Toxins

24 pages, 4815 KiB

Open AccessFeature PaperArticle

The Clot Thickens: Differential Coagulotoxic and Cardiotoxic Activities of Anguimorpha Lizard Venoms

by James Dobson, Abhinandan Chowdhury, Jeremie Tai-A-Pin, Harold van der Ploeg, Amber Gillett and Bryan G. Fry

Toxins 2024, 16(6), 283; https://doi.org/10.3390/toxins16060283 - 20 Jun 2024

Viewed by 786

Abstract

Despite their evolutionary novelty, lizard venoms are much less studied in comparison to the intense research on snake venoms. While the venoms of helodermatid lizards have long been assumed to be for defensive purposes, there is increasing evidence of toxic activities more useful [...] Read more.

Despite their evolutionary novelty, lizard venoms are much less studied in comparison to the intense research on snake venoms. While the venoms of helodermatid lizards have long been assumed to be for defensive purposes, there is increasing evidence of toxic activities more useful for predation than defence (such as paralytic neurotoxicity). This study aimed to ascertain the effects of Heloderma, Lanthanotus, and Varanus lizard venoms on the coagulation and cardiovascular systems. Anticoagulant toxicity was demonstrated for the Varanus species studied, with the venoms prolonging clotting times in human and bird plasma due to the destructive cleavage of fibrinogen. In contrast, thromboelastographic analyses on human and bird plasmas in this study demonstrated a procoagulant bioactivity for Heloderma venoms. A previous study on Heloderma venom using factor-depleted plasmas as a proxy model suggested a procoagulant factor was present that activated either Factor XI or Factor XII, but could not ascertain the precise target. Our activation studies using purified zymogens confirmed FXII activation. Comparisons of neonate and adult H. exasperatum, revealed the neonates to be more potent in the ability to activate FXII, being more similar to the venom of the smaller species H. suspectum than the adult H. exasperatum. This suggests potent FXII activation a basal trait in the genus, present in the small bodied last common ancestor. This also indicates an ontogenetic difference in prey preferences in the larger Heloderma species paralleing the change in venom biochemistry. In addition, as birds lack Factor XII, the ability to clot avian plasma suggested an additional procoagulant site of action, which was revealed to be the activation of Factor VII, with H. horridum being the most potent. This study also examined the effects upon the cardiovascular system, including the liberation of kinins from kininogen, which contributes to hypotension induction. This form of toxicity was previously described for Heloderma venoms, and was revealed in this study was to also be a pathophysiological effect of Lanthanotus and Varanus venoms. This suggests that this toxic activity was present in the venom of the last common ancestor of the anguimorph lizards, which is consistent with kallikrein enzymes being a shared toxin trait. This study therefore uncovered novel actions of anguimorph lizard venoms, not only contributing to the evolutionary biology body of knowledge but also revealing novel activities to mine for drug design lead compounds. Full article

(This article belongs to the Special Issue Venom Components Acting on the Hemostatic System: Structural and Mechanistic Insights)

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10 pages, 1878 KiB

Open AccessBrief Report

Botulinum Toxin and Deep Brain Stimulation in Dystonia

by Julia Carvalhinho Carlos de Souza, Ananda Carolina Moraes Falcone, Renata Montes Garcia Barbosa, Miriam Carvalho Soares, Renato Munhoz, Marina Farah, Tamine Capato, Sara Carvalho Barbosa Casagrande, Marcela Ferreira Cordellini, Gabriel de Castro Micheli, João Carlos Papaterra Limongi, Egberto Reis Barbosa, Clarice Listik and Rubens Gisbert Cury

Toxins 2024, 16(6), 282; https://doi.org/10.3390/toxins16060282 - 20 Jun 2024

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Abstract

Deep Brain Stimulation (DBS) is a recognized treatment for different dystonia subtypes and has been approved by the Food and Drug Administration (FDA) since 2003. The European Federation of Neurological Societies (EFNS) and the International Parkinson and Movement Disorders Society (MDS) recommend DBS [...] Read more.

Deep Brain Stimulation (DBS) is a recognized treatment for different dystonia subtypes and has been approved by the Food and Drug Administration (FDA) since 2003. The European Federation of Neurological Societies (EFNS) and the International Parkinson and Movement Disorders Society (MDS) recommend DBS for dystonia after failure of botulinum toxin (BoNT) and other oral medications for dystonia treatment. In addition, several long-term studies have demonstrated the continuous efficacy of DBS on motor and quality of life (QoL) scores. However, there are only a few reports comparing the overall impact of surgical treatment in BoNT protocols (e.g., dosage and number of selected muscles before and after surgery). This retrospective multicenter chart-review study analyzed botulinum toxin total dosage and dosage per muscle in 23 dystonic patients before and after DBS surgery. The study’s primary outcome was to analyze whether there was a reduction in BoNT dosage after DBS surgery. The mean BoNT dosages difference between baseline and post-surgery was 293.4 units for 6 months, 292.6 units for 12 months, and 295.2 units at the last visit. The median total dose of BoNT in the preoperative period was 800 units (N = 23). At the last visit, the median was 700 units (p = 0.05). This represents a 12.5% reduction in BoNT median dosage. In conclusion, despite the limitations of this retrospective study, there was a significant reduction in BoNT doses after DBS surgery in patients with generalized dystonia. Full article

(This article belongs to the Special Issue Botulinum Toxins: New Uses in the Treatment of Diseases (Volume II))

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12 pages, 1021 KiB

Open AccessArticle

Exploring the Efficacy of Using Geotrichum fermentans, Rhodotorula rubra, Kluyveromyce marxiamus, Clay Minerals, and Walnut Nutshells for Mycotoxin Remediation

by Gintarė Vaičiulienė, Jurgita Jovaišienė, Rimvydas Falkauskas, Algimantas Paškevičius, Neringa Sutkevičienė, Audronė Rekešiūtė, Šarūnė Sorkytė and Violeta Baliukonienė

Toxins 2024, 16(6), 281; https://doi.org/10.3390/toxins16060281 - 20 Jun 2024

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Abstract

The aim of this study was to evaluate the effectiveness of nine different biological compounds to reduce mycotoxins concentrations. The hypothesis of this study was that a static in vitro gastrointestinal tract model, as an initial screening tool, can be used to simulate [...] Read more.

The aim of this study was to evaluate the effectiveness of nine different biological compounds to reduce mycotoxins concentrations. The hypothesis of this study was that a static in vitro gastrointestinal tract model, as an initial screening tool, can be used to simulate the efficacy of Geotrichum fermentans, Rhodotorula rubra, Kluyveromyce marxiamus yeast cell walls and their polysaccharides, red and white clay minerals, and walnuts nutshells claiming to detoxify AFB1, ZEA, DON, and T-2 toxin mycotoxins. Mycotoxin concentrations were analyzed using high-performance liquid chromatography (HPLC) with fluorescent (FLD) and ultraviolet detectors (UV). The greatest effects on reducing mycotoxin concentrations were determined as follows: for AFB1, inserted G. fermentans cell wall polysaccharides and walnut nutshells; for ZEA, inserted R. rubra and G. fermentans cell walls and red clay minerals; for DON, R. rubra cell wall polysaccharides and red clay minerals; and for T-2 toxin, R. rubra cell walls, K. marxianus, and G. fermentans cell wall polysaccharides and walnut nutshells. The present study indicated that selected mycotoxin-detoxifying biological compounds can be used to decrease mycotoxin concentrations. Full article

(This article belongs to the Special Issue Mycotoxins Occurrence in Feed and Their Influence on Animal and Human Health)

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17 pages, 4829 KiB

Open AccessArticle

Naturally and Anthropogenically Induced Lingulodinium polyedra Dinoflagellate Red Tides in the Galician Rias (NW Iberian Peninsula)

by Ricardo Prego, Roberto Bao, Manuel Varela and Rafael Carballeira

Toxins 2024, 16(6), 280; https://doi.org/10.3390/toxins16060280 - 19 Jun 2024

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Abstract

Despite the fact that the first red tide reported on the coasts of the Iberian Peninsula was due to Lingulodinium polyedra, knowledge about their frequency and, particularly, about the environmental conditions contributing to bloom initiation is still scarce. For this reason, L. [...] Read more.

Despite the fact that the first red tide reported on the coasts of the Iberian Peninsula was due to Lingulodinium polyedra, knowledge about their frequency and, particularly, about the environmental conditions contributing to bloom initiation is still scarce. For this reason, L. polyedra bloom episodes were observed and studied in three Galician rias during the summer season based on the 1993–2008 record database period; additionally, samples were collected in summer 2008. Proliferations of L. polyedra occurred in the rias of Ares and Barqueiro in June and August, respectively, while in the Ria of Coruña, they persisted from the end of June to early September. Red tides developed when the surface temperature reached 17 °C, with “seasonal thermal window” conditions, and when salinities were ≥30, i.e., an “optimal salinity window”; when these parameters were lower than these thresholds, cyst germination decreased. A cyst transport mechanism from sediments to the surface must also exist; this mechanism was found to be natural (tidal currents) in the ria of Barqueiro or anthropogenic (dredging) in the rias of Ares and Coruña. Surface temperatures during summer were usually favorable for cyst germination (85 to 100%) during the 1993–2008 period; however, water temperatures below 10 m depth only rarely reached the 17 °C threshold (2 to 18%). During this 16-year period, dredging activities could explain 71% (Coruña) and 44% (Ares) of the recorded bloom events. When a bloom episode developed in early summer, favorable conditions did not lead to a new red tide, probably due to the lag period required by cysts for germination. Moreover, blooms did not develop when high densities of diatoms (>1,000,000 cells·L⁻¹) remained in the water column as a result of summer upwelling pulses occurring in specific years. The temperature–sediment disturbance pattern found in this study provides a useful tool for the prevention of eventual risks resulting from red tides of this dinoflagellate. Full article

(This article belongs to the Special Issue Unraveling the Environmental Threat of Harmful Algae Blooms (HABs): Causes and Impacts)

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18 pages, 2355 KiB

Open AccessArticle

A Validation of the Equivalence of the Cell-Based Potency Assay Method with a Mouse LD₅₀ Bioassay for the Potency Testing of OnabotulinumtoxinA

by Yingchao Yang, Huajie Zhang, Liyong Yuan, Shuo Wang and Xiao Ma

Toxins 2024, 16(6), 279; https://doi.org/10.3390/toxins16060279 - 19 Jun 2024

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Abstract

(1) Background: At present, the only potency assay approved in China for the in-country testing of botulinum toxin type A for injection products is the mouse bioassay (MBA). The Chinese market for neurotoxin products is rapidly expanding, but MBAs are subject to high [...] Read more.

(1) Background: At present, the only potency assay approved in China for the in-country testing of botulinum toxin type A for injection products is the mouse bioassay (MBA). The Chinese market for neurotoxin products is rapidly expanding, but MBAs are subject to high variability due to individual variations in mice, as well as variations in injection sites, in addition to the limited number of batches tested for one MBA. Compared with the mLD₅₀ method, the cell-based potency assay (CBPA) developed for the potency testing of onabotulinumtoxinA (BOTOX) by AbbVie not only does not use any experimental animals but also allows for significant time and cost savings. Due to the significant benefits conferred by the replacement of the mLD₅₀ assay with CBPA in China, the CBPA method has been transferred, validated, and cross-validated to demonstrate the equivalence of the two potency methods. (2) Methods: The differentiated SiMa cells were treated with both BOTOX samples and the reference standard, and the cleaved SNAP25₁₉₇ in the cell lysates was quantified using Chemi-ECL ELISA. A 4-PL model was used for the data fit and sample relative potency calculation. The method accuracy, linearity, repeatability, and intermediate precision were determined within the range of 50% to 200% of the labeled claim. A statistical equivalence of the two potency methods (CBPA and mLD₅₀) was initially demonstrated by comparing the AbbVie CBPA data with NIFDC mLD₅₀ data on a total of 167 commercial BOTOX lots (85 50U lots and 82 100U lots). In addition, six lots of onabotulinumtoxinA (three 50U and three 100U) were re-tested as cross-validation by these two methods for equivalence. (3) Results: The overall assay’s accuracy and intermediate precision were determined as 104% and 9.2%, and the slope, R-square, and Y-intercept for linearity were determined as 1.071, 0.998, and 0.036, respectively. The repeatability was determined as 6.9%. The range with the acceptable criteria of accuracy, linearity, and precision was demonstrated as 50% to 200% of the labeled claim. The 95% equivalence statistic test using margins [80%, 125%] indicates that CBPA and mLD₅₀ methods are equivalent for both BOTOX strengths (i.e., 50U and 100U). The relative potency data from cross-validation were within the range of ≥80% to ≤120%. (4) Conclusions: The CBPA meets all acceptance criteria and is equivalent to mLD₅₀. The replacement of mLD₅₀ with CBPA is well justified in terms of ensuring safety and efficacy, as well as for animal benefits. Full article

(This article belongs to the Section Bacterial Toxins)

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19 pages, 878 KiB

Open AccessArticle

Assessment of Mycotoxin Exposure and Associated Risk in Pregnant Dutch Women: The Human Biomonitoring Approach

by Hannah P. McKeon, Marloes A. A. Schepens, Annick D. van den Brand, Marjolein H. de Jong, Marleen M. H. J. van Gelder, Marijn L. Hesselink, Marta M. Sopel and Marcel J. B. Mengelers

Toxins 2024, 16(6), 278; https://doi.org/10.3390/toxins16060278 - 18 Jun 2024

Viewed by 593

Abstract

Mycotoxins are toxic secondary metabolites produced by various fungi that can contaminate food crops, which, in turn, may lead to human exposure. Chronic exposure to mycotoxins can cause adverse health effects including reproductive and developmental toxicity. Pregnant women and their foetuses present a [...] Read more.

Mycotoxins are toxic secondary metabolites produced by various fungi that can contaminate food crops, which, in turn, may lead to human exposure. Chronic exposure to mycotoxins can cause adverse health effects including reproductive and developmental toxicity. Pregnant women and their foetuses present a vulnerable group for exposure to mycotoxins that can cross the placenta. Human biomonitoring of mycotoxins provides a real-life approach to estimate internal exposure. In this pilot study, 24-h urine samples from 36 pregnant Dutch women were analysed for aflatoxin M1 (AFM1), total deoxynivalenol (DON), de-epoxy-deoxynivalenol (DOM-1), total zearalenone (ZEN), total α-zearalenol (α-ZEL), total β-zearalenol (β-ZEL) and total zearalanone (ZAN), where ‘total’ refers to mycotoxins and their conjugated forms. Serum samples from these women were analysed for fumonisin B1 (FB1) and ochratoxin A (OTA). All samples were measured using liquid chromatography–tandem mass spectrometry (LC-MS/MS). The most prevalent mycotoxins were total DON, total ZEN and OTA, with a detection frequency of 100%. DOM-1, total α-ZEL and total β-ZEL were detected but to a lesser extent, while AFM1, total ZAN and FB1 were undetected. Median concentrations were 4.75 μg total DON/L, 0.0350 μg DOM-1/L, 0.0413 μg total ZEN/L, 0.0379 μg total α-ZEL/L, 0.0189 μg total β-ZEL/L, and 0.121 μg OTA/L. The calculated median concentration for total ZEN and its metabolites was 0.105 μg/L. Based on two separate risk assessment approaches, total DON exposure in this group was considered to be of low concern. Similarly, exposure to total ZEN and its metabolites in this group was of low concern. For OTA, the risk of non-neoplastic effects was of low concern based on exposure in this group, and the risk of neoplastic effects was of low concern in the majority of participants in this group. The findings of this pilot study confirm the presence of mycotoxins in the urine and serum of pregnant Dutch women, with total DON, total ZEN, and OTA most frequently detected. Exposure to all measured mycotoxins was considered to be of low concern in this group, except for exposure to OTA, which was of low concern for the majority of participants. The study’s findings offer valuable insights but should be confirmed using a larger and more diverse sample of the Dutch general population. Full article

(This article belongs to the Special Issue Mycotoxins: Risk Assessment, Biomonitoring and Toxicology)

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18 pages, 1541 KiB

Open AccessReview

Biocontrol of Occurrence Ochratoxin A in Wine: A Review

by Slaven Zjalic, Ksenija Markov, Jelena Loncar, Zeljko Jakopovic, Marzia Beccaccioli and Massimo Reverberi

Toxins 2024, 16(6), 277; https://doi.org/10.3390/toxins16060277 - 17 Jun 2024

Viewed by 308

Abstract

Viticulture has been an important economic sector for centuries. In recent decades, global wine production has fluctuated between 250 and almost 300 million hectoliters, and in 2022, the value of wine exports reached EUR 37.6 billion. Climate change and the associated higher temperatures [...] Read more.

Viticulture has been an important economic sector for centuries. In recent decades, global wine production has fluctuated between 250 and almost 300 million hectoliters, and in 2022, the value of wine exports reached EUR 37.6 billion. Climate change and the associated higher temperatures could favor the occurrence of ochratoxin A (OTA) in wine. OTA is a mycotoxin produced by some species of the genera Aspergillus and Penicillium and has nephrotoxic, immunotoxic, teratogenic, hepatotoxic, and carcinogenic effects on animals and humans. The presence of this toxin in wine is related to the type of wine—red wines are more frequently contaminated with OTA—and the geographical location of the vineyard. In Europe, the lower the latitude, the greater the risk of OTA contamination in wine. However, climate change could increase the risk of OTA contamination in wine in other regions. Due to their toxic effects, the development of effective and environmentally friendly methods to prevent, decontaminate, and degrade OTA is essential. This review summarises the available research on biological aspects of OTA prevention, removal, and degradation. Full article

(This article belongs to the Section Mycotoxins)

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23 pages, 4099 KiB

Open AccessArticle

Investigating Snake-Venom-Induced Dermonecrosis and Inflammation Using an Ex Vivo Human Skin Model

by Jaffer Alsolaiss, Gail Leeming, Rachael Da Silva, Nessrin Alomran, Nicholas R. Casewell, Abdulrazaq G. Habib, Robert A. Harrison and Cassandra M. Modahl

Toxins 2024, 16(6), 276; https://doi.org/10.3390/toxins16060276 - 17 Jun 2024

Viewed by 547

Abstract

Snakebite envenoming is a neglected tropical disease that causes >100,000 deaths and >400,000 cases of morbidity annually. Despite the use of mouse models, severe local envenoming, defined by morbidity-causing local tissue necrosis, remains poorly understood, and human-tissue responses are ill-defined. Here, for the [...] Read more.

Snakebite envenoming is a neglected tropical disease that causes >100,000 deaths and >400,000 cases of morbidity annually. Despite the use of mouse models, severe local envenoming, defined by morbidity-causing local tissue necrosis, remains poorly understood, and human-tissue responses are ill-defined. Here, for the first time, an ex vivo, non-perfused human skin model was used to investigate temporal histopathological and immunological changes following subcutaneous injections of venoms from medically important African vipers (Echis ocellatus and Bitis arietans) and cobras (Naja nigricollis and N. haje). Histological analysis of venom-injected ex vivo human skin biopsies revealed morphological changes in the epidermis (ballooning degeneration, erosion, and ulceration) comparable to clinical signs of local envenoming. Immunostaining of these biopsies confirmed cell apoptosis consistent with the onset of necrosis. RNA sequencing, multiplex bead arrays, and ELISAs demonstrated that venom-injected human skin biopsies exhibited higher rates of transcription and expression of chemokines (CXCL5, MIP1-ALPHA, RANTES, MCP-1, and MIG), cytokines (IL-1β, IL-1RA, G-CSF/CSF-3, and GM-CSF), and growth factors (VEGF-A, FGF, and HGF) in comparison to non-injected biopsies. To investigate the efficacy of antivenom, SAIMR Echis monovalent or SAIMR polyvalent antivenom was injected one hour following E. ocellatus or N. nigricollis venom treatment, respectively, and although antivenom did not prevent venom-induced dermal tissue damage, it did reduce all pro-inflammatory chemokines, cytokines, and growth factors to normal levels after 48 h. This ex vivo skin model could be useful for studies evaluating the progression of local envenoming and the efficacy of snakebite treatments. Full article

(This article belongs to the Special Issue Advances in Venom Immunology and Allergy)

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15 pages, 1958 KiB

Open AccessArticle

Comparative Analysis of Maize Physico-Chemical Parameters and Mycotoxin Levels in Dual Environments

by Bruna Carbas, Sílvia Barros, Andreia Freitas, Ana Sanches Silva and Carla Brites

Toxins 2024, 16(6), 275; https://doi.org/10.3390/toxins16060275 - 17 Jun 2024

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Abstract

Maize (Zea mays L.) stands as a vital staple food globally, holding significant nutritional and economic value. However, its susceptibility to mycotoxin contamination under stressful environmental conditions poses a considerable concern. This study aimed to assess the quality and pasting characteristics of [...] Read more.

Maize (Zea mays L.) stands as a vital staple food globally, holding significant nutritional and economic value. However, its susceptibility to mycotoxin contamination under stressful environmental conditions poses a considerable concern. This study aimed to assess the quality and pasting characteristics of maize varieties across two distinct regions and examine the occurrence of mycotoxins influenced by climatic factors. Five maize varieties were cultivated in triplicate in the Golegã and Coruche regions. The nutritional composition (protein, fat, fiber, ash, starch, and lutein), pasting properties, and mycotoxin levels were evaluated. A statistical analysis revealed notable differences in the nutritional profiles of the maize varieties between the two regions, particularly in the protein and lutein content. The peak viscosity ranged from 6430 to 8599 cP and from 4548 to 8178 cP in the maize varieties from the Coruche and Golegã regions, respectively. Additionally, a significant correlation was observed between the climatic conditions and the grain nutritional quality components (p < 0.05). The M variety showed the highest ash content, protein content, final viscosity, and setback viscosity and the lowest peak viscosity. The Y variety revealed the lowest fat, fiber, and lutein content and the maximum peak viscosity. The incidence of mycotoxins was notably higher in the varieties from Coruche, which was potentially attributable to higher temperatures and lower precipitation levels leading to more frequent drought conditions. Fumonisin B1 was detected in 58% of the varieties from Coruche and 33% of the samples from Golegã, while deoxynivalenol was found in 87% and 80% of the varieties from Coruche and Golegã, respectively. The H variety, which was harvested in Coruche, exhibited the highest number of fumonisins and higher amounts of protein, lutein, and fat, while fumonisins were not detected in the Golegã region, which was potentially influenced by the precipitation levels. The K variety revealed higher protein and lutein contents, a lower amount of fat, excellent pasting properties (a higher peak viscosity and holding strength and a lower peak time), and no fumonisins B1 or B2. This variety may be considered well adapted to higher temperatures and drier conditions, as verified in the Coruche region. In conclusion, our study underscored the profound impact of environmental factors on the quality and occurrence of mycotoxins in maize varieties. Full article

(This article belongs to the Special Issue Toxigenic Fungi and Mycotoxins: From Toxin Biosynthesis to Toxicity Penetration)

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21 pages, 360 KiB

Open AccessReview

Grass–Endophyte Interactions and Their Associated Alkaloids as a Potential Management Strategy for Plant Parasitic Nematodes

by Nyambura G. Mwangi, Mark Stevens, Alistair J. D. Wright, Simon G. Edwards, Martin C. Hare and Matthew A. Back

Toxins 2024, 16(6), 274; https://doi.org/10.3390/toxins16060274 - 15 Jun 2024

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Abstract

Claviceptaceous endophytic fungi in the genus Epichloë mostly form a symbiotic relationship with cool-season grasses. Epichloë spp. are capable of producing bioactive alkaloids such as peramines, lolines, ergot alkaloids, and indole-diterpenes, which protect the host plant from herbivory by animals, insects, and nematodes. [...] Read more.

Claviceptaceous endophytic fungi in the genus Epichloë mostly form a symbiotic relationship with cool-season grasses. Epichloë spp. are capable of producing bioactive alkaloids such as peramines, lolines, ergot alkaloids, and indole-diterpenes, which protect the host plant from herbivory by animals, insects, and nematodes. The host also benefits from enhanced tolerance to abiotic stresses, such as salt, drought, waterlogging, cold, heavy metals, and low nitrogen stress. The bioactive alkaloids produced can have both direct and indirect effects towards plant parasitic nematodes. Direct interaction with nematodes’ motile stages can cause paralysis (nematostatic effect) or death (nematicidal effect). Indirectly, the metabolites may induce host immunity which inhibits feeding and subsequent nematode development. This review highlights the different mechanisms through which this interaction and the metabolites produced have been explored in the suppression of plant parasitic nematodes and also how the specific interactions between different grass genotypes and endophyte strains result in variable suppression of different nematode species. An understanding of the different grass–endophyte interactions and their successes and failures in suppressing various nematode species is essential to enable the proper selection of grass–endophyte combinations to identify the alkaloids produced, concentrations required, and determine which nematodes are sensitive to which specific alkaloids. Full article

(This article belongs to the Collection Toxic and Pharmacological Effect of Plant Toxins)

16 pages, 306 KiB

Open AccessReview

Hot-Water Immersion (HWI) or Ice-Pack Treatment (IPT) as First Aid for Human Envenomation by Marine Animals? Review of Literature

by Łukasz Niżnik, Karolina Jabłońska, Michał Orczyk, Martyna Orzechowska, Judyta Jasińska, Barbara Smoliniec, Agnieszka Hućko, Piotr Kosowicz, Anna Klocek, Paweł Słoma, Aleksandra Roztoczyńska, Joanna Toporowska-Kaźmierak and Kamil Jurowski

Toxins 2024, 16(6), 273; https://doi.org/10.3390/toxins16060273 - 15 Jun 2024

Viewed by 520

Abstract

Envenomation by marine animals poses a significant health concern globally, affecting both local residents and tourists in coastal regions. The primary objective of this review is to critically evaluate the existing scientific literature to determine the most effective first-aid treatment for envenomations caused [...] Read more.

Envenomation by marine animals poses a significant health concern globally, affecting both local residents and tourists in coastal regions. The primary objective of this review is to critically evaluate the existing scientific literature to determine the most effective first-aid treatment for envenomations caused by marine animals, specifically whether hot-water immersion (HWI) or ice-pack treatment (IPT) provides the best immediate care. This comprehensive review covers a wide range of marine envenomations, from jellyfish stings to stingray injuries. While our focus is primarily on the efficacy of HWI and IPT, we also explore the role of cold-water treatment as a result of its relevance and similarity to ice-pack applications. In addition, we examine other treatments mentioned in the literature, such as medications or vinegar, and highlight their findings where applicable. To provide a clear and structured overview, we summarised the articles in separate tables. These tables categorise the type of research conducted, the marine species studied, the region of origin of the marine species, and the key findings of each study. Our analysis of the available evidence indicates a general consensus in the scientific community on the effectiveness of HWI or IPT for envenomation by marine animals. However, when treating those injuries, it is crucial to consider all factors since there is no universally superior treatment due to the diverse nature of marine habitats. Full article

(This article belongs to the Section Animal Venoms)

14 pages, 4440 KiB

Open AccessArticle

How to Overcome a Snail? Identification of Putative Neurotoxins of Snail-Feeding Firefly Larvae (Coleoptera: Lampyridae, Lampyris noctiluca)

by Jonas Krämer, Patrick Hölker and Reinhard Predel

Toxins 2024, 16(6), 272; https://doi.org/10.3390/toxins16060272 - 14 Jun 2024

Viewed by 315

Abstract

The larvae of some lampyrid beetles are highly specialized predators of snails. They have been observed to climb on the shells of their prey and use this exposed position to bite and inject secretions potentially originating from the midgut. Besides serving the purpose [...] Read more.

The larvae of some lampyrid beetles are highly specialized predators of snails. They have been observed to climb on the shells of their prey and use this exposed position to bite and inject secretions potentially originating from the midgut. Besides serving the purpose of extra-oral digestion (EOD), injected compounds also seem to have a paralyzing effect. Up to now, the toxins causing this paralyzing activity have not been identified. In the current study, we provide a first compositional analysis of the midgut secretion from lampyrid larvae, with a focus on identifying putative neurotoxins causing the observed paralyzing effect. For this purpose, we utilized a combined proteo-transcriptomic approach to characterize the compounds present in the midgut secretion of larval stages of Lampyris noctiluca. In terms of the absolute numbers of identified compounds, the midgut secretion is dominated by hydrolyzing enzymes comprising peptidases, carboxylesterases, and glycosidases. However, when considering expression levels, a few rather short cysteine-rich peptides exceed all other compounds. Some of these compounds show moderate similarity to putative neurotoxins identified in the venom of other arthropods and could be responsible for paralyzing effects. In addition to these potential toxins, we provide a list of peptides typical of the midgut secretion of L. noctiluca, supplemented by the corresponding precursor sequences. Full article

(This article belongs to the Section Animal Venoms)

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20 pages, 5540 KiB

Open AccessArticle

Phylogenetic Tracing of Evolutionarily Conserved Zonula Occludens Toxin Reveals a “High Value” Vaccine Candidate Specific for Treating Multi-Strain Pseudomonas aeruginosa Infections

by Payam Benyamini

Toxins 2024, 16(6), 271; https://doi.org/10.3390/toxins16060271 - 14 Jun 2024

Viewed by 464

Abstract

Extensively drug-resistant Pseudomonas aeruginosa infections are emerging as a significant threat associated with adverse patient outcomes. Due to this organism’s inherent properties of developing antibiotic resistance, we sought to investigate alternative strategies such as identifying “high value” antigens for immunotherapy-based purposes. Through extensive [...] Read more.

Extensively drug-resistant Pseudomonas aeruginosa infections are emerging as a significant threat associated with adverse patient outcomes. Due to this organism’s inherent properties of developing antibiotic resistance, we sought to investigate alternative strategies such as identifying “high value” antigens for immunotherapy-based purposes. Through extensive database mining, we discovered that numerous Gram-negative bacterial (GNB) genomes, many of which are known multidrug-resistant (MDR) pathogens, including P. aeruginosa, horizontally acquired the evolutionarily conserved gene encoding Zonula occludens toxin (Zot) with a substantial degree of homology. The toxin’s genomic footprint among so many different GNB stresses its evolutionary importance. By employing in silico techniques such as proteomic-based phylogenetic tracing, in conjunction with comparative structural modeling, we discovered a highly conserved intermembrane associated stretch of 70 amino acids shared among all the GNB strains analyzed. The characterization of our newly identified antigen reveals it to be a “high value” vaccine candidate specific for P. aeruginosa. This newly identified antigen harbors multiple non-overlapping B- and T-cell epitopes exhibiting very high binding affinities and can adopt identical tertiary structures among the least genetically homologous P. aeruginosa strains. Taken together, using proteomic-driven reverse vaccinology techniques, we identified multiple “high value” vaccine candidates capable of eliciting a polarized immune response against all the P. aeruginosa genetic variants tested. Full article

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12 pages, 1462 KiB

Open AccessReview

Pierisin, Cytotoxic and Apoptosis-Inducing DNA ADP-Ribosylating Protein in Cabbage Butterfly

by Azusa Takahashi-Nakaguchi, Yu Horiuchi, Masafumi Yamamoto, Yukari Totsuka and Keiji Wakabayashi

Toxins 2024, 16(6), 270; https://doi.org/10.3390/toxins16060270 - 14 Jun 2024

Viewed by 335

Abstract

Pierisin-1 was serendipitously discovered as a strong cytotoxic and apoptosis-inducing protein from pupae of the cabbage butterfly Pieris rapae against cancer cell lines. This 98-kDa protein consists of the N-terminal region (27 kDa) and C-terminal region (71 kDa), and analysis of their biological [...] Read more.

Pierisin-1 was serendipitously discovered as a strong cytotoxic and apoptosis-inducing protein from pupae of the cabbage butterfly Pieris rapae against cancer cell lines. This 98-kDa protein consists of the N-terminal region (27 kDa) and C-terminal region (71 kDa), and analysis of their biological function revealed that pierisin-1 binds to cell surface glycosphingolipids on the C-terminal side, is taken up into the cell, and is cleaved to N- and C-terminal portions, where the N-terminal portion mono-ADP-ribosylates the guanine base of DNA in the presence of NAD to induce cellular genetic mutation and apoptosis. Unlike other ADP-ribosyltransferases, pieisin-1 was first found to exhibit DNA mono-ADP-ribosylating activity and show anti-cancer activity in vitro and in vivo against various cancer cell lines. Pierisin-1 was most abundantly produced during the transition from the final larval stage to the pupal stage of the cabbage butterfly, and this production was regulated by ecdysteroid hormones. This suggests that pierisn-1 might play a pivotal role in the process of metamorphosis. Moreover, pierisin-1 could contribute as a defense factor against parasitization and microbial infections in the cabbage butterfly. Pierisin-like proteins in butterflies were shown to be present not only among the subtribe Pierina but also among the subtribes Aporiina and Appiadina, and pierisin-2, -3, and -4 were identified in these butterflies. Furthermore, DNA ADP-ribosylating activities were found in six different edible clams. Understanding of the biological nature of pierisin-1 with DNA mono-ADP-ribosylating activity could open up exciting avenues for research and potential therapeutic applications, making it a subject of great interest in the field of molecular biology and biotechnology. Full article

(This article belongs to the Special Issue ADP-Ribosylation and Beyond)

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17 pages, 1476 KiB

Open AccessArticle

Nanostructured Magnetic Particles for Removing Cyanotoxins: Assessing Effectiveness and Toxicity In Vitro

by Alejandro Cao, Natalia Vilariño, Lisandra de Castro-Alves, Yolanda Piñeiro, José Rivas, Ana M. Botana, Cristina Carrera, María J. Sainz and Luis M. Botana

Toxins 2024, 16(6), 269; https://doi.org/10.3390/toxins16060269 - 13 Jun 2024

Viewed by 325

Abstract

The rise in cyanobacterial blooms due to eutrophication and climate change has increased cyanotoxin presence in water. Most current water treatment plants do not effectively remove these toxins, posing a potential risk to public health. This study introduces a water treatment approach using [...] Read more.

The rise in cyanobacterial blooms due to eutrophication and climate change has increased cyanotoxin presence in water. Most current water treatment plants do not effectively remove these toxins, posing a potential risk to public health. This study introduces a water treatment approach using nanostructured beads containing magnetic nanoparticles (MNPs) for easy removal from liquid suspension, coated with different adsorbent materials to eliminate cyanotoxins. Thirteen particle types were produced using activated carbon, CMK-3 mesoporous carbon, graphene, chitosan, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-oxidised cellulose nanofibers (TOCNF), esterified pectin, and calcined lignin as an adsorbent component. The particles’ effectiveness for detoxification of microcystin-LR (MC-LR), cylindrospermopsin (CYN), and anatoxin-A (ATX-A) was assessed in an aqueous solution. Two particle compositions presented the best adsorption characteristics for the most common cyanotoxins. In the conditions tested, mesoporous carbon nanostructured particles, P1-CMK3, provide good removal of MC-LR and Merck-activated carbon nanostructured particles, P9-MAC, can remove ATX-A and CYN with high and fair efficacy, respectively. Additionally, in vitro toxicity of water treated with each particle type was evaluated in cultured cell lines, revealing no alteration of viability in human renal, neuronal, hepatic, and intestinal cells. Although further research is needed to fully characterise this new water treatment approach, it appears to be a safe, practical, and effective method for eliminating cyanotoxins from water. Full article

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

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30 pages, 3531 KiB

Open AccessSystematic Review

Machine Learning Applied to the Detection of Mycotoxin in Food: A Systematic Review

by Alan Inglis, Andrew C. Parnell, Natarajan Subramani and Fiona M. Doohan

Toxins 2024, 16(6), 268; https://doi.org/10.3390/toxins16060268 - 12 Jun 2024

Viewed by 401

Abstract

Mycotoxins, toxic secondary metabolites produced by certain fungi, pose significant threats to global food safety and public health. These compounds can contaminate a variety of crops, leading to economic losses and health risks to both humans and animals. Traditional lab analysis methods for [...] Read more.

Mycotoxins, toxic secondary metabolites produced by certain fungi, pose significant threats to global food safety and public health. These compounds can contaminate a variety of crops, leading to economic losses and health risks to both humans and animals. Traditional lab analysis methods for mycotoxin detection can be time-consuming and may not always be suitable for large-scale screenings. However, in recent years, machine learning (ML) methods have gained popularity for use in the detection of mycotoxins and in the food safety industry in general due to their accurate and timely predictions. We provide a systematic review on some of the recent ML applications for detecting/predicting the presence of mycotoxin on a variety of food ingredients, highlighting their advantages, challenges, and potential for future advancements. We address the need for reproducibility and transparency in ML research through open access to data and code. An observation from our findings is the frequent lack of detailed reporting on hyperparameters in many studies and a lack of open source code, which raises concerns about the reproducibility and optimisation of the ML models used. The findings reveal that while the majority of studies predominantly utilised neural networks for mycotoxin detection, there was a notable diversity in the types of neural network architectures employed, with convolutional neural networks being the most popular. Full article

(This article belongs to the Special Issue Novel Approaches in Mycotoxins Research: Detection, Prevention and Mode of Action)

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15 pages, 1992 KiB

Open AccessArticle

Long-Term Enhancement of Botulinum Toxin Injections for Post-Stroke Spasticity by Use of Stretching Exercises—A Randomized Controlled Trial

by In-Su Hwang, Jin-Whan Ryu, Sol Jin, Soo-A Kim and Min-Su Kim

Toxins 2024, 16(6), 267; https://doi.org/10.3390/toxins16060267 - 11 Jun 2024

Viewed by 486

Abstract

Botulinum toxin A (BONT/A) injections play a central role in the treatment of upper limb spasticity in stroke patients. We proposed structured stretching exercises to enhance the effect of post-stroke spasticity relief of the upper limbs following BONT/A injections. A total of 43 [...] Read more.

Botulinum toxin A (BONT/A) injections play a central role in the treatment of upper limb spasticity in stroke patients. We proposed structured stretching exercises to enhance the effect of post-stroke spasticity relief of the upper limbs following BONT/A injections. A total of 43 patients who had a stroke with grade 2 spasticity or higher on the Modified Ashworth Scale (MAS) in their upper-limb muscles were randomly assigned to the intervention (n = 21) or control group (n = 22). The former received structured stretching exercises after their BONT/A injections for 20 min, 5 days per week, for 6 months at a hospital, while the others conducted self-stretching exercises at home. The outcome measures were assessed before the intervention (T0) and after three (T1) and six months (T2). Significantly greater improvements in the MAS scores of the elbows, wrists, and fingers were found in the intervention group’s patients at T1 and T2. The behavioral outcome measures, including shoulder pain, activities of daily living, and quality of life, and our electrophysiological studies also showed a significantly higher enhancement in this patient group. In conclusion, the structured stretching exercises plus BONT/A injections for six months showed a superior effect in relieving post-stroke upper-limb spasticity compared to self-stretching exercises. Full article

(This article belongs to the Special Issue The Botulinum Toxin and Spasticity: Exploring New Horizons)

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36 pages, 4406 KiB

Open AccessReview

Update on Non-Interchangeability of Botulinum Neurotoxin Products

by Mitchell F. Brin, Mariana Nelson, Nazanin Ashourian, Amy Brideau-Andersen and John Maltman

Toxins 2024, 16(6), 266; https://doi.org/10.3390/toxins16060266 - 10 Jun 2024

Viewed by 718

Abstract

The growing use of botulinum neurotoxins (BoNTs) for medical and aesthetic purposes has led to the development and marketing of an increasing number of BoNT products. Given that BoNTs are biological medications, their characteristics are heavily influenced by their manufacturing methods, leading to [...] Read more.

The growing use of botulinum neurotoxins (BoNTs) for medical and aesthetic purposes has led to the development and marketing of an increasing number of BoNT products. Given that BoNTs are biological medications, their characteristics are heavily influenced by their manufacturing methods, leading to unique products with distinct clinical characteristics. The manufacturing and formulation processes for each BoNT are proprietary, including the potency determination of reference standards and other features of the assays used to measure unit potency. As a result of these differences, units of BoNT products are not interchangeable or convertible using dose ratios. The intrinsic, product-level differences among BoNTs are compounded by differences in the injected tissues, which are innervated by different nerve fiber types (e.g., motor, sensory, and/or autonomic nerves) and require unique dosing and injection sites that are particularly evident when treating complex therapeutic and aesthetic conditions. It is also difficult to compare across studies due to inherent differences in patient populations and trial methods, necessitating attention to study details underlying each outcome reported. Ultimately, each BoNT possesses a unique clinical profile for which unit doses and injection paradigms must be determined individually for each indication. This practice will help minimize unexpected adverse events and maximize efficacy, duration, and patient satisfaction. With this approach, BoNT is poised to continue as a unique tool for achieving individual goals for an increasing number of medical and aesthetic indications. Full article

(This article belongs to the Section Bacterial Toxins)

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14 pages, 957 KiB

Open AccessSystematic Review

Mushroom Poisoning-Related Cardiac Toxicity: A Case Report and Systematic Review

by Giuseppe Balice, Maxime Boksebeld, Quentin Barrier, Sara Boccalini, Behrouz Kassai-Koupai, Nathalie Paret and Guillaume Grenet

Toxins 2024, 16(6), 265; https://doi.org/10.3390/toxins16060265 - 10 Jun 2024

Viewed by 389

Abstract

We encountered a case of mushroom intoxication complicated by “toxic-like” myocarditis. Because of the lack of systematized knowledge on this subject, we performed a systematic review of the literature on cardiac toxicity in mushroom poisoning (MP). The aim of this study was to [...] Read more.

We encountered a case of mushroom intoxication complicated by “toxic-like” myocarditis. Because of the lack of systematized knowledge on this subject, we performed a systematic review of the literature on cardiac toxicity in mushroom poisoning (MP). The aim of this study was to identify and describe the severity, the causal relationship, and the mushroom species involved in other reported cardiac events associated with MP. We included 39 studies in our review. We found 106 cases of cardiac events associated with MP, including 18 deaths. A wide variety of cardiac manifestations were reported, ranging from the simple elevation of cardiac enzymes (n = 61) to ventricular tachycardia (n = 14), acute heart failure (n = 18), and myocarditis (n = 7). Causal relationship between cardiac manifestations and mushroom poisoning was assessed for 42 patients, applying the algorithm validated by the French Toxicovigilance Coordination Committee. Twenty-three cases (54.8%) had a “possible” causal relationship, eight cases (19%) a “probable” relationship, and ten cases (23.8%) a “very probable” relationship. Several fungal genera were involved in reported cases, including Amanita but also rarer ones like Russula and Tricholoma. In conclusion, we showed that cases of cardiac toxicity following MP have been documented in the existing literature, and for some of them, we assessed a strong causal relationship. Full article

(This article belongs to the Section Mycotoxins)

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36 pages, 1268 KiB

Open AccessArticle

Temporal Dynamics and Influential Factors of Taste and Odor Compounds in the Eastern Drinking Water Source of Chaohu Lake, China: A Comparative Analysis of Global Freshwaters

by Lixia Shang, Fan Ke, Xiangen Xu, Muhua Feng and Wenchao Li

Toxins 2024, 16(6), 264; https://doi.org/10.3390/toxins16060264 - 9 Jun 2024

Viewed by 376

Abstract

The escalating proliferation of cyanobacteria poses significant taste and odor (T/O) challenges, impacting freshwater ecosystems, public health, and water treatment costs. We examined monthly variations in four T/O compounds from September 2011 to August 2012 in Chaohu Lake’s eastern drinking water source (DECL). [...] Read more.

The escalating proliferation of cyanobacteria poses significant taste and odor (T/O) challenges, impacting freshwater ecosystems, public health, and water treatment costs. We examined monthly variations in four T/O compounds from September 2011 to August 2012 in Chaohu Lake’s eastern drinking water source (DECL). More importantly, we compared the reported T/O occurrence and the related factors in freshwater bodies worldwide. The assessment of T/O issues indicated a severe and widespread problem, with many cases surpassing odor threshold values. Remarkably, China reported the highest frequency and severity of odor-related problems. A temporal analysis revealed variations in odor occurrences within the same water body across different years, emphasizing the need to consider high values in all seasons for water safety. Globally, T/O issues were widespread, demanding attention to variations within the same water body and across different layers. Algae were crucial contributors to odor compounds, necessitating targeted interventions due to diverse odorant sources and properties. A correlation analysis alone lacked definitive answers, emphasizing the essential role of further validation, such as algae isolation. Nutrients are likely to have influenced the T/O, as GSM and MIB correlated positively with nitrate and ammonia nitrogen in DECL, resulting in proposed control recommendations. This study offers recommendations for freshwater ecosystem management and serves as a foundation for future research and management strategies to address T/O challenges. Full article

(This article belongs to the Special Issue Monitoring and Management of Algal and Cyanobacterial Blooms)

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18 pages, 8972 KiB

Open AccessArticle

Characterization of Taxonomic and Functional Dynamics Associated with Harmful Algal Bloom Formation in Recreational Water Ecosystems

by Faizan Saleem, Rachelle Atrache, Jennifer L. Jiang, Kevin L. Tran, Enze Li, Athanasios Paschos, Thomas A. Edge and Herb E. Schellhorn

Toxins 2024, 16(6), 263; https://doi.org/10.3390/toxins16060263 - 7 Jun 2024

Viewed by 393

Abstract

Harmful algal bloom (HAB) formation leads to the eutrophication of water ecosystems and may render recreational lakes unsuitable for human use. We evaluated the applicability and comparison of metabarcoding, metagenomics, qPCR, and ELISA-based methods for cyanobacteria/cyanotoxin detection in bloom and non-bloom sites for [...] Read more.

Harmful algal bloom (HAB) formation leads to the eutrophication of water ecosystems and may render recreational lakes unsuitable for human use. We evaluated the applicability and comparison of metabarcoding, metagenomics, qPCR, and ELISA-based methods for cyanobacteria/cyanotoxin detection in bloom and non-bloom sites for the Great Lakes region. DNA sequencing-based methods robustly identified differences between bloom and non-bloom samples (e.g., the relative prominence of Anabaena and Planktothrix). Shotgun sequencing strategies also identified the enrichment of metabolic genes typical of cyanobacteria in bloom samples, though toxin genes were not detected, suggesting deeper sequencing or PCR methods may be needed to detect low-abundance toxin genes. PCR and ELISA indicated microcystin levels and microcystin gene copies were significantly more abundant in bloom sites. However, not all bloom samples were positive for microcystin, possibly due to bloom development by non-toxin-producing species. Additionally, microcystin levels were significantly correlated (positively) with microcystin gene copy number but not with total cyanobacterial 16S gene copies. In summary, next-generation sequencing-based methods can identify specific taxonomic and functional targets, which can be used for absolute quantification methods (qPCR and ELISA) to augment conventional water monitoring strategies. Full article

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

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21 pages, 3255 KiB

Open AccessReview

Specific Amino Acid Residues in the Three Loops of Snake Cytotoxins Determine Their Membrane Activity and Provide a Rationale for a New Classification of These Toxins

by Peter V. Dubovskii and Yuri N. Utkin

Toxins 2024, 16(6), 262; https://doi.org/10.3390/toxins16060262 - 4 Jun 2024

Viewed by 460

Abstract

Cytotoxins (CTs) are three-finger membrane-active toxins present mainly in cobra venom. Our analysis of the available CT amino acid sequences, literature data on their membrane activity, and conformational equilibria in aqueous solution and detergent micelles allowed us to identify specific amino acid residues [...] Read more.

Cytotoxins (CTs) are three-finger membrane-active toxins present mainly in cobra venom. Our analysis of the available CT amino acid sequences, literature data on their membrane activity, and conformational equilibria in aqueous solution and detergent micelles allowed us to identify specific amino acid residues which interfere with CT incorporation into membranes. They include Pro9, Ser28, and Asn/Asp45 within the N-terminal, central, and C-terminal loops, respectively. There is a hierarchy in the effect of these residues on membrane activity: Pro9 > Ser28 > Asn/Asp45. Taking into account all the possible combinations of special residues, we propose to divide CTs into eight groups. Group 1 includes toxins containing all of the above residues. Their representatives demonstrated the lowest membrane activity. Group 8 combines CTs that lack these residues. For the toxins from this group, the greatest membrane activity was observed. We predict that when solely membrane activity determines the cytotoxic effects, the activity of CTs from a group with a higher number should exceed that of CTs from a group with a lower number. This classification is supported by the available data on the cytotoxicity and membranotropic properties of CTs. We hypothesize that the special amino acid residues within the loops of the CT molecule may indicate their involvement in the interaction with non-lipid targets. Full article

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

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29 pages, 703 KiB

Open AccessReview

Embracing the Versatility of Botulinum Neurotoxins in Conventional and New Therapeutic Applications

by Christine Rasetti-Escargueil and Stefano Palea

Toxins 2024, 16(6), 261; https://doi.org/10.3390/toxins16060261 - 4 Jun 2024

Viewed by 606

Abstract

Botulinum neurotoxins (BoNTs) have been used for almost half a century in the treatment of excessive muscle contractility. BoNTs are routinely used to treat movement disorders such as cervical dystonia, spastic conditions, blepharospasm, and hyperhidrosis, as well as for cosmetic purposes. In addition [...] Read more.

Botulinum neurotoxins (BoNTs) have been used for almost half a century in the treatment of excessive muscle contractility. BoNTs are routinely used to treat movement disorders such as cervical dystonia, spastic conditions, blepharospasm, and hyperhidrosis, as well as for cosmetic purposes. In addition to the conventional indications, the use of BoNTs to reduce pain has gained increased recognition, giving rise to an increasing number of indications in disorders associated with chronic pain. Furthermore, BoNT-derived formulations are benefiting a much wider range of patients suffering from overactive bladder, erectile dysfunction, arthropathy, neuropathic pain, and cancer. BoNTs are categorised into seven toxinotypes, two of which are in clinical use, and each toxinotype is divided into multiple subtypes. With the development of bioinformatic tools, new BoNT-like toxins have been identified in non-Clostridial organisms. In addition to the expanding indications of existing formulations, the rich variety of toxinotypes or subtypes in the wild-type BoNTs associated with new BoNT-like toxins expand the BoNT superfamily, forming the basis on which to develop new BoNT-based therapeutics as well as research tools. An overview of the diversity of the BoNT family along with their conventional therapeutic uses is presented in this review followed by the engineering and formulation opportunities opening avenues in therapy. Full article

(This article belongs to the Special Issue Clinical Applications and Diversity of Botulinum Toxins)

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10 pages, 6594 KiB

Open AccessCommunication

Tetrodotoxin Derivatization with a Newly Designed Boron Reagent Leads to Conventional Reversed-Phase Liquid Chromatography

by Shimba Kawasue, Kyoko Kuniyoshi, Masashi Uema and Naomasa Oshiro

Toxins 2024, 16(6), 260; https://doi.org/10.3390/toxins16060260 - 4 Jun 2024

Viewed by 448

Abstract

Tetrodotoxin (TTX) is a representative natural toxin causing pufferfish food poisoning, which is especially prominent in East and Southeast Asia, including Japan. TTX has been analyzed through post-column derivatization high-performance liquid chromatography (HPLC), ion-pair LC-MS(/MS), and hydrophilic interaction liquid chromatography (HILIC)-MS(/MS) as alternatives [...] Read more.

Tetrodotoxin (TTX) is a representative natural toxin causing pufferfish food poisoning, which is especially prominent in East and Southeast Asia, including Japan. TTX has been analyzed through post-column derivatization high-performance liquid chromatography (HPLC), ion-pair LC-MS(/MS), and hydrophilic interaction liquid chromatography (HILIC)-MS(/MS) as alternatives to the mouse bioassay method. However, post-column derivatization requires a system for online derivatization reactions, and with the ion-pair LC-MS approach, it is difficult to remove residual ion-pair reagents remaining in the equipment. Moreover, HILIC-MS provides poor separation compared to reversed-phase (RP) HPLC and requires a long time to reach equilibration. Therefore, we decided to develop a TTX analytical method using pre-column derivatization and RP HPLC for the rapid assessment of outbreak samples, including food remnants. In this study, we focused on the vic-diol moiety of TTX and designed a new derivatization reagent coded as NBD-H-DAB. This NBD-H-DAB was synthesized from 4-hydrazino-7-nitro-2,1,3-benzoxadiazole (NBD-H) and 3-fluoro-2-formylphenylboronic acid (FFPBA) with a simple reaction system and rapidly converted to its boronate form, coded NBD-H-PBA, in an aqueous reaction solution. The NBD-H-PBA demonstrated appropriate hydrophobicity to be retained on the RP analytical column and successfully detected with a UV spectrometer. It was easily reacted with the vic-diol moiety of TTX (C6 and C11) to synthesized a boronic ester. The derivatized TTX could be detected using the RP HPLC-UV, and the limit of detection in the fish flesh samples was 0.06 mg/kg. This novel pre-column derivatization of TTX with NBD-H-PBA proves capable for the analysis of TTX. Full article

(This article belongs to the Special Issue Analytical Chemistry Techniques in Toxin Detection)

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15 pages, 1337 KiB

Open AccessArticle

Exploring the Impact of Efavirenz on Aflatoxin B1 Metabolism: Insights from a Physiologically Based Pharmacokinetic Model and a Human Liver Microsome Study

by Orphélie Lootens, Marthe De Boevre, Elke Gasthuys, Sarah De Saeger, Jan Van Bocxlaer and An Vermeulen

Toxins 2024, 16(6), 259; https://doi.org/10.3390/toxins16060259 - 4 Jun 2024

Viewed by 661

Abstract

Physiologically based pharmacokinetic (PBPK) models were utilized to investigate potential interactions between aflatoxin B1 (AFB1) and efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor drug and inducer of several CYP enzymes, including CYP3A4. PBPK simulations were conducted in a North European Caucasian and Black [...] Read more.

Physiologically based pharmacokinetic (PBPK) models were utilized to investigate potential interactions between aflatoxin B1 (AFB1) and efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor drug and inducer of several CYP enzymes, including CYP3A4. PBPK simulations were conducted in a North European Caucasian and Black South African population, considering different dosing scenarios. The simulations predicted the impact of EFV on AFB1 metabolism via CYP3A4 and CYP1A2. In vitro experiments using human liver microsomes (HLM) were performed to verify the PBPK predictions for both single- and multiple-dose exposures to EFV. Results showed no significant difference in the formation of AFB1 metabolites when combined with EFV (0.15 µM) compared to AFB1 alone. However, exposure to 5 µM of EFV, mimicking chronic exposure, resulted in increased CYP3A4 activity, affecting metabolite formation. While co-incubation with EFV reduced the formation of certain AFB1 metabolites, other outcomes varied and could not be fully attributed to CYP3A4 induction. Overall, this study provides evidence that EFV, and potentially other CYP1A2/CYP3A4 perpetrators, can impact AFB1 metabolism, leading to altered exposure to toxic metabolites. The results emphasize the importance of considering drug interactions when assessing the risks associated with mycotoxin exposure in individuals undergoing HIV therapy in a European and African context. Full article

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

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10 pages, 698 KiB

Open AccessCommunication

Role of Diagnostic Nerve Blocks in the Goal-Oriented Treatment of Spasticity with Botulinum Toxin Type A: A Case–Control Study

by Mirko Filippetti, Stefano Tamburin, Rita Di Censo, Martina Adamo, Elisa Manera, Jessica Ingrà, Elisa Mantovani, Salvatore Facciorusso, Marco Battaglia, Alessio Baricich, Andrea Santamato, Nicola Smania and Alessandro Picelli

Toxins 2024, 16(6), 258; https://doi.org/10.3390/toxins16060258 - 3 Jun 2024

Viewed by 659

Abstract

The goal-setting process is pivotal in managing patients with disabling spasticity. This case–control study assessed the role of diagnostic nerve blocks in guiding the goal-setting process within goal-targeted treatment of spasticity with botulinum neurotoxin-A. In this case–control study, patients with disabling spasticity underwent [...] Read more.

The goal-setting process is pivotal in managing patients with disabling spasticity. This case–control study assessed the role of diagnostic nerve blocks in guiding the goal-setting process within goal-targeted treatment of spasticity with botulinum neurotoxin-A. In this case–control study, patients with disabling spasticity underwent either a goal-setting process based on the patient’s needs and clinical evaluation (control group) or additional diagnostic nerve block procedures (case group). All enrolled patients underwent a focal treatment with botulinum neurotoxin-A injection and a 1-month follow-up evaluation during which goal achievement was quantified using the goal attainment scaling-light score system. Data showed a higher goal achievement rate in the case group (70%) than in the control group (40%). In conclusion, diagnostic nerve blocks may help guide the goal-setting process within goal-targeted treatment of spasticity with botulinum neurotoxin-A towards more realistic and achievable goals, thereby improving the outcomes of botulinum neurotoxin-A injection. Future studies should better explore the role of diagnostic nerve blocks to further personalize botulinum neurotoxin-A according to individual patients’ preferences and requirements. Full article

(This article belongs to the Special Issue Botulinum Neurotoxin as Novel Therapy of Spasticity and Disorder Movement)

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19 pages, 3821 KiB

Open AccessArticle

Unveiling Tst3, a Multi-Target Gating Modifier Scorpion α Toxin from Tityus stigmurus Venom of Northeast Brazil: Evaluation and Comparison with Well-Studied Ts3 Toxin of Tityus serrulatus

by Diogo Vieira Tibery, João Antonio Alves Nunes, Daniel Oliveira da Mata, Luis Felipe Santos Menezes, Adolfo Carlos Barros de Souza, Matheus de Freitas Fernandes-Pedrosa, Werner Treptow and Elisabeth Ferroni Schwartz

Toxins 2024, 16(6), 257; https://doi.org/10.3390/toxins16060257 - 3 Jun 2024

Viewed by 369

Abstract

Studies on the interaction sites of peptide toxins and ion channels typically involve site-directed mutations in toxins. However, natural mutant toxins exist among them, offering insights into how the evolutionary process has conserved crucial sequences for activities and molecular target selection. In this [...] Read more.

Studies on the interaction sites of peptide toxins and ion channels typically involve site-directed mutations in toxins. However, natural mutant toxins exist among them, offering insights into how the evolutionary process has conserved crucial sequences for activities and molecular target selection. In this study, we present a comparative investigation using electrophysiological approaches and computational analysis between two alpha toxins from evolutionarily close scorpion species of the genus Tityus, namely, Tst3 and Ts3 from T. stigmurus and T. serrulatus, respectively. These toxins exhibit three natural substitutions near the C-terminal region, which is directly involved in the interaction between alpha toxins and Nav channels. Additionally, we characterized the activity of the Tst3 toxin on Nav1.1-Nav1.7 channels. The three natural changes between the toxins did not alter sensitivity to Nav1.4, maintaining similar intensities regarding their ability to alter opening probabilities, delay fast inactivation, and induce persistent currents. Computational analysis demonstrated a preference for the down conformation of VSD4 and a shift in the conformational equilibrium towards this state. This illustrates that the sequence of these toxins retained the necessary information, even with alterations in the interaction site region. Through electrophysiological and computational analyses, screening of the Tst3 toxin on sodium isoform revealed its classification as a classic α-NaTx with a broad spectrum of activity. It effectively delays fast inactivation across all tested isoforms. Structural analysis of molecular energetics at the interface of the VSD4-Tst3 complex further confirmed this effect. 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)

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22 pages, 4089 KiB

Open AccessArticle

Identification of a Novel Aflatoxin B₁-Degrading Strain, Bacillus halotolerans DDC-4, and Its Response Mechanisms to Aflatoxin B₁

by Jia Guo, Hanlu Zhang, Yixuan Zhao, Xiaoxu Hao, Yu Liu, Suhong Li and Rina Wu

Toxins 2024, 16(6), 256; https://doi.org/10.3390/toxins16060256 - 31 May 2024

Viewed by 366

Abstract

Aflatoxin B₁ (AFB₁) contamination is a food safety issue threatening human health globally. Biodegradation is an effective method for overcoming this problem, and many microorganisms have been identified as AFB₁-degrading strains. However, the response mechanisms of these microbes [...] Read more.

Aflatoxin B₁ (AFB₁) contamination is a food safety issue threatening human health globally. Biodegradation is an effective method for overcoming this problem, and many microorganisms have been identified as AFB₁-degrading strains. However, the response mechanisms of these microbes to AFB₁ remain unclear. More degrading enzymes, especially of new types, need to be discovered. In this study, a novel AFB₁-degrading strain, DDC-4, was isolated using coumarin as the sole carbon source. This strain was identified as Bacillus halotolerans through physiological, biochemical, and molecular methods. The strain’s degradation activity was predominantly attributable to thermostable extracellular proteins (degradation rate remained approximately 80% at 90 °C) and was augmented by Cu²⁺ (95.45% AFB₁ was degraded at 48 h). Alpha/beta hydrolase (arylesterase) was selected as candidate AFB₁-degrading enzymes for the first time as a gene encoding this enzyme was highly expressed in the presence of AFB₁. Moreover, AFB₁ inhibited many genes involved in the nucleotide synthesis of strain DDC-4, which is possibly the partial molecular mechanism of AFB₁’s toxicity to microorganisms. To survive under this stress, sporulation-related genes were induced in the strain. Altogether, our study identified a novel AFB₁-degrading strain and explained its response mechanisms to AFB₁, thereby providing new insights for AFB₁ biodegradation. Full article

(This article belongs to the Section Mycotoxins)

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24 pages, 7201 KiB

Open AccessReview

A Guide to the Clinical Management of Vipera Snakebite in Italy

by Matteo Riccardo Di Nicola, Marta Crevani, Ignazio Avella, Anna Cerullo, Jean-Lou C. M. Dorne, Giovanni Paolino and Caterina Zattera

Toxins 2024, 16(6), 255; https://doi.org/10.3390/toxins16060255 - 31 May 2024

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Abstract

The genus Vipera encompasses most species of medically significant venomous snakes of Europe, with Italy harbouring four of them. Envenomation by European vipers can result in severe consequences, but underreporting and the absence of standardised clinical protocols hinder effective snakebite management. This study [...] Read more.

The genus Vipera encompasses most species of medically significant venomous snakes of Europe, with Italy harbouring four of them. Envenomation by European vipers can result in severe consequences, but underreporting and the absence of standardised clinical protocols hinder effective snakebite management. This study provides an updated, detailed set of guidelines for the management and treatment of Vipera snakebite tailored for Italian clinicians. It includes taxonomic keys for snake identification, insights into viper venom composition, and recommendations for clinical management. Emphasis is placed on quick and reliable identification of medically relevant snake species, along with appropriate first aid measures. Criteria for antivenom administration are outlined, as well as indications on managing potential side effects. While the protocol is specific to Italy, its methodology can potentially be adapted for other European countries, depending on local resources. The promotion of comprehensive data collection and collaboration among Poison Control Centres is advocated to optimise envenomation management protocols and improve the reporting of epidemiological data concerning snakebite at the country level. Full article

(This article belongs to the Special Issue Venomous Snakes: Taxonomy, Toxicology and Clinical Management of Envenomation)

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17 pages, 889 KiB

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Indoxyl Sulfate-Induced Macrophage Toxicity and Therapeutic Strategies in Uremic Atherosclerosis

by Takuya Wakamatsu, Suguru Yamamoto, Shiori Yoshida and Ichiei Narita

Toxins 2024, 16(6), 254; https://doi.org/10.3390/toxins16060254 - 31 May 2024

Viewed by 328

Abstract

Cardiovascular disease (CVD) frequently occurs in patients with chronic kidney disease (CKD), particularly those undergoing dialysis. The mechanisms behind this may be related to traditional risk factors and CKD-specific factors that accelerate atherosclerosis and vascular calcification in CKD patients. The accumulation of uremic [...] Read more.

Cardiovascular disease (CVD) frequently occurs in patients with chronic kidney disease (CKD), particularly those undergoing dialysis. The mechanisms behind this may be related to traditional risk factors and CKD-specific factors that accelerate atherosclerosis and vascular calcification in CKD patients. The accumulation of uremic toxins is a significant factor in CKD-related systemic disorders. Basic research suggests that indoxyl sulfate (IS), a small protein-bound uremic toxin, is associated with macrophage dysfunctions, including increased oxidative stress, exacerbation of chronic inflammation, and abnormalities in lipid metabolism. Strategies to mitigate the toxicity of IS include optimizing gut microbiota, intervening against the abnormality of intracellular signal transduction, and using blood purification therapy with higher efficiency. Further research is needed to examine whether lowering protein-bound uremic toxins through intervention leads to a reduction in CVD in patients with CKD. Full article

(This article belongs to the Special Issue Uremic Toxins Lowering Strategies in Chronic Kidney Disease)

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Toxins, Volume 16, Issue 6 (June 2024) – 52 articles

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