Toxins

21 pages, 2525 KiB

Open AccessEditor’s ChoiceArticle

A Novel Cytotoxic Mechanism for Triple-Negative Breast Cancer Cells Induced by the Type II Heat-Labile Enterotoxin LT-IIc through Ganglioside Ligation

by Natalie D. King-Lyons, Aryana S. Bhati, John C. Hu, Lorrie M. Mandell, Gautam N. Shenoy, Hugh J. Willison and Terry D. Connell

Toxins 2024, 16(7), 311; https://doi.org/10.3390/toxins16070311 - 11 Jul 2024

Viewed by 2082

Abstract

Triple-negative breast cancer (TNBC), which constitutes 10–20 percent of all breast cancers, is aggressive, has high metastatic potential, and carries a poor prognosis due to limited treatment options. LT-IIc, a member of the type II subfamily of ADP-ribosylating—heat-labile enterotoxins that bind to a [...] Read more.

Triple-negative breast cancer (TNBC), which constitutes 10–20 percent of all breast cancers, is aggressive, has high metastatic potential, and carries a poor prognosis due to limited treatment options. LT-IIc, a member of the type II subfamily of ADP-ribosylating—heat-labile enterotoxins that bind to a distinctive set of cell-surface ganglioside receptors—is cytotoxic toward TNBC cell lines, but has no cytotoxic activity for non-transformed breast epithelial cells. Here, primary TNBC cells, isolated from resected human tumors, showed an enhanced cytotoxic response specifically toward LT-IIc, in contrast to other enterotoxins that were tested. MDA-MB-231 cells, a model for TNBC, were used to evaluate potential mechanisms of cytotoxicity by LT-IIc, which induced elevated intracellular cAMP and stimulated the cAMP response element-binding protein (CREB) signaling pathway. To dissect the role of ADP-ribosylation, cAMP induction, and ganglioside ligation in the cytotoxic response, MDA-MB-231 cells were exposed to wild-type LT-IIc, the recombinant B-pentamer of LT-IIc that lacks the ADP-ribosylating A polypeptide, or mutants of LT-IIc with an enzymatically inactivated A1-domain. These experiments revealed that the ADP-ribosyltransferase activity of LT-IIc was nonessential for inducing the lethality of MDA-MB-231 cells. In contrast, a mutant LT-IIc with an altered ganglioside binding activity failed to trigger a cytotoxic response in MDA-MB-231 cells. Furthermore, the pharmacological inhibition of ganglioside expression protected MDA-MB-231 cells from the cytotoxic effects of LT-IIc. These data establish that ganglioside ligation, but not the induction of cAMP production nor ADP-ribosyltransferase activity, is essential to initiating the LT-IIc-dependent cell death of MDA-MB-231 cells. These experiments unveiled previously unknown properties of LT-IIc and gangliosides in signal transduction, offering the potential for the targeted treatment of TNBC, an option that is desperately needed. Full article

(This article belongs to the Section Bacterial Toxins)

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22 pages, 2744 KiB

Open AccessEditor’s ChoiceReview

Shining a Light on Venom-Peptide Receptors: Venom Peptides as Targeted Agents for In Vivo Molecular Imaging

by Chun Yuen Chow and Glenn F. King

Toxins 2024, 16(7), 307; https://doi.org/10.3390/toxins16070307 - 4 Jul 2024

Cited by 1 | Viewed by 2559

Abstract

Molecular imaging has revolutionised the field of biomedical research by providing a non-invasive means to visualise and understand biochemical processes within living organisms. Optical fluorescent imaging in particular allows researchers to gain valuable insights into the dynamic behaviour of a target of interest [...] Read more.

Molecular imaging has revolutionised the field of biomedical research by providing a non-invasive means to visualise and understand biochemical processes within living organisms. Optical fluorescent imaging in particular allows researchers to gain valuable insights into the dynamic behaviour of a target of interest in real time. Ion channels play a fundamental role in cellular signalling, and they are implicated in diverse pathological conditions, making them an attractive target in the field of molecular imaging. Many venom peptides exhibit exquisite selectivity and potency towards ion channels, rendering them ideal agents for molecular imaging applications. In this review, we illustrate the use of fluorescently-labelled venom peptides for disease diagnostics and intraoperative imaging of brain tumours and peripheral nerves. Finally, we address challenges for the development and clinical translation of venom peptides as nerve-targeted imaging agents. 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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20 pages, 4165 KiB

Open AccessEditor’s ChoiceArticle

Bioremediation of Aflatoxin B₁ by Meyerozyma guilliermondii AF01 in Peanut Meal via Solid-State Fermentation

by Wan Zhang, Changpo Sun, Wei Wang and Zhongjie Zhang

Toxins 2024, 16(7), 305; https://doi.org/10.3390/toxins16070305 - 4 Jul 2024

Cited by 4 | Viewed by 1819

Abstract

The use of microorganisms to manage aflatoxin contamination is a gentle and effective approach. The aim of this study was to test the removal of AFB₁ from AFB₁-contaminated peanut meal by a strain of Meyerozyma guilliermondii AF01 screened by the [...] Read more.

The use of microorganisms to manage aflatoxin contamination is a gentle and effective approach. The aim of this study was to test the removal of AFB₁ from AFB₁-contaminated peanut meal by a strain of Meyerozyma guilliermondii AF01 screened by the authors and to optimize the conditions of the biocontrol. A regression model with the removal ratio of AFB₁ as the response value was established by means of single-factor and response surface experiments. It was determined that the optimal conditions for the removal of AFB₁ from peanut meal by AF01 were 75 h at 29 °C under the natural pH, with an inoculum of 5.5%; the removal ratio of AFB₁ reached 69.31%. The results of simulating solid-state fermentation in production using shallow pans and fermentation bags showed that the removal ratio of AFB₁ was 68.85% and 70.31% in the scaled-up experiments, respectively. This indicated that AF01 had strong adaptability to the environment with facultative anaerobic fermentation detoxification ability. The removal ratio of AFB₁ showed a positive correlation with the growth of AF01, and there were no significant changes in the appearance and quality of the peanut meal after fermentation. This indicated that AF01 had the potential to be used in practical production. Full article

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10 pages, 538 KiB

Open AccessEditor’s ChoiceArticle

Enhancing Botulinum Toxin Injection Precision: The Efficacy of a Single Cadaveric Ultrasound Training Intervention for Improved Anatomical Localization

by Camille Heslot, Omar Khan, Alexis Schnitzler, Chloe Haldane, Romain David and Rajiv Reebye

Toxins 2024, 16(7), 304; https://doi.org/10.3390/toxins16070304 - 2 Jul 2024

Cited by 2 | Viewed by 1884

Abstract

Ultrasound guidance can enhance existing landmark-based injection methods, even through a brief and single exposure during a cadaveric training course. A total of twelve participants were enrolled in this training program, comprising nine physical medicine and rehabilitation specialists, one pediatrician, and two physician [...] Read more.

Ultrasound guidance can enhance existing landmark-based injection methods, even through a brief and single exposure during a cadaveric training course. A total of twelve participants were enrolled in this training program, comprising nine physical medicine and rehabilitation specialists, one pediatrician, and two physician assistants. For each participant, one upper-limb muscle and one lower-limb muscle were randomly chosen from the preselected muscle group. Subsequently, participants were tasked with injecting both of their chosen cadaveric muscles with 1 mL of acrylic paint using a manual needle palpation technique, relying solely on their knowledge of anatomic landmarks. Participants then underwent a personalized, one-to-one ultrasound teaching session, lasting approximately five minutes, conducted by two highly experienced instructors. Following this instructive phase, participants were tasked with a second round of injections, targeting the same two muscles in the lower and upper limbs. However, this time, the injections were performed using anatomical landmarks and ultrasound guidance. To facilitate differentiation from the initial injections, a distinct color of acrylic paint was employed. When employing the anatomical landmark-based approach, the overall success rate for injections was 67%, with 16 out of 24 targeted muscles accurately injected. With the incorporation of ultrasound guidance, the success rate was 92%, precisely targeting 22 out of the 24 muscles under examination. There was an improvement in injection accuracy achievable through the integration of ultrasound guidance, even with minimal training exposure. Our single cadaveric ultra-sound training program contributes valuable insights to the utilization of ultrasound for anatomy training to help optimize the targeting of BoNT-A. Full article

(This article belongs to the Special Issue Uses of Botulinum Toxin Injection in Medicine)

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24 pages, 4815 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

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

Cited by 4 | Viewed by 2405

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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36 pages, 4406 KiB

Open AccessEditor’s ChoiceReview

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

Cited by 10 | Viewed by 5030

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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29 pages, 703 KiB

Open AccessEditor’s ChoiceReview

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

Cited by 11 | Viewed by 7313

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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24 pages, 7201 KiB

Open AccessEditor’s ChoiceReview

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

Cited by 8 | Viewed by 4354

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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18 pages, 633 KiB

Open AccessEditor’s ChoiceReview

Challenges of Diphtheria Toxin Detection

by Marta Prygiel, Ewa Mosiej, Maciej Polak, Katarzyna Krysztopa-Grzybowska, Karol Wdowiak, Kamila Formińska and Aleksandra A. Zasada

Toxins 2024, 16(6), 245; https://doi.org/10.3390/toxins16060245 - 26 May 2024

Cited by 1 | Viewed by 4660

Abstract

Diphtheria toxin (DT) is the main virulence factor of Corynebacterium diphtheriae, C. ulcerans and C. pseudotuberculosis. Moreover, new Corynebacterium species with the potential to produce diphtheria toxin have also been described. Therefore, the detection of the toxin is the most important test in [...] Read more.

Diphtheria toxin (DT) is the main virulence factor of Corynebacterium diphtheriae, C. ulcerans and C. pseudotuberculosis. Moreover, new Corynebacterium species with the potential to produce diphtheria toxin have also been described. Therefore, the detection of the toxin is the most important test in the microbiological diagnosis of diphtheria and other corynebacteria infections. Since the first demonstration in 1888 that DT is a major virulence factor of C. diphtheriae, responsible for the systemic manifestation of the disease, various methods for DT detection have been developed, but the diagnostic usefulness of most of them has not been confirmed on a sufficiently large group of samples. Despite substantial progress in the science and diagnostics of infectious diseases, the Elek test is still the basic recommended diagnostic test for DT detection. The challenge here is the poor availability of an antitoxin and declining experience even in reference laboratories due to the low prevalence of diphtheria in developed countries. However, recent and very promising assays have been developed with the potential for use as rapid point-of-care testing (POCT), such as ICS and LFIA for toxin detection, LAMP for tox gene detection, and biosensors for both. Full article

(This article belongs to the Special Issue Multi Methods for Detecting Natural Toxins)

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15 pages, 3020 KiB

Open AccessEditor’s ChoiceArticle

The Possible Role of Mycotoxins in the Pathogenesis of Endometrial Cancer

by Márkó Unicsovics, Zsófia Molnár, Miklós Mézes, Katalin Posta, György Nagyéri, Szabolcs Várbíró, Nándor Ács, Levente Sára and Zsuzsanna Szőke

Toxins 2024, 16(6), 236; https://doi.org/10.3390/toxins16060236 - 23 May 2024

Cited by 7 | Viewed by 3144

Abstract

Endometrial cancer is one of the most common cancer types among women. Many factors can contribute to the development of this disease, including environmental factors and, thus, eating habits. Our study aims to determine the levels of various mycotoxins and their metabolites in [...] Read more.

Endometrial cancer is one of the most common cancer types among women. Many factors can contribute to the development of this disease, including environmental factors and, thus, eating habits. Our study aims to determine the levels of various mycotoxins and their metabolites in the blood serum and endometrial tissue samples of participants with previously proven endometrial cancer and to find possible contributions to cancer development. In the cohort clinical trial, 52 participants aged between 44 and 86 were studied. The participants were divided into two groups: patients or matched controls. All patients had previously histologically diagnosed endometrial cancer. The cancer patients were divided into low-grade endometrioid and low- plus high-grade endometrioid groups. Controls had no history of endometrial malignancy or premalignancy. Blood serum and endometrial tissue samples were obtained from all study patients. We compared the concentrations of total Aflatoxins (Afs), Deoxynivalenol (DON), Ochratoxin-A (OTA), T2-toxin and HT2 toxin (T2/HT2 toxin), Zearalenone (ZEN), alpha-Zearalenol (α-ZOL), and Fumonisin B1 (FB1) in the serum and endometrium between the different study groups. As a result, we can see a significant correlation between the higher levels of Afs and zearalenone and the presence of endometrial cancer. In the case of Afs, DON, OTA, T2/HT2 toxins, ZEN, and alpha-ZOL, we measured higher endometrial concentrations than in serum. Considering the effect of mycotoxins and eating habits on cancer development, our results might lead to further research exploring the relationship between certain mycotoxins and endometrium cancer. Full article

(This article belongs to the Special Issue Advances in Contamination, Detection and Risk Assessment of Mycotoxins)

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10 pages, 4613 KiB

Open AccessEditor’s ChoiceArticle

Borrelia burgdorferi 0755, a Novel Cytotoxin with Unknown Function in Lyme Disease

by Sam T. Donta

Toxins 2024, 16(6), 233; https://doi.org/10.3390/toxins16060233 - 21 May 2024

Viewed by 3580

Abstract

The pathophysiology of Lyme disease, especially in its persistent form, remains to be determined. As many of the neurologic symptoms are similar to those seen in other toxin-associated disorders, a hypothesis was generated that B. burgdorferi, the causative agent of Lyme disease, [...] Read more.

The pathophysiology of Lyme disease, especially in its persistent form, remains to be determined. As many of the neurologic symptoms are similar to those seen in other toxin-associated disorders, a hypothesis was generated that B. burgdorferi, the causative agent of Lyme disease, may produce a neurotoxin to account for some of the symptoms. Using primers against known conserved bacterial toxin groups, and PCR technology, a candidate neurotoxin was discovered. The purified protein was temporarily named BbTox, and was subsequently found to be identical to BB0755, a protein deduced from the genome sequence of B. burgdorferi that has been annotated as a Z ribonuclease. BbTox has cytotoxic activity against cells of neural origin in tissue culture. Its toxic activity appears to be directed against cytoskeletal elements, similar to that seen with toxins of Clostridioides difficile and Clostridioides botulinum, but differing from that of cholera and E. coli toxins, and other toxins. It remains to be determined whether BbTox has direct cytotoxic effects on neural or glial cells in vivo, or its activity is primarily that of a ribonuclease analogous to other bacterial ribonucleases that are involved in antibiotic tolerance remains to be determined. Full article

(This article belongs to the Section Bacterial Toxins)

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14 pages, 1000 KiB

Open AccessEditor’s ChoiceReview

A Historical Perspective on Uremia and Uremic Toxins

by Björn Meijers, Ward Zadora and Jerome Lowenstein

Toxins 2024, 16(5), 227; https://doi.org/10.3390/toxins16050227 - 15 May 2024

Cited by 9 | Viewed by 3815

Abstract

Uremia, also known as uremic syndrome, refers to the clinical symptoms in the final stage of renal failure. The definition of the term has changed over time due to an improved comprehension of the kidney’s function and the advancement of dialysis technology. Here, [...] Read more.

Uremia, also known as uremic syndrome, refers to the clinical symptoms in the final stage of renal failure. The definition of the term has changed over time due to an improved comprehension of the kidney’s function and the advancement of dialysis technology. Here, we aim to present an overview of the various concepts that have developed regarding uremia throughout the years. We provide a comprehensive review of the historical progression starting from the early days of Kolff and his predecessors, continuing with the initial research conducted by Niwa et al., and culminating in the remote sensing hypothesis of Nigam. Additionally, we explore the subsequent investigation into the function of these toxins as signaling molecules in various somatic cells. Full article

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

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15 pages, 4425 KiB

Open AccessEditor’s ChoiceArticle

Specificity of DNA ADP-Ribosylation Reversal by NADARs

by Bara Cihlova, Yang Lu, Andreja Mikoč, Marion Schuller and Ivan Ahel

Toxins 2024, 16(5), 208; https://doi.org/10.3390/toxins16050208 - 28 Apr 2024

Cited by 5 | Viewed by 3184

Abstract

Recent discoveries establish DNA and RNA as bona fide substrates for ADP-ribosylation. NADAR (“NAD- and ADP-ribose”-associated) enzymes reverse guanine ADP-ribosylation and serve as antitoxins in the DarT-NADAR operon. Although NADARs are widespread across prokaryotes, eukaryotes, and viruses, their specificity and broader physiological roles [...] Read more.

Recent discoveries establish DNA and RNA as bona fide substrates for ADP-ribosylation. NADAR (“NAD- and ADP-ribose”-associated) enzymes reverse guanine ADP-ribosylation and serve as antitoxins in the DarT-NADAR operon. Although NADARs are widespread across prokaryotes, eukaryotes, and viruses, their specificity and broader physiological roles remain poorly understood. Using phylogenetic and biochemical analyses, we further explore de-ADP-ribosylation activity and antitoxin functions of NADAR domains. We demonstrate that different subfamilies of NADAR proteins from representative E. coli strains and an E. coli-infecting phage retain biochemical activity while displaying specificity in providing protection from toxic guanine ADP-ribosylation in cells. Furthermore, we identify a myxobacterial enzyme within the YbiA subfamily that functions as an antitoxin for its associated DarT-unrelated ART toxin, which we termed YarT, thus presenting a hitherto uncharacterised ART-YbiA toxin–antitoxin pair. Our studies contribute to the burgeoning field of DNA ADP-ribosylation, supporting its physiological relevance within and beyond bacterial toxin–antitoxin systems. Notably, the specificity and confinement of NADARs to non-mammals infer their potential as highly specific targets for antimicrobial drugs with minimal off-target effects. Full article

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18 pages, 1822 KiB

Open AccessEditor’s ChoiceReview

Microcystin Contamination in Irrigation Water and Health Risk

by Mohammed Haida, Fatima El Khalloufi, Richard Mugani, Yasser Essadki, Alexandre Campos, Vitor Vasconcelos and Brahim Oudra

Toxins 2024, 16(4), 196; https://doi.org/10.3390/toxins16040196 - 19 Apr 2024

Cited by 9 | Viewed by 3438

Abstract

Microcystins (MCs), natural hepatotoxic compounds produced by cyanobacteria, pose significant risks to water quality, ecosystem stability, and the well-being of animals, plants, and humans when present in elevated concentrations. The escalating contamination of irrigation water with MCs presents a growing threat to terrestrial [...] Read more.

Microcystins (MCs), natural hepatotoxic compounds produced by cyanobacteria, pose significant risks to water quality, ecosystem stability, and the well-being of animals, plants, and humans when present in elevated concentrations. The escalating contamination of irrigation water with MCs presents a growing threat to terrestrial plants. The customary practice of irrigating crops from local water sources, including lakes and ponds hosting cyanobacterial blooms, serves as a primary conduit for transferring these toxins. Due to their high chemical stability and low molecular weight, MCs have the potential to accumulate in various parts of plants, thereby increasing health hazards for consumers of agricultural products, which serve as the foundation of the Earth’s food chain. MCs can bioaccumulate, migrate, potentially biodegrade, and pose health hazards to humans within terrestrial food systems. This study highlights that MCs from irrigation water reservoirs can bioaccumulate and come into contact with plants, transferring into the food chain. Additionally, it investigates the natural mechanisms that organisms employ for conjugation and the microbial processes involved in MC degradation. To gain a comprehensive understanding of the role of MCs in the terrestrial food chain and to elucidate the specific health risks associated with consuming crops irrigated with water contaminated with these toxins, further research is necessary. Full article

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17 pages, 10327 KiB

Open AccessEditor’s ChoiceArticle

Edodin: A New Type of Toxin from Shiitake Mushroom (Lentinula edodes) That Inactivates Mammalian Ribosomes

by Lucía Citores, Sara Ragucci, Claudia C. Gay, Rosita Russo, Angela Chambery, Antimo Di Maro, Rosario Iglesias and José M. Ferreras

Toxins 2024, 16(4), 185; https://doi.org/10.3390/toxins16040185 - 10 Apr 2024

Cited by 3 | Viewed by 2792

Abstract

Ribosome-inactivating proteins (RIPs) are a group of proteins with rRNA N-glycosylase activity that irreversibly inhibit protein synthesis and consequently cause cell death. Recently, an RIP called ledodin has been found in shiitake; it is cytotoxic, strongly inhibits protein synthesis, and shows rRNA N-glycosylase [...] Read more.

Ribosome-inactivating proteins (RIPs) are a group of proteins with rRNA N-glycosylase activity that irreversibly inhibit protein synthesis and consequently cause cell death. Recently, an RIP called ledodin has been found in shiitake; it is cytotoxic, strongly inhibits protein synthesis, and shows rRNA N-glycosylase activity. In this work, we isolated and characterized a 50 kDa cytotoxic protein from shiitake that we named edodin. Edodin inhibits protein synthesis in a mammalian cell-free system, but not in insect-, yeast-, and bacteria-derived systems. It exhibits rRNA N-glycosylase and DNA-nicking activities, which relate it to plant RIPs. It was also shown to be toxic to HeLa and COLO 320 cells. Its structure is not related to other RIPs found in plants, bacteria, or fungi, but, instead, it presents the characteristic structure of the fold type I of pyridoxal phosphate-dependent enzymes. Homologous sequences have been found in other fungi of the class Agaricomycetes; thus, edodin could be a new type of toxin present in many fungi, some of them edible, which makes them of great interest in health, both for their involvement in food safety and for their potential biomedical and biotechnological applications. Full article

(This article belongs to the Special Issue Biological Activities of Ribosome Inactivating Proteins II)

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46 pages, 7856 KiB

Open AccessEditor’s ChoiceReview

Overview of Bacterial Protein Toxins from Pathogenic Bacteria: Mode of Action and Insights into Evolution

by Michel R. Popoff

Toxins 2024, 16(4), 182; https://doi.org/10.3390/toxins16040182 - 8 Apr 2024

Cited by 11 | Viewed by 9033

Abstract

Bacterial protein toxins are secreted by certain bacteria and are responsible for mild to severe diseases in humans and animals. They are among the most potent molecules known, which are active at very low concentrations. Bacterial protein toxins exhibit a wide diversity based [...] Read more.

Bacterial protein toxins are secreted by certain bacteria and are responsible for mild to severe diseases in humans and animals. They are among the most potent molecules known, which are active at very low concentrations. Bacterial protein toxins exhibit a wide diversity based on size, structure, and mode of action. Upon recognition of a cell surface receptor (protein, glycoprotein, and glycolipid), they are active either at the cell surface (signal transduction, membrane damage by pore formation, or hydrolysis of membrane compound(s)) or intracellularly. Various bacterial protein toxins have the ability to enter cells, most often using an endocytosis mechanism, and to deliver the effector domain into the cytosol, where it interacts with an intracellular target(s). According to the nature of the intracellular target(s) and type of modification, various cellular effects are induced (cell death, homeostasis modification, cytoskeleton alteration, blockade of exocytosis, etc.). The various modes of action of bacterial protein toxins are illustrated with representative examples. Insights in toxin evolution are discussed. Full article

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

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11 pages, 4216 KiB

Open AccessEditor’s ChoiceArticle

High-Voltage Toxin’Roll: Electrostatic Charge Repulsion as a Dynamic Venom Resistance Trait in Pythonid Snakes

by Uthpala Chandrasekara, Emilie M. Broussard, Darin R. Rokyta and Bryan G. Fry

Toxins 2024, 16(4), 176; https://doi.org/10.3390/toxins16040176 - 4 Apr 2024

Viewed by 2705

Abstract

The evolutionary interplay between predator and prey has significantly shaped the development of snake venom, a critical adaptation for subduing prey. This arms race has spurred the diversification of the components of venom and the corresponding emergence of resistance mechanisms in the prey [...] Read more.

The evolutionary interplay between predator and prey has significantly shaped the development of snake venom, a critical adaptation for subduing prey. This arms race has spurred the diversification of the components of venom and the corresponding emergence of resistance mechanisms in the prey and predators of venomous snakes. Our study investigates the molecular basis of venom resistance in pythons, focusing on electrostatic charge repulsion as a defense against α-neurotoxins binding to the alpha-1 subunit of the postsynaptic nicotinic acetylcholine receptor. Through phylogenetic and bioactivity analyses of orthosteric site sequences from various python species, we explore the prevalence and evolution of amino acid substitutions that confer resistance by electrostatic repulsion, which initially evolved in response to predatory pressure by Naja (cobra) species (which occurs across Africa and Asia). The small African species Python regius retains the two resistance-conferring lysines (positions 189 and 191) of the ancestral Python genus, conferring resistance to sympatric Naja venoms. This differed from the giant African species Python sebae, which has secondarily lost one of these lysines, potentially due to its rapid growth out of the prey size range of sympatric Naja species. In contrast, the two Asian species Python brongersmai (small) and Python bivittatus (giant) share an identical orthosteric site, which exhibits the highest degree of resistance, attributed to three lysine residues in the orthosteric sites. One of these lysines (at orthosteric position 195) evolved in the last common ancestor of these two species, which may reflect an adaptive response to increased predation pressures from the sympatric α-neurotoxic snake-eating genus Ophiophagus (King Cobras) in Asia. All these terrestrial Python species, however, were less neurotoxin-susceptible than pythons in other genera which have evolved under different predatory pressure as: the Asian species Malayopython reticulatus which is arboreal as neonates and juveniles before rapidly reaching sizes as terrestrial adults too large for sympatric Ophiophagus species to consider as prey; and the terrestrial Australian species Aspidites melanocephalus which occupies a niche, devoid of selection pressure from α-neurotoxic predatory snakes. Our findings underline the importance of positive selection in the evolution of venom resistance and suggest a complex evolutionary history involving both conserved traits and secondary evolution. This study enhances our understanding of the molecular adaptations that enable pythons to survive in environments laden with venomous threats and offers insights into the ongoing co-evolution between venomous snakes and their prey. Full article

(This article belongs to the Section Animal Venoms)

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20 pages, 2131 KiB

Open AccessEditor’s ChoiceReview

Botulinum Toxin Injections to Manage Sequelae of Peripheral Facial Palsy

by Fabienne Carré, Jérémy Amar, Frédéric Tankéré and Claire Foirest

Toxins 2024, 16(3), 161; https://doi.org/10.3390/toxins16030161 - 20 Mar 2024

Cited by 2 | Viewed by 6329

Abstract

Long-standing facial palsy sequelae cause functional, aesthetic, and psychological problems in patients. Botulinum toxin is an effective way to manage them, but no standardized recommendations exist. Through this non-systematic review, we aimed to guide any practitioner willing to master the ins and outs [...] Read more.

Long-standing facial palsy sequelae cause functional, aesthetic, and psychological problems in patients. Botulinum toxin is an effective way to manage them, but no standardized recommendations exist. Through this non-systematic review, we aimed to guide any practitioner willing to master the ins and outs of this activity. We reviewed the existing literature and completed, with our experience as a reference center, different strategies of botulinum toxin injections used in facial palsy patients, including history, physiopathology, facial analysis, dosages, injection sites, and techniques, as well as time intervals between injections. The reader will find all the theorical information needed to best guide injections according to the patient’s complaint, which is the most important information to consider. Full article

(This article belongs to the Special Issue Application of Botulinum Toxins in Non-spastic and Neurodegenerative Disorders)

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20 pages, 912 KiB

Open AccessEditor’s ChoiceArticle

Paradoxical Exception to Island Tameness: Increased Defensiveness in an Insular Population of Rattlesnakes

by William K. Hayes, Carl E. Person, Gerad A. Fox, Julie L. King, Erick Briggs and Eric C. K. Gren

Toxins 2024, 16(3), 157; https://doi.org/10.3390/toxins16030157 - 18 Mar 2024

Cited by 3 | Viewed by 4403

Abstract

Island tameness results largely from a lack of natural predators. Because some insular rattlesnake populations lack functional rattles, presumably the consequence of relaxed selection from reduced predation, we hypothesized that the Santa Catalina Island, California, USA, population of the southern Pacific rattlesnake ( [...] Read more.

Island tameness results largely from a lack of natural predators. Because some insular rattlesnake populations lack functional rattles, presumably the consequence of relaxed selection from reduced predation, we hypothesized that the Santa Catalina Island, California, USA, population of the southern Pacific rattlesnake (Crotalus helleri, which possesses a functional rattle), would exhibit a decrement in defensive behavior relative to their mainland counterparts. Contrary to our prediction, rattlesnakes from the island not only lacked tameness compared to mainland snakes, but instead exhibited measurably greater levels of defensiveness. Island snakes attempted to bite 4.7 times more frequently as we endeavored to secure them by hand, and required 2.1-fold more time to be pinned and captured. When induced to bite a beaker after being grasped, the island snakes also delivered 2.1-fold greater quantities of venom when controlling for body size. The additional venom resulted from 2.1-fold larger pulses of venom ejected from the fangs. We found no effects of duration in captivity (2–36 months), which suggests an absence of long-term habituation of antipredator behaviors. Breeding bird surveys and Christmas bird counts indicated reduced population densities of avian predators on Catalina compared to the mainland. However, historical estimates confirmed that populations of foxes and introduced mammalian predators (cats and pigs) and antagonists (herbivorous ungulates) substantially exceeded those on the mainland in recent centuries, and therefore best explain the paradoxically exaggerated defensive behaviors exhibited by Catalina’s rattlesnakes. These findings augment our understanding of anthropogenic effects on the behaviors of island animals and underscore how these effects can negatively affect human safety. Full article

(This article belongs to the Section Animal Venoms)

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31 pages, 678 KiB

Open AccessEditor’s ChoiceReview

Hidden Hazards Revealed: Mycotoxins and Their Masked Forms in Poultry

by Hamada Okasha, Bochen Song and Zhigang Song

Toxins 2024, 16(3), 137; https://doi.org/10.3390/toxins16030137 - 6 Mar 2024

Cited by 17 | Viewed by 4578

Abstract

The presence of mycotoxins and their masked forms in chicken feed poses a significant threat to both productivity and health. This review examines the multifaceted impacts of mycotoxins on various aspects of chicken well-being, encompassing feed efficiency, growth, immunity, antioxidants, blood biochemistry, and [...] Read more.

The presence of mycotoxins and their masked forms in chicken feed poses a significant threat to both productivity and health. This review examines the multifaceted impacts of mycotoxins on various aspects of chicken well-being, encompassing feed efficiency, growth, immunity, antioxidants, blood biochemistry, and internal organs. Mycotoxins, toxic substances produced by fungi, can exert detrimental effects even at low levels of contamination. The hidden or masked forms of mycotoxins further complicate the situation, as they are not easily detected by conventional methods but can be converted into their toxic forms during digestion. Consequently, chickens are exposed to mycotoxin-related risks despite apparently low mycotoxin levels. The consequences of mycotoxin exposure in chickens include reduced feed efficiency, compromised growth rates, impaired immune function, altered antioxidant levels, disturbances in blood biochemical parameters, and adverse effects on internal organs. To mitigate these impacts, effective management strategies are essential, such as routine monitoring of feed ingredients and finished feeds, adherence to proper storage practices, and the implementation of feed detoxification methods and mycotoxin binders. Raising awareness of these hidden hazards is crucial for safeguarding chicken productivity and health. Full article

(This article belongs to the Special Issue Metabolism and Toxicology of Mycotoxins and Their Masked Forms)

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20 pages, 2055 KiB

Open AccessEditor’s ChoiceReview

Bee Venom: Composition and Anticancer Properties

by Goran Gajski, Elina Leonova and Nikolajs Sjakste

Toxins 2024, 16(3), 117; https://doi.org/10.3390/toxins16030117 - 29 Feb 2024

Cited by 24 | Viewed by 12082

Abstract

Among the various natural compounds used in alternative and Oriental medicine, toxins isolated from different organisms have had their application for many years, and Apis mellifera venom has been studied the most extensively. Numerous studies dealing with the positive assets of bee venom [...] Read more.

Among the various natural compounds used in alternative and Oriental medicine, toxins isolated from different organisms have had their application for many years, and Apis mellifera venom has been studied the most extensively. Numerous studies dealing with the positive assets of bee venom (BV) indicated its beneficial properties. The usage of bee products to prevent the occurrence of diseases and for their treatment is often referred to as apitherapy and is based mainly on the experience of the traditional system of medical practice in diverse ethnic communities. Today, a large number of studies are focused on the antitumor effects of BV, which are mainly attributed to its basic polypeptide melittin (MEL). Previous studies have indicated that BV and its major constituent MEL cause a strong toxic effect on different cancer cells, such as liver, lung, bladder, kidney, prostate, breast, and leukemia cells, while a less pronounced effect was observed in normal non-target cells. Their proposed mechanisms of action, such as the effect on proliferation and growth inhibition, cell cycle alterations, and induction of cell death through several cancer cell death mechanisms, are associated with the activation of phospholipase A₂ (PLA₂), caspases, and matrix metalloproteinases that destroy cancer cells. Numerous cellular effects of BV and MEL need to be elucidated on the molecular level, while the key issue has to do with the trigger of the apoptotic cascade. Apoptosis could be either a consequence of the plasmatic membrane fenestration or the result of the direct interaction of the BV components with pro-apoptotic and anti-apoptotic factors. The interaction of BV peptides and enzymes with the plasma membrane is a crucial step in the whole process. However, before its possible application as a remedy, it is crucial to identify the correct route of exposure and dosage of BV and MEL for potential therapeutic use as well as potential side effects on normal cells and tissues to avoid any possible adverse event. Full article

(This article belongs to the Section Animal Venoms)

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15 pages, 1034 KiB

Open AccessEditor’s ChoiceArticle

Association of Urinary Mycotoxins with Sperm Quality: A Case-Control Study in Southern Nigeria

by Friday Ebhodaghe Okonofua, Lorretta Favour Chizomam Ntoimo, Emmanuel Iyayi Unuabonah, Titus Afred Makudali Msagati, Oladiran Ayodeji, Michael Aziken, Akhere Omonkhua, Victor Ohenhen, Celestina Olafusi and Moses O. Alfred

Toxins 2024, 16(3), 119; https://doi.org/10.3390/toxins16030119 - 29 Feb 2024

Cited by 4 | Viewed by 3187

Abstract

The objective of this study was to determine the association between mycotoxins and the quality of spermatozoa in Nigeria. We designed a prospective case-control study involving 136 men diagnosed with reduced sperm count and quality in five infertility clinics in southwest Nigeria and [...] Read more.

The objective of this study was to determine the association between mycotoxins and the quality of spermatozoa in Nigeria. We designed a prospective case-control study involving 136 men diagnosed with reduced sperm count and quality in five infertility clinics in southwest Nigeria and 154 normal fertile controls. Sperm analysis was conducted in accordance with the recommendations of the World Health OrganizationWHO, while Liquid Chromatography–Mass Spectrometry was used to assay three metabolites of mycotoxins (zearalenone, ochratoxin A, and deoxyvinelol) in the urine samples of cases and controls. The data were analysed with descriptive statistics and non-parametric linear regression. The results showed no overall significant difference in levels of these metabolites between the cases and control groups. In contrast, higher levels of zearalenone and ochratoxin A significantly decreased sperm motility in the cases. Similarly, an increase in the level of ochratoxin A decreased sperm morphology in the unadjusted model in the cases. We conclude that exposure to mycotoxins reduces the quality of spermatozoa (motility and morphology) in Nigerian men but may have no effect on sperm count. Efforts to reduce the exposure of men to mycotoxins are important interventions to improve sperm quality and reduce the prevalence of male infertility in the country. Full article

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20 pages, 1353 KiB

Open AccessEditor’s ChoiceReview

Complexing Protein-Free Botulinum Neurotoxin A Formulations: Implications of Excipients for Immunogenicity

by Michael Uwe Martin, Juergen Frevert and Clifton Ming Tay

Toxins 2024, 16(2), 101; https://doi.org/10.3390/toxins16020101 - 10 Feb 2024

Cited by 6 | Viewed by 6682

Abstract

The formation of neutralizing antibodies is a growing concern in the use of botulinum neurotoxin A (BoNT/A) as it may result in secondary treatment failure. Differences in the immunogenicity of BoNT/A formulations have been attributed to the presence of pharmacologically unnecessary bacterial components. [...] Read more.

The formation of neutralizing antibodies is a growing concern in the use of botulinum neurotoxin A (BoNT/A) as it may result in secondary treatment failure. Differences in the immunogenicity of BoNT/A formulations have been attributed to the presence of pharmacologically unnecessary bacterial components. Reportedly, the rate of antibody-mediated secondary non-response is lowest in complexing protein-free (CF) IncobotulinumtoxinA (INCO). Here, the published data and literature on the composition and properties of the three commercially available CF-BoNT/A formulations, namely, INCO, Coretox^® (CORE), and DaxibotulinumtoxinA (DAXI), are reviewed to elucidate the implications for their potential immunogenicity. While all three BoNT/A formulations are free of complexing proteins and contain the core BoNT/A molecule as the active pharmaceutical ingredient, they differ in their production protocols and excipients, which may affect their immunogenicity. INCO contains only two immunologically inconspicuous excipients, namely, human serum albumin and sucrose, and has demonstrated low immunogenicity in daily practice and clinical studies for more than ten years. DAXI contains four excipients, namely, L-histidine, trehalosedihydrate, polysorbate 20, and the highly charged RTP004 peptide, of which the latter two may increase the immunogenicity of BoNT/A by introducing neo-epitopes. In early clinical studies with DAXI, antibodies against BoNT/A and RTP004 were found at low frequencies; however, the follow-up period was critically short, with a maximum of three injections. CORE contains four excipients: L-methionine, sucrose, NaCl, and polysorbate 20. Presently, no data are available on the immunogenicity of CORE in human beings. It remains to be seen whether all three CF BoNT/A formulations demonstrate the same low immunogenicity in patients over a long period of time. Full article

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

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30 pages, 9946 KiB

Open AccessEditor’s ChoiceReview

Predatory and Defensive Strategies in Cone Snails

by Zahrmina Ratibou, Nicolas Inguimbert and Sébastien Dutertre

Toxins 2024, 16(2), 94; https://doi.org/10.3390/toxins16020094 - 7 Feb 2024

Cited by 8 | Viewed by 5561

Abstract

Cone snails are carnivorous marine animals that prey on fish (piscivorous), worms (vermivorous), or other mollusks (molluscivorous). They produce a complex venom mostly made of disulfide-rich conotoxins and conopeptides in a compartmentalized venom gland. The pharmacology of cone snail venom has been increasingly [...] Read more.

Cone snails are carnivorous marine animals that prey on fish (piscivorous), worms (vermivorous), or other mollusks (molluscivorous). They produce a complex venom mostly made of disulfide-rich conotoxins and conopeptides in a compartmentalized venom gland. The pharmacology of cone snail venom has been increasingly investigated over more than half a century. The rising interest in cone snails was initiated by the surprising high human lethality rate caused by the defensive stings of some species. Although a vast amount of information has been uncovered on their venom composition, pharmacological targets, and mode of action of conotoxins, the venom–ecology relationships are still poorly understood for many lineages. This is especially important given the relatively recent discovery that some species can use different venoms to achieve rapid prey capture and efficient deterrence of aggressors. Indeed, via an unknown mechanism, only a selected subset of conotoxins is injected depending on the intended purpose. Some of these remarkable venom variations have been characterized, often using a combination of mass spectrometry and transcriptomic methods. In this review, we present the current knowledge on such specific predatory and defensive venoms gathered from sixteen different cone snail species that belong to eight subgenera: Pionoconus, Chelyconus, Gastridium, Cylinder, Conus, Stephanoconus, Rhizoconus, and Vituliconus. Further studies are needed to help close the gap in our understanding of the evolved ecological roles of many cone snail venom peptides. Full article

(This article belongs to the Special Issue Feature Review in Animal Venoms: Venom Apparatus Anatomy, Mode of Action/Delivery Mechanisms, and Major Toxin Families)

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13 pages, 3878 KiB

Open AccessEditor’s ChoiceArticle

Bee Venom Stimulates Growth Factor Release from Adipose-Derived Stem Cells to Promote Hair Growth

by Jung Hyun Kim, Tae Yoon Kim, Bonhyuk Goo and Yeoncheol Park

Toxins 2024, 16(2), 84; https://doi.org/10.3390/toxins16020084 - 4 Feb 2024

Cited by 4 | Viewed by 4992

Abstract

Limited evidence suggests that stimulating adipose-derived stem cells (ASCs) indirectly promotes hair growth. We examined whether bee venom (BV) activated ASCs and whether BV-induced hair growth was facilitated by enhanced growth factor release by ASCs. The induction of the telogen-to-anagen phase was studied [...] Read more.

Limited evidence suggests that stimulating adipose-derived stem cells (ASCs) indirectly promotes hair growth. We examined whether bee venom (BV) activated ASCs and whether BV-induced hair growth was facilitated by enhanced growth factor release by ASCs. The induction of the telogen-to-anagen phase was studied in mice. The underlying mechanism was investigated using organ cultures of mouse vibrissa hair follicles. When BV-treated ASCs were injected subcutaneously into mice, the telogen-to-anagen transition was accelerated and, by day 14, the hair weight increased. Quantitative polymerase chain reaction (qPCR) revealed that BV influenced the expression of several molecules, including growth factors, chemokines, channels, transcription factors, and enzymes. Western blot analysis was employed to verify the protein expression levels of extracellular-signal-regulated kinase (ERK) and phospho-ERK. Both the Boyden chamber experiment and scratch assay confirmed the upregulation of cell migration by BV. Additionally, ASCs secreted higher levels of growth factors after exposure to BV. Following BV therapy, the gene expression levels of alkaline phosphatase (ALP), fibroblast growth factor (FGF)-1 and 6, endothelial cell growth factor, and platelet-derived growth factor (PDGF)-C were upregulated. The findings of this study suggest that bee venom can potentially be utilized as an ASC-preconditioning agent for hair regeneration. Full article

(This article belongs to the Section Animal Venoms)

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14 pages, 1745 KiB

Open AccessEditor’s ChoiceArticle

TDP-43 and Alzheimer’s Disease Pathology in the Brain of a Harbor Porpoise Exposed to the Cyanobacterial Toxin BMAA

by Susanna P. Garamszegi, Daniel J. Brzostowicki, Thomas M. Coyne, Regina T. Vontell and David A. Davis

Toxins 2024, 16(1), 42; https://doi.org/10.3390/toxins16010042 - 12 Jan 2024

Cited by 9 | Viewed by 3711

Abstract

Cetaceans are well-regarded as sentinels for toxin exposure. Emerging studies suggest that cetaceans can also develop neuropathological changes associated with neurodegenerative disease. The occurrence of neuropathology makes cetaceans an ideal species for examining the impact of marine toxins on the brain across the [...] Read more.

Cetaceans are well-regarded as sentinels for toxin exposure. Emerging studies suggest that cetaceans can also develop neuropathological changes associated with neurodegenerative disease. The occurrence of neuropathology makes cetaceans an ideal species for examining the impact of marine toxins on the brain across the lifespan. Here, we describe TAR DNA-binding protein 43 (TDP-43) proteinopathy and Alzheimer’s disease (AD) neuropathological changes in a beached harbor porpoise (Phocoena phocoena) that was exposed to a toxin produced by cyanobacteria called β-N-methylamino-L-alanine (BMAA). We found pathogenic TDP-43 cytoplasmic inclusions in neurons throughout the cerebral cortex, midbrain and brainstem. P62/sequestosome-1, responsible for the autophagy of misfolded proteins, was observed in the amygdala, hippocampus and frontal cortex. Genes implicated in AD and TDP-43 neuropathology such as APP and TARDBP were expressed in the brain. AD neuropathological changes such as amyloid-β plaques, neurofibrillary tangles, granulovacuolar degeneration and Hirano bodies were present in the hippocampus. These findings further support the development of progressive neurodegenerative disease in cetaceans and a potential causative link to cyanobacterial toxins. Climate change, nutrient pollution and industrial waste are increasing the frequency of harmful cyanobacterial blooms. Cyanotoxins like BMAA that are associated with neurodegenerative disease pose an increasing public health risk. Full article

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

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14 pages, 500 KiB

Open AccessEditor’s ChoiceReview

Use of Antibiotics following Snakebite in the Era of Antimicrobial Stewardship

by Helena Brenes-Chacon, José María Gutiérrez and María L. Avila-Aguero

Toxins 2024, 16(1), 37; https://doi.org/10.3390/toxins16010037 - 11 Jan 2024

Cited by 7 | Viewed by 5239

Abstract

Even though there are guidelines for the management of snakebite envenoming (SBE), the use of antibiotics in this pathology remains controversial. The aim of this study is to provide a narrative review of the literature and recommendations based on the best available evidence [...] Read more.

Even though there are guidelines for the management of snakebite envenoming (SBE), the use of antibiotics in this pathology remains controversial. The aim of this study is to provide a narrative review of the literature and recommendations based on the best available evidence regarding antibiotic use in SBE. We performed a narrative review of relevant literature regarding SBE and antibiotic use as prophylaxis or treatment. A total of 26 articles were included. There is wide use of antibiotics in SBE; nevertheless, infection was not necessarily documented. The antibiotics used varied according to the study, from beta lactams to lincosamide and nitroimidazoles, and from monotherapy to combined antimicrobials. The most common recommendations were to manage skin and soft tissue infections and avoid infectious complications, but these suggestions are not necessarily based on bacteriological findings. Prophylactic use of antibiotics in SBE is discouraged in most studies. Antibiotic prescription in SBE should be based on the susceptibility of microorganisms isolated from the affected tissue or identified in snakes’ oral cavities. Antibiotics should be reserved only for patients with a demonstrated infection, or those at a high risk of developing an infection, i.e., presenting severe local envenoming, local signs of infection, or those with incorrect manipulation of wounds. Prospective studies are needed to correlate microbiological findings at the wound site and the response to antibiotic use. Full article

(This article belongs to the Special Issue Pre-clinical and Clinical Management of Snakebite Envenomation)

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19 pages, 1297 KiB

Open AccessEditor’s ChoiceReview

Jelleine, a Family of Peptides Isolated from the Royal Jelly of the Honey Bees (Apis mellifera), as a Promising Prototype for New Medicines: A Narrative Review

by William Gustavo Lima, Julio Cesar Moreira Brito, Rodrigo Moreira Verly and Maria Elena de Lima

Toxins 2024, 16(1), 24; https://doi.org/10.3390/toxins16010024 - 2 Jan 2024

Cited by 4 | Viewed by 8196

Abstract

The jelleine family is a group of four peptides (jelleines I–IV) originally isolated from the royal jelly of honey bee (Apis mellifera), but later detected in some honey samples. These oligopeptides are composed of 8–9 amino acid residues, positively charged (+2 [...] Read more.

The jelleine family is a group of four peptides (jelleines I–IV) originally isolated from the royal jelly of honey bee (Apis mellifera), but later detected in some honey samples. These oligopeptides are composed of 8–9 amino acid residues, positively charged (+2 to +3 at pH 7.2), including 38–50% of hydrophobic residues and a carboxamide C-terminus. Jelleines, generated by processing of the C-terminal region of major royal jelly proteins 1 (MRJP-1), play an important biological role in royal jelly conservation as well as in protecting bee larvae from potential pathogens. Therefore, these molecules present numerous benefits for human health, including therapeutic purposes as shown in preclinical studies. In this review, we aimed to evaluate the biological effects of jelleines in addition to characterising their toxicities and stabilities. Jelleines I–III have promising antimicrobial activity and low toxicity (LD₅₀ > 1000 mg/Kg). However, jelleine-IV has not shown relevant biological potential. Jelleine-I, but not the other analogues, also has antiparasitic, healing, and pro-coagulant activities in addition to indirectly modulating tumor cell growth and controlling the inflammatory process. Although it is sensitive to hydrolysis by proteases, the addition of halogens increases the chemical stability of these molecules. Thus, these results suggest that jelleines, especially jelleine-I, are a potential target for the development of new, effective and safe therapeutic molecules for clinical use. Full article

(This article belongs to the Special Issue New Insights into Structure and Function of Arthropod Toxins and Other Toxins: Tribute to Professor Hervé Rochat)

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39 pages, 4591 KiB

Open AccessEditor’s ChoiceReview

Hosts and Heterologous Expression Strategies of Recombinant Toxins for Therapeutic Purposes

by Luana di Leandro, Martina Colasante, Giuseppina Pitari and Rodolfo Ippoliti

Toxins 2023, 15(12), 699; https://doi.org/10.3390/toxins15120699 - 13 Dec 2023

Cited by 2 | Viewed by 4255

Abstract

The production of therapeutic recombinant toxins requires careful host cell selection. Bacteria, yeast, and mammalian cells are common choices, but no universal solution exists. Achieving the delicate balance in toxin production is crucial due to potential self-intoxication. Recombinant toxins from various sources find [...] Read more.

The production of therapeutic recombinant toxins requires careful host cell selection. Bacteria, yeast, and mammalian cells are common choices, but no universal solution exists. Achieving the delicate balance in toxin production is crucial due to potential self-intoxication. Recombinant toxins from various sources find applications in antimicrobials, biotechnology, cancer drugs, and vaccines. “Toxin-based therapy” targets diseased cells using three strategies. Targeted cancer therapy, like antibody–toxin conjugates, fusion toxins, or “suicide gene therapy”, can selectively eliminate cancer cells, leaving healthy cells unharmed. Notable toxins from various biological sources may be used as full-length toxins, as plant (saporin) or animal (melittin) toxins, or as isolated domains that are typical of bacterial toxins, including Pseudomonas Exotoxin A (PE) and diphtheria toxin (DT). This paper outlines toxin expression methods and system advantages and disadvantages, emphasizing host cell selection’s critical role. Full article

(This article belongs to the Special Issue Immunotoxins: Current Status and Future Perspectives)

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16 pages, 767 KiB

Open AccessEditor’s ChoiceArticle

A Randomized, Double-Blind, Active Control, Multicenter, Phase 3 Study to Evaluate the Efficacy and Safety of Liztox^® versus Botox^® in Post-Stroke Upper Limb Spasticity

by Dong Hyun Ye, Min Ho Chun, Yoon Ghil Park, Nam-Jong Paik, Shi-Uk Lee, Seung Don Yoo and Deog Young Kim

Toxins 2023, 15(12), 697; https://doi.org/10.3390/toxins15120697 - 12 Dec 2023

Cited by 2 | Viewed by 3670

Abstract

Botulinum toxin type A (BTX-A) injection is a commonly used therapeutic intervention for upper limb spasticity in stroke patients. This study was designed as a randomized, active-drug-controlled, double-blind, multicenter, phase 3 clinical trial to evaluate the safety and efficacy of Liztox^® in [...] Read more.

Botulinum toxin type A (BTX-A) injection is a commonly used therapeutic intervention for upper limb spasticity in stroke patients. This study was designed as a randomized, active-drug-controlled, double-blind, multicenter, phase 3 clinical trial to evaluate the safety and efficacy of Liztox^® in comparison to onabotulinum toxin A (Botox^®) for individuals with post-stroke upper limb spasticity. The primary outcome was the alteration in wrist flexor muscle tone from the initial assessment to the fourth week, evaluated using the modified Ashworth scale (MAS). Secondary outcomes included MAS score changes for the wrist at weeks 8 and 12 from baseline; MAS score changes for finger and elbow flexors; and changes in the Disability Assessment Scale (DAS), Subject’s Global Assessment (SGA), the Investigator’s Global Assessment (IGA), and Caregiver Burden Scale (CBS) at weeks 4, 8, and 12 from baseline. The MAS score for wrist flexor spasticity decreased by −1.14 ± 0.59 in the Liztox^® group and −1.22 ± 0.59 in the Botox^® group from baseline to week 4. The difference [97.5% confidence interval (CI)] between the test and control groups was 0.08 [−∞, 0.26], confirming the non-inferiority of the test group compared to the control group. Furthermore, there were consistent improvements in the IGA, SGA, and CBS scores across all assessment intervals, with no statistically significant variances detected between the two groups. No safety-related concerns were reported during the study. In conclusion, Liztox^® injection proved to be a secure and efficacious intervention for managing upper extremity spasticity in post-stroke patients. Full article

(This article belongs to the Special Issue Botulinum Toxins Injections for Hypertonic Limbs—Is It So Effective?)

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17 pages, 1783 KiB

Open AccessEditor’s ChoiceArticle

Comparative Analysis of Secondary Metabolites Produced by Ascochyta fabae under In Vitro Conditions and Their Phytotoxicity on the Primary Host, Vicia faba, and Related Legume Crops

by Eleonora Barilli, Pierluigi Reveglia, Francisco J. Agudo-Jurado, Vanessa Cañete García, Alessio Cimmino, Antonio Evidente and Diego Rubiales

Toxins 2023, 15(12), 693; https://doi.org/10.3390/toxins15120693 - 9 Dec 2023

Viewed by 3000

Abstract

Ascochyta blight, caused by Ascochyta fabae, poses a significant threat to faba bean and other legumes worldwide. Necrotic lesions on stems, leaves, and pods characterize the disease. Given the economic impact of this pathogen and the potential involvement of secondary metabolites in [...] Read more.

Ascochyta blight, caused by Ascochyta fabae, poses a significant threat to faba bean and other legumes worldwide. Necrotic lesions on stems, leaves, and pods characterize the disease. Given the economic impact of this pathogen and the potential involvement of secondary metabolites in symptom development, a study was conducted to investigate the fungus’s ability to produce bioactive metabolites that might contribute to its pathogenicity. For this investigation, the fungus was cultured in three substrates (Czapek-Dox, PDB, and rice). The produced metabolites were analyzed by NMR and LC-HRMS methods, resulting in the dereplication of seven metabolites, which varied with the cultural substrates. Ascochlorin, ascofuranol, and (R)-mevalonolactone were isolated from the Czapek-Dox extract; ascosalipyrone, benzoic acid, and tyrosol from the PDB extract; and ascosalitoxin and ascosalipyrone from the rice extract. The phytotoxicity of the pure metabolites was assessed at different concentrations on their primary hosts and related legumes. The fungal exudates displayed varying degrees of phytotoxicity, with the Czapek-Dox medium’s exudate exhibiting the highest activity across almost all legumes tested. The species belonging to the genus Vicia spp. were the most susceptible, with faba bean being susceptible to all metabolites, at least at the highest concentration tested, as expected. In particular, ascosalitoxin and benzoic acid were the most phytotoxic in the tested condition and, as a consequence, expected to play an important role on necrosis’s appearance. Full article

(This article belongs to the Special Issue Biological Activities and Potential Applications of Phytotoxins)

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17 pages, 1786 KiB

Open AccessEditor’s ChoiceReview

Botulinum Toxin Treatment for Cancer-Related Disorders: A Systematic Review

by Delaram Safarpour and Bahman Jabbari

Toxins 2023, 15(12), 689; https://doi.org/10.3390/toxins15120689 - 8 Dec 2023

Cited by 6 | Viewed by 5470

Abstract

This systematic review investigates the effect of botulinum neurotoxin (BoNT) therapy on cancer-related disorders. A major bulk of the literature is focused on BoNT’s effect on pain at the site of surgery or radiation. All 13 published studies on this issue indicated reduction [...] Read more.

This systematic review investigates the effect of botulinum neurotoxin (BoNT) therapy on cancer-related disorders. A major bulk of the literature is focused on BoNT’s effect on pain at the site of surgery or radiation. All 13 published studies on this issue indicated reduction or cessation of pain at these sites after local injection of BoNTs. Twelve studies addressed the effect of BoNT injection into the pylorus (sphincter between the stomach and the first part of the gut) for the prevention of gastroparesis after local resection of esophageal cancer. In eight studies, BoNT injection was superior to no intervention; three studies found no difference between the two approaches. One study compared the result of intra-pyloric BoNT injection with preventive pyloromyotomy (resection of pyloric muscle fibers). Both approaches reduced gastroparesis, but the surgical approach had more serious side effects. BoNT injection was superior to saline injection in the prevention of esophageal stricture after surgery (34% versus 6%, respectively, p = 0.02) and produced better results (30% versus 40% stricture) compared to steroid (triamcinolone) injection close to the surgical region. All 12 reported studies on the effect of BoNT injection into the parotid region for the reduction in facial sweating during eating (gustatory hyperhidrosis) found that BoNT injections stopped or significantly reduced facial sweating that developed after parotid gland surgery. Six studies showed that BoNT injection into the parotid region prevented the development of or healed the fistulas that developed after parotid gland resection—parotidectomy gustatory hyperhidrosis (Frey syndrome), post-surgical parotid fistula, and sialocele. Eight studies suggested that BoNT injection into masseter muscle reduced or stopped severe jaw pain after the first bite (first bite syndrome) that may develop as a complication of parotidectomy. Full article

(This article belongs to the Special Issue Application of Botulinum Toxins in Diseases Treatment)

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17 pages, 1087 KiB

Open AccessEditor’s ChoiceArticle

Turmeric Powder Counteracts Oxidative Stress and Reduces AFB1 Content in the Liver of Broilers Exposed to the EU Maximum Levels of the Mycotoxin

by Neenu Amminikutty, Veronica Spalenza, Watanya Jarriyawattanachaikul, Paola Badino, Maria Teresa Capucchio, Elena Colombino, Achille Schiavone, Donato Greco, Vito D’Ascanio, Giuseppina Avantaggiato, Sihem Dabbou, Carlo Nebbia and Flavia Girolami

Toxins 2023, 15(12), 687; https://doi.org/10.3390/toxins15120687 - 7 Dec 2023

Cited by 9 | Viewed by 3068

Abstract

The most frequent adverse effects of AFB1 in chicken are low performance, the depression of the immune system, and a reduced quality of both eggs and meat, leading to economic losses. Since oxidative stress plays a major role in AFB1 toxicity, natural products [...] Read more.

The most frequent adverse effects of AFB1 in chicken are low performance, the depression of the immune system, and a reduced quality of both eggs and meat, leading to economic losses. Since oxidative stress plays a major role in AFB1 toxicity, natural products are increasingly being used as an alternative to mineral binders to tackle AFB1 toxicosis in farm animals. In this study, an in vivo trial was performed by exposing broilers for 10 days to AFB1 at dietary concentrations approaching the maximum limits set by the EU (0.02 mg/kg feed) in the presence or absence of turmeric powder (TP) (included in the feed at 400 mg/kg). The aims were to evaluate (i) the effects of AFB1 on lipid peroxidation, antioxidant parameters, histology, and the expression of drug transporters and biotransformation enzymes in the liver; (ii) the hepatic accumulation of AFB1 and its main metabolites (assessed using an in-house-validated HPLC-FLD method); (iii) the possible modulation of the above parameters elicited by TP. Broilers exposed to AFB1 alone displayed a significant increase in lipid peroxidation in the liver, which was completely reverted by the concomitant administration of TP. Although no changes in glutathione levels and antioxidant enzyme activities were detected in any treatment group, AFB1 significantly upregulated and downregulated the mRNA expression of CYP2A6 and Nrf2, respectively. TP counteracted such negative effects and increased the hepatic gene expression of selected antioxidant enzymes (i.e., CAT and SOD2) and drug transporters (i.e., ABCG2), which were further enhanced in combination with AFB1. Moreover, both AFB1 and TP increased the mRNA levels of ABCC2 and ABCG2 in the duodenum. The latter changes might be implicated in the decrease in hepatic AFB1 to undetectable levels (<LOD) in the TP supplemented group. Overall, our findings further support the use of TP as an effective feeding strategy to prevent AFB1-related adverse effects in broilers. Full article

(This article belongs to the Special Issue Mycotoxins in Farm Animals: Health Disorders and Preventive Strategies)

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16 pages, 2712 KiB

Open AccessEditor’s ChoiceCommunication

ADDovenom: Thermostable Protein-Based ADDomer Nanoparticles as New Therapeutics for Snakebite Envenoming

by Stefanie K. Menzies, Raquel Arinto-Garcia, Fernanda Gobbi Amorim, Iara Aimê Cardoso, Camille Abada, Thomas Crasset, Fabien Durbesson, Rebecca J. Edge, Priscila El-Kazzi, Sophie Hall, Damien Redureau, Richard Stenner, Johara Boldrini-França, Huan Sun, António Roldão, Paula M. Alves, Robert A. Harrison, Renaud Vincentelli, Imre Berger, Loïc Quinton, Nicholas R. Casewell and Christiane Schaffitzel Show full author list Hide full author list

Toxins 2023, 15(12), 673; https://doi.org/10.3390/toxins15120673 - 28 Nov 2023

Cited by 2 | Viewed by 3441

Abstract

Snakebite envenoming can be a life-threatening medical emergency that requires prompt medical intervention to neutralise the effects of venom toxins. Each year up to 138,000 people die from snakebites and threefold more victims suffer life-altering disabilities. The current treatment of snakebite relies solely [...] Read more.

Snakebite envenoming can be a life-threatening medical emergency that requires prompt medical intervention to neutralise the effects of venom toxins. Each year up to 138,000 people die from snakebites and threefold more victims suffer life-altering disabilities. The current treatment of snakebite relies solely on antivenom—polyclonal antibodies isolated from the plasma of hyperimmunised animals—which is associated with numerous deficiencies. The ADDovenom project seeks to deliver a novel snakebite therapy, through the use of an innovative protein-based scaffold as a next-generation antivenom. The ADDomer is a megadalton-sized, thermostable synthetic nanoparticle derived from the adenovirus penton base protein; it has 60 high-avidity binding sites to neutralise venom toxins. Here, we outline our experimental strategies to achieve this goal using state-of-the-art protein engineering, expression technology and mass spectrometry, as well as in vitro and in vivo venom neutralisation assays. We anticipate that the approaches described here will produce antivenom with unparalleled efficacy, safety and affordability. Full article

(This article belongs to the Section Animal Venoms)

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20 pages, 10566 KiB

Open AccessEditor’s ChoiceArticle

An Assessment of Potential Threats to Human Health from Algae Blooms in the Indian River Lagoon (USA) 2018–2021: Unique Patterns of Cytotoxicity Associated with Toxins

by Esther A. Guzmán, Tara A. Peterson, Priscilla L. Winder, Kirstie T. Francis, Malcolm McFarland, Jill C. Roberts, Jennifer Sandle and Amy E. Wright

Toxins 2023, 15(11), 664; https://doi.org/10.3390/toxins15110664 - 17 Nov 2023

Cited by 4 | Viewed by 4734

Abstract

The Indian River Lagoon (IRL), a 156-mile-long estuary located on the eastern coast of Florida, experiences phytoplankton bloom events due to increased seasonal temperatures coupled with anthropogenic impacts. This study aimed to gather data on the toxicity to human cells and to identify [...] Read more.

The Indian River Lagoon (IRL), a 156-mile-long estuary located on the eastern coast of Florida, experiences phytoplankton bloom events due to increased seasonal temperatures coupled with anthropogenic impacts. This study aimed to gather data on the toxicity to human cells and to identify secondary metabolites found in water samples collected in the IRL. Water samples from 20 sites of the IRL were collected during the wet and dry seasons over a three-year period. A panel of cell lines was used to test cytotoxicity. Hemagglutination, hemolysis, and inhibition of protein phosphatase 2A (PP2A) were also measured. Cytotoxic blooms were seen both in the south (Microcystis) and the north (Pyrodinium) of the IRL. Each toxin induced a consistent pattern of cytotoxicity in the panel of human cell lines assayed. During blooms, cytotoxicity due to a single type of toxin is obvious from this pattern. In the absence of blooms, the cytotoxicity seen reflected either a mixture of toxins or it was caused by an unidentified toxin. These observations suggest that other toxins with the potential to be harmful to human health may be present in the IRL. Moreover, the presence of toxins in the IRL is not always associated with blooms of known toxin-producing organisms. Full article

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

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17 pages, 1533 KiB

Open AccessEditor’s ChoiceReview

Current Knowledge of Individual and Combined Toxicities of Aflatoxin B1 and Fumonisin B1 In Vitro

by Xiangrong Chen, Mohamed F. Abdallah, Xiangfeng Chen and Andreja Rajkovic

Toxins 2023, 15(11), 653; https://doi.org/10.3390/toxins15110653 - 13 Nov 2023

Cited by 15 | Viewed by 4130

Abstract

Mycotoxins are considered the most threating natural contaminants in food. Among these mycotoxins, aflatoxin B1 (AFB1) and fumonisin B1 (FB1) are the most prominent fungal metabolites that represent high food safety risks, due to their widespread co-occurrence in several food commodities, and their [...] Read more.

Mycotoxins are considered the most threating natural contaminants in food. Among these mycotoxins, aflatoxin B1 (AFB1) and fumonisin B1 (FB1) are the most prominent fungal metabolites that represent high food safety risks, due to their widespread co-occurrence in several food commodities, and their profound toxic effects on humans. Considering the ethical and more humane animal research, the 3Rs (replacement, reduction, and refinement) principle has been promoted in the last few years. Therefore, this review aims to summarize the research studies conducted up to date on the toxicological effects that AFB1 and FB1 can induce on human health, through the examination of a selected number of in vitro studies. Although the impact of both toxins, as well as their combination, were investigated in different cell lines, the majority of the work was carried out in hepatic cell lines, especially HepG2, owing to the contaminants’ liver toxicity. In all the reviewed studies, AFB1 and FB1 could invoke, after short-term exposure, cell apoptosis, by inducing several pathways (oxidative stress, the mitochondrial pathway, ER stress, the Fas/FasL signaling pathway, and the TNF-α signal pathway). Among these pathways, mitochondria are the primary target of both toxins. The interaction of AFB1 and FB1, whether additive, synergistic, or antagonistic, depends to great extent on FB1/AFB1 ratio. However, it is generally manifested synergistically, via the induction of oxidative stress and mitochondria dysfunction, through the expression of the Bcl-2 family and p53 proteins. Therefore, AFB1 and FB1 mixture may enhance more in vitro toxic effects, and carry a higher significant risk factor, than the individual presence of each toxin. Full article

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

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33 pages, 1542 KiB

Open AccessEditor’s ChoiceReview

Current Trends in Mycotoxin Detection with Various Types of Biosensors

by Krisztina Majer-Baranyi, Nóra Adányi and András Székács

Toxins 2023, 15(11), 645; https://doi.org/10.3390/toxins15110645 - 6 Nov 2023

Cited by 11 | Viewed by 4701

Abstract

One of the most important tasks in food safety is to properly manage the investigation of mycotoxin contamination in agricultural products and foods made from them, as well as to prevent its occurrence. Monitoring requires a wide range of analytical methods, from expensive [...] Read more.

One of the most important tasks in food safety is to properly manage the investigation of mycotoxin contamination in agricultural products and foods made from them, as well as to prevent its occurrence. Monitoring requires a wide range of analytical methods, from expensive analytical procedures with high-tech instrumentation to significantly cheaper biosensor developments or even single-use assays suitable for on-site monitoring. This review provides a summary of the development directions over approximately a decade and a half, grouped according to the biologically sensitive components used. We provide an overview of the use of antibodies, molecularly imprinted polymers, and aptamers, as well as the diversity of biosensors and their applications within the food industry. We also mention the possibility of determining multiple toxins side by side, which would significantly reduce the time required for the analyses. Full article

(This article belongs to the Special Issue Evaluating Mycotoxins in Food Safety: Novel and Traditional Food or Feed Products and New Strategies of Biomonitoring)

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11 pages, 1922 KiB

Open AccessEditor’s ChoiceArticle

Synergistic Effects of Essential Oils and Organic Acids against Aspergillus flavus Contamination in Poultry Feed

by Tim Satterlee, Callie Megan McDonough, Scott E. Gold, Chongxiao Chen, Anthony E. Glenn and Anthony Pokoo-Aikins

Toxins 2023, 15(11), 635; https://doi.org/10.3390/toxins15110635 - 31 Oct 2023

Cited by 3 | Viewed by 3157

Abstract

Organic acids and essential oils are commonly used in the poultry industry as antimicrobials and for their beneficial effects on gut health, growth performance, and meat quality. A common postharvest storage fungal colonist, Aspergillus flavus, contaminates corn, the primary component of poultry [...] Read more.

Organic acids and essential oils are commonly used in the poultry industry as antimicrobials and for their beneficial effects on gut health, growth performance, and meat quality. A common postharvest storage fungal colonist, Aspergillus flavus, contaminates corn, the primary component of poultry feed, with the highly detrimental mycotoxin, aflatoxin. Aflatoxin adversely affects poultry feed intake, feed conversion efficiency, weight gain, egg production, fertility, hatchability, and poultry meat yield. Both organic acids and essential oils have been reported to inhibit the growth of A. flavus. Thus, we evaluated if the inhibitory synergy between combined essential oils (cinnamon, lemongrass, and oregano) and organic acids (acetic, butyric, and propionic) prevents A. flavus growth. The study confirmed that these compounds inhibit the growth of A. flavus and that synergistic interactions do occur between some of them. Overall, cinnamon oil was shown to have the highest synergy with all the organic acids tested, requiring 1000 µL/L air of cinnamon oil and 888 mg/kg of butyric acid to fully suppress A. flavus growth on corn kernels. With the strong synergism demonstrated, combining certain essential oils and organic acids offers a potentially effective natural method for controlling postharvest aflatoxin contamination in poultry feed. Full article

(This article belongs to the Section Mycotoxins)

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15 pages, 1771 KiB

Open AccessEditor’s ChoiceReview

A 15-Year Retrospective Review of Ciguatera in the Madeira Islands (North-East Atlantic, Portugal)

by Pedro Reis Costa, Catarina Churro, Susana Margarida Rodrigues, Bárbara Frazão, Miguel Barbosa, Lia Godinho, Lucía Soliño, Viriato Timóteo and Neide Gouveia

Toxins 2023, 15(11), 630; https://doi.org/10.3390/toxins15110630 - 27 Oct 2023

Cited by 4 | Viewed by 2954

Abstract

The first ciguatera fish poisoning (CFP) in Portugal dates from 2008 when 11 people reported CFP symptoms after consuming a 30 kg amberjack caught around the Selvagens Islands (Madeira Archipelago). Since then, 49 human poisonings have been reported. The emergence of a new [...] Read more.

The first ciguatera fish poisoning (CFP) in Portugal dates from 2008 when 11 people reported CFP symptoms after consuming a 30 kg amberjack caught around the Selvagens Islands (Madeira Archipelago). Since then, 49 human poisonings have been reported. The emergence of a new threat challenged scientists and regulators, as methods for toxic microalgae analyses and ciguatoxin (CTX) detection were not implemented. To minimise the risk of ciguatera, the Madeira Archipelago authorities interdicted fisheries in Selvagens Islands and banned the capture of amberjacks weighing more than 10 kg in the entire region of Madeira Archipelago. The accurate identification and quantification of the benthic toxin-producing algae species spreading to new areas require efforts in terms of both microscopy and molecular techniques. Two ciguatera-causing dinoflagellates, Gambierdiscus excentricus and Gambierdiscus australes, were identified in the Madeira Island and Selvagens sub-archipelago, respectively. Regarding the CTX analysis (N2a cell-based assay and LC-MS) in fish, the results indicate that the Selvagens Islands are a ciguatera risk area and that fish vectoring CTX are not limited to top predator species. Nevertheless, advances and improvements in screening methods for the fast detection of toxicity in seafood along with certified reference material and sensitive and selective targeted analytical methods for the determination of CTX content are still pending. This study aims to revise the occurrence of ciguatera cases in the Madeira Archipelago since its first detection in 2008, to discuss the risk management strategy that was implemented, and to provide a summary of the available data on the bioaccumulation of CTX in marine fish throughout the marine food web, taking into consideration their ecological significance, ecosystem dynamics, and fisheries relevance. Full article

(This article belongs to the Special Issue Ciguatoxins 2022–2023)

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15 pages, 2959 KiB

Open AccessEditor’s ChoiceArticle

Ensemble Machine Learning of Gradient Boosting (XGBoost, LightGBM, CatBoost) and Attention-Based CNN-LSTM for Harmful Algal Blooms Forecasting

by Jung Min Ahn, Jungwook Kim and Kyunghyun Kim

Toxins 2023, 15(10), 608; https://doi.org/10.3390/toxins15100608 - 10 Oct 2023

Cited by 78 | Viewed by 7589

Abstract

Harmful algal blooms (HABs) are a serious threat to ecosystems and human health. The accurate prediction of HABs is crucial for their proactive preparation and management. While mechanism-based numerical modeling, such as the Environmental Fluid Dynamics Code (EFDC), has been widely used in [...] Read more.

Harmful algal blooms (HABs) are a serious threat to ecosystems and human health. The accurate prediction of HABs is crucial for their proactive preparation and management. While mechanism-based numerical modeling, such as the Environmental Fluid Dynamics Code (EFDC), has been widely used in the past, the recent development of machine learning technology with data-based processing capabilities has opened up new possibilities for HABs prediction. In this study, we developed and evaluated two types of machine learning-based models for HABs prediction: Gradient Boosting models (XGBoost, LightGBM, CatBoost) and attention-based CNN-LSTM models. We used Bayesian optimization techniques for hyperparameter tuning, and applied bagging and stacking ensemble techniques to obtain the final prediction results. The final prediction result was derived by applying the optimal hyperparameter and bagging and stacking ensemble techniques, and the applicability of prediction to HABs was evaluated. When predicting HABs with an ensemble technique, it is judged that the overall prediction performance can be improved by complementing the advantages of each model and averaging errors such as overfitting of individual models. Our study highlights the potential of machine learning-based models for HABs prediction and emphasizes the need to incorporate the latest technology into this important field. Full article

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

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17 pages, 1968 KiB

Open AccessEditor’s ChoiceArticle

Discovery of an Insect Neuroactive Helix Ring Peptide from Ant Venom

by Valentine Barassé, Laurence Jouvensal, Guillaume Boy, Arnaud Billet, Steven Ascoët, Benjamin Lefranc, Jérôme Leprince, Alain Dejean, Virginie Lacotte, Isabelle Rahioui, Catherine Sivignon, Karen Gaget, Mélanie Ribeiro Lopes, Federica Calevro, Pedro Da Silva, Karine Loth, Françoise Paquet, Michel Treilhou, Elsa Bonnafé and Axel Touchard

Toxins 2023, 15(10), 600; https://doi.org/10.3390/toxins15100600 - 5 Oct 2023

Cited by 6 | Viewed by 3132

Abstract

Ants are among the most abundant terrestrial invertebrate predators on Earth. To overwhelm their prey, they employ several remarkable behavioral, physiological, and biochemical innovations, including an effective paralytic venom. Ant venoms are thus cocktails of toxins finely tuned to disrupt the physiological systems [...] Read more.

Ants are among the most abundant terrestrial invertebrate predators on Earth. To overwhelm their prey, they employ several remarkable behavioral, physiological, and biochemical innovations, including an effective paralytic venom. Ant venoms are thus cocktails of toxins finely tuned to disrupt the physiological systems of insect prey. They have received little attention yet hold great promise for the discovery of novel insecticidal molecules. To identify insect-neurotoxins from ant venoms, we screened the paralytic activity on blowflies of nine synthetic peptides previously characterized in the venom of Tetramorium bicarinatum. We selected peptide U₁₁, a 34-amino acid peptide, for further insecticidal, structural, and pharmacological experiments. Insecticidal assays revealed that U₁₁ is one of the most paralytic peptides ever reported from ant venoms against blowflies and is also capable of paralyzing honeybees. An NMR spectroscopy of U₁₁ uncovered a unique scaffold, featuring a compact triangular ring helix structure stabilized by a single disulfide bond. Pharmacological assays using Drosophila S2 cells demonstrated that U₁₁ is not cytotoxic, but suggest that it may modulate potassium conductance, which structural data seem to corroborate and will be confirmed in a future extended pharmacological investigation. The results described in this paper demonstrate that ant venom is a promising reservoir for the discovery of neuroactive insecticidal peptides. Full article

(This article belongs to the Special Issue Ant Venom)

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17 pages, 1558 KiB

Open AccessEditor’s ChoiceArticle

Use of Yeast Cell Wall Extract for Growing Pigs Consuming Feed Contaminated with Mycotoxins below or above Regulatory Guidelines: A Meta-Analysis with Meta-Regression

by Alexandra C. Weaver, Daniel M. Weaver, Nicholas Adams and Alexandros Yiannikouris

Toxins 2023, 15(10), 596; https://doi.org/10.3390/toxins15100596 - 3 Oct 2023

Cited by 2 | Viewed by 3454

Abstract

Using a random-effects meta-analysis, the performance of growing pigs under a mycotoxin challenge (MT) with or without supplementation of yeast cell wall extract (YCWE, Mycosorb^®, Alltech Inc.) was evaluated. Both MT and YCWE were also compared to animal controls not receiving [...] Read more.

Using a random-effects meta-analysis, the performance of growing pigs under a mycotoxin challenge (MT) with or without supplementation of yeast cell wall extract (YCWE, Mycosorb^®, Alltech Inc.) was evaluated. Both MT and YCWE were also compared to animal controls not receiving mycotoxins (CTRL). Meta-regression was used to further explore the impacts of MT at/below (category 1) or above (category 2) global regulatory guidelines. Following the screening, 23 suitable references (30 mycotoxin treatments) were used. Overall, MT lowered average daily gain (ADG, p < 0.001) and average daily feed intake (ADFI, p < 0.0001) from CTRL by −84 and −165 g, respectively. Inclusion of YCWE during mycotoxin challenges (YCWE+MT, average 2.1 kg/ton) tended to result in greater ADG (+17 g, p = 0.068) compared to MT treatments. The gain-to-feed ratio (G:F) was not impacted by MT or YCWE+MT. Further investigation by meta-regression revealed that pigs fed MT in category 1 had lower ADG (−78.5 g, p < 0.001) versus CTRL, while YCWE+MT had higher ADG (+48 g, p < 0.001) over MT and was similar to CTRL. The ADFI was not impacted, although YCWE+MT had ADFI values similar to the CTRL. In category 2, ADG and ADFI of pigs fed MT were lower than CTRL (−85.1 and −166 g, respectively, p < 0.0001), with a tendency for YCWE+MT to result in higher ADFI (+25.3 g, p = 0.062). In summary, the inclusion of YCWE provided benefits to performance during common mycotoxin challenge levels (at or below regulatory guidelines). Full article

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

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18 pages, 2656 KiB

Open AccessEditor’s ChoiceSystematic Review

The Occurrence of Non-Regulated Mycotoxins in Foods: A Systematic Review

by Octavian Augustin Mihalache, Marthe De Boevre, Luca Dellafiora, Sarah De Saeger, Antonio Moretti, Laetitia Pinson-Gadais, Nadia Ponts, Florence Richard-Forget, Antonia Susca and Chiara Dall’Asta

Toxins 2023, 15(9), 583; https://doi.org/10.3390/toxins15090583 - 20 Sep 2023

Cited by 18 | Viewed by 4312

Abstract

The aim of this systematic review is to provide an update on the occurrence and co-occurrence of selected non-regulated mycotoxins and provide an overview of current regulations. Fifteen non-regulated mycotoxins were found in 19 food categories worldwide. On top of that, 38 different [...] Read more.

The aim of this systematic review is to provide an update on the occurrence and co-occurrence of selected non-regulated mycotoxins and provide an overview of current regulations. Fifteen non-regulated mycotoxins were found in 19 food categories worldwide. On top of that, 38 different combinations of non-regulated mycotoxins were found, with mixtures varying from binary combinations up to 12 mycotoxins. Taking into consideration the amount of evidence regarding the prevalence and co-occurrence of non-regulated mycotoxins, future steps should be taken considering continuous monitoring, scientific exchange, and generation of high-quality data. To enhance data quality, guidelines outlining the minimum quality criteria for both occurrence data and metadata are needed. By doing so, we can effectively address concerns related to the toxicity of non-regulated mycotoxins. Furthermore, obtaining more data concerning the co-occurrence of both regulated and non-regulated mycotoxins could aid in supporting multiple chemical risk assessment methodologies. Implementing these steps could bolster food safety measures, promote evidence-based regulations, and ultimately safeguard public health from the potential adverse effects of non-regulated mycotoxins. Full article

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

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21 pages, 1833 KiB

Open AccessEditor’s ChoiceReview

Aspergillus flavus and Fusarium verticillioides and Their Main Mycotoxins: Global Distribution and Scenarios of Interactions in Maize

by Xiangrong Chen, Mohamed F. Abdallah, Sofie Landschoot, Kris Audenaert, Sarah De Saeger, Xiangfeng Chen and Andreja Rajkovic

Toxins 2023, 15(9), 577; https://doi.org/10.3390/toxins15090577 - 18 Sep 2023

Cited by 19 | Viewed by 4732

Abstract

Maize is frequently contaminated with multiple mycotoxins, especially those produced by Aspergillus flavus and Fusarium verticillioides. As mycotoxin contamination is a critical factor that destabilizes global food safety, the current review provides an updated overview of the (co-)occurrence of A. flavus and [...] Read more.

Maize is frequently contaminated with multiple mycotoxins, especially those produced by Aspergillus flavus and Fusarium verticillioides. As mycotoxin contamination is a critical factor that destabilizes global food safety, the current review provides an updated overview of the (co-)occurrence of A. flavus and F. verticillioides and (co-)contamination of aflatoxin B1 (AFB1) and fumonisin B1 (FB1) in maize. Furthermore, it summarizes their interactions in maize. The gathered data predict the (co-)occurrence and virulence of A. flavus and F. verticillioides would increase worldwide, especially in European cold climate countries. Studies on the interaction of both fungi regarding their growth mainly showed antagonistic interactions in vitro or in planta conditions. However, the (co-)contamination of AFB1 and FB1 has risen worldwide in the last decade. Primarily, this co-contamination increased by 32% in Europe (2010–2020 vs. 1992–2009). This implies that fungi and mycotoxins would severely threaten European-grown maize. Full article

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

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27 pages, 3347 KiB

Open AccessEditor’s ChoiceReview

Recent Developments in Vaccine Design: From Live Vaccines to Recombinant Toxin Vaccines

by Sonal Gupta and Sabine Pellett

Toxins 2023, 15(9), 563; https://doi.org/10.3390/toxins15090563 - 8 Sep 2023

Cited by 28 | Viewed by 10483

Abstract

Vaccines are one of the most effective strategies to prevent pathogen-induced illness in humans. The earliest vaccines were based on live inoculations with low doses of live or related pathogens, which carried a relatively high risk of developing the disease they were meant [...] Read more.

Vaccines are one of the most effective strategies to prevent pathogen-induced illness in humans. The earliest vaccines were based on live inoculations with low doses of live or related pathogens, which carried a relatively high risk of developing the disease they were meant to prevent. The introduction of attenuated and killed pathogens as vaccines dramatically reduced these risks; however, attenuated live vaccines still carry a risk of reversion to a pathogenic strain capable of causing disease. This risk is completely eliminated with recombinant protein or subunit vaccines, which are atoxic and non-infectious. However, these vaccines require adjuvants and often significant optimization to induce robust T-cell responses and long-lasting immune memory. Some pathogens produce protein toxins that cause or contribute to disease. To protect against the effects of such toxins, chemically inactivated toxoid vaccines have been found to be effective. Toxoid vaccines are successfully used today at a global scale to protect against tetanus and diphtheria. Recent developments for toxoid vaccines are investigating the possibilities of utilizing recombinant protein toxins mutated to eliminate biologic activity instead of chemically inactivated toxins. Finally, one of the most contemporary approaches toward vaccine design utilizes messenger RNA (mRNA) as a vaccine candidate. This approach was used globally to protect against coronavirus disease during the COVID-19 pandemic that began in 2019, due to its advantages of quick production and scale-up, and effectiveness in eliciting a neutralizing antibody response. Nonetheless, mRNA vaccines require specialized storage and transport conditions, posing challenges for low- and middle-income countries. Among multiple available technologies for vaccine design and formulation, which technology is most appropriate? This review focuses on the considerable developments that have been made in utilizing diverse vaccine technologies with a focus on vaccines targeting bacterial toxins. We describe how advancements in vaccine technology, combined with a deeper understanding of pathogen–host interactions, offer exciting and promising avenues for the development of new and improved vaccines. Full article

(This article belongs to the Special Issue Toxin-Host Interaction of Clostridium Toxins)

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14 pages, 3931 KiB

Open AccessEditor’s ChoiceArticle

Presence, Co-Occurrence, and Daily Intake Estimates of Aflatoxins and Fumonisins in Maize Consumed in Food-Insecure Regions of Western Honduras

by Luis Sabillón, Jackeline Alvarado, Alejandra Leiva, Rodrigo Mendoza, Raúl Espinal, John F. Leslie and Andréia Bianchini

Toxins 2023, 15(9), 559; https://doi.org/10.3390/toxins15090559 - 7 Sep 2023

Cited by 2 | Viewed by 2517

Abstract

Foodborne mycotoxins are a significant food safety risk in developing countries. Our objective was to determine the occurrence of and exposure levels to aflatoxins (AFs) and fumonisins (FBs) in maize intended for human and animal consumption in food-insecure regions of western Honduras. Total [...] Read more.

Foodborne mycotoxins are a significant food safety risk in developing countries. Our objective was to determine the occurrence of and exposure levels to aflatoxins (AFs) and fumonisins (FBs) in maize intended for human and animal consumption in food-insecure regions of western Honduras. Total AFs and FBs were quantified with a monoclonal antibody-based affinity spectrofluorimetric method. FBs were detected in 614/631 samples of maize destined for human consumption at 0.3 to 41 mg/kg (mean, 2.7 mg/kg). Of the 614 positive samples, 147 had FB levels exceeding the U.S. Food and Drug Administration (FDA) advisory threshold of 4.0 mg/kg. AFs were detected in 109/631 samples of maize for human consumption with concentrations between 1.0 and 490 µg/kg (mean, 10 µg/kg). AF levels in 34 samples exceeded the FDA regulatory limit (i.e., 20 µg/kg). The average probable daily intake of AFs in western Honduras ranged from 0 to 260 ng/kg body weight/day, and for FBs, the average probable daily intake ranged from 17 to 53 μg/kg body weight/day. AFs and FBs co-occurred in 106/631 samples with 60 samples containing both toxins at levels greater than the FDA regulatory levels. Samples of maize intended for animal feed had significantly higher AF (mean, 22 µg/kg) and FB (mean, 7.6 mg/kg) contamination levels than those observed in samples destined for human consumption. Thus, the maize supply chain in western Honduras is contaminated with mycotoxins at levels that pose health risks to both humans and livestock. More effective mycotoxin surveillance and implementation of effective mitigation strategies are needed to reduce mycotoxin contamination and exposure. Full article

(This article belongs to the Special Issue Occurrence and Determination of Mycotoxins)

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19 pages, 4401 KiB

Open AccessEditor’s ChoiceArticle

Identification of Acid Hydrolysis Metabolites of the Pimelea Toxin Simplexin for Targeted UPLC-MS/MS Analysis

by Zhi Hung Loh, Natasha L. Hungerford, Diane Ouwerkerk, Athol V. Klieve and Mary T. Fletcher

Toxins 2023, 15(9), 551; https://doi.org/10.3390/toxins15090551 - 5 Sep 2023

Cited by 2 | Viewed by 2780

Abstract

Pimelea poisoning of cattle is a unique Australian toxic condition caused by the daphnane orthoester simplexin present in native Pimelea pasture plants. Rumen microorganisms have been proposed to metabolise simplexin by enzymatic reactions, likely at the orthoester and epoxide moieties of simplexin, but [...] Read more.

Pimelea poisoning of cattle is a unique Australian toxic condition caused by the daphnane orthoester simplexin present in native Pimelea pasture plants. Rumen microorganisms have been proposed to metabolise simplexin by enzymatic reactions, likely at the orthoester and epoxide moieties of simplexin, but a metabolic pathway has not been confirmed. This study aimed to investigate this metabolic pathway through the analysis of putative simplexin metabolites. Purified simplexin was hydrolysed with aqueous hydrochloric acid and sulfuric acid to produce target metabolites for UPLC-MS/MS analysis of fermentation fluid samples, bacterial isolate samples, and other biological samples. UPLC-MS/MS analysis identified predicted hydrolysed products from both acid hydrolysis procedures with MS breakdown of these putative products sharing high-resolution accurate mass (HRAM) fragmentation ions with simplexin. However, targeted UPLC-MS/MS analysis of the biological samples failed to detect the H₂SO₄ degradation products, suggesting that the rumen microorganisms were unable to produce similar simplexin degradation products at detectable levels, or that metabolites, once formed, were further metabolised. Overall, in vitro acid hydrolysis was able to hydrolyse simplexin at the orthoester and epoxide functionalities, but targeted UPLC-MS/MS analysis of biological samples did not detect any of the identified simplexin hydrolysis products. Full article

(This article belongs to the Special Issue Toxic Compounds from Poisonous Plants: Identification and Analytical Methods)

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13 pages, 1027 KiB

Open AccessEditor’s ChoiceSystematic Review

Is Botulinum Toxin Effective in Treating Orofacial Neuropathic Pain Disorders? A Systematic Review

by Matteo Val, Robert Delcanho, Marco Ferrari, Luca Guarda Nardini and Daniele Manfredini

Toxins 2023, 15(9), 541; https://doi.org/10.3390/toxins15090541 - 1 Sep 2023

Cited by 9 | Viewed by 3706

Abstract

Background: The aim of this paper is to provide a systematic review of the literature regarding the clinical use of botulinum toxin (BTX) to treat various orofacial neuropathic pain disorders (NP). Methods: A comprehensive literature search was conducted using Medline, Web of Science, [...] Read more.

Background: The aim of this paper is to provide a systematic review of the literature regarding the clinical use of botulinum toxin (BTX) to treat various orofacial neuropathic pain disorders (NP). Methods: A comprehensive literature search was conducted using Medline, Web of Science, and the Cochrane Library databases. Only randomized clinical trials (RCT) published between 2003 and the end of June 2023, investigating the use of BTX to treat NP, were selected. PICO guidelines were used to select and tabulate the articles. Results: A total of 6 RCTs were selected. Five articles used BTX injections to treat classical trigeminal neuralgia, and one to treat post-herpetic neuralgia. A total of 795 patients received BTX injections. The selected studies utilised different doses and methods of injections and doses. All the selected studies concluded superiority of BTX injections over placebo for reducing pain levels, and 5 out 6 of them highlighted an improvement in the patient’s quality of life. Most of the studies reported transient and mild side effects. Conclusion: There is evidence of the efficacy of BTX injections in orofacial pain management. However, improved study protocols are required to provide direction for the clinical use of BTX to treat various orofacial neuropathic pain disorders. Full article

(This article belongs to the Special Issue Therapeutic Uses and Efficacy of Botulinum Toxin in Orofacial Medicine: From the Standpoint of Dental Professionals)

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16 pages, 14537 KiB

Open AccessEditor’s ChoiceArticle

Intramuscular Bleeding and Formation of Microthrombi during Skeletal Muscle Damage Caused by a Snake Venom Metalloprotease and a Cardiotoxin

by Medha Sonavane, José R. Almeida, Elanchezhian Rajan, Harry F. Williams, Felix Townsend, Elizabeth Cornish, Robert D. Mitchell, Ketan Patel and Sakthivel Vaiyapuri

Toxins 2023, 15(9), 530; https://doi.org/10.3390/toxins15090530 - 28 Aug 2023

Cited by 5 | Viewed by 3702

Abstract

The interactions between specific snake venom toxins and muscle constituents are the major cause of severe muscle damage that often result in amputations and subsequent socioeconomic ramifications for snakebite victims and/or their families. Therefore, improving our understanding of venom-induced muscle damage and determining [...] Read more.

The interactions between specific snake venom toxins and muscle constituents are the major cause of severe muscle damage that often result in amputations and subsequent socioeconomic ramifications for snakebite victims and/or their families. Therefore, improving our understanding of venom-induced muscle damage and determining the underlying mechanisms of muscle degeneration/regeneration following snakebites is critical to developing better strategies to tackle this issue. Here, we analysed intramuscular bleeding and thrombosis in muscle injuries induced by two different snake venom toxins (CAMP—Crotalus atrox metalloprotease (a PIII metalloprotease from the venom of this snake) and a three-finger toxin (CTX, a cardiotoxin from the venom of Naja pallida)). Classically, these toxins represent diverse scenarios characterised by persistent muscle damage (CAMP) and successful regeneration (CTX) following acute damage, as normally observed in envenomation by most vipers and some elapid snakes of Asian, Australasian, and African origin, respectively. Our immunohistochemical analysis confirmed that both CAMP and CTX induced extensive muscle destruction on day 5, although the effects of CTX were reversed over time. We identified the presence of fibrinogen and P-selectin exposure inside the damaged muscle sections, suggesting signs of bleeding and the formation of platelet aggregates/microthrombi in tissues, respectively. Intriguingly, CAMP causes integrin shedding but does not affect any blood clotting parameters, whereas CTX significantly extends the clotting time and has no impact on integrin shedding. The rates of fibrinogen clearance and reduction in microthrombi were greater in CTX-treated muscle compared to CAMP-treated muscle. Together, these findings reveal novel aspects of venom-induced muscle damage and highlight the relevance of haemostatic events such as bleeding and thrombosis for muscle regeneration and provide useful mechanistic insights for developing better therapeutic interventions. Full article

(This article belongs to the Special Issue Pre-clinical and Clinical Management of Snakebite Envenomation)

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15 pages, 341 KiB

Open AccessEditor’s ChoiceReview

Modified Mycotoxins and Multitoxin Contamination of Food and Feed as Major Analytical Challenges

by Ksenija Nešić, Kristina Habschied and Krešimir Mastanjević

Toxins 2023, 15(8), 511; https://doi.org/10.3390/toxins15080511 - 19 Aug 2023

Cited by 8 | Viewed by 2774

Abstract

Mycotoxins, as natural products of molds, are often unavoidable contaminants of food and feed, to which the increasingly evident climate changes contribute a large part. The consequences are more or less severe and range from economic losses to worrying health problems to a [...] Read more.

Mycotoxins, as natural products of molds, are often unavoidable contaminants of food and feed, to which the increasingly evident climate changes contribute a large part. The consequences are more or less severe and range from economic losses to worrying health problems to a fatal outcome. One of the best preventive approaches is regular monitoring of food and feed for the presence of mycotoxins. However, even under conditions of frequent, comprehensive, and conscientious controls, the desired protection goal may not be achieved. In fact, it often happens that, despite favorable analytical results that do not indicate high mycotoxin contamination, symptoms of their presence occur in practice. The most common reasons for this are the simultaneous presence of several different mycotoxins whose individual content does not exceed the detectable or prescribed values and/or the alteration of the form of the mycotoxin, which renders it impossible to be analytically determined using routine methods. When such contaminated foods enter a living organism, toxic effects occur. This article aims to shed light on the above problems in order to pay more attention to them, work to reduce their impact, and, eventually, overcome them. Full article

(This article belongs to the Section Mycotoxins)

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