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Toxins
Volume 14
Issue 7
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Toxins, Volume 14, Issue 7 (July 2022) – 86 articles

Cover Story (view full-size image): Antivenoms are life-saving snakebite therapeutics directed against crude venom, but the extensive venom toxin variation among snake species restricts their geographical utility. In this study, the authors explore the value of using specific snake venom serine protease toxins, recombinantly expressed in mammalian HEK293F cells, as immunogens for generating antibodies directed towards a specific toxin class. Recombinant ancrod, RVV-V, and batroxobin were used to generate murine antibodies, which were shown to bind to and inhibit the fibrinogenolytic activity of the toxin immunogens and crude venoms. These findings strengthen the case for the use of recombinant toxins as supplemental immunogens to stimulate focused and desirable antibody responses capable of neutralizing the specific venom-induced pathological effects associated with snakebites. View this paper
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13 pages, 328 KiB  
Article
Deterministic and Probabilistic Dietary Exposure Assessment to Deoxynivalenol in Spain and the Catalonia Region
by Jose A. Gallardo, Sonia Marin, Antonio J. Ramos, German Cano-Sancho and Vicente Sanchis
Toxins 2022, 14(7), 506; https://doi.org/10.3390/toxins14070506 - 20 Jul 2022
Cited by 6 | Viewed by 2465
Abstract
Deoxynivalenol (DON) remains one of the most concerning mycotoxins produced by the Fusarium genus due to the wide occurrence in highly consumed cereal-based food and its associated toxicological effects. Previous studies conducted in Spain and other European countries suggested that some vulnerable groups [...] Read more.
Deoxynivalenol (DON) remains one of the most concerning mycotoxins produced by the Fusarium genus due to the wide occurrence in highly consumed cereal-based food and its associated toxicological effects. Previous studies conducted in Spain and other European countries suggested that some vulnerable groups such as children could be exceeding the tolerable daily intakes. Thus, the aim of this study was to conduct a comprehensive and updated dietary exposure assessment study in Spain, with a specific analysis in the region of Catalonia. Cereal-based food samples collected during 2019 were analysed using liquid chromatography coupled to tandem mass spectrometry for multi-mycotoxin detection including DON and its main metabolites and derivatives. Consumption data were gathered from the nation-wide food surveys ENALIA and ENALIA2 conducted in Spain, and a specific survey conducted in Catalonia. The data were combined using deterministic and semi-parametric probabilistic methods. The results showed that DON was widely present in cereal-based food highly consumed in Spain and the Catalonia region. Exposure to DON among the adult population was globally low; however, among infants aged 3–9 years, it resulted in the median of 192 ng/kg body weight/day and the 95th percentiles of 604 ng/kg body weight/day, that would exceed the most conservative safety threshold for infants. Bread and pasta were the main contributing foodstuffs to the global exposure to DON, even among infants; thus, those foods should be considered a priority for food control or to develop strategies to reduce the exposure. In any case, further toxicological and epidemiological studies are required in order to refine the safety thresholds accounting for the sensitivity of the infant population. Full article
(This article belongs to the Special Issue Occurrence and Determination of Mycotoxins)
15 pages, 1547 KiB  
Article
In Vitro Toxicity of Chinese Russell’s Viper (Daboia siamensis) Venom and Neutralisation by Antivenoms
by Mimi Lay, Qing Liang, Geoffrey K. Isbister and Wayne C. Hodgson
Toxins 2022, 14(7), 505; https://doi.org/10.3390/toxins14070505 - 20 Jul 2022
Cited by 4 | Viewed by 2302
Abstract
Daboia siamensis (Russell’s viper) is a highly venomous and medically important snake in China, as well as much of Asia. There is minimal information on the pharmacological activity of the venom of the Chinese species, and currently no commercially available specific antivenom in [...] Read more.
Daboia siamensis (Russell’s viper) is a highly venomous and medically important snake in China, as well as much of Asia. There is minimal information on the pharmacological activity of the venom of the Chinese species, and currently no commercially available specific antivenom in China. This has led to the use of non-specific antivenoms to treat D. siamensis envenomation. In this study, the in vitro neurotoxicity and myotoxicity of D. siamensis venom was examined and the efficacy of four antivenoms was investigated, including the recently developed Chinese D. siamensis monovalent antivenom (C-DsMAV) and three commercially available antivenoms (Thai D. siamensis (Thai-DsMAV) monovalent antivenom, Deinagkistrodon acutus monovalent antivenom (DaAV), and Gloydius brevicaudus monovalent antivenom (GbAV). D. siamensis venom (10–30 µg/mL) caused the concentration-dependent inhibition of indirect twitches in the chick biventer cervicis nerve muscle preparation, without abolishing contractile responses to exogenous agonists ACh or CCh, indicating pre-synaptic neurotoxicity. Myotoxicity was also evident at these concentrations with inhibition of direct twitches, an increase in baseline tension, and the partial inhibition of ACh, CCh, and KCl responses. The prior addition of C-DsMAV or Thai-DsMAV prevented the neurotoxic and myotoxic activity of D. siamensis venom (10 µg/mL). The addition of non-specific antivenoms (GbAV and DaAV) partially prevented the neurotoxic activity of venom (10 µg/mL) but failed to neutralize the myotoxic effects. We have shown that D. siamensis venom exhibits in vitro weak presynaptic neurotoxicity and myotoxicity, which can be prevented by the pre-addition of the Chinese and Thai Russell’s viper antivenoms. Non-specific antivenoms were poorly efficacious. There should be further development of a monospecific antivenom against D. siamensis envenomation in China. Full article
(This article belongs to the Special Issue Insights into the Action and Application of Animal Toxins)
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27 pages, 4617 KiB  
Article
Deepening the Whole Transcriptomics of Bovine Liver Cells Exposed to AFB1: A Spotlight on Toll-like Receptor 2
by Silvia Iori, Marianna Pauletto, Irene Bassan, Federico Bonsembiante, Maria Elena Gelain, Anisa Bardhi, Andrea Barbarossa, Anna Zaghini, Mauro Dacasto and Mery Giantin
Toxins 2022, 14(7), 504; https://doi.org/10.3390/toxins14070504 - 20 Jul 2022
Cited by 11 | Viewed by 3725
Abstract
Aflatoxin B1 (AFB1) is a food contaminant metabolized mostly in the liver and leading to hepatic damage. Livestock species are differently susceptible to AFB1, but the underlying mechanisms of toxicity have not yet been fully investigated, especially in ruminants. Thus, the aim of [...] Read more.
Aflatoxin B1 (AFB1) is a food contaminant metabolized mostly in the liver and leading to hepatic damage. Livestock species are differently susceptible to AFB1, but the underlying mechanisms of toxicity have not yet been fully investigated, especially in ruminants. Thus, the aim of the present study was to better characterize the molecular mechanism by which AFB1 exerts hepatotoxicity in cattle. The bovine fetal hepatocyte cell line (BFH12) was exposed for 48 h to three different AFB1 concentrations (0.9 µM, 1.8 µM and 3.6 µM). Whole-transcriptomic changes were measured by RNA-seq analysis, showing significant differences in the expression of genes mainly involved in inflammatory response, oxidative stress, drug metabolism, apoptosis and cancer. As a confirmatory step, post-translational investigations on genes of interest were implemented. Cell death associated with necrosis rather than apoptosis events was noted. As far as the toxicity mechanism is concerned, a molecular pathway linking inflammatory response and oxidative stress was postulated. Toll-Like Receptor 2 (TLR2) activation, consequent to AFB1 exposure, triggers an intracellular signaling cascade involving a kinase (p38β MAPK), which in turn allows the nuclear translocation of the activator protein-1 (AP-1) and NF-κB, finally leading to the release of pro-inflammatory cytokines. Furthermore, a p38β MAPK negative role in cytoprotective genes regulation was postulated. Overall, our investigations improved the actual knowledge on the molecular effects of this worldwide relevant natural toxin in cattle. Full article
(This article belongs to the Special Issue Mechanism of Action of Mycotoxins)
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16 pages, 2541 KiB  
Article
Deoxynivalenol Biosynthesis in Fusarium pseudograminearum Significantly Repressed by a Megabirnavirus
by Ke Li, Dongmei Liu, Xin Pan, Shuwei Yan, Jiaqing Song, Dongwei Liu, Zhifang Wang, Yuan Xie, Junli Dai, Jihong Liu, Honglian Li, Xiaoting Zhang and Fei Gao
Toxins 2022, 14(7), 503; https://doi.org/10.3390/toxins14070503 - 19 Jul 2022
Cited by 5 | Viewed by 2430
Abstract
Deoxynivalenol (DON) is a mycotoxin widely detected in cereal products contaminated by Fusarium. Fusarium pseudograminearum megabirnavirus 1 (FpgMBV1) is a double-stranded RNA virus infecting Fusarium pseudograminearum. In this study, it was revealed that the amount of DON in F. pseudograminearum was significantly [...] Read more.
Deoxynivalenol (DON) is a mycotoxin widely detected in cereal products contaminated by Fusarium. Fusarium pseudograminearum megabirnavirus 1 (FpgMBV1) is a double-stranded RNA virus infecting Fusarium pseudograminearum. In this study, it was revealed that the amount of DON in F. pseudograminearum was significantly suppressed by FpgMBV1 through a high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) assay. A total of 2564 differentially expressed genes were identified by comparative transcriptomic analysis between the FpgMBV1-containing F. pseudograminearum strain FC136-2A and the virus-free strain FC136-2A-V-. Among them, 1585 genes were up-regulated and 979 genes were down-regulated. Particularly, the expression of 12 genes (FpTRI1, FpTRI3, FpTRI4, FpTRI5, FpTRI6, FpTRI8, FpTRI10, FpTRI11, FpTRI12, FpTRI14, FpTRI15, and FpTRI101) in the trichothecene biosynthetic (TRI) gene cluster was significantly down-regulated. Specific metabolic and transport processes and pathways including amino acid and lipid metabolism, ergosterol metabolic and biosynthetic processes, carbohydrate metabolism, and biosynthesis were regulated. These results suggest an unrevealing mechanism underlying the repression of DON and TRI gene expression by the mycovirus FpgMBV1, which would provide new methods in the detoxification of DON and reducing the yield loss in wheat. Full article
(This article belongs to the Special Issue Research on Pathogenic Fungi and Mycotoxins in China (Volume II))
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15 pages, 1026 KiB  
Article
Could the Presence of Thrips AFFECT the Yield Potential of Genetically Modified and Conventional Maize?
by Ľudovít Cagáň, Peter Bokor and Oxana Skoková Habuštová
Toxins 2022, 14(7), 502; https://doi.org/10.3390/toxins14070502 - 19 Jul 2022
Viewed by 2164
Abstract
Maize pests like Ostrinia nubilalis and Diabrotica virgifera virgifera are eradicated using genetically modified maize. This study’s goal was to see if the genetically modified maize MON810 is also toxic to thrips communities on maize. The impact of Bt maize on thrips diversity [...] Read more.
Maize pests like Ostrinia nubilalis and Diabrotica virgifera virgifera are eradicated using genetically modified maize. This study’s goal was to see if the genetically modified maize MON810 is also toxic to thrips communities on maize. The impact of Bt maize on thrips diversity and abundance, as well as yield losses, was studied in the field in Borovce for three years (Slovakia). The study used 10 Bt and 10 non-Bt maize cultivars. Thrips were monitored every two weeks during the season using transparent sticky traps installed on the experimental plots (one per plot, 20 per year). In total, 3426 thrips were caught. Thrips populations usually peak around the end of July at BBCH55. Among the species identified were Limothrips denticornis, Limothrips cerealium, Haplothrips aculeatus, Frankliniella schultzei, Frankliniella occidentalis, Thrips tabaci, Aeolothrips fasciatus, Frankliniella tenuicornis, and Chirothrips spp. We found that MON810 maize had no effect on the occurrence or composition of thrips. Their presence was affected by the maize growth phase and growing seasons and partially by the weather. The direct effect on the grain yield was not confirmed. Our research contributed to scientific knowledge of thrips communities found on maize plants in Central Europe, including Bt maize. Full article
(This article belongs to the Special Issue Insecticidal Toxins from Bacillus thuringiensis 2021–2022)
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20 pages, 2267 KiB  
Article
Effect of Different N:P Ratios on the Growth, Toxicity, and Toxin Profile of Gymnodinium catenatum (Dinophyceae) Strains from the Gulf of California
by Francisco E. Hernández-Sandoval, José J. Bustillos-Guzmán, Christine J. Band-Schmidt, Erick J. Núñez-Vázquez, David J. López-Cortés, Leyberth J. Fernández-Herrera, Carlos A. Poot-Delgado and Manuel Moreno-Legorreta
Toxins 2022, 14(7), 501; https://doi.org/10.3390/toxins14070501 - 18 Jul 2022
Cited by 8 | Viewed by 3040
Abstract
The harmful microalgae Gymnodinium catenatum is a unique naked dinoflagellate that produces paralytic shellfish poisoning toxins (PSTs). This species is common along the coasts of the Mexican Pacific and is responsible for paralytic shellfish poisoning, which has resulted in notable financial losses in [...] Read more.
The harmful microalgae Gymnodinium catenatum is a unique naked dinoflagellate that produces paralytic shellfish poisoning toxins (PSTs). This species is common along the coasts of the Mexican Pacific and is responsible for paralytic shellfish poisoning, which has resulted in notable financial losses in both fisheries and aquaculture. In the Gulf of California, G. catenatum has been related to mass mortality events in fish, shrimp, seabirds, and marine mammals. In this study, the growth, toxin profiles, and toxin content of four G. catenatum strains isolated from Bahía de La Paz (BAPAZ) and Bahía de Mazatlán (BAMAZ) were evaluated with different N:P ratios, keeping the phosphorus concentration constant. All strains were cultivated in semi-continuous cultures (200 mL, 21.0 °C, 120 µmol photon m−2s−1, and a 12:12 h light-dark cycle) with f/2 + Se medium using N:P ratios of: 4:1, 8:1, 16:1, 32:1, and 64:1. Paralytic toxins were analyzed by HPLC with fluorescence detection. Maximum cellular abundance and growth were obtained at an N:P ratio of 64:1 (3188 cells mL−1 and 0.34 div day−1) with the BAMAZ and BAPAZ strains. A total of ten saxitoxin analogs dominated by N-sulfocarbamoyl (60–90 mol%), decarbamoyl (10–20 mol%), and carbamoyl (5–10 mol%) toxins were detected. The different N:P ratios did not cause significant changes in the PST content or toxin profiles of the strains from both bays, although they did affect cell abundance. Full article
(This article belongs to the Special Issue Effects of Harmful Algal Blooms on Aquatic Organisms)
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8 pages, 781 KiB  
Case Report
Neurotoxicity and Other Clinical Manifestations of a Common European Adder (Vipera berus) Bite in Romania
by Gabriela Viorela Nițescu, Coriolan Emil Ulmeanu, Maria-Dorina Crăciun, Alina Maria Ciucă, Alexandru Ulici, Ioan Ghira and Davide Lonati
Toxins 2022, 14(7), 500; https://doi.org/10.3390/toxins14070500 - 18 Jul 2022
Cited by 5 | Viewed by 1998
Abstract
Most cases of envenomation by common European vipers (Vipera berus) have not been reported to have neurotoxic manifestations. However, these manifestations have been demonstrated in some cases of envenomation by subspecies of V. berus, found in the Carpathian Basin region [...] Read more.
Most cases of envenomation by common European vipers (Vipera berus) have not been reported to have neurotoxic manifestations. However, these manifestations have been demonstrated in some cases of envenomation by subspecies of V. berus, found in the Carpathian Basin region of south-eastern Europe. Here, we report the case of a 5-year-old girl from the south of Romania who presented symptoms of neurotoxicity, as well as other systemic and local symptoms, after being bitten by an adder of the V. berus subspecies. Treatment consisted of monovalent antivenom, a corticosteroid, and prophylactic enoxaparin. Neurotoxic manifestations of envenomation as well as other local and systemic symptoms improved within 5 days of treatment. The presented case shows that venom from V. berus subspecies found in the Carpathian Basin can have neurotoxic effects. This case also confirmed the efficacy of monospecific antivenom treatment in bringing about rapid and complete remission, following envenomation. Full article
(This article belongs to the Special Issue Snakebite Clinics and Pathogenesis: From Preclinical to Resource Mapping Studies)
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12 pages, 887 KiB  
Article
Combination of Bacillus velezensis RC218 and Chitosan to Control Fusarium Head Blight on Bread and Durum Wheat under Greenhouse and Field Conditions
by Juan Palazzini, Agustina Reynoso, Nadia Yerkovich, Vanessa Zachetti, María Ramírez and Sofía Chulze
Toxins 2022, 14(7), 499; https://doi.org/10.3390/toxins14070499 - 18 Jul 2022
Cited by 11 | Viewed by 2337
Abstract
Fusarium graminearum sensu stricto is, worldwide, the main causal agent of Fusarium head blight in small cereal crops such as wheat, barley, and oat. The pathogen causes not only reductions in yield and grain quality but also contamination with type-B trichothecenes such as [...] Read more.
Fusarium graminearum sensu stricto is, worldwide, the main causal agent of Fusarium head blight in small cereal crops such as wheat, barley, and oat. The pathogen causes not only reductions in yield and grain quality but also contamination with type-B trichothecenes such as deoxynivalenol. Prevention strategies include the use of less susceptible cultivars through breeding programs, cultural practices, crop rotation, fungicide application, or a combination of them through an integrated pest management. Additionally, the use of more eco-friendly strategies by the evaluation of microorganisms and natural products is increasing. The effect of combining Bacillus velezensis RC218 and chitosan on Fusarium Head Blight (FHB) and deoxynivalenol accumulation under greenhouse and field conditions in bread and durum wheat was evaluated. Under greenhouse conditions, both B. velezensis RC218 and chitosan (0.1%) demonstrated FHB control, diminishing the severity by 38 and 27%, respectively, while the combined treatment resulted in an increased reduction of 54% on bread wheat. Field trials on bread wheat showed a biocontrol reduction in FHB by 18 to 53%, and chitosan was effective only during the first year (48% reduction); surprisingly, the combination of these active principles allowed the control of FHB disease severity by 39 and 36.7% during the two harvest seasons evaluated (2017/18, 2018/19). On durum wheat, the combined treatment showed a 54.3% disease severity reduction. A reduction in DON accumulation in harvested grains was observed for either bacteria, chitosan, or their combination, with reductions of 50.3, 68, and 64.5%, respectively, versus the control. Full article
(This article belongs to the Special Issue Impact of Host-Fungi-Environment Interaction on Parent and Modified Mycotoxin Co-occurrence)
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19 pages, 408 KiB  
Review
Clinical Application of Botulinum Neurotoxin in Lower-Urinary-Tract Diseases and Dysfunctions: Where Are We Now and What More Can We Do?
by Hann-Chorng Kuo
Toxins 2022, 14(7), 498; https://doi.org/10.3390/toxins14070498 - 18 Jul 2022
Cited by 14 | Viewed by 4154
Abstract
Botulinum toxin A (Botox) had been considered a promising drug that has an effect on functional disorders of the lower urinary tract. Because Botox exhibits anti-inflammatory and antispasmodic effects, Botox injection into the bladder can decrease detrusor contractility, reduce bladder hypersensitivity, and eliminate [...] Read more.
Botulinum toxin A (Botox) had been considered a promising drug that has an effect on functional disorders of the lower urinary tract. Because Botox exhibits anti-inflammatory and antispasmodic effects, Botox injection into the bladder can decrease detrusor contractility, reduce bladder hypersensitivity, and eliminate painful sensations. Injecting Botox into the bladder outlet can relax the hyperactivity of the bladder neck, and of the urethral smooth and striated muscles. Based on these therapeutic effects, Botox has been widely applied to treat lower-urinary-tract dysfunctions (LUTDs) such as overactive bladder and neurogenic detrusor overactivity. However, this treatment has not been licensed for use in other LUTDs such as interstitial cystitis, voiding dysfunction due to benign prostatic hyperplasia in men, and dysfunctional voiding in women. Botox has also not been approved for the treatment of children with overactive bladder and dysfunctional voiding; in patients with spinal cord injuries with detrusor sphincter dyssynergia and autonomic dysreflexia; or for poorly relaxed external sphincter in non-neurogenic patients. This article reviews the current knowledge regarding Botox treatment for LUTDs and discusses the potential clinical applications of Botox, as well as work that can be conducted in the future. Full article
(This article belongs to the Special Issue Application of Botulinum Neurotoxin in Lower Urinary Tract Dysfunctions: Where Are We Now?)
14 pages, 334 KiB  
Article
Comparative Effects of Deoxynivalenol, Zearalenone and Its Modified Forms De-Epoxy-Deoxynivalenol and Hydrolyzed Zearalenone on Boar Semen In Vitro
by Panagiotis D. Tassis, Nicole Reisinger, Veronika Nagl, Eleni Tzika, Dian Schatzmayr, Nikolaos Mittas, Athina Basioura, Ilias Michos and Ioannis A. Tsakmakidis
Toxins 2022, 14(7), 497; https://doi.org/10.3390/toxins14070497 - 18 Jul 2022
Cited by 5 | Viewed by 2149
Abstract
Deoxynivalenol (DON) and zearalenone (ZEN) are described as detrimental factors to sow and boar fertility. In comparison, literature reports on the impact of modified forms of DON and ZEN, such as de-epoxy-DON (DOM-1) and hydrolyzed ZEN (HZEN), on swine reproduction are scarce. The [...] Read more.
Deoxynivalenol (DON) and zearalenone (ZEN) are described as detrimental factors to sow and boar fertility. In comparison, literature reports on the impact of modified forms of DON and ZEN, such as de-epoxy-DON (DOM-1) and hydrolyzed ZEN (HZEN), on swine reproduction are scarce. The aim of our study was to compare the effects of DON, DOM-1, ZEN and HZEN on boar semen in vitro. To this end, pooled boar semen ejaculates from two adult boars were treated with either 50.6 μM DON, 62.8 μM ZEN or equimolar concentrations of DOM-1 and HZEN, respectively (dilution volume of v/v 0.7% DMSO in all cases). Effects on semen motility, morphology, viability, hypo-osmotic swelling test reaction and DNA integrity were investigated hourly up to four hours of incubation. DON negatively affected particular parameters evaluated with a computer-assisted sperm analysis system (CASA), such as immotile spermatozoa and progressive motile spermatozoa, whereas those effects were absent in the case of DOM-1 treatment. In contrast to HZEN, ZEN affected almost all CASA parameters. Furthermore, only ZEN decreased the proportion of viable spermatozoa and increased the proportion of spermatozoa with abnormalities. In conclusion, DON and ZEN negatively affected boar semen in vitro, whereas equimolar concentrations of DOM-1 and HZEN did not induce harmful effects. Full article
(This article belongs to the Section Mycotoxins)
18 pages, 2847 KiB  
Article
A First Look at the Inhibitory Potential of Urospatha sagittifolia (Araceae) Ethanolic Extract for Bothrops atrox Snakebite Envenomation
by Antonio L. Vera-Palacios, Juan D. Sacoto-Torres, Josselin A. Hernández-Altamirano, Andres Moreno, Maria C. Peñuela-Mora, David Salazar-Valenzuela, Noroska G. S. Mogollón and José R. Almeida
Toxins 2022, 14(7), 496; https://doi.org/10.3390/toxins14070496 - 17 Jul 2022
Cited by 9 | Viewed by 3809
Abstract
Bothrops atrox snakebites are a relevant problem in the Amazon basin. In this biodiverse region, the ethnomedicinal approach plays an important role as an alternative to antivenom therapy. Urospatha sagittifolia (Araceae) is a plant used for this purpose; however, its neutralizing properties have [...] Read more.
Bothrops atrox snakebites are a relevant problem in the Amazon basin. In this biodiverse region, the ethnomedicinal approach plays an important role as an alternative to antivenom therapy. Urospatha sagittifolia (Araceae) is a plant used for this purpose; however, its neutralizing properties have not been scientifically accessed. To fill this gap, we investigated the ability of U. sagittifolia to modulate the catalytic activity of Bothrops atrox venom, and their toxic consequences, such as local damage and lethality. The venom profile of B. atrox was assessed by chromatography and electrophoresis. Inhibition of the three main enzymatic and medically important toxins from the venom was evaluated using synthetic substrates and quantified by chromogenic activity assays. Additionally, the neutralization of lethality, hemorrhage and edema were investigated by in vivo assays. The possible interactions between venom proteins and plant molecules were visualized by polyacrylamide gel electrophoresis. Finally, the phytochemical constituents present in the ethanolic extract were determined by qualitative and quantitative analyses. The ethanolic extract reduced the activity of the three main enzymes of venom target, achieving ranges from 19% to 81% of inhibition. Our in vivo venom neuralizations assays showed a significant inhibition of edema (38.72%) and hemorrhage (42.90%). Additionally, lethality was remarkably counteracted. The highest extract ratio evaluated had a 75% survival rate. Our data support the biomedical value of U. sagittifolia as a source of natural enzyme inhibitors able to neutralize catalytically active B. atrox venom toxins and their toxic effects. Full article
(This article belongs to the Special Issue Snakebite Clinics and Pathogenesis: From Preclinical to Resource Mapping Studies)
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5 pages, 3270 KiB  
Case Report
Envenoming by a Marine Blood Worm (Glycera)
by Daniela M. Durkin, Alison N. Young, Kent Khtikian, Zuzana Karjala, Arin L. Isenstein, Bryan G. Fry and Matthew R. Lewin
Toxins 2022, 14(7), 495; https://doi.org/10.3390/toxins14070495 - 17 Jul 2022
Cited by 2 | Viewed by 4864
Abstract
Bites from venomous marine annelid ‘bloodworms’ (e.g., Glycera spp.) do not appear to have been described in the medical literature despite being seemingly well-known to bait diggers and fishermen. The few laboratory study reports describe their venom composition and physiological effects in vitro [...] Read more.
Bites from venomous marine annelid ‘bloodworms’ (e.g., Glycera spp.) do not appear to have been described in the medical literature despite being seemingly well-known to bait diggers and fishermen. The few laboratory study reports describe their venom composition and physiological effects in vitro to be primarily proteolytic enzymes and neurotoxins apparently used for predation and defense. Herein, we present the report of a symptomatic envenoming suffered by a marine ecologist bitten while performing her field research. The local effects included a rapid onset of pain, swelling, and numbness at the bite site “as if injected with local anesthetic”. Additional signs and symptoms appearing over a two-week period were consistent with both delayed venom effects and potentially secondary infection. The late signs and symptoms resolved during a course of antibiotic treatment with doxycycline prescribed as a precaution and lack of resources to consider a wound culture. Comments about annelid bites sporadically appear in the popular literature, especially pertaining to the fishing industry, under names such as ‘bait-diggers hand’. While these bites are not known to be dangerously venomous, they seem to produce painful local symptoms and possibly increase the risk of marine bacterial infections that could be associated with more serious outcomes. More cases need to be formally described to better understand the natural history of these types of envenomation. Full article
(This article belongs to the Special Issue Venom-Induced Tissue Damage)
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9 pages, 1699 KiB  
Case Report
Medical Management after Lancehead Snakebite in North Amazon: A Case Report of Long-Term Disability
by Isadora S. Oliveira, Carla B. Ananias, Jilvando M. Medeiros, Michelle V. S. Franco, Isabela G. Ferreira, Felipe A. Cerni, Eliseu A. Sandri, Wuelton M. Monteiro and Manuela B. Pucca
Toxins 2022, 14(7), 494; https://doi.org/10.3390/toxins14070494 - 16 Jul 2022
Cited by 7 | Viewed by 2279
Abstract
Snakebites are a major public health problem in indigenous communities in Brazil, leading to acute local and systemic damage with resulting deficiencies. Long-term musculoskeletal disabilities related to snakebites have been a neglected area of research. Bothrops (lancehead) snakes are responsible for most of [...] Read more.
Snakebites are a major public health problem in indigenous communities in Brazil, leading to acute local and systemic damage with resulting deficiencies. Long-term musculoskeletal disabilities related to snakebites have been a neglected area of research. Bothrops (lancehead) snakes are responsible for most of the permanent sequelae related to snakebites in Latin America. Here, we present a case report of a 32-year-old male indigenous patient who was envenomed by a Bothrops species. The patient was clinically followed for a period of approximately 2 years and 6 months, during which time he experienced a loss of musculoskeletal tissue and required several medical procedures such as debridement, tissue reconstruction, and physical therapy, which resulted in a recovery of mobility, though with a permanent sequelae in gait. This case report shows how snakebites have a significant impact on health systems, as victims require physiotherapy, plastic surgery, and orthopedics services, as well as social support for reintegration into their local communities. Full article
(This article belongs to the Special Issue Snakebite Clinics and Pathogenesis: From Preclinical to Resource Mapping Studies)
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32 pages, 4441 KiB  
Article
Cocktails of Mycotoxins, Phytoestrogens, and Other Secondary Metabolites in Diets of Dairy Cows in Austria: Inferences from Diet Composition and Geo-Climatic Factors
by Felipe Penagos-Tabares, Ratchaneewan Khiaosa-ard, Marlene Schmidt, Eva-Maria Bartl, Johanna Kehrer, Veronika Nagl, Johannes Faas, Michael Sulyok, Rudolf Krska and Qendrim Zebeli
Toxins 2022, 14(7), 493; https://doi.org/10.3390/toxins14070493 - 15 Jul 2022
Cited by 10 | Viewed by 3907
Abstract
Dairy production is a pivotal economic sector of Austrian and European agriculture. Dietary toxins and endocrine disruptors of natural origin such as mycotoxins and phytoestrogens can affect animal health, reproduction, and productivity. This study characterized the profile of a wide spectrum of fungal, [...] Read more.
Dairy production is a pivotal economic sector of Austrian and European agriculture. Dietary toxins and endocrine disruptors of natural origin such as mycotoxins and phytoestrogens can affect animal health, reproduction, and productivity. This study characterized the profile of a wide spectrum of fungal, plant, and unspecific secondary metabolites, including regulated, emerging, and modified mycotoxins, phytoestrogens, and cyanogenic glucosides, in complete diets of lactating cows from 100 Austrian dairy farms. To achieve this, a validated multi-metabolite liquid chromatography/electrospray ionization–tandem mass spectrometric (LC/ESI–MS/MS) method was employed, detecting 155 of >800 tested metabolites. Additionally, the most influential dietary and geo-climatic factors related to the dietary mycotoxin contamination of Austrian dairy cattle were recognized. We evidenced that the diets of Austrian dairy cows presented ubiquitous contamination with mixtures of mycotoxins and phytoestrogens. Metabolites derived from Fusarium spp. presented the highest concentrations, were the most recurrent, and had the highest diversity among the detected fungal compounds. Zearalenone, deoxynivalenol, and fumonisin B1 were the most frequently occurring mycotoxins considered in the EU legislation, with detection frequencies >70%. Among the investigated dietary factors, inclusion of maize silage (MS) and straw in the diets was the most influential factor in contamination with Fusarium-derived and other fungal toxins and metabolites, and temperature was the most influential among the geo-climatic factors. Full article
(This article belongs to the Special Issue Mycotoxins in Food and Feed: Detection and Identification)
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17 pages, 2568 KiB  
Article
Transcriptome Analysis Reveals the Algicidal Mechanism of Brevibacillus laterosporus against Microcystis aeruginosa through Multiple Metabolic Pathways
by Yulei Zhang, Jieyi Li, Zhangxi Hu, Dong Chen, Feng Li, Xianghu Huang and Changling Li
Toxins 2022, 14(7), 492; https://doi.org/10.3390/toxins14070492 - 15 Jul 2022
Cited by 9 | Viewed by 2788
Abstract
It is widely accepted that eutrophication has played an important role in the formation of harmful cyanobacterial blooms in recent decades, which impacts water quality and ecological environment and causes huge economic losses. Algicidal bacteria have a promising application prospect in controlling cyanobacterial [...] Read more.
It is widely accepted that eutrophication has played an important role in the formation of harmful cyanobacterial blooms in recent decades, which impacts water quality and ecological environment and causes huge economic losses. Algicidal bacteria have a promising application prospect in controlling cyanobacterial blooms in aquaculture water. Here, the process of the algicidal bacterium Brevibacillus laterosporus strain Bl-zj acting on Microcystis aeruginosa was explored using transcriptome analysis to elucidate the algicidal mechanism. The results of the co-culture of bacterium and alga showed a strong alga-lysing effect of B. laterosporus against M. aeruginosa with an extreme morphology deformation of the algal cells. A total of 2744 differentially expressed genes of B. laterosporus were identified, which were mainly involved in the metabolism of amino acid, carbohydrate, and lipid. In the co-cultured group, the expression of genes mainly enriched in valine, leucine and isoleucine degradation, and fatty acid degradation were significantly increased. However, the expression of the genes related to ribosome were mainly inhibited. Transcriptome analysis showed that B. laterosporus obtained ATP and energy by the degradation of valine, leucine, isoleucine, and fatty acids, and destroyed algal cells by efflux pump transporters, secretion of hydrolytic enzymes, antibiotics, proteases, and other secondary metabolites, resulting in algal death and achieving the algicidal effect. Full article
(This article belongs to the Special Issue Ecology and Toxicology of Cyanobacteria and Cyanotoxins)
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10 pages, 2297 KiB  
Article
Can Isoquinoline Alkaloids Affect Platelet Aggregation in Whole Human Blood?
by Mst Shamima Parvin, Marcel Hrubša, Jaka Fadraersada, Alejandro Carazo, Jana Karlíčková, Lucie Cahlíková, Jakub Chlebek, Kateřina Macáková and Přemysl Mladěnka
Toxins 2022, 14(7), 491; https://doi.org/10.3390/toxins14070491 - 15 Jul 2022
Cited by 4 | Viewed by 1970
Abstract
Isoquinoline alkaloids have multiple biological activities, which might be associated with positive pharmacological effects as well as negative adverse reactions. As bleeding was suggested to be a side effect of the isoquinoline alkaloid berberine, we decided to ascertain if different isoquinoline alkaloids could [...] Read more.
Isoquinoline alkaloids have multiple biological activities, which might be associated with positive pharmacological effects as well as negative adverse reactions. As bleeding was suggested to be a side effect of the isoquinoline alkaloid berberine, we decided to ascertain if different isoquinoline alkaloids could influence hemocoagulation through the inhibition of either platelet aggregation or blood coagulation. Initially, a total of 14 compounds were screened for antiplatelet activity in whole human blood by impedance aggregometry. Eight of them demonstrated an antiplatelet effect against arachidonic acid-induced aggregation. Papaverine and bulbocapnine were the most potent compounds with biologically relevant IC50 values of 26.9 ± 12.2 μM and 30.7 ± 5.4 μM, respectively. Further testing with the same approach confirmed their antiplatelet effects by employing the most physiologically relevant inducer of platelet aggregation, collagen, and demonstrated that bulbocapnine acted at the level of thromboxane receptors. None of the alkaloids tested had an effect on blood coagulation measured by a mechanical coagulometer. In conclusion, the observed antiplatelet effects of isoquinoline alkaloids were found mostly at quite high concentrations, which means that their clinical impact is most likely low. Bulbocapnine was an exception. It proved to be a promising antiplatelet molecule, which may have biologically relevant effects. Full article
(This article belongs to the Special Issue Toxicity of Plant Derived Substances)
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12 pages, 1553 KiB  
Article
Insights into the Cardiotoxic Effects of Veratrum Lobelianum Alkaloids: Pilot Study
by Amir Taldaev, Roman P. Terekhov, Elizaveta V. Melnik, Maria V. Belova, Sergey V. Kozin, Andrey A. Nedorubov, Tatyana Ya. Pomerantseva and Galina V. Ramenskaya
Toxins 2022, 14(7), 490; https://doi.org/10.3390/toxins14070490 - 15 Jul 2022
Cited by 6 | Viewed by 2471
Abstract
Jervine, protoveratrine A (proA), and protoveratrine B (proB) are Veratrum alkaloids that are presented in some remedies obtained from Veratrum lobelianum, such as Veratrum aqua. This paper reports on a single-center pilot cardiotoxic mechanism study of jervine, proA, and proB in [...] Read more.
Jervine, protoveratrine A (proA), and protoveratrine B (proB) are Veratrum alkaloids that are presented in some remedies obtained from Veratrum lobelianum, such as Veratrum aqua. This paper reports on a single-center pilot cardiotoxic mechanism study of jervine, proA, and proB in case series. The molecular aspects were studied via molecular dynamic simulation, molecular docking with cardiac sodium channel NaV1.5, and machine learning-based structure–activity relationship modeling. HPLC-MS/MS method in combination with clinical events were used to analyze Veratrum alkaloid cardiotoxicity in patients. Jervine demonstrates the highest docking score (−10.8 kcal/mol), logP value (4.188), and pKa value (9.64) compared with proA and proB. Also, this compound is characterized by the lowest calculated IC50. In general, all three analyzed alkaloids show the affinity to NaV1.5 that highly likely results in cardiotoxic action. The clinical data of seven cases of intoxication by Veratrum aqua confirms the results of molecular modeling. Patients exhibited nausea, muscle weakness, bradycardia, and arterial hypotension. The association between alkaloid concentrations in blood and urine and severity of patient condition is described. These experiments, while primary, confirmed that jervine, proA, and proB contribute to cardiotoxicity by NaV1.5 inhibition. Full article
(This article belongs to the Special Issue Toxicity and Therapeutic Potential of Plant Alkaloid)
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15 pages, 1071 KiB  
Article
Divergent Specialization of Simple Venom Gene Profiles among Rear-Fanged Snake Genera (Helicops and Leptodeira, Dipsadinae, Colubridae)
by Peter A. Cerda, Jenna M. Crowe-Riddell, Deise J. P. Gonçalves, Drew A. Larson, Thomas F. Duda, Jr. and Alison R. Davis Rabosky
Toxins 2022, 14(7), 489; https://doi.org/10.3390/toxins14070489 - 15 Jul 2022
Cited by 4 | Viewed by 2593
Abstract
Many venomous animals express toxins that show extraordinary levels of variation both within and among species. In snakes, most studies of venom variation focus on front-fanged species in the families Viperidae and Elapidae, even though rear-fanged snakes in other families vary along the [...] Read more.
Many venomous animals express toxins that show extraordinary levels of variation both within and among species. In snakes, most studies of venom variation focus on front-fanged species in the families Viperidae and Elapidae, even though rear-fanged snakes in other families vary along the same ecological axes important to venom evolution. Here we characterized venom gland transcriptomes from 19 snakes across two dipsadine rear-fanged genera (Leptodeira and Helicops, Colubridae) and two front-fanged genera (Bothrops, Viperidae; Micrurus, Elapidae). We compared patterns of composition, variation, and diversity in venom transcripts within and among all four genera. Venom gland transcriptomes of rear-fanged Helicops and Leptodeira and front-fanged Micrurus are each dominated by expression of single toxin families (C-type lectins, snake venom metalloproteinase, and phospholipase A2, respectively), unlike highly diverse front-fanged Bothrops venoms. In addition, expression patterns of congeners are much more similar to each other than they are to species from other genera. These results illustrate the repeatability of simple venom profiles in rear-fanged snakes and the potential for relatively constrained venom composition within genera. Full article
(This article belongs to the Section Animal Venoms)
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21 pages, 1245 KiB  
Review
Mycotoxins of Concern in Children and Infant Cereal Food at European Level: Incidence and Bioaccessibility
by Cheila Pereira, Sara C. Cunha and José O. Fernandes
Toxins 2022, 14(7), 488; https://doi.org/10.3390/toxins14070488 - 15 Jul 2022
Cited by 10 | Viewed by 3176
Abstract
Cereals are of utmost importance for the nutrition of infants and children, as they provide important nutrients for their growth and development and, in addition, they are easily digestible, being the best choice for the transition from breast milk/infant formula to solid foods. [...] Read more.
Cereals are of utmost importance for the nutrition of infants and children, as they provide important nutrients for their growth and development and, in addition, they are easily digestible, being the best choice for the transition from breast milk/infant formula to solid foods. It is well known that children are more susceptible than adults to toxic food contaminants, such as mycotoxins, common contaminants in cereals. Many mycotoxins are already regulated and controlled according to strict quality control standards in Europe and around the world. There are, however, some mycotoxins about which the level of knowledge is lower: the so-called emerging mycotoxins, which are not yet regulated. The current review summarizes the recent information (since 2014) published in the scientific literature on the amounts of mycotoxins in infants’ and children’s cereal-based food in Europe, as well as their behaviour during digestion (bioaccessibility). Additionally, analytical methods used for mycotoxin determination and in vitro methods used to evaluate bioaccessibility are also reported. Some studies demonstrated the co-occurrence of regulated and emerging mycotoxins in cereal products used in children’s food, which highlights the need to adopt guidelines on the simultaneous presence of more than one mycotoxin. Although very little research has been done on the bioaccessibility of mycotoxins in these food products, very interesting results correlating the fiber and lipid contents of such products with a higher or lower bioaccessibility of mycotoxins were reported. LC-MS/MS is the method of choice for the detection and quantification of mycotoxins due to its high sensibility and accuracy. In vitro static digestion models are the preferred ones for bioaccessibility evaluation due to their simplicity and accuracy. Full article
(This article belongs to the Special Issue Mechanism of Action of Mycotoxins)
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12 pages, 2886 KiB  
Review
A Systematic Review and Meta-Analysis of the Inhibitory Effects of Plant-Derived Sterilants on Rodent Population Abundance
by Xuanye Wen, Shuai Yuan, Limei Li, Quanhua Dai, Li Yang, Fan Jiang and Xiao Lin
Toxins 2022, 14(7), 487; https://doi.org/10.3390/toxins14070487 - 15 Jul 2022
Cited by 3 | Viewed by 2342
Abstract
Owing to their low minimal environmental risk and other ethical considerations, plant-derived sterilants are used to control rodent populations. However, the effects of plant-derived sterilants are not immediate, and their efficacy on rodent control is controversial, which negatively affects sterilant research and application. [...] Read more.
Owing to their low minimal environmental risk and other ethical considerations, plant-derived sterilants are used to control rodent populations. However, the effects of plant-derived sterilants are not immediate, and their efficacy on rodent control is controversial, which negatively affects sterilant research and application. Here, a meta-analysis of the available literature was conducted to evaluate the effects of two plant-derived sterilants, triptolide and curcumol, on rodent populations. Using a random-effects and a fixed-effects model, we calculated the weighted mean difference (WMD) and relative risk (RR) and their corresponding 95% confidence intervals (95% CIs). After the application of plant-derived sterilants, the rodent population density tended to decrease. Three outcome-related measures in rodents, i.e., capture rate (RR = 0.31, 95% CI [0.20, 0.47]), pregnancy rate (RR = 0.49, 95% CI [0.40, 0.61]), and sperm survival rate (WMD = −17.53, 95% CI [−28.96, −6.06]), significantly decreased, as shown by a significant reduction of ovarian, uterine, and testicular organ coefficients. However, the number of effective rodent holes did not change significantly after the interventions, indicating that the studied sterilants did not directly eradicate the rodent populations. This study provides a theoretical basis for elucidating the inhibitory mechanisms of plant-derived sterilants on rodent populations and for the rational use of these sterilants. Full article
(This article belongs to the Special Issue Toxic Secondary Plant Metabolites: Toxicology, Medicine, Pharmacology, Ecotoxicology and Crop Protection)
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19 pages, 3711 KiB  
Article
Study on the Mechanism of Mesaconitine-Induced Hepatotoxicity in Rats Based on Metabonomics and Toxicology Network
by Qian Chen, Kai Zhang, Mingjie Jiao, Jiakang Jiao, Dongling Chen, Yihui Yin, Jia Zhang and Fei Li
Toxins 2022, 14(7), 486; https://doi.org/10.3390/toxins14070486 - 14 Jul 2022
Cited by 12 | Viewed by 2867
Abstract
Mesaconitine (MA), one of the main diterpenoid alkaloids in Aconitum, has a variety of pharmacological effects, such as analgesia, anti-inflammation and relaxation of rat aorta. However, MA is a highly toxic ingredient. At present, studies on its toxicity are mainly focused on the [...] Read more.
Mesaconitine (MA), one of the main diterpenoid alkaloids in Aconitum, has a variety of pharmacological effects, such as analgesia, anti-inflammation and relaxation of rat aorta. However, MA is a highly toxic ingredient. At present, studies on its toxicity are mainly focused on the heart and central nervous system, and there are few reports on the hepatotoxic mechanism of MA. Therefore, we evaluated the effects of MA administration on liver. SD rats were randomly divided into a normal saline (NS) group, a low-dose MA group (0.8 mg/kg/day) and a high-dose MA group (1.2 mg/kg/day). After 6 days of administration, the toxicity of MA on the liver was observed. Metabolomic and network toxicology methods were combined to explore the effect of MA on the liver of SD rats and the mechanism of hepatotoxicity in this study. Through metabonomics study, the differential metabolites of MA, such as L-phenylalanine, retinyl ester, L-proline and 5-hydroxyindole acetaldehyde, were obtained, which involved amino acid metabolism, vitamin metabolism, glucose metabolism and lipid metabolism. Based on network toxicological analysis, MA can affect HIF-1 signal pathway, MAPK signal pathway, PI3K-Akt signal pathway and FoxO signal pathway by regulating ALB, AKT1, CASP3, IL2 and other targets. Western blot results showed that protein expression of HMOX1, IL2 and caspase-3 in liver significantly increased after MA administration (p < 0.05). Combined with the results of metabonomics and network toxicology, it is suggested that MA may induce hepatotoxicity by activating oxidative stress, initiating inflammatory reaction and inducing apoptosis. Full article
(This article belongs to the Collection Toxic and Pharmacological Effect of Plant Toxins)
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18 pages, 4548 KiB  
Review
Gambierdiscus and Its Associated Toxins: A Minireview
by Da-Zhi Wang, Ye-Hong Xin and Ming-Hua Wang
Toxins 2022, 14(7), 485; https://doi.org/10.3390/toxins14070485 - 14 Jul 2022
Cited by 9 | Viewed by 5329
Abstract
Gambierdiscus is a dinoflagellate genus widely distributed throughout tropical and subtropical regions. Some members of this genus can produce a group of potent polycyclic polyether neurotoxins responsible for ciguatera fish poisoning (CFP), one of the most significant food-borne illnesses associated with fish consumption. [...] Read more.
Gambierdiscus is a dinoflagellate genus widely distributed throughout tropical and subtropical regions. Some members of this genus can produce a group of potent polycyclic polyether neurotoxins responsible for ciguatera fish poisoning (CFP), one of the most significant food-borne illnesses associated with fish consumption. Ciguatoxins and maitotoxins, the two major toxins produced by Gambierdiscus, act on voltage-gated channels and TRPA1 receptors, consequently leading to poisoning and even death in both humans and animals. Over the past few decades, the occurrence and geographic distribution of CFP have undergone a significant expansion due to intensive anthropogenic activities and global climate change, which results in more human illness, a greater public health impact, and larger economic losses. The global spread of CFP has led to Gambierdiscus and its toxins being considered an environmental and human health concern worldwide. In this review, we seek to provide an overview of recent advances in the field of Gambierdiscus and its associated toxins based on the existing literature combined with re-analyses of current data. The taxonomy, phylogenetics, geographic distribution, environmental regulation, toxin detection method, toxin biosynthesis, and pharmacology and toxicology of Gambierdiscus are summarized and discussed. We also highlight future perspectives on Gambierdiscus and its associated toxins. Full article
(This article belongs to the Special Issue Marine Biotoxins: Predicting and Cumulative Risk Assessment)
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11 pages, 1497 KiB  
Article
Impact of Cyanotoxin Ingestion on Liver Cancer Development Using an At-Risk Two-Staged Model of Mouse Hepatocarcinogenesis
by Igor Mrdjen, Jiyoung Lee, Christopher M. Weghorst and Thomas J. Knobloch
Toxins 2022, 14(7), 484; https://doi.org/10.3390/toxins14070484 - 14 Jul 2022
Cited by 4 | Viewed by 2215
Abstract
Exposure to cyanobacterial hepatotoxins has been linked to the promotion and increased incidence of liver cancer in pre-clinical and epidemiologic studies. The family of hepatotoxins, microcystins (MCs), are produced by over 40 cyanobacterial species found in harmful algal blooms (HABs) worldwide, with MC-LR [...] Read more.
Exposure to cyanobacterial hepatotoxins has been linked to the promotion and increased incidence of liver cancer in pre-clinical and epidemiologic studies. The family of hepatotoxins, microcystins (MCs), are produced by over 40 cyanobacterial species found in harmful algal blooms (HABs) worldwide, with MC-LR being the most common and potent MC congener. In the current study, we hypothesized that the low-dose chronic ingestion of Microcystis cyanotoxins via drinking water would promote liver carcinogenesis in pre-initiated mice. Four groups of C3H/HeJ mice received one intraperitoneal (i.p.) injection of diethylnitrosamine (DEN) at 4 weeks of age. Three weeks later, the mice were administered ad libitum drinking water containing one of the following: (1) reverse osmosis, deionized water; (2) water containing 500 mg/L phenobarbital (PB500); (3) water with purified MC-LR (10 µg/L) added; or (4) water containing lysed Microcystis aeruginosa (lysate; 10 µg/L total MCs). The exposure concentrations were based on environmentally relevant concentrations and previously established Ohio EPA recreational water MC guidelines. Throughout the 30-week exposure, mouse weights, food consumption, and water consumption were not significantly impacted by toxin ingestion. We found no significant differences in the number of gross and histopathologic liver lesion counts across the treatment groups, but we did note that the PB500 group developed lesion densities too numerous to count. Additionally, the proportion of lesions classified as hepatocellular carcinomas in the MC-LR group (44.5%; p < 0.05) and lysate group (55%; p < 0.01) was significantly higher compared to the control group (14.9%). Over the course of the study, the mice ingesting the lysate also had a significantly lower survival probability (64.4%; p < 0.001) compared to water (96.8%), PB500 (95.0%), and MC-LR (95.7%) exposures. Using cyanotoxin levels at common recreational water concentration levels, we demonstrate the cancer-promoting effects of a single cyanotoxin MC congener (MC-LR). Furthermore, we show enhanced hepatocarcinogenesis and significant mortality associated with combinatorial exposure to the multiple MCs and bioactive compounds present in lysed cyanobacterial cells—a scenario representative of the ingestion exposure route, such as HAB-contaminated water and food. Full article
(This article belongs to the Special Issue Analytical, Toxicological and Molecular Biological Assessment of Cyanobacterial Toxins)
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15 pages, 3838 KiB  
Article
Roughness of Production Conditions: Does It Really Affect Stability of IgG-Based Antivenoms?
by Sanja Mateljak Lukačević, Tihana Kurtović, Juraj Borić and Beata Halassy
Toxins 2022, 14(7), 483; https://doi.org/10.3390/toxins14070483 - 13 Jul 2022
Cited by 3 | Viewed by 1710
Abstract
Antivenoms contain either pure animal IgGs or their fragments as an active substance, and are the only specific therapeutics against envenomation arising from snakebites. Although they are highly needed, the low sustainability of such preparations’ manufacture causes constant global shortages. One reason for [...] Read more.
Antivenoms contain either pure animal IgGs or their fragments as an active substance, and are the only specific therapeutics against envenomation arising from snakebites. Although they are highly needed, the low sustainability of such preparations’ manufacture causes constant global shortages. One reason for this is the stability of the product, which contributes not only to the manufacture sustainability, but the product safety as well. It has been hypothesized that the roughness of conditions to which IgGs are exposed during downstream purification disturbs their conformation, making them prone to aggregation, particularly after exposure to secondary stress. The aim of this research was to investigate how the roughness of the downstream purification conditions influences the stability properties of purified IgGs. For this purpose, equine IgGs were extracted from unique hyperimmune plasma by two mild condition-based operational procedures (anion-exchange chromatography and caprylic acid precipitation) and three rougher ones (ammonium sulphate precipitation, cation-exchange chromatography and protein A affinity chromatography). The stability of the refined preparations was studied under non-optimal storage conditions (37 °C, 42 °C, and a transiently lower pH) by monitoring changes in the aggregate content and thermal stability of the pure IgGs. Mild purification protocols generated IgG samples with a lower aggregate share in comparison to the rougher ones. Their tendency for further aggregation was significantly associated with the initial aggregate share. The thermal stability of IgG molecules and the aggregate content in refined samples were inversely correlated. Since the initial proportion of aggregates in the samples was influenced by the operating conditions, we have shown a strong indication that each of them also indirectly affected the stability of the final preparations. This suggests that mild condition-based refinement protocols indeed generate more stable IgGs. Full article
(This article belongs to the Section Animal Venoms)
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15 pages, 2150 KiB  
Article
Exploration of Mycotoxin Accumulation and Transcriptomes of Different Wheat Cultivars during Fusarium graminearum Infection
by Kailin Li, Dianzhen Yu, Zheng Yan, Na Liu, Yingying Fan, Cheng Wang and Aibo Wu
Toxins 2022, 14(7), 482; https://doi.org/10.3390/toxins14070482 - 13 Jul 2022
Cited by 2 | Viewed by 2213
Abstract
Fusarium graminearum is one of the most devastating diseases of wheat worldwide, and can cause Fusarium head blight (FHB). F. graminearum infection and mycotoxin production mainly present in wheat and can be influenced by environmental factors and wheat cultivars. The objectives of this [...] Read more.
Fusarium graminearum is one of the most devastating diseases of wheat worldwide, and can cause Fusarium head blight (FHB). F. graminearum infection and mycotoxin production mainly present in wheat and can be influenced by environmental factors and wheat cultivars. The objectives of this study were to examine the effect of wheat cultivars and interacting conditions of temperature and water activity (aw) on mycotoxin production by two strains of F. graminearum and investigate the response mechanisms of different wheat cultivars to F. graminearum infection. In this regard, six cultivars of wheat spikes under field conditions and three cultivars of post-harvest wheat grains under three different temperature conditions combined with five water activity (aw) conditions were used for F. graminearum infection in our studies. Liquid chromatography tandem mass spectrometry (LC–MS/MS) analysis showed significant differences in the concentration of Fusarium mycotoxins deoxynivalenol (DON) and its derivative deoxynivalenol-3-glucoside (D3G) resulting from wheat cultivars and environmental factors. Transcriptome profiles of wheat infected with F. graminearum revealed the lower expression of disease defense-factor-related genes, such as mitogen-activated protein kinases (MAPK)-encoding genes and hypersensitivity response (HR)-related genes of infected Annong 0711 grains compared with infected Sumai 3 grains. These findings demonstrated the optimal temperature and air humidity resulting in mycotoxin accumulation, which will be beneficial in determining the conditions of the relative level of risk of contamination with FHB and mycotoxins. More importantly, our transcriptome profiling illustrated differences at the molecular level between wheat cultivars with different FHB resistances, which will lay the foundation for further research on mycotoxin biosynthesis of F. graminearum and regulatory mechanisms of wheat to F. graminearum. Full article
(This article belongs to the Special Issue Evaluation and Prevention of Mycotoxin Contamination and Toxicological Effects)
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13 pages, 2223 KiB  
Article
Evaluating Antivenom Efficacy against Echis carinatus Venoms—Screening for In Vitro Alternatives
by Siddharth Bhatia, Avni Blotra and Karthikeyan Vasudevan
Toxins 2022, 14(7), 481; https://doi.org/10.3390/toxins14070481 - 13 Jul 2022
Cited by 10 | Viewed by 3126
Abstract
In India, polyvalent antivenom is the mainstay treatment for snakebite envenoming. Due to batch-to-batch variation in antivenom production, manufacturers have to estimate its efficacy at each stage of IgG purification using the median effective dose which involves 100–120 mice for each batch. There [...] Read more.
In India, polyvalent antivenom is the mainstay treatment for snakebite envenoming. Due to batch-to-batch variation in antivenom production, manufacturers have to estimate its efficacy at each stage of IgG purification using the median effective dose which involves 100–120 mice for each batch. There is an urgent need to replace the excessive use of animals in snake antivenom production using in vitro alternatives. We tested the efficacy of a single batch of polyvalent antivenom from VINS bioproducts limited on Echis carinatus venom collected from three different locations—Tamil Nadu (ECVTN), Goa (ECVGO) and Rajasthan (ECVRAJ)—using different in vitro assays. Firstly, size-exclusion chromatography (SEC-HPLC) was used to quantify antivenom–venom complexes to assess the binding efficiency of the antivenom. Secondly, clotting, proteolytic and PLA2 activity assays were performed to quantify the ability of the antivenom to neutralize venom effects. The use of both binding and functional assays allowed us to measure the efficacy of the antivenom, as they represent multiple impacts of snake envenomation. The response from the assays was recorded for different antivenom–venom ratios and the dose–response curves were plotted. Based on the parameters that explained the curves, the efficacy scores (ES) of antivenom were computed. The binding assay revealed that ECVTN had more antivenom–venom complexes formed compared to the other venoms. The capacity of antivenom to neutralize proteolytic and PLA2 effects was lowest against ECVRAJ. The mean efficacy score of antivenom against ECVTN was the greatest, which was expected, as ECVTN is mainly used by antivenom manufacturers. These findings pave a way for the development of in vitro alternatives in antivenom efficacy assessment. Full article
(This article belongs to the Special Issue Snakebite Clinics and Pathogenesis: From Preclinical to Resource Mapping Studies)
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14 pages, 2438 KiB  
Article
Vegetative Insecticidal Protein Vip3Aa Is Transported via Membrane Vesicles in Bacillus thuringiensis BMB171
by Yizhuo Zhang, Xuelian Li, Hongwei Tian, Baoju An, Bing Yan and Jun Cai
Toxins 2022, 14(7), 480; https://doi.org/10.3390/toxins14070480 - 13 Jul 2022
Cited by 2 | Viewed by 2095
Abstract
Vegetative insecticidal protein Vip3Aa, secreted by many Bacillus thuringiensis (Bt) strains during the vegetative growth stage, represents the second-generation insecticidal toxin. In recent years, significant progress has been made on its structure and action mechanism. However, how it is translocated across the cytoplasmic [...] Read more.
Vegetative insecticidal protein Vip3Aa, secreted by many Bacillus thuringiensis (Bt) strains during the vegetative growth stage, represents the second-generation insecticidal toxin. In recent years, significant progress has been made on its structure and action mechanism. However, how it is translocated across the cytoplasmic membrane into the environment remains a mystery. This work demonstrates that Vip3Aa is not secreted by the General Secretion (Sec) System. To reveal the secretory pathway of Vip3A, we purified the membrane vesicles (MVs) of B. thuringiensis BMB171 and observed by TEM. The size of MVs was determined by the dynamic light scattering method, and their diameter was approximately 40–200 nm, which is consistent with the vesicles in Gram-negative bacteria. Moreover, Vip3A could be detected in the purified MVs by Western blot, and immunoelectron microscopy reveals Vip3A antibody-coated gold particles located in the MVs. After deleting its signal peptide, chitinase B (ChiB) failed to be secreted. However, the recombinant ChiB, whose signal peptide was substituted with the N-terminal 39 amino acids from Vip3A, was secreted successfully through MVs. Thus, this sequence is proposed as the signal region responsible for vesicle transport. Together, our results revealed for the first time that Vip3Aa is transported to the medium via MVs. Full article
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17 pages, 3173 KiB  
Article
Gill Junction Injury and Microbial Disorders Induced by Microcystin-Leucine Arginine in Lithobates catesbeianus Tadpoles
by Huiling Jiang, Jun He, Hui Wang, Lingling Zheng, Xiaoran Wang, Huijuan Zhang, Hailong Wu and Yilin Shu
Toxins 2022, 14(7), 479; https://doi.org/10.3390/toxins14070479 - 13 Jul 2022
Cited by 6 | Viewed by 2320
Abstract
Microcystin-LR (MC-LR) is widely present in waters around the world, but its potential toxic effects and mechanisms on amphibian gills remain unknown. In the present study, tadpoles (Lithobates catesbeianus) were exposed to environmentally realistic concentrations of 0.5, 2 μg/L MC-LR, and [...] Read more.
Microcystin-LR (MC-LR) is widely present in waters around the world, but its potential toxic effects and mechanisms on amphibian gills remain unknown. In the present study, tadpoles (Lithobates catesbeianus) were exposed to environmentally realistic concentrations of 0.5, 2 μg/L MC-LR, and 0 μg/L MC-LR (Control) for 30 days with the objective to unveil the impairment of gill health. The lysozyme was downregulated, while pattern recognition receptors and complement and adaptive immune processes were upregulated and the ability of gill supernatant to inhibit pathogenic bacteria decreased in the 0.5 and 2 μg/L MC-LR groups. The transcriptions of epithelial barrier components (e.g., CLDN1) were significantly decreased in MC-LR-exposed gills, while the gill content of lipopolysaccharide (LPS) endotoxins and the transcriptions of downstream responsive genes (e.g., TLR4 and NF-κB) were concurrently increased. In addition, the number of eosinophils and the expression of pro-inflammatory cytokines (e.g., IL-1β and TNF-α) were increased. These results imply that exposure of tadpoles to low environmentally concentrations of MC-LR leads to inflammation, increased permeability, and a reduced ability to inhibit pathogenic bacteria. The epithelial cells of inner gill filaments increased and transcriptions of hypoxic stress genes (e.g., HIF-1α, FLT1, and SERPINE1) were upregulated within the exposed group. As a consequence, exposure to MC-LR may lead to hypoxic stress. MC-LR exposure also drove gill microbiota to a dysbiosis. The relative abundance of Elizabethkingia was positively correlated with content of LPS and transcriptions of NF-κB and TNF-α. Overall, this study presents the first evidence about the pronounced impacts of MC-LR exposure on gills of amphibians, highlighting the susceptibility of early developing tadpoles to the environmental risks of MC-LR. Full article
(This article belongs to the Special Issue Ecology and Toxicology of Cyanobacteria and Cyanotoxins)
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19 pages, 6329 KiB  
Article
Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861
by Hossein Panjideh, Nicole Niesler, Alexander Weng and Hendrik Fuchs
Toxins 2022, 14(7), 478; https://doi.org/10.3390/toxins14070478 - 13 Jul 2022
Cited by 5 | Viewed by 2888 | Correction
Abstract
Immunotoxins do not only bind to cancer-specific receptors to mediate the elimination of tumor cells through the innate immune system, but also increase target cytotoxicity by the intrinsic toxin activity. The plant glycoside SO1861 was previously reported to enhance the endolysosomal escape of [...] Read more.
Immunotoxins do not only bind to cancer-specific receptors to mediate the elimination of tumor cells through the innate immune system, but also increase target cytotoxicity by the intrinsic toxin activity. The plant glycoside SO1861 was previously reported to enhance the endolysosomal escape of antibody-toxin conjugates in non-hematopoietic cells, thus increasing their cytotoxicity manifold. Here we tested this technology for the first time in a lymphoma in vivo model. First, the therapeutic CD20 antibody obinutuzumab was chemically conjugated to the ribosome-inactivating protein dianthin. The cytotoxicity of obinutuzumab-dianthin (ObiDi) was evaluated on human B-lymphocyte Burkitt’s lymphoma Raji cells and compared to human T-cell leukemia off-target Jurkat cells. When tested in combination with SO1861, the cytotoxicity for target cells was 131-fold greater than for off-target cells. In vivo imaging in a xenograft model of B-cell lymphoma in mice revealed that ObiDi/SO1861 efficiently prevents tumor growth (51.4% response rate) compared to the monotherapy with ObiDi (25.9%) and non-conjugated obinutuzumab (20.7%). The reduction of tumor volume and overall survival was also improved. Taken together, our results substantially contribute to the development of a combination therapy with SO1861 as a platform technology to enhance the efficacy of therapeutic antibody-toxin conjugates in lymphoma and leukemia. Full article
(This article belongs to the Special Issue Immunotoxin and beyond—Past, Present and Future Perspectives)
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18 pages, 2774 KiB  
Article
Study on In Vitro Metabolism and In Vivo Pharmacokinetics of Beauvericin
by Yu Yuan, Guangpeng Meng, Yuanbo Li and Chunjie Wu
Toxins 2022, 14(7), 477; https://doi.org/10.3390/toxins14070477 - 12 Jul 2022
Cited by 7 | Viewed by 3136
Abstract
Beauvericin (BEA) is a well-known mycotoxin produced by many fungi, including Beaveria bassiana. The purpose of this study was to evaluate the in vitro distribution and metabolism characteristics as well as the in vivo pharmacokinetic (PK) profile of BEA. The in vitro metabolism [...] Read more.
Beauvericin (BEA) is a well-known mycotoxin produced by many fungi, including Beaveria bassiana. The purpose of this study was to evaluate the in vitro distribution and metabolism characteristics as well as the in vivo pharmacokinetic (PK) profile of BEA. The in vitro metabolism studies of BEA were performed using rat, dog, mouse, monkey and human liver microsomes, cryopreserved hepatocytes and plasma under conditions of linear kinetics to estimate the respective elimination rates. Additionally, LC-UV-MSn (n = 1~2) was used to identify metabolites in human, rat, mouse, dog and monkey liver microsomes. Furthermore, cytochrome P450 (CYP) reaction phenotyping was carried out. Finally, the absolute bioavailability of BEA was evaluated by intravenous and oral administration in rats. BEA was metabolically stable in the liver microsomes and hepatocytes of humans and rats; however, it was a strong inhibitor of midazolam 1′-hydroxylase (CYP3A4) and mephenytoin 4′-hydroxylase (CYP2C19) activities in human liver microsomes. The protein binding fraction values of BEA were >90% and the half-life (T1/2) values of BEA were approximately 5 h in the plasma of the five species. The absolute bioavailability was calculated to be 29.5%. Altogether, these data indicate that BEA has great potential for further development as a drug candidate. Metabolic studies of different species can provide important reference values for further safety evaluation. Full article
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