species of increasing clinical relevance. The device was tested in a real-world setting at Belvís Park in Santiago de Compostela, Spain, where hornets were successfully captured and transported to the hospital without anesthesia or limb removal. The design features adjustable mesh sizes, allowing compatibility with various hymenopteran taxa. Using StingReady, nine patients underwent SCTs with no need for direct insect handling during the hospital procedure. The process improved patient safety and comfort while preserving the insect’s natural stinging behavior, thereby enhancing test reliability. This study demonstrates that StingReady significantly improves SCT methodology, offering a practical, reproducible, and ethically sound alternative for evaluating VIT efficacy across diverse hymenopteran species. Full article

(This article belongs to the Section Animal Venoms)

► Show Figures

Figure 1

15 pages, 3111 KiB

Open AccessEditor’s ChoiceArticle

The Impact of Biocontrol Agents on the Metabolome of Penicillium nordicum Strains and Its Relation to Ochratoxin A Production on Dry-Cured Ham

by Eva Cebrián, Elia Roncero, João Luz, Mar Rodríguez, Marta Sousa Silva, Carlos Cordeiro and Félix Núñez

Toxins 2025, 17(5), 236; https://doi.org/10.3390/toxins17050236 - 9 May 2025

Viewed by 504

Abstract

Throughout the process of dry-cured ham, moulds such as P. nordicum, a producer of ochratoxin A (OTA), grow on its surface. The use of combined biocontrol agents (BCAs) is a promising strategy for controlling this hazard. The goal of this study is [...] Read more.

Throughout the process of dry-cured ham, moulds such as P. nordicum, a producer of ochratoxin A (OTA), grow on its surface. The use of combined biocontrol agents (BCAs) is a promising strategy for controlling this hazard. The goal of this study is to assess the effect of D. hansenii, S. xylosus, and P. chrysogenum as BCAs on the metabolome of two strains of P. nordicum and to understand the differences between both strains. Each ochratoxigenic strain was inoculated both individually and in combination with the BCAs onto ham for 30 days under the environmental conditions experienced during traditional ripening. Untargeted metabolomics was performed through mass spectrometry using a Q-Exactive Plus Orbitrap. The BCAs caused alterations in the metabolomes of both ochratoxigenic moulds, mainly in phenylalanine catabolism and the valine, leucine, and isoleucine biosynthesis pathways, although with some differences. In the absence of the BCAs, the metabolomes of both types of P. nordicum were globally changed, despite these being moulds of the same species. In conclusion, these data help us to understand the differences between OTA-producing strains in dry-cured ham and confirm the need to demonstrate the efficacy of BCAs against a wide range of toxigenic moulds before they can be used to minimise OTA contamination in the meat industry. Full article

(This article belongs to the Special Issue Occurrence, Toxicity, Metabolism, Analysis and Control of Mycotoxins)

► Show Figures

Figure 1

11 pages, 4941 KiB

Open AccessEditor’s ChoiceArticle

Consistent Killers: Conservation of Thrombin-Like Action on Fibrinogen by Bushmaster (Lachesis Species) Venoms Underpins Broad Antivenom Cross-Reactivities

by Lee Jones and Bryan G. Fry

Toxins 2025, 17(5), 224; https://doi.org/10.3390/toxins17050224 - 2 May 2025

Viewed by 1934

Abstract

Snakebite represents a significant public health challenge in Central and South America, with Lachesis (Bushmaster) species posing unique clinical challenges due to their severe envenomation effects arising from a combination of potent venom and copious venom yields. Using in vitro coagulation assays, we [...] Read more.

Snakebite represents a significant public health challenge in Central and South America, with Lachesis (Bushmaster) species posing unique clinical challenges due to their severe envenomation effects arising from a combination of potent venom and copious venom yields. Using in vitro coagulation assays, we analyzed the coagulotoxic venom effects from four distinct localities: L. muta from Surinam and French Guiana and L. stenophrys from Costa Rica and Panama. This study examined the venom’s impact on human plasma and fibrinogen and evaluated the efficacy of two regionally available antivenoms (PoliVal-ICP and Antivipmyn-Tri) in neutralizing the pathophysiological effects. Our results demonstrated a remarkable consistency in the pseudo-procoagulant venom activity (also known as: thrombin-like) across different species and localities. Antivenom efficacy testing revealed that both the PoliVal-ICP and Antivipmyn-Tri antivenoms effectively neutralized the venom effects across localities for both species, with the ICP antivenom showing the highest neutralization capacity. These toxicology findings highlight the biochemical conservation of venom composition across Lachesis species which underpins effective cross-neutralization in antivenom treatment. Full article

(This article belongs to the Section Animal Venoms)

► Show Figures

Graphical abstract

21 pages, 1231 KiB

Open AccessEditor’s ChoiceReview

Detection of Mycotoxins in Cereal Grains and Nuts Using Machine Learning Integrated Hyperspectral Imaging: A Review

by Md. Ahasan Kabir, Ivan Lee, Chandra B. Singh, Gayatri Mishra, Brajesh Kumar Panda and Sang-Heon Lee

Toxins 2025, 17(5), 219; https://doi.org/10.3390/toxins17050219 - 27 Apr 2025

Cited by 1 | Viewed by 1501

Abstract

Cereal grains and nuts are the world’s most produced food and the economic backbone of many countries. Food safety in these commodities is crucial, as they are highly susceptible to mold growth and mycotoxin contamination in warm, humid environments. This review explores hyperspectral [...] Read more.

Cereal grains and nuts are the world’s most produced food and the economic backbone of many countries. Food safety in these commodities is crucial, as they are highly susceptible to mold growth and mycotoxin contamination in warm, humid environments. This review explores hyperspectral imaging (HSI) integrated with machine learning (ML) algorithms as a promising approach for detecting and quantifying mycotoxins in cereal grains and nuts. This study aims to (1) critically evaluate current non-destructive techniques for processing these foods and the applications of ML in identifying mycotoxins through HSI, and (2) highlight challenges and potential future research directions to enhance the reliability and efficiency of these detection systems. The ML algorithms showed effectiveness in classifying and quantifying mycotoxins in grains and nuts, with HSI systems increasingly adopted in industrial settings. Mycotoxins exhibit heightened sensitivity to specific spectral bands within HSI, facilitating accurate detection. Additionally, selecting only relevant spectral features reduces ML model complexity and enhances reliability in the detection process. This review contributes to a deeper understanding of the integration of HSI and ML for food safety applications in cereal grains and nuts. By identifying current challenges and future research directions, it provides valuable insights for advancing non-destructive mycotoxin detection methods in the food industry using HSI. Full article

(This article belongs to the Special Issue Mycotoxins in Food and Feeds: Human Health and Animal Nutrition)

► Show Figures

Figure 1

16 pages, 3855 KiB

Open AccessEditor’s ChoiceArticle

A 20-Year Retrospective Analysis of Plant Poisoning Cases at the Naval Hospital, Varna, Bulgaria

by Stanila Stoeva-Grigorova, Maya Radeva-Ilieva, Stela Dragomanova, Gabriela Kehayova, Simeonka Dimitrova, Simeon Marinov, Petko Marinov, Marieta Yovcheva, Diana Ivanova and Snezha Zlateva

Toxins 2025, 17(4), 197; https://doi.org/10.3390/toxins17040197 - 12 Apr 2025

Viewed by 997

Abstract

The nature and epidemiology of plant intoxications are still not well understood, with recent data being limited. The present study aims to report cases of plant poisoning in the clinical practice of the Clinical Toxicology Department at the Naval Hospital—Varna, Bulgaria, over a [...] Read more.

The nature and epidemiology of plant intoxications are still not well understood, with recent data being limited. The present study aims to report cases of plant poisoning in the clinical practice of the Clinical Toxicology Department at the Naval Hospital—Varna, Bulgaria, over a 20-year period (2003–2023). A documentary retrospective analysis of the hospitalized cases of poisoning with poisonous plants and their grouping into toxidromes was performed. During the study period, patients with plant poisoning admitted to our hospital unit accounted for 0.35% of a total of 12,857 hospitalized individuals. The distribution across the toxidromes based on clinical presentation revealed the highest frequency of anticholinergic, cyanogen, and ricin toxidromes. The majority of the intoxications resulted from unintentional exposure to plant toxins in adult individuals. Most cases followed a mild to severe clinical course, with patient discharge occurring between 2 and 5 days. No fatalities were recorded, thanks to the reported treatment methods. A relatively low incidence of plant-related poisonings was observed, with their predominant manifestations affecting the gastrointestinal, nervous, and cardiovascular systems. Increased reporting of epidemiological data and clinical experiences in the management of plant intoxications would substantially enhance researchers’ understanding of them and facilitate the development of a standardized treatment protocol. Full article

(This article belongs to the Section Plant Toxins)

► Show Figures

Figure 1

17 pages, 1736 KiB

Open AccessEditor’s ChoiceArticle

Electrical Cell Impedance Sensing (ECIS): Feasibility of a Novel In Vitro Approach to Studying Venom Toxicity and Potential Therapeutics

by Abhinandan Choudhury, Kaitlin Linne, Tommaso C. Bulfone, Tanvir Hossain, Abu Ali Ibn Sina, Philip L. Bickler, Bryan G. Fry and Matthew R. Lewin

Toxins 2025, 17(4), 193; https://doi.org/10.3390/toxins17040193 - 11 Apr 2025

Viewed by 1831

Abstract

Snakebite envenoming is often discussed in terms of lethality and limb loss, but local tissue injury and coagulotoxic effects of venom are significantly more common acute manifestations of snakebite envenoming (SBE). Local tissue injury and the hemorrhagic and coagulotoxic effects of venom are [...] Read more.

Snakebite envenoming is often discussed in terms of lethality and limb loss, but local tissue injury and coagulotoxic effects of venom are significantly more common acute manifestations of snakebite envenoming (SBE). Local tissue injury and the hemorrhagic and coagulotoxic effects of venom are challenging to study in live animals and can be ethically fraught due to animal welfare concerns such that attention to the 3Rs of animal welfare motivates the development of in vitro techniques in this arena. Herein, we tested the use of a wound-healing study technique known as Electric Cell-Substrate Impedance Sensing (ECIS) to assess populations of cultured cells exposed to venom with or without sPLA₂ and/or metalloprotease inhibitors (varespladib and marimastat, respectively). For comparison, the StarMax coagulation analyzer for coagulotoxicity was further used to evaluate the venoms and the neutralizing capabilities of the abovementioned direct toxin inhibitors (DTIs) against the same venoms examined using ECIS. Three viper and three elapid venoms that were examined for their effects on H1975 cells were Agkistrodon contortrix (Eastern Copperhead), Crotalus helleri (Southern Pacific Rattlesnake), and Vipera ammodytes (Horned Viper) and Naja atra (Chinese Cobra), Naja mossambica (Mozambique Spitting Cobra), and Naja nigricollis (Black-necked Spitting Cobra), respectively. The combination of cellular and coagulation techniques appears to usefully discriminate the in vitro capabilities and limitations of specific inhibitors to inhibit specific venom effects. This study suggests that ECIS with or without concomitant coagulation testing is a feasible method to generate reproducible, meaningful preclinical data and could be used with any type of cell line. Importantly, this approach is both quantitative and has the potential of reducing animal use and suffering during the evaluation of potential therapeutics. To further evaluate the potential of this method, rescue studies should be performed. Full article

(This article belongs to the Special Issue Venoms and Drugs)

► Show Figures

Figure 1

9 pages, 238 KiB

Open AccessEditor’s ChoiceReview

Safety of Onabotulinumtoxin-A for Chronic Migraine During Pregnancy and Breastfeeding: A Narrative Review

by Antonio Russo, Luigi Francesco Iannone, Ilaria Orologio, Veronica Rivi, Alberto Boccalini, Flavia Lo Castro, Marcello Silvestro and Simona Guerzoni

Toxins 2025, 17(4), 192; https://doi.org/10.3390/toxins17040192 - 11 Apr 2025

Viewed by 1576

Abstract

Onabotulinumtoxin-A (onabotA) is a neurotoxin widely used for several indications, including chronic migraine (CM) preventive treatment, due to its well-demonstrated efficacy, tolerability, and safety. However, onabotA safety during pregnancy and breastfeeding remains unclear, as these populations are typically excluded from clinical trials. The [...] Read more.

Onabotulinumtoxin-A (onabotA) is a neurotoxin widely used for several indications, including chronic migraine (CM) preventive treatment, due to its well-demonstrated efficacy, tolerability, and safety. However, onabotA safety during pregnancy and breastfeeding remains unclear, as these populations are typically excluded from clinical trials. The action of onabotA starts locally at the injection sites, modulating the pain pathway with minimal systemic absorption, which theoretically minimizes risks to the fetus or breastfeeding infant. Preclinical studies demonstrate that onabotA does not distribute systemically in significant amounts after administration, although adverse fetal outcomes in rats and rabbits were reported when injected at high doses. Limited human data suggest that onabotA exposure during pregnancy may not be associated with major malformations or significant adverse outcomes for the fetus, especially when used at therapeutic doses for migraine prevention during the first trimester or earlier. Data on breastfeeding are even scarcer but indicate a low likelihood of drug transfer into breast milk. This narrative review highlights the available evidence on the use of onabotA in pregnancy and breastfeeding women, including real-word evidence, with a focus on the use for CM. Full article

23 pages, 6254 KiB

Open AccessEditor’s ChoiceArticle

Computational Immunogenetic Analysis of Botulinum Toxin A Immunogenicity and HLA Gene Haplotypes: New Insights

by Eqram Rahman, Parinitha Rao, Munim Ahmed, William Richard Webb and Jean D. A. Carruthers

Toxins 2025, 17(4), 182; https://doi.org/10.3390/toxins17040182 - 6 Apr 2025

Cited by 1 | Viewed by 1728

Abstract

Botulinum toxin A (BoNT-A) is widely used in both therapeutic and aesthetic settings; however, the formation of neutralizing antibodies (NAbs) remains a critical concern, leading to treatment failure. Immunogenic responses are known to vary between individuals due to HLA polymorphisms. Although some claim [...] Read more.

Botulinum toxin A (BoNT-A) is widely used in both therapeutic and aesthetic settings; however, the formation of neutralizing antibodies (NAbs) remains a critical concern, leading to treatment failure. Immunogenic responses are known to vary between individuals due to HLA polymorphisms. Although some claim that neurotoxin-associated proteins (NAPs) shield BoNT-A from immune detection or are themselves immunogenic, there is limited molecular evidence supporting either view. This study applies computational immunogenetics to explore BoNT-A immunogenicity, focusing on HLA binding and the influence of accessory proteins. Epitope mapping, molecular docking, and HLA binding predictions were used to evaluate interactions between BoNT-A epitopes and selected class II HLA alleles (HLA-DQA1*01:02, HLA-DQA1*03:03, HLA-DQB1*06:04, HLA-DQB1*03:01, and HLA-DRB1*15:01). To assess the potential immunomodulatory role of NAPs, molecular dynamics (MD) simulations, solvent-accessible surface area (SASA) analysis, and electrostatic potential mapping were also conducted. Key epitopes—L11, N25, and C10—showed strong binding affinities to HLA-DQA1*01:02, HLA-DQB1*06:04, and HLA-DQA1*03:03, indicating a potential immunodominant role. NAPs did not obstruct these epitopes but slightly increased their exposure and appeared to stabilize the toxin structure. Electrostatic mapping and binding free energy calculations suggested no significant immunogenic shift in the presence of NAPs. BoNT-A immunogenicity appears to be influenced by HLA allele variability, reinforcing the value of patient-specific genetic profiling. The presumed immunogenic role of NAPs remains unsubstantiated at the molecular level, underscoring the need for evidence-based evaluation over commercial rhetoric. While these findings provide valuable molecular insight, it is important to acknowledge that they are derived entirely from in silico analyses. As such, experimental validation remains essential to confirm the immunological relevance of these predicted interactions. Nonetheless, this computational framework offers a rational basis for guiding future clinical research and the development of HLA-informed BoNT-A therapies. Full article

(This article belongs to the Section Bacterial Toxins)

► Show Figures

Figure 1

19 pages, 1146 KiB

Open AccessEditor’s ChoiceSystematic Review

Botulinum Toxin in the Treatment of Hair and Scalp Disorders: Current Evidence and Clinical Applications

by Sofia M. Perez, Sarah A. AlSalman, Betty Nguyen and Antonella Tosti

Toxins 2025, 17(4), 163; https://doi.org/10.3390/toxins17040163 - 25 Mar 2025

Viewed by 3212

Abstract

Botulinum toxin (BoNT) is well-recognized throughout dermatology for its cosmetic indications and growing therapeutic value. Recent studies have trialed BoNT in the treatment of hair and scalp disorders, many of which lack long-term effective treatments and significantly impact quality of life. In this [...] Read more.

Botulinum toxin (BoNT) is well-recognized throughout dermatology for its cosmetic indications and growing therapeutic value. Recent studies have trialed BoNT in the treatment of hair and scalp disorders, many of which lack long-term effective treatments and significantly impact quality of life. In this review, we summarize the current clinical literature on this topic to comprehensively evaluate the efficacy, safety, and clinical value of BoNT in treating hair and scalp conditions. A literature search on PubMed/MEDLINE and Scopus identified 40 articles reporting the use of 25–200 units of BoNT-A or B in 689 patients with hair loss (79.5%), scalp seborrheic dermatitis/hyperseborrhea (10%), craniofacial hyperhidrosis (9%), folliculitis decalvans/dissecting folliculitis (0.86%), scalp pain (0.43%), or linear scleroderma (0.29%). Most studies on BoNT therapy for androgenetic alopecia (AGA) reported mild or non-significant hair growth; however, considerable variability in outcome measures complicates the ability to draw definitive conclusions or justify the use of BoNT over established AGA therapies. BoNT-A and B showed consistent efficacy in treating craniofacial hyperhidrosis with minimal side effects. Additional scalp conditions may benefit from BoNT therapy, but the evidence is limited, and larger, controlled studies are needed to better understand BoNT’s clinical value in these conditions. Full article

(This article belongs to the Special Issue Botulinum Toxins: New Uses in the Treatment of Diseases (2nd Edition))

► Show Figures

Figure 1

20 pages, 4179 KiB

Open AccessEditor’s ChoiceArticle

Microbiological and Mycotoxicological Quality of Common Wheat in Romania in the Extremely Dry 2023–2024 Agricultural Year

by Valeria Gagiu, Elena Mirela Cucu, Alina Alexandra Dobre, Gina Pusa Pirvu, Oana Alexandra Oprea, Cristian Mihai Pomohaci, Elena Mateescu, Nastasia Belc and Doru Ioan Marin

Toxins 2025, 17(4), 154; https://doi.org/10.3390/toxins17040154 - 22 Mar 2025

Viewed by 3379

Abstract

This study examines the microbiological and mycotoxicological quality of common wheat in Romania in the extremely dry 2023–2024 agricultural year. Common wheat grown in the West Plain, Southern Hilly Area, Transylvania, and northern Moldavia (45–48° N, 21–27° E) had higher moisture content, water [...] Read more.

This study examines the microbiological and mycotoxicological quality of common wheat in Romania in the extremely dry 2023–2024 agricultural year. Common wheat grown in the West Plain, Southern Hilly Area, Transylvania, and northern Moldavia (45–48° N, 21–27° E) had higher moisture content, water activity, Fusarium-damaged kernels, and deoxynivalenol levels. This was due to moderate temperatures, abundant precipitation, and soil water reserves in May, followed by moderate drought from June to August. Conversely, common wheat from the Oltenia Plain, the Southern Plain, and southern Moldavia (43–46° N, 23–28° E) had the lowest contamination levels, attributed to extreme temperatures and drought during June–August. Common wheat from Dobrogea (45° N, 28° E) showed the highest total fungi contamination, which was influenced by precipitation at harvest. Although microbiological and mycotoxicological contamination was low, it negatively affected the physico-chemical and sensory–colorimetric parameters of common wheat, particularly in the West Plain, Oltenia Plain, and Dobrogea. Consequently, there could be significant economic losses for farmers, storekeepers, millers, and bakers, as well as a decline in the quality of finished foods. Moreover, the coexistence of deoxynivalenol and total aflatoxins in common wheat grown in the northwest of the country indicates the spread of contamination due to dry conditions and climate change. Full article

(This article belongs to the Collection Impact of Climate Change on Fungal Population and Mycotoxins)

► Show Figures

Figure 1

14 pages, 888 KiB

Open AccessEditor’s ChoiceArticle

Snake Venom Makeover: Age-Dependent Variations in Procoagulant Biochemistry of Egyptian Saw-Scaled Viper (Echis pyramidum pyramidum) Venom

by Alex Barker, Lee Jones, Lachlan A. Bourke, Lorenzo Seneci, Abhinandan Chowdhury, Aude Violette, Rudy Fourmy, Raul Soria, Matt Aldridge and Bryan G. Fry

Toxins 2025, 17(3), 149; https://doi.org/10.3390/toxins17030149 - 19 Mar 2025

Cited by 2 | Viewed by 2715

Abstract

Echis species (saw-scaled vipers) are WHO Category 1 medically significant venomous snakes with potent procoagulant venoms, which cause lethal venom-induced consumptive coagulopathy in human victims. Despite clinical presentations of bites varying significantly between individuals within the same species, the contribution of age-related changes [...] Read more.

Echis species (saw-scaled vipers) are WHO Category 1 medically significant venomous snakes with potent procoagulant venoms, which cause lethal venom-induced consumptive coagulopathy in human victims. Despite clinical presentations of bites varying significantly between individuals within the same species, the contribution of age-related changes in the venom biochemistry has not been investigated. This study investigated the ontogenetic changes in Echis pyramidum pyramidum venom and its impact on therapeutic efficacy. The efficacy of various antivenoms (Echitab, Echitab+ ICP, Inosan MENA, Inosan Pan African, and SAVP-Echis) was tested against both venom phenotypes. While both neonate and adult venoms were procoagulant, there were differences in the underlying biochemistry. Neonate venom was found to potently pathophysiologically activate Factor VII and Factor X, and to a lesser degree Factor XII. In contrast, adult venom was a slower clotter, less potent in activating FVII, equipotent with neonate venom on FXII, and inactive on FX. This is the first documentation of FVII and FXII activation for any Echis venom. The significant ontogenetic toxicological variations in Echis species were shown to impact antivenom efficacy. Among the tested antivenoms, SAVP-Echis was the most effective against both venom phenotypes, with adult venom being better neutralized. These findings suggest the need for a reconsideration of venom mixture selection in antivenom production through the inclusion of neonate venom. Additionally, the results indicate differential ontogenetic predatory ecology, providing a foundation for future natural history investigations. Full article

(This article belongs to the Special Issue Snake Bite and Related Injury)

► Show Figures

Figure 1

22 pages, 629 KiB

Open AccessEditor’s ChoiceArticle

Investigation into Paralytic Shellfish Toxins and Microcystins in Seabirds from Portugal

by Lucía Soliño, Andrew D. Turner, Begoña Ben-Gigirey, Ryan P. Alexander, Karl J. Dean, Robert G. Hatfield, Benjamin H. Maskrey and María V. Mena Casero

Toxins 2025, 17(3), 135; https://doi.org/10.3390/toxins17030135 - 13 Mar 2025

Cited by 1 | Viewed by 859

Abstract

Microalgae form the basis of marine food webs, essential in sustaining top predators including seabirds. However, certain species of microalgae synthesize biotoxins, which can accumulate in shellfish and fish and may cause harm to marine animals feeding on them. Toxins produced by dinoflagellates [...] Read more.

Microalgae form the basis of marine food webs, essential in sustaining top predators including seabirds. However, certain species of microalgae synthesize biotoxins, which can accumulate in shellfish and fish and may cause harm to marine animals feeding on them. Toxins produced by dinoflagellates have been previously observed to be poisonous to seabirds. Also, in freshwater and brackish habitats, cyanobacteria have caused bird mortality events. In this work, we analyze the prevalence of six families of biotoxins (paralytic shellfish toxins (PSTs), microcystins (MCs), anatoxins, amnesic shellfish toxins (ASTs), cylindrospermopsin, and tetrodotoxins (TTXs)) in 340 samples from 193 wild birds admitted to a wildlife rehabilitation centre in south Portugal. Furthermore, we consider the clinical picture and signs of 17 birds that presented quantifiable levels of biotoxins in their tissues. The relationship between toxin burdens and the symptomatology observed, as well as possible biotoxin sources, are discussed. Based on previously published research data, we conclude that, in these birds, the biotoxins are unlikely to be the only cause of death but might contribute to some extent to a reduction in birds’ fitness. Full article

(This article belongs to the Special Issue Harmful Algal Blooms in Waters: Characterization, Monitoring and Management)

► Show Figures

Figure 1

15 pages, 968 KiB

Open AccessEditor’s ChoiceArticle

Learnings from Separate Aconitum Poisonings in British Columbia and Ontario, Canada in 2022

by Lorraine McIntyre, Stefanie Georgopoulos, Dorianna Simone, Emily Newhouse, JoAnne Fernandes, David A. McVea, Arnold Fok, Ania-Maria McIntyre, Bryn Shurmer, Marie-Claude Gagnon, Michael Chan, Marina Chiaravalloti, Nikita Saha Turna, Debra Kent, Dennis Leong, Katherine Paphitis, Christina Lee and the Outbreak Investigation Teams

Toxins 2025, 17(3), 125; https://doi.org/10.3390/toxins17030125 - 7 Mar 2025

Cited by 1 | Viewed by 2944

Abstract

Background: Three aconitine poisoning events occurred in two Canadian provinces in 2022: one in British Columbia (BC) and two in Ontario (ON). Aconitine is a potent alkaloid found in several species of the plant Aconitum, containing cardiotoxins and neurotoxins. It is used [...] Read more.

Background: Three aconitine poisoning events occurred in two Canadian provinces in 2022: one in British Columbia (BC) and two in Ontario (ON). Aconitine is a potent alkaloid found in several species of the plant Aconitum, containing cardiotoxins and neurotoxins. It is used in traditional Chinese medicine (TCM) for pain management, and in powdered form, Aconitum is similar in appearance to sand ginger (Kaempferia galanga), which can lead to poisonings from misidentification and mislabeling. Methods: Aconitine poisoning is rare in Canada; here, we compare communications, collaborations, laboratory testing options and actions during investigations. Results: Fourteen cases occurred from the consumption of sand ginger: in BC (n = 2), purchased at an Asian health food store; in ON (n = 11), Kaempferia galanga powder (KGP) spices were used to prepare meals at a restaurant, and in one ON case, KGP was purchased. Traceback found product imported from China contained aconitine levels ranging from 1304 to 5500 ppm. Later investigations revealed mislabeling of Aconitum as KGP from the same imported lot (January 2020). Plant DNA testing found no KGP in any spice packets, including lots not linked to illness, suggestive of adulteration. Conclusion: Method development for aconitine in BC led to an improved response time for testing in ON. BC and ON updated outbreak response protocols and communications. Full article

(This article belongs to the Special Issue Plant Toxin Emergency)

► Show Figures

Figure 1

18 pages, 3357 KiB

Open AccessEditor’s ChoiceArticle

by Pennapa Thongararm, Marisa Chancharoen, Nutchapong Suwanwong, Somsak Ruchirawat, Mathuros Ruchirawat, Bogdan I. Fedeles, Robert G. Croy and John M. Essigmann

Toxins 2025, 17(3), 112; https://doi.org/10.3390/toxins17030112 - 27 Feb 2025

Viewed by 1080

Abstract

Aflatoxin B₁ (AFB₁) and sterigmatocystin (ST) are mycotoxins that pose significant threats to human and animal health owing to their mutagenic, carcinogenic, and toxic properties. They are structurally similar and widely believed to exert their biological effects via the generation [...] Read more.

Aflatoxin B₁ (AFB₁) and sterigmatocystin (ST) are mycotoxins that pose significant threats to human and animal health owing to their mutagenic, carcinogenic, and toxic properties. They are structurally similar and widely believed to exert their biological effects via the generation of DNA-damaging epoxides at their respective terminal furan rings. Despite structural identity in the warhead portion of each toxin, this work shows that distal parts of each molecule are responsible for the distinctive mutational fingerprints seen in gptΔ C57BL/6J mouse embryo fibroblasts (MEFs). The two toxins differ structurally in the puckered cyclopentenone ring of AFB₁ and in the planar xanthone functionality of ST. While both toxins mainly induce GC→TA mutations, the aforementioned differences in structure apparently trigger unique patterns of mutations, as revealed by high-resolution duplex sequencing of MEF genomes. AFB₁ is more mutagenic than ST and displays its transversion mutations in a pattern with primary and secondary hotspots (underscored) in 5′-CGC-3′ and 5′-CGG-3′ contexts, respectively. ST displays a modest 5′-CGG-3′ hotspot while its other GC→TA transversions are more uniformly distributed in a pattern resembling established oxidative stress mutational spectra. This research delineates the mutational spectra of AFB₁ and ST, establishing these patterns as possible early-onset biomarkers of exposure. Full article

(This article belongs to the Special Issue 65 Years On from Aflatoxin Discovery—a Themed Issue in Honor of Professor John D. Groopman)

► Show Figures

Graphical abstract

21 pages, 3970 KiB

Open AccessEditor’s ChoiceReview

It’s a Small World After All: The Remarkable but Overlooked Diversity of Venomous Organisms, with Candidates Among Plants, Fungi, Protists, Bacteria, and Viruses

by William K. Hayes, Eric C. K. Gren, David R. Nelsen, Aaron G. Corbit, Allen M. Cooper, Gerad A. Fox and M. Benjamin Streit

Toxins 2025, 17(3), 99; https://doi.org/10.3390/toxins17030099 - 20 Feb 2025

Cited by 2 | Viewed by 3839

Abstract

Numerous organisms, including animals, plants, fungi, protists, and bacteria, rely on toxins to meet their needs. Biological toxins have been classified into three groups: poisons transferred passively without a delivery mechanism; toxungens delivered to the body surface without an accompanying wound; and venoms [...] Read more.

Numerous organisms, including animals, plants, fungi, protists, and bacteria, rely on toxins to meet their needs. Biological toxins have been classified into three groups: poisons transferred passively without a delivery mechanism; toxungens delivered to the body surface without an accompanying wound; and venoms conveyed to internal tissues via the creation of a wound. The distinctions highlight the evolutionary pathways by which toxins acquire specialized functions. Heretofore, the term venom has been largely restricted to animals. However, careful consideration reveals a surprising diversity of organisms that deploy toxic secretions via strategies remarkably analogous to those of venomous animals. Numerous plants inject toxins and pathogenic microorganisms into animals through stinging trichomes, thorns, spines, prickles, raphides, and silica needles. Some plants protect themselves via ants as venomous symbionts. Certain fungi deliver toxins via hyphae into infected hosts for nutritional and/or defensive purposes. Fungi can possess penetration structures, sometimes independent of the hyphae, that create a wound to facilitate toxin delivery. Some protists discharge harpoon-like extrusomes (toxicysts and nematocysts) that penetrate their prey and deliver toxins. Many bacteria possess secretion systems or contractile injection systems that can introduce toxins into targets via wounds. Viruses, though not “true” organisms according to many, include a group (the bacteriophages) which can inject nucleic acids and virion proteins into host cells that inflict damage rivaling that of conventional venoms. Collectively, these examples suggest that venom delivery systems—and even toxungen delivery systems, which we briefly address—are much more widespread than previously recognized. Thus, our understanding of venom as an evolutionary novelty has focused on only a small proportion of venomous organisms. With regard to this widespread form of toxin deployment, the words of the Sherman Brothers in Disney’s iconic tune, It’s a Small World, could hardly be more apt: “There’s so much that we share, that it’s time we’re aware, it’s a small world after all”. Full article

► Show Figures

Figure 1

29 pages, 2015 KiB

Open AccessEditor’s ChoiceReview

Targeting Enterotoxins: Advancing Vaccine Development for Enterotoxigenic Escherichia coli ETEC

by Josune Salvador-Erro, Yadira Pastor and Carlos Gamazo

Toxins 2025, 17(2), 71; https://doi.org/10.3390/toxins17020071 - 6 Feb 2025

Cited by 2 | Viewed by 2854

Abstract

Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrheal disease worldwide, particularly in children in low- and middle-income countries. Its ability to rapidly colonize the intestinal tract through diverse colonization factors and toxins underpins its significant public health impact. Despite extensive research [...] Read more.

Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrheal disease worldwide, particularly in children in low- and middle-income countries. Its ability to rapidly colonize the intestinal tract through diverse colonization factors and toxins underpins its significant public health impact. Despite extensive research and several vaccine candidates reaching clinical trials, no licensed vaccine exists for ETEC. This review explores the temporal and spatial coordination of ETEC virulence factors, focusing on the interplay between adherence mechanisms and toxin production as critical targets for therapeutic intervention. Advancements in molecular biology and host–pathogen interaction studies have uncovered species-specific variations and cross-reactivity between human and animal strains. In particular, the heat-labile (LT) and heat-stable (ST) toxins have provided crucial insights into molecular mechanisms and intestinal disruption. Additional exotoxins, such as EAST-1 and hemolysins, further highlight the multifactorial nature of ETEC pathogenicity. Innovative vaccine strategies, including multiepitope fusion antigens (MEFAs), mRNA-based approaches, and glycoconjugates, aim to enhance broad-spectrum immunity. Novel delivery methods, like intradermal immunization, show promise in eliciting robust immune responses. Successful vaccination against ETEC will offer an effective and affordable solution with the potential to greatly reduce mortality and prevent stunting, representing a highly impactful and cost-efficient solution to a critical global health challenge. Full article

► Show Figures

Figure 1

31 pages, 758 KiB

Open AccessEditor’s ChoiceReview

Aflatoxin B1: Challenges and Strategies for the Intestinal Microbiota and Intestinal Health of Monogastric Animals

by Hyunjun Choi, Yesid Garavito-Duarte, Alexa R. Gormley and Sung Woo Kim

Toxins 2025, 17(1), 43; https://doi.org/10.3390/toxins17010043 - 17 Jan 2025

Cited by 4 | Viewed by 2706

Abstract

The objective of this review is to investigate the impacts of aflatoxins, particularly aflatoxin B1 (AFB₁), on intestinal microbiota, intestinal health, and growth performance in monogastric animals, primarily chickens and pigs, as well as dietary interventions to mitigate these effects. Aflatoxin [...] Read more.

The objective of this review is to investigate the impacts of aflatoxins, particularly aflatoxin B1 (AFB₁), on intestinal microbiota, intestinal health, and growth performance in monogastric animals, primarily chickens and pigs, as well as dietary interventions to mitigate these effects. Aflatoxin B1 contamination in feeds disrupts intestinal microbiota, induces immune responses and oxidative damage, increases antioxidant activity, and impairs jejunal cell viability, barrier function, and morphology in the small intestine. These changes compromise nutrient digestion and reduce growth performance in animals. The negative impact of AFB₁ on the % change in average daily gain (ΔADG) of chickens and pigs was estimated based on meta-analysis: ΔADG (%)_chicken = −0.13 × AFB₁ intake per body weight (ng/g·d) and ΔADG (%)_pig = −0.74 × AFB₁ intake per body weight (µg/kg·d), indicating that increasing AFB₁ contamination linearly reduces the growth of animals. To mitigate the harmful impacts of AFB₁, various dietary strategies have been effective. Mycotoxin-detoxifying agents include mycotoxin-adsorbing agents, such as clay and yeast cell wall compounds, binding to AFB₁ and mycotoxin-biotransforming agents, such as specific strains of Bacillus subtilis and mycotoxin-degrading enzyme, degrading AFB₁ into non-toxic metabolites such as aflatoxin D1. Multiple mycotoxin-detoxifying agents are often combined and used together to improve the intestinal health and growth of chickens and pigs fed AFB₁-contaminated feeds. In summary, AFB₁ negatively impacts intestinal microbiota, induces immune responses and oxidative stress, disrupts intestinal morphology, and impairs nutrient digestion in the small intestine, leading to reduced growth performance. Supplementing multi-component mycotoxin-detoxifying agents in feeds could effectively adsorb and degrade AFB₁ co-contaminated with other mycotoxins prior to its absorption in the small intestine, preventing its negative impacts on the intestinal health and growth performance of chickens and pigs. Full article

(This article belongs to the Special Issue Aspergillus flavus and Aflatoxins (3rd Edition))

► Show Figures

Figure 1

22 pages, 3875 KiB

Open AccessEditor’s ChoiceReview

Venoms and Extracellular Vesicles: A New Frontier in Venom Biology

by Auwal A. Bala, Naoual Oukkache, Elda E. Sanchez, Montamas Suntravat and Jacob A. Galan

Toxins 2025, 17(1), 36; https://doi.org/10.3390/toxins17010036 - 14 Jan 2025

Cited by 2 | Viewed by 2292

Abstract

Extracellular vesicles (EVs) are nanoparticle-sized vesicles secreted by nearly all cell types under normal physiological conditions. In toxicological research, EVs have emerged as a crucial link between public health and multi-omics approaches, offering insights into cellular responses to disease-causing injury agents such as [...] Read more.

Extracellular vesicles (EVs) are nanoparticle-sized vesicles secreted by nearly all cell types under normal physiological conditions. In toxicological research, EVs have emerged as a crucial link between public health and multi-omics approaches, offering insights into cellular responses to disease-causing injury agents such as environmental and biological toxins, contaminants, and drugs. Notably, EVs present a unique opportunity to deepen our understanding of the pathophysiology of envenomation by natural toxins. Recent advancements in isolating and purifying EV cargo, mass spectrometry techniques, and bioinformatics have positioned EVs as potential biomarkers that could elucidate biological signaling pathways and provide valuable information on the relationship between venomous toxins, their mechanisms of action, and the effectiveness of antivenoms. Additionally, EVs hold promise as proxies for various aspects of envenomation, including the toxin dosage, biological characterization, injury progression, and prognosis during therapeutic interventions. These aspects can be explored through multi-omics technology applied to EV contents from the plasma, saliva, or urine samples of envenomated individuals, offering a comprehensive integrative approach to understanding and managing envenomation cases. Full article

(This article belongs to the Special Issue Transcriptomic and Proteomic Study on Animal Venom: Looking Forward)

► Show Figures

Figure 1

17 pages, 5927 KiB

Open AccessEditor’s ChoiceArticle

Pulsed Electric Field Induces Significant Changes in the Metabolome of Fusarium Species and Decreases Their Viability and Toxigenicity

by Adam Behner, Jana Palicova, Anna-Hirt Tobolkova, Nela Prusova and Milena Stranska

Toxins 2025, 17(1), 33; https://doi.org/10.3390/toxins17010033 - 11 Jan 2025

Cited by 2 | Viewed by 1689

Abstract

Fusarium fungi are widespread pathogens of food crops, primarily associated with the formation of mycotoxins. Therefore, effective mitigation strategies for these toxicogenic microorganisms are required. In this study, the potential of pulsed electric field (PEF) as an advanced technology of increasing use in [...] Read more.

Fusarium fungi are widespread pathogens of food crops, primarily associated with the formation of mycotoxins. Therefore, effective mitigation strategies for these toxicogenic microorganisms are required. In this study, the potential of pulsed electric field (PEF) as an advanced technology of increasing use in the food processing industry was investigated to minimize the viability of Fusarium pathogens and to characterize the PEF-induced changes at the metabolomic level. Spores of four Fusarium species (Fusarium culmorum, Fusarium graminearum, Fusarium poae, and Fusarium sporotrichioides) were treated with PEF and cultured on potato dextrose agar (PDA) plates. The viability of the Fusarium species was assessed by counting the colony-forming units, and changes in the mycotoxin content and metabolomic fingerprints were evaluated by using UHPLC-HRMS/MS instrumental analysis. For metabolomic data processing and compound identification, the MS-DIAL (v. 4.80)–MS-CleanR–MS-Finder (v. 3.52) software platform was used. As we found out, both fungal viability and the ability to produce mycotoxins significantly decreased after the PEF treatment for all of the species tested. The metabolomes of the treated and untreated fungi showed statistically significant differences, and PEF-associated biomarkers from the classes oxidized fatty acid derivatives, cyclic hexapeptides, macrolides, pyranocoumarins, carbazoles, and guanidines were identified. Full article

(This article belongs to the Section Mycotoxins)

► Show Figures

Figure 1

44 pages, 3456 KiB

Open AccessEditor’s ChoiceReview

Species Differences in the Biotransformation of Aflatoxin B1: Primary Determinants of Relative Carcinogenic Potency in Different Animal Species

by David L. Eaton, David E. Williams and Roger A. Coulombe

Toxins 2025, 17(1), 30; https://doi.org/10.3390/toxins17010030 - 9 Jan 2025

Cited by 7 | Viewed by 2377

Abstract

It has been known since the early days of the discovery of aflatoxin B1 (AFB1) that there were large species differences in susceptibility to AFB1. It was also evident early on that AFB1 itself was not toxic but required bioactivation to a reactive [...] Read more.

It has been known since the early days of the discovery of aflatoxin B1 (AFB1) that there were large species differences in susceptibility to AFB1. It was also evident early on that AFB1 itself was not toxic but required bioactivation to a reactive form. Over the past 60 years there have been thousands of studies to delineate the role of ~10 specific biotransformation pathways of AFB1, both phase I (oxidation, reduction) and phase II (hydrolysis, conjugation, secondary oxidations, and reductions of phase I metabolites). This review provides a historical context and substantive analysis of each of these pathways as contributors to species differences in AFB1 hepatoxicity and carcinogenicity. Since the discovery of AFB1 as the toxic contaminant in groundnut meal that led to Turkey X diseases in 1960, there have been over 15,000 publications related to aflatoxins, of which nearly 8000 have addressed the significance of biotransformation (metabolism, in the older literature) of AFB1. While it is impossible to give justice to all of these studies, this review provides a historical perspective on the major discoveries related to species differences in the biotransformation of AFB1 and sets the stage for discussion of other papers in this Special Issue of the important role that AFB1 metabolites have played as biomarkers of exposure and effect in thousands of human studies on the toxic effects of aflatoxins. Dr. John Groopman has played a leading role in every step of the way—from initial laboratory studies on specific AFB1 metabolites to the application of molecular biomarkers in epidemiological studies associating dietary AFB1 exposure with liver cancer, and the design and conduct of chemoprevention clinical trials to reduce cancer risk from unavoidable aflatoxin exposures by alteration of specific AFB1 biotransformation pathways. This article is written in honor of Dr. Groopman’s many contributions in this area. Full article

(This article belongs to the Special Issue 65 Years On from Aflatoxin Discovery—a Themed Issue in Honor of Professor John D. Groopman)

► Show Figures

Graphical abstract

15 pages, 23082 KiB

Open AccessEditor’s ChoiceArticle

Reduction in Renal Heme Oxygenase-1 Is Associated with an Aggravation of Kidney Injury in Shiga Toxin-Induced Murine Hemolytic-Uremic Syndrome

by Antonio N. Mestekemper, Wiebke Pirschel, Nadine Krieg, Maria K. Paulmann, Christoph Daniel, Kerstin Amann and Sina M. Coldewey

Toxins 2024, 16(12), 543; https://doi.org/10.3390/toxins16120543 - 14 Dec 2024

Viewed by 1453

Abstract

Hemolytic-uremic syndrome (HUS) is a systemic complication of an infection with Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli, primarily leading to acute kidney injury (AKI) and microangiopathic hemolytic anemia. Although free heme has been found to aggravate renal damage in hemolytic diseases, the [...] Read more.

Hemolytic-uremic syndrome (HUS) is a systemic complication of an infection with Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli, primarily leading to acute kidney injury (AKI) and microangiopathic hemolytic anemia. Although free heme has been found to aggravate renal damage in hemolytic diseases, the relevance of the heme-degrading enzyme heme oxygenase-1 (HO-1, encoded by Hmox1) in HUS has not yet been investigated. We hypothesized that HO-1, also important in acute phase responses in damage and inflammation, contributes to renal pathogenesis in HUS. The effect of tamoxifen-induced Hmox1 gene deletion on renal HO-1 expression, disease progression and AKI was investigated in mice 7 days after HUS induction. Renal HO-1 levels were increased in Stx-challenged mice with tamoxifen-induced Hmox1 gene deletion (Hmox1^R26Δ/Δ) and control mice (Hmox1^lox/lox). This HO-1 induction was significantly lower (−43%) in Hmox1^R26Δ/Δ mice compared to Hmox1^lox/lox mice with HUS. Notably, the reduced renal HO-1 expression was associated with an exacerbation of kidney injury in mice with HUS as indicated by a 1.7-fold increase (p = 0.02) in plasma neutrophil gelatinase-associated lipocalin (NGAL) and a 1.3-fold increase (p = 0.06) in plasma urea, while other surrogate parameters for AKI (e.g., periodic acid Schiff staining, kidney injury molecule-1, fibrin deposition) and general disease progression (HUS score, weight loss) remained unchanged. These results indicate a potentially protective role of HO-1 in the pathogenesis of Stx-mediated AKI in HUS. Full article

(This article belongs to the Section Bacterial Toxins)

► Show Figures

Figure 1

19 pages, 5894 KiB

Open AccessEditor’s ChoiceArticle

Application of Pulsed Electric Field During Malting: Impact on Fusarium Species Growth and Mycotoxin Production

by Nela Prusova, Marcel Karabin, Lukas Jelinek, Jana Chrpova, Jaroslava Ovesna, Pavel Svoboda, Tereza Dolezalova, Adam Behner, Jana Hajslova and Milena Stranska

Toxins 2024, 16(12), 537; https://doi.org/10.3390/toxins16120537 - 12 Dec 2024

Cited by 3 | Viewed by 1241

Abstract

The increasing contamination of cereals by micromycetes and mycotoxins during malting still poses an unresolved food safety problem. This study characterises the potential of the novel, rapidly developing food production technology of Pulsed Electric Field (PEF) to reduce the viability of Fusarium fungi [...] Read more.

The increasing contamination of cereals by micromycetes and mycotoxins during malting still poses an unresolved food safety problem. This study characterises the potential of the novel, rapidly developing food production technology of Pulsed Electric Field (PEF) to reduce the viability of Fusarium fungi and the production of mycotoxins during malting. Barley, artificially inoculated with four Fusarium species, was treated by PEF with two different intensities and then malted using a standard Pilsner-type technology. Concentrations of fungi were quantified by RT-PCR, expression of fungal growth-related genes was assessed using mRNA sequencing, and mycotoxin levels were analysed by U-HPLC-HRMS/MS. Despite the different trends for micromycetes and mycotoxins after application of variously intense PEF conditions, significant reductions were generally observed. The greatest decrease was for F. sporotrichioides and F. poae, where up to six fold lower levels were achieved for malts produced from the PEF-treated barley when compared to the control. For F. culmorum and F. graminearum, up to a two-fold reduction in the PEF-generated malts was observed. These reductions mostly correlated with a decrease in relevant mycotoxins, specifically type A trichothecenes. Full article

(This article belongs to the Section Mycotoxins)

► Show Figures

Graphical abstract

39 pages, 6873 KiB

Open AccessEditor’s ChoiceReview

Exploring Mycolactone—The Unique Causative Toxin of Buruli Ulcer: Biosynthetic, Synthetic Pathways, Biomarker for Diagnosis, and Therapeutic Potential

by Gideon Atinga Akolgo, Kingsley Bampoe Asiedu and Richard Kwamla Amewu

Toxins 2024, 16(12), 528; https://doi.org/10.3390/toxins16120528 - 6 Dec 2024

Cited by 1 | Viewed by 2951

Abstract

Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of Buruli ulcer. The aim of this paper is to review the chemistry, biosynthetic, and synthetic pathways of mycolactone A/B to help develop an understanding of the mode of [...] Read more.

Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of Buruli ulcer. The aim of this paper is to review the chemistry, biosynthetic, and synthetic pathways of mycolactone A/B to help develop an understanding of the mode of action of these polyketides as well as their therapeutic potential. The synthetic work has largely been driven by the desire to afford researchers enough (≥100 mg) of the pure toxins for systematic biological studies toward understanding their very high biological activities. The review focuses on pioneering studies of Kishi which elaborate first-, second-, and third-generation approaches to the synthesis of mycolactones A/B. The three generations focused on the construction of the key intermediates required for the mycolactone synthesis. Synthesis of the first generation involves assignment of the relative and absolute stereochemistry of the mycolactones A and B. This was accomplished by employing a linear series of 17 chemical steps (1.3% overall yield) using the mycolactone core. The second generation significantly improved the first generation in three ways: (1) by optimizing the selection of protecting groups; (2) by removing needless protecting group adjustments; and (3) by enhancing the stereoselectivity and overall synthetic efficiency. Though the synthetic route to the mycolactone core was longer than the first generation, the overall yield was significantly higher (8.8%). The third-generation total synthesis was specifically aimed at an efficient, scalable, stereoselective, and shorter synthesis of mycolactone. The synthesis of the mycolactone core was achieved in 14 linear chemical steps with 19% overall yield. Furthermore, a modular synthetic approach where diverse analogues of mycolactone A/B were synthesized via a cascade of catalytic and/or asymmetric reactions as well as several Pd-catalyzed key steps coupled with hydroboration reactions were reviewed. In addition, the review discusses how mycolactone is employed in the diagnosis of Buruli ulcer with emphasis on detection methods of mass spectrometry, immunological assays, RNA aptamer techniques, and fluorescent-thin layer chromatography (f-TLC) methods as diagnostic tools. We examined studies of the structure–activity relationship (SAR) of various analogues of mycolactone. The paper highlights the multiple biological consequences associated with mycolactone such as skin ulceration, host immunomodulation, and analgesia. These effects are attributed to various proposed mechanisms of actions including Wiskott–Aldrich Syndrome protein (WASP)/neural Wiskott–Aldrich Syndrome protein (N-WASP) inhibition, Sec61 translocon inhibition, angiotensin II type 2 receptor (AT2R) inhibition, and inhibition of mTOR. The possible application of novel mycolactone analogues produced based on SAR investigations as therapeutic agents for the treatment of inflammatory disorders and inflammatory pain are discussed. Additionally, their therapeutic potential as anti-viral and anti-cancer agents have also been addressed. Full article

(This article belongs to the Section Mycotoxins)

► Show Figures

Figure 1

13 pages, 6199 KiB

Open AccessEditor’s ChoiceArticle

Bicistronic Vector Expression of Recombinant Jararhagin-C and Its Effects on Endothelial Cells

by Karla Fernanda Ferraz, Lhiri Hanna De Lucca Caetano, Daniele Pereira Orefice, Paula Andreia Lucas Calabria, Maisa Splendore Della-Casa, Luciana Aparecida Freitas-de-Sousa, Emidio Beraldo-Neto, Sabri Saeed Sanabani, Geraldo Santana Magalhães and Patricia Bianca Clissa

Toxins 2024, 16(12), 524; https://doi.org/10.3390/toxins16120524 - 3 Dec 2024

Cited by 1 | Viewed by 1128

Abstract

Jararhagin-C (JarC) is a protein from the venom of Bothrops jararaca consisting of disintegrin-like and cysteine-rich domains. JarC shows a modulating effect on angiogenesis and remodeling of extracellular matrix constituents, improving wound healing in a mouse experimental model. JarC is purified from crude [...] Read more.

Jararhagin-C (JarC) is a protein from the venom of Bothrops jararaca consisting of disintegrin-like and cysteine-rich domains. JarC shows a modulating effect on angiogenesis and remodeling of extracellular matrix constituents, improving wound healing in a mouse experimental model. JarC is purified from crude venom, and the yield is less than 1%. The aim of this work was to obtain the recombinant form of JarC and to test its biological activity. For this purpose, the bicistronic vector pSUMOUlp1 was used. This vector allowed the expression of the recombinant toxin JarC (rJarC) in fusion with the small ubiquitin-related modifier (SUMO) as well as the SUMO protease Ulp1. After expression, this protease was able to efficiently remove SUMO from rJarC inside the bacteria. rJarC free from SUMO was purified at the expected molecular mass and recognized by polyclonal anti-jararhagin antibodies. In terms of biological activity, both the native and recombinant forms showed no toxicity to the HUVEC cell line CRL1730 and were effective in modulating cell migration activity in the experimental in vitro model. These results demonstrate the successful production of rJarC and the preservation of its biological activity, which may facilitate further investigations into the therapeutic potential of this snake venom-derived protein. Full article

(This article belongs to the Special Issue Animals Venom in Drug Discovery: A Valuable Therapeutic Tool)

► Show Figures

Figure 1

14 pages, 920 KiB

Open AccessEditor’s ChoiceArticle

Age Is Just a Number: Ontogenetic Conservation in Activation of Blood Clotting Factors VII, X, and XII by Caucasus Blunt-Nosed Viper (Macrovipera lebetina obtusa) Venoms

by Katrina Kempson, Abhinandan Chowdhury, Aude Violette, Rudy Fourmy, Raul Soria and Bryan G. Fry

Toxins 2024, 16(12), 520; https://doi.org/10.3390/toxins16120520 - 2 Dec 2024

Cited by 3 | Viewed by 3719

Abstract

This study examined the pathophysiological effects of venoms from neonate and adult specimens of the viperid snake Macrovipera lebetina obtusa, focusing on their ability to activate various blood clotting factors in human plasma. All venoms exhibited strong procoagulant properties. In concentration–response tests, [...] Read more.

This study examined the pathophysiological effects of venoms from neonate and adult specimens of the viperid snake Macrovipera lebetina obtusa, focusing on their ability to activate various blood clotting factors in human plasma. All venoms exhibited strong procoagulant properties. In concentration–response tests, the clotting potency of the neonate venoms fell within the range of their parents’ maximum clotting velocities and areas under the curve. Intriguingly, females were more potent than males within each age group, but this requires a larger sample size to confirm. Antivenom neutralization efficacy was equipotent across age groups. The venoms potently activated Factor X (FX) robustly, consistent with previous knowledge of this genus. For the first time, the ability to activate Factors VII (FVII) and XII (FXII) was identified in this genus, with FXII exhibiting particularly strong activation. The study found no significant ontogenetic variation in procoagulant venom potency on human plasma, convergent with the Daboia genus, the other large-bodied lineage within the Palearctic viperid clade. However, the activation of FXII and FVII reveals previously undocumented pathways in the procoagulant activity of these venoms, contributing to the broader understanding of venom evolution and its clinical impacts. These findings have implications for venom biodiscovery and the development of antivenoms, highlighting the complexity of clotting factor activation beyond traditional investigations that have myopically focused upon FX and prothrombin pathways, thereby underscoring the importance of exploring additional clotting factors. Full article

(This article belongs to the Section Animal Venoms)

► Show Figures

Figure 1

30 pages, 2355 KiB

Open AccessEditor’s ChoiceReview

The Role of Snake Venom Proteins in Inducing Inflammation Post-Envenomation: An Overview on Mechanistic Insights and Treatment Strategies

by Sudharshan Rao, Nisha Reghu, Bipin Gopalakrishnan Nair and Muralidharan Vanuopadath

Toxins 2024, 16(12), 519; https://doi.org/10.3390/toxins16120519 - 2 Dec 2024

Cited by 2 | Viewed by 3655

Abstract

The intricate combination of organic and inorganic compounds found in snake venom includes proteins, peptides, lipids, carbohydrates, nucleotides, and metal ions. These components work together to immobilise and consume prey through processes such as paralysis and hypotension. Proteins, both enzymatic and non-enzymatic, form [...] Read more.

The intricate combination of organic and inorganic compounds found in snake venom includes proteins, peptides, lipids, carbohydrates, nucleotides, and metal ions. These components work together to immobilise and consume prey through processes such as paralysis and hypotension. Proteins, both enzymatic and non-enzymatic, form the primary components of the venom. Based on the effects they produce, venom can be classified as neurotoxic, hemotoxic, and cytotoxic. Studies have shown that, after envenomation, proteins in snake venom also contribute significantly to the induction of inflammatory responses which can either have systemic or localized consequences. This review delves into the mechanisms by which snake venom proteins trigger inflammatory responses, focusing on key families such as phospholipase A₂, metalloproteinases, serine proteases, C-type lectins, cysteine-rich secretory proteins, and L-amino acid oxidase. In addition, the role of venom proteins in activating various inflammatory pathways, including the complement system, inflammasomes, and sterile inflammation are also summarized. The available therapeutic options are examined, with a focus on antivenom therapy and its side effects. In general, this review offers a comprehensive understanding of the inflammatory mechanisms that are triggered by snake venom proteins and the side effects of antivenom treatment. All these emphasize the need for effective strategies to mitigate these detrimental effects. Full article

(This article belongs to the Special Issue Snake Venom: Toxicology and Associated Countermeasures)

► Show Figures

Figure 1

22 pages, 1624 KiB

Open AccessEditor’s ChoiceArticle

Mycotoxin Challenge in Dairy Cows: Assessment of the Efficacy of an Anti-Mycotoxin Agent by Adopting an In Vitro Rumen Simulation Method

by Erica Fiorbelli, Marco Lapris, Michela Errico, Antonella Della Badia, Insaf Riahi, Gabriele Rocchetti and Antonio Gallo

Toxins 2024, 16(11), 490; https://doi.org/10.3390/toxins16110490 - 13 Nov 2024

Cited by 3 | Viewed by 2284

Abstract

To protect ruminants from the harmful effects of mycotoxins, anti-mycotoxin agents can be added to the dietary ration, thus guaranteeing animal health and production. Therefore, the objective of this study was to evaluate the in vitro ruminal initial sequestration (weak binding) and subsequent [...] Read more.

To protect ruminants from the harmful effects of mycotoxins, anti-mycotoxin agents can be added to the dietary ration, thus guaranteeing animal health and production. Therefore, the objective of this study was to evaluate the in vitro ruminal initial sequestration (weak binding) and subsequent desorption (strong binding) of an anti-mycotoxin agent based on a mixture of adsorbing material, turmeric and milk thistle extracts and yeast-based components to adsorb or bio-convert aflatoxins (AF), fumonisins B1 and B2 (FB), trichothecene deoxynivalenol (DON), T-2 and HT-2 toxins, and zearalenone (ZEN). Two doses were tested: Dose 1 simulated 30 mg/cow/d, while Dose 2 simulated 90 mg/cow/d of the anti-mycotoxin agent. Each treatment involved three analytical replicates at each of three incubation times (1, 4, and 24 h post-incubation), with two independent experimental runs providing experimental replicates. Analytical methods, including UHPLC-HRMS and multivariate analyses, were used to both quantify mycotoxin concentrations and reveal dose-dependent reductions, with statistical validations indicating significant changes in mycotoxin levels across both dose and time. The results indicated that the anti-mycotoxin agent was able to highly bind AFB1, T2, and HT-2 toxins since its concentration was always under the limit of detection (<1 ppb). Regarding ZEN (weak binding mean: 94.6%; strong binding mean: 62.4%) and FBs (weak binding mean: 58.7%; strong binding mean: 32.3%), orthogonal contrasts indicated that the anti-mycotoxin agent was able to effectively bind these toxins using Dose 1 (p < 0.05). This finding suggests that Dose 1 may be sufficient to achieve the targeted effect and that a further increase does not significantly improve the outcome. Regarding DON, a strong linear relationship was observed between dose and adsorption. However, the complex interactions between the mycotoxin, the ruminal environment, and the anti-mycotoxin agent made it difficult to establish a clear dose–effect relationship (p > 0.10). UHPLC-HRMS analysis identified over 1500 mass features in rumen samples, which were further analyzed to assess the effects of the anti-mycotoxin agent. Hierarchical clustering analysis (HCA) revealed significant changes in the untargeted metabolomic profiles of samples treated with mycotoxins compared to control samples, particularly after 24 h with the anti-mycotoxin treatments. Clear differences were noted between strong binding and weak binding samples. Further analysis using orthogonal partial least squares discriminant analysis (OPLS-DA) highlighted distinct metabolomic profiles, with stronger predictive ability in the strong binding group (Q² cumulative value of 0.57) compared to the weak binding group (0.30). The analysis identified 44 discriminant compounds in the strong binding model and 16 in the weak binding model. Seven compounds were common to both groups, while silibinin, known for its antioxidant and anti-inflammatory properties, was found among the unique compounds in the weak binding group. Overall, the findings suggest that both doses of the anti-mycotoxin agent significantly influenced the chemical profiles in the rumen, particularly enhancing the binding of mycotoxins, thereby supporting the role of phytogenic extracts in mitigating mycotoxin effects. Full article

(This article belongs to the Special Issue Mitigation and Detoxification Strategies of Mycotoxins)

► Show Figures

Figure 1

28 pages, 13740 KiB

Open AccessEditor’s ChoiceArticle

A Novel P-III Metalloproteinase from Bothrops barnetti Venom Degrades Extracellular Matrix Proteins, Inhibits Platelet Aggregation, and Disrupts Endothelial Cell Adhesion via α5β1 Integrin Receptors to Arginine–Glycine–Aspartic Acid (RGD)-Containing Molecules

by Pedro Henrique de Caires Schluga, Debora Larangote, Ana Maria de Melo, Guilherme Kamienski Lobermayer, Daniel Torrejón, Luciana Souza de Oliveira, Valeria Gonçalves Alvarenga, Dan Erick Vivas-Ruiz, Silvio Sanches Veiga, Eladio Flores Sanchez and Luiza Helena Gremski

Toxins 2024, 16(11), 486; https://doi.org/10.3390/toxins16110486 - 9 Nov 2024

Cited by 2 | Viewed by 2049

Abstract

Viperid snake venoms are notably abundant in metalloproteinases (proteins) (SVMPs), which are primarily responsible for inducing hemorrhage and disrupting the hemostatic process and tissue integrity in envenomed victims. In this study, barnettlysin-III (Bar-III), a hemorrhagic P-III SVMP, was purified from the venom of [...] Read more.

Viperid snake venoms are notably abundant in metalloproteinases (proteins) (SVMPs), which are primarily responsible for inducing hemorrhage and disrupting the hemostatic process and tissue integrity in envenomed victims. In this study, barnettlysin-III (Bar-III), a hemorrhagic P-III SVMP, was purified from the venom of the Peruvian snake Bothrops barnetti. Bar-III has a molecular mass of approximately 50 kDa and is a glycosylation-dependent functional metalloproteinase. Some biochemical properties of Bar-III, including the full amino acid sequence deduced from its cDNA, are reported. Its enzymatic activity is increased by Ca²⁺ ions and inhibited by an excess of Zn²⁺. Synthetic metalloproteinase inhibitors and EDTA also inhibit its proteolytic action. Bar-III degrades several plasma and ECM proteins, including fibrin(ogen), fibronectin, laminin, and nidogen. Platelets play a key role in hemostasis and thrombosis and in other biological process, such as inflammation and immunity, and platelet activation is driven by the platelet signaling receptors, glycoprotein (GP)Ib-IX-V, which binds vWF, and GPVI, which binds collagen. Moreover, Bar-III inhibits vWF- and convulxin-induced platelet aggregation in human washed platelets by cleaving the recombinant A1 domain of vWF and GPVI into a soluble ectodomain fraction of ~55 kDa (sGPVI). Bar-III does not reduce the viability of cultured endothelial cells; however, it interferes with the adhesion of these cells to fibronectin, vitronectin, and RGD peptides, as well as their migration profile. Bar-III binds specifically to the surface of these cells, and part of this interaction involves α5β1 integrin receptors. These results contribute to a better comprehension of the pathophysiology of snakebite accidents/incidents and could be used as a tool to explore novel and safer anti-venom therapeutics. Full article

(This article belongs to the Section Animal Venoms)

► Show Figures

Figure 1

15 pages, 2138 KiB

Open AccessEditor’s ChoiceArticle

Machine Learning Framework for Conotoxin Class and Molecular Target Prediction

by Duc P. Truong, Lyman K. Monroe, Robert F. Williams and Hau B. Nguyen

Toxins 2024, 16(11), 475; https://doi.org/10.3390/toxins16110475 - 3 Nov 2024

Cited by 1 | Viewed by 1707

Abstract

Conotoxins are small and highly potent neurotoxic peptides derived from the venom of marine cone snails which have captured the interest of the scientific community due to their pharmacological potential. These toxins display significant sequence and structure diversity, which results in a wide [...] Read more.

Conotoxins are small and highly potent neurotoxic peptides derived from the venom of marine cone snails which have captured the interest of the scientific community due to their pharmacological potential. These toxins display significant sequence and structure diversity, which results in a wide range of specificities for several different ion channels and receptors. Despite the recognized importance of these compounds, our ability to determine their binding targets and toxicities remains a significant challenge. Predicting the target receptors of conotoxins, based solely on their amino acid sequence, remains a challenge due to the intricate relationships between structure, function, target specificity, and the significant conformational heterogeneity observed in conotoxins with the same primary sequence. We have previously demonstrated that the inclusion of post-translational modifications, collisional cross sections values, and other structural features, when added to the standard primary sequence features, improves the prediction accuracy of conotoxins against non-toxic and other toxic peptides across varied datasets and several different commonly used machine learning classifiers. Here, we present the effects of these features on conotoxin class and molecular target predictions, in particular, predicting conotoxins that bind to nicotinic acetylcholine receptors (nAChRs). We also demonstrate the use of the Synthetic Minority Oversampling Technique (SMOTE)-Tomek in balancing the datasets while simultaneously making the different classes more distinct by reducing the number of ambiguous samples which nearly overlap between the classes. In predicting the alpha, mu, and omega conotoxin classes, the SMOTE-Tomek PCA PLR model, using the combination of the SS and P feature sets establishes the best performance with an overall accuracy (OA) of 95.95%, with an average accuracy (AA) of 93.04%, and an f1 score of 0.959. Using this model, we obtained sensitivities of 98.98%, 89.66%, and 90.48% when predicting alpha, mu, and omega conotoxin classes, respectively. Similarly, in predicting conotoxins that bind to nAChRs, the SMOTE-Tomek PCA SVM model, which used the collisional cross sections (CCSs) and the P feature sets, demonstrated the highest performance with 91.3% OA, 91.32% AA, and an f1 score of 0.9131. The sensitivity when predicting conotoxins that bind to nAChRs is 91.46% with a 91.18% sensitivity when predicting conotoxins that do not bind to nAChRs. Full article

(This article belongs to the Special Issue Conotoxins: Evolution, Classifications and Targets)

► Show Figures

Graphical abstract

17 pages, 2038 KiB

Open AccessEditor’s ChoiceArticle

Integrated Approach to Cyclopiazonic Acid Cytotoxicity Using In Vitro (2D and 3D Models) and In Silico Methods

by Carmen Martínez-Alonso, Luana Izzo, Yelko Rodríguez-Carrasco and María-José Ruiz

Toxins 2024, 16(11), 473; https://doi.org/10.3390/toxins16110473 - 3 Nov 2024

Cited by 2 | Viewed by 1683

Abstract

Cyclopiazonic acid (CPA) is an indole-tetramic acid neurotoxin produced by Aspergillus and Penicillium genera present mainly in fruit, cereals and nuts. This study compares the cytotoxicity produced by CPA after 24, 48 and 72 h of exposure using both monolayers and 3D spheroids [...] Read more.

Cyclopiazonic acid (CPA) is an indole-tetramic acid neurotoxin produced by Aspergillus and Penicillium genera present mainly in fruit, cereals and nuts. This study compares the cytotoxicity produced by CPA after 24, 48 and 72 h of exposure using both monolayers and 3D spheroids in human neuroblastoma SH-SY5Y cells. Furthermore, CPA toxicokinetics was evaluated using in silico models. Cytotoxicity increased dose- and time-dependently, as shown by the MTT assay. The lowest CPA IC₅₀ values were found in the monolayer study compared to the 3D spheroids at all exposure times (24 h: 864.01 vs. 1132; 48 h: 437 vs. 1069; 72 h: 392 vs. 567 nM). The CPA exposure on SH-SY5Y spheroid organization and morphology was also studied. Morphological changes, including spheroid disaggregation, were observed after mycotoxin exposure. The in silico methods, SwissADME and admetSAR, were used for short and full ADMEt profiles of CPA. The ADMEt predictive profile shows high gastrointestinal absorption and ability to penetrate the blood–brain barrier. Including in silico studies emphasizes the comprehensive approach to understanding mycotoxin toxicity and risk assessment. By combining in vitro 3D spheroid models with computational simulations, this study aims to provide a holistic perspective on the effects of CPA, enhancing the accuracy and relevance of our findings. Full article

(This article belongs to the Special Issue Toxins: 15th Anniversary)

► Show Figures

Figure 1

15 pages, 1288 KiB

Open AccessEditor’s ChoiceReview

Botulinum Toxin for the Treatment of Raynaud’s Conditions of the Hand: Clinical Practice Updates and Future Directions

by Patrick O’Donohoe, Jake McDonnell, Justin Wormald, Lylas Aljohmani, Kevin Cronin, Laura Durcan, Oran Kennedy and Roisin Dolan

Toxins 2024, 16(11), 472; https://doi.org/10.3390/toxins16110472 - 1 Nov 2024

Cited by 1 | Viewed by 2436

Abstract

Raynaud’s conditions of the hand, referred to commonly as Raynaud’s phenomenon, both primary and secondary, represents a spectrum of disorders affecting the digits, characterised by recurrent episodes of vasospasm that result in a triad of symptoms: pain, pallor, and cyanosis. Various therapies, ranging [...] Read more.

Raynaud’s conditions of the hand, referred to commonly as Raynaud’s phenomenon, both primary and secondary, represents a spectrum of disorders affecting the digits, characterised by recurrent episodes of vasospasm that result in a triad of symptoms: pain, pallor, and cyanosis. Various therapies, ranging from conservative hand therapy techniques to surgical sympathectomy, have been explored with inconsistent results. Recently, the local administration of botulinum toxin type-A (BTX-A) has re-emerged as a treatment option for this condition. This review delves into the mechanistic pathways of BTX-A therapy, optimal dosing concentrations, administration techniques, and its safety profile. A critical analysis of published studies to date demonstrates varied clinical efficacy of BTX-A in Raynaud’s conditions based on patient-reported outcome measures and objective measures of outcomes assessment. Thus, in order to accurately assess the clinical effectiveness of BTX-A in future robust studies, this review emphasises the importance of streamlining patient selection to minimise heterogeneity in disease severity, optimising recruitment to ensure adequate statistical power, and establishing sensitive outcome measures to monitor response and discern treatment efficacy. Additionally, addressing concerns such as minimising antibody resistance, extending the duration of treatment effects on tissues, and exploring new modalities to assess hand perfusion will be focal points for future research and BTX-A drug development. Full article

(This article belongs to the Special Issue Botulinum Toxins: New Uses in the Treatment of Diseases (2nd Edition))

► Show Figures

Figure 1

15 pages, 4082 KiB

Open AccessEditor’s ChoiceArticle

From Venom to Vein: Factor VII Activation as a Major Pathophysiological Target for Procoagulant Australian Elapid Snake Venoms

by Uthpala Chandrasekara, Abhinandan Chowdhury, Lorenzo Seneci, Christina N. Zdenek, Nathan Dunstan and Bryan G. Fry

Toxins 2024, 16(10), 430; https://doi.org/10.3390/toxins16100430 - 6 Oct 2024

Cited by 4 | Viewed by 1796

Abstract

Australian elapid snake venoms are uniquely procoagulant, utilizing blood clotting enzyme Factor Xa (FXa) as a toxin, which evolved as a basal trait in this clade. The subsequent recruitment of Factor Va (FVa) as a toxin occurred in the last common ancestor of [...] Read more.

Australian elapid snake venoms are uniquely procoagulant, utilizing blood clotting enzyme Factor Xa (FXa) as a toxin, which evolved as a basal trait in this clade. The subsequent recruitment of Factor Va (FVa) as a toxin occurred in the last common ancestor of taipans (Oxyuranus species) and brown snakes (Pseudonaja species). Factor II (prothrombin) activation has been stated as the primary mechanism for the lethal coagulopathy, but this hypothesis has never been tested. The additional activation of Factor VII (FVII) by Oxyuranus/Pseudonaja venoms has historically been considered as a minor, unimportant novelty. This study aimed to investigate the significance of toxic FVII activation relative to prothrombin activation by testing a wide taxonomical range of Australian elapid species with procoagulant venoms. The activation of FVII or prothrombin, with and without the Factor Va as a cofactor, was assessed, along with the structural changes involved in these processes. All procoagulant species could activate FVII, establishing this as a basal trait. In contrast, only some lineages could activate prothrombin, indicating that this is a derived trait. For species able to activate both zymogens, Factor VII was consistently more strongly activated than prothrombin. FVa was revealed as an essential cofactor for FVII activation, a mechanism previously undocumented. Species lacking FVa in their venom utilized endogenous plasma FVa to exert this activity. The ability of the human FXa:FVa complex to activate FVII was also revealed as a new feedback loop in the endogenous clotting cascade. Toxin sequence analyses identified structural changes essential for the derived trait of prothrombin activation. This study presents a paradigm shift in understanding how elapid venoms activate coagulation factors, highlighting the critical role of FVII activation in the pathophysiological effects upon the coagulation cascade produced by Australian elapid snake venoms. It also documented the novel use of Factor Va as a cofactor for FVII activation for both venom and endogenous forms of FXa. These findings are crucial for developing better antivenoms and treatments for snakebite victims and have broader implications for drug design and the treatment of coagulation disorders. The research also advances the evolutionary biology knowledge of snake venoms. Full article

(This article belongs to the Special Issue Animal Venoms: Unraveling the Molecular Complexity (2nd Edition))

► Show Figures

Figure 1

15 pages, 6767 KiB

Open AccessEditor’s ChoiceArticle

Preparation of Soybean Dreg-Based Biochar@TiO₂ Composites and the Photocatalytic Degradation of Aflatoxin B₁ Exposed to Simulated Sunlight Irradiation

by Jian Zhang, Zhiwei Ying, He Li, Xinqi Liu, Dongge Ma and Hailong Yu

Toxins 2024, 16(10), 429; https://doi.org/10.3390/toxins16100429 - 5 Oct 2024

Cited by 7 | Viewed by 1361

Abstract

Aflatoxin B₁ (AFB₁) is a highly toxic carcinogen severely harmful to humans and animals. This study fabricated SDB-6-K-9@TiO₂ composites via the hydrothermal synthesis method to reduce AFB₁. The structural characterization results of the photocatalytic composites showed that [...] Read more.

Aflatoxin B₁ (AFB₁) is a highly toxic carcinogen severely harmful to humans and animals. This study fabricated SDB-6-K-9@TiO₂ composites via the hydrothermal synthesis method to reduce AFB₁. The structural characterization results of the photocatalytic composites showed that TiO₂ was successfully loaded onto SDB-6-K-9. The different photocatalytic degradation conditions, photocatalyst kinetics, recycling performance, and photocatalytic degradation mechanism were investigated. Photocatalysis with 6 mg of 4%SDB-6-K-9@TiO₂ in a 100 μg/mL AFB₁ solution presented a reduction of over 95%, exhibiting excellent performance, high stability, and reusability even after five cycles of photocatalytic experiments. Active species trapping experiments confirmed that holes (h⁺) played the most critical role. After structural analysis and identification of the photocatalytic degradation products, the photodegradation path and photocatalytic oxidation mechanism of 4%SDB-6-K-9@TiO₂ were postulated. The results show a new way to improve TiO₂’s photocatalytic performance, providing a certain theoretical basis for the effective AFB₁ reduction. Full article

(This article belongs to the Collection Aflatoxins)

► Show Figures

Figure 1

38 pages, 7473 KiB

Open AccessEditor’s ChoiceReview

Exploring the Diversity and Function of Serine Proteases in Toxicofera Reptile Venoms: A Comprehensive Overview

by Julia F. D. Vidal, Matheus F. Schwartz, Aisel V. Garay, Napoleão F. Valadares, Renata V. Bueno, Ana Carolina L. Monteiro, Sônia Maria de Freitas and João Alexandre R. G. Barbosa

Toxins 2024, 16(10), 428; https://doi.org/10.3390/toxins16100428 - 3 Oct 2024

Cited by 4 | Viewed by 2897

Abstract

Toxicofera reptile venoms are composed of several toxins, including serine proteases. These proteases are glycosylated enzymes that affect the prey’s hemostatic system. Their actions extend across the coagulation cascade, the kallikrein–kinin system, and platelet activation. Despite their specificity for different substrates, these enzymes [...] Read more.

Toxicofera reptile venoms are composed of several toxins, including serine proteases. These proteases are glycosylated enzymes that affect the prey’s hemostatic system. Their actions extend across the coagulation cascade, the kallikrein–kinin system, and platelet activation. Despite their specificity for different substrates, these enzymes are homologous across all toxicoferans and display high sequence similarity. The aim of this review is to compile decades of knowledge about venom serine proteases, showing the diversity of biochemically and biophysically characterized enzymes, their structural characteristics, advances in understanding their origin and evolution, as well as methods of obtaining enzymes and their biotechnological applications. Full article

(This article belongs to the Special Issue From Animal Venoms to Solutions: In Honor of Professor Lourival D. Possani on the Occasion of His 85th Birthday)

► Show Figures

Figure 1

20 pages, 3372 KiB

Open AccessEditor’s ChoiceArticle

Salinity as an Abiotic Stressor for Eliciting Bioactive Compounds in Marine Microalgae

by Adrián Macías-de la Rosa, Lorenzo López-Rosales, Antonio Contreras-Gómez, Asterio Sánchez-Mirón, Francisco García-Camacho and María del Carmen Cerón-García

Toxins 2024, 16(10), 425; https://doi.org/10.3390/toxins16100425 - 1 Oct 2024

Cited by 7 | Viewed by 2022

Abstract

This study investigated the impact of culture medium salinity (5–50 PSU) on the growth and maximum photochemical yield of photosystem II (Fv/Fm) and the composition of carotenoids, fatty acids, and bioactive substances in three marine microalgae (Chrysochromulina rotalis [...] Read more.

This study investigated the impact of culture medium salinity (5–50 PSU) on the growth and maximum photochemical yield of photosystem II (Fv/Fm) and the composition of carotenoids, fatty acids, and bioactive substances in three marine microalgae (Chrysochromulina rotalis, Amphidinium carterae, and Heterosigma akashiwo). The microalgae were photoautotrophically cultured in discontinuous mode in a single stage (S1) and a two-stage culture with salt shock (S2). A growth model was developed to link biomass productivity with salinity for each species. C. rotalis achieved a maximum biomass productivity (Pmax) of 15.85 ± 0.32 mg·L⁻¹·day⁻¹ in S1 and 16.12 ± 0.13 mg·L⁻¹·day⁻¹ in S2. The salt shock in S2 notably enhanced carotenoid production, particularly in C. rotalis and H. akashiwo, where fucoxanthin was the main carotenoid, while peridinin dominated in A. carterae. H. akashiwo also exhibited increased fatty acid productivity in S2. Salinity changes affected the proportions of saturated, monounsaturated, and polyunsaturated fatty acids in all three species. Additionally, hyposaline conditions boosted the production of haemolytic substances in A. carterae and C. rotalis. Full article

(This article belongs to the Special Issue Advances in Microalgae Toxins: Production, Detection, and Application 2.0)

► Show Figures

Figure 1

25 pages, 3146 KiB

Open AccessEditor’s ChoiceReview

Continuous Treatment with IncobotulinumtoxinA Despite Presence of BoNT/A Neutralizing Antibodies: Immunological Hypothesis and a Case Report

by Michael Uwe Martin, Clifton Ming Tay and Tuck Wah Siew

Toxins 2024, 16(10), 422; https://doi.org/10.3390/toxins16100422 - 1 Oct 2024

Cited by 2 | Viewed by 3451

Abstract

Botulinum Neurotoxin A (BoNT/A) is a bacterial protein that has proven to be a valuable pharmaceutical in therapeutic indications and aesthetic medicine. One major concern is the formation of neutralizing antibodies (nAbs) to the core BoNT/A protein. These can interfere with the therapy, [...] Read more.

Botulinum Neurotoxin A (BoNT/A) is a bacterial protein that has proven to be a valuable pharmaceutical in therapeutic indications and aesthetic medicine. One major concern is the formation of neutralizing antibodies (nAbs) to the core BoNT/A protein. These can interfere with the therapy, resulting in partial or complete antibody (Ab)-mediated secondary non-response (SNR) or immunoresistance. If titers of nAbs reach a level high enough that all injected BoNT/A molecules are neutralized, immunoresistance occurs. Studies have shown that continuation of treatment of neurology patients who had developed Ab-mediated partial SNR against complexing protein-containing (CPC-) BoNT/A was in some cases successful if patients were switched to complexing protein-free (CPF-) incobotulinumtoxinA (INCO). This seems to contradict the layperson’s basic immunological understanding that repeated injection with the same antigen BoNT/A should lead to an increase in antigen-specific antibody titers. As such, we strive to explain how immunological memory works in general, and based on this, we propose a working hypothesis for this paradoxical phenomenon observed in some, but not all, neurology patients with immunoresistance. A critical factor is the presence of potentially immune-stimulatory components in CPC-BoNT/A products that can act as immunologic adjuvants and activate not only naïve, but also memory B lymphocyte responses. Furthermore, we propose that continuous injection of a BoN/TA formulation with low immunogenicity, e.g., INCO, may be a viable option for aesthetic patients with existing nAbs. These concepts are supported by a real-world case example of a patient with immunoresistance whose nAb levels declined with corresponding resumption of clinical response despite regular INCO injections. Full article

(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)

► Show Figures

Figure 1

10 pages, 756 KiB

Open AccessEditor’s ChoiceArticle

Comparative Effects of Acetate- and Citrate-Based Dialysates on Dialysis Dose and Protein-Bound Uremic Toxins in Hemodiafiltration Patients: Exploring the Impact of Calcium and Magnesium Concentrations

by Diana Rodríguez-Espinosa, Elena Cuadrado-Payán, Naira Rico, Mercè Torra, Rosa María Fernández, Miquel Gómez, Laura Morantes, Gregori Casals, Maria Rodriguez-Garcia, Francisco Maduell and José Jesús Broseta

Toxins 2024, 16(10), 426; https://doi.org/10.3390/toxins16100426 - 1 Oct 2024

Cited by 1 | Viewed by 1488

Abstract

Modern hemodialysis employs weak acids as buffers to prevent bicarbonate precipitation with calcium or magnesium. Acetate, the most used acid, is linked to chronic inflammation and poor dialysis tolerance. Citrate has emerged as a potential alternative, though its effect on dialysis efficiency is [...] Read more.

Modern hemodialysis employs weak acids as buffers to prevent bicarbonate precipitation with calcium or magnesium. Acetate, the most used acid, is linked to chronic inflammation and poor dialysis tolerance. Citrate has emerged as a potential alternative, though its effect on dialysis efficiency is not clear. This study aims to compare the efficacy of acetate- and citrate-based dialysates, focusing on protein-bound uremic toxins and dialysis doses. This single-center prospective crossover study includes prevalent patients participating in a thrice-weekly online hemodiafiltration program. Four dialysates were tested: two acetate-based (1.25 and 1.5 mmol/L calcium) and two citrate-based (1.5 mmol/L calcium with 0.5 and 0.75 mmol/L magnesium). Pre- and post-dialysis blood samples of eighteen patients were analyzed for urea, creatinine, p-cresyl sulfate, indoxyl sulfate, and albumin. Statistical significance was assessed using paired t-tests and repeated measures of ANOVA. There were no significant differences in dialysis dose (Kt), urea, creatinine, or indoxyl sulfate reduction ratios between acetate- and citrate-based dialysates. However, a significant decrease in the reduction ratio of p-cresyl sulfate was observed with the acetate dialysate containing 1.25 mmol/L calcium and the citrate dialysate with 0.5 mmol/L magnesium compared to the acetate dialysate containing 1.5 mmol/L calcium and the citrate dialysate with 0.75 mmol/L magnesium (51.56 ± 4.75 and 53.02 ± 4.52 vs. 65.25 ± 3.38 and 58.66 ± 4.16, p 0.007). No differences in dialysis dose were found between acetate- and citrate-based dialysates. However, citrate dialysates with lower calcium and magnesium concentrations may reduce the albumin displacement of p-cresyl sulfate. Further studies are needed to understand the observed differences and optimize the dialysate composition for the better clearance of protein-bound uremic toxins. Full article

(This article belongs to the Section Uremic Toxins)

► Show Figures

Figure 1

24 pages, 400 KiB

Open AccessEditor’s ChoiceReview

History and Toxinology of Palytoxins

by Harriet L. Hammond and Chad J. Roy

Toxins 2024, 16(10), 417; https://doi.org/10.3390/toxins16100417 - 26 Sep 2024

Cited by 2 | Viewed by 2734

Abstract

Palytoxins are a group of highly potent and structurally complex marine toxins that rank among some of the most toxic substances known to science. Palytoxins are naturally synthesized by a variety of marine organisms, including Palythoa zoanthids, Ostreopsis dinoflagellates, and Trichodesmium cyanobacteria, and [...] Read more.

Palytoxins are a group of highly potent and structurally complex marine toxins that rank among some of the most toxic substances known to science. Palytoxins are naturally synthesized by a variety of marine organisms, including Palythoa zoanthids, Ostreopsis dinoflagellates, and Trichodesmium cyanobacteria, and are widely distributed in tropical and temperate regions where they can bioaccumulate in marine life. The evolution of research on palytoxins has been an intricate exchange between interdisciplinary fields, drawing insights from chemistry, biology, medicine, and environmental science in efforts to better understand and mitigate the health risks associated with this family of toxins. In this review, we begin with a brief history covering the discovery of this group of toxins and the events that led to its isolation. We then focus on the chemical structure of these compounds and their proposed mechanism of action. Finally, we review in vitro, ex vivo, and in vivo studies related to their toxicity, with the aim to provide a broad overview of the current knowledge on palytoxin toxinology. Full article

(This article belongs to the Section Marine and Freshwater Toxins)

17 pages, 3157 KiB

Open AccessEditor’s ChoiceArticle

Caffeic Acid Phenethyl Ester Administration Reduces Enterotoxigenic Bacteroides fragilis-Induced Colitis and Tumorigenesis

by Soonjae Hwang, Minjeong Jo, Ju-Eun Hong, Woo-Seung Kim, Da-Hye Kang, Sang-Hyeon Yoo, Kyungsu Kang and Ki-Jong Rhee

Toxins 2024, 16(9), 403; https://doi.org/10.3390/toxins16090403 - 18 Sep 2024

Cited by 4 | Viewed by 1948

Abstract

The human colonic commensal enterotoxigenic Bacteroides fragilis (ETBF) is associated with chronic colitis and colon cancer. ETBF colonization induces colitis via the Bacteroides fragilis toxin (BFT). BFT secreted by ETBF cause colon inflammation via E-cadherin cleavage/NF-κB signaling. ETBF promotes colon tumorigenesis via interleukin [...] Read more.

The human colonic commensal enterotoxigenic Bacteroides fragilis (ETBF) is associated with chronic colitis and colon cancer. ETBF colonization induces colitis via the Bacteroides fragilis toxin (BFT). BFT secreted by ETBF cause colon inflammation via E-cadherin cleavage/NF-κB signaling. ETBF promotes colon tumorigenesis via interleukin 17A (IL-17A)/CXCL-dependent inflammation, but its bioactive therapeutics in ETBF-promoted tumorigenesis remain unexplored. In the current study, we investigated the caffeic acid phenethyl ester (CAPE) in the murine model of ETBF colitis and tumorigenesis. In this study, we observed that CAPE treatment mitigated inflammation induced by ETBF in mice. Additionally, our findings indicate that CAPE treatment offers protective effects against ETBF-enhanced colon tumorigenesis in a mouse model of colitis-associated colon cancer induced by azoxymethane (AOM) and dextran sulfate sodium. Notably, the decrease in colon tumorigenesis following CAPE administration correlates with a reduction in the expression of IL-17A and CXCL1 in the gastrointestinal tract. The molecular mechanism for CAPE-induced protection against ETBF-mediated tumorigenesis is mediated by IL-17A/CXCL1, and by NF-κB activity in intestinal epithelial cells. Our findings indicate that CAPE may serve as a preventive agent against the development of ETBF-induced colitis and colorectal cancer (CRC). Full article

(This article belongs to the Section Bacterial Toxins)

► Show Figures

Figure 1

21 pages, 4548 KiB

Open AccessEditor’s ChoiceArticle

Exposure of Cattle Breeding Herds to Naturally Co-Contaminated Zearalenone and Deoxynivalenol: The Relevance of a Urinary Mycotoxin Monitoring System for Herd Health and Food Safety

by Oky Setyo Widodo, Seiichi Uno, Emiko Kokushi, Osamu Yamato, M. Fariz Fadillah Mardianto, Urara Shinya, Yuto Kano, Chiho Kawashima, Yasuo Fushimi, Tetsushi Ono, Masayasu Taniguchi and Mitsuhiro Takagi

Toxins 2024, 16(9), 402; https://doi.org/10.3390/toxins16090402 - 18 Sep 2024

Cited by 1 | Viewed by 1738

Abstract

The widespread presence of Fusarium mycotoxins in animal feed is a global issue, not only for the health of livestock but also for ensure the safety of food as an end product. High concentrations of zearalenone (ZEN) and deoxynivalenol (DON) have been detected [...] Read more.

The widespread presence of Fusarium mycotoxins in animal feed is a global issue, not only for the health of livestock but also for ensure the safety of food as an end product. High concentrations of zearalenone (ZEN) and deoxynivalenol (DON) have been detected in the diets of Japanese Black (JB) and Holstein Friesian (HF) breeding herds. Consequently, we monitored serum biochemical parameters over a long time in both herds, focusing on anti-Müllerian hormone (AMH) levels and acute-phase inflammation. Additionally, urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) and progesterone levels were measured in the HF herd. The JB herd, a ZEN-dominant model with low DON contamination, demonstrated ZEN levels that exceeded the Japanese limit in the purchased total mixed rations (TMR). Conversely, the HF herd, which primary consumes DON-dominant feed with low ZEN contamination, had high DON levels in the dent corn silage. Specifically, the JB herd’s TMR contained 1.79 mg/kg ZEN and 0.58 mg/kg DON, whereas the HF herd’s silage had 15.3 mg/kg DON (dried sample) and 0.1 mg/kg ZEN. Enzyme-linked immunoassay were used to measure urinary ZEN-DON levels following confirmation through liquid chromatography-tandem mass spectrometry. Urinary ZEN-DON levels measured were significantly correlated (p < 0.05, r > 0.6) in both herds. In the HF herd, AMH levels increased (p = 0.01) and serum amyloid A (SAA) levels decreased (p = 0.02) when contaminated and at the end of the monitoring period. Additionally, urinary ZEN and DON levels were significantly correlated with SAA levels (ZEN: p = 0.00, r = 0.46; DON: p = 0.03, r = 0.33), with an increase in ZEN and DON levels resulting in higher SAA levels. The JB herd showed no significant differences. Additionally, in the HF herd, 8-OHdG/Cre levels increased significantly during major contamination periods (p < 0.05). Clinical data from the HF herd indicated an increase in mastitis cases and treatment rates during periods of major contamination. Abortion rates in the HF herd decreased from 22.9% (before monitoring) to 8.9% (during the high contamination period) and finally to 1% (at the end of the monitoring period), with corresponding increases in progesterone levels. ZEN-DON contamination adversely affects breeding cattle’s productivity, reproductive performance, and health. Therefore, monitoring urinary ZEN-DON is valuable for detecting contaminants and ensuring the safety of food products. Full article

(This article belongs to the Special Issue Toxicity Assessment, Rapid Detection and Control of Foodborne Mycotoxins: Advances and Prospects)

► Show Figures

Figure 1

16 pages, 37816 KiB

Open AccessEditor’s ChoiceArticle

Combinatory Effects of Acrylamide and Deoxynivalenol on In Vitro Cell Viability and Cytochrome P450 Enzymes of Human HepaRG Cells

by Julia Beisl, Kristina Jochum, Yi Chen, Elisabeth Varga and Doris Marko

Toxins 2024, 16(9), 389; https://doi.org/10.3390/toxins16090389 - 10 Sep 2024

Cited by 1 | Viewed by 1782

Abstract

Acrylamide (AA) can be formed during the thermal processing of carbohydrate-rich foods. Deoxynivalenol (DON), a mycotoxin produced by Fusarium spp., contaminates many cereal-based products. In addition to potential co-exposure through a mixed diet, co-occurrence of AA and DON in thermally processed cereal-based products [...] Read more.

Acrylamide (AA) can be formed during the thermal processing of carbohydrate-rich foods. Deoxynivalenol (DON), a mycotoxin produced by Fusarium spp., contaminates many cereal-based products. In addition to potential co-exposure through a mixed diet, co-occurrence of AA and DON in thermally processed cereal-based products is also likely, posing the question of combinatory toxicological effects. In the present study, the effects of AA (0.001–3 mM) and DON (0.1–30 µM) on the cytotoxicity, gene transcription, and expression of major cytochrome P450 (CYP) enzymes were investigated in differentiated human hepatic HepaRG cells. In the chosen ratios of AA–DON (10:1; 100:1), cytotoxicity was clearly driven by DON and no overadditive effects were observed. Using quantitative real-time PCR, about twofold enhanced transcript levels of CYP1A1 were observed at low DON concentrations (0.3 and 1 µM), reflected by an increase in CYP1A activity in the EROD assay. In contrast, CYP2E1 and CYP3A4 gene transcription decreased in a concentration-dependent manner after incubation with DON (0.01–0.3 µM). Nevertheless, confocal microscopy showed comparably constant protein levels. The present study provided no indication of an induction of CYP2E1 as a critical step in AA bioactivation by co-occurrence with DON. Taken together, the combination of AA and DON showed no clear physiologically relevant interaction in HepaRG cells. Full article

(This article belongs to the Special Issue Current Research on Mycotoxins in Food and Feed: From Detection and Unravelling of Toxicity to Control)

► Show Figures

Graphical abstract

14 pages, 2658 KiB

Open AccessEditor’s ChoiceArticle

Mitigation of Deoxynivalenol (DON)- and Aflatoxin B1 (AFB1)-Induced Immune Dysfunction and Apoptosis in Mouse Spleen by Curcumin

by Azhar Muhmood, Jianxin Liu, Dandan Liu, Shuiping Liu, Mahmoud M. Azzam, Muhammad Bilawal Junaid, Lili Hou, Guannan Le and Kehe Huang

Toxins 2024, 16(8), 356; https://doi.org/10.3390/toxins16080356 - 13 Aug 2024

Cited by 2 | Viewed by 2056

Abstract

In the context of the potential immunomodulatory properties of curcumin in counteracting the detrimental effects of concurrent exposure to Deoxynivalenol (DON) and Aflatoxin B1 (AFB1), a comprehensive 28-days trial was conducted utilizing 60 randomly allocated mice divided into four groups. Administration of curcumin [...] Read more.

In the context of the potential immunomodulatory properties of curcumin in counteracting the detrimental effects of concurrent exposure to Deoxynivalenol (DON) and Aflatoxin B1 (AFB1), a comprehensive 28-days trial was conducted utilizing 60 randomly allocated mice divided into four groups. Administration of curcumin at a dosage of 5 mg/kg body weight in conjunction with DON at 0.1 mg/kg and AFB₁ at 0.01 mg/kg body weight was undertaken to assess its efficacy. Results indicated that curcumin intervention demonstrated mitigation of splenic structural damage, augmentation of serum immunoglobulin A (IgA) and immunoglobulin G (IgG) levels, elevation in T lymphocyte subset levels, and enhancement in the mRNA expression levels of pro-inflammatory cytokines TNF-α, IFN-γ, IL-2, and IL-6. Furthermore, curcumin exhibited a suppressive effect on apoptosis in mice, as evidenced by decreased activity of caspase-3 and caspase-9, reduced expression levels of pro-apoptotic markers Bax and Cytochrome-c (Cyt-c) at both the protein and mRNA levels, and the maintenance of a balanced expression ratio of mitochondrial apoptotic regulators Bax and Bcl-2. Collectively, these findings offer novel insights into the therapeutic promise of curcumin in mitigating immunosuppression and apoptotic events triggered by mycotoxin co-exposure. Full article

(This article belongs to the Section Mycotoxins)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Editor’s Choice Articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI